Office Practice of Neurology, Second Edition

CHURCHILL LIVINGSTONE An Imprint of Elsevier Science The Curtis Center Independence Square West Philadelphia, Pennsylvania 19106

OFFICE PRACTICE OF NEUROLOGY Copyright © 2003, Elsevier Science (USA). All rights reserved.

ISBN 0-443-06557-8

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail: [email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions.’ Distributed in the United Kingdom by Churchill Livingstone, Robert Stevenson House, 1-3 Baxter’s Place, Leith Walk, Edinburgh EH1 3AF, Scotland, and by associated companies, branches, and representatives throughout the world. Churchill Livingstone and the sailboat design are registered trademarks.

NOTICE Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the editors assumes any liability for any injury and/or damage to persons or property arising from this publication. Previous edition copyrighted 1996 Library of Congress Cataloging-in-Publication Data Office practice of neurology/edited by Martin A. Samuels, Steven Feske.—2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 0-443-06557-8 1. Neurology. 2. Ambulatory medical care. I. Samuels, Martin A. II. Feske, Steven. [DNLM: 1. Nervous System Diseases—diagnosis. 2. Nervous System Diseases—therapy. 3. Ambulatory Care. WL 140 O32 2003] RC346 .O34 2003 616.8—dc21

Acquisitions Editor: Susan Pioli Developmental Editor: Melissa Dudlick Printed in the United States Last digit is the print number:

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In memory of Michael S. Pessin, M.D., esteemed friend and colleague. His outstanding clinical skills and research talents inspired many to follow a career in Stroke Neurology. His patients benefited from his vast knowledge, his dedication and his compassion.

Contributors

Robert J.Adams, MD Presidential Distinguished Chair Department of Neurology Medical College of Georgia Augusta, Georgia

JamesW. Albers, MD, PhD Professor of Neurology University of Michigan Medical School Department of Neurology University of Michigan Health System Ann Arbor, Michigan

Lloyd M. Alderson, MD, DSc Assistant Professor of Neurology Brown University School of Medicine Providence, Rhode Island

Michael P. Alexander, MD Associate Clinical Professor of Neurology Harvard Medical School; Department of Behavioral Neurology Beth Israel Deaconess Medical Center Boston Massachusetts

Anthony A. Amato, MD Associate Professor of Neurology Harvard Medical School; Vice Chairman Department of Neurology and Chief, Neuromuscular Division Brigham and Women’s Hospital Boston, Massachusetts

Sepideh Amin-Hanjani, MD Instructor Department of Surgery (Neurosurgery) Harvard Medical School Neurosurgical Service; Massachusetts General Hospital Boston, Massachusetts

Richard M. Armstrong, MD Bastrop, Texas

Gerald M. Aronoff, MD, FAADEP Chairman, Department of Pain Medicine Presbyterian HospitaVPresbyterian Orthopedic Hospital Charlotte, North Carolina

Ajay I<. Arora, MD Tetsuo Ashizawa, MD Professor and John Sealy Chair of Neurology The University of Texas Medical Branch Galveston, Texas

Viken L. Babikian, MD Professor of Neurology Boston University School of Medicine; Co-Director, Stroke Service Boston Medical Center Boston, Massachusetts

JoachimM. Baehring, MD Assistant Professor of Neurology and Neurosurgery Yale University School of Medicine New Haven, Connecticut

Zahid H. Bajwa, MD Assistant Professor of Anesthesia (Neurology) Harvard Medical School; Director, Education and Clinical Pain Research Beth Israel Deaconess Medical Center Boston, Massachusetts

Robert W. Baloh, MD Professor of Neurology University of California, Los Angeles Los hgeles, California

Patrick D. Barnes, MD Richard J. Barohn, MD Professor and Chairman, Department of Neurology University of Kansas Medical Center Kansas City, Kansas

Steven M. Baskin, MD Director, The New England Institute for Behavioral Medicine Stamford, Connecticut

Isabelita R. Bella, MD Assistant Professor Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts

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Contributors

Richard J. Benjamin, MBChB, PhD

JonBrillman, MD

Assistant Professor Department of Pathology Harvard Medical School; Medical Director: Blood Bank Department of Pathology Brigham and Women’s Hospital Boston, Massachusetts

Chairman Department of Neurology Allegheny General Hospital Pittsburgh, Pennsylvania

Alan R. Berger, MD Professor and Chair, Department of Neurology University of FIorida Health Science Center, Jacksonville; Director, Neuroscience Center Shands Jacksonville Jacksonville,Florida

Edward B. Bromfield, MD Assistant Professor Department of Neurology Harvard Medical School; Chief, Division of EEG and Epilepsy Brigham and Women’s Hospital Boston, Massachusetts

Robert H. Brown, Jr.,MD, D.Phil

Associate Clinical Professor Department of Rehabilitation Medicine Boston University School of Medicine Boston, Massachusetts

Professor of Neurology, Harvard Medical School; Associate in Neurology; Director, Day Neuromuscular Laboratory; Director, Neuromuscular Clinic Massachusetts General Hospital Boston, Massachusetts

Marcel0 E. Sisal, MD

JohnC.M. Brust, MD

The New England Center for Headache Stamford, Connecticut; Albert Einstein College of Medicine Bronx, New York

Department of Neurology Harlem Hospital Center; Columbia University College of Physicians and Surgeons New York, New York

JosCBiller, MD

Louis R. Caplan, MD

Professor and Chairman Department of Neurology Indiana University School of Medicine Indianapolis, Indiana

Professor of Neurology Harvard Medical School; Chief, Cerebrovascular Section Department of Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts

Susan Biener Bergman, MD

Peter McLaren Black, MD, PhD Ingraham Professor of Neurosurgery Harvard Medical School; Chief, Division of Neurosurgery Brigham and Women’s Hospital and Children’s Hospital Boston, Massachusetts

Charles F. Bolton, MD, CM, MS, FRCP(C) Professor of Neurology Mayo Clinic Rochester, Minnesota

David Borsook, MD, PhD Neuroradiology Staff Massachusetts General Hospital Boston, Massachusetts

Lawrence M. Brass, MD Department of Neurology Yale University School of Medicine New Haven, Connecticut

David A. Chad, MD Professor of Neurology and Pathology University of Massachusetts Medical School; Director, MDA C h i c ; Attending Neurologist UMass Memorial Health Care Worchester, Massachusetts

Michael E. Charness, MD Associate Professor of Neurology Harvard Medical School; Chief, Neurology Service, VA Boston Healthcare System; Associate Chief of Neurology Brigham and Women’s Hospital Boston, Massachusetts

Contributors

Marc I. Chimowitz, MD, MB, ChB

Basil T. Darras, MD

Professor of Neurology; Director Cerebrovascular Program Emory University Atlanta, Georgia

Associate Professor of Neurology Harvard Medical School; Director, Neuromuscular Program Children’s Hospital of Boston Boston, Massachusetts

Catherine Cho, MD Department of Neurology Mount Sinai School of Medicine New York, New York

Patricia H. Davis, MD

Cathy Chuang, MD

Associate Professor Department of Neurology University of Iowa Iowa City, Iowa

Wmthrop H. Churchill,MD

David M. Dawson, MD

Associate Professor of Medicine Harvard Medical School; Division of Hematology Brigham and Women’s Hospital Blood Bank Boston, Massachusetts

Director, Partners Neurology Residency Program Brigham and Women’s Hospital Boston, Massachusetts

Alan R. Cohen, MD, FACS, FAAP Rainbow Professor of Neurosurgery and Pediatrics Case Western Reserve University School of Medicine; Chief of Pediatric Neurosurgery Rainbow Babies and Children’s Hospital Cleveland, Ohio

Douglas G. Cole, MD

JohnP. Conomy, MD, JD Clinical Professor of Neurology Case Western Reserve University; President, Health Systems Design Corporation Cleveland, Ohio

Clifford C. Dacso, MD, MPH Professor of Medicine; John S. Dunn Senior Research Chair in General Internal Medicine Baylor College of Medicine Houston, Texas

Kirk R. Daffher, MD Associate Professor of Neurology Harvard Medical School; Chief, Division of Cognitive and Behavioral Neurology Brigham and Women’s Hospital Boston, Massachusetts

Josep0.Dalmau, MD, PhD Associate Professor of Neurology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Lisa M. DeAngelis, MD Chairman, Department of Neurology; Chief, Neurology Service Memorial Sloan-Kettering Cancer Center New York, New York

Umberto De Girolami, MD Professor Department of Pathology Harvard Medical School; Director of Neuropathology Brigham and Women’s Hospital and Children’s Hospital Boston, Massachusetts

L. Dana DeWitt, MD

Luis D’Olhaberriague,MD, PhD Neurologist Chicago, Illinois

Frank W. Drislane, MD Associate Professor of Neurology Harvard Medical School; Neurologist Beth Israel Deaconess Medical Center Boston, Massachusetts

Edward J. Dropcho, MD Professor, Department of Neurology Indiana University Medical Center; Chief, Neurology Service Indianapolis Veterans Affairs Medical Center Indianapolis, Indiana

Bruce Ehrenberg, MD Associate Professor, Department of Neurology Tufts University School of Medicine Boston, Massachusetts

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Contributors

Marc E. Eichler, MD

JosephH. Friedman, MD

Associate Surgeon Department of Neurosurgery Brigham and Women’s Hospital Boston, Massachusetts

Professor and Chief, Section on Parkinson’s Disease and Movement Disorders Department of Clinical Neuroscience Brown University School of Medicine; Chief, Division of Neurology Memorial Hospital of Rhode Island Pawtucket, Rhode Island

Conrad0 J. Estol, MD, PhD Director, Neurology Center for Treatment and Rehabilitation Buenos Aires, Argentina

Bradley K. Evans, MD

Matthew P. Frosch, MD, PhD

Medical Director Northern Michigan Neurology Traverse City, Michigan

Assistant Professor of Pathology Harvard Medical School; Massachusetts General Hospital Boston, Massachusetts

Gilbert J. Fanciullo, MD, MS

Melissa Frumin, MD

Associate Professor of Anesthesiology Dartmouth Medical School; Director, Sections of Pain Medicine and Palliative Care Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Instructor, Department of Psychiatry Harvard Medical School; Neuropsychiatrist Brigham and Women’s Neurology Group Brigham and Women’s Hospital Boston, Massachusetts

Robert G. Feldman, MD Chairman Emeritus and Professor of Neurology; Professor of Pharmacology and Environmental Health Boston UniversitySchool of Medicine and the School of Public Health Boston, Massachusetts

Anthony J. Furlan, MD

Steven K. Feske, MD

Director, Virginia Merrill Bloedel Hearing Research Center Otolaryngology-HNS University of Washington Seattle, Washington

Assistant Professor of Neurology Harvard Medical School; Director Stroke Division Department of Neurology Brigham and Women’s Hospital Boston, Massachusetts

Scott M. Fishman, MD Division of Pain Management University of California Davis Medical Center Sacramento, California

Barry S. Fogel, MD Department of Psychiatry Brigham and Women’s Hospital Boston, Massachusetts

Roy L. Freeman, MD Associate Professor of Neurology, Harvard Medical School; Director, Autonomic and Peripheral Nerve Laboratory Beth Israel Deaconess Medical Center Boston, Massachusetts

The Cleveland Clinic Cleveland, Ohio

George A. Gates, MD

David S. Geckle, MD, FACS Co-chief, Department of Neurosurgery Chippenham and Johnston-Willis Medical Center Richmond, Virginia

Thomas P. Giordano, MD Assistant Professor Department of Medicine Baylor College of Medicine; Staff Physician, Department of Medicine Harris County Hospital District Houston, Texas

Me1 B. Glenn, MD Associate Professor, Department of Physical Medicine and Rehabilitation Harvard Medical School; Director of Outpatient and Community Brain Injury Rehabilitation Spaulding Rehabilitation Hospital Boston, Massachusetts

Contributors

Martin A. Goldstein, MD

Michael L. Gruber, MD

Harvard Medical School Boston, Massachusetts

Department of Neurology University of Minnesota Minneapolis, Minnesota

Associate Professor of Neurology New York University School of Medicine New York, New York; Medical Director of the Brain Tumor Center of New Jersey Summit, New Jersey; Co-Chair of Neuro-Oncology, Cancer Institute of New Jersey New Brunswick, New Jersey

Clifton L. Gooch, MD

Ludwig Gutmann, MD

Associate Clinical Professor of Neurology Columbia University; Director, EMG Laboratory Columbia Presbyterian Medical Center; New York, New York

Hazel Ruby McQuain Professor of Neurology Robert C. Byrd Health Sciences Center Morgantown, West Virginia

Christopher M. Gomez, MD

Francesc R. Graus, MD Service of Neurology, Hospital Clinic Barcelona, Spain

Harry S. Greenberg, MD Professor of Neurology and Neurosurgery University of Michigan Ann Arbor, Michigan

Walter A. Hall, MD, MB Professor of Neurosurgery University of Minnesota School of Medicine Minneapolis, Minnesota

Mark Hallett, MD Chief, Human Motor Control Section National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland

Stephen B. Greenberg, MD

JulieE. Hammack, MD

Acting Chair, Department of Medicine Baylor College of Medicine; Chief of Medicine, Ben Taub General Hospital Houston, Texas

Assistant Professor, Department of Neurology Mayo Clink Rochester, Minnesota

Melvin Greer, MD Bob Paul Family Professor of Neurology University of Florida Gainesville, Florida

Robert C. Griggs, MD Professor and Chair of Neurology University of Rochester School of Medicine and Dentistry; Chief, Department of Neurology Strong Memorial Hospital Rochester, New York

Sheldon G. Gross, DDS Director, Connecticut Center for Oral and Facial Pain Bloomfield, Connecticut

Stuart A. Grossman, MD Professor, Departments of Oncology, Medicine, and Neurosurgery Johns Hopkins School of Medicine Baltimore, Maryland

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Yadollah Harati, MD Department of Neurology Baylor College of Medicine Houston, Texas

Richard L. Harris, MD Clinical Professor of Medicine Baylor College of Medicine Houston, Texas

Christ0 her H. Hawkes, BSc, MD, FRCP (Edin), FRCP (fond) Consultant Neurologist, Essex Centre for Neurology & Neurosurgery Oldchurch Hospital Romford, Essex, United Kingdom

Michael T. Hayes, MD Assistant Professor of Neurology Tufts University School of Medicine; Staff Neurologist, St. Elizabeth's Medical Center of Boston Boston, Massachusetts

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Contributors

David N. Herrmann, MD

Tom J. Jeerakathil,MD, BSc, FRCPC

Assistant Professor of Neurology and Pathology and Laboratory Medicine Neuromuscular Disease Center University of Rochester Rochester, New York

Assistant Professor of Neurology, Department of Medicine University of Alberta Edmonton, Alberta, Canada

Fred H. Hochberg, MD Attending Neurologist Massachusetts General Hospital Boston, Massachusetts

Dave Hollander, MD, FRCP(C) Assistant Professor, Department of Neurology Tufts University School of Medicine Boston, Massachusetts

Gregory L. Holmes, MD Professor of Medicine (Neurology) and Pediatrics Dartmouth Medical School Hanover, New Hampshire; Chief, Division of Neurology Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Donald R. Johns,MD Associate Professor of Neurology and Ophthalmology Harvard Medical School; Director, Division of Neuromuscular Disease Beth Israel Deaconess Medical Center; Associate Director, Center for the Integration of Medicine and Innovative Technology (CIMIT) Boston, Massachusetts

H. Royden Jones,Jr.,MD Clinical Professor of Neurology Harvard Medical School; Jaime-Ortiz-Patino Chair in Neurology Chairman, Division of Medical Specialties Lahey Clinic Burlington, Massachusetts; Directory, Electromyography Laboratory Children’s Hospital Boston, Massachusetts

Liangge Hsu,MD

Henry J. Kaminski, MD

Assistant Professor of Radiology Harvard Medical School; Department of Neuroradiology Brigham and Women’s Hospital Boston, Massachusetts

Associate Professor of Neurology Case Western Reserve University; Attending Neurologist University Hospitals of Cleveland; Attending Neurologist Cleveland Veterans Affairs Medical Center Cleveland, Ohio

Daniel M. Jacobson,MD Clinical Assistant Professor, Department of Ophthalmology and Neurology University of Wisconsin Medical School Madison, Wisconsin; Director of Neuro-ophthalmology Service, Marshfield Clinic Mansfield, Wisconsin

Robert N. Jamison,PhD Associate Professor of Anesthesiology Perioperative and Pain Medicine and Psychiatry Harvard Medical School Boston, Massachusetts

JosephJankovic,MD Professor of Neurology; Director, Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, Texas

Percy N. Karanjia, MD, MRCP Clinical Associate Professor of Neurology University of Wisconsin, Madison; Marshfield Clinic, Department of Neurology Marshfield, Wisconsin

Carlos S. Kase, MD Professor of Neurology Boston University School of Medicine; Visiting Neurologist Department of Neurology Boston Medical Center Boston, Massachusetts

Contributors

Bashar Katirji, MD

Lauren B. Krupp, MD

Professor of Neurology Case Western Reserve University School of Medicine; Chief, Neuromuscular Division; Director, EMG Laboratory University Hospitals of Cleveland Cleveland, Ohio

Professor, Department of Neurology State University of New York at Stony Brook Stony Brook, New York

JonathanS. Katz, MD Department of Veterans Affairs Palo Alto Health Care System Palo Alto, California

Nathaniel P. Katz, MD Assistant Professor of Anesthesia Harvard Medical School Boston. Massachusetts

JohnJ. Kelly, Jr.,MD Professor and Chairman, Department of Neurology George Washington University Medical Center Washington, DC

Drew S. Kern, MS Research Associate Colorado Neurological Institute Movement Disorders Center Englewood, Colorado

Shahram Khoshbin, MD Associate Professor of Neurology Harvard Medical School; Department of Neurology Brigham and Women’s Hospital Boston, Massachusetts

Howard S. Kirshner, MD Professor of Neurology Vanderbilt University School of Medicine Nashville, Tennessee

Edwin H. Kolodny, MD Bernard A. and Charlotte Marden Professor and Chairman Department of Neurology New York University School of Medicine New York, New York

Bruce R. Korf, MD, PhD

David B. Kudrow, MD Director, California Medical Clinic for Headache Santa Monica, California

Rajeev Kumar, MD Director, Functional Neurosurgery Program Colorado Neurological Institute Movement Disorders Center Englewood, Colorado

Robert S. Kunkel, MD Consultant, Department of Neurology Cleveland Clinic Foundation Cleveland, Ohio

Roger Kurlan, MD Professor, Department of Neurology; Professor, Center for Aging and Developmental Biology University of Rochester School of Medicine and Dentistry Rochester, New York

David Lacomis, MD Associate Professor of Neurology and Pathology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Eugene C. Lai,MD, PhD Associate Professor, Department of Neurology Baylor College of Medicine; Houston VA Medical Center Houston, Texas

Robert Laureno, MD Professor of Neurology, George Washington University; Chairman, Department of Neurology Washington Hospital Center Washington, DC

Susan LaViolette, MD Lexington Physical Therapy Associates Lexington, Massachusetts

J.Douglas Lee, MD

Wayne H. and Sara Crews Finley Professor and Chair, Department of Genetics University of Alabama at Birmingham Birmingham, Alabama

Medical Director of Pharmacy Services Marshfield Clinic Marshfield, Wisconsin

Walter J.Koroshetz, MD

Clinical Assistant Professor of Medicine Ohio State University Columbus, Ohio

Vice Chair, Department of Neurology Massachusetts General Hospital Boston, Massachusetts

Edward J.Levine, MD

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Contributors

Robert Aaron Levine, MD

Eric L. Logigian, MD

Assistant Professor of Neurology Harvard Medical School; Assistant Neurologist Massachusetts General Hospital; Assistant in Otolaryngology (Neurology) Massachusetts Eye and Ear Infirmary Boston, Massachusetts

Professor of Neurology; Director, EMG Laboratory; Unit Chief, Neuromuscular Disease Center University of Rochester Medical Center Rochester, New York

Steven R. Levine, MD Professor of Neurology; Director, Cerebrovascular Education Stroke Program Mount Sinai School of Medicine New York, New York

Peter LeWitt, MD, MMedSc Professor of Neurology Wayne State University School of Medicine Detroit, Michigan; William Beaumont Hospital Research Institute Royal Oak,Michigan

Mark H. Libenson, MD Assistant Professor of Pediatrics and Neurology Tufts University School of Medicine; Director, Epilepsy Center for Children Floating Hospital for Children at Tufts-New England; Co-Director, Electroencephalography Laboratory Tufts-New England Medical Center Boston, Massachusetts

Richard B. Lipton, MD Professor and Vice Chair Department of Neurology Albert Einstein College of Medicine Bronx, New York

Grant T. Liu, MD Associate Professor of Neurology and Ophthalmology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Elizabeth W. Loder, MD, FACP Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts

JayS. Loeffler, MD Andres Soriano Professor of Radiation Oncology Harvard Medical School Boston, Massachusetts

Betsy B. Love, MD Volunteer Clinical Associate Professor of Neurology Indiana University College of Medicine Indianapolis, Indiana

Steven Lovitt, MD University of Texas San Antonio, Texas

JeffreyD. Macklis, MD, D.HST Associate Professor of Neurology (Neuroscience) Harvard Medical School; Director, MGH-HMS Center for Nervous System Repair Massachusetts General Hospital Boston, Massachusetts

h i K. Mankodi, MD Department Fellow University of Rochester School of Medicine Rochester, New York

Frederick J. Marshall, MD Coordination Center University of Rochester Rochester, New York

Randall S. Marshall, MD Neurology Institute New York, New York

JeanK. Matheson, MD Assistant Professor of Neurology Harvard Medical School; Medical Director, Sleep Disorders Center Beth Israel Deaconess Medical Center Boston, Massachusetts

Kathleen McEvoy, MD, PhD Department of Neurology Mayo Clinic Rochester, Minnesota

Contributors

Robert R. McKendall, MD

Thorkild V.Norregaard, MD

Associate Professor of Neurology and Microbiology and Immunology University of Texas Galveston, Texas

Assistant Professor of Surgery Harvard Medical School; Department of Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts

Daniel Miller, MD Department of Neurology Cleveland VA Medical Center Cleveland, Ohio

Edison Miyawaki, MD Instructor, Department of Neurology Harvard Medical School; Brigham and Women’s Hospital Boston, Massachusetts

J. P. Mohr, MD Sciarra Professor of Clinical Neurology Departments of Neurology and Neurosurgery College of Physicians and Surgeons of Columbia University New York, New York

Fiona Molloy, MD Clinical Associate and Senior Investigator Human Motor Control Section, NINDS National Institutes of Health Bethesda, Maryland

Patricia M. Moore, MD Pittsburgh, Pennsylvania

Michael Mufson, MD Assistant Professor of Psychiatry Harvard Medical School; Staff Psychiatrist, Brigham and Women’s Hospital; Director of Psychiatry West Roxbury Veterans Administration Hospital Boston, Massachusetts

Kathryn N. North, MD Associate Professor University of Sydney; Head, Neurogenetics Research Unit Deputy Head, Institute for Neuromuscdar Research Sydney, Australia

Cormac A. O’Donovan, MB, BCh, BAO Assistant Professor of Neurology and Internal Medicine Wake Forest University School of Medicine Winston-Salem, North Carolina

Chima 0.Ohaegbulam, MD Resident, Department of Neurosurgery Brigham and Women’s Hospital; Children’s Hospital, Boston Boston, Massachusetts

Richard K. Olney, MD Professor, Department of Neurology; Director, ALS Center; Director, Electromyography Laboratory Clinical Neurophysiology Laboratories University of California, San Francisco; San Francisco Medical Center San Francisco, California

Russell C. Packard, MD Professor of Neuropsychiatry Texas Tech University Health Sciences Center Lubbock, Texas

Sharon P. Nations, MD

JohnK. Park, MD, PhD

Assistant Professor, Neurology University of Texas Southwestern Dallas, Texas

Head, Surgical and Molecular Neuro-Oncology Unit National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland

Craig Patrick Nolan, MD Attending Physician, Department of Neurology North Shore-Long Island Jewish Health Care System Manhasset, New York

Patrick E. Nolan, MD Department of Internal Medicine University of South Alabama, College of Medicine Mobile, Alabama

Roy A. Patchell, MD Department of Neurology University of Kentucky Medical Center Lexington, Kentucky

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Contributon

JohnR. Peteet, MD

David C. Preston, MD

Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts

Director, Neuromuscular Service University Hospitals of Cleveland; Associate Professor of Neurology Case Western Reserve University Cleveland, Ohio

Ronald C. Petersen, MD, PhD Cora Kanow Professor of Alzheimer’s Disease Research Mayo Medical School Mayo Clinic Rochester, Minnesota

Kendra Peterson, MD Department of Neurology Stanford University Medical Center Stanford, California

JacksonB. Pickett, MD Neurology Service Veterans Administration Medical Center Charleston, South Carolina

William F. Pirl, MD Instructor in Psychiatry Harvard Medical School; Assistant in Psychiatry Massachusetts General Hospital Boston, Massachusetts

Scott R. Plotkin, MD, PhD Neuro-Oncology Fellow Massachusetts General Hospital Boston, Massachusetts

Bruce H. Price, MD Chief, Department of Neurology McLean Hospital Belmont, Massachusetts

Amy Pruitt, MD Associate Professor of Neurology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Michael T. Pulley, MD, PhD Assistant Professor, Department of Neurology; Director, EMG Laboratory University of Florida College of Medicine Jacksonville,Florida

Naren Ramakrishna, MD, PhD Instructor, Radiation Oncology Harvard Medical School; Department of Radiation Oncology Brigham and Women’s Hospital; Division of Radiation Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Alan M. Rapoport, MD Scott L. Pomeroy, MD, PhD Associate Professor Harvard Medical School; Director of Neuro-oncology Department of Neurology; Senior Associate Children’s Hospital Boston Boston. Massachusetts

Frisso Potts, MD Instructor, Department of Neurology Harvard Medical School Boston, Massachusetts

Daniel Press, MD Instructor, Department of Neurology Harvard Medical School; Beth Israel Deaconess Medical Center Boston, Massachusetts

Clinical Professor of Neurology Columbia University School of Physicians and Surgeons New York, New York; Director and Founder, The New England Center for Headache Stamford, Connecticut

Paula Ravh, MD Associate Professor of Clinical Neurology University of Massachusetts Medical Center Worcester, Massachusetts

Elizabeth M. Raynor, MD Assistant Professor of Neurology Harvard Medical School; Director, Electromyography Laboratory Beth Israel Deaconess Medical Center Boston, Massachuetts

Contributors

Lawrence D. Recht, MD

Robert L. Ruff, MD

Professor, Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts

Professor of Neurology and Neurosciences Case Western Reserve University; Chief, Neurology Service Louis Stokes Cleveland Veterans Affairs Medical Center Cleveland, Ohio

Kurt Reed, MD Department of Pathology The Marshfield Clinic Marshfield, Wisconsin

Dorene M. Rentz, PsyD Department of Neurology Division of Cognitive and Behavioral Neurology Brigham and Women’s Hospital; Harvard Medical School Boston, Massachusetts

JamesA. Russell, DO Department of Neurology Lahey Clinic Medical Center Burlington, Massachusetts

Thomas D. Sabin, MD Professor, Department of Neurology Tufts University School of Medicine Boston, Massachusetts

Gary S. Richardson, MD

Ahmed H. Sadek, MD

Senior Research Scientist, Endocrine Division Henry Ford Hospital Detroit, Michigan

Department of Neurology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

JeffreyM. Robbins, LICSW

Eileen Salmanson, LICSW

Teaching Associate in Neurology Harvard Medical School; Senior Social Worker Brigham and Women’s Hospital Boston, Massachusetts

Teaching Associate Harvard Medical School; Senior Clinical Social Worker Department of Neurology Brigham and Women’s Hospital Boston, Massachusetts

Diana L. Rodriguez, MD Bellaire, Texas

Nalini Samuel, MD

Loren Rolak, MD

Neurologist Detroit, Michigan

Director, Marshfield Multiple Sclerosis Center Marshfield Clinic Marshfield, Wisconsin

Martin A. Samuels, MD

Michael Ronthal, MbBCh, FRCP, FRCPE Associate Professor of Neurology, Harvard Medical School; Deputy Chief, Department of Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts

Patrick A. Roth, MD Hackensack, New Jersey

JeffreyD. Rothstein, MD Department of Neurology Johns Hopkins University Baltimore, Maryland

Professor of Neurology Harvard Medical School; Neurologist-in-Chief and Chairman, Department of Neurology Brigham and Women’s Hospital Boston, Massachusetts

Steven C. Schachter, MD Professor, Department of Neurology Harvard Medical School; Director of Research Department of Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts

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Contributors

David Schiff, MD

Fred D. Sheftell, MD

Associate Professor of Neurology Department of Neurological Surgery and Medicine; Co-Director, Neuro-Oncology Center University of Virginia Medical Center Charlottesville, Virginia

Director, The New England Center for Headache Stamford, Connecticut; Clinical Assistant Professor, New York Medical College Valhda, New York

Donald Schorner, MD

Professor and Chair, Department of Radiation Oncology The Huntsman Cancer Institute at the University of Utah Salt Lake City, Utah

Professor, Department of Neurology Harvard Medical School; Director, Laboratory of Clinical Neurophysiology; Chief, Comprehensive Epilepsy Program Beth Israel Deaconess Medical Center Boston, Massachusetts

H. Christian Schumacher, MD Postdoctoral Stroke Research Fellow Doris and Stanley Tananbaum Stroke Center Neurological Institute, New York-Presbyterian Hospital; College of Physicians and Surgeons, Columbia University New York, New York

R. Michael Scott, MD Professor of Surgery Harvard Medical School; Director of Clinical Pediatric Neurosurgery Children’s Hospital, Boston Boston, Massachusetts

Elizabeth A. Sekul, MD Department of Pediatrics Medical College of Georgia Augusta, Georgia

Barbara E. Shapiro, MD, PhD Associate Professor of Neurology Case Western Reserve University; Director, Neuromuscular Research University Hospitals of Cleveland; Case Western Reserve University Cleveland, Ohio

Nutan Sharma, MD Instructor in Neurology, Harvard Medical School; Associate Neurologist, Brigham and Women’s Hospital; Assistant in Neurology, Massachusetts General Hospital Boston, Massachusetts

JeremyM. Sheher, MD, PhD Professor of Neurology Upstate Medical University Syracuse, New York

Dennis C. Shrieve, MD, PhD

Joao0.Siffert, MD Medical Director, CNS Division Pfizer, Inc. New York, New York

Cathy A. Sila, MD Associate Medical Director Cerebrovascular Center Section of Stroke and Neurologic Intensive Care Cleveland Clinic Foundation Cleveland, Ohio

Carlos Singer, MD Associate Professor, Department of Neurology University of Miami School of Medicine Miami, Florida

Marca L. Sipski, MD Associate Professor and Interim Chairman; Project Director, South Florida Model SCI System Department of Rehabilitation Medicine University of Miami School of Medicine Miami, Florida

Linda A. Specht, MD Franciscan Children’s Hospital Brighton, Massachusetts

Egilius L.H. Spierings,MD, PhD Associate Clinical Professor of Neurology Harvard Medical School; Consultant in Neurology Brigham and Women’s Hospital Boston, Massachusetts

Steven Spindel, MD HealthFirst Medical Group, PC Portland, Oregon

Contributors

Barney J. Stern, MD

Siew Koon Teoh, MD

Professor, Department of Neurology Emory University Atlanta, Georgia

Clinical Instructor in Radiology Harvard Medical School; Department of Radiology Mt. Auburn Hospital Cambridge, Massachusetts

Lael A. Stone, MD Staff Neurologist Cleveland Clinic Foundation Cleveland, Ohio

Guillermo A. Suarez, MD Assistant Professor of Neurology Mayo Medical School; Consultant, Department of Neurology Mayo Clinic Rochester, Minnesota

Lewis R. Sudarsky,MD Director of Movement Disorders Department of Neurology Brigham and Women’s Hospital; Associate Professor of Neurology Harvard Medical School Boston, Massachusetts

Kathryn Swoboda, MD Assistant Professor, Department of Neurology; Adjunct Assistant Professor, Department of Pediatrics University of Utah School of Medicine

Daryl W. Thompson, MD Department of Neurology Truman Medical Center Kansas City, Missouri

William R. Tyor, MD Professor, Department of Neurology Medical University of South Carolina; Chief, Neurology Service Ralph H. Johnson VA Medical Center Charleston, South Carolina

Nagagopal Venna, MD, MRCP( l),MRCP (UK) Associate Professor of Neurology Harvard Medical School; Director, Neurology Clinic Massachusetts General Hospital Boston, Massachusetts

David M. Vernick, MD Chief, Division of Otolaryngology Beth Israel Deaconess Medical Center Boston, Massachusetts

William T. T h a n , MD Department of Neurology University of Iowa Hospital and Clinics Iowa City, Iowa

Nancy J. Tarbell, MD Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts

Daniel Tarsy, MD Associate Professor, Department of Neurology Harvard Medical School; Chief, Movement Disorders Center Department of Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts

Philip A. Teal, MD Department of Neurology University of British Columbia School of Medicine Vancouver, British Columbia, Canada

Aljoeson Walker, MD Department of Neurology Medical University of South Carolina Charleston, South Carolina

Carol A. Warfield, MD Professor of Anaesthesia, Harvard Medical School; Chairwoman of Anaesthesia Beth Israel Deaconess Medical Center Boston, Massachusetts

Cheryl Waters, MD The Neurological Institute New York, New York

Lawrence R. Wechsler, MD Pittsburgh Neurology Group Pittsburgh, Pennsylvania

Randall E. Weeks, PhD Director, The New England Institute for Behavioral Medicine Stamford, Connecticut

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Contributors

David H. Weinberg, MD

Asa J. Wdbourn, MD

Assistant Professor, Department of Neurology Tufts University School of Medicine; Director, Clinical Neurophysiology Laboratory St. Elizabeth’s Medical Center Boston, Massachusetts

Clinical Professor of Neurology Case Western Reserve University School of Medicine; Director, EMG Laboratory Department of Neurology The Cleveland Clinic Cleveland, Ohio

Sandra Weintraub, PhD Professor of Psychiatry and Neurology; Director, Neuropsychiatry Program Northwestern University Feinberg School of Medicine Chicago, Illinois

Temple W. Williams, Jr.,MD John S. Dunn Professor of Medicine Baylor College of Medicine Houston, Texas

Dennis Y. Wen, MD, FACS

Barth L. Wilsey, MD

Elgin Barrington Neurosurgery Regional Cancer Center Provena St. Joseph Hospital Elgin, Illinois

Division of Pain Management University of California Davis Medical Center Sacramento, California

Patrick Y.C. Wen, MD

Professor, Department of Neurology, Boston University School of Medicine Boston, Massachusetts

Associate Professor of Neurology Harvard Medical School; Director, Division of Neuro-Oncology Department of Neurology Brigham and Women’s Hospital; Medical Director, Center for Neuro-Oncology Dana-Farber Cancer Institute Boston, Massachusetts

JaniceF. Wiesman, MD Assistant Professor of Neurology Boston University School of Medicine; Director, EMG Laboratory Boston Medical Center Boston, Massachusetts

Philip A. Wolf, MD

G. Bryan Young,MD Department of Neurological Sciences London Health Sciences Center, Victoria Campus London, Ontario, Canada

Amir Zamani, MD Neuroradiologist Brigham and Women’s Hospital Boston, Massachusetts

Preface

Charcot begins his Lectures on the Diseases of the Nervous System by noting that, “The task of the clinical observer may be regarded as differing much from that of the nosographer.” His point is that he will base his lectures on cases with all their individual peculiarities rather than on “abstract pictures of diseases.” The point is very relevant to the format of presentation of medical information, or of information in any discipline that has a sphere of practice where theory confronts the real world. Although this is not a case-based text, we intend it to be a very practical one. Our original purpose in writing and editing Ofice Prachce of Neurology was to create a unique text that would supply practicing physicians with a clinical resource to which they might refer in caring for outpatients with neurologic diseases. Specifically, we wanted the freedom to adjust focus within the text to correspond to the common experience of physicians in practice. The discussions should open up to depth and detail for those problems that are common, and especially those chronic problems that require some finesse in long-term management and that are often given too short a treatment in standard texts. This point is made by the experience we have all had of reading an article in a text looking for direction and then thinking, “Yes, I know all of that, but what do I do now?”Without trying to be comprehensive, we also wanted to provide enough breadth to cover the major problems that any practicing neurologist might encounter, including those that may be rare but which must be considered when the clinical context demands. To do this, we established a free format, allowing some topics to spread to several chapters, for example, when discussing stroke or Parkinson’s disease, and compressing to brief topic-focused single chapters when addressing the many tumors and infections of the nervous system, each individually uncommon, yet together representing a very common and important group of disorders. We feel that this format allowed us to create the most usable book, though at times it strained our strong inclinations to follow an outline constrained more by the abstract logic of nomenclature and the esthetic need for topical balance of treatment. We hope that the community of physicians will continue to support this approach. The major changes in this edition are an expanded section on multiple sclerosis to address more fully the clinical issues that arise in this common neurologic disease as well as added chapters on neurologic issues of sexual dysfunction and genetic testing. Many chapters have been completely rewritten, and others have been updated to keep up with the fast pace of change. Once again, we must confront the outpatient focus implied in the book‘s title, and the allocation of space and a few discrepancies raised by topics included in the book. Neurology is largely an outpatient specialty, hence this limitation does not amputate the corpus a great deal. As in the first edition, we have chosen to exclude a discussion of coma and of neurologic intensive care, since physicians deal with these problems exclusively in the inpatient setting. Again, we have chosen to include discussions of

certain disorders that will be diagnosed and treated in the hospital when such discussions constitute part of a larger discussion within which completeness seems to demand their inclusion. The sections on stroke, epilepsy, infectious diseases, and oncology all include discussions that fit this description. We think that these extensions are necessary for coherence and hope that our readers will not fault us too greatly for these deviations from a purely outpatient focus. The major consideration that should justify a second edition is the emergence of enough new information that alters practice sufficiently to render the first edition out of date. Certainly this criterion has been satisfied since the writing of the first edition. Major advances have been made in almost every field. Molecular genetics continues to open up new understanding of once-obscure disorders. Perhaps the explosion of new information about the progressive ataxias is the best example of this. Molecular studies have also shed light on our understanding of Alzheimer’s disease and other dementias, Huntington’s disease, familial stroke, headache syndromes, and many other diseases. Since the first edition, major large-scale studies have been completed. The Asymptomatic Carotid Atherosclerosis Study and the North American Symptomatic Carotid Endarterectomy Trial offer data on the use of carotid endarterectomy in asymptomatic patients and symptomatic patients with mild-to-moderate stenosis, raising important clinical considerations about extending the use of carotid endarterectomy for stroke prevention. At least one major clinical trial, the DATATOP study of selegiline for Parkinson’s disease, has undergone an important second look. In the short time since the first edition, major new therapies have been introduced for many diseases. In a casual count, we identified over 20 new drugs or applications adding new therapies for stroke, seizures, multiple sclerosis, migraine, Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. For a book of practice, these rapid changes have made a new edition essential. This book is the cooperative work of many dedicated people. We greatly appreciate the work of all of the contributors and section editors who have freely given their time and effort in the planning and writing of this book. These are our valued colleagues in neurology and its many allied fields. We also wish to thank our editors at Elsevier Science, Churchill Livingstone, and Graphic World Publishing Services, Susan Pioli, Melissa Dudlick, and Michael McConnell who, tactfully, kept us going to the end. We continue to learn from our day-to-day encounters with patients and with our colleagues as we try to tackle the endlessly challenging task of diagnosing and treating those with neurologic disorders. We hope that this book puts some of that experience onto paper in a way that brings the highest quality neurologic care to as many patients as possible. Martin A. Samuels, M.D. Steven K. Feske, M.D.

Table of Contents

Pt. I

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Sect. 1

Principles of Diagnoses: The General Approach to Neurologic Diagnoses

Sect. 2

Principles of Diagnoses: Common Presenting Symptoms and Findings

Sect. 3

Principles of Diagnoses: Special Tests

Sect. 4

Principles of Treatment

Pt. II

Cerebrovascular Disease

Sect. 1

General Aspects of Cerebrovascular Disease

Sect. 2

Common Pathogeneses of Stroke

Sect. 3

Less Common Causes of Stroke

Sect. 4

Clinical Features and Management of Cerebrovascular Disease

Pt. III

Immune and Infectious Diseases

Sect. 1

Immune-Mediated Disease

Sect. 2

Infectious Diseases

Sect. 3

Spirochetal Infections

Sect. 4

Fungal and Parasitic Infections

Sect. 5

Viral Infections

Sect. 6

Nerves and Muscle

Sect. 7

Other Infections and Mimickers

Pt. IV

Spinal Cord and Peripheral Neuromuscular Disease

Sect. 1

Diseases of the Spinal Cord

Sect. 2

Motor Neuron Disease

Sect. 3

Diseases of Peripheral Nerve

Sect. 4

Diseases of Neuromuscular Transmission

Sect. 5

Diseases of Muscle

Pt. V

Movement Disorders

Sect. 1

Parkinson's Disease and Parkinsonian Syndromes

Sect. 2

Non-Parkinsonian Movement Disorders

Pt. VI

Behavioral Neurology and Epilepsy

Sect. 1

Behavioral Neurology

Sect. 2

Epilepsy

Sect. 3

Disorders of Sleep

Sect. 4

Psychiatric and Social Issues in Neurologic Practice

Pt. VII

Neuro-Oncology

Sect. 1

Brain Tumors: General Aspects

Sect. 2

Specific Tumor Types

Sect. 3

Spinal Cord Tumors

Sect. 4

Neurologic Complications of Systemic Cancer

Pt. VIII

Neurology in General Medicine

Sect. 1

Cardiology and Cardiac Surgery

Sect. 2

Pulmonary Disorders

Sect. 3

Nephrology and Urology

Sect. 4

Gastroenterology and Hepatology

Sect. 5

Hematology

Sect. 6

Endocrinology and Metabolism

Sect. 7

Toxins and Drug Effects

Sect. 8

Organ Transplantation

Sect. 9

Rheumatology

Pt. IX

Headache and Pain

Sect. 1

General Aspects of Headache

Sect. 2

Headache Symptoms and their Treatment

Sect. 3

Special Headache Problems

Sect. 4

General Aspects of Pain

Sect. 5

Generalized and Regional Pain Syndromes

Sect. 6

Treatment of Pain Appendix A Appendix B Index

SECTION

1

PRINCIPLES OF DIAGNOSIS: THE GENERAL APPROACH TO NEUROLOGIC DIAGNOSIS

1

Neurologic History and Examination rn

Steven K. Feske

In every branch of medicine, the history and physical examinations are performed to answer several questions, including the following: In which parts of the body is there dysfunction? What is the underlying cause of the dysfunction? That is, from what disease is the patient suffering? Our goal in evaluating the patient with neurologic disease is to answer these questions. Special to the neurologic evaluation is the precision with which it is possible and clinically relevant to pinpoint the site of dysfunction within the nervous system. We cannot answer these questions directly, however, we must do so by making inferences from what we can observe, either by the history or by the examination. The more immediate goal of the patient’s history and physical examination, then, is to establish a firm basis from which to make reliable inferences. In taking a history, we want to answer several more immediate questions: What happened? Which neurologic structures does this implicate? What was the context for the illness? Over what period of time did the illness develop? In performing our neurologic examination, we want to answer the following additional questions: What sites of neurologic dysfunction might explain the neurologic signs that we can elicit? Do these signs fall into a known pattern of dysfunction or syndrome? Are there signs of medical illness that may be relevant to the neurologic disease? What is the degree of dysfunction? In other words, our questions in the history and examination are directed to seek information about the localization, context, and timing of the disease process and, finally, the degree of disability. By virtue of its intricate anatomic organization, the nervous system lends itself to a particularly fine analysis of localization. Because diseases tend to cause dysfunction in predictable sites, whether in certain tissue compartments (as in meningitis and subarachnoid hemorrhage), vascular territories (as in stroke), tissue types (as in multiple sclerosis), or neuronal systems (as in amyotrophic lateral sclerosis), the neurologist’s focus on neurologic localization is critical to accurate diagnosis. The most informative examinations are those that are organized around working hypotheses about the possible localization of the lesion or lesions. Therefore, this review of the techniques used in the clinical encounter strongly stresses neurologic localization. The purpose of this chapter is to summarize an approach to the assessment of neurologic problems by the traditional patient history and physical examination. The discussion points out useful ways to organize and develop the evaluation, but it does not describe the examination in detail. This is accomplished in various sections of the book where different anatomic sites and groups of disease are discussed: mental status examination (Ch. 135), cranial nerves (Chapters 6 to 1l), motor and reflex examinations (Chapter 2

2), sensory examinations (Chapter 5), coordination (Chapters 3 and 124), and gait and station (Chapter 4).

PURPOSE OF EVALUATION It is important to establish the purpose of a particular evaluation at the outset. This may be to diagnose an as yet unexplained problem; to follow the progression of a disease, either to make a diagnosis based on the course of the disease over time or to follow the progression of response to therapy in the case of an established diagnosis; or to assess the functional status of a patient with a disabling illness, such as stroke, multiple sclerosis, or Parkinson’s disease. One’s attention to certain details and recording methods may vary depending on the purpose.

APPROACH TO THE PATIENT HISTORY AND PHYSICAL EXAMINATION For diagnostic purposes, history is elicited to develop the nature of the complaints and the details of the events leading to them and to discover any medical, psychological, and social context that may offer epidemiologic clues to the cause. Both the patient history and physical examination are used to identify the site or sites in the nervous system that have malfunctioned. Armed with this information and a solid foundation of medical and neurologic knowledge, one tries to identify the medical or neurologic syndrome into which the disease may fit. Often this suggests a cause or allows the examiner to generate a restricted list of possible etiologic diagnoses that can be further pruned by special tests. For the assessment of functional status and disease progression, details concerning the limitations of various functions must be explored along with the effects of these limitations on activities of daily living.

NEUROLOGIC HISTORY Chief Complaint It is helpful for consulting physicians to establish from the outset the reason for a visit, both as understood by the patient and as expressed by the referring physician. This allows the consultant to address specific questions posed by the patient and referring physician and, in some cases, to identify discrepancies of understanding and intent that may be important for diagnosis and management. At the outset, it is necessary to get a clear sense of the reliability of the patient as historian and the possible need to seek other sources of history, for example, when the problem is

Chapter 1

dementia, confusion, or loss of consciousness or when it has a complexity or emotional impact that might influence reporting. Reliable family members or other close contacts or witnesses must be sought and questioned. In such cases, it may be necessary to compare several accounts to understand the history. History of Present Illness When possible, it is helpful to listen to the patient describe the problem in his or her own words, initially without much direction from the examiner. This allows the patient to present a story with emphasis on what has seemed most important to him or her and to bring in associated information that seems to be relevant. Many patients, given the floor, focus on characteristic symptoms that strongly suggests a diagnosis. Having heard this story, the examiner can begin to develop hypotheses about the possible causes of the problem and then direct the patient with specific questions that will help to distinguish between these possible causes. In some cases, such as transient events, it is important to develop the history of the onset of the event in second-by-second detail in an effort to distinguish such diagnoses as syncope, seizure, transient ischemic attack, and migraine. In cases where there has been an alteration in awareness or when other circumstances render the patient less than fully reliable, it is necessary to obtain the history from any available witnesses. Pain, weakness, numbness, paresthesias, other forms of dysfunction, and other related symptoms should be distinguished and characterized in detail, including sites, quality, temporal course, and modifiers. The occurrence of similar or related symptoms in the past or the accumulation of symptoms over a long period of time may be important. In multiple sclerosis, a history of prior episodes suggestive of involvement of different anatomic sites is important. With transient ischemic attacks, very similar symptoms may recur many times. In epilepsy, recurrent seizures typically are stereotyped at onset. In chronic progressive illnesses, various symptoms may have emerged as subtle changes in the past and now become prominent symptoms, as is common in Parkinson’s disease. Precipitating factors may give clues to the cause. In cases of syncope, postural changes may prompt symptoms. In multiple sclerosis, exposure to warm temperatures may provoke them. Many factors may trigger migraines. Emotional stimuli may trigger anxiety symptoms, but they also may exacerbate the manifestations of various neurologic diseases, including Parkinson’s disease, other tremors, and migraines. The time of day at which symptoms occur may be the clue to the precipitating cause. Increased intracranial pressure typically causes morning headaches, as does caffeine withdrawal. Tumor-related pain often is worse at night. The examiner should ask about past evaluations and past treatments for the current problem or similar ones and the patient’s responses to these. Such background may provide specific diagnostic information. Insight into the nature of the illness at an earlier time, perhaps before a confounding treatment was started, is based on responses to therapy. It is important to recognize that this may be a source of frustration for the patient if diagnosis has been elusive or therapy unsuccessful. It may also be a source of bias for the examiner, which must be acknowledged and accepted or rejected with caution. Finally, to close the history of present illness, it is often best to develop the part of the history that is most relevant to the examiner’s favored hypotheses about the cause of the problem at hand. This includes directly relevant epidemiologic information usually sought in the review of the medical history.

Neurologic Hidory and Examination

3

Past Medical History It is prudent in most cases to review a list of major common medical and neurologic problems to fill in the patient’s personal history. In my experience, a general question about past medical problems fails to elicit much relevant information, and a quick review of the following list will quickly bring out most past illnesses that have been established diabetes mellitus, hypertension, heart disease, lung disease, gastrointestinal disease, renal disease, thyroid disease, arthritis, skin disease, cancer, stroke, seizure, and migraine. A history of use of alcohol, other drugs, and cigarettes and other habits relevant to health should be sought in most cases. In many cases, it is helpful to ask about risk factors for human immunodeficiency virus infection. Past trauma and surgery should be reviewed. In many cases when seeing adults, the early childhood history is not explored; however, it can be informative when evaluating patients with epilepsy and many chronic diseases with early onset. In patients with mild motor, cognitive, or behavioral abnormalities, movement disorders, or hydrocephalus, all having gone unnoticed, the explanation sometimes is a mild static encephalopathy suggested by a history of prematurity or early childhood problems. It is important to elicit the medications that the patient is taking because in some cases they are the source of the problem, as often occurs in cases of syncope, dizziness, and confusion. They also give clues to otherwise unmentioned underlying problems. Knowing the current medications also will be important later when further evaluation and treatments are being planned. Place of origin or travel may greatly color the assessment of a finding. Cerebral calcifications in a native of Central or South America, the Indian subcontinent, or Southeast Asia all raise the likely possibility of cysticercosis, an unlikely explanation in patients from temperate climates. Various tropical diseases are suggested by exposure. Lyme disease is endemic to certain areas and rare in others. Human immunodeficiency infection has become more widespread but still has a higher incidence in sub-Saharan Africa, Haiti, and many urban areas. Human T cell leukemia virus type I infection is found mainly in the West Indies, parts of Africa, and Japan. Behget’s disease is more common in the Near East and the Pacific rim of eastern Asia, although many cases are now found in other areas. Several hereditary diseases also have been linked to restricted areas of the world. Machado-Joseph disease occurs in patients from Portugal, the Cape Verdean Islands, and areas populated by emigration from these sites, such as Brazil, Japan, and several areas in the United States. Of course, there are many other examples. Exposure to animals is occasionally important. Mosquitos, ticks, and other insects bear many diseases, including encephalitis, Rocky Mountain spotted fever, and Lyme disease. Diseases associated with large animals include encephalitis borne by horses, Lyme disease borne by white-tailed deer, brucellosis borne by cattle, rabies borne by various small domestic and wild mammals, cat-scratch disease and toxoplasmosis borne by cats, and leptospirosis borne by rats. None of these are common. Unusual exposure may come from unusual work, such as laboratory technicians handling infectious pathogens. Family History Family history can provide important clues to diagnosis and, occasionally, incentive for screening and preventive treatment for several common diseases. Hypertension, diabetes, early atheroscle-

4

Principles of Ambulatoy Neurology and the Approach to Clinical Problems W

rosis, migraine, epilepsy, and major depression all occur with a higher incidence in some families, although the genetic basis in most cases of these disorders is complex and obscure. It is interesting to notice that many patients report no family history of illnesses such as migraine, but when asked simply whether anyone has frequent headaches, they acknowledge that a close family member has “routine headaches.” For certain familial diseases, such as Huntington’s disease, hereditary neuropathies, and myotonic dystrophy, the family history is very important for diagnosis. Again, with diseases such as the last two mentioned, it is common to be told initially that there is no family history of the disease but to find on closer questioning or on examination of family members that there is. When familial diseases with established patterns of inheritance are being considered, it is important to construct a family tree with information as far back as possible. This often entails interviewing or examining family members. Social History

When an illness has behavioral consequences, it is important to know the educational level, marital status, family situation, and occupation of the patient. Recent life events, new schools, new jobs, relocation, or the death of a close friend or relative can contribute to illnesses that have an emotional component. This information is also of great importance in planning for the chronic care needs of patients with disabilities. Occupational risks are also important in many illnesses, such as carpal tunnel syndrome in patients who work at a computer or do other repetitive manual jobs.

Principles of Diagnosis: The General Approach

the neurologic examination. It is possible to carry out an exhaustive examination at great length. However, for a diagnostic examination, our goal is to apply a focused, detailed examination directed at the problem at hand, to apply a core screening examination to test the integrity of the nervous system as a whole, and to screen for significant medical illness. For an examination of functional status, our goal is to establish the level of function of a system in as objectifiable a manner as possible and to document it in a reproducible format for future comparison. A complete neurologic examination should include the elements described in this section. Mental Status

The mental status examination can be done, in large part, by observation during history-taking. In patients with apparently normal mental function for whom the mental state is not brought into question by the complaints, the examiner usually can demonstrate a normal core of mental functions in this manner. When the mental state is in question, the examiner should elaborate the mental status examination. Specific tests and general observation should address the patient’s level of consciousness, orientation, attention, motivational tone, and affect or mood. These state functions provide the necessary substrate for normal interactions and the proper use of the more discrete mental functions. Language and memory should be tested and, when relevant, further mental status tests looking for evidence of focal disease should be done. Many of these are mentioned later in this chapter in the discussion of localization. The mental status examination is discussed in detail in Chapter 135.

System Review After the apparently relevant information is elicited in the patient history, a quick system review covers all the bases when the diagnosis is still in question. This is intended to elicit symptoms that patients may not spontaneously volunteer but that may be clues to unconsidered and contributory illnesses, as opposed to the questions concerning past diagnoses of symptoms of major concern that were sought earlier in the history of present illness and past medical history. Fever, chills, weight loss, and night sweats are important symptoms that suggest infectious or neoplastic disease. Surveying symptoms relevant to proper functioning of the head and neck, lungs, heart, digestive tract, urinary tract, endocrine system, and joints can be done quickly in most cases. Although one usually obtains most of the relevant information in earlier questioning, an unexpected history of major weight loss may turn one’s thinking toward a malignancy. A history of lung disease and adenopathy in a patient with a facial palsy will make one think seriously of sarcoidosis, even though it is a rare cause. An unexpected history of diarrhea may make one seriously consider a rare case of Whipple’s disease in a patient with spontaneous nystagmus and hypothalamic dysfunction. Although a thorough review of systems is not often rewarded by such rare diagnostic surprises, it is a good practice that sometimes provides important clues.

NEUROLOGIC EXAMINATION Many available books describe the neurologic and medical physical examination in great detail, and the reader is referred to those mentioned at the end of this chapter for a detailed discussion of

Cranial Nerves

By testing smell and central and peripheral vision, visualizing the optic fundi, and testing pupils, lids, voluntary and reflex eye movements, hearing, facial sensation, facial movements, and oral, lingual, palatal, and sternocleidomastoid and trapezius movements, the examiner has screened for cranial nerve dysfunction. Each cranial nerve can be tested in further detail when its function is in question. Chapters 6 to 11 address many specific aspects of the examination. It is important to develop hypotheses of localization to consider the potential anatomic localization of a lesion when testing cranial nerves. For example, in a patient with unilateral complete upper lid ptosis and a down-and-out eye with impaired adduction and vertical ductions consistent with oculomotor palsy, it is important to look for pupillary involvement and for trochlear, abducens, and trigeminal (V1 and V2) involvement that might suggest a lesion in the cavernous sinus, sparing V2 in the superior orbital fissure, proptosis and chemosis that might suggest orbital infiltration, or other cranial nerve lesions that might suggest multifocal disease in the brainstem or subarachnoid space. Motor Fundion

Muscles should be inspected for normal bulk, and abnormal postures and spontaneous movements of the muscles, body, and limbs should be noted. The muscle tone is noted to be decreased, normal, or increased. Hypertonicity should be characterized as spastic, paratonic (gegenhalten), the lead pipe (often called cogwheel) rigidity of parkinsonism, or other types of rigidity, such

Chapter 1

as muscle spasm, myotonia, and voluntary rigidity. Power in the basic muscle groups should be assessed and recorded in a reproducible format. A common system is to record the power along a functional scale of five units, as follows: 5/5 = full power, 4/5 = movement against some resistance, 3/5 = movement against gravity, 2/5 = movement with gravity eliminated, 1/5 = a trace of movement, and 0/5 = no visible movement. A screening examination should test the neck and major proximal and distal muscle groups of the extremities. Again, the decision to perform a more detailed examination is hypothesis-based. For example, a hypothesis that the lesion involves the cervical roots or brachial plexus should prompt the individual testing of multiple C5 (rhomboid, supraspinatus, infraspinatus, deltoid, biceps), C6 (biceps, brachioradialis, teres major), C7 (triceps, wrist and finger extensors), C8 (finger flexors, abductor pollicis brevis, opponens pollicis), and T1 (abductor digiti minimi, interossei) muscles for power, atrophy, and fasciculations. A hypothesis that carpal tunnel syndrome is the cause demands testing of the abductor pollicis brevis and opponens pollicis and contrasting them with muscles innervated by the ulnar nerve and the finger flexors that are in the forearm proximal to the carpal tunnel. Chapter 2 discusses the motor examination in greater detail. Sensory Function

The appreciation of light touch, deep pressure, pinprick, temperature, vibration, joint position, and cortical sensation should be tested. By strategically choosing the points to test, this screening can be completed quickly. I usually test light touch on the distal extremities, pinprick and temperature sensation at certain strategic sites on the dermatomal map (C3, supraclavicular fossa; C4, acromioclavicularjoint; C5, lateral upper arm and lateral epicondyle; C6, thumb; C7, index and middle finger; C8, little finger; T1, medial epicondyle; T2, axilla; L1, inguinal crease; L2, anterior thigh; L3, medial knee; L4, medial malleolus; L5, dorsum of the foot between the great and second toes; S1, lateral heel; and S2, medial aspect of the popliteal fossa), and vibration and joint position in the fingers and toes. Cortical sensation is tested with graphesthesia, stereognosis, and two-point discrimination in the hands. This examination should be abnormal when there are deficits from peripheral neuropathies, various isolated neuropathies, the most common radiculopathies, myelopathies, and brain lesions; more detailed tests can be done, when indicated, to add precision and answer specific questions. For example, when a spinal cord lesion is suspected, thoracic dermatomes should be tested and a sensory level sought. Sensory testing is necessarily in part subjective and can be misleading if not carefully performed. The examination seeks to define meaningful patterns of abnormal function that can be reproduced on repeat testing. Findings should be recorded carefully for future comparison. Details of the sensory examination are discussed in Chapter 5.

Reflexes The deep tendon reflexes are tested at the biceps (CS), brachioradialis (C6), triceps (C7), finger flexors (C8), knees (L2-L4), and ankles (Sl). Additional ones can be added to answer localizing questions: jaw jerk (above the foramen magnum), hip adductors (L2-L4), and tibialis posterior (L5). The degree of response, reproducibility, and symmetry of the reflexes are noted. Mass spread of the reflex to adjacent segments is noted. The main

Neurologic History and Examination

5

pathologic reflex that is included in the screening examination is a scratch to the lateral sole looking for the Babinski sign. The reflexes usually are recorded on a scale of 4 units, where 0/4 is absent, 1/4 and 2/4 are two degrees usually considered within normal limits when symmetrical (although symmetrically 1/4 reflexes may be abnormal in certain contexts, such as a young person with early Guillain-Barrk syndrome), 3/4 is hyperreflexic, and 4 4 is hyperreflexic with clonus. Some authors use different definitions of these quantitative values, so there is little uniformity across examiners. “Trace” and plus and minus signs are sometimes added to this scale to express intermediate degrees, but there is even less reproducibility between examiners for these finer distinctions. It is most important that one establish as much consistency and conformity as possible to enhance communication. The reflex examination is discussed in Chapter 2.

Tests of coordination, including rapid alternating movements and finger-to-nose and heel-to-shin maneuvers look for cerebellar ataxia, dysmetria, dysdiadochokinesia, intention tremor and may also elicit pyramidal and extrapyramidal features. These and other tests can help to assess cerebellar as well as pyramidal and extrapyramidal motor function and sensory function. Station and Gait

The patient should be observed standing with the feet together and the eyes open and closed (Romberg sign) and walking while balance, stride, armswing, and posture are noted. Heel-to-toe (tandem) walking completes the screening neurologic examination. Analysis is complex, but characteristic features of gait may provide localizing clues. Gait is discussed in detail in Chapter 4. Medical Status A general medical examination should include as much detail as is necessary to address the problem. It is often important to know the vital signs, to examine head and neck structure and pulses and to listen for bruits, to listen to the heart for murmurs and abnormal rhythms, to palpate the abdomen for hepatosplenomegaly, to note the extremities for abnormalities of form (e.g., pes cavus), joint changes, or abnormal lymph nodes, and to inspect the skin for marks, such as cafk-au-lait spots, telangiectasias, petechiae, or other lesions.

NEUROLOGIC LOCALlZATlON The nervous system is organized in a way that lends itself to precise localization of the anatomic site or sites of dysfunction. By identifying the subsystem of the nervous system affected by a disease (along with the context and timing of the illness) one can often accurately infer the nature of the disease process, so localization is a major goal of the neurologic examination. Therefore, the rest of the discussion of the diagnostic history and examination is organized around the knowledge used to localize the lesion. The first question one asks is, “What is the gross location of the lesion?” That is, is it in the muscle, neuromuscular junction, peripheral nerve, nerve plexus, nerve root, anterior horn cell, spinal cord, or brain? Is it on the left or right side of the brain, spinal cord, or body? If one can successfully make this determi-

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: The General Approach

6

TABU 1-1. Localization of Forebrain Lesions Site

Finding

Left frontal lobe

Anterior aphasia (Broca's, transcortical motor), aphemia ldeomotor apraxia L Voluntary rightward saccades, left gaze preference Right hemiparesis, t deep tendon reflex, and Babinski sign Motor neglect of left world ldeomotor apraxia 1Voluntary leftward saccades, right gaze preference Left hemiparesis, 'T deep tendon reflex, and Babinski sign Perseveration, impersistence, stimulus-bound responses Impaired executive functions: planning, sequencing, judgment, insight, abstract reasoning Impaired motor (Luria) sequencing Snout, root, grasp, and palmomental reflexes Gegenhalten (paratonic rigidity) Disinhibition, aggressive impulsivity Anosmia Memory disturbance Abulia + akinetic mutism Incontinence "Magnetic" gait Bilateral leg weakness Behavioral changes (cingulate gyrus) Right cortical sensory loss (astereognosis, agraphesthesia, 1two-point discrimination) Anomic aphasia, transcortical sensory aphasia dysgraphia, dyscalculia, left-right disorientation, finger agnosia Right inferior quadrantanopsia Left cortical sensory loss (as above) Left-sided neglect, anosognosia Constructional apraxia, dressing apraxia Left inferior quadrantanopsia Posterior aphasia (Wernicke's, transcortical sensory) Conduction aphasia Amnesia for verbal material (usually bilateral lesions) Right superior quadrantanopsia Dysprosody, amusia, nonverbal auditory agnosia Amnesia for nonverbal material (usually bilateral lesions) Left superior quadrantanopsia

Right frontal lobe

Bilateral frontal lobes

Orbitofrontal Frontal convexity Midline frontal Left parietal lobe

Right parietal lobe

Left temporal lobe

Right temporal lobe

Bilateral temporal lobes Medial Perisylvian Occipital lobe Left Parieto-occipital Temporo-occipital

Thalamus

Basal ganglia

Amnesia Cortical deafness Auditory agnosia Contralateral homonymous hemianopsia (macular sparing) Alexia without agraphia (requires lesion of splenium of corpus callosum) Balint syndrome (simultanagnosia, optic ataxia, ocular apraxia): impaired visuospatial localization Visual agnosias (including prosopagnosia, color agnosia, achrornatopsia) Visual amnesia Confusional state Agitated confusional state Decreased level of consciousness Amnesia Aphasia (transcortical sensory) Hemisensory loss Cerebellar ataxia Parkinsonism Aphasia (transcortical motor) Hyperkinetic syndromes (e.g., hemiballism with subthalamic nucleus infarction)

nation, then one should try to make a more exact estimate of the precise localization within the nervous tissue. Information relevant to such localization is presented throughout the text. Tables 1-1 through 1-5 summarize some of the commonly used or classically described clues. As an example of this approach, clues that the brain is the site of concern include behavioral and cognitive symptoms; symptoms on one-half of the body, including more than one of the three possible locations (face, arm, and leg); a lack of peripheral pain, except headache; and features of an upper motor neuron or cortical sensory lesion. Having chosen to TABU1-2. Localization of Brainstem Lesions Site

Midbrain Tectum and pretectum Tegmenturn

Cerebral peduncles Red nucleus Ascending cerebellar fibers Pons Tegmentum

Basis pontis

Finding

Parinaud syndrome (large pupils with nearlight dissociation, convergenceretraction nystagmus, impaired upgaze, eyelid retraction) Abnormal pupils: midrange, unequal, irregularly shaped Impaired vertical eye movements Anterior IN0 Skew deviation Decreased arousal Nuclear CN 111 lesions (including bilateral ptosis and superior rectus deficits) Nuclear CN IV lesions (contralateral CN IV deficit) Weber syndrome (ipsilateral CN 111, contralateral hemiparesis) Benedikt syndrome (ipsilateral CN 111, contralateral tremor) Claude syndrome (ipsilateral CN 111, contralateral cerebellar ataxia) lpsilateral gaze palsy ("wrong-way eyes'') lntranuclear ophthalmoplegia One-and-a-half syndrome Skew deviation CN V, VI, VII, and Vlll lesions Contralateral hemiparesis Contralateral ataxia Dysarthria

Medulla Lateral

Wallenberg syndrome (ipsilateral CN V, ipsilateral Hornefs syndrome, contralatera1 loss of pain and temperature below the neck [spinothalamic tract], vertigo and ipsilateral nystagmus, ipsilateral CN IX and X deficits, skew deviation) lpsilateral CN XI1 deficit, contralateral hemiMedial paresis, contralateral medial lemniscus deficit (ioint Dosition and vibration) Abbreviations: CN, cranial nerve; INO, internuclear ophthalmoplegia.

TABLE 1-5. Localization of Cerebellar Lesions Site

Finding

Cerebellar hemisphere

lpsilateral ataxia (intention tremor, dysdiadochokinesia, dysmetria) lpsilateral hypotonicity Gait ataxia with widened base Truncal titubation Dysarthria (ataxic speech) Abnormal eye movements Skew deviation Hypometric and hypermetric saccades, micro- and macro-square-wave jerks, breakdown of smooth pursuit movements, opsoclonus Contralateral head tilt (cerebellopontine angle tumor)

Midline Vestibulocerebellum

Chapter 1

TABLE 1-4. Localization of Spinal Cord Lesions Site

Finding

Bilateral signs LMN signs at the level of the lesion UMN signs below the lesion Marked spasticity with majestic Babinski signs Absent jaw jerk Sensory level at or below the level of the lesion Craniocervical Neck pain, head tilt junction Downbeating nystagmus UMN signs of all four extremities Cervical spinal Neck pain cord Root signs at the dermatomal level of the lesion in the neck, shoulders, or arms Long tract signs below the level of the lesion (usually bilateral) Sensory level at or below the level of the lesion Spastic bowel and bladder (later) Thoracic spinal Back pain cord Root signs at the level of the lesion Paraparesis: long tract signs below the level of involvement Sensory level below the level of involvement Spastic bowel and bladder Conus medullaris Early bowel, bladder, and sexual dysfunction; usually areflexic (LMN) bladder (S3-Cocl) Early perineal hypesthesia No motor signs in legs (a pure) Distal motor signs with loss of ankle jerks (if epiconus. L4-52) Cauda equina See Table 1-5 ‘ Anterior cord AHC (LMN) involvement at the level of the lesion syndrome Corticospinal trad involvement below the lesion Spinothalamic tract involvement below the lesion Sparing of the dorsal columns Spastic bowel and bladder Central cord synSegmental loss of pain and temperature at the drome levels of the lesion UMN signs below the lesion Sparing of dorsal column modalities Sacral sparing Brown-Skquard lpsilateral corticospinal tract signs below the le(hemicord) synsion drome lpsilateral loss of vibration and joint position sense below the lesion Contralateral loss of pain and temperature below the lesion Band of ipsilateral hwesthesia to all modalities at the l d e l of the l A o n Abbrenations: AHC, anterior horn cell; LMN, lower motor neuron; UMN, upper motor neuron.

Spinal cord

Neurologic History and Examination

7

postoperatively to have weakness of the left quadriceps with spared hip adduction, tibialis anterior, extensor hallucis longus, gastrocnemius, and hamstring function, with sensory loss in the distribution of the saphenous nerve (medial shin) and dropped knee jerk with preserved ankle jerk and flexor plantar response. In this case, the lower motor neuron motor and reflex findings and the consistent sensory findings limited to the distribution of the left femoral nerve suggest that the weak leg is caused by a left femoral neuropathy from compression during surgery. Again, the localizing examination and history allow focused testing and management plans. FUNCTIONAL ASSESSMENT When following the course of a chronic disease and making recommendations about chronic care needs, an assessment that answers questions about the degree of disability and provides a standard of comparison of patients and of a single patient over time is needed. A descriptive evaluation of function in the various areas-behavioral and cognitive, visual, auditory, motor, sensory, ambulatory, and ability to perform activities of daily living such as personal hygiene, bathroom activities, shopping, cooking, eating, and housekeeping-can be tailored to the situation at hand. For some diseases, standardized disability scales have been adopted by many practitioners. The expanded disability status scale is commonly used to follow the course of patients with multiple sclerosis and to define patient groups for clinical research. This is shown in the Appendix. The unified Parkinson’s disease rating scale often is used to standardize disability measurement and recording in patients with Parkinson’s disease. This is discussed in Chapter 114 and shown in the appendix.

TABLE 1-5. Localization of Lower Motor Neuron Lesions

Site

Finding

Anterior horn cells

Evolves to involve all four extremities (may not at first)-LMN involvement of the lower extremities may distinguish it from cervical spondylosis-in ALS Atrophy, fasciculations, and weakness Hypotonicity and loss of reflexes Tongue and other involvement above the neck (in ALS)

look closely at the brain for the lesion, one can ask whether the lesion is diffuse or discrete and localized. Diffuse brain disease usually causes impairment of the state functions mentioned earlier. Such lesions underlie mainly cases of impaired level of consciousness and impaired attention. Some cases of impaired motivation and altered mood also result from global disease. These conditions almost always include an impairment in attention. Many special tests can be applied to probe for various focal brain lesions. It is helpful to organize the examination around the site one is testing and, when looking for evidence of disease at a locus, to test multiple functions governed by that locus. The outcome of the diagnostic assessment should be a formulation along the lines of the following: A man is noted postoperatively to have decreased motivation, apathy, paucity of speech, right leg weakness, increased deep tendon reflexes at the right knee and ankle, a right Babinski sign, and subtle sensory signs. From these data one might infer that the lesion was a stroke (sudden onset)in the left anterior cerebral artery territory and plan appropriate confirmatory evaluation and management. In contrast, a man is noted

Roots

Cauda equina

Nerve Mononeuropathy

Usually with associated UMN signs (in ALS) Dermatomal pain and paraesthesias Unilateral (unless multiple, as in CBS) Dermatomal sensory loss Myotomal weakness Isolated 1 DTR Low back and perineal pain LMN deficits of the lower extremities (may be asymmetric) Early areflexic bladder and bowel

Pain and paraesthesias in sensory nerve distribution (light touch loss typically involves greater area than pinprick loss) Sensory and motor deficit characteristic of a p e ripheral nerve Polyneuropathy Usually distally predominant stocking-glove distribution Deficit gradient from distal to proximal Symmetric deficits Loss of motor, sensory, or autonomic function, deDendinn on the nerves involved LOSS & anMeYjerks in most Abbreviobbns: A S , amyotrophic lateral sclerosis; DTR, deep tendon reflex; GBS, Cuillain-Barre syndrome; LMN, lower motor neuron; UMN, upper motor neuron.

Plincipler of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Common PresentingSymptoms

8

SUGGESTED READINGS Brazis PW, Masdeu JC, Biller J: Localization in Clinical Neurology. 2nd Ed. Little, Brown, Boston, 1990 Haerer A F DeJong’s The Neurologic Examination. 5th Ed. JB Lippincott, Philadelphia, 1992 Haymaker W: Bing’s Local Diagnosis in Neurological Diseases. 15th Ed. Mosby, St Louis, 1969 Hoehn MM, Yahr M D Parkinsonism: onset, progression and mortality. Neurology 1 2 4 2 7 4 2 , 1967

SECTION

Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444-1452, 1983 Mesulam MM: Principles of Behavioral Neurology. FA Davis, Philadelphia, 1985 Sipe JC, Knobler RL, Braheny SL et ak A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology 341368-1372, 1984 Van Hilten JJ, van der Zwan AD, Zwinderman AH, Roos RAC Rating impairment and disability in Parkinson’s disease: evaluation of the UPDRS. Mov Disord 9:84-88, 1994

2

PRINCIPLES OF DIAGNOSIS: COMMON PRESENTING SYMPTOMS AND FINDINGS

2

Weakness Michael Ronthal

Deficits in the motor system present primarily with weakness. This chapter is intended to help with the localization and diagnosis of weakness of somatic muscles. The first step is to define broadly whether the deficit is caused by a central lesion-that is, affecting upper motor neurons (UMNs)-or by a peripheral process affecting the lower motor neurons (LMNs). The UMNs encompass the central motor pathway from the cortex to, but not including, the anterior horn cell. The LMNs include the anterior horn cell, the motor nerves, endplates, and, for purposes of the localizing examination, the muscles. Careful examination of the patient usually allows differentiation between central and peripheral processes.

PATIENT HISTORY As in all clinical diagnostic problems, data gathering begins with

elicitation of the patient’s history. The patient complaint of “weakness:’ like other primary complaints, may include a wide range of problems and hide a multitude of disorders. For example, dyspnea of effort, rheumatologic pain produced by movement, ataxia, or even numbness may be meant. It is therefore important to probe into exactly what the patient means and to ask for localization of the symptoms. If the complaint truly is weakness, it is often useful to ask the direct question, “In what daily life tasks does the weakness manifest?” Difficulty brushing hair and problems going up stairs may signify primarily a proximal distribution of weakness, suggestive of a myopathic process; difficulty with finger movements, a more distal distribution, suggests neuropathy; and weak legs suggest a myelopathy. Lateralized symptoms suggest a cranial process.

The evolution of the complaint over time may yield valuable clues about the pathologic process. Sudden onset often implies a stroke; progressive lateralized weakness suggests an expanding mass lesion; and fluctuating weakness, particularly if related to repetitive effort, might suggest an endplate disorder. Suddenonset, short-lived episodes might suggest the diagnosis of transient ischemic attacks or even atypical seizures. Associated symptoms and events may be crucial to the diagnosis. The presence of palpitations at the onset of an episode of lateralized weakness supports cardiogenic emboli as the prime disorder. A vaccination or flulike illness 10 to 14 days before the onset may indicate a postinfectious syndrome at any level of the motor neuraxis. Inquiry as to the exact activity before onset sometimes facilitates the diagnosis, as in the so-called Saturday night radial nerve palsy syndrome, a pressure palsy sustained at a time of drunken stupor. Muscular pain on exercise might suggest a metabolic myopathy. The patient’s occupational history may be of diagnostic importance. Exposure to lead might be the cause of a wrist drop, and pressure palsy or carpal tunnel syndrome may be suspected given the clue of specific work-related activities. A history of urinary bladder dysfunction is important. Frequency of micturition with urgency, urgency incontinence, and small quantities of urine voided each time implies a small, spastic, irritable bladder, often seen in UMN syndromes. Cauda equina syndromes also may cause bladder dysfunction, often retention. In general, once neurogenic dysuria appears, the problem acquires a sense of urgency in diagnosis and treatment. Abrupt neurogenic bladder dysfunction constitutes an emergency.

Chapter2

PHYSICAL SIGNS The patient must be cooperative and pain-free for an accurate objective motor strength evaluation. The examiner attempts to resist or overcome the strength of the muscles. Muscle strength can be tested with the muscle at maximum contraction (having moved the joint it controls to its mechanical limit), as the joint begins to move, or at midposition. In the upper limbs, h g e r flexion is best tested starting with the patient’s fingers fully flexed over the examiner’s fingers. Hand intrinsics, usually abductors, are tested in full abduction, extensors of fingers and wrists in full extension, biceps and triceps with the elbow joint held at a right angle, and the deltoid with the arm abducted to shoulder height. In the lower limbs, hip flexion is best tested at midposition with the patient supine; quadriceps, foot and toe dorsiflexion, and toe plantar flexion are evaluated at maximum contraction. Plantar flexion is tested starting with the foot at midposition, hamstrings with the knee bent to a right angle, and thigh abductors with the patient lying on the side and abducting the uppermost thigh against the examiner’s pressure. If the patient is not cooperative, the power of the muscle being tested waxes briefly, and then strength falls away rapidly or fluctuates. This is commonly called give-way weakness. To test the power of the muscle in question, the examiner should resist the movement requested for only a second or two; during the short time span, normal or full power is likely to have been exerted before the give-way. Give-way implies either that there is a psychogenic component to the weakness or that pain associated with the movement inhibits the exertion of full strength. Because the muscles vary in their strength, how can we be sure that there really is weakness and not just normal variability? How do we document and record weakness? If the examiner can overcome the power of a muscle, exerting resistance close to the joint that it moves and using an equivalent muscle of his or her own (e.g., fingers test finger strength), then that muscle is graded as weak. The most widely used grading system uses five grades: 5 is normal, 4 is weak, 3 is the ability to overcome gravity, 2 is movement with gravity eliminated, 1 is a flicker of movement, and 0 is paralysis. Within grade 4, there may be varying degrees of weakness. It is therefore common practice to expand grade 4 in some way. Various examiners use different systems. Provided that the system is constant and can be replicated by the examiner, any of these will do. A good system is simply to allow mild, moderate, and severe degrees of grade 4 weakness. Once accurately documented, the progress of the weakness, for better or for worse, can be followed.

Weakness

9

catch of tone that rapidly settles-so-called clasp-knife rigiditysuggests an UMN lesion. With the patient supine and relaxed, when the leg is passively rotated from side to side, the foot is normally floppy at the ankle and lags behind the rotatory movement. If the foot and leg move en bloc, hypertonia is present. With the patient supine and relaxed, the examiner places hands under each popliteal fossa to gently support the legs. Quite abruptly the knees are jerked upward from this rest position. A normal response is for the heels to move proximally, scraping along the examining couch. If they jerk upward and then come to rest on the couch, spasticity is present. Clonus at the ankles is tested for by abruptly passively dorsiflexing the foot on the ankle with the knee bent. Repetitive clonic jerking contractions of the calf muscles may fade after a few beats or be sustained. HyperrefZexia refers to exaggerated tendon reflex responses. In extreme hyperreflexia, the reflex is repetitive or clonic. The limb to be tested should be supported so that it is perfectly relaxed, and the reflex hammer should be allowed to fall on the tendon close to the neighboring joint and bounce off. The reflexes are commonly recorded in the chart on a stick figure using a “plus” grading system, which should be constant for any particular examiner. Thus, biceps, triceps, and brachioradialis reflexes are recorded in the upper limb, and knee and ankle reflexes are recorded in the lower limb. Whereas hypertonia and hyperreflexia imply disinhibition of the hal common pathway, a nonpyramidal or extrapyramidal effect, the extensor plantar response implies a pyramidal tract lesion. The lateral aspect of the sole is scraped from heel to little toe with a somewhat sharp object, often the end of a key. The full extensor response is extension of the great toe, fanning of the other toes, and contraction of the tensor fascia lata. This last sign can be extremely helpful if doubt exists as to the toe responses. Experimentally, a pure pyramidal tract lesion causes a flaccid paralysis or paresis with an extensor plantar response. On occasion, slowness of voluntary rapid alternating movements may be the only sign of pyramidal tract involvement. In UMN lesions, the superficial or cutaneous reflexes often are suppressed or absent. The abdominal reflexes are elicited by gently scratching the abdominal wall in all four quadrants; the abdominal wall normally contracts spasmodically. This reflex may be absent unilaterally on the side of a hemiplegia. In males, the cremasteric reflex is elicited by gently scratching the upper inner aspect ot the thigh in broad sweeps. Normally the cremasteric muscle contracts and elevates the ipsilateral side of the scrotum.

Anatomic Substrate for Upper Motor Neuron Lesions ASSOCIATED PHYSICAL SIGNS It is incumbent on the examiner to differentiate weakness of central origin from that caused by peripheral processes. The associated signs and the patterns of weakness help with this differentiation. Upper Motor Neuron Lesions Hypertonia and hyperreflexia, often combined with extensor plantar responses, are the clues to UMN localization. Hypertonia or spasticity is evaluated by passively moving the limbs at the joints, commonly at the knees, wrists, and elbows. A

Descending Corticospinal Tract This is the major descending motor pathway. The tract is composed of axons of mainly cortical frontal cells, including the pyramidal cells of Betz of the contralateral hemisphere. This is therefore a crossed tract, the decussation occurring in the lower medulla as the pyramidal decussation. Seventy-five to 90 percent of fibers cross to become the lateral corticospinal tract. The remainder descend in the uncrossed ventral or direct pyramidal tract situated ventromedially in the anterior funiculus. The lateral corticospinal tract fibers terminate on the anterior horn of the central gray matter. Ten to 20 percent synapse directly with anterior horn cells. The rest terminate as arborizations around intercalated cells in the intermediate or ventral gray matter. This major motor tract shows a

10

Principles of Ambulatory Neurology and the Approach to Clinical Problems

somatotopic arrangement of fibers in the cord such that those destined for sacral regions are laterally placed and those destined for cervical regions are medially situated with an orderly arrangement between. Extrapyramidal Descending Tracts. The major nonpyramidal descending tracts originate in the brainstem. Their cells of origin receive connections from higher levels, and the tracts are named according to their brainstem level. They function in conjunction with the pyramidal tract to allow smooth and coordinated movement and have excitatory and inhibitory effects on the motor neurons of the cord. The tectospinal, reticulospinal, and vestibulospinal tracts lie in the anterior funiculus, and the rubrospinal tract lies in the lateral funiculus just ventral to the corticospinal tract. The more medially situated pathways-that is, those in the anterior funiculus as described earlier-are phylogenetically older and control axial and proximal muscles, those governing balance and posture. The rubrospinal tract is more concerned with distal muscles, those governing dexterity and fine movements. In humans, this latter function has largely been taken over by the corticospinal system, and the rubrospinal tract is vestigial. Lower Motor Neuron Lesions

The hallmarks of LMN-associated signs are flaccidity, areflexia, and flexor plantar responses, provided that the foot flexor muscles retain the ability to contract. Testing is as described earlier. Fasciculations in the presence of weakness point to the anterior horn cell as the likely site of disorder. The anatomic substrate is composed of the varied anatomy of the cranial nerves, anterior horn cells, spinal nerves, nerve plexuses, individual peripheral nerves, neuromuscular junctions, and muscles.

Anterior Horn Cell. In degenerative diseases affecting the anterior horn cells, such as motor neuron disease (MND), there is no specific pattern. On occasion, the disease process may affect limbs sequentially but in a diffuse pattern. The patient often presents with a combination of UMN and LMN signs. Therefore, there may be atrophy with weakness predominantly in “LMN muscles,” but there is also hyperreflexia. Fasciculations may be prominent. If all the signs are localized to a midcervical level, cervical spondylosis is the likely diagnosis. If fasciculations are seen in noncervical myotomes or there are bulbar signs, MND is likely. The electromyogram may be used as a diagnostic tool to study masseter and tongue muscles. Electromyographic signs of diffuse and bulbar denervation strongly support the diagnosis of MND. At times cervical spondylosis and MND coexist in the same patient. Spinal Nerve Root. Root involvement causes a myotomal pattern of weakness that varies with the root involved. Because of overlapping innervation, as described in anatomic texts, it may be bewildering to sort out involvement of one root from another. Experimentally, to produce segmental radicular paralysis, at least two roots must be cut. In practice, we see weakness rather than paralysis, and it is usually possible to localize radicular weakness fairly accurately using a modified and simplified anatomy (Tables 2-1 and 2-2). The presence of a clearly defined root lesion, W

TABLE 2-1. Celvical Myotomesa

Segmental Level

c5 C6, 7 C6 c7 C8 T1

PATTERNS OF WEAKNESS On occasion, the expected associated signs to support UMN versus LMN localization of a lesion are equivocal or absent. In that circumstance, the pattern of weakness in the limbs can be extremely useful in diagnosis.

When the deficit is very severe, a paralysis is seen, and no pattern is evident. In more moderate and often subtle deficits, typical patterns of weakness are consistently present. In the upper limb, the pattern of weakness in UMN lesions is that of weakness of extensor muscles. The muscles that are preferentially involved (i.e., the weaker muscles) are deltoid, triceps, wrist and finger extensors, and finger abductors. Conversely, biceps, shoulder adductor muscles, wrist and finger flexors, and finger adductors are mostly spared. In the lower limb, hip flexors, foot and toe dorsiflexors, hamstrings, and thigh abductors are weaker than quadriceps and toe and foot plantar flexors.

Segmental Level L1, L2 L3

L3, L4 L4 L5

L5, s1

s1

LMN Patterns

LMN patterns of weakness vary with the site of disorder, which may vary, ranging from dysfunction of anterior horn cell through spinal nerve root, plexus, nerve, endplate, and muscle itself.

Muscles

Action

Deltoid Biceps and brachialis Triceps Brachioradialis Extensor carpi radialis Extensor digitorum Flexor digitorum lnterossei Abductor digiti V

Shoulder abduction Elbow flexion Elbow extension Elbow flexion in half supination Radial wrist extension Finger extension Finger flexion Finger abduction Little finger abduction

’Clinically useful main segmental innervation of muscle groups is shown. It should be appreciated that the nerve supply of all muscles is of multisegmental origin and that this table is intended to help with clinical localization rather than to present a complete anatomic guide.

W TABLE 2-2.

Upper Motor Neuron Patterns

Principles of Diagnosis: Common Presenting Symptoms

Lumbosacral Myotornesa Muscles

Action

lliopsoas Adductor longus Adductor brevis Adductor magnus Adductor minirnus Quadriceps femoris Tibialis anterior Extensor hallucis longus Extensor hallucis brevis Extensor digitorum longus Extensor digitorum brevis Gluteus rnedius Semitendinosus Semirnembranosus Biceps femoris Gastrocnemius Soleus Flexor digiti brevis

Hip flexion

Hip adduction Knee extension Ankle extension

Toe extension Hip abduction Knee flexion

Ankle flexion Toe flexion

aClinicallyuseful main segmental innervation of muscle groups is shown. It should be appreciated that the nerve supply of almost all muscles is of multisegmental origin and that this table is intended to help with clinical localization rather than to present a complete anatomic guide.

Chapter2 W

Weakness

11

TABLE 1-5. Principal Motor Innervation of Peripheral Nervesa Nerve

Muscles

Action

Axillary Musculocutaneous

Deltoid Biceps Brachialis flexor carpi radialis flexor digitorum sublimis Flexor digitorum profundus (lateral half) Pronator teres Pronator quadratus Abductor pollicis brevis Opponens pollicis brevis Flexor pollicis longus Flexor pollicis brevis flexor carpi ulnaris flexor digitorum profundus (medial half) Abductor digiti minimi All other intrinsics of hand Triceps Brachioradialis Extensor carpi radialis and ulnaris Supinator Extensor Pollicis brevis Pollicis longus lndicus proprius Digiti V proprius Digiti communis lliopsoas Quadriceps Adductor longus Adductor brevis Adductor magnus Gluteus medius Gluteus minimus Gluteus maximus Biceps femoris Semitendinosus Semimembranosus

Shoulder abduction Flexion of elbow

Median

Ulnar

Radial

Femoral Obturator Superior gluteal Sciatic Sciatic branches Peroneal (deep) Peroneal (superficial) Tibia1

Pudendal

Tibialis anterior Extensor digitorum longus Extensor hallucis longus Peroneus Gastrocnemius Soleus Flexor Digitorum longus Hallucis longus Digitorum brevis Hallucis brevis Perineal and sphincters

Radial flexion of wrist Flexion of middle phalanges (digiti Il-V) flexion of distal phalanges (digiti II and 111) Pronation of forearm Abduction of thumb Opposition of thumb flexion of distal phalanx of thumb flexion of proximal phalanx of thumb Ulnar flexion of wrist flexion of distal phalanges (digiti IV and V) Abduction digiti V Finger abduction or adduction Extension at elbow flexion of forearm Extension at wrist with radial or ulnar deviation Supination of forearm Extension of thumb (proximal) Extension of thumb (distal) Extension of index (proximal) Extension of little finger (proximal) Extension of digits 11-V (proximal) flexion of thigh at hip Extension of leg at knee Adduction of thigh at hip Abduction of thigh at hip Extension of thigh at hip Flexion of leg at knee Doniflexion of foot Extension of toes Extension of great toe Pronation of foot Plantar flexion of foot Flexion of distal phalanges 11-IV flexion of distal phalanx I flexion of middle phalanges 11-V flexion of middle phalanx I Closure of sphincters Contraction of Delvic floor

'Clinically useful main segmental innervation of muscle groups is shown. It should be appreciated that this table is intended to help with clinical localization rather than to present a complete anatomic guide.

diagnosed by way of myotomal weakness, dermatomal sensory loss, or a dropped reflex, is the only clear pointer to segmental localization within the spinal cord. Nerve Plexus. The next level, moving distally, is the plexus: brachial in the upper limb and lumbosacral in the lower limb. For plexus localization, the pattern of weakness fits neither a pure root distribution nor a single pure peripheral nerve distribution. Peripheral Nerve. Although there is some variability, each single peripheral nerve consistently supplies specific muscles, which allows localization based on the deficit found (Table 2-3). Diffuse peripheral neuropathy causes a distal wasting and weakness syndrome. In severe cases, the weakness is so widespread as to cause total body paralysis with atonic muscles and areflexia. If onset is acute or subacute, this suggests the diagnosis of Guillain-Barrk syndrome.

Neuromuscular Junction. Variability in weakness over minutes or hours with waxing and waning suggests the diagnosis of myasthenia gravis. The diagnosis is established by demonstrating a myasthenic reaction or by reversing the signs with an injection of edrophonium. By definition, a myasthenic reaction is increasing muscle weakness with exercise or weakness brought on by activity of the muscle being tested. It must be demonstrated that a muscle becomes weaker the more it is used. For eye muscles, prolonged lateral or vertical gaze results in progressive diplopia or observable progressive weakness of the extraocular muscles being exercised. In the limbs, one offers continual resistance to the muscle being exercised while evaluating its strength. Weakness ensues and becomes progressively worse. Pressure must be exerted continually, not intermittently, because even a brief rest can allow restoration of power.

12

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Muscle. Weakness localized to the pelvic and shoulder girdle muscles (i.e., proximal muscle weakness) supports the diagnosis of a myopathic disorder. Chronic spinal muscular atrophy, a neuropathic degenerative anterior horn cell syndrome, often shows the same distribution.

ADDITIONAL CLUES TO LOCALIZATION The presence of cognitive deficits suggests that the lesion is in or undercuts the cortex. Primarily proximal (i.e., limb girdle) weakness of an UMN type supports the notion of a high-convexity lesion. On the left side, this is often accompanied by a transcortical aphasia. This site of deficit often is caused by an infarct in the watershed region and is seen primarily after an episode of acute circulatory failure with severe hypotension or after carotid occlusion with inadequate collateral perfusion. A very dense hemiplegia without cognitive loss suggests that the lesion is in the deep white matter, often in the internal capsule. A mild hemiparesis with prominent ataxia or dysarthria suggests a lacunar infarction in the posterior limb of the internal capsule or in the pons. At times, lacunae in the corona radiata or larger lesions in the contralateral frontal lobe also cause an ataxic hemiparesis. The finding of a cranial nerve deficit on one side with a UMN weakness on the contralateral side places the lesion in the brainstem precisely at the level of the cranial nerve involved. This is called an alternating hemiplegia or hemiparesis. Spinothalamic sensation may be affected in a similar fashion contralateral to a lateral medullary lesion, resulting in a so-called harlequin pattern of loss. Neck extensor muscles normally are very strong. Their power is tested by resting one’s arms on the patient’s shoulders and pushing forward with the fingers on the back of the head against maximal resistance. Weakness of the neck extensors has few causes, which include myopathy, myasthenia, MND, and myotonic dystrophy. Paraparesis suggests myelopathy. The long tract weakness is in UMN distribution, often with other helpful signs, such as spasticity or hyperreflexia. Extensor plantar responses are hard signs to support the diagnosis of UMN dysfunction, but flexor responses in the presence of the other UMN cluster of signs do not negate the diagnosis. Just as in the sensory deficit of myelopathy, because of the so-called onion peeling somatotopic distribution of fibers within the major descending and ascending tracts, segmental localization based on UMN weakness can be difficult. The level of pathology is deduced by the finding of myotomal weakness, dermatomal sensory loss, or a dropped reflex (i.e., a root sign). Thus, the root signs of cord pathology are the counterpart of cranial nerve signs of brainstem pathology and allow accurate segmental localization. Bladder symptoms often help to raise the suspicion of

Principles of Diagnosis: Common Presenting Symptoms

myelopathy. The typical UMN bladder is of low capacity, hypertonic, and irritable. Therefore, urgency, frequency, and urgency incontinence are characteristic. In brachial plexopathy, the combination of deltoid weakness (axillary nerve) with triceps weakness and wrist drop (radial nerve) localizes to the posterior cord of the plexus. The diagnosis of a more proximal brachial plexopathy may be strongly supported by the finding of Horner’s syndrome. Lateralized weakness of flexor hip girdle muscles may be of lumbosacral plexus origin. Here, diagnosis may be aided using the following paradigm: Weakness of hip adductors, hip flexors, and quadriceps suggests high lumbar radiculopathy; weakness of adductors alone indicates an obturator nerve lesion, and weakness of quadriceps alone localizes to the femoral nerve; and weakness of any two of the three groups supports the diagnosis of a plexus lesion. On occasion, a root lesion at L4 causes mild to moderate quadriceps weakness with an absent patellar reflex. In wrist drop, there may be spurious weakness of the finger flexors. Because these can function at maximal power only if the wrist is extended, when testing this movement the wrist should be held in passive forced extension. A proximal radial nerve palsy can be distinguished from cervical radiculopathy (C6-C7) by testing strength and bulk in the lower fibers of pectoralis major. If weakness is present here, the localization is likely to be fairly close to the root; the patient places hands on hips and forcefully adducts, and the examiner places fingers posterior to the muscle in the anterior axillary fold and pushes forward. In LMN foot drop, the common differential diagnosis is between a common peroneal palsy at the knee and a lumbar radiculopathy ( L P L 5 ) . In the former, foot inversion (posterior tibia1 nerve) is spared and is normal. In radiculopathy, both foot inversion and eversion are weak, as are knee flexion and hip abduction.

SUGGESTED READINGS Berardelli A, Sabra AF, Hallett M et a 1 Stretch reflexes of triceps surae in patients with upper motor neuron syndromes. J Neurol Neurosurg Psychiatry 46:54-60, 1983

Bishop B: Spasticity: its physiology and management. Part 1. Neurophysiology of spasticity: classical concepts. Phys Ther 57:371-376, 1977 Davidoff RA: Skeletal muscle tone and the misunderstood stretch reflex. Neurology 42:951-963, 1992 Georgopoulos A P Higher order motor control. Ann Rev Neurosci 14:361-377, 1991

Messina C: Pathophysiology of muscle tone. Funct Neurol 5:217-223, 1990

Young RR: Physiologic and pharmacologic approaches to spasticity. Neurol Clin 5:529-539, 1987 Younger DS: Differential diagnosis of progressive flaccid weakness. Semin Neurol 13:241-246, 1993

Chapter 3

3

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Movement Disorders

13

Movement Disorders Daniel Tarsy

Movement disorders are neurologic conditions characterized by abnormalities of movement and posture. These are broadly and somewhat arbitrarily divided into akinetic and hyperkinetic or dyskinetic syndromes. Because akinesia often is accompanied by rigidity, the term akinetic-rigid syndromes is used to designate what is usually called parkinsonism. The hyperkinetic or dyskinetic syndromes comprise disorders characterized by excessive or poorly regulated movements or postures and include tremor, chorea, ballismus, dystonia, dyskinesia, myoclonus, and tics. Most of these conditions are attributable to disorders of the basal ganglia or extrapyramidal system, but it is important to realize that many have not been well localized in the nervous system. By tradition, motor disorders caused by cerebellar, pyramidal tract, motor neuron, peripheral nerve, or muscle diseases are not included in this category and therefore are not discussed here. AKINETIC-RIGID SYNDROMES Akinetic-rigid syndromes are the most common movement disorders that necessitate neurologic evaluation and include various combinations of akinesia, rigidity, and disturbed balance and posture. Tremor is commonly associated with akinesia and rigidity and is discussed separately later in this chapter. The most common cause of these signs is idiopathic Parkinson’s disease, but they also occur in other forms of parkinsonism, in which they are commonly accompanied by other neurologic signs. Idiopathic Parkinson’s disease is the most common akineticrigid syndrome to present in middle to late life and is discussed in detail in Chapters 114 to 118. Major features are tremor, rigidity, akinesia, and postural abnormality. Patients typically present between ages 50 and 70 with complaints of tremor, usually accompanied by unilateral or asymmetric clumsiness of one hand and sometimes the leg on the same side. During initial evaluation, mild midline or contralateral symptoms or signs often are elicited from family members or observed during examination. These may include mildly reduced vocal or facial expression that is often mistaken for depression, a stare with reduced eyeblink frequency, slowing in routine activities of daily living, hesitation arising from deep chairs, flexed posture, and shuffling gait while turning. The characteristic rest tremor of Parkinson’s disease is not always present and, when absent, often results in a delayed presentation with midline akinetic signs. In more advanced cases, signs of akinesia and postural disturbance predominate. Progressive mutism, dysphagia, severe gait disturbance, freezing, and falls caused by loss of postural reflexes may produce severe disability. The presence of such midline signs in advanced cases makes differentiation from other causes of parkinsonism more difficult than early in the disease. A classification of the more common parkinsonian syndromes is listed in Table 3-1. Broad categories include primary idiopathic Parkinson’s disease caused by degeneration of substantia nigra; secondary forms of pure parkinsonism such as neurolepticinduced, toxic, or postencephalitic parkinsonism; parkinsonism caused by multiple system atrophy; parkinsonism associated with other degenerative or metabolic neurologic disorders, some of which are hereditary; and parkinsonism caused by miscellaneous

acquired structural or metabolic abnormalities. Any disorder that impairs nigral, striatal, or pallidal function may produce an akinetic-rigid syndrome. The term parkinsonism-plus is potentially confusing because it is often used to refer to both multiple system atrophy and other, less specific multisystem degenerations, in which parkinsonism occurs in combination with other neurologic manifestations such as progressive supranuclear palsy. The clinical characteristics and differential diagnosis of the akinetic-rigid syndromes are discussed in greater detail in Part V of this book. It is sobering to note that, according to recent studies, 10% to 25% of patients diagnosed with idiopathic Parkinson’s disease have been found to have other causes of parkinsonism at postmortem examination. The absence of resting tremor in a patient with akinesia, rigidity, and postural disturbance indicates that one may be dealing with one of the other akinetic-rigid syndromes. This is particularly true if symmetric and midline motor manifestations appear early in the clinical course. Another useful clue to other forms of parkinsonism is the presence of pyramidal tract signs, cerebellar ataxia, nystagmus, oculomotor abnormalities, early and severe dementia, frontal release signs, sensory findings, or prominent autonomic disturbances early in the illness. Parkinsonian syndromes caused by multiple system atrophy typically are the most difficult to distinguish on clinical grounds from idiopathic Parkinson’s disease. Multiple system atrophy is discussed in greater detail in Chapter 119. This specific group of three disorders comprises Shy-Drager syndrome, striatonigral degeneration, and the sporadic form of olivopontocerebellar atrophy. These are pathologically similar disorders distinguished clinically by the signs and symptoms that are most prominent TABU5-1. More Common Akinetic-Rigid Syndromes Idiopathic Parkinson’s disease Postencephaliiicparkinsonism Parkinsonism caused by drugs or toxins Multiple system atrophy Striatonigral degeneration Shy-Drager syndrome Olivopontocerebellardegeneration (sporadic) Other degenerative diseases Progressive supranuclear palsy Acquired hepatocerebral degeneration Corticobasal ganglionic degeneration Genetically determined disorders Rigid Huntington’s disease Wilson’s disease Hallervorden-Spatzdisease Pallidal degenerations Olivopontocerebellardegeneration (familial) Basal ganglia calcification Juvenile parkinsonism Dopa-responsive dystonia Metabolic disorders Acquired secondary parkinsonism Multiple cerebral infarcts Postanoxic Hydrocephalus Punch-drunk syndrome Mass lesions (tumor, arterioventricularmalformation) (Modified from Weiner WJ, Lang AE: Movement Disorders:A Comprehensive Survey. Futura, M t Kisco, NY, 1989, with permission.)

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

early and merge as they progress. The presence of autonomic failure, such as orthostatic hypotension, bladder dysfunction, and impotence preceding the onset of significant motor disturbance indicates Shy-Drager syndrome. Predominant parkinsonism manifested by a rapidly progressive akinetic-rigid syndrome and mild and variable tremor suggests striatonigral degeneration. Cerebellar ataxia early in the course followed by parkinsonism and variable combinations of corticospinal tract deficits, oculomotor signs, pseudobulbar signs, lower cranial nerve palsies, optic atrophy and retinal degeneration, and muscle atrophy are the hallmarks of olivopontocerebellar atrophy. Other extrapyramidal features such as chorea and dystonia may also occur in olivopontocerebellar atrophy and complicate differential diagnosis. Clinical differentiation between these three forms of multiple system atrophy usually is difficult and somewhat arbitrary. Because currently they are believed to be different clinical manifestations of a common neuropathology with a characteristic marker, the presence of oligodendroglial cytoplasmic inclusions, they are best grouped together under the diagnostic heading multiple system atrophy The most common clinical features of multiple system atrophy are parkinsonism with prominent akinesia, postural instability, and falls; impotence, postural hypotension, and bladder dysfunction; mild pyramidal signs without clinically important spasticity or weakness; and cerebellar ataxia. Less common but unique and helpful signs include respiratory stridor, myoclonic finger jerks, and antecollis. Mild action tremor may be present and is more common than rest tremor. Dementia is notably absent in these disorders. Progressive supranuclear palsy sometimes is included in the category of parkinsonism-plus syndromes but should be considered separate from multiple system atrophy because of its distinctive clinical presentation and neuropathology. The condition is best known for paralysis of voluntary vertical and horizontal gaze but produces a number of other highly characteristic motor manifestations that may precede the abnormal eye movements. Early symptoms include gait instability, sudden unexplained falls, generalized slowing, visual complaints, speech and swallowing difficulty, sleep disturbance, and personality change. By contrast with idiopathic Parkinson’s disease, gait instability and falling are prominent early in the disease and often are the presenting manifestation. There are a number of characteristic neurologic findings in progressive supranuclear palsy. Supranuclear gaze palsy impairs downward gaze more than upward gaze and also affects horizontal gaze. Initial eye findings may be subtle and limited to impaired saccadic movements. Progressive gaze difficulty and abnormalities of convergence and central fixation produce visual complaints such as difficulty reading and descending stairs, trouble focusing, and diplopia. Oculocephalic eye movements are disinhibited, consistent with a supranuclear gaze paralysis. Other eye findings may include blepharospasm, levator inhibition with impaired voluntary eyelid opening, and square-wave jerks. Often a characteristic, sometimes astonished-appearing facial expression is produced by the prominent stare, upper eyelid retraction, deep facial furrows, and impaired voluntary gaze that is very different from the facial masking of Parkinson’s disease. Gait is lurching or stumbling, typically difficult to classify, and associated with impaired balance and tendency to fall easily. Rigidity is more marked in axial than limb muscles, but limb spasticity and dystonia may be prominent as late manifestations. Posture is erect, and there may be neck hyperextension. Tremor is uncommon but may occur. There is usually a pseudobulbar palsy with spastic dysarthria, dysphagia, and emotional release. Bilateral

Principles of Diagnosis: Common Presenting Symptoms

corticospinal tract findings are present, including hyperreflexia, spasticity, and extensor plantar responses. Dementia usually is not prominent early in the disease, although the abnormal facial expression and bradykinesia often convey a false impression of cognitive deficit. Cognitive function typically is difficult to evaluate late in the disease because of pseudobulbar anarthria but may be impaired and often is associated with behavioral disturbance. Parkinsonism may occur in association with a number of other primary, degenerative neurologic disorders such as familial olivopontocerebellar atrophy, Huntington’s disease, pallidal degenerations, corticobasal ganglionic degeneration, Alzheimer’s and Pick‘s diseases, basal ganglia calcification, Creutzfeldt-Jakob disease, Wilson’s disease, and a number of metabolic and storage diseases of the nervous system. Differentiation of these disorders from idiopathic Parkinson’s disease usually is assisted by the rest of the neurologic history and examination. Acquired neurologic disorders that produce secondary parkinsonism usually can be differentiated clinically from idiopathic Parkinson’s disease by history and examination and are described in Chapter 123. Neuroleptic- or metoclopramide-induced parkinsonism is symmetric in distribution and more commonly associated with an action tremor than the typical resting tremor of idiopathic Parkinson’s disease. However, asymmetry and rest tremor may also be observed. In such cases, often seen in older patients, the possibility of underlying subclinical Parkinson’s disease aggravated by dopamine-blocking medications should be considered. Parkinsonism caused by toxin exposure is rare and usually is evident from the patient’s medical history. Postencephalitic parkinsonism has disappeared as the population of patients with encephalitis lethargica has declined. Occasional cases following viral encephalitis continue to occur but typically appear early without the prolonged latency characteristic of classic postencephalitic parkinsonism. Other common causes of secondary parkinsonism include cerebrovascular disease with multiple small infarcts, anoxic encephalopathy, hydrocephalus, head trauma, brain tumor or arteriovenous malformation, and acquired hepatocerebral degeneration. Depending on the distribution of pathology, acquired brain disorders that cause parkinsonism usually are associated with dementia, corticospinal tract findings, pseudobulbar palsy, and gait ataxia. Severe dementia early in the clinical course can be a useful clue that one is dealing with secondary parkinsonism. Although multiple system atrophy also produces multisystem involvement, dementia is notably absent in multiple system atrophy, whereas autonomic manifestations usually are not present in the acquired disorders that produce parkinsonism. A number of genetically mediated disorders may produce parkinsonism, although other neurologic manifestations are usually present. The most important of these are the rigid form of Huntington’s disease, Wilson’s disease, familial olivopontocerebellar atrophy including Azorean disease (SCA 3), HallervordenSpatz disease, the pallidal degenerations, basal ganglia calcification, neuroacanthocytosis, dopa-responsive dystomia, juvenile parkinsonism, and rare metabolic and storage diseases usually seen in children or young adults such as GM, gangliosidosis and Gaucher’s disease. Approach to the Patient History-taking should be directed toward eliciting symptoms of akinesia. Akinesia is an impaired ability to move in the absence of paralysis and includes bradykinesia, or slowness of movement, and

Chapter 3

hypokinesia, or reduced amplitude of movement. Akinesia is responsible for most parkinsonian symptoms described by the patient and family, all of which relate to slowness and difficulty initiating, implementing, and maintaining motor movements. The pattern of akinetic symptoms depends on whether there is unilateral, midline, or bilateral involvement. Idiopathic Parkinson’s disease usually begins unilaterally or asymmetrically and typically presents with clumsiness and impaired dexterity in activities of daily living such as shaving, brushing teeth, washing, dressing, using eating utensils, and writing. Shoulder or hip pain is an occasional early manifestation of limb akinesia. Midline involvement may produce facial masking with a staring and anxious expression, which may lead to a mistaken diagnosis of depression. Other midline symptoms may include soft and monotonic speech; stuttering; drooling; difficulty rising from a deep chair, turning in bed, or getting out of a car; and gait abnormality with short, shuffling steps and reduced armswing. More severe midline akmesia causes impaired turning, propulsive and festinating gait, and episodes of freezing. History related to cognitive, autonomic, and sensory function should be elicited from all patients. Dementia accompanies a number of the akinetic-rigid syndromes but is uncommon in multiple system atrophy. In Parkinson’s disease, dementia is a late feature that occurs in approximately 25% to 30% of patients. When dementia is more severe and appears early, other akineticrigid syndromes such as multi-infarct dementia, Lewy body disease, normal pressure hydrocephalus, and Creutzfeldt-Jakob disease should be considered. Depression and passivity often characterize Parkinson’s disease and may lead to a mistaken impression of dementia. In multiple system atrophy, autonomic symptoms typically precede motor symptoms, whereas they appear later in idiopathic Parkinson’s disease. Constipation, urinary frequency, nocturia, and sexual dysfunction are particularly common in more advanced Parkinson’s disease, whereas they appear earlier in multiple system atrophy. Orthostatic hypotension is a hallmark of multiple system atrophy but may also occur in milder form in Parkinson’s disease with or without antiparkinson medications. Sensory symptoms such as pain and paresthesia occasionally occur in idiopathic Parkinson’s disease and are of uncertain origin. Symptoms or signs of impaired cortical sensation are unique to corticobasal ganglionic degeneration. Akinesia is readily evident throughout the neurologic examination during simple observation and when the patient is asked to carry out specific motor tasks. Facial expression and eyeblink frequency are reduced, and spontaneous gestures and repositioning movements may be lacking. Delay in initiating movements results in prolonged reaction time when a patient is asked to perform a movement. Slowness of movement usually is detectable by observation and confirmed by tests of distal and more proximal rapid alternating movements, including finger tapping, fist opening and closing, forearm pronation and supination, and foot tapping. In addition to being slow, there is a fatiguing of repetitive movements that produces a characteristic decremental pattern different from the more regular slowing produced by weakness and the poorly checked, ataxic movements produced by cerebellar dysfunction. In patients with tremor, repetitive movements may activate and assume the frequency of the associated tremor. Writing and drawing are slow and associated with fatiguing and micrographia. Patients should be tested for ability to rise from a chair without use of their hands and should be observed walking back and forth in a long corridor. Postural abnormalities are common and may consist of postural deformity or postural instability. Examples of

Movement Disorders

I5

postural deformity include flexion of the neck, trunk, and joints of the extremities, which produces the characteristic simian posture of Parkinson’s disease. Postural instability occurs late in the course of Parkinson’s disease but may appear earlier in other akineticrigid syndromes such as progressive supranuclear palsy. Postural instability is manifested by impaired balance, unstable gait, retropulsion, and propulsive gait. There is a predisposition to sudden, unpredictable falls and failure of normal righting reflexes to prevent falls once they begin. The pull test and sternal shove are formal tests of righting responses in which the examiner either pulls back on the shoulders or shoves on the sternum. A mild deficit in postural righting reflexes is associated with several backward steps before balance is corrected. A more severe deficit produces falling backward en bloc without corrective movements of the arms or legs. Rigidity is appreciated only during the formal examination and is an uncertain contributor to subjective motor symptoms. Many symptoms and signs that at one time were commonly attributed to muscle rigidity are actually caused by akinesia and are known to remain after successful alleviation of rigidity with stereotactic thalamotomy. Rigidity is perceived as an increase in resistance to passive movement of the extremities or axial musculature. In the extremities, rigidity is equally distributed in flexors and extensors of the limb and may be associated with a cogwheel phenomenon if there is accompanying rest or action tremor. Mild rigidity may be elicited by reinforcement maneuvers such as having the patient perform repetitive movements of the contralateral limb.

TREMOR Tremor is by far the most commonly observed movement disorder and occurs from time to time in most normal individuals, in whom it emerges as a result of exaggerated physiologic tremor. Tremor is defined as a rhythmic, oscillatory, and usually sinusoidal movement of a portion of the body with a constant frequency and variable amplitude. Tremor occurs as a result of either alternating or synchronous contractions of antagonistic muscles. Tremors may be broadly classified into static and action tremors. Static tremors include tremors present at rest (rest tremor) and tremors present with the arms and hands held in a fixed posture (postural tremor). Action tremors may be divided into postural tremor and tremor that increases during goal-directed movement (intention tremor). Intention tremor sometimes is also called kinetic or terminal tremor. Because these categories are confusingly overlapping and inconsistently applied, tremors are classified here as resting, postural-action, and intention in type (Table 3-2). (More detailed discussions of tremor may be found in Chapter 125.) Rest Tremor

The most common cause of rest tremor is Parkinson’s disease. This is most evident when the affected body part is supported and completely at rest and tremor temporarily dampens or disappears entirely during voluntary activity. Because of its suppression with activity, it usually produces less functional disability than posturalaction or intention tremors. However, as soon as the body part assumes a new posture, the tremor often reemerges, potentially interfering with eating, writing, and similar motor activities. Significant postural or action tremor does occur in some patients with Parkinson’s disease and is more disabling than rest tremors. In most cases, however, rest tremor produces disability through its undesirable cosmetic effect and social embarrassment. Rest tremors characteristically fluctuate in amplitude and may appear

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

rn TAW 3-2. Common Tremors Rest tremor Parkinson’s disease Parkinsonian syndromes Midbrain (rubral) tremor Wilson’s disease Severe essential tremor Postural-action tremor Enhanced physiologic tremor Essential tremor Primary writing tremor Other extrapyramidal disorders Parkinson’s disease Wilson’s disease Dystonia Cerebellar disease Peripheral neuropathy Intention tremor (cerebellar outflow) Cerebellar disease Multiple sclerosis Midbrain stroke Midbrain trauma (Modified from Weiner WJ, Lang AE: Movement Disorders: A ComprehensiveSurvey. Futura, Mt. Kisco, NY, 1989, with permission.)

and disappear depending on the degree of patient repose, on whether the patient feels he or she is under public observation, or on other unidentifiable factors. In idiopathic Parkinson’s disease, tremor usually appears first in one upper extremity and later spreads to involve the ipsilateral lower limb, followed by the contralateral side. Leg or foot tremor is more commonly caused by Parkinson’s disease than essential tremor. When the tremor is limited to distal muscles of the hand it often produces a characteristic pill-rolling tremor. Tremor frequency is usually 4 to 6 Hz. When it increases in severity, it may become more continuous, larger in amplitude, and more proximal in distribution, but tremor frequency remains constant. The face, lips, and jaw may be involved, but unlike essential tremor or cerebellar disease, Parkinson’s disease usually does not produce head tremor. Rest tremor may also occur in isolation in other extrapyramidal disorders, such as akinetic-rigid syndromes, in which tremor is usually less prominent; with Wilson’s disease and non-Wilsonian hepatocerebral degeneration; and as a result of midbrain injury caused by stroke or trauma. An isolated low-amplitude rest tremor of the hand or jaw unaccompanied by other manifestations of parkinsonism sometimes occurs in older adults in whom it often does not progress to Parkinson’s disease. This is to be distinguished from tremor-predominant Parkinson’s disease, which occurs in younger patients who display other mild parkinsonian signs but often have a good prognosis for slow progression. Rest tremor also occurs as a spillover phenomenon in a variety of disorders in which severe postural-action tremors predominate, such as Wilson’s disease, severe forms of familial essential tremor, and other cerebellar or extrapyramidal syndromes. Rubral tremor is tremor that occurs after midbrain injury but is caused by lesions of superior cerebellar peduncle and possibly substantia nigra rather than red nucleus. This tremor is constant, occurs at rest, and either remains unchanged or, more commonly, increases with action and goal-directed activity.

Postural-Adon Tremor Postural and action tremors are the largest group of tremors and are elicited during examination under two circumstances: with the

Principles of Diagnosis: Common Presenting Symptoms

upper extremities suspended against gravity in a fixed posture and during the course of goal-directed activity. Physiologic Tremor. All people have a very low-amplitude, high-frequency tremor of about 10 to 12 Hz that is not visible under ordinary circumstances. Physiologic tremor results from a combination of mechanisms, including intrinsic motor neuron firing rates, suprasegmental influences on motor unit firing patterns, stretch reflex oscillations, and peripheral P-adrenergic mechanisms. Enhanced physiologic tremor is the most common cause of abnormal tremor. Many factors increase physiologic tremor, most by the common mechanism of increased sympathomimetic activity. Common drugs that increase adrenergic activity include P-adrenergic agonists such as terbutaline, isoproterenol, and epinephrine; amphetamines; tricyclic antidepressants; levodopa; nicotine; and xanthines such as theophylline and caffeine. Anxiety, excitement, fright, muscle fatigue, hypoglycemia, alcohol and narcotic withdrawal, thyrotoxicosis, fever, and pheochromocytoma also enhance physiologic tremor by adrenergic mechanisms. Miscellaneous toxic causes of increased physiologic tremor with unknown mechanisms include lithium, corticosteroids, sodium valproate, bromides, mercury, lead, and arsenic. Because enhanced physiologic tremor is the most common cause of postural-action tremor, it is apparent that a medical rather than primary neurologic cause for postural-action tremor will be found in most cases. Essential Tremor. Essential tremor is a very common cause of postural-action tremor and is discussed in detail in Chapter 125. It is typically called familial tremor when there is a family history, benign essential tremor when it is sporadic, and senile tremor when it appears for the first time after age 65. The use of benign as a modifier for essential tremor has historically been used to distinguish it from Parkinson’s disease and other extrapyramidal disorders rather than as an indicator of its severity and is best omitted because essential tremor is often associated with significant disability. Essential tremor often resembles enhanced physiologic tremor but results from abnormal central rather than peripheral nervous system mechanisms. However, in some cases patients with essential tremor may develop superimposed enhanced physiologic tremor because of anxiety or other adrenergic mechanisms, thereby increasing the severity of the tremor and potentially causing diagnostic confusion. Subclasses of postural-action tremor based largely on the frequency and amplitude of the tremor have been suggested. These include benign essential tremor of low amplitude and higher frequency; more severe essential tremor of higher amplitude and lower frequency, often associated with rest tremor; postural-action tremor occurring with other neurologic disorders such as parkinsonism, dystonia, or peripheral neuropathy; and enhanced physiologic tremor. Essential tremor most commonly affects the distal upper extremities, but it can also cause tremor of the head, voice, chin, trunk, and lower extremities. In the upper extremities, tremor becomes immediately apparent when the arms are held outstretched and typically increases at the very end of goal-directed movements such as drinking from a glass or finger-nose testing. If tremor oscillations increase steadily before arrival at the target rather than at the very termination of goal-directed activity, cerebellar outflow tremor should be considered, although a distinction between the two often is difficult. Lower extremity tremor rarely occurs in isolation and usually is only associated with severe essential tremor. Head tremor may be vertical or horizontal, and, although usually associated with upper extremity

Chapter 3

or voice tremor, is the predominant manifestation of essential tremor in some patients. By definition, tremor should be the only manifestation of essential tremor. The most common differential diagnosis is with parkinsonian tremor. Although differentiation from classic rest tremor should be straightforward, some patients with Parkinson’s disease have a postural-action tremor indistinguishable from essential tremor. In early cases of parkinsonian postural tremor, the presence of subtle bradykinesia or micrographia may assist in diagnosing Parkinson’s disease, although these signs may not appear until later in the course. The presence of ataxia, dysmetria, proximal distribution of tremor, or gait disorder usually suggests a cerebellar disorder rather than essential tremor, although in some severe familial tremors, mild cerebellar signs appear to coexist with tremor. The presence of head tremor is particularly useful in separating essential tremor from parkinsonian tremor, in which head tremor usually is limited to the jaw or lips. Head tremor is also common in cervical dystonia, in which it may be caused by either a coincidence of the two disorders or a manifestation of dystonic spasm. Voice tremor rarely occurs in isolation and, when it does, should be differentiated from spasmodic dysphonia. Voice tremor produces a quavering voice unaccompanied by the straining and voice breaks characteristic of spasmodic dysphonia. Essential Tremor Variants. Many postural-action tremors associated with essential or parkinsonian tremor are most severe during the act of writing. However, when tremor occurs exclusively while writing and not during other voluntary motor activities, it is called primary writing tremor. This tremor is limited to the upper extremity while writing and causes largeamplitude supination-pronation movements at a frequency of 5 to 6 Hz. The low frequency and large amplitude of the tremor, its occasional association with writer’s cramp, its resistance to propranolol, and its occasional response to anticholinergic drugs suggest a closer relationship to dystonia than essential tremor. Orthostatic tremor is limited to the legs and trunk, occurs exclusively while standing, and is absent while sitting or walking. Both high- and low-frequency tremors have been described; their relationship to essential tremor is uncertain. In cases of highfrequency tremor, the movements of the lower extremities may be so low in amplitude as to initially escape clinical detection. Cerebellar Tremors. Cerebellar tremors may be either postural-action or intention in type and, in severe cases, can spill over to occur at rest. They are low in frequency, at about 3 to 4 Hz, and are associated with ataxia and dysmetria. Rubral tremor is caused by disturbances of cerebellothalamic projections rather than of the red nucleus itself and is characteristically present at rest, but it increases during postural fixation and voluntary activity. Titubation of the head and neck may be associated with cerebellar tremor and is distinguished from essential head tremor by the presence of other cerebellar findings. Other Extrapyramidal Disorders. Postural-action tremor may occur in Parkinson’s disease, other parkinsonian syndromes, Wilson’s disease, and idiopathic torsion dystonia. Parkinsonian postural-action tremor is the most common of these and is discussed earlier. In Wilson’s disease, postural-action tremor may be present in isolation or together with both rest and intention tremor. There is a high coincidence of postural-action tremor in dystonia, especially in cervical dystonia and writer’s cramp. Neuropathic Tremor. Tremor is sometimes associated with large-fiber peripheral neuropathy. This association is most commonly observed in hereditary neuropathies, during the recovery phase of some cases of Guillain-Barr6 syndrome, and in chronic

Movement Disorders

17

inflammatory demyelinating polyneuropathy. Muscle weakness and loss of proprioceptive or muscle spindle inputs have been offered as explanations for this tremor. The type of tremor observed under these circumstances is variable and may be high-frequency and low-amplitude in type or low-frequency, high-amplitude and associated with proprioceptive or cerebellar ataxia. IntentionTremor

Intention tremor is caused by disturbances of the cerebellar outflow projection system mediated by the dentate nucleus and superior cerebellar peduncle. This large-amplitude tremor typically increases in severity as the body part moves closer to its target, in contrast to postural-action tremors, which either remain constant throughout the range of motion or increase at terminal fixation. These tremors are large in amplitude because of involvement of proximal muscles and sometimes are difficult to distinguish from severe cerebellar ataxia and dysmetria. Nonetheless, the frequent association with ataxia, dysmetria, titubation, and other cerebellar signs is common and identifies the cerebellar origin of intention tremor. The most common causes are multiple sclerosis, midbrain trauma, and stroke. Degenerative diseases of the dentate nucleus and cerebellar outflow pathways, severe forms of essential tremor, Wilson’s disease, hepatocerebral degeneration, and mercury poisoning may also produce intention tremor. Rubral tremor is caused by lesions of the dentatothalamic projection system running through and near the red nucleus, which produce a combination of rest, postural-action, and intention tremor.

Approach to the Patient Patient history concerning onset of tremor usually is straightforward because this is a highly visible symptom readily evident to the patient and family members. Examination of old signatures may be useful in determining precise time of onset. Whether one is dealing with a rest, postural-action, or intention tremor usually is difficult to discern from patient history alone and is best left to the examination. Distribution of tremor and associated motor symptoms should be elicited, but here, too, it is usually more reliable to identify them by examination than through history. Precipitating, aggravating, or relieving factors, such as caffeine, alcohol, medications, exercise, fatigue, or stress, should be elicited. Family history is important in cases of essential or parkinsonian tremor. Examination begins with observations of the tremor made during the interview. Many patients with tremor are more symptomatic early during the examination because of stress than after they become comfortable with the situation. Patients should be observed while seated, lying down with the relevant body part fully supported, and ambulating. Horizontal or vertical head tremor usually is associated with essential tremor but may also occur in cervical dystonia and midline cerebellar syndromes. Face, jaw, and lip tremors are more commonly a manifestation of parkinsonism, but palatal tremor should be sought as an indication of palatal myoclonus. Voice tremor is readily audible but may be enhanced by having the patient hold a prolonged note. Extremity tremor is observed with the affected limb fully supported at rest, with the limb elevated against gravity, and during goal-directed movements. Most rest tremors cease with changes in limb posture but reappear within several seconds after repositioning. Action-postural tremors are best elicited with the patient’s arms held outstretched, with the patient’s index fingers

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

held an inch apart in front of the face, during slow patient finger-nose maneuvers, and while the patient drinks from a paper cup. Writing and drawing may demonstrate the large, tremulous, angulated loops of essential tremor or the micrographia of parkinsonism. Lower extremity tremor should be assessed at rest, during heel-shin testing, and while standing and walking. Leg tremor is more commonly caused by parkinsonism than essential tremor. Frequency of tremor should be documented at rest and during postural and action maneuvers. Enhanced physiologic tremor is high in frequency (10 to 12 Hz), essential tremor can be low- or high-frequency, and parkinsonian rest tremor usually is low in frequency (4 to 6 Hz). Psychogenic tremors often vary in frequency from moment to moment and may subside or entrain when the patient is asked to carry out a complex repetitive motor task with the contralateral limb. CHOREA

The term chorea means “dance” and is used to refer to an involuntary movement disorder characterized by a panoply of randomly appearing irregular, purposeless, jerky movements of various portions of the body, extremities, and face. The character, location, and duration of individual movements is unpredictable, although individual patients usually exhibit a certain repertoire of recurrent abnormal movements and postures that become stereotyped and characteristic for them. Involuntary movements usually are quick and jerky but may sometimes occur in the form of more prolonged alterations of posture. Quicker movements may resemble myoclonus or tics, whereas slower movements may appear dystonic. Early manifestations of chorea can be subtle and sometimes resemble fidgetiness more than a movement disorder. The patient and family often are unaware of abnormal movements at this stage and may report only motor restlessness. Early subjective complaints usually consist of clumsiness, dropping of objects, and loss of fine motor coordination of the extremities. Later in the course, unsteady gait, abnormal postures of the arms and hands while walking, and impaired balance may become prominent. Examination may reveal a wide variety of involuntary movements of the face, extremities, and trunk. In mild chorea, involuntary movements may be infrequent, of small amplitude, and isolated, giving an appearance difficult to distinguish from myoclonus or tics. Some choreic movements can be partly suppressed or successfully obscured by incorporation into semipurposeful movements. In more advanced chorea, movements occur nearly continuously and appear to spread fluidly from site to site over the body. Abnormal facial expression is particularly prominent in chorea associated with Huntington’s disease because of a unique combination of reduced facial expression with superimposed involuntary facial movements such as elevation or frowning movements of the eyebrows, increased eye blinking, pursing or puckering of the lips, blowing out of the cheeks, and various movements of the tongue and jaw. Abnormal movements and postures of the trunk may include back arching, trunk flexion and extension, neck stretching, shoulder shrugging, and pelvis rocking. Abnormal limb movements can be distributed proximally or distally and may include sudden and sustained twisting or extension postures of an arm or leg, distal twisting movements of the wrist or hands, small-amplitude, jerky movements of the hands or fingers, extensor posturing of the large toes, and piano-playing movements of individual fingers. The overall appearance often conveyed is that of a marionette being unpre-

Principles of Diagnosis: Common Presenting Symptoms

dictably jerked about by its strings. Respiratory dyskinesia may also be a manifestation of chorea and produce irregular breathing, grunting noises, and air gulping. Depending on the cause of the chorea, other motor abnormalities may coexist with the involuntary movements and may be a greater source of disability than the chorea itself. This is particularly true in Huntington’s disease, in which dysarthria, gait disturbance, and eye movement abnormality may be prominent. Motor impersistence is particularly common in Huntington’s disease and is manifest by inability to maintain a strong grip or keep the tongue protruded for more than several seconds. Oculomotor abnormalities in Huntington’s disease may include impaired saccadic movements and saccadic pursuit. The gait typically is abnormal in Huntington’s disease and is associated with more abnormal movements and postures than are evident when the patient is sitting down. This may produce a broad-based lurching and ataxic gait disorder over and above the effects of the chorea. In advanced cases, gait and balance become severely compromised, leading to multiple falls and wheelchair confinement. The differential diagnosis of chorea in the adult is broad and includes a large number of hereditary, degenerative, and acquired disorders (Table 3-3). For practical purposes, the more common causes of chorea in adulthood other than Huntington’s disease include tardive dyskinesia caused by antipsychotic drugs; choreoathetosis caused by stimulants, antiparkinson drugs, or anticonvulsants; cerebrovascular causes such as basal ganglia lacunar infarction and subthalamic hemorrhage; systemic diseases such as acquired hepatolenticular degeneration, systemic lupus erythematosus, and phospholipid antibody syndrome, and metabolic disorders such as hyperthyroidism, hypoparathyroidism, and acute electrolyte imbalance; Sydenham’s chorea; senile chorea; and hereditary disorders such as Wilson’s disease, benign familial chorea, neuroacanthocytosis, neurometabolic disorders, and paroxysmal choreoathetosis. Huntington’s disease is discussed in greater detail in Chapter 126. When there is a family history of chorea or other movement disorder, differentiation from benign familial chorea, hereditary spinocerebellar ataxia, Wilson’s disease, and paroxysmal dyskinesias is necessary. In benign familial chorea, onset occurs in very early childhood and is not associated with akinetic-rigid features, cognitive changes, or progression. Wilson’s disease rarely produces isolated chorea without other neurologic manifestations. The paroxysmal dyskinesias are discussed separately. The various causes of sporadic adult-onset chorea can usually be identified by history and appropriate laboratory tests. Huntington’s disease may appear to be sporadic because of unavailability of accurate family history or source of genetic mutation. In such cases, the diagnosis may be established by DNA analysis for identification of excessive triplet repeats. Senile chorea occurs after age 65, is not associated with dementia, and is often limited to orofacial dyskinesia. Tardive dyskinesia (discussed in Chapter 127) may be differentiated from other choreiform disorders by the presence of more repetitive, stereotyped movements that predominantly, but not exclusively, involve muscles of the face, mouth, and tongue. Abnormal movements often are more dystonic than choreic, and the lack of progression, together with absence of other motor abnormalities such as motor impersistence, dysarthria, and gait ataxia help to distinguish tardive dyskinesia from Huntington’s disease. Chorea caused by infarcts in basal ganglia is abrupt in onset and usually unilateral, although bilateral involvement occasionally occurs. Chorea may be the predominant manifestation of acquired

Chapter 3

TABLE5-5. Causes of Chorea Hereditary disorders Neurometabolic disorders Wilson’s disease Lesch-Nyhan disease Abnormal carbohydrate metabolism (e.g., galactosemia) Abnormal lipid metabolism (e.g., CM, and CM, gangliosidosis) Amino acidopathies (e.g., glutaric acidemia) Huntington‘s disease Hallervorden-Spatzdisease Neuroacanthocytosis Sea-blue histiocytosis Ataxia telangiectasia Machado-Joseph disease Olivopontocerebellar atrophy Paroxysmal dystonic choreoathetosis Paroxysmal kinesigenic choreoathetosis Benign familial chorea Drug-induced disorders Neuroleptics Stimulants Amphetamines Methylphenidate Pemoline Cocaine Caffeine Aminophylline Antiparkinsonian agents Anticonvulsants Oral contraceptives Opiates Antihistamines Systemic illnesses Systemic lupus erythematosus and the antiphospholipid antibody syndrome Acquired hepatolenticular degeneration Polycythemia rubra Vera Vasculitis Behget‘s disease Toxins Carbon monoxide Alcohol Manganese Toluene Metabolic disorders Hyperthyroidism Hypoparathyroidism Hypernatremia and hyponatremia Hyperglycemia and hypoglycemia Hypocalcemia Hypomagnesemia Infections and parainfectious disorders Sydenham’s chorea Other postinfectious encephalitides Viral encephalitis NeopIasia Primary and metastatic brain tumors Cerebrovascular disorders Basal ganglion infarction Central nervous system hemorrhages Arteriovenous malformation Others Pregnancy (chorea gravidarum) Senile chorea Cerebral palsy Kernicterus (Modified from Weiner WJ, Lang AE: Movement Disorders: A ComprehensiveSurvey. Futura, Mt. Kisco, NY, 1989, with permission.)

hepatolenticular degeneration caused by cirrhosis and portal hypertension. However, various combinations of tremor, akinesia, and rigidity are usually also present, together with asterixis and stigmata of chronic liver disease. Chorea caused by drug intoxications or metabolic derangements is also abrupt in onset, usually associated with other acute neurologic manifestations, and iden-

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tifiable by medical history and laboratory studies. Chorea caused by streptococcal infection, systemic lupus erythematosus, pregnancy, or oral contraceptives often is mild, is usually transient or fluctuating, and should be readily identifiable by history and appropriate laboratory studies. Approach to the Patient History-taking must be directed at gathering possible clues to the large number of known medical and neurologic causes of chorea mentioned earlier. Family history, age of onset, progression, and associated cognitive or personality changes are particularly important with regard to Huntington’s disease, benign hereditary chorea, degenerative diseases, and neurometabolic disorders. Acute onset in an adult should suggest drugs or drug withdrawal, systemic lupus, hyperthyroidism, recurrences of Sydenham’s chorea caused by oral contraceptives or pregnancy, or basal ganglia stroke. Examination is observational in search of choreiform orofacial, extremity, or truncal movements. Subtle chorea may be difficult to distinguish from fidgety movements, some of which become incorporated into volitional movements. Dorsiflexion posturing of the large toe and piano-playing movements of the fingers while walking are characteristic of choreiform disorders. Involuntary respiratory movements and grunting noises are also often associated with chorea. Impersistence of tongue protrusion is typical of chorea but may be remarkably absent in severe orolingual dyskinesia caused by neuroleptic drugs. Oculomotor abnormalities are present in Huntington’s disease but also in other extrapyramidal disorders. Repetitive and goal-directed movements may appear awkward because of either the chorea or other associated motor dysfunction. Gait may be ataxic in severe chorea, especially in Huntington’s disease, in which motor abnormalities typically exceed the effects of chorea. Dementia or other extrapyramidal signs, such as dystonia, akinesia, rigidity, tremor, myoclonus, or tics, suggest a degenerative or neurometabolic disorder.

BALLISMUS Ballismus consists of throwing or flinging movements of the limbs that are usually high in amplitude and velocity and involve proximal more than distal musculature. Movements are irregular and unpredictable but tend to be more continuous and higher in frequency than choreic movements. In most cases, ballismus is limited to one side of the body and is called hemiballismus. The proximal distribution and rotatory character of the movements often are used to distinguish ballismus from chorea, but the distinction may be arbitrary, and there is much overlap in the characteristics of the two disorders and their pathologic substrate. Mild forms of hemiballismus sometimes present as a gait disorder with proximal jerking movements of one leg. Hemiballismus is usually caused by a focal destructive lesion of the contralateral subthalamic nucleus or its connections with globus pallidus but occasionally has also been associated with lesions in the putamen, caudate nucleus, and thalamus. The most common cause is hemorrhage or infarction in the subthalamic nucleus. Although much less common, other focal processes, such as abscess, tumor, tuberculoma, toxoplasmosis, arteriovenous malformation, and multiple sclerosis, have also produced hemiballismus. The most common structural cause of ballismus is basal ganglia infarction, but it may also occur as a severe manifestation of degenerative disorders that produce chorea, such as Huntington’s disease. Toxic

ZQ

Principles of Ambulatory Neurology and the Approach to Clinical Problems W

or metabolic abnormalities such as nonketotic hyperglycemia or intoxications with medications such as levodopa or anticonvulsants may also produce ballismus.

Principlesof Diagnosis: Common PresentingSymptoms

structural abnormality in the contralateral putamen or thalamus. Common causes of dystonia are listed in Table 3-4. Primary Dystonia

DYSTONIA Dystonia is a disorder of abnormal posture and movement characterized by sustained muscle contraction that causes torsional and repetitive movements and abnormal postures. Dystonia is variously used to describe a specific type of focal or regional abnormal movement or posture, a syndrome that occurs secondary to a large number of specific nervous system diseases, or a primary disorder known as idiopathic torsion dystonia. Dystonic movements may be slow or rapid and are typically repetitive and patterned, by contrast with chorea, which is random and unpredictable, and myoclonus, which is rapid, rhythmic, and not associated with twisting changes in posture. Rapid dystonic movements sometimes are difficult to distinguish from myoclonus, and the term myoclonus dystonia is used. In some cases, rapid movements associated with dystonia are caused by a patient’s attempt to resist the abnormal posture, as in patients with cervical dystonia in whom as the head pulls to one side, it may jerk intermittently in the opposite direction. The frequent association of postural-action tremor with focal dystonia also accounts for the presence of additional hyperkinetic movements in many cases. Dystonic movements are characteristically more prominent during the execution of voluntary movements. Action dystonia consists of involuntary movements present only during voluntary use of a group of muscles and absent at rest. Some are task specific and occur only with specific patterns of movement, such as occupational cramp disorders of the upper extremity; jaw, tongue, or vocal cord spasms while speaking; pharyngeal contractions while swallowing; and foot or toe dystonias while walking. As an action dystonia progresses, it may be precipitated by movements in body parts other than the involved area. In some cases, the dystonia progresses to produce a fixed posture at rest. Dystonia may be increased by fatigue or stress and improved or abolished by rest. Some patients discover sensory tricks that partially or completely suppress the abnormal movements of postures. These unusual characteristics of dystonia, together with otherwise normal neurologic examination results, sometimes lead to a mistaken diagnosis of conversion reaction. Dystonia is classified in a number of ways, including age of onset, body distribution, and cause. Age classification is broadly divided into childhood- and adult-onset dystonia. Distribution may be focal in one limb or body part, segmental in two or more adjacent body parts, multifocal in scattered body parts, or generalized with face, limb, and axial involvement or may have a hemidystonic distribution. Etiologic classification is divided into primary idiopathic, genetic, and secondary symptomatic forms. Patients with idiopathic dystonia show no evidence of an identifiable cause of their symptoms, and neurologic examination results are normal apart from dystonic manifestations. Childhoodonset dystonia usually is generalized and may be idiopathic, genetic, or caused by underlying metabolic or structural disease. Idiopathic generalized dystonia in childhood typically begins focally, often in one lower extremity, and becomes generalized, whereas symptomatic forms are more likely to be generalized from onset. Adult-onset idiopathic dystonia usually remains focal or becomes segmental in distribution and rarely becomes generalized. Hemidystonia is nearly always secondary to an identifiable

Primary dystonia is broadly divided into idiopathic generalized torsion dystonia and focal, segmental, and multifocal dystonia. Generalized Dystonia. Generalized dystonia usually begins in childhood but may also appear in young adulthood, prior to the age of 26. It typically has a focal onset involving the foot, hand, cranial, or axial muscles before spreading over months to years to involve adjacent and distant body regions. Childhood-onset torsion dystonia commonly begins in the lower extremity, whereas adult-onset torsion dystonia more commonly starts in the upper extremity, axial, or cranial musculature. Action dystonia is particularly common at the start but usually progresses to more constant dystonia and eventually to fixed dystonic postures. In children, inversion of one ankle and toe-walking are common presenting signs that initially may be alleviated by running, dancing, or walking backward. Later, dystonia spreads to other body regions and eventually causes major gait disturbance over a period of approximately 5 to 10 years. Childhood-onset general-

TABLE 3-4. More Common Dystonias Primary dystonia (idiopathic torsion dystonia) Hereditary Autosomal dominant Autosomal recessive X-linked recessive Paroxysmal dystonia Sporadic Childhood- or adult-onset; generalized, segmental, or focal Secondary dystonia Hereditary neurologic disorders caused by identifiable metabolic defect Wilson’s disease Dopa-responsive dystonia Cangliosidosis Metachromatic leukodystrophy Lesch-Nyhan syndrome Aminoacidurias Neurologic disorders (often hereditary) with undefined metabolic defect Leigh’s disease Hallervorden-Spatz disease Neuronal ceroid-lipofuscinosis Dystonic lipidosis Basal ganglia calcification Ataxia-telangiectasis Neuroacanthocytosis Degenerativedisorders Rigid Huntington‘s disease Parkinson’s disease Pallidal degenerations Olivopontocerebellar degeneration Progressivesupranuclear palsy Corticobasal ganglionic degeneration Acquired dystonia Perinatal brain injury, anoxia, kernicterus Anoxia, carbon monoxide Manganese toxicity Neuroleptic and antiparkinson drugs Stroke Head trauma Atrioventricular malformation Brain tumor Multiple sclerosis Peripheral trauma Psychogenic (Modified from Weiner WJ, Lang AE: Movement Disorders:A ComprehensiveSurvey. Futura, Mt. Kisco, NY, 1989. with permission.)

Chapter 3

ized torsion dystonia usually is genetically determined with an autosomal dominant pattern (DYT1). Autosomal recessive and sex-linked recessive patterns of inheritance also occur. Focal and segmental dystonias usually involve the upper extremity, cranial, and cervical musculature, do not progress after the first several months to years, and almost always appear in adulthood. Most of these are sporadic, but a family history of focal dystonia has been observed in up to 25% of cases. The clinical characteristics of these focal disorders are described in greater detail in Chapter 129, where their treatment with botulinum toxin is discussed. Cervical Dystonia. Cervical dystonia or spasmodic torticollis is the most common focal dystonia that comes to medical attention. It usually begins in middle life, when, unlike in childhood, it is almost never caused by a structural abnormality of the cervical spine. Several abnormal head positions occur, consisting of various combinations of torticollis (rotation), laterocollis (lateral tilt), retrocollis (head extension), and antecollis (head flexion). Unlike in most other forms of dystonia, pain and discomfort are common and nearly always located in the posterior cervical region, usually ipsilateral to the direction of head deviation. Sensory tricks that suppress the dystonia, such as placing a finger or hand on the chin or back of the neck, are more common than in other dystonias. Most patients exhibit tonic head deviation, but clonic jerking or dystonic tremor is sometimes prominent and usually caused by attempts to suppress the abnormal posture. Head tremor caused by an associated essential tremor may also occur. Cranial Dystonia. Cranial dystonia, also known as Meige syndrome, produces dystonic movements of the eyelids, face, tongue, and jaw. Blepharospasm is the most common manifestation and produces increased eyeblink frequency, forced closure of the eyelids, and apraxia of eyelid opening. Differential diagnosis includes secondary forms of blepharospasm caused by neuroleptic drugs, Parkinson’s disease, progressive supranuclear palsy, and rare brainstem lesions. Driving, bright lights, watching television, and reading are common aggravating factors. There may be a variety of accompanying movements of the face, jaw, neck, or forehead that are secondary abortive attempts to control the blepharospasm and do not necessarily suggest a diagnosis of Meige syndrome. Oromandibular dystonia is the second most common manifestation of cranial dystonia. It may occur alone but usually accompanies other cranial dystonias such as blepharospasm; lingual, platysmal, or pharyngeal dystonia; and spasmodic dysphonia. Differential diagnosis includes tardive dystonia, edentulous jaw movements, and bruxism. Patterns of abnormal movements include jaw opening, jaw closing, and jaw deviation. The various movements typically occur synchronously in repetitive fashion. Oromandibular dystonia causes major disability, including pain, speech impairment, dysphagia, and oral trauma. Spasmodic dysphonia or laryngeal dystonia is an action dystonia in which involuntary adduction or abduction of the vocal cords is activated by speech. Adductor dysphonia is far more common and results from approximation of the vocal cords caused by contraction or tensing of the thyroarytenoid muscles during speech. This causes a characteristic strained and staccato voice pattern with frequent voice breaks. In abductor dysphonia, there is involuntary separation of the vocal cords caused by posterior cricoarytenoid contraction, which results in a breathy or whispered voice. Historically, spasmodic dysphonia was usually misdiagnosed as psychogenic in origin. Although this is usually not the case, it is sometimes appropriate to consider a psychological cause with the

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assistance of appropriate laryngologic evaluation and laboratory voice evaluation techniques. Differential diagnosis includes essential voice tremor, extrapyramidal dysarthria, and structural or inflammatory vocal cord abnormalities. Limb Dystonia. Limb dystonia is discussed in detail in Chapter 129. Writer’s cramp is the most common of the occupational cramp disorders but is not limited to people who do a good deal of writing. Simple writer’s cramp is a task-specific disorder in which other fine motor activities are unimpaired. In dystonic writer’s cramp other manual activities of the hand become involved and there may eventually be progression to dystonia at rest and involvement of adjacent body parts. Patients present with complaints of slowness and deterioration of handwriting. Excessive squeezing of a pen by the index finger and thumb, involuntary extension movements of individual fingers away from the pen, and involuntary flexion or extension movements of the wrist occur individually or in various combinations. A variety of other cramps or craft palsies have been described affecting musicians, typists, tailors, and other occupations that are similar in their manifestations and are discussed in Chapter 130. Limb dystonia affecting the lower extremity is uncommon as a manifestation of primary dystonia and is more usually caused by acquired injury of the central or peripheral nervous system but primary cases do occur. Paroxysmal Dystonia. Paroxysmal dystonia is a rare disorder that may occur in primary idiopathic form or secondary to a variety of underlying neurologic disorders. Familial forms, as well as some sporadic cases, appear to be primary and associated with a normal neurologic examination. Paroxysmal dystonic choreoathetosis produces episodic dystonic movements that may occur several times daily and often are precipitated by alcohol, caffeine, or stress. Paroxysmal kinesogenic choreoathetosis typically produces more frequent episodes, is precipitated by sudden body or limb movements, and usually responds to treatment with anticonvulsant medications. Secondary forms of these disorders also occur and have a variety of causes, including multiple sclerosis, supplementary motor area seizures, endocrine or metabolic disorders, cerebral palsy, and psychogenic disorders.

Secondary Dystonia The vast majority of dystonias are secondary and occur in the setting of underlying neurologic disorders. They are therefore nearly always associated with other neurologic findings in addition to dystonia. Dystonia may be associated with diseases with known metabolic defects, such as Wilson’s disease, dopa-responsive dystonia, ganghosidosis, metachromatic leukodystrophy, and aminoacidurias. Dystonia may be prominent in disorders with suspected metabolic defects, such as dystonic lipidosis, ceroid lipofuscinosis, Leigh‘s disease, basal gangha calcification, neuroacanthocytosis, and ataxia telangiectasia. A large number of degenerative diseases of the basal ganglia, such as Parkinson’s disease, progressive supranuclear palsy, Huntington’s disease, olivopontocerebellar atrophy, and pallidal degenerations, produce dystonia together with other extrapyramidal manifestations. Miscellaneous structural and toxic disorders that produce dystonia, many of which are associated with abnormal brain imaging, include perinatal anoxia or kernicterus, stroke, head trauma, multiple sclerosis, neoplasm, vascular malformations, neuroleptic and antiparkinson drugs, manganese toxicity, and peripheral trauma.

22

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Approach to the Patient It should be clear from this chapter that age of onset, distribution of dystonia, pattern of progression, and presence or absence of other neurologic findings are particularly helpful in evaluating a dystonic syndrome. Childhood forms usually become generalized regardless of whether they are primary or secondary. Delayed onset of dystonia may occur after perinatal brain injury caused by kernicterus, anoxia, or trauma. Adult forms of primary dystonia usually are nonprogressive and remain focal or segmental. Generalized or lower extremity dystonia in an adult therefore should raise the possibility of an identifiable underlying cause. Hemidystonia in a child or adult is strongly indicative of a contralateral basal ganglia abnormality. Action dystonia is more commonly a feature of primary dystonia, whereas the early appearance of a fixed dystonic posture is indicative of secondary dystonia. Diurnal variability should raise the possibility of dopa-responsive dystonia, which is remarkably sensitive to very small amounts of levodopa. Birth, development, medication, toxin, trauma, and family history are all important in identifying secondary dystonia. Examination of patients with dystonia should emphasize careful observation under a variety of circumstances, especially as they carry out tasks that reportedly precipitate or aggravate their dystonia. Similar to tic disorders, some dystonias such as blepharospasm may be less evident in the office situation than suggested by the history. Variability of dystonia under different circumstances often is a hallmark of the disorder and should not necessarily imply a psychogenic cause. The presence of other abnormal central or peripheral neurologic findings should trigger a search for an underlying cause. In the absence of such findings, such a search is less likely to be fruitful. For example, the presence of tremor and akinesia should suggest Wilson's disease; cerebellar ataxia should suggest olivopontocerebellar atrophy, ataxia telangiectasia, or storage disorders; abnormal eye findings should suggest olivopontocerebellar atrophy, dystonic lipidosis, Huntington's disease, or Leigh's disease; and anterior horn cell or peripheral nerve findings should raise the question of metachromatic leukodystrophy, neuroacanthocytosis, ataxia telangiectasia, or olivopontocerebellar atrophy.

MYOCLONUS The term myoclonus refers to quick, shocklike muscle contractions that produce brief and sudden movements of a limb or body part. Myoclonus presents in a number of patterns that should be described carefully to assist in its clinical classification. Frequency of muscle jerks may be individual and infrequent or constant and repetitive. Amplitude of movements may range from barely detectable movements within a limb to large jerks of the entire body. In most cases, the pattern of myoclonus is irregular, but it can be rhythmic. The distribution may be focal in one part of the body, segmental involving adjacent body regions, multifocal involving multiple body regions, or generalized involving the entire body. Myoclonus occurring in more than one body part may be asynchronous or synchronous. Muscle jerks may occur spontaneously, as a reflex response to inputs from sudden visual, auditory, or tactile stimuli, or as a result of active or passive voluntary movements. Myoclonus occurs in a large variety of neurologic disorders (Table 3-5). Most of these are central nervous system in origin, but myoclonus occasionally occurs in peripheral neurologic disorders,

Principles of Diagnosis: Common Presenting Symptoms

TABLE 5-5. Common Causes of Myoclonus Physiologic myoclonus (normal subjects) Nocturnal Anxiety Hiccup Essential myoclonus (no known cause; no other manifestations) Hereditary Sporadic Benign neonatal sleep myoclonus Epileptic myoclonus (seizures predominate; no encephalopathy) Fragments of epilepsy Isolated epileptic myoclonic jerks Epilepsia partialis continua Idiopathic stimulus-sensitive myoclonus Photosensitive myoclonus Myoclonic absences Childhood myoclonic epilepsies Infantile spasms Myoclonic astatic epilepsy Clyptogenic myoclonus epilepsy Juvenile myoclonus epilepsy Benign familial myoclonus epilepsy Baltic myoclonus Symptomatic myoclonus (encephalopathy predominates) Storage disease Lafora body disease Lipidoses Ceroid-lipofuscinosis Sialidosis (cherry-red spot myoclonus) Spinocerebellar degeneration Ramsay Hunt syndrome Friedreich's ataxia Ataxia telangiectasia Basal ganglion degeneration Wilson's disease Torsion dystonia Hallervorden-Spatz disease Progressive supranuclear palsy Huntington's disease Corticobasal ganglionic degeneration Dementias CreuMeldt-Jakob disease Alzheimer's disease Viral encephalopathies Subacute sclerosing panencephalitis Encephalitis lethargica Herpes simplex virus encephalitis Other viral encephalitides Postinfectious encephalitis Metabolic Hepatic failure Dialysis encephalopathy Hyponatremia Hyperglycemia and hypoglycemia Infantile myoclonic encephalopathy with polymyoclonus Toxic encephalopathies Bismuth Heavy metals Methyl bromide DDT Drugs (eg, levodopa, tricyclics) Physical encephalopathies Hypoxia Head trauma Heat stroke Electric shock Decompression injury Focal central nervous system Stroke Tumor Trauma Olivodentate lesions (palatal myoclonus) Spinal cord lesions (segmental myoclonus) Psychogenic (Modified from Weiner WJ, Lang AE: Movement Disorders: A ComprehensiveSurvey. Futura, Mt. Kisco, NY, 1989, with permission.)

Chapter 3

such as hemifacial spasm, and rarely as an unusual manifestation of nerve or nerve root injuries. Unfortunately, the clinical features of myoclonus discussed earlier may not allow reliable classification of myoclonus by cause or neuroanatomic origin. The various causes and clinical features of myoclonic syndromes are discussed in detail in Chapter 132. The more common causes include physiologic myoclonus, such as sleep startles, nocturnal myoclonus, and hiccup; epileptic myoclonus associated with idiopathic seizure disorders, benign or progressive myoclonic epilepsies of childhood, and epilepsy partialis continua; essential myoclonus, an early-onset hereditary or sporadic benign disorder that is usually action induced and may overlap with essential tremor and myoclonus-dystonia; and symptomatic myoclonus caused by a wide variety of structural and metabolic disorders, such as storage diseases, cerebellar and basal ganglia degenerations, mitochondrial encephalopathies, dementias such as Alzheimer’s disease and Creutzfeldt-Jakob disease, encephalitis, systemic metabolic disorders usually associated with asterixis, hypoxic and toxic encephalopathies, and focal damage to the brain or spinal cord from a variety of causes. Approach to the Patient

A history of myoclonic jerks usually is elicited from the patient or family, although small-amplitude myoclonus, especially in patients with more serious neurologic manifestations, may be noticed only by the examiner. A history of toxin exposure or drug use is important. Precipitants and circumstances under which the myoclonus appears should be elicited. Asterixis or negative myoclonus often presents as dropping of objects or sudden falls caused by lapses in extensor muscle tone. Action myoclonus is characteristic of essential myoclonus, for which there may be a family history, but it is also the haltmark of postanoxic myoclonus, for which there should be an obvious history of acute cerebral anoxia. The most common forms of physiologic myoclonus occur only during sleep but usually are adequately described by the patient’s spouse. In other cases, all-night sleep recordings may be necessary for evaluation. Myoclonus commonly accompanies idiopathic epilepsy. This myoclonus may be stimulus sensitive and often occurs at times of reduced seizure control. The presence of myoclonus in a child either with or without epilepsy should prompt assessment of cognitive function and school performance. Symptomatic forms of myoclonus usually are accompanied by other manifestations of what is usually a prominent underlying neurologic disorder. In many patients, myoclonus may not be evident on routine neurologic examination. Efforts to elicit myoclonus by providing sudden auditory, tactile, or muscle stretch stimuli should be made. The muscle jerks should be characterized according to frequency, amplitude, rhythmicity, and distribution. Focal myoclonus limited to distal portions of one extremity suggests a cortical origin, whereas segmental involvement, especially if bilateral, may indicate a brainstem or spinal origin. Multifocal myoclonus is characteristic of systemic metabolic disorders, such as uremia or hepatic failure. When multiple body regions are involved, electromyographic study of synchrony and order of activation of muscle groups may be useful in identifymg cortical and subcortical forms of myoclonus. Action myoclonus should be searched for in muscles of the limbs, face, and trunk. Action myoclonus of the upper extremities should be distinguished from severe postural-action or intention tremor, with which it sometimes coexists. Myoclonus usually is lower in frequency and

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23

more quick and jerky in its appearance than tremor. Myoclonus present at rest must be distinguished from chorea, which is usually more random, unpredictable, and multifocal in character. Tics usually produce more complex movements and postures, are more suppressible, and often are associated with inner tension and other subjective sensations. Because myoclonus often is accompanied by other manifestations of an underlying neurologic disorder, careful examination for associated cerebellar, extrapyramidal, and cognitive abnormalities is necessary for differential diagnosis. TICS

Tics are a common phenomenon at one time or another in a large number of neurologically normal individuals. Tourette syndrome is the best-known neurologic condition characterized by the presence of motor and vocal tics and is discussed in detail in Chapter 131. Motor tics most commonly appear as brief, high-velocity jerking movements of individual muscles, groups of muscles, or parts of the body. They are random and variable in pattern and frequency and usually can be voluntarily suppressed for limited periods of time. An infinite variety of motor tics may occur and may be classified as simple or complex and clonic or dystonic in type. Common examples of simple motor tics include eye blinking, blepharospasm, facial grimacing, platysma contractions, head jerking, shoulder shrugging, abdominal or pelvic contractions, and arm or leg jerking. Complex motor tics produce patterned and coordinated movements that involve one or more regional groups of muscles and may appear purposeful, such as repetitive neck or limb shaking or stretching, hitting or touching movements, and whole-body movements such as turning, squatting, or jumping. Complex motor tics often are characterized by ritualistic, obsessive, and compulsive features and, in severe tic disorders such as Tourette syndrome, may include echopraxia and copropraxia. Clonic tics are brief, jerky, and characteristic of simple tics, whereas dystonic tics are slower and more protracted movements that usually occur as part of complex tics. Vocal tics are characteristic of Tourette’s syndrome and, like motor tics, may be simple or complex in type. Simple vocal tics include nonverbal noisemaking such as sniffing, coughing, throat clearing, humming, grunting, hooting, squealing, or barking. Complex vocal tics include verbal utterances, such as coprolalia, echolalia, cheers, and oaths, as well as nonverbal tics such as belching, hiccuping, and panting. Motor tics are somewhat more common in the face, neck, and shoulders than in the trunk and extremities. Neither motor nor vocal tics occur in response to external stimuli, but both often increase during or after stressful situations. They often occur as an effort to relieve an internal urge and are at least temporarily suppressible. This is especially characteristic of dystonic tics in which uncomfortable internal sensations, sometimes called sensory tics, are experienced in localized body regions, leading to repeated efforts to gain relief by movements or muscle contractions. A period of tic suppression typically is followed by a temporary flurry of increased tic frequency, which the person will sometimes seek to carry out in private. Approach to the Patient

The diagnosis of tic disorder should be readily apparent from the history provided by the patient and family members. Simple

24

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

motor tics such as increased eye blinking often are mistakenly attributed to eye irritation, whereas simple vocal tics such as sniffing, throat clearing, or coughing often are blamed on nose or throat irritations. Many motor tics initially are thought to be normal phenomena and do not attract medical attention. It is typically when increasing numbers of more complex tics appear that patients present themselves or are brought by family members for neurologic evaluation. The description of an inner urge relieved by movement or muscle contraction is nearly pathognomonic of tics. However, this is mainly characteristic of dystonic tics and may not be prominent in patients with primarily simple tics. A history of fluctuating and changing tics over the course of months or years is particularly typical of Tourette syndrome but may be absent in patients with transient or chronic motor tic disorder. Except for the presence of tics, neurologic examination results are normal in most patients who present for evaluation of tic disorder. Tourette syndrome may be accompanied by learning disabilities, attention deficit disorder, and obsessive-compulsive disorder but not by abnormalities of the elementary neurologic examination. The presence of other neurologic findings should suggest a secondary tic disorder. Tics are best observed during the course of the interview rather than during the formal examination. Often they are more prominent while the patient is sitting and quietly listening to the examiner than while he or she is actively engaged in relating the history. It is not unusual for patients with mild tics to exhibit little evidence of tics while in the presence of the examiner. In such cases, it is useful to observe the patient while he or she is in the waiting room or through a one-way mirror or to listen for vocal tics through a closed examining room door. Mild choreic and dystonic manifestations may be present in patients with Tourette syndrome and difficult to separate from tics. Although ability to suppress movements is characteristic of tics, this feature may also be found in chorea, dystonia, or athetosis. Most dystonic and many simple tics are more reliably differentiated from dystonia or chorea by the inner urge and release that characterize tics and the historical features of the disorder. Clinical criteria for the diagnosis of Tourette syndrome include childhood or adolescent onset, multiplicity of tics, presence of vocal tics, a historical pattern of variation in type and severity of tics over time, and suppressibility. Tourette syndrome must be differentiated from transient tic disorder and chronic motor tic disorder. Transient tics are common in children and may closely resemble Tourette syndrome but last less than a year and usually are not accompanied by vocal tics. Chronic motor tic disorder appears in childhood or adult life but usually is limited to a single motor tic that remains constant in severity over an extended period of time. Both of these disorders may be present in family members of a patient with Tourette syndrome. Rare startle disorders characterized by sudden complex movements, such as hyperekplexia, jumping disease, latah, and myriachit, differ from tics in being triggered by external stimuli and unaccompanied by more usual tic manifestations. Secondary tic disorders may occur after chronic neuroleptic, amphetamine, or levodopa treatment; accompanying mental retardation; in postencephalitic syndromes; as sequelae of head trauma, stroke, and carbon monoxide poisoning; and in neuroacanthocytosis. In these cases, the history and presence of other neurologic findings suggest a secondary tic disorder.

PSYCHOGENIC MOVEMENT DISORDERS As in other categories of neurologic disease, psychogenic causes sometimes merit consideration in evaluating a movement disorder. Movement disorder specialty clinics are seeing increasing numbers of patients with movement disorders with psychological causes. These include psychogenic dystonia, tremor, and gait disorder, which are the most common of the group, as well as psychogenic myoclonus, paroxysmal syndromes, and startle disorders. Unfortunately, the diagnosis of many movement disorders is based primarily on an observed pattern of symptoms and signs with few or no available methods of laboratory confirmation. This is especially true for hyperkinetic syndromes, in which the incidence of psychogenic disorders is higher than for hypokinetic disorders. Because the diagnosis commonly rests on clinical criteria, it is important to be careful before attributing an unusual movement disorder to psychological causes. This is particularly important because historically a number of movement disorders, especially dystonias and tics, have been incorrectly attributed to psychological causes. Criteria have been recommended for the likelihood that a psychogenic movement disorder is present. A documented psychogenic disorder is one in which the manifestations are rapidly and completely eliminated by psychological treatment such as psychotherapy, suggestion therapy, or placebo or the patient is documented to be free of signs when unknowingly observed. With the exception of tics, acute drug-induced dyskinesias, and rare cases of cervical dystonia, organic movement disorders almost never remit suddenly and spontaneously; therefore such remission indicates psychogenic movement disorder. A clinically established psychogenic disorder is one that is inconsistent over time or is incongruent with the known pattern of an established movement disorder and is accompanied by obvious psychiatric disturbance, other psychosomatic disorders, and other neurologic signs that are definitely psychogenic. A probable psychogenic disorder is one in which the movements appear inconsistent or incongruent but there are no other findings to indicate a psychogenic cause or the movements appear consistent and congruent but other psychogenic findings or somatizations are present. One may be suspicious of a possible psychogenic disorder if the movement disorder appears consistent and congruent with an organic disorder but occurs in the setting of an obvious emotional disturbance. Approach to the Patient

Certain clues in the history and examination may suggest the possibility of a psychogenic disorder. These include sudden onset, multiplicity of abnormal movements, inconsistency during the examination or from one examination to another, abnormal movements and postures that do not fit with recognized patterns, large-amplitude shaking movements, bizarre gait, excessive startle responses to a variety of stimuli, overly slow and deliberate voluntary movements, variable tremor frequency, marked relief of involuntary movements with distraction, a dystonia beginning as a fixed posture, and false weakness or sensory signs. Although these clues, together with an obvious psychiatric disorder, other somatizations, and identifiable secondary gain, may suggest a psychogenic cause, it is important to view these signs in the context of the diagnostic criteria outlined earlier. This is especially true because one is sometimes dealing with rare, unique, or highly unusual movement disorders with variable manifestations that

Chapter 4 W

often are also associated with psychiatric disturbance. Finally, as with any apparently psychogenic disorder, one has to be alert to the possibility that psychogenic abnormal movements may occur in patients with an underlying organic movement disorder. Inpatient or extended outpatient evaluation, reasonable and necessary laboratory tests, observed and unobserved video recording, psychiatric evaluation, and physical medicine evaluation and treatment should all be considered in evaluating such patients. SUGGESTED READINGS

Gait Impairment and Falls

25

Fahn S: Psychogenic movement disorders. In Marsden CD, Fahn S (eds):

Movement Disorders 111. Butterworth-Heinemann, London, 1994 Fahn S, Marsden CD, Calne DB: Classification and investigation of dystonia. In Marsden CD, Fahn S (eds): Movement Disorders 11. Butterworth, London, 1987 Jankovic J, Stone L Dystonic tics in patients with Tourette’s syndrome. Mov Disord 6248, 1991 Koller WC, Busenbark K, Gray C et al: Classification of essential tremor. Clin Neuropharmacol 15:81, 1992 Lang AE: Movement disorder symptomatology. In Bradley WG, Daroff RB, Fenichel GM, Marsden CD (eds): Neurology in Clinical Practice. Butterworth-Heinemann, Boston, 1991

Dewey Jr RB, Jankovic J: Hemiballism-hemichorea.Clinical and pharmacologic findings in 21 patients. Arch Neurol 46:862, 1989

4

Gait Impairment and Falls Lewis R. Sudarsky

Gait is a fundamental motor performance and a distinctive attribute of each person. Walking undergoes characteristic changes over the lifespan. It is very sensitive to diseases of the nervous system, and the neurologic examination is not complete until the gait has been observed. Gait disorders are particularly common among the very young and the very old. Delay in learning to walk can be the presenting manifestation of developmental or acquired neurologic disease in early childhood. Gait abnormalities have been recorded in 15% of people over age 65. By age 80, one person in four uses a mechanical aid to assist ambulation. Among people 85 and older, the prevalence of gait disorder approaches 40%. Falls are the main cause of accidental injury and the sixth leading cause of death in older adults, and gait disorders contribute measurably to the risk of falls and fall-related injury. In some instances, insecure ambulation and a history of falls are cause for nursing home admission. Nonambulatory nursing home residents have accelerated morbidity and mortality. PRINCIPAL PAllERNS OF GAIT DISORDER AND THEIR CAUSE To maintain a stable gait, the nervous system must simultaneously generate motor activity for locomotion and maintain balance. Locomotion involves phasic activity of trunk and limb muscles that coordinates the loading, unloading, and advance of the legs during the stance and swing phase. To prevent instability and falls, the nervous system also has to maintain a state of dynamic equilibrium, managing the center of mass in relation to the base of support. The enormous heterogeneity of gait disorders observed clinically reflects the complexity of the anatomy involved in locomotion. A network of subcortical motor centers participate in the coordinated management of postural control and locomotion. The mesencephalic locomotor region, physiologically defined, lies in the region of the nucleus cuneiformis and (cholinergic) pedunculopontine nucleus. Locomotor synergies are executed through the reticular formation and reticulospinal pathway. Cortical modulation adapts the performance to suit a complex hierarchy of

purposes and environmental needs. Balance is particularly dependent on sensory afferent systems that update the nervous system on the body’s orientation with respect to the support surface and the vertical. Because of this anatomic complexity, there is a large potential for trouble, and walking is vulnerable to neurologic disease at every level. Gait disorders have been classified descriptively, based on abnormal physiology and biomechanics, and etiologically. In practice, many failing gaits look fundamentally similar. This overlap reflects common patterns of adaptation to declining performance. Gait disorder must be viewed as the product of a neurologic deficit and a functional adaptation. The unique features of the failing gait often are overwhelmed by the adaptive response. An example is the phenomenon of the cautious gait in older adults. Many people with disorders of balance or locomotion adopt a timid or cautious style of walking, using short steps and a widened base of support like a person crossing a patch of ice. This pattern is entirely nonspecific; it is just a response to perceived imbalance. A 1983 study conducted at our institution examined the common causes of gait disorder in a neurology office practice. Patients over 65 who were referred for an undiagnosed gait disorder were examined. The study excluded patients with joint deformity and those on neuroleptic drugs. Older people often have comorbidity from arthritis, and minor orthopedic deformity is a common source of gait abnormality. Table 4-1 includes more recent experience with patients seen between 1990 and 1994. In approximately 10% to 15% of older patients, no etiologic factors can be identified after a complete workup and lab studies. These cases are sometimes called senile gait, although it is unlikely that they represent a true morbid entity.

Spastic Gait Spastic gait is characterized by stiffness and bounce in the legs and a tendency to circumduct and scuff the feet. In extreme instances, the legs cross from increased tone in the adductors. Shoes often reflect an uneven pattern of wear across the outside.

26

Principles of Ambulatory Neurology and the Approach to Clinical Problems

TABLE 4-1. Classification of Gait Disorder by Causea Cause Myelopathy Parkinsonism Hydrocephalus Multiple infarcts Cerebellar degeneration Sensory deficits Toxic or metabolic Psychogenic causes Other causes Unknown causes

1990-1994

~otal

%

8 5 2 8 4

12 9 6 10 4

20 14 8 18 8

16.7 11.7 6.7 15.0 6.7

9 3 1 3 7

13 0 3 3 10

22 3 4 6 17

18.3 2.5

1980-1982~

Principles of Diagnosis: Common Presenting Symptoms

Hyperkinetic movement disorders also produce characteristic and recognizable gait disturbances. Tardive dyskinesia is the cause of some of the odd, stereotypic gait disorders seen in chronic psychiatric patients. The gait in Huntington’s disease is characterized by unpredictable choreic movements that give a dancing quality, like a marionette. In dystonic gait muscular spasms produce a dysfunctional posture of the legs, sometimes with torsion of the trunk. Dystonia may disappear when the patient walks backwards.

3.3 5.0 14.2

h = 120 patients. bDatafrom Sudarsky Land Ronthal M: Gait disorders among elderly patients, Arch Neurol 40:740-743, 1983.

Myelopathy from cervical spondylosis is a common cause of spastic or spastic-ataxic gait in older adults. Spondylotic bars and ligamentous hypertrophy narrow the canal, causing mechanical compression and vascular compromise of the cervical spinal cord. Some degree of standing imbalance and bladder dysfunction (urgency, incontinence) accompany a mild spastic paresis of the legs. Magnetic resonance imaging (MRI) has improved the ease of diagnosis, although it sometimes demonstrates advanced pathology in the cervical spine in minimally symptomatic patients. Other causes of myelopathy in older adults include vitamin B,, deficiency and degenerative disease (e.g., primary lateral sclerosis, hereditary spastic paraplegia). Demyelinating disease and trauma are the leading causes of myelopathy in younger patients. In chronic progressive myelopathy of unknown cause, thorough workup with laboratory and imaging tests often establishes a diagnosis of multiple sclerosis. Myelopathy is sometimes caused by a structural lesion, such as tumor or dural or spinal vascular malformation. Traumatic spinal injury may be incomplete or partial, such that the patient remains ambulatory. Motor vehicle and diving accidents, commonly alcohol related, are the usual causes at our institution. Tropical spastic paraparesis related to human T-cell lymphotrophic virus type I (HTLV-I) is endemic in parts of the Caribbean and South America. With cerebral spasticity, involvement of the upper extremities sometimes is observed, and dysarthria usually is an associated feature. Common causes include vascular disease (stroke) and multiple sclerosis. In the cerebral palsy population, a mild spastic diplegia is the most common syndrome.

Extrapyramidal Disorder Parkinson’s disease is common, affecting 1.5% of the population over 65. In the Rotterdam epidemiologic study, the prevalence of Parkinson’s disease was 4.3% for the population over 85 years of age, and 5.9% had a parkinsonian syndrome. The flexed posture and shuffling gait are characteristic and distinctive. There may be difficulty with initiation and a tendency to turn en bloc. Patients sometimes accelerate (festinate) with progression or display retropulsion. Some patients with atypical parkinsonism present with axial stiffness, postural instability, and a shuffling gait (see Chapter 114). Drug-induced parkinsonism is increasingly recognized in ambulatory practice as a cause of impaired gait and balance. It is particularly common in a chronic care setting (see Chapter 123).

Frontal Gait Disorder (Gait Apraxia) Frontal gait disorder is more common in older adults and has a variety of causes. The term gait apraxia is sometimes used, although the disorder is more properly a higher-level motor deficit rather than a true apraxia. Typical features include a wide base of support, short stride, shuffling on the floor, and difficulty with starts and turns. Many exhibit a peculiar difficulty with gait initiation, descriptively characterized as freezing gait or gait ignition failure. The term lower body parkinsonism is also used to describe this condition. In studies seeking clinicopathologic correlation, lesions often are found in the deep frontal white matter. Communicating hydrocephalus in the adult often presents with a gait disorder, often a combination of frontal gait and disequilibrium. MRI demonstrates ventricular enlargement, an enlarged flow void about the aqueduct, and a variable degree of periventricular white matter change. A dynamic test is necessary to confirm the presence of hydrocephalus. The response to lumbar puncture, with removal of 30 to 50 mL of cerebrospinal fluid, has been used as a screening procedure (see Chapter 16). Another common cause of the frontal gait disorder is vascular disease, particularly small vessel disease involving the basal ganglia and periventricular white matter. Gait disorder often is seen in hypertensive patients with ischemic lesions of the deep hemisphere white matter (Binswanger’s disease). The MRI is very sensitive to change in these regions, and clinical correlation is needed to support the diagnosis. The clinical syndrome includes mental change (variable in degree), dysarthria, pseudobulbar affect, and gait disorder with postural instability, increased tone, and hyperreflexia in the lower limbs.

Cerebellar Gait Disorders of the cerebellum have a dramatic impact on gait and postural control. Gordon Holmes described the cerebellar gait in a group of patients with gunshot injuries. The ataxic gait is characterized by a wide base, lateral instability of the trunk, irregular stepping, and decompensation of balance when attempting to walk tandem. Cerebellar patients have well-defined abnormalities of balance on platform posturography. They show wide variation in their tendency to fall in the real world. Posterior fossa tumors can present with an ataxic gait. Multiple sclerosis can produce ataxia and postural instability. Inherited and sporadic forms of cerebellar degeneration are described in Chapter 124. Other causes include toxins and paraneoplastic cerebellar degeneration. Sensory Ataxia and Disequilibrium Patients with chronic imbalance caused by a disorder of sensory systems are the single largest group, approaching 20% in our

Chapter 4

series. Balance depends on high-quality afferent information from the visual and vestibular systems and proprioceptive information from the lower limbs. When this information is degraded, standing balance is impaired, and instability results. The sensory ataxia of tabetic neurosyphilis is a classic example. The contemporary equivalent is the patient with neuropathy affecting large-fiber afferents. The stance in such patients is destabilized by eye closure (Romberg’s test). Patients have been described with imbalance from bilateral vestibular loss caused by disease or by exposure to ototoxic drugs. Some older patients exhibit a syndrome of imbalance from the combined effect of multiple sensory deficits. Such patients, often older and diabetic, complain of unsteadiness and exhibit impaired postural support. In the recent past, cataract surgery with external lenses has been a factor in the decompensation of some such patients. Neuromuscular Disease Patients with neuromuscular disease often have an abnormal gait, although it is not typically a presenting feature. With distal weakness from peripheral neuropathy, the step height often is increased to compensate for foot drop, and the sole of the foot may slap on the floor during weight acceptance. Neuropathy may be associated with a degree of sensory imbalance, as described earlier. Patients with myopathy or muscular dystrophy most often have proximal weakness. Weakness of the hip girdle may produce a degree of excess pelvic rotation (waddle). Toxic and Metabolic Disorders Unquestionably the most common cause of difficulty walking is alcohol intoxication. Toxicity from medications and metabolic disturbances can impair motor function and gait. Static equilibrium is disturbed, and patients are easily displaced backward. This is particularly dramatic in patients with chronic renal disease and those with hepatic failure in whom asterixis may impair postural support. Sedative drugs, especially neuroleptics and long-acting benzodiazepines, affect postural control and increase the risk of falls. These disorders are important to recognize because they are treatable. Psychogenic Gait Disorder Psychogenic disturbances of gait are among the most spectacular disorders encountered in neurology. Odd gyrations of posture (astasia-abasia) and dramatic fluctuations over time may be observed with hysterical conversion disorders. Patients with extreme anxiety sometimes walk with exaggerated caution, as if walking on a slippery surface. Depressed patients exhibit primarily slowness, a manifestation of psychomotor retardation, and lack of purpose in their stride. Other IdentifiableCauses Occasionally patients presenting with gait disorder have an intracranial mass lesion. Subdural hematoma should be ruled out in the patient with subacute evolution and a history of falls. Lumbar spinal stenosis can also limit ambulation and produce a postural flexion that increases with walking and is relieved by sitting down.

H

Gait Impairment and Falls

27

APPROACH TO THE PATIENT WITH A SLOWLY PROGRESSIVE DISORDER OF AMBULATION In eliciting the history, it is helpful to inquire about the pace of the illness. Stepwise evolution or sudden progression suggests vascular disease. Gait disorder may be associated with urinary urgency and incontinence, particularly in patients with subcortical frontal disease or spinal disease. Back pain or headache may be clues to a structural disorder, particularly in patients whose illness evolves over weeks to months. First awareness of a balance problem often follows a fall. It is always important to review the use of alcohol and medications that can affect gait and balance. Because the list of possible diagnoses is lengthy, information on localization derived from the neurologic examination can be helpful in narrowing the search. This examination often is most informative, despite its focus on corticospinal systems, which play a minor role in locomotor control. Gait observation provides a more immediate sense of the patient’s degree of disability. Cadence (steps per minute), velocity, and stride length can be recorded by timing a patient over a fixed distance. Watching the patient get out of a chair provides a good functional assessment of balance. Characteristic patterns of abnormality sometimes are observed, although failing gaits often look fundamentally similar, as reviewed earlier. Brain imaging studies (computed tomography or MRI) often are informative in patients with an undiagnosed gait disorder. MRI is sensitive for cerebral lesions of vascular or demyelinating disease and is a good screening test for occult hydrocephalus. Many older adults with gait and balance difficulty have lesions in the periventricular region and centrum semiovale. Although controversy persists about the clinical relevance of these lesions in older adults, a substantial burden of white matter disease inevitably affects cerebral control of locomotion.

EPIDEMIOLOGY OF FALLS Prospective studies estimate that 20% to 30% of people over age 65 fall each year. The proportion is higher in hospitalized older adults and nursing home residents. Roughly one of four falls results in serious injury and 5% in a fracture. Eight percent of people over age 75 suffer a serious fall-related injury each year. By age 80, one in five women will have fractured a hip. For each person physically disabled, there are others whose functional independence is constrained by fear of falling. In a study conducted in New Haven, Connecticut, 18% of older adults acknowledged that they voluntarily limited their activity (walking out of the home, shopping, bathing) because of fear of falling. An epidemiologic, multiple-risk-factor model has been applied to study the problem of falls in older adults. Independent risk factors for fall-related injury include cognitive impairment, decreased bone density, gait and balance impairment, and the presence of specific chronic illnesses, notably diabetes and stroke. In the prospective study of Tinetti et a1 (1988) of people over age 75, cognitive impairment and the use of sedative medications substantially increased the risk of falling. A possible environmental factor was mentioned in 44% of the events. Tinetti and colleagues devised a functional assessment for gait and balance. They observed a direct correlation between number of gait and balance abnormalities recorded and risk of falling. In a more recent study, the same group looked at inability to get up after a fall. The phenomenon is more prevalent than generally

28

Principles of Ambulatory Neurology and the Approach to Clinical Problems W

thought. Thirty-nine percent of 660 fall events were associated with an inability to get up, and 3% of subjects were on the floor more than an hour. Such events were more likely to be associated with hospitalization. Absent evidence of serious cardiovascular disease, there was a marginally higher risk of death or functional decline over the next year.

A NEUROLOGIC PERSPECTIVE ON RECURRENT FALLS Although falling is not a common cause for neurologic referral, there are some special circumstances, such as syncope and seizures, in which neurologic evaluation is sought. In epidemiologic surveys, 80% to 90% of fall events occur among 10% of patients, a group described as recurrent fallers. Some of these patients are frail older adults with a large burden of chronic disease. Recurrent falls sometimes indicate a serious balance problem, a failure of postural control mechanisms. Neurologic evaluation may be appropriate for these patients. A hierarchy of postural control systems can be demonstrated in physiologic studies. Static balance is examined by recording excursions of the center of pressure on a force platform. Sway can also be examined during eye closure and with other forms of sensory deprivation. Automatic postural adjustments maintain balance during quiet stance. Reactive postural adjustments can be recorded in the leg muscles beginning 110 msec after a perturbation. These are long-loop responses, not to be confused with the monosynaptic ankle stretch reflex. They are probably mediated at a brainstem level. As a last resort, rescue reactions protect against large displacements to prevent slipping and tripping falls. Anticipatory postural responses integrate balance control with other voluntary movement. All these physiologic adjustments depend on a redundancy of sensory information from vestibular, visual, and proprioceptive afferents. In the office, balance can be tested by simple functional measures such as one-limb stance, tandem stance, and response to posterior sternal displacement (pull test). Modest changes in balance function have been described in fit older adults. Those who exhibit substantial imbalance are likely to have neurologic disorders affecting postural control. Parkinson’s disease and other akinetic-rigid disorders can cause postural instability and falling. Patients with cerebellar degeneration likewise exhibit poorly coordinated postural synergies, and ataxic patients commonly present with falls. Sensory deficits involving proprioception, vestibular, or visual function can affect standing balance. Patients with bilateral vestibular deficits and those with severe sensory neuropathy are particularly unsteady in stance. Fife and Baloh (1993) have described a group of patients over age 75 with disequilibrium and a sense of imbalance in whom bilateral deficits can be demonstrated on sensitive laboratory tests of vestibular function. Vestibular testing may be appropriate for patients who exhibit balance difficulty that cannot be characterized using standard neurologic assessment. Sheldon’s classic study (1960) identified drop attacks and postural hypotension as the cause of a substantial number of falls. Drop attacks are defined as sudden lapses of postural tonus and collapse without loss of consciousness. In contemporary prospective studies of falls, drop attacks are a rare occurrence. They are probably a benign phenomenon, although some such cases are associated with serious cardiovascular disease. Orthostatic hypotension is identified as a factor in 5% to 10% of falls and should always be considered as a treatable cause. Postural hypotension is a common phenomenon in people over age 65, especially those on potent antihypertensive and vasodilator medications. Primary

Principles of Diagnosis: Common Presenting Symptoms

neurologic diseases, such as autonomic neuropathy or multiplesystem atrophy, are identified in occasional patients. A correlation between cognitive impairment and falls is observed in community-based studies and in chronic care facilities and nursing homes. The pathophysiology of falls in this context is not well understood. There may be a failure of attention or integrative control of posture at a high level. Sedative drugs are also associated with a higher risk of falls and fall-related injury. Neuroleptic drugs and benzodiazepines presumably compromise balance control systems at a brainstem or spinal level. Subdural hematoma is always a concern in the patient with repeated falls. The significance of the cranial trauma may not emerge from the patient history. A low threshold for imaging studies is appropriate in this context, particularly if a disturbance in alertness or lateralized neurologic findings are apparent. INTERVENTION TO REDUCE THE RISK OF FALL-RELATED INJURY Therapeutic intervention often is recommended for the older adults at substantial risk for falls, even if no neurologic disease is identified. Several intervention strategies have been studied. A home visit is a helpful practical step to look for environmental hazards. Attention is focused on adequate lighting, installation of grab bars and nonslip surfaces in bathrooms, and elimination of slipping and tripping hazards from the floor. In some instances, the stairwells can be modified. Rehabilitation techniques focus on the patient rather than the environment in an attempt to make the patient more resilient and less prone to injurious falls. High-intensity resistance strength training is now used to increase muscle mass in nursing home residents in their eighth and ninth decade. Improvements are realized in carriage and gait, which should translate to a reduction in falls. Sensory balance training using a platform and visual feedback can enhance the stability of older adults, and the benefits can be maintained over 6 months by a 10- to 20-minute-per-day home program. This strategy is most successful in patients with vestibular and somatosensory balance disorders. The National Institute on Aging recently sponsored a multicenter study of intervention techniques to reduce the risk of fall-related injury (FICSIT trial). Two strategies emerged as having a measurable benefit in fall risk reduction. The Yale Health and Aging study used a targeted, multiple-risk-factor abatement effort. Prescription medications were adjusted, and home-based exercise programs were tailored to the patients’ needs. The targeted intervention was associated with a 44% reduction in the number of falls, compared with a control group of patients who had periodic social visits. The other strategy of proven success involves the use of tai chi exercises, which accomplish some of the same benefits as high-tech sensory balance training.

SUGGESTED READINGS Alexander NB: Postural control in older adults. J Am Geriatr SOC 42:93-108, 1994

Bronstein AM, Brandt T, Woollacott M (eds): Clinical Disorders of Balance, Posture and Gait. Arnold, London, 1996 De Rijk MC, Breteler MMB, Graveland GA et al: Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology 45:2143-2146, 1995 Fife TD, Baloh RW: Disequilibrium of unknown cause in older people. Ann Neurol 34:694-702, 1993

Chapter 5

Keane JR, Hysterical gait disorders: 60 cases. Neurology 39:586-589, 1989 Masdeu J, Sudarsky L, Wolfson LI: Gait Disorders of Aging: Falls and Therapeutic Strategies. Lippincott-Raven, Philadelphia, 1997 Meisner I, Weibers DO, Swanson JH et al: The natural history of drop attacks. Neurology 36:1029-1034, 1986 Nutt JG, Marsden CD, Thompson PD: Human walking and higher level gait disorders, particularly in the elderly. Neurology 43:268-279, 1993 Sheldon JH: On the natural history of falls in old age. BMJ 21685-1690, 1960

5

rn Sensory Loss and Paresthesias

19

Sudarsky L Gait disorders in the elderly. N Engl J Med 322:1441-1446, 1990

Tinetti ME, Baker DI, McAvay G et al: A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med 331:821-827, 1994

Tinetti ME, Speechley M, Ginter S: Risk factors for falls among elderly persons living in the community. N Engl J Med 319:1701-1707, 1988 Tinette ME, Williams CS: Falls, injuries due to falls, and the risk of admission to a nursing home. N Engl J Med 337:1279-1284, 1997

Sensory Loss and Paresthesias Thomas D. Sabin and David M. Dawson

PARESTHESIAS Although many aspects of neurology increasingly depend on neuroimaging, electrophysiologic testing, and other laboratory data, the bedside sensory assessment remains a necessity for the clinician. During history-taking the patient must be asked to describe abnormal sensory experiences. Burning, stinging, coldness, and heat suggest a problem in small-fiber systems; tingling, pins and needles, or “electricity” are more often features of malfunction in the large-fiber systems. Paresthesias are spontaneous abnormal sensations, whereas dysesthesias usually are unpleasant distortions of actual sensory stimuli in the patient’s daily activities or during examination. The paresthesias of hyperventilation concentrate in the palms of the hands, around the mouth, and in the soles of the feet. The length of axons adds to the probability of tingling of hands and feet, but the richness of innervation accounts for the perioral symptoms. Lhermitte’s sign consists of an abnormal sensation that extends down the spine when the neck is flexed. Cervical cord lesions, particularly multiple sclerosis, are found in such patients; apparently neck movement stretches the cord or dura. Vitamin B,, deficiency and cord compression may also cause Lhermitte’s sign. When both the centrally and peripherally directed axons of dorsal root ganglia are affected in sensory neuropathies (nitrous oxide, pyridoxine, cisplatin, carcinomatous), Lhermitte’s sign is common. Some neurotic patients with nonanatomic paresthesias seem able to “tune in” to the normal ongoing bombardment of afferent information that is ignored when attentional mechanisms are functioning normally. These patients have paresthesias every time they think about them and may develop a positive feedback system that causes increasing anxiety and more paresthesias. Strange sensations that ultimately come to focus on the genitalia are also often without a neurologic basis. A virtual symphony of paresthesias may be described by patients with panic disorders. When a sensory complaint is not accompanied by any abnormality in the sensory examination, the examiner must rely on a mastery of neuroanatomy because the distribution and quality of the paresthesias remain the only keys to a correct diagnosis. TECHNIQUES OF SENSORY EXAMINATION Elaborate quantification of sensory thresholds has only limited diagnostic use in daily practice because these methods focus on a

few sites, and no overall pattern of sensory change is discerned. Because a complete sensory examination is infinite, the physician and the patient are best served by one that is guided by a full patient history and is done at the end of the neurologic examination. In this way, abnormalities already suspected can be documented rapidly. The patient’s eyes usually should be closed for the sensory examination. When charting deficits, stimuli should always begin in the abnormal area and move toward the normal. The reverse technique will reveal a very different sensory map. The experienced examiner is aware that the style of the examination may affect the results. An apparent difference in sensory thresholds between the two sides of the body can be induced by suggestion and the mode of examination. With little effort, the examiner can sculpt a full-blown hemisensory loss in susceptible patients. We urge that all sensory abnormalities be charted on a simple outline diagram. This discipline forces the examiner to commit to a localization and facilitates follow-up comparisons. Sensory deficits can be conveniently grouped into superficial and deep modalities.

SuperfScial Modalities These cutaneous sensations are tested ordinarily as pain, temperature, and light touch. The bedside examination for pain sensibility usually is directed toward pinprick sensation. There are pain pathways that subserve a more primitive type of pain sensation that is less well localized and slower to appear in consciousness, sometimes called second pain, slow pain, or protopathic pain. The pain of a pinprick that is localized precisely and felt immediately is also known as first pain, fast pain, or epicritic pain. Cutaneous pain sense is tested by holding a sharp, sterile pin between the thumb and index finger with sufficient pressure so that it slides slightly on each contact with the patient. This causes no skin penetration and produces a constant stimulus. There are natural variations in thresholds over the surface of the body; increased sensitivity in and around the axillae, lips, and groin must be taken into account. Calluses can completely blunt the appreciation of pinprick. Comparison of one side of the body with a homologous area on the other side of the body often is useful. A rapid series of pinprick stimuli may cause temporal summation and give a false pattern of loss. This is particularly likely to occur at the fading border of peripheral neuropathies, the

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

upper border of spinal cord lesions, or with lesions involving the second sensory cortex in the parietal operculum or the thalamus. Temporal summation is a major reason why use of the “pinwheel” device for pinprick testing is discouraged. A second error occurs when the examiner does not appreciate the importance of skin temperature in the determination of sensory thresholds. Because the distal extremities tend to be cooler, a “pseudoneuropathy” to pin and temperature may be diagnosed by the overzealous examiner mapping out the normal increase in threshold in the cooler distal parts of the body. When the patient is able to discern the sharpness of the pinpoint using preserved discriminative touch but is not actually reporting the painful qualities of the pin, another type of error may occur. Make sure the patient is reporting pain. Watching for a wince may help. Even in a confused patient, one can often rapidly map out an area of sensory loss to pinprick sensation simply by watching the patient’s facial expressions with pinprick stimuli. Areas of temperature loss often overlap with the areas of loss of sensitivity to pinprick. The most efficient way to confirm this pattern of loss is to use brief contact with a cool piece of metal such as the side of a tuning fork. This method will detect a subtler degree of sensory loss than comparing hot and cold. An ice cube in a thin plastic bag is useful for charting areas of complete loss of temperature sense. Because temperature is perceived on the basis of transfer of heat, skin temperatures may substantially alter thresholds. Uncomfortable distortion of cold stimuli is an early sign of small-fiber neuropathy. Superficial touch stimuli can be graded satisfactorily if the examiner simply uses his or her own fingertip or a wisp of cotton fibers. (Caution: Touching a hair results in a 100-fold amplification of signal.) Because patients often report qualitative alterations in touch perception in areas where pinprick and temperature sensation are reduced, the documentation of a true dissociated sensory loss relies on the presence of normal touch thresholds. A set of graded nylon filaments, as available in the SemmesWeinstein Aesthesiometer (Research Media Inc., Hicksville, NY), helps solve this problem. The ticklish quality of a light stroking touch is absent in these areas of diminished pinprick and temperature sense.

Principles of Diagnosis: Common Presenting Symptoms

vibration sense. Cortical sensory loss is suggested when position sense is absent but vibration sense is intact.

PAllERNS OF SENSORY CHANCE The remainder of this chapter is devoted to discussion of common patterns of sensory abnormalities and is arranged anatomically, beginning with intracutaneous nerve damage and following the pathways to the sensory cortex. lntracutaneous Sensory Loss Destruction of nerve endings and networks within the skin and superficial nerves is characteristic of the superficial neuropathy of leprosy. In high-resistance (tuberculoid) leprosy, there is a patch of sensory loss that does not obey the distribution of named peripheral nerves or roots; it is often associated with a hypopigmented skin lesion, which has an elevated border. The loss is mostly to pinprick and temperature. Touch is sometimes sufficiently preserved so that the patient can tell the difference between the sharp and the blunt end of the pin using preserved discriminative sensation alone even though there is complete analgesia in the region. In low host resistance (lepromatous) forms of leprosy, the bacterial growth rate, which is greatest in the coolest tissues, determines the pattern (Fig. 5-1). The early involvement of the helices of the ears, the tip of the nose, malar areas, and the extensor surfaces (along with the preservation of reflexes) are important clues to this unique temperature-linked variety of sensory loss caused by intracutaneous infection. A pattern of pain and temperature loss somewhat resembling that of lepromatous leprosy occurs in tabes dorsalis (Fig. 5-2).

fi

0

Normal Pinprick

0

Decreased

@ Lost

---\

,1

Deep Sensory Modalities Position sense is tested by inducing small-amplitude movements in the patient’s distal digits. The digits should be grasped laterally to eliminate pressure cues. Some patients must be discouraged from using small palpatory movements of the digit to enhance position sense. One-degree displacements should be reported, but if a very slow drift is induced in the digit, more movement is needed. Sensory ataxia and pseudochorea or pseudoathetosis in the outstretched hands appear when position sense loss is substantial. If there is distal position sense loss, then proximal joints should be assessed. The hip joints may be tested by having the blindfolded patient track the great toe with the opposite index finger. Romberg’s sign is elicited by having the patient stand with the feet together and then close the eyes. The test is positive only if the posture is stable until the eyes are closed and then severe swaying or falling develops. A 128-Hz tuning fork is used to assess vibration sense over the distal digits. The skeletal system transmits this modality widely. There is a normal falloff in vibration sense with aging. Demyelinating neuropathies cause elevated thresholds because of the demand for rapid conduction velocities needed to transmit

FIG. 5-1. Temperature-linked loss of pain sense in lepromatous leprosy. (From Sabin TD, Swift IR: Chapter 74. In Dyck RJ, Thomas PK (eds): Leprosy in Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993, with permission.)

Chapter 5

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Sensory Loss and Paresthesias

31

testing should be done with the patient’s eyes open so the ink line can be seen. If a patient claims to have completely numb hands, he or she should have great difficulty in picking up a coin from a flat surface without bringing it to the edge. Naive patients with feigned sensory loss will respond with “yes” or “no” to each pinprick with the eyes closed. A sad commentary on our times is the patient who has been professionally trained to have “sensory loss” along a textbook nerve root distribution. Fortunately, this education usually is not enough to dupe the sophisticated examiner.

Sensory and Mixed Nerves Tingling paresthesias progressing to sensory loss with the greatest extent of loss affecting the modality of light touch is characteristic of a progressive mononeuropathy. Sensory complaints are common even with involvement of pure motor nerves. Such nerves do contain the sensory fibers subserving muscle pain and static and phasic stretch receptors. Motor nerve compression often causes numbness and stiffness as well as pain. If one nerve alone is involved, then a search for compression usually yields the answer. When multiple named nerves are affected, a mononeuritis multiplex such as that seen in certain collagen vascular diseases, diabetes, and leprosy should be considered. Polyneuropathy

FIG. 5-2. Distribution of pain and temperature loss in Hitzig‘s zones of tabes dorsalis. The arrows indicate the manner of progression. (From Holmes C: Tabes dorsalis. p. 21 5. In Nelson Loose-Leaf Medicine. Vol. 6. Thomas Nelson & Sons, New York, 1920, with permission.)

Symmetric areas of pain and temperature loss known as Hitzig’s zones develop on the abdominal protuberance around the breasts, the extensor surfaces of the forearms, and the anterior tibia1 region, as well as the tip of the nose and malar areas (the mask of Duchenne). This sensory loss is presumed to result from the dorsal root lesions of tabes, but it is of interest that the treponeme of syphilis shares thermosensitivity with Mycobacterium leprae and is also capable of intracutaneous destruction of nerve endings, as evidenced by the numb primary chancre. An argument against a cutaneous origin for all of the disturbances of pain in tabes is the remarkable loss of deep pain sensation. Pressure applied to the Achilles tendons (Abadie’s sign), the testicles, or periosteum does not cause pain. Loss of deep pain sensation in the joints allows the accumulation of painless injuries resulting in Charcot’s joints. Delayed response to pinprick is another singular feature seen in some patients with tabes. Pinpricks given too rapidly could confuse the examiner because the patient might be responding to a pinprick delivered several seconds before.

Functional Loss of Pinprick Sensation Occasionally one encounters a patient with a nonanatomic patch of apparent total analgesia that may be related to hysteria, somatic delusions, or disability-seeking behavior. This can rapidly be sorted out by making a pinprick map on which the return from absent to normal sensation usually occurs across a distinct line, which should be inked in on the patient’s skin. A similar absence of vibration sense across that same ink line, especially at a site where there is underlying bone to widely disperse the vibratory stimulation, reveals the nature of the apparent sensory loss. This

The typical pattern of sensory loss in most sensory or sensorimotor polyneuropathies is distal and symmetric. A stocking-glove sensory loss that features abrupt loss of all modalities at sharply demarcated borders just above the ankles and the wrist is yet another variety of functional sensory loss. The loss of sensation in polyneuropathy is most often related to axonal length, so that “knee socks” are present before the “gloves.” Rather than an abrupt change to normal, there is a broad zone where the sensation on the limbs gradually returns. The greatest intensity of paresthesias and dysesthetic temporal summation is found where the sensory loss gradually fades to normal. This distal loss ultimately can progress to affect proximal limbs, and then the nerves traversing the body wall are involved. A “teardrop” plate of sensory loss appears over the anterior torso (Fig. 5-3). This loss is widest in the lower abdomen because of the obliquity of the nerves and becomes narrower in the upper chest region, where the nerves follow the shorter ribs. This sensory loss may progress across the chest and be mistaken for a spinal sensory level. We have seen patients in whom there is just 10 or 12 cm of sensory sparing on either side of the midline of the back. In cases with dying-back type of neuropathy, sensory loss may be found in the distal branches of the first division of the trigeminal nerve in the posterior scalp. The distance from Gasser’s ganglion out to the most distal reaches of this supply is about 28 cm. With a good sensory witness, the measurement from sensory ganglia to the border of abnormal sensation is constant over the head, torso, and four extremities. A distal symmetric pattern of deficits also emerges with randomly scattered nerve lesions because of the statistical likelihood of accumulating more lesions in longer fibers. This is well known in chronic mononeuritis multiplex from vasculitis; with time the sensory and motor deficits from individual nerves fuse, and the resulting pattern may resemble a diffuse symmetric axon loss type of neuropathy. Only a few clues exist to help the examiner determine that a polyneuropathy is demyelinating, and these clues usually do not come from the sensory examination. Proximal weakness and

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Principles of Ambulatory Neurology and the Approach to C h ical Problems w

n

n

Principles of Diagnosis: Common Presenting Symptoms

directed axons occurs. The first symptoms in such gangliopathies may begin in the face or over the torso and then spread distally, but sometimes the abnormalities appear in a widespread fashion simultaneously in both proximal and distal areas of the body. Proximal Predilection Neuropathy Porphyric neuropathy is an acute process that may be associated with paralysis in the proximal musculature and a sensory loss over the torso and proximal limbs with sparing of the distal extremities. This is reflected by a loss of proximal deep tendon reflexes with a preservation of ankle jerks. One theory on the mechanism for this extraordinary pattern is that an endotoxin is brought back to the cell bodies by suicide retrograde transport, and the cells with shortest axons are injured first, resulting in a progressive proximalto-distal sequence of deficits. Tangier disease may also spare distal sensation. Nerve Roots

widespread loss of reflexes argue for demyelinating rather than axonal neuropathy.

Individual Roots. Nerve root impingement by a herniated disc in the lumbar or cervical spine may cause only tingling paresthesias within its distribution. If there is sensory loss, pinprick is most affected and usually only in a small portion of the dermatome because extensive overlap is a feature of root innervation. Tenderness of the nerve in which the entrapped root travels may indicate severe compression; tenderness along the course of nerves is otherwise a rare feature on physical examination. Sensory Complaints in Cuillain-Bard Syndrome. In some cases of Guillain-Barre syndrome, sensory complaints are very prominent. The distribution of the deficits in this disease varies widely, probably because of individual differences in the bloodbrain, root, and nerve barrier. The distribution of “leakiness” to large immunologically active molecules that attack myelin determines the pattern of lesions. Some patients develop almost all their lesions in the nerve roots, so that proximal and distal sensory complaints (and paralysis) occur from the onset. The disturbance in IA afferents with distortion of kinesthesia may be the cause of the ataxia in the Miller Fisher variant of Guillain-Barrk syndrome.

Sensory Cangliopathies

Spinal Cord Syndromes

In sensory gangliopathies, a clear distal-to-proximal pattern is not present because there is a direct toxic or immune attack on dorsal root ganglia. Large-fiber sensations are most affected, and the patients often are severely handicapped as a result of loss of proprioceptive and kinesthetic input from proximal and distal sources. The ataxia in these disorders is prominent. Widespread areflexia accompanies the loss of position and vibration sense. This constellation may be seen in an acute sensory gangliopathy and the chronic ataxic neuropathy that may be associated with antimyelin-associated glycoprotein antibodies, subacute carcinomatous sensory neuropathy associated with antibodies to dorsal root ganglia antigen, Sjogren’s syndrome, and pyridoxine toxicity. Pyridoxine toxicity illustrates the two possible variations in the basic patterns of sensory loss in the gangliopathies. In experimental models, if the dose of pyridoxine is very large, early necrosis of the dorsal root ganglion cells with secondary degeneration of both the distally directed and centrally directed axons occurs immediately, whereas lower toxic doses allow survival of the dorsal root ganglia cells but prevents them from maintaining axons so that a distal-to-proximal degeneration of the centrally and peripherally

Sensory information undergoes both segregation by modalities and processing upon entering the cord. Substantial constriction of expansion on pinprick responsivity in experimentally isolated dorsal root receptive fields occurs with either selective ablation of the dorsal or ventral part of Lissauer’s tract with application of various pharmacologic agents. Once the sensory information is in the major sensory tracts, then compression by extrinsic lesions of the spinal cord causes clinical symptoms and deficits in the longest fiber systems first, so that paresthesias and sensory loss begin in the feet and gradually ascend to the level of the compressive lesion. A narrow segmental band of ipsilateral multimodal sensory loss caused by involvement of roots or root entry zone may be the only sensory clue to the precise level of a compressive lesion. The segregation of various sensory modalities accounts for several important clinical features in the bedside sensory examination. Because fibers carrying pinprick and temperature sensation decussate within a few segments of entering the spinal cord, the fibers subserving the lowest sacral segments are most superficial, so extrinsic compressive lesions produce early loss of

FIG. 5-3. Advanced distal, symmetric sensory loss in sensory polyneuropathy with sensory loss over the anterior torso in a 43-year-old man with amyloid neuropathy. (From Sabin TD, Ceschwind N, Waxman SG: Patterns of clinical deficits in peripheral nerve disease. p. 433. In Waxman SC (ed): Physiology and Pathobiology of Axons. Raven Press, New York, 1978, with permission.)

Chapter 5

pain and temperature in sacral segments. Intramedullary cord lesions tend to spare these superficial fibers and produce sacral sparing (see Fig. 82-3). Because touch sensation is represented in the ipsilateral dorsal column system and in the crossed spinothalamic system, a careful search for the differential affection of pinprick and temperature versus position and vibration sense often is the key to unraveling spinal cord sensory syndromes. Brown-Siquard Syndrome. With hemisection of the cord, there is an ipsilateral band of loss of all modalities at the level of the lesion caused by destruction of the fibers of all modalities at the root entry zone. Loss of position and vibration sense occurs below the level of the lesion on the same side, but on the opposite side of the body, there is only loss of pinprick and temperature sensation, whereas touch is preserved on both sides (Fig. 5-4). In the full-blown syndrome, ipsilateral upper motor neuron paralysis is present below the level of the lesion. Brown-Skquard syndrome is nearly always present in incomplete form, but subtle variations on this pattern of sensory change are reliable indicators of lesion site. Certain monkey experiments indicate that the crossed pain and temperature loss are caused by a physiologic state that can be abolished if there is complete section of the ventral fimiculus on the side of the hemisection. This lesion actually causes the pain and temperature loss to switch to the ipsilateral side, presumably through disinhibition of the systems serving these modalities. We have not seen an example of this phenomenon in human diseases; however, the fact that the loss of pinprick and temperature sensation lasts only weeks or months after surgical tractotomy points to the physiologic state as a critical factor.

FIG. 5-4. Brown-Skquard syndrome. Hemisection of the spinal cord showing ipsilateral loss of position and vibration sense and crossed 10sof pinprick and temperature senstion below the lesion. (From Sabin TD, Geschwind N: The neurologic examination. p. 38. In Mark VH (ed): Tice's Practice of Surgery (Neurosurgery). Harper & ROW, Hagerstown, PA, 1973, with permission.)

Sensory Loss and Paresthesias

33

FIG- 5-5- Suspended sensory loss. A syrinx has interrupted crossing pain and temperature fibers from C3 to midthoracic levels, but the spinothalamic tracts themselves are spared. (From Sabin TD, Geschwind N: ,The neurologic examination.'p. 39. in Mark VH (ed): Tice's Practice of Surgery (Neurosurgery). Harper & Row, Hagerstown, PA, 1973, with permission.)

Dorsal Columns. The information destined for the dorsal columns passes from the dorsal roots directly into these sensory tracts, resulting in lamination with the sacral areas and feet closest to the midline and the upper cervical segments most laterally. A demyelinating lesion in the center of the dorsal columns therefore will cause intense tingling of the feet, and as the lesion spreads laterally, tinghg in the hands may develop. Such a patient often is misdiagnosed as having a neuropathy, but the preservation of ankle jerks rules this out. The diagnosis of peripheral neuropathy in which large-fiber tinghng is prominent should consistently be associated with loss of deep tendon reflexes because the IA fibers subserving the afferent loop of these reflexes are part of the heavily myelinated group and the ankle jerks rely on the function of only a few of the longest of them. Suspended Sensory Loss. The suspended sensory loss of central cord lesions is the most powerful diagnostic sensory syndrome of the spinal cord. The disruption of the pain and temperature pathways in the anterior white commissure as they cross the cord causes a profound loss of these modalities in all segments so affected (Fig. 5-5). The sensory loss is dissociated because there is excellent preservation of position, touch, and vibration in the areas devoid of pain and temperature sense. The patient will discriminate sharp from dull on the basis of well-preserved discriminative touch alone in the abnormal areas. Reversed dissociated sensory loss is C ~ ~ n i o m Junction. hl one of the sensory syndromes that Occurs With lesions at the junction between spinal cord and medulla. Basilar invagination, odontoid abnormalities, and foramen magnum meningioma are

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

the most common causes. A loss of position and vibration limited to the upper extremities and upper torso is highly diagnostic of compression near the site of the decussation of the medial lemniscus. These patients have pseudochorea in the upper extremities and may demonstrate upper motor neuron findings that are also limited to the upper extremities. Loss of vibration sense over the clavicles is an unusual bedside finding in these patients. Brainstem Syndromes

The dissociation of large- and small-fiber modalities continues in the lower brainstem because the medial lemniscus remains distant from the spinothalamic system until the two converge in the rostra1 brainstem before entering the thalamus. The lateral medullary syndrome with ipsilateral loss of pain and temperature in the face and crossed loss of these sensations over the rest of the body is the most common pattern seen in clinical practice. The medial medullary syndrome with loss of large-fiber modalities and upper motor neuron signs on the opposite side of the body and ipsilateral tongue paralysis is extremely rare. One patient has been described with bilateral small lateral brainstem strokes with a universal loss of pinprick and temperature sensation but preserved deep pain to testicular, periosteal, and tendon pressure. Thalamic Lesions

Lesions of the thalamus are capable of eliminating all modalities of sensation from the opposite side of the body. In this hemisensory loss, there is some sparing near the midline because of bilateral representation of paramedian sites. In the thalamic DejerineRoussy syndrome there usually is a very small lesion; the patient may have minimal signs at time of onset, but over a period of a few weeks, severe spontaneous pain or stimulus-provoked, spreading, intense protopathic pain appears. The pain may be a dull, boring pressure that “explodes” over half of the body. The pain seems to resemble the intense forehead pain caused by eating ice cream too rapidly. This pain can also be imitated by plunging the hand and forearm into ice water. Within a few seconds after the stinging discomfort has disappeared, a severe, boring ache in the shoulder and upper arm appears that rapidly becomes intolerable. One of our patients with a thalamic syndrome had pain provoked by specific kinds of stimulation in all modalities except smell. The taste of salty foods or minimal tactile stimulation provoked the pain. Specific sounds, such as his wife’s ironing, could cause the pain, and each sweep of the iron was associated with a wave of pain over the affected side of the body. This particular patient did not respond to medical treatment but improved after a stereotactic lesion was placed in the centrum medianum of the thalamus.

Principles of Diagnosis: Common Presenting Symptoms

Cortical sensory testing assesses this organization of sensory space. The ability to localize stimuli with the eyes closed using a single index finger and to discriminate between being touched with one or two close points are simple bedside tests for this function. Stimuli that are about 1 mm apart can be detected on the normal fingertips, whereas they may have to be as far as 7 cm apart in areas of the back. An unfolded paper clip is an adequate, inexpensive device for testing two-point discrimination. Dissociation of position from vibration sense is a useful way to tell a cortical from a subcortical lesion. Vibration sense is present with cortical lesions but absent with subcortical and thalamic disorders. An excellent screening device for cortical sensory disorder is graphesthesia. Some normal patients are unable to decipher numbers written on their skin, but if they can do this task, no other cortical sensory disorder is likely. Hemisensory extinction of bilateral touch or pinprick stimuli may be seen with large parietal lesions. The patient reports stimuli only on the side of the body opposite the intact hemisphere with simultaneous stimuli but detects stimuli on each side when stimuli do not occur at the same time. Temporal and spatial summation overcome extinction, and the phenomenon can be tested in several modalities. Proximal over distal extinction also occurs on the same side of the body. Patients with damage to the cortical sensory systems rarely complain of powerful paresthesias unless they are part of a seizure or migraine. Large destructive hemispheric lesions cause the patient to say one side has “gone numb.” Acutely, there is profound sensory loss to all modalities, most severe around the face and distal extremities, with relative preservation of the trunk and proximal limb girdles, roughly reflecting the proportions of sensory cortex subserving these areas. This sensory loss rapidly abates, flaccidity disappears, and spasticity appears. Motor disorders, even when they are “pure,” often result in sensory com-

Cortical Sensory Loss Elementary sensory modalities are elaborated by the cerebral cortex into a much more complex sensory experience that has the qualities of space, weight, form, and texture. There is experimental evidence to support the clinical observations that the regions of cortical sensory representation are not fixed anatomically or “hard-wired” but may fluctuate according to the function of the innervated regions. Monkey experiments show a reallocation of up to 14 mm of the sensory cortex after prolonged peripheral deafferentation.

FIG. 5-6. Area of gross impairment of superficial and deep pain after a penetrating wound affecting the sensory cortex subserving this area. (From Marshall J: Sensory disturbances in cortical wounds with special reference to pain. J Neurol Neurosurg Psychiatry 14:187-204, 1957, with permission.)

Chapter 6

plaints, and surely the limb without normal tone or movement must feel very different, even though sensory pathways apparently are undisturbed according to the usual tests. The feeling that a limb is missing or gone from the body often is associated with anosognosia. This phenomenon can be viewed as the opposite of the phantom limb experience: The patient believes the limb does not exist because brain awareness of it has been ablated. When the limb is amputated, the patient continues to sense its phantom existence because its neural presence remains. There is a paradox regarding pain perception and the sensory cortex: Pain sensation is intact with complete ablation of sensory cortex, but with focal lesions of the sensory cortex, pain loss appears on the opposite side of the body (Fig. 5-6). The muscles in the affected areas showed absent deep pain sensibility when injected with hypertonic saline. This suggests that widespread destruction of the sensory cortices may be necessary to disinhibit the thalamic mechanism needed to bring pain to consciousness. Focal lesions of the second sensory cortex in the parietal operculum may produce a pseudothalamic syndrome with localized spontaneous pain that is more restricted and less severe than in the thalamic Dejerine-Roussy syndrome. Lesions undercutting the sensory association cortex may disconnect cortical pain representation from the limbic system and cause an asymbolia to pain. This seems to be a common but rarely described transient phenomenon in association with conduction aphasia.

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Disorders of the Eyes and Eyelids

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SUGGESTED READINGS Denny-Brown D: The enigma of crossed sensory loss with cord hemisection. pp. 889-895. In Bonica JJ, Chrubosik J, Cusins M (eds): Advances in Pain Research and Therapy. Vol. 3. Raven Press, New York, 1979 Denny-Brown D: The tract of Lissauer in relation to sensory transmission in the dorsal horn of spinal cord in the macaque monkey. J Comp Neurol 151:175-200, 1973 Marshall J: Sensory disturbances in cortical wounds with special reference to pain. J Neurol Neurosurg Psychiatry 14187-204, 1951 Pons TB, Garraghty PE, Ommaya AK et ak Massive cortical reorganization after sensory deafferentation in adult macaques. Science 252:18571860, 1991 Sabin T D Classification of peripheral neuropathy: the long and the short of it. Muscle Nerve 8:711-719, 1986 Sabin T D Temperature-linked sensory loss. A unique pattern in leprosy. Arch Neurol 3:257-262, 1969 Venna N, Sabin TD: Universal dissociated anesthesia due to bilateral brainstem infarcts. Arch Neurol 42:918-922, 1985 Waxman SG, Brill MHY, Geschwind N et ak Probability of conduction deficit as related to fiber length in random-distribution models of peripheral neuropathies. J Neurol Sci 1:39-53, 1976 Weiss JA, White J C Correlation of IA afferent conduction with the ataxia of Fisher syndrome. Muscle Nerve 9327, 1986 Xu Yue, Sladky JT, Brown MJ:Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication. Neurology 39:10771083, 1989

Disorders of the Eyes and Eyelids Grunt T. Liu

Because a significant portion of the nervous system subserves vision, neurologic disorders often present with ophthalmic complaints. Lesions of the visual pathways can produce visual loss, whereas brainstem abnormalities or cranial neuropathies may result in ocular motility disturbances or abnormalities of the pupil or eyelid. The first section of this chapter reviews disorders of the afferent visual pathway, extending from the retina to occipital lobe; later sections deal with motility disturbances, disorders of the pupil, and disorders of the eyelids.

DISORDERS OF THE AFFERENT VISUAL PATHWAYS The afferent visual pathways include the structures responsible for receiving, transmitting, and processing visual information: the eyes, optic nerves, chiasm, tracts and radiations, and the striate cortex. Higher-order processing occurs in visual association areas in extrastriate cortex. This chapter reviews the neuroanatomic features of these structures responsible for vision and describes a framework for diagnosing neurologic disorders affecting the visual pathways.

Neuroanatomy The Eyes. The eyes are the primary sensory organs of the visual system. Before reaching the retina, light travels through the

ocular media, consisting of the cornea, anterior chamber, lens, and vitreous. The size of the pupil, like the aperture of a camera, regulates the amount of light reaching the retina. The cornea and lens focus light rays to produce a clear image on the retina, and the ciliary muscle can change the lens shape to adjust for objects at different distances (accommodation). Retinal photoreceptors hyperpolarize in response to light. Cone photoreceptors are more sensitive to color and are concentrated in the middle of the retina, or macula, the center of which is the fovea. Rod photoreceptors, more important for night vision, predominate in the retinal periphery. Visual information is processed via horizontal, bipolar, and amacrine cells before reaching the ganglion cells, the axons of which make up the innermost portion of the retina and converge to form the optic disk and optic nerve (Fig. 6-1, Plate 6- 1). The optic disk represents the intraocular portion of the optic nerve anterior to the lamina cribrosa. The retina normally is transparent, and the orange-red color visible on funduscopy results from the pigment epithelium and choroidal circulation. The retina nasal to the macula receives visual information from the temporal field, and the temporal retina from the nasal field. The superior and inferior halves of the retina have a similar crossed relationship with respect to lower and upper fields of vision. The ophthalmic artery, a branch of the internal carotid,

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

Principles of Diagnosis: Common PresentingSymptoms

A

Fovea

Macula

B

Vein‘

Arteriole

FIG. 6-1. (A) Normal left fundus. (B) Illustration identifying important structures.

provides most of the blood supply to the eye, although there are external carotid anastomoses. The first major branch of the ophthalmic artery, the central retinal artery, pierces the dura of the optic nerve behind the globe, then travels within the nerve to emerge at the optic disk to supply the inner two thirds of the retina. The ophthalmic artery also gives rise to the posterior ciliary arteries, which supply the optic nerve head, choroid, and outer one third of the retina. Optic Nerve, Chiasm, and Tract The optic nerve has four major portions: intraocular, intraorbital, intracanalicular, and intracranial. Posterior to the lamina cribrosa, optic nerve axons are myelinated by oligodendrocytes similar to those in white matter tracts in the brain and spinal cord. The optic nerves join at the optic chiasm, which lies in the suprasellar region, superior to the diaphragma sella and inferior to

the third ventricle and hypothalamus. At the chiasm, fibers from nasal retina cross, whereas the fibers from temporal retina remain ipsilateral (see Fig. 6-3). Although somewhat controversial, it is thought that the most ventral axons from the inferior nasal retina bend temporarily into the contralateral optic nerve (Wilbrand’s knee). The ratio of crossed to uncrossed fibers is 53% to 47%. Ipsilateral temporal fibers and contralateral nasal fibers join to form the optic tracts. Ceniculocalcarine Pathway. At the lateral geniculate nucleus, a part of the thalamus located above the ambient cistern, the ganglion cell axons in the optic tract synapse with neurons destined to become the optic radiations. This latter structure is divided functionally and anatomically. Fibers coursing through the temporal lobe, called Meyer’s loop, subserve visual information from the lower retina and connect to the inferior bank of the

Chapter 6

calcarine cortex. The parietal portion of the optic radiations relays information from upper retina to the superior bank of the calcarine cortex. Most of the optic radiations derive their blood supply from the middle cerebral artery. The mesial temporal section is supplied in part by branches of the posterior cerebral artery. Striate Cortex. Brodmann area 17 (or V1, primary or striate cortex) is the end organ of the afferent visual system and is located in the calcarine cortex in the occipital lobe. Most of the striate cortex, especially the portion situated posteriorly, is devoted to macular vision. Superior and inferior banks of calcarine cortex subserve contralateral inferior and superior quadrants, respectively. The majority of the occipital lobe is supplied by the posterior cerebral artery with a contribution from the middle cerebral artery in the occipital pole region. Visual Association Areas. Higher processing of visual information occurs, for example, in the lingual and fusiform gyri bordering the inferior calcarine bank in area V4, which is responsible for color vision. In an oversimplification, temporal lobe structures govern visual recognition and memory, whereas parietal lobe areas are responsible for spatial analysis. PatSent History

The temporal profile of the onset of visual loss might suggest a cause, and its monocularity or binocularity aids in localization. In general, acute visual deficits have ischemic or inflammatory causes or may result from a vitreous hemorrhage or retinal detachment. Chronic or progressive visual loss may suggest a compressive, infiltrative, or degenerative process, but cataracts, refractive error, open-angle glaucoma, and retinal disorders such as age-related macular degeneration or diabetic retinopathy also should be considered. Monocular visual loss implies a lesion in one eye or optic nerve, whereas binocular visual loss usually results from involvement of both eyes or optic nerves or of the chiasm, tract, radiations, or occipital lobe. Common complaints associated with visual loss include “blurry vision” or “gray vision.” In addition to these negative symptoms, patients with lesions of the visual pathways may also complain of positive phenomena (e.g., flashing or colored lights [phosphenes],jagged lines, or formed hallucinations). The complexity of the visual images is nonlocalizing.

Examination Patients with visual loss need an accurate assessment of acuity, color vision, visual fields, pupillary reactivity, and funduscopic appearance. If possible, best corrected visual acuity should be tested for each eye: distance vision with a standard Snellen chart and near vision using a handheld card. A pinhole can correct most refractive errors. Acuity can be recorded as 20/30, for instance, where the numerator refers to the distance (in feet) from which the patient sees the letters and the denominator the distance from which a normal patient sees the same letters. Eyes unable to see the largest Snellen letters (20/200 or 20/400) should be graded according to their ability to count fingers (CF), see hand motions (HM), or have light perception (LP). Complete blindness is called no light perception (NLP). Color can be tested with standard pseudoisochromatic Ishihara plates, pigmentbased color vision tests in which the patient is asked to identify

Disorders of the Eyes and Eyelids

37

numbers or geometric shapes on pages of colored dots. Contrast sensitivity testing with sine-wave gratings is a useful adjunct, especially when results are abnormal despite other normal parameters. Precise documentation of visual fields entails threshold perimetry or kinetic testing with a Goldmann perimeter or tangent screen. Because it is shorter and allows interaction with the examiner, the kinetic technique may be more appropriate for screening and for patients with significant neurologic impairment. Threshold computerized perimetry of the central 30 degrees of vision, although sometimes lengthy and tedious, is in many instances a more objective and more reproducible test for patients with optic neuropathies. At the bedside, visual fields can be documented carefully in all four quadrants of each eye using finger confrontation methods by asking the patient to “count fingers” or “tell me when you see the finger wiggling.” Alternatively, a laser pointer directed against a wall may be used for visual field testing. In aphasic, intubated, uncooperative, stuporous, or very young patients, responses such as finger mimicry, pointing to targets presented, visually elicited eye movements, or reflex blink to visual threat can be gross indications of intact visual fields. Subjective hand or color comparison may elicit defects respecting vertical or horizontal meridians. The visual fields of each eye should be examined separately. The posterior pole of the eye can be examined through an undilated pupil with a direct ophthalmoscope. Details of the optic nerve, retinal vasculature, macula, and peripapillary retina should be appreciated. A pharmacologically dilated pupil and indirect ophthalmoscopy are needed for a thorough examination of the retinal periphery. Ocular causes of visual loss such as corneal or lens opacities, retinal detachments, or glaucoma should be excluded by an ophthalmologist. In general, patients with cataracts complain of blurry vision with glare, especially with automobile headlights, and those with glaucoma have peripheral visual field loss but preserved central acuity; the visual loss associated with both of these problems is insidious. Retinal detachments may present acutely with flashes of light, floaters, or peripheral field loss. Ancillary Visual Testing. Electrophysiologic testing such as a visual evoked potential (VEP) or electroretinogram (ERG) can confirm the localization to optic nerve or retina, but these tests should never replace the clinical examination. VEPs measure the cortical activity in response to flash or patterned stimuli and are abnormal in the presence of a lesion in the afferent visual pathway. ERGS, which measure rod and cone photoreceptor function, are particularly helpful in sorting out the retinal dystrophies and degenerations.

Topical Diagnosis

Figure 6-2 illustrates the visual field deficits characteristic of various lesions in the afferent visual pathway. Homonymous defects are those present in both eyes with the same laterality, whereas a hemianopia is loss of one-half of the visual field, respecting the vertical (usually) or horizontal meridian. Congruity is the symmetry of the field defect in both eyes. Information garnered from the patient history and examination, in combination with the neuroanatomic principles outlined earlier, usually is sufficient for localization. The next step is identifymg the pathologic process.

38

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Locst Ion

Principlesof Diagnosis: Common Presenting Symptoms Fleld Detect

LeftEveRiaMEve

Comment

00

No light perception left eye

1

Left OpticNenfe

2

chiasm

Bitemporal hemianopsia

3

RiMOpIicTraci

~nCOtQNOUS left

4

Lefl Lateral Geniculate Nucleus

Right homonymous sedoranopia (lateral choroidal artery)

homonymous hemianopia

-orInCongNOUS right homonymous hemianopia

R

A

5

Left Temporal Lobe

Right homonymous upper quadrant defect (“pie in the sky”)

6

Left Parietal Lobe

Right homonymous defect. denser inferiorly

7

Left Occiplal Lobe (upper bank)

00

Right homonymous lower quadrananopsia (macular sparing)

8

Left Occiplal Lobe (lower bank)

QQ

Right homonymous upper quadrananopsia (macular sparing)

9

Rim Occipital Lobe

B

Left homonymous hemianopia (macular sparing)

FIG. 6-2. Visual pathways: correlation of lesion site and field defect, view of underside of the brain. Homonymous refers to a defect present in both eyes with the same laterality, whereas hemianopia refers to visual loss that respects the vertical meridian. Congruous fields are symmetrical in both eyes. Note that lesions of upper or lower occipital banks produce quadrantic defects, whereas lesions within temporal and parietal lobes cause field defects that tend not to respect the horizontal meridian. (From Kandel E et al: Principles of Neural Science. McCraw-Hill/Appleton & Lange, New York, 2000, p. 437, with permission.)

Clinical Diagnoses by Lesion Site Retina. The vascular and degenerative retinal disorders are important to neurologists because these problems may indicate underlying neurologic disease. Transient monocular blindness (amaurosis fugax) begins typically with a “gray shade” that encroaches on vision superiorly, falls downward, then resolves after seconds or minutes. This symptom is commonly the result of an atheromatous internal carotid lesion that embolizes to the retinal circulation, sometimes producing yellow cholesterol (Hollenhorst) plaques lodging at retinal vascular bifurcations (Plate 6-2). Emboli from calcific cardiac valves can cause similar symptoms but tend to be white. Other causes associated with amaurosis fugax include giant cell arteritis, retinal migraine, vasospasm, and cardiac thromboembolus. After more persistent interruption of blood supply, permanent visual loss may result from a branch or central retinal artery

occlusion with a characteristic funduscopic appearance: a normal optic disk, vessel attenuation, segmentation of the blood column (called “box-carring” of arterial blood flow), retinal edema (pale and opaque), and a macular cherry-red spot (Plate 6-3). The latter results from the visible perfused choroid in the macular region, surrounded by opaque, infarcted ganglion cell axons, which are absent in the macula. Central retinal artery occlusion warrants urgent ophthalmic evaluation and consideration for ocular massage, anterior chamber paracentesis, acetazolamide, or carbon dioxide. Thrombolytic therapy has also been advocated for a subgroup of these patients. Patients with retinal artery occlusion or amaurosis fugax should undergo evaluation of the carotid system first by auscultation to detect bruits, then by ultrasound or magnetic resonance imaging angiography ( M U ) to rule out stenoses; echocardiography, transesophageal in some instances, to exclude a cardiac thrombus, myxoma, patent foramen ovale, or valvular lesion;

Chapter 6 W

Holter monitoring in patients with suspected cardiac arrhythmias such as atrial fibrillation; and in older adults in whom giant cell arteritis should be considered, urgent measurement of the erythrocyte sedimentation rate and C-reactive protein. The retinal examination can aid in the diagnosis of metabolic and energy disorders. A macular cherry-red spot can be seen in Tay-Sachs disease and sialidosis. Pigmentary disturbances are nonspecific but may suggest Hallervorden-Spatz disease, abetalipoproteinemia, neuronal ceroid lipofuscinosis, Refsum’s disease, or mucopolysaccharidosis. Patients with mitochondrial disorders such as Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, and MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) may develop a preferentially macular salt-and-pepper pigmentary retinopathy. Retinal findings in neurocutaneous syndromes (phakomatoses) often are diagnostic. Examples include tapioca-like hamartomas in tuberous sclerosis, capillary angiomas in von Hippel-Lindau disease, retinal arteriovenous malformations in Wyburn-Mason syndrome, and choroidal angiomas in Sturge-Weber syndrome. Optic Nerve. The hallmarks of an optic neuropathy are decreased visual acuity and color vision, unilateral visual field loss, and an afferent pupillary defect. Common field deficits include central, arcuate, and altitudinal scotomas, enlarged blind spots, and constriction. The most common optic neuropathy is glaucoma (elevated intraocular pressure), but the usual causes of optic neuropathies of neurologic importance are inflammation, vascular abnormalities, compression, infection, nutritional deficits, or elevated intracranial pressure. The ophthalmoscopic appearance of a pathologic optic disk depends on the cause and temporal profile of the optic neuropathy. Glaucomatous disks have enlarged cups, but the disk rim has normal color. Optic disk swelling, characterized by hyperemia, nerve fiber layer edema, obscuration of vessels, venous congestion, and peripapillary hemorrhages, usually indicates an acute or subacute process and is the result of axoplasmic stasis secondary to optic nerve injury, elevated intracranial pressure, compression, or infiltration (Plate 6-4). Funduscopy is normal acutely in retrobulbar optic neuropathies, which by definition have no disk swelling, and the pathology presumably is more proximal, away from the optic nerve head. Almost all optic neuropathies, once chronic, manifest with some degree of optic disk pallor, indicating atrophy (Plate 6-5). Optic neuritis is the optic neuropathy most familiar to neurologists. Affected patients typically are young; many have or will develop multiple sclerosis. Visual loss results from inflammatory demyelination of the optic nerve. Although ocular involvement can be simultaneous, patients usually present with acute monocular visual loss with pain exacerbated by eye movements, and two thirds of cases are retrobulbar. Magnetic resonance imaging (MRI) may demonstrate optic nerve enhancement. By 1 year, 95% of patients regain at least 20/40 acuity without treatment, but many still have minor color, visual field, and pupillary abnormalities. Some volunteer Uhthoffs symptom, a transient loss of vision in the previously affected eye during periods of elevated body temperature such as exercise or showering. In previously healthy patients, the Optic Neuritis Treatment Trial demonstrated that pulse intravenous methylprednisolone hastens recovery, but the level of visual function ultimately is similar to that of patients given placebo. Patients given oral prednisone had a higher incidence of recurrent attacks. According to the results from several series, 38% to 71% of patients eventually develop multiple sclerosis, and the risk is highest in

Disorders of the Eyes and Eyelids

39

people with characteristic white matter lesions on MRI at presentation. In the Optic Neuritis Treatment Trial, multiple sclerosis did not develop in any patient with a normal MRI scan who had painless visual loss, severe optic disk edema, disk or peripapillary hemorrhage, or macular exudate. Although less predictive, the following other tests are also associated with the development of multiple sclerosis if positive at the time of the first attack of optic neuritis: cerebrospinal fluid (CSF) oligoclonal bands, increased CSF immunoglobulin G (IgG) synthesis, human leukocyte antigen (HLA)-DR2antigen, and somatosensory evoked potentials. Nonarteritic anterior ischemic optic neuropathy, an idiopathic, presumed vascular insult to the optic nerve head, causes acute, painless loss of acuity and a central scotoma or altitudinal field defect accompanied by disk swelling. In contrast to optic neuritis, the prognosis for visual recovery is poor, affected patients usually are 50 or older, and a cupless optic disk, hypertension, and diabetes are apparent risk factors. In the Ischemic Optic Neuropathy Decompression Trial, approximately one third of patients who received no treatment recovered three or more lines of vision. Approximately one third of patients have subsequent involvement of the fellow eye. There is no effective medical or surgical treatment. In all patients with anterior ischemic optic neuropathy, symptoms of giant cell arteritis (jaw claudication, headache, scalp tenderness, weight loss, fatigue, and polymyalgia rheumatica) should be excluded through careful history taking, and an urgent erythrocyte sedimentation rate and C-reactive protein should be obtained (Plate 6-6). Most patients with arteritic visual loss are more than 60 years old and have systemic symptoms or an elevated sedimentation rate. In my opinion, patients suspected of having visual loss caused by giant cell arteritis should immediately receive high-dose intravenous methylprednisolone without waiting for temporal artery biopsy results. Intravenous corticosteroids may be more effective than oral prednisone in these patients by reducing the risk of fellow eye involvement and increasing the chances for some visual recovery. Histopathologic evidence of active arteritis may be present even up to 7 weeks after initiation of corticosteroids, but most biopsies should be performed within 1 week to ensure the greatest yield. Posterior (retrobulbar) ischemic optic neuropathy is rarely idiopathic and suggests giant cell arteritis, systemic lupus erythematosus, or a compressive lesion. Pseudotumor cerebri (idiopathic intracranial hypertension) should be mentioned here because its major morbidity is visual loss related to optic nerve dysfunction. Patients should satisfy the following (modified Dandy) criteria (see Smith, 1985): signs and symptoms caused by elevated intracranial pressure, normal neurologic examination results except for an abducens palsy, modern neuroimaging (MRI and MRI-venogram, preferably) excluding a mass lesion or other cause of elevated intracranial pressure, and normal CSF parameters, except an elevated opening pressure (more than 250 mm H,O). Patients usually are young, obese women and may complain of headache, transient visual obscurations (seconds), pulsatile intracranial noises, or double vision. Almost uniformly, patients have papilledema (Plates 6-4 and 6-7), and other causes of disk elevation, such as pseudopapilledema (optic nerve drusen) (Plate 6-8) or congenital nerve head elevation, should be excluded. Typically, visual acuity and color are preserved, but optic nerve-related visual field defects, best detected with threshold perimetry, are present in more than 90% of patients and include enlarged blind spots, generalized constriction, and inferior nasal field loss. The modern manage-

40

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

ment of pseudotumor cerebri is based on the severity and progression of visual deficits. Patients with no or mild visual loss should be treated with weight reduction, symptomatic headache therapy, and acetazolamide, whereas those failing medical therapy with severe or progressive visual loss are candidates for optic nerve sheath decompression or lumboperitoneal shunting. Serial lumbar punctures probably have no role in the management of this disorder. Lumboperitoneal shunting can also be performed in patients with headache as their primary symptom and for those

who fail sheath decompression. In rare malignant cases, patients may be refractory to all therapies and develop chronic atrophic papilledema with debilitating visual loss. A detailed review of all optic neuropathies is beyond the scope of this chapter; however, Table 6-1 lists several according to cause and frequency. The list can be overwhelming, but the cause of most optic neuropathies is apparent after eliciting a careful patient history and conducting a thorough examination. Glaucoma, optic neuritis, and ischemic optic neuropathy are the most commonly

TAW 6-1. Optic Neuropathies, According to Cause and Frequency Cause

Common

Uncommon

Compressive

Metastases Canalicular lntraorbital Sellar mass lesions (see Table 6-2) Spheno-orbital meningioma

Congenital disc anomalies

Congenital disc elevation Optic nerve head drusen Optic nerve hypoplasia

Bone dysplasias Carotid-ophthalmic aneurysm Ectatic carotid Nasopharyngeal tumor Orbital mass lesion Arteriovenous malformation Dermoid Hemangioma Lymphangioma Mucocele Venous varix Orbital pseudotumor Paranasal tumor Sinus disease Thyroid eye (Graves’s) disease Coloboma Disk aplasia Megalopapilla Morning glory syndrome Optic nerve pit Adrenoleukodystrophy Charcot-Marie-Tooth Diabetes and deafness Friedreich’s ataxia Kjer‘s dominant optic atrophy Leber‘s hereditary optic neuropathy Metachromatic leukodystrophy Mucopolysaccharidoses Pelizaeus-Metzbacherdisease Recessive optic atrophy Tay-Sachs Cat scratch CIyptococcus Cytomegalovirus Herpes zoster Human immunodeficiency virus? lntraocular nematode infection Lyme disease Orbital cellulitis Syphilis Toxoplasmosis Tuberculosis Carcinomatous meningitis Leukemia Lymphoma Optic nerve metastases Guillain-Barrk syndrome Histiocytosis Neuromyelitis optica Neuroretinitis Optic perineuritis Optochiasmatic arachnoiditis Post-vaccination Sarcoidosis Steroid-responsive perineuritis (pseudotumor variant) Systemic lupus erythematosus Malignant optic nerve glioma

Heredodegenerative

Infectious

Infiltrative

Inflammatory

Acute disseminated encephalomyelitis Optic neuritis

Neoplastic (primary)

Childhood optic nerve glioma Perioptic meningioma Cobalamin (B,J Thiamine (B,) Tobacco or alcohol amblyopia

Nutritional (deficiency)

Jamaican Niacin Table continued on followingpage

Chapter 6 W Disorders of the Eyes and Eyelids

41

TAME6-1. Optic Neuropathies, According to Cause and Frequency Continued Cause

Common

Uncommon

Toxic

Ethambutol Methanol

Vascular

Ischemic optic neuropathy Blood loss Giant cell arteritis Hypotension Nonarteritic Papillophlebitis

Other

Glaucoma Papilledema Pseudotumor cerebri Trauma

Amantadine Amiodarone Arsenic BCNU (intracarotid) Carbon tetrachloride Chloramphenicol Chlorpropamide Ciprofloxacin Cis-platinum Digitalis Disulfiram Ethchlorvynol Ethylene glycol 5-Fluorouracil Hexachlorophene Hydroquinones lsoniazid Lead Penicillamine Quinine Thallium Toluene Vincristine Carotid-cavernous sinus fistula Cataract extraction Diabetic papillopathy Hypotony Migraine Ophthalmic artery occlusion Radiation-induced (delayed) Big blind spot syndrome Uremia

encountered and have characteristic presentations as described, but several other optic neuropathies also have telltale features. Tobacco or alcoholic amblyopia is associated with cecocentral scotomas; Leber’s hereditary optic neuropathy follows a maternal inheritance pattern, usually presents in young men with profound, sometimes sequential visual loss, has a typical fundus picture with pseudo-disk edema and peripapillary telangiectasias, and is associated with specific mitochondrial DNA mutations. Optic nerve gliomas are associated with neurofibromatosis type I. Hereditary, nutritional, and toxic factors usually are evident in the patient history. Progressive visual loss accompanied by optic atrophy implies a compressive lesion, such as aneurysm of tumor. Thin section MRI of the orbits with fat suppression and gadolinium can confirm optic nerve inflammation or establish the cause of a mass lesion. Lumbar puncture with cytology may be necessary in instances of suspected neoplastic infiltration. Optic Chiasm. Temporal field defects respecting the vertical meridian, in either or both eyes, suggest a chiasmal process. Although a bitemporal hemianopsia is classic, the actual pattern of field loss depends on the chiasm’s position and the exact location of the culprit lesion (Fig. 6-3). If the chiasm is postfixed or in the lesion affects the anterior portion of the chiasm, patients may present with an optic neuropathy or a junctional scotoma resulting from involvement of the ipsilateral optic nerve and Wilbrand’s knee. Central hemianopic scotomas or optic tract syndromes may be the product of prefixed chiasms or more posteriorly situated lesions. Patients with chiasmal field loss often are without visual complaints unless acuity is abnormal, and a temporal field defect

may not be apparent until the patient reads only the nasal half of the acuity chart. Rarely, others may complain of double vision caused by an inability to align the noncorresponding nasal visual fields of each eye (hemifield slide phenomenon). Color vision may be altered only in defective fields, and asymmetrical lesions may produce an afferent pupillary defect. Lesions solely of the chiasm rarely cause optic disk swelling without third ventricular compression, but chronic processes may lead to optic atrophy. Seesaw nystagmus can occur in association with sellar lesions, and the presence of ocular motor palsies suggests cavernous sinus involvement (see “Disorders of Eye Movements” later in this chapter). Chiasmal syndromes usually are caused by sellar and suprasellar compressive masses (Fig. 6-4), and this differential diagnosis is best considered according to the patient’s age because many lesions are congenital (Table 6-2). Historical evidence of pituitary dysfunction, such as galactorrhea, hypothyroidism, amenorrhea, decreased libido, hypogonadism, hypoadrenalism, hypercortisolism (Cushing’s syndrome), or acromegaly, should be investigated. Hypothalamic involvement may manifest with diabetes insipidus, feeding disorders, temperature dysregulation, precocious puberty, or Russell’s diencephalic syndrome (hyperkinesis, euphoria, and emaciation). Visual loss in these instances is insidious, and medical or surgical decompression may result in partial or complete visual recovery, especially in patients without optic atrophy. Most processes that cause optic neuropathies, especially the infectious, infiltrative, and inflammatory ones (Table 6-1), can also affect the chiasm. Congenital malformation and vascular infarction of the chiasm are uncommon but can occur. MRI of the sellar region, especially with coronal and sagittal

42

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

Locatlon

Field Defect WLEYB l3ulhLW

1

RightOpticNerve

2

Junction of Right Optic Nerve and Chiasm

3

c m

4

Posterior Chiasm

5

LeftOptiiTraU

Comment

0 Central blemporal hemianopic scotomas

0

kICOI‘QrUOUS

right

homonymous hemianopia

FIG. 6-3.Optic chiasm: correlation of lesion site and field defect. Note that the most ventral nasal fibers (mostly from inferior nasal retina) temporarily travel within the fellow optic newe in Wilbrand‘s knee. (Adapted from Hoyt WF, Luis 0: The primate chiasm: details of visual fiber organization studied by silver impregnation techniques. Arch Ophthalmol 70:69-85,1963,with permission.)

thin sections, is the neuroimaging procedure of choice in this setting. Computed tomographic (CT) scanning, by demonstrating calcification associated with craniopharyngiomas or bony erosion caused by a meningioma, may be complementary. Mass lesions in this region obviously necessitate endocrine and neurosurgical evaluation. Optic Tract and lateral Ceniculate Body. Isolated syndromes of the optic tract and lateral geniculate body are suggested by incongruous homonymous hemianopias. Complete lesions of the tract or geniculate lead to complete homonymous hemianopias, however. Optic tract lesions may be associated with asymmetrically impaired visual acuity (usually worse in the eye ipsilateral to the lesion) and a contralateral afferent pupillary defect. Extremely rare pupillary findings include contralateral mydriasis (Behr’s pupil) and hemianopic pupillary reactivity (Wernicke’s pupil; see “Disorders of the Pupils” later in this chapter). Because of presynaptic interruption, patients may have bilateral optic atrophy with ipsilateral temporal pallor and

contralateral “bow tie” or “band” atrophy. As stated previously, sellar and parasellar masses, especially craniopharyngiomas and aneurysms, may involve the tract. Isolated tract syndromes may also result from demyelination. Clinically, lateral geniculate and tract syndromes may be difficult to distinguish. The unique exceptions are related to the geniculate’s dual vascular supply. A posterior choroidal artery infarction causes a congruous homonymous horizontal wedgeshaped sectoranopia, and an anterior choroidal artery syndrome leads to upper and lower homonymous sectoranopias. There should be no afferent pupillary defect with a pure geniculate lesion (see “Disorders of the Pupils” later in this chapter). Optic Radiations. Interruption of Meyer’s loop classically causes congruous or incongruous contralateral homonymous field defects denser superiorly (“pie in the sky”), whereas high parietal lesions are associated with deficits more prominent inferiorly. In reality, there is wide variation, and complete disruption of the optic radiations leads to a dense homonymous hemianopia (Fig.

Chapter 6

6-5). Visual acuity is normal in unilateral cases but may be

abnormal with bilateral lesions. The pupils always react normally in acquired lesions posterior to the optic tract. Hemianopias caused by lesions of the radiations usually have additional lateralizing and localizing signs. Temporal lobe lesions may lead to personality changes and complex partial seizures or fluent aphasias if the left side is involved, and the usual cause is neoplastic, such as a low-grade glioma. Left neglect accompanying a left hemianopia implies a right parietal lesion, whereas aphasias suggest a left-sided process. A homonymous field defect accompanied by ipsilateral sensory loss, astereognosis, or graphesthesia implies a parietal localization, whereas one associated with a dense ipsilateral hemiparesis involving face, arm, and leg might suggest a more deep-seated lesion with involvement of the internal capsule.

Disorders of the Eyes and Eyelids

43

Patients with hemianopias caused by parietal lesions have abnormal pursuit and optokinetic responses when stripes or objects are drawn toward the side of the lesion, indicating concurrent involvement of deep, descending parieto-occipital pursuit fibers. Parietal mass lesions can be distinguished from middle cerebral artery occlusion by a more insidious course, history of headache, and papilledema. Occipital lobe. Unilateral striate cortex lesions, most commonly caused by vascular insult or mass lesion, produce congruous homonymous hemianopias respecting the vertical meridian, and processes preferentially affecting upper or lower banks of calcarine cortex lead to quadrantic field defects. Altitudinal hemianopias with respect to the horizontal meridian are the result of bilateral upper or lower bank disturbances. Patients may

A

FIG. 6-4. (A) T I -weighted MRI, coronal view, demonstrating a craniopharyngioma (curved arrow), with homogeneous high-signal characteristics, compressing the optic chiasm (straight arrow). (6) Goldmann visual fields of the same patient, demonstrating a bitemporal hemianopsia resulting from chiasmal compression.

44 W TABLE 6-2.

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

Sellar and Suprasellar Compressive Lesions According to Age Group, Cause, and Frequency

Axe croup

More Common

Less Common

Pediatricyoung adult

Chiasmal-hypothalamic glioma Craniopharyngioma

Middle age-older adult

Aneurysm (internal carotid) Craniopharyngioma Meningioma Pituitary adenoma Pituitary apoplexy

Arachnoid cyst Arteriovenous malformation Choristomas Dermoid Empty sella syndrome Epidermoid Ganglioglioma Germ cell tumors Choriocarcinoma Embryonal carcinoma Endodermal sinus tumor Cerminoma Teratoma Pituitary adenoma Rathke‘s pouch cyst Malignant optic glioma Metastases to chiasm, sella, or suprasellar region Sphenoethmoidal mucocele Histiocytosis L p p h o m c hypophysitis Meningitis Bacterial Tuberculous Sarcoidosis

No particular age

complain of blurry vision in the defective field as if they were looking through water or smoked glass. Others may be unaware of their deficit until they have a car accident or family members notice the patient bumping into household objects. Posterior cerebral artery occlusions may not involve the occipital pole, which also receives distal branches from the middle cerebral artery, thereby sparing macular vision. Bilateral cortical representation of the macula may also account for some instances of sparing. Acuity and color vision are unaffected with unilateral occipital injury and are diminished only after bilateral geniculocalcarine lesions. A variable but characteristictemporal crescent in the unpaired 60- to 90-degree field of the eye ipsilateral to the hemianopia results from preservation of the anterior portion of the striate cortex, which subserves only the temporal vision of the contralateral eye. Homonymous hemianopic central scotomas also localize almost exclusively to a unilateral occipital lobe lesion. Patients may have a gaze preference away from the hemianopia, and the optokinetic response is normal in the setting of occipital lobe infarction and abnormal with occipital mass lesions with edema extending into the parietal lobe (Cogan’s rule). Occipital stroke-related hemianopias usually are isolated unless proximal posterior cerebral artery occlusion causes an ipsilateral hemiparesis, third-nerve palsy, or ataxia from mesencephalic infarction, or memory or personality changes from mesial-temporalor thalamic involvement. Bilateral posterior cerebral artery occlusion may result in tunnel fields with preservation of central vision only, but often bilateral processes lead to cortical blindness. Such patients have no reflex blink to threat or optokinetic response, and their intact pupitlary light responses distinguish them from those with bilateral optic nerve involvement. Cortically blind patients with Anton syndrome confabulate and deny their blindness, in some

instances because additional cerebral lesions have altered memory, recognition, and behavior. Positive visual phenomena, such as colored shapes, people, or objects, may occur within the blind field, or visual images may persist (palinopsia). Constant visual hallucinations typically are “release” phenomena, whereas those that are episodic usually represent irritative (convulsive) foci. Other unique and unusual features after occipital lobe injury include the recovery of motion perception, called the Riddoch phenomenon, and blindsight, which is unconscious vision in the blind hemifield. Both of these may in part represent the residual capacities of a “second,” more primitive retinal-tectal-pulvinar subcortical, extrastriate visual pathway. Headaches preceded by transient hemianopic phenomena, with or without scintillationsor phosphenes, usually indicate migraine. Some patients may present only with the visual prodrome, without the headache, in so-called acephalgic migraine. Rarely, patients with complicated migraine may develop occipital lobe infarction and fixed hemianopic defects. Other causes should be entertained in the differential diagnosis of occipital lobe dysfunction. Posterior cerebral artery infarction may occur in the setting of transtentorial herniation. Hypertensive encephalopathy or eclampsia may cause transient hemianopias or cortical blindness. In older adults, Alzheimer’s disease should be considered, and in this age group, posteriorly situated hemorrhages are uncommon secondary to long-standing hypertension and instead should suggest amyloid angiopathy. Infectious causes include abscesses, progressive multifocal leukoencephalopathy, and Creutzfeldt-Jakob disease. In children, meningoencephalitis, MELAS, and adrenal leukodystrophy should be considered. Postictal hernianopias are uncommon. In patients with permanent, dense hemianopias as their only neurologic deficit, I have attempted adaptive hemianopic Fresnel paste-on prisms with limited success. Higher Cortical Lesions. With involvement of visual association areas, patients may have additional visual symptoms unexplained by field deficits. Although subjective complaints usually are vague (“blurry” or “I’m having trouble seeing”),many are easily characterized after further investigation. Inferior occipital lobe injury involving lingual and fusiform gyri may result in a contralateral homonymous upper quadrantanopsia and defective color vision in the otherwise intact inferior quadrant (cerebral hemiachromatopsia). Patients with a left-sided lesion and coinvolvement of the splenium of the corpus callosum or adjacent periventricular white matter may develop alexia without agraphia (or pure alexia or “word blindness”), a disconnection syndrome characterized by a right homonymous field deficit and an inability to access lexical visual information processed in the right occipital lobe. Inability to recognize visualized objects (visual agnosia) despite a normal afferent pathway often suggests bilateral medial occipitotemporal lesions disrupting the inferior longitudinal fasciculus, a white matter pathway connecting striate cortex with visual association areas in temporal lobe. Prosopagnosia, resulting from similar lesions or damage directly to the fusiform face areas in this region, is a dramatic visual agnosia for faces only. Recent evidence has demonstrated that lateral occipitotemporal lesions affecting Brodmann area 39 (area V5), believed to be analogous to monkey area MT, may result in defective motion perception. Right hemispheric lesions, especially those involving the inferior parietal lobule, may result in neglect or inattention to

Chapter 6

Disorders of the Eyes and Eyelids

4s

A

FIG. 6-5. (A) T I -weighted MRI with gadolinium, axial view, demonstrating a contrast-enhancing parietal lobe anaplastic glioma (arrow) with mass effect and surrounding edema. (B) Coldmann visual fields of the same patient, demonstrating a left homonymous hemianopia caused by interruption of the optic radiations.

visual, tactile, and auditory stimuli in left hemispace, dressing and constructional apraxia, or spatial disorientation. Hemineglect can be present even without visual field deficits. The degree of visual inattention varies from dense neglect of all stimuli on one side to subtle instances in which the patient is able to detect objects in left and right fields if shown separately but ignores the ones on the left when presented bilaterally (double simultaneous stimulation). Balint’s syndrome consists of ocular apraxia (a deficit in shifting gaze), optic ataxia (a defect in reaching under visual guidance), and simultanagnosia (an inability to perceive a whole scene in its entirety, or visual disorientation). The deficits, which sometimes include absent blink to threat, may reflect bilaterally defective visual attention because the culprit lesions typically are

bilateral occipitoparietalin the areas important for visual attention and foveal refixation. The accompanyingvisual field defect usually is inferior and altitudinal, but sometimes the fields are normal. The usual cause is watershed infarction in the setting of hypoperfusion after cardiac or respiratory arrest, but patients with Alzheimer’s disease may also present with complex visual disturbances consisting of any or all of the elements of Balint’s syndrome. Functional Wsual Loss. Clinicians should always be wary about functional (hysterical) visual loss when there is a mismatch between the patient’s complaints and the examination results or when the visual loss is nonphysiologic. Examples of the latter include monocular temporal field loss that persists binocularly or

46

Principles of Ambulatoy Neurology and the Approach to Clinical Problems rn Principles of Diagnosis: Common PresentingSymptoms

constricted visual fields on tangent screen testing that fail to expand physiologically when the patient is moved from 1 to 2 m away from the screen and the target size is doubled (tubular fields). Mismatches include complaints of no light perception in one eye and normal vision in the other with normal stereo vision or without an afferent pupillary defect in the supposed defective eye. An optokinetic response in a patient claiming blindness is also evidence of a functional disorder. DISORDERS OF EYE MOVEMENTS Eye movements facilitate refoveation and maintenance of visual fixation. Diagnostically, it is easiest to consider ocular motility disorders in two major groups: those that are primarily ophthalmoparetic, with impairment of eye movements, and those that are characterized by nystagmus or inappropriate saccades (too little versus too much). With this framework in mind, this section reviews history-taking, examination techniques, and the diagnosis of important eye movement abnormalities encountered in neurologic practice.

Patrent Histoy Patients with ophthalmoparesis usually have double vision (diplopia), but other common complaints include blurry vision, dizziness (dysequilibrium), and an inability to focus. Those with chronic and symmetrical processes, and others with dysconjugate eye movements but poor vision, complete unilateral ptosis, or long-standing suppression of one eye (amblyopia), may not have any visual complaints. Patients should be asked whether the diplopia is binocular because monocular double vision usually suggests refractive error, conversion disorder, or, in rare instances, cerebral dysfunction. Two other questions will help isolate the involved muscle: Is the diplopia vertical, often implying a vertical rectus or oblique dysfunction, or horizontal, usually suggesting medial or lateral rectus impairment? Is the diplopia worse in any cardinal position of gaze? The double vision should be maximal in the direction of action of the paretic muscle. For instance, horizontal binocular diplopia that is worse in left gaze and at distance suggests left lateral rectus dysfunction. The temporal profile and accompanying symptoms often suggest cause and localization. A history of acute, painful diplopia can be consistent with a vasculopathic cranial mononeuropathy, orbital process, or cavernous sinus lesion. Insidious painless diplopia in association with other bulbar signs such as hoarseness or dysphagia may indicate a chronic meningitis or myasthenia gravis. However, the latter often produces ptosis and fluctuating symptoms with diurnal variation. Sudden diplopia with ataxia, dysarthria, dysphagia, or vertigo usually indicates a brainstem process such as demyelination or vascular infarction; posterior fossa masses with similar symptoms usually are accompanied by headache, nausea and vomiting, and papilledema caused by fourth ventricular compression and noncommunicating hydrocephalus. Patients with nystagmus or inappropriate saccades often complain of dizziness (vertigo) or may experience the illusion of environmental motion (oscillopsia).

Examination The ocular motility examination consists of observation in primary gaze, evaluation of ductions and vergences, then detection of misalignment.

The presence of any obvious ocular misalignment or abnormal, spontaneous eye movements should be assessed first in primary gaze while the patient fixates on a distant target. An esotropia means one eye is deviated inward relative to the other, whereas an exotropia is one eye deviated outward relative to the other. Any vertical misalignment is described by the laterality of the higher eye (e.g., a left hypertropia indicates that the left eye is higher than the right). Adjunctive observations should include the presence or absence of head turn or tilt, pupillary reactivity, examination of the eyelids, palpebral fissures, and orbicularis oculi and relative proptosis either by inspection or quantitatively by Hertel exophthalmometry. Ductions are monocular eye movements, and lateral rotations are called abduction, medial rotations are called adduction, upward rotations are called elevation, and downward rotations are called depression. Ductions can be tested by having the patient voluntarily direct gaze in the cardinal fields (up and right, up, up and left, right, left, down and right, down, and down and left). Limitation of eye movement despite pushing on the globe with a cotton-tipped swab (at the limbus after instillation of a topical anesthetic agent) suggests mechanical restriction (positive forced duction test). An intact Bell's phenomenon, the upward rotation of the globe elicited by having patients try to close their eyes while the examiner holds the lids open, indicates intact nuclear and infranuclear oculomotor nerve function for upgaze. Vergences are binocular eye movements. Convergence can be evaluated by having patients look at their thumb or other accommodative target as it approaches their nose, and both eyes should adduct with pupillary constriction. Pursuit movements should then be tested by having the patients keep the head still and visually track a target moved horizontally or vertically. The speed and accuracy of saccades, which are high-velocity conjugate eye movements, should be examined by asking the patient to look eccentrically then quickly refixate on a target in primary gaze (the examiner's nose, for instance). Optokinetic nystagmus can be elicited by rotating a striped drum or moving a striped tape horizontally and vertically and asking the patient to count the stripes as they go by. The slow phases of optokinetic nystagmus are generated as the patient follows a target; the optokinetic nystagmus fast phase is a corrective saccade to view the next target. Oculocephalic responses can be evaluated by having the patient fix on a stationary target while the examiner gently rotates the head and extends and flexes the neck. The stimulus is from proprioceptive afferents in the neck or the vestibular system. In addition, with an arm extended and the chair rotated, most patients should be able to maintain visual fixation on their thumb; difficulty with this task suggests an inability to suppress the vestibulo-ocular response. When rotated around the examiner, infants, normally with poor fixation, manifest a vestibulo-ocular response with tonic eye deviation toward the direction of rotation followed by quick corrective jerks. The vestibulo-ocular response can be tested in comatose patients by cold caloric stimulation with ice water injected into an ear. Ophthalmoparesis often is evident on evaluation of ductions alone; however, more subtle instances of misalignment may necessitate cover or Maddox rod testing. While the patient fixates on a target in distance, any refixation movement of the fellow eye after monocular occlusion confirms a tropia (Fig. 6-6). An outward movement of the uncovered eye signifies esotropia, an inward movement implies exotropia, and a downward movement indicates hypertropia. In the absence of a tropia, alternately covering each eye breaks binocular fusion and can reveal a latent phoria.

Chapter 6

Esotropia

Disorders of the Eyes and Eyelids

47

Hypertropia

Exotropia

/

/

FIG. 6-6. Cover testing for ocular misalignment. In each case, the patient is fixing with the nonparetic right eye. Upon occlusion of the right eye, the misaligned left eye is forced to fixate. Esotropic eyes move laterally to fixate, whereas exotropic eyes move medially and hypertropic eyes move downward to fixate. Therefore, ocular deviations can be determined by the direction of the fixation movements.

No horizontal deviation

\

Esodeviation

Exodeviation

I 0

-0-

'I'

No veltical deviation

-

Right hyperdeviation

Left hyperdeviation

\I0

-0-

\I0

'I'

-0)I'

\I0

-0)I\

FIG. 6-7. Maddox rod testing for ocular misalignment. By convention, the Maddox rod is always placed over the right eye, and the patient is asked to fixate on a distant, bright white light. A binocular patient's right eye sees a red line, whereas the uncovered left eye sees the white light The illustrations on the right are drawn from the patient's perspective. Top row: To evaluate horizontal ocular deviations, the bars on the Maddox rod are aligned horizontally, so the patient sees a vertical red line with the right eye. If there is no horizontal deviation, the patient perceives the red line passing through the white light. If the eyes are esodeviated, the red line, whose image would abnormally fall on the nasal retina, appears to the right of the white light ("uncrossed diplopia"). Exodeviated eyes result in the red line appearing to the left of the light ("crossed diplopia") because the red image would abnormally fall on temporal retina. Bottom row: To evaluate vertical deviations, the bars on the Maddox rod should be oriented vertically, so the patient sees a horizontal red line with the right eye. The red line passes through the white light when there is no vertical deviation, whereas a red line perceived below the light implies a right hyperdeviation, and a white light perceived below the red line indicates a left hyperdeviation (i.e., the lower image corresponds to the hyperdeviatedeye). This test characterizes the ocular misalignment but by itself it does not indicate which eye has the abnormal motility.

The Maddox rod (Fig. 6-7), containing parallel half-cylinders, can help detect small deviations but by itself does not identify the paretic eye. If misalignment is detected, the direction of gaze that produces the greatest separation between images should be determined by moving the fixation light in the cardinal positions. Vertical deviations should also be evaluated with the head tilted toward the right and left shoulders.

Ophthalmopamis In a logical, hierarchic control of eye movements, the supranuclear centers in the cortex and brainstem (see Fig. 6-14) direct the three ocular motor cranial nerves (111, IV, and VI), which in turn innervate the six extraocular muscles of each eye (Fig. 6-8). Supranuclear and nuclear structures have additional vestibular, cerebellar, and basal ganglia input.

48

Principles of Ambulatoy Neurologyand the Approach to Clinical Problems

Principles of Diagnosis: Common Presenting Symptoms

FIG. 6-8. Oculomotor nuclear complex and innervation of the extraocular muscles. Note that the central caudal nucleus (CCN) supplies both lid levaton, and the superior rectus subnucleus (SR) and superior oblique nucleus (SO) innervate the contralateral muscle. Other oculomotor subnuclei: E-W, Edinger-Westphal; 10, inferior oblique; IR, inferior rectus; and MR, medial rectus. LR, lateral rectus nucleus. (From Claser JS, Bachynski B: lnfranuclear disorders of eye movement. p. 407. In Claser JS (ed): Neuro-ophthalmology. 3rd Ed. Lippincott, Williams & Wilkins, Philadelphia, 1999; adapted from Wamick R: Representationof the extra-ocular muscles in the oculomotor nuclei of the monkey. J Comp Neurol98:449-495, 1953, with permission.)

A

E

CD

FIG. 6-9. Complete left fascicular third-nerve palsy caused by mesencephalic infarction. The left eye has (A) complete ptosis, (B) defective upgaze, (C) absent adduction, (0) a down and out position in primary gaze with a large, unreactive pupil, (€) intact abduction, and (9deficient downgaze.

The oculomotor nerve (111) activates the medial rectus (adduction), inferior rectus (depression),and superior rectus and inferior oblique (elevation) muscles, as well as the pupillary sphincter muscle (constriction) and levator palpebrae of the upper lid (Fig. 6-8). A complete, isolated infranuclear third-nerve palsy causes ipsilateral elevation, adduction, and depression weakness, accompanied by abduction, hypodeviation, pupillary mydriasis, and ptosis (Fig. 6-9).

The trochlear nerve (IV) supplies the superior oblique muscle, which intorts the eye and depresses it in adduction. Patients with superior oblique paresis complain of vertical diplopia, often with a torsional component, and they have an ipsilateral hypertropia worse on contraversive (contralateral conjugate) horizontal gaze and ipsilateral head tilt (Parks’s three-step test, best demonstrated with alternate cover or Maddox rod testing; Fig. 6-10). The abducens nerve (VI) innervates the lateral rectus muscle,

PLATE 6-1. Normal left fundus (see Fig. 7-1).

PLATE 6-2. View of the retina and retinal vessels in the left eye supratemporal to the optic disc. Four Hollenhorst plaques, seen as shiny yellow lesions at arterial bifurcations, can be seen. This patient had a left internal carotid artery occlusion.

PLATE 6-5. Central retinal artery occlusion with opaque retinal edema, macular cherry-red spot, and arteriolar attenuation. (Courtesy of Steven L. Caletta, M.D.)

PLATE 6-4. Acute papilledema due to pseudotumor cerebri (left eye). Note peripapillary hemorrhages superiorly and infratemporally, disc hyperemia, venous tortuosity, and obscuration of vessels at the disc margin owing to newe fiber layer elevation. The round light area in the upper right of the plate is a photographic artifact.

PLATE 6-5. Optic disc pallor several months after nonarteritic ischemic optic neuropathy.

PLATE 6-6. Pallid disc swelling of anterior ischemic optic neuropathy owing to giant cell arteritis (20/200 vision). Note the peripapillaly hemorrhage superiorly.

PLATE 6-7. Chronic papilledema ("champagne cork" appearance) owing to pseudotumor cerebri. Note whitish exudate overlying the disc as well as venous dilation and tortuosity.

PLATL 6-8.Pseudopapilledemacaused by optic newe head drusen.

Chapter 6

which abducts the eye. Patients with a lateral rectus palsy complain of binocular horizontal double vision worse on ipsiversive gaze and at a distance. In many cases, the limitation of abduction is evident (Fig. 6-1 I), but in more subtle instances, alternate cover or Maddox rod testing would confirm an esotropia largest on ipsiversive gaze. In adults, the most common identifiable cause of acquired third- and sixth-nerve palsies is vascular insufficiency caused by diabetes, hypertension, or atherosclerosis. The most common identifiable cause of a fourth-nerve palsy is head trauma. However, not infrequently, the cause of an isolated single ocular motor palsy is undetermined. In children, common causes of acquired third-, fourth-, and sixth-nerve palsies are trauma and neoplasms (Table 6-3). In all age groups, when the ocular motor palsies occur in combination, a cause is almost always identified.

49

Disorders of the Eyes and Eyelids

Often, the ophthalmoparesis and abnormal motility pattern are characteristic, but historical features or accompanying neurologic findings often aid in localization and diagnosis. Nuclear and lnfranuclear Disorders in the Brainstem. The oculomotor complex lies within the mesencephalic periaqueductal gray matter, and unique features include the central caudal subnucleus, which subserves bilateral levator function, and the superior rectus subnuclei, which each innervate the contralateral superior rectus muscle (Fig. 6-8). A unilateral lesion of the third-nerve nucleus therefore results in bilateral ptosis worse ipsilaterally, ipsilateral mydriasis, ipsilateral palsy of the medial rectus, inferior rectus and inferior oblique muscles, and bilateral superior rectus palsies. Lesions of the midbrain tegmentum can affect the oculomotor nerve fascicles as they travel ventrally, often with crossed neuro-

A

D

C

E

F

FIG. 6-10. Traumatic left fourth-nerve palsy, three-step test: (A) right gaze, (6) primary gaze, (C) left gaze, (0)right head tilt, (E) left head tilt, and (0preference for a right head turn (left gaze) and right head tilt, which minimizes the patient's vertical diplopia. Step 1: Which eye is hypertropic? (left; see 6).Step 2: Is hypertropia worse in left or right gaze? (right; compare A and 0.Step 3: Is hypertropia worse in left or right head tilt?(left; compare D and IF). The left hypertropia, which is worse in right gaze and left head tilt, is consistent with weakness of the left superior oblique muscle.

50

Principles of Ambulatory Neurology and the Approach to Clinical Problems

A

B

C

FIG. 6-1 1. Left sixth-nerve palsy caused by obstructive hydrocephalus with intracranial hypertension: (A) normal right gaze, (s) normal primaly gaze, (C) defective abduction of the left eye.

Principles of Diagnosis: Common PresentingSymptoms

logic signs. Involvement of the fascicle as it passes through the crossing dentatorubrothalamic fibers produces an ipsilateral oculomotor palsy and contralateral ataxia (Claude’s syndrome). A lesion of the cerebral peduncle results in ipsilateral oculomotor palsy and contralateral hemiparesis (Weber’s syndrome), and a larger process also involving the red nucleus can cause the same findings plus contralateral involuntary limb movements or tremor (Benedikt’s syndrome). The usual cause of a nuclear or fascicular oculomotor palsy is infarction in the territory of a mesencephalic paramedian penetrating vessel arising from the proximal posterior cerebral artery, but other causes include metastatic tumors and abscesses. The trochlear nucleus lies ventral to the aqueduct in the pontomesencephalic junction, caudal to the oculomotor complex. Fourth-nerve axons decussate near the roof of the aqueduct and exit the brainstem dorsally just beneath the inferior colliculi to innervate the contralateral superior oblique muscle. Lesions involving the decussation (anterior medullary vellum), usually the result of trauma, characteristically cause bilateral fourth nerve palsies. The abducens nucleus lies immediately ventral to the genu of the facial nerve (facial colliculus in dorsal pons), and the fascicles travel ventrally before exiting the pons. The nucleus also gives rise to fibers that ascend within the medial longitudinal fasciculus to reach the contralateral medial rectus subnucleus in the mesencephalon. Thus, a lesion in the region of the sixth-nerve nucleus would result in an ipsiversive conjugate gaze palsy and ipsilateral facial weakness. A lesion of the caudal ventral pons involving the abducens fascicle and corticospinal tract would result in a lateral rectus palsy and a contralateral hemiparesis (Raymond’s syn-

TABU 6-3.Causes of Acquired Third-, Fourth-, and Sixth-Nerve Palsies According to Frequency and Age Croupa c4umoaoc

h u b

Newe Palw

Cause

Cranial nerve 111

Undetermined Vascular Head trauma Aneurysm NeopIasm Other

23.1 20.7 16.2 13.8 11.7 14.5

Cranial nerve IV

Undetermined Head trauma Vascular NeopIasm Aneurysm Other

36.0 32.0 18.6 4.1 1.7 7.6

Cranial nerve VI

Undetermined Vascular Head trauma NeopIasm Aneurysm Other

29.6 17.7 16.7 14.6 3.6 17.9

Multiple (any combination of cranial nerve 111, IV, or VI)

Neoplasm Head trauma Aneurysm Undetermined Vascular Other

34.4 21.0 10.9 8.4

46

5.0 20.2

CaUH

Trauma Undetermined Neoplasm Ophthalmoplegic migraine Surgical.. Meningitis Other Trauma Undetermined Hydrocephalus Meningitis Neoplasm Surgical Other Trauma Neoplasm Undetermined Viral infection Hydrocephalus Meningitis Surgical Other Trauma Neoplasm Aneurysm Surgical Meningitis Other

Vascular refers to associated diabetes mellitus, hypertension, or atherosclerosis. bData from Rush JA, Younge BR: Paralysis of cranial nerves 111, IV, and VI. Arch Ophthalmol 99:76-79. 1981. ‘Data from Kodsi SR. Younge BR: Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 114:568-574, 1992.

%

40.0 17.1 14.3 8.6 8.6 2.9 8.6 36.8 21.1 10.5 5.3 5.3 5.3 15.8 42.0 20.5 14.8 3.4 2.3 2.3 1.1 13.6 55.6 16.7 11.1 5.6 5.6 5.6

Chapter 6 w

drome). Embolic or thrombotic occlusion of paramedian penetrating branches of the basilar artery is the usual cause of disturbances in these areas, but demyelination, vascular malformations, and metastases should also be considered. Mobius’s syndrome is characterized by a congenital bifacial paresis caused in part by agenesis, malformation, or injury to the facial nerve nuclei. Often the sixth nerve nuclei are also affected, resulting in defective horizontal eye movements. In Duane’s retraction syndrome, an abduction deficit is accompanied by ipsilateral globe retraction and narrowing of the palpebral fissure during adduction, and in one autopsy case, the oculomotor nerve anomalously innervated the lateral rectus muscle. In amyotrophic lateral sclerosis and the spinal muscle atrophies, the nuclei of the ocular motor nerves usually are spared. lnfranuclear Disorders: Subarachnoid Space, Cavernous Sinus, and Orbital Apex. The three ocular motor nerves traverse

the subarachnoid space at the skull base before reaching the cavernous sinus, and ultimately they pass through the superior orbital fissure to innervate the extraocular muscles just distal to the orbital apex. Acute bacterial and chronic fungal, tuberculous, spirochetal (syphilitic and Lyme Borrelia), and inflammatory (sarcoid) meningitic processes may affect the ocular motor nerves within the subarachnoid space, and other cranial nerves may be involved. Carcinomatous or lymphomatous meningitis may produce a similar clinical picture, sometimes accompanied by radicular signs and symptoms indicating more widespread meningeal involvement. The ocular motor nerves can be involved in Guillain-Barrk syndrome, the Miller Fisher variant (ophthalmoparesis, ataxia, and areflexia), and chronic inflammatory demyelinating polyneuropathy, usually in the setting of systemic weakness. CSF examination is essential for diagnosing and sorting out these infectious, neoplastic, and inflammatory disorders. In the subarachnoid space, posterior communicating aneurysms may compress the third nerve, almost always with pupillary dilation. A third-nerve palsy accompanied by altered mental status and ipsilateral hemiparesis should suggest uncal herniation, causing third-nerve compression and contralateral impingement of the cerebral peduncle along the tentorial edge (Kernohan’s notch). The sixth nerve, as it climbs along the clivus and then over the petrous apex, is vulnerable to injury during downward brainstem shifts resulting from supratentorial masses (“false localizing sign”). Changes in intracranial pressure that occur in pseudotumor cerebri (intracranial hypertension) or after lumbar puncture (intracranial hypotension) may also cause sixth-nerve palsies. Injury to the ocular motor nerves in this area may result from trauma and skull base tumors such as chordomas, clivus meningiomas, and chondrosarcomas. The third and fourth nerves, as well as the first and second divisions of the trigeminal nerve (V, and V2),lie along the lateral wall of the cavernous sinus, whereas the sixth nerve, internal carotid artery, and third-order oculosympathetic fibers from the superior cervical ganglion lie more medially (Fig. 6-12). Cavernous sinus involvement would be suggested by any combination of unilateral third-, fourth-, or sixth-nerve dysfunction accompanied by hypesthesia of the forehead, cornea, or cheek or by Horner’s syndrome. Complete interruption of all three ocular motor nerves would result in total ophthalmoplegia, ptosis, and mydriasis. Idiopathic granulomatous inflammation of the cavernous sinus (Tolosa-Hunt) is characterized by painful ophthalmoplegia, and affected patients have a rapid response to corticosteroids. Sellar masses (Table 6-2), if large enough, may compress cavernous sinus

Disorders of the Eyes and Eyelids

51

structures, and the clinical scenario of acute headache, visual loss, and ophthalmoplegia should suggest pituitary apoplexy. The differential diagnosis of cavernous sinus lesions also includes metastases, infection (mucormycosis in an immunocompromised patient), septic cavernous sinus thrombosis, carotid-cavernous sinus fistulas, and intracavernous aneurysms. Thin section MRI through the sellar region with coronal views and gadolinium is optimal for detecting and discerning cavernous sinus pathology. Ischemic ocular motor palsies, typically associated with hypertension or diabetes, often are preceded by orbital ache or pain. The ischemic third-nerve palsies, characterized by pupillary sparing, may be caused by infarction of the nerve in the intracavernous or subarachnoid portions or within the mesencephalon. Most patients with vasculopathic ocular motor palsies recover spontaneously within 8 to 12 weeks. Except for sparing of V,, lesions of the superior orbital fissure are clinically difficult to distinguish from those of the cavernous sinus, and the differential diagnosis is similar. The orbital apex syndrome consists of third-, fourth- and sixth-nerve paresis, V, distribution sensory loss, oculosympathetic paresis, and visual loss caused by optic nerve involvement. Patients with traumatic or chronic compressive third-nerve palsies (but typically not diabetes- or hypertension-related ones) may develop aberrant regeneration, or synlunesis. Common abnormal motility patterns include lid elevation during adduction or depression and miosis during adduction. lnfranuclear Disorders: Neuromuscular Junction. The extraocular muscles are involved in more than 90% of patients with myasthenia gravis. Fifty percent present with motility abnormalities or ptosis only, and of this group, one half remain “ocular myasthenics,” whereas the other half develop generalized symptoms, usually within 2 years. The diagnosis is supported by painlessness, diurnal variation, fatigability, and eyelid signs such as ptosis or Cogan’s lid twitch (see “Disorders of the Eyelids” later in this chapter). Any eye muscle can be affected, and the motility pattern may mimic a pupil-sparing third-, fourth-, or sixth-nerve palsy as well as supranuclear disturbances such as a conjugate gaze palsy, internuclear ophthalmoplegia, or one-and-a-half syndrome. As a rule, the pupil is uninvolved. Resolution of appreciable ptosis or motility deficits after administration of intravenous edrophonium (Tendon test) helps establish the diagnosis, but interpretation is more difficult with subtle ocular abnormalities. Acetylcholine receptor antibody levels, abnormal in one half of patients with solely ocular myasthenia, and electromyography with repetitive stimulation and single-fiber studies are important complementary tests. Acetylcholinesterases usually fail to control the diplopia, which often necessitates additional corticosteroids, immunosuppression, or thymectomy. Eye muscle involvement is unusual in Lambert-Eaton myasthenic syndrome, although rare patients may develop ptosis, minor motility disturbances, or sluggish pupillary responses. Ocular motility and pupillary reactivity may be affected in botulism. lnfranuclear Disorders: Ocular Myopathies. Restrictive thyroid myopathy is a common cause of diplopia in middle-aged patients. The double vision typically is insidious and painless, often accompanied by complaints of dry eye caused by reduced tear film and decreased blink rate. One or both eyes may be proptotic with eyelid edema, lid retraction, and lagophthalmos (see “Disorders of the Eyelids” later in this chapter). Restriction of elevation with a positive forced duction test is characteristic of the disorder (Fig. 6-13), but any muscle or combination may be

52

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Principles of Diagnosis: Common Presenting Symptoms

FIG. 6-12. Cavernous sinus, coronal view. Note that the third and fourth cranial nerves are located in the wall of the cavernous sinus, whereas the sixth nerve lies freely next to the carotid artery. Because the carotid siphon is cut in cross-section, two arterial lumens are seen; the sympathetic plexus surrounds the more caudal portion of cavernous carotid artery. The sphenoid sinus is medial and inferior to this region, whereas the optic chiasm lies directly above the pituitary gland. 111, oculomotor nerve; IV trochlear nerve; VI, abducens nerve; V,, ophthalmic division of the trigeminal nerve; V, maxillary division of the trigeminal nerve. (From Caletta SL: Cavernous sinus syndromes. p. 610. In Margo CE, Hamed LM, Mames RN (eds): Diagnostic Problems in Clinical Ophthalmology. WB Saunders, Philadelphia, 1994, with permission.)

A

C

D

FIG. 6-13. Thyroid eye (Graves's) disease causing left elevation deficit. (A) In primary gaze, there is a right hypertropia and left proptosis. (B) On attempted upgaze, the left eye has no elevation; forced duction test was positive. (C) CT scan of the orbits, axial view, demonstrating bilaterally enlarged medial rectus (/urger arrows) and lateral rectus muscles (smaller arrows). (0)CT scan, coronal view of the orbits, showing diffusely enlarged extraocular muscles; the inferior rectus on the left (arrow) is especially large and accounts for the tethering of the left eye in attempted upgaze and the positive forced duction test.

Chapter 6

involved. Affected patients have either primary hyperthyroidism (Graves’s disease), primary hypothyroidism (Hashimoto’s thyroiditis), or hypothyroidism caused by treated hyperthyroidism. For unknown reasons, the extraocular muscles develop lymphocytic and plasmacytic infiltration with secondary production of acid mucopolysaccharides and fibrosis. CT and MRI scanning of the orbits may demonstrate thickening of the extraocular muscles (Fig. 6-13). Thyroxine (TJ, free T, index, triiodothyronine (TJ, and thyroid-stimulating hormone (TSH) should all be evaluated if dysthyroid myopathy is suspected, although many patients are clinically euthyroid. The disorder often is self-limited, but treatment modalities include head elevation during sleep, corticosteroids, radiation, and surgical orbital decompression. Optic nerve compression caused by expansion of orbital contents necessitates urgent surgery or radiation. Insidious, symmetrical loss of eye movements, lack of diplopia, bilateral ptosis, and weakness of orbicularis oculi characterize chronic progressive external ophthalmoplegia caused by mitochondrial dysfunction (external refers to extraocular muscles; internal refers to the pupillary sphincter). Kearns-Sayre syndrome, typified by chronic progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects, is associated with mitochondrial DNA deletions. Patients with oculopharyngeal dystrophy, myotonic dystrophy, myotubular myopathy, congenital fiber-type disproportion, Bassen-Kornzweig syndrome (abetalipoproteinemia) , and Refsum’s disease may also develop slowly progressive ptosis and ophthalmoparesis. The congenital fibrosis syndromes are rare familial disorders in which patients are born with bilateral ptosis and ophthalmoparesis in association with fibrosis of the extraocular muscles. In one reported case, the superior division of the oculomotor nerve was absent, suggesting that at least some of the abnormalities may result from defective congenital innervation of the extraocular muscles. Orbital myositis, with inflammation of muscles only, and orbital pseudotumor, with involvement of muscles and other contiguous structures, are characterized by painful double vision and restrictive ophthalmoplegia. Usually idiopathic but sometimes associated with systemic lupus erythematosus or Crohn’s disease, they probably represent the orbital versions of the Tolosa-Hunt syndrome. The pain and diplopia usually respond to oral corticosteroids. Isolated metastases to extraocular muscles are uncommon, but orbital metastasis from lung or breast carcinoma or lymphoma can involve the extraocular muscles. CT or MRI usually reveals an orbital soft tissue mass. Although uncommon, extraocular muscle ischemia caused by giant cell arteritis should be considered in any patient over 60 years of age with diplopia. Supranuclear Disorders: Cortical Lesions. The frontal eye fields (FEFs), located in premotor cortex area 8, initiate contraversive horizontal eye deviation. Therefore, patients with a frontal lobe tumor or stroke may have a voluntary contraversive horizontal gaze deficit and an ipsiversive gaze preference. Epileptogenic frontal foci may result in contraversive gaze deviation and nystagmus. Patients with hemianopias or visual neglect may have a gaze preference away from the defective hemifield and into the good field. Deep parietal lesions may cause a homonymous hemianopia and poor tracking of objects (optokinetic stimuli are best) moving ipsilaterally because of interruption of the optic radiations and adjacent descending corticobulbar fibers from the parieto-

Disorders of the Eyes and Eyelids

53

occipitotemporal pursuit area. This combination is highly localizing because patients with lesions limited to the occipital lobe have hemianopias but normal optokinetic responses. Bilateral parietal lesions, usually caused by watershed infarction, can lead to deficient initiation of voluntary eye movements but preservation of reflex saccades and pursuit (ocular motor apraxia). This abnormality also can be congenital or part of Baht’s syndrome (see “Disorders of the Afferent Visual Pathways” earlier in this chapter). Supranuclear Disorders: Brainstem Lesions. Each FEF activates the contralateral paramedian pontine reticular formation. Neurons of the paramedian pontine reticular formation in turn excite the adjacent sixth-nerve nucleus, which, via the medial longitudinal fasciculus, innervates the contralateral medial rectus subnucleus (Fig. 6-14A). Upgaze and downgaze, also under voluntary control by the FEFs, are initiated by neurons in the mesencephalic rostral interstitial nucleus of the medial longitudinal fasciculus and regulated by cells in the interstitial nucleus of Cajal, areas that exert supranuclear control over the third- and fourth-nerve nuclei (Fig. 6-14B, C). The vestibular nuclei have direct and indirect connections with the third- and fourth-nerve nuclei, via the medial longitudinal fasciculus. MESENCEPHALON. The dorsal midbrain (Parinaud’s) syndrome is characterized by a supranuclear vertical gaze paresis (upward more than downward), lid retraction, convergence-retraction nystagmus, pupillary light-near dissociation, and pseudoabduction deficits caused by excessive convergence tone. Affected patients have difficulty with voluntary vertical gaze, but oculocephalic and pursuit eye movements are normal. Hydrocephalus, compression of the pretectum by pineal region or thalamic masses, and infarction are the usual causes. The abnormality of vertical gaze results from involvement of supranuclear fibers for upgaze, which originate from the rostral interstitial nucleus of the medial longitudinal fasciculus and interstitial nucleus of Cajal and cross dorsally in the posterior commissure (Fig. 6- 14B, C). Skew deviation, a supranuclear vertical ocular misalignment secondary to disruption of vestibular influences, can occur after midbrain injury with the hypertropic eye ipsilateral to the lesion. PONS. Disruption of the median longitudinal fasciculus in the pons results in an internuclear ophthalmoplegia typified by an ipsilateral adduction deficit, contralateral abducting nystagmus, and preservation of convergence. The side of the adduction deficit determines the side of the internuclear ophthalmoplegia. In a young adult, an internuclear ophthalmoplegia suggests demyelination, but bilateral internuclear ophthalmoplegias are virtually diagnostic. Other causes include tumor or vascular infarction or malformation. Damage to the paramedian pontine reticular formation results in an ipsilateral conjugate gaze palsy. The combination of an internuclear ophthalmoplegia with a ipsiversive conjugate palsy is a pontine one-and-a-half syndrome, caused by simultaneous ipsilateral involvement of the paramedian pontine reticular formation and median longitudinal fasciculus. Damage to either of these structures in addition to the corticospinal tracts results in Foville’s syndrome, consisting of a facial palsy, conjugate gaze paresis, and contralateral hemiparesis, and the RaymondCestan syndrome, characterized by an internuclear ophthalmoplegia and contralateral hemiparesis. MEDULLA.Both skew deviation, with the hypertropic eye contralateral to the lesion, and ipsilateral conjugate gaze deviation may be associated with lateral medullary infarcts (Wallenberg’s syndrome).

54

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Principles of Diagnosis: Common Presenting Symptoms

A

FIG. 6-14. Summary of eye movement control. (A) Generation of horizontal saccades. In this schematic drawing (ventral view), the pathways for a rightward saccade are depicted. The frontal and other cortical eye fields from the left (L) hemisphere send fibers that decussate then reach the right (R) paramedian pontine reticular formation (PPRF). Burst neurons in the right PPRF excite cell bodies in the right sixth nerve (vlth) nucleus, which in turn innervatesthe ipsilateral lateral rectus (LR) muscle, which abducts the right eye (RE). Another set of neurons from the right sixth nerve nucleus cross the midline then ascend within the left medial longitudinal fasciculus (MLF). These reach the left medial rectus (MR) subnucleus in the oculomotor complex (Illrd) in the midbrain, which issues third nerve neurons (Illrd n.) that supply the left medial rectus muscle to adduct the left eye (LE). (B) Horizontal pursuit pathways. Neurons from the parietal lobe descend ipsilaterally to the pontine nuclei. A postulated double decussation of pursuit pathways in the brainstem and cerebellum then occurs. The first decussation consists of excitatory mossy fiber projections from the pontine nuclei to granule cells, which excite basket cells and stellate cells in the contralateral cerebellar flocculus. The basket and stellate cells inhibit Purkinje cells, which in turn inhibit neurons in the medial vestibular nucleus (MVN). The second decussation consists of excitatory projections from the MVN to the opposite abducens nucleus (vl), leading to ipsilateral gaze deviation. (Adapted with permission from Johnston JL et al: Paresis of contralateral smooth pursuit and normal vestibular smooth eye movements after unilateral brainstem lesions. Ann Neurol 31:495-502, 1992. Reprinted from Liu GT, Volpe NJ, Caletta SL: Neuro-ophthalmology: Diagnosis and Management. WB Saunders, Philadelphia, 2001, with permission.) Basal Ganglia Disorders. In progressive supranuclear palsy, a supranuclear deficit in downward eye movements may be an early and prominent finding. Patients may complain of blurry vision, trouble going down stairs, or difficulty focusing. As the disease progresses, first upward, then horizontal eye movements may be affected, and in the late stages, there may be complete ophthalmoplegia. Patients with Parkinson’s disease may have hypometric saccades and pursuit, and patients with Huntington’s disease may have defective initiation of saccades, but these are inconsistent findings and unhelpful in diagnosing these two disorders. Treatment. The ophthalmoparesis in some of the disorders described, such as ischemic and traumatic ocular motor palsies, usually resolves spontaneously. Other cases, such as those caused by myasthenia gravis or bacterial meningitis, improve as the underlying cause is treated. In the meantime, patients with

diplopia can wear a patch over one eye to resolve the double vision, or one lens of a pair of eyeglasses can be taped over. The eye being patched should be alternated daily in children to prevent amblyopia. Some authors have advocated botulinum toxin injections into the antagonist muscle of a paretic eye. For instance, in a left lateral rectus palsy, the left medial rectus palsy is injected with botulinum to decrease the likelihood of medial rectus contraction and facilitate recovery of binocularity when the lateral rectus palsy recovers. Patients with ophthalmoparesis who do not improve spontaneously and whose examination results remain stable for 6 months may be candidates for eye muscle surgery. Surgical correction of palsies of single muscles, such as a lateral rectus and superior oblique palsy, is more straightforward than cases where multiple muscles may be involved, as in thyroid eye disease.

Chapter 6

Disorders of the Eyes and Eyelids

55

FIG. 6-14. Continued (C, 0)Major pathways subserving vertical eye movements. (C) Upward eye movements. Neurons from the rostra1 interstitial nucleus of the medial longitudinal fas‘ciculus (riMLF), which contain burst neurons for vertical saccades, project ipsilaterally to the oculomotor nuclear complex. There fibers divide, with some crossing at this level, to innervate the superior rectus and inferior oblique subnuclei bilaterally. On the other hand, fibers from the interstitial nucleus of Cajal (inc), the neural integrator for vertical gaze, cross within the posterior commissure (PC) before reaching the oculomotor complex and the superior rectus and inferior oblique subnuclei. (0) Downgaze eye movements. For downgaze, each riMLF supplies the ipsilateral inferior rectus subnucleus and the fourth nerve nucleus (IVth n.), which innervates the contralateral superior oblique muscle. Axons from the inC cross via the posterior commissure, then innervate the contralateral inferior rectus subnucleus and fourth nerve nucleus. (From Eye movement disorders: conjugate gaze abnormalities. In Liu CT, Volpe NJ, Caletta SL: Neuro-ophthalmology: Diagnosis and Management. WB Saunders, Philadelphia, 2001, with permission.)

Nystagmus and Inappropriate Saccades Nystagmus. Nystagmus is a to-and-fro rhythmic oscillation of the eyes. Most types of nystagmus fall in two groups: pendular nystagmus, with symmetrical oscillations, and jerk nystagmus, which has slow and fast phases. The latter determines the direction (as in “leftward-beating nystagmus”). Pathologic nystagmus usually results from posterior fossa or peripheral vestibular abnormalities, but some subtypes are unique and highly localizable. Pendular eye movements in infancy usually indicate congenital nystagmus, whose other characteristic features include binocularity, appearance at age 2 to 4 months during development of visual fixation, superimposition of jerk nystagmus in end-gaze, lack of oscillopsia, and dampening by convergence. Patients with a null point, where the amplitude of the nystagmus is smallest and vision is best, may adopt a head turn to achieve this eye position. The nystagmus waveforms do not distinguish the patients with

congenital nystagmus caused by abnormal visual pathways (e.g., retinopathies, optic nerve hypoplasia, periventricular leukomalacia) from those with normal vision. Acquired forms of pendular nystagmus in childhood include the Heimann-Bielschowsky phenomenon, a slow monocular vertical oscillation associated with unilateral visual loss (e.g., caused by an optic nerve glioma), and spasmus nutans, a benign, self-limited disorder typified by the triad of asymmetrical nystagmus, head bobbing, and torticollis. In rare instances, patients with chiasmal gliomas or other suprasellar tumors may develop a spasmus nutans-like syndrome, but concurrent visual loss, optic,atrophy, or endocrine abnormalities usually are evident. Acquired pendular nystagmus in adults may result from lesions in the cerebellar pathways, usually after demyelination or infarction. In oculopalatal myoclonus, 3-Hz pendular ocular oscillations are accompanied by synchronous movements of the palate and sometimes face and pharynx. The disorder is a delayed complica-

56

Principles of Ambulatory Neurology and the Approach to Clinical Problems rn Principles of Diagnosis: Common Presenting Symptoms

tion of injury to the central tegmental tract or dentatorubral pathway (Mollaret’s triangle) and is associated with olivary hypertrophy. Trihexyphenidyl may be effective in this disorder. Horizontal jerk nystagmus usually signifies an abnormality in the vestibulocerebellar pathways. As a general rule, nystagmus that is right-beating in right gaze and left-beating in left gaze (bidirectional, direction-changing, or gaze-evoked nystagmus) reflects a posterior fossa process disrupting the neural integrator, a network responsible for gaze holding. Structures that make up the neural integrator include the cerebellar flocculus and paraflocculus, the nucleus prepositus hypoglossi, and the adjacent medial vestibular nucleus. Symmetrical gaze-evoked nystagmus may result from sedatives or anticonvulsants, whereas cerebellar lesions may produce an asymmetrical bidirectional nystagmus greater in amplitude ipsilaterally. Physiologic end-gaze nystagmus, usually present only in extremes of gaze, has a smaller amplitude and higher frequency than pathologic nystagmus. Jerk nystagmus that is horizontal and unidirectional or has a torsional component usually indicates a vestibular abnormality. Purely vertical, horizontal, or torsional nystagmus suggests a nuclear (central) vestibular lesion such as a lateral medullary infarction. Cold water irrigation of the tympanic membrane mimics a destructive lesion of the vestibular end organ (peripheral) by producing nystagmus with an ipsilateral slow phase and contralateral fast phase; warm water irrigation mimics an irritative lesion and produces an ipsilateral fast phase (the mnemonic COWS cold, opposite; warm, same). Peripheral vestibular abnormalities include labyrinthitis, Mkniere’s disease, benign positional vertigo, or neuronitis (see Chapter 9). Bilateral cold water irrigation produces conjugate downgaze, whereas bilateral warm water irrigation elicits upgaze. Downbeat nystagmus is very suggestive of a cervicomedullary junction disturbance, such as an Arnold-Chiari malformation, foramen magnum meningioma, or drug toxicity. Periodic alternating nystagmus, which can be congenital or acquired, has the same localization and is characterized by repetitive cycles of horizontal nystagmus beating in one direction for 90 seconds, then 10 seconds in a neutral phase, followed by 90 seconds of nystagmus beating in the opposite direction. Many patients respond to baclofen. Asymmetry of optokinetic nystagmus has localizing value with regard to parietal lesions, as discussed in “Disorders of the Afferent Visual Pathways” earlier in this chapter. Convergence-retraction nystagmus, a dramatic condition in which the globes turn inward and retract into the orbit, occurs in association with dorsal midbrain lesions (Parinaud’s syndrome) and is elicited during attempted upward saccades. Seesaw nystagmus, in which alternately one eye elevates and intorts while the other depresses and extorts, is associated with chiasmal disturbances and mesencephalic lesions. Saccadic Abnormalities. Hypermetric saccades overshoot the target, whereas hypometric saccades undershoot. Saccadic dysmetria, a sign of vestibulocerebellar dysfunction, often is accompanied by gaze-evoked nystagmus and appendicular and gait ataxia. Often, the direction of the hypermetria lateralizes to the side of a cerebellar hemispheric lesion. Inappropriate Saccades. Square-wavejerks are characterized by small-amplitude back-to-back horizontal saccades away from fixation, with an intersaccadic interval. They may occur in progressive supranuclear palsy or schizophrenia and represent the subtle end of the spectrum of eye movement abnormalities grouped under saccadic intrusions. Saccadic oscillations occur around fixation, usually after a saccade and in the setting of

cerebellar disease. Ocular flutter, typified by back-to-back bursts of horizontal saccades without an intersaccadic interval, and opsoclonus, in which the eyes conjugately saccade in random, chaotic directions (“saccadomania”), are the dramatic saccadic intrusions. Both occur in association with meningoencephalitis and drug toxicity and as a paraneoplastic phenomenon in children harboring occult neuroblastoma or in adults with breast, lung, and gynecologic cancers. Miscellaneous Conditions. Superior oblique myokymia is an intermittent rapid contraction of the superior oblique muscle and causes diplopia and monocular oscillopsia. Carbamazepine is the treatment of choice. Treatment. As indicated earlier, some forms of nystagmus respond to pharmacologic treatments. Medications that can be tried include baclofen, gabapentin, and clonazepam. Congenital nystagmus can be treated with base-out prisms in both eyes to induce convergence or with other prism strategies to help move the eyes into the null position. Another alternative is the Kestenbaum surgical procedure, in which the attachments of the extraocular muscles are relocated to shift the null position to primary gaze, thereby eliminating the head turn. Retrobulbar injections of botulinum toxin may be used to treat patients with acquired pendular nystagmus associated with oscillopsia and visual acuity loss. Injections into specific muscles have also been advocated. Although they are successful in decreasing the amplitude of the nystagmus and improving visual acuity in some instances, many patients develop ptosis or diplopia. Eye Movements in Coma In comatose patients, the positions of the eyes and any spontaneous movements should be observed first. Conjugate lateral eye deviation may indicate a destructive lesion in the ipsilateral frontal lobe or contralateral pons or a seizure focus in the contralateral cerebral hemisphere. Rarely, a thalamic lesion causes “wrong-way eyes,” with contraversive horizontal eye deviation. Conjugate downward eye deviation implies a dorsal midbrain lesion or hydrocephalus. Dysconjugate eyes might suggest an extraocular muscle palsy, although depressed mentation often uncovers a latent esophoria or exophoria. A pupil involving third-nerve palsy might indicate uncal herniation or posterior communicating artery aneurysm. If ocular motor function in the brainstem is intact, there may be roving eye movements, characterized by conjugate or dysconjugate slow ocular deviations in random directions. Periodic alternating or ‘)ing-pong” gaze refers to slow, repetitive, back and forth, horizontal conjugate eye movements. Spontaneous nystagmus is unusual in coma except in dorsal midbrain lesions associated with convergence-retraction nystagmus. Patients with ocular bobbing, usually comatose because of severely destructive pontine lesions, have a fast conjugate downward deviation followed by a slow upward correction to midposition. Ocular dipping, a slow downward deviation followed by a quick upward movement of the eyes, has the same neuroanatomic localization. Comatose patients exhibiting spontaneous full, conjugate eye movements, as well as normal pupillary reactivity and eyelids, can be considered to have intact third-, fourth-, and sixth-nerve function and preserved internuclear connections. Patients with absent or abnormal spontaneous eye movements should be tested using oculocephalic (head turning or doll’s head) or oculovestibular (ice water caloric) maneuvers. Cervical spine trauma and tympanic membrane perforation should be excluded before these

Chapter 6 fl

tests are performed. The normal oculocephalic response is conjugate eye deviation away from the head turn. In comatose patients with intact brainstem function but abnormal cortical influences, the oculocephalic response may be overly brisk (disinhibited), and ice water stimulation in one ear may result in ipsiversive eye deviation without the contraversive corrective phase. These maneuvers may uncover a vertical gaze paresis, skew deviation, sixth-nerve palsy, or internuclear ophthalmoplegia useful for brainstem localization. In early metabolic coma, the oculocephalic and oculovestibular reflexes usually are preserved. Absent oculocephalic and oculovestibular reflexes may indicate diffuse brainstem dysfunction and are seen in late transtentorial (rostral-caudal) herniation and brain death.

Disorders of the Eyes and Eyelids

57

DISORDERS OF THE PUPILS

The pupil has three major functions: to vary the quantity of light reaching the retina, minimize the spherical aberrations of the peripheral cornea and lens, and increase depth of field. This section reviews pupillary abnormalities encountered in neurologic settings. Neuroanatomy

The pupillary light reflex is mediated by a parasympathetic pathway (Fig. 6-15), and light directed in either eye leads to bilateral pupillary constriction (miosis). Light is transmitted via

FIG. 6-15. Pupillary light reflex: parasympathetic pathway. Light entering one eye (straight black arrow, bottom right) stimulates the retinal photoreceptors (RET), resulting in excitation of ganglion cells, whose axons travel within the optic nerve (ON), partially decussate in the chiasm (CHI), then leave the optic tract (OT) (before the lateral geniculate nucleus [LCN]) and pass through the brachium of the superior colliculus (SC) before synapsing at the mesencephalic pretectal nucleus (PTN). This structure connects bilaterally within the oculomotor nuclear complex at the Edinger-Westphal (E-W) nuclei, which issue parasympathetic fibers that travel within the third nerve (inferior division) and terminate at the ciliary ganglion (CC) in the orbit. Postsynaptic cells innervate the pupillary sphincter, resulting in miosis. Note that light in one eye causes bilaterally pupillary constriction. (Adapted from Slamovits TL, Claser JS: The pupils and accommodation. p. 528. In Claser I S (ed): Neuro-ophthalmology. 3rd Ed. Lippincott, Williams & Wilkins, Philadelphia, 1999, with permission.)

T

the anterior visual pathway and reaches parasympathetic structures in the midbrain; parasympathetic fibers to the eye exit within the third nerve before synapsing at the ciliary ganglion. Pupillary dilation (mydriasis) is the function of the oculosympathetic system, which contains three neurons beginning in the hypothalamus and ending at the iris and eyelids (Fig. 6-16). Examination

Pupillary size can be measured in light and dark using the pupil scale available on most near acuity cards. Transient fluctuations in pupillary diameter are normal and are called hippus. Pupillary light reactivity should be tested with a bright light, such as a halogen transilluminator or indirect ophthalmoscope, while the patient views a distant target (to prevent accommodation). With the light shined in one eye, the ipsilateral pupillary light reflex is the direct response, whereas the contralateral is the consensual response. In the swinging flashlight test, the light is alternately directed at each eye (without too much hesitation between eyes

and with equal exposure to light in both eyes) to compare each pupil's constriction to light (Fig. 6-17). Pupillary miosis can also be elicited during accommodation to a near target (thumb, pen, or written material). The examiner should also screen for afferent visual pathway, ocular motility, and eyelid abnormalities. Pupillay AbnonnalWes Caused by Lesions of the Afferent Visual Pathways

In a subtotal unilateral optic neuropathy or severe retinal or macular abnormality, both pupils have the same size, but the direct and consensual pupillary light responses may be diminished when light is directed into the involved eye. In unilateral blindness (no light perception) caused by complete optic nerve or retinal

A

B

\\I/

FIG. 6-16. Sympathetic innervation of the pupil and eyelids. First-order hvpothalamic (central) neurons descend throuah the brainstem (midbrain, pons,. meduila) and cervical spinal cord: These fibers then synapse with preganglionic neurons, whose cell bodies lie in the intermediolateral gray column and whose axons exit the cord ipsilaterally at C8, T1, and T2. These second-order fibers then travel rostrally via the sympathetic chain and terminate in the superior cervical ganglion. The postganglionic axons ascend within the carotid plexus, which surrounds the internal carotid artery, to reach the cavernous sinus and arrive at the iris via branches of the first division of the trigeminal nerve and then the long ciliary nerve. Sudomotor fibers to the lower face follow the external carotid then facial arteries. Sympathetic fibers to Muller's muscles also travel within the carotid plexus into the cavernous sinus and then may join branches of the third nerve before reaching the upper and lower eyelids.

C

FIG. 6-17. Swinging flashlight test revealing a left relative afferent pupillary defect in the hypothetical setting of visual loss in the left eye caused by an optic neuropathy. (A) Pupillary sizes are equal at rest in ambient lighting. (B) Light stimulation of the good right eye results in brisk bilateral pupillary constriction. (C) Light stimulation of the defective left eye produces weaker pupillary constriction, and the pupils dilate.

Chapter 6 W

1-

The Small Pupil

Disorders of the Eyes and Eyelids

59

The Dilated Pupil

Examine light reaction Anisocoria greater in light or dark? ocular / motilityy

Check for dilatation lag Ptosis? 10% cocaine test

iris structure

constriction

n r l Hornets syndrome

MRI and

I Hydroxyamphetamine I Anisocoria decreases

J

p l i t y

examination

Negative Physiologic anisocoria

\ ocular

mrl damage

(0.125%)

Pupil/ constricts

\NO

constriction

I

1/

increases

I

Pupil

" 1 -

neurologic signs

Consider chest CT Neck MRI Brain MRI

FIG. 6-18. A diagnostic approach to anisocoria. The chart guides the workup of an abnormal pupil and assumes the other pupil is normal. (Reprinted from Caletta SL, Liu CT, Volpe NJ: Neuro-ophthalmology.In Evans R (ed): Diagnostic Testing in Neurology. Neurol Clin 14:212, 1996, with permission. Adapted from Thompson HS, Pilley S F Unequal pupils: a flow chart for sorting out the anisocorias. Surv Ophthalmol 21:45, 1976, with permission.)

injury, the pupillary light reflex is absent (amaurotic). During the swinging flashlight test, when light is directed in the unaffected eye, both pupils react normally. When the light is returned to the abnormal eye, both pupils dilate because of the weaker pupillary constriction (relative afferent pupillary defect; Fig. 6-17). Even if each pupil constricts to light but a secondary redilation (pupillary escape) occurs in one eye, the interpretation is the same; this is what Marcus Gunn originally described. Abnormal visual acuity and color vision, a central scotoma, and a relative afferent pupillary defect collectively are highly suggestive of an optic neuropathy, although a large macular lesion could produce similar findings. In bilateral optic nerve disease, a relative afferent pupillary defect may not be present unless the visual loss is highly asymmetrical. A severe unilateral visual loss without a relative afferent pupillary defect may be functional. Visual loss caused by corneal, lens, and vitreous opacities and refractive errors does not produce a relative afferent pupillary defect, but rarely, an amblyopic eye may have a relative afferent pupillary defect. Asymmetrical chiasmal syndromes may be associated with a relative afferent pupillary defect, especially if an eye has subnormal visual acuity. Isolated optic tract lesions may have a contralateral relative afferent pupillary defect, despite normal visual acuities, because the defective temporal field in the contralateral eye is larger than the nasal field of the ipsilateral eye. Behr's pupil (a large

contralateral pupil) and Wernicke's hemianopic pupil (one that reacts more briskly to light projected from within the intact hemifield than to light within the abnormal field) are associated with optic tract syndromes, but these are rare in clinical practice. As a rule, isolated lesions of the geniculate, optic radiations, and visual cortex do not affect pupillary size or reactivity.

Asymmetricalpupillary size is called anisocoria. Pupillary inequality greater in light suggests that the larger pupil is abnormal, with a parasympathetic defect, pharmacologic blockade, or iris damage. A greater difference in darkness implies either oculosympathetic paresis or, less commonly, nonpathologic simple (essential) anisocoria. The latter occurs in 15% to 30% of the normal population, is characterized by normal pupillary constriction and dilation, and may be less evident in light because of mechanical limitations of the iris. More often in clinical practice, simple anisocoria is characterized by a difference in pupillary sizes that is unchanged in light and dark. Often, the simple anisocoria is evident on old photographs or a driver's license. Figure 6- 18 is an algorithm for evaluating anisocoria when only one pupil is abnormal.

60

hinciples of Ambulatory Neurology and the Approach to Clinical Problems W

Parasympathetic Disruption: Disorders of Pupillary Constriction. Lesions affecting the dorsal midbrain, causing Parinaud’s

syndrome, may interfere with pupillary reactivity by disrupting ganglion cell axons entering the brachium of the superior colliculus. Bilaterally, the pupils may be midposition to large, poorly reactive to light, but briskly reactive to near stimuli because of intact supranuclear influences on midbrain accommodative centers (pupillary light-near dissociation). Ectopic pupils (corectopia) may occur in patients with severe midbrain damage. In this condition, the pupil is displaced upward and inward, presumably because of disruption of parasympathetic pupillary fibers in the midbrain. In a complete third-nerve palsy, the pupil is large and unreactive to light or near stimuli, either directly or consensually (internal ophthalmoplegia; Fig. 6-9). A nuclear or fascicular lesion in the midbrain rarely causes mydriasis alone and is almost always accompanied by ptosis or ophthalmoparesis. On the other hand, processes in the subarachnoid space such as meningitis, aneurysmal compression (posterior communicating or internal carotid), and uncal herniation (Hutchinson’s pupil) may present with a dilated pupil with minimal other indications of a third-nerve palsy. Pupil-sparing third-nerve palsies in middle-aged and older patients usually are related to diabetes or hypertension. An aneurysm that presents initially with external ophthalmoparesis or ptosis typically involves the pupil within several days. Abnormal miosis during ocular adduction or depression may be a sign of aberrant regeneration in association with a third-nerve palsy due to head trauma or compression. Pupils dilated as part of an ophthalmic evaluation with tropicamide or cyclopentolate (both anticholinergic agents) or accidentally by a patient who has contact with atropine or a scopolamine patch and then touches his or her eye generally are large (7 to 8 mm) and unreactive. One percent pilocarpine drops do not constrict these pharmacologically dilated pupils but are effective in third-nerve palsy-related mydriasis. Tonic pupils result from damage to the ciliary ganglion or the postganglionic short ciliary nerves that innervate the pupillary sphincter and ciliary muscles. Characteristically, they are large, have light-near dissociation (Fig. 6-19), and redilate slowly after constriction. In some instances, the near response may also be defective. Patients may have accommodation paresis, resulting in difficulty with near vision. On slit lamp examination, the pupils may be irregular, with sectorial paralysis or vermiform movements. Chronically, a tonic pupil may become miotic and smaller than the fellow pupil. Tonic pupils may be isolated after viral illnesses or eye or orbital trauma, or part of Adie’s syndrome, which also includes absent deep tendon reflexes. They may also occur in association with dysautonomias, diabetes mellitus, Guillain-BarrC syndrome, or Miller Fisher syndrome. Because of iris sphincter denervation hypersensitivity, tonic pupils constrict after administration of dilute (0.125%) pilocarpine (Fig. 6-19), which does not affect most normal pupils. Tonic pupils usually have a benign cause, necessitating only symptomatic treatment, such as refractive correction for reading or dilute pilocarpine for photophobia. Argyll Robertson pupils also exhibit light-near dissociation with a brisk near response but are typically miotic with poor dilation in the dark (Fig. 6-20). Although nonspecific, they are highly suggestive of syphilis and should therefore prompt serologic testing. The lesion responsible for the pupdlary abnormality is uncertain but may result from a disturbance in the midbrain light

Principles of Diagnosis: Common PresentingSymptoms

reflex pathway between the pretectal nucleus (Fig. 6-15) and Edinger-Westphal nuclei. Ocular causes of unreactive pupils, including direct eye trauma, angle closure glaucoma, and iritis, should be addressed by an ophthalmologist with a slit lamp examination. In spasm of the near reflex, miosis is associated with convergence and accommodation. Usually indicative of a h n c tional disorder, this symptom rarely may be associated with brainstem lesions. Sympathetic Disruption: Disorders of Pupillary Dilation. Interruption of any of the three oculosympathetic neurons may result in Horner’s syndrome, characterized by unilateral miosis, facial anhidrosis, and upper and lower eyelid ptosis (Fig. 6-21). Often, the patient has no ocular complaints. The miotic pupil dilates slowly in the dark (dilation lag), so the anisocoria is accentuated in darkness. The eyelid abnormality may give the false impression that the eye is set back in the orbit (pseudoenophthalmos). Because sympathetic sudomotor fibers to the lower face follow the external carotid then facial arteries, lesions of the third-order neuron distal to the carotid bifurcation result in loss of sweating only on the medial aspect of the forehead and side of the nose. In contrast more proximal lesions, including those of the first- and second-order neurons, disrupt sweating on a whole side of the face. In a study of inpatients with acquired oculosympathetic palsy (Keane, 1979), 63% had involvement of the first-order neuron, usually caused by lateral medullary or other brainstem stroke. Cerebral infarction or hemorrhage, intracranial tumor (presumably involving the hypothalamus), syrinx, and transverse myelopathy were other central causes. Twenty-one percent were caused by disruption of the preganglionic, or second-order neuron (the ganglion referred to is the superior cervical ganglion; therefore, preganglionic refers to the second-order neuron and postganglionic to the third-order neuron), in most instances resulting from thoracic (e.g., Pancoast’s tumors) and neck tumors but also from surgical and nonsurgical trauma such as attempted direct carotid artery puncture. Third-order neuron (postganglionic) injury was least common (13%), with cavernous sinus tumors, trauma, and vascular (cluster) headache as listed causes. Carotid dissection should always be considered in the setting of ipsilateral Horner’s syndrome, carotidynia, dysgeusia, and neurologic symptoms consistent with ipsilateral cerebral ischemia. By interrupting the blood supply to the superior cervical ganglion or carotid plexus, carotid thrombosis can cause oculosympathetic paresis. Horner’s syndrome and ipsilateral third-, fourth-, V,, V,, or sixth-nerve involvement indicates a cavernous sinus process. In two outpatient series, the central neuron was implicated in only 9% and 15% of the patients. The second-order neuron was the most common lesion site in one study (Maloney et al, 1980), whereas the third-order neuron was most common in another (Grimson and Thompson, 1975). Causes in children include occult neuroblastoma in the upper thorax or cervical sympathetic chain and birth-related brachial plexus trauma. Because iris melanocytes require oculosympathetic input, congenital Horner’s syndromes can be associated with an ipsilateral lighter-colored iris (iris heterochromia). The diagnosis of Horner’s syndrome associated with a lateral medullary stroke, brachial plexus injury, or spinal cord trauma, for instance, often is straightforward. However, the distinction between ipsilateral ptosis and miosis caused by oculosympathetic paresis and other causes, such as physiologic anisocoria combined

Chapter 6 H Disorders of the Eyes and Eyelids

61

A

B

C

FIG. 6-19. Idiopathic right tonic pupil. (A) The right pupil is midposition and larger than the left, poorly reactive to light, but (B) reactive to near stimulus (the examiner's thumb). The patient complained of blurry vision in the right eye while attempting to look at near objects.

with levator dehiscence-disinsertion on the side of the miotic pupil (so-called pseudo-Horner's syndrome), may necessitate pharmacologic testing. Cocaine, which blocks norepinephrine reuptake at the sympathetic nerve terminal in the iris dilator muscle, allows a relative increase of neurotransmitter available for the postsynaptic receptors. Iris dilator tone depends on the intactness of each neuron in the oculosympathetic pathway; interruption of any one of the three neurons results in decreased norepinephrine release by the third-order neuron, and cocaine will have little or no effect. Therefore, after topical instillation of 10%

cocaine into the eyes (the corneas have to be pristine without previous intraocular pressure measurements or corneal reflex testing during that office visit because disturbances of the corneal epithelium alter cocaine absorption), repeated 1 minute later, then checked after 45 minutes, a Horner pupil will remain miotic or dilate poorly, and an unaffected one will dilate normally (Fig. 6-21). In simple anisocoria, both pupils dilate with cocaine. If the cocaine test indicates oculosympathetic paresis (i.e., a positive cocaine test), 24 to 48 hours later 1% hydroxyamphetamine drops can be applied (and repeated after 5 minutes, and

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Principles of Diagnosis: Common Presenting Symptoms

A

C

FIG. 6-20. Argyll Robertson pupils in tabes dorsalis (absent deep tendon reflexes, loss of vibratory sense and proprioception in the lower extremities, and Charcot‘s joints). The pupils are (A) small and (B) poorly reactive to light, but (C) constrict to near stimuli. (Courtesy of J. Lawton Smith, MD.)

then examined 30 minutes later) topically to both eyes to test whether the lesion is preganglionic or postganglionic. The ability of the third-order neuron to synthesize norepinephrine is independent of the other two neurons. Hydroxyamphetamine, which enhances release of presynaptic norepinephrine, will dilate a Horner pupil only if the third-order neuron is intact. Thus, in a third-order Horner’s syndrome, the involved pupil will not dilate

with hydroxyamphetamine, but in first- or second-order sympathetic interruption, both pupils will dilate. In practice, the diagnosis of Horner’s syndrome usually is a clinical one based on examination findings, with cocaine used only to confirm equivocal cases. Hydroxyamphetamine is becoming more difficult to acquire because of decreasing commercial availability. This, coupled with the high false negative rate of the

Chapter 6

hydroxyamphetamine test, encourages clinicians in most instances to localize the Horner’s syndrome and make management decisions based largely on clinical grounds. In adults with Horner’s syndrome, two situations necessitate radiologic investigation regardless of clinical or pharmacologic localization (because neither is perfect). First, in any middleaged or older patient, especially one with a history of smoking, with an isolated, unexplained Horner’s syndrome, a chest radiograph should be performed to rule out an apical lung tumor. Second, Horner’s syndrome accompanied by ipsilateral headache

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63

or eye pain, with or without ipsilateral cerebral or ocular ischemic symptoms, necessitates MRI and MRA of the neck to exclude a carotid dissection or thrombosis. Axial fat suppression MR images through the neck are especially important in this setting. Oculosympathetic spasm is irritation of the oculosympathetic pathway, resulting in unilateral pupillary mydriasis, occasionally accompanied by ipsilateral facial flushing and hyperhydrosis. Cervical cord lesions, thoracic tumors, and carotid artery puncture have been reported causes.

A

B

C

FIG. 6-21. Left Horner‘s syndrome caused by cervical spinal cord trauma. (A) In room light, the left pupil is miotic, and there is left upper lid ptosis. (B) The anisocoria is greater in the dark. (C) After instillation of 10% cocaine at 0 and 1 minutes into both eyes, which were then checked 45 minutes later, the normal right pupil dilated, whereas the left pupil remained the same, confirming oculosympathetic paresis on the left.

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Principles of Diagnosis: Common PresentingSymptoms

Pupils in Neuromuscular Disease

In general, the pupils are unaffected in myasthenia gravis. Patients with botulism who develop defective release of acetylcholine can have bilaterally dilated pupils and accommodative paresis with varying degrees of ptosis and ophthalmoparesis. Pupils in Coma

Pupillary signs may be extremely important in evaluating comatose patients, especially with regard to localization. As stated earlier, hypothalamic lesions may cause small but reactive pupils through oculosympathetic paresis, whereas thalamic and mesencephalic lesions may result in third-nerve palsies, midposition or large pupils with light-near dissociation, or, less likely, pupillary corectopia. Destructive lesions of the pons may disrupt the descending oculosympathetic pathways and result in bilateral pinpoint pupils. Pupillary dilation may be the first sign of uncal herniation before other signs of third-nerve paresis develop. In metabolic encephalopathies, the pupils may be small but remain reactive to light until midbrain dysfunction ensues. Opiate intoxication causes pinpoint pupils resembling those seen with large pontine lesions. Atropine poisoning causes dilated and fixed pupils. DISORDERS OF THE EYELIDS The upper and lower eyelids protect the eye. Aside from insufficient eyelid closure, which is discussed with facial palsy in Chapter 7, ptosis (drooping), retraction (abnormal elevation), and abnormal blinking are the most important neurologic eyelid disorders. This section reviews the differential diagnosis of these and other eyelid abnormalities encountered by neurologists. Neuroanatomy

The levator palpebrae superioris muscle, with minor contributions from Miiller’s and the frontalis muscles, maintains the normal position of the upper eyelid. Both levator muscles are supplied by the central caudal nucleus of the oculomotor complex (Fig. 6-8), Miiller’s muscle is innervated by oculosympathetic neurons (Fig. 6-16), and the frontalis receives fibers from the facial nerve. Eyelid position depends mainly on the resting tone of the levator muscles, which varies according to the patient’s state of arousal, with alert patients having wider palpebral fissures than drowsy ones. Experimental lesions of the frontal lobes, angular gyrus, and temporal lobes may produce ptosis, and experimental stimulation of areas within frontal, temporal, and occipital lobes may produce eyelid opening, but the exact nature of the cortical control of the eyelids is unclear. Recent evidence suggests that vertical eye movements and lid position are coordinated in the midbrain by the nucleus of the posterior commissure, whose neurons synapse in an intermediary area called the M-group (supraoculomotor area, or supra 111). Neurons from this region project to and inhibit the central caudal nucleus (Fig. 6-22). Therefore, in upgaze, the levator muscles contract and the eyelids open, whereas during downgaze, nuclei of the posterior commissure neurons fire, allowing eyelid relaxation. Each nucleus of the posterior commissure lies dorsolateral to the third-nerve nucleus, and neurons from the nucleus of the posterior commissure on each side travel through the posterior commissure in the dorsal midbrain en route to the M-group.

FIG. 6-22. Theoretical scheme of lid-eye coordination. The inhibitory

pathways from the nucleus of the posterior commissure (nPC) cross within the posterior commissure (PC), then connect to an intermediary region called the M-group (M) (supraoculomotor area, or supra 111). The M-group exerts control over the central caudal nucleus (CCN) in the oculomotor nuclear complex (Illrd n.). Note that fibers from the interstitial nucleus of Cajal (inc) mediating vertical gaze (see also Fig. 6-14C, 0) also pass through the posterior commissure before innervating the third and fourth nerve nuclei. Therefore, lesions of the posterior commissure may cause both vertical gaze paresis and eyelid retraction. (From Liu GT, Volpe NJ, Galetta SL (eds): Neuroophthalmology: Diagnosis and Management. WB Saunders, Philadelphia, 2001, p. 465, with permission.) Hering’s law of equal innervation, which refers to the yoking of agonist muscles, applies to both levator muscles. Therefore, ptosis on one side may be accompanied by lid retraction on the other because of the excess tonus needed to keep the ptotic lid open (Fig. 6-23). Examination

First, the eyelids and their position should be observed at rest with the eyes straight ahead. The palpebral fissure, the opening between the upper and lower eyelids, usually measures between 9 and 15 mm in height (in the middle) when the lids are open. In an adult, normally the upper eyelid covers the top of the cornea (Fig. 6-24), whereas the lower eyelid lies at or just below the limbus (junction of cornea and sclera). In a neonate, the upper eyelid may be above the cornea, and the lower lid just above the limbus. Any obvious abnormalities in the shape or size of the lid also should be noted. An upper eyelid above the limbus (“scleral show”) implies that the palpebral fissure is widened, and disorders causing lid retraction or poor eyelid closure should be considered. Fissure narrowing suggests either excessive orbicularis contraction or ptosis caused by a neurogenic, myogenic, or mechanical problem. Next, the lids should be examined during eye movements. During horizontal conjugate gaze, the palpebral fissure widens in the abducting eye in approximately one half of normal individuals, and in about 15%, the lid elevates in the adducting eye as well. During upgaze, levator tone increases to lift the upper eyelid,

Chapter 6

Disorders of the Eyes and Eyelids

65

whereas in downgaze, the eyelids should relax and follow the eyes smoothly. If when the patient looks at a target moved downward the eyelids lag behind (lid lag or lagophthalmos), thyroid eye disease should be suspected. In any patient with a suspected eyelid abnormality, ocular motility and the pupils should also be evaluated carefully.

Ptosis A

A detailed differential diagnosis of ptosis is outlined in Table 6-4, but the text here concentrates on the most common causes. Causes should be considered according to age (congenital versus acquired in adulthood), acuity of onset, the appearance of the eyelid, and accompanying neurologic signs. Isolated ptosis in the neonate usually is caused by congenital maldevelopment of the levator palpebrae or its tendon, which also causes incomplete lowering of the eyelid in downgaze. Occasionally, the involved eye has deficient elevation (double elevator palsy), and if both eyes are ptotic, neither eye may have normal

B

TABLE 6-4. Causes of ptosis

C

FIG. 6-23. (A) Pseudoretraction of the right upper eyelid associated with ptosis of the left upper eyelid in ocular myasthenia gravis. This is a consequence of Hering's law. Note how the eyebrows are elevated, indicating frontalis contraction as the patient attempts to keep the eyelids open. (B) When the ptotic eyelid is elevated manually, the pseudoretracted lid falls. Note the eyebrows have relaxed. (C) After intravenous administration of edrophonium, the left ptosis and right pseudoretraction resolve. (From Liu GT, Volpe NJ, Galetta SL (eds): Neuro-ophthalmology: Diagnosis and Management. WB Saunden, Philadelphia, 2001, p. 471, with permission.)

upper lid

Width of Palpebral Fissure

lower lid

/

limbus

iris FIG. 6-24. Normal eye and eyelids. The palpebral fissure is the opening between the upper and lower lids, and its width should be measured along the 12-o'clock meridian of the cornea (at the pupil). Normally, the upper lid covers the limbus (junction of cornea and sclera), whereas the lower lid usually lies at or just below it.

Congenital Isolated With double-elevator palsy Anomalous synkineses (including Marcus Gunn jaw-winking) Lid or orbital tumors (hemangioma, dermoid) Birth trauma (third-nerve palsy, Horner's syndrome) Neurofibromatosis (neurofibroma) Neonatal myasthenia (transient) Congenitalfibrosis syndrome Acquired Myogenic Chronic progressive external ophthalmoplegia (CPEO) Kearns-Sayresyndrome ("CPEO-plus") Myotonic dystrophy Oculopharyngeal dystrophy Topical steroid eyedrops Disorder of neuromusculartransmission Myasthenia gravis Lambed-Eaton syndrome Botulism Neurogenic Hornet's syndrome Oculomotor nerve palsy Cortical ptosis Obtundation, drowsiness, coma Apraxia of eyelid opening Mechanical Inflammatory (edema, allergy, chalazion, hordeolum, blepharitis, conjunctivitis) CicatriciaI Tumor (lid, orbit) Blepharochalasis Levator dehiscence-disinsertionsyndrome Aging Inflammation (ocular, lids, orbit) Surgery (ocular, orbital, postcataract) Trauma Pseudoptosis Dermatochalasis Duane retraction syndrome Microphthalmos/phthisis bulbi Enophthalmos Pathologic lid retraction of the opposite eye Chronic (old) Bell's palsy Voluntary blepharospasm Hypotropia Hysteria Adapted from Thompson BM, Corbett JJ, Kline LB, Thompson HS: Pseudo-Homer's syndrome. Arch Neurol 39:108-111, 1982, and Claser JS (ed): Neuro-ophthalmology. 3rd Ed. Lippincott,Williams & Wilkins, Philadelphia, 1999, pp. 59-63, with permission.

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upgaze. Patients with Marcus Gunn jaw-winking have a ptotic eyelid that retracts during contraction of the external pterygoid muscle (e.g., nursing, chewing, mouth opening, or moving jaw forward or side to side; Fig. 6-25), presumably from anomalous innervation of the levator by the trigeminal nucleus (trigeminooculomotor synlunesis). Neurofibromas and lid tumors such as hemangiomas should also be suspected in children with ptosis. Oculomotor palsies and Horner’s syndrome related to birth trauma should also be considered in this age group. Acquired painless ptosis of gradual onset often is caused by levator dehiscence-disinsertion, but neurologic causes include disorders of neuromuscular transmission or myogenic causes. In myasthenia gravis, the ptosis may fluctuate, with a tendency to worsen at the end of the day, and the lids usually are affected bilaterally and asymmetrically. Ptosis may be the only manifestation of myasthenia gravis, or there may be varying degrees of accompanying orbicularis oculi weakness, ophthalmoparesis, or generalized weakness, and the pupils are normal. Fatigue, Cogan’s lid twitch, and curtaining are other important eyelid signs in myasthenia, although they are nonspecific and may be seen with ptosis caused by other disorders. In sustained upgaze, a myasthenic eyelid may fatigue and droop. Cogan’s lid twitch is a “jump” in eyelid position elicited by having the myasthenic patient look down for several seconds then back up to primary gaze, during which the upper eyelid may overshoot, then fall back down because of rapid recovery and then fatigability of the levator muscle. With unilateral ptosis (the abnormal one) and contralateral lid retraction (the normal one, obeying Hering’s law), manual elevation of the ptotic lid may allow the retracted one to fall slowly, in so-called curtaining (see Fig. 6-23). Myasthenic lids may also flutter near the lash margin. Edrophonium may dramatically

A

Principles of Diagnosis: Common Presenting Symptoms

elevate a ptotic lid in myasthenia (Fig. 6-26), thereby establishing the diagnosis, and acetylcholine receptor antibodies and electromyography may also be helpful. Patients with Lambert-Eaton syndrome may have bilateral ptosis, usually without ophthalmoparesis. In chronic progressive external ophthalmoplegia, the ptosis usually is symmetrical and accompanied by bilateral ophthalmoparesis and orbicularis oculi weakness. In myotonic dystrophy, bilateral ptosis is associated with bifacial weakness, “hatchet facies,” temporal balding, and myotonia. Acquired painless ptosis of sudden onset strongly suggests a neurologic cause, especially in unilateral cases with pupillary involvement. Mild unilateral ptosis accompanied by miosis and pupillary dilation lag in the dark implies Horner’s syndrome (see “Disorders of the Pupils” earlier in this chapter), whereas more prominent unilateral ptosis with adduction, elevation, and depression deficits, with or without pupillary mydriasis, suggests an infranuclear third-nerve palsy (see “Disorders of Eye Movements” earlier in this chapter). A unilateral nuclear oculomotor lesion causes bilateral ptosis (nuclear ptosis) worse ipsilaterally, ipsilateral third-nerve dysfunction, and bilateral superior rectus weakness (see “Disorders of Eye Movements”). A unilateral cerebral hemispheric lesion may in rare instances cause contralateral or bilateral ptosis (cortical ptosis) without third-nerve or sympathetic involvement. Deficient voluntary lid elevation (apraxia of eyelid opening) can mimic levator paralysis until the patient opens the eyes without ptosis after a sudden command or stimulation. This disorder occurs insidiously in association with extrapyramidal disorders such as Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, and, rarely, acutely with hemispheric lesions. Non-neurologic causes of ptosis probably are more common in

B

FIG. 6-25. Marcus Cunn jaw-wink phenomenon. (A) This man has had ptosis of the right upper eyelid since birth (congenital ptosis). (13) Upon opening his mouth, the right upper eyelid elevates, presumably because of congenital aberrant innervation of the levator palpebrae muscle (normally third nerve) by the motor nucleus of the trigeminal nerve 0. Chewing, sucking, and moving the jaw from side to side also elicit right upper eyelid elevation. (Courtesy of Brian R. Watts, MD.)

Chapter 6 rn

Disorders of the Eyes and Eyelids

67

A

B

FIG. 6-26. (A) Bilateral ptosis in ocular myasthenia gravis (left eyelid much worse than right eyelid). The patient also had bilateral ophthalmoparesis and orbicularis weakness. (6) Both eyelids elevated after intravenous administration of 10 mg of edrophonium.

the general population than the causes discussed earlier, and these disorders should be suspected in isolated cases. In particular, in many older adults the aponeurosis of the levator muscle may dehisce or disinsert from the tarsal plate of the upper eyelid. The eyelids usually are affected bilaterally, but levator function is still preserved. Dermatochalasis, the hanging of skin over the eyelid caused by loss of skin elasticity, may mimic ptosis (pseudoptosis). In addition, ptosis may be suspected incorrectly when in fact the upper eyelid of the other eye is pathologically retracted. Other than treating the primary cause, ptosis can be managed by taping the eyelids open or with eyelid “crutches” attached to eyeglasses. Surgical management of ptosis is more effective in chronic cases, and popular procedures include shortening of the levator muscle or aponeurosis and Miiller’s muscle resection.

Eyelid Retraction The two most common causes of eyelid retraction are thyroid eye disease and dorsal midbrain lesions. Thyroid lid retraction,

sometimes the only ocular abnormality in these patients, is unilateral or bilateral and often is accompanied by lid lag (Fig. 6-27). The exact mechanism is unclear. Exposure keratopathy and dry eye can complicate the lid retraction and lid lag, especially in patients with infrequent blinking. Artificial tears usually are sufficient, but some thyroid patients with lid retraction need surgical levator lengthening or excision of Miiller’s muscle. Supranuclear eyelid retraction caused by dorsal midbrain dysfunction (Collier’s sign) usually is bilateral and often associated with the supranuclear vertical gaze paresis characteristic of Parinaud’s syndrome (Fig. 6-28). Pupillary light-near dissociation and convergence-retraction nystagmus may also be observed. The eyelid retraction is exacerbated on attempted upgaze, but usually the lids relax on downgaze. Children with hydrocephalus may develop bilateral lid retraction and tonic downward eye deviation (“setting sun sign”) caused by periaqueductal involvement. Schmidtke and Buttner-Ennever (1992) postulated that neurogenic lid retraction can result from either a unilateral lesion of the nucleus of the posterior commissure or interruption of the

Principles of Ambulatory Neurology and the Approach to Clinical Problems

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Principles of Diagnosis: Common Presenting Symptoms

posterior commissure, both of which would result in decreased inhibition of levator neurons in the central caudal nucleus (Fig. 6-22). A unilateral lesion involving the nucleus of the posterior commissure and the oculomotor fascicle would produce an ipsilateral third-nerve palsy with ptosis and contralateral lid retraction (plus-minus lid syndrome). Rarely, lid lag can accompany lid retraction in patients with these dorsal midbrain disturbances. Lid retraction may also be associated with parkinsonism, myotonia, myositis, sympathetic overexcitation, Marcus Gunn jaw-winking, pseudoretraction caused by contralateral ptosis, and oculomotor synlunesis (eyelid elevation during adduction). Abnormal Blinking A blink is a temporary closure of both eyelids and normally does not interfere with the continuity of vision. The mean spontaneous blink rate is 16 f 9 blinks per minute. Stimulation of the cornea or eyelashes normally produces a blink, and this reflex, mediated by the trigeminal and facial nerves, can be abnormal if corneal sensation or eyelid closure is defective. Other normal blink reflexes include blinking to bright light or dazzle (brainstem mediated)

A

FIG. 6-28. Eyelid retraction caused by dorsal midbrain infarction (Collier‘s sign). The patient also had a mild supranuclear upgaze paresis as part of Parinaud’s syndrome. (Courtesy of Steven L. Galetta, MD.)

and to a threatening gesture such as a menacing hand. Evidence suggests that this blink to visual threat is cortically mediated because patients with hemianopias from occipital and parietal lesions as well as those with visual neglect from right parietal lesions may not blink when menaced from within the defective field. Decreased spontaneous blink rates may be characteristic of thyroid eye disease or parkinsonism, although reflex blinking can be increased in the latter (Myerson sign, in which the patient persistently blinks with each tap by the examiner on the forehead). Increased blink rates are associated with schizophrenia and Tourette’s syndrome. Essential blepharospasm is an idiopathic disorder characterized by involuntary bilateral eyelid closure ranging from increased blink frequency to severe, sustained spasms of the orbicularis oculi. The treatment of choice is localized injections of botulinum toxin around the eyelids. Blepharospasm accompanied by dystonic movements of the lower face or neck is called Meige’s syndrome. In hemifacial spasm, the whole face on one side contracts with eyelid closure and elevation of the corner of the mouth. This disorder may be idiopathic or may indicate vascular compression of the facial nerve, and it should be distinguished from facial tics that begin in childhood and from focal seizures, which should correlate with an abnormal electroencephalogram. Botulinum injections and neurosurgical decompression of the facial nerve trunk near a tortuous or dolichoectatic artery of the posterior circulation have both been advocated as effective therapies. Small unilateral contractions of the facial muscles characterize facial myokymia, which, when associated with ipsilateral facial contracture and weakness (spastic-paretic facial contracture), suggests a pontine lesion rostra1 to the seventh nerve nucleus. Eyelid myokymia, small annoying twitches of the upper or lower eyelids, usually is benign and may be caused by stress, fatigue, nicotine, or caffeine.

B

FIG. 6-27. (A) Eyelid retraction and (6) lid lag (the lids fail to relax in downgaze) related to hyperthyroidism (Graves’s disease). This 80-yearold man presented with 2 months of horizontal double vision and a 30-pound weight loss over 1 year. He had partially restricted eye movements in all directions of gaze, and MRI revealed enlargement of several extraocular muscles. The patient was emaciated and in atrial fibrillation. The pupils were partially dilated by rnydriatic drops.

SUGGESTED READINGS Neuro-ophthalmology Glaser JS (ed): Neuro-ophthalmology. 3rd Ed. Lippincott, Williams & Wilkins, Philadelphia, 1999 Liu GT, Volpe NJ, Galetta S L Neuro-ophthalmology: Diagnosis and Management. WB Saunders, Philadelphia, 2001

Chapter 7

Miller NR, Newman NJ (eds): Walsh and Hoyt’s Clinical Neuroophthalmology. 4th Ed. Williams & Willcins, Baltimore, 1998

Disorders of the Afferent Visual Pathways Albert DM, Jakobiec FA (eds): Principles and Practice of Ophthalmology. 2nd Ed. WB Saunders, Philadelphia, 1999 Beck RW, Cleary PA, Trobe JD et ak The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 329:1764-1769, 1993 Ischemic Optic Neuropathy Decompression Trial Research Group: Ischemic optic neuropathy decompression trial: twenty-four-month update. Arch Ophthalmol 118:793-797, 2000 Liu GT, Glaser JS, Schatz NJ, Smith J L Visual morbidity in giant cell arteritis: clinical characteristics and prognosis for vision. Ophthalmology 101:1779-1785, 1994 Optic Neuritis Study Group: Visual function five years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 115:1545-1552, 1997 Smith J L Whence pseudotumor cerebri? [editorial] J Clin Neuroophthalmol 555-56, 1985 Wall M: Idiopathic intracranial hypertension. Neurol Clin 9:73-95, 1991

Disorders of Eye Movements Bhidayasiri R, Plant GT, Leigh RJ: New concepts of mechanisms for vertical gaze. Development of a scheme to interpret the effects of brain stem lesions. Neurology 54:1985-1993, 2000 Kodsi SR, Younge BR Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 114568574, 1992 Leigh RJ, Averbuch-Heller L, Tomsak RL et ak Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology. Ann Neurol 36:129-141, 1994 Leigh RJ, Zee DS: The Neurology of Eye Movements. 3rd Ed. Oxford University Press, New York, 1999 Liu GT, Crenner CW, Logigian EL et ak Midbrain syndromes of Benedikt, Claude, and Nothnagel: setting the record straight. Neurology 42: 1820-1822, 1992 Plum F, Posner JB: The Diagnosis of Stupor and Coma. 3rd Ed. FA Davis, Philadelphia, 1980 Richards DW, Jones FR, Younge BR Causes and prognosis in 4,270 cases of paralysis of the oculomotor, trochlear, and abducens cranial nerves. Am J Ophthalmol 113:489-496, 1992 Rush JA, Younge BR Paralysis of cranial nerves 111, N, and VI. Arch Ophthalmol9976-79, 1981

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Silverman IE, Liu GT, Volpe NJ, Galetta S L The crossed paralyses: the original brainstem syndromes of Millard-Gubler, Foville, Weber, and Raymond-Cestan. Arch Neurol 52:635-638, 1995 Spector RH: Vertical diplopia. Surv Ophthalmol 38:31-62, 1993

Disorders of the Pupils Burde RM, Landau WM: Clinical neuromythology XII. Shooting backward with Marcus Gunn: a circular exercise in paralogic. Neurology 43:2444-2447, 1993 Grimson BS, Thompson HS: Drug testing in Horner’s syndrome. pp. 265-270. In Glaser JS, Smith JL (eds): Neuro-ophthalmology. Symposium of the University of Miami and the Bascom Palmer Eye Institute. Vol. VIII. CV Mosby, St Louis, 1975 Keane J R Oculosympathetic paresis. Analysis of 100 hospitalized patients. Arch Neurol 3613-16, 1979 Loewenfeld IE The Pupil. Anatomy, Physiology, and Clinical Applications. Vol 1. Wayne State University Press, Detroit, 1993 Maloney WF,Younge BR, Moyer NJ: Evaluation of the causes and accuracy of pharmacologic localization in Horner’s syndrome. Am J Ophthalmol 90394-402, 1980 Morris JGL, Lee J, Lim C L Facial sweating in Horner’s syndrome. Brain 107751-758, 1984 Plum F, Posner JB: The Diagnosis of Stupor and Coma. 3rd Ed. FA Davis, Philadelphia, 1980 Thompson BM, Corbett JJ, Kline LB, Thompson H S Pseudo-Homer’s syndrome. Arch Neurol 39:108-111, 1982 Thompson HS, Pilley SFJ: Unequal pupils. A flow chart for sorting out the anisocorias. Surv Ophthalmol 21:45-48, 1976

Disorders of the Eyelids Caplan LR Ptosis. J Neurol Neurosurg Psychiatry 37:l-7, 1974 Galetta SL, Gray LG, Raps EC et ak Unilateral ptosis and contralateral eyelid retraction from a thalamic-midbrain infarction. J Clin Neuroophthalmol 13:221-224, 1993 Karson CN, LeWitt PA, Calne DB, Wyatt RJ: Blink rates in parkinsonism. Ann Neurol 12:580-583, 1982 Lepore FE Bilateral cerebral ptosis. Neurology 37: 1043-1046, 1987 Liu GT, Ronthal M Reflex blink to visual threat. J Clin Neuroophthalmol 12~47-56, 1992 Schmidtke K, Buttner-Ennever JA Nervous control of eyelid function. A review of clinical, experimental and pathological data. Brain 115:227247, 1992 Thompson BM, Corbett JJ, Kline LB, Thompson H S Pseudo-Homer’s syndrome. Arch Neurol 39:108-111, 1982

FacialPalsv 4

George A. Gates

Facial palsy (FP), the most common cranial neuropathy, distorts and impairs facial function, often to a distressing degree. FP affects speech, eating, and other activities that use the lip musculature (such as playing a wind instrument) and places the cornea at risk for ulceration caused by inadequate lid function. Patients with FP often are afraid they have had a stroke or have a tumor. Most are dismayed about their prognosis and the risks and complications of treatment, and many are confused by contradictory evidence about optimal therapy. Most cases of FP are idiopathic (IFP), formerly called Bell’s palsy. IFP occurs suddenly in otherwise

rn healthy people and has few symptoms besides pain and weakness of one side of the face. The palsy is nearly always unilateral and is intratemporal (peripheral) in location. In 85% of patients with IFP, spontaneous recovery begins after several weeks and is satisfactory in most. However, this benign scenario does not apply to the appreciable number of cases of FP that are caused by specific disorders, such as systemic infection, invasive disease of the middle ear cleft, and skull base neoplasm or trauma, where the chances for spontaneous recovery are low. Most patients with FP recover spontaneously, but a minority

Prinaples of Ambulatoy Neurology and the Approach to Clinical Problems

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need prompt intervention. For accuracy and cost-effectiveness, the physician should follow a logical, stepwise diagnostic approach as a basis for treatment. On one hand, it is important not to assume that all cases of FP are IFP. On the other hand, for reasons of cost, it is advisable to be prudent in ordering tests. Nonetheless, patients with unusual causes often are misdiagnosed and, as a consequence, mistreated. Because society tolerates delayed or inaccurate diagnosis poorly, physicians may order a large battery of initial studies to reduce the risk of later legal action. This chapter reviews the types of peripheral FP that the neurologist is likely to see in a consultative office practice. A brief review of the pertinent anatomy and physiology is given, followed by a synopsis of etiologic considerations and a discussion of current therapies. The term palsy is used to indicate any weakness of the facial muscles upon voluntary effort. Paresis implies present but diminished movement, and paralysis indicates absence of volitional movement. ANATOMIC CONSIDERATIONS Description The facial nerve arises from the facial nucleus and loops around the abducens nucleus and exits the pons just anterior to the root entry zone of cranial nerve VIII (Fig. 7-1). It crosses the cerebellopontine angle slightly anterior to the cochleovestibular nerve, from which it picks up the newus intermedius. In the fundus of the internal auditory canal, the facial nerve exits through a separate foramen superior to the transverse crest and anterior to

the vertical crest. Within the temporal bone, the nerve has four segments with differing susceptibility to disease or injury. Each segment is defined by a bend or genu, in which the direction of the nerve changes markedly. Labyrinthine Segment. The first part of the fallopian canal is the short, narrow labyrinthine segment that passes in immediate proximity to the basilar turn of the cochlea in front and the superior (anterior) semicircular canal behind. Here the nerve is tightly encased in bone with little soft tissue support. Ceniculate Segment. The nerve then widens markedly because of the geniculate ganglion, which houses the cell bodies of the special sensory fibers that supply taste sense to the anterior two thirds of the tongue. The greater superficial petrosal nerve arises anteriorly at the geniculum to exit via the hiatus of the facial canal, traverses the middle cranial fossa, and synapses in the sphenopalatine ganglion. It carries secretomotor fibers from the salivatory nucleus in the pons to the sphenopalatine ganglion, from which postganglionic fibers pass to the lacrimal gland. Injury of the facial nerve at or proximal to the level of the geniculate ganglion results in a marked decrease of lacrimation on the ipsilateral side. Tympanic Segment. The nerve then turns posteriorly to cross the middle ear in the tympanic segment of the fallopian canal. This segment lies adjacent to the oval window, and in 15% of people, the nerve is exposed to the middle ear mucosa because of incomplete bony closure of the canal. At the external genu, the next bend of the facial nerve, it turns inferiorly beneath the ledge of the lateral semicircular canal to enter the vertical mastoid segment. There may be great variability in this segment, with the

Lacrimal

Greater

'JllP

Principlesof Diagnosis: Common PresentingSymptoms

TI

Chorda

P

Stylomastoid foramen

FIG. 7-1. The anatomy of the facial nerve and related structures.

Chapter 7

nerve passing beneath the oval window or even splitting in two to surround the oval window. Mastoid Segment The greatest frequency of positional variation occurs in the mastoid segment. The external genu may be at the level of the inferior end of the lateral semicircular canal or several millimeters posterior to it. This is the area most often injured in mastoid surgery. The very short motor branch to the stapedius muscle exits in the upper part of this segment. Lesions of the facial nerve above this level are associated with loss of the stapedius (acoustic) reflex. Below this, the chorda tympani nerve exits the main trunk just 4 mm above the stylomastoid foramen, passing antegrade to cross the middle ear between incus and malleus. The chorda tympani can often be seen otoscopically at this point. It carries taste fibers to the anterior two thirds of the tongue and secretomotor parasympathetic fibers to the submandibular and sublingual salivary glands. Lesions above the takeoff of the chorda tympani nerve result in loss of taste sensation and decreased salivation from these two glands. After exiting the temporal bone at the stylomastoid foramen, the nerve takes its fourth bend as it turns in an anterosuperior direction to pass through the parotid gland on its way to the facial muscles. The nerves to the postauricular muscles and to the posterior belly of the digastric muscle arise at the stylomastoid foramen level. From the stylomastoid foramen to the motor endplates, the nerve length varies from 8 to 12 cm in the adult, depending on patient’s size and the muscle group in question. The soft tissue structures that surround the facial nerve in the fallopian canal form a multilayered sheath, consisting of the periosteal lining of the inside of the fallopian canal; the layer of vessels, primarily veins, that surround and cushion the nerve proper (the fallopian canal is the primary vascular channel for the temporal bone); and the epineurium, which, in a single fascicular nerve such as the facial, is contiguous with the perineurium. The perineurium is a thin, epithelioid layer of cells and connective tissue that surrounds the entire monofascicular intratemporal facial nerve. It acts as a diffusion barrier to prevent extracellular fluid from entering or leaving the endoneurium. It has radial fibrous connections that segregate the fascicle into compartments. Clinical Implications

The long intraosseous course (33 mm) of the fallopian canal through the temporal bone renders the facial nerve vulnerable to trauma of the skull base. In addition, because of its intimate proximity to the middle ear cleft, the nerve often is involved by inflammatory processes arising therein. The narrowness of the intralabyrinthine segment of the proximal fallopian canal appears to be an important factor in poor recovery from lesions affecting the proximal portion of the nerve. With the exception of this short segment, the nerve is surrounded by a cushion; here, the nerve is encased in a bony sleeve. This leaves little room for expansion when the nerve is injured or infiltrated by disease. The multilayered sheath surrounding the facial nerve is thought to be a factor in the pathogenesis of FP. The sheath limits the inflammatory swelling of the nerve and probably contributes to the increase in pressure that occurs in IFP and trauma. Cutting the sheath is essential in decompression. The perineurium limits the egress of inflammatory endoneurial fluid, which probably delays recovery from inflammatory lesions. The facial nerve carries motor, secretomotor, pain, and special sense (taste) fibers. Throughout its intratemporal course, the facial nerve is a single fascicle, and the axonal fibers are distributed

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71

randomly across its cross-sectional area. Therefore, it is unusual to develop a weakness of a single part of the face (e.g., the forehead) from a discrete injury, such as a partial section of the nerve; rather, there is weakness of all parts of the face. Because of this admixture of fibers, faulty reinnervation (synkmesis) is a common sequel of facial neuropathy, even in the absence of measurable degeneration of the nerve. Testing the functions subserved by the fibers carried in these branches of the facial nerve should permit a judgment to be made about the level of the lesion. Clinical applications of the topographic anatomy of the facial nerve are discussed later in this chapter. CLASSlFlCAllON In 1943, Seddon created a classification of nerve injuries that serves as a convenient conceptual framework for describing degrees of injury. In neurapraxia (conduction block), the axon is anatomically normal, and full recovery is expected. The majority of patients with IFP have a neurapraxic lesion. In axonotmesis, Wallerian degeneration of some axons occurs, and good but not perfect recovery results from regeneration of these axons through intact nerve sheaths. The degree of recovery is proportional to the number of degenerating axons and the number that reinnervate the appropriate motor endplates. The major sequel of axonotmesis is synlunesis, which is thought to result from misdirection of regenerating axons. Patients with complete paralysis caused by IFP usually have an axonotmetic lesion. Neurotmesis is interruption of both the axon and the sheath, and recovery in this instance is much poorer. Here, the loss of axons and the potential for misdirected regeneration is greater. Trauma is the prototypical cause of neurotmesis. Sunderland’s five-degree classification system expands Seddon’s neurotmesis into three levels of injury. First and second degrees of injury correspond to Seddon’s neurapraxia and axonotmesis, respectively. Third degree implies loss of endoneural tubes; fourth degree, the interruption of the perineurium; and fifth degree, complete physical transection of the nerve. Spontaneous recovery predictions are based on the degree of damage: (1) complete, (2) synlunesis, (3) incomplete with synlunesis, (4) poor, and (5) minimal or none. First-degree injury is seen in mild cases of IFP with paresis; second-degree, with paralysis caused by IFP or herpes zoster oticus; third-degree, with more invasive inflammatory lesions; fourth-degree, from contusion associated with blunt trauma; and fifth-degree, from penetrating trauma (e.g., knife wound). CLINICAL SYNDROMES Idiopathic Fadal Palsy Most cases of FP have no obvious cause and therefore represent IFP. The older term Bell’s palsy, given in honor of great British neurologist Sir Charles Bell, is best avoided because it is often used as a generic term for FP of any type. IFP usually afflicts adults and generally resolves without sequelae. Causes. Theories of causation abound. Autonomic dysfunction, allergy, and reactivation of latent herpes simplex virus infection have been proposed over the years; the latter is currently the most supported theory. Evidence of viral causes is indirect, but no other theory appears more likely. Mori and colleagues (1982) studied 299 patients over the age of 10 with a clinical diagnosis of Bell’s palsy during the 15-year period ending in 1981. They found

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Principles of Ambulatoy Neurology and the Approach to Clinical Problems

that the yearly incidence of a significant rise in the serum complement-fixing antibody to the following viruses varied from 25% to 37% of cases; herpes simplex was noted in 35 cases, varicella-zoster in 21, influenza virus (A and B) in 39, and mumps virus and adenovirus in 11 cases each. Because increases in serum antibodies to these viruses also occur in the general population without FP, meaningful interpretation of these uncontrolled data is difficult. Perhaps the most direct evidence of herpes simplex infection as the cause comes from Murakami and colleagues, who found herpes simplex DNA by polymerase chain reaction in the endoneurial fluid from the facial nerve and in the adjacent posterior auricular muscle of patients with idiopathic facial palsy but not in control patients nor in patients with the Ramsay Hunt syndrome, who were found to harbor varicella-zoster virus DNA. A spate of recent reports showing improved outcomes for patients with IFP treated with an antiviral agent, acyclovir, lend support to viral causes (see Steiner and Martin 1999 for a review). Histopathology. The known histologic changes occurring in IFP are the result of chance examinations and are all at the light microscopic level and consist of intraneural hemorrhages, edema, and cellular infiltration and perivascular lymphocytic infiltrates in the fallopian canal. The spectrum of pathology in the average case is unknown, and attempts to develop an animal model have not been successful. It seems clear that the cases associated with severe degeneration and poor outcome have involvement of the nerve proximally in the intralabyrinthine segment. Evidence from intraoperative electric stimulation suggests that the level of distal extension varies and that many sites in the fallopian canal are affected. However, these observations can be made only in cases undergoing surgical decompression because of severe degeneration of the nerve, and they may not apply to all cases of IFP. Natural History. Most cases are of rapid onset, generally within a few hours. In 40%, the patient is able to move the face, though weakly (paresis). In the rest, the face is totally paralyzed. Even in the latter group, degeneration of the nerve is not the rule; neurapraxia (conduction block) is the most common finding. Recovery from neurapraxia is prompt and complete. Incomplete recovery rates varied from 15% to 43% of cases in a series spanning 15 years reported by Pietersen. Incomplete recovery may result from another cause indistinguishable clinically (except for the poor recovery) from IFP, such as aforrnefruste of Ramsay Hunt syndrome. Recovery of some degree of facial motion is the rule, and absence of any return by 3 months after onset raises the possibility that the presumptive diagnosis of IFP is incorrect. Facial Palsy Caused by Systemic Infection

Viral. FP is known to occur in varicella-zoster virus, EpsteinBarr virus (infectious mononucleosis), measles, rubella, rabies, mumps, cytomegalovirus, infectious hepatitis, and human immunodeficiency virus infections. Herpes zoster oticus, described by J. Ramsay Hunt and also known as the cephalic zoster syndrome, is characterized by severe retroauricular pain; vesicles in the tympanic membrane, external auditory canal, and pinna as well as the base of the tongue; redness of the chorda tympani nerve; complete facial paralysis; hyperacusis with dysacusis; and vertigo. It is more prevalent in older patients, and the outlook for complete recovery is poor, although most are not left with a disabling defect. Bacterial. Numerous bacterial disorders cause systemic neuropathy, which may include FP. Well-known but rare examples in North America are tetanus, brucellosis, typhoid fever, leptospirosis, and diphtheria. In general, it is unlikely that FP would be the

Principles of Diagnosis: Common Presenting Symptoms

sole manifestation of the underlying disorder. Approximately 10% of patients with Lyme disease, a systemic spirochetal infection with Borrelia burgdorferi that follows the bite of the deer tick, Zxodes dammini, develop FP, and in one quarter of these cases, the palsy is bilateral. Of note, full recovery of facial function occurred in 86% of a study group of patients with Lyme disease, with or without treatment, in an average of 30 days. Occasionally, a patient with exposure history and symptoms suggestive of Lyme disease but negative serologies has a mimicker of Lyme disease such as ehrlichiosis. Chronic granulomatous disorders known to be associated with facial paralysis are sarcoidosis (in which bilateral palsy is not uncommon), leprosy, and syphilis. Facial Palsy Associated with Middle Ear Disease

FP was a common complication of middle ear and mastoid disease in the preantibiotic era. Acute otitis media is still an occasional cause of FP in children. Children experience FP infrequently, and seldom is the cause idiopathic. However, most cases of FP secondary to middle ear disease are caused by cholesteatoma or chronic otitis media. It is generally assumed that FP occurring in the course of acute otitis media results from congenital dehiscences in the fallopian canal, which permit diffusion of inflammatory mediators into the exposed nerve. In this instance, the FP remits as the otitis media subsides. Subacute otitis media with masked infection of the mastoid (so-called masked mastoiditis) is an occasional cause of FP in children. Clinically, the patient’s tympanic membrane and middle ear may have recovered from the acute inflammation and may be normal upon examination. Persistent pain over the mastoid and subtle radiographic evidence of clouding and demineralization are the chief clinical manifestations. Prompt facial nerve decompression is indicated. In chronic otitis media, the facial nerve may be involved at any point within the temporal bone but most often in the mastoid segment. Cholesteatomatous or osteitic erosion of bone is the pathologic mechanism. Prompt surgical decompression is essential to prevent irreversible paralysis. Immunocompromised patients, notably older diabetics, may develop a progressive infection of the external ear canal known as necrotizing or malignant otitis externa. The facial nerve is the most common of the posterior cranial nerves to be involved in necrotizing otitis externa. The site of lesion usually is extratemporal, and the mechanism of palsy is a neurotoxin elaborated by the causative organism Pseudomonus aeruginosa. Except for local debridement, surgical therapy is contraindicated. Appropriate and intensive antipseudomonal antibiotic therapy with hyperbaric oxygen in advanced cases is usually curative. Facial Palsy Caused by Neoplasm

Primary neoplasms of the facial nerve are rare and generally suspected clinically only when the presumed diagnosis of IFP is proved erroneous by the absence of any signs of recovery by 3 months. Schwannomas of the facial nerve usually grow to substantial size before weakness of the face occurs, and only about one quarter of patients present with FP. Neoplasms involving the facial nerve secondarily are more common. Among these, the acoustic neuroma (vestibular schwannoma) and other cerebellopontine angle tumors are important but rare causes. Patients with neoplasms of the temporal bone, such as the glomus jugulare tumor, may present with FP.

Chapter 7

Facial Palsy Caused by Trauma The second most common cause of FP is trauma, which includes penetrating as well as closed head injury. External injury is far more common than iatrogenic lesions. Birth trauma, secondary to forceps application or extension of the head during version, is rare; excellent recovery is the rule. Patients with delayed-onset FP after blunt head trauma are treated expectantly as for IFP. If the paralysis is of immediate onset, there is no recovery of motion in 25% or more of cases. Therefore, surgical decompression usually is recommended in traumatic facial paralysis of immediate onset because one cannot ensure physical integrity of the nerve. Facial Palsy in Primary Neurologic Disorders Cuillain-Bar& Syndrome. FP of more proximal origin is generally related to infection, most often the postinfectious polyneuritis syndrome of Guillain-Barri-. FP is common in Guillain-Barri- syndrome but rarely the sole manifestation of it. Bilateral FP (facial diplegia) often is seen in this syndrome. Other causes of facial diplegia are sarcoidosis and Lyme disease. Infectious polyneuritis is a self-limited disorder, and therapy is directed toward general support of the patient. Melkersson Syndrome. A rare disorder, the MelkerssonRosenthal syndrome, is characterized by recurrent, sometimes alternating FP associated with facial edema, granulomatous cheilitis, and fissured tongue (lingua plicata). The pathogenic mechanisms underlying this enigmatic disorder are unknown; an autosomal dominant pattern has been postulated. Spontaneous but incomplete recovery is the rule, but recurrence is common. Because repeated episodes result in progressively poorer recovery, surgical decompression may be considered after two episodes. After decompression my patients have reported recurrent episodes of facial swelling but do not experience the recurrent facial palsy, which suggests anecdotally that the underlying process continues even if facial paralysis has been prevented.

DIAGNOSTIC EVALUATION Patient History and Physical Examination

Important aspects of the patient history are the rapidity of progression and any related events at the time of onset. Pain is common, more so in older patients with IFP. A history of chronic otorrhea should be sought. Intermittent spasm or facial tic and a palsy that progresses slowly suggest a slow-growing neoplasm as the cause. In most cases of IFP, the onset is fairly rapid-over a few hours to 1 or 2 days-and no other symptoms except pain are present. The physical examination should establish first that all branches of the facial nerve are affected (upper motor lesions spare the forehead and orbicularis oculi) and, second, the extent of the palsy. Is tone present? Is any movement present? Grading the degree of weakness using the House-Brackmann scale is useful (Table 7-1). Examination of the cornea for abrasion or ulceration should be routine, as should testing for absence of the corneal reflex that might be seen with a large cerebellopontine angle lesion. Special attention must be paid to the tympanic membrane and external auditory canal, looking for even subtle signs of inflammation, especially if there has been a recent history of otalgia, ear pressure, or otorrhea. Any patient with abnormalities of the tympanic membrane should be referred to an otologist for

Facial Palsy

73

rn TABLE 7-1. House-Brackmann Facial Paralysis Rating Scale Stane

Dexri~on

I II

Normal facial motion Slight weakness Mild to moderate weakness Moderate to severe weakness Near total paralysis (minimal motion) Complete paralysis

111

IV V VI

’As modified to apply to the acute stage of paralysis. Additional descriptorsfor synkinesis, tic, and contracture may be used to describe the recovery stage of facial paralysis. Interpretation of this scale varies, but in general, stages I and VI correspond to 100% and 0% motion; stages II and V correspond to 5% to 25% loss or persistence of motion, respectively; and stages 111 and IV correspond to 25% to 50% loss and 50% to 75% loss of motion, respectively.The scale implies assessment of voluntary motion but may be applied to loss of involuntary motion, such as that seen in central lesions; however, this should be noted separately.

otomicroscopic evaluation. A crust on the drumhead, for example, might be the only sign of a cholesteatoma. Occasionally, the chorda tympani nerve appears red as it passes across the underside of the posterosuperior aspect of the tympanic membrane. This is a subtle sign of Ramsay Hunt syndrome. Be careful to examine behind the pinna: Battle’s sign (postauricular ecchymosis) is a common but subtle sign of recent trauma. Physical Examination of Facial Motor Function. Three degrees of motor impairment are seen in lower motor nerve lesions: paresis, paralysis with tone, and flaccid paralysis. Paresis describes weakness of voluntary motion; paralysis indicates absence of motion. Paralysis with preservation of muscle tone is typical in most cases of IFP. Flaccid paralysis (i.e., with sagging of the face) occurs infrequently (and generally in older patients) and indicates a severe loss of neuronal input to the facial muscles, so the extent of nerve dysfunction is judged to be maximal. There are also three clinical phases of palsy. The first is loss of emotional expression: The patient is not able to smile at a joke, for example, but can smile voluntarily. The second phase is loss of voluntary motion. The third is loss of resting tone. Recovery from paralysis follows the reverse order: For example, recovery of facial tone precedes restoration of voluntary motion. This progression of clinical findings applies to all peripheral lesions regardless of the specific origin. Upper motor neuron facial palsy involves only the lower part of the face because of the bilateral innervation of the neurons supplying the upper face and eyelids. Hearing Testing. Tuning fork tests are useful to search for hearing loss on the side of the palsy. Placing a stethoscope in the patient’s ears and sounding a tuning fork softly and again loudly at the bell may reveal unequal suprathreshold hearing. In Ramsay Hunt syndrome, the patient may experience the sound louder or distorted on the affected side, especially with the louder stimulus. Clinical hearing tests such as the finger rub or whispered-voice testing are commonly used by neurologists for screening purposes. However, these clinical tests are imprecise, and little weight should be placed on them for diagnosis. Any complaint of hearing loss or asymmetry of these screening tests should be followed by standard audiometric testing. Head and Neck Examination. Careful palpation of the parotid gland and upper neck should always be done. FP occurs often in cases of parotid malignancy. The onset FP in parotid malignancy is slow and often begins in one branch. It may be the presenting symptom in deep-seated tumors, some of which are detectable only by scanning. Metastatic squamous cell carcinoma and lymphoma are other invasive lesions that may cause FP.

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

Staging of Palsy Staging is a dynamic process that may change over the first 3 weeks of the disorder. Therefore, patients should be observed closely during this time before a final staging and prognosis is offered. The most useful clinical staging system is the simplest: the House-Brackmann scale, shown in Table 7- 1. This has been widely used by otologic surgeons and has shown great merit because it is applicable to all types of facial nerve disorders and is easily learned and used. The stages are not meant to imply equal intervals of function or dysfunction. Stage I indicates normal voluntary facial function (i.e., 100% normal), and stage VI indicates complete absence of motor function (0% function). Stage I1 patients have very mild weakness (5% to 10%) detectable by close inspection, and stage V patients have only slight volitional motion (90% to 95% loss) that also requires close inspection to detect. Stage I11 and IV cases have obvious decrements, with stage I11 being slightly better than a theoretical 50% decrease in motion and stage IV being slightly worse. These stages are convenient estimates of function. More elaborate systems have been proposed for research purposes. The classification applies only to an overall assessment of voluntary movement, which encompasses the parameters of strength, range, and speed of motion. In practical terms, however, one compares the magnitude of maximum displacement of distinct structures (e.g., oral commissure, brow elevation, eye closure) from their resting position on the opposite sides of the face. Patients with IFP who have residual facial motion (paresis) should be considered a distinct group because they recover satisfactorilywithout treatment and do not need additional testing after the history has been elicited and the physical examination conducted. These patients would be staged I1 to IV, depending on the degree of paresis. Patients with grade V to VI IFP should undergo electrical testing and basic topognostic testing (Schirmer’s) in anticipation of delayed recovery. Topognosis

It is useful for patients with complete paralysis to study the various branches of the facial nerve in an attempt to localize the site or level of the lesion. Most important are the status of ipsilateral lacrimal function and acoustic reflex. Patients with a poor prognosis are potential candidates for surgical decompression. The site of lesion materially affects the surgical approach. Schirmer‘s II Test. Lesions at or proximal to the geniculate ganglion usually affect lacrimal function to a noticeable degree. Tests of resting lacrimal activity (Schirmer’s I) are less sensitive than stimulated function tests (Schirmer’s 11). Absence or severe diminution of lacrimation generally indicates a poor prognosis because of both the nature of the lesion and its proximal site. Proximal lesions recover slowly and incompletely as a rule because of the long distance over which regenerated axons must pass and because the cause, which is often the varicella-zoster virus, usually is associated with severe neural degeneration. The stimulated Schirmer’s I1 test is done with porous paper strips placed over the lower lid into the conjunctival sac; after a short wait, both nasal cavities are touched briefly with cotton applicators to stimulate reflex lacrimation. The reason for waiting is to let the tears pooled in the lower fornix to wet the paper to achieve a starting point from which to note further wetting by stimulated lacrimation. Generally, the degree of wetting is measured after 1 or 2 minutes, and the two sides are compared. A

Principles of Diagnosis: Common PresentingSymptoms

reduction to 25% of the normal side indicates a significant impairment. Usually, there is little if any flow on the abnormal side when the lesion is at the geniculate ganglion. The test may be falsely positive in trauma cases in which the greater superficial petrosal nerve is injured independently of the facial nerve. Stapedius Reflex. Both stapedius muscles contract reflexively in response to the loudness of a sound presented to either ear. Also known as the acoustic reflex, it is best measured with an electroacoustic immittance audiometer that can test the reflex ipsilaterally and contralaterally. Loss of the efferent limb of the reflex is seen in most cases of facial paralysis, and recovery of the reflex precedes the return of facial motion. The reflex may be normal in patients with paretic lesions and has no localizing value in that instance. Absence of the stapedius reflex is expected in all cases of intratemporal facial paralysis arising proximal to the stapedius muscle, and its return is an early sign of recovery that usually precedes recovery of facial motion. The test takes only 1 to 2 minutes per ear and is widely available in otologists’ offices. The chief value of the test is to exclude the uncommon case of FP of occult extracranial origin, such as neoplasm in the parotid gland. Taste and Salivation. Loss of taste and stimulated submandibular salivation are to be expected in most cases of FP. Because of the variability in taste testing in normal people, taste testing has little value for localization or prognosis in routine cases. Similarly, saliva flow measurements are no longer used in clinical practice. Electrical Studies

Assessment of neural status by electrical tests is useful only for patients with complete paralysis. The tests are almost always normal in paretic patients. Threshold of Stimulability. The normal facial nerve can be stimulated using a square wave pulse with an active electrode on the overlying skin and an indifferent electrode at a distance. By varying the current intensity, one can determine the electrical threshold of the nerve (i.e., the amount of current flow necessary to produce a just visible twitching of the face). The test is most reproducible when the thin skin over the branch to the eyelid is selected and the skin is thoroughly cleaned. Avoid electrode paste: It promotes lateral spread of the current and artifactually raises the observed threshold. The average threshold for the nerve to the orbicularis in my hands is 0.75 mA, and for the marginal mandibular branch, it is 1.0 mA. I use as abnormal a threshold of 2.0 mA. There appears to be little justification to use the old criterion of abnormality (a 3-mA difference between the two sides of the face) that was advocated in Europe in the 1960s. I use the Hilger facial nerve stimulator and stimulate over the nerve to the orbicularis oculi and over the marginal mandibular nerve. The normal nerve and the neurapraxic nerve distal to the lesion have identical thresholds; rising thresholds indicate degeneration. Given that axonal degeneration proceeds distally at a slow rate, it may take 72 hours or more for the electrical thresholds on the face to become abnormal. Retention of normal thresholds after 72 hours in the presence of a complete facial paralysis suggests that the lesion is neurapraxic and that recovery will be complete. However, thresholds may worsen over the first week or two, so it is advisable to retest in the first 3 weeks. Absence of stimulability indicates severe degeneration and indicates a poorer prognosis. Elevated thresholds suggest partial degeneration, but the correlation of abnormal thresholds with outcome is too variable to use

Chapter 7

for clinical decision making. Thresholds of the regenerated nerve remain elevated, although at levels lower than during the acute episode. Maximal Nerve Stimulation. Advocates of this test suggest that it becomes abnormal sooner than threshold tests and provides better clinical evidence of nerve degeneration. It is done with the facial nerve stimulator turned to a suprathreshold level. The examiner visually compares the strength of the response on the two sides using a scale of 0 to 4. A score of 4 is assigned if the two sides have equal contraction, and a score of 2 is given when the palsied side contracts only 50% of the normal side. The test is more painful than the threshold test and is subject to interpretation by the examiner. In my experience, the maximal stimulation test results parallel the nerve excitability threshold test results. Others rely heavily on the maximal stimulation test results to indicate neural degeneration, which corresponds to a score of 0 to 1 (25% or less of the normal side). Nerve Conduction. Nerve conduction studies also use percutaneous stimulation, and in general the results parallel those of threshold testing. Needle electrodes placed in the muscle record the response, and the internal circuitry of the stimulator-recorder calculates the conduction velocity. Electromyography. The electromyogram (EMG) is used to verify that degeneration has occurred and is also used on occasion to determine whether regeneration is under way. Unfortunately, the EMG cannot detect fibrillations, the EMG hallmark of degeneration, until nearly 3 weeks after the onset of the paralysis, too late to make any useful treatment decision. On the other side of the coin, voluntary motor units are noticeable on the EMG weeks before any return of visible facial motion. Such information may be of interest and reassurance to concerned patients. Electroneuronography. Electroneuronography (ENOG) compares the amplitude of the compound muscular action potential evoked by percutaneous stimulation over the main trunk of the nerve and recorded via skin electrodes on the two sides of the face. It presumes that the number of functioning axons is proportional to the height of the evoked electric potential. Test results may vary with the positioning of the electrodes and the skill of the examiner; variations of up to 20% between sides of normal subjects have been noted. Some use ENOG as an indicator of the need for facial nerve decompression in IFP, herpes zoster oticus, and trauma. A compound muscular action potential decrease on the affected side to less than 10% of that on the normal side indicates substantial degeneration of the nerve and warrants consideration of decompression (see “Surgical Treatment” later in this chapter for a full discussion). Correspondingly, when the ENOG on the affected side is greater than that amount, the spontaneous outcome is likely to be favorable.

Laboratory Tests Hematologic. If systemic infection is suspected, the peripheral blood should be studied to determine the hemoglobin, hematocrit, white blood cell count, and sedimentation rate. Antibodies to specific disorders may be ordered at the physician’s discretion. The value of the routine blood studies is marginal in young patients with facial paresis caused by IFP. However, in older patients with IFP, the prevalence of diabetes mellitus is higher than in the general population, and screening for systemic metabolic disorders is appropriate. A fasting blood sugar and urinalysis should be done in older patients who have not had periodic

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assessment of their health status. Routine tests for systemic disease generally are not warranted in cases of IFP in the absence of some indication in the patient history and physical examination of an underlying process. Radiologic. Routine imaging of the temporal bone or posterior cranial fossa is not indicated in patients with paresis caused by suspected IFP who have a normal otologic examination. It is highly unusual to discover occult mastoid disease in patients with no prior history and normal physical examination results. Magnetic resonance imaging (MRI) studies have shown transient increases in gadolinium uptake in some cases of acute FP, but this finding has no value in medical treatment decisions. In patients with recurrent FP, slowly progressive palsy, or an abnormal physical examination, computed tomography (CT) and MRI studies of the temporal bone and posterior fossa are vital. Temporal bone pathology, including facial nerve schwannoma, would be suspected. Patients with a presumptive diagnosis of IFP who do not show any evidence of recovery by 3 months, and certainly by 6 months, should have a complete neuroradiographic examination to evaluate the possibility of an occult cause. CT scans are very helpful in assessing widening of the fallopian canal, with the possibility of facial neuroma in mind.

MANAGEMENT OF IDIOPATHIC FACIAL PARALYSIS The principal treatment decision-to use short burst of corticosteroid or not-is based on degree of paralysis, presence of pain, and indicators of poor prognosis. Patients with paresis recover fully and therefore do not need therapy. However, pain relief is notable after the administration of a corticosteroid agent. Corticosteroid is given to prevent worsening of the process causing the paralysis. Therefore, the earlier the onset of therapy, the better. Although the evidence of a better outcome in patients with IFP treated with corticosteroid is not consistent, it is generally persuasive. Antiviral therapy has become a common adjunct to corticosteroid treatment since the first edition of this book. In cases of suspected herpes zoster oticus, acyclovir therapy is recommended. For patients with suspected Lyme disease, a course of an appropriate antimicrobial agent should be considered.

Corticosteroid Treatment The chief pharmacologic agent used for IFP is one of the oral glucocorticoids, most often prednisone or methylprednisolone. The preponderance of evidence indicates efficacy of corticosteroid therapy in terms of return of function as well as relief of pain. Three randomized double-blinded studies have been reported. The first (May et al, 1976) had insufficient numbers of cases to justify its negative conclusions; the second (Wolf et al, 1978) showed improved outcomes in the corticosteroid-treatedpatients in all categories, but none of the differences were statistically significant except for the prevention of crocodile tears. The third (Austin et al, 1993) compared the status of patients with IFP treated with 60 mg/day prednisone (n = 35) with those given placebo (n = 41), using a prospective randomized double-blind design. There was a 75% decrease in ENOG evidence of degeneration in the prednisone group ( P = .06) and a significantdifference (P = .03) in the number of subjects having a poor result (grade 111: 0% treatment versus 17% control). Interestingly, the incidence of

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

autonomic synkinesis was about 11% in both groups, which is in contrast to the results of Wolf and colleagues. These results support the use of prednisone in cases of grade V to VI IFP to reduce the incidence of poor results in those at greatest risk. Stennert in West Germany used an intensive in-hospital multiple-drug regimen in a nonrandomized uncontrolled study (Stennert, 1981). The agents used were large dosages of corticosteroid (200 to 250 mg of prednisone daily), intravenous rheomacrodex, and oral pentoxifylline. Ninety-four percent of the patients had complete recovery, often before discharge from the hospital, which is in contrast to the untreated spontaneous complete recovery rate of 71% noted by Pietersen (1982). Whether this high recovery rate results from the timing of treatment, the duration of treatment, a single agent, or the combination is not known. Such a regimen, which involved hospitalization for 2 weeks, would not be considered cost-effective in the United States. Currently, some neurologists in Europe advocate large short-term dosages of prednisone (1 to 2 g daily for 3 to 5 days) and report a very high rate of success (Stennert, personal communication, 2000). The anecdotal success of this approach invites a systematic study with appropriate controls and outcome measures. Oral prednisone is used in my institution for patients with complete paralysis, beginning with 60 to 80 mg/day for 6 days, with a progressive taper over the next 4 days. There appears to be little justification for treating patients with paresis. The use of corticosteroid in patients with palsy (i.e., House-Brackmann grade 11to IV) to prevent degeneration is controversial, but it may be used if no contraindications exist when the physician’s judgment leads to suspicion of impending degeneration. The patients are examined weekly during the first 3 weeks to monitor their palsy, nerve excitability thresholds, and corneal integrity. Patients with incomplete paralysis who show worsening of their palsy or rising thresholds are started on prednisone. Should the paralysis be complete and electrical thresholds rise progressively during the first 3 weeks, the patient is sent for ENOG testing and counseled on the usefulness of surgical decompression, its complications, and the controversy surrounding its indications (see “Surgical Treatment” later in this chapter). Acyclovir Acyclovir is a virostatic drug that is effective against replicating viruses. It has been used for herpes zoster oticus and IFP. Reports of administration to patients with herpes zoster oticus have been uncontrolled; intravenous dosing (5 mg/kg every 8 hours for 3 to 8 days) followed by oral administration of 400 mg five times daily for 2 weeks was the most common regimen. Resolution was faster and better than with historical controls (Uri et al, 1992). Adour (1994) randomly assigned 94 patients with IFP to receive acyclovir 200 mg orally five times a day plus prednisone (1 mg/kg orally) or placebo and prednisone and found significantly better outcomes in the group taking acyclovir.

Principles of Diagnosis: Common Presenting Symptoms

be sought. Antimicrobial therapy is the primary treatment. Amoxicillin (500 mg three or four times daily), tetracycline (500 mg four times daily), or doxycycline (100 mg twice daily) given orally on an outpatient basis for 3 to 4 weeks is the recommended initial therapy. Counseling and Reassurance Patients often assume that their facial paralysis is caused by a stroke, and many are distraught because of the facial deformity and the fear that it may progress. It is important to specifically reassure the patient in this regard when the diagnosis is IFP. Eye Protection Corneal exposure and drying are common sequelae of facial paralysis, particularly when tone is lost and ectropion results. The normal pump action of the orbicularis oculi, which holds the lid against the globe, is lost, and the tears accumulate in the lower conjunctival sac rather than spreading out across the surface of the globe. Blinking ceases with facial paralysis, and therefore an important mechanism for preserving corneal humidification is lost. Two aspects of eye treatment should be noted. First is the use of artificial tears; the second relates to use of ointment and taping the eyelids at night. Patients should be advised about the risks of corneal exposure and instructed to instill methylcellulose solution into the affected eye regularly during the day. This will help keep the cornea moist. Ointments may provide slightly better protection, but they keep the patient from seeing clearly. A commercially available moisture chamber is helpful for patients who work outdoors to keep wind and particles out of the eye while keeping vision near normal. At night, the upper lid should be taped closed with a strip of quarter-inch paper tape placed obliquely from the middle of the upper lid down to the malar eminence (not straight down across the cornea). This will ensure eye protection during sleep. Patients who are young and have adequate eye protection because of good lid tone and an active Bell’s phenomenon (upward rolling of the globe during lid closure) may not need taping, but older patients usually do. I recommend it to all, both for safety’s sake and to call attention to the risk of eye damage as a result of the facial paralysis. Should the patient develop eye pain, a slit lamp examination after fluorescein staining of the cornea is mandatory. I inspect the stained cornea with an ophthalmoscope routinely during follow-up care. Consultation with an ophthalmologist is requested if the paralysis is prolonged, the lagophthalmos is severe, or corneal abrasion or ulceration occurs. Physical Therapy Unfortunately, no amount of physical maneuvering will affect the rate of recovery of the affected nerve. Some have used massage, external straps, and electric stimulation to treat patients with idiopathic facial paralysis. They are not needed.

Lyme Disease

Prosthetics

The diagnosis of Lyme disease in a patient with apparent IFP should be sought through a history of tick bites, arthralgias, and erythema migrans. Serologic confirmation of B. burgdorfri should

When recovery is incomplete, lower lip weakness and asymmetry are common. A modified denture or dental appliance can be made by a prosthodontist to push out the lower lip and improve facial

Chapter 7

symmetry at rest. Such devices are cumbersome and rarely used. Better results follow surgical sling procedures when recovery fails. Surgical Treatment Decompression. Surgical decompression of the facial nerve has been the main treatment of traumatic paralysis and has been applied in severe cases of IFP for more than 50 years. Surgical treatment consists of removing one half the circumference of the bony fallopian canal at the site of the lesion and incising the tripartite nerve sheath. It is advocated as a means of halting the progression of neural degeneration in cases with clear-cut evidence of degeneration. Once the degeneration is complete, surgical decompression probably has little value. It is also advocated for patients with apparent idiopathic facial paralysis in whom there is no evidence of recovery after 3 months. In this situation, decompression is used as a means of surgical exploration of the nerve to rule out a nerve tumor or occult invasive infection. Although evidence of efficacy of decompression for IFP has been sparse, the procedure is still advocated by some neurotologists in selected cases. A recent, nonrandomized, multicenter clinical trial reported by Gantz et al. (1999) provides new evidence of effectiveness of early surgical decompression via the middle cranial fossa in high-risk cases of IFP. To be effective, surgical decompression should encompass the involved segments of the nerve, particularly the labyrinthine segment. Early techniques focused on the vertical segment of the nerve, which is accessible with minimal morbidity. However, later research has indicated that it is the intralabyrinthine segment that is involved in the severe cases, which necessitates decompression via a middle fossa minicraniotomy. Gantz et al (1982) found that the block is proximal to the geniculate ganglion in the majority of cases and that Schirmer’s test was misleading in 39% of cases. Therefore, in IFP, the operation must begin in the intralabyrinthine segment and extend distally until a normal nerve is encountered. In the large anecdotal literature, there are few controlled studies. Fisch (1982) studied 14 patients with severe facial paralysis caused by IFP and showed a difference of 15 percentage points in outcome (78.8% recovery versus 63.9%) between the 7 patients who chose decompression and the 7 who did not. All 14 patients had 95% to 100% degeneration within 1 to 14 days after onset. For patients with herpes zoster oticus, the difference was 22 points (70.2% [5 patients] versus 48.3% [2 patients]). The recent report by Gantz et al (1999) compared patients with criterion level of degeneration (ENOG greater than 90% within 14 days and EMG documentation of the absence of voluntary motor potentials) undergoing middle fossa facial nerve decompression with similar patients electing not to have surgical therapy. Nineteen (58%) of the latter group had a poor outcome (House-Brackmann I11 or IV), whereas 91% (31) of the surgical cases had a good outcome (House-Brackmann I or 11). Of interest, 54 of the patients not reaching criteria for treatment had a good outcome (HouseBrackmann I or 11). These new data warrant a reexamination of surgical therapy for IFP. The Gantz procedure is logical within the current theoretical understanding of the disorder and was used only for the small group of informed patients whose outcome is predicted to be poor by ENOG. It is also used for patients with traumatic lesions of the facial nerve of immediate onset in whom laceration is suspected and in those with delayed onset in whom severe degeneration

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occurs. For informed patients who are willing to accept the small risk of auditory complications to achieve the greatest chance of minimizing undesirable sequelae of their paralysis, early surgical intervention by a skilled, experienced neurotologic surgeon is a reasonable option.

PROGNOSIS

The outlook for complete recovery in IFP is good as long as some motion persists. Once the paresis progresses to paralysis, the prognosis depends on the degree of degeneration, which is estimated by electrical tests. A rising threshold suggests axonal degeneration and signals the need for ENOG, which gives a more precise estimate of the degree of degeneration. If the ENOG falls to less than 10% of the normal side within 21 days after the onset of paralysis, the outlook for normal recovery is poor.

SEQUELAE Most cases of idiopathic facial paralysis are neurapraxic in type, and recovery is rapid and complete. Pietersen (1982) reported that 71% of 1100 cases of IFP occurring in a Danish county over a 15-year period had perfect recovery, usually within a 6-week period. This time course is compatible with the Gates-Mikiten hypothesis of endoneurial fluid formation as the cause of neurapraxia and its gradual resorption through the perineurial sheath as the mechanism for recovery. In approximately 30% of cases, recovery is not complete, and various stigmata of axonal degeneration appear: persistent weakness, motor synkinesis, spasm, contracture, and crocodile tears. Regeneration is a slow and usually incomplete process. Regenerating axons elongate at the rate of 1 mm/day. Therefore, after degeneration of the nerve within the proximal labyrinthine segment, it would take 400 days for the new axons to reach the motor endplates.

Weakness During regeneration, s o n s sprout, proliferate, and push forward to the motor endplates. Even under ideal circumstances, return of muscle strength to normal is unusual. The extent of return is proportional to the number, size, and degree of myelination of the fibers that return to their original motor endplate. Some fibers may not regenerate, and others may be diverted to other muscle groups. Therefore, the number of axons reaching the muscle is reduced. In addition, the regenerated axons that do reach the appropriate muscles are smaller and less well myelinated than the original fibers. Therefore, impulses are transmitted more slowly and with greater variation in speed. Because motor strength depends on coordinated impulse transmission, a regenerated nerve is nearly always an impaired one.

Motor Synkinesis Axons regenerate by first forming multiple buds, which may become diverted from their original axon sheaths and end in other muscle fibers. When this happens, the patient has great difficulty

Principles of Ambulatory Neurologyand the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

78

moving each muscle group independently; the resultant mass action of muscle is called synkinesis. A typical example is eye closure (or blinking) when, for example, one tries to smile. In this case it is apparent that some fibers of the nerve branch to the orbicularis oris had found their way into the orbicularis oculi. Synkinesis is the clinical hallmark of axonal degeneration.

Spasm and Contradure Involuntary muscle spasms are common sequelae of severe degeneration. In addition, contracture and permanent distortion of the face are also noted. Prevention of these complications is an important goal of therapy. Persistent spasm may be treated successfully with injection of botulinum toxin.

Autonomic Synkinesis (Crocodile Tears) The facial nerve carries two groups of sympathomimetic fibers: those to the nose and lacrimal gland (via the greater superficial petrosal nerve) and those to the submandibular gland (via the chorda tympani). Faulty regeneration when the lesion is quite proximal may result in autonomic synkinesis. Therefore, during meals, discharges of the salivary fibers, which have been rerouted to the lacrimal gland, result in diffuse tearing instead of salivation.

SUMMARY FP is a common problem resulting from epidemics of IFP, which probably results from herpes virus infection. The history and physical examination are adequate evaluation for paretic patients who fit the diagnostic criteria of IFP. Most cases resolve satisfactorily without therapy. Extensive evaluation is reserved for those who have complete paralysis and electrical test evidence of degeneration. These cases should receive corticosteroid and antiviral therapy. Diabetics appear to have a higher prevalence of IFP than the general population, and older patients should be screened for glucose intolerance. Patients with complete paralysis and ENOG evidence of severe degeneration while receiving corticosteroid are at risk for unsatisfactory outcome and should be counseled about surgical decompression.

SUGGESTED READINGS Adour K K Bell's palsy: synopsis by an otologist. Eur Arch Otorhinolaryngo1 Suppl:6245, 1994 Adour KK, Ruboyianes JM, Von Doersten PG et al: Bell's palsy treatment with acyclovir and prednisone compared with prednisone alone: a double-blind, randomized, controlled trial. Ann Otol Rhinol Laryngol 105~371-378, 1996

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Austin JR, Peskind SP, Austin SG, Rice DH: Idiopathic facial nerve paralysis: a randomized double blind controlled study of placebo versus prednisone. Laryngoscope 103:132&1333, 1993 Clark JR, Carlson RD, Sasaki CT et ak Facial paralysis in Lyme disease. Laryngoscope 95:1341-1345, 1985 Fisch U: Results of surgery versus conservative treatment in Bell's palsy and herpes zoster oticus. pp. 273-278. In Graham MD, House WF (eds): Disorders of the Facial Nerve. Raven Press, New York, 1982

Gantz BJ, Gmur A, Fisch U: Intraoperative evoked electromyography in Bell's palsy. Am J Otolaryngol 3:273-278, 1982 Gantz BJ, Rubinstein JT, Gidley P, Woodworth GG: Surgical management of Bell's palsy. Laryngoscope 109:1177-1188, 1999 Gates G A Nerve excitabilitytesting: technical pitfalls and threshold norms using absolute values. Laryngoscope 103:379-385, 1993 Gates GA, Mikiten TM: The idiopathic facial paralyses (Bell's palsies). pp. 279-286. In Graham MD, House WF (eds): Disorders of the Facial Nerve. Raven Press, New York, 1982 House JW, Brackmann DE Facial nerve grading system. Otolaryngol Head Neck Surg 93:146-147, 1985 May M, Klein SR, Taylor FH: Idiopathic (Bell's) facial palsy: natural history defies steroid or surgical treatment. Laryngoscope 95:406-409, 1985

May M, Wette R, Hardin WB, Sullivan J: The use of steroids in Bell's palsy: a prospective controlled study. Laryngoscope 86:llll-1122, 1976 Morgan M, Nathwani D: Facial palsy and infection: the unfolding story. Clin Infect Dis 2:263-271, 1992 Mori H, Kita M, Takahashi H et al: Bell's palsy and virus: analysis of 299 cases for six years. Facial Nerve Res 2:83-86, 1982 Murakami S, Mizobuchi M, Nakashiro Y et ak Bell's palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med 12427-30, 1996 Murakami S, Hato N, Horiuchi J et ak Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol41:353-357, 1997 Pietersen E: Natural history of Bell's palsy. In Graham MD, House WF (eds): Disorders of the Facial Nerve. Raven Press, New York, 1982 Seddon HJ: Three types of nerve injury. Brain 66:237-288, 1943 Sigal LH: Current recommendations for the treatment of Lyme disease. Drugs 43:683-699, 1992 Steiner I, Mattan Y: Bell's palsy and herpes viruses: to (acyc1o)vir or not to (acyclo)vir?J Neurol Sci 179:19-23, 1999 Stennert E Pathomechanisms in cell metabolism: a key to treatment of Bell's palsy. Ann Otol Rhinol Laryngol 190577-583, 1981 Sunderland S: The peripheral nerve trunk in relation to injury. A classification of nerve injury. pp. 133-141. In Nerves and Nerve Injury. Churchill Livingstone, Edinburgh, 1978 Uri N, Greenberg E, Meyer W, Kitzes-Cohen R Herpes zoster oticus: treatment with acyclovir. Ann Otol Rhinol Laryngol 101:161-162, 1992

Wolf SM, Wagner JH, Davidson S, Forsyth A Treatment of Bell's palsy with prednisone: a prospective randomized study. Neurology 28:158161, 1978

Dizziness and Vertigo Robert W Baloh

Dizziness is a common symptom caused by many different pathophysiologic mechanisms and a variety of disorders (Table 8-1). Because the evaluation and management differ markedly depending on the category of dizziness, it is critical that the examining physician first determine the type of dizziness before

proceeding with diagnostic studies. The history usually provides the key information for classifjmg the general type of dizziness. The sensation of spinning nearly always indicates a vestibular disorder. Patients with nonvestibular dizziness occasionally report a sensation of spinning inside the head, but the environment

Chapter 8

Dizziness and Vertigo

79

TABU8-1. Mechanisms and Common Causes of Dizziness Mechanism

Common Causes

Vertigo

Imbalance of tonic vestibular signals

Presyncopal dizziness

Pancerebral ischemia

Hypoglycemic dizziness

Inadequate brain glucose; increased circulating catecholamines Impaired central integration of sensoly signals Depression of central nervous system function Loss of vestibulospinal, proprioceptive, or cerebellar function

Benign positional vertigo, viral neurolabyrinthitis,Mbniere’s syndrome, migraine, vertebrobasilar insufficiency Hyperventilation,orthostatic hypotension, vasovagal syncope, cardiac arrhythmia insulin treatment of diabetes mellitus; alcoholism, insulinsecreting tumors Anxiety, phobias, panic syndrome Alcohol, tranquilizers, anticonvulsants Ototoxicity, peripheral neuropathy, stroke, cerebellar degeneration

Psychophysiologic dizziness Drug intoxication Disequilibrium

remains still, and they do not have nystagmus. Patients with vestibular lesions often liken the sensation to that of being drunk or motion sick; they feel off-balance and may tilt or fall to one side. Patients with presyncopal or hypoglycemic dizziness typically use terms such as lightheaded, floating, giddy, or swimming. The sensation that one has left one’s own body is characteristic of psychophysiologic dizziness. Drugs can produce several different types of dizziness. Most sedating drugs cause a nonspecific dizziness described as a fogginess, cloudiness, or giddiness that is presumably caused by diffuse depression of the central nervous system. Alcohol can cause this nonspecific dizziness but can also produce a positional vertigo and nystagmus caused by differential changes in specific gravity of the endolymph and cupula. The common anticonvulsants phenytoin and carbamazepine cause disequilibrium and ataxia through both acute and chronic cerebellar dysfunction. Most of the commonly used antihypertensive drugs predispose patients to orthostatic hypotension and presyncopal dizziness. Patients often use the term dizziness to describe a sensation of imbalance or disequilibrium that occurs only when they are standing or walking. Such imbalance is common with acute unilateral peripheral vestibular lesions, but it is transient and invariably associated with subjective vertigo. Both the vertigo and imbalance are compensated within a few days. Patients who slowly lose vestibular function, on one side or both sides, typically do not experience vertigo but describe a vague feeling of imbalance and unsteadiness on their feet. Bilateral vestibular loss can cause persistent unsteadiness that may be incapacitating, particularly in older patients. Ototoxic drugs, such as the aminoglycosides, produce a characteristic combination of gait unsteadiness and oscillopsia caused by loss of vestibulospinal and vestibulo-ocular reflex function, respectively. Imbalance associated with loss of proprioceptive function is nearly always associated with other findings of peripheral neuropathy. When imbalance is caused by loss of vestibulospinal or proprioceptive function, it is typically more pronounced in the dark, when the patient is unable to use vision to compensate for the loss. On the other hand, patients with cerebellar lesions have severe imbalance even with vision. Vertigo is an episodic phenomenon, whereas other types of dizziness usually are more persistent. Exceptions include presyncopal dizziness caused by postural hypotension or cardiac arrhythmias or hypoglycemic dizziness caused by excessive insulin or lack of food intake. Patients with psychophysiologic dizziness often report being dizzy from morning to night without change for months to years at a time. Vertigo is invariably aggravated by head movements, whereas other types of dizziness may even improve with head or body movements. Episodes of dizziness induced by position change suggest a vestibular cause if postural hypotension

has been ruled out. Although stress can aggravate both vestibular and nonvestibular dizziness, dizziness that is reliably precipitated by stress suggests a nonvestibular cause. Episodes of dizziness occurring only in specific situations such as when the patient is driving on a freeway or shopping in a busy supermarket suggest a psychophysiologic cause. Nausea and vomiting are common with vertigo but uncommon with other types of dizziness. Associated auditory or neurologic symptoms suggest a vestibular disorder; presyncopal symptoms and syncope suggest a nonvestibular disorder.

EXAMINATION Evaluation of the dizzy patient should include a general medical examination and a complete otologic and neurologic examination. Whenever possible, the examining physician should attempt to reproduce the patient’s dizziness. Bedside provocative tests can assist in making a pathophysiologic diagnosis. Rapid head movements commonly induce vertigo because they accentuate an imbalance within the vestibular pathways. Even after compensation has occurred, head movements or change in position can lead to episodes of vertigo. Patients with perilymph fistula develop brief episodes of vertigo precipitated by changes in middle ear pressure commonly associated with coughing or sneezing. A bedside fistula test can be performed by pressing the tragus into the ear canal or by changing the pressure in the canal with a pneumatoscope. A brief spell of vertigo and nystagmus indicates a positive test. Presyncopal dizziness caused by orthostatic hypotension can develop immediately on standing or insidiously after several minutes of standing. The diagnosis is made by documenting an acute or progressive decline in mean blood pressure of more than 15 torr while the patient is in the erect position. In patients with autonomic insufficiency, the pulse rate may remain unchanged despite the hypotension. In patients suspected of hyperventilating, it is helpful to have the patient voluntarily overbreathe to reproduce symptoms and provide insight into the mechanism. Examination of a patient complaining of disequilibrium should focus on gait assessment. Patients are encouraged to walk as they normally do and to narrow their base by walking in tandem. Acute unilateral peripheral vestibular lesions cause falling toward the side of the lesion, but within a few days balance returns to normal. Patients with bilateral peripheral vestibular loss have more difficulty compensating and usually show persistent imbalance on tandem walking tests, particularly with eyes closed. The broadbased ataxic gait of cerebellar disorders usually is easily distinguished from the milder gait disorders associated with vestibular or sensory loss.

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Principles of Ambulatory Neurologyand the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

Bedside Tests of Vestibular Function A unilateral or bilateral vestibular loss can be identified at the bedside by rapidly turning the head to the side while the patient fixates on the examiner’s nose (the head thrust test). Normally the eyes move smoothly in the orbit to maintain fixation. In patients with vestibular loss, the eyes deviate from the target, and catch-up saccades are needed. Rotating the head slowly back and forth (the doll’s eye test) induces compensatory eye movements that depend on both the visual and vestibular systems. Because of the combined visual and vestibular input, a patient with complete loss of vestibular function and normal visual pursuit may have normal-appearing compensatory eye movements on this test. The doll’s eye test is a useful bedside test of vestibular function in a comatose patient, however, because such patients cannot generate visual tracking eye movements. In this setting slow conjugate compensatory eye movements indicate normally functioning vestibulo-ocular pathways. Because the vestibulo-ocular reflex has a much higher frequency range than the smooth pursuit system, a semiquantitative bedside test of vestibular function can be made by having the patient shake his or her head back and forth at frequencies above one cycle per second while reading a standard visual acuity chart. A decrease in visual acuity of more than one line compared with testing with the head still suggests an abnormal vestibulo-ocular reflex. Patients with compensated vestibular lesions (peripheral or central) may develop a transient spontaneous nystagmus after vigorous head-shaking (so-called head-shaking nystagmus). With unilateral peripheral vestibular lesions, the nystagmus beats toward the intact side. The caloric test uses a nonphysiologic stimulus to induce endolymphatic flow in the horizontal semicircular canal and horizontal nystagmus by creating a temperature gradient from one side of the canal to the other. With a cold caloric stimulus, the column of endolymph nearest the middle ear falls because of its increased density. This causes the cupula to deviate away from the utricle and produces horizontal nystagmus with the fast phase directed away from the stimulated ear. A warm stimulus produces the opposite effect, causing ampullipetal endolymph flow and nystagmus directed toward the stimulated ear (cold opposite, warm same [COWS]). Because of its ready availability, ice water usually is used for bedside caloric testing. To bring the horizontal canal into the vertical plane, the patient lies in the supine position with head tilted 30 degrees forward. Infusion of a few milliliters of ice water induces a burst of nystagmus usually lasting a minute or so. A comatose patient shows only a slow tonic deviation toward the side of stimulation. More than a 20% asymmetry in nystagmus duration suggests a lesion on the side of decreased response. However, this should always be confirmed with standard bithermal caloric testing (described later in this chapter).

Tests for Pathologic Nystagmus Nystagmus by definition is a nonvoluntary rhythmic oscillation of the eyes. It usually has a clearly defined slow and fast component

alternating in directions. By convention, the direction of the fast component defines the direction of nystagmus. Physiologic nystagmus is nystagmus that occurs in normal subjects (e.g., caloric-induced nystagmus), whereas pathologic nystagmus implies an underlying abnormality. Spontaneous nystagmus is nystagmus that occurs with the patient seated, eyes in the primary position, and without external stimulation. Gaze-evoked nystagmus is induced by changes in gaze position. Nystagmus that is not present in the sitting position but is present in some other head and body position is called positional nystagmus. Examination for pathologic nystagmus should include a careful search for spontaneous, gaze-evoked, and positional nystagmus. Spontaneous nystagmus may be present with fixation, or it may occur only when fixation is inhibited. There are several simple methods for inhibiting fixation at the bedside. Frenzel glasses consist of +30 lenses mounted in a frame that contains a light source on the inside so that the patient’s eyes are easily visualized. An ophthalmoscope can also be used to block fixation and bring out a spontaneous nystagmus. While the fundus of one eye is being viewed, the patient is asked to lightly cover the other eye. Features that distinguish between spontaneous nystagmus of peripheral and central origin are summarized in Table 8-2. Spontaneous nystagmus of peripheral vestibular origin typically is inhibited with fixation and does not change direction with gaze, whereas that of central origin usually is prominent with fixation and often changes direction with change in the direction of gaze. Several varieties of central nystagmus have localizing value (Table 8-3). Patients with gaze-evoked nystagmus are unable to maintain stable conjugate eye deviation away from the primary position. The eyes drift back toward the center, and corrective saccades (fast components) are needed to reset the desired gaze position. Gaze-evoked nystagmus therefore is always in the direction of gaze. The site of abnormality can be anywhere from the neuromuscular junction to the multiple brain centers controlling conjugate gaze. Dysfunction of the so-called oculomotor integrator may be a common mechanism for several types of gaze-evoked nystagmus. Two general types of positional nystagmus can be identified on the basis of nystagmus duration: static and paroxysmal (also known as positioning nystagmus). One induces static positional nystagmus by slowly placing the patient into the supine and right lateral and then left lateral positions. This type of positional nystagmus persists as long as the position is held. Because direction-changing and direction-fixed static positional nystagmus occur with both peripheral and central vestibular lesions, their presence indicates only a dysfunction somewhere in the vestibular system. As with spontaneous nystagmus, however, lack of suppression with fixation and signs of associated brain stem dysfunction suggest a central lesion. Paroxysmal positional nystagmus is induced, after a brief delay, by a rapid change from erect sitting to supine head-hanging left or head-hanging right (the Dk-Hallpike test). It is initially high in frequency but dissipates rapidly (within 30 seconds to a minute). The most common variety of paroxysmal

TABLE8-2. Differentiation Between Spontaneous Nystagmus of Peripheral and Central Origin Peripheral Central

Appearance

Fixation

Gaze

Mechanism

localization

Combined torsional, horizontal Often pure vertical, horizontal, or torsional

Inhibited

Unidirectional (Alexander‘s law) Usually changes direction

Asymmetrical loss of peripheral vestibular tone Imbalance in central ocular motor tone, usually central vestibular, may be visual

Labyrinthine or vestibular nerve Central nervous system, usually brainstem or cerebellum

Usually little effect

Chapter 8

Different Types of Central Nystagrnus Localization

Common Causes

Downbeat

Cervical-medullary junction (flocculus?)

Upbeat

Caudal midline brainstem Cerebellovestibular pathways Cerebellum

Chiari malformation, cerebellar atrophy, multiple sclerosis Infarction, tumor, multiple sclerosis Infarction, multiple sclerosis, syrinx Cerebellar atrophy, infarction Multiple sclerosis, infarction Pineal tumors, infarction

Periodic alternating Rebound Dissociated Convergenceretraction Palato-ocular myoclonus

Medial longitudinal fasciculus Pretectum Mollaret triangle, olivodentatorubral pathwavs

Infarction, degenerative disease

positional nystagmus, so-called benign paroxysmal positional nystagmus, usually has a 3- to 10-second latency before onset and rarely lasts longer than 30 seconds. The nystagmus usually is torsional with fast phase directed upward (i.e., toward the forehead). It is usually prominent only in one head-hanging position, and a burst of nystagmus in the reverse direction occurs when the patient resumes the sitting position. Another key feature is that the vertigo and nystagmus that the patient experiences with the initial positioning rapidly decrease with repeated positioning (fatigability). ~

LABORATORY EVALUATION Eledronystagmography

Electronystagmography (ENG) is a technique for precise quantification of both physiologic and pathologic nystagmus. Electrooculography and video-oculography are the most common methods used to record eye movements. A standard ENG test battery includes tests of visual ocular control (saccades, smooth pursuit, and optokinetic nystagmus), a search for pathologic nystagmus with fixation and with eyes open in darkness, and a bithermal caloric test. An ENG test is helpful in identifylng a vestibular lesion and localizing it within the peripheral and central pathways. With the bithermal caloric test, each ear is irrigated for a fixed duration (30 to 40 seconds) with a constant flow rate of water that is 7°C below body temperature (30°C) and 7OC above body temperature (44°C). The main advantages of this test method are that both ampullipetal and ampullifugal endolymph flow are serially induced in each horizontal semicircular canal, the caloric stimulus is highly reproducible from patient to patient, and the test is well-tolerated by most patients. The major limitation is the need for constant temperature baths and plumbing to maintain continuous circulation of water through the infusion hose. The response to caloric stimulation can be assessed in several ways. The simplest method is to measure the duration of nystagmus after each infusion using a stopwatch. Before the development of ENG, this was the only practical way to quantify the bithermal caloric test. With ENG, one can measure the velocity profile of the slow phases and calculate the maximum slow phase velocity after each stimulus. The vestibular paresis formula ((R30"+ R44") - (L3Oo+ L44O)) X 100 R30" + R44" + L3Oo + L44"

81

compares the maximum slow phase velocity of right-sided responses with that of left-sided responses, and the directional preponderance formula

W TABLE 8-3. Localizing Value and Common Causes of

we

Dizziness and Vertigo

((L30"+ R44") - (L44"+ R30")) x 100 L3Oo + R44" + L44" + R30°

compares the maximum slow phase velocity of nystagmus to the right with that of nystagmus to the left in the same subject. Dividing by the total response normalizes the measurements to remove the large variability in absolute magnitude of normal caloric responses. The finding of a significant vestibular paresis (greater than 25%) with bithermal caloric stimulation suggests a lesion in the vestibular system that is located anywhere from the end organ to the vestibular nerve root entry zone in the brain stem. It is a reliable sign of a unilateral peripheral vestibular lesion. A significant directional preponderance on caloric testing (greater than 30%) indicates an imbalance in the vestibular system but is nonlocalizing, occurring with both peripheral and central vestibular lesions. RotationalTesting

Rotational tests have several advantages over caloric tests. Multiple graded stimuli can be applied in a short period, and rotational testing usually is less bothersome to patients than caloric testing. Unlike caloric testing, a rotational stimulus to the semicircular canals is unrelated to physical features of the external ear or temporal bone; therefore, a more exact relationship between stimulus and response is possible. All three semicircular canals can be tested, and both active and passive rotations can be used. Rotational testing is most useful for evaluating patients with presumed bilateral peripheral vestibular loss (e.g., caused by ototoxic drug exposure) because both labyrinths are stimulated simultaneously and the degree of remaining function is accurately quantified. Because the variance associated with normal rotational responses is less than that associated with caloric responses, diminished function is identified earlier. Artifactually diminished caloric responses occasionally occur in patients with angular narrow external canals or with thickened temporal bones. Because a rotational stimulus is unrelated to these factors, rotationinduced nystagmus is normal in such patients. Furthermore, patients with absent caloric responses may have decreased but measurable rotation-induced nystagmus, particularly at higher stimulus velocities. The ability to identify remaining vestibular function even when s m d is an important advantage of rotational testing, particularly when the physician is contemplating ablative surgery or monitoring the effects of ototoxic drugs. For sinusoidal rotation, results are reported as gain (peak slow phase eye velocity/peak head velocity) and phase (timing between the peak velocity of eye and head) at different frequencies. Posturography

Body sway is a normal phenomenon that occurs in everyone. Excessive sway is more common in older people than in young people and more common in patients with balance problems than in age-matched controls. Because sway tends to be small when subjects stand on a stable platform, moving platforms (dynamic posturography) have been developed in an attempt to increase test sensitivity. The platform can be tilted or linearly displaced, and the sway can be measured immediately after the movement or during the movement. Furthermore, in an effort to dissect the different

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Principles of Ambulatory Neurologyand the Approach to Clinical Problems

sensory contributions to the maintenance of balance, systems have been developed to manipulate somatosensation and vision selectively. With these devices, the angle of sway is fed back to a dynamic posture platform or to a movable visual surround so that movement about the ankle joint or movement of the visual surround is sway-referenced. Posturography is a method for quantifylng balance. It is not a diagnostic test and is of little use for localizing a lesion. It can be helpful for following the course of a patient and may serve as a quantitative measure of the response to therapy. As noted earlier, sway increases in older people, and several studies have shown that the frequency of falls increases as sway increases, suggesting that posturography may be a useful clinical tool for identifylng older people at risk for falling.

NeuroEmaging Computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionized the diagnosis of lesions involving the temporal bone and posterior fossa. MRI can identify small acoustic neuromas confined to the internal auditory canal, tumors that are missed with CT. Contrast infusion further increases the sensitivity of MRI for identifylng small tumors. MRI can also reliably identify gliomas of the brainstem and cerebellum, tumors that may be isodense on CT. CT is useful for identifying bony erosion, hemorrhage, or calcificationin tumors. Deciding whether to order neuroimaging studies is easy in patients with dizziness and associated neurologic symptoms and signs but is difficult in patients with isolated dizziness. Acoustic neuromas and other cerebellopontine angle tumors rarely present with vertigo because they slowly compress the vestibular nerve, and the brain compensates. Rarely cerebellar infarcts can present with just vertigo and imbalance, but as a general rule isolated attacks of vertigo indicate a peripheral vestibular lesion, so neuroimaging will not be helpful.

DIAGNOSIS AND TREATMENT OF COMMON NEUROTOLOGICSYNDROMES (Table 8-4) Benign Paroxysmal PositionalVertigo Benign paroxysmal positional vertigo (BPPV) is by far the most common cause of vertigo. Patients with this condition develop brief episodes of vertigo with position change, typically when turning over in bed, getting in and out of bed, bending over and straightening up, or extending the neck to look up. So-called top shelf vertigo is nearly always caused by BPPV. It can be seen in

Principles of Diagnosis:Common Presenting Symptoms

association with other ear diseases and after head trauma, but in the majority of cases it is an isolated finding (particularlyin older people). The diagnosis rests on finding the characteristic fatigable positioning nystagmus after a rapid change from the sitting to head-hanging position. BPPV results from free-floating debris (calcium carbonate crystals) usually in the posterior semicircular canal that moves under the influence of gravity. The debris forms a clot in the canal; when it moves, it displaces the cupula, resulting in a burst of nystagmus and vertigo. Dispersion of the debris with repeated movements accounts for fatigability of the vertigo and nystagmus. This canalithiasis mechanism explains a simple bedside treatment of BPPV that cures most patients. If the history and physical findings are typical, no further evaluation is necessary. If the history or findings are atypical, however, the condition must be distinguished from other causes of positional vertigo that may occur with tumors or infarcts in the posterior fossa. Management. Once the diagnosis of the posterior canal variant of BPPV is confirmed with the Dix-Hallpike positional test, a positioning maneuver is performed to liberate the clot of debris from the posterior semicircular canal. We use a modified Epley maneuver as shown in Figure 8-1. The key feature of this maneuver is to move the patient from one head-hanging position to the other so that the clot rotates around the posterior semicircular canal. Once the clot enters the utricle, it presumably becomes attached to the membrane or dissolves and can no longer interfere with semicircular canal dynamics. Cure rates higher than 90% have been consistently reported after a single session with this liberatory maneuver. The maneuver should be repeated until the patient is free of vertigo and nystagmus. Between 10% and 20% of patients have an exacerbation within a week or two after performing the maneuver, and as many as 50% have an exacerbation at some time. Patients with the uncommon horizontal canal variant of BPPV exhibit a brief burst of horizontal nystagmus beating toward the ground when their head is turned to either side while they are in the supine position. It is treated by rolling the patient toward the side with lesser nystagmus through 360 degrees (so-called barbecue rotation). Acute Peripheral Vestibulopathy

One of the most common clinical neurologic syndromes at any age is the acute onset of vertigo, nausea, and vomiting lasting for several days and not associated with auditory or neurologic symptoms. Most affected patients gradually improve over a few weeks, but some, particularly older patients, can have persistent

TABLE8-4. Diagnosis and Management of Common Neurotologic Syndromes Benign paroxysmal positional vertigo Acute unilateral vestibulopathy Chronic bilateral vestibulopathy Mkniere's syndrome Migraine Vertebrobasilar insufficiency

Diagnosis

Management

Brief (4min), positioning-inducedvertigo and nystagmus Prolonged (days) vertigo, spontaneous nystagmus, unilateral reduced caloric response Vertigo infrequent, disequilibrium and oscillopsia, bilateral reduced caloric response Vertigo (hours), tinnitus (roaring), hearing loss, ear fullness, spontaneous nystagmus, fluctuating hearing levels Recurrent vertigo (minutes to hours), headache, visual aura, motion sensitivity, family history

Maneuver to remove debris from semicircular canal

Abrupt vertigo (minutes), disequilibrium and oscillopsia, other neurologic symptoms and signs, risk factors for vascular disease

Antivertiginous drugs first few days, begin vestibular rehabilitation as soon as possible Stop ototoxin, vestibular rehabilitation low salt diet (1 g Na+/day), f diuretic, antivertiginous drugs during attack, surgery for intractable cases (<5W

Control potential triggers (foods, stress); antimigraine drugs (p-blockers, calcium channel blockers, acetazolamide) Antiplatelet drugs; if spells continue, anticoagulation (heparin or warfarin)

Chapter 8

Dizziness and Vertigo

83

FIG. 8-1. Method for treating benign positional vertigo affecting the right ear. The procedure is reversed for treating the left ear. The drawing of the labyrinth illustrates the position of the debris as it moves around the posterior semicircular canal (PSC) and into the utricle (UT). ( I ) Patient in upright position. (2) Patient is moved rapidly to head-hanging right (Dix-Hallpike test). (3) Operator moves to head of bed, repositioning hands. (4) Head is rotated quickly to the left with right ear upward. Position maintained for 30 seconds. (5) Patient rolls onto the left side while operator rapidly rotates head leftward until the nose is toward ground. Position maintained for 30 seconds. (6) Patient is rapidly lifted into the sitting position, now facing left. The sequence is repeated until no nystagmus can be elicited. The patient is instructed to avoid lying flat for 2 days to prevent the debris from reentering the posterior canal.

symptoms for months. About 50% of such patients report an upper respiratory tract illness within a few weeks before the onset of vertigo. This syndrome occasionally occurs in epidemics, may affect several members of the same family, and may often erupt in the spring and early summer. All of these facts suggest a viral origin, but attempts to isolate an agent have been unsuccessful except for occasional findings of a herpes zoster infection. Pathologic studies showing atrophy of one or more vestibular nerve trunks, with or without atrophy of their associated sense organs, are evidence of vestibular nerve site and probably viral origin in many patients with this syndrome. In some patients, attacks of acute vestibulopathy, usually less severe, recur months or years after the initial attack. Whether this represents reactivation of a latent virus or some other pathophysiologic mechanism is unknown. Vertigo often follows a blow to the head that does not result in temporal bone fracture, so-called labyrinthine concussion. Although they are protected by a bony capsule, the delicate labyrinthine membranes are susceptible to blunt trauma. Blows to the occipital or mastoid region are particularly likely to produce labyrinthine damage. More commonly, calcium carbonate crystals are dislodged from the macules, leading to typical BPPV. Fistulas of the oval and round windows can result from impact noise, deep water diving, severe physical exertion, or blunt head injury without skull fracture. The mechanism of the rupture is a sudden

negative or positive pressure change in the middle ear or a sudden increase in cerebrospinal fluid pressure transmitted to the inner ear via the cochlear aqueduct or the internal auditory canal. Clinically the rupture leads to the onset of vertigo and hearing loss. A perilymph fistula should be seriously considered when there is a clear relationship between the onset of vertigo and the onset of severe exertion, barometric change, head injury, or impact noise. Occlusion of the internal auditory artery leads to a sudden profound loss of both auditory and vestibular function. However, ischemia confined to the anterior vestibular artery distribution can result in isolated vertigo caused by infarction of only the vestibular labyrinth. This diagnosis usually should be considered only in older patients, particularly those with a history of transient ischemic attacks, stroke, or known atheroscleroticvascular disease. It can be seen in association with hyperviscosity syndromes such as hyperlipidemia, polycythemia, macroglobulinemia, and sickle cell anemia. After recovering from the acute manifestations, patients may develop episodes of typical BPPV months or years later. The positional vertigo presumably results from an ischemic necrosis of the utricular macula, causing a release of otoconia that make their way into the long arm of the posterior semicircular canal. Management. Treatment of patients who present with isolated episodes of auditory or vestibular loss is controversial because the pathophysiology often is uncertain. As suggested earlier, unless there is convincing evidence to support a vascular or

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Principles of Ambulatoy Neurologyand the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

nonviral infectious cause, the patient should be treated as having viral neurolabyrinthitis; that is, with symptomatic treatment. Although steroids have been recommended for their antiinflammatory effect, there have been no controlled studies to assess the risk-benefit ratio for these drugs. More than half of the patients with vestibular neurolabyrinthitis are left with permanent loss of vestibular function (as documented by serial caloric examinations),but the central nervous system is able to adapt to the vestibular loss, and residual symptoms usually are minimal once the compensation has occurred. Vestibular rehabilitation should be started immediately after the acute nausea and vomiting symptoms subside and should be continued until the dizziness and imbalance are minimal. Although antiviral agents such as cytosine arabinase and acyclovir have been used for treating systemic viral illnesses in children, it is unclear whether the hearing loss that is often associated with disorders such as cytomegalovirus and rubella infections is altered by such treatment. There have been no reports on the efficacy of antiviral agents in adults with viral neurolabyrinthitis. Patients who lose vestibular function on one side because of trauma or vascular occlusion recover through central compensation despite the continued loss of function. As with viral neurolabyrinthitis, management consists of early symptomatic treatment to relieve nausea and vomiting followed immediately by vestibular rehabilitation to accelerate the compensation process. Patients with suspected perilymph fistulas typically are prescribed bed rest for several days to allow the fistula to close spontaneously. A small percentage of patients need exploration of the middle ear and surgical repair of the fistula.

Chronic Bilateral Vestibulopathy Unlike patients with an acute imbalance in vestibular tone, patients with bilateral vestibulopathy often present with subtle symptoms of nonspecific dizziness and disequilibrium that may be difficult to distinguish from other neurologic causes of disequilibrium. The associated oscillopsia may be incorrectly interpreted as a problem with vision, leading to an ophthalmologic evaluation. By far the most common cause of bilateral vestibulopathy is ototoxic drug damage from aminoglycosides. Such patients may experience vertigo during the acute phase if the toxic effect is asymmetrical. More often there is a gradual, progressive, symmetrical loss of vestibular function leading to imbalance but not vertigo. Unfortunately, many patients being treated with ototoxic drugs are initially bedridden and unaware of the vestibular impairment until they recover from the acute illness and try to walk. Then they discover that they are unsteady on their feet and that the environment tends to jiggle in front of their eyes (oscillopsia). Although the aminoglycosides usually produce auditory and vestibular damage, some such as streptomycin and gentamicin are remarkably specific for the vestibular system, whereas others such as kanamycin, tobramycin, and amikacin cause more damage to the auditory system. The ototoxicity of aminoglycosides results from hair cell damage in the inner ear. Because they are excreted almost exclusively by glomerular filtration, patients with renal impairment are at high risk for developing ototoxicity. Management. The clinician must be constantly alert for early symptoms of ototoxic drugs. This is particularly important in the patient who is seriously ill and confined to bed or in a patient who has renal impairment. Younger patients usually adapt to

bilateral vestibular loss by using other sensory signals to replace the lost vestibular signals. Older patients may be left permanently disabled. Vestibular rehabilitation can help patients learn to substitute other sensory signals for the vestibular loss. The best treatment is prevention. If the drug is discontinued early during the course of symptoms, the disorder may stabilize or improve.

MQniire‘s Syndrome Mknihre’s syndrome typically develops with a sensation of fullness and pressure along with tinnitus and decreased hearing in one ear. Vertigo follows rapidly, reaching a maximum intensity within minutes and then slowly subsiding over several hours. The patient usually is left with a sense of unsteadiness and dizziness for days after the acute vertiginous episode. In the early stages, the hearing loss is completely reversible, but in later stages a residual hearing loss remains. Tinnitus may persist between episodes but usually increases in intensity immediately before or during the acute episode. It is typically described as a roaring sound like the sound of the ocean or a hollow seashell. Such episodes occur in irregular intervals for years, with periods of remission unpredictably intermixed. Eventually severe permanent hearing loss develops, and the episodic nature spontaneously disappears (burnt-out phase). About one third of patients develop bilateral Mkniere’s. Variations from this classic picture occur, particularly in the early stages of the disease process, but the diagnosis remains uncertain until the combination of fluctuating hearing loss and vertigo occurs. Some patients experience abrupt episodes of falling to the ground without loss of consciousness or associated neurologic symptoms. These episodes have been called otolithic catastrophes based on the presumed sudden stimulation of an otolith organ by the increased inner ear pressure. So-called delayed Mknihre’s syndrome develops in an ear that was damaged years before, usually by a viral or bacterial infection. When the hearing loss is profound, as it often is, the episodic vertigo is not accompanied by fluctuating hearing levels and tinnitus. Management. Medical management of Mkniere’s syndrome consists of symptomatic treatment of the acute spells of vertigo and long-term prophylaxis with salt restriction and diuretics. The mechanism by which a low-salt diet decreases the frequency and severity of attacks with Mkniere’s syndrome is unclear, but there is strong empirical evidence for its efficacy. We recommend salt restriction to 1 g of sodium per day, with a minimum therapeutic trial of 6 months to a year. Food intake should be regularly distributed throughout the day. Binges (particularly food with high sugar or salt content) should be avoided. Occasionally, patients notice that certain foods (e.g., alcohol, coffee, or chocolate) may precipitate attacks. Diuretics (acetazolamide 250 mg twice daily or hydrochlorothiazide50 mg twice daily) provide additional benefit in some patients, although they cannot replace a salt restriction diet.

Migraine Vertigo is a common symptom with migraine, occurring either with the headaches or in separate isolated episodes. Furthermore, vertigo attacks can predate the onset of headaches, and in some cases vertigo is the only manifestation of migraine (a so-called migraine equivalent). The diagnosis of migraine should be entertained in any patient with chronic recurrent attacks of vertigo of unknown cause. The duration of attacks is variable, so migraine

Chapter 8 W

can mimic several other common neurotologic vertigo syndromes. The magnitude of the problem is apparent when one considers that migraine may affect as many as 25% of women and 15% of men, and vertigo attacks occur in at least a quarter of these. The diagnosis of migraine-associated vertigo is straightforward when the vertigo is part of an aura that is followed by typical unilateral throbbing headache. The diagnosis becomes more problematic when the vertigo attacks and headache occur independently or the vertigo attacks occur without headaches. Long-standing motion sensitivity including carsickness and a clear family history of migraine help support the diagnosis. Also, some patients have typical migraine visual aura or other focal neurologic symptoms unassociated with headache. Bickerstaff described a type of migraine in which the aura consisted of posterior fossa symptoms such as vertigo, ataxia, dysarthria, and tinnitus along with visual phenomena consistent with ischemia in the distribution of the posterior cerebral arteries. He emphasized that the symptoms were particularly common in adolescent girls and commonly in association with their menstrual period. Others have subsequently described a more widespread age distribution. One must be alert to the possibility of posterior fossa migraine in any patient presenting with transient vertigo and other posterior fossa symptoms. In some patients the headache is not severe and is adequately managed by aspirin, sleep, or mild analgesics and sedatives. Many of these patients are much more concerned about the aura phenomena than their headaches. Management. If infrequent, vertigo attacks associated with migraine can be treated with symptomatic medications that produce sedation and relieve nausea. As with the headache, if the patients can fall asleep, the symptoms often are gone when they awaken. Migraine prophylactic medications can be useful in patients with frequent recurrent attacks of vertigo or in patients with a persistent motion sick sensation that can go on for days or weeks at a time. We have found that acetazolamide (250 mg twice a day) is particularly effective for preventing vestibular symptoms associated with migraine. Propranolol (80 to 160 mg/day) and amitriptyline (75 to 1.50 mg/day) are also effective for relieving headache and vertigo associated with migraine.

Acousdc Neuroma Acoustic neuromas (vestibular schwannomas) usually begin in the internal auditory canal, producing symptoms by compressing the nerves in the narrow confines of the canal. As the tumor enlarges, it protrudes through the internal auditory meatus, producing a funnel-shaped erosion of the bone surrounding the canal, stretching adjacent nerves over the surface of the mass, and deforming the brain stem and cerebellum. Acoustic neuromas account for about 5% of intracranial tumors and more than 90% of cerebellopontine angle tumors. By far the most common symptoms associated with acoustic neuromas are slowly progressive unilateral hearing loss and tinnitus from compression of the cochlear nerve. Rarely, acute hearing loss occurs, apparently from compression of the labyrinthine vasculature. Vertigo occurs in fewer than 20% of patients, but approximately 50% complain of mild imbalance or disequilibrium. Management. With few exceptions, the management of tumors in the internal auditory canal and cerebellopontineangle is surgical. Occasionally, one might follow the course of a patient with a small acoustic neuroma, particularly if the patient is an older adult or has underlying medical problems. These tumors can

Dizziness and Vertigo

85

remain confined to the internal auditory canal for years; symptoms may be limited to those of the VIIIth nerve.

Vertebrobasilar lnsuffldency Vertebrobasilar insufficiency (VBI) is a common cause of vertigo in older people. Whether the vertigo originates from ischemia of the labyrinth, brainstem, or both structures is not always clear because the blood supply to the labyrinth, VIIIth nerve, and vestibular nuclei originates from the same source, the vertebrobasilar circulation. Vertigo with VBI is abrupt in onset, usually lasts minutes, and is often associated with nausea, vomiting, and severe imbalance. Associated symptoms resulting from ischemia in the remaining territories supplied by the posterior circulation include visual blurring or blacking out, diplopia, drop attacks, weakness and numbness of the extremities, and headache. These symptoms occur in episodes, either in combination with the vertigo or separately. Vertigo may be an isolated initial symptom of VBI, but repeated episodes of vertigo without other symptoms should suggest another diagnosis. VBI usually is caused by atherosclerosis of the subclavian, vertebral, and basilar arteries. Emboli in the posterior circulation probably are more common than has been generally appreciated. About one in five posterior circulation infarcts is cardioembolic, and another one in five is caused by interarterial embolism, arising most often from occlusive lesions of the extracranial and intracranial vertebral arteries. Other less common causes of arterial occlusion include dissection, arteritis, polycythemia, and hypercoagulation syndromes. Occasionally episodes of VBI are precipitated by postural hypotension, Stokes-Adams attacks, or mechanical compression from cervical spondylosis. Regarding the latter, cervical spondylosis is extremely common in older adults, but documented cases of mechanical compression of vertebral arteries are rare. Occasionally, cerebellar infarction presents with severe vertigo, vomiting, and ataxia without associated brainstem symptoms and signs that might suggest the erroneous diagnosis of an acute peripheral vestibular disorder. The key differential point is the finding of cerebellar signs (gait ataxia and gaze-evoked nystagmus). Such patients must be watched carefully for several days because they may develop progressive brain stem dysfunction caused by compression by a swollen cerebellum. The diagnosis of VBI or stroke within the posterior circulation usually can be made at the bedside based on the characteristic combination of symptoms and signs. One should focus on risk factors for atherosclerosis including history of coronary artery disease, hypertension, diabetes mellitus, and hyperlipidemia. In younger patients without obvious risk factors for atherosclerosis, one should consider the possibility of traumatic or spontaneous arterial dissection and other systemic illnesses that might predispose to hypercoagulation syndrome. Specific stroke syndromes in the distribution of a single vessel are now easily identified with MRI. Magnetic resonance angiography (MRA) is a rapidly developing technology that is displacing conventional angiography for evaluating the vertebrobasilar circulation. Overall there is a good correlation between MRA and conventional angiography, although, depending on anatomic variations and the positioning of the subject, the distal vertebrobasilar artery may be difficult to visualize with MRA. The neuroradiologist should be alerted in advance when it is important to visualize these structures so that the technician can position the patient properly.

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

Management. Treatment of VBI usually consists of controlling risk factors (diabetes, hypertension, hyperlipidemia) and the use of antiplatelet drugs. Anticoagulation (heparin and warfarin) is reserved for patients with frequent incapacitatingepisodes or for patients with symptoms and signs suggestinga stroke in evolution, particularly with basilar artery thrombosis, or with arterial dissection.

Other Central Causes of Vertigo Familial Ataxia Syndromes. Vestibular symptoms and signs are common with several of the hereditary ataxia syndromes including spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7, Friedreich‘s ataxia, Refsum’s disease, and episodic ataxia type 2 (EA-2). In most of these disorders, the symptoms are slowly progressive, with the cerebellar ataxia and incoordination overshadowing the vestibular symptoms. Head movement-induced oscillopsia commonly occurs because the patient is unable to suppress the vestibulo-ocular reflex with fixation. Patients with EA-2 have episodes of vertigo, nausea, and vomiting that may be misinterpreted as a peripheral vestibular disorder such as Menitre’s syndrome. The key to the diagnosis in all of these inherited syndromes is the finding of ataxia of trunk and extremities and the characteristic oculomotor signs, including several varieties of central nystagmus. Diagnostic DNA tests are now available for most of these disorders. Chiari Malformation. With the Chiari congenital malformation, the brainstem and cerebellum are elongated downward into the cervical canal, causing pressure on both the caudal midline cerebellum and the cervicomedullary junction. Symptoms and signs can be delayed until adulthood, in which case they are usually unassociated with any other developmental defects. The most common neurologic symptom is a slowly progressive unsteadiness of gait, which patients often describe as dizziness. Vertigo and hearing loss are uncommon, occurring in about 10% of patients. Spontaneous downbeat nystagmus is particularly common with Chiari malformation, but other forms of central nystagmus also occur. Dysphagia, hoarseness, and dysarthria can result from stretching of the lower cranial nerves, and obstructive hydrocephalus can result from occlusion of the basilar cisterns. MRI is the procedure of choice for identifying Chiari malformations; midline sagittal sections clearly show the level of the cerebellar tonsils. Multiple Sclerosis. Vertigo is the initial symptom in about 5% of patients with multiple sclerosis and is reported sometime during the disease in as many of 50%. The typical bout of vertigo associated with multiple sclerosis lasts from hours to days, although positional vertigo lasting seconds is also a common feature. The key to the diagnosis is to find disseminated lesions within the nervous system occurring with a remitting and exacerbating course. Nearly all varieties of central spontaneous and positional nystagmus occur with multiple sclerosis, and occasionally patients show typical peripheral vestibular nystagmus when the lesion affects the root entry zone of the vestibular nerve. MRI of the brain identifies white matter lesions in about 95% of patients with multiple sclerosis, although similar lesions are sometimes seen in patients without the clinical criteria for the diagnosis of multiple sclerosis. Vertigo and Focal Seizures. Vestibular symptoms are common with focal seizures, particularly those originating in the temporal and parietal lobes. Common associated symptoms include an abnormal epigastric sensation, nausea, mastication, and

Principles of Diagnosis: Common PresentingSymptoms

salivation. Visual illusions and hallucinations are also commonly associated, suggesting a close functional relationship between cortical visual and vestibular projections. The key to differentiating vertigo with seizures from other causes of vertigo is that seizures are almost invariably associated with an altered level of consciousness. There are usually associated stereotyped motor phenomena, and the patient usually is unresponsive for part of the seizure. Episodic vertigo as an isolated manifestation of a focal seizure disorder is a rarity if it occurs at all. The diagnosis rests on finding characteristic EEG changes and focal structural lesions on neuroimaging. Management Although the genes have been identified, so far there are no proven treatments for the common SCA syndromes. Regular physical therapy to maintain range of motion about all joints is critical to avoid painful contractions. A special diet low in phytanic acid can be effective in controlling the progressive symptoms and signs with Refsum’s disease. Acetazolamide is effective for relieving the episodic symptoms in patients with familial periodic ataxia and SCA-6. The usual dosage is 250 mg two or three times a day. How acetazolamide works is unknown, but improvement seems to correlate with lowering the pH of the cerebellum. In patients with Chiari type I malformations, suboccipital decompression of the foramen magnum region can stop the progression and occasionally lead to improvement in neurologic symptoms and signs. Management of multiple sclerosis and focal seizure disorders is discussed in detail in other sections of this book. SYMPTOMATIC TREATMENT OF VERTIGO Treatment of vertigo can be divided into three general categories: specific, symptomatic, and rehabilitative. Whenever a specific therapy such as those discussed in the prior section exists, obviously it is the treatment of choice. However, in many cases there is no specific therapy, or symptomatic treatment is combined with specific therapy. A major change in treatment strategy that has evolved over the past several years is that vestibular rehabilitation therapy should be begun as soon as possible after an acute vestibular lesion. Prolonged use of sedating, symptomatic medications is contraindicated because it can slow down the vestibular compensation process. The commonly used antivertiginous drugs and their dosages are listed in Table 8-5. It is often difficult to predict which drug or combinations of drugs will be most effective in a given patient; some respond to one drug but not to others in the same class. The mechanism of action of these drugs is not completely known, although most have been shown to decrease the efficacy of transmission from primary to secondary vestibular neurons or to decrease the overall excitability of neurons in the vestibular nucleus. The choice of a drug or combination of drugs is based on the known effects of each drug (Table 8-5) and on the severity and time course of symptoms. In patients with acute severe vertigo, sedation is desirable, and drugs such as promethazine and diazepam are particularly useful. If nausea and vomiting are severe, the antiemetics prochlorperazine and metoclopramide can be combined with another antivertiginous medication. The patient with chronic recurrent vertigo usually is attempting to carry on normal activities, so sedation is undesirable. In this setting meclizine, dimenhydrinate, and scopolamine are often useful. Vestibular rehabilitation exercises are designed to retrain the

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TABU8-5. Dosage and Effects of Commonly Used Antivertiginous Medications Sedation

Antiemetic Actions

Dryness of Mucous Membranes

0.2 mg PO q4-6h or 0.5 mg transderrnally q3d

+

+

+++

25 rng PO q4-6h 50 mg PO or IM q4-6h or 100 rng suppository q8h 25-50 rng PO or IM or as suppository q4-6h 5 Or 10 mg PO, IM, or IV q4-6h 5 or 10 rng PO or IM q6h or 25-mg suppository ql2h 5 or 10 rng PO, IM,or IV q4-6h

+ +

+ +

+ +

++ +++ +

++ + +++

+

+++

Class

DNK

Dosage

Anticholinergic agent

Scopolamine

Antihistamine

Meclizine Dirnenhydrinate Prornethazine

Benzodiazepine

Diazepam

Phenothiazine

Prochlorperazine

Benzamide

Metocloprarnide

eye and body musculature gradually to use visual and somatosensory signals to compensate for loss of vestibular signals. Eye and head movements are performed in bed as soon as possible after acute vertigo, nausea, and vomiting have subsided. More vigorous exercises while standing and moving about are then gradually introduced as the patient recovers. For example, walking across a room, up and down a slope, and up and down steps with eyes open and closed can be introduced within the first few days. Games that entail eye-hand coordination are ideal as the patient progresses with recovery. The patient should be encouraged to seek out the head positions and movements that cause dizziness as far as can be tolerated because the more frequently dizziness is induced, the more quickly compensation occurs. Grouping patients together for vestibular exercises often is ideal because they can encourage each other, and beginners can witness the progress of long-term members. The purpose of the exercises should be explained to each patient, and each should receive written instructions outlining an exercise regimen. The exercises usually are continued for 1 to 3 months. During this time, the patient is encouraged to return to a normal schedule of work and leisure activity as soon as possible.

9

Precautions

Asthma, prostate enlargement, older people Asthma, glaucoma

Pregnancy, prior drug addiction ' Liver disease, extrapyramidal reactions

+

Bowel obstruction, liver or renal disease

SUGGESTED READINGS Baloh RW, Halmagyi GM (eds): Disorders of the Vestibular System. Oxford University Press, New York, 1996 Baloh RW, Honrubia V: Clinical Neurophysiology of the Vestibular System. 3rd Ed. Oxford University Press, New York, 2001 Brandt T Vertigo. Its MultisensorySyndromes. 2nd Ed. Springer, London, 1999 Gomez CR, Cruz-Flores S, Malkoff MD et ak Isolated vertigo as a manifestation of vertebrobasilar ischemia. Neurology 4794-97, 1996 Halmagyi GM, Fattore CM, Curthoys IS, Wade S: Gentamicin vestibulotoxicity. Otolaryngol Head Neck Surg 1 1 1:571-574, 1994 Hotson JR, Baloh RW: Acute vestibular syndrome. N Engl J Med 339680-685, 1998 Lee H, Lopez I, Ishiyama A, Baloh RW Can migraine damage the inner ear? Arch Neurol 57:1631-1634,2000 Li JC, Li CJ, Epley JM, Weinberg J: Cost-effective management of benign positional vertigo using canalith repositioning. Otolaryngol Head Neck Surg 122:334-339, 2000 Pulst SM, Perlman S: Hereditary ataxias. pp. 231-263. In Pulst SM (ed): Neurogenetics. Oxford University Press, New York, 2000 Schuknecht HF: Pathology of the Ear. Lea & Febiger, Philadelphia, 1993

Hearing Loss and Tinnitus Robert Aaron Levine

Although a significant portion of the nervous system is devoted to hearing, neurologic disorders rarely present with auditory complaints, as compared with the visual system or even the vestibular system with which the auditory system shares its end organ. The auditory system provides information about our acoustic environment. Not only can it detect the presence of sound within a frequency range of approximately50 to 20,000 Hz,but also it can interpret various aspects about the sound including its intensity (loudness), spectral content (pitch), the sound source location, and more meaningful aspects of the sound such as the type of object generating the sound, the linguistic significance, including its prosody, and the affective content of the sound.

AUDITORY ANATOMY The auditory system consists of a collector of acoustic energy, the external and middle ears, whose function is to efficiently deliver the acoustic energy to the inner ear (cochlea), where the sound is transduced into neural signals (Fig. 9-1). These impulses are then transmitted by the auditory nerve to the central nervous system (CNS), where they are interpreted. The pinna and external auditory canal up to the tympanic membrane make up the external ear. The middle ear is a small cavity vented by the Eustachian tube and spanned by a chain of the three smallest bones in the body: the malleus, attached to the tympanic

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Principles of Diagnosis: Common Presenting Symptoms

r

FIG. 9-1. The peripheral auditory system. (From Kessel RC, Kardon RH: Tissues and Organs, a Text-Atlas of Scanning Electron Microscopy. WH Freeman, San Francisco, 1979, with permission.)

membrane; the stapes, attached to the oval window of the cochlea; and the incus, attached to the malleus and stapes. The two smallest muscles of the body attach to two of these three ossicles. The tensor tympani, innervated by the trigeminal nerve, attaches to the malleus, and the stapedius, innervated by the facial nerve, attaches to the neck of the stapes. The stapedius contracts to intense sound to dampen stapes motion and thereby protect the inner ear. The snail-shaped bony cochlea consists of two and a half turns of a fluid-filled tube divided into three compartments. The top and bottom divisions (scala vestibuli and scala tympani; Fig. 9-2) contain perilymph, which is very similar to cerebrospinal fluid (CSF) in composition. The middle division, scala media, contains endolymph,which, unlike the perilymph, is high in potassium and low in sodium and has a potential of about +80 mV relative to the other two scalae. The perilymph usually is in direct communication with the CSF through a tiny canal, the cochlear aqueduct, and the scalae tympani and vestibuli communicate with each other at the top of the cochlea via the helicotrema. The endolymph is produced within the cochlea by the stria vascularis, which lines the outer wall of the scala media. The endolymphatic space extends through the vestibular aqueduct as the endolymphatic duct and terminates under the dura of the petrous bone as the endolymphatic sac, where the endolymph is resorbed (Fig. 9-3). Reissner’s membrane separates scala media from scala vestibuli, and the basilar membrane separates the scala media from the scala tympani. The organ of Corti sits on the basilar membrane and projects into scala media. Included in the organ of Corti are 15,000 hair cells, arrayed as three rows of outer hair cells and one row of inner hair cells. The outer hair cells have contractile elements that combine with the physical properties of the basilar membrane to

perform a frequency decomposition of the incoming sound so that the cochlea is “tonotopically”organized. The apex of the cochlea is most sensitive to low-frequency sounds (as low as 50 Hz) and the base of the cochlea to high-frequency sounds (up to 20,000 Hz). This tonotopic organization is maintained in the auditory nerve and throughout the CNS. A total of 30,000 afferent and 1800 efferent auditory nerve fibers innervate the organ of Corti. Two types of afferent nerve fibers have been identified. Type I1 nerve fibers are smaller in diameter and nonmyelinated and account for about 5% of the total. Their afferent fiber dendrites synapse on the base of the outer hair cells. In contrast, 95% are type I nerve fibers, whose dendrites synapse on the inner hair cells, where the major acoustic to neural transduction occurs. Type I and I1 cell bodies form the spiral ganglion, which lies within the bony shelf of the modiolus, central to but not within the organ of Corti. Each axon projects to the ipsilateral cochlear nucleus. Physiologically little is known about type I1 nerve fibers, but type I nerve fibers are characterized by sharp tuning: at low sound levels they respond best to a very narrow range of frequencies that correspond to the tuning of the basilar membrane region they innervate, and at high levels they respond to all frequencies below but not above their best frequency. In the absence of sound, type I neurons have spontaneous activity; they discharge continuously at rates ranging from about 1 to 80 per second. To a sound just at threshold these nerves do not increase their overall discharge rate but synchronize their discharges to the sound’s waveform. Only at higher sound levels does the rate of firing increase. The internal auditory artery is the exclusive arterial supply to the inner ear, and in 80% of people it is a branch of the anterior inferior cerebellar artery (AICA). It sometimes emerges directly

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spiral

FIG. 9-1. An axial cross-section of one turn of the cochlea. (Adapted from Bloom W, Fawcett DW: A Textbook of Histology. 1975, with permission.)

FIG. 9-5. Schematic diagram of the inner ear fluid system. Endolymph is shown as solid black. (From Schuknecht HF: Pathology of the Ear. Hanrard University Press, Cambridge, MA, 1974, with permission.)

from the basilar artery, and in about 2% to 3% of cases it is a branch of the posterior inferior cerebellar artery (PICA). Before reaching the cochlea, the internal auditory artery divides into the anterior vestibular artery and the common cochlear artery, which later splits into the main cochlear artery and the vestibulocochlear artery. Usually the apical three quarters of the cochlea is supplied by the main cochlear artery, and the basal quarter of the cochlea is supplied by the cochlear ramus of the vestibulocochlear artery. In the internal auditory canal, the auditory nerve also receives collaterals from arteries supplying the dura mater and petrous bone. In the cerebellopontine angle and in the root entry zone, a network of anastomosing vessels from the AICA, PICA, and vertebral arteries (e.g., the inferior lateral pontine artery and lateral medullary artery) provide the nerve’s blood supply. The auditory nerve enters the lateral brainstem at the pon-

tomedullary junction. Each type I and I1 nerve fiber terminates by bifurcating into two major branches, one for each of the two divisions of the cochlear nucleus: the dorsal cochlear nucleus, located dorsolaterally to the restiform body, and the ventral cochlear nucleus, located ventrolateral to the restiform body. The dorsal cochlear nucleus outputs project through the dorsal acoustic stria to the contralateral inferior colliculus, whereas the ventral cochlear nucleus has multiple projections via the intermediate and ventral acoustic striae, both ipsilateral and contralaterally, including to the opposite cochlear nucleus, the superior olivary complex bilaterally, both lateral lemnisci, and the inferior colliculi (Fig. 9-4). The richness of connections of the ventral cochlear nucleus suggests that many auditory functions are processed by the ventral cochlear nucleus. Although human studies have not identified the functions of the cochlear nuclei subdivisions, animal studies have found only disordered vertical (including front-back) sound localization with lesions of the dorsal cochlear nucleus, whereas most other hearing functions are impaired by ventral cochlear nucleus lesions. The cochlear nuclei receive a rich blood supply from multiple sources, including branches of AICA and PICA. The trapezoid body and superior olivary complex are rostral and medial to the cochlear nuclei in the tegmentum of the lower third of the pons just dorsal to the base of the pons. The trapezoid body is the major decussation of the auditory pathway. However, unlike in other sensory systems the decussation is not complete and total, so that rostral to the trapezoid body the ears are bilaterally represented. Caudal to the trapezoid body, the auditory system can be considered strictly unilaterally represented. Consequently, a unilateral lesion involving the auditory nerve, cochlear nuclei, or dorsal, intermediate, or ventral acoustic striae can cause a unilateral hearing loss, but hearing loss does not result from a unilateral lesion of the structures rostral to the trapezoid body, such as lateral lemniscus, inferior colliculus, medial geniculate body, or auditory cortex. The superior olivary complex is involved in binaural processing and is composed of several nuclei, the most prominent of which is the medial superior olive, which receives inputs from both ventral

Principles of Ambulatory Neurology and the Approach to Clinical Problems

Principles of Diagnosis: Common Presenting Symptoms

A

FIG. 9-4. The central auditory system. (A) Dorsal view of the monaural auditory neural pathway. The cerebellum and overlying cortex have been removed. (Adapted from Nieuwenhuys R, Voogd 1, van Huijzen C: The Human Central Nervous System: A Synopsis and Atlas. 3rd Ed. Springer, Berlin, 1988, with permission.) (6) Functional map of the monaural auditory pathway. Functional MRI images obtained from sound to one ear only are superimposed upon the anatomic map of Fig. 9-4A. Note that both inferior colliculi and auditory cortices are activated by stimulating only one ear. The most intense regions of activation are solid black, the lowest levels are solid white, and gray regions are intermediate. (Courtesy of I. Sigalovsky and 1. Melcher, Massachusetts Eye & Ear Infirmary, with permission.)

Chapter 9 w

cochlear nuclei and is sensitive to differences in the timing of the sounds at the two ears. As the lowest part of the auditory system to receive major inputs from the two sides, the superior olivary complex is also involved in an initial assessment of the intensity differences of the sounds being received from the two sides. Penetrating branches of the basilar artery or anterior inferior cerebellar artery provide this region’s blood supply. Outputs of the superior olivary complex project both ipsilaterally and contralaterally. Some project to the inferior colliculus through the lateral lemnisci, whereas others terminate in one of the nuclei of the lateral lemniscus. The lateral lemnisci extend from the lateral and rostral trapezoid body in the mid-pons to the inferior colliculi of the tectum of the midbrain. Almost all ascending and descending auditory tracts synapse in the inferior colliculus. The commissure of the inferior colliculi connects the two inferior colliculi across the quadrigeminal plate, whereas the commissure of Probst connects the dorsal nucleus of the lateral lemniscus to the opposite inferior colliculus. The blood supply of this region is from penetrating branches of the basilar for the caudal lateral lemniscus and more rostrally from branches of both the superior cerebellar artery and posterior cerebral artery. The brachium of the inferior colliculus is a pathway carrying fibers between the inferior colliculus and the ipsilateral medial geniculate body, which is located in the metathalamus, the caudal subpial portion of the thalamus. This region receives its blood supply through the thalamogeniculate and posterior choroidal arteries. The auditory radiations pass through the posterior limb of the internal capsule or sublenticularly to reach the auditory cortex of the temporal lobe. The primary auditory cortex occupies the region of Heschl’s gyrus of the superior temporal lobe. For different people there are liely to be variations in its exact location. Surrounding the primary auditory cortex area are the association cortices, extending medially nearly to the insula, posteriorly to the parietal operculum, and anteriorly nearly to the orbitofrontal cortex. Branches of the middle cerebral artery supply this part of .the temporal lobe. Interhemispheric fibers connecting the right and left auditory cortices pass through the posterior corpus callosum, whose blood supply is via the pericallosal artery, a branch of the anterior cerebral artery. Paralleling the afferent auditory pathway at all levels is a descending auditory pathway extending from the cortex to the cochlea. These two systems interact at multiple levels.

HEARING LOSS Hearing loss may result from involvement of any part of the auditory system from ear canal to auditory cortex. However, rostral to the auditory decussation (the trapezoid body of the lower pons) hearing is bilaterally represented so that a unilateral lesion at or above the trapezoid body does not cause any obvious hearing loss, although there may be very subtle hearing complaints. To cause hearing loss, lesions rostral to the trapezoid body must be bilateral, in which case the hearing loss symmetrically involves both ears, such as cortical deafness from involvement of both auditory cortices. For this reason hearing loss from CNS involvement is rare. Far and away the most common causes of hearing loss occur at the periphery and generally do not fall within the purview of the neurologist. For this reason only a general survey is provided in this chapter.

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Localization of Hearing Loss The first step in evaluating a hearing loss is determining whether the loss involves the external or middle ear, which causes interruption of a sound‘s access to the inner ear and is called a conductive hearing loss. Otherwise the hearing loss is called sensorineural. Sensorineural hearing loss can be either cochlear (i.e., involving the sensory apparatus involved in transduction of the sound to neural signals) or retrocochlear (i.e., involving the auditory neural system). Determination of the locus of the hearing loss depends on diagnostic studies. Diagnostic Studies Audiogram. The audiogram is the backbone of evaluating any hearing loss. The audiogram should be obtained in almost all subjects with a hearing complaint. It compares pure tone behavioral thresholds for bone and air conduction at the six octave frequencies between 250 and 8000 Hz and is the definitive way of assessing whether hearing loss is conductive or sensorineural. A standardized test of speech discrimination is part of the usual audiogram. This test tends to be poorer with neural than with cochlear types of hearing loss. Usually a tympanogram is included as part of the full audiogram. It assesses the middle ear by measuring tympanic membrane compliance as a function of changes in the static pressure applied to the external auditory Canal. Auditory Evoked Potentials. Electrical recordings from the middle ear or ear canal, the electrocochleogram, can detect the auditory nerve potential (AP)and two types of cochlear hair cell potentials: summating potential (SP) and cochlear microphonics. The SP to AP amplitude ratio, if high, can be supportive but not diagnostic of Mkniere’s syndrome. Electrical brain activity elicited by acoustical stimuli, or auditory evoked potentials (AEPs), can be measured with scalp electrodes. AEPs consist of a series of waves that are classified into early, middle, and late responses according to their latency after the acoustic stimulus. They are generated by subpopulations of neurons that respond synchronously to the acoustic stimulus. Early potentials, also called brainstem auditory evoked responses (BAERs), consist of up to seven waves occurringwithin 10 msec of the click stimuli. Waves I, 111, and V are the most reliable. These waves reflect mainly neuronal activity in the auditory nerve (wave I), the spherical cell projection from the ventral cochlear nucleus to the superior olivary complex (wave 111), and to the contralateral lateral lemniscus or inferior colliculus (wave V). Waves may be absent because of nonresponsive or desynchronized neurons. Delay or absence of the potentials after the first wave has been highly correlated with a neural (retrocochlear)hearing loss. Therefore, the BAERs have become an important tool for screening for acoustic neuromas and are the basis of classifymg a diverse group of hearing disorders as “auditory neuropathies.” Because patient response is not needed, this technique can also provide an objective estimate of hearing threshold in patients who can not provide a reliable behavioral response such as young children, mentally retarded patients, or malingerers. The BAERs can also be performed using bone conduction. Consequently, a conductive hearing loss can also be detected electrophysiologically. It is interesting to note that a close relationship exists between these electrophysiologic measurements and psychoacoustic functions that entail precise neuronal timing. For instance, the synchronization and latencies of the BAERs waves are closely

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Principles of Ambulatory Neurologyand the Approach to Clinical Problems W

related to the ability to discriminate interaural time differences, suggesting that acoustic timing information is contained in the precise latencies of the brainstem potentials. Middle latency responses are recorded with a latency of 10 to 50 msec. In part, they are generated by the auditory cortex. Long latency cortical responses occur between 50 and 500 msec after the stimulus and are generated mainly in the auditory cortex. Middle latency responses and cortical responses are abolished when the cortical or subcortical auditory areas are damaged bilaterally, giving rise to the clinical picture of central deafness. In unilateral or partial bilateral lesions, they usually remain normal. Special stimulus paradigms permit the recording of endogenous long latency responses, which appear to relate to specific higher auditory processing. Attention to acoustic stimuli can be evaluated by the cognitive potential (P-300) occurring at a latency of about 300 msec after the stimulus. P-300 is very sensitive to diffuse ischemia even when there is no overt cognitive decline. Otoacoustic Emissions. Another method for distinguishing between cochlear and retrocochlear locus for hearing loss involves measurement of otoacoustic emissions. The outer hair cells of the cochlea can produce acoustic energy that can be detected with a sensitive microphone system placed in the external auditory canal. In about 60% of normal ears spontaneous otoacoustic emissions can be detected (i.e., without any auditory stimulation a very faint sound can be detected by such a recording system). Another category of otoacoustic emissions are transient evoked emissions, or cochlear echoes. To a brief sound presented to the ear, the cochlea emits back a much lower-level but spectrally similar sound. Frequency-specific otoacoustic emissions can be used to assess restricted regions of the outer hair cells. One such technique is distortion product otoacoustic emissions, which involves presenting to the ear tones of two different frequencies (fl and f2) and detecting in the echo a tone of a third frequency (2fl - f2). The presence of evoked or spontaneous otoacoustic emissions implies that the outer hair cells of the cochlea tonotopically correspondingto the emission frequency are physiologically intact. Therefore, distortion product otoacoustic emissions are an important diagnostic tool for differentiating between a hearing loss caused by outer hair cell dysfunction and by other causes. These evoked otoacoustic emissions can be modulated by sounds presented to the opposite ear via the auditory efferent system of the caudal pons, including the olivocochlear bundle, which reaches the cochlea via the vestibular nerve. Contralateral modulation of otoacoustic emissions can be abolished by brainstem lesions. Stapedius Reflex Measurements. With electroacoustic measurements of the tympanic membrane impedance, stapedius muscle contractions can be readily detected in response to ipsilateral or contralateral sound. Thus, within a few minutes objective information about the functional state of the middle ear, the inner ear, the auditory nerve, the facial nerve, and the central auditory pathways in the lower brainstem can be obtained. Ipsilateral and contralateral measurements can distinguish between right, left, and midline lesions involving the lower brainstem. Imaging. Contrast magnetic resonance imaging (MRI) is the gold standard for detecting abnormalities of the cerebellopontine angle, particularly acoustic neuromas. Likewise, MRI scanning often can detect lesions involving the central auditory pathway. X-ray computed tomographic (CT) scanning can provide exquisite detail of bony involvement of the temporal bone and mastoid process.

Principles of Diagnosis: Common Presenting Symptoms

Laboratoty Studies. Unless there are other clinical manifestations of a systemic illness, generally there is no role of blood work in evaluating hearing loss. The two exceptions are the fluorescent treponemal antibody test for late latent syphilis, which is a cause of MCniere’s syndrome, and the Western blot immunoassay for immune-mediated sensorineural hearing loss, which presents as a subacute bilateral progressive hearing loss.

CONDUCTIVE HEARING LOSS (EXTERNAL OR MIDDLE EAR)

In conductive hearing loss, unlike sensorineural hearing loss, once the sound reaches the inner ear, then hearing is normal. Because sound can reach the cochlea not only through the normal eardrum-ossicular chain pathway but also through sound transmission by the skull (bone conduction), which bypasses the external and middle ear, comparisons of hearing through bone and air conduction are the basis for distinguishing between a conductive and sensorineural hearing loss. Bedside tests using a 512-Hz tuning fork, the Rinne and Weber, can provide a crude assessment of the type of hearing loss. The Rinne test compares bone conduction (with the base of the tuning fork placed against the mastoid process) with air conduction (with the tuning fork placed near the external auditory meatus of the same side), and the Weber test (with the base of the tuning fork placed in the center of the forehead) assesses where a boneconducted sound is perceived when presented equally to both cochleae. In a conductive hearing loss, with the Rinne test the tuning fork is heard louder against the mastoid than next to the ear. With the Weber test the sound is lateralized to the side with the greater conductive hearing loss. The pure tone audiogram distinguishes between conductive and sensorineural hearing loss. External ear causes of a conductive hearing loss are apparent from examining the ear canal. Middle ear causes of conductive hearing loss sometimes have associated abnormalities of the tympanic membrane such as a perforation, bulging or retraction, or inflammatory changes. Evaluation of a conductive hearing loss, particularly when the tympanic membrane appears normal, can be aided by an assessment of the mobility of the tympanic membrane. This can be done at the bedside by otoscopically observing tympanic membrane motion when the pressure in the external auditory canal is changed with a handheld bulb. The tympanogram more precisely assesses the mobility of the tympanic membrane. A noncompliant or stiffer tympanic membrane suggests fluid in the middle ear, whereas a hypermobile tympanic membrane suggests a discontinuity of the ossicular chain. Table 9-1 lists causes of a conductive hearing loss.

PERIPHERAL SENSORINEURAL HEARING LOSS (COCHLEA OR AUDITORY NERVE)

Distinguishing between a cochlear and a neural locus for a nonconductive peripheral hearing loss can be difficult at times because the examination of the ear usually is unrevealing. The whole clinical picture must be taken into account to come to a tentative locus of the hearing loss as well as a cause. These include the temporal profile of the illness, associated signs and symptoms, family history, and medications or toxins.

Chapter 9

TABU9-1. Causes of Conductive Hearing Loss External auditory canal Cerumen obstruction Foreign body obstruction Atresia (failure to develop) External otitis Tympanic membrane Perforation Thickening Ossicles Discontinuity Resorption Fixation (otosclerosis) Middle ear Effusion Tumor

Some pure tone threshold patterns of the audiogram point to a specific diagnosis such as the 4-kHz notch. This refers to an elevation of thresholds limited to tones at or near 4 kHz. This pattern is typical of a noise-induced hearing loss caused by hair cell loss in the 4-kHz region of the basilar membrane. A predominantly low-frequency hearing loss, particularly if fluctuating, suggests another cochlear disorder, Mknikre’s syndrome. There are no pure tone threshold patterns characteristic of a neural hearing loss, but performance on a standardized test of speech discrimination, which forms part of the standard audiogram, tends to be poorer for neural hearing 1osses.

COCHLEAR HEARING LOSS Disorder of Hair Cells Prerbycusis. Presbycusis, the hearing loss associated with aging, is almost universal. It is slowly progressive, but the rate of progression varies between individuals and appears to depend on multiple factors. Genetic factors clearly play a role, as do environmental factors; most prominent among them is noise exposure. A high-frequency symmetricalloss is most common and pathologically involves hair cell loss. Other audiometric patterns are associated with degeneration of stria vascularis or the auditory neurons. Noise-Induced Hearing Loss. Noise-induced hearing loss is caused by hair cell loss and can result from a single exposure or long-standing chronic exposure. Again, individuals vary widely in their susceptibility to noise-induced hearing loss. Tinnitus or transient hearing loss from noise exposure do not predict permanent hearing loss from noise exposure. Serial audiometry is the only certain way to assess susceptibility to noise in a given patient. Ototoxicity. Ototoxicity from medications such as aminoglycoside antibiotics, loop diuretics, and cisplatin all can be irreversible; the hair cell is their site of action. The chance of ototoxicity increases when patients receive multiple potentially ototoxic drugs. Impaired elimination of these drugs, such as from renal insufficiency, predisposes to ototoxicity. Other medications such as salicylates, macrolide antibiotics, tretinoin, and quinines can cause a transient reversible hearing loss and probably have their effect on the hair cell. Vigilant monitoring of drug levels, renal function, and hearing are the keys to preventing irreversible ototoxicity.

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Disorders of Cochlear Fluid Homeostasis Mlnihre‘s Syndrome. MkniPre’s syndrome (or endolymphatic hydrops) is characterized by paroxysmal attacks consisting of a quadrad of symptoms: fluctuating low-frequencyhearing loss, roaring tinnitus, several hours of vertigo, and ear fullness. Typically, there is full recovery after early attacks. Attacks may then recur, but over highly variable intervals. With recurrences recovery becomes incomplete. About one in seven patients eventually develop Mknikre’s syndrome in the opposite ear. Formes frustes of this syndrome do occur. In particular, episodic low-frequency fluctuating hearing loss with a contemporaneous roaring tinnitus and aural fullness may occur without vertigo. The attacks are thought to be caused by rupture of the distended partition separating the scala media from the scala vestibuli. Aside from the audiometric documentation of recovery from a low-frequency hearing loss, there are no diagnostic studies confirming the diagnosis of Mknikre’s syndrome. An electrocochleogram with a high summating potential to action potential ratio suggests Mknikre’s syndrome. If the fluorescent treponemal antibody test is positive, treatment with antibiotics and steroids should be considered; otherwise, salt restriction and salt-wasting diuretics may reduce the recurrence rate. In refractory cases, ablation procedures can control the vestibular but not the auditory symptoms. Perilymphatic Fistula. A communication between the perilymph of the inner ear fluids and the middle ear through a defect in the round window, oval window, or bony labyrinth can cause hearing loss, vertigo, and tinnitus. Unlike in MeniPre’s syndrome, the hearing loss and tinnitus tend to be high frequency (e.g., hissing, crickets), with no recovery. The defect can be caused by barotrauma (e.g., airplane or diving descent), head trauma, Valsalva maneuver, or erosion of the bony labyrinth caused by an inflammatory or neoplastic process or after middle ear surgery such as stapedectomy.The diagnosis can be suggested by the fistula test, or the induction of nystagmus (as seen at the bedside or by electronystagmography)from positive or negative pressure applied to the external auditory canal. If symptoms persist and the findings are suggestive, then the middle ear can be explored for a fistula with patching of the defect. Generally the hearing loss and tinnitus are stabilized but not improved by patching the oval and round windows. Lumbar Puncture. Lumbar puncture with a CSF leak is rarely associated with hearing loss. It is thought to occur when there is a widely patent cochlear duct, so that lowered CSF pressure disrupts cochlear function by lowering scala tympani pressure.

DISORDERS OF THE AUDITORY NERVE Cerebellopontine Angle Tumors

The most common presentation of such tumors is a gradual unilateral sensorineural hearing loss with minimal if any vestibular complaints. Dizziness and facial weakness, in general, are either nonexistent or very minor accompaniments of acoustic neuromas at any time. The audiometric pattern is variable. They are more likely to have poor speech discrimination, acoustic reflex decay, and pure tone decay. Other presentations do occur, including unilateral tinnitus only or sudden hearing loss with or without subsequent recovery. The sudden hearing loss probably is caused by compromise of the blood supply to the inner ear from the tumor’s pressure on the internal auditory artery.

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Any asymmetrical sensorineural hearing loss must be considered suspect for a cerebellopontine angle tumor. Alternatives to obtaining the gold standard contrast-enhanced MRI scan immediately are using the short-latency brainstem auditory evoked potentials, a good but imperfect test, to decide whether to proceed to the MRI scan; or following the patient with repeat audiograms at 6-month intervals, looking for progression of the hearing loss as an indication to go on to the MRI scan. By far the most common cerebellopontine angle tumor is the acoustic neuroma, which is a benign Schwann cell tumor usually arising from the superior division of the vestibular nerve and therefore more properly called a vestibular schwannoma. Once detected, the tumor can be surgically removed, irradiated, or followed for progression by audiometry and MRI scanning, because acoustic neuromas often are slow growing. Surgery risks immediate and radiation delayed hearing loss and facial paralysis. Optimal management guidelines have not been determined. Rarely patients can present with bilateral acoustic neuromas as part of neurofibromatosis type 2, an autosomal dominant disease whose gene locus is on chromosome 22. These patients usually present at an earlier age (15 to 30 years) than the sporadic unilateral acoustic neuroma and can have other brain and spinal tumors as well as a few caf6 au lait spots and posterior capsular lens opacities. Other Auditory Neuropathies A syndrome encompassing hearing impairment and poor speech discrimination with a mild to moderate elevation of pure tone thresholds affecting predominantly the low frequencies or all frequencieshas been called an auditory neuropathy. No pathology has been reported, but tests of outer hair cells function (cochlear microphonics and transient evoked otoacoustic emissions) are normal as compared with tests of auditory nerve function. The compound action potential of the auditory nerve, which corresponds to wave I of the brainstem auditory evoked responses, is abnormallysmall or absent, as are the later waves of the brainstem auditory evoked responses. Acoustically activated reflexes that involve the efferent pathways from the pons to the outer hair cells or to the middle ear muscles usually are absent. In a subgroup of these patients, transient worsening of hearing occurs when febrile. This syndrome often is associated with a peripheral neuropathy either at the time of presentation or as a later development. Thus, it has been associated with Friedreich‘s ataxia, Charcot-MarieTooth disease, and mitochondrial disorders. It has also been associated with prematurity, neonatal hypoxia, and neonatal hyperbilirubinemia.

Sensory or Neural Hearing Loss Immune-Mediated Disorders. Several systemic immunemediated disorders can cause a subacute hearing loss, presumably through an inflammatory involvement of the cochlea. These include temporal arteritis, lupus erythematosus, polyarteritis nodosa, Behqet’s disease, Wegener’s granulomatosis, relapsing polychondritis, and Cogan’s syndrome. In addition, it may occur as a primary disorder with no other organ involvement. If treated promptly with immunosuppression, the hearing loss may be controlled. Meningeal Hearing Loss. Unilateral or bilateral hearing loss can occur with an acute bacterial meningitis and with carcinoma-

tous meningitis. Prompt use of steroids can lessen the risk of hearing loss from bacterial meningitis, at least in children. Viral Infections. Viral infections can cause hearing loss. Well-established causes are congenital rubella, mumps, measles, influenza, herpes zoster (as part of Ramsay-Hunt syndrome or chickenpox), acquired immunodeficiency syndrome, and cytomegalovirus. Sudden Idiopathic Hearing Loss. Unilateral sensorineural hearing loss that develops abruptly or evolves over a few hours with no symptoms involving other organ systems except possibly some mild vestibular symptoms is consistent with the syndrome of sudden idiopathic hearing loss. It is a diagnosis of exclusion. Rarely is a cause identified. A comprehensivehistory and physical examination must be performed to exclude rare causes of an abrupt unilateral hearing loss such as a coagulopathy, vasculopathy, or a cerebellopontine angle tumor. Anterior inferior cerebellar artery occlusion proximal to the internal auditory artery can cause a sudden hearing loss, but it is profound with prominent vestibular symptoms and dysarthria as well as other neurologic signs, including ipsilateral facial palsy, sensory loss of the ipsilateral face (multimodal) and contralateral trunk and extremities (pain and temperature), Horner’s syndrome, and limb dysmetria. On the other hand, bilateral sudden profound deafness with vestibular symptoms can be a sign of vertebrobasilar occlusive disease. Typically patients with sudden hearing loss are young or middle-aged and have no risk factors for vascular disease. Their hearing loss is not profound. Pathologic studies favor a viral cause. If the hearing loss is moderate, recovery from sudden idiopathic hearing loss can be benefitted by a course of steroids. Prednisone 80 mg daily for 5 days followed by a taper over a week is recommended when the hearing loss is between 30 and 90 dB. Conductive or Sensory or Neural Hearing Loss Head Injury. A closed head injury can cause a conductive or sensorineural hearing loss. Acutely a conductive hearing loss can result from laceration of the tympanic membrane, fracture or dislocation of the ossicles, or blood in the external or middle ear, which is often a sign of a temporal bone fracture. The initial treatment is observation because conductive hearing loss from trauma can spontaneously resolve over several weeks. A sensorineural hearing loss can result from head trauma with or without a temporal bone fracture. Fractures can cause a profound sensorineural hearing loss with severe vertigo or be limited to the high frequencies. Hearing loss without fracture usually is worse for the ear closest to the impact and most commonly is limited to the high frequencies. Genetic and Developmental Hearing Loss. Hearing loss related to genetic factors can be present at birth or develop any time later in life. Likewise, the hearing loss can be an isolated symptom (nonsyndromic) or be associated with other organ involvement (syndromic) and can be conductive, sensorineural,or both. Some of the more common syndromic forms of hearing loss are Usher’s syndrome (retinitis pigmentosa), Pendred’s syndrome (goiter), and Alport’s syndrome (nephritis). The mode of inheritance can be autosomal dominant or recessive; X-linked is very rare. Genetic factors can also interact with other factors, such as noise trauma and toxins, to lead to a hearing loss. Genetic factors may be the major determinant of the degree of presbycusis. If so,

Chapter 9 W

then it can be said that genetic factors are the single most common category of chronic hearing impairment.

CNS DISORDERS Patients with focal CNS lesions seldom complain about problems with their hearing. Many times, hearing complaints, even when present, are not prominent but are overshadowed by more prominent complaints involving other neurologic systems. The hearing complaints from CNS involvement can include hearing loss, tinnitus, auditory hallucinations, hyperacusis, or more subtle types of hearing impairment, such as difficulty decoding speech, even though there is no difficulty detecting the speech sounds. Patients almost never complain of difficulties with sound localization, even though performance is abnormal whenever lesions involve the brainstem auditory pathway. When explicit auditory complaints occur, they may be of diagnostic value. When a stroke-related symptom complex localizes to the lateral pontomedullary region, the presence of a unilateral hearing loss indicates that the anterior inferior cerebellar artery and not the posterior inferior cerebellar artery is the vessel involved because many of the neurologic symptoms associated with strokes involving these two arteries overlap. The sudden onset of bilateral hearing loss especially with dizziness or vertigo can be the first sign of basilar artery occlusive disease, but hearing loss or tinnitus are essentially never symptoms of a transient ischemic attack. Phantom auditory perceptions can occur in brainstem and cortical lesions. Probably the most common auditory symptom spontaneously reported by stroke patients is tinnitus. It occurs ipsilaterally with brainstem lesions caudal to the trapezoid body and bilaterally with higher-level lesions. Hyperacusis may occur with midbrain involvement. Rarely gross central auditory disorders from stroke are mistaken for acute psychosis or peripheral deafness. Auditory dysfunction from CNS lesions varies with the location and extent of auditory pathway involvement and the pathologic process. Unlike at the periphery, pure tone audiometry and speech discrimination often are normal. Monaural hearing loss only occurs for lesions peripheral to the superior olivary complex and trapezoid body, and bilateral hearing loss occurs for more rostral lesions only if the auditory pathway involvement is bilateral. If any kind of hearing impairment does occur with unilateral auditory pathway involvement rostral to the auditory decussation, the impairments usually are subtle. Therefore, they are not detected with standard audiometry; other types of testing are needed. Such testing includes assessment of hearing performance that includes integration of the sound inputs from the two ears (i.e., binaural fusion), such as sound localization; identification of distorted monaural stimuli that have been altered to decrease the redundancy of auditory cues such as speech in noise or filtered speech; detection of competing stimuli at the two ears; or recognition of various aspects of more complex auditory stimuli such as music, speech, and environmental sounds. The pathologic process likewise affects the symptoms associated with a lesion in any location. For instance, multiple sclerosis lesions involving the trapezoid body impair sound localization based on the detection of differences in the time of arrival of sounds at the two ears but not on differences in the sound level at the two ears. In contrast, stroke in the same location impairs both.

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A straightforward explanation for these differences is as follows. Demyelinating lesions may affect only the timing of neural impulses but, unlike stroke, will not block such impulses from reaching their ultimate target, the binaural processors in the superior olivary complex. Therefore, demyelinatinglesions may be symptomatic only for functions that entail exquisite timing of neural impulses such as the right-left location of sounds based on timing differences at the two ears. Behavioral Methods for Evaluating Central Auditory Function Sound localizationand Binaural Sound LateralintionTests.

Sound localization is based on binaural cues (interaural differences), or differences in the sounds that arrive at the two ears (i.e., differences in either the time of arrival or the intensity of the sounds at the right and left ears), or on monaural spectral cues (e.g., the frequency-dependent pattern of sound filtering caused by the angle of incidence of the sound with the external ear). Interaural differences are used mainly for left-right localization, whereas spectral cues are used for vertical and back-front localization. For interaural time or interaural intensity differences, headphone tests can measure the smallest such difference that a subject can detect reliably (“just noticeable difference”)and assess a patient’s ability to lateralize. Patients with brainstem lesions often have highly pathologic results in these binaural tests, whereas patients with cochlear hearing losses or with unilateral or bilateral cortical lesions usually perform normally. Free-field tests using speakers can also assess sound localization. Patients with cortical lesions can have impaired sound localization for the sound field contralateral to the lesion and also with sound localization in the vertical plane. Masking level Difference. An important binaural function is the detection of one sound in the presence of competing sounds (the cocktail party effect). A headphone test, masking level difference, can assess for this by comparing the threshold of a binaural tone in the presence of identical noise at the two ears under two conditions: with the tone in phase at the two ears and out of phase at the two ears. In normal subjects there is a major improvement in threshold for the out-of-phase condition. Masking level difference can be abnormal for brainstem lesions. Other Fusion Tests. Evaluation of fusion ability can also be tested by presenting nonredundant complementary auditory information to the two ears (e.g., by presenting low-frequency components of a word to one ear and the high-frequency components of the same word simultaneously to the other ear or by switching a monaural sentence between the two ears a few times per second). Normal subjects are able to fuse the auditory signals from the two ears and understand the content of the auditory stimulus. This binaural fusion ability is impaired in brainstem lesions and seems to be closely related to the ability to lateralize sounds with interaural differences in time and intensity. Distorted Stimuli. Listening tasks with distorted stimuli such as accelerated, retarded, and filtered speech often are poorly performed in patients with temporal lobe or inferior colliculus lesions, even when pure tone audiometry and speech discrimination are normal. Speech discrimination in the presence of background noise typically is impaired in patients with cortical lesions. Competing Stimuli. Dichotic listening tests consist of simultaneously delivering different stimuli, such as words, sentences, or

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

musical stimuli, to the two ears. Dichotic stimulation creates a perceptual conflict between the two ears. In normal subjects this test can reveal the dominant hemisphere. Unilateral lesions of the auditory radiations or cortex typically produce poor performance for the contralateral ear with dichotic testing. However, lesions of the dominant hemisphere sometimes can disconnect the auditory areas of the two hemispheres and thereby produce poor performance for the ipsilateral ear, so-called paradoxical ear extinction. Hearing Impairment as Related to Level of CNS Involvement Brainstem lesions. Brainstem lesions can cause hearing loss, phantom auditory perceptions (tinnitus or hallucinations), or hyperacusis. These may be associated with widespread or focal disease. Hyperacusis, which is a heightened sensitivity to sounds, is the least common of auditory complaints and is always bilateral, but hearing loss or tinnitus can be either bilateral or unilateral. Assorted auditory hallucinations (or tinnitus) of a minor nature are not uncommon with lower brainstem lesions. Transient musical hallucinations occasionally can occur with brainstem stroke, usually resulting from involvement of the caudal pontine tegmentum unilaterally. Peduncular hallucinations, which result from midbrain strokes, are predominantly visual with occasionally a minor auditory component. Involvement of the unilateral lateral lemniscus, brachium of inferior colliculus, or medial geniculate body generally includes no auditory complaints, whereas with a unilateral inferior colliculus lesion there can be difficulties with speech discrimination for the contralateral ear and sound localization for the contralateral sound field. Small pontine lesions involving the trapezoid body or lateral lemniscus are not associated with auditory complaints or abnormal audiograms. However, tests of sound lateralization are abnormal. Patients with involvement of the trapezoid body tend to hear all sounds toward the middle, whereas patients with focal lesions involving the lateral lemniscus tend to hear all sounds toward the sides.

Hemispherical Lesions Cortical Deafness. Cortical deafness is rare but occurs with bilateral temporal lobe lesions or with bilateral subcortical lesions interrupting the ascending auditory pathways. Patients appear deaf, although some reflex responses such as turning toward a sudden loud sound may be preserved. With recovery, some auditory capacities may reemerge. BAERs and acoustic reflexes are preserved in cortical deafness, but middle latency responses usually are impaired, and the long latency auditory evoked potentials are absent. Hemianacusia. Unilateral cortical temporal lesions can produce subtle hearing dysfunction. Pure tone thresholds and speech discrimination remain largely preserved, but tests with distorted and dichotic stimuli are abnormal. Right-left and up-down sound localization can be impaired in the sound field contralateral to the temporal lobe lesion. In addition, there are differences between right and left lesions. Patients with left temporal lobe lesions can have impaired temporal discrimination but normal spectral performance and vice versa for right temporal lobe lesions. Auditory Agnosias. In its most general sense, auditory agnosia is impaired hearing limited to certain classes of sounds.

Principles of Diagnosis: Common Presenting Symptoms

For example, pure word deafness is the incapacity to recognize speech sounds without other features of aphasia. Patients can communicate by reading, writing, and lip-reading. Pure tone thresholds usually are preserved, but speech discrimination is abolished. Evoked potentials are preserved. Word deafness results mostly from bilateral temporal lesions interrupting the connections between the two primary auditory cortices to Wernicke’s area, but it can result from a unilateral posterior temporal lobe lesion of the dominant hemisphere because it isolates Wernicke’s area from the input from both primary auditory cortices. Phonagnosia is the inability to identify a speaker by his or her voice. Amusia is a disorder of music perception such as impaired ability to recognize melodies. It is commonly associated with right temporal lesions, but left-sided lesions also may produce musical perception disorders, especially melody and written music identification. Professional musicians may differ from naive subjects with the effect of cortical lesions on their musical capacities. Finally, sometimes nondominant or bilateral temporal lobe damage can cause an agnosia for environmental sounds. TINNITUS

Tinnitus is a primitive auditory perception that occurs in the absence of an external sound. It differs from any other auditory symptom in one important respect. Tinnitus is multifactorial, and many of these factors are nonauditory. Although tinnitus can be associated with almost any type of hearing loss, one in five profoundly deaf people have no tinnitus, and one of five audiometrically normal people have chronic tinnitus. Therefore, hearing loss is neither necessary nor sufficient for the complaint of tinnitus. In fact about half of all cases seen in a tinnitus clinic are idiopathic. The evaluation of a tinnitus complaint should include the standard elements of any medical evaluation, with close attention to the circumstances surrounding the onset of the tinnitus including any association with new medications, psychosocial stressors, a concurrent medical illness, other auditory, vestibular, or neurologic complaints, or a head, neck, or dental disorder. Exacerbating and remitting factors should be sought, including diurnal variations in the tinnitus. The most important features of the tinnitus percept that must be ascertained are its quality, particularly whether or not it is pulsatile; its location, whether it is heard in one ear or not; its variability, whether it is intermittent or constant; and its pitch, whether it is predominantly low- or high-frequency in character. In addition to the standard otologic physical examination, in general the tinnitus examination should include inspection of the teeth for evidence of bruxism, listening around the ear and neck for sounds similar to their tinnitus, and palpation of the craniocervical musculature for muscle tension and tenderness with special attention to any asymmetries. All patients should have a recent audiogram. Tinnitus Quality: Specific

Some types of tinnitus have such characteristic features that the description alone is the major determinant of the direction of the diagnostic approach. Many of these are described as strictly in or near one ear, and some are not clearly lateralized. Most are “somatosounds”: physical sounds generated by the body and heard by one or both ears.

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Tinnitus Always Unilateral Schwartze’s sign (a red hue behind the tympanic membrane on COARSE lm~mmm SOUNDSCOINCIDENTw m JAW OR H w MOVEMENTS. otoscopy). Detection of a bruit ipsilateral to the pulsatile tinnitus

Such tinnitus is typical of a foreign body such as cerumen, water (or other liquids), or a hair resting against the tympanic membrane. Inspection of the ear canal reveals the source. FLUTERING. Stapedius muscle contractions tend to be described as a fluttering. If the fluttering is associated with facial movements, then stapedial contractions are highly likely to be causing the fluttering sound. This is most commonly seen chronically after recovery from Bell’s palsy, unilateral facial paralysis. When the affected side of the face contracts, the ipsilateral stapedius muscle also contracts because of aberrant facial nerve regeneration (synlunesis). Abnormalities in the pattern of the stapedial reflex or acoustic impedance measurements corresponding to the characteristics of the patient’s tinnitus can occur. When fluttering unilateral tinnitus occurs in isolation with no other associated signs or symptoms, no further diagnostic studies are needed. Medications, such as clonazepam, can sometimes suppress the fluttering; otherwise, the stapedius tendon can be cut. Static-like intermittent tinnitus that is unilateral and occurs in patients over age 50 may be caused by a vascular loop compressing the auditory nerve. Treatment with carbamazepine or others drugs (phenytoin, baclofen, or gabapentin), used for treating trigeminal neuralgia, appears to be beneficial for some patients. Tonal high-frequency unilateral tinnitus that can be heard by listening next to the patient’s ear has been reported to resolve temporarily with curarization and permanently with sectioning the middle ear muscle tendons. Tinnitus May Be Unilateral or Nonlateralized PulunLE. Whether the tinnitus is pulsatile should be established at the outset of the evaluation. If pulsatile, then the next step is to determine whether it is related to the cardiac cycle as follows: compare the examiner’s silent count of the patient’s radial pulse with the patient’s silent count of the pulsations of his or her tinnitus. The examiner indicates when the counting interval starts and stops, and then the two counts are compared. If the counts are almost identical, then the pulsatile tinnitus is cardiac related, and a vascular source must be sought. However, if the two counts are discordant, then the tinnitus is not cardiac related, and other causes must be considered. The patient’s history can give clues to the source of the pulsatile tinnitus. An association with headaches, visual blurring, and menstrual irregularities in an obese woman indicates benign intracranial hypertension. Abrupt onset with unilateral neck or head pains suggests a carotid dissection. Changes in tinnitus intensity with head turning suggest a venous source for the tinnitus, from a source ipsilateral to the direction that decreases the tinnitus. If the patient can obliterate the tinnitus with localized pressure in the periauricular region, then an emissary vein probably is causing the tinnitus. An associated fluctuating hearing loss raises the possibility of microvascular compression of the auditory nerve causing the pulsatile tinnitus. The physical examination also can provide key information about the pulsatile tinnitus. A crescentic purple coloration to the tympanic membrane is diagnostic of a glomus jugulare tumor. Otoscopic observation of a red mass behind the tympanic membrane is evidence of an aberrant carotid artery, dehiscent jugular bulb, or vascular tumor. A unilateral conductive hearing loss in association with ipsilateral pulsatile tinnitus and an otherwise normal examination suggests otosclerosis, as does

suggests that the tinnitus is from the same source as the bruit. The source of the bruit then must be sought. If the bruit is localized to the region of the carotid artery bifurcation, then fibromuscular dysplasia, atherosclerotic carotid stenosis, or carotid dissection is suspected; an associated ipsilateral Horner’s syndrome suggests a carotid dissection. If the bruit is more widely distributed, such as throughout the periauricular region or beyond, a dural arteriovenous fistula becomes likely. If it is heard over the globe, a carotid-cavernous sinus fistula is suspected, particularly if there should be an associated proptosis. Obliteration or reduction in the intensity of the pulsatile tinnitus with ipsilateral jugular compression (light or moderate pressure below the angle of the jaw) implicates a venous source of the tinnitus, whereas a decrease in the tinnitus with ipsilateral carotid compression implicates an arterial source arising from the carotid system. If venous pulsations are seen in at least one of the optic fundi, then CSF pressure is normal, and raised intracranial pressure can be ruled out. The diagnostic studies after the initial visit are guided by the findings of the clinical evaluation and laboratory studies (Fig. 9-5). Because high-cardiac output states such as anemia or hyperthyroidism can cause pulsatile tinnitus (usually bilateral), all patients should have a thyroid profile and a hematocrit. If a carotid lesion is suspected, then either a duplex ultrasound study of the carotid or magnetic resonance angiography should be performed. If a retrotympanic mass is suspected, then a high-resolution contrastenhanced CT scan of the temporal bones should be obtained. Otherwise, a contrast-enhanced MRI scan of the temporal bone and cranium should be obtained. The MRI scan may not detect anomalous arterial patterns such as a persistent stapedial artery, so a noncontrast high-resolution CT scan of the temporal bone is performed, if the MRI scan is normal. If still no cause is apparent and neither papilledema nor retinal venous pulsations were observed (by the examiner or a neuro-ophthalmologic consultant), then CSF pressure should be measured via a lumbar puncture. If all the above noninvasive imaging studies have been unremarkable and raised intracranial pressure has been ruled out, then cerebral angiography should be considered because a dural arteriovenous malformation sometimes can go undetected by any other diagnostic study, even though there may or may not be a thrill or bruit on physical examination. However, it should be recalled that if no bruit is detected on examination, the likelihood is very high that no acoustic source for the pulsatile tinnitus will be detected, despite an exhaustive search. Therefore, it is likely that some pulsatile tinnitus is not a somatosound but is pulsatile on a neural basis, such as from microvascular compression. CLICKING A rare form of tinnitus, clicking tinnitus, appears to be caused by contractions of tensor tympani or the nasopharyngeal muscles controlling the patency of the Eustachian tube (dilator tubae, salpingopharyngeus, or tensor veli palatini). It can sometimes be bilateral as well, in which case it is usually associated with palatal myoclonus. The diagnosis can be established by inspection of the nasopharynx either directly or with nasopharyngoscopy for muscle contractions coincident with the clicking. Unilateral tinnitus evoked by external sounds or the patient’s own vocalization probably is caused by myoclonus of one of the middle ear muscles. Often the examiner can hear the clicking by listening carefully at the external auditory canal with his or her ear, a stethoscope, or a low-noise microphone system placed in the external auditory canal, as is used for measuring otoacoustic

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Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Common Presenting Symptoms

Clinical and Laboratory Evaluation

I

0 Abnormal

J-

J-

j Normal

J-

I Contrast MRI

1 Fundoscopy of Retina

Venous

No Venous

I Angiogram I Puncture FIG. 9-5. Pulsatile tinnitus: diagnostic algorithm. Laboratory studies should include a hematocrit and thyroid profile. 0, thin section computed tomography of temporal bone; MRA, magnetic resonance angiography of cervical and intracranial vasculature; MRI, magnetic resonance imaging. (After Sismanis A, Smoker WR: Pulsatile tinnitus: recent advances in diagnosis. Laryngoscope 104(6):681-688, 1994.)

emissions. Sometimes tympanic membrane acoustic impedance measurements have abnormalities that correspond to this type of tinnitus, or inspection of the tympanic membrane can reveal movements coincident with the clicking. AUTOPHONY (ECHOING OF THE Voiu), OR BLOWINGTINNITUS. The characteristics of this type of tinnitus are so unique that the history alone can make the diagnosis of a patulous ipsilateral Eustachian tube. Patients describe a blowing sound with respiration and an echoing quality to their own voice. Confirmatory features include disappearance of their complaints when their head is in a dependent position and abnormally large changes in the tympanic membrane acoustic impedance with respirations. Estrogen nose drops once or twice daily for 6 weeks sometimes can cause enough mucosal edema to close the Eustachian tube and relieve this type of tinnitus. unlike in the HALLUCINATIONS (NONVERBAL, STEREOTYPED REP-). hallucinations associated with psychoses, these patients have no associated thought disorder, and they are not hearing voices with meaningful, personally relevant content. Rather, the hallucinations are either musical, in which patients report hearing one or a series of familiar tunes incessantly, or auditory, in which a variety of different sounds are described. Typically the strictly musical hallucinations occur in older adults (more commonly in women) with a long-standing progressive moderate to severe bilateral hearing loss. The tunes can be vocal or instrumental. Although they are usually bilateral, they can be unilateral, even with a bilateral hearing loss. Occasionally they

can be precipitated by a new medication, and the hallucinations resolve when the medication is stopped. If the presentation is typical, no brain imaging is necessary. Auditory hallucinations differ from musical hallucinations in several respects. Their onset usually is abrupt and is associated with focal neurologic findings caused by a brainstem stroke or space-occupying lesion. There usually is no major preexisting chronic hearing loss, and the hallucinations usually are not only musical but may include a variety of other sounds such as bells or a waterfall. They often are transient. Brain imaging is necessary. Tinnitus Quality: Nonspecific

Included in this category are a variety of descriptors of tinnitus such as buzzing, tonal, hissing, humming, ringing, roaring, rushing, whistling and whooshing, and crickets. None of these descriptors point to a specific diagnosis. Though nonspecific, roaring often is associated with Mknihre’s syndrome. Because the quality of the tinnitus is nonspecific, aids in making a diagnosis must come from sources other than how the tinnitus sounds. Associated symptoms, circumstances surrounding the onset of the tinnitus, and ameliorating and exacerbating factors are some of the pointers to the diagnostic entity that is accounting for the tinnitus symptom. In attempting to arrive at a diagnosis for tinnitus in which the characteristics of tinnitus are nonspecific, several important considerations must be kept in mind (Table 9-2). The first is that three types of tinnitus are very common in the general population.

Chapter 9

About 50% of people have chronic tinnitus; when queried, about 20% of people indicate that they have chronic ongoing tinnitus and another 30% have tinnitus if asked to listen attentively in the quiet. Eighty-five percent of people have transient (typically less than a minute) unilateral tonal tinnitus with a blocked feeling of the same ear. About 55% of people experience transient tinnitus after exposure to loud sound, lasting from a few minutes to several hours or even days. A second important consideration is that for any pathologic process that is well known to be associated with tinnitus, not all patients with this diagnosis develop tinnitus. Therefore, the presence of tinnitus and a pathologic process by itself does not imply that the two are related. Because there is no obligatory association between the pathologic process and tinnitus, it remains possible that even though a patient with tinnitus has a disease known to be associated with tinnitus, his or her tinnitus may not be related to that disease; rather, the tinnitus and the pathologic process could coexist but be unrelated. Because tinnitus is common in the general population, a third consideration is that the pathologic process only draws the patient’s attention to his or her preexisting tinnitus. Furthermore, if the disease itself did not cause the tinnitus, but hearing loss is part of the disease, the hearing loss could be unmasking the preexisting tinnitus. Just as bringing a normal subject into a low-noise environment can make the subject aware of tinnitus he or she had not appreciated previously, so can a hearing loss unmask tinnitus. Therefore, the question always remains in any patient with nonspecific tinnitus whether the tinnitus was preexisting and unmasked by hearing loss or by the patient’s attention being drawn to his or her hearing. Because nonspecific tinnitus can be physiologic but is not obligatorily associated with any pathologic process, establishing a diagnosis that accounts for any tinnitus is more problematic than for most medical symptoms. In general, a level of confidence is associated with any diagnosis that might account for a symptom. For tinnitus some relationships increase this confidence. The first is a temporal association between the tinnitus and the diagnostic consideration. For example, in Mihiere’s syndrome, if the tinnitus fluctuates with the hearing loss and vertigo, then this strengthens the confidence of the association between the tinnitus and Mhiere’s syndrome. Another way the confidence of the diagnosis is strengthened is if the pitch of the tinnitus corresponds to the audiometric hearing loss pattern. Considering again Mkniere’s syndrome, where early in the illness low-frequencyhearing loss often predominates, if the tinnitus is described as roaring or the pitch match is a lowfrequency one, then the confidence of the relationship between the Mknikre’s syndrome and the tinnitus is strengthened. Likewise, changes in the tinnitus percept that are closely coupled to changes in physical findings strengthen the association between the two. Another consideration in establishing a cause is that the cause may be multifactorial. Tinnitus can be considered a threshold phenomenon, such that although any one factor, such as chronic progressive hearing loss, may not be sufficient to elicit a tinnitus

TABU9-2. Nonspecific Tinnitus: Reasons for Difficulties in

Establishing a Diagnosis Tinnitus is common in the general population. Tinnitus can be multifactorial. For any disease, not all subiects develop tinnitus.

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complaint, two or more factors may synergistically lead to the tinnitus becoming symptomatic. Closely related to the threshold idea is the concept of triggering factors that can lead to symptomatic chronic tinnitus. Such factors include psychosocial stress, viral infection or the postviral state, medications or withdrawal from medications, and head and neck somatic factors (e.g., temporomandibular joint syndrome, ear syringing, trauma including whiplash). Clinical experience suggests that the clinical problem of tinnitus can be precipitated by one or more of these triggering factors. Although a triggering factor may appear to be responsible for precipitating the tinnitus, often the tinnitus persists despite resolution of the triggering factor. If, as often occurs, none of these confidence-raising factors is evident, any association with a preexisting condition such as chronic hearing loss should be considered very tenuous. In such a case, the most conservative position is “idiopathic, possibly related to condition X.” As Coles writes, “If the probability is assessed as being over 50% that a particular condition is causing the tinnitus,. . .most cases of tinnitus would have to be classified as ‘unknown’” (i.e., idiopathic). With these considerationsin mind, we next consider diagnostic entities that appear to be associated with nonspecific tinnitus. Tinnitus Always Unilateral NMR WITH VESTIBULAR SYMPTOMS Conductive Hearing Loss. Any type of unilateral conductive

hearing loss, such as cerumen impaction, ossicular discontinuity, or otosclerosis, can be associated with tinnitus of that ear. The tinnitus may be related at least in part to an unmasking of a “normal” underlying tinnitus, as discussed earlier. Otosclerosis sometimes may be associated with inner ear involvement, which could be contributing to the tinnitus as well. Otoacoustic Emissions. Although spontaneous otoacoustic emissions are common (75% of females and 45% of males with normal or near normal inner ears), tinnitus caused by spontaneous otoacoustic emissions is uncommon; it is said to account for tinnitus in 1% to 2% of patients. The diagnosis is established by measuring an emission whose suppression abolishes the tinnitus. The emission can be suppressed in either of two ways: presentation of a low-level tone near the emission frequency or the use of aspirin (325 mg four times a day for at least 4 days). Some anecdotal reports suggest that trigger factors such as noise exposure might be associated with some cases of tinnitus thought to be related to otoacoustic emissions. MAYBE Wrm VESTIBULAR SYMPTOMS Mhniere’s Syndrome. As a syndrome this condition is defined

by tinnitus as one of its cardinal features. The full-blown picture consists of episodic attacks of intense vertigo persisting for hours, fluctuating unilateral hearing loss typically involving the lower frequencies (in the early stages), ear fullness, and a roaring low-frequency tinnitus. Early in its course there may be no persistent symptoms; however, with recurrent episodes any or all of the symptoms can persist and cumulatively progress with each recurrence. Although the tinnitus often is described as roaring early in the illness, with more advanced stages of the syndrome, the tinnitus tends to become more variable in its description. Formes frustes of this syndrome may occur. In particular, episodic low-frequency fluctuating hearing loss with a contemporaneous roaring tinnitus and aural fullness may occur without vertigo.

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Perilymphatic Fistula. As in MCniere’s syndrome, hearing loss, vertigo, and tinnitus may occur together in patients with a perilymphatic fistula. However, the tinnitus and hearing loss tend to be high frequency (e.g., hissing, crickets). Repair of the leak does not correct the hearing loss or tinnitus. Herpes Zoster Oticus (Ramsay-Hunt Syndrome). Intense ear pain followed by ipsilateral tinnitus, hearing loss, vertigo, and facial paralysis is recognized as caused by herpes zoster once vesicles appear on the pinna, external auditory canal, or tympanic membrane. CerebellopontineAngle Tumors. Any unilateral tinnitus with or without unilateral sensorineural hearing loss must be considered suspect for a cerebellopontine angle tumor, even though only about 3% of all patients with acoustic neuromas first present complaining of unilateral tinnitus only, and the incidence of cerebellopontine angle tumors in patients with unilateral tinnitus is about 0.5%. CNS: Caudal to Trapezoid Body. The hallmark of tinnitus caused by a disorder of the CNS is other neurologic system involvement. If the central auditory nervous system involvement occurs between the ear and the trapezoid body (where the auditory inputs from the two sides intermix and some cross the midline), then there may be an associated ipsilateral hearing loss with unilateral tinnitus. The type of associated neurologic involvement depends crucially on the location of the lesion. With unilateral tinnitus it can include dizziness, diplopia, limb ataxia, ipsilateral facial weakness, ipsilateral facial paresthesias, but contralateral limb paresthesias. The tinnitus often is transient. Intrinsic or extrinsic neoplasms, stroke, demyelinating disease, inflammatory diseases, and meningitides can all lead to unilateral tinnitus and hearing loss. The diagnosis is established by the pattern of neurologic system involvement, the temporal profile of the illness, and the results of ancillary diagnostic studies such as MRI scanning, CSF examination, or arteriography. Sudden Idiopathic Hearing Loss. Patients can present with an abrupt unilateral tinnitus as their only complaint and upon evaluation are found to have a corresponding unilateral hearing loss of which they may have been unaware. More typically they complain of both the hearing loss and tinnitus or hearing loss alone. The hearing loss and tinnitus are abrupt in onset and always unilateral. The quality of the tinnitus usually is closely related to the pattern of the pure tone audiogram. Vestibular symptoms, should they occur, usually are not prominent. Once other rare but identifiable causes have been considered, such as cerebellopontine angle tumor, cochlear ischemia, syphilis, or herpes zoster, then the diagnosis of sudden idiopathic hearing loss is secure.

Tinnitus May Be Unilateral or Nonlateralized ALWAYS wrm HEARN I G Loss Acute Acoustic Trauma. There is no difficulty establishing the diagnosis of tinnitus caused by acoustic trauma when the history is one of immediate development of hearing loss and tinnitus after an intense sound exposure with partial or complete recovery of hearing (temporary threshold shift) over a few days. On the other hand, if the audiogram is normal or the tinnitus does not immediately follow intense sound exposure, then other causes for the tinnitus must be sought. Chronic Progressive Hearing Loss (Presbycusis, Chronic Acoustic Trauma, Hereditary Hearing Loss). These three conditions can be considered together because they affect only hearing, generally have a symmetrical hearing loss, and are slowly progressive, albeit at different rates. The establishment of a causal relationship

between chronic progressive hearing loss and tinnitus is problematic because there is no perceptible change in the hearing or audiogram associated with the onset of the tinnitus, which is often described as abrupt. What has been well established is that the prevalence and reported loudness of tinnitus increase with increasing hearing loss. However, for any patient with chronic progressive hearing loss and recent onset of tinnitus a triggering factor or other cause for the tinnitus must be sought. The association between tinnitus and chronic progressive hearing loss must be considered tenuous. Autoimmune Inner Ear Disease. This condition is like chronic progressive hearing loss except that the progression of the hearing loss is measured in weeks or months rather than years. Because of its more rapid time course, the association of tinnitus with the disease is more compelling. Blood tests detecting inner ear antibodies support the diagnosis. MAYBE No HEARN I G Loss Somatic (Head or Upper Cervical). Observations abound sup-

porting the notion that head and neck somatic events can be associated with tinnitus. About 20% of tinnitus clinic patients report that they can modulate their tinnitus somatically, such as by clenching the teeth or pushing on the head. Systematic studies find that more than 75% of people with tinnitus can modulate their tinnitus in a variety of ways. Most commonly it intensifies, but sometimes the tinnitus can become quieter, particularly if it is unilateral. Less often patients describe changes in its pitch or location. Occasionally changes can persist a minute or two after the manipulation is over. Tinnitus generally is included among the features associated with pain in the temporal or preauricular region that goes by various names such as Costen’s syndrome, craniomandibular disorder, and temporomandibular joint (TMJ) syndrome. Welldesigned studies have shown a higher incidence of tinnitus in normal-hearing subjects with TMJ syndrome than in controls. The same is true regarding whiplash. From multiple other observations and case reports, the concept of tinnitus associated with whiplash and TMJ syndrome can be generalized to include tinnitus associated with any disorder of the upper cervical region and head, including dental pain. The tinnitus temporally associated with unilateral somatic disorders is localized to the ipsilateral ear. Therefore, unilateral tinnitus with no associated auditory or vestibular symptoms such as hearing loss must be suspected for an ipsilateral head or neck somatic disorder. The physical examination should include inspection of the teeth for evidence of bruxism, such as excessive wear of the bottom incisors; palpation of the head and neck musculature for tender muscles under increased tension; and forceful systematic isometric contraction of muscle groups of the head, neck, and jaw for their effects on the patient’s tinnitus. Somatic modulation is one of at least three factors that have been associated with changes in tinnitus attributes. First, as described earlier, most if not all patients can somatically modulate their tinnitus. Stress is a second such factor. Patients consistently describe that they are more bothered by their tinnitus when under stress. Whether this is because the volume of tinnitus changes or because the patient focuses his or her attention on the tinnitus often cannot be distinguished by the patient. In fact, it could be that stress acts through somatic modulation to increase tinnitus loudness because contractions of craniocervical musculature such as clenching the teeth, furrowing the brow, or grimacing often accompany stress. Therefore, one way by which stress may lead to

Chapter 9

TMLE 9-3. Tinnitus Properties Suggesting a Somatic

Component lntermittency Large fluctuations in loudness Variability of location Diurnal loudness changes Localized ipsilateral to a head or upper cervical disorder

increased tinnitus loudness is through increasing head and neck muscle tension, which in turn lead to louder tinnitus by the somatic mechanism. Third, some subjects clearly associate an increase in their tinnitus loudness with exposure to loud sound, and in some the louder tinnitus can persist for hours after the exposure has ended. Therefore, if a patient reports that his or her tinnitus is intermittent or has wide fluctuations in loudness or other qualities, and there is neither exposure to intense sound nor evidence for stress, then somatic modulation must be suspected. A history of variations in tinnitus loudness then raises suspicion for a somatic factor modulating the percept’s loudness (Table 9-3). At one extreme are patients who describe that they have periods when their tinnitus cannot be heard, even in the quiet. Others report wide variations in the loudness of their tinnitus. For still others, their tinnitus is unilateral when it is quiet but becomes nonlateralized when the tinnitus is louder. Such phenomena suggest that there are ongoing somatically mediated factors modulating the tinnitus percept. Diurnal fluctuations in the tinnitus percept also suggest that somatic modulation is operative. Patients who describe their tinnitus as louder upon awakening raise the possibility that somatic factors (such as bruxism or neck positioning) are active during sleep and are causing an increase in tinnitus loudness. Others describe that their tinnitus usually has vanished by the time they awaken and then returns a few hours into the day; this scenario suggests that during the day they are reactivating their tinnitus through somatic mechanisms, such as the tonic muscle contractions needed to support the head in an upright position or clenching related to the stress of daily activities. Finally, others describe that their tinnitus is louder after awakening from a nap in a chair; this may relate to somatic factors such as stretching of the neck muscles when their head passively falls forward while dozing in a sitting position. In general, although a somatic factor on its own can cause tinnitus, much more often somatic factors combine with other factors (such as chronic hearing loss) to act as trigger factors or modulators. Trauma. The contemporaneous association between head trauma, hearing loss, and tinnitus makes the diagnosis straightforward. The association with trauma becomes less certain when some of these elements are missing, such as a delay between the trauma and the onset of the tinnitus. The longer the delay, the less the confidence in any association. Tinnitus but no hearing loss after trauma liewise makes the association more tenuous and raises the possibilitythat trauma is only indirectly causing tinnitus, such as through a somatic mechanism. mstinf&ous Tinnitus. Occasionally patients report the onset of tinnitus after an upper respiratory infection. Whether this is cause and effect has never been established. Because upper respiratory infections are common, and idiopathic tinnitus not uncommon, chance association of the two is to be expected. It is the general impression that tinnitus with upper respiratory infections has its onset several days after the onset of the illness.

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This suggests that the association may be more than at a chance level. Such tinnitus has not been accompanied by hearing loss. Medication Related (Including Withdrawal Syndromes). The temporal association of the onset of the tinnitus with exposure to a medication establishes the diagnosis, particularly if the tinnitus resolves when the medication is withdrawn. An association is less clear when tinnitus begins just after a new medication was begun but does not remit when the medication is discontinued. Such instances raise the possibility that the new medication acted as a trigger for the tinnitus. Aside from high-dose aspirin and quinine, which can also cause reversible hearing impairment, the association of tinnitus with medications is anecdotal. Cisplatin, aminoglycoside antibiotics, and loop diuretics can cause permanent hearing loss and probably tinnitus. Transient tinnitus can be a part of a sedative withdrawal syndrome. CNS Disorder: Rostra1 to Trapezoid Body. Available evidence indicates that for CNS lesions rostral to the trapezoid body (such as involving the inferior colliculus), tinnitus usually is transient and bilateral. Idiopathic. Often, despite an exhaustive evaluation of nonspecific tinnitus, no specific diagnosis can be made with any high degree of confidence, so the diagnosis of idiopathic tinnitus is made. Treatments for finnitus

If a specific cause of the patient’s tinnitus can be determined, then treatment (if available) should be directed toward the underlying condition. Unfortunately, even if it cures the underlying condition, treatment does not always ensure that the tinnitus will resolve. If the tinnitus is idiopathic, the cause of the tinnitus is uncorrectable, or its correction does not abolish the tinnitus, then often simply providing a caring concern for the patient’s complaint and ruling out any serious underlying condition, as well as reassuring the patient that the tinnitus rarely worsens and is not a harbinger of deafness, will suffice. In these cases no further treatment is needed. Otherwise, several nonspecific treatments are available for those distressed by their tinnitus. Medications. The acute distress of recent-onset tinnitus often can be ameliorated with a sedative and an antidepressant combination, such as clonazepam and sertraline. Pharmacologic management of the sleep disorder is always very helpful. Anecdotes abound concerning use of medication and abolishing tinnitus. However, well-designed studies have not identified any medications that abolish nonspecific tinnitus on a long-term basis. Intravenous lidocaine often stops tinnitus transiently (less than 1 hour); the oral analogues of lidocaine have not proved beneficial. One study found both nortriptyline and placebo helpful in chronic tinnitus, but nortriptyline was significantly superior. The benzodiazepines oxazepam and clonazepam (but not diazepam and flurazepam) have been reported to quiet tinnitus, but only alprazolam has been shown in a double-blind trial to reduce loudness of tinnitus. If tinnitus can be caused by auditory nerve compression from a vascular loop syndrome, then anticonvulsants probably could suppress such tinnitus. However, the syndrome has not yet been delineated. Drawing on the analogies to tic douloureux and hemifacial spasm, it is likely that such patients would be over age 50 with tinnitus that is unilateral and intermittent. Shifting of Attention. The fundamental problem with troublesome tinnitus is that the patient is unable to “learn to live with it.” He or she is unable to ignore the tinnitus to the point that it

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interferes with the patient’s ability to concentrate and sleep. Many behavioral techniques have reported success with shifting attention away from the tinnitus. If done well by the patient, they are all probably equally effective. The techniques include hypnosis, “self-hypnosis,” tinnitus imagery, progressive muscle relaxation, cognitive behavioral therapy, and tinnitus retraining therapy. Cognitive therapy has been particularly well studied. Marking. Masking entails using an external sound to mask or cover up the tinnitus. With a masker the patient hears the masking sound and not her or his tinnitus. Anything that generates a sound can be used as a masker. Commonly used items are fans, air conditioning units, radios, and televisions. Sometimes effective masking can be produced by the use of bedside maskers, commercial and custom-made audiotapes, and even radio static. Also available are devices resembling hearing aids (and worn in the ear) that present a selected band of noise to the patient’s ear. Masking seems to work for only a few patients, but tinnitus retraining therapy appears to be more effective. It involves 6 to 24 months of counseling combined with the use of bilateral in-the-ear noise-generators set at a low level so that both the noise and the tinnitus can be heard. Amplification. If a patient has a hearing loss and the tinnitus is in the medium or low pitches, often a hearing aid will help. Electrical Stimulation. Patients who receive a cochlear im-

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Principlesof Diagnosis: Common PresentingSymptoms

plant to treat their profound hearing loss find that this direct electrical stimulation of the auditory nerve from within the cochlea nearly always improves their tinnitus. Extracochlear electrical stimulation via the middle ear appears promising, from some preliminary studies. Other. Additionally, some patients have reported finding help through a variety of other remedies that are of unproven value as yet. It is important to remember that a natural remission can occur, perhaps coinciding with the start of a new treatment or spontaneously with no treatment at all.

SUGGESTED READINGS Coles R Tinnitus. pp. 1-34. In Stephens D (ed.): Scott-Brown’s Otolaryngology, Vol. 2, Audiology. 6th Ed. Butterworth Heinemann, Oxford, 1997 Cone-Wesson B, Rance G Auditory neuropathy: a brief review. Curr Opin Otolaryngol Head Neck Surg 8:42 1-425, 2000 Hausler R, Levine RA: Auditory dysfunction in stroke. Acta Otolaryngol 120(6):689-703, 2000 Levine RA: Diagnostic issues in tinnitus: a neuro-otological perspective. Semin Hear 22:23-36, 2000 Nadol JB Jr: Hearing loss. N Engl J Med 329(15):1092-1102, 1993 Tyler R (ed.): Tinnitus Handbook. Singular/Thomson Learning, San Diego, CA, 2000

Disorders of Smell and Taste Christopher Hawkes

It is common practice to lump smell and taste sensation together, yet the two modalities develop individually from an embryologic standpoint and are almost completely separate in the brain at the subcortical level. Phylogenetically, olfaction developed first; taste is a newer thalamic-dependent feature. The fact that so many patients confuse the two should not permit their assimilation by clinicians. According to Hoffman and coworkers, at least 2.7 million (1.4%) Americans have some form of chronic olfactory dysfunction.

ANATOMY AND PHYSIOLOGY OF OLFACTION Anatomy There are two noses (right and left), and each has a triple innervation: trigeminal, olfactory, and autonomic. The trigeminal component supplies most of the inner mucosal lining of the nose with perception of touch, temperature, pain, tickle, and itching. Most odorous compounds stimulate all three in varying proportion. For example, vanillin is one of few specific olfactory stimulants, whereas ammonia has powerful trigeminal and olfactory components. It has been suggested that the trigeminal nerve contributes partially to smell appreciation, but the issue has never been fully resolved. Certainly anosmics can detect “impure” smells (i.e., those with a trigeminal component such as menthol or camphor). The olfactory receptor area is small and located high in the nasal cavity in the upper septal zone, cribriform plate, and medial wall of the superior and to a lesser extent middle turbinate. The anatomy as seen by coronal magnetic resonance imaging (MFU) is

shown in Figure 10- 1. Histologically, the olfactory epithelium consists of a sheet of supporting cells with interspersed olfactory neurons that form knoblike protrusions above the level of the supporting cells. The olfactory knobs have 3 to 50 ciliary processes that contain receptors. They form tight junctions with adjacent supporting cells and openings of Bowman’s glands. Bowman’s glands secrete mucus essential for olfaction. The mucus contains a protein, olfactory binding protein, that sticks to odorant molecules and assists in transmitting the odorant to membrane proteins within the cell membrane of the olfactory dendrite and supporting cells. Olfactory analysis (like taste) has to take place in a fluid environment. There are an estimated 12 million olfactory receptor cells in the human. (This number is dwarfed by approximately 4 billion in the equivalent canine area.) The axons of the bipolar olfactory cells are just 0.2 pm in diameter, making them some of the thinnest in the nervous system, and consequently they conduct slowly, at about 1 m/second. Groups of these unmyelinated axons are enclosed in one sleeve of a neurolemmal cell, so axons are almost in direct contact with each other (a gap of only 100 A), and crosstalk between them is possible. Apart from cochlear neurons, the olfactory neurons are the only ones in the central nervous system that are capable of regeneration, and they turn over continually. There are no data for humans, but it is estimated from animal work that they live for about 35 days, and this explains why a few people with, for example, post-traumatic anosmia may eventually recover. The general somatic nerve supply to the nose derives from branches of the trigeminal nerve. The anterior and posterior ethmoid nerves, which are branches of the nasociliary nerve

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and septal areas. The third extends to the primary olfactory cortex, which is medially situated in the temporal lobe and consists of the prepyriform cortex, an area adjacent to the lateral olfactory stria (Fig. 10-2A) and the rostral part of the uncus; and the limen insulae and uncus, sometimes called the intermediate pyriform cortex. The limen insulae is a tongue of cortex just medial to the anterior perforated substance (Fig. 10-2A), and the uncus is a hooklike structure when viewed from below, situated deeply and medially within the temporal lobe, continuous laterally with the amygdaloid body. There are important connections from the primary olfactory cortex to the orbitofrontal cortex, which is an association area concerned with smell identification and discrimination. Cortical areas that are directly concerned with smell appreciation when stimulated consist only of the prepyriform and intermediate pyriform cortex. Unlike the neural connections for all other sensory modalities including taste, most impulses reach the cerebral cortex without first relaying through the thalamus. This fact emphasizes the primitive origins of the rhinencephalon,which evolved long before other sensory paths. Some have suggested that the olfactory bulb is the equivalent of the thalamus, but olfactory signals eventually do reach the thalamus (mediodorsal nucleus), where they interact with trigeminal afferents. FIG. 10-1. MRI scan (coronal TI-weighted) in a healthy 45-year-old woman showing frontal lobes, orbits, olfactory bulbs, olfactory sulcus, and gyrus rectus. The superior turbinate and infundibulum are not clearly shown because of the posterior coronal section. E, part of the ethmoid sinuses that are often honeycomb structures; I, right inferior turbinate; M, right middle turbinate; OFC, orbitofrontal cortex.

(ophthalmic division of V), supply the upper part of the nasal cavity. The posterior part of the nasal cavity is fed by the nasopalatine nerve, which is a branch of the maxillary nerve. Autonomic supply to the nose comes from the sphenopalatine ganglion. Vascular disturbance in this ganglion is said to cause a form of facial pain associated with nasal congestion known as sphenopalatine neuralgia. It can be abolished sometimes by applying cocaine to the ganglion. The nasal cavity is perfused by tributaries of the external and internal carotid arteries. Theoretically, impaired blood supply in the ethmoidal arteries could interfere with olfaction, but this has not been described in practice, probably because of good collateral supply. The anatomy of the bulb is complex. It contains 20 or more neurotransmitters. Axons of the olfactory cells make contact with the dendrites of mitral and tufted cells (i.e., axodendritic synapses) and in so doing form curious-looking clumps called glomeruli. There are only 12,000 glomeruli available to handle messages from 12 million olfactory axons (i.e., 1000:1 convergence). Impulses next pass along the olfactory tracts, which lie on the undersurface of the frontal lobes. Some fibers project back to the contralateral olfactory bulb (Fig. 10-2A). The central connections split in three directions. The first extends to the septal area and from there via the stria medullaris to the habenular nucleus, thalamic intralaminar nuclei, and interpeduncular nucleus (Fig. 10-2B). Another branch from the septal area connects via the cingulate gyrus to the hippocampal formation, which is part of the limbic system (Fig. 10-2C). The second extends to the amygdaloid nucleus (Fig. 10-20). Connections from here go to and from the neocortex and parahippocampal gyrus, the dorsomedial nucleus of thalamus, and the preoptic

Physiology During normal inspiration 5% to 10% of the air reaches the olfactory receptors, but the act of sniffing redirects 20% of the air (approximately250 mL) from its usual mainly horizontal path up to the olfactory cleft. Sniffing enhances olfactory perception and identification to a small extent, and this aspect is important in diseases in which respiratory function is compromised. An important function of the nose is to warm and humidify incoming air, facilitating olfaction. The nose filters potentially harmful particles, but even more significant and not widely appreciated is the outstanding ability of the nasal mucosa to detoxlfy incoming chemicals, a function surpassed only by that of the liver. The nasal mucosa exerts cytochrome p-4504ependent mono-oxygenase activity, allowing it to detoxify a variety of drugs and harmful xenobiotics. Surprisingly,only one nostril is ever fully patent at a time in 80% of healthy people, and this varies throughout the day in the “nasal cycle.” The precise reason for this apparent economy is ill understood, but it has to be taken into account when testing smell sense unilaterally. The human nose can detect certain chemicals at extremely low concentration. For example, methoxy-isobutylpyraine (musty) may be detected in a concentration of 0.0002 ppb, and those not congenitally anosmic to it may detect androstenone (urinous) at a concentration of 0.2 ppb. It is estimated that there are about 1000 human olfactory receptor genes but most, around 70%, are pseudogenes (i.e., they have no function). This contrasts with the rodent with only 5% pseudogenes and confirms that olfaction has become less important in the course of primate evolution. The human olfactory receptor gene family is distributed over several chromosomes. Zozulya and colleagues (2001) identified 347 putative functional receptor genes widely dispersed on all but 6 chromosomes, with many (155) on chromosome 11 and most of the others on chromosomes 1, 9, and 6. Binding of an odor takes place on the ciliary process of the olfactory cell. This triggers a G-protein (guanosine 5’triphosphate-binding regulatory protein)-mediated increase in

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FIG. 10-2. (A) Anatomy of the olfactory bulbs and the three major divisions connecting to the brain. (6) Some connections of the limbic system and septa1 area. (From Noback CR, Demarest RI: The Human Nervous System. 3rd Ed. McCraw-Hill, New York, 1981, with permission.)

second messenger cyclic adenosine monophosphate (AMP). Cyclic AMP and probably other second messengers such as inositol triphosphate activate ion channels to control the flow of sodium and calcium across the ciliary membrane. This amplifymg cascade then probably opens calcium-activated chloride channels and generates an action potential. This potential, which can be recorded from the surface of the olfactory epithelium, is of remarkably long duration: 100 to 200 msec or more. Coding of Olfactory Information. According to the stereo-

chemical theory proposed by Amoore (1967), smell differentiation relates to variation in molecular shape of the odor in question, which locks onto and activates specific receptor sites on olfactory neurons. Unfortunately, this does not predict how all chemicals smell: Some structurally different chemicals have the same odor, whereas others that are just stereoisomers smell quite different (e.g., spearmint and caraway). In the human olfactory epithelium, receptor cells sensitive to a particular odor respond to stimuli by variation of discharge frequency rate according to odor concen-

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FIG. 10-2. Continued (C) The Papez circuit: hippocampus via fornix to mamillary body, via mamillothalamictract to anterior nuclear group of thalamus, via cingulate gyrus to hippocampus. (0) Connections of the limbic system and amygdaloid body. (From Noback CR, Demarest RI: The Human Nervous System. 3rd Ed. McCraw-Hill, New York, 1981, with permission.)

tration. It appears that all receptor cells respond in varying degrees to the majority of odorants irrespective of their physicochemical properties. It is surmised that receptor cells have varying sensitivitiesand that a population pattern is generated from many cells with similar sensitivity. Neurons that are activated by an individual smell or class of smells have not yet been found in humans. A transient decrease or loss of smell perception occurs for varying periods after odor exposure because of receptor fatigue.

For example, continuous inhalation of lemon or orange vapor can result in complete loss of smell sense for up to 11 minutes in healthy people. Unlike the eye and ear, the ability of the nose to localize and lateralize olfactory signals is poorly developed. Unless the head can be moved, it appears impossible for the position of an odor to be perceived. If the signal is introduced directly into the nostril, it may be lateralized only if the odor has some coexisting trigeminal

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component (e.g., menthol). There are interesting differences in transmission of odors according to their hedonic properties, with pleasant emotions represented mainly in the left cerebral hemisphere and unpleasant on the right. Lesions of the amygdalohypothalamic pathways impair odor and taste aversions, odor preference learning, and odor-mediated aspects of reproduction, suggesting a major role in feeding and neuroendocrine function. There is clinical evidence that medial bilateral temporal lobe lesions interfere with smell sense, but only the ability to identify or discriminate smells correctly is lost, not odor detection. Removal of either temporal lobe results in significant reduction of olfactory discrimination ipsilateral to the side of nasal stimulation. Impairment is also seen ipsilaterallywith removal of either frontal lobe, but if the right frontal lobe is removed (including the orbitofrontal cortex), discriminatory loss affects both nostrils. Therefore, the right orbitofrontal cortex, which receives signals from both temporal lobes, appears to be dominant for higher olfactory analysis. Specific Anosmia. Some people are unable to detect certain odors, but their smell sense is otherwise normal. This is called specific anosmia or smell blindness and is analogous to color blindness. There are more than 76 types of specific anosmia, and the most common ones are listed in Table 10-1. Almost half the healthy population are unable to detect androstenone. This compound has a sweaty or urinous odor and is suspected to have aphrodisiac properties in animals and humans. Smell blindness probably is inherited, but the genetic mechanism for most compounds is poorly understood. Blind Smell. Sobel and colleagues (1999) coined this term, which must be carefully distinguished from smell blindness. Blind smell implies detection of odor by the brain in the absence of conscious perception. To demonstrate this phenomenon, functional MRI (fMRI) was used to localize brain activation induced by high and low concentrations of estratetraenol acetate, a putative human pheromone with a “chemical-like” smell. Although subjects reported verbally that they were unable to detect either concentration, their forced-choice guesses were better than chance for the higher concentration, and both concentrations produced significant brain activation on MRI, mainly in the right orbitofrontal cortex. In other words, these subjects were able to detect odor at a subconscious level, without being fully aware that they could do so. These observations complement earlier work on “blind sight,” by which a subject correctly localizes objects although they cannot be seen consciously.

Influences on Olfaction Age, Gender, and Smoking. The effect of aging on olfactory ability in all aspects after the sixth decade is well documented. A

osmia Compound

Odor Quality

Androstenone lsobutyraldehyde Cineole Pyrroline Pentadecalactone Carvone Trimethylamine lsovaleric acid

Sweaty or urinous Malty Camphorous Spermous Musky Minty Fishy Sweaty

Percentage Anosmic 47 36 33 12 12 8 6 3

Adapted from Wysocki U, Beauchamp CK: Individual differences in human olfaction. pp. 353-373. In Wysocki 0,Kare MR (eds.): Chemical Senses. Vol. 3: Genetics of Perception and Communication. Marcel Dekker, New York, 1991

Principles of Diagnosis: Common Presenting Symptoms

healthy 90-year-old will identify correctly only half the odors identified by a 20-year-old. Aging influences odor perception at a later time in women, and older women score higher on the University of Pennsylvania Smell Identification Test (UPSIT) than men of the same age. Women are found to outperform men on most psychophysical tests, but the effects are not marked. Healthy older adults have diminished capacity to identify, discriminate, and remember odors, but UPSIT score does not correlate with memory score as measured on the Wechsler Memory Scale. Tobacco smoking has a small effect on smell identification and relates to the quantity smoked. A very heavy smoker may have an UPSIT-40 score up to 4 points lower than that of a nonsmoker; smoking cessation causes a gradual improvement of smell function. CLINICAL EVALUATION METHODS Anosmia is an absence of smell sense; hyposmia or microsmia is a reduction of it. Dysosmia is a distortion of smell and is divided into parosmia, in which the distortion is in response to a specific stimulus, and phantosmia, in which no external stimulus is present. Cacosmia is a form of dysosmia in which the distortion is unpleasant. Torquosrnia is a rarely used term referring to a smell distortion akin to burning. Hyperosmia is a hypersensitivity to common odors. Osmophobia is a dislike of certain smells, and presbyosmia is the natural decline in smell sense with age. In heterosmia, all odors smell the same.

History and Examination Patients may not recognize that there is a problem with smell unless this faculty is essential for their work or hobbies (e.g., for a chef or wine taster). Therefore, patients must be questioned specifically about it. Even when asked, a significant percentage of patients are unaware of impairment, especially if there is cognitive impairment, if the defect is unilateral, if the anosmia is longstanding, or if it came on gradually. When anosmia is present, the patient often confuses it with loss of taste, stating that food tastes bland, but only rarely are the two modalities impaired in tandem. The history should be directed particularly to exclude local nasal or sinus disease. It is helpful to know the time of onset of the smell problem and whether it dated to any cause, such as upper respiratory tract infection, nasal or sinus disease, head, nasal, or neck trauma, work in a dusty environment, nasal or sinus surgery. Smoking habits should be documented. A drug history may be revealing, and many systemic diseases such as diabetes or renal failure may be relevant. Smell impairment, like deafness, can be categorized into conductive and sensorineural types. Before any assessment of smell ability can be made, it is essential to determine whether the inhaled air can reach the olfactory receptors in the nose. If smell loss arises because air is unable to reach the olfactory epithelium, it is conductive. Because of the physiologic nasal cycle, in most people only one nostril is open at a time. One should be alert to patients who mouth-breathe because they may have local disease that could affect their ability to smell. If the patient has nasal congestion from upper respiratory infection, hay fever, or migraine attack, then no reliable assessment can be made. Fluctuation of hyposmia with the degree of nasal congestion is a clue that it is conductive in origin. Improvement may be noticed after activities that reduce nasal congestion, such as exercise, heavy lifting, and showering. Simple inspection with a pair of nasal

Chapter 10

forcepsmay reveal the patency of the nasal airway peripherally and whether there is obstruction from congestion, polyps, or deviation of the nasal septum. This method detects only about 50% of relevant disorders because the olfactory epithelium is located high in the attic; endoscopy is needed to allow direct inspection of this area. Nasal endoscopy is the only means of examining the olfactory epithelium and can be extremely helpful in differentiating congenital and traumatic anosmia from viral anosmia and for identifymg nasal tumors, particularly polyps arising high in the nasal cavity. All cranial nerves should be examined in someone with a smell problem. The optic and trigeminal are the most essential cranial nerves for valuation. An abnormal visual field, pupillary defect, or optic disk swelling or atrophy might suggest the presence of a frontal lobe tumor or related structural disorder. The sensory component of the trigeminal nerve is of particular relevance. Common sensation should be assessed over the face with cotton wool and a pin. Pain pathways in the nasal mucosa are shared with itching and thermal sensation so that nasal tickle is a useful and less well-known stimulant of pain pathways in the nasal mucosa. Nasal tickle is examined by gently moving a wisp of cotton wool inside one nostril. Normal people respond by flinching rapidly, and asymmetry suggests a disorder of trigeminal fine nerve fibers. Patients with frontal lobe lesions may have primitive reflexes such as a pout or grasp reflex. Simple tests of cognitive function such as the Mini-Mental Status test are a useful means of detecting Alzheimer’s disease (AD), a disorder regularly associated with olfactory impairment. A demented patient with memory problems will have difficulty with smell identification tests, so that tests of threshold or simple perception are more appropriate. Examination should include the ears and upper respiratory tract.

Special Tests of Olfaction Rhinomanometry, nasal cytology, the ciliary motility test, and various skin tests are more relevant to general throat, nose, and ear complaints than neurology. Nasal mucosal biopsy is of value in diagnosing malignant and granulomatous disorders, particularly Wegener’s disease and sarcoidosis. Identification and Threshold Tests. Simple olfactory testing is rendered particularly difficult because of the supply of the nose from two sensory nerves (i.e., the olfactory and trigeminal nerves). The majority of commonly used test odors cause simultaneous activation of trigeminal and olfactory nerve endings within the nose (especially ammonia, menthol, and camphor). For a simple basic screening test, vanilla, chocolate, and coffee are good stimulants and may be identified by most patients. Phenylethyl alcohol is also worth including; it is obtainable as a liquid and gives a roselike odor. Doty showed many years ago that anosmic patients could detect acetone, pyridine, toluene, methanol, amyl-acetate (banana), menthol, linalool (soapy), camphor, methylethyl ketone (glue smell), and many more odors. The detection pathway probably is via trigeminal stimulation, so a smell test kit that incorporates any of the above odors has dubious value unless the concentrations are very carefully defined. UPSIT. If more detailed analysis is needed, one may use the University of Pennsylvania Smell Identification Test (UPSIT). This uses the scratch and sniff principle (i.e., odor is released by scratching an impregnated cardboard strip). For each of 40 test smells in the standard kit, the subject makes a forced choice from four alternatives. Normative values are available for nearly 2000 Americans standardized for age and sex (Fig. 10-3), but outside

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Disorders of Smell and Taste

the United States it is essential to establish local control scores. In general, healthy people under 60 years should score at least 30 out of 40, whereas anosmics score an average of 10 5. Clever malingerers score 0 to 5 as they intentionally deselect the correct answer and they are likely to scratch the impregnated strip less vigorously than a genuine hyposmic. The UPSIT-40 has proved a reliable procedure and is useful for both routine clinical and medicolegal cases. However, it is affected by differences in cognitive function he., the more intelligent person may not recognize the correct odor but could identify those that are wrong, and deduce the correct answer by elimination). This drawback offsets its usefulness in AD, for example, where smell memory, concentration, and reasoning may be affected and tests of perception or threshold would be more appropriate. Non-Americans may have difficulty with some of the forced choices (e.g., skunk, pumpkin pie, and root beer). To avoid this problem, there is an international version that has just 12 odorants. Although this is good for basic dinical screening, it is not suitable for a research purposes because it provides insufficient statistical power. For more rapid examinations, there is a pocket smell test with just three common odors. A rival procedure uses Sniffin’ Sticks, or felt-tip pens impregnated with various smells. Published normative data are available for more than 1000 German people and may be expressed as a threshold, discrimination, and identification (TDI) score. However, it is essential to establish local population control data if any research investigation is contemplated. Sniffin’ Sticks are more time-consuming to use if the TDI score is needed, but in the long run they are much cheaper after the initial outlay. A more refined approach is to determine the absolute level of a particular odorant that can be detected. Air dilution olfactometry would be the method of choice, but this involves complex apparatus and is not practical for ordinary clinical investigation. A good compromise is to use an odorant such as phenylethyl alcohol (rose smelling) in varying dilutions contained in small flasks held under the nose (“sniff bottles”). Somewhat similar is the T & T olfactometer, or perfumists’ strip. Threshold tests are less influenced by cognitive function and, theoretically at least, should be better than identification procedures. Threshold tests correlate well with the UPSIT, but they take much longer to perform, so most people prefer identification tests as long as cognitive function is normal. There is no specific test for dysosmia, although the majority of patients with this complaint have some degree of olfactory loss, typically of mild or moderate severity. Plain radiographs have substantial limitations; they do not provide sufficient detail for structures such as the osteomeatal complex. In particular, more detailed images are needed when endoscopic surgery is to be performed. Computed tomographic (CT) scanning is the most useful and cost-effective technique for evaluating sinonasal tract inflammatory disorders. Coronal CT scans are particularly valuable in assessing paranasal anatomy. Scanning with thin cuts (5 mm) identifies bony structures in the ethmoid, cribriform plate, and olfactory cleft, as well as the temporal bone in proximity to cranial nerve VII or chorda tympani nerves; however, CT scanning is less effective than MRI in defining soft tissue disease. CT used with intravenous contrast media increases sensitivity for vascular lesions, tumors, abscess cavities, and meningeal or parameningeal processes. MRI is superior to CT scanning in evaluating soft tissues, but it defines bony structures less well and tends to overemphasize mucosal disease. MRI is the technique of choice for assessing the olfactory bulbs, olfactory tracts, facial nerves, and intracranial causes of chemosensory dysfunction. It is also the preferred technique for

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AGE GROUP FIG. 10-3. Scores on the University of Pennsylvania Smell Identification Test as a function of age and sex. Numbers by data points indicate sample sizes. (From Doty RL, Shaman P, Applebaum SL, et al: Smell identification ability: changes with age. Science 226:1441-1443, 1984, with permission.)

evaluating the skull base for invasion by sinonasal tumors. Gadolinium enhancement helps to detect dural or leptomeningeal involvement at the skull base. Brain Mapping. This is an alternative method of image enhancement that allows spatial distribution of the electroencephalogram (EEG) to be displayed in the form of a contour map. The result is aesthetically pleasing and allows the distribution of brain activity to be visualized more readily than simple inspection of the EEG. fh4RI and positron emission tomography are the most sophisticated measurements of cerebral activity in response to odor. Initial studies have confirmed that the main olfactory association area is in the right orbitofrontal cortex.

DISORDER OF OLFACTION Disorders of Olfactory Perception Distortion in the perception of an odor is known as parosmia (rarely known as troposmia). If the sensation is unpleasant, the phenomenon is called cacosmia. Such distortions are common when there is local nasal disease-typically infection in the sinuses or nose itself-but may be found when there is trauma to the olfactory nerve or bulb after head injury or chemical exposure. Parosmia may be associated with normal or diminished smell sensitivity. Minor degrees of parosmia are not necessarily abnormal; for example, unpleasant smells can linger for several hours and may be rekindled by other olfactory stimuli. Hyperosmia. This is a disorder of perception in which there are varying degrees of increased sensitivity to one or more aromas. It has been observed in Addison's disease and some cases of head injury and may follow abrupt drug withdrawal. A minority of

clinicians doubt the existence of the condition in association with physical disease. Certainly some neurotic patients complain of undue sensitivity to odors when there is no proof of actual change in odor perception threshold. Conversely, it has been shown by smell perception tests that about 2% of healthy people are hyperosmic to pyridine. During or before migraine attacks some report temporary heightened and unpleasant smell perception (osmophobia) in a manner comparable to photophobia and phonophobia. Many patients with persisting hypersomia are initially depressed or soon become so. It can form part of a more generalized syndrome of multiple chemical sensitivity (MCS) in which numerous symptoms are connected with repeated exposure to environmental chemicals. When Doty and colleagues (1988) tested 18 patients with MCS for hypersensitivity to two odors, there was no difference in olfactory detection threshold, but there was a high level of depression, increased nasal resistance to odors, and disordered respiratory rate. This suggested there was a complex mixture of physical, psychiatric, and autonomic problems. Hallucinations. An olfactory hallucination is a disorder of smell perception in the absence of odor in the environment. The patient claims to smell an odor that no one else can. If the patient is convinced of its presence and also gives it personal reference despite all evidence to the contrary, it is then a delusion and sometimes called olfactory reference syndrome. Olfactory hallucinations may result from disorder almost anywhere along the smell pathway, from the nose to the primary olfactory cortex in the medial aspect of the temporal lobes. The orbitofrontal cortex, which is a suspected association area, probably does not cause hallucinations if diseased. Patients with local nasal problems such as infection or trauma may complain of a continuous or intermittent unpleasant smell (phantosmia) in the absence of any

Chapter 10

external stimulus. The aura that characterizes uncinate epileptic attacks is most often unpleasant and is difficult to remember or describe in detail. Conceivably this relates to a simultaneous disturbance in the hippocampal formation, which is known to be concerned with short-term memory as well as smell. Apart from uncinate seizures, olfactory hallucinations and delusions usually signify a psychiatric illness. There is complaint of a large variety of smells, mainly foul. A patient may mistakenly believe that a foul smell emanates from himself or herself (intrinsic hallucination), and the patient may attribute this smell to something wrong with his or her nose. In others the smell seems to come from an external source (extrinsic hallucination). Pryse-Phillips(1975) found olfactory symptoms to be an early and predominating complaint in half of his patients with typical endogenous depression and called this olfactory reference syndrome. Stereotactic lesions of the amygdala can abolish both olfactory hallucinations and the accompanying psychiatric disorder, which would imply that the amygdaloid nuclei are the source of hallucinatory activity. Olfactory hallucinations and delusions are seen in senile dementia, sometimes in the absence of depression. They are also associated with alcohol withdrawal symptoms. Agnosia. Failure to recognize or identify aromas in the presence of normal ability to discriminate differences between them is called olfactory agnosia. Extremely few cases of this have been described, a surprising fact in view of the well-recognized forms of agnosia in the visual and auditory spheres. It has been associated with right inferior temporal lesions in association with agnosia for familiar faces (prosopagnosia). Effect of Drugs. Many drugs are believed to interfere with smell sense (Table 10-2). It should be emphasized that several reports relate to single examples, and often no formal smell or taste examination has been undertaken. Considering how many patients (and clinicians) confuse the two modalities, the alleged associationsshould be viewed with circumspection.It must also be considered that the disease for which a drug is given (e.g., diabetes or thyroid disorder) rather than the drug itself may be the cause of smell dysfunction. Sudden withdrawal of benzodiazepines or antidepressants may produce hyperosmia.

Disease Affecting Olfaction About 50% of those presenting to rhinology clinics have conductive loss. Once this subset is eliminated, one has to consider lesions of the first cranial nerve. This takes a long time, and damage may

TMLE 10-2. Drugs Reported to Interfere with Smell Sense DNg CrOUp

Example

Calcium channel blocker Lipid lowering Antibiotic and antifungal Antithyroid Opiate Antidepressant Sympathomimetic Antiepileptic Nasal decongestant

Nifedipine, amlodipine, diltiazem Cholestyramine, clofibrate, pravastatin Streptomycin, doxycycline, terbinafine Carbimazole Codeine, morphine Amitriptyline Dexamphetamine, phenmetrazine Phenytoin Phenylephrine, pseudoephedrine, oxymetazoline (long-term use probably needed for damage) Smoking, argyria (topical application of silver nitrate), cadmium fumes, phenothiazines, pesticides, betnesol-N, cocaine (snorted) See Table 10-4

Miscellaneous Organic solvents

Disorders of Smell and Taste

109

TABLE 10-3. Main Disease Categories Causing Smell Disturbance Disease Category

Example

Local nasal Endocrinopathy

Polyps, hay fever, sinus disease Diabetes; Addison's, Cushing's, and Klinefeltefs syndromes; pseudohypoparathyroidism, Kallman's syndrome, septooptic dysplasia Common cold, influenza, herpes encephalitis, acquired immunodeficiencysyndrome, prion disease Usually severe posterior or lateral impact Olfactory aura, complex partial seizure Before, during, or after attack During relapse or in more advanced disease Nasophatyngeal carcinoma, Wegenef s granulomatosis, olfactory groove meningioma or neuroblastoma, facial Paget's disease, Sjogren's syndrome See Table 10-5

Viral and infective Head injury Epilepsy Migraine Multiple sclerosis Tumors and inflammatory disease Neurodegenerative disease

involve multiple sites, sometimes simultaneously. Causes are arbitrarily divided into peripheral and central causes, although it is inevitable that there will be some overlap. Peripheral Causes Local Nasal Disease. This is the most common cause of anosmia and is called conductive when air is prevented from reaching the olfactory receptors. Any obstructive or inflammatory process can be responsible (Table 10-3). If there is chronic nasal sinus disease, the mucus clearance rate is reduced because of disordered ciliary motility. This along with inflammation contributes to hyposmia. Recent studies indicate that in as many as 70% of those with olfactory disturbance, the nasal airway may remain patent despite obstruction of the nasal vault. Nasal dryness in connection with excessive surgery, atrophic rhinitis, or Sjogren's syndrome causes anosmia. Wral and Infectious Illness. This is the most common nonconductive cause of anosmia. Even the common cold may damage olfaction temporarily or permanently. Hepatitis, flulike infections, herpes simplex encephalitis, and variant CreutzfeldtJakob disease are rare causes of olfactory dysfunction and are presumed to relate to direct viral attack on the olfactory pathways, either peripherally in the nasal olfactory epithelium or olfactory bulb or centrally in the temporal lobes. In contrast to those of conductive anosmia, the symptoms are stable. In postviral anosmia, patients tend to be older and female, complain of dysosmia, and improve gradually over 5 years. Toxic Anosmia. Numerous compounds are alleged to cause anosmia; the majority occur at work and may promote lawsuits. Compounds suspected to cause acute olfactory loss after brief exposure with some prospect of recovery include formaldehyde, hydrogen cyanide, hydrogen selenide, hydrogen sulfide, sulfuric acid, and zinc sulphate. Many instances are single case reports, and usually patients' symptomatic accounts have been relied on in the absence of formal olfactory testing. The associations for which more substantive evidence is available is given in Table 10-4. Head Injury. There are both peripheral and central causes of smell disturbance relating to head injury, but the peripheral variety is far more common. The main sites of damage are the sinonasal tract, cribriform plate entry zone with tearing of the

110 W TABLE10-4.

Principlesof Ambulatory Neurology and the Approach to Clinical Problems

Main Compounds That May Cause Permanent Hyposmia on Chronic Exposure

Compounds

Examples

Metallic

Chrome, lead, mercury, nickel, silver, steel, zinc, cadmium Carbon disulfide, carbon monoxide, chlorine, hydrazine, nitrogen dioxide, ammonia, sulfur dioxide, and fluorides Acetone, acetophenone, benzine, chloromethane, menthol, pentachlorophenol, and trichloroethylene Cement, hardwood, lime, printing, and silica Asphalt, fragrances, lead-based paint, paprika, spices, tobacco, varnishes, waste water refining, cutting oils

Nonmetallic inorganic compounds Organic compounds Dust exposure Manufacturing processes

olfactory nerves, cortical contusion, or hemorrhage in the inferior frontal lobe or temporal poles. In the primarily neurologic sphere, head injury is the most common cause of anosmia, usually attributed to shearing of olfactory nerve fibers as they emerge from the cribriform plate to enter the bulb, but lesions of the central pathways are also recognized. A gentle blow to the head or even acceleration forces (e.g., whiplash injury) may on rare occasion be sufficient to cause anosmia, a point relevant to medicolegal work. Anosmia is most likely to result (according to traditional wisdom) if the front or back or the head is struck rather than the sides because the opportunity for shearing forces on the frontal lobes is greater with anteroposterior injury. In a detailed survey of 179 head-injured patients assessed by UPSIT and MRI, Doty and colleagues found that occipital and side impact caused most damage and frontal the least. Intracranial hemorrhage per se can result in anosmia and ageusia (taste loss) as well. Lesions that have been associated with post-traumatic anosmia usually are located in the temporal lobes, but recent functional imaging studies (single photon emission computed tomography) suggest that the orbitofrontal cortex is hypoperfused, and these patients regularly have other frontal lobe dysfunction. The frequency of traumatic anosmia has been estimated at 7% in head injury of all varieties, rising to 30% when injury is severe and particularly when there is cerebrospinal fluid rhinorrhea. However, many earlier studies, some of which were based on more than 1000 cases, have used unsophisticated measurement or simply relied on patients’ symptoms. Sometimes olfactory assessment has been undertaken within the first few weeks of injury, at a time when local nasal swelling or fracture would result in conductive anosmia and a good prospect of recovery. The percentage who recover from post-traumatic anosmia probably relates to the duration of post-traumatic amnesia, with those amnesic for more than 7 days having the poorest outcome. In the above study by Doty and coworkers (1997), 67% had anosmia, 20% had microsmia, and only 13% had normal smell sense, a far higher proportion of abnormality than previously documented. The prevalence of parosmia was found to be about 41%, but it decreased to 15% over 8 years. Recovery was poor: Of 66 patients who could be retested, 36% improved slightly, 45% were unchanged, and 18% actually worsened. Only three patients recovered from initial anosmia. This is much lower than expected in view of the ability of olfactory neurons to regenerate. One reason for failed recovery may relate to the presence of scar tissue in the cribriform plate, which acts as a barrier to regenerating neurons. Another reason would be the presence of traumatic lesions in the frontal and temporal zones, suggesting centrally based anosmia and less prospect of recovery. Clearly

Principles of Diagnosis: Common Presenting Symptoms

some will have both peripheral and central lesions. Finally, MRI volumetric studies showed in men with post-traumatic anosmia that olfactory bulb volume was reduced. The higher prevalence in men was thought to relate to more severe trauma. The presence of bulb hypovolemia is a useful objective sign that would clearly give objective support to patients’ symptoms, especially where there was doubt. Although the Doty study (1997) paints a fairly gloomy picture, there may be selection bias because all subjects were seen in a specialist referral center. Also, the follow-up rate is low (66 of 179 originally seen), and this would tend to increase artificially the rate of abnormality (i.e., those who recovered would be less likely to return for assessment). Nonetheless, it is the most elaborate study of post-traumatic anosmia so far, and although it probably overstates the magnitude of the problem, it concurs well with clinical experience (i.e., that most patients with complete anosmia lasting more than a few months after head trauma do not get better). Tumors and Nasal Inflammatory Disease. Smell sense is lost regularly when the nose is invaded by tumor. Malignant disease such as adenocarcinoma, squamous carcinoma, or olfactory neuroblastoma may affect the ethmoid or sphenoid sinuses. Lymphoma may invade the nasal passages or sinuses, and granulomatous diseases such as congenital syphilis, sarcoidosis, lupus, and particularly Wegener’s granulomatosis are associated with anosmia. Many of the latter produce a characteristic “saddle-nose” deformity. Endocrine Disease. This is less often responsible for anosmia, but depression of smell sense is recognized in Addison’s disease, Cushing’s syndrome, diabetes, myxoedema, pseudohypoparathyroidism, and Turner’s syndrome. Kallman’s syndrome is an X-linked or autosomal recessive neuronal migration disorder with endocrine deficiency. It is characterized by usually complete anosmia caused by aplasia of the olfactory bulb in association with hypogonadism. In the related condition of congenital maldevelopment of the optic and septal areas (septo-optical aplasia), there is also anosmia and endocrine deficiency.

CENTRALCAUSES Neurodegenerative Disease Of great interest to the neurologist is the observation that certain diseases associated with neuronal degeneration, such as AD, Korsakoff‘s psychosis, and Parkinson’s disease (PD) are accompanied by olfactory disturbance (Figs. 10-4 and 10-5). Konakoff’s Psychosis. Patients with the alcoholic form of Korsakoff‘s psychosis have difficulty in discrimination but no loss of sensitivity. How much of their problem relates to cognitive dysfunction (especially memory) is debated, but the consensus view is that the impairment does not relate to any defect in olfactory acuity, learning ability, or memory. It is likely that the lesion responsible for olfactory discriminatory problems in Korsakoffs psychosis lies in the dorsomedial nucleus of the thalamus, which has important connections with the orbitofrontal cortex, the main area for olfactory identification and discrimination. Idiopathic Parkinson‘s Disease. Many clinicians have noted anecdotally that olfactory loss may precede idiopathic Parkinson’s disease (IPD) by several years, but there have been no long-term prospective investigations as yet. Most olfactory studies in IPD have used clinical diagnostic criteria, and none have correlated changes in life with those found postmortem. This is relevant because the diagnostic error rate of neurologists contrasted with autopsy diagnosis is 10% to 26%. The rhinencephaloii has not

Chapter 10

Disorders of Smell and Taste

111

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FIG. 10-4. Sample of olfactory evoked response in normal person. Upper pair of traces are deriied from U and PZ in a healthy 53-year-old woman. The third tracing is an eye artifact monitor. The next pair of tracings is from a 59-year-old patient with idiopathic Parkinson's disease. There is clear delay of responses at U and PZ. Note the slightly larger response from PZ in both cases. Bottom trace is again the eye movement channel. The stimulant was a 200-msec pulse of HS , at a concentration of 20 ppm in both cases. Filters are set at 1 to 50 Hz. Squares represent 6.25 pV on the vertical axis and 200 msec on the horizontal axis.

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FIG. 10-5. Mechanisms of traumatic olfactory dysfunction. (A) Injury to sinonasal tract (B) Tearing of the olfactory nerves. (C) Cortical contusions and hemorrhage. (From Costanzo RM, DiNardo U, Zasler ND: Head injury and olfaction. In Doty RL (ed.): Handbook of Olfaction and Gustation. Marcel Dekker, New York, 1995, with permission.)

been investigated systematically in PD without dementia. Dystrophic neurites but no L e y bodies have been found in autopsyderived olfactory epithelium of patients with IPD, but several patients displayed accumulation of amyloid precursor protein fragments, which would not allow distinction from AD. All three varieties of synuclein (a, p, y) are expressed in olfactory neuroepithelium, particularly a-synuclein, but the expression of a-synuclein was found to be no different from that of other degenerative diseases (Lewy body disease, AD, multiple-system atrophy) and seemingly healthy controls. Lewy bodies are present

in the olfactory bulb, particularly in the anterior olfactory nucleus, and their morphology resembles the cortical counterpart. It has been shown that loss of anterior olfactory neurons correlates with disease duration. Threshold detection and identification tests have been found to be consistently abnormal, but no correlation was found with age, sex, disease duration, cognition, motor function, tremor, or use of antiparkinsonian medication. Further evaluation in subtypes of clinically defined IPD showed that women with mild disability and tremor-dominant disease had a significantly higher age-matched

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hinciples of Ambulatory Neurologyand the Approach to Clinical Problems W

Principles of Diagnosis: Common Presenting Symptoms

by the International UPSIT- 12 test and a cognitive screening procedure. They found that hyposmia and particularly anosmia significantly increased the risk of subsequent cognitive failure. Anosmics at baseline who had at least one ApoE-4 allele had nearly five times the risk of subsequent cognitive decline. Another group examined prospectively the olfactory identification score in patients with mild cognitive impairment. Those scoring 34 or less on the UPSIT-40 who were also unaware of their defect were more at risk of developing AD within 2 years. In theory, unawareness might have been a manifestation of their cognitive impairment, but insight usually is preserved well in the early stages of AD. Down's Syndrome (DS). Most people with Down's syndrome (DS) eventually develop Alzheimer-type dementia. In adolescents with DS (McKeown et al.), low identification and discrimination scores were found that were similar to those of other children of comparable age and cognitive function. They concluded that patients with DS first evidence loss of olfactory function at a time when AD-type pathology is just commencing and inferred that smell testing could not be used in DS to predict the onset of later AD. However, the UPSIT scores of their DS group were of similar magnitude to those seen in older patients with DS, and it could be argued that olfactory impairment is an early change predating Alzheimer-like cognitive impairment. Although it may be true that hyposmia precedes the AD-type dementia of DS, it might simply reflect the ease of detecting smell impairment compared with very early cognitive decline. Characteristic AD pathology may be present in silent cortical areas, which are difficult to probe by current techniques. In schizophrenia there is quite severe olfactory impairment on identification, threshold sensitivity, and odor memory tests. It is interesting that UPSIT scores decline with disease duration in linear fashion, raising the possibility of a disease progression

UPSIT-40 score than men with moderate to severe disability and little or no tremor. In broad terms, around 80% of patients with idiopathic PD have some form of olfactory defect (Fig. 10-6). Alzheimer's Disease. There was initial excitement when it was suggested that AD could be identified by sampling olfactory neuroepithelium obtained at autopsy. Changes in morphology, distribution, and immunoreactivity of neuronal structures were typical of AD. Unfortunately, subsequent studies have cast doubt on this, and although changes characteristic of AD have been confirmed, they are not specific; similar changes are seen in patients with IPD and even some healthy older adults. There were subsequent attempts to diagnose possible AD by olfactory mucosal biopsy. Further difficulties have been found Apart from the lack of specific changes, it may be difficult to identify olfactory neurons because the neuroepithelium tends to be replaced progressively by respiratory epithelium with aging, and this process may be more rapid in AD. Numerous psychophysical studies of olfaction in presumed AD have shown abnormalities and, in some, a correlation of dementia severity with anosmia. The majority have used clinical criteria for diagnosis, and rarely have autopsy data been available. Severe abnormalities have been documented in most cases for identification, recognition, and threshold detection. In a meta-analysis, defects in olfaction shown by patients with AD and PD were uniform, although there was a trend toward better performance on threshold tests than recognition and identification tests. Unfortunately, no measure could distinguish the two conditions. It has been suggested that hyposmia is an early and consistent change in AD. Indeed, some studies imply that elevation of olfactory threshold may be the first change before cognitive impairment sets in. In a prospective population-based study by Graves and coworkers, 1836 healthy people were tested at baseline

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age(yrs) FIG. 10-6. University of Pennsylvania Smell Identification Test (UPSIT) scores in Parkinson's disease compared with healthy controls. The continuous line is the best fit by age for controls. The long dotted line represents the 95% confidence limit for controls. The fine dotted line is the best fit for patients with Parkinson's disease by age. Each + represents the actual UPSIT score for one patient.

PLATE 10-1. The main three nelves concerned with taste and their connection to the solitary tract nucleus in the medulla. Special visceral afferent fibers (red) terminate in the rostra1 (gustatory) areas of the solitary nucleus. General visceral afferent fibers (blue) terminate in the caudal portion of the nucleus. (From Sweazey RD: Olfaction and taste. In Haines DE (ed.): Fundamental Neuroscience. Churchill Livingstone, New York, 1997, with permission.)

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rn TMLE 10-5. Relative Olfactory Dysfunction in Neurodegenerative Conditions Disease

Severity of Smell Loss

++++ Idiopathic PD Guam PD-dementia complex ++++ Alzheimer‘s disease +++ Lewy body disease +++ Familial PD: affected/at risk (excluding Park +++/+ 1-1 0 mutations) Multiple-system atrophy ++ Drug-induced PD ++ X-linked dystonia-parkinsonism (“Lubag”) ++ Huntington‘s chorea + Motor neuron disease + Progressive supranuclear palsy O/+ MPTP parkinsonism 0 Corticobasal degeneration 0 Essential tremor 0 Most of these values are based on small patient numbers except for idiopathic PD. Abbreviations: ++++, marked damage; +, mild; 0, normal; PD, Parkinson’s disease. marker. Varying degrees of olfactory impairment have been described in other extrapyramidal conditions, and they are summarized in Table 10-5. Epilepsy. The best-known olfactory impairment is the uncinate aura. This is an epileptic aura that according to orthodox teaching is caused by irritation of the anteromedial part of the temporal lobe (Fig. 10-7). The uncus is a primary olfactory area. Recent pathologic studies suggest that the adjacent amygdala is the site of olfactory aura, so the term uncinate attack may be a misnomer. The hallucination usually is unpleasant (e.g., gas or oil) and may occur in isolation. Sometimes it is followed by a complex partial or secondary generalized tonic-clonic convulsion. Epilepsy in the frontal lobe does not appear to cause olfactory impairment, but if a frontal lobe is removed, there is impaired discrimination, which as expected is bilateral if the right orbitofrontal cortex is ablated. Epilepsy is associated with a generalized decline in olfactory function, but those with complex partial seizures have more impairment than those with generalized epilepsy. Rarely, anticonvulsant therapy such as phenytoin may cause hyposmia (Table 10-2). Migraine. Sufferers of migraine occasionally report that an attack is provoked by exposure to certain smells. These usually are of the intense trigeminal variety such as gasoline, acetone, or strong perfume. During an attack smells may aggravate the headache, and rarely hyperosmia is reported, persisting beyond the headache phase. Multiple Sclerosis. Pathologically there is evidence of demyelination in the olfactory tracts and the periventricular region of the temporal lobes, so hyposmia in this disorder would not be surprising. On the basis of UPSIT and olfactory evoked potential (OEP), about 15% to 20% of patients with multiple sclerosis have some impairment of smell sense. Sometimes patients report abrupt deterioration of smell sense during a relapse, and recovery may be spontaneous or follow steroid treatment. Recently it has been shown that hyposmia correlates with the number of cortical plaques measured by MRI. Tumors and Inflammatory Disease. In the cranium the olfactory groove meningioma causes anosmia by pressure on the olfactory tract, which lies in the olfactory groove (Fig. 10-8). In the early phase anosmia is rarely detected because the patient does not notice unilateral anosmia and the clinician, if he or she tests for it at all, will be even less likely to examine each nostril

FIG. 10-7. TZ-weighted axial MRI scan of a large middle cerebral aneurysm involving the anteromedial part of the right temporal lobe (uncus). This was a 52-year-old woman who complained of unpleasant olfactory hallucinations (uncinate fits), some of which were followed by a generalized tonic-clonic convulsion. Usually uncinate fits are caused by a malignant glioma in the temporal lobe. MCA, middle cerebral artery.

individually. The temporal lobe glioma may produce uncinate fits. Because the tumor is unilateral and many of the temporal lobe functions are duplicated contralaterally, it may grow large before clinical presentation, particularly if it involves the nondominant side. There is usually no anosmia because the olfactory tracts project bilaterally. Miscellaneous Causes. Superficial siderosis, caused by deposition of hemosiderin on the meninges, can involve the olfactory tract. Such patients usually are deaf and ataxic. In Refsum’s disease the typical features are polyneuropathy, ichthyosis, deafness, and retinitis pigmentosa. It is less well recognized that most patients with Refsum’s syndrome are anosmic. Impaired smell appreciation is occasionally seen in lymphoma and paraneoplastic disorder. INVESTIGATION, TREATMENT, AND GENERAL MANAGEMENT OF OLFACTORY DISEASE Investigation of Smell Loss

The varieties of tests for smell loss have been described already. Of these the international, 12-odorant UPSIT probably is best for routine clinical purposes. Smell identification perception and threshold tests cannot distinguish conductive from perceptive (sensorineural) anosmia. Conductive anosmia must be excluded first, and this is investigated best by anterior rhinoscopy and nasal endoscopy. These two procedures miss only about 10% of disorders. The presence of local nasal disease may be evaluated further by rhinomanometry, ciliary motility, and skin tests if

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polyps, steroids may be of great value because of their antiinflammatory and antiedema effect. They are more beneficial when given systemically than topically. Surgery for polyps is indicated only for very large medically refractory polyps or where there is diagnostic uncertainty. For the patient hyposmic from head injury, steroids have also been tried. The rationale is that scarring around the cribriform plate area may impede growth of centripetal olfactory neurons, and if the scarred tissue can be softened then connection with the bulb might be reestablished. There are no large randomized trials to validate their use. Any beneficial effect probably results from reduction in local nasal edema, and long-term benefit is dubious.

Hyperosmia

FIG. 10-8. Coronal MRI brain scan to show olfactory groove meningioma on left. The dark region above the tumor is edema. This was a 75-year-old woman who, unknown to her, was anosmic just on the left side.

necessary. If there is any doubt about the diagnosis, a highresolution CT scan of the nose and paranasal sinuses should be performed. Ear, nose, and throat surgeons prefer CT scanning, whereas MRI imaging is often requested by neurologists investigating anosmia because it delineates the olfactory path both peripherally and centrally. It gives good images of the nose and sinuses as well as the brain. If peripheral causes are excluded, then MRI is the procedure of choice. It excels in demonstrating vascular and traumatic lesions of the brain and can be adapted to quantitative measurement of the olfactory bulbs and hippocampus. In schizophrenia and diseases with severe perceptive anosmia such as PD, there are no characteristic changes; likewise, in AD there is typically temporoparietal atrophy but no specific lesion in cortical olfactory areas. Depending on the clinical context, a blood screen may be indicated, testing in particular the blood count (for anemia, drug effects), sedimentation rate (vasculitic disease, malignancy), B,, and folate level (nutritional state), glucose (diabetes and pituitary disease), calcium and phosphate (parathyroid function, Paget’s disease), thyroid function (myxoedema), electrolytes (renal disease, Addison’s or Cushing’s disease), liver function tests (cirrhosis), autoimmune tests such as antineutrophil cytoplasmic autoantibodies for Wegener’s granulomatosis, anti-Ro and anti-La for Sjogren’s disease, and immunoglobulin E (hay fever). Further investigation depends on complexity and whether there is a question of malingering, as may be the case in compensation claims.

Tmatment Therapy directed at the underlying cause is the obvious treatment for local nasal inflammatory disease and tumor, whether it is growing in the sinuses or intracranially. Any process that is obstructing the flow of air to the olfactory mucosa should be corrected surgically or with topical steroids or anti-inflammatory spray. Systemic steroids are used for granulomas affecting the nose such as sarcoidosis and, often with cyclophosphamide, for Wegener’s granulomatosis. If hyposmia is associated with nasal

Treatment of hyperosmia is unsatisfactory. Anecdotally the only compounds that seem to be of benefit are antiepileptic preparations. This is a matter of personal choice, but many use carbamazepine or sodium valproate. With both compounds it is important to start at a low dosage and then build up toward clinical benefit or limiting side effects. An antidepressant might help whether used alone or in conjunction with an anticonvulsant.

General Advice and Vocational Issues Anosmic patients and even those experiencing natural decline of smell function through aging should be given guidance. A significant number of older adults die of gas poisoning each year. Consumption of infected food probably causes minor ailments and, on occasion, food poisoning in older adults. Nutritional problems and weight loss in older adults may relate to anosmia as food loses its appeal. Indeed, it is suspected that the common finding of weight loss in patients with advanced PD relates to hyposmia. A smoke detector is essential for the kitchen and in every room where there may be a fire. It is preferable to have a detector in all bedrooms, particularly in those belonging to smokers. An electric cooker is preferable to a gas-operated one. If gas is installed, patients should purchase a detector for this as well. Propane, butane, and petroleum spirit (gasoline) are heavier than air, so detectors should be placed near the ground. Natural gas and smoke are lighter than air, so the detectors for these must be placed near the ceiling or top of the stairwell. Anosmic people may have difficulty detecting spoiled food, which can be hazardous to eat even if kept in the refrigerator. They should be encouraged to discard leftover food and ideally should ask someone with normal smell sense to check all food before consumption. Finally, the patient should be advised on how to enhance the appeal of food with artificial flavorings.

TASTE The National Health Interview Survey of about 80,000 adults estimated that 1.1 million Americans (0.6%) have a taste problem. Age was a major factor with those over 65 years old, accounting for 40% of disability. In the University of Pennsylvania Smell & Taste Center, taste complaints were dwarfed by olfactory complaints; only 4% of patients with chemosensory complaints presented with such a problem, but this may relate in part to patients’ expectation of useful treatment. Ageusia is loss of taste, hypogeusia is diminution of taste, dysgeusia is distortion of taste, and hypergeusia is increased taste perception. The olfactory equivalents of cacosmia (cacogeusia),

Chapter 10

phuntosmiu (phantogeusia), purosrniu (parugeusia), osmophobia (gustutophobia), and torquosmia ( torquegeusiu) are rarely used descriptors. In heterogeusia everything tastes the same, and this appears to be a common complaint in dyspeptic patients. Presbygeusia is the natural age-related decline of taste appreciation. Anatomy and Physiology

Taste receptors are distributed throughout the tongue and to lesser degree over the rest of the oral cavity, pharynx, and esophagus. A taste bud consists of a clump of receptor cells that form visible swellings or papillae of four varieties named after their shape: circumvallate (a battlement surrounded by a moat), foliate (leaf-shaped), filiform (thread shaped), and fungiform (mushroom-shaped; Fig. 10-9). Each bud has a central pore at the apex to allow entry of liquid. The circumvallate and large fungiform papillae are found in the root of the tongue, whereas the foliate papillae occupy the posterolateral margins. The dorsal surface of the tongue is occupied mainly by filiform papillae with interspersed smaller fungiform. There are an estimated 4600 taste buds in the human tongue, and their cells regenerate roughly every 10 days, but this process does not include their axons. The tongue receives four nerves (V, VII, IX, and X), of which three are directly concerned with taste, so that there is spare capacity. Common sensation (i.e., touch pain and temperature) is provided over the anterior two thirds by the trigeminal nerve through its lingual branch. The posterior one third and adjacent soft palate are fed by the glossopharyngeal nerve (Plate 10-1). Taste perception for the anterior two thirds is through the chorda tympani, which joins the facial nerve in the middle ear. The chorda tympani also contains secretomotor fibers destined for the submandibular and sublingual salivary glands so that a lesion of this nerve impairs taste twice by damaging visceral afferent fibers and causing the mouth to become dry. The posterior third of the tongue for taste and common sensation is also supplied by the glossopharyngeal nerve, whose afferent fibers ascend to the

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inferior ganglion of IX and then into the medulla. The fewer taste buds in the epiglottis, larynx, and upper third of the esophagus are supplied by branches of the vagus (Plate 10-1). Salivation is controlled by the superior and inferior salivatory nuclei (located in the rostral part of the dorsal vagal nucleus in the medulla) through fibers that join the chorda tympani and glossopharyngeal nerves. The three taste nerves terminate in the nucleus of the solitary tract (NST), a linear structure in the medulla that is sandwiched between the spinal nucleus of V laterally and the dorsal nucleus of X medially (Plate 10-1). Fibers from the chorda tympani terminate in its rostral section; IX terminates in the midportion and X in the caudal part, so that the tongue is represented in a rostrocaudal fashion in NST, with the tip of the tongue the most superior part. From here there is a monosynaptic uncrossed projection direct to the thalamus. The thalamic gustatory nucleus is the parvicellular portion of ventroposteromedial nucleus (VPMpc), essentially a medial extension of ventroposteromedial nucleus that receives the main trigeminal input (Plate 10-1). From VPMpc there is projection to the frontal operculum and insular cortex that is probably the primary cortical taste center. Projections go from these areas to a secondary taste area in the orbitofrontal cortex and from there to the amygdala and lateral hypothalamus (i.e., joining the limbic system). Recall that olfactory signals also reach the orbitofrontal cortex (mainly on the right side), so this zone integrates taste, vision, olfaction, and probably touch (Fig. 10-10). Functional MRI studies confirm this projection and show activation in the frontal operculum, insula, and orbitofrontal cortices for both olfactory and taste stimulation. Positron emission tomography studies show increased blood flow in the amygdala and left orbitofrontal cortex during exposure to offensive odorants and tastants. It is probable that taste signals are represented bilaterally in the cerebral cortex, although the main projection from medulla and thalamus is ipsilateral, and the left cortex probably is dominant for taste recognition in right-handed people. The orbitofrontal cortex also receives information about the sight of objects and faces from the amygdala and cortical visual areas.

FIG. 10-9. Surface anatomy of the tongue. (From Miller IJ: Anatomy of the peripheral taste system. In Doty RL (ed.): Handbook of Olfaction and Gustation. Marcel Dekker, New York, 1995, with permission.)

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w Principles of Diagnosis: Common PresentingSymptoms

VISION v1

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va visual cortex - - - <. - - - - -

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Olfxtory Bulb FIG. 10-10. Central taste pathways showing how they converge centrally with olfactory and visual pathways VPMpc, ventroposteromedial thalamic nucleus, parvicellular region; V1, V2, and V4, visual cortical areas. (From Rolls ET: Central taste anatomy and neurophysiology. In Doty RL (ed.): Handbook of Olfaction and Gustation. Marcel Dekker, New York, 1995, with permission.)

Neurons therein learn the visual stimuli associated with reinforcing (pleasant) tastes, but the reverse can be acquired (i.e., aversion to unpleasant tastes or visual signals). The central convergence of taste, smell, and visual information at cortical level may explain in part why so many purely anosmic patients complain of a lack of taste and have difficulty distinguishing smell from taste loss (Fig. 10-10). The classic primary varieties of taste are sweet, sour, salty, and bitter. According to traditional teaching, salty and sweet are located at the front, sour on the lateral border, and bitter at the rear of the tongue. Some maintain that sour and bitter perceptions are best appreciated over the palate. A fifth primary taste has been proposed called umami (a Japanese word meaning delicious or savory) that is elicited by the taste of L-glutamate, the main component of monosodium glutamate. Sour and salty tastes are transduced mainly by ion channels located at the apex of the taste receptor cell. The diuretic amiloride is a sodium channel blocker, and many reports show that amiloride diminishes the intensity of sodium chloride taste when applied to the tip of the tongue, possibly by decreasing its sourness. The antiseptic chlorhexidine, known to block sodium channels, reduces the saltiness of various salts but less so the bitterness of several compounds. In ciguatera poisoning, a metallic taste is sometimes experienced that may relate to the ability of the ciguatera toxin to block sodium channels in the tongue. Sour taste is mediated by hydrogen ions and transduced by receptor cells located mainly in the posterior and lateral border of the tongue (fungiform, foliate, and circumvallate papillae). Sweet and bitter

taste are transduced mainly by receptors coupled to G proteins that exert their effects through second messengers acting on specific intracellular targets such as kinases or basolateral channels. A recently discovered G protein known as a-gustducin (structurally related to rod and cone transducin in the retina) probably is concerned with bitter and sweet perception. Umami taste is thought to be transduced by both receptors and apical ion channels. Synaptic neurotransmitters or neuromodulators released at synapses in taste buds have not yet been identified with certainty. The best evidence is for serotonin, but adrenergic, cholinergic, and peptidergic transmitters may also be involved. Function of Saliva

Saliva has a dominant role in taste appreciation. Moisture allows chewed-up food to be conveyed to the taste buds for analysis. Drying of the mouth, seen in Sjogren's syndrome, is associated with ageusia, as is more viscous saliva as is in cystic fibrosis. Saliva digests starch through salivary amylase, which in turn produces a mildly sweet taste. Phenylthiocarbamide has a bitter taste that is not universally perceived, and the ability to detect it has been claimed to depend on the chemical constitution of a person's saliva. The perception of saltiness may depend on ambient concentrations of sodium and potassium in saliva to which taste cells adapt. This process probably determines the threshold to various salts. Sourness relates to the pH of saliva and its buffering capacity. Saliva contains small quantities of a zinc metalloprotein that was initially called gustin but has subsequently been found to

Chapter 10

be identical to carbonic anhydrase VI. Zinc deficiency, which may impair taste, may produce its effects via this compound. If the rate of saliva production is diminished, the health of the mouth is reduced and patients complain of pain, burning, and metallic taste. Many drugs are excreted into saliva and produce a metallic or other unpleasant taste; these include tetracyclines, captopril, lithium carbonate, and penicillamine (Table 10-6). Taste Threshold and Taste Blindness

The threshold for stimulation of sour by hydrochloric acid is on average 0.0009 M, for salt by sodium chloride 0.01 M, for sweet by sucrose 0.01 M, and for bitter by quinine 0.000008 M. Therefore, the sensitivity for bitter is much higher, and this may have developed for protective purposes because most poisonous substances have a bitter taste. The term taste blindness or spec$% ageusia refers to inherited lack of taste detection for certain chemicals (e.g., phenylthiocarbamide) in the presence of preserved taste for other compounds and is comparable to specific anosmia and color blindness. In contrast to smell blindness, few examples of specific ageusia have been described in humans. However, inherited ageusia is of major interest because of the prospect that genetic studies might lead to the identification of specific taste receptors and their associated genes. Clinical Measurementof Taste History and Examination. Patients rarely volunteer a problem with taste appreciation, and when they do it often indicates a disorder of smell sense. Once more the patient must be asked specifically whether there is a problem. Note should be made of

TABLE10-6. Drugs That May Cause Taste Disorders Drug Category

Examples

Antihelrninthic Antithyroid

Levarnisole Carbirnazole, rnethylthiouracil, propylthiouracil Chlorhexidine Penicillarnine,colchicine, gold salts, allopurinol, nonsteroidal anti-inflammatory drugs Bleornycin, a-interferon, interleukin-2, methotrexate, vincristine, doxorubicin, chlorarnbucil, procarbazine, cisplatin, 5-fluorouracil Arnphotericin B, griseofulvin Tetracycline, sulfonarnides, penicillins, cephalosporins, etharnbutol Metronidazole, pentarnidine Idoxuridine, zidovudine, didanosine, protease inhibitors (e.g., indinavir, ritonavir) Nifedipine, arnlodipine, diltiazern

Antiseptic Anti-inflammatory Antimitotic

Antifungal Antibiotic Antiprotozoal Antiviral Calcium channel blocker Anticholinergic Diuretic Antiarrhythrnic Oral hypoglycemic agents Antiepileptic Antipsychotic or antidepressant Drugs used in Parkinson’s disease Miscellaneous

Benzhexol, tricyclic antidepressants, oxybutynin Acetazolarnide, arniloride, frusernide, hydrochlorothiazide Arniodarone, procainarnide, propranolol Phenformin, glipizide Phenytoin, carbarnazepine Trifiuoperazine, lithium carbonate, arnitriptyline, clomipramine, paroxetine, sertraline Levodopa, pergolide, benzhexol, selegiline Theobrornine, theophylline, quinine, strychnine, surnatriptan nasal spray, rnetocloprarnide, cirnetidine, disulfirarn, pesticides, lead, industrial solvents and paints

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the onset, duration, drug or chemical exposure, nutritional status, smoking habit, and type of taste disorder (e.g., distorted or lost). It is essential to examine the tongue, dentures or teeth, and pharynx for signs of infection. Particular note should be made of the fungiform papillae at the root of the tongue because their number is reduced in a variety of autonomic neuropathies. If methylene blue is applied to the dorsum of the tongue, the taste pores remain stained blue if they are innervated. If the patient complains of dysgeusia that is of peripheral origin, then it will be helped by application of local anesthetic applied to tongue. Assessment of salivary flow can be made subjectively by simple inspection of the secretory ducts in the floor and side of the mouth. There are two main objective methods. In the spit method, the subject expels saliva at regular intervals (e.g., every minute for 10 minutes). In the suction method, saliva is continuously aspirated for a typical period of 5 minutes. The suction method is preferred by subjects, but both methods are fairly reliable and give a flow rate of about 0.5 mL/minute. Patients with a dry mouth also may have a dry eye (Sjogren’s syndrome), and this may be assessed by Schirmer’s test, in which a thin strip of filter paper is placed on the inferior conjunctival fornix. The degree of wetting in millimeters on each side is measured and compared with normal values. Because taste and olfaction are so often confused, the sense of smell should be evaluated. The remaining cranial nerves, particularly V-XII, should be assessed. Trigeminal sensation over the anterior two thirds of the tongue, glossopharyngeal sensation over the posterior one third of the tongue, and its associated gag reflex are highly relevant. Tests of facial muscles give indirect evidence of the integrity of the chorda tympani in its proximal course. The auditory nerve should be tested because of its closeness to the nervus intermedius. Cranial nerves IX, X, and XI pass through the jugular foramen, so they must be examined. The hypoglossal nerves may be evaluated when the mouth is inspected for local disease. Neurologic examination of the limbs would be relevant, especially if there is question of a lesion affecting the posterior fossa. Taste Measurement There are two broad categories of taste measurement: whole mouth and regional. For preliminary evaluation in a busy clinical setting, the following five would be suitable as whole mouth assessment: sweet (1 M sucrose), salty (1 M sodium chloride), bitter (0.001 M quinine hydrochloride), sour (0.032 citric acid), and umami (1 M monosodium glutamate). These make colorless solutions that can be tested by asking the subject to sample 5 mL without swallowing, then spit it out. The mouth is rinsed with distilled water, and 1 minute should elapse between tests to avoid receptor fatigue. Clearly this will not detect lesions of a single nerve. For more accurate whole mouth testing there are two methods. The most popular is the three-cup method. In this subjects are presented at each trial with three drops of liquid, only one of which contains the taste stimulus; the other two contain water. A threshold measurement can be derived from this, and that is defined as the concentration at which the subject chooses the drop containing the stimulus on either three trials in a row or on two of three trials. More recent methods of whole mouth testing use either tablets or filter strips impregnated with standard stimulants. They have been found easy to use and portable. They can be self-administered and appear ideal for clinical use, but neither is available commercially yet. The simplest regional test is electrogustometry. This uses direct current anodic (H+)stimuli from a small metallic disk placed on the tongue. In healthy people this produces a taste described variously as metallic, sour-salty, or sour. If the current is reversed so that the cathode is the stimulus, the taste quality changes to

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sweet or bitter, but the quality of sensation is less distinct, and so anodal stimulus is preferable. The threshold for anodal stimulus varies over the tongue, but the two sides should be within 25% of each other (e.g., 8 pA for the front of the tongue, 13 pA for the posterior, and 20 pA for the palate). In patients with Bell’s palsy involving the chorda tympani, the threshold for the ipsilateral anterior tongue usually is above 40 pA. Taste Disorder: Investigation and Treatment

Pure loss of taste is quite uncommon, and apart from the lower referral rate for this condition the presence of three major afferent routes for taste from the periphery provides a backup system in case of a single nerve failure. Even in lesions of the chorda tympani, taste is sometimes preserved, possibly through an alternative pathway traveling in the mandibular division of V. It should not be forgotten that taste perception declines with age, so that reduced taste sense found in a 75-year-old may be a simple aging effect. Peripheral Taste Disorder. Much of this has been referred to already in the context of taste blindness and salivary function. Dysgeusia (i.e., metallic, bitter or salty taste) is more common than hypogeusia. Heavy smoking probably accounts for most instances of ageusia. Other common causes of ageusia relate to salivary problems. Without moisture, taste cannot be appreciated. Poor mouth hygiene often contributes to ageusia or dysgeusia, and phantogeusia sometimes is complained of, especially in the presence of candida infection. The possibility of unhealthy teeth or dentures, gingivitis, oral thrush, cryptic tonsillitis, and chronic sialadenitis should be investigated. Sjogren’s syndrome is an autoimmune exocrinopathy causing dry mouth and eyes that affects an estimated 1 million Americans. The situation is compounded further if there is associated trigeminal neuropathy involving taste afferents in the lingual nerve such that the tactile pleasure of food and drink is abolished as well. In cystic fibrosis there are hyperviscous saliva and impaired taste. Many nursing home residents have dry mouth (xerostomia), which has been attributed to various factors including medication, mouth breathing, and dietary insufficiency. Of the latter, fiber, vitamin B,, calcium, and perhaps zinc appear to be the most important. Dry mouth is severe in patients who have received irradiation to the head or neck. This is because of both salivation reduction from direct injury to the salivary glands and damaged taste buds. Normally taste recovers after irradiation in a few months because of the regenerative capacity of the receptor cells. Influenza1 illness can affect taste in addition to smell, and there is evidence of pathologic change in the taste buds. A variety of oral and pharyngeal tumors affect taste by involving the chorda tympani or lingual nerve. The situation often is aggravated by the onset of malnutrition in such patients. Neuropathy. Taste disorder is common in neuropathy, especially in patients with autonomic involvement. In familial dysautonomia (Riley-Day syndrome), there is a reduced number of fungiform and circumvallate papillae with impaired perception of sweet and salty flavors. Ageusia may be the presenting symptom of AL-type amyloid and appears to be an almost universal feature in established cases. Approximately 70% of insulin-dependent diabetics suffer taste impairment, and this correlates well with the presence of peripheral neuropathy. Non-insulin-dependent diabetics have impairment partly reversed by correcting the blood glucose level, but it is not correlated with somatic or autonomic nerve function. Taste loss may be a presenting feature of

Principles of Diagnosis: Common Presenting Symptoms

Guillain-Barrk syndrome, where the facial nerve is regularly affected on one or both sides. In leprosy, taste impairment is extremely common, particularly in the lepromatous type (70%). In Bell’s palsy the chorda tympani is involved typically when inflammation affects the geniculate ganglion or more proximally because the nerve must pass though the ganglion (where its cell bodies lie) to join the nervus intermedius and reach the rostral medulla. Patients complain rarely of a taste problem, but examination may show unilateral loss over the anterior two thirds of the tongue. Metabolic and Endocrine Disease. Elevation of taste recognition threshold has been observed in renal disease, and this applies particularly for sweet and sour stimuli. The mechanism of this is not known, but dialysis improves it. Given that patients with advanced renal disease suffer from axonal polyneuropathy, a taste neuropathy analogous to diabetes seems to be a possible mechanism. Patients with liver cirrhosis occasionally report impaired taste, but the mechanism is not understood. Apart from diabetes there are other endocrine diseases known to impair taste, especially thyroid disorders. Taste impairment has been described in about 80% of cases of hypothyroidism and dysgeusia in about 40%. The burning mouth syndrome or dysgeusia is reported in about 20% of those receiving thyroxine, and treatment of thyrotoxic patients with methylthiouracil can impair taste sensitivity (Table 10-6). Gustatory symptoms are reported in pituitary deficiency states and Cushing’s syndrome as well as adrenal insufficiency. Trauma. The chorda tympani is vulnerable to trauma in the middle ear because it is superficially placed on the upper aspect of the eardrum, so middle ear disease or surgery and head trauma are common causes of injury. Because the chorda tympani has a secretomotor component to the submandibular and sublingual salivary glands as well as a gustatory component, there may be a taste problem from dry mouth even if the taste fibers within it recover. The lingual nerve may be damaged by jaw trauma, difficult intubation, laryngoscopy, wisdom tooth extraction, or internal carotid artery dissection. Any of these may produce taste and common sensory loss over the anterior two thirds of the tongue. The jugular foramen transmits three cranial nerves (IX, X, and XI); when they are all affected it is sometimes called Vernet’s syndrome. This foramen is only rarely the site of diseases such as neuroma (growing on any of these three nerves), meningioma, epidermoid, or glomus jugulare tumor. Typical symptoms are those of hoarse voice, nasal speech, dysphagia, and sternomastoid weakness. The glossopharyngeal nerve usually is affected, in which case taste over the posterior third of the tongue is included. Central Taste Disorder

Head injury probably is the most common central cause of taste disorder. The overall prevalence in head injury is approximately 0.5%, and it is estimated that 6% of those with posttraumatic anosmia also have ageusia. Recovery from taste loss is said to be more likely than recovery from anosmia, perhaps because most lesions are peripheral and there are three nerves concerned with taste appreciation. It is suspected that sweet taste (chorda tympani) recovers more rapidly than bitter (glossopharyngeal nerve). Based on Sumner’s literature review of 18 head-injured patients and another 8 personal cases with bilateral ageusia, there is a crude relationship between duration of post-traumatic amnesia and recovery of taste: If there is no amnesia or if it does

Chapter 10 W

not exceed 24 hours, then recovery of taste can be expected within 3 months. If amnesia lasts more than 24 hours, recovery, if any, may take up to 5 years. Brainstem damage can cause ageusia, but the paucity of reports in the literature may relate to inadequate documentation of physical signs. It has been observed in unilateral medullary vascular lesions where the solitary tract or its nucleus is involved. In the lateral medullary (Wallenberg’s) syndrome it would be difficulton anatomic grounds to spare the solitary tract, but taste loss is rarely documented. It would also be hard to avoid the superior part of the dorsal vagal nucleus (i.e., salivatory nuclei), so ipsilateral impairment of salivation should be detectable. Paramedian medullary infarcts (medial medullary syndrome) would be expected to spare the dorsolaterally situated solitary nucleus. A pontine plaque of demyelination has been found to cause ageusia in multiple sclerosis, and there are individual cases of ageusia caused by pontine or midbrain hemorrhage. There are a few reports of vascular or demyelinating thalamic lesions causing taste loss, usually when VPMpc is damaged. Bilateral thalamotomy for PD has been noted to produce taste disturbance. Gustatory impairment is recognized with cortical lesions, particularly the orbitofrontal cortex and insular zone; head injury is the most common reason for damage in these areas. In theory a small lesion in either of these cortical regions could affect taste while sparing smell, but this awaits description. Patients with epilepsy may experience an aura of taste, although it is much less common than the olfactory variety. The seizure focus is located in the opercular region or amygdaloid nucleus and is claimed to be more common in right hemisphere lesions. Drugs Causing Taste Disturbance. An estimated 250 drugs are believed to impair taste. Some of these are listed in Table 10-6. Because saliva is an excretory pathway for many drugs, this is not surprising; drugs may cause taste impairment either by altering transduction mechanisms or by producing a taste of their own. Sweet appreciation is thought to be least affected by drugs because of the large number of taste buds over the anterior tongue. Therefore, a patient with drug-induced loss to sweet will have damage to a large number of taste buds. Many alleged associations of drugs with taste disorder are based on small numbers and are only rarely confirmed by formal testing. Certain compounds alleged to cause taste impairment might actually be causing primary smell loss. It also must be considered that the disease for which a drug is given may be the cause of taste dysfunction, not the drug itself (e.g., diabetes, thyroid disorder). In most instances the site or mode of action is not known with certainty. Some are anticholinergic and act by just causing a dry mouth, such as tricyclic antidepressants or anticholinergic drugs for PD or bladder inhibition. Antiproliferative drugs may damage the salivary acinar cells or the cell turnover in taste buds. Amiloride blocks sodium channels known to be present in taste receptors, and this alters the perception of salt. Impaired taste through modification of taste receptor sodium channels may be the mechanism underlying side effects from antiepileptic drugs such as phenytoin and carbamazepine. The antiseptic chlorhexidine also is thought to alter taste in this manner. Antineoplastic and antimicrobial drugs that disrupt DNA or protein synthesis (e.g., procarbazine, griseofulvin) can damage taste by reducing the rate of turnover of taste receptor cells. Certain bittertasting compounds including caffeine, theobromine, theophylline, quinine, and strychnine are known to alter second messenger systems (e.g., guanosine 5’-triphosphatedependent CAMP synthesis in the taste receptor) and thereby interfere with bitter

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appreciation. Sulfhydryl-containing drugs such as penicillamine, 5-thiopyridoxine, and captopril disturb taste, perhaps through their ability to chelate zinc, or more simply they may be excreted in saliva. Toxins and Pollutants. Less is known about taste disturbance from pollution than from smell. There are probably more causes relating to taste than smell loss because of the excretory ability of saliva, although little is known about the excretory properties of Bowman’s glands. Employees having repeated contact with pesticides, such as agricultural workers, may report a persistent bitter or metallic taste in the mouth. A garlic-like odor is characteristic of organophosphorus exposure and may be accompanied by other complaints such as hypersalivation, small pupils, muscle twitching, or psychiatric problems. Sweet metallic taste has been reported by workers cutting brass pipes (metal fume fever) and in silver jewelry workers because of lead poisoning. Industrial solvents vaporize readily and more likely affect smell than taste, but reduced taste has been noted by printers. Painters are also susceptible, especially when solvent-based rather than water-based paint is used. Ciguatera poisoning and cobra or rattlesnake bites have been associated with temporary or prolonged taste disorder, probably because of their ability to interfere with ionic channels in the taste bud. According to Indian folklore, if a patient has been bitten by a snake of unknown variety and cannot detect the burning of chili sauce in the mouth, then he or she has been bitten by a cobra! Miscellaneous Causes. Patients with depression report taste disorder often relating to anticholinergic side effects of their medication. Those with schizophrenia occasionally develop gustatory hallucinations or taste impairment that likewise is in part an unwanted effect of their drug therapy. Rarely, patients with multiple sclerosis develop taste impairment during relapse or even at presentation. Patients with human immunodeficiency virus infection often complain of disturbed taste (and smell), a problem that appears to be related to the disease per se as well as the effect of antiviral medication (Table 10-6). The burning mouth syndrome is a multifactorial disorder affecting chiefly postmenopausal women. It also may trouble those with diabetes, Sjogren’s syndrome, Parkinson’s disease, pernicious anemia, dry mouth, or depression. Patients complain of a burning pain chiefly in the anterior two thirds of the tongue, lips, and anterior hard palate. There is persistent dysgeusia and altered taste perception. Whether the mechanism is peripherally or centrally mediated is unknown, and some doubt it has an organic basis. The condition probably is multifactorial, but an organic basis is likely, especially in disease known to cause trigeminal neuropathy such as diabetes or Sjogren’s syndrome. Investigation of Taste Disorder. This must start with a history and examination. For outpatient testing, the basic five tastants are appropriate (i.e., sucrose, saline, quinine, citric acid, and monosodium glutamate), or electrogustometry can be used for simple regional testing. The sense of smell must also be evaluated using the 12-odor International UPSIT or Sniffin’ Sticks. A blood screen should be performed testing the blood count (for anemia, drug effects), sedimentation rate (vasculitic disease, malignancy), B,, and folate level (nutritional state), glucose (diabetes and pituitary disease), thyroid function (myxoedema), electrolytes (renal disease, Addison’s or Cushing’s disease), liver function tests (cirrhosis), and autoimmune tests (Sjogren’s disease). Further investigation depends on complexity and whether there is a question of malingering, as may be the case in compensation claims. If cranial nerve VII is affected, a thorough

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examination of the outer and middle ear is appropriate, possibly supplemented by CT or MRI scan of the petrous temporal bone. If there is a suspected neurologic disorder affecting the brain stem or cortex (e.g., vascular, neoplastic, or traumatic), then MRI of the brain is needed. Disorder of cranial nerves IX, X, or XI requires MRI of the posterior fossa, possibly supplemented by special views of the jugular foramen. MRI of the brain or neck is the procedure of choice because it has better sensitivity, particularly for intracerebral lesions. For good resolution of bone (eg., erosion or fracture), a CT scan is preferable. Treatment of Taste Disorder. The main drug that has been tried is zinc, but this should be given only where there is good evidence of deficiency, a very rare situation. However, zinc salts are prescribed regularly, often out of therapeutic desperation. For all other cases treatment is directed toward the underlying problem. A thorough examination of the mouth and pharynx is needed to detect evidence of infection. If the patient is troubled by dysgeusia or phantogeusia, it is more likely that there is a local problem in the mouth. Candida infection is easily eradicated with an antifungal mouthwash (e.g., nystatin). An artificial saliva such as Xerolube may help those with xerostomia. The cholinergic drug pilocarpine promotes salivary flow and is worth trying in these patients. The initial dosage of 5 mg four times daily has been found to alleviate in part the dry mouth associated with radiation to the head and neck region. Patients with dysgeusia as part of the burning mouth syndrome may be helped by using a topical anesthetic (e.g., Dyclonine 1.0%) as a mouthwash. Antidepressants or antiepileptic drugs may be tried for this syndrome. If a drug is suspected (Table 10-6), a trial of withdrawal is appropriate, even if the drug is not known to cause taste impairment. If these causes are eliminated then imaging of the head should be considered. General Advice for Those with Gustatory Problems. To compensate for the bland taste of food, some patients eat excessively, put on weight, and consume more sugar, salt, and spice. They should be advised against this and persuaded to measure spices, herbs, and other flavorings added to food and compensate by increasing the odor and appearance of food where possible. High salt intake may be harmful, especially in hypertensive patients, and excess sugar aggravates diabetes or obesity. Counseling by a dietitian is advisable. Wine tasters, food tasters, and chefs will all be at particular disadvantage if they lose their sense of taste, and a career change would be hard to avoid. Some find it difficult to come to terms with ageusia and often need counseling. Contact with lay societies specializing in smell and taste disorder should be considered.

SUGGESTED READINGS Amoore J E Effects of chemical exposure on olfaction in humans. pp. 155-190. In Barrow CS (ed.): Toxicology of the Nasal Passages. McGraw-Hill, New York, 1986 Amoore JE: Specific anosmia: a clue to the olfactory code. Nature 2141095-1098, 1967 Bartoshuk LM, D u e VB, Miller IJ: PTC/PROP tasting: anatomy, psychophysics, and sex effects. Physiol Behav 561165-1171, 1994 Barz S, Hummel T, Pauli E et al: Chemosensory event-related potentials in response to trigeminal and olfactory stimulation in idiopathic Parkinson’s disease. Neurology 49: 1424-143 1, 1997 Cullen MM, Leopold DA Disorders of smell and taste. Med Clin North Am 83:57-74, 1999 Doty RL, Brugger WE, Jurs P C Intranasal trigeminal stimulation from odorous volatiles: psychometric responses from anosmic and normal humans. Physiol Behav 20:175-185, 1978

Principles of Diagnosis: Common Presenting Symptoms

Doty RL, Deems DA, Frye RE et al: Olfactory sensitivity, nasal resistance, and autonomic function in patients with multiple chemical sensitivities. Arch Otolaryngol Head Neck Surg 114:1422-1427, 1988 Doty RL, Deems DA, Stellar S: Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38:1237-1244, 1988 Doty RL, Genow A, Hummel T Scratch density differentiates microsmic from normosmic and anosmic subjects on the University of Pennsylvania Smell Identification Test. Percept Mot Skills 86:211-216, 1998 Doty RL, Yousem DM, Pham LT et al: Olfactory dysfunction in patients with head trauma. Arch Neurol 541131-1140, 1997 Fera MAD, Mott AE, Frank M E Iatrogenic causes of taste disturbances: radiation therapy, surgery and medication. pp. 785-792. In Doty RL (ed.): Handbook of Olfaction and Gustation. Marcel Dekker, 1995 Frank ME, Hettinger TP, Clive JM: Current trends in measuring taste. pp. 669-688. In Doty RL (ed.): Handbook of Olfaction and Gustation. Marcel Dekker, New York, 1995 Frye RE, Schwartz BS, Doty RL Dose-related effects of cigarette smoking on olfactory function. JAMA 263:1233-1236, 1990 Graves AB, Bowen JD, Rajaram L et al: Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E €4 status. Neurology 53:1480-1487, 1999 Hawkes CH: Is Parkinson’s disease a primary olfactory disorder? QJM 92:473-480, 1999 Henkin RI: Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 11:318-377, 1994 Hoffman HJ, Ishii EK, MacTurk RH: Age-related changes in the prevalence of smell/taste problems among the United States adult population. Results of the 1994 disability supplement to the National Health Interview Survey (NHIS) Ann Acad Sci 855:716-722, 1998 Jones JM, Watkins CA, Hand JS et a1 Comparison of three salivary flow rate assessment methods in an elderly population. Community Dent Oral Epidemiol 28:177-184, 2000 Kaplan MD, Baum BJ: The functions of saliva. Dysphagia 8:225-229, 1993 Kurtz DB, White TL, Hornung DE, Belknap E What a tangled web we weave: discriminating between malingering and anosmia. Chem Senses 24~697-700, 1999 McKeown DA, Doty RL, Per1 DP et al: Olfactory function in young adolescents with Down’s syndrome. J Neurol Neurosurg Psychiatry 6k412-414, 1996 Murphy C, Quinonez C, Nordin S: Reliability and validity of electrogustometry and its application to young and elderly persons. Chem Senses 20499-503, 1995 Pryse-Phillips W: Disturbance in the sense of smell in psychiatric patients. Proc R SOCMed 68:472-474, 1975 Rolls ET Central taste anatomy and physiology. pp. 549-573. In Doty RL (ed.): Handbook of Olfaction and Gustation. Marcel Dekker, New York, 1995 Seiden AM, Duncan HJ: The diagnosis of a conductive olfactory loss. Laryngoscope 1 1 1:9-14, 2001 Sobel N, Prabhakaran V, Hartley CA et al: Blind smell: brain activation induced by an undetected air-borne chemical. Brain 122:209-217, 1999 Sumner D: Disturbances of the senses of smell and taste after head injuries. pp. 1-25. In Vinken PJ, Bruyn GW (eds.): Handbook of Neurology. Vol. 2 4 Injuries of the Brain and Skull. Amsterdam, 1976 Wenning GK, Shephard B, Hawkes C et al: Olfactory function in typical parkinsonian syndromes. Acta Neurol Scand 9 1:247-250, 1995 Wysocki CJ, Beauchamp GK: Individual differences in human olfaction. pp. 353-373. In Wysocki CJ, Kare MR (eds.): Chemical Senses. Vol. 3: Genetics of Perception and Communication. Marcel Dekker, New York, 1991 Wysocki CJ, Gilbert AN: National Geographic smell survey. Effects of age are heterogenous. Ann N Y Acad Sci 561:12-28, 1989 Zozulya S, Echeverri F, Nguyen T The human olfactory receptor repertoire. Genome Biol 2: 2001

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Dysarthria and Dysphagia

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Dysarthria and Dysphagia Nagagopal Venna

Disorders of swallowing and articulation of speech are common in neurology practice. Although many cases are seen acutely as part of rapidly evolving conditions such as stroke, they regularly present as subacute or chronic problems in the office for diagnosis or for treatment as the long-term sequelae of conditions such as stroke and severe head trauma. They may evolve as life-threatening complications in the course of known, recurrent disorders such as myasthenia gravis or progressive degenerative diseases such as amyotrophic lateral sclerosis or multisystem atrophies, necessitating urgent evaluation and therapy. Dysarthria causes impairment of verbal communication in everyday life and, in severe cases, can be devastating in its impact on the patient’s psychological and professional life. Dysphagia often leads to malnutrition, recurrent aspiration pneumonia, and even death from asphyxiation caused by upper airway obstruction. When these two disturbances affect the patient together, as is often the case, quality of life is seriously diminished. Because these disturbances may be the leading symptoms of a variety of central nervous system and peripheral neuromuscular diseases, their accurate diagnosis takes a comprehensive and multidisciplinary approach. Functional assessment of speech and swallowing, specific treatment of the underlying disease, and symptomatic speech and swallowing therapies contribute to the well-being of affected patients. NEUROBIOLOGY OF SPEECH AND SWALLOWING The immense range of speech articulation and the choreography of swallowing are intricate functions entailing integration of the cerebral cortex of the frontoparietal operculum, basal ganglia, the motor and sensory nuclei of the trigeminal, facial, glossopharyngeal, vagus, and hypoglossal nerves, and their bilateral corticobulbar tracts linked in complex networks. A swallowing center in the floor of the fourth ventricle and the nucleus of the tractus solitarius in the medulla serve some of the integrative functions of these systems. The masseters and pterygoids of the jaws innervated by the trigeminal motor nuclei of the rostra1 pons and the buccolabial and the digastric muscles controlled by the facial nerve nuclei in the pons help in the voluntary oral phase of preparation for swallowing and for speech modulation. The medulla provides a large part of the extensive neural substrate for swallowing by innervating the muscles of the soft palate, pharynx, and larynx through the nucleus ambiguus of the vagus, the intrinsic and extrinsic muscles of the tongue by the hypoglossal nuclei, and the musculature of the esophagus by the dorsal motor nucleus of the vagus. The sensation of the oropharynx and palate subserved by the glossopharyngeal nerve and its nucleus tractus solitarius in the medulla is necessary for the normal triggering of swallowing. Because of the overlap of their anatomic networks, dysarthria and dysphagia often, but not always, occur together. A CLINICAL APPROACH TO DIAGNOSIS OF DYSPHAGIA AND DYSARTHRIA Detailed history of the leading symptoms and the accompanying neurologic disturbances and the context in which the speech and

swallowing difficulties arose will set the stage for diagnostic evaluation. The onset and the temporal evolution of the dysarthria and dysphagia, whether they are intermittent, paroxysmal, or continuous; fluctuations in their intensity by fatigue; and provoking and aggravating factors provide important clues to their pathophysiology. For dysphagia, history of coughing and choking while eating or drinking, difficulty clearing secretions from the throat, recurrent aspiration pneumonia, or unexplained fevers indicate the inadequacy of airway protection. Changes in breathing patterns, sleep apnea, emotional lability, ptosis, and double vision point to the involvement of the neighboring structures in the brainstem. In the focused examination of dysarthria, listening to the patient speak for an extended period of time is the most sensitive and key technique. This can be facilitated by having the patient read from a book or newspaper and by audiotaping a segment of the conversation for later detailed analysis. The speech can be delineated further by noting the fluency, amount, volume of voice, rate of production, clarity of enunciation, and sustainability or fatigability after prolonged talking. Other characteristics to observe are prosody, modulation of volume and pitch, interruptions and pauses, and other unusual features such as the foreign accent. Repetition of phrases such as “British constabulary,” “Methodist episcopal,” “Ulster constabulary,” and “artillery” can bring out the dysarthria further. Repetition of labial, lingual, and guttural sounds exemplified by “me, me, la, la, and go, go” helps identify difficulty with specific muscle groups of articulation. The impairment of the precision and intelligibility of speech can be highlighted by asking the patient to repeat monosyllabic words such as “mom,” “dad,” and “coke” and polysyllabic words such as “sprinkle,” “gingerbread,” and “television.” These observations form the basis for a categorization of dysarthria that predicts its pathophysiology. The slow, slurred, and strained speech with imprecise pronunciation of consonants characterizes spastic dysarthria of bilateral corticobulbar dysfunction, commonly seen in pseudobulbar palsy. The uneven slurring of speech with impaired modulation of loudness and cadence and an unnatural, equal emphasis on all syllables indicates the scanning speech of ataxic dysarthria resulting from injury to the cerebellum or its connections. Multiple sclerosis and cerebellar degenerations are common causes of this form of dysarthria. The low, soft speech punctuated by bursts of rapid, accelerating, festinating utterances and a monotonous quality from lack of natural variation of volume and pitch is typical for hypokinetic dysarthria of basal ganglia disorders exemplified by Parkinson’s disease. Palilalia, in which syllables, words, and phrases are uncontrollably repeated, may accompany this form of dysarthria. Speech that is too rapid sometimes and too slow at others with inappropriate pauses in the flow of speech, sudden stoppages, and prolonged stretching out of sounds characterizes hyperkinetic dysarthria, another type of dysarthria caused by basal ganglionic diseases and illustrated by Huntington’s disease. In dystonic dysarthria speech is strained, uneven, and accompanied by exaggerated distortions of the face, head, and neck because of overflow of patterned movements, as evident in patients with

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dystonia musculorum deformans. The voice trailing off and turning nasal with prolonged talking accompanied by hand support for the drooping jaw is the telltale sign of fatigable flaccid dysarthria of myasthenia gravis. Persistently hypernasal voice, decreased precision of consonant sounds, and breathy quality of speech point to flaccid dysarthria of lower motor neuron diseases such as progressive bulbar paralysis. Mixed spastic-flaccid dysarthria causes the speech to be slow, strained, and nasal and is commonly seen in amyotrophic lateral sclerosis, a form of motor neuron disease in which both upper and lower motor neurons of the brainstem degenerate. Complex dysarthria with components of spasticity, bradykinesia, ataxia, and dystonia defying the preceding categorization may be encountered in diffuse brain dysfunction of severe closed head trauma, Wilson’s disease, and multisystem atrophies. Episodic dysarthria occurring in paroxysmal fashion is seen in conditions such as brainstem transient ischemic attacks and migraine. In many mild cases, however, one can only conclude that the speech is not normally articulated without fitting a particular category. The foreign accent syndrome is a rare and curious alteration of speech articulation in which the pattern of speech has a sound similar to that of a nonnative speaker with loss of the inflections natural for the patient. Lesions reported to cause this peculiar syndrome have been in the left cerebral hemispheric putamen, dorsal surface, or subcortical white matter of the frontal lobes. Swallowing can be examined cautiously by observing the patient eat a small quantity of soft food or drink water if the patient is alert and cognitively intact and cooperative. One should note nasal regurgitation or coughing. However, apparently smooth swallowing does not rule out difficulty with swallowing and, particularly, silent aspiration. Pooling of secretions in the mouth and pharynx should be sought. Further neurologic examination is focused on the neuromuscular apparatus for speech and swallowing. The trigeminal motor function is tested by palpating the masseters while the jaw is clenched and relaxed. Lateral pterygoid strength is judged by lateral movements and protrusion and forceful opening of the jaw. Markedly exaggerated jaw reflex, sometimes with clonus, indicates bilateral corticobulbar tract dysfunction above the level of the rostra1 pontine motor nuclei of the trigeminal nerves, although slight changes or absence of the reflex are unreliable indicators of disease. Facial nerve-innervated lip strength is shown by whistling, sucking through a straw or over a gloved finger, and puckering the lips. The buccinator strength is tested by blowing the cheeks. Sensation of the soft palate and posterior pharynx can be assessed by touching with a long cotton-wool applicator during testing for the gag reflex. The gag, which is subserved by the IX nerve for afferents and by the X nerve for pharyngeal constriction, is variable or absent in some normal people, and its significance is judged by associated findings. The examiner should observe movement of the soft palate up and posteriorly in good illumination during phonation and listen for a nasal quality of voice. Rhythmic oscillation of the soft palate at a rate of 80 to 100/minute is known as palatal myoclonus and is a unique but rare sign developing as a sequela of brainstem central tegmental tract injury. Considering possible motor neuron disease, the tongue should be examined for wasting at the lateral margins and fibrillations while the tongue rests on the floor of the mouth. Strength in protrusion and side-to-side movements should be tested. Licking the lips and swiping the teeth with the tip of the tongue are useful ways to test the range of tongue functions. Neighborhood signs that suggest myasthenia gravis are ptosis

Principles of Diagnosis: Common Presenting Symptoms

evoked by sustained upgaze, constant ptosis, and impaired extraocular movements. Severely restricted downgaze is an important clue to progressive supranuclear palsy. Weakness of the sternocleidomastoid muscles is common with many myopathies and myasthenia, and extensor dystonia of the neck may provide a clue for progressive supranuclear palsy. Important evidence for localizing speech and swallowing abnormalities often is readily detected by comprehensive examination of sensory, motor, and reflex functions of the limbs and of gait and posture. Dysphagia and dysarthria caused by upper motor neuron, extrapyramidal, and peripheral neuromuscular syndromes can be well delineated by careful history and clinical examination to suggest a working diagnosis. However, the causes of speech and swallowing disturbances can be quite cryptic. Unlike isolated dysarthria, dysphagia occurring alone often has a nonneurologic cause. Formulating the dysphagia and dysarthria syndrome into one based on central nervous system versus peripheral neuromuscular system is an important first step. With central processes the syndrome can be further characterized as caused by upper motor neuron-corticobulbar dysfunction, basal ganglionic, cerebellar, or multiple-system derangement. In the peripheral neuromuscular syndromes, categorizing the condition as motor neuron disorder, multiple cranial neuropathies, generalized sensorimotor neuropathy, neuromuscular junction failure, or myopathy gives a useful framework for further delineation. The occurrence of both central and peripheral nerve and muscle dysfunction suggests motor neuron disease, multisystem atrophies, or paraneoplastic or mitochondrial disorders. The evolution of the symptomsfluctuating, paroxysmal, or persistent-is a useful guide to the disorders as outlined in Tables 11-1,11-2, and 11-3, although there is overlap between them. Dysarthria and dysphagia whose basis is

TABLE11-1. Acute Syndromes of Dysphagia and Dysarthria Neuromuscularjunction disorders Myasthenia gravis Botulinum poisoning Multiple cranial neuropathies Acute Cuillain-Barre syndrome (generalized and cervico-bulbarpharyngeal) Lyme disease Diphtheritic polyneuropathy Brainstem disorders Stroke Lateral medullary infarction Pontine infarction caused by basilar artery occlusion Lacunar infarctions of the corticobulbar tracts, especially in pons Cerebellar hemorrhage with medullary compression Infection Poliomyelitis Tetanus Rabies Listerial rhomboencephalitis Herpes simplex encephalitis Paraneoplastic Brainstem encephalitis with lung, breast, testicular, and other cancers Basal ganglionic and internal capsule disorders Stroke Infarction Putaminal hemorrhage Acute dystonic reaction caused by neuroleptic and antiemetic drugs Cerebral cortex Stroke Opercular syndrome caused by perisylvian infarction Cerebellum Infarction and hemorrhage Postinfectious cerebellitis Drug intoxications: anticonvulsant medications

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TABLE 11-2. Subacute Syndromes of Dysphagia and Dysarthria Muscle diseases Polymyositis Inclusion body myositis Neuromuscular junction diseases Myasthenia gravis Multiple cranial neuropathies Skull base tumors: jugular foramen syndrome Foramen magnum meningioma Clivus chordoma Nasopharyngealcarcinoma Basal meningeal infiltrations Systemic lymphoma Carcinomatosis Tuberculosis Syphilis, fungal infections Sarcoidosis Brainstem disorders Demyelinating diseases Multiple sclerosis Central pontine myelinolysis Tumors Lymphoma Infections Progressive multifocal leukoencephalopathy Whipple's disease Granulomatous diseases Behcet's disease Paraneoplastic disorders Lung, breast, testicular, and other cancers Cerebellar diseases Paraneoplastic degeneration: small cell cancer of the lung. gynecologic and breast cancer, Hodgkin's disease, and other cancers Drug toxicity Antiseizure medications 5-Fluorouracil and AraC

not apparent on examination can be caused by an early presentation of a neuromuscular disease or a restricted presentation of a more generalized disorder (Tables 11-4 and 11-5).

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TABLE 11-3.Chronic Syndromes Dysphagia and Dysarthria Muscle diseases Polymyositis Inclusion body myositis Muscular dystrophies Myotonic dystrophy Oculopharyngeal muscular dystrophy Mitochondrial myopathies Brainstem diseases Structural abnormalities of the skull base Chiari malformation Syringobulbia Motor neuron disorders Amyotrophic lateral sclerosis Progressive bulbar palsy Postpolio syndrome Basal ganglionic diseases Parkinson's disease Huntington's disease Wilson's disease Progressive supranuclear palsy Tardive dyskinesias and dystonias Generalized dystonias Cerebral hemispheric diseases Multiple cerebral lacunar infarctions Chronic ischemic leukoencephalopathy (Binswanget's disease) Chronic progressive multiple sclerosis Multisystem disorders Severe closed head trauma Multisystem atrophies Spinocerebellar ataxias: acquired, genetic, toxic, and paraneoplastic Wilson's disease Mitochondrial encephalomyopathies

TABLE 11-4. Causes of Episodic Dysarthria and Dysphagia Myasthenia gravis Brainstem transient ischemic episodes Basilar artery migraine Multiple sclerosis Paroxysmal cerebellar ataxias

Laboratory Tests Laboratory tests are guided by the findings from the history and physical examination. For patients suspected of having peripheral neuromuscular disorders, serum creatine phosphokinase, acetylcholine receptor antibodies, electromyography, nerve conduction studies, and repetitive nerve stimulation with emphasis on cranial nerves and their muscles are appropriate. Muscle biopsy and genetic markers for dystrophies may be needed in some cases. When basal meningeal processes, multiple cranial neuropathies, or skull base disorders are suspected, a combination of magnetic resonance imaging (MRI) with gadolinium with attention to the craniocervical junction and analysis of cerebrospinal fluid and endoscopic examination of the nasopharynx may be needed. Cerebral leukoencephalopathies, including strokes and multiple sclerosis, spinocerebellar ataxia syndromes, and multiple-system atrophies display characteristic MRI abnormalities. Paraneoplastic autoantibodies in the serum and cerebrospinal fluid can be tested in patients with dysarthria and dysphagia of brainstem origin. Complex dysarthria evolving in a young person suggests Wilson's disease and can be confirmed by slit lamp eye examination and serum copper and ceruloplasmin levels. Chest radiographs may show pneumonia characteristically affecting the right lower lobe. Chest computed tomography scan may show ground glass appearance from recurrent aspirations even when the chest radiograph is normal.

TABLE 11-5. Causes of "Isolated" Dysphagia and Dysarthria Syndromes Oculopharyngeal muscular dystrophy Polymyositis or inclusion body myositis Myasthenia gravis Multiple sclerosis Restricted variant of Guillain-Barre syndrome Paraneoplastic brainstem encephalitis Acute dystonic reactions Tetanus. earlv generalized or cephalic form

Multidisciplinary ConsuMons Speech and swallowing is a well-established specialty, and consultation generally is readily available; this is an integral part of the functional assessment, treatment, and rehabilitation. A modified barium swallow, performed by a radiologist while the speech and swallowing specialist observes, has become a valuable and standard test. This enables the clinician to examine all phases of swallowing and scrutinize the oral, laryngopharyngeal, and esophageal anatomy and the formation and progress of the bolus. The effect of the consistency of the food, the position of the head, and the compensatory maneuvers on the swallowing can be assessed. Videotape of the swallowing dynamics can be studied in detail and used in patient and caregiver education and rehabilita-

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tion. Evaluations by the ear, nose, and throat (ENT) specialist and gastroenterologist, pulmonologist, and nutritionist often are needed for diagnosis and treatment. DYSPHAGIA AND DYSARTHRIA IN SELECTED DISEASES Muscle Diseases Myotonic Dystrophy. Masticatory, pharyngeal, and esophageal muscles may be affected by myotonia and weakness in this common form of muscular dystrophy in adults. The food bolus tends to stagnate in the hypopharynx, leading to aspiration. Oculopharyngeal Dystrophy. Slowly deteriorating dysphagia is the dominant symptom of this adult-onset dystrophy and is caused by failure of the oropharyngeal part of swallowing. The accompanying progressive bilateral ptosis is characteristic. Family history should be sought when considering this autosomal dominant disorder. Mitochondria1 Disorders. In the rare mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), dysarthria and dysphagia may be prominent. Associated ophthalmoparesis and recurrent gastrointestinal symptoms of pseudo-obstruction suggest the diagnosis. Neuromuscular Junction Diseases Myasthenia Cravis. Fatigability and nasal quality of speech (similar to breathing helium) with prolonged talking and dysphagia are common and serious occurrences in the oculobulbar and generalized forms of myasthenia. They are often the leading symptoms at diagnosis and may appear with alarming rapidity in myasthenic crisis, presaging life-threatening ventilatory failure. The swallow study reveals fatigue of jaw muscles and tongue movements with repeated chewing, fatigue of deglutition on repeated swallows, and stasis of food in the oropharynx. The swallowing abnormalities on the study often are more severe than symptoms suggest and may reveal silent tracheobronchial aspiration. Cranial Neuropathies Cuillain-Bard Syndrome. Dysarthria and oropharyngeal dysphagia are common as this acute inflammatory demyelinating neuropathy spreads from the limbs. A variant type with paralysis limited to the arms, neck, and pharyngeal muscles (cervicobrachial-pharyngeal form) occurs occasionally and follows the natural history of the generalized disease.

Motor Neuron Disease Amyotrophic lateral Sclerosis. Gradual but inexorable decline of ability to swallow and speak are common in the later stages of bulbar amyotrophic lateral sclerosis (ALS). The dysfunction is caused by a combination of spastic weakness of corticobulbar degeneration and flaccid weakness of the palate, pharynx, and tongue. Speech is labored and slow and has a nasal quality. Swallowing difficulty begins with the need for slow and small bites of food and the need to concentrate on drinking liquids. It then progresses to an inability to chew and swallow solids, culminating in malnutrition. Interestingly, major aspiration is uncommon in ALS because the gradual pace of the dysphagia allows compensation.

Principles of Diagnosis: Common Presenting Symptoms

Brainstem Diseases Paraneoplastic Brainstem Encephalitis. This syndrome, with subacute evolution of dysphagia, dysarthria, and ocular palsies in adults, has been increasingly recognized as a remote complication of cancer of the lung, female genital organs, testis, prostate, breast, and parotid gland. These syndromes often are associated with antibodies thought to play a role in their pathogenesis: anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-Ta (Ma2), anti-Ma antibodies, and others. The primary neoplasm typically is occult at the onset of the neurologic symptoms. Basal Ganglionic Diseases Parkinson’s Disease. Dysarthria, a less recognized symptom of Parkinson’s disease, has been studied extensively in recent years. About 70% of patients experience a slowly progressive dysarthria as a result of rigidity and bradykinesia of the muscles of the chest wall, jaws, lips, tongue, oropharynx and the vocal cords. Speech becomes soft in volume, monotonous because of decreased normal inflections, indistinct in enunciation, and impaired in the range of pitch of voice, as in shouting and singing. Characteristically, there is disordered rate of speech, with outbursts of speech and sometimes slowness with long, inappropriate pauses. Difficulty in swallowing is seen in about 50% of patients and is caused by the bradykinesia and rigidity of the masticatory, oral, lingual, and pharyngeal muscles and by the inability of the cricopharyngeus sphincter to relax adequately. Eating becomes slow, with difficulty in moving the bolus of food to the back of the mouth, impaired ability to initiate swallowing, use of multiple, small swallows, and a tendency to choke on liquids. Bradykinesia of the pharynx causes food to stick to the throat after swallowing. In severe cases, aspiration may occur, as may malnutrition and weight loss. Barium swallow study shows disorganized, ineffective, repetitive rocking motions of the tongue. Huntington‘s Disease. Choreic hyperkinesis interferes with the speech coordination, resulting in speech that is intermittently interrupted by sudden, forced breaths, abrupt breakdowns of speech, and harshness of voice. Dysphagia mirrors the speech with rapid, uncontrolled swallowing. Dyskinesia of the respirations is common and breaks down the synchronization of the breathing and swallowing. Aerophagia and aspiration into the respiratory tract may occur. Progressive Supranuclear Palsy. A mixed spastic-dystonic dysarthria is an early and prominent feature of this condition in association with postural instability, extensor neck dystonia, and paralysis of downgaze. Cerebral Disorders Stroke. Dysphagia is common in the acute phase of stroke and contributes significantly to morbidity and mortality by way of major aspiration. Risk of aspiration is particularly high when bulbar muscle weakness is associated with loss of oropharyngeal sensation. With the common, large cerebral hemispheric middle cerebral artery territory infarction involving the basal ganglia and with putaminal hemorrhage, the deficit is mediated by injury to the corticobulbar tracts. The parietofrontal operculum is the cortical center for the speech and swallowing sensorimotor apparatus, and the rare infarction localized to this area can cause

Chapter 11

striking dysarthria and dysphagia even when the stroke is small. Brainstem infarctions often result in dysphagia and dysarthria by direct destruction of the medullary nuclei of the vagus and glossopharyngeal nerves. The most common of these is the lateral medullary infarction. Pontine infarction caused by basilar artery thrombosis is regularly accompanied by impaired swallowing and speech with bilateral ischemic damage to the corticobulbar tracts. Basis pontis lacunae in the distribution of the paramedian penetrating artery underlie the well-known dysarthria-clumsy hand syndrome, where slurring of speech is prominent. In most cases of stroke from unilateral infarctions, the dysphagia and dysarthria resolve remarkably well over a few weeks to months. Patients with bilateral brainstem infarctions tend to have lasting impairments. Dysarthria in stroke sometimes can be striking, in contrast to the associated trifling sensorimotor deficits with lesions in certain regions of the brain. Examples of this are the opercular infarction and deep, small infarctions of the genu and anterior limb of the internal capsule perfused by the penetrating branches of the anterior cerebral artery.

Cerebellar Diseases

Ataxic dysarthria is a dominant, early, and common symptom of diffuse and focal cerebellar lesions. After infarction or hemorrhage, dysarthria is particularly prominent with left hemispheric injury and occasionally is the sole manifestation of this lesion. In the chronic progressive cerebellar degenerations, speech eventually may become unintelligible.

Multisystem Disorders

Dysarthria and dysphagia often are prominent, early, and progressively debilitating in Wilson’s disease. Dysarthria in this disease has features of a complex mixed dysarthria with spastic, dystonic, and ataxic features. Spinocerebellar degenerative ataxias almost always manifest with ataxic dysarthria as an early symptom that evolves into serious disability with unintelligible speech and dysphagia in the later stages. A similar disorder develops later in the course of many patients with multisystem atrophies, including olivopontocerebellar atrophy.

TREATMENT OF DYSPHAGIA AND DYSARTHRIA Specific Treatments Only a few of the diseases causing dysphagia and dysarthria are amenable to specific therapy. Immunomodulation by prednisone, azathioprine, or cyclosporine may reverse the neuromuscular problems caused by myasthenia gravis. In myasthenic crisis with severe dysarthria, dysphagia, and ventilatory failure, short-term treatment with intravenous immunoglobulin or plasmapheresis is helpful. In patients with ongoing dysphagia and dysarthria, judicious timing of pyridostigmine an hour or so before meals can maximize swallowing. The bulbar and respiratory failure of Guillain-Barrk syndrome are improved and recovery hastened by plasmapheresis or intravenous y-globulin. The dysarthria and swallowing impairment encountered in stroke usually improve spontaneously with time. Patients often need supportive therapy with tube feedings during the acute phase.

Dysarthria and Dysphagia

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Supportive and Symptomatic Treatments

For most of the remaining diseases associated with dysphagia and dysarthria, treatment is symptomatic. This palliative therapy often is very helpful. A multidisciplinary team approach with speech and swallowing, ENT, gastroenterology, pulmonary, and nutrition specialists in conjunction with the neurologist is needed for long-term treatment and rehabilitation. Close involvement and education of caregiving family members is crucial in the patients with chronic disability. Therapies for Dysphagia. Postural techniques with chin tuck, sometimes combined with head tilt, are commonly used to improve swallowing in patients who cannot control food boluses in the mouth and have unilateral pharyngeal weakness. Other techniques used for neuromuscular oropharyngeal weakness are multiple small swallows and the supraglottic technique, with breath-holding during the swallow followed by forceful cough to push away residual food from the larynx, preventing aspiration. Changing the consistency of food to purke and semisolids, improving the flavor of food, presenting smaller boluses, and training the patient to swallow with deliberation can all be helpful. These techniques should be prescribed and administered by a speech and swallowing specialist based on an understanding of pathophysiology, and they are most successful in cognitively intact and motivated patients aided by the participation of caregivers. These measures should be combined with consultation with a nutritionist to maintain adequate food intake, especially for patients with chronic dysphagia. Training the spouse or other caregiver in first aid for choking can be lifesaving for patients with severe dysphagia. The aim of the team is to maintain oral feeding for as long as is safely possible. However, progression to severe dysphagia may necessitate tube feeding by percutaneous endoscopic gastrostomy. Therapies for Dysarthria. As with the neuromuscular causes of dysphagia, dysarthria can be treated by specific modalities in a few diseases only. In most cases temporary or long-term alternative modes of communication are needed if the dysarthria is severe and speech unintelligible, as in patients with ALS or severe oromandibular dystonia and spinocerebellar degenerations. Prosthetic devices include a lift for the palate that facilitates closure of the nasopharynx and reduces hypernasal speech from paresis of the soft palate, as seen in ALS. A voice amplifier can be helpful for severe hypophonia in Parkinson’s disease. Writing and electronic devices that transcribe pictures or words on a board into a typed transcript when patients point are readily available. More sophisticated computers that synthesize speech can be helpful in some situations and are increasingly available. Behavioral techniques to improve speech intelligibility are devised and administered by speech pathologists and include training to speak in a slow, measured manner using stress and prosody with deliberate effort.

SUGGESTED READINGS Dray TG, Hillel AD,Miller RM:Dysphagia caused by neurological deficits. Otolaryngol Clin North Am 31507-523, 1998 Duffy J R Motor Speech Disorders: Substrate, Differential Diagnosis and Management. Mosby, St Louis, 1995 Gregory RP, Smith PT, Rudge R Tardive dyskinesia presenting as severe dysphagia. J Neurol Neurosurg Psychiatry 55: 1203-1204, 1992 Kagel M, Leopald N Dysphagia in Huntington’s disease: a 16-year retrospective. Dysphagia 7:106-114, 1992

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Kahrilas P Anatomy, physiology and pathophysiology of dysphagia. Acta Otorhinolaryngol Belg 48:97-117, 1994 Khan 0, Campbell WW: Myasthenia gravis presenting as dysphagia: clinical considerations. Am J Gastroenterol 89(7):1083-1085, 1994 Kidd D, Lawson J, Nesbitt R, MacMahon J: The natural history and clinical consequences of aspiration in acute stroke. Q J Med 88:409-413, 1995 Leopald NA, Kagel M C Pharyngo-esophageal dysphagia in Parkinson’s disease. Dysphagia 12:ll-18, 1997 Litvan E, Sasrty N, Sonies B C Characterizing swallowingabnormalities in progressive supranuclear palsy. Neurology 48:1654-1662, 1997 Miller J A Neurophysiology of swallowing. Dysphagia 1:91-100, 1986 Perlman A L Dysphagia in stroke patients. Semin Neurol 16(4):341-348,

Pollack I, Pang D, Kokoschis S, Putnam P Neurogenic dysphagia resulting from Chiari malformations. Neurosurg 30(5):709-719, 1992 Riminton DS, Chambers S , Parkin PJ et ak Inclusion body myositis presenting solely as dysphagia. Neurology 43:1241-1243, 1993 Sonies BC: Evaluation and treatment of speech and swallowing disorders associated with myopathies. Curr Opin Rheumatol 9:486-495, 1997 Sonies BC, Dalakas MC Dysphagia in post-polio syndrome. N Engl J Med 324:1162-1167, 1991 Wang L, Karmody CS: Dysphagia as the presenting symptom of tetanus. Arch Otolaryngol Head Neck Surg 11 1:342, 1985

1996

12

Transient Events Frank W. Drislane

Transient neurologic symptoms come in a tremendous variety and can be particularly vexing because the symptoms usually have resolved by the time of evaluation and patients often have a difficult time describing them. The history usually contains most of the diagnostic information, but the neurologic examination remains important. As elsewhere in neurology, localization assists diagnosis. Considering the neural structures or functions affected during a spell helps to organize the many possibilities and guide investigations. Transient events may affect the whole brain (usually leading to loss of consciousness), may affect particular functions that are not precisely localized, or may have a localizable focal onset. With this perspective on localization, one considers the epidemiology or risk factors of an individual patient, associated earlier symptoms, and the onset, progression, and nature of the event. This is usually sufficient to bring one diagnosis to the fore, although many transient events remain unexplained. The variety of pathophysiologic processes that produce transient symptoms is great, and this chapter concentrates on differentiating one syndrome from another rather than on managing individual diseases.

SYNCOPE AND NEAR-SYNCOPE Syncope, a sudden nonepileptic loss of consciousness, is caused by a global diminution in brain metabolism. Most episodes are caused by a generalized decrease in brain perfusion and oxygen delivery. Often, perfusion declines over seconds, and the patient has premonitory symptoms such as lightheadedness, gradually dimming vision, generalized weakness, occasional tinnitus or vertigo, nausea, or peripheral paresthesias. Observers may note pallor or sweating. Respiration continues, but blood pressure usually declines. The pulse, often weak, may be faster or slower, depending on the mechanism of syncope. Muscle tone is diminished. A few brief clonic jerks of the limbs are common accompaniments, but jerking may be more prolonged (convulsive syncope), especially if the head remains elevated. Incontinence is rare. With a gradual onset, falls are also more gradual, and patients may be able to protect themselves to some degree. Injuries are less common than with the more sudden epileptic falls. Most syncope is strongly related to body position, occurring with the subject upright and usually relieved quickly on reclining. When the

patient is lying down, perfusion improves, and most recover quickly, often within seconds and much faster than with seizures. Rarely does unconsciousness last for more than a few minutes. Subsequently, brief confusion is common, but a long postsyncopal confusion is not. Causes of Syncope Causes of syncope include mechanisms of diminished cerebral perfusion (Table 12- 1), including insufficient blood volume, inadequate or malfunctioning peripheral vasoconstrictive reflexes necessary for the maintenance of blood pressure, and cardiac disease. Decreased Perfusion VOLUMELoss. Volume loss, as in hemorrhage, is a primary

consideration. Adrenal failure may also diminish blood volume. A drop in blood pressure of more than 15 mm Hg or a pulse increase of more than 20 beatdminute on rising from lying to standing suggests hypovolemia or inadequate postural reflexes. Volumedependent syncope is exacerbated by starvation, inadequate fluid intake, diuretics, and deconditioning and prompted by prolonged standing, especially in a warm environment, which promotes peripheral vasodilation. Loss OF POSTURAL REFLEXES.Even with an adequate intravascular volume, syncope occurs when postural reflexes fail. Baroreceptors in the carotid sinus, aortic arch, and elsewhere in thoracic structures prompt a reflex diminution in vagal tone and a sympathetic response, increasing heart rate and peripheral vasoconstriction when effective intravascular volume diminishes. Interruption of this reflex can occur in the afferent or efferent limb, either centrally or in the peripheral autonomic nervous system. Central causes of autonomic failure include Parkinson’s disease, Shy-Drager syndrome, striatonigral degeneration, and other multisystem atrophies (see Chapter 119). These diseases often include degeneration of brainstem nuclei that serve as essential relay stations in effecting postural reflexes. Pure autonomic failure includes both central and peripheral autonomic nervous system pathology. Spinal cord injuries above the upper thoracic sympathetic outflow may also impair postural reflexes. Surgical sympathectomy may have the logical side effect of

Chapter 12

TABLE12-1. Causes of Transient Global Dysfunction or Syncope Hypoperfusion Volume loss Acute hemorrhage Diuretics, starvation Hypoadrenalism (Addison‘s disease) Inadequate postural reflexes Autonomic dysfunction Central Parkinson’s disease Striatonigral degeneration Multiple-system atrophy Pure autonomic failure Peripheral Baroreceptor dysfunction Familial dysautonomia Pure autonomic failure Spinal cord disease Sympathectomy Cuillain-Barre syndrome Neuropathies (e.g., diabetes, amyloidosis, rarely porphyria) Antihvpertensive medications and others, including phenothiazines. tri&lics, levodopa Increased vagal tone (vasovagal, vasodepressor, neurocardiogenic syncope) Emotional stimulus (e.g., pain, fear, unpleasant sight) Carotid sinus hypersensitivity Clossopharyngeal neuralgia Situational (combination of mechanisms) Micturition syncope Cough syncope Valsalva maneuver Breath-holding spells Hyperventilation Cardiac Electrical Conduction Sinoatrial (sick sinus syndrome) Atrioventricular, including complete heart block Atrial arrhythmias (e.g., atrial fibrillation, supraventricular tachycardias) Ventricular arrhythmias (e.g., ventricular tachycardia, associated with long QT syndrome) Valvular, especially aortic stenosis, prosthetic valve malfunction Other obstructions to flow Hypertrophic cardiomyopathies Congenital heart disease Atrial myxomas Pericardial tamponade Chest masses Impaired venous return Cough (tussive) syncope Pericardial tamponade Abdominal and thoracic masses Pulmonary hypertension Low-output cardiac failure Myocardial infarction Cardiomegalies Some congenital diseases Acute intracranial hypertension Cerebrospinal fluid obstruction, third ventricular tumors and cysts, and other masses Hemorrhage Metabolic impairment with adequate perfusion Inadequate oxygen delivery Hypoxia Carbon monoxide and other poisonings Anemia, hemoglobinopathies Impaired metabolism Hypoglycemia Poisons

.,.

syncope as a result of interruption of a needed postural reflex. Peripherally, Guillain-BarrC syndrome (which may affect autonomic nerves with or without others) and autonomic neuropathies (see Chapter 14) may cause severe postural hypotension.

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Autonomic neuropathies cause syncope primarily through blood pressure changes rather than by their effects on the heart rate, which may be abnormally regular. The most important cause is diabetes, with amyloidosis and porphyria as rarer causes. Alcohol may lead to other causes of syncope but generally causes a sensory neuropathy with less autonomic nerve damage. Other symptoms of autonomic dysfunction include abnormalities in temperature and sweating regulation, gastrointestinal dysmotility, and sphincter and sexual dysfunction. Antihypertensive medications often interfere with vasoconstriction, and phenothiazines, tricyclic antidepressants, and levodopa can contribute to syncope. INCREASED VACAL TONE. Even if peripheral vasoconstriction functions properly most of the time, syncope may be caused by excessive vagal stimulation. Probably the most common mechanism of syncope is a sudden parasympathetic surge precipitated by the stress of perceived hypovolemia, that is, vasovagal (vasodepressor) or neurocardiogenic syncope. It is especially common in adolescents and young adults, often with an emotional precipitant, such as pain, fear, or an unpleasant sight, such as blood, blood drawing, or another’s injury. It usually provides seconds of premonitory warning symptoms, such as nausea, gastrointestinal distress, sweating, and pupillary dilation. The presumed mechanism involves a sudden activation of baroreceptors or stretch receptors in the atrium or arterial tree leading to a vigorous cardiac contraction, in turn triggering a vagal excess with both bradycardia and peripheral vasodilation. The bradycardia often is more noticeable (and can be distinguished from the tachycardia or unchanged pulse seen in the syncope of inadequate postural reflexes or autonomic disorders), but it is the vasodilation that appears to be more important in syncope. It is caused by both the increased vagal tone and a sudden withdrawal of sympathetic activity. The bradycardia may lead to more serious arrhythmias, such as conduction block or sinus arrest. Usually, loss of consciousness is brief and recovery rapid. Carotid sinus hypersensitivity can cause excessive vagal activity. Carotid sinus massage usually leads to a reflex bradycardia in normal subjects, but an excessive reaction can cause syncope. There is usually an identifiable precipitant such as a tight collar or turning the head. The bradycardia, rather than vasodilation, then leads to syncope. Glossopharyngeal neuralgia may also lead to bradycardic syncope, more commonly in older patients. There should usually be a history of pain in the throat before the syncope, sometimes precipitated by speaking, swallowing, or other oral movements. SmAnow Smcom. Some syncopal episodes have a characteristic precipitant, and many act through the same vagally mediated mechanisms. Micturition syncope typically occurs in older men when they arise to urinate at night. There is a postural component of arising to a standing position, and mechanical effects alone can decrease venous return to the heart. Cutaneous vasodilation from a warm sleeping environment may contribute. Urination may diminish the sympathetic stimulus of a full bladder. Many of the same factors allow a vigorous Valsalva maneuver to lead to syncope. Cough syncope occurs in patients with severe chronic obstructive pulmonary disease during paroxysms of prolonged coughing rather than from a single cough alone. The buildup of intrathoracic pressure and diminished venous return are likely to be the main contributors. Treatment is aimed at the pulmonary disease. Vasovagal or neurocardiogenic syncope and the situational syncope from carotid sinus activity or other causes can all be labeled reflex syncope.

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Breath-holding spells may cause syncope in the same way, particularly after hyperventilation and a Valsalva maneuver, as practiced in adolescent pranks. Breath-holding spells also occur in children under age 5, often triggered by crying or emotional stimuli, and can lead to loss of consciousness, with some clonic jerking limb movements suggesting epilepsy. Interictally, however, the neurologic examination and electroencephalogram (EEG) usually remain normal. Both cyanotic and pallid forms have been described. The latter appears to involve increased vagal tone and bradycardia. Some breath-holding spells can also be epileptic in origin. CARDIACDISEASE.Although not the most common, the most important and serious cause of syncope is cardiac disease. In contrast to most other forms of syncope, cardiac syncope need not occur in the upright position and may be much more rapid and lead to injury. Cardiac arrhythmias are particularly important, especially in older patients, and may be the sign of serious ischemic or other cardiac disease. Complete or third-degree heart block may cause a very rapid loss of consciousness with no evident cardiac pulse and long intervals of ventricular silence on the electrocardiogram (ECG); ventricular arrhythmias may supervene. Sick sinus syndrome and sinus node disease may lead to severe bradycardias and syncope. Sinoatrial node block often leads to a ventricular escape rhythm and less severe symptoms than with complete heart block. Paroxysmal supraventricular tachycardias are less life-threatening than heart block and ventricular arrhythmias. They more often lead to palpitations or presyncope than to complete loss of consciousness. Ventricular tachycardias are more dangerous, and therapy remains controversial and difficult. The long QT syndrome is a marker for risk of ventricular arrhythmias. Syncope during exertion raises concern about inadequate cardiac output and a cardiac cause of syncope, possibly structural. Valvular disease, especially aortic stenosis, can lead to lifethreatening syncope. Left ventricular outflow obstructions (as in hypertrophic cardiomyopathies) may be detected by a careful cardiac examination and, certainly, by echocardiography. Rarely, myxomas can cause sudden cardiac obstruction. Other mechanisms of cardiac syncope include prosthetic valve malfunction, pulmonary hypertension, and pulmonary embolism. Low-output cardiac failure after a myocardial infarction or in congenital heart disease, sometimes worsened by hypoxia, may also lead to syncope. Pericardial tamponade and chest tumors can also cause mechanical obstruction to cardiac output. Cardiac syncope is more likely to be manifested during exertion, including competitive sports, when cardiac output cannot meet demand; exertional vasodilation in large muscles may help precipitate the syncope. INCREASED INTRACRANIAL PRESSURE.A sudden increase in intracranial pressure with acute or intermittent hydrocephalus may decrease perfusion. Colloid cysts may obstruct cerebrospinal fluid outflow; these attacks are very rare and should be positional and typically accompanied by headache. Other mass lesions such as tumors or the effects of a sudden hemorrhage may decrease perfusion through pressure effects. Metabolic Causes. Although most cases of syncope can be attributed to diminished brain perfusion, cerebral metabolism may be interrupted in other ways. Acute hypoxia or diminution of oxygen-carrying capacity through anemias, hemoglobinopathies, or poisoning by toxins, such as carbon monoxide, can also cause syncope. Finally, cerebral metabolism requires glucose, and

hypoglycemia may cause syncope, typically in diabetic patients after an excess of insulin, sometimes precipitated by exertion. Usually, there is a prodrome of hunger, altered behavior, and agitation with sympathetic activation, including tachycardia, before a gradual loss of consciousness.

Near-Syncope Some spells are difficult to distinguish from syncope. Nearsyncope or presyncope often includes lightheadedness and the same premonitory symptoms as early syncope, and it may have the same causes. The evaluation is similar to that for syncope, although the symptoms are of an even less certain nature. Hypovolemia may lead to a feeling of generalized weakness and presyncope rather than to actual syncope. Hyperventilation and hypocarbia diminish cerebral blood flow through vasoconstriction and are a common cause of near-syncope in young people, often associated with anxiety. Perioral and acral paresthesias are common. Reproduction of symptoms by hyperventilation is confirmatory. Psychiatric problems such as anxiety and panic attacks may present similarly.

Mimickers of Syncope Epilepsy, transient ischemic attacks (TIAs), and migraine cause many transient symptoms but rarely syncope alone. Seizures can cause a sudden loss of consciousness, but there is almost always a history of seizures and other current signs of a seizure. Seizures more often cause an immediate loss of consciousness rather than a prolonged prodrome and are more likely to lead to physical injury, incontinence, and a prolonged postictal confusional state. A few brief clonic jerks may accompany syncope and do not implicate seizures. Although globally diminished brain perfusion may be considered a TIA in the broadest sense, the usual carotid or vertebrobasilar TIAs have symptoms and signs of focal ischemia and rarely cause syncope. Vertebrobasilar ischemia and migraine can impair consciousness, but almost always with other posterior circulation deficits, including cranial nerve signs, and the onset of symptoms is generally slower.

Evaluation of Syncope The evaluation of a patient with syncope starts with a second-bysecond history of the episode’s very beginning, including the patient’s position, activities such as exertion or change in posture, and precipitating events such as urination or an unpleasant sight. Premonitory symptoms, and whether a subject falls or is injured, help to narrow the possible causes. Witnesses are crucial in describing the onset of syncope and the patient’s appearance (e.g., agitated or pallid). The suddenness and duration of loss of consciousness are important, as is the speed of recovery. Staring, automatisms, or stereotyped motor activity are important clues suggesting seizures. In younger patients, hyperventilation and vagally mediated syncope are more common. Impaired venous return and baseline low blood pressures in pregnancy may predispose to syncope. Cardiac disease is of more concern in older adults, in those with sudden loss of consciousness, and in patients with other history of cardiac illness such as known coronary artery disease, chest pain, congestive failure, arrhythmias, or syncope during exertion. A family history of hypertrophic cardiomyopathy is important.

Chapter 12 H Transient Events

Medication history is always important. As noted, medications with potentially adverse effects on autonomic function include antihypertensives, calcium channel blockers, diuretics, phenothiazines, levodopa, and tricyclic antidepressants. Alcohol can contribute to syncope in many ways. Physical examination during the episode, including blood pressure and cardiac rhythm, can make the diagnosis. In the right context, bradycardia during the event suggests vagally mediated syncope. The evaluation must include orthostatic vital signs and a cardiac examination. The neurologic examination looks for persistent signs of prior focal disease such as strokes; a peripheral neuropathy may be related to many possible diagnoses. Basal ganglia disorders with autonomic failure should be recognizable from the associated motor abnormalities, which are not transient. Reproduction of symptoms through hyperventilation or carotid sinus massage can be very helpful, but the latter has risks and must be performed in a setting with the capacity for resuscitation. Almost every patient should undergo an ECG, and if there is increased concern about cardiac illness by history (e.g., of chest pain, orthopnea, or higher age), more extensive cardiac testing such as echocardiography and monitoring for arrhythmias may be appropriate. An abnormal ECG may not give a specific diagnosis but can be a correlate of cardiac disease that warrants more investigation. Exercise tolerance testing is considered with a high suspicion of ischemic cardiac disease and after a cardiologist’s evaluation. Patients with dangerous arrhythmias may need invasive electrophysiologiccardiac testing to define the arrhythmia and its possible source or medications that might ameliorate it. The bradycardia and hypotension of neurocardiogenicsyncope can be replicated or confirmed by tilt table testing (sometimeswith provocative isoproterenol infusions) if the diagnosis is in doubt or if syncope is repetitive or injurious, but the predictive value of the test is limited. The EEG may show flattening during an episode of syncope, but this is seldom available. Subsequently, nonepileptic electroencephalographic abnormalities tend to confuse the diagnosis. Seizures are a rare cause of syncope alone; EEGs generally are unnecessary without a clinical suspicion of seizures. Some patients with syncope prove to have epilepsy eventually, but the diagnosis usually is made through observation of subsequent events. Without suspicion of focal lesions or raised intracranial pressure, computed tomographic and magnetic resonance scans usually are unnecessary. The cause of syncope often remains undetermined, even after a thorough investigation. Fortunately, the prognosis generally is excellent if serious cardiac disease has been excluded. Accordingly, the search for cardiac causes of syncope is the most important part of the investigation. Seizures and TIAs are unlikely causes of most cases of pure syncope, and presumptive treatment with anticonvulsants or anticoagulation is ill advised without a secure diagnosis. The diagnosis may emerge with follow-up and continued observation. ~~

SPELLS WITHOUT SYNCOPE OR CLEAR FOCAL ONSET Spells that provide neither the consideration of cerebral perfusion nor precise neurologic localization to aid in diagnosis can be among the most difficult to evaluate (Table 12-2). Still, the epidemiologic background, time course, and nature of the spell can narrow the possibilities and guide testing. There are too many kinds of spells for all to be detailed here, but some of the more common ones are described.

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W TABU12-2. Causes of Spells without Syncope or Clear

Focal Signs Confusional states Complex partial seizures, complex partial status epilepticus Absence seizures, absence status Migraine Dialysis dysequilibrium Porphyria Psychiatric disease Fluctuatingencephalopathies (e.g., medication, metabolic, toxic, infectious) Memory loss Transient global amnesia Benzodiazepines, anticholinergics Alcoholic blackouts Fugue states Less transient, including head injury, Wernicke’s disease, postictal state, electroconvulsive therapy, dementia Drop attacks Vertebrobasilar ischemia Anterior cerebral ischemia Foramen magnum and upper cord lesions Acute vestibulopathies, Mbnibre’s disease Raised intracranial pressure Severe asterixis, myoclonus Cataplexy Imbalance, including cerebral and cerebellar lesions, basal ganglia disorders, myelopathy, myopathy, peripheral neuropathies,sensory deprivation (excluding impaired consciousness with syncope, presyncope, or drop seizures) Sleep disorders Narcolepsy, cataplexy Parasomnias, including somnambulism, night terrors, paroxysmal dystonias, rapid eye movement sleep or behavior disorder Base of the brain masses Dizziness (including presyncope, imbalance) Vertigo (e.g., benign positional vertigo, MkniBre’s disease, eighth cranial nerve lesions) Temporal lobe seizures Posterior fossa lesions, multiple sclerosis, head injury, ear pathology Hallucinations Visual, including withdrawal states, occipital lesions, occasional seizures, migraine, midbrain lesions, ocular deafferentation Auditory, includingtemporal lobe seizures, schizophrenia Psychiatric episodes Panic attacks, anxiety disorders Episodic dyscontrol Pseudoseizures

Confusional Spells

Confusional spells are particularly difficult because neither the patient nor observers may be able to recall details of the spell well. Confusional states are characterized by a marked diminution in attention, with a patient shifting attention too frequently and too widely to focus on any task. This usually implies bilateral brain dysfunction, particularly in the limbic system. Thinking may be very disorganized. Delirium implies some agitation amid the confusion. Complex partial seizures are one of the most important of the many causes of confusional spells. The onset is focal (“partial”), and confusion or other alterations in consciousness occur when seizures spread to involve limbic structures bilaterally. Complex partial seizures typically have neither the focal motor onset of a simple partial seizure nor the convulsions of a generalized seizure, although they may progress to secondarily generalized convulsions. Often, there are prolonged periods of uninterruptible staring or automatisms, such as blinking, chewing, smacking, licking, or other orobuccal movements, or repetitive, stereotyped behavior, such as picking at clothing. Psychiatrically based spells

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may have a clear precipitant and no automatisms. Complex partial seizures seldom have a clear precipitant, although sleep deprivation, infection, toxic and metabolic factors, head injury, endocrinologic changes such as pregnancy, and lowered anticonvulsant levels can contribute. Many different abnormal behaviors are possible in complex partial seizures, but an individual patient usually has stereotyped spells. The greater the number of symptoms and the more varied the behavior, the less likely is the diagnosis of epilepsy. Complex partial seizures usually last no more than a few minutes but may be difficult to distinguish from prolonged postictal confusional states. The strangest behavior may occur postictally, and witnesses may be injured when trying to restrain a confused patient postictally; this is not “ictal violence.” In the evaluation of complex partial seizures, the history of the earliest onset of symptoms is crucial. Unless specifically asked, patients do not necessarily remember such symptoms as olfactory hallucinations before subsequent aspects of a spell. Staring spells and automatisms are seldom noticed by patients but are very important observations of witnesses. Complex partial status epilepticus is much less common and may involve frequent complex partial seizures or a prolonged recovery between recurrent seizures. The EEG is crucial in diagnosis. Prolonged absence seizures may also produce confusional episodes. Patients often display blinking or simple automatisms. They can generally continue walking without falling or hurting themselves. Absence status may continue for days. A history of seizures increases clinical suspicion, but the patient may have been off medications and seizure-free for years. Absence status may recur after years in older patients or may arise anew, particularly after benzodiazepine withdrawal. A characteristic EEG confirms the diagnosis. Intravenous benzodiazepines may interrupt nonconvulsive status quickly. Medications are among the most common causes of confusion. Benzodiazepines and other medications for sleep are common offenders, particularly in older adults or those with other medical problems. Medications for Parkinson’s disease, antihypertensives, steroids, antipsychotics, and seizure medications, particularly at high dosages, are possible problems. Anticholinergics and antihistamines, sometimes in over-the-counter remedies, can cause confusion. Polypharmacy should always raise concern about medication interactions and possible side effects. Most episodes of confusion caused by medications are more prolonged than brief spells, with the time course of the confusion related to that of the medication’s metabolism. Dialysis dysequilibrium is characterized by hours of confusion during or just after hemodialysis. It may also include seizures and headaches. The setting provides the diagnosis. TIAs rarely cause confusion alone without focal neurologic signs. Strokes, especially in the right hemisphere, can cause confusion; often, this symptom of the stroke may resolve over days. Confusional migraine is uncommon but may lead to several hours of confusion or even stupor, especially in adolescents with a history of migraine. Porphyria may produce episodic confusion and altered behavior. Most confused behavior is not so transient. Among the most common causes are metabolic abnormalities, infection, and medications. Medication withdrawal can cause similar confusion, and all of these causes are more likely to affect older patients or those already impaired through strokes, dementia, or other illnesses. These episodes rarely abate within hours but may

Principles of Diagnosis: Common Presenting Symptoms

fluctuate a good deal. Confusion may be precipitated by trauma and sensory or sleep deprivation. Wernicke’s encephalopathy can occur suddenly; often attention is normal, and there are oculomotor signs as well as ataxia and confusion. Psychiatric illnesses that cause confusion rarely fluctuate so quickly. The evaluation of patients with transient confusion relies heavily on the earlier history, seeking evidence of seizure disorders and the history of medication use, psychiatric illness, or other chronic illnesses that make a patient vulnerable. Witnesses may observe helpful signs such as blinking or abnormal movements, possibly suggesting seizures. Confusion may fluctuate in metabolic encephalopathies, so blood testing for such abnormalities is important. With a suspicion of seizures, and occasionally without, the EEG can be informative, not only for epilepsy but also for corroborating a diffuse encephalopathy if this is not already clear clinically. Thiamine and glucose treatment are usually appropriate. Transient Memory Loss

Sudden, transient, and isolated memory loss is uncommon but can be dramatic. Transient global amnesia is a well-recognized syndrome. It includes a sudden onset of anterograde amnesia lasting several hours. Many authors exclude cases attributable to head injury, epilepsy, or migraine, but these diagnoses are not always obvious at presentation. Transient global amnesia generally occurs in subjects over 50 years old. About one third have some intense emotional experience as a precipitant. A minority have recurrences. Immediate recall can be normal in some, and long-present memory is preserved, but memory for the recent past and for new information is severely impaired. There is often minimal retrograde amnesia. Most patients are slightly agitated and characteristically repeat over and over the same questions about what is happening to them, appearing unable to learn the new information given to them. Patients usually are attentive, and semantic memory, language function, personal identity, visuospatial capabilities, and social interactions are preserved. Newly presented information must be tested to demonstrate the amnesia. Patients may be labeled as having acute confusional episodes, but most are not confused and can focus on a task and reason effectively. The amnesia usually resolves within 8 hours, although mild symptoms may linger for days, and events during the episode are lost permanently. The cause is a subject of much debate, but several different processes can produce the same result. Brief and recurrent episodes, especially without the repetitive questioning behavior, suggest the possibility of epilepsy. Particularly in these cases, an EEG is appropriate, but the structures serving memory are deep, and abnormalities may be missed. Vascular disease in older patients may also produce electroencephalographic abnormalities not diagnostic of seizures. The low recurrence rate lessens the likelihood of seizures. Few cases of transient global amnesia appear to be epileptic, but memory can be altered in a postictal state. Several reported cases have occurred in clear migraine attacks. Other characteristic symptoms such as visual auras, subsequent headache, and a positive family history are strongly suggestive. The common precipitants and benign course also suggest migraine. Most cases have no obvious cause. Some authors find a correlation with vascular risk factors and postulate simultaneous bilateral hippocampal ischemia as a result of posterior circulation vascular disease. Vertebral angiography has led to transient global amnesia, and thalamic lesions, including masses, have been found.

Chapter 12

Most memory loss is presumed to involve bilateral structures that subtend memory function in the medial temporal lobes (particularly hippocampus) or in the thalamus, but in a few cases left-sided mesial temporal or thalamic lesions have produced an indistinguishable syndrome, probably caused in part by the dependence of testing on verbal function. The benign course, otherwise normal neurologic examination, and low recurrence rate argue that most patients with transient global amnesia need minimal investigation and no treatment, particularly younger patients with a suggestion of migraine. A history of headache, seizures, head injury, and recent medication are pertinent, but a patient may not remember them, and witnesses are valuable. Visual field testing can indicate a posterior circulation stroke or other lesion. Older patients with cardiovascular risk factors should be investigated as for TIAs. Patients with histories suggestive of seizures merit EEGs, preferably after sleep deprivation, and examinations for focal lesions. Benzodiazepines produce an occasional isolated amnesia, even without sedation; their widespread use produces many episodes. Amnesia occurs with all different benzodiazepines and is dose related. As in transient global amnesia, semantic memory and reasoning usually are preserved, and subjects may function normally in complex tasks, only to realize a large gap in memory subsequently. The amnesia usually is not apparent to observers because behavior and performance remain normal. There appears to be a disruption in new learning and consolidation rather than in retrieval. The effect may last a few hours. Indeed, midazolam often is used by anesthesiologists, in part for its amnestic effects during medical procedures. Anticholinergics may produce both anterograde and retrograde amnesia. Older patients and those receiving other psychotropic medications, including alcohol, are more susceptible. Alcoholic blackouts are hours to days of amnesia for performed activities during heavy alcohol use rather than a loss of consciousness. Performance is more likely to decline during alcoholic amnesia than with benzodiazepines. Chronic alcoholism and prior head injury may contribute. Fugue states are more prolonged episodes of apparently purposeful behavior, including driving long distances, with preservation of performance but with amnesia for actions and their rationale. Many are associated with depression or other psychiatric illness, and this history should be sought. Head injury and medication use are also pertinent. Briefer episodes can represent a seizure or postictal state. Often an EEG is warranted, but most fugue states are more prolonged than typical seizures. Often, an isolated memory loss is suspected, but a more extensive examination shows a confusional state. These are often caused by acute metabolic derangements, medications, other toxins, or infections. Episodes usually are more prolonged. Right hemisphere strokes or mass lesions may produce a confusional state, also of longer duration, and not memory loss per se. Seizures and postictal states usually produce prominent confusion rather than pure amnesia, although memory loss alone may be reported subsequently. Dementias produce nontransient memory loss as part of more extensive cognitive dysfunction. Head trauma, especially with bitemporal injury, is one of the most common causes of memory loss. Acutely, an injury may be forgotten, and the amnesia may be brief, lasting minutes or hours. In some cases, the trauma (especially if repeated) may be severe enough to cause prolonged memory loss, not just a spell. The history or examination for trauma may make the diagnosis clear. Wernicke’s disease, the residua of herpes encephalitis, and

Transient Events

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electroconvulsive therapy for depression can also produce more prolonged memory deficits. Psychiatric disease or factitious memory loss must be suspected when patients appear to have forgotten overlearned materials such as their own names and have preservation of language function with apparent loss of reasoning. The evaluation of patients with isolated amnesia includes a history that looks for similar prior episodes, migraine, head injury, epilepsy, or psychiatric illness. History and laboratory studies look for benzodiazepine, alcohol, or other medication use. The examination should exclude a confusional state and check for visual field loss and other neurologic deficits. Treatment can only be aimed at a specific diagnosis rather than at memory loss per se.

Drop Attacks The term drop attack should be reserved for a sudden fall without impairment of consciousness. It implies a sudden dysfunction of truncal and leg muscle tone or sudden leg weakness. Without affecting consciousness, such attacks implicate lower brainstem or spinal cord structures where postural maintenance reflexes and control of the trunk and both legs are governed in a region compact enough to be affected by a single process. In older patients, hypoperfusion and syncope or near-syncope are always important considerations when it is uncertain that consciousness has been maintained. Cardiac syncope can occur suddenly, with rapid recovery, and the loss of consciousness may be forgotten. Because of the high morbidity rate, it is very important not to mistake cardiac syncope for drop attacks. With truly maintained consciousness, brainstem ischemia is a major consideration. Pontine ischemia that affects the corticospinal tracts bilaterally can cause a loss of tone with preserved consciousness. Compression of ventral brainstem structures by a mass or ectatic basilar artery can do the same. With severe vertebrobasilar or cervical spine disease, compression of one vertebral artery by head turning can be sufficient. Brainstem ischemia is more common in older patients, usually includes other signs of cranial nerve dysfunction or ataxia, and usually comes on gradually. Much more rarely, transient anterior cerebral ischemia can lead to bilateral leg weakness. Just a bit caudally, foramen magnum mass lesions can compress the brainstem or upper spinal cord. Especially with prior rheumatoid arthritis or severe cervical spondylosis, neck movement may cause transient compression. This can be exacerbated by trauma. Often, the examination shows signs of a myelopathy. Rarely, mass lesions or midline, third ventricular cysts cause sudden obstruction of cerebrospinal fluid pathways and acute hydrocephalus, leading to drop attacks. Usually, headaches are suggestive. Atonic seizures may be called drop attacks but include a loss of consciousness. They can be rapid and dangerous. Most are generalized or generalize rapidly from a frontal or other focus. More violent myoclonic seizures explain some falls. Most patients with atonic seizures also have other seizures, and many suffer from Lennox-Gastaut syndrome or other childhood epilepsies with several seizure types. Tonic seizures, often part of Lennox-Gastaut syndrome also, may cause falls by sudden rigid extension of the legs and trunk. Some seizures remain focal but include enough weakness or limb malfunction to cause falls. Seizures tend to be stereotyped, and most cause falls with a longer loss of consciousness. They are an unlikely explanation for isolated drop attacks without other clear seizure types, especially in adults. Occasionally,

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myoclonus or asterixis in the legs or trunk can be severe enough to cause drops. Other than simply tripping, patients may fall because of imbalance. This may be caused by cerebral, cerebellar, vestibular, spinal cord, or peripheral nerve dysfunction. Weakness, as a result of myopathy, infarcts, or other deficits, and spasticity are possible causes, as is impaired sensation (particularly somesthetic, although impaired vision and hearing can contribute). Parkinson’s disease and other basal ganglia disorders often impair postural reflexes. The falls may be transient, but basal ganglia disease, myelopathy, and peripheral neuropathy should be evident on neurologic examination. Patients with vestibular disease severe enough to cause imbalance and falls often have vertigo. Sudden, nearly violent vestibular dysfunction and imbalance may occur in Mhikre’s disease; this should include sensorineural hearing loss and tinnitus along with vertigo and generally occurs in older patients. Medications are always a concern and may exacerbate prior neurologic illness. Nonneurologic diseases such as arthritis and orthopedic problems can also prompt falls. A few authors have described a curious entity of isolated falls occurring during walking, often recurring a few times a year, in women over age 40 with no leg weakness, myelopathy, basal ganglia disorder, or other identifiable cause. The legs seem to give out suddenly. Some events are prompted by pregnancy, suggesting a hormonal influence, although the cause is unclear. Finally, cataplexy may be the purest form of drop attack, with a perfectly maintained consciousness and sudden atonia, often precipitated by a sudden emotional stimulus such as fear or laughter. Respiration and eye movements are maintained. Patients may remain atonic for several minutes. In many patients, cataplexy may take the form of a brief head nod or drop rather than a complete fall. Cataplexy appears to represent the atonia of rapid eye movement (REM) sleep occurring in waking. The abnormalities in tone at inappropriate times with regard to sleep, as well as the abnormal dreaming or hallucinations in wakefulness, indicate abnormalities in upper brainstem structures that control the onset of dreaming and atonia. At least some cataplexy is found in most patients with narcolepsy, and almost all cataplexy is part of narcolepsy. Less often, it may occur with other brainstem lesions or masses at the base of the skull. Evaluation of drop attacks begins with a history, which seeks to determine whether syncope, especially cardiac, or seizures were actually involved. Prior cardiac disease, palpitations, TIAs, headache, hearing loss, vertigo, any sensory loss (including visual and auditory), or symptoms of narcolepsy are of interest. Medication history is always pertinent. The exact onset of the fall and the progression are important, and witnesses are valuable. The examination looks for raised intracranial pressure, evidence of old cerebrovascular disease, basal ganglia disorders with alterations in tone or movement, signs of a myelopathy (including spasticity), ataxia, and a search for weakness, especially in the legs. With such varied causes, drop attacks can have no single therapy. One must treat the underlying cause, and anticoagulation for presumed TIAs or anticonvulsants for possible seizures are inappropriate without a reasonable diagnosis.

Episodic Ataxia There are unusual conditions causing a sudden generalized incoordination or ataxia of limbs, trunk, gait, and speech. The symptoms are not focal or lateralized but involve cerebellar

Principles of Diagnosis: Common Presenting Symptoms

structures and their connections. Attacks occur without weakness, sensory changes, or alterations in consciousness. There are two uncommon but well-described syndromes of episodic ataxia (EA), both autosomal dominant inherited illnesses caused by defects in voltage-gated ion channel function (i.e., channelopathies). EA- 1 produces ataxia and dysarthria lasting just seconds to minutes and is associated with myokymia between episodes, an observation that should help in the diagnosis. It is caused by a potassium channel dysfunction caused by a genetic defect on chromosome 12. Acetazolamide, and sometimes anticonvulsants, can help prevent episodes. EA-2 causes ataxia lasting hours to days, sometimes precipitated by exertion, stress, or alcohol use. The illness should present by early adulthood. Nystagmus usually is present even between episodes. It is also quite responsive to acetazolamide. EA-2 is associated with calcium channel dysfunction and a genetic abnormality on chromosome 19. Most episodic ataxias are caused by EA-1 or EA-2, but some episodes are caused by other chronic illnesses, particularly enzyme deficiencies usually diagnosed in childhood, such as pyruvate decarboxylase deficiency or maple syrup urine disease. Both episodic ataxias may be associated with a milder progressive ataxia and cerebellar atrophy, possibly caused by damage during the recurrent episodes. The episodic ataxias are similar in many ways to the periodic paralyses, which produce occasionally profound widespread muscle weakness associated with hyperkalemia or hypokalemia, and they are considered to be analogous channelopathies (see Chapter 112). Many of these conditions can be recognized by their widespread rather than focal clinical manifestations, the associated electrolyte abnormalities in the cases of periodic paralyses, and the family histories. Many may be confused with epilepsy. Most patients can be helped substantially with lifestyle changes (e.g., avoiding sudden carbohydrate loads, changing exercise patterns) or with medications. Different defects in the same calcium channel-producing gene that causes EA-2 can cause familial hemiplegic migraine or a spinocerebellar atrophy (SCA 6). Patients and families with one of these conditions may have some features of the other, and other instances of epilepsy and migraine may have related pathophysiology.

Sleep Disorders Sleep disorders can produce transient or paroxysmal symptoms in addition to cataplexy. Narcoleptic sleep attacks can be sudden, and patients can have lapses in attention or fall asleep at inappropriate times, suggesting syncope. Patients may have “microsleeps” even while driving a car, all without realizing at the time, or remembering later, that they were sleepy. The history may suggest narcolepsy, especially if associated with cataplexy, sleep paralysis, or hallucinations at the onset or end of sleep. Sometimes, the EEG can help differentiate sudden attacks of sleepiness from seizures, showing drowsiness and sleep in the former; postictal slowing is not the same as a sleepy record. Other paroxysms of abnormal movement or behavior may occur during sleep. Parasomnias, including sleepwalking and night terrors, occur in slow wave sleep rather than in REM; patients are amnestic for the attacks. Similar episodes can be epileptic. REM sleep behavior disorder can lead to very disruptive activities during dreaming without the usual atonia. The restless legs syndrome may respond to levodopa, and nocturnal dystonias can be responsive to anticonvulsants. Polysomnography with EEG can

Chapter 12 rn Transient Events

help distinguish parasomnias and movement disorders of sleep from nocturnal seizures.

Dizziness is a useless term clinically and must be differentiated further. Three categories encompass much of dizziness. Lightheadedness often is presyncope, and investigations follow the same rationale; this may be the most common type of dizziness. Imbalance or unsteadiness suggests incoordination, weakness, or disturbances in tone or sensation, as discussed earlier regarding falling spells and ataxia. Finally, “dizziness” can mean vertigo or the perception of movement in the absence of true movement; most is rotational. Vertigo often is associated with unilateral vestibular system dysfunction, but the laterality is not always clear at the time of presentation, especially with transient symptoms (see Chapter 8). Brief episodes of severe rotational vertigo with nausea and gait instability and a definite relationship to head position are strongly suggestive of benign positional vertigo. Episodes often last less than a minute. They may recur months after apparent resolution. Often, the neurologic examination is normal. Patients with benign symptoms need no treatment, but Epley canalith repositioning maneuvers may be helpful in many cases (see Chapter 8). Attacks of vertigo with nausea and vomiting along with hearing loss and tinnitus suggest MCniere’s disease; its acute vestibular dysfunction can even lead to falls without loss of consciousness. Both of these conditions involve extra-axial vestibular dysfunction (i.e., in inner ear structures or in the eighth cranial nerve). Less commonly, abnormal input to the vestibular system caused by cervical spine or other neck disease can lead to vertigo. Vertigo from brainstem disease often is less severe and may be associated with diplopia, facial numbness, absent corneal reflexes, dysarthria, dysphagia, or abnormal visual fields or acuity (i.e., neighborhood signs of brainstem or posterior circulation dysfunction). Less dramatic vertigo (sometimes translational rather than rotational) can occur with temporal lobe seizures. Occasionally, vertigo, tinnitus, and hearing loss can be part of presyncope. Strokes can produce more lasting vertigo, but TIAs involving the basilar and internal auditory artery supplying the eighth cranial nerve can also include vertigo. Less transient vertigo can occur with chronic ear disease such as infections, skull fractures or other head injury, barotrauma, and aminoglycoside toxicity. Cerebellopontine angle tumors more often present with hearing loss than with vertigo. Posterior fossa tumors and multiple sclerosis produce more persistent symptoms and signs. The examination focuses on peripheral ear and eighth cranial nerve dysfunction, including signs of infection, hearing loss, and associated cranial nerve and brainstem signs. Hearing loss on audiometry can help diagnose Mknihre’s disease. Provocative maneuvers involving head turning and vestibular apparatus positioning, such as the Hallpike maneuver, attempt to elicit the patient’s typical symptoms and concomitant nystagmus.

Hallucinations Hallucinations often localize to a sensory region. Visual hallucinations are common in migraine and occipital seizures. They may also occur along with delirium in encephalopathies, including those caused by metabolic derangements, medications, and medication withdrawal, particularly from alcohol. Poor visual

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acuity predisposes to visual hallucinations. Elevated intracranial pressure can lead to fleeting bilateral visual loss; visual loss is discussed more extensively in Chapter 6. Auditory hallucinations may occur with temporal lobe dysfunction, including seizures. Epileptic auditory hallucinations generally are less well formed, varied, and directive than those in schizophrenia.

Psychiatric Conditions Psychiatric diseases can also produce paroxysmal symptoms. Panic attacks can come on abruptly and include autonomic symptoms such as palpitations, nausea, sweating, and flushing, along with feelings of shortness of breath, choking, vertigo, lightheadedness, tremor, chest pain, depression, fear, and a feeling of impending doom. Paresthesias can follow hyperventilation. A sense of depersonalization is less common, and very rare attacks may lead to a loss of consciousness, possibly through hyperventilation. Many panic attacks can be diagnosed on the basis of the autonomic and respiratory symptoms, along with fear or dread. Alteration in consciousness raises the question of complex partial seizures. Panic attacks often occur in patients with related psychiatric problems, and many have an emotional precipitant. Lateralized symptoms are unlikely, and loss of consciousness or injury are rare. More than with seizures, there is variability in symptoms from episode to episode, and EEGs should remain normal. EEG monitoring during the episodes can be very helpful in distinguishing the two. Episodic dyscontrol with angry or even directed and violent reactions to seemingly minor though identifiable stimuli generally is considered a psychiatric problem. Episodes last for minutes, usually followed by profuse apologies. Between episodes, patients have normal behavior and are not psychotic. Earlier head injury, encephalitis, and mild or moderate mental retardation are common settings. With a well-identified precipitant and no other clear signs of seizures, these episodes are rarely epileptic. Nonepileptic seizures or pseudoseizures may produce bizarre spells. Unfortunately for diagnostic simplicity, perhaps one half of patients with nonepileptic seizures also have true epilepsy. Often, patients have severe psychiatric problems and have a model for seizure manifestations. Epileptic seizures are more often stereotyped; pseudoseizures last longer and tend to have more variety. They may be provoked by suggestion or stress, include poorly coordinated movements and more complex vocalizations, and usually do not respond to anticonvulsants. Pseudoseizures occur more often with an audience and essentially never during sleep. Injuries are rare. Actions or violence may appear more directed, and patients may resist examination during the event. EEG monitoring can help, but many seizures, including frontal seizures, can have unusual manifestations and be difficult to record. Interictal EEGs are of less value because epileptic patients may have normal EEGs, and pseudoseizures occur in patients with epilepsy. Thus, a diagnosis of epilepsy cannot be absolutely ruled out but can be rendered less likely, provided that the typical spells are recorded and the EEG shows a normal background without epileptic changes or postictal slowing. A diagnosis of nonepileptic seizures helps to minimize medication toxicity and points the way to psychiatric therapy, although this is not always curative. FOCAL OR LOCALIZED SYMPTOMS Clear focal symptoms help to make the neurologic diagnosis of transient symptoms in the traditional way, through localization

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(Table 12-3). The three primary diagnostic entities are TIAs, epileptic seizures, and migraine. They can cause very similar spells, but several features may help to distinguish one from the other (Table 12-4). Transient Ischemic Attacks

TIAs are temporary dysfunction of brain tissue caused by inadequate blood flow. Vague spells and “dizziness” unaccompanied by localizable symptoms do not constitute TIAs; symptoms must correspond to dysfunction of an identifiable vascular territory. Carotid artery territory TIAs often produce contralateral hand and arm weakness and sensory loss. Face and leg symptoms often

TAW 12-3. Causes of Transient Events with Focal Onset Common Transient ischemic attacks Epilepsywith partial onset Migraine Less common Overlap syndromes (migraine seizure k ischemia) Mass lesions Multiple sclerosis Movement disorders Amvloid annioDathv

*

Principles of Diagnosis: Common Presenting Symptoms

are less severe, particularly with primary involvement of the middle cerebral artery, but the signs and symptoms change depending on the vascular territory involved (e.g., leg weakness is more likely with anterior cerebral artery ischemia). Carotid TIAs can be limited to ipsilateral visual symptoms with involvement of the ophthalmic artery. In the hemisphere dominant for language they can produce aphasia; less often, language disturbances occur in isolation. TIAs, without completed strokes, may be more common in the vertebrobasilar territory and often include combinations of diplopia, ataxia, vertigo, dysarthria, unilateral or bilateral visual symptoms, and weakness on one or both sides, especially in the legs. Although isolated vertigo or imbalance can be a posterior circulation TIA, there are usually other associated symptoms and signs. TIAs should have the same manifestations as strokes, if only briefly. TIAs usually present suddenly, often in older patients with a history or risks of vascular disease. Symptoms are almost always negative (i.e., a loss of function) rather than positive phenomena, such as involuntary movements or visual sensations or hallucinations. Alteration in consciousness and confusion are rare, but an aphasia may be mistaken for confusion. The definition of TIAs as lasting less than 24 hours is somewhat misleading because most last just minutes, and events of more than an hour are less common. The history of a patient with TIAs should include a search for risk factors and a history of similar or related events, including

TABLE12-4. Differentiating Features of Common Spells with Focal Symptoms Epidemiology, risks

Family history Precipitants Localization; clinical features

Seizure

Transient Ischemic Attack

Migraine

Any age; different age-related syndromes Birth or childhood injury, mental retardation, head injury, stroke, encephalitis, childhood febrile seizure

Older patient Risk of vascular disease

Younger Women:men 3:l

-

++

+

Infection, sleep disturbance, head injury, medication change, stress, hormonal change; not postural Several foci possible, including motor Positive symptoms (e.g., motor and hallucinations)

Activity (embolic) Upright posture; poor perfusion Cardiac arrhythmia Must correspond to a vascular territoy: Carotid: unilateral, especially in limbs; aphasia Vertebrobasilar: brainstem, occipital, can be unilateral or bilateral in legs; vertigo, diplopia, dysarthria Negative symptoms (e.g., paralysis) Lasts minutes usually Often maximal at onset but may stutter

Time course

March over seconds May progress to complex partial, generalized seizures

Altered consciousness

Not in simple partial seizure, but with progression to complex partial and generalized seizures

Rare

Appearance to observers

Motor abnormalities, jerking common Staring, automatisms, incontinence, falls in some with progression Focal at the onset Postictal focal deficits May have old focal lesions Often normal except for prior and predisposing lesions, including cortical maldeveloprnent May have epileptiform abnormalities, depending on type and localization of seizures

Sudden loss of function, weakness, clumsiness, dysarthria, aphasia

Examination Imaging studies Electroencephalogram

Evidence of vascular disease May have focal or multifocal deficits, some old New (and old) vascular lesions Often with focal or multifocal slowing Epileptiform abnormalities not rare

Foods, medication Stress Hormonal change Posterior cerebrum common Visual symptoms, including positive hallucinations; some negative

March over minutes, can be 20 minutes Often precedes headache by 20-30 minutes Rare May occur in adolescents with basilar migraine, but with slow onset and incomplete Often appears normal Occasional slurring, clumsiness Usually normal during and between episodes Almost always normal Often normal Prominent focal slowing may long outlast the episode

Chapter 12

transient monocular blindness when carotid disease is suspected. TIAs tend to be stereotyped, although emboli may recur in different vascular territories. Cardiogenic emboli often occur during activity. New headaches may follow cerebral ischemia. Cocaine use may cause transient or more permanent ischemia, and medication history is important in evaluating any transient event. Neurologists rarely have the opportunity to examine a patient during a TIA, but the examination is still important afterward; the event is not transient if signs persist. Funduscopic examination can show vascular disease or even emboli themselves. Cardiac examination for arrhythmias and murmurs is important. Rarely, a blood pressure difference between the two arms signifies subclavian stenosis causing vertebrobasilar ischemia, exacerbated by arm use in a steal syndrome. The neurologic examination (including testing of cognition, visual fields, cranial nerves, and more distal motor and sensory function) may show that an event is not transient or may show evidence of prior strokes. By definition, TIAs resolve. Investigation is directed at preventing recurrences or strokes by looking for causes of strokes. Focal symptoms warrant a search for focal lesions, and magnetic resonance imaging (MRI) is the most sensitive and useful test, particularly with diffusion-weighted imaging in the acute setting. Cardiac testing and hematologic evaluation for hypercoagulable states usually are appropriate. Direct evaluation of individual vessels depends on the clinical localization. In older patients, temporal arteritis and erythrocyte sedimentation rates are too often overlooked. More extensive evaluations are appropriate in younger patients and in those with new symptoms rather than recurrences of the same symptom.

In addition to the falls, loss of consciousness, and confusional spells described earlier, seizures produce focal or partial symptoms. Seizures often occur in patients with risk factors such as congenital, birth, or other early injuries, prior meningitis or encephalitis, strokes, tumors, or head injury. They are precipitated by irregular sleep, medications, infection, head injury, stress, or hormonal flux. Certain seizure syndromes are age-related, and a substantial minority of patients have family histories of epilepsy. When seizure symptoms spread over the body, the progression is rapid, usually within seconds. The resolution of seizures is slower and may take hours. Some lead to a confusional state or prolonged focal deficits (motor, sensory, or cognitive) postictally (e.g., Todd's paralysis) for up to hours. Seizures have a great variety, but repeated episodes tend to be stereotyped in the same patient. Accordingly, a tremendous variety of paroxysmal symptoms is unlikely to indicate that a patient has epilepsy. Simple partial or focal seizures leave consciousness unaffected, and patients can report focal symptoms. With a progression to complex partial seizures, however, there is an impairment of consciousness, and amnesia for the event may occur. The observations of patients and witnesses are crucial. Family members may report many more spells than the patients themselves. The exact onset of symptoms is important; uninterruptible staring spells and orobuccal automatisms are useful clues. Jerking motor activity, the character of hallucinations, and the time course of spells all help to characterize a seizure. Patients usually refer to focal seizure onsets as auras. Some begin with olfactory or other hallucinations, and patients do not necessarily report these symptoms without being asked. Some features of an episode may suggest or discourage a diagnosis of epilepsy (Table 12-5).

H TABLE 12-5.

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Myths about Spells and Seizures

"I don't have seizures anymore, just frequent auras."

The "aura" is the partial onset of the seizure (although auras may also be part of migraine); it may progress to a convulsion. "Incontinence and tongue-biting are reliable signs of convulsions." These symptoms occur more often with seizures than with other paroxysmal attacks, but their absence does not argue strongly against epilepsy; even with convulsions, they are found in a minority of patients. "Bilateral motor activity without loss of consciousness indicates pseudoseizure." Some bilateral jerking activity, especially when prolonged and somewhat irregular, along with apparently purposeful behavior, suggests pseudoseizure. Nevertheless, complex partial seizures of frontal origin may include bilateral leg activity such as bicycling or running, with a preserved consciousness and even memory of the event. "The patient has several bizarre symptoms. It must be temporal lobe epilepsy." Seizures tend to be stereotyped from episode to episode. An indMdual seizure may progress from an olfactory hallucination, to a staring spell, to a generalized convulsion; in addition, some patients have a few types of seizures. Nevertheless, a wide variety of symptoms is unlikely to be attributable to epilepsy. "Drop attacks are commonly caused by seizures." Atonic seizures are rare and generally found in patients with refractory seizure disorders, including several types of seizures. They usually include a loss of consciousness. "An EEC will diagnose epilepsy (rule out seizures)." Electroencephalographic findings aid in diagnosing seizures and may indicate an individual type of epilepsy, but up to one half of patients with epilepsy have a normal EEC at a gven time. Also, many electroencephalographic abnormalities are not diagnostic of epilepsy, and epileptiform discharges occur occasionally without clinical epilepsy. The EEC must be used with the clinical history and observations. Abbreviations: EEG, electroencephalogram.

The history should include a family history and that of gestation, delivery, and early development, as well as prior illnesses or injuries that predispose to seizures. The general examination searches for related findings (e.g., the skin lesions in tuberous sclerosis or other neurocutaneous syndromes) and neurologic deficits that indicate a greater risk of seizures. As with TIAs, focal seizures mandate a search for focal lesions, usually by MRI. Interictal EEG epileptiform abnormalities increase the likelihood of seizures, but discharges can occur without epilepsy, and electroencephalographic abnormalities are also found in vascular disease, migraine, and other illnesses. Abnormalities such as focal slowing are insufficient to diagnose seizures, and there are artifacts and normal variants with sharp features on EEG. EEGs may remain normal in patients with seizures, especially with a frontal focus. When symptoms are frequent enough, long-term electroencephalographic monitoring can be diagnostic if electrographic seizure activity is recorded at the time of symptoms. Postictal slowing can also be a useful finding. Seizure diagnosis is detailed further in Chapter 145. Migraine

Migraine is extremely common, affecting approximately 18% of women and 6% of men in the United States (see Chapter 209). Many have headaches alone, but migraine often includes unilateral or bilateral positive visual symptoms, visual loss, or unilateral sensory and motor symptoms. Its pathophysiology is poorly understood, but cerebral vasculature and trigeminal nerve nociceptive afferents are involved; however, the progressive cortical dysfunction of spells does not respect vascular boundaries. Focal symptoms typically occur in patients with known migraine and in patients much younger than those with TIAs. Spells usually

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

precede a typical headache but can occur without headache. A family history of migraine is very common. New symptoms may occur with new stresses, including hormonal (e.g., a woman with no prior migraine but with a significant family history may have new migrainous visual symptoms, without headache, during pregnancy). A gradual onset of symptoms is typical. With limb involvement, numbness may march over a period of up to 30 minutes, compared with the spread of seizures over seconds. The neurologic deficit tends to precede the headache by 20 minutes and may last 20 to 30 minutes, often resolving during the headache; some are more prolonged. Positive visual symptoms are more suggestive of migraine or seizure than of TIAs. The visual perception of jagged bright lines (sometimes described as in the shape of an old stockade-lined fort), a “fortification spectrum,” is strongly suggestive of migraine. Marked focal electroencephalographic slowing in migraine may outlast the neurologic deficit or headache by many hours. Basilar artery migraine usually occurs in children and adolescents with a history of migraine and often includes brainstem dysfunction such as vertigo, diplopia, ataxia, and dysarthria; bilateral visual field loss is another possible posterior circulation deficit. In more severe episodes, loss of consciousness occurs over minutes but is less severe than with seizures, typically with ready rousability. Confusion may last hours. Visual symptoms often are first. Motor symptoms are generally clumsiness and weakness, not positive signs such as limb jerking. Recovery is usually rapid. The first presentation can be extremely difficult to diagnose; when cranial nerve or brainstem signs are prominent and when consciousness is impaired, it is important to exclude posterior fossa mass lesions by MRI. In many cases, benefit from typical migraine medication can be a diagnostic aid. Paroxysmal vertebrobasilar symptoms in children rarely represent ischemia and are more likely to be migraine. Overlap Syndromes

Among migraine, seizures, and ischemia, there are many complicated overlapping syndromes. Rarely, migraine can lead to focal ischemia and a stroke. Vascular disease probably is the most common cause of new focal seizures in older adults. Focal lesions may lead to symptomatic migraine headaches. Headaches often occur postictally. In some syndromes, such as benign occipital epilepsy of childhood, it may be impossible to separate migraine from epilepsy. These patients have prominent focal occipital spike wave discharges and a very high incidence of migraine. Seizures typically occur during the migraine aura but may follow attacks of migraine. Clonic movements, complex partial seizures, and generalized convulsions may follow typical migrainous visual phenomena. Negative phenomena such as blindness may occur with occipital seizures. The family history is often positive, but manifestations are uncommon in adults. The prognosis is usually excellent. Concurrent migraine and epilepsy can also be traced to mitochondria1 encephalopathies. Other Causes of Focal Symptoms

Less often, transient focal symptoms arise from causes other than epilepsy, ischemia, or migraine. Mass lesions may present with transient focal symptoms, possibly caused by venous insufficiency or focal seizures. The neurologic examination may show less

Principles of Diagnosis: Common Presenting Symptoms

transient signs. Multiple sclerosis can produce focal weakness, sensory changes, or incoordination lasting minutes or hours, but there is almost always other, nontransient evidence of the disease such as optic nerve or eye movement dysfunction, spasticity, or ataxia. Transient multiple sclerosis symptoms usually last much longer. They may occur with an increase in body temperature. Occasionally, multiple sclerosis causes brief tonic spasms that resemble tonic seizures, and some of these may respond to anticonvulsants. Multiple sclerosis may lead to paroxysmal attacks of dystonia; anticonvulsants and acetazolamide may help these, as well. Epileptic seizures also occur in about 5% of patients with multiple sclerosis. Occasionally, movement disorders can present paroxysmally lasting minutes, hours, or days. Some such movement disorders occur in the context of multiple sclerosis, cerebral palsy, or hypoparathyroidism. There are other primarily paroxysmal movement disorders, such as paroxysmal kinesigenic choreoathetosis that causes brief (seconds to minutes) episodes of involuntary movements precipitated by voluntary movement. Consciousness and strength are unaffected, but events can occur dozens of times in a day. EEGs usually are normal. Anticonvulsant medications often are extremely helpful, although the condition is not considered epilepsy. Paroxysmal nocturnal dystonias may appear to fall within the movement disorder category, but almost all such nocturnal events are manifestations of frontal lobe epilepsy. The best recognized is autosomal dominant nocturnal frontal lobe epilepsy, associated with a genetic defect in the nicotinic acetylcholine receptor gene on chromosome 21. The epileptic basis of this disorder remained undiscovered until recently, probably because the manifestation was dystonic and because frontal epileptiform discharges can be very difficult to record on EEG. The response to anticonvulsants generally is very good. Amyloid angiopathy, a pathologic deposition of amyloid beta protein in the cerebral arteries, is now recognized as a cause of spontaneous intraparenchymal hemorrhage in older adults. Patients with symptoms mimicking TIA, migraine, and nonconvulsive seizures have been described (see Chapter 33). When the evaluation for TIA and seizure is negative in older adults with recurrent spells, and antiplatelet or antithrombotic therapies are being considered, MRI with magnetic susceptibility sequences can serve as a sensitive identifier of the multiple small intraparenchymal hemorrhages characteristic of amyloid angiopathy. Tourette’s syndrome and other tic disorders are occasionally mistaken for seizures. The grunting, barking, or forced and occasionally obscene vocalizations may be difficult to manage. Tics often respond to neuroleptic medications but with potential complications. Tardive dyskinesias occur after antipsychotic medication use but may be inconsistent in appearance (see Chapter 127). Often, basal ganglia dysfunction is evident, as in Parkinson’s disease, and this is not intermittent. In a startle syndrome called hyperekplexia, a sudden stimulus (usually noise) leads to violent body stiffening and falls. The syndrome is familial but not epileptic. Sudden movement disorders such as chorea, athetosis, and hemiballismus occur in basal ganglia disorders, including those caused by strokes. Usually, the neurologic examination is abnormal, and scans may show lesions, especially in vascular cases. Transient neurologic symptoms challenge the neurologist with a bewildering array of diagnostic possibilities. The events have usually resolved before one has a chance to observe them, and witnesses must always be sought. Nevertheless, a reasonable diagnosis usually can be reached by considering which part of the

Chapter 13

brain is involved, along with epidemiologic factors, the time course and character of events, and some characteristic features of certain syndromes. Foremost consideration is given to the more threatening diagnoses such as cardiac disease, epilepsy, and cerebrovascular disease, although many causes of transient symptoms are benign. Often, it is more prudent to wait for recurrence of events for additional data rather than prescribe therapy without a clear diagnosis. SUGGESTED READINGS Andermann F, Lugaresi E: Migraine and Epilepsy. Butterworth, Boston, 1987 Carnfield PR, Metrakos K, Andermann F: Basilar migraine, seizures, and severe epileptiform EEG abnormalities. Neurology 28:584-588, 1978 Griggs RC, Moxley RT, Lafrance RA, McQuillen J: Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 28:1259-1264, 1978

13

Respiratory Dysfunction

137

Kaplan PW: Nonconvulsive status epilepticus in the emergency room. Epilepsia 37:643-650, 1996 Kapoor WN, Karpf M, Wieand S et al: A prospective evaluation and follow-up of patients with syncope. N Engl J Med 309197-204, 1983 Lueders H, Lesser Rp: Epilepsy: Electroclinical Syndromes. SpringerVerlag, London, 1987 McLeod JG, Tuck RR: Disorders of the autonomic nervous system. Ann Neurol21:419-430, 519-529, 1987 Meissner I, Wiebers DO, Swanson JW, O’Fallon WM: The natural history of drop attacks. Neurology 361029-1034, 1986 Sandson TA, Price BH: Transient global amnesia. Semin Neurol 15:183187, 1995 Shen WK, Gersh BJ: Syncope: mechanisms, approach, and management. pp. 605-640. In Low P (ed): Clinical Autonomic Disorders. Boston, Little, Brown, 1993 Thomas P, Beaumanoir A, Genton P et ak “De novo” absence status of late onset: report of 11 cases. Neurology 42:104-110, 1992 Thorpy MJ: Handbook of Sleep Disorders. Marcel Dekker, New York, 1990

Respiratory Dysfunction David Lacomis

Respiratory dysfunction usually is caused by cardiopulmonary disorders or upper airway obstruction; however, neurologic diseases may also impair respiration. Such nervous system disorders may present with acute respiratory dysfunction and necessitate emergency assessment, or they may progress more insidiously and so come to the attention of the neurologist or primary care physician in ambulatory practice. In many of these patients, such as those with Guillain-Barre syndrome, associated clinical features reveal the cause of the respiratory disorder. In others, such as some patients with amyotrophic lateral sclerosis, respiratory dysfunction may appear alone. As with all nervous system diseases, clinical diagnosis is founded on an understanding of the neuroanatomy and the pathologic processes that may occur in the relevant structures. ~

~~____________ ~~

~

~~

NEUROANATOMY OF RESPIRATION Muscles of Respiration A respiratory bellows mechanism moves air repetitively into and

out of the lung alveoli, allowing gas exchange to occur. The inspiratory phase of this biphasic process is active; the expiratory phase is predominantly passive. During quiet inspiration, the diaphragm, which is attached to the xiphoid process, the lower six ribs, and the upper lumbar vertebrae, performs most of the work. When this dome-shaped circumferential muscle group contracts, its central tendon is pulled down and forward, causing the abdominal viscera to descend and the abdomen to protrude. The central tendon then becomes fixed. Further expansion of the chest cavity is accomplished by elevation of the lower ribs and forward displacement of the sternum and upper ribs. The resultant increase in intrathoracic volume lowers intrapleural and intrapulmonary pressures, causing air to rush into the lungs from the upper air passages. Intercostal and scalene as well as paraspinal and sternocleidomastoid muscles serve as accessory muscles of

respiration to increase the thoracic volume further during deep respiration or when there is respiratory compromise. Muscles of the upper airway (genioglossus, pharyngeal constrictors, and the laryngeal and neck strap muscles) work to keep the airway open. During normal expiration, there is passive recoil of the thoracic cage and lungs along with abdominal and intercostal muscle contraction, causing an elevation in intrathoracic pressure and the expulsion of air from the lungs. Peripheral Nerve Supply of the Respiratory Muscles and Lung

The diaphragm is innervated bilaterally by the phrenic nerves, which are derived from the third, fourth, and fifth cervical segments and their respective anterior horn cells and motor roots. The phrenic nerves descend across the scalene muscles, diving deep to the internal jugular veins, and enter the thorax in front of the internal thoracic artery. In the thorax, the nerves then descend anterior to the roots of the lungs, traverse the fibrous pericardium and mediastinal pleura, and, finally, innervate the diaphragm. The left phrenic nerve also passes anterior to the arch of the aorta. Thus, the phrenic nerves are vulnerable to injury at multiple sites from the neck to the lower thorax. Intercostal and respiratory paraspinal muscles are supplied by thoracic spinal roots. Abdominal muscles are innervated by lower thoracic and upper lumbar segments. The strap muscles of the neck (sternohyoideus, sternothyroideus, thyrohyoideus, and omohyoideus) are supplied by the upper cervical roots, the sternocleidomastoid muscles by the spinal accessory nerves predominantly, and the nasopharyngeal muscles by the ninth, tenth, and twelfth cranial nerves. Pulmonary innervation to bronchial muscles, glands, blood vessels, and mucous membranes is both sympathetic and parasympathetic. The parasympathetic supply is from the vagal nerve and mediates bronchoconstriction by

Chapter 13

brain is involved, along with epidemiologic factors, the time course and character of events, and some characteristic features of certain syndromes. Foremost consideration is given to the more threatening diagnoses such as cardiac disease, epilepsy, and cerebrovascular disease, although many causes of transient symptoms are benign. Often, it is more prudent to wait for recurrence of events for additional data rather than prescribe therapy without a clear diagnosis. SUGGESTED READINGS Andermann F, Lugaresi E: Migraine and Epilepsy. Butterworth, Boston, 1987 Carnfield PR, Metrakos K, Andermann F: Basilar migraine, seizures, and severe epileptiform EEG abnormalities. Neurology 28:584-588, 1978 Griggs RC, Moxley RT, Lafrance RA, McQuillen J: Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 28:1259-1264, 1978

13

Respiratory Dysfunction

137

Kaplan PW: Nonconvulsive status epilepticus in the emergency room. Epilepsia 37:643-650, 1996 Kapoor WN, Karpf M, Wieand S et al: A prospective evaluation and follow-up of patients with syncope. N Engl J Med 309197-204, 1983 Lueders H, Lesser Rp: Epilepsy: Electroclinical Syndromes. SpringerVerlag, London, 1987 McLeod JG, Tuck RR: Disorders of the autonomic nervous system. Ann Neurol21:419-430, 519-529, 1987 Meissner I, Wiebers DO, Swanson JW, O’Fallon WM: The natural history of drop attacks. Neurology 361029-1034, 1986 Sandson TA, Price BH: Transient global amnesia. Semin Neurol 15:183187, 1995 Shen WK, Gersh BJ: Syncope: mechanisms, approach, and management. pp. 605-640. In Low P (ed): Clinical Autonomic Disorders. Boston, Little, Brown, 1993 Thomas P, Beaumanoir A, Genton P et ak “De novo” absence status of late onset: report of 11 cases. Neurology 42:104-110, 1992 Thorpy MJ: Handbook of Sleep Disorders. Marcel Dekker, New York, 1990

Respiratory Dysfunction David Lacomis

Respiratory dysfunction usually is caused by cardiopulmonary disorders or upper airway obstruction; however, neurologic diseases may also impair respiration. Such nervous system disorders may present with acute respiratory dysfunction and necessitate emergency assessment, or they may progress more insidiously and so come to the attention of the neurologist or primary care physician in ambulatory practice. In many of these patients, such as those with Guillain-Barre syndrome, associated clinical features reveal the cause of the respiratory disorder. In others, such as some patients with amyotrophic lateral sclerosis, respiratory dysfunction may appear alone. As with all nervous system diseases, clinical diagnosis is founded on an understanding of the neuroanatomy and the pathologic processes that may occur in the relevant structures. ~

~~____________ ~~

~

~~

NEUROANATOMY OF RESPIRATION Muscles of Respiration A respiratory bellows mechanism moves air repetitively into and

out of the lung alveoli, allowing gas exchange to occur. The inspiratory phase of this biphasic process is active; the expiratory phase is predominantly passive. During quiet inspiration, the diaphragm, which is attached to the xiphoid process, the lower six ribs, and the upper lumbar vertebrae, performs most of the work. When this dome-shaped circumferential muscle group contracts, its central tendon is pulled down and forward, causing the abdominal viscera to descend and the abdomen to protrude. The central tendon then becomes fixed. Further expansion of the chest cavity is accomplished by elevation of the lower ribs and forward displacement of the sternum and upper ribs. The resultant increase in intrathoracic volume lowers intrapleural and intrapulmonary pressures, causing air to rush into the lungs from the upper air passages. Intercostal and scalene as well as paraspinal and sternocleidomastoid muscles serve as accessory muscles of

respiration to increase the thoracic volume further during deep respiration or when there is respiratory compromise. Muscles of the upper airway (genioglossus, pharyngeal constrictors, and the laryngeal and neck strap muscles) work to keep the airway open. During normal expiration, there is passive recoil of the thoracic cage and lungs along with abdominal and intercostal muscle contraction, causing an elevation in intrathoracic pressure and the expulsion of air from the lungs. Peripheral Nerve Supply of the Respiratory Muscles and Lung

The diaphragm is innervated bilaterally by the phrenic nerves, which are derived from the third, fourth, and fifth cervical segments and their respective anterior horn cells and motor roots. The phrenic nerves descend across the scalene muscles, diving deep to the internal jugular veins, and enter the thorax in front of the internal thoracic artery. In the thorax, the nerves then descend anterior to the roots of the lungs, traverse the fibrous pericardium and mediastinal pleura, and, finally, innervate the diaphragm. The left phrenic nerve also passes anterior to the arch of the aorta. Thus, the phrenic nerves are vulnerable to injury at multiple sites from the neck to the lower thorax. Intercostal and respiratory paraspinal muscles are supplied by thoracic spinal roots. Abdominal muscles are innervated by lower thoracic and upper lumbar segments. The strap muscles of the neck (sternohyoideus, sternothyroideus, thyrohyoideus, and omohyoideus) are supplied by the upper cervical roots, the sternocleidomastoid muscles by the spinal accessory nerves predominantly, and the nasopharyngeal muscles by the ninth, tenth, and twelfth cranial nerves. Pulmonary innervation to bronchial muscles, glands, blood vessels, and mucous membranes is both sympathetic and parasympathetic. The parasympathetic supply is from the vagal nerve and mediates bronchoconstriction by

138

Principles of Ambulatory Neurologyand the Approach to Clinical Problems

stimulating muscle contraction; the sympathetic influence is inhibitory and facilitates relaxation of bronchial smooth muscles and hence bronchodilation.

Central Control of Respiration

The upper motor neuron pathways governing respiratory control are complex and have been reviewed in detail by Kelly and Luce (1991) (Fig. 13-1). Both automatic and voluntary control mechanisms orchestrate the complex movements of respiration. The afferent limb of the automatic component begins with pulmonary and respiratory muscle stretch mechanoreceptors and with blood oxygen and C 0 2chemoreceptorslocated on the floor of the fourth ventricle and in the aortic and carotid bodies. These receptors provide sensory input to specialized neurons in the medulla, the central respiratory pattern generator. The dorsal respiratory group is adjacent to the tractus solitarius and contains “inspiratory” neurons; the ventral group is associatedwith the nucleus ambiguus and retroambiguus and contains inspiratory and expiratory neurons. Centers in the pons, including the so-called pneumotaxic center, and in the pontomedullary junction modulate respiratory control. Efferent fibers travel to the contralateral lungs and pharyngeal and laryngeal muscles via the vagus nerve and to the respiratory muscles via the phrenic and intercostal nerves and their spinal roots. The associated spinal cord pathways are located ventrolaterally. Voluntary overdrive mechanisms, such as those governing breath-holding and voluntary hyperventilation, have not been fully characterized, but the motor cortex, reticular activating

Principles of Diagnosis: Common PresentingSymptoms

system, cerebellum, midbrain, and forebrain all have postulated roles. Much of the pathway that mediates respiration is also involved in producing hiccups. This phenomenon results from repetitive contraction of the diaphragm while the glottis is closed. Phrenic, vagal, and sympathetic afferents are involved in addition to phrenic efferents. These nerves are controlled by the central respiratory structures in the brainstem. Therefore, a lesion along this extended pathway may cause hiccups with or without respiratory dysfunction. SYMPTOMS AND SIGNS OF NEUROGENIC RESPIRATORY DYSFUNCCION

Dyspnea usually is the first symptom of respiratory dysfunction from any cause. In addition to the well-known features from the history and neurologic examination that may suggest nervous system disease, certain nonspecific and respiratory symptoms and signs should lead to consideration of neurogenic respiratory dysfunction. Lethargy, morning headache, anxiety, fatigue, poor sleep, hypersomnolence, and confusion may be reported. Dyspnea may worsen with exertion and when the patient is supine because the diaphragm then works against gravity. The resting respiratory rate may be increased, and accessory muscles of respiration may be called into action at rest. Neurogenic respiratory dysfunction may also worsen during sleep, especially rapid eye movement sleep, when there is atonia of all respiratory muscles, except the diaphragm, and when central control mechanisms are less responsive to afferent input. Patients with isolated neurogenic respiratory dysfunction

Voluntary overdrive: cerebral cortex + Efferent limb

Afferent limb

Upper airway muscles and SCM; scalenes and accessory muscles

Diaphragm

8

VRG (Ventral respiratory group)

Pneumotaxic center

FIG. 13-1. The neuroanatomic pathways of respiration are outlined. SCM, sternocleidomastoid muscle. (Adapted from Kelly BJ, Luce JM: The diagnosis and management of neuromuscular diseases causing respiratory failure. Chest 99:1485-1494, 1991, with

permission.)

Chapter 13 1 Respiratory Dysfunction

159

FIG. 15-2. Lung volumes at rest and after forced inspiration and expiration. FRC, functional residual capacity; RV, residual volume; TV, tidal volume.

usually have normal breath sounds. Percussion may reveal evidence of decreased diaphragmatic excursion. The overall pattern of respiration can be evaluated by observing the rhythmicity of breathing (or of diaphragmatic contraction by electromyography [EMG]). The chest radiograph may be clear or reveal platelike atelectasis or elevated hemidiaphragms. Fluoroscopy, especially in conjunction with the sniff test, may confirm abnormal diaphragmatic movements. However, recognizing the phenomenon of alveolar hypoventilation may be the most important clue that a neurogenic process is causing respiratory compromise.

ALVEOLAR HYPOVENTlLATlON Alveolar hypoventilation occurs when ventilation of the alveoli is low in relation to 0, consumption and CO, production such that the partial oxygen tension (Po,) falls and the partial carbon dioxide tension (Pco,) rises. The hypoxemia may improve after supplemental 0, is administered, but hypercapnia can improve only after the ventilatory rate increases when respiratory muscle weakness precludes an increase in the tidal volume. Both central and peripheral nervous system diseases may cause alveolar hypoventilation. This is characterized by arterial blood gas measurements that demonstrate hypoxemia and hypercapnia with a normal alveolar-arterial oxygen gradient (A-a gradient).* Although hypercapnia and hypoventilation may also occur with pulmonary diseases, many lung diseases also produce hypoxemia by causing ventilation-perfusioninequalities rather than hypoventilation. This results in an elevation of the A-a 0, gradient. Of course, the A-a gradient may rise when alveolar pathology complicates alveolar hypoventilation caused by neurogenic respi*If you know the Fio,, Pa,, and Po,, the A-a gradient can be calculated as follows:

A-a gradient = P A O-~Pao, (normal e l 5 to 30 mm Hg, depending on the age) PA02 = FIO, (PB - P,,o) - Pa2/O.8 PA02 = 0.21 (760 - 47) - 1.25 (Pa,) hence, PAO,= 150 - 1.25 (Pa,) Pao, is measured directly. In these equations, PAO,= alveolar Po,, Pao, = arterial Po,, Fio, = fractional O2 inspired (Fio, of room air is 0.21), PB = barometric pressure, PHz0= partial pressure of H,O (47 mm Hg when saturated), and 0.8 is the respiratory quotient.

ratory failure. This is common, for example, when neurogenic hypoventilation results in atelectasis or pharyngeal weakness is complicated by aspiration pneumonitis. Fortunately, alveolar hypoventilation does not occur until the advanced stages of neurogenic respiratory failure. Therefore, in the early stages clinicians must rely on other measures, including pulmonary function tests, to determine whether the respiratory dysfunction is caused by a neurologic disorder.

PULMONARY FUNCllON TESTS The mechanical and metabolic aspects of respiration that are most useful in evaluating suspected neurogenic respiratory dysfunction are those that can be readily measured, followed over time, and used to distinguish pulmonary from neurologic causes of respiratory compromise. Static and dynamic lung volumes and expiratory and inspiratory pressures meet these criteria. Static Lung Volumes

Total lung capacity is the volume of air present in the chest after full inspiration (Fig. 13-2). During quiet ventilation, the volume of air inspired and expired in one breath is the tidal volume, normally 500 to 750 mL. The vital capacity (VC) is perhaps the most commonly measured bedside volume. It is the amount of air that can be moved into or out of the lungs on a single breath, normally about 65 mg/kg. The forced vital capacity (FVC) is the volume of air that can be exhaled forcefully after a maximal inspiration. The volume of air left in the lungs at the end of quiet expiration is the functional residual capacity (FRC), and the amount remaining at the end of maximal expiration is the residual volume (RV). Unlike the other lungs volumes defined earlier, RV and FRC cannot be measured by spirometry. Gas dilution techniques or body plethysmography are needed. RV, but not FRC, depends on expiratory muscle strength in addition to the elastic recoil of the chest wall and airway closure. It is useful to follow lung volumes, especially the FVC, in patients with neuromuscular diseases that may affect respiration because improvement in the FVC may parallel clinical improvement and reflect successful therapy; a falling FVC can warn the clinician of impending respiratory failure.

140

Principles of Ambulatoy Neurology and the Approach to Clinical Problems

:!

----------------

I

!-

1

!+,

Normal

2

3

4 5 Seconds

6

7

8

FIG. 13-3. Representative time-volume curves from a normal patient (bottom curve), a patient with an obstructive pulmonary disorder (top curve), and a patient with restrictive pulmonary disorder (middle curve) are superimposed. FEV,, forced expiratory volume in the first second of expiration; FVC, forced vital capacity. In the obstructive disorder, the F N , is markedly reduced and the FVC is mildly reduced. In the restrictive disorder, the FEV, and FVC are symmetrically reduced.

lime-Volume Curves and Flow-Volume Loops Lung volumes may also be measured against time. For example, the forced expiratory volume in 1 second (FEV,) is the volume of air expired in 1 second after a maximal inspiration. The midmaximal forced expiratory flow (FEF,,-,,) measures the flow during the middle half of the VC (i.e., from 75% to 25% of VC). The FEV, and the FEF2,-,, generally do not depend on respiratory muscle strength. In addition to effort, they depend on the elastic recoil of the lungs and airway resistance and compliance. These measures can be plotted as time-volume curves (Fig. 13-3). A forced expiration can also be plotted as a flow-volume tracing comparing expiratory flow from total lung capacity to RV with inspiratory flow back to total lung capacity. On flow volume tracings, the midpoints of expiration (V,,E) and inspiration (V5,1) can be determined. These points should come at about equal times for both phases of the respiratory cycle, creating a V,,E to V,,I ratio of 1. If there is an alteration in the expiratory or inspiratory phase of respiration, this ratio will readily reflect it. The flow-volume loop is useful in evaluating possible upper airway obstruction, which may be caused by bulbar weakness as well as other extrathoracic or intrathoracic processes. Flowvolume loops from patients with bulbar or upper airway muscle weakness may reveal oscillations in inspiratory or expiratory flow or both. Flow plateaus in either phase of respiration may also be demonstrated (Fig. 13-4).

RestrictiveVersus Obstructive Patterns and Disorders The FEV, to FVC ratio is particularly useful in distinguishing restrictive from obstructive patterns on pulmonary function tests (Table 13-1). These patterns correlate with primary pulmonary

Principles of Diagnosis: Common Presenting Symptoms

obstructive and restrictive diseases, but restrictive patterns may also point toward other extrapulmonary processes, such as respiratory muscle weakness or kyphoscoliosis. Normal patients usually have an FEV, and FVC that are at least 80% of the predicted values obtained from a normal population, and normal subjects can usually expire 80% of their FVC in 1 second. The FEV, to FVC ratio normally is 0.70 or greater. With restrictive disorders, there is a decrease in both the VC and air flow because of limitations in lung and chest wall expansion, for example, from pulmonary fibrosis, vascular disease, mass lesions compressing the pulmonary space, kyphoscoliosis, or ankylosing spondylitis. Moderate to severe respiratory muscle weakness is another important cause of a restrictive pattern. In restrictive disorders, the FVC and FEV, are symmetrically reduced (Fig. 13-3). With respiratory muscle weakness, the FVC also may be significantly lower in the supine position than in the upright position. In some primary restrictive pulmonary diseases associated with increased lung recoil, the FEV, may actually be elevated. Thus, the FEV, to FVC ratio generally remains greater than 0.70 in all restrictive disorders. In addition, other lung volumes, including total lung capacity, RV, and FRC, are low in most restrictive disorders. Descending to the RV depends on expiratory muscle strength, so that it may be higher in some patients with neuromuscular disease than in the usual restrictive pattern. In obstructive disorders in which air expulsion is impeded, the FEV, is significantly reduced whereas the FVC is preserved or mildly reduced (Fig. 13-3). Therefore, the FEV, to FVC ratio is less than 70%. In addition, obstructive diseases of pulmonary origin, (e.g., chronic bronchitis) usually are associated with a high RV or FRC. Patients with neuromuscular diseases usually do not

1L

II 1 sec

FIG. 13-4. Example of a flow-volume loop from a patient with amyotrophic lateral sclerosis. There are inspiratory flow oscillations and a reduced inspiratory flow volume 011).VE,expiratoryflow volume. (The inner circle represents tidal volume. The inspiratory phase of respiration is depicted below the horizontal meridian, and the expiratory phase is above the horizontal meridian). (Modified from Vincken W, Elleker C, Cosio MC: Detection of upper ainnray muscle involvement in neuromuscular disorders using the flow-volume loop. Chest 90:52-77, 1986, with permission.)

Chapter 13 W TMLE 13-1.

141

Respiratov Dysfunction

Classic Findings on Pulmonary Function Testing in Restrictive and Obstructive Disorders” M E A S U R E S OF

Restrictive pattern Neurornuscular disease Non-neurornuscular disease Obstructive pattern

FWl

vc

DEC DEC-INC DEC

DEC DEC N/DEC

FWi/FVC

>70% >70% ~70%

PUN-

FUrrcnOn

MW

DEC~ N/DEC DEC

FEF2S-7,

DEC DEC DEC

Rv

FRC

INC DEC INC

DEC DEC INC

Abbreviations: DEC, decreased; N, normal; INC, increased; W,, forced expiratory volume in 1 second; VC, vital capacity; WC, forced vital capacity; MW, maximal voluntary ventilarnidrnaxirnal forced expiratory flow; RV, residual volume; FRC, functional residual capacity. tion; FEF,,-,, ’Some variability in these patterns is expected between individuals. bMay be decreased out of proportion to the W , .

manifest this obstructive pattern unless there is an associated pulmonary disease. Assessment of Respiratory Muscle Fdgue

Most lung volumes, including expiratory flows, are not affected by mild losses of respiratory muscle strength. One exception may be the maximal voluntary ventilation (MW), which is measured as the amount of air exchanged during 12 to 15 seconds of maximal effort with the reported value extrapolated to 1 minute. Because the maximum number of breaths one can take in 1 minute is about 35 to 40, the M W is usually about 35 to 40 times as great as the FEV,. Like the FEV,, the M W depends on the effort and pulmonary mechanics, but it is also a measure of endurance and is affected by respiratory muscle power and fatigue. Disorders that cause a decrease in FEV, also affect MW, but a reduction in M W out of proportion to a reduction in FEV, should raise suspicion that a neuromuscular disorder is affecting respiration if the patient has given a full effort. lnsplratory and Expiratory Pressures

When lung volumes are still normal in the early stages of neurogenic respiratory dysfunction, maximum inspiratory and expiratory forces may be reduced. These forces can be measured as pressures at the mouth by a manometer and also depend on effort, lung volume, mouth seal, age, and sex. The maximum expiratory pressure (PE,,) is normally 100 to 200 cm H,O, while the maximum inspiratory pressure (Pimm), also called the negative inspiratory force, usually is -70 cm H,O or more (i.e., more parallels diaphragm negative). In theory, because the PI,, function, it should be the more sensitive indicator of respiratory muscle weakness. In practice, PE,, may be more sensitive. In one study, it was abnormal in 87% of patients with respiratory dysfunction of neuromuscular origin. Many of these tests are best suited to the study of the lower motor neuron limb of the neurologic pathways of respiratory control. Clinical assessment of the upper motor neuron pathway is more difficult. The overall pattern of respiration can be evaluated by observing the rhythmicity of respiration or of the contractions of the diaphragm by EMG. Minute ventilation, the product of the tidal volume and the respiratory rate, also gives a measure of the overall integrity of breathing. The mouth occlusion pressure, the mouth pressure response to random occlusion of the airway during inspiration, is determined by an involuntary reaction and may also be decreased in lesions of central control. Central chemical drive can be assessed by CO, inhalation techniques and by the response to hypoxia. Once the presence of a neurogenic cause of respiratory

dysfunction has been confirmed using the measures of respiratory physiology just outlined, one’s knowledge of general and respiratory neuroanatomy can be directed toward determining the anatomic localization of the lesion. LOCALIZATION AND CAUSES OF NEUROGENIC RESPIRATORY DYSFUNCTION Upper Motor Neuron Disorders Upper motor neuron disorders that affect automatic respiration usually produce central (primary) alveolar hypoventilation. Although these patients exhibit resting hypoxemia and hypercapnia, they can normalize their blood gases with increased respiratory effort because of intact voluntary overdrive mechanisms. They are most vulnerable to hypoxia and hypercapnia when they are asleep, when voluntary mechanisms are inactive, and when the central automatic driving mechanisms are inadequate (Ondine’s curse). Lung volumes and inspiratory and expiratory pressures usually are not reduced. The most common site of a lesion that affects central respiratory control is the medulla oblongata. Usually, other brainstem signs accompany such a lesion. Imaging studies, especially magnetic resonance imaging, may be helpful in identifymg a structural abnormality. Upper cervical spinal cord lesions can also produce this syndrome. The following pathologic processes, discussed later in this book, may cause central alveolar hypoventilation. W W W W W

W

Tumor Encephalitis and polio Infarction or hemorrhage Trauma C 1 4 2 subluxation Demyelination Chiari malformations Degenerative diseases (e.g., Leigh’s disease) Association with Hirschsprung’s disease Drugs Idiopathic

A unique association occurs with Hirschsprung’s disease. In these rare patients, the combination of congenital brainstem and neural intestinal lesions raises the possibility that a developmental abnormality in serotonergic neurons in both the intestine and brainstem may lead to gut atonia and Ondine’s curse. In addition to structural lesions, drugs such as sedatives and narcotics can impair central respiratory control, especially in patients with underlying central nervous system or pulmonary disorders. Many brainstem lesions that cause coma can lead to central neurogenic hyperventilation (midbrain), apneustic (pontine), or

Principles of Ambulatoy Neurology and the Approach to Clinical Problems

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ataxic (medullary) breathing. This subject has been reviewed by Plum and Posner (1982). More subtle dysfunction of the central sleep generator can cause central sleep apnea. High cervical spinal cord lesions (C4 and above), usually traumatic, produce a variety of respiratory abnormalities, from Ondine’s curse to persistent apnea, as a result of bilateral hemidiaphragm paralysis. Lower cervical and thoracic lesions may affectupper airway, paraspinal, intercostal, and abdominal muscle innervation and lead to decreased expiratory and inspiratory pressures and a restriction in lung and chest wall expansion. Hypoventilation and atelectasis may then become chronic problems. Pathologic processes above the brainstem may also affect respiration in more subtle fashion, but their mechanisms and clinical significance are not clear. The cerebral cortex, for example, innervates the contralateral hemidiaphragm. Thus, a cortical lesion, such as a stroke, may weaken the diaphragm, but such unilateral lesions do not appear to produce respiratory dysfunction. Cerebellar atrophy occasionally has been associated with a disordered rhythm of breathing. Disorders of the basal ganglia, especially Parkinson’s disease, may cause dyspnea. Respiratory muscle rigidity with associated shallow breathing, impaired laryngeal and respiratory muscle coordination, and airway obstruction are proposed causes. Other movement disorders, such as tardive dyskinesia, may occasionally interfere with the rhythm of respiration. Lower Motor Neuron Disorders

Lower motor neuron disorders (Table 13-2) account for the majority of neurologic diseases that affect respiration and ultimately result in alveolar hypoventilation. These disorders may cause diaphragmatic dysfunction and present with dyspnea, especially on exertion and when supine. Other signs of lower motor neuron disease, including limb and sometimes extraocular and oropharyngeal (bulbar) muscle weakness, often accompany the respiratory dysfunction. The degree of limb and bulbar weakness does not correlate well with the degree of respiratory muscle weakness. However, in some neuromuscular diseases, significant proximal limb weakness is more likely to accompany respiratory muscle weakness than is isolated distal limb weakness. Serious underlying diaphragm weakness is asymptomatic in many H TABU13-2. Peripheral Nervous System Disorders Associated

with Respiratory Dysfunction Anatomic Localization

Anterior horn cell

Disease

Amyotrophic lateral sclerosis Polio or postpolio syndrome Tetanusa Peripheral netve Cuillain-Barre syndrome Charcot-Marie-Tooth disease Critical illness polyneuropathy Neuromuscular junction Myasthenia gravis Botulism Lambert-Eaton myasthenic syndrome Muscle Dystrophies Inflammatory myopathies Acid maltase deficiency Mitochondria1rnyopathies Toxic myopathies Critical illness myopathy Hypokalernia and rhabdornyolysis HvDoDhosDhatemia ‘Predominantly affects spinal cord interneurons.

Principles of Diagnosis:Common Presenting Symptoms

patients predisposed by their underlying disease to have eventual respiratory decompensation; therefore, the physician should routinely assess the respiratory function in any patient presenting with one of the disorders in Table 13-2. CLINICAL AND LABORATORY ASSESSMENT IN PATIENTS WITH LOWER MOTOR NEURON RESPIRATORY DYSFUNCTION

When respiratory muscle weakness of lower motor neuron origin is identified, the physician should try to determine the precise anatomic localization (i-e.,anterior horn cell, motor root, peripheral nerve, neuromuscular junction, or muscle) and the cause of the neurologic lesion. The detailed neurologic history and examination help to localize the process unless it is isolated to respiratory muscles, a rare occurrence. A pertinent laboratory screen should then be undertaken. In addition to routine serologic studies, measurements of the level of serum creatine kinase and antibody titers to the acetylcholine receptor may be especially useful in suspected muscle diseases and myasthenia gravis. In the latter case, an edrophonium test may also be helpful (see Chapter 103). EMG helps to identify the level of the motor unit affected in patients with respiratory muscle weakness. In addition to routine nerve conduction studies and needle examination of the limbs and paraspinal muscles, repetitive nerve stimulation is done to assess the function of the neuromuscular junction. If myasthenia gravis is highly suspected and repetitive stimulation of a distal and proximal nerve is normal, single-fiber EMG, although nonspecific, increases the sensitivity of diagnosis of a generalized neuromuscular junction disorder to nearly 100% if two muscles are studied. Unfortunately, some patients are unable to cooperate with this demanding examination (see Chapter 103). Electrophysiologic evaluation of the phrenic nerves is now being performed more commonly in many centers and may be useful for anatomic localization of the lesion causing respiratory dysfunction, especially with lesions producing axonal loss. The phrenic nerves can be stimulated percutaneously at the posterior border of the sternocleidomastoidmuscles. Magnetic stimulation of the phrenic nerves is also being performed in some centers. EMG of the diaphragm can also be performed with minimal risk of pneumothorax. One technique has been reviewed by Bolton (1993). Evidence of denervation may be seen with anterior horn cell diseases, upper cervical root degeneration, or other lesions of the phrenic nerves producing axonal loss. Myotonic discharges may be recorded from the diaphragm and suggest a myotonic disorder, but typical motor unit potential changes of myopathy are difficult to separate from normal diaphragmatic motor unit potentials. Therefore, the EMG of the diaphragm does not specifically identify myopathy. Repetitive stimulation of the phrenic nerve for evaluation of neuromuscular junction transmission is technically difficult, but it may be useful in identifymg a neuromuscular junction defect as a cause of neurogenic respiratory failure. SPECIFIC LOWER MOTOR NEURON DISEASES Anterior Horn Cell Diseases

Amyotrophic lateral sclerosis is the most common disorder of the anterior horn cells (and upper motor neurons) that affects respiration, and it does so often. Such patients often have bulbar and limb weakness and fasciculations in addition to upper motor neuron signs. In the early stages of their illness, however, rare

Chapter 13

patients may have only subtle limb weakness or fasciculations, and exertional dyspnea or hypoventilation may be the presenting manifestation of their disease. Preferential phrenic nerveassociated motor neuron loss may cause such a presentation. Treatment is mainly supportive, and it may include riluzole. Long-term management of respiratory failure is based on ethical and medical factors. Some patients do well with intermittent noninvasive positive airway pressure ventilation via the nasal or oral route, and some benefit from continuous home mechanical ventilation via tracheostomy. (Amyotrophic lateral sclerosis is discussed in Chapter 86.)

Poliomyelitis Poliomyelitis, now rare in developed countries, was once a common cause of respiratory failure. Lower brainstem or cervical segment involvement leads to respiratory paralysis. Cerebrospinal fluid pleocytosis and an associated viral syndrome are important diagnostic clues. Rarely, patients with a remote history of polio develop hypoventilation as a component of the postpolio syndrome, especially if the VC falls below 50% of the predicted value. These patients usually have residual respiratory weakness caused by their initial bout with poliomyelitis. (Poliomyelitisis discussed in Chapter 69. Postpolio syndrome is discussed in Chapter 88.)

Tetanus Tetanus affects spinal cord inhibitory interneurons rather than anterior horn cells and may cause respiratory dysfunction by impairing diaphragm relaxation. Recognition of a recent wound and associated clinical features, such as muscle rigidity, are helpful in making the diagnosis. (Tetanus is discussed in Chapter 56.)

Peripheral Neuropathies Guillain-Barrk syndrome, an acute inflammatory demyelinating polyneuropathy, is the most common cause of acute neurogenic respiratory failure. Approximately 20% to 33% of patients with Guillain-Barrk syndrome need ventilatory assistance. Respiratory failure, if it occurs, usually does so in the first 2 weeks of the illness. Patients with respiratory failure also tend to have the greatest generalized weakness, but again, there is no reliable correlation between limb and respiratory muscle weakness. Fortunately, most recover with good supportive care, and plasma exchange and intravenous immunoglobulin shorten the duration of mechanical ventilation. (Guillain-Bard syndrome is discussed in Chapter 92.) Rarely, porphyria, vasculitis, heavy metals such as arsenic, paralytic shellfish poisons, and other toxins, including organophosphates, produce a neuropathic syndrome associated with respiratory failure. Intensive care unit patients may also develop phrenic nerve axonal loss and polyneuropathy in association with sepsis and multiorgan failure, called critical illness polyneuropathy. Some patients with the demyelinating form of Charcot-MarieTooth disease (hereditary motor and sensory neuropathy type I) may develop mild respiratory dysfunction, although this clinical observation has not been made frequently. These patients with Charcot-Marie-Tooth disease and those without respiratory symptoms have normal lung volumes but may have low inspiratory and expiratory pressures. Unilateral phrenic nerve injury or compression usually does not cause respiratory failure unless it is associated with a

Respiratory Dysfunction

143

pulmonary disorder or another cause of respiratory muscle weakness. Bilateral phrenic nerve injury, which may rarely occur intraoperatively, does cause respiratory failure.

NeuromuscularJunction Disorders Approximately 30% of patients with myasthenia gravis have respiratory muscle weakness, and 10% to 15% may develop respiratory failure as a major component of myasthenic crisis. Most of these patients have already been diagnosed with myasthenia gravis, but some present with respiratory distress as their initial complaint, often after a precipitating illness or after administration of drugs, such as neuromuscular junction blocking agents. An acetylcholinesteraseinhibitor overdose can also cause respiratory muscle weakness. (Myasthenia gravis is discussed in Chapter 103.) Botulism, a presynaptic neuromuscular junction disorder in which acetylcholine release is blocked by an ingested neurotoxin, may cause respiratory failure along with gastrointestinal symptoms, pupillary paralysis, and extraocular and bulbar weakness. (Botulism is discussed in Chapter 105.) Respiratory dysfunction occurs in about 6% of patients with another rare presynaptic disorder, Lambert-Eaton myasthenic syndrome. The respiratory dysfunction may develop spontaneously, or it may be precipitated by anesthesia. The diagnosis often is confused with myasthenia gravis, but the presence of lowamplitude motor responses that markedly increase in amplitude after a brief period of exercise should help to distinguish Lambert-Eaton myasthenic syndrome from myasthenia gravis. (Lambert-Eaton myasthenic syndrome is discussed in Chapter 104.) Tick paralysis is caused by the bite and persistent attachment of a tick, most commonly Derrnacentor andersoni, usually along the hairline of a child. It may cause respiratory and limb paralysis as a result of neuromuscular junction blockade. Complete removal of the tick cures this illness. Some snake, spider, and scorpion toxins also cause respiratory muscle paralysis. Drugs, such as magnesium in antacids, aminoglycosides, lithium, and acetylcholinesterase inhibitors may potentiate or cause defects in neuromuscular transmission. Myopathic Disorders Long-standing severe dystrophies, especially Duchenne’s muscular dystrophy, produce respiratory muscle weakness that causes a restrictive disorder, atelectasis, and hypoventilation. Superimposed scoliosis in many patients exacerbates the restrictive limitation. Thus, surgery for scoliosis often is performed early after boys with Duchenne’s muscular dystrophy become wheelchairbound and before pulmonary function deteriorates further. (Muscular dystrophies are discussed in Chapter 107.) Rare patients with myotonic dystrophy develop alveolar hypoventilation with a restrictive spirometric pattern, probably as a result of respiratory muscle weakness. Myotonic discharges may be identified by EMG of the diaphragm. Some patients with myotonic dystrophy may also develop hypersomnolence of central origin. (Myotonic dystrophy is discussed in Chapters 107 and 112.) Acid maltase deficiency is a rare glycogen storage disease that occurs in infantile, childhood, and adult forms. In the adult form, up to one third of the patients present with respiratory failure. Most patients also have proximal weakness, an elevation in creatine kinase levels, and increased insertional activity with

144

Principles of Ambulatory Neurologyand the Approach to Clinical Problems

Principles of Diagnosis: Common Presenting Symptoms ~

~~

complex repetitive discharges and even myotonic discharges in affected muscles, especially the paraspinals. Muscle pathology and biochemical studies reveal a vacuolar myopathy with low or absent acid maltase activity. (Acid maltase deficiency is discussed in Chapter 110.) Rarely patients with mitochondrial and severe congenital myopathies also develop respiratory failure. Acquired myopathies, especially the inflammatory disorders polymyositis and dermatomyositis, often are associated with respiratory muscle weakness of varying degrees, as identified by pulmonary function studies. Overt respiratory failure is less common. Respiratory muscle weakness may be the presenting feature in up to 4% of patients with polymyositis. (Inflammatory myopathies are discussed in Chapter 108.) Myopathies caused by toxins, such as alcohol, may also involve respiratory muscles. In particular, the combination of high-dose intravenous corticosteroids and neuromuscular blocking agents administered to some critically ill patients, especially those in status asthmaticus and after organ transplantation, can cause a myopathy (critical illness myopathy) that often affects respiratory muscles. Reversible loss of myosin thick filaments and muscle membrane inexcitability seem to cause the weakness in these patients. Hypophosphatemia can cause rapidly reversible respiratory weakness, probably on the basis of muscle dysfunction, but the anatomic localization of the abnormality is uncertain. Severe hypokalemia with or without rhabdomyolysis can cause limb and respiratory muscle weakness. Other electrolyte disturbances, such as hyponatremia, hyperkalemia, hypercalcemia, and hypermagnesemia, may also result in generalizedweakness without preferential diaphragm involvement.

MANAGEMENT OF NEUROGENIC RESPIRATORY DYSFUNCIION Treatments for the specific disorders mentioned in this chapter are discussed in later chapters that address these diseases. Here are some general guidelines for managing neurogenic respiratory failure. To handle this problem expertly, it is often helpful to enlist the assistance of colleagues in critical care and pulmonary medicine. Acute Management

This subject has been recently reviewed by Wijdicks and Bore1 (1998). As with all causes of respiratory distress, assessing airway, respiration, and vital signs is the first step. Patients must be individually evaluated regarding the need for acute intervention (e.g., hospitalization, intensive care unit management, endotracheal intubation) based on the clinician’s judgment and laboratory assessment. Evidence of intercurrent illnesses, especially pulmonary infections, should be sought. Electrolyte abnormalities and other metabolic disturbances can also worsen respiratory weakness. A chest radiograph, arterial blood gas measurement, and bedside FVC, PE,,,, or PI,, should be obtained on all patients. There is usually a correlation between the clinical state and inspiratory and expiratory pressures. A PE,, of less than 40 cm H,O may be associated with the inability to clear secretions, and a PI,, of less than -20 cm H 2 0 (absolute value) may indicate imminent progression to hypoventilation with hypercapnia. However, facial muscle weakness may lead to spuriously low readings. The inability of a patient to count to 20 in one breath is a useful bedside test suggesting that the VC is less than 18 mL/kg. With

A

Respiratory pathophysiology

Ventilatory management

Normal I

\

65 mUka

Poor cough-secretions accumulate Sigh mechanismcompromisedatelectasis; hypoxemia begins

/ /

/

30mUkg 25 mUkg

10 mUkg

Hypercapnia

/

\

Chest physical therapy Incentive spirometry to minimize ongoing atelectasis

lntubate electively for positive pressure ventilation; several high-volume breaths per minute

Sigh lost-atelectasis and shunting

Hypoventilation

\ \

5 mVkg

\

Positive pressure ventilation to aid Cop exchange and prevent fatigue (IMV) Full ventilation

\

FIG. 13-5. Relationship between vital capacity, pathophysiology of lung function, and suggested therapy in respiratoly failure. (From Ropper AH: Neurological and Neurosurgical Intensive Care. 3rd Ed. Raven Press, New York, 1993, with permission.)

Chapter 14 W Autonomic Dysfunction

progression of diaphragm weakness to the point that the VC is less than 15 mL/kg, respiratory failure with hypoxemia and hypercapnia often occurs and may culminate in stupor and coma if untreated. With such a decline in the VC, paradoxic respirations may develop such that the abdomen moves inward instead of outward as the rib cage expands. If intercostal (expiratory) muscle weakness is also present, the rib cage may move inward instead of outward as the abdomen expands. Based on the VC and associated respiratory pathophysiology, Ropper (1993) has devised an approach to respiratory management that applies to all patients with neurogenic respiratory dysfunction (Fig. 13-5). In general, tracheal intubation is undertaken when mechanical ventilation is needed or when airway protection is desired to prevent aspiration. In patients with worsening neuromuscular respiratory muscle weakness, tracheal intubation usually should be performed before significant hypercapnia occurs. In addition, use of paralytic agents should be minimized. If anesthetics are used in patients with certain myopathies, such as myotonic dystrophy, one should be vigilant for the possible development of malignant hyperthermia. Chronic Management

Patients with chronic neurologic disorders that cause respiratory muscle weakness need good pulmonary toilet with postural drainage and chest physiotherapy. They may benefit from incentive inspiratory spirometry. Preventive care is also paramount. If they are bed-bound, patients should be turned frequently and have pressure points padded, and they should receive prophylaxis for venous thrombosis. Good nutrition and mobilization with physical and occupational therapy are important. Patients should receive influenza and pneumococcal vaccinations. Underlying pulmonary and neurologic diseases and intercurrent illnesses should be treated aggressively. Alveolar hypoventilation may be treated with supplemental oxygen, but positive-pressure mechanical ventilation via tracheostomy may be necessary to prevent hypercapnia. Some patients may need only intermittent ventilation. In lieu of tracheostomy, these patients who need only intermittent ventilation may benefit from intermittent positive-pressure ventilation delivered by nasal or oral mask, especially at night. This technique allows respiratory muscles to rest and improves ventilatory performance in some patients. Oxygen saturation, hypercapnia, and symptoms of hypoventilation may all improve. These patients may also benefit from negative-pressure (cuirass) ventilation. Finally, in some

14

145

patients with chronic central neurogenic hypoventilation, phrenic nerve pacing may be considered. ACKNOWLEDGMENTS

I appreciate the careful and thoughtful reviews of the manuscript by David Chad (Neurology Department, University of Massachusetts Medical Center) and Ronald Stiller (Pulmonary and Critical Care Medicine, University of Pittsburgh Medical Center).

SUGGESTED READINGS Bach JR, Alba AS: Management of chronic alveolar hypoventilation by nasal ventilation. Chest 97:53-57, 1990 Bolton CF: AAEM minimonograph #40: clinical neurophysiology of the respiratory system. Muscle Nerve 16809-818, 1993 Burki N: Measurements of ventilatory regulation. Clin Chest Med 10215-226, 1989 Demerits M, Beckers J, Rochette F, Bulcke J: Pulmonary function in moderate neuromuscular disease without respiratory complaints. Eur J Respir Dis 63:6247, 1982 Eichacker PQ, Spiro A, Sherman M et al: Respiratory muscle dysfunction in hereditary motor sensory neuropathy, type I. Arch Intern Med 148:1739-1740, 1988 Fostad H, Nilsson S: Intractable singultus: a diagnostic and therapeutic challenge. Br J Neurosurg 7:255-262, 1993 Griggs RC, Donohoe KM, Utell MJ et al: Evaluation of pulmonary function in neuromuscular disease. Arch Neurol 38:9-12, 1981 Haddad GG, Mazza NM, Defendini R et ak Congenital failure of autonomic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore) 57:517-524, 1978 Kelly BJ, Luce JM: The diagnosis and management of neuromuscular diseases causing respiratory failure. Chest 99:1485-1494, 1991 Plum F, Posner J B The Diagnosis of Stupor and Coma. 3rd Ed. FA Davis, Philadelphia, 1982 Pokey MI, LyaU RA, Moxham J, Leigh P N Respiratory aspects of neurological disease. J Neurol Neurosurg Psychiatry 665-15, 1999 Ropper AH: Neurologicaland Neurosurgical Intensive Care. 3rd Ed. Raven Press, New York, 1993 Vincken W, Elleker G, Cosio M G Detection of upper airway muscle involvement in neuromuscular disorders using the flow-volume loop. Chest 90:52-57, 1986 Vincken W, Elleker G, Cosio M G Determinants of respiratory muscle weakness in stable chronic neuromuscular disease. Am J Med 82:53-58, 1987 Wijdicks EFM, Bore1 CO: Respiratory management in acute neurologic illness. Neurology 5O:ll-20, 1998

Autonomic Dvsfunction Roy Freeman

The extensive afferent and efferent connections of the autonomic nervous system provide the anatomic basis for the diverse constellation of symptoms that accompany the autonomic degenerative diseases. This chapter covers the common diseases of the autonomic nervous system, the pathophysiology of dysautonomia, and the treatment of the features of autonomic dysfunction that are most frequently encountered by the practicing neurologist:

orthostatic hypotension, bladder dysfunction, and the disorders of gastrointestinal motility. DISEASES OF THE AUTONOMIC NERVOUS SYSTEM A wide variety of disorders may produce the signs and symptoms of autonomic dysfunction. Careful history taking and physical

Chapter 14 W Autonomic Dysfunction

progression of diaphragm weakness to the point that the VC is less than 15 mL/kg, respiratory failure with hypoxemia and hypercapnia often occurs and may culminate in stupor and coma if untreated. With such a decline in the VC, paradoxic respirations may develop such that the abdomen moves inward instead of outward as the rib cage expands. If intercostal (expiratory) muscle weakness is also present, the rib cage may move inward instead of outward as the abdomen expands. Based on the VC and associated respiratory pathophysiology, Ropper (1993) has devised an approach to respiratory management that applies to all patients with neurogenic respiratory dysfunction (Fig. 13-5). In general, tracheal intubation is undertaken when mechanical ventilation is needed or when airway protection is desired to prevent aspiration. In patients with worsening neuromuscular respiratory muscle weakness, tracheal intubation usually should be performed before significant hypercapnia occurs. In addition, use of paralytic agents should be minimized. If anesthetics are used in patients with certain myopathies, such as myotonic dystrophy, one should be vigilant for the possible development of malignant hyperthermia. Chronic Management

Patients with chronic neurologic disorders that cause respiratory muscle weakness need good pulmonary toilet with postural drainage and chest physiotherapy. They may benefit from incentive inspiratory spirometry. Preventive care is also paramount. If they are bed-bound, patients should be turned frequently and have pressure points padded, and they should receive prophylaxis for venous thrombosis. Good nutrition and mobilization with physical and occupational therapy are important. Patients should receive influenza and pneumococcal vaccinations. Underlying pulmonary and neurologic diseases and intercurrent illnesses should be treated aggressively. Alveolar hypoventilation may be treated with supplemental oxygen, but positive-pressure mechanical ventilation via tracheostomy may be necessary to prevent hypercapnia. Some patients may need only intermittent ventilation. In lieu of tracheostomy, these patients who need only intermittent ventilation may benefit from intermittent positive-pressure ventilation delivered by nasal or oral mask, especially at night. This technique allows respiratory muscles to rest and improves ventilatory performance in some patients. Oxygen saturation, hypercapnia, and symptoms of hypoventilation may all improve. These patients may also benefit from negative-pressure (cuirass) ventilation. Finally, in some

14

145

patients with chronic central neurogenic hypoventilation, phrenic nerve pacing may be considered. ACKNOWLEDGMENTS

I appreciate the careful and thoughtful reviews of the manuscript by David Chad (Neurology Department, University of Massachusetts Medical Center) and Ronald Stiller (Pulmonary and Critical Care Medicine, University of Pittsburgh Medical Center).

SUGGESTED READINGS Bach JR, Alba AS: Management of chronic alveolar hypoventilation by nasal ventilation. Chest 97:53-57, 1990 Bolton CF: AAEM minimonograph #40: clinical neurophysiology of the respiratory system. Muscle Nerve 16809-818, 1993 Burki N: Measurements of ventilatory regulation. Clin Chest Med 10215-226, 1989 Demerits M, Beckers J, Rochette F, Bulcke J: Pulmonary function in moderate neuromuscular disease without respiratory complaints. Eur J Respir Dis 63:6247, 1982 Eichacker PQ, Spiro A, Sherman M et al: Respiratory muscle dysfunction in hereditary motor sensory neuropathy, type I. Arch Intern Med 148:1739-1740, 1988 Fostad H, Nilsson S: Intractable singultus: a diagnostic and therapeutic challenge. Br J Neurosurg 7:255-262, 1993 Griggs RC, Donohoe KM, Utell MJ et al: Evaluation of pulmonary function in neuromuscular disease. Arch Neurol 38:9-12, 1981 Haddad GG, Mazza NM, Defendini R et ak Congenital failure of autonomic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore) 57:517-524, 1978 Kelly BJ, Luce JM: The diagnosis and management of neuromuscular diseases causing respiratory failure. Chest 99:1485-1494, 1991 Plum F, Posner J B The Diagnosis of Stupor and Coma. 3rd Ed. FA Davis, Philadelphia, 1982 Pokey MI, LyaU RA, Moxham J, Leigh P N Respiratory aspects of neurological disease. J Neurol Neurosurg Psychiatry 665-15, 1999 Ropper AH: Neurologicaland Neurosurgical Intensive Care. 3rd Ed. Raven Press, New York, 1993 Vincken W, Elleker G, Cosio M G Detection of upper airway muscle involvement in neuromuscular disorders using the flow-volume loop. Chest 90:52-57, 1986 Vincken W, Elleker G, Cosio M G Determinants of respiratory muscle weakness in stable chronic neuromuscular disease. Am J Med 82:53-58, 1987 Wijdicks EFM, Bore1 CO: Respiratory management in acute neurologic illness. Neurology 5O:ll-20, 1998

Autonomic Dvsfunction Roy Freeman

The extensive afferent and efferent connections of the autonomic nervous system provide the anatomic basis for the diverse constellation of symptoms that accompany the autonomic degenerative diseases. This chapter covers the common diseases of the autonomic nervous system, the pathophysiology of dysautonomia, and the treatment of the features of autonomic dysfunction that are most frequently encountered by the practicing neurologist:

orthostatic hypotension, bladder dysfunction, and the disorders of gastrointestinal motility. DISEASES OF THE AUTONOMIC NERVOUS SYSTEM A wide variety of disorders may produce the signs and symptoms of autonomic dysfunction. Careful history taking and physical

146

Principles of Ambulatory Neurology and the Approach to Clinical Problems

rn TABU 14-1. Autonomic Dysfunction with Central Nervous System Manifestations Multiple-system atrophy with autonomic failure (Shy-Drager syndrome) With cerebellar features (MSA-C, olivopontocerebellar atrophy) With extrapyramidal features (MSA-P, striatonigral degeneration) Parkinson’s disease Brain tumors (brainstem, cerebellum, diencephalon) Wernicke’s disease Multiple cerebral infarcts Syringomyelia and syringobulbia Hydrocephalus Multiple sclerosis Myelopathies Traumatic Inflammatory Pernicious anemia System degenerative Tabes dorsalis Progressive supranuclear palsy Huntington‘s disease Amyotrophic lateral sclerosis

examination with appropriate use of special investigations usually permit an accurate clinical diagnosis of these diseases. A useful practical approach is to classify the disorders associated with autonomic failure into diseases accompanied by predominantly central nervous system features, diseases accompanied by predominantly peripheral nervous system features, and diseases without neurologic features (Tables 14-1, 14-2, and 14-3).

Autonomic Dysfunction With Central Nervous System Features There are numerous disorders with autonomic manifestations and central necvous system signs. Of these diseases, multiple-system atrophy (MSA) with autonomic failure and idiopathic Parkinson’s disease most often produce clinically significant autonomic dysfunction. MSA is a degenerative disorder of the central nervous system that affects extrapyramidal (striatonigral degeneration), cerebellar (olivopontocerebellar atrophy), and autonomic neurons. Patients with MSA typically present with autonomic symptoms such as orthostatic hypotension, bowel and bladder dysfunction, anhidrosis, and impotence, together with motor dysfunction that can involve the extrapyramidal, cerebellar, and pyramidal systems. Impotence in men, urinary incontinence, and orthostatic hypotension are the most common symptoms of MSA. The symptoms of orthostatic hypotension usually lead patients to seek medical attention. In contradistinction to idiopathic Parkinson’s disease, MSA is more likely to have a symmetrical onset and is less responsive to levodopa and dopamine agonists. The resting Parkinsonian tremor is rarely present in MSA, whereas inspiratory stridor, vocal cord paralysis, and antecollis commonly occur. Initial rigidity and early motor fluctuations in response to therapy are also more common in patients with MSA. The median survival of MSA usually is less than 10 years, although exceptions occur. Pathologic studies have demonstrated cell loss and gliosis that include the striatonigral, olivopontocerebellar, and autonomic systems. An argyrophilic, filamentous, intracytoplasmic oligodendroglial inclusion is a specific histopathologic hallmark of MSA. These inclusions are also present in the nuclei of other glial cells and neurons. Several recent reports have indicated that these filamentous inclusions are immunoreactive for a-synuclein, suggesting that MSA and the

Principles of Diagnosis: Common Presenting Symptoms

rn TABLE14-2. Autonomic Dysfunction with Peripheral Nervous System Manifestations Diabetes Amyloidosis Cuillain-Barre syndrome Acute and subacute autonomic neuropathies Chronic inflammatory polyneuropathy Hereditary neuropathies Hereditary sensory and autonomic neuropathies Fabry‘s disease Navajo Indian neuropath Hereditary motor and sensory neuropathy Tangier disease Infectious diseases Chagas’s disease Human immunodeficiencyvirus neuropathy Botulism Diphtheria Leprosy Toxic neuropathies Vacor Vincristine Perhexiline maleate cis-Platinum Taxol Organic solvents Acrylamide Heavy metals Connective tissue diseases Sjogren‘s syndrome Systemic lupus erythematosus Rheumatoid arthritis Pernicious anemia Porphyria Uremia Alcoholic neuropathy Hepatic disease Paraneoplastic neuropathies Lambert-Eaton syndrome Dopamine P-hydroxylase deficiency Adie’s syndrome

rn TABLE14-3. Isolated Autonomic Dysfunction Pure autonomic failure Medications Antihypertensive agents Tricyclic agents Monoamine oxidase inhibitors Dopamine blocking agents Aging Endocrine diseases Adrenocortical deficiency Pheochromocytoma Surgical sympathectomy Mitral valve prolapse Hypovolemia Electrolyte disturbance Hyperbradykinism

Lewy body disorders, Parkinson’s disease, and Lewy body dementia have a common underling neuropathologic characteristic. The autonomic symptoms accompanying Parkinson’s disease usually are not as severe as those seen in patients with MSA. They characteristically occur late in the course of the illness and often are associated with levodopa and dopamine agonist therapy. Nevertheless, autonomic dysfunction often is the source of significant morbidity for the patient with Parkinson’s disease. There are many other disorders with autonomic dysfunction and central nervous system signs, but the autonomic symptoms usually are of secondary importance, and these disorders are unlikely to be confused with MSA or Parkinson’s disease (Table 14-1).

Chapter 14 H Autonomic Dysfunction

Autonomic Dysfunction with Peripheral Nervous System Features

Autonomic dysfunction occurs with most peripheral neuropathies, particularly those that predominantly involve the small or unmyelinated fibers. This review covers those peripheral neuropathies in which autonomic dysfunction is a clinically significant manifestation. A complete list of peripheral neuropathies with autonomic manifestations is found in Table 14-2. Diabetes Mellitus. Diabetes mellitus is the most common cause of autonomic neuropathy in the developed world. A constellation of signs and symptoms of cardiovascular, gastrointestinal, urogenital, thermoregulatory,sudomotor, and pupillomotor dysfunction occur. An increased resting heart rate is often observed in diabetic patients. With progression of the autonomic neuropathy, some patients display a fixed heart rate that responds only minimally to physiologic stimuli. The initial tachycardia is caused by a vagal cardiac neuropathy. The resting tachycardia may be followed by a decrease in heart rate and ultimately a fixed heart rate caused by progressive cardiac sympathetic nervous system dysfunction. Orthostatic hypotension occurs in diabetes as a consequence of efferent sympathetic vasomotor denervation, causing reduced vasoconstriction of the splanchnic and other peripheral vascular beds. There is an increased frequency of sudden death in patients with autonomic neuropathy. Proposed causes for sudden unexplained death in diabetics have included cardiorespiratory arrest caused by cardiac arrhythmias, silent cardiac ischemia, and sleep apnea. Bladder symptoms associated with autonomic neuropathy include hesitancy, poor stream, increased intervals between micturition, and a sense of inadequate bladder emptying. These symptoms may be followed by urinary retention and overflow incontinence. Detrusor muscle sensory abnormalities are the earliest bladder autonomic manifestation. These sensory abnormalities impair bladder sensation and increase the threshold for initiating the micturition reflex. A decrease in detrusor activity (detrusor areflexia) follows that leads to incomplete bladder emptying, an increased postvoid residual volume, decreased peak urinary flow rate, bladder overdistention, and ultimately urinary retention. Impotence is a common symptom in diabetic men. Reported incidence has ranged from 30% to 75% of diabetic men. Impotence may be the earliest symptom of diabetic autonomic neuropathy, although sensory, vascular, and psychogenic causes, alone or in varying combinations, also may be responsible for this symptom. Sympathetically mediated ejaculatory failure may precede the appearance of impotence, although impotence can occur with retained ability to ejaculate and experience orgasm. Autonomic dysfunction occurs throughout the gastrointestinal tract, producing several specific clinical syndromes. Diabetic gastroparesis may manifest as nausea, postprandial vomiting, bloating, belching, loss of appetite, and early satiety. Food residue is retained in the stomach because of impaired gastric peristalsis compounded by lower intestinal dysmotility. Gastroparesis often impairs the establishment of adequate glycemic control. Denervation of the vagus nerve may play a role in this disorder. Constipation is the most commonly reported gastrointestinal autonomic symptom and is found in up to 60% of diabetics. The pathophysiologyof diabetic constipation is poorly understood but may reflect loss of the postprandial gastrocolicreflex. Diarrhea and other lower gastrointestinal tract symptoms may also occur. Diabetic diarrhea is profuse and watery and typically occurs at

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night. The diarrhea can last for hours or days and often alternates with constipation. Fecal incontinence, caused by anal sphincter incompetence or reduced rectal sensation, is another manifestation of diabetic autonomic neuropathy. The pathogenesis of diabetic diarrhea includes abnormalities in gastrointestinal motility, decreased gut transit time, reduced a2-adrenergic receptormediated fluid absorption, bacterial overgrowth, pancreatic insufficiency, coexistent celiac disease, and abnormalities in bile salt metabolism. Diabetic autonomic neuropathy initially results in a loss of thermoregulatory sweating in a stocking-glove distribution that can extend to the upper aspects of the limbs and anterior abdomen, conforming to the well-recognized length dependency of diabetic neuropathy. This process ultimately results in global anhidrosis that usually accompanies a profound generalized autonomic neuropathy. Hyperhidrosis also may accompany diabetic autonomic neuropathy. Excessive sweating may occur as a compensatory phenomenon involving proximal regions such as the head and trunk that are spared in a dying-back neuropathy. Gustatory sweating, an abnormal production of sweating that appears over the face, head, neck, shoulders, and chest after eating even nonspicy foods, is occasionally observed. Amyloid Neuropathy. Autonomic dysfunction often accompanies the polyneuropathy of both primary and familial amyloidosis. Autonomic dysfunction is not common in myelomaassociated amyloidosis. Patients with amyloid neuropathy typically present with distal sensory symptoms such as numbness, paresthesias, and dysesthesias, although the autonomic manifestations occasionally may be the presenting feature of amyloid neuropathy. On examination there are signs of a sensorimotor polyneuropathy that predominantly involves the small fibers that mediate pain and temperature sensation. Characteristic autonomic signs and symptoms include postural hypotension, diarrhea, constipation, fecal incontinence, disturbances in bladder function, pupillary abnormalities, and erectile failure. These autonomic manifestations are similar to those described for diabetic autonomic neuropathy. Sick sinus syndrome and AV conduction deficits often are present. Tests assessing cardiac vagal function often are abnormal. The variant transthyretin, in which methionine substitutes for valine at position 30, is the point mutation that is the most common cause of familial amyloid polyneuropathy in the United States. Other transthyretin mutations and mutations in apolipoprotein A-I and gelsolin also give rise to familial amyloid polyneuropathy. Primary amyloidosis (AL. amyloidosis) is characterized by the deposition of insoluble fibrillar proteins in the extracellular space of various tissues and organs. Peripheral neuropathy, which may be the presenting feature of the disease or an incidental finding, is present in up to 20% of patients with AL. Cardiovascular, gastrointestinal, and urogenital system autonomic dysfunction are common. Proposed mechanisms of injury include pressure exerted by amyloid deposits on peripheral nerves, dorsal nerve root ganglia, or autonomic ganglia and ischemic damage caused by amyloid infiltration of epineural and intraneural blood vessel walls. Acute and Subacute Autonomic Neuropathies. Autonomic manifestations usually accompany the Guillain-Bar& syndrome, although they are usually overshadowed by motor features of that disorder. However, autonomic manifestations may be the sole or predominant feature of an acute or subacute peripheral neuropathy. The hallmark of these autonomic neuropathies is the acute or subacute presentation of varying combinations of orthostatic

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hypotension, constipation, bladder atony, impotence, secretomotor paralysis, and blurring of vision associated with tonic pupils. Sensorimotor manifestations may accompany the autonomic manifestations but are not the predominant aspect of the presentation. The autonomic manifestations of this disorder may involve both the sympathetic and parasympathetic divisions of the autonomic nervous system (pandysautonomia) or the parasympathetic nervous system alone (cholinergic dysautonomia). Only 40% of patients recover fully to premorbid status. For an estimated 12%, symptoms persist to a significant degree. Full or partial recovery, when reported, occurs over the course of months to years. Autonomic testing in the recovery phase of illness in these patients often shows evidence of persisting subclinical autonomic dysfunction. Acute dysautonomia has been described in relation to the Epstein-Barr virus, streptococcal infection, and herpes simplex infection, in addition to other undiagnosed viral syndromes. Associations with malignancies and connective tissue diseases have been described in other cases. Immune-Mediated Autonomic Neuropathies. Autonomic dysfunction has been associated with the presence of specific autoantibodies. The subacute appearance of autonomic symptoms that include orthostatic hypotension, pupillomotor dysfunction, sudomotor dysfunction, constipation, urinary retention, impotence, and xerophthalmia has been associated with the presence of anti-Hu antibodies in patients with malignancies, especially small cell lung cancer. These antibodies also are found in patients with a paraneoplastic sensory neuronopathy and encephalomyelitis. In one large series, the autonomic nervous system was involved in 28% of patients with anti-Hu antibodies and was the predominant symptom in a third of these patients. Dysautonomia may be an isolated manifestation of a paraneoplastic disorder or part of a generalized paraneoplastic syndrome. For example, paraneoplastic constipation and intestinal pseudoobstruction have been associated with small cell carcinoma of the lung. Such patients have inflammatory infiltrates of the myenteric plexus of the stomach and antineuronal antibodies. Autonomic neuropathies have been documented in case reports in association with pancreatic carcinoma, Hodgkin’s disease, and testicular cancer. Dysautonomia is a common manifestation of the LambertEaton syndrome in patients with and without malignancies. Symptoms suggesting cholinergic dysfunction, such as dry mouth, erectile and ejaculatory failure, constipation, blurred vision, and impaired sweating, are most common. Autonomic tests, demonstrating unresponsive pupils that constrict to dilute pilocarpine, reduced sweating, and salivary and lacrimal secretomotor failure suggest that the abnormality is predominantly limited to the parasympathetic nervous system, although mild sympathetic nervous system abnormalities may be present. Autonomic tests have demonstrated both cholinergic and adrenergic abnormalities. Autonomic features associated with the Lambert-Eaton syndrome have been associated with seropositivity for P/Q-type Ca2+ channel antibodies. High levels of autoantibodies specific for nicotinic acetylcholine receptors in the autonomic ganglia also have been found in patients with idiopathic and paraneoplastic autonomic neuropathy. Characteristic clinical features in these patients included a subacute onset, gastrointestinal dysmotility, and abnormal pupillary responses to light and accommodation. A positive correlation between high levels of ganglionic receptor antibodies and the severity of autonomic dysfunction exists, suggesting that the antibodies may have a pathogenic role in these autonomic neuropathies.

Principles of Diagnosis: Common Presenting Symptoms

Hereditary Autonomic Neuropathies. The hereditary autonomic neuropathies are a heterogeneous group of disorders, some of which cause significant involvement of autonomic fibers. A list is provided in Table 14-2. The hereditary sensory and autonomic neuropathies (HSAN) are characterized by prominent sensory loss without motor involvement and by often striking dysautonomia. The autonomic manifestations are modest in autosomal dominant sensory neuropathy (HSAN type I) and autosomal recessive sensory neuropathy (HSAN type 11), with the possible exception of bladder dysfunction. These disorders are associated with severe sensory loss with acral injuries. Autonomic manifestations are prominent in HSAN type 111, or Riley-Day syndrome (familial dysautonomia, FD) . This autosomal recessive disorder is seen primarily in Ashkenazi Jewish children. The incidence of FD is 1 in 3700 live births among Ashkenazi Jews, and the carrier frequency is 1 in 32. The defective gene causing familial dysautonomia has been mapped to the long arm of chromosome 9 (9q31). The majority (99.5%) of patients with FD have a single noncoding mutation in the gene IKBKAE! The clinical features of this disease include insensitivity to pain and temperature but sparing visceral pain, absence of tears, hypoactive corneal and tendon reflexes, and absence of fungiform papillae. Poor suck and feeding, esophageal reflux with vomiting and aspiration, and a dyscoordinated swallow may be the first clinical manifestations. Later in the course of the illness, vibratory sensory loss and impaired appendicular coordination manifest. Autonomic disturbances may be prominent at any point in the disease course. Autonomic manifestations include episodic hyperhidrosis, vasomotor instability with defective temperature homeostasis, postural hypotension, hypertensive crises, and supersensitivity to cholinergic and adrenergic agents. Orthostatic hypotension often is present. Congenital insensitivity to pain with anhidrosis (anhidrotic sensory neuropathy) is a disorder with autosomal recessive inheritance (HSAN type IV). It manifests in the first months of life with insensitivity to pain, anhidrosis, episodes of unexplained fever, and retardation of motor development. Virtual absence of unmyelinated fibers has been noted in peripheral nerves. Deletion, splice, and missense mutations have been documented in the tyrosine kinase domain of the TRK A/NGF receptor gene in patients with this disorder. Fabry’s disease, or angiokeratoma corporis diffusum, is an X-linked, recessively inherited disorder that is associated with deficiency of the enzyme a-galactosidase A (ceramide trihexosidase). The enzyme deficiency results in the accumulation of ceramide trihexoside and other neutral glycosphingolipids in homozygotes. There is extensive lipid deposition in various tissues that include the skin, nervous system, vascular endothelium, kidney, cardiovascular system, and eye. The neurologic manifestations of this disorder are secondary to the deposition of glycolipid in autonomic and dorsal root ganglia, in perineurial cells, and in unmyelinated and myelinated axons. Young males with this disorder typically present with severe distal extremity paroxysmal pains and tenderness, a truncal reddish-purple macular papular rash, and angiectases of the skin, conjunctiva, nail bed, and oral mucosa. The autonomic manifestations include hypohidrosis or anhidrosis, reduced saliva and tear formation, impaired cutaneous flare response to scratch and histamine, and disordered intestinal motility. Patients’ gastrointestinal symptoms may be as severe as their sensory complaints. Pupillary constriction to dilute pilocarpine has been documented, suggesting denervation supersensitivity, although cardiovascular autonomic reflexes in one series were

Chapter 14

normal. The generalized presentation of the anhidrosis has suggested sweat gland dysfunction that may be caused by intracytoplasmic inclusions in the eccrine glands rather than autonomic neuropathy as a mechanism for the anhidrosis. Neuropathologic studies have demonstrated degeneration and loss of unmyelinated fibers. Fabry’s disease can be diagnosed by assaying the enzyme a-galactosidase A in leukocytes or skin fibroblasts. Infectious Diseases. The peripheral neuropathies associated with a number of infectious diseases have accompanying autonomic manifestations. Autonomic dysfunction may occur in patients with human immunodeficiency virus infection. The symptoms of dysautonomia have included orthostatic hypotension, syncope, presyncope, sweating disturbances, bladder and bowel dysfunction, and impotence. There is an increasing incidence of Chagas’s disease in the United States, and the autonomic manifestations of this disease should be considered in the differential diagnosis of dysautonomia. Chagas’s disease, which is caused by a parasitic infection by TTypanosoma auzi, is associated in the late stages of illness with severe cardiovascular and gastrointestinal dysautonomia. The pathogenesis of the autonomic dysfunction is unresolved and may be caused by direct neural injury during the acute illness or a persisting immune-mediated response. Reduced bowel motility, sialorrhea, megaesophagus, and megacolon are the most common gastrointestinal manifestations of this disease. Cardiovascular manifestations include impairment in the blood pressure response to standing, resting bradycardia, anhidrosis, conduction abnormalities, arrhythmias, cardiac failure, and cardiomegaly. Isolated Autonomic Nervous System Dysfunction Pure autonomic failure (PAF) is an idiopathic peripheral autonomic nervous system degeneration that, in contrast to ShyDrager syndrome, has no motor manifestations. There are also no signs or minimal signs of a somatic peripheral neuropathy. Because this disorder is slowly progressive and has a significantly better prognosis than Shy-Drager syndrome, it is important to differentiate between these two disorders. The autonomic features of Shy-Drager syndrome may precede the other neurologic signs by several years, preventing an early definitive diagnosis. Patients with PAF typically have a low resting plasma norepinephrine level caused by degeneration or dysfunction of the postganglionic sympathetic neuron. The plasma norepinephrine level, which in normal subjects increases by 100% to 200% when moving from the supine to the upright position, does not change significantlyin patients with PAF. However, there is a wide scatter of results within the group of patients with PAF that often makes it difficult to classify individual patients. Cardiovascular autonomic tests show impairment with a severity that is equivalent to that seen in patients with MSA. Lewy bodies have been observed in distal axons. Accumulation of a-synuclein in affected neurons has been documented in cases of pure autonomic failure. Other conditions with isolated autonomic manifestations are listed in Table 14-3.

SIGNS, SYMPTOMS, AND TREATMENT OF AUTONOMIC FAILURE Orthostatic Hypotension The assumption of the upright posture results in a complex sequence of physiologic reactions in response to the pooling of approximately 500 cc of blood in the lower extremities and splanchnic circulation. There is a decrease in venous return to the

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heart, and the reduced ventricular filling results in diminished cardiac output and blood pressure. These hemodynamic changes provoke a baroreceptor-initiated compensatory reflex mediated via the central nervous system and effected by the peripheral efferent autonomic outflow. These compensatory mechanisms increase peripheral resistance, venous return, and cardiac output and thus limit the fall in blood pressure. The normal response to the assumption of the erect posture is a fall in systolic blood pressure (5 to 10 mm Hg), an increase in diastolic blood pressure (5 to 10 mm Hg), and an increase in the pulse rate (10 to 25 beats per minute). Should these mechanisms fail, the symptoms of cerebral hypoperfusion ensue. The hallmark of neurogenic orthostatic hypotension from both central and peripheral causes is the failure to release norepinephrine appropriately upon standing. Normally norepinephrine is released into the synaptic cleft in response to standing, resulting in a twofold to threefold increase in plasma norepinephrine. Treatment of Orthostatic Hypotension. Patient education is the cornerstone of the management of orthostatic hypotension. Patients with orthostatic hypotension should move from a supine to standing position in gradual stages, particularly in the morning, when orthostatic tolerance is lowest. Maneuvers such as straining, coughing, and raising the arms above the head should be avoided. The removal of potential reversible causes of orthostatic hypotension is the first and most important management step. Medications such as diuretics, antihypertensive agents, antianginal agents, and antidepressants are the most common offending agents. The excessive natriuresis and reduction in central blood volume can be attenuated or minimized by increasing sodium intake with high-sodium foods or salt tablets. Raising the head of the bed 10 to 20 degrees activates the renin-angiotensin-aldosterone system and decreases the nocturnal diuresis. Raising the head of the bed TAM 14-4. Pharmacologic Agents Used to Treat Orthostatic Hypotension Mineralocorticoids 9-a-fludrocortisone Syrnpathomimetic agents Ephedrine Pseudoephedrine Phenylephrine Methylphenidate Dextroamphetamine Tyramine (with monamine oxidase inhibition) Midodrine Clonidine Yohimbine DL- and 1-dihydroxyphenylserine Nonspecific pressor agents Ergot derivatives Caffeine Somatostatin analogues p-Adrenergic blocking agents Propranolol Pindolol Xamoterol Prenalterol Prostaglandin synthetase inhibitors lndomethacin flurbiprofen Ibuprofen Naproxen Dopamine blocking agents Metoclopramide Domperidone V1 and V2 receptor agonists Desmopressin acetate Lysine-vasopressin ErvthroDoietin

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may also reduce the supine hypertension that is prevalent in these patients, either as a consequence of baroreceptor denervation or as a side effect of treatment. Severe supine hypertension often limits therapeutic intervention, although surprisingly, most patients tolerate sustained supine blood pressures without untoward effect. The use of custom-fitted elastic stockings permits the application of a graded pressure to the lower extremity and abdomen. These stockings minimize peripheral blood pooling in the lower extremities and splanchnic circulation. Unfortunately, nonpharmacologic measures help only the mildly afflicted, and pharmacologic intervention usually is needed. Numerous agents from diverse pharmacologic groups have been implemented in treating orthostatic hypotension (Table 14-4). The therapeutic goal is merely to ameliorate all symptoms while minimizing side effects. There is rarely the need to restore normotension. The most effective pharmacologic measures include mineralocorticoids, direct and indirect sympathomimetic agents, other pressors, prostaglandin synthesis inhibitors, and recently reported erythropoietin. 9-a-Fluorohydrocortisone (fludrocortisone acetate), a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension. This agent has a long duration of action and may be taken once or twice daily. Fludrocortisone increases the blood volume and may enhance the sensitivity of blood vessels to circulating catecholamines. Treatment is initiated with a 0.1-mg tablet and can be increased to 1 mg daily, although little benefit is obtained by increasing beyond 0.5 mg. Unfortunately, treatment may be limited by supine hypertension caused by an increase in the peripheral vascular resistance. Other side effects include ankle edema, hypokalemia, and rarely congestive heart failure. Potassium supplementation usually is needed, particularly when higher dosages are used. Direct and indirect sympathomimetic agents have a long history of use in treating orthostatic hypotension. Commonly used a,-adrenoreceptor agonists include those with direct and indirect effects (ephedrine and pseudoephedrine), those with direct effects (midodrine), and those with only indirect effects (methylphenidate and dextroamphetamine sulphate). These agents, with the exception of midodrine, cross the blood-brain barrier, and central sympathomimetic side effects such as anxiety, tremulousness, tachycardia, and supine hypertension may occur. The peripheral a-agonist midodrine, which has received U.S. Food and Drug Administration approval for treating orthostatic hypotension, does not cross the blood-brain barrier, thereby avoiding the central sympathomimetic side effects. Potential side effects of this agent include pilomotor reactions and pruritus. Most patients respond to the interventions described earlier. A more complete list of medications used to treat orthostatic hypotension is presented in Table 14-4. Autonomic Dysfunction of the Urinary Bladder

The bladder wall is composed of three layers of interdigitating smooth muscle and serves as a receptacle for the storage and appropriate evacuation of urine. This smooth muscle (the detrusor muscle) forms the internal sphincter at the junction of the bladder neck and urethra. The bladder has parasympathetic, sympathetic, and somatic innervation. The parasympathetic nerves originate in the intermediolateral column of the second, third, and fourth sacral segments of the spinal cord and provide the major excitatory input to the urinary bladder. Activation of these muscarinic, cholinergic, postganglionic nerves produces detrusor muscle contraction.

TABLE 14-5. Classification of Bladder Dysfunction Detrusor hyperreflexia (or normoreflexia) Coordinated sphincters Striated sphincter dyssynergia Smooth muscle sphincter dyssynergia Nonrelaxing smooth muscle sphincter Detrusor areflexia Coordinated sphincter Nonrelaxing striated sphincter Denervated striated sphincter Nonrelaxingsmooth muscle sphincter

The sympathetic nerve supply to the bladder originates in the intermediolateral column of spinal segments T10-L2 and passes through the sympathetic ganglia to reach the hypogastric plexus via the splanchnic nerves. Postganglionic sympathetic neurons then innervate the dome of the bladder, producing inhibition via the P-adrenergic receptors of the detrusor muscle and excitation at the a-adrenergic receptors of the internal sphincter, bladder base, and urethra via the hypogastric nerves. The striated muscle of the external urethral sphincter is innervated by the pudendal nerves, which originate from the lateral anterior horn cells of the second, third, and fourth sacral segments, a region known as the sphincter motor nucleus or Onuf's nucleus. This sphincter is under voluntary control but undergoes reflex relaxation during micturition. Afferent fibers mediating bladder sensation and reflex bladder contraction are carried by sympathetic, parasympathetic, and somatic nerves to the spinal cord. The Treatment of Bladder Dysfunction. The innervation of the bladder provides the basis for understanding bladder autonomic dysfunction. There are several different schemas classifying voiding dysfunction. The classification of Krane and Siroky (1992; Table 14-5) incorporates a functional description of detrusor muscle and sphincter function and provides a logical basis for instituting therapy. Therapies directed at reducing bladder hyperreflexia and maintaining urinary continence may alternately decrease bladder contractility or increase bladder outlet resistance or use other means to bypass vesicular or sphincteric abnormalities. Therapies for bladder hypomotility, conversely, attempt to increase bladder contractility, decrease outlet resistance, or both. The nonpharmacologic interventions that include toileting regimens, Credk maneuver, intermittent catheterization, indwelling Foley catheterization, palliative or definitive surgical interventions, and biofeedback often are used in concert with medications. The patient's customized therapy is best pursued with the aid of urologic consultation. Individualized treatment regimens should be guided by the history, examination, urodynamic studies, and measurement of the postvoid residual volume. PHARMACOTHERAFY FOR BLADDER HYPERREFLEXIA. The pharmacotherapy for urinary incontinence caused by detrusor hyperreflexia attempts to decrease bladder contractility or increase outlet resistance. Atropine and associated antimuscarinic substances depress involuntary bladder contractions. The antimuscarinic agents oxybutynin (5 mg two to four times daily) and tolterodine (2 mg two times daily) are the agents most commonly used to treat bladder hyperreflexia. The antimuscarinic effects of tolterodine may be more specific to the bladder, and the anticholinergic side effects of this medication, particularly dry mouth, are reported to be less common than with oxybutynin. Extended-release formulations of these medications are available (oxybutynin 5 to 30 mg daily and tolterodine 4 mg daily). The medications that decrease bladder contractility may be used in conjunction with therapy increasing bladder outlet

Chapter 14

resistance. The bladder neck and proximal urethra are richly populated by a-adrenergic receptors, which, when stimulated, result in smooth muscle contraction. a-Adrenergic agonists are the principal agents used to increase bladder outlet resistance; ephedrine (25 to 50 mg four times per day), pseudoephedrine (30 to 60 mg four times per day), and others have been studied. Sympathomimetic side effects such as elevated blood pressure, anxiety, and insomnia may limit the dosage, and tachyphylaxis may develop. Sphincter characteristics during urodynamic studies may be helpful in guiding the use of these agents. Additional therapies are listed in Table 14-6. RIARMACOTHERAPY FOR BLADDER Hmmonm. Stimulation of muscarinic, postganglionic receptors results in enhanced bladder contractility. Bethanechol chloride is a parasympathomimetic drug with selective action at the urinary bladder. It is effective in chronic states of detrusor atony or hypotonicity, although it has also been used to facilitate reflex bladder contraction in patients with suprasacral cord injury. Typical oral dosages range from 25 to 100 mg four times daily. The cholinergic agonist carbachol chloride, which may have additional ganglion-stimulatingproperties, also may enhance bladder motility. These agents are of limited therapeutic benefit, and when the postvoiding residual volume is greater than 100 cc, clean intermittent self-catheterization should be considered. Autonomic Dysfunction of the GastrointestinalTrad

The autonomic control of the gastrointestinaltract is mediated by the extrinsic parasympathetic and sympathetic nervous systems and the intrinsic enteric nervous system. The parasympathetic input to the gut originates from the vagus and pelvic nerves from the second through fourth sacral segments. The postsynaptic cholinergic neurons provide excitatory input to the gastrointestinal tract. The sympathetic nervous system provides inhibitory input to the gastrointestinal tract. Extrinsic sympathetic efferents W

TABLE 14-6. Therapy of Bladder Hypermotility

Behavioral therapy Timed bladder emptying Biofeedback Catheterization and collecting devices Clean intermittent self-catheterization Urine collection devices Condom catheters indwelling catheters Incontinence briefs and pads Pharmacotherapy to inhibit bladder contractility Anticholinergic agents Smooth muscle relaxants Polysynaptic inhibitors Calcium channel antagonists P-Adrenergic agonists a-Adrenergic antagonists Prostaglandin synthetase inhibitors Tricyclic antidepressants Dimethyl sulfoxide Bromocriptine Pharrnacotherapy to increase outlet resistance PAdrenergic antagonists a-Adrenergic agonists Tricyclic antidepressants Estrogen Surgical therapy Denelvation procedures Augmentation cystoplasty Vesicourethral suspension Bladder outlet reconstruction Treatment of urinary tract infection Treatment of autonomic dysreflexia

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TABLE 14-7. Pharmacotherapy of Bowel Hypomotility Bulk agents Bran Psyllium Methylcellulose Laxatives and cathartics Osmotic laxatives and cathartics Lactulose Sorbitol Magnesium salts Sodium phosphate Polyethylene glycol-saline solutions Glycerin suppositories Contact cathartics Diphenylmethane derivatives Phenolphthalein Bisacodyl tablets or suppositories Anthraquinone derivatives Senna Cascara Ricinoleic acid (castor oil) Stool softeners and lubricants Mineral oil Dulcosates Prokinetic agents Metoclopramide Domperidone Erythromycin Cholinomimetics Bethanechol Acetylcholinesterase inhibitors Opioid antagonists MisoDrostol

arise in the intermediolateral gray column synapse in the celiac, superior, and inferior mesenteric ganglia and ramify throughout the gastrointestinal tract in the distribution of their respective arterial trunks. The enteric nervous system is composed of a myenteric plexus located between the inner circular and outer longitudinal smooth muscle layers (Auerbach’s plexus) and a submucosal plexus (Meissner’s plexus). At least five types of intrinsic enteric neurons have been identified, and any individual neuron may contain multiple neuropeptides. Motor excitation is mediated by the cholinergic substance P neurons, and inhibition is mediated by the dynorphin vasoactive intestinal polypeptide neurons. Even in the absence of extrinsic autonomic nervous system influences, the enteric nervous system governs basic gut functions. Treating Bowel Hypomotility. An increase in dietary fiber (up to 25 @day), with water (10 oz four times per day) and exercise is the first line of therapy for most patients. The use of psyllium (up to 30 @day)or methylcellulose (up to 6g/day) with a concomitant increase in fluid intake further increases stool bulk. Some caution should be exercised with these agents; for example, high fiber may be disadvantageous in diabetic gastroparesis because of distention and cramping pain that can be associated with its use or because of the potential for bezoar formation. Stool softeners (e.g., docusate sodium 100 to 500 mg/day) or lubricants (e.g., mineral oil) together with an osmotic laxative (e.g., lactulose 15 to 60 mL/day) may be used if the aforementioned measures are ineffective. Glycerin suppositories or sodium phosphate enemas stimulate evacuation by promoting fluid retention in the rectum (Table 14-7). The contact cathartics such as the diphenylmethanederivatives (phenolphthalein and bisacodyl) and the anthraquinones (senna and cascara) should be used sparingly, although the use of these agents usually cannot be avoided in patients with constipation caused by autonomic failure. Extensive use of these agents may damage the myenteric plexus, producing cathartic bowel.

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Benzamide metoclopramide (5 to 20 mg orally, 30 minutes before meals and at bedtime) accelerates gastric emptying and has a central antiemetic action. In diabetics with concurrent gastroparesis and constipation, metoclopramide therapy may improve both symptoms, although its effect on colonic motility is less well defined, Tolerance to metoclopramide therapy has been described. Patients maintained in the long term on metoclopramide theoretically may be at risk for developing tardive dyskinesia and other dopamine antagonist-related side effects. Concurrent renal failure may increase risk of acute toxicity. Domperidone, a peripheral antidopaminergic agent, may provide symptomatic relief in patients with gastroparesis, although it is not clear that this medication improves objective measures of gastric emptying. Erythromycin and related macrolide compounds exhibit strong in vitro affinity for motilin receptors and have agonist properties that mimic the prokinetic action of exogenous motilin, a gastrointestinal polypeptide. Single intravenous doses of erythromycin shorten postprandial, gastric emptying time to normal levels in diabetics with gastroparesis. Oral erythromycin (250 mg three times per day) also improves gastric emptying, although not to the degree noted after a single parented administration. The somatostatin analogue octreotide may stimulate intestinal motor complexes, and this agent has been used to treat sclerodermatous pseudo-obstruction. However, somatostatin is known to impair motor responses to feeding, and treatment with octreotide in other conditions has been associated with hypomotility and bacterial overgrowth. Nausea and abdominal cramping pain occur with administration of the medication. Fat malabsorption and cholelithiasis have been described with chronic use. Rare patients who do not respond to medical therapy may need colonic surgery. Such patients should have documented slow colonic transit time and intact rectal sphincter function. Pharmacotherapy of Bowel Hypermotility. Before the diagnosis of neurogenic diarrhea, other causes must systematically be excluded. One theory regarding the pathogenesis of diabetic diarrhea holds that gastric and small bowel hypomotility may predispose to the proliferation of bacteria, which deconjugate bile salts and thus inhibit micelle formation. Steatorrhea and diarrhea thus result indirectly as a consequence of neurogenic hypomotility. A trial of tetracycline (500 to 1000 mg per day) therefore is conducted in most patients with unexplained chronic diarrhea, especially when steatorrhea is present. Treatment with prokinetic agents may also improve diarrhea. Should these measures fail, opioid agonists should be used. These agents decrease peristalsis and increase rectal sphincter tone. The synthetic opioids (diphenoxylate and loperamide) are preferable to alcohol solutions of opium. In the individual case, empiric management with tetracycline, opiates, prokinetic agents, psyllium, anticholinergics, and others often is needed. An alternative theory implicates a dysregulation of a*adrenoreceptor-mediated intestinal ion transport in diabetic diarrhea. Clonidine, a specific a,-adrenergic receptor agonist, may be used to treat diarrhea in dosages of up to 1.2 mg per day. The somatostatin analogue octreotide has been studied as a potential antidiarrheal agent in small numbers of patients with various conditions. As noted earlier, it may have a prokinetic action, but somatostatin has also been shown to inhibit stimulated water secretion in the gut. Fecal Incontinence. Studies of idiopathic fecal incontinence have found delayed conduction in pudendal nerves supplying the external sphincter and denervation changes in pelvic muscles. Impaired rectal sensation may be responsible for incontinence in

Principles of Diagnosis: Common Presenting Symptoms

such cases because detecting the presence of stool in the anal canal is essential to normal continence. Other authors have argued that the neuropathy is secondary to prolonged straining at stool and traction on pudendal nerves. Medical treatments generally attempt to rectify conditions that are either associated with or predispose to fecal incontinence. Use of high-fiber diets and bulking agents may be beneficial because a semiformed stool is more easily controlled than liquid feces. Fecal disimpaction is indicated in some cases. Daily tap water enemas aid in clearing residua in the rectum between evacuations and may allow functional continence. Antidiarrheal agents may benefit patients for whom incontinence and diarrhea coexist. Biofeedback based on the patient’s perception of a distensible balloon in the rectum and training to increase external sphincter pressure has met with success in some reports, although the response to biofeedback probably depends on the state of afferent pathways from the rectum. A majority of patients who undergo surgical sphincter repair may regain continence for solid stool, although the presence of pelvic floor neuropathy is associated with poorer outcome. Other surgical interventions, including colostomy, artificial anal sphincters, and creation of a reconstructed anal sphincter with muscle grafts, may be necessary in treatment-resistant cases.

SUGGESTED READINGS Anderson KE: The overactive bladder: pharmacologic basis of drug treatment. Urology 50:74-84, 1997 Arai K, Kato N, Kashiwado K, Hattori T Pure autonomic failure in association with human alpha-synucleinopathy. Neurosci Lett 296: 171-173, 2000 Axelrod FB: Hereditary sensory and autonomic neuropathies. Familial dysautonomia and other HSANs. Clin Auton Res 12(Suppl 1):12-14, 2000 Bannister R, Mathias CJ: Clinical features and investigations of the primary autonomic failure syndromes. In Bannister R, Mathias CJ (eds.): Autonomic Failure. Oxford University Press, Oxford, UK, 1992 Benarroch EE: New findings on the neuropathology of multiple system atrophy. Auton Neurosci 96:5942, 2002 Ben Shlomo Y,Wenning GK, Tison F, Quinn N P Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology 48:384-393, 1997 Blaivas J G The neurophysiology of micturition: a clinical study of 550 patients. J Urol 127:958-963, 1982 Brunton L L Agents affecting gastrointestinal water flux and motility, digestants, and bile acids. In Gilman AG, Rall TW, Nies AS, Taylor P (eds.): The Pharmacological Basis of Therapeutics. Pergamon, New York, 1990 Cable WJ, Kolodny EH, Adams RD: Fabry disease: impaired autonomic function. Neurology 32:498-502, 1982 Camdessanche JP,Antoine JC,Honnorat J et ak Paraneoplastic peripheral neuropathyassociated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 125:16&175, 2002 Camilleri M:Disorders of gastrointestinal motility in neurologic diseases. Mayo Clin Proc 652325446, 1990 Pemberton JH: Clinical Camilleri M, Thompson WG, Fleshman JW, management of intractable constipation. Ann Intern Med 121:520528, 1994 Dalmau J, Graus F, Rosenblum MK, Posner JB: Anti-Hu-associated paraneoplastic encephalomyelitislsensory neuronopathy. A clinical study of 71 patients. Medicine 71:59-72, 1992 Dyck PJ: Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In Dyck PJ, Thomas PK, Griffin JWet al (eds.): Peripheral Neuropathy. Vol. 2. WB Saunders, Philadelphia, 1993

Chapter 14 H Autonomic Dysfunction

Falk RH, Comenzo RL, Skinner M: The systemic amyloidoses. N Engl J Med 3372398-909, 1997 Fedorak RN, Field M, Chang E B Treatment of diabetic diarrhea with clonidine. Ann Intern Med 102:197-199, 1985 Feldman M, Schiller LR Disorders of gastrointestinal motility associated with diabetes mellitus. Ann Intern Med 98:37&384, 1983 Fowler CJ: Investigation of the neurogenic bladder. J Neurol Neurosurg Psychiatry 605-13, 1996 Freeman R The peripheral nervous system and diabetes. In Weir G, Kahn R, King GL (eds.): Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins, Philadelphia, 2000 Freeman R Pure autonomic failure. In Robertson D, Biaggioni I (eds.): Disorders of the Autonomic Nervous System. Harwood Academic Publishers, Luxembourg, 1995 Freeman R Treatment of orthostatic hypotension: midodrine and other pressor drugs. In Robertson D, Low PA, Polinsky RJ (eds.): Primer on the Autonomic Nervous System. Academic Press, New York, 1996 Freeman R, Miyawaki E The treatment of autonomic dysfunction. [Review]. J Clin Neurophysiol 1061-82, 1993 Freeman R, Roberts MS, Friedman LS, Broadbridge C Autonomic function and human immunodeficiency virus infection. Neurology 40575-580, 1990 Furness JB: Types of neurons in the enteric nervous system. J Auton Nerv Syst 81~87-96,2000 Gilman S, Low PA, Quinn N et ak Consensus statement on the diagnosis of multiple system atrophy. J Auton Nerv Syst 74189-192, 1998 Goyal RK, Hirano I: The enteric nervous system. N Engl J Med 334:110&1115, 1996 Hague K, Lento P, Morgello S et ak The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature [Review].Acta Neuropathol (Berl) 94:192-196, 1997 Hart RG, Kanter M C Acute autonomic neuropathy. Two cases and a clinical review. Arch Intern Med 150:2373-2376, 1990 Hilsted J, Low PA Diabetic autonomic neuropathy. In Low PA (ed.): Clinical Autonomic Disorders. Lippincott-Raven, Philadelphia, 1997 Hund E, Linke RP, Willig F, Grau A Transthyretin-associatedneuropathic amyloidosis.Pathogenesis and treatment. Neurology 5643 1435,2001 Indo Y, Tsuruta M, Hayashida Y et ak Mutations in the T W N G F receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13:485-488, 1996 Iosa D, Dequattro V, De-Ping Lee D et ak Pathogenesis of cardiac neuro-myopathy in Chagas’ disease and the role of the autonomic nervous system. J Auton Nerv Syst 30S83-S88, 1990 Kaufmann H, Hague K, Per1 D: Accumulation of alpha-synuclein in autonomic nerves in pure autonomic failure. Neurology 56980-981, 200 1 Khurana RK: Paraneoplastic autonomic dysfunction. In Low PA (ed.): Clinical Autonomic Disorders. Lippincott-Raven, Philadelphia, 1993 Kunze WA, Furness JB: The enteric nervous system and regulation of intestinal motility. Annu Rev Physiol 61:117-142, 1999 Kyle RA, Dyck PJ: Amyloidosis and neuropathy. In Dyck PJ, Thomas PK, Griffin JW et al (eds.): Peripheral Neuropathy. WB Saunders, Philadelphia, 1993 Kyle RA, Gertz MA: Systemic amyloidosis. Crit Rev Oncol Hematol 1049-87, 1990 Lennon VA, Sas DF, Busk MF et ak Enteric neuronal autoantibodies in pseudoobstruction with small cell lung carcinoma. Gastroenterology 100:137-142, 1991 Locke GR 111, Pemberton JH, Phillips S F American Gastroenterological

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Association medical position statement: guidelines on constipation. Gastroenterology 119:1761-1766, 2000 Madoff RD, Williams JG, Caushaj PF: Fecal incontinence. N Engl J Med 326~1002-1007, 1992 Mamdani MB, Walsh RL, Rubino FA et ak Autonomic dysfunction and Eaton-Lambert syndrome. J Auton Nerv Syst 12:315-320, 1985 Orthostatic hypotension, multiple system atrophy (the Shy-Drager syndrome) and pure autonomic failure. J Auton Nerv Syst 58:123-124, 1996 Papp MI, Lantos PL The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 117:235-243, 1994 Saraiva MJM, Costa PP, Goodman DS: Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type: family studies of transthyretin (prealbumin)-methionine-30 variant. J Clin Invest 76:217 12177, 1985 Schiller LR, Santa Ana CA, Schmulen AC et ak Pathogenesis of fecal incontinence in diabetes mellitus: evidence for internal-anal-sphincter dysfunction. N Engl J Med 307:166&1671, 1982 Spillantini MG, Crowther RA, Jakes R et al: Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205-208, 1998 Spillantini MG, Goedert M: The alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci 920:1&27, 2000 Staskin DR Classification of voiding dysfunction. In Krane RJ, Siroky MB (eds.): Clinical Neuro-Urology. Little, Brown, Boston, 1992 Thomas PK Autonomic involvement in inherited neuropathies. Clin Auton Res 2:51-56, 1992 Tuck RR, McLeod J G Autonomic dysfunction in Guillain-BarrC syndrome. J Neurol Neurosurg Psychiatry 44983-990, 1981 Valdovinos MA, Camilleri M, Zimmerman BR Chronic diarrhea in diabetes mellitus: mechanisms and an approach to diagnosis and treatment. Mayo Clin Proc 68691-702, 1993 Vernino S, Low PA, Fealey RD et ak Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 343:847-855,2000 Waterman SA Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clin Auton Res 11:145-154, 2001 Wein AJ: Evaluation and treatment of urinary incontinence: practical uropharmacology. Urol C l i North Am 18:269-281, 1991 Wein AJ: Pharmacologic options for the overactive bladder. Urology 51:43-47, 1998 Wein AJ, Van Arsdalen K, Levin RM: Pharmacologic therapy. In Krane RJ, Siroky MB (eds.): Clinical Neuro-Urology.Little, Brown, Boston, 1992 Wenning GK, Ben Shlomo Y, Hughes A et al: What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry 68434440, 2000 Wingate DL Autonomic dysfunction and the gut. In Bannister R, Mathias CJ (eds.): Autonomic Failure. Oxford University Press, Oxford, UK, 1992 Wood J D Physiology of the enteric nervous system. In Johnson LR, Christensen J, Jackson MJ et al (eds.): Physiology of the Gastrointestinal Tract. Raven Press, New York, 1987 Ziegler MG. Lake CR, Kopin IJ: The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med 296:293-297, 1977 Zochodne DW: Autonomic involvement in Guillain-Barrk syndrome: a review. Muscle Nerve 121145-1155, 1994

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Principlesof Ambulatory Neurology and the Approach to Clinical Problems W

Principlesof Diagnosis: Common PresentingSymptoms

Sexual Dysfunction Carlos Singer and Marca L. Sipski

Many neurologic disorders can affect sexual function. Sexual dysfunction may be a primary complaint or, more often, a problem secondary to the primary neurologic ones, which may go unaddressed by the patient and physician. Such disorders often necessitate cooperation between primary care physicians, urologists, gynecologists, endocrinologists, neurologists, and specialists in rehabilitation, sleep, and sexual disorders. The neurologist should understand the basic neuroanatomy and neurophysiology of the sexual response and the approach to diagnosis and therapy to serve as a consultant in managing the neurologic aspects of these disorders. This chapter presents an overview of this anatomy and physiology along with a review of the major categories of sexual dysfunction in men and women and an approach to evaluation and therapy. NEUROANATOMICAND NEUROPHYSIOLOCIC ISSUES

Sexual function can be controlled by psychogenic or reflexogenic mechanisms in both men and women. The psychogenic response is initiated by stimuli in the higher brain centers, resulting in sympathetic stimulation. The reflexogenic response is elicited by manual local stimulation of the genitalia via the sacral somatic innervation and elicits a parasympathetically mediated response. In men the center for reflexogenic erections is located in the S2-S4 sacral segments. Direct genital manipulation is transmitted to this center via the pudendal nerve (somatic nervous system). Its efferent erectogenic message is relayed by the parasympathetics via the pelvic nerves (nervi erigentes). At the level of terminals in the penile vasculature, an interaction with the noncholinergic nonadrenergic system (nitric oxide) occurs, resulting in dilation of the sinusoidal spaces of the penis, thereby initiating the erection. The penile engorgement compresses the draining veins, allowing maintenance of the erection. The thoracolumbar sympathetic center for erection responds to psychogenic stimuli and sends erectogenic messages via the hypogastric plexus and nerves that connect (and interact) with the parasympathetic system. A similar pattern has been determined in women. Based on studies of patients with spinal cord injuries (SCIs), it has been postulated that psychogenic lubrication occurs in response to signals from higher brain centers that travel down the lateral columns of the spinal cord near the pyramidal tracts and connect to and are facilitated by the thoracolumbar sympathetic pathways. Reflex lubrication would predictably be controlled by sacral parasympathetics. The preganglionic fibers of the parasympathetic branch involved in sexual response originate from the gray matter of the second, third, and fourth sacral segments of the spinal cord. These fibers enter the hypogastric plexus and synapse with the postganglionic fibers, which are distributed along the branches of the internal pudendal arteries. In men, seminal emission is the deposition of semen from the prostate, seminal vesicles, and distal vasa deferentia into the posterior urethra that precedes ejaculation. The afferent stimuli (genital stimulation and cerebral activity) follow the same pathways as in erectile function. The efferent signal then travels via the hypogastric sympathetic nerves. Ejaculation implies antegrade

propulsion of semen from the posterior urethra through the penile meatus. The afferent stimuli are the same as for seminal emission plus those resulting from the passage of semen into the posterior urethra. The efferent arm involves coordination between the somatic efferent nerves (S2-S4 via pudendal nerves) and efferent autonomic nerves (T12-L2 via hypogastric nerves). This allows rhythmic contractions of the striated pelvic floor musculature, compressing the urethra, and simultaneous closure of the bladder neck. The result is antegrade propulsion of the ejaculate. In women, smooth muscle contractions of the fallopian tubes, uterus, and periurethral glands during orgasm have been equated to emission in men and probably are mediated by the thoracolumbar sympathetics. Events paralleling ejaculation include contractions of striated muscles of the pelvic floor and perineal area and the anal sphincter mediated through the sacral parasympathetics in conjunction with somatic efferents. Recent data based on laboratory-based analyses of women with spinal cord injuries suggest that the ability to experience orgasm requires an intact sacral spinal reflex arc. MALE SEXUAL DYSFUNCTION

Male sexual dysfunction may present as an isolated complaint or as part of multiple somatic or psychological complaints. In some instances, it may be the manifestation of a disorder of the central or peripheral nervous system. In other instances the causes are outside the nervous system and involve one or more combinations of endocrinologic, drug-induced, urologic, vascular, and psychological mechanisms. Erectile Dysfunction Definitions and Clinical Aspects. Erectile dysfunction (ED), often called impotence, can be defined as the persistent inability to obtain or sustain an erection adequate for intromission, pelvic thrusting, and, in the absence of ejaculatory difficulties, ejaculation. ED may be primary or secondary depending on the respective absence or presence of a premorbid period of normal sexual function. Seven percent of otherwise intact men across the age spectrum have impotence. The figure increases to one third of men in their sixties, although two thirds of these impotent men still have preserved sexual drive. Clinical features that point to organic mechanisms, be they neurologic or non-neurologic, are a progressive onset first affecting maintenance of erections, gradually evolving into inability to achieve full erections. There is a gradual increase in the proportion of partial erections, a sense of decreased firmness, a tendency to rush through the sexual intercourse for fear of losing the erection, and an easy loss of firmness if minor distractions occur. Spontaneous morning erections progressively decrease in frequency and firmness. Sexual drive usually is preserved in the early stages of the condition. It tends to decrease much later, more commonly as a consequence of depression, itself a reaction to the dysfunction. If sexual drive is affected from the start, depression,

Chapter 15

endocrine dysfunction, and frontal lobe dysfunction should be ruled out. Psychogenic or drug-induced ED may start abruptly. Presence of decreased sexual drive at the outset suggests depression, but drug effectand hormonal imbalance should also be considered. In psychogenic ED, full erections may be possible with masturbation, sexual fantasy, or a different sexual partner. Morning erections may continue as frequent and as firm as before the onset of ED. The spouse’s participation during the interview may provide information indicating marital disharmony. Psychogenic impotence is further suggested by normal nocturnal penile tumescence (NPT) studies. Concurrent autonomic symptoms in the urinary, gastrointestinal, thermoregulatory, and cardiovascular spheres should be reviewed. If symptoms of autonomic failure are present, neuropathies or parkinsonism (multiple-system atrophy, Parkinson’s disease) should be considered. A detailed drug history may lead to medication adjustments, making it unnecessary to embark on a more costly diagnostic evaluation. Data on drugs that can cause sexual dysfunction are readily available, such as the yearly update provided in The Medical Letter. Alcohol and recreational drug use are also risk factors for ED. Concurrent atherosclerotic or peripheral vascular disease and heavy smoking may point to a vasculogenic mechanism. Diabetes is a common cause of ED through vascular and neuropathic mechanisms. Endocrinologic causes (hypothyroidism, hyperprolactinemia, hypoandrogenism) are likely to be associated with a decrease in sexual drive. Surgical procedures (e.g., prostate surgery, aortoiliac surgery, sympathectomy), pelvic radiation therapy, dialysis, and urologic structural abnormalities (e.g., hypogenitalism, Peyronie’s disease), predispose men to sexual dysfunction. The general and neurologic examination may provide additional clues to the cause. Distal sensory deficits to light touch, pin, temperature, or vibration and decreased or absent reflexes suggest neuropathy. The bulbocavernosus reflex may be decreased or absent in neuropathies. Mild cogwheel rigidity, unilateral slowness of finger tapping, decreased arm swing, or other early signs of parkinsonism should be sought. Orthostatic hypotension may suggest dysautonomia, as seen in peripheral neuropathies, Parkinson’s disease, or multiple-system atrophy. Saddle anesthesia, sensory level, spasticity, and other signs suggestive of myelopathies may also be detected in early stages, although they are likely to be symptomatic. Decreased or absent peripheral pulses may point to vasculogenic impotence. Peyronie’s disease and other urologic deformities will be apparent upon inspection. Diagnostic Evaluation of Erectile Dysfunction. The diagnostic evaluation of ED includes a determination of the contribution of organic and psychological mechanisms. After the history and physical examination, the presence of depression, spousal strain, and marital discord should be determined with a choice of available published scales. Examples include the Beck‘s Depression Inventory and the Locke-Wallace Marital Adjustment Test. NPT studies are the best method to determine organicity. These studies record erectile activity during rapid eye movement (REM) sleep by placement of mercury-filled strain gauges around the penis. The electrical resistance of the gauges increases as the mercury-filled tubing elongates and narrows. This change in impedance is transduced into voltage and recorded as a continuous tracing of circumference change. At the same time, sleep stages are also recorded. If adequate REM periods are generated during sleep, the concurrent presence or absence of firm erections can be docu-

Sexual Dysfunction

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mented reliably. A normal NPT study should identify most men with a predominantly psychogenic impotence, and the absence of firm erections strongly suggests organic ED. Snap-gauge bands, the stamp test, and portable take-home monitoring devices are alternative but less reliable methods because they cannot ascertain whether REM sleep has occurred, so false positives (absence of firm erections caused by absence of REM sleep) are likely. Even if the preliminary clinical and NPT evidence suggests psychogenicity, endocrine dysfunction should be evaluated with serum levels of prolactin, thyroid hormone, luteinizing hormone, follicle-stimulating hormone, total testosterone, and free testosterone. Given a prevalence of impotence of 60% in diabetic men, all impotent men should be checked for diabetes. This can be done by screening with a fasting blood glucose, or glycosylated hemoglobin, or more definitively ruling it out with a &hour glucose tolerance test. Once NPT studies confirm an organic contribution, the physician must decide on clinical grounds whether to investigate neurogenic mechanisms. The results of such tests may be of interest for the general understanding of the case but are not likely to determine a specific treatment. Bulbocavernosus reflex latency determination addresses the question of neuropathic contribution and may indirectly point to coexisting autonomic dysfunction of the penile organ. Abnormal pudendal evoked responses in the presence of normal bulbocavernosus reflex values suggest dysfunction in spinal cord, brainstem, or supratentorial sensory pathways. Biothesiometry, a measurement of penile vibration perception threshold, may be the only test to detect a sensory deficit as a mechanism of impotence. Electromyography of the sphincters may point to multiple-system atrophy if signs of reinnervation are discovered. (This last finding results from selective atrophy of Onuf‘s nucleus in the anterior horn of the sacral spinal cord. Neurons from Onuf‘s nucleus innervate the urethral and anal sphincters. The more superficial anal sphincter is more easily examined by needle electromyography.) Before referring to the sex therapist or the urologist, the primary care physician or consultant neurologist should be able to direct the initial portion of the diagnostic workup of erectile dysfunction. What follows falls in the hands of the urologist, but the well-informed clinician may remain actively involved as an additional source of guidance to the patient. The patterns of practice of urologists vary. Some limit themselves to intracavernous pharmacoactive agents used as diagnostic and therapeutic procedures and then move on to nonspecific treatment with suction erection devices or implants. Others may actively investigate vasculogenic mechanisms with the intent of undertaking a more specific surgical procedure if warranted. Hemodynamic penile studies, using duplex ultrasound scanning before and after intracavernosal injection of pharmacoactive agents, explore for presence of vascular insufficiency. The quality of response to intracavernous pharmacotherapy is also subject to analysis. A partial (less than firm) erection or a firm erection that can be sustained only for a short period of time (i.e., less than half an hour) suggests venous insufficiency, especially if hemodynamic studies are normal. A delay of more than 30 minutes in achieving a full erection suggests arteriogenic impotence. Similarly, if higher than standard dosages of pharmacoactive agents must be used to induce a firm erection or if a firm erection is unattainable, this also suggests arteriogenic impotence. Psychogenic and endocrinogenic ED respond to standard dosages of intracavernous agents. Neurogenic ED may necessitate slightly higher dosages, but not as high as the arteriogenic group.

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Suspected venous insufficiency can be confirmed by determining the flow necessary for an intracavernous infusion of saline to maintain a firm erection (cavernosometry). Radiopaque dye is then injected, with actual visualization of the venous leak (cavernosography). It is preferable to perform this study after penile injection of a pharmacoactive agent because this allows for a lessened fluid and contrast load and provides a more physiologic assessment of the venous occlusive mechanism. Pudendal angiography is indicated only if a patient with suspected arterial insufficiency is deemed to be a suitable candidate for reconstructive surgery. Invasive procedures involve significant discomfort and morbidity and should not be undertaken in a patient content with having his ED treated by less invasive or less specific means. Treatment of Erectile Dysfunction. The importance of the clinical history cannot be overemphasized. The clinician should first consider discontinuing or substituting medications, especially if their institution appears to have preceded the sexual dysfunction by a short time interval. A hormonal abnormality can be treated with specific measures best addressed by an endocrinologist. Depression, marital discord, a history suggestive of a psychogenic component, or a normal NPT study should prompt referral to a psychologist specialized in the field of sexual dysfunction. Neurogenic impotence and vasculogenic impotence can be treated with a variety of nonspecific therapeutic modalities. Use of oral sildenafd citrate has allowed successful treatment of ED regardless of cause. It is a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase, enhancing erection by augmenting nitric oxide-mediated relaxation pathways, through increased cGMP accumulation in the corpus cavernosum. Onset of effect occurs within the first hour of intake, and it dissipates within 3 to 5 hours. Side effects include transient headache, flushing, dyspepsia, rhinitis, and visual disturbances such as changes in the perception of color or brightness. Concomitant use of nitrates is an absolute contraindication. The patient (or his partner) may choose to learn selfadministration of intracavernous vasoactive agents. They are more likely to be effective in patients with intact vascular mechanisms. The synthetic prostanoid prostaglandin E l (PGE1, alprostadil) is the most widely used agent. Mixtures of papaverine hydrochloride and phentolamine mesylate are equally effective. They have a lower incidence of pain but a much higher incidence of priapism and fibrotic nodules. In deciding to use intracavernous pharmacotherapy, the clinician should take into account the potential for hypotension, especially in patients with preexisting coronary artery disease. A formulation of alprostadil has also been approved for intraurethral administration. Suction erection devices are a nonpharmacologic, nonsurgical intervention with low incidence of side effects. A measure of manual strength and dexterity is necessary for their successful use. Prosthesis implants represent the option of last resort of neurogenic, arteriogenic, and venogenic erectile dysfunction. These devices come in semirigid and multicomponent inflatable varieties. The semirigid devices are low in cost and are easy to implant but have an aesthetically less desirable detumescent phase. The multicomponent inflatable prostheses are superior, providing greater mechanical reliability and patient satisfaction. However, reoperation may be necessary in case of certain complications such as postoperative infection, device erosion, or component failure. More specific surgical treatment modalities may be undertaken in carefully selected instances. Venogenic impotence can be treated with penile vein dissection and ligation. Arteriogenic impotence may be amenable to revascularization procedures.

Ejaculatory Disturbances Definitions, Concepts, and Clinical History EJAcumnoN. Premature ejaculation is the most comPREMATURE

mon male sexual dysfunction. Prevalence estimates range between 22% and 38%. Defining premature ejaculation has proven to be a daunting task. Some have suggested .basing the definition on existing normative data on the average time of intercourse (7 to 10 minutes). Others prefer to disregard this “stopwatch” approach because there is a lack of consensus as to what is a normal time period. Masters and Johnson define premature ejaculation as the inability to delay ejaculation long enough to allow the woman to reach orgasm in at least 50% of a couple’s sexual encounters. This definition assumes absence of orgasmic dysfunction in the woman. The DSM-IVR defines premature ejaculation as “persistent and recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it. The clinician must take into account factors that affect the duration of the excitement phase such as age, novelty of the sexual partner or situation, and recent frequency of sexual activity.” Therefore, premature ejaculation may occur intravaginally or extravaginally. In addition, the DSM-IVR requires that the disturbance cause “marked distress or interpersonal difficulty” and that it not be due “exclusively to the direct effects of a substance (e.g., withdrawal from opioids).” Perhaps a more practical definition is the one that views premature ejaculation as a tendency to ejaculate at lower levels of sexual arousal. One possible mechanism is a lower rate of sexual intercourse as compared with control subjects, a notion with obvious therapeutic implications. EIACUUTORYINCOMPETENCE AND DRYEJAcumoN. Ejaculatory incompetence, also known as retarded ejaculation, implies an inability to ejaculate despite adequate erectile function with absence of both the orgasmic sensation and the ejaculate. It is currently viewed as psychogenic in the majority of cases. Organic factors such as spinal cord injury or disease, diabetes, or certain medications must be considered. This condition must be distinguished from “dry” ejaculation, in which there is an absence of ejaculate in the presence of an orgasmic sensation. This latter phenomenon suggests either defective seminal emission or retrograde ejaculation. Presence of semen or fructose in a postmasturbation urine sample points to the latter. Either dysfunction represents an organic sympathetic disturbance. Diagnostic Evaluation of Ejaculatory Disturbances. To date there are no specific neurophysiologic tests for evaluating ejaculatory dysfunction. For the neurologist or internist, the first task is to define (by virtue of the clinical history) the kind of ejaculatory dysfunction and the potential mechanisms (drugs, past surgeries, trauma). The physical examination may detect signs of neuropathy, myelopathy, or dysautonomia. It is not unusual for erectile dysfunction to be accompanied by the inability to ejaculate, in which case it is the former dysfunction that will necessitate the kind of diagnostic evaluation mentioned earlier. PREMATURE EJACULATION. Premature ejaculation is viewed primarily as a psychogenic problem. Numerous mechanisms have been invoked, including generalized or performance anxiety, unconscious negative feelings (hostility, fear) toward women, and unresolved marital problems. In addition to purely intrapsychic or relationship factors, a constitutionally faster ejaculatory reflex

Chapter 15 rn Sexual Dysfunction

(based on shorter latency of bulbocavernosus reflex) has also been invoked. This latter finding appears to apply to primary premature ejaculators (premature ejaculation from the beginning of their sexual lives) but cannot be used for diagnosis because of the overlap of results with controls. The physician should be aware of the rare instances in which organic dysfunction is associated with premature ejaculation. The index of suspicion for an organic cause increases in cases where the problem is preceded by a period of normal performance (secondary failure of ejaculatory control). Organic causes of premature ejaculation may include urologic conditions such as urethritis, prostatitis, and benign prostatic hypertrophy. Careful review of the literature reveals poor substantiation of the belief that these urologic conditions cause premature ejaculation. Better accepted causes of premature ejaculation are instances in which the sympathetic nervous system has been directly lesioned (abdominal aortic aneurysm surgery and pelvic fractures). Premature ejaculation has also been reported after withdrawal from antipsychotics or narcotics, with the use of desipramine, and with alcoholism. The postulated association with cardiovascular disease, arteriosclerosis, or venous leakage is also poorly substantiated. It has been stated that premature ejaculation may be caused by certain neurologic conditions such as multiple sclerosis, spinal cord tumors, polyneuritis, and alcoholic neuropathy. A closer review of some of the quoted sources fails to reveal with clarity the evidence on which these statements are based, particularly in the case of multiple sclerosis and spinal cord tumors. We still recommend that the clinician search for elements in the history or neurologic examination that raise the possibility of a true organic neurologic disorder underlying premature ejaculation. If clinically warranted, further neurologic investigation (i.e., magnetic resonance imaging, evoked responses, and cerebrospinal fluid analysis to rule out multiple sclerosis) may be necessary. Otherwise, there are no neurologic or non-neurologic paraclinical investigations specifically indicated for premature ejaculation, and referral to a sexologist or sex therapist is the next recommended step. ‘‘DRY‘.EJAcuwnoN. The patient with a complaint of “dry” ejaculation, which is the experience of the orgasmic sensation without the concomitant anterograde propulsion of ejaculate, warrants evaluation for an organic disturbance. To distinguish retrograde ejaculation from defective seminal emission, a postmasturbation urine sample is analyzed for the presence of spermatozoa or fructose. Certain drugs may induce either dry or retrograde ejaculation. Phenothiazines have long been known to affect ejaculation. Tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and amphetamines are also capable of affecting ejaculation. Methyldopa, clonidine, and guanethidine are the most likely offenders of the antihypertensive agents by virtue of their interaction with sympathetic neurotransmission. There are also numerous urologic causes of retrograde ejaculation, which should be considered before invoking a neurogenic mechanism. The most common is transurethral resection of the prostate, but retropubic prostatectomy, bladder neck surgery, and trauma (i.e., pelvic fracture) are additional causes. A variety of congenital conditions causing bladder neck incompetence and conditions that mechanically obstruct the urethra are also worth noting. The neurologic mechanisms of ejaculatory and seminal dysfunction have in common a disruption of the sympathetic outflow. Erectile difficulties may or may not be concurrently present.

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Surgeries most commonly associated with retrograde ejaculation or defective seminal emission include lumbar sympathectomy, retroperitoneal lymph node dissection, aortoiliac surgery, or colorectal surgery (e.g., abdominoperineal resection). Diabetes and other autonomic neuropathies also have to be considered. Of the myelopathies and myeloradiculoneuropathies,multiple sclerosis and spinal trauma are the most frequently mentioned. The possibility of ejaculatory dysfunction in the presence of relative preservation of erectile capacity has been well documented in spinal trauma victims. In some cases a clear cause cannot be found (idiopathic retrograde ejaculation). EJACULATORY INCOMPEENCE. There are no routine additional tests that can be ordered to investigate the disorder. The clinician should conduct a careful history and examination looking for possible coexisting or causative drug-induced or neurologic disorders. Subsequent laboratory or radiologic tests depend on their clinical findings. Once organic causes have been excluded, referral to a sex therapist will allow evaluation of psychogenic mechanisms. Treatment of Ejaculatory Disturbances. In cases of premature or incompetent ejaculation, referral to a sex therapist is recommended. Sex therapy techniques such as the “pausesqueeze” method have been suggested to treat premature ejaculation. Pharmacologic agents have also been used. They include topical anesthetics, neuroleptics, tricyclics, monoamine oxidase inhibitors, benzodiazepines, and a-blockers. Intracavernous pharmacotherapy with a papaverine and phentolamine mixture has also been reported successful in small series. A number of criticisms have been raised regarding these pharmacologic trials. Many of the trials are uncontrolled and involve small numbers of subjects. More recently, serotonin reuptake inhibitors taken a few hours before intercourse have been reported effective in placebocontrolled trials. Pharmacologic treatment can be considered in patients reluctant to accept or who have failed sex therapy. The other organic ejaculatory dysfunctions may respond to withdrawal of certain medications. The monthly medical publication The Medical Letter publishes a yearly update on the subject. The distinction between retrograde ejaculation and defective seminal emission is particularly relevant to couples seeking assistance for infertility. Vibratory stimulation, transrectal electrical stimulation, and intrathecal injections of neostigmine are techniques designed to obtain ejaculates for artificial insemination. FEMALE SEXUAL DYSFUNCTION DefSnlons and Clinical Aspects Recently a new international classification for female sexual dysfunctions was developed. Based on this classification, female sexual dysfunction is described in one of four categories: desire disorders (hypoactive sexual desire and sexual aversion disorder), sexual arousal disorder, orgasmic disorder, and sexual pain disorders (dyspareunia, vaginismus, and other sexual pain disorders). It follows that some neurologic disorders result in altered sexual response directly as a result of the neurologic disorder. However, to be considered a sexual dysfunction it must also be accompanied by significant personal distress, so not all alterations in sexual function occurring as a result of neurologic disorders would be considered sexual dysfunctions. In general, for women with neurologic disorders one must first obtain information about the woman’s premorbid sexual functioning and how her function was affected by the neurologic disorder. The woman should be questioned about the use of

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medications that can affect sexual function, surgical procedures, and the impact of her neurologic disorder on sensation and motor function. Partner issues should be reviewed, including the woman’s sexual preferences, her satisfaction with relationships, and whether her sexual dysfunction is situational. Additionally,the impact af associated psychological concerns and medical problems must be considered. Physical examination in women with spinal cord dysfunction should include particular attention to whether there is preservation of the ability to perceive pinprick and light touch sensation in the T11-L2 dermatomes because the combined ability to perceive these sensations has been related to the ability to achieve psychogenic genital vasocongestion. Furthermore, the presence of perianal sensation and an intact bulbocavernosus and anal wink reflex should be sought because women with complete lower motor neuron injuries affecting their sacral segments have been found to be significantlyless likely to achieve orgasm than women with all other patterns of spinal cord injury. In women with cerebral dysfunction, the loss of motor and sensory function in addition to the impact of other motor dysfunction on sexual activity should be considered. Moreover, the presence of speech and perceptual problems and their impact on sexual activity and the ability of the woman to engage in a sexual or other relationship should be considered. In women with neuropathy, the presence of autonomic neuropathy and the loss of motor or sensory function in the genital region and their impact on sexual response should be considered. Additionally, for all women a general physical and pelvic examination should be performed to assess estrogen status and circulatory function. DifferentialDiagnosis

There are no readily available tests for female sexual dysfunction. Instead, clinicians should direct their diagnostic workup to seek underlying neurologic or medical conditions and then apply their knowledge of the prevalence and mechanisms of sexual dysfunction in these disorders to provide counseling and assist other therapists. The differential diagnosis of sexual dysfunction in the woman with a neurologic disorder must take into account the impact of the neurologic disorder on sexual response. In addition, the impact of iatrogenic factors such as medications and surgery, concomitant medical and psychologic factors, preexisting sexual concerns, partner factors, and age-related factors must be considered. Once all these factors are taken into account, a sexual diagnosis can be entertained. Although the list is not exhaustive, the impact of various neurologic disorders on female sexual function is described later in this chapter. Because of the limited information that is available, these discussions are grouped based on common locations of neuropathology. Brain Disorders. Overall, the impact of various brain disorders on female sexual function is not well known. Various studies have reported a decrease in sexual satisfaction in women with traumatic brain injury and stroke. Additionally, decreased frequency of orgasm and decreased lubrication are noted with both groups. Parkinson’s disease has been reported to cause a decrease in libido and frequency of sexual activity in association with an increase in sexual complaints. Women with hypothalamic dysfunction have been reported to have menstrual irregularities, decreased desire, and lubrication and orgasm problems. Unfortunately, all studies have been self-reports, and many women suffering from brain dysfunction have concomitant issues, which

Principlesof Diagnosis: Common PresentingSymptoms

can affect their sexual function. These may include advanced age, diabetes mellitus, vascular dysfunction, use of medications, aphasia, and motor and sensory loss. Therefore, it remains uncertain whether specific patterns of brain dysfunctionwill result in specific alterations in female sexual response. Controlled laboratory-based analyses of the impact of specific locations of cerebral pathology on sexual response are needed. Spinal Disorders. A significant amount of research has addressed the impact of spinal cord dysfunction (SCD) on female sexual function. Women with spinal cord injuries (SCIs) report decreased sexual satisfaction and frequency of activity. Laboratory-based studies of women with SCIs have shown that the ability to perceive pinprick and light touch sensation in the T11-L2 dermatomes predicts the ability to achieve psychogenic lubrication. The sensory experience associated with orgasm has been shown to be similar in women with SCI and able-bodied women. A significantly lower ability to achieve orgasm as compared with able-bodied women (50% SCI, 100% able-bodied) was noted in the laboratory; moreover, greater latency to orgasm in women with SCI was reported as compared with able-bodied women. Women with complete lower motor neuron dysfunction affecting their sacral spinal segments have been found to be significantly less likely than women with all other levels and degrees of SCI to achieve orgasm. Although extensive studies have been performed in women with SCIs, minimal research has looked at the impact of other spinal disorders on female sexual response. However, because the end result of the neuropathology should be the same, it is recommended that the information available through the study of women with SCIs also be used when counseling women with spinal cord dysfunctions such as spina bifida and metastatic carcinoma. Multiple Sclerosis. Because multiple sclerosis can affect both the brain and spinal cord, it follows that its effect on sexual function depends on where the neuropathology exists in the individual patient. Studies have linked changes in lubrication and orgasm capacity with pelvic floor weakness and bladder and bowel dysfunction. Anorgasmia has been correlated with the total area of plaques observed in the brain on magnetic resonance imaging. Overall sexual dysfunction has been documented in nearly three quarters of women with multiple sclerosis, with complaints of decreased libido, anorgasmia, and decreased lubrication being common. Because sexual function entails a coordinated response from the autonomic nervous system, one would expect that women with autonomic neuropathies would experience sexual dysfunction. The most common group of women with neuropathy potentially experiencing sexual dysfunction is women with diabetes mellitus (DM). Women with DM have been studied via multiple self-report studies, and complaints of decreased desire, decreased lubrication and arousal, and orgasmic dysfunction have been recorded. Whether these sexual dysfunctions are associated with the presence of neuropathy has not been definitively documented. Moreover, only two studies have assessed the sexual response of women with DM in a laboratory, and these studies produced conflicting findings about whether the sexual responsiveness of women with DM differed from that of those without DM. Management

The first step in managing sexual dysfunction in women with neurologic disorders is to obtain a good history and physical

Chapter 16

examination and to determine whether there are any treatable sources of sexual dysfunction, such as the use of medications. Once these sources of dysfunction are eliminated, one should educate the woman as much as possible about the impact that her particular neurologic problem might have on her sexual function. Education of the partner, review of other emotional and partner issues, and referral for sexual counseling should be considered. No documented therapies have been approved to improve sexual function in women with neurologic disorders; however, one recent report found that women with SCIs reported greater levels of subjective sexual arousal with the use of sildenafil as compared with placebo. Therefore, off-label use of this medication can be tried, and future studies should consider the potential for other medications to improve female sexual function.

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studied. No specific diagnostic test is readily available for female sexual dysfunction. Management currently depends on education and referral to a sexual counselor. Clinicians cognizant of sexual dysfunction medicine will be able to conduct the initial evaluation of these disorders and may be able to assist with counseling and referral to the appropriate professionals (sleep disorder specialist, endocrinologist, urologist, neurorehabilitationist, and sex therapist). By adopting a more active supervisory role, they ensure an adequate diagnostic evaluation and patient selection for the different treatment modalities. SUGGESTED READINGS Male Sexual Dysfunction

SUMMARY

Disorders of sexual performance in men include erectile and ejaculatory disturbances and should be distinguished from disorders in which a decrease in sexual desire is the principal rather than secondary mechanism. Clinical history is pivotal to characterize the dysfunction adequately and to search for the presence of risk factors or potential drug-induced conditions. Erectile dysfunction may be organic, psychogenic, or a combination of both. Nocturnal penile tumescence studies are crucial for reliable evaluation of these categories. Iatrogenic, endocrine, neurogenic, and vasculogenic mechanisms may underlie organic ejaculation dysfunction. There are no specific tests available to confirm the presence of the latter three mechanisms. Treatments may be specific or nonspecific to the cause. Ejaculatory disturbances include premature ejaculation and ejaculatory incompetence (primarily psychogenic) and dry ejaculation (exclusively organic). Dry ejaculation can be caused by defective seminal emission or retrograde ejaculation and can be distinguished by examination of a postmasturbation urine sample. Disorders of sexual performance in women include desire disorders, sexual arousal disorders, orgasmic disorders, and sexual pain disorders. Clinical history and examination are also pivotal in determining the underlying cause. The prototypical causes in the neurologic patient are represented by traumatic brain injury, spinal cord injury, and multiple sclerosis. Knowledge garnered as to prevalence and mechanisms in these conditions can then be used to try to understand the disorders that have been less well

16

Boller F, Frank E: Sexual Dysfunction in Neurological Disorders. Diagnosis, Management, and Rehabilitation. Raven Press, New York, 1982 Fowler CJ (ed): Neurology of Bladder, Bowel, and Sexual Dysfunction. Butterworth-Heinemann,Boston, 1999 Lechtenberg R, Old DA Sexual Dysfunction. Neurologic, Urologic and Gynecologic Aspects. Lea & Febiger, Malvern, PA, 1994 Schover LR, Jensen S B Sexuality and Chronic Illness. A Comprehensive Approach. Guilford Press, New York, 1988 Singer C, Weiner WJ: Sexual Dysfunction: A Neuro-Medical Approach. Futura, Armonk, NY, 1994

Female Sexual Dysfunction Basson R, Berman J, Burnett A et ak Report of the international development conference on female sexual dysfunction:definitions and classifications. J Urol 1632388, 2000 Korpelainen JT, Kauhanen JL,Kemola H et ak Sexual dysfunction in stroke patients. Acta Neurol Scand 98:400, 1998 Korpelainen JT,Nieminen P, Myllyla W: Sexual functioning among stroke patients and their spouses. Stroke 30715, 1999 Sipski ML, Alexander CJ (eds.): Maintaining Sexuality with Disability and Chronic Illness: A Practitioner’s Guide. Aspen Publishers, Gaithersburg, MD, 1997 Sipski ML, Alexander CJ,Rosen RC Sexual arousal and orgasm in women: effects of spinal cord injury. Ann Neurol4936-45, 2001 Sipski ML, Alexander CJ, Rosen RC, Hamer RM: Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury. Urology 55:812-815, 2000 Wermuth L, Stenager E Sexual problems in young patients with Parkinson’s disease. Acta Neurol Scand 91:453, 1995

Hydrocephalus and Disorders of Cerebrospinal Fluid Flow Sepideh Amin-Hanjani, William F. Pirl, Steven K. Feske, and Peter M. Black

Hydrocephalus is ventricular dilation caused by a disturbance in cerebrospinal fluid (CSF) circulation. This disturbance can occur anywhere in the CSF system. It is important to recognize hydrocephalus in the office practice of neurology and internal medicine because it can be associated with common complaints

such as headache, gait disturbance, and memory difficulty, and it can be treated successfully. Several terms are used to describe the anatomy of the particular hydrocephalic problem. Communicating hydrocephalus is characterized by continuity of the CSF in the ventricular system with the

Chapter 16

examination and to determine whether there are any treatable sources of sexual dysfunction, such as the use of medications. Once these sources of dysfunction are eliminated, one should educate the woman as much as possible about the impact that her particular neurologic problem might have on her sexual function. Education of the partner, review of other emotional and partner issues, and referral for sexual counseling should be considered. No documented therapies have been approved to improve sexual function in women with neurologic disorders; however, one recent report found that women with SCIs reported greater levels of subjective sexual arousal with the use of sildenafil as compared with placebo. Therefore, off-label use of this medication can be tried, and future studies should consider the potential for other medications to improve female sexual function.

Hydrocephalusand Disorders of Cerebrospinal Fluid Flow

159

studied. No specific diagnostic test is readily available for female sexual dysfunction. Management currently depends on education and referral to a sexual counselor. Clinicians cognizant of sexual dysfunction medicine will be able to conduct the initial evaluation of these disorders and may be able to assist with counseling and referral to the appropriate professionals (sleep disorder specialist, endocrinologist, urologist, neurorehabilitationist, and sex therapist). By adopting a more active supervisory role, they ensure an adequate diagnostic evaluation and patient selection for the different treatment modalities. SUGGESTED READINGS Male Sexual Dysfunction

SUMMARY

Disorders of sexual performance in men include erectile and ejaculatory disturbances and should be distinguished from disorders in which a decrease in sexual desire is the principal rather than secondary mechanism. Clinical history is pivotal to characterize the dysfunction adequately and to search for the presence of risk factors or potential drug-induced conditions. Erectile dysfunction may be organic, psychogenic, or a combination of both. Nocturnal penile tumescence studies are crucial for reliable evaluation of these categories. Iatrogenic, endocrine, neurogenic, and vasculogenic mechanisms may underlie organic ejaculation dysfunction. There are no specific tests available to confirm the presence of the latter three mechanisms. Treatments may be specific or nonspecific to the cause. Ejaculatory disturbances include premature ejaculation and ejaculatory incompetence (primarily psychogenic) and dry ejaculation (exclusively organic). Dry ejaculation can be caused by defective seminal emission or retrograde ejaculation and can be distinguished by examination of a postmasturbation urine sample. Disorders of sexual performance in women include desire disorders, sexual arousal disorders, orgasmic disorders, and sexual pain disorders. Clinical history and examination are also pivotal in determining the underlying cause. The prototypical causes in the neurologic patient are represented by traumatic brain injury, spinal cord injury, and multiple sclerosis. Knowledge garnered as to prevalence and mechanisms in these conditions can then be used to try to understand the disorders that have been less well

16

Boller F, Frank E: Sexual Dysfunction in Neurological Disorders. Diagnosis, Management, and Rehabilitation. Raven Press, New York, 1982 Fowler CJ (ed): Neurology of Bladder, Bowel, and Sexual Dysfunction. Butterworth-Heinemann,Boston, 1999 Lechtenberg R, Old DA Sexual Dysfunction. Neurologic, Urologic and Gynecologic Aspects. Lea & Febiger, Malvern, PA, 1994 Schover LR, Jensen S B Sexuality and Chronic Illness. A Comprehensive Approach. Guilford Press, New York, 1988 Singer C, Weiner WJ: Sexual Dysfunction: A Neuro-Medical Approach. Futura, Armonk, NY, 1994

Female Sexual Dysfunction Basson R, Berman J, Burnett A et ak Report of the international development conference on female sexual dysfunction:definitions and classifications. J Urol 1632388, 2000 Korpelainen JT, Kauhanen JL,Kemola H et ak Sexual dysfunction in stroke patients. Acta Neurol Scand 98:400, 1998 Korpelainen JT,Nieminen P, Myllyla W: Sexual functioning among stroke patients and their spouses. Stroke 30715, 1999 Sipski ML, Alexander CJ (eds.): Maintaining Sexuality with Disability and Chronic Illness: A Practitioner’s Guide. Aspen Publishers, Gaithersburg, MD, 1997 Sipski ML, Alexander CJ,Rosen RC Sexual arousal and orgasm in women: effects of spinal cord injury. Ann Neurol4936-45, 2001 Sipski ML, Alexander CJ, Rosen RC, Hamer RM: Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury. Urology 55:812-815, 2000 Wermuth L, Stenager E Sexual problems in young patients with Parkinson’s disease. Acta Neurol Scand 91:453, 1995

Hydrocephalus and Disorders of Cerebrospinal Fluid Flow Sepideh Amin-Hanjani, William F. Pirl, Steven K. Feske, and Peter M. Black

Hydrocephalus is ventricular dilation caused by a disturbance in cerebrospinal fluid (CSF) circulation. This disturbance can occur anywhere in the CSF system. It is important to recognize hydrocephalus in the office practice of neurology and internal medicine because it can be associated with common complaints

such as headache, gait disturbance, and memory difficulty, and it can be treated successfully. Several terms are used to describe the anatomy of the particular hydrocephalic problem. Communicating hydrocephalus is characterized by continuity of the CSF in the ventricular system with the

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subarachnoid space of the brain and spinal cord. Noncommunicating hydrocephalus occurs when there is a blockage in the ventricular system or its outlets so that the ventricles and the subarachnoid space are not in continuity. It is important to recognize this distinction because a lumbar puncture is unsafe in the noncommunicating form. Hydrocephalus ex vacuo is not actually a form of hydrocephalus but rather is a state of increased ventricular size resulting from loss of adjacent parenchymal tissue mass. Although hydrocephalus has many different manifestations, it is instructive to group cases into two clinical syndromes: high-pressure hydrocephalus and normal-pressure hydrocephalus (NPH), with gradations between them. Another abnormality of CSF dynamics, called pseudotumor cerebri or benign intracranial hypertension, represents a syndrome of increased intracranial pressure (ICP) without associated ventriculomegaly. At the other end of the spectrum lie symptoms related to low CSF pressure, known as the syndrome of intracranial hypotension. This chapter describes the clinical presentations, diagnosis, and management of CSF flow abnormalities in adults. Similar principles apply in children. Pseudotumor cerebri is also discussed in Chapter 6.

HYDROCEPHALUS Clinical Presentation: High-pressure Hydrocephalus The onset of high-pressure hydrocephalus can be acute, over hours to days, or chronic, over weeks to months. High-pressure hydrocephalus can be life-threatening, causing obtundation, coma, and death. Its symptoms are related to increased ICP. Headache is the most common complaint. The headache, usually bifrontal, is most severe in the morning; it tends to be worse when the patient lies flat and to be relieved by sitting, and it can be exacerbated by coughing. It can progress to a generalized headache and may even wake the patient at night. Nausea and vomiting commonly occur in association with the headache and are also most severe in the morning. The nausea is not associated with head movements or any abdominal discomfort. The patient may also complain of visual changes, including decreased visual acuity, diplopia, and an inability to look up. “Graying-out” of vision may occur if a pressure wave causes serious optic nerve vascular compromise. The gait disorder typically is an unsteady, broad-based gait that may first appear as slow and uncertain and then develop into short, staggering steps. Changes in mental status can range from impairment of recent memory, to confusion, to a depression of the level of consciousness. Signs of frontal lobe disorder with slowness of response, inattentiveness, distractibility, inability to plan or sustain complex actions, and perseveration may be present. However, in contrast to primary cortical dementias, such as Alzheimer’s disease, there is no aphasia, agnosia, or apraxia. Physical examination may reveal papilledema from increased ICP, but this is not invariably present. Testing of extraocular movements may reveal a lateral rectus weakness caused by compression of abducens nerve fibers. This is a sign of generalized increased ICP; it is not a localizing sign even when it is unilateral. Paralysis of upward gaze and of accommodation results from pressure on the tectal plate. Truncal ataxia may be present. Almost all cases of high-pressure hydrocephalus in adults are caused by an obstruction of flow through the ventricular system or subarachnoid pathways. This results in increased mean pulsatile pressures in the ventricular system and a consequent increase in

Principles of Diagnosis: Common Presenting Symptoms

TABU 16-1. Some Causes of Adult Normal-Pressure Hydrocephalus Cause Subarachnoid hemorrhage Idiopathic Head injury Tumors Prior surgery Aqueduct stenosis Meningitis Others

Percentage

34 34 11 6 5 3 3 4

Modified from Kakman R Low pressure hydrocephalus. p. 29. In Wells CE (ed): Dementia. FA Davis, Philadelphia, 1977, with permission.

ventricular size. The ventricles continue to expand until the pressure can no longer be compensated, eventually leading to central herniation and death. An obstruction can occur anywhere along the CSF pathway. The causes are the same as those listed in Table 16-1 for NPH. Even with a specific cause, there may be no localizing signs to help the examiner discern the underlying cause. Subarachnoid hemorrhage is the most common cause of obstruction, with hydrocephalus occurring in as many as 67% of cases of subarachnoid hemorrhage. Because of this frequency, patients with a subarachnoid hemorrhage should be monitored for symptoms of hydrocephalus for up to 3 weeks after the event. Tumors causing obstruction of the ventricles or their outflow are another important cause of high-pressure hydrocephalus. In addition to intraventricular tumors, tumors may also obstruct the ventricular system extrinsically. Posterior compression of the third ventricle can result from a pineal tumor or inferior compression from a craniopharyngioma or pituitary adenoma. Similarly, the fourth ventricle can be compressed by posterior fossa tumors. Aqueduct stenosis, a congenital disorder that may present in adulthood, should also be seriously considered in the differential diagnosis. Clinical Presentation: Normal Pressure Hydrocephalus

NPH is characterized by enlargement of the ventricles and normal CSF pressure. It has a number of known causes, but the most common type is idiopathic NPH, which comprises about 50% of cases. It is best diagnosed by its clinical presentation: the classic triad of gait disturbance, disturbances in mentation (usually slowing of thought and action), and urinary incontinence. Symptoms of high-pressure hydrocephalus such as headache, nausea and vomiting, and visual changes are not seen. Gait Disorder. Gait disturbance is the most prominent symptom in NPH and is usually the earliest in onset. It has been described as unsteady or uneven, and patients often complain of falling. The gait is characterized by its wide base, slow speed, short steps, and vertical ataxia. (Patients place their feet on the ground with variable force.) Patients sometimes describe feelings of weakness in their legs, and they may actually be consuming more energy in walking than is normal. The problems with walking can progress to complete inability to walk and even inability to stand or sit because of unsteadiness. However, the gait disorder appears to be more of a frontal gait apraxia, which poses difficulties in organizing a smooth gait, rather than an actual ataxia. The same patients with NPH who are unable to walk demonstrate unimpaired functioning of the legs when lying on their back. There may also be some upper extremity involvement with tremor and deterioration of handwriting.

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Gait disorders are regularly encountered in older adults, and NPH accounts for only a small percentage of these cases. Some features of the disordered gait of NPH may help to distinguish it from other causes of gait disorder, although the distinction often may be difficult. Patients with Alzheimer’s disease may have a gait disorder, but compared to NPH, the gait tends to be shuffling and scuffing with increased double-support stride. It occurs late in Alzheimer’s disease, after cognitive deterioration. Cerebellar ataxia must also be considered in the differential diagnosis. In contrast to the vertical ataxia of NPH, in cerebellar ataxia, movements of the legs are more variable in the transverse and sagittal planes. Other features of cerebellar incoordination, such as dysmetria and terminal tremor, are not present in NPH. Parkinson’s disease is also characterized by a gait disorder and may be confused with NPH because both can display bradykinesia, increased tone, and dysarthria. However, the parkinsonian gait is described as hesitant with festination, en bloc turning, flexed posture, and lack of accessory movements such as arm swinging. In addition, cogwheel rigidity and masked facies are distinguishing features of Parkinson’s disease. Patients with Binswanger’s disease or multi-infarct dementia may also present with a frontal gait disorder that is indistinguishable from NPH, although patients with NPH tend to present at a later age and more often have gait disturbance at onset. Disturbance of Mentation. A variety of mental changes have been described in NPH, ranging from mild memory loss to severe dementia. Impairment of recent memory is the most common complaint. However, a more characteristic finding in NPH than memory loss is a general slowing of thought and action. A loss of initiative, spontaneity, and interest may progress to apathy and abulia. Responses and voluntary movements are slow and delayed. Some cognitive impairment may be present with verbal abilities unaffected, whereas nonverbal tasks such as copying, drawing, and arranging objects become difficult. Changes in mood, behavior, and personality may also be evident. This clinical picture represents a subcortical type of dementia, often encountered in older adults, which may be very difficult to distinguish from other subcortical dementias such as multi-infarct dementia, from depression, and, at times, from cortical dementias such as Alzheimer’s disease. Alzheimer’s disease can be distinguished by aphasia, agnosia, and apraxia, which are not components of the dementia of NPH. The changes in mentation seen in Alzheimer’s disease occur much earlier than the gait disturbance, which is usually a late symptom. In NPH, gait disorder usually precedes or occurs concurrently with changes in mentation. Major depression may present as a pseudodementia with memory loss and psychomotor retardation; however, neurovegetative symptoms and depressed mood should be present. Incontinence is generally not seen in depression. Binswanger’s disease and the multi-infarct state may cause a dementia very similar to that of NPH and pose a diagnostic difficulty that can be resolved only by other tests, such as magnetic resonance imaging (MRI). Incontinence. Urinary incontinence is the third part of the NPH triad, and although it is common in NPH, it is not seen with the same frequency as gait disorder and changes in mentation. It may occur as a late symptom. The incontinence ranges from a sense of urgency to a frontal lobe type of incontinence in which the appropriate awareness of the need to urinate is lost, leading to a loss of sphincter control. Fecal incontinence is rare. Urinary incontinence can also be seen in atrophic processes such as Alzheimer’s disease. Physical Examination. The physical examination reveals no focal signs unless there is a specific cause of NPH, such as tumor.

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Papilledema is absent, and extraocular movements and upward gaze are intact. Tone may be normal, or a frontal, paratonic-type hypertonicity may be appreciated. Weakness is not present, but limb movement may be slow. Increased tendon reflexes may be observed, and a positive Babinski sign may be present in one or both feet. Sucking or grasping reflexes may appear in later stages. No sensory loss is seen. Cerebellar ataxia is not present. Patients may be unable to perform tandem walking, and they often have positive Romberg signs. Gait difficulties are as described earlier in this chapter. Etiology. NPH can be caused by anything that results in low-grade scarring or obstruction of the ventricular system or subarachnoid pathways. The causes are listed in Table 16-1. Subarachnoid hemorrhage is the most common cause of NPH with a known cause. Other causes include meningitis, partial obstruction of the CSF pathways by tumor, cranial radiation, and neurosurgery, particularly after a posterior fossa operation. NPH may follow trauma that causes a subarachnoid hemorrhage that subsequently obstructs the basal cisterns. Less commonly, it may follow an obstruction of a major venous sinus or the third ventricle and its outflow. Aqueduct stenosis more often leads to high-pressure hydrocephalus, but it may cause NPH as well. Idiopathic NPH, seen in a large number of cases, is more common in patients who are over 60. They are the most difficult group to treat. Pathogenesis. In the pathogenesis of NPH, Hakim and Adams (1965) have suggested that there is an initial rise in CSF pressure that leads to ventricular enlargement. This enlargement is maintained despite normal pressure because of the relationship of pressure and area described by LaPlace’s law (pressure = force/ area). The increased force on the ventricular wall is distributed at a lower pressure over the greater area of the enlarged ventricular wall. Even though the pressure appears normal most of the day, continuous ICP monitoring in some patients also shows periods of increased ICP waves at night. Investigation Studies

The purpose of ancillary testing in patients with hydrocephalus is twofold to establish a reliable diagnosis and to predict the utility of CSF diversion in treating the disorder. Once a patient has presented with a clinical picture suggestive of hydrocephalus, the initial diagnostic test of choice is computed tomography (CT) or MRI. An unenhanced scan visualizes the ventricular contours, and contrast enhancement may reveal otherwise indistinguishable underlying lesions. The cardinal features of hydrocephalus include enlargement of ventricles, with rounding of the ventricular contour; the presence of periventricular lucencies, especially around the frontal horns (although this finding on MRI is not specific); and normal-sized or diminished subarachnoid spaces. Enlargement of the subarachnoid spaces and prominent cortical sulci suggest atrophy with ex vacuo ventricular enlargement. There are advantages to MRI over CT. MRI is better than CT for identifying underlying lesions, such as small periaqueductal or posterior fossa tumors. MRI is also the modality best equipped to assess parenchymal disease seen with Binswanger’s disease or multi-infarct dementia, which may be difficult to distinguish from NPH on clinical grounds alone. Furthermore, sagittal imaging with MRI may help to distinguish hydrocephalus from atrophy by showing features that suggest hydrocephalus, such as thinning and bowing of the corpus callosum. However, periventricular hypointensity on TI-weighted MRI is less specific and can be seen

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in the setting of edema, ischemia, demyelination, and other disorders. In addition to anatomic determinations, MFU can show CSF flow patterns through the aqueduct of Sylvius. A variety of MRI techniques have been applied to establish flow and pulsatility patterns through the Sylvian aqueduct in patients with hydrocephalus. Recent reports suggest that these techniques may have value in differentiating the various types of hydrocephalus, although their reliabilityin predicting shunt responsiveness in NPH remains to be determined. Cisternography has been used in the past to evaluate CSF dynamics in patients with ventricular enlargement and suspected NPH. However, it appears to have little usefulness today. It is performed by intrathecal injection of a radioactive isotope (isotope cisternography) or contrast material and serial CT scanning (CT cisternography). The passage of the isotope or contrast into the ventricles and subarachnoid space is visualized. A normal pattern shows flow over the convexities and not into the ventricles. The typical pattern of NPH is ventricular entry and stasis without ascent over the convexities. Most patients show a mixed pattern. Recent reports indicate that cisternography provides no additional diagnostic accuracy over the combination of clinical and CT criteria. Determination of CSF pressure by lumbar puncture is an important component of diagnosis in some patients. Patients who do not have findings of high-pressure hydrocephalus and are suspected clinically to have NPH without an identifiable cause should undergo lumbar puncture. An opening pressure less than 180 mm H,O in this group of patients is consistent with a diagnosis of idiopathic NPH. The value of shunting in such patients may be further elucidated by a lumbar puncture with removal of approximately 50 mL fluid. Alternatively, serial lumbar punctures, which presumably create an ongoing dural leak acting as a temporary shunt, can be performed. Clinical improvement after large-volume lumbar puncture, especially of gait, predicts a good response to shunting. Temporary lumbar drainage has been suggested as a further maneuver for predicting shunt responsiveness. Continuous ICP monitoring can also help to identify patients with idiopathic NPH who are likely to benefit from CSF diversion. Monitoring can be performed using a frontal ventricular catheter, lumbar catheter, or epidural transducer, all of which allow prolonged pressure recording over at least 24 hours. Increased baseline CSF pressure or pressure waves (A or B waves) can be used as criteria for shunt responsiveness. B waves appear particularly useful. An adjunct to prolonged pressure recording is the use of infusion tests to assess resistance to CSF absorption. Lumbar infusion of normal saline has been shown to detect prolonged increases in ICP, indicating deficits in CSF absorptive capacity. A well-proven technique involves measuring CSF conductance by lumboventricular perfusion. Outflow resistance greater than 12.5 mL/minute/mm Hg has been correlated with improvement after shunting. The disadvantages of these testing modalities are their invasiveness and potential for equivocal measurements of CSF outflow resistance. They may offer prognostic information for shunting in a selected group of patients with idiopathic NPH in whom less invasive testing has been inconclusive. Recently the acetazolamide challenge test, looking at changes in cerebral blood flow and ICP in response to acetazolamide administration, has been advocated as a diagnostic test in patients with suspected NPH, but its reliability has yet to be determined.

There is some evidence that functional tests such as single photon emission computed tomography, which shows patterns of cerebral blood flow; positron emission tomography, which demonstrates brain metabolism; and magnetic resonance spectroscopy, which measures ratios of chemical markers in the brain, may help to differentiate NPH from other causes of dementia and may also be of some predictive value in determining shunt responsiveness. However, these tests are still under investigation and need further validation before they enter mainstream clinical practice. Electroencephalography and evoked responses have no utility in the diagnosis of hydrocephalus.

Decision Making and Management The optimal management of a patient with suspected hydrocephalus relies on the strength of the clinical diagnosis and the validity of ancillary tests aimed at prognostication. When making management decisions, it is useful to consider separately the clinical entities that result from high- and normal-pressurehydrocephalus. The patient with symptoms of increased ICP and ventriculomegaly, who is acutely deteriorating as indicated by a worsening level of consciousness or loss of vision, needs emergent neurosurgical consultation for placement of ventriculostomy. In less acute situations involving high-pressure hydrocephalus, CSF diversion by operative placement of a shunt is indicated. In cases of hydrocephalus secondary to an obstructive mass, however, primary management that includes removal of the mass may relieve the hydrocephalus. Operative removal is increasingly the treatment of choice, given recent improvements in microsurgical technique, although there may be a need for CSF diversion at a later date. Preoperative shunting carries the risk of upward tentorial herniation with large midline cerebellar masses, as well as the potential for spreading malignant cells to the peritoneum via the shunt. Another method of CSF diversion that has regained popularity in recent years is intracranial CSF diversion by means of endoscopic fenestration of the third ventricle. This procedure typically is performed in cases with lateral and third ventricles enlarged disproportionately to fourth ventricles. A fenestration is created in the floor of the third ventricle into the basal CSF cisterns, thus avoiding the need for permanent shunt placement. The definitive treatment for NPH is shunting, but poor responses in some groups and possible complications must be considered in the decision to proceed with shunt placement. Patients with the diagnosis of NPH as supported by the clinical syndrome and CT findings should undergo careful evaluation for an underlying cause. When a clear cause is present, such as recent subarachnoid hemorrhage, meningitis, evidence of aqueduct stenosis, or obstructive tumor, shunting is the treatment of choice and is associated with good outcome. As with high-pressure hydrocephalus caused by a mass, it is reasonable to remove an obstructive lesion as primary management for NPH. For cases of idiopathic NPH the decision is more complex. Numerous clinical findings and tests have been advocated as predictors of shunt responsiveness, some of which are discussed earlier in this chapter. Many studies have addressed this issue. The following parameters have consistently proven to be good prognosticators for shunt response: NPH of known cause Shorter duration of symptoms (although long duration is not a contraindication) Prominent gait disturbance

Chapter 16

Improvement after serial lumbar punctures or lumbar drainage Altered CSF dynamics as demonstrated by long-term monitoring or infusion testing, especially lumboventricular perfusion A CT scan showing periventricular lucency Studies of shunt responsiveness report response rates in the range of 30% to 80%. In our experience about two thirds of patients improve and perhaps 5% may worsen in some way with shunt placement. Differences in outcome may result from differential selection for shunting and analysis of outcomes. Standardized preshunting selection criteria may increase the likelihood of improvement. Of special interest are patients with ventricular enlargement who are free of symptoms related to hydrocephalus. The incidental finding of ventriculomegaly on imaging in such patients should prompt careful evaluation for subtle symptoms or signs of hydrocephalus. If the patient is truly asymptomatic, no further investigation or intervention is indicated; however, interval follow-up to assess the possible development of symptoms is warranted.

PSEUDOTUMOR CEREBRI (BENIGN INTRACRANIAL HYPERTENSION) Pseudotumor cerebri is a syndrome of increased ICP without ventriculomegalyor intracranial mass or inflammation. Although the cause is not known, several features seem to contribute to the mechanism of ICP elevation. Prior subarachnoid hemorrhage, central nervous system infection, and marked CSF protein elevation, as may be seen in inflammatory demyelinating radiculoneuropathies, may lead to a syndrome identical to idiopathic pseudotumor cerebri. This suggests that the functional lesion is an increased resistance to CSF flow at the level of the arachnoid granulations. Modeling of such a lesion suggests that it could cause ICP elevation without ventriculomegaly. Also, conditions that raise central venous pressure, such as obesity and chronic obstructive pulmonary disease with right-sided heart failure, may contribute to an identical state of intracranial hypertension. Raised intracranial venous pressure contributes a hydrostatic resistance to absorption of CSF at the level of the arachnoid granulations. It is probable that both lesions contribute to the decompensation of CSF homeostasis that culminates in symptomatic pseudotumor cerebri.

Clinical Presentation The most common patient is a young, obese woman. The major clinical symptoms are headache and visual symptoms that reflect the elevated ICP. The headache usually is dull and continuous and often nonspecific in quality, or it may have features suggestive of elevated ICP, such as worsening in the early morning, in the recumbent position, and with coughing or straining. Patients may complain of visual blurring, scotomas, or visual obscurations. The last are sudden, brief losses of vision in one or both eyes attributable to ICP elevations. Patients may also complain of double vision caused by an abducens paresis. It is thought that the abducens nerve is vulnerable to high ICP because of its long exposure to the subarachnoid space, Pulsatile tinnitus has also been reported as a symptom suggestive of pseudotumor cerebri. When ICP elevation is severe, nausea, vomiting, and depression of

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TABLE 16-2. Causes of Pseudotumor Cerebri Increased venous pressure Sinus obstruction High-flow arteriovenous malformation lntracranial dural arteriovenous fistula Chronic obstructive pulmonary disease with cor pulmonale Obstructive sleep apnea Endocrine related Pregnancy, menarche, oral contraceptives Obesity Corticosteroid use or withdrawal Hypoparathyroidism Thyroid replacement Toxic or metabolic Hypervitaminosis A or hypovitaminosis A Drug related (e.g., nalidixic acid, tetracycline, lithium, growth hormone) Malnutrition or refeeding Idiopathic

the level of alertness may occur, as with intracranial hypertension from other causes. The common physical findings are diminished visual acuity, enlargement of the blind spots, and constriction of the visual fields. Almost all patients have papilledema with loss of spontaneous venous pulsations and blurring and elevation of the optic disc head. Pseudotumor cerebri with normal disks has been reported but is rare. Eye movements may be normal, or there may be unilateral or bilateral abducens paresis. Trochlear nerve paresis has been reported, but this is rare. The neurologic examination is otherwise typically normal. Much of the history-taking and examination is directed toward identifying or excluding potential underlying causes (Table 16-2). By far, the most common underlying contributor is obesity. However, idiopathic pseudotumor cerebri has been reported as a result of vitamin A toxicity and toxicity to tetracyclines, lithium, and more recently to recombinant human growth hormone. It has also been reported to occur after withdrawal of corticosteroid therapy. Therefore, all of these exposures should be sought in the history. Conditions that have resulted in blood products, inflammation, or protein elevation in the subarachnoid space may cause an identical clinical syndrome, so a history of such problems should be sought as well. Also, pregnancy may cause a patient to decompensate and come to medical attention, so women with child-bearing potential should be tested for pregnancy. Conditions that obstruct the cerebral venous drainage may cause an identical condition of elevated ICP. Cerebral venous thrombosis may present with isolated intracranial hypertension. Also, patients with intracranial dural arteriovenous fistulas or patients having had endovascular therapy affecting cerebral venous drainage may have intracranial hypertension. Therefore, given the availability of noninvasive and sensitive brain imaging with MRI, it is best to rule out such disorders with brain MRI and with magnetic resonance venogram sequences. Although small series have shown that the yield of such imaging will be low if done on patients with suspected idiopathic pseudotumor cerebri, there is no other noninvasive way to exclude such treatable lesions. Patients with inflammatory conditions, such as sarcoidosis, systemic lupus erythematosus, or Behget’s disease, can also present with isolated, and often recurrent, intracranial hypertension. CSF analysis is necessary to exclude such inflammatory disorders as well as infections and leptomeningeal infiltration with tumor. Medical conditions that might underlie intracranial hypertension include obesity, chronic obstructive lung disease with cor pulmonale, pickwickian syndrome, obstructive sleep apnea, and

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possibly primary aldosteronism. These should be considered, especially when the presentation is atypical, such as in older patients, men, and nonobese patients. Also, cranial synostoses may predispose patients to intracranial hypertension.

Investigational Studies The diagnosis of pseudotumor cerebri is confirmed by radiologic imaging followed by lumbar puncture. Imaging of the brain by CT or MRI will show no mass lesions or other underlying cause of elevated ICP. The ventricles may be normal or small and slitlike. An “empty sella” is a common finding, and such patients may have normal pituitary function or only subtle abnormalities. MRI and magnetic resonance venography exclude cerebral venous sinus thrombosis. Lumbar puncture reveals elevated ICP, usually greater than 300 mm H20, and CSF that is characteristically normal in composition or shows only a low CSF protein level. There is no evidence of inflammation or protein elevation in truly idiopathic cases. Other investigations may be needed to address possible underlying conditions, as discussed earlier.

Principlesof Diagnosis: Common PresentingSymptoms

INTRACRANIAL HYPOTENSION

Clinical Presentation As with syndromes of elevated ICP, headache often is the presenting symptom of intracranial hypotension. Symptoms can develop after lumbar puncture, CSF shunts, spinal surgery or trauma, or invasive tumor eroding the skull base, but they often develop spontaneously with no apparent precipitating factor. The hallmark of intracranial hypotension is postural headache, worst when in the upright posture and completely relieved in the recumbent posture. When spontaneous, the cause is believed to be a dural tear, often in the cervical or thoracic spinal region, with resultant CSF leak from the subarachnoid space. The loss of CSF causes low ICP. The loss of the buoyant effect of the CSF causes traction on dural and vascular elements, especially in the upright position. The leak may not be evident and may be difficult to localize. The headache may be accompanied by nausea, vomiting, dizziness, and meningismus. Straining and coughing tend to exacerbate the headache. Other presentations include cranial nerve palsy, especially sixth nerve palsy. Visual symptoms can also be present in the form of photophobia or blurred vision.

Decision Making and Management The most important therapeutic goal is to preserve vision. Patients should have a periodic ophthalmologic examination with perimetry testing of the visual fields. And any deterioration should prompt more aggressive therapies to preserve vision. All obese patients should be encouraged to lose weight. A weight loss of several percent in many cases greatly lowers the ICP. Medical therapy may also include acetazolamide. There is some controversy about the mechanism and effectiveness of this agent. It decreases production of CSF and probably promotes absorption. Most patients tolerate it well; occasionally patients complain of distal paresthesias. Electrolytes should be followed, although significant metabolic acidosis is uncommon at the usual therapeutic dosages. Patients may begin with long-acting acetazolamide 500 mg twice daily. Dosages of 500 to 2000 mg, and occasionally more, may be effective. Most patients appear to respond well to acetazolamide even when efforts to lose weight are unsuccessful, as is often the case. Patients may respond to single or serial lumbar puncture and CSF drainage. This can be used as a temporizing therapy in patients with reversible causes or sometimes until spontaneous remission occurs. When medical therapy is inadequate, surgical therapy with optic nerve sheath fenestration or CSF drainage by lumboperitoneal or ventriculoperitoneal shunting may be necessary. Optic nerve sheath fenestration is preferred when visual loss is the issue because of its lower complication rate. However, when headaches are a major problem, it cannot be expected to relieve them. Pseudotumor cerebri in pregnancy raises some special issues. Pregnant women should not try to lose weight during the pregnancy, but weight gain should be carefully limited to 20 lb or less. Although not an established teratogen and probably safe during pregnancy, acetazolamide is best reserved until after the first trimester. If vision is stable, sometimes lumbar punctures can be used to temporize until delivery provides relief. However, when visual loss is progressive or when other effects of severe intracranial hypertension occur, then surgical decompression should be performed during pregnancy.

Investigational Studies In cases of suspected spontaneous intracranial hypotension, the diagnosis can be confirmed by lumbar puncture, which demonstrates a low ICP, generally less than 50 mm H20. CSF may be normal, but slight elevation of CSF protein and lymphocytic pleocytosis, consistent with relative flow stasis, may mimic CSF inflammatory and infectious disorders. Enhanced MRI typically reveals a diffuse dural enhancement, often accompanied by dural thickening, felt to represent engorgement of dural vasculature in the setting of reduced ICP. Additional findings can include subdural fluid collections and descent of the brain including downward displacement of the cerebellar tonsils. Radioisotope cisternography or contrast myelography can be used to detect sites of CSF leakage, often identified within the cervical or cervicothoracic regions.

Decision Making and Management In cases of iatrogenic intracranial hypotension occurring after dural puncture, the problem generally is self-limiting over the course of 2 to 4 days. Use of oral or intravenous hydration or caffeine has not consistently proven beneficial. Symptomatic headache relief can be achieved with the use of an abdominal binder to indirectly increase epidural venous pressure. The syndrome is most effectively treated with placement of an epidural blood patch, performed by inserting 10 to 20 mL of autologous blood into the epidural space in proximity to the level of the dural puncture. The procedure carries an initial success rate of greater than 90%. Spontaneous intracranial hypotension is a more elusive problem, but it can potentially be treated with a blood patch. This procedure has been successful both after localization of the dural leak and also blindly when no site of leakage can be identified. Surgical intervention to eliminate the source of the leak occasionally is warranted. Various other treatments have been advocated including complete bed rest for more than 2 weeks, continuous

Chapter 16

intrathecal or epidural saline infusions, and the conservative measures used to treat headaches after dural puncture. Shunts

Shunt Systems. Currently the commonly used systems for CSF diversion are ventriculoperitoneal,ventriculoatrial, ventriculopleural, and lumboperitoneal shunts. The most widely used is the ventriculoperitoneal shunt. The components of a typical CSF diversion system include the following: Proximal catheter: ventricular or lumbar catheter. A ventricular catheter is inserted into the right frontal horn via a right frontal or right parieto-occipital burr hole. A lumbar catheter for lumbar CSF diversion is an option in communicating hydrocephalus and carries the advantage of avoiding ventricular puncture and general anesthesia. However, lumbar shunts have a much greater tendency for obstruction and have generally fallen out of favor, except in conditions such as pseudotumor cerebri when the baseline ventricular size is small. Distal tubing. Silastic tubing is attached to the proximal catheter and tunneled subcutaneously to the distal site of drainage, that is, the peritoneal cavity (ventriculoperitoneal and lumboperitoneal shunts), the right atrium via the common facial vein (ventriculoatrial shunt), or the pleural cavity (ventriculopleural shunt). Valve. A valve is interposed between the proximal and distal shunt components, usually near the site of the ventricular catheter. It regulates the pressure and prevents retrograde flow of shunted CSF. Several valve designs exist, including spring-loaded, slit, or resistance valves, which vary by their mechanism of outflow regulation. These are fixed-pressure valves functioning at high, medium, or low settings. More recently, variable-pressure valves, which allow percutaneous adjustment of pressure settings, have become available. These valves allow the surgeon to fine-tune ICP in shunted patients without the need for reoperation. The ideal opening pressure of the valve for hydrocephalic patients is controversial. Ancillary components: ventricular reservoir and antisiphon device. Ventricular reservoirs are commonly placed proximal to the valve system in ventricular shunts and are generally palpable. They serve as an access for extracranial measurement of the ICP, CSF removal, and testing of the shunt system. When shunted patients are in an upright position, the ICP may become subatmospheric, leading to overdrainage. Antisiphon devices are designed to prevent intraventricular pressure from falling below atmospheric pressure at the level of the antisiphon device, thus preventing overdrainage.

Shunt-Related Complications. The most important shuntrelated complications are discussed in the following sections. OBSTRUCTION.Shunt obstruction can be insidious, intermittent, or sudden and presents with clinical deterioration indicative of shunt malfunction. The ventricular catheter may become obstructed by debris, coagulum, or contact with choroid plexus or brain secondary to decreased size of the ventricles. Proximal catheter obstruction is the most common cause of shunt

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malfunction. The distal end may become blocked in ventriculoperitoneal shunts by omentum or peritoneal adhesions. Tapping a reservoir may confirm shunt obstruction and define where it is. Shunt blockage necessitates surgical exploration and revision. INFECTIO The N. rate of shunt infections in adults is less than 5%, which is lower than the rate in the pediatric population. Infection can manifest in several ways: wound infection at the site of shunt insertion, ventriculitis and meningitis, or secondary infection of the vascular system, including endocarditis (ventriculoatrial shunts) and peritoneal infection (ventriculoperitoneal shunts). However, most commonly, shunt infection presents insidiously as shunt malfunction, and typical findings of meningitis generally are not present. Most infections occur immediately after or within a few months of shunt insertion and generally are attributed to bacterial contamination during surgery. Shunt infection may also occur in the setting of systemic infection, such as pneumonia or urinary tract infection. The most common pathogens are Sraphylococcus epiderrnidis and, less often, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The general approach to shunt infection is removal of the entire shunt system and external ventricular drainage until the infection has cleared after a full course of intravenous antibiotics. SUBDURAL COLLECTIONS.Collections of low-protein fluid, called subdural hygromas, may develop after placement of a shunt with low pressure. These probably represent effusions that develop in response to the excess space in the cranial vault unoccupied by brain matter. Subdural collections of blood or fluid generally are a result of overdrainage. Use of higher-pressure valves or variablepressure valves that allow graded ventricular decompression may decrease the incidence of this complication. For symptomatic collections, burr hole drainage is attempted initially. It may be necessary to temporarily clamp off the shunt so that the brain can expand and occlude the subdural space or to place a shunt catheter in the subdural collection. Subdural hematomas may form after the shunting of hydrocephalus as a result of tears in the cortical bridging veins when the brain matter has not yet adequately expanded to fully occupy the increased cranial space caused by fluid drainage. Even minor head trauma can increase the risk of subdural hematoma. Symptoms of overdrainage often mimic those of OVERDRAINACE. underdrainage; they include headache, nausea and vomiting, lethargy, diplopia, impaired upgaze, and visual impairment. However, unlike those of increased ICP, the symptoms of overdrainage typically are worse when the patient is upright and are relieved when lying down. Overdrainage can give rise to two distinct syndromes: the low ICP syndrome, which can be distinguished by positional measurement of ICP, and the slit ventricle syndrome, which is apparent on CT or MRI as reduction of the ventricles to subnormal size. The latter syndrome is more prominent in the pediatric population but may be seen in adults who were initially shunted at a young age. Encroachment of the ventricular walls onto the draining catheter leads to intermittent or complete CSF obstruction with accompanying signs and symptoms of suddenly increased ICP. For unclear reasons that may relate to decreased compliance of the system, the ventricles do not enlarge despite shunt obstruction. Both of these syndromes necessitate shunt revision with substitution of a new system, perhaps incorporating an antisiphon device or a valve with higher opening pressure. MECHANICAL FAILURE. Disconnection of shunt components or fracture of the Silastic tubing at stress points may occur, especially

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with head trauma. Palpation of the subcutaneous shunt tubing throughout its length may reveal a gap or bulge at the site of disconnection. A radiographic shunt series, comprising a selection of films showing anteroposterior and lateral views of the skull, chest, kidneys, ureter, and bladder and lateral views of the abdomen, depending on shunt type, can be helpful in determining the site of disconnection. Surgical exploration and revision are necessary in cases of mechanical failure. SHUNT Tm-SpEanc CoMmxnoNs. Ventricular shunts carry a small risk (approximately5%) of seizures;the incidence of seizures may be decreased with the use of an occipital rather than a frontal catheter. Prophylactic anticonvulsant medication is not indicated in routine management. Ventriculoatrial shunts carry the unique risk of thromboembolic episodes such as pulmonary embolism; with the shunt materials currently in use, these risks are small. Lumboperitoneal shunts often obstruct and have been associated with acquired tonsillar herniation. Evaluation of a Patient with Suspected Shunt Malfunction. Shunt malfunction must be suspected in patients presenting with headache, nausea and vomiting, lethargy, or visual changes. These patients should be evaluated for signs of increased ICP, including papilledema and abducens or upward gaze palsy. Alternatively, shunt malfunction may manifest as a recurrence of prior hydrocephalic symptoms, such as worsening of gait, memory, or incontinence. In fact, regression of clinical improvements at any time after shunt placement should raise the question of shunt malfunction. The clinical deterioration often is stereotyped in any one patient. Malfunction is most often a consequence of obstruction, infection, or malposition of the shunt system. On physical examination, palpation of the shunt tubing may reveal disconnection. Palpation and compression of the valve suggest blockage of the ventricular catheter if the valve can be compressed but refills very slowly, Blockage in the valve or distally is likely if the valve is incompressible. A normally working shunt should allow easy valve emptying and refill within 5 to 30 seconds. However, valve pumping is not considered to be a reliable indicator of shunt function, and some shunt systems have no palpable valve. A shunt series is of variable benefit because disconnection is an uncommon cause of shunt malfunction. It is indicated if there is clear suspicion of disconnection on examination. To determine the CSF pressure, lumbar puncture or tapping of the shunt reservoir can be performed. Lumbar puncture is preferable if it can be performed safely because shunt tapping carries a 1% risk of infection. A shunt tap should be considered an invasive procedure and necessitates meticulous attention to sterile technique. Neurosurgical consultation before the procedure is warranted. An attempt to withdraw CSF after puncture of the reservoir may help to localize the site of malfunction. Inability to withdraw suggests proximal obstruction at the level of the ventricular catheter. Easy withdrawal suggests distal obstruction. It is important to note that flushing of the system via shunt tap is unwise because it may further increase an already decompensating ICP. A shuntogram can be performed by injecting water-soluble iodine contrast dye into the reservoir, followed by serial radiographs over 30 minutes. The test is aimed at defining a site of obstruction and indicating the rate of dye clearance from the system. However, results often are inconclusive, and shuntograms are not commonly used. Ultimately, surgical exploration can identify the source of malfunction. It is important to exclude infection in any malfunction, so CSF should be analyzed at the time of lumbar puncture, shunt tap, or operative revision.

Principles of Diagnosis: Common Presenting Symptoms

SUGGESTED READINGS Adams RD, Victor M: Principles of Neurology. 5th Ed. McGraw-Hill, New York, 1993 Benzel EC, Pelletier AL., Levy PG Communicating hydrocephalus in adults: prediction of outcome after ventricular shunting procedures. Neurosurgery 26655, 1990 Black PM: Hydrocephalus and vasospasm following subarachnoid hemorrhage from ruptured intracranial aneurysm. Neurosurgery 18:12, 1986 Black PM, Hakim R, Olsen Bailey N The use of the Codman-Medos programmable Hakim valve in the management of patients with hydrocephalus: illustrative cases. Neurosurgery 3 4 1 110, 1994 Black PM, Ojemann RG, Tzouras A CSF shunts for dementia, incontinence and gait disturbances. Clin Neurosurg 32:632, 1985 Boon AJ, Tans JT, Delwel EJ et al: The Dutch normal-pressure hydrocephalus study. How to select patients for shunting: An analysis of four diagnostic criteria. Surg Neurol 53(3):201-207, 2000 Borgesen SE, Gjerris F The predictive value of conductance to outflow of CSF in normal pressure hydrocephalus. Brain 105:65, 1982 Brightball TC, Goodwin RS, Ford RG Magnetic resonance imaging of intracranial hypotension syndrome with pathophysiological correlation. Headache 40292-299, 2000 Corbett JJ, Digre K Idiopathic intracranial hypertension: an answer to, “the chicken or the egg?” Neurology 58:5-6, 2002 Crockard HA, Hanlon K, Duda EE, Mullan J F Hydrocephalus as a cause of dementia: evaluation by computerized tomography and intracranial pressure monitoring. J Neurol Neurosurg Psychiatry 40:736, 1977 Digre KB, Varner MW, Corbett JJ: Pseudotumor cerebri and pregnancy. Neurology 34721-729, 1984 Fisher C M Hydrocephalus as a cause of disturbancesof gait in the elderly. Neurology 32:1358, 1982 Friedman DI: Pseudotumor cerebri. Neurosurg Clin N Am 10609-621, 1999 Gallassi R, Morreale A, Montagna P et al: Binswanger’s disease and normal-pressure hydrocephalus: a clinical and neuropsychological comparison. Arch Neurol48:1156, 1991 Haan J, Thomeer RTWM: Predictive value of temporary external lumbar drainage in normal pressure hydrocephalus. Neurosurgery 22:388, 1988 Hakim R, Black PM: Correlation between lumboventricular perfusion and MRI-CSF flow studies in idiopathic normal pressure hydrocephalus. Surg Neurol4914-20, 1998 Hakim S, Adams RD: The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure: observations on cerebrospinal fluid hydrodynamics. J Neurol Sci 2:307, 1965 Hussey F, Schanzer B, Katzman R A simple constant-infusion manometric test for measurement of CSF absorption. 11. Clinical studies. Neurology 20:665, 1970 Jagust WJ, Friedland RP, Budinger TF: Positron emission tomographywith [ “F] fluorodeoxyglucosedifferentiates normal pressure hydrocephalus from Alzheimer-type dementia. J Neurol Neurosurg Psychiatry 4 8 1091, 1985 Kamiya K, Yamashita N, Nagai H, Mizawa I: Investigation of normal pressure hydrocephalus by 1231-IMPSPECT. Neurol Med Chir 31:503, 1991 Katayama S, Asari S, Ohmoto T Quantitative measurement of normal and hydrocephalic cerebrospinal fluid flow using phase contrast cine MR imaging. Acta Med Okayama 47:157, 1993 Katzman R Low pressure hydrocephalus. In Wells CD (ed.): Dementia. FA Davis, Philadelphia, 1977 Larsson A, Jensen C, Bilting M et al: Does the shunt opening pressure influence the effect of shunt surgery in normal pressure hydrocephalus? Acta Neurochir (Wien) 117:15, 1992 Larsson A, Wikkelso C, Bilting M, Stephensen H: Clinical parameters in 74 consecutive patients shunt operated for normal pressure hydrocephalus. Acta Neurol Scand 84475, 1991 Mascalchi M, Ciraolo L, Bucciolini M et al: Fast multiphase MR imaging

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of aqueductal CSF flow: 2. Study in patients with hydrocephalus.AJNR 11:597, 1990 McQuarrie IG, Saint-Louis L, Scherer PB: Treatment of normal pressure hydrocephalus with low versus medium pressure cerebrospinal fluid shunts. Neurosurgery 15:484, 1984 Miyake H, Ohta T, Kajimoto Y et ak Diamox challenge test to decide indications for cerebrospinal fluid shunting in normal pressure hydrocephalus. Acta Neurochir 141:1187-1193, 1999 Morgan MK, Johnston IH, Spittaler PJ: A ventricular infusion technique for the evaluation of treated and untreated hydrocephalus. Neurosurgery 29832, 1991 Nitz WR, Bradley WG, Watanabe AS et al: Flow dynamics of cerebrospinal fluid assessment with phase-contrast velocity MR imaging performed with retrospective cardiac gating. Radiology 183:395, 1992 OCarroll CP, Brant-ZawadzkiM: The syndrome of spontaneous intracranial hypotension. Cephalalgia 19:8&87, 1999 Puca A, Anile C, Maira G, Rossi G: Cerebrospinal fluid shunting for hydrocephalus in the adult: factors related to shunt revision. Neurosurgery 29322, 1991 Pudenz RH, Foltz E L Hydrocephalus: overdrainage by ventricular shunts: a review and recommendations. Surg Neurol35:200, 1991 Raftopoulos C, Chaskis C, Delecluse F et ak Morphological quantitative analysis of intracranial pressure waves in normal pressure hydrocephalus. Neurol Res 14389, 1992 Roman G C White matter lesions and normal-pressure hydrocephalus: Binswanger’s disease or Hakim syndrome?AJNR 12:40, 1991 Shiino A, Matsuda M, Morikawa S et ak Proton magnetic resonance spectroscopy with dementia. Surg Neurol39: 143, 1993 Sindou M, Guyotat-Pelissou, Chidiac A, Goutelle A Transcutaneous pressure adjustable valve for the treatment of hydrocephalus and

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arachnoid cysts in adults: experience with 75 cases. Acta Neurochir (Wien) 121:135, 1993 Sorensen PS, Jansen EC, Gjerris F Motor disturbance in normal-pressure hydrocephalus: special reference to stance and gait. Arch Neurol 143:34, 1986 Sudarsky L, Ronthal M: Gait disorders among elderly patients: a survey study of fifty patients. Arch Neurol40740, 1983 Symon L, Dorsch NWC Use of long-term intracranial pressure measurement to assess hydrocephalic patients prior to shunt surgery. J Neurosurg 42:258, 1975 Tam& N, Nagashima T, Ehara K et ak Hydrocephalic oedema in normal-pressure hydrocephalus. Acta Neurochir 51(Suppl):348, 1990 Vanneste J, Augustin P, Davies GAG et ak Normal-pressure hydrocephalus: is cisternography still useful in selecting patients for a shunt? Arch Neurol 49:366, 1992 Vanneste J, Augustin P, Dirven C et ak Shunting normal-pressure hydrocephalus:do the benefits outweigh the risks? A multicenter study and literature review. Neurology 42:54, 1992 Waldemar G, Schmidt JF, Delecluse F et ak High resolution SPECT with 99MTc-d,l-HMPAO in normal pressure hydrocephalus before and after shunt operation. J Neurol Neurosurg Psychiatry 56:655, 1993 Welch K, Shillito JS, Strand R et ak Chiari I malformation: an acquired disorder? J Neurosurg 55:604, 1981 Wikkelso C, Anderson H, Bloomstrand C, Lindqvist G The diical effect of lumbar puncture in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 45:64, 1982 Wood JH, Bartlet D, James AE, Udvarhelyi G B Normal-pressure hydrocephalus: diagnosis and patient selection for shunt surgery. Neurology 24517, 1974

Traumatic Brain Injury Michael P. Alexander

This chapter covers three aspects of traumatic brain injury (TBI) that may involve neurologists: the mild injury in the emergency room, the spectrum of problems of severe TBI, and the office management of mild TBI, including that of the patient who never recovers.

ACUTE MANAGEMENT OF munmnc BRAIN INJURY In the United Kingdom 10% of all emergency room visits are for TBI, mostly minor. Of the patients with minor TBI, most have no neurologic deterioration and do not need hospital care. Approximately 2% deteriorate and may need neurosurgical management. As summarized by Vollmer and coworkers (1991), “the major practical problem in [minor TBI] involves developing a management scheme that prevents delay in treatment of the small number of intracranial complications without causing excessive rates of hospitalization, inconvenience, and cost to the vast majority of patients.” In the mid-1980s in both the United Kingdom and the United States, multidisciplinary groups proposed management schemes. During the same decade, prospective studies from Scotland provided data sufficient to stratify overall risk for different segments of the minor TBI population. This stratification of risk has been supported by several additional investigations. The large prospective series carried out by Teasdale and colleagues (1990) in Glasgow illuminates the real locus of risk. A

Glasgow Coma Scale (GCS) score of 15 with no skull fracture carries a 1 in 6000 risk of deterioration. A GCS score of 15 with a skull fracture carries a risk of 1 in 32. A GCS score of 13 or 14 without skull fracture has a risk of 1 in 21, but with skull fracture the risk increases to 1 in 4. In the entire group, a skull fracture alone raises the risk of deterioration 400-fold. Studies from the United States also demonstrate the substantially lower risk of deterioration in the GCS 15 group (approximately 2% overall in several studies) compared with the GCS 13 or 14 group. Most investigators now do not consider a patient with a GCS score of 13 or 14, that is, with any impairment of consciousness in the emergency room, as a minor, low-risk case. The Glasgow Coma Scale is given in Table 17-1. In the United Kingdom, Shackford and colleagues (1992) identified several criteria as the indicators of increased risk, and it is recommended that any patient with even one criterion be admitted for observation and computed tomography (CT) scanning. These criteria are as follows: Confusion o r altered level of consciousness in the emergency room (i.e., GCS 13 to 14) Skull fracture Neurologic signs or severe headache or vomiting Difficult assessment (e.g., young age, intoxication) Other high-risk medical conditions (e.g., use of anticoagulants) N o reliable home observer

Chapter 17

of aqueductal CSF flow: 2. Study in patients with hydrocephalus.AJNR 11:597, 1990 McQuarrie IG, Saint-Louis L, Scherer PB: Treatment of normal pressure hydrocephalus with low versus medium pressure cerebrospinal fluid shunts. Neurosurgery 15:484, 1984 Miyake H, Ohta T, Kajimoto Y et ak Diamox challenge test to decide indications for cerebrospinal fluid shunting in normal pressure hydrocephalus. Acta Neurochir 141:1187-1193, 1999 Morgan MK, Johnston IH, Spittaler PJ: A ventricular infusion technique for the evaluation of treated and untreated hydrocephalus. Neurosurgery 29832, 1991 Nitz WR, Bradley WG, Watanabe AS et al: Flow dynamics of cerebrospinal fluid assessment with phase-contrast velocity MR imaging performed with retrospective cardiac gating. Radiology 183:395, 1992 OCarroll CP, Brant-ZawadzkiM: The syndrome of spontaneous intracranial hypotension. Cephalalgia 19:8&87, 1999 Puca A, Anile C, Maira G, Rossi G: Cerebrospinal fluid shunting for hydrocephalus in the adult: factors related to shunt revision. Neurosurgery 29322, 1991 Pudenz RH, Foltz E L Hydrocephalus: overdrainage by ventricular shunts: a review and recommendations. Surg Neurol35:200, 1991 Raftopoulos C, Chaskis C, Delecluse F et ak Morphological quantitative analysis of intracranial pressure waves in normal pressure hydrocephalus. Neurol Res 14389, 1992 Roman G C White matter lesions and normal-pressure hydrocephalus: Binswanger’s disease or Hakim syndrome?AJNR 12:40, 1991 Shiino A, Matsuda M, Morikawa S et ak Proton magnetic resonance spectroscopy with dementia. Surg Neurol39: 143, 1993 Sindou M, Guyotat-Pelissou, Chidiac A, Goutelle A Transcutaneous pressure adjustable valve for the treatment of hydrocephalus and

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arachnoid cysts in adults: experience with 75 cases. Acta Neurochir (Wien) 121:135, 1993 Sorensen PS, Jansen EC, Gjerris F Motor disturbance in normal-pressure hydrocephalus: special reference to stance and gait. Arch Neurol 143:34, 1986 Sudarsky L, Ronthal M: Gait disorders among elderly patients: a survey study of fifty patients. Arch Neurol40740, 1983 Symon L, Dorsch NWC Use of long-term intracranial pressure measurement to assess hydrocephalic patients prior to shunt surgery. J Neurosurg 42:258, 1975 Tam& N, Nagashima T, Ehara K et ak Hydrocephalic oedema in normal-pressure hydrocephalus. Acta Neurochir 51(Suppl):348, 1990 Vanneste J, Augustin P, Davies GAG et ak Normal-pressure hydrocephalus: is cisternography still useful in selecting patients for a shunt? Arch Neurol 49:366, 1992 Vanneste J, Augustin P, Dirven C et ak Shunting normal-pressure hydrocephalus:do the benefits outweigh the risks? A multicenter study and literature review. Neurology 42:54, 1992 Waldemar G, Schmidt JF, Delecluse F et ak High resolution SPECT with 99MTc-d,l-HMPAO in normal pressure hydrocephalus before and after shunt operation. J Neurol Neurosurg Psychiatry 56:655, 1993 Welch K, Shillito JS, Strand R et ak Chiari I malformation: an acquired disorder? J Neurosurg 55:604, 1981 Wikkelso C, Anderson H, Bloomstrand C, Lindqvist G The diical effect of lumbar puncture in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 45:64, 1982 Wood JH, Bartlet D, James AE, Udvarhelyi G B Normal-pressure hydrocephalus: diagnosis and patient selection for shunt surgery. Neurology 24517, 1974

Traumatic Brain Injury Michael P. Alexander

This chapter covers three aspects of traumatic brain injury (TBI) that may involve neurologists: the mild injury in the emergency room, the spectrum of problems of severe TBI, and the office management of mild TBI, including that of the patient who never recovers.

ACUTE MANAGEMENT OF munmnc BRAIN INJURY In the United Kingdom 10% of all emergency room visits are for TBI, mostly minor. Of the patients with minor TBI, most have no neurologic deterioration and do not need hospital care. Approximately 2% deteriorate and may need neurosurgical management. As summarized by Vollmer and coworkers (1991), “the major practical problem in [minor TBI] involves developing a management scheme that prevents delay in treatment of the small number of intracranial complications without causing excessive rates of hospitalization, inconvenience, and cost to the vast majority of patients.” In the mid-1980s in both the United Kingdom and the United States, multidisciplinary groups proposed management schemes. During the same decade, prospective studies from Scotland provided data sufficient to stratify overall risk for different segments of the minor TBI population. This stratification of risk has been supported by several additional investigations. The large prospective series carried out by Teasdale and colleagues (1990) in Glasgow illuminates the real locus of risk. A

Glasgow Coma Scale (GCS) score of 15 with no skull fracture carries a 1 in 6000 risk of deterioration. A GCS score of 15 with a skull fracture carries a risk of 1 in 32. A GCS score of 13 or 14 without skull fracture has a risk of 1 in 21, but with skull fracture the risk increases to 1 in 4. In the entire group, a skull fracture alone raises the risk of deterioration 400-fold. Studies from the United States also demonstrate the substantially lower risk of deterioration in the GCS 15 group (approximately 2% overall in several studies) compared with the GCS 13 or 14 group. Most investigators now do not consider a patient with a GCS score of 13 or 14, that is, with any impairment of consciousness in the emergency room, as a minor, low-risk case. The Glasgow Coma Scale is given in Table 17-1. In the United Kingdom, Shackford and colleagues (1992) identified several criteria as the indicators of increased risk, and it is recommended that any patient with even one criterion be admitted for observation and computed tomography (CT) scanning. These criteria are as follows: Confusion o r altered level of consciousness in the emergency room (i.e., GCS 13 to 14) Skull fracture Neurologic signs or severe headache or vomiting Difficult assessment (e.g., young age, intoxication) Other high-risk medical conditions (e.g., use of anticoagulants) N o reliable home observer

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Principles ofAmbulatoy Neurology and the Approach to Clinical Problems W

W TABU 17-1. The Clasgow Coma Scale

Eye Opening None

To pain To speech Spontaneous

1 2

3 4

Not attributable to ocular swelling Pain stimulus is applied to chest or limbs Nonspecific response to speech or shout, does not imply the patient obeys command to open eyes Eyes are open, but this does not imply intact awareness

Motor Response

No response Extension

1 2

Abnormal flexion

3

Withdrawal

4

Localized pain

5

Obeys commands

6

Flaccid "Decerebrate." Adduction, internal rotation of shoulder, and pronation of the forearm "Decorticate." Abnormal flexion, adduction of the shoulder Normal flexor response; withdraws from pain stimulus with abduction of the shoulder Pain stimulus applied to supraocular region or fingertip causes limb to move so as to attempt to remove it Follows simple commands

Using the U.K. criteria, all 5 patients would have been admitted for observation or CT scanning: 4 for focal signs and 1 for intoxication. (Recall that all 310 were actually admitted.) Using the U.S. criteria, 4 would have had immediate CT scan (focal signs), and 1 would have been observed. It is impossible to predict how many others would have been observed. Servadei and associates (1993) reported 113 patients with GCS scores of 15 who were referred to a neurosurgical center because of a positive CT scan; 95% also had a skull fracture on radiograph. The 5 patients without fracture included 4 with ''small'' hemorrhages not necessitating surgery and 1 child who would have been observed or had a CT scan by both U.S. and U.K. criteria. This is a clinical management problem that every hospital with an emergency room probably should resolve through a quality improvement project. The current literature supports the following scheme (Fig. 17-1): Any patient with minor TBI with focal signs or GCS scores of 13 or 14 (i.e., altered mental state) in the emergency room should have a head CT scan. Patients with GCS 15 and no focal signs should be sent home if there was no loss of consciousness or amnesia, there are no worrisome medical issues, there is no intoxication, they are older than 14 years, and the home setting is secure. Patients with a GCS score of 15 and no focal signs but had unequivocal loss of consciousness and amnesia should have a CT or, if not available, plain skull radiography. If CT is negative, patients should be sent home. If skull radiographs are negative for fracture and if there are no medical issues, patients may be sent home. If plain films demonstrate a skull fracture, patients should be sent for CT or be kept for observation depending on relative costs, time of day, and local preferences.

Verbal Response

Self-explanatory Moaning and groaning but no recognizable words Intelligible speech (e.g., shouting or swear3 inappropriate ing) but no sustained or coherent conversation 4 Patient responds to questions in a converConfused sational manner, but the responses indicate varying degrees of disorientation and confusion 5 Normal orientation to time, place, and Oriented Derson Summed Glasgow Coma !kale Score = E + M + V (3 to 15). No response incomprehensible

1 2

In the United States, Masters and colleagues (1987) proposed a three-tiered strategy. For the mildest cases with no loss of consciousness, a normal neurologic examination, and no clinical signs of basilar skull fracture, discharge to home is appropriate. For patients with a history of loss of consciousness and amnesia but with normal examination results, extended observation and consideration of CT are recommended. For patients with GCS scores of 13 or 14 or with focal signs, immediate CT is indicated. There are problems with both sets of recommendations. The U.K. criteria generate a large number of admissions. The patients probably are not closely observed, given the low risk of clinical problems, and the high number of admissions are costly. Recent analysis suggests also that the criteria are too easily ignored, often just to avoid the paperwork of admissions in a low-risk group. The U.S. criteria probably underestimate the value of skull radiographs in narrowing the population at risk. The U.S. criteria for moderate cases ignore the large number of likely missed skull fractures with the markedly increased risk of possible deterioration. It has also been difficult to implement the use of these criteria. Recent studies clarify how these apparently different approaches, which entail observation, skull radiographs, and CT scans, result in fairly similar outcomes. Taheri and coworkers (1993) in the United States reported 310 consecutive admissions with a GCS score of 15; 5 (1.6%) patients deteriorated (i.e., needed neurosurgery). AU 5 patients who deteriorated were among the 10 patients with skull fracture. Of the 273 patients who had skull radiographs but no fracture, there were no delayed deteriorations.

Principles of Diagnosis: Common Presenting Symptoms

Shackford's group, in their major multicenter U.S. study, used a retrospective analysis of the role of CT in minor TBI assessment and came to similar conclusions, although the nature of the study limits its utility for prospective management decisions. A more important discovery was the frighteningly high number of admitted patients (30.2%) who had no documentation of any follow-up neurologic examination. CT scanning is the practice preference. In small hospitals without CT, local preferences should be spelled out as specific practice guidelines, and a quality improvement committee should follow compliance for risk management purposes. BEHAVIORAL NEUROLOGY OF SEVERE TRAUMATIC BRAIN INJURY

Patients with severe TBI usually are treated by neurosurgeons, often in the intensive care unit when they need respiratory assistance. There are only a few points to note regarding acute care: H

H

There is no definite role for prophylactic anticonvulsants beyond the first week after the injury. The value of dexamethasone is unknown. Even hyperventilation is of uncertain overall value, balancing reduced edema against vasoconstriction with possible ischemia, although it is always reasonable management. New classes of agents that may reduce or block cell death in the acute period are under study, and these may become available in the near future.

Chapter 17

ER GCS 13-14

ER GCS 15 FOCAL SIGNS

ER GCS 15 NO FOCAL SIGNS UNEQUIVOCAL LOC OR AMNESIA

ER NO NO NO

W

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GCS 15 FOCAL SIGNS LOC AMNESIA

\ El

FRACTURE PRESENT

\N O

MEDICAL PROBLEMS AGE 14

F R AC T u R E

-1NTOXlCATlON

- NO TO ALL

POOR HOME SETTING

I

\ pKl

YES TO ANY

0 BSERVATION FIG. 17-1. Suggested emergency room (ER) management of mild TBI. Cr, computed tomography; CCS, Clasgow Coma Scale; LOC, loss of consciousness.

A specific diagnosis of the injury type is needed for the neurologic treatment of severe TBI survivors at a rehabilitation center. DiffuseAxonal Injury

Sudden acceleration-deceleration is the most important physical agent of TBI. Powerful inertial forces are generated. The microscopic structure of the brain leaves it most susceptible to inertial shear injury. Shearing disrupts axons and small blood vessels. Axonal disruptions lead to eventual cell death and, perhaps, to downstream neuronal injury from release of excitatory neurotransmitters. Small blood vessel injury can produce simple petechial hemorrhages, which are maximal in parasagittal white matter-increasing centripetally from the cortex to deep white matter-or focal or diffuse edema. This entire neuropathologic picture is called diffuse axonal injury, and clinical severity is directly related to the extent of neuronal and vascular damage. Recovery from diffuse axonal injury is highly correlated with several measures of injury severity, including GCS, duration of coma, and duration of post-traumatic amnesia. The clinical evolution of diffuse axonal injury beginning with coma follows characteristic stages: 1. Coma: no eye opening, no verbalization, no meaningful

response

have no motor impairments, severe cases may include a variety of motor deficits reflecting parasagittal, deep white matter lesions, superior cerebellar outflow and midbrain tegmental lesions, and, in the most severe cases, deeper brainstem lesions. As a rule, patients should receive inpatient rehabilitation until the transition from stage 5 to stage 6, from which point they can be treated at home. The transition from coma to functional competence depends on the severity of diffuse axonal injury. The mildest possible diffuse axonal injuries probably are “ding” injuries in sports. Careful assessment of a well-motivated patient with “ding” demonstrates recovery over 7 to 10 days. For injuries with brief loss of consciousness and 20 to 60 minutes of post-traumatic amnesia, the common concussion, the recovery period probably is 1% to 6 months. For more severe mild TBI with post-traumatic amnesia lasting longer than 60 to 90 minutes (GCS 13 or 14), recovery might take 4 to 12 months. As severity measures increase, recovery takes longer. These times are much longer than most neurologists realize. Recovery in this context refers to demonstrable cognitive and motor deficits. In many cases, recovery really means “resolution of all deficits.” In others, usually among more severe injuries, recovery means reaching a stable plateau of residual deficits. In all patients normal processes of adaptation, learning, and plasticity allow lifelong improvement of function. Only the most severe cases stall at stages 2 through 5.

2. Unresponsive wakefulness: eye opening (vegetative state) 3. Mute vigilance: watchful, irregular - direct responsiveness

F o a l Cerebral Contusions

Note that even at stage 7, there may be residual cognitive impairments. Although many patients with diffuse axonal injury

In addition to diffuse axonal injury, TBI can cause focal cerebral contusions. These may occur directly at a point of contact, but most are caused by inertial forces driving the basal frontal and temporal cortex into rough adjacent bony surfaces. Focal cerebral contusions are abrasions that originate in cortex, include disruption of vascular structures, and may cause physical disruption, ischemic injury, or hemorrhagic injury of adjacent white matter. , These abrasions may be seen anywhere, but the inferior and anterior temporal and orbital and polar frontal regions are most

I

4. Responsive confusional state: severe impairment in attention and memory, which may be quiet, agitated, or fluctuating 5. Oriented cognitive impairment: recovered day-to-day memory and usually independent basic self-care (physical limitations allowing) 6. Supervised functional independence 7. Independent functional competence

I

.

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hinciples of Ambulatory Neurology and the Approach to Clinical Problems

common. Focal cerebral contusions have very poor correlation with the markers for severity of diffuse axonal injury, that is, the initial GCS score and loss of consciousness. In fact, patients with focal cerebral contusions may never, or only transiently, have been unconscious; that is, they may have had apparently minor TBI. Patients with multiple focal cerebral contusions, especially those with accompanying subdural hematomas, have a very high mortality rate. The clinical profile of focal cerebral contusions depends on location, number, and size. In the most common locations, behavioral problems predominate. Damage to orbital frontal cortex produces poor regulation of emotions with overreactivity, irritability, social disruptiveness, and lability. Damage to the polar frontal cortex produces impaired complex, motivated behaviors with shallow and distractible problem solving and disorganized complex social behaviors. Recovery depends on size, depth, and number of these contusions; they are often bilateral and symmetrical. The timing of recovery is similar to other focal destructive lesions, such as infarcts and hemorrhages. Recovery is potentially rapid for 2 to 4 months and then is flatter. It is important to note the similarity between the cognitive clinical profiles of late severe diffuse axonal injury and frontal focal cerebral contusions and also to note the markedly different probabilities of very late recovery between severe diffuse axonal injury (good) and focal cerebral contusions (poor). Hypoxic-Ischemic Injury

Although diffuse axonal injury and focal cerebral contusions are the defining injuries of TBI, hypoxic-ischemic injury is also, common in more severe cases and in certain cases of herniation, often from epidural hematomas. DiKuse hypoxic-ischemic injury is caused by a mixture of factors, including edema, increased intracranial pressure, local vascular damage, and systemic shock or chest or airway injury impairing ventilation; there may be no specific clinical markers beyond clinical suspicion. Diffuse hypoxic-ischemic injury has a dramatically worse prognosis for recovery for any given duration of loss of consciousness, falling to essentially zero when the loss of consciousness associated with this injury lasts for 7 days. Focal hypoxic-ischemic injury usually is caused by posterior cerebral artery entrapment lesions caused by herniation. Clinical consequences are the same as those predicted for more common posterior cerebral artery infarctions and depend on whether it is temporal or occipital and whether it is left, right, or bilateral. Recovery patterns mimic infarctions of more common origins. Mixed Pathologies Many patients have a mixture of pathologies, with GCS scores determined by severity of diffuse axonal injury or severity of early herniation. Duration of coma is determined by severity of diffuse axonal injury or hypoxic-ischemic injury. Post-traumatic amnesia is determined by severity of diffuse axonal injury, severity of diffuse hypoxic-ischemic injury, or location of focal cerebral contusions. Long-term outcome is determined by severity of diffuse axonal injury and diffuse hypoxic-ischemic injury and by location, size, and number of focal cerebral contusions and focal hypoxic-ischemic injury. The long-term prospects of patients over 40 years old are delayed and constrained. Patients with severe TBI seen months to years after injury and after acute rehabilitation may present because of seizures or some

Principles of Diagnosis: Common PresentingSymptoms

other neuromedical problem such as headaches or spasticity, because of behavioral or cognitive problems, or for advice about the next stages in rehabilitation. Competence in detailed mental status assessment and absolute clarity about the relative role of diffuse axonal injury and focal cerebral contusions in the clinical profile are necessary for behavioral and cognitive diagnoses because of their differing prognoses. If not previously performed, magnetic resonance imaging (MRI) is essential. It has advantages in revealing old focal cerebral contusions, particularly for demonstrating basal focal cerebral contusions without bone artifact, and for demonstrating residual signs of petechial hemorrhages from diffuse axonal injury (paramagnetic foci). Neuropsychological assessment is essential in characterizing cognitive limits and strengths. Treatment

Treatment issues that arise in the late assessment of patients with severe TBI are of two types: retraining or remediation and behavioral. The late rehabilitation recommendations are determined by three factors: the patient’s profile of deficits, the probable prognosis for improvement and learning as determined by the neuropathology, and financial, personal, and social resources. Rehabilitation of severe TBI is emotionally draining for patients and families. It is expensive and may take a long time and enormous patience. As noted earlier, the deficits usually are predominantly cognitive and behavioral. Neuropsychological and neuropsychiatric assessment are essential to proper characterization. Postacute rehabilitation of cognitive deficits takes several possible forms. There are programs that attempt to combine direct treatment of cognitive deficits with compensatory strategies for the patient, family, and workplace or school. The claims of direct treatment of attentional, memory, or other cognitive deficits are controversial for three reasons. First, it has been hard to demonstrate efficacy beyond natural recovery. Second, it has been difficult to demonstrate generalization of any recovered process for tasks beyond those trained. Third, the treatment tasks often lack common sense. If you want a patient to be able to work as a receptionist again, why have that patient do computer vigilance tasks? Why not do simplified “receptionist vigilance” tasks? Programs of direct treatment often are called cognitive rehabilitation, and they demand skepticism. The only class I study of this form of cognitive rehabilitation was unable to show any benefit, despite an adequate sample size, excellent compliance, careful follow-up, and psychosocial support. A second type of program emphasizes the compensation strategies and directly treats only tasks of functional relevance, such as budgeting, handling checks, riding public transportation, and filling out applications. These programs do not suffer from the three weaknesses of direct treatment programs, but they must be judged by how they match treatment goals with reasonable neurological prognoses and the patients’ real-life needs. These programs may also be called cognitive rehabilitation. The two types of programs differ in the claims that they make for treatment. Physicians should know the structure of the programs to which they refer patients. For some patients behavioral disorders are a primary obstacle to functional recovery. Behavioral management also depends on precise diagnosis. Only a taste of the diagnostic dilemmas can be presented here. For instance, does a patient with a unilateral frontal polar contusion have low motivation because of limitations

Chapter 17

in higher-order mental processes such as goal setting, setting mental representation of strategies to goals, or organizing complex activities? Or is the patient depressed? Or both? Does a patient with disinhibition and intrusive behavior have an attentional problem related to severe diffuse axonal injury, to orbitofrontal injury, to anxiety, or to a combination of these? Neuropsychiatric assessment may clarify these questions. Treatment may involve behavioral treatment, perhaps cognitively based, as in the second program type described above, or perhaps behaviorally based. Treatment may also be pharmacologic. There are two overriding lessons about drug treatment. First, there are no magic potions for the patient with TBI. For every patient with periodic agitation who responds to haloperidol, there is another who does not but who responds to benzodiazepines. There are concrete reasons not to use all known drugs in patients with TBI, such as motor side effects or worsened alertness. Claims for several generations of mood regulators in TBI, such as carbamazepine, propanolol, and valproic acid are only weakly supported. Second, when a clear psychiatric disorder is established, even if it is believed to be neurogenic, treatment should start with the same agents that have been efficacious in the purely psychiatric form of the disorder. Patients with severe diffuse axonal injury often can make good functional recovery even if their basic neurologic deficits and limitations do not change. Careful use of progressively more demanding rehabilitation programs leading to vocational and educational programs is always justified. Patients with substantial frontal focal cerebral contusions typically do not benefit greatly, but behavioral and compensatory strategies may improve their function within a particular setting if realistic goals are set.

BEHAVIORAL NEUROLOGY OF MINOR TRAUMATIC BRAIN INJURY

As reviewed earlier, minor TBI is defined by injury characteristics, not by outcome characteristics. Some patients with minor TBI have a bad functional outcome, and some with severe TBI have an excellent outcome; the outcome does not define the injury. As mentioned earlier, there is no reliable biologic marker for severity, although functional imaging or cognitive evoked potentials may yet provide such a marker. At present, minor TBI is defined by a melange of clinical measures: GCS at first examination, duration of loss of consciousness, and duration of post-traumatic amnesia. There are patients with minor TBI by those measures who have intracerebral hemorrhages, or “complicated minor TBI.” Complicated cases should be set aside from this discussion and considered as part of the spectrum of severe TBI. As outlined earlier, it is currently believed that diffuse axonal injury underlies all of these injuries, with minor TBI cases simply having less injury than severe ones. There may be crucial idiosyncratic differences in the location of diffuse axonal injury between cases that account for differences in outcome, but at present these potential differences cannot be detected clinically or with imaging. This uncertainty should induce humility in clinicians willing to write off deficits as psychogenic. Although it is customary to view GCS scores of 13 to 15 as minor, both in the emergency room and in outcome, there are probably differences between patients who have a GCS score of 15 and those who have GCS scores of 13 or 14. The mildest TBIs are the “ding” injuries and, perhaps, the pure inertial injuries from whiplash without loss of consciousness. In the modal mild TBI, there is brief loss of consciousness (less than 1 to 2 minutes),

Traumatic Brain Injury

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post-traumatic amnesia, including much of the accident scene or even transport to the emergency room (20 to 60 minutes), and a GCS score of 15 in the emergency room. Retrograde amnesia often is remarkably brief if inquired about after post-traumatic amnesia has cleared. In more severe mild TBI, loss of consciousness may last up to 1 hour and post-traumatic amnesia up to 24 hours, and GCS scores may be 13 or 14 in the emergency room. These cases clearly shade into severe TBI with GCS scores of 11 to 12 and post-traumatic amnesia of 1 to 2 days. The more prolonged the injury measures, the more severe the injury. This discussion briefly covers four topics: the natural history of neurologic recovery; the other injuries associated with brain injury, such as head and neck, vestibular, and psychological injuries, that together produce the postconcussive syndrome; the natural history of postconcussive syndrome; and the persistent postconcussive syndrome. Neurologic Recovery The primary neurologic deficits of minor TBI are in attention and memory. It is arguable that other deficits, in complex mental operations often called executive functions and in behavioral regulation, are caused by these two primary deficits. Many patients also complain of sleep disorders. This may represent primary damage to sleep structures, or it may be caused by superimposed pain states, medications, enforced inactivity,or attentional deficits. Numerous studies have demonstrated that recovery of attention and memory takes a long time even in the mildest cases. “Ding” injuries seem to take 7 to 10 days to recover. The modal cases may take 1% to 6 months. Increasing age above 40 years may prolong these times. In the last few years there have been numerous reports on mild TBI in athletes. Boxing, soccer, football, and hockey have high rates of concussion. The major consequences in these patients probably result from the number of actual concussions, not the cumulative occurrence of nonconcussive head injuries. The time to recover from these mild “ding” injuries, even in wellconditioned, young, highly motivated athletes, is several days. During that time reaction times are prolonged, and the risk of additional injury is high. This is the rationale for restricting risk even in apparently unaffected or recovered subjects for at least a few days. Whether a second concussion shortly after the first can produce catastrophic brain injury (“second impact syndrome”),at least in adults, is controversial, but a second concussion before an earlier concussion has recovered greatly prolongs recovery time. In the later stages of recovery, deficits may be subtle, and well-designed tasks, such as information processing, choice reaction times, and stressed recall tasks, may be needed to demonstrate them. Some patients may even have effectively recovered and still show subtle deficits. The more subtle the deficits, the more they are affected by situational, psychological, comorbid medical, and premorbid personal factors. The same mild deficit in sustained attention may be much more symptomatic in a 46-year-old police officer with daily headaches and a sick spouse than in a 19-year-old part-time student who is otherwise asymptomatic and living with parents. There is no formula that maps neuropsychologicaldeficits (at least mild ones) directly onto functional status. There are no known treatments that accelerate recovery. Note that the times to recover are much longer than the “few days’ rest” often prescribed. The key management action is to arrange sufficient time for recovery, allowing for comorbid injuries, age, and employment status.

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Principles of Ambulatoy Neurology and the Approach to Clinical Problems

Injuries Associated with PostconcussiveSyndrome

When heads hit windshields, more than the brain may be injured. The head may be injured, with lacerations, abrasions, fractures, and other injuries. The peripheral vestibular system may be disrupted. The neck may be strained. For that matter, systemic injuries may be severe enough to cause the minor TBI to be overlooked as care is directed to other life-threatening injuries. Finally, patients with mild TBI may have an experience that patients with severe TBI never have. They may remember the injury circumstances if not the actual point of injury. The psychological traumas-anxiety, fear, guilt-are accessible to many patients with mild TBI. Headache, cervical strain, and peripheral vestibular disorders are dealt with elsewhere in this text, but a few points relevant to TBI should be mentioned here. Patients with evidence of cervical soft tissue injury need early appropriate symptomatic treatment: limited immobilization, including cervical pillows, physical therapy, and analgesics. The emergence of headaches unrelated to simple local trauma is nearly universal after minor TBI. Most of these clear in days to weeks, and simple analgesics are sufficient. Acute peripheral vestibular injury can be treated with rest and vestibular suppressants, such as clonazepam, although sedation may be an unacceptable side effect in these patients, and the medications may slow adaptation and recovery. Patients with severe psychological trauma, including feelings of responsibility for a fatality, nightmares, or avoidance behaviors, should receive early counseling. Depression and anxiety have independent incidences of more than 40% in the first 6 months after concussion. The likely time course of recovery must be established early. Patients should understand the high probability of recovery, but they should receive assistance during this time. Natural History of Postconcussive Syndrome

The interaction of neurologic deficits, pain, vestibular injury, psychological trauma, other systemic injuries, and psychosocial disruptions, such as financial loss, temporary unemployment, and increased time at home, is the postconcussive syndrome. The most common symptoms are headache, poor memory, poor sleep, poor concentration, dizziness, anxiety, depression, and a variety of sensory sensitivities (e.g., photophobia, positional vertigo, hyperacusis). Most are multifactorial. Symptoms decline after the first few weeks to 40% to 50%, after a few months to 30%, and by 1 year to 15% to 20%. Treatment was discussed earlier in this chapter. The neurologic injury takes time to heal. Symptomatic treatment of other injuries is essential. Psychological counseling may be needed. A plan for gradual restitution of preinjury activities will prevent patients from returning too quickly and failing or from struggling in their routine activities and thus increasing psychological stress. Penistent Postconcussive Syndrome

Postconcussive syndrome is considered persistent when it is present for 1 year; in many patients, symptoms increase over time. Several studies have shown that symptoms in patients with persistent postconcussive syndrome undergo a shift from purely somatic initially to increasingly psychological vegetative symptoms. A number of factors are said to be associated with an increased risk of persistent postconcussive syndrome: female sex, ongoing litigation, low socioeconomic status, prior mild TBI,

Principles of Diagnosis: Common PresentingSymptoms

severity of initial neck pain, and preinjury emotional state. Note that differences in mildness from “dings” to a GCS score of 13 have not been implicated. However, no one factor is a very potent predictor. Dikmen and colleagues (1986) eloquently described the role of postinjury psychological factors in persistent postconcussive syndrome while observing that these factors have largely eluded prospective definition. Lishman (1988) provided an elegant description of how physiogenesis is transformed to psychogenesis. In recent years, some prospective analyses have yielded insights into persistent postconcussive syndrome. For example, these patients have more significant head and neck pain than their recovered counterparts. That chronic pain alone can produce symptoms of cognitive impairment is well known. Patients with persistent postconcussive syndrome are much more likely to have reached diagnostic criteria for specific psychiatric disorders by 6 months after the injury. Depression is most common. Global anxiety, at times with features of posttraumatic stress disorder, is also common. Memory of the injury scene may be a factor in the qualities of post-traumatic stress disorder. Peripheral vestibular disorder is a potent contributor to the anxiety that develops in a large number of patients with acute vestibular disease within 6 months of onset. Even frank phobic disorder can develop. That depression or anxiety can produce symptoms, and even signs, of cognitive dysfunction is also well known. Depressed patients with cognitive impairment even have a consistent pattern of frontal hypoperfusion in positron emission tomography studies. Much effort is spent trying to prove brain injury in these patients. Single photon emission computed tomography (SPECT) scans have little value. They have high negative predictive value (normal scan correlates with good outcome) but poor positive predictive value (abnormal scan has little correlation with outcome). Late SPECT abnormalities in symptomatic patients are similar to the SPECT “abnormalities” in depression. They neither prove or disprove brain injury, and they do not facilitate treatment. Finally, patients with persistent postconcussive syndrome have a larger number of chronic social problems than their recovered counterparts. As patients remain symptomatic, and perhaps even worsen, families become transformed. The families of patients with persistent postconcussive syndrome have a different belief structure: The patient is disabled; the doctors can’t or aren’t trying to find the cause; the family’s role is to take over and support the disabled patient. Arguments about injury characteristics, negative CT scans, and depression fall flat against this belief structure. Very few patients are frankly malingering. Treatment of persistent postconcussive syndrome often is unrewarding. Few approaches are open. First, symptomatic treatment should be offered where appropriate. This might include analgesia, vestibular suppressants, counseling, and physical therapy. Antidepressants can be used as headache treatments or sleeping aids. Antianxiety agents can be used as vestibular suppressants. Physical therapy for neck pain can be used to mobilize the patient into a schedule, a home program, and some fitness activities. Because these patients actually have trivial neurologic impairments, they are often ideal for cognitive rehabilitation programs designed for the patient with late severe TBI. Only programs of the second type described earlier are appropriate. Because of these patients’ good neurologic recovery, programs to reenter community activities and to practice interviews and time management can be quite successful. Treatment of basic

Chapter 18

psychiatric symptoms is an essential part of this plan. Depressed patients with TBI are no more swayed by cajoling and encouragement than functionally depressed patients. Treatment of these patients is quite difficult and entails simultaneous attention to somatic symptoms and to psychological processes. Two mistakes to avoid are attributing persistent postconcussive syndrome to malingering or to pending litigation without further neuropsychiatric assessment and endlessly pursuing symptomatic treatment of one somatic complaint without attempting to place the treatment in a broader medical, rehabilitative, and psychological context. SUGGESTED READINGS Alexander M P In the pursuit of proof of brain damage after whiplash injury. Neurology 51:336-340, 1998 Alexander M P Neuropsychiatric correlates of persistent postconcussive syndrome. J Head Trauma Rehabil 7:60, 1992 Bicik I, Radanov BP, Schafer N et al: PET with 18-fluorodeoxyglucoseand hexamethylpropyleneamine oxime SPECT in late whiplash syndrome. Neurology 51:345-350, 1998 Dikmen S, McLean A, Temkin N, Wyler A Neuropsychological and psychosocial consequences of minor head injury. J Neurol Neurosurg Psychiatry 491227, 1986 Eagger S, Luxon LM, Davies R4 et al: Psychiatric morbidity in patients with peripheral vestibular disorder: a clinical and neuro-otological study. J Neurol Neurosurg Psychiatry 55:383, 1992 Katz DI, Alexander M P Predicting outcome and course of recovery in patients admitted to rehabilitation. Arch Neurol 51:661, 1994 Kelly JP Sports related head injuries. J Head Trauma Rehab 13:1-65, 1998

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Goel V, Grafman J: Role of the right prefrontal cortex in ill-structured planning. Cognit Neuropsychol 17:415-436,2000 Lishman WA Physiogenesis and psychogenesis in the “post-concussional syndrome.” Br J Psychiatry 153:460, 1988 Masters SJ, McClean PM, Arcarese 7.5 Skull x-ray examinations after head trauma: recommendationsby a multidisciplinary panel and validation study. N Engl J Med 31684, 1987 McAllister TW, Saykin AJ, Flashman LA et al. Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study. Neurology 53:1300-1308, 1999 Mittenberg W, Tremont G, Zielinski R et al: Cognitive-behavioral prevention of postconcussion syndrome. Arch Clin Psychology 10: 139-145, 1996 Salazar AM, Warden DL, Schwab K et al: Cognitive rehabilitation for traumatic brain injury: a randomized trial. JAMA 283:3123-3124, 3075-3081,2000 Servadei F, Vergoni G, Nasi MT et al: Management of low-risk head injuries in an entire area: results of an 18 month survey. Surg Neurol 39:269, 1993 Shackford SR, Ward SI, Ross SE et al: The clinical utility of computed tomographic scanning and neurologic examination in the management of patients with minor head injuries. J Trauma 33:385, 1992 Shallice T, Burgess PW Deficits in strategy application following frontal lobe damage in man. Brain 114727-741, 1991 Taheri PA, Karamanoukian H, Gibbons K et al: Can patients with minor head injuries be safely discharged home? Arch Surg 128:289, 1993 Teasdale GM, Murray G, Anderson E et al: Risks of acute traumatic intracranial haematoma in children and adults: implications for managing head injuries. BMJ 300363, 1990 Vollmer DG, Dacey RG, Jane J A Craniocerebral trauma. p. 63. In Joynt R (ed): Clinical Neurology. Lea & Febiger, Philadelphia, 1991 Williams DH, Levin HS, Eisenberg HM: Mild head injury classification. Neurosurgery 27:422, 1990

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Laboratory Evaluation Steven K. Feske

The neurologic history and examination often allow the physician to make an anatomic or syndromic diagnosis. Additional studies, including laboratory tests, electrophysiology, neuroimaging, and biopsy can add precision to this diagnosis and often support an etiologic diagnosis. The chapters in this section describe the use of many ancillary tests that are helpful in neurologic diagnosis. The goal of these chapters is to provide a brief general description of the nature and interpretation of commonly used tests. More specific information about the indications and interpretations of certain tests can be found in the discussions of particular diseases.

This chapter addresses selected general laboratory tests significant in neurologic diagnosis. TESTS OF COAGULATION Stroke is the most common life-threateningneurologic disease and among the most common causes of death. The neurologist must understand the laboratory tests that contribute to the proper evaluation and management of vascular disease. The coagulation system is shown in Figure 18-1. The cascade of reactions following

Chapter 18

psychiatric symptoms is an essential part of this plan. Depressed patients with TBI are no more swayed by cajoling and encouragement than functionally depressed patients. Treatment of these patients is quite difficult and entails simultaneous attention to somatic symptoms and to psychological processes. Two mistakes to avoid are attributing persistent postconcussive syndrome to malingering or to pending litigation without further neuropsychiatric assessment and endlessly pursuing symptomatic treatment of one somatic complaint without attempting to place the treatment in a broader medical, rehabilitative, and psychological context. SUGGESTED READINGS Alexander M P In the pursuit of proof of brain damage after whiplash injury. Neurology 51:336-340, 1998 Alexander M P Neuropsychiatric correlates of persistent postconcussive syndrome. J Head Trauma Rehabil 7:60, 1992 Bicik I, Radanov BP, Schafer N et al: PET with 18-fluorodeoxyglucoseand hexamethylpropyleneamine oxime SPECT in late whiplash syndrome. Neurology 51:345-350, 1998 Dikmen S, McLean A, Temkin N, Wyler A Neuropsychological and psychosocial consequences of minor head injury. J Neurol Neurosurg Psychiatry 491227, 1986 Eagger S, Luxon LM, Davies R4 et al: Psychiatric morbidity in patients with peripheral vestibular disorder: a clinical and neuro-otological study. J Neurol Neurosurg Psychiatry 55:383, 1992 Katz DI, Alexander M P Predicting outcome and course of recovery in patients admitted to rehabilitation. Arch Neurol 51:661, 1994 Kelly JP Sports related head injuries. J Head Trauma Rehab 13:1-65, 1998

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Goel V, Grafman J: Role of the right prefrontal cortex in ill-structured planning. Cognit Neuropsychol 17:415-436,2000 Lishman WA Physiogenesis and psychogenesis in the “post-concussional syndrome.” Br J Psychiatry 153:460, 1988 Masters SJ, McClean PM, Arcarese 7.5 Skull x-ray examinations after head trauma: recommendationsby a multidisciplinary panel and validation study. N Engl J Med 31684, 1987 McAllister TW, Saykin AJ, Flashman LA et al. Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study. Neurology 53:1300-1308, 1999 Mittenberg W, Tremont G, Zielinski R et al: Cognitive-behavioral prevention of postconcussion syndrome. Arch Clin Psychology 10: 139-145, 1996 Salazar AM, Warden DL, Schwab K et al: Cognitive rehabilitation for traumatic brain injury: a randomized trial. JAMA 283:3123-3124, 3075-3081,2000 Servadei F, Vergoni G, Nasi MT et al: Management of low-risk head injuries in an entire area: results of an 18 month survey. Surg Neurol 39:269, 1993 Shackford SR, Ward SI, Ross SE et al: The clinical utility of computed tomographic scanning and neurologic examination in the management of patients with minor head injuries. J Trauma 33:385, 1992 Shallice T, Burgess PW Deficits in strategy application following frontal lobe damage in man. Brain 114727-741, 1991 Taheri PA, Karamanoukian H, Gibbons K et al: Can patients with minor head injuries be safely discharged home? Arch Surg 128:289, 1993 Teasdale GM, Murray G, Anderson E et al: Risks of acute traumatic intracranial haematoma in children and adults: implications for managing head injuries. BMJ 300363, 1990 Vollmer DG, Dacey RG, Jane J A Craniocerebral trauma. p. 63. In Joynt R (ed): Clinical Neurology. Lea & Febiger, Philadelphia, 1991 Williams DH, Levin HS, Eisenberg HM: Mild head injury classification. Neurosurgery 27:422, 1990

3 PRINCIPLES OF DIAGNOSIS: SPECIAL TESTS

18

Laboratory Evaluation Steven K. Feske

The neurologic history and examination often allow the physician to make an anatomic or syndromic diagnosis. Additional studies, including laboratory tests, electrophysiology, neuroimaging, and biopsy can add precision to this diagnosis and often support an etiologic diagnosis. The chapters in this section describe the use of many ancillary tests that are helpful in neurologic diagnosis. The goal of these chapters is to provide a brief general description of the nature and interpretation of commonly used tests. More specific information about the indications and interpretations of certain tests can be found in the discussions of particular diseases.

This chapter addresses selected general laboratory tests significant in neurologic diagnosis. TESTS OF COAGULATION Stroke is the most common life-threateningneurologic disease and among the most common causes of death. The neurologist must understand the laboratory tests that contribute to the proper evaluation and management of vascular disease. The coagulation system is shown in Figure 18-1. The cascade of reactions following

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Principles of Diagnosis: Special Tests

Therefore, it depends on the normal function of factor VII of the extrinsic pathway and the common pathway downstream to it. The prothrombin time can be prolonged by any disease or medication affecting these factors. Warfarin inhibits synthesis of the vitamin K-dependent factors 11, VII, IX, and X. Three of these are necessary for proper function of the extrinsic and common pathways, and the prothrombin time is a sensitive assay of the intensity of anticoagulation by warfarin. Until recently, it was customary to report the prothrombin time as a ratio of the patient's value and a control value: PT,/PT,. Recommendations for the desirable intensity of anticoagulation were published as prothrombin time ratios. In recent years, it has been suggested that the prothrombin time value be reported as a standardized ratio, that is, the international normalized ratio (INR). This value normalizes differences based on the variable sensitivities of lots of reagent thromboplastin. The INR is defined as INR= (PT,/PT,)'S'

FIG. 18-1. The coagulation cascade, anticoagulant inhibitory systems,

and tests of coagulation function. The interactions of the four anticoagulant systems are shown in ovals: antithrombin 111 (AT Ill), protein C and S system (PCa/PS), tissue factor pathway inhibitor (TFPI), and plasmin. Some of the functional tests of coagulation are shown in rectangles: activated partial thrornboplastin time ( a m , prothrombin time (PT), thrombin time 0,Russell's viper venom test (RW), protamine sulfate test (PST), and D-dimer. FDP, fibrin degradation products; Fg, fibrinogen; 11, prothrombin; PL, cellular phospholipid surface; TF, tissue factor. (Modified from Nachman RT, Silverstein R: Hypercoagulable states. Ann Intern Med 120:520, 1994, with permission.)

from the activation of factor X constitutes the common pathway. The cascade of reactions beginning with the activation of factor XI1 and including the reactions of the common pathway constitutes the intrinsic pathway. Activation of factor X via factor VII and tissue factor and the resultant cascade of reactions through the common pathway constitute the extrinsic pathway. Normal coagulation depends on the interaction of the coagulant proteins that exist in blood as proenzymes and three anticoagulant systems-the protein C-protein S system, the antithrombin 111 system, and the tissue factor pathway inhibitor (TFPI) system-along with a fourth plasmin fibrinolytic system. Many functional and antigenic tests have been devised to assess the state of the coagulant systems. The sites of entry of the anticoagulant inhibitory systems and the fibrinolytic system and the sites of reagent activation or sampled products of many of the assays of coagulation are also shown in Figure 18-1; the descriptions of the tests of coagulation that follow refer to this figure.

Prothrombin lime The prothrombin time is the time in seconds that it takes plasma to clot after the addition of thromboplastin (tissue factor).

where PT, is the patient's prothrombin time in seconds, PT, is the mean of a series of control values, and IS1 is the international sensitivity index, a measure of the sensitivity (reactivity) of the thromboplastin used. The IS1 is calculated by the manufacturer of the thromboplastin or the laboratory and is a property of the particular lot of thromboplastin. A thromboplastin with a sensitivity equal to that of the World Health Organization standard has an IS1 of 1 and therefore yields an INR equal to the prothrombin time ratio. With less sensitive thromboplastins (higher ISI) the prothrombin time value for a given INR is lower, and the range of values is narrower; for more sensitive thromboplastins, the range of values for prothrombin time is wider, and subtler abnormalities of coagulation can be detected. An INR of 1.4 or less suggests hemodynamically adequate levels of coagulation factors. Recent recommendations for the desirable intensity of anticoagulation in various clinical situations are discussed in Chapter 25 and in Part 11.

Activated Partial Thromboplastin lime The activated partial thromboplastin time (aPTT), usually called simply PTT, is the time in seconds that it takes plasma to clot after the addition of a contact agent that fully activates factors XI1 and XI along with calcium and phospholipid. These reagents activate factors XI1 and XI, so the PTT depends on the normal function of these factors and the other factors of the intrinsic pathway. It can be prolonged by any disease or medication affecting these factors. It is more sensitive than the prothrombin time for detecting acquired circulating anticoagulants, often called lupus anticoagulants. It is also sensitive to the multiple-level effects of heparin and therefore is used as the functional assay of adequate heparinization. For most indications for which full heparinization is desirable, a PTT of 2 to 2.5 times the normal value is the therapeutic goal. Heparin therapy is discussed in Chapter 25.

AntbFactor Xa Activity Because they have low antithrombin activity, low-molecularweight heparins (LMWH) and heparinoids minimally affect the standard aPPT. For routine use, weight-adjusted dosing is adequate without monitoring. However, in patients with renal insufficiency, pregnancy, severe obesity, and other conditions that affect the pharmacokinetics of LMWH, monitoring should be done using anti-factor Xa activity. Using this assay, the goal

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175

therapeutic range should be about 0.3 to 0.7 U/mL; this corresponds to a heparin level by the protamine titration method of 0.2 to 0.4 U/mL and very roughly to an aPTT of 1.8 to 2.5 (up to 4.2) times control.

polymerase chain reaction testing. This heterozygouslesion occurs in about 2% to 15% of Caucasians of European descent.

It is widely accepted that hereditary and acquired dysfunction of these coagulation systems can cause thromboembolic disease, including strokes. Tests for the presence of hypercoagulability are now a part of the evaluation of stroke and other thrombotic events when the more common risk factors are absent. Abnormalities of two of the three anticoagulant systems, the protein C-protein S and antithrombin 111 systems, have been associated with thrombosis, although their association to arterial strokes is less clear. Decreased tissue factor pathway inhibitor activity may play a role in many thrombotic disorders; the clinical implications of reduced TFPI activity are now being actively studied. Also, abnormalities of fibrinogen and the plasmin fibrinolytic system can rarely cause clinical thrombosis.

A mutation of the prothrombin gene called prothrombin 20210A is associated with elevated plasma levels of prothrombin and venous thromboembolism. As for the factor V Leiden mutation, this lesion may clearly underlie cerebral venous sinus thrombosis. Data concerning an associated elevated risk of arterial strokes are conflicting. The mutation occurs in about 1% of Caucasians and 6% of Spaniards.

Protein C and Protein S Protein C is a vitamin K-dependent serine protease, that is, one of a family of proteolytic enzymes with serine in the active site. Protein S is its vitamin K-dependent cofactor. The protein C-protein S complex inactivates factors Va and VIIIa. This probably prevents thrombus formation at the capillary level. Decreased levels or dysfunctional molecules with low enzymatic activity can cause hereditary hypercoagulable states. Also, many conditions can cause acquired deficiencies. Assays for antigenic levels and enzymatic activity exist for both proteins. Protein S can be measured in the free (active) and bound states. Because they are vitamin K-dependent, these proteins are depleted by warfarin. It is best to wait 1 to 2 weeks after warfarin therapy has been discontinued to measure them. If warfarin therapy cannot be stopped, the ratio of protein C antigen to prothrombin antigen can estimate the effective level.

Prothrombin 2021OA

Fibrinogen Elevated fibrinogen has been identified in the Framingham study as a risk factor for stroke in men, although because no treatment has yet been recommended in its presence, it has not been useful to measure fibrinogen levels routinely. Dysfibrinogenemia,synthesis of an abnormal fibrinogen molecule, usually is associated with pathologic hemorrhage; however, thrombosis rarely occurs. Fibrinogen function can be assayed with tests of the final steps of the coagulation cascade, the thrombin time and the reptilase clotting time. The thrombin time is the time in seconds that it takes for plasma to clot after the addition of thrombin. This tests the generation of a fibrin clot from the existing fibrinogen. Reptilase hydrolyzes fibrinogen to promote clotting directly. Both of these clotting times are prolonged in the presence of an abnormal fibrinogen. An antigenic assay for the fibrinogen level is also available.

The Plasmin Fibdnolytic System Abnormal plasmin generation is a rare cause of hypercoagulability. These disorders can also be hereditary or acquired. Antigenic and functional assays are available in special circumstances; however, because these disorders are rare, screening is not routine.

Antithrombin 111

The Antiphospholipid Antibody Syndrome

Antithrombin 111 is a vitamin K-dependent serine protease inhibitor that irreversibly inactivatesfactors XIIa, XIa, IXa, Xa, and IIa (thrombin), all serine proteases. Heparins bind to antithrombin 111, enhancing its natural anticoagulant effects. As with proteins C and S, decreased activity can result from hereditary decreased synthesis with low levels of a normal molecule or synthesis of a dysfunctional molecule, or a deficiency state can be acquired from loss of hepatic synthetic function. Antigenic and functional activity assays are available.

The presence of circulating antibodies to negatively charged phospholipids has been associated with pathologic thrombosis. The mechanism of thrombogenesis is unknown but probably a result of a reaction of the antibody with phospholipid of the endothelial cell or platelet membrane. Several tests are available to look for the presence of such antibodies. So far, their optimal use and interpretation have not been clarified. These antibodies were originally identified in patients with systemic lupus erythematosus and named lupus anticoagulants because of their effect in prolonging phospholipid-dependent coagulation times. Binding to phospholipid inhibits the generation of the thrombin activator complex, which is produced by the interaction of factors Xa and Va and phospholipid (Fig. 18-1). This may prolong the PTT and, less commonly, the prothrombin time. This prolongation is not corrected by the addition of normal plasma in mixing studies when a circulating anticoagulant is present. However, these routine tests are not sensitive indicators of a lupus anticoagulant. Russell's viper venom test and the kaolin clotting time depend on the direct activation of factor X. These are more sensitive screening tests for a lupus anticoagulant. Using these tests to define the lupus anticoagulant, the false-negative rate of the PTT is 22% to 33%. Therefore, one of these two tests may be used to screen for lupus

Activated Protein C Resistance and Factor V Leiden The factor V Leiden mutation at the cleavage site for activated protein C results in resistance of factor V to inactivation by activated protein C, causing thrombophilia. This mutation is the most common hereditary risk factor for venous thrombosis. The increased risk includes cerebral venous thrombosis. Although reports suggest an increased risk of arterial stroke in young patients with this genetic lesion, an increased risk for arterial strokes has not been firmly established. Laboratory screening for this lesion is done using a coagulation assay for protein C resistance. The genetic lesion can be confirmed directly by

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anticoagulants. Russell’s viper venom test has been favored because it is simple, easy to perform, not influenced by inhibitors of factors VIII and IX (which can confound the interpretation of the kaolin clotting time), and does not necessitate a confirmatory test (as does the kaolin clotting time). (The kaolin clotting time corrects with the addition of phospholipid but not normal plasma.) In many laboratories, dilute aPTT assay and platelet neutralization tests for phospholipid dependence have replaced other tests as sensitive assays to detect a lupus anticoagulant. Although not as specific for the antiphospholipid antibody syndrome as the lupus anticoagulant, antigenic tests for the presence of antibodies to cardiolipin are more sensitive and reproducible, and they allow a quantitative assessment. Enzymelinked immunosorbent assays (ELISA) for immunoglobulin G (IgG), IgM, and IgA anticardiolipin antibodies are available. Specificity for clinical disease, such as thrombosis, fetal loss, and thrombocytopenia, correlates with higher titers and with the presence of anticardiolipin of the IgG class. Harris and colleagues (1987) have recommended cutoff values for interpreting the clinical significance of anticardiolipin antibodies (Table 18- 1). Most laboratories report this test as positive if values are at the lower end of the moderate positive range seen in Table 18-1. Harris and colleagues (1986) reported that predictive values for disease increase with increasing titers. It has been found that anticardiolipin antibodies bind to an epitope on the phospholipid-binding protein P2-glycoprotein I. Pathogenic antibodies depend on this P2-glycoprotein I binding in in vitro studies. This has led to an assay for P2-glycoprotein I. The presence of antibodies to P2-glycoprotein I also suggests clinical antiphospholipid antibody syndrome. Tests for other antiphospholipid antibodies are available, but their clinical relevance is less clear. The tests for lupus anticoagulant and antibodies to cardiolipin or phospholipid-binding protein are discordant. Depending on the method used to test for the lupus anticoagulant, it detects 50% to 94% of those with anticardiolipin by ELISA. A positive anticardiolipin test detects 70% to 80% of those with a lupus anticoagulant by a sensitive assay. Because of this discordance, it is recommended that, in the appropriate clinical setting, screening be done with both the ELISA for anticardiolipin subclasses and P2-glycoprotein I and a sensitive test for a lupus anticoagulant. A positive anticardiolipin value can then be quantitated to estimate the risk of thrombosis (Table 18-1).

Disseminated lntravascular Coagulation Disseminated intravascular coagulation (DIC) can be an acute and fulminant process, usually accompanied by hemorrhage or a subtle subacute or chronic process that can lead to hemorrhage or pathologic thrombosis. Therefore, screening tests for DIC some-

TABLE 18-1. The Clinical Significance of Anticardiolipin Titers Antibody Class

IgC WmL) IgM (Il/mL)

Normal 55

23

low Positive

Moderate Positive

High Positive

6-1 4 4-5

15-80 6-50

90 >50

Adapted from Harris EN et al: Evaluation of the anticardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp lmmunol 68:215, 1987, with permission.

w

Principles of Diagnosis: Special Tests

times are an appropriate part of the evaluation of thromboembolic disease. A battery of tests is available to assay the several steps in this coagulopathy. Consumption of fibrinogen, thrombin, and coagulation factors higher up in the clotting cascade leads to a fall in the fibrinogen level and a prolongation of the clotting times: partial thromboplastin, prothrombin, and thrombin times. If the fibrinogen was high at the start, it may remain in the normal range. Consumption of platelets results in a fall in the platelet count and prolongation of the bleeding time. Intravascular fibrin deposition in the small vessels causes a microangiopathic hemolytic anemia, which is detected by a fall in the hemoglobin and hematocrit and schizocytes on a peripheral blood smear. If thrombosis and fibrinolysis are activated, fibrin monomer and fibrin degradation products are formed. Fibrin degradation products can be quantitated and usually are greater than 40 pg/mL in DIC. The serial dilution protamine sulfate test detects fibrin monomer and fibrin degradation products. Protamine sulfate causes the dissociation of soluble complexes of fibrin monomer and fibrin degradation products. Because these complexes prevent polymerization, this dissociation by protamine sulfate allows polymerization to proceed. A positive test means that fibrin monomer and fibrin degradation products are present and that fibrinogen and fibrinolysis have been activated. The protamine sulfate test is a sensitive but nonspecific test of DIC. The D-dimer is produced when plasmin induces lysis of crosslinked fibrin, so it serves as a marker of thrombus formation and lysis. The most common laboratory abnormalities in DIC, in decreasing order of frequency, are thrombocytopenia, D-dimer elevation, and elevation of PT, aPTT, and thrombin time and depletion of fibrinogen.

IMMUNOLOGIC MARKERS OF DISEASE Many neurologic diseases have an established or presumed autoimmune origin. These include many inflammatory medical diseases with neurologic complications, many neuropathies, myasthenia gravis, and many paraneoplastic syndromes. Many autoantibodies are useful in clinical diagnosis. Further discussions of most of the tests described in this section are found in later chapters discussing the diseases with which they are associated.

Autoantibodies in Rheumatic Disease Rheumatic disease enters into the differential diagnosis of several neurologic disorders, including neuropathies, sensory neuronopathy, myositis, aseptic meningitis, and stroke. Autoantibodies are never diagnostic; however, in the appropriate clinical context, they can support the diagnosis of an underlying rheumatic disease (Table 18-2). Rheumatoid Factors. The routinely used rheumatoid factor tests for the presence of IgM antibodies to certain immunoglobulins. This test is about 90% sensitive for typical rheumatoid arthritis. However, it is nonspecific and can be positive in many other rheumatic and nonrheumatic diseases, many of which cause neurologic disease, including systemic lupus erythematosus (SLE), dermatomyositis, Sjogren’s syndrome, sarcoidosis, and endocarditis. Ninety percent of patients with Sjogren’s syndrome have rheumatoid factors. Antinuclear Antibodies. More than 90% of patients with SLE have high titers of antinuclear antibodies (ANAs). These also are nonspecific. The pattern of nuclear immunofluorescent staining can add specificity. A peripheral staining pattern is specific for

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rn TABU 18-2. Some Autoantibodies in Immunologically Mediated Diseases with Neurologic Complications Antigen

Clinical Significance

Rheumatoid factors ANA Double-stranded DNA, peripheral pattern Single-stranded DNA, peripheral pattern Antihistone, homogeneous Sm, speckled RNP, speckled

Nonspecific, sensitive for RA and Sjogren’s syndrome Nonspecific Specific for SLE, active renal disease Nonspecific, very sensitive for SLE In SLE and drug-induced LE; if present alone, suggestive of drug-induced LE Specific for SLE, renal and CNS disease Nonspecific: PM with MCTD, SLE, Sjogren’s syndrome, scleroderma Jo- 1 PM with interstitial lung disease PM-Scl PM with scleroderma Ro (SSA) SLE, Sjogren‘s syndrome La (SSB) Primary Sjogren’s syndrome, if no other autoantibodies are present CANCA Vasculitis from Wegenet‘s granulomatosis or microscopic periarteritis pANCA GlomeruloneDhritis: . . also classic PAN and other vasculitides and rheumatic diseases Abbreviations: AN& antinuclear antibodies; c4NCA, antineutrophilic cytoplasmic antibodies, cytoplasmic pattern; CNS, central nervous system; LE, lupus erythematosus; MOD, mixed connective tissue disease; PAN, polyarteriiis nodosa; pANCq pen-nuclear pattern; PM, polymyositis; RA, rheumatoid arthritis; RNP, ribonudear protein; SLE, systemic lupus erythematosus. Adapted from Condemi JJ: Autoimmune diseases. JAMA 268:2883, 1992, with permission.

active SLE. Diffuse and speckled patterns are nonspecific. Antibodies to certain nuclear antigens are more specific for SLE. These include antibodies to double-stranded DNA and anti-Sm. Antibodies to the antigens Ro (also called SSA) and La (also called SSB) and single-strandedDNA are nonspecific;they are present in most patients with clinical SLE and a negative ANA screen. Antihistone antibodies also appear in lupus and, when found alone, suggest that it is drug induced. A positive ANA is found in about 70% of patients with Sjogren’s syndrome. The staining pattern usually is diffuse or speckled. Antibodies to the small nuclear ribonuclear proteins Ro and La are often seen as well, although they are nonspecific. The presence of isolated anti-La antibodies suggests primary Sjogren’s syndrome. Mixed connective tissue disease enters into the diagnosis of neuropathies, myositis, and aseptic meningitis. High titers of antibodies to ribanuclear protein (also called extractable nuclear antigens because they are soluble in aqueous buffers) are characteristic of this disease, although they too are nonspecific. Polymyositis can occur in association with various rheumatic diseases. Characteristic ANAs may accompany these different syndromes. As noted earlier, ribonuclear protein is found in polymyositis with mixed connective tissue disease. Autoantibodies to Jo-1 accompany polymyositis in interstitial lung disease. Autoantibodies to PM-Scl, a nucleolar antigen, accompany polymyositis in scleroderma. Autoantibodies in Systemic Vasculitis: Antineutrophilic Cytoplasmic Antibodies

Antineutrophilic cytoplasmic antibodies (ANCA) bind with enzymes within granules of polymorphonuclear leukocytes. Two patterns can be detected by immunofluorescent staining: a cytoplasmic pattern detected by ELISA and a perinuclear pattern detected by indirect immunofluorescence. The cytoplasmic pattern has a high sensitivity and specificity for two types of systemic vasculitis: Wegener’s granulomatosisand microscopic periarteritis. The perinuclear pattern is most commonly found in crescentic necrotizing glomerulonephritis, but it can be seen with low sensitivity and specificity in other inflammatory diseases, such as classic periarteritis nodosa and other systemic vasculitides, rheumatoid arthritis, SLE, inflammatory bowel disease, and chronic liver disease.

Autoantibodies in Myasthenia Gravis Acetylcholine Receptor Antibodies. Antibodies to the nicotinic acetylcholine (ACh) receptor are detected by Western blot analysis. They are found 75% to 95% of the time in patients with acquired generalized myasthenia gravis, with only rare false positives reported. The sensitivity is reduced to about 50% to 70% in myasthenia gravis limited to the ocular muscles. These antibodies have been implicated in the pathogenesis of myasthenia gravis to establish it convincingly as an autoimmune disease. In the appropriate clinical setting, a positive test can corroborate the diagnosis of adult and neonatal myasthenia gravis. However, the levels of these autoantibodies do not correlate with disease activity in populations, although there may be a correlation in a given case. These autoantibodies are also found in cases of drug-induced myasthenia. They are not present in congenital myasthenia. Antistriated Muscle Antibodies. In patients with myasthenia gravis, the presence of antibodies to striated muscle suggests that the patient harbors a thymoma. Autoadbodies En Paraneoplastic Syndromes

Several paraneoplastic neurologic syndromes have been associated with specific autoantibodies (Table 18-3). Although these autoantibodies have not been as clearly implicated in the pathogenesis of the neurologic syndrome as have ACh receptor antibodies in myasthenia gravis, when present they can help to direct the physician to the appropriate search for underlying tumors, and they can provide evidence that a given syndrome is a remote effect of cancer. Anti-Yo Antibodies. Anti-Yo antibodies react with an antigen found in the cytoplasm of cerebellar Purkinje cells. A subset of patients with paraneoplastic subacute cerebellar degeneration have these antibodies in the serum and cerebrospinal fluid (CSF). Almost all patients with subacute cerebellar degeneration and a high titer of anti-Yo antibodies have been women with ovarian, breast, or other gynecologic malignancies. Only rare cases of other malignancies have been reported, including lung cancer and lymphoma. Therefore, the presence of these antibodies should prompt a careful search for an underlying gynecologic malignancy. This should include exploratory pelvic surgery in patients with normal mammograms and no other indication of tumor. Tumor diagnosis may be delayed until long after the onset of the

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Principles of Diagnosis:Special Tests

TAW 18-3. Autoantibodiesin Paraneoplastic Neurologic Syndromes Antibodv

Most Common Tumor Tmes

Clinical Syndrome ~

Anti-Yo Anti-Hu Anti-Ri Anti-CVZ Anti-Ma Anti-Ta Anti-CAR Anti-VCCC Anti-MAC

Subacute cerebellar degeneration Subacute sensory neuronopathy, limbic and brainstem encephalitis, subacute cerebellar degeneration Opsoclonus in adults, cerebellar dysfunction Encephalomyelitis, cerebellar degeneration, peripheral neuropathy, optic neuritis Brainstem and cerebellar dysfunction Limbic and brainstem encephalitis Retinal deneneration Lambert-Elaton myasthenic syndrome Paraproteinemia with indolent sensorimotor neuropathy

Ovarian, breast, other gynecologic cancers SCLC, neuroblastoma Breast cancer, gynecologic cancers, SCLC SCLC and other cancers Lung, breast, parotid, colon cancer Testicular cancer SCLC and other cancers SCLC MCUS

Abbreviations: CAR, cancer-associatedretinopathy; MAG, myelin-associatedglycoprotein; MGUS, monoclonal gammopathy of undetermined significance; SCLC, small cell lung cancer; VGCC voltagegated calcium channels.

neurologic syndrome. Patients with the syndrome of subacute cerebellar degeneration without anti-Yo antibodies are most likely to have lung cancer, especially small cell cancer, or Hodgkin’s disease. Rarely, other cancers, such as lymphomas, have been identified, or no tumor has been found. Anti-Hu Antibodies. Anti-Hu antibodies react with an antigen found in neuronal nuclei. Most patients with these antibodies in serum or CSF have been found to harbor a small cell cancer. Rarely other tumors have been found prostate carcinoma, neuroblastoma, and chondromyxosarcoma. Tumor diagnosis may be delayed, and rarely no tumor has been found. Several neurologic syndromes may accompany these antibodies. The major associated syndromes include subacute sensory neuronopathy; paraneoplastic encephalomyelitis, including limbic encephalitis, brainstem encephalitis, and myelitis; and cerebellar degeneration with loss of Purkinje cells (anti-Yo negative). The presence of these antibodies in the context of these neurologic syndromes should prompt a careful search for a small cell carcinoma or other, less common tumor. High titers of them in a patient with known small cell carcinoma support the paraneoplastic cause of the neurologic findings. Low titers are found in about 16% of all patients with small cell carcinoma. Anti-Ri Antibodies. Anti-Ri antibodies also react with a neuronal nuclear antigen. These antibodies are found in high titers in the serum and CSF of patients with paraneoplastic opsoclonus associated with breast cancer. They have not been found in childhood opsoclonus-myoclonuswith or without neuroblastoma or in breast cancer without opsoclonus. Their presence should stimulate a search for an underlying breast tumor or other malignancy. Anti-Ma/Ta Antibodies. The anti-Ma antibodies react with proteins expressed in neurons and spermatogenic cells of the testes. Both anti-Ma1 and anti-Ma2 (anti-Ta) antibodies may be found in the serum and CSF of patients with brainstem and cerebellar syndromes. The anti-Ma antibodies may occur in association with many tumor types, including lung, breast, parotid, and colon cancers. The anti-Ta (anti-Ma2) antibodies are associated with testicular cancer. Anti-CVZ Antibodies. Anti-CV2 antibodies react with oligodendroglial cytoplasmic antigens in the white matter of the central nervous system. They have also been shown to bind to peripheral nerve antigens. These antibodies have been found in patients with cerebellar degeneration, encephalomyelitis, sensorimotor neuropathy, optic neuritis, and other neurologic syndromes. The most common tumor type found in patients with the anti-CV2 antibody is small cell lung cancer, but a variety of other cancers has been associated with it.

Cancer-Associated Retinopathy Antibodies. The cancerassociated retinopathy antigen and possibly other ocular antigens are the targets of autoantibodies of cancer-associatedretinopathy. High titers of these antibodies have been associated with paraneoplastic retinal degeneration. This syndrome is rare. Most patients have had small cell lung cancer. Other associated cancers include those of the breast, prostate, colon, and cervix. Anti-Voltage-Gated Calcium Channels. Autoantibodies to voltage-gated calcium channels at nerve terminals have been found in some patients with small cell lung cancer, some of whom have had the Lambert-Eaton myasthenic syndrome. About 50% to 60% of patients with Lambert-Eaton myasthenic syndrome, whether with or without cancer, have been found to have such antibodies in their serum. This finding strongly suggests an autoimmune origin for this syndrome. Antibodies to Myelin-Associated Glycoprotein and Sulfated Glucuronyl Paragloboside. Several different syndromes of

neuroradiculopathy accompany monoclonal paraproteinemias. About one fourth to one half of the patients with an IgM monoclonal spike on serum protein electrophoresis have serum antibodies to myelin-associated glycoprotein (MAG), a glycoprotein that participates in myelin interactions with the axon, and antibodies to sulfated glucuronyl paragloboside (SGPG), contained in peripheral nerve axons. Usually these monoclonal IgM proteins have K-light chains; however, occasionally IgM-h immunoglobulins are found with similar anti-MAG and anti-SGPG activity. These patients typically have a demyelinating sensorimotor neuropathy with indolent progression and elevated CSF protein. Although it has not been shown that these antibodies are responsible for the neuropathy, treatment that lowers the M protein may be effective.

Autoantibodies in Other Diseases Anti-CM, Ganglioside Antibodies. Gangliosides are macromolecules made up of an oligosaccharide with at least one acid sugar associated with the lipid ceramide. They are widely distributed in the membranes of the central and peripheral nervous system tissues. Anti-GM, ganglioside antibodies have been found in the serum of some patients with a lower motor neuron syndrome that resembles amyotrophic lateral sclerosis (ALS). This syndrome is more common in males and is characterized by lower motor neuron dysfunction, typically without upper motor neuron signs, with less atrophy than in anterior horn cell disease, and with a more prolonged course, multifocal motor conduction block, and high titers of anti-GM,

Chapter 18

ganglioside antibodies. It has been called multifocal motor neuropathy with conduction block. An ELISA is available, and serum titers above 1:350 are considered specific for the syndrome. Typically they are much higher. Low titers, 1:300 or less, are nonspecific and may be found with central nervous system (CNS) damage from, for instance, multiple sclerosis and ALS. Multifocal motor neuropathy with conduction block has been successfully treated with cyclophosphamide. Because it cannot be distinguished reliably by the clinical examination from lower motor neuron forms of motor system disease, nerve conduction studies and assays of GM, ganglioside antibodies have been useful to define it. Successful treatment usually results in a fall in antibody titers, so the antibody test has also been used to follow the response to treatment. Other antiganglioside antibodies have been identified and associated with disease, such as the GQlb ganglioside associated with the Miller-Fisher variant of Guillain-Barre syndrome. Antibodies to Glutamic Acid Decarboxylase. Glutamic acid decarboxylase is the enzyme that catalyzes the formation of y-aminobutyric acid (GABA) from glutamic acid. GABA is a major inhibitory neurotransmitter in the CNS, and glutamic acid decarboxylase is present in high concentrations in the terminals of GABAergic neurons. Antibodies to glutamic acid decarboxylase have been found in the serum and CSF of about 60% of patients with the stiff man syndrome. They have also been found in some patients with insulin-dependent diabetes, a disease with a probable autoimmune mechanism that may co-occur with it. It has been hypothesized that an autoimmune attack on GABAergic neurons causes the stiff man syndrome. Although this hypothesis remains to be proven, these autoantibodies have been used along with clinical and electrophysiologicfindings as a possible marker for the syndrome.

TESTS OF INFECTION Bacterial cultures and viral isolation from CSF, blood, and other tissues and fluids are used to diagnose many infectious neurologic diseases. Titers of specific immunoglobulins can also be used to indicate past infection (IgG) or recent infection (IgM or a fourfold or higher rise of IgG titers from acute to convalescent specimens drawn 4 to 6 weeks apart). In many cases, however, the diagnosis is not easily made by culture, viral isolation, or antibody titers. This section discusses some of the other tests used to diagnose neurologic infections.

Antigen Detection Bacterial meningitis usually can be diagnosed by Gram stain and culture of CSF and blood. At times, especially when patients have already received antibiotics, all stains and cultures are negative. Latex agglutination has largely replaced counterimmunoelectrophoresis to identify the antigens of many of the more common organisms that cause meningitis. Tests are available for Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococci, and Cryptococcus neoformans. These tests have sensitivitiesin the 80% to 100% range, although reports vary, and one study of the meningococcal latex agglutination test found it to be only 33% sensitive. The cryptococcal antigen is widely used for diagnosis and to follow the response to treatment. It is about 95% sensitive. False positives are rare.

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179

Polymerase Chain Reaction With the proper primers, a heat-resistant DNA polymerase, and a process of repeated heating and cooling to denature and rehybridize DNA, minute quantities of DNA can be amplified and detected in tissues. RNA can be similarly detected after synthesis of a complementary DNA (cDNA) using reverse transcriptase. This technique has been developed into sensitive and specific clinical tests for an increasing number of pathogens, including herpes simplex viruses, varicella-zoster virus, cytomegalovirus, EpsteinBarr virus, JC virus, Tomplasma gondii, Mycobacterium tuberculosis, Borrelia burgdorferi, and many others. Polymerase chain reaction for herpes simplex virus is very sensitive when specimens are collected early in the infection; however, the sensitivity falls off significantly in the days after presentation. Specificity for active CNS disease is good. Herpes simplex virus DNA is not found in the CSF of patients with latent herpes simplex virus infection but no CNS disease or non-herpes simplex virus neurologic disease.

Serology for Syphilis The Venereal Disease Research Laboratories (VDRL) test is a flocculation test that detects antibodies produced by treponemal infection. These antibodies, called reagins, are produced upon the invasion of host tissues. The rapid plasma reagin test is a refinement of the VDRL. It uses purified cardiolipin-lecithincholesterol antigen to detect the anticardiolipin antibodies produced by treponemal infection. It is more sensitive than the VDRL. The advantage of the VDRL is that it can be quantitated, and its titer reflects disease activity. After treatment, the titer usually falls, and the test becomes nonreactive over 6 to 12 months. Occasionally, a positive serum reaction of low titer (1:1, 1 2 , or slightly greater) persists after successful treatment. The VDRL can also be used to assay CSF. The CSF VDRL is very specific. Although false-positive tests can occur with contamination of the CSF with reactive blood or with CSF paraproteinemias and autoimmune disease, such false positives are rare. However, the sensitivityof the CSF VDRL is reported to be low. False-negative rates of up to 63% have been reported. Although this estimate may be too high, and false-negative rates as low as 6% have been reported, with current data it remains unreliable as a final criterion for diagnosing neurosyphilis. All positive nontreponemal tests should be confirmed by a serum treponemal test to eliminate false-positive serologies. Treponemal tests assay directly for antibodies to treponemal antigens. The two most commonly used tests are the fluorescent treponemal antibody absorption (FTA-ABS) and the microhemagglutination assay for Treponemapallidum (MHA-TP). These tests use antigens to nonpathogenic treponemes to "absorb" the nonspecific treponemal group antigens. With the serum free of these antigens, the tests detect the presence of specific serum antibodies by their reaction with T. pallidum. These tests are more sensitive and specific for syphilis than the nontreponemal tests. The reaction does not vary with treatment and once reactive will remain so indefinitely.To increase its positive predictive value, it is best used as a confirmatory test when the reagin test is reactive. Most authors do not recommend using the treponemal tests on CSF because they are so sensitive that the passive diffusion of tiny amounts of blood into the CSF causes a false-positive reaction. There is no clear consensus for the best approach to diagnosing neurosyphilis. Minimal findings probably should include a reac-

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Plinciples of Ambulatoy Neurology and the Approach to Clinical Problems

tive serum treponemal test and an abnormal CSF (more than 5 WBC/mm3 or protein greater than 45 mg/dL). Yet with neither a positive CSF VDRL nor clinical disease consistent with neurosyphilis, the diagnosis must be questioned. Serologic Tests for Lyme Disease

Culture of B. burgdorferi is difficult and not useful for routine diagnosis of Lyme disease. Diagnosis therefore has depended on the presence of positive serologic tests in the appropriate clinical setting. Screening usually is done with ELISA for IgG, but the humoral response is delayed, so that the sensitivity is poor in the first few weeks of infection. Enzyme immunoassay (EIA) antibody capture assays are also available for Igh4 (and IgA), which may increase the sensitivity in early disease. Because of cross-reactivity with other antigens, the false-positive rate for these serologic tests is high in the presence of many other inflammatory diseases. Western blotting has been used to confirm the diagnosis of Lyme disease in indeterminate cases. Dressler and associates (1993) have proposed criteria for positive Western blots based on the presence of characteristic bands: two of the common IgM bands in early Lyme disease and five of the common IgG bands after the first few weeks. Their sensitivity and specificity data are shown in Table 18-4. Polymerase chain reaction for B. burgdorferi has been introduced as a test with high sensitivity and specificity; however, its use with the other diagnostic tests for Lyme disease has not yet been well defined. For all serologic tests and for polymerase chain reaction, it is important to remember that positive tests may persist long after successful treatment, and they alone are not indications of active infection. CEREBROSPINAL FLUID ANALYSIS

CSF analysis provides important information for diagnosis in many neurologic diseases. The lumbar puncture is safe and quickly and easily performed in most patients. The exceptions to this constitute the absolute or relative contraindications to lumbar puncture: patients with local infection at the puncture site, those with brain masses or masses involving the spinal cord above the puncture site, and those with bleeding diatheses or on anticoagulant therapy. When the physician cannot successfully reach the subarachnoid space using the usual technique, fluoroscopy can visually guide the insertion of the spinal needle. When CSF must be obtained above a spinal mass or infection, the neurosurgeon or neurologist can achieve this by lateral Cl-C2 puncture. In many cases of bleeding diatheses, an infusion of coagulation factors, such as fresh frozen plasma, cryoprecipitate, platelets, DDAVP, or

TABLE 18-4. Sensitivity and Specificity of Serologic Tests for Lyme Disease Sensitivity (46)

Specificity (%)

40 32

94 100

IgG ELSA

89

IgC Western blot

83

72 95

Early Lyme disease IgM ELSA IgM Western blot Lyme disease after first weeks

Positive enzyme-linked immunosorbent assay (ELISA) results include indeterminate cases (1 :200 to 1 :400). Adapted from Dressler F, Whalen JA, Reinhardt BN, Steere A C Western blotting in the serodiagnosisof Lyme disease. 1 Infect Dis 167:398, 1993, with permission.

Principles of Diagnosis: Special Tests

a specific factor can precede the procedure to allow sampling. In some cases, CSF is obtained upon the placement of an intracranial pressure monitor or ventricular catheter for monitoring or therapy. Normal CSF is clear and colorless. The normal pressure in the lumbar subarachnoid space with the patient relaxed in the decubitus position is 50 to 200 mm CSF (4 to 15 mm Hg). With normal CSF flow, the pressure decreases with inspiration and increases with expiration and jugular compression (Queckenstedt test). Pigments

The CSF can be colored by pigments that are the products of hemoglobin breakdown after its release from lysed erythrocytes (RBCs). Initially, oxyhemoglobin can be detected as a pink or orange pigment. Bilirubin stains the CSF yellow. It may not be detectable for up to 12 hours after the release of RBCs into the CSF. Eventually, methemoglobin may stain the fluid dark yellow or brown. The presence of such pigments is one cause of xanthochromia. Xanthochromia can be detected by visual inspection or, with greater sensitivity, by spectrophotometry. Clinically, xanthochromia is primarily of interest in distinguishing subarachnoid hemorrhage from blood introduced into the CSF by minor trauma during the lumbar puncture (traumatic tap). In a study of serial samples of CSF in patients with well-established diagnoses of subarachnoid hemorrhage, Vermeulen ( 1989) found that with spectrophotometric analysis, all of these patients had xanthochromia after 12 hours, which persisted for 2 weeks. Many, and perhaps most, patients will have xanthochromia before 12 hours have elapsed, but earlier samples have not been reported in systematic studies. Based on these data, the authors recommend that lumbar puncture be delayed for 12 hours after subarachnoid hemorrhage to avoid the scenario of the uninterpretable tap without xanthochromia. Although the spectrophotometric analysis of xanthochromia is very sensitive under these conditions of delay, it is less specific, and traumatic puncture can be accompanied by xanthochromia. The issue is important because other techniques traditionally used to differentiate these two diagnoses are known to be unreliable, as follows: Declining RBC counts. It is customary to establish the RBC count in an early and a late collection tube. If this results in a normal later tube, then it reliably indicates a traumatic tap. However, a fall to a significant but smaller number of RBCs is not reliable and can occur in subarachnoid hemorrhage. Clotting of CSF blood. Blood introduced by a traumatic tap may clot within minutes, unlike the defibrinogenated blood after subarachnoid hemorrhage. However, this test is reliable only when large numbers of RBCs are present. Crenation of RBCs. Crenation of normal RBCs occurs by an osmotic loss of water. Although the presence of crenated RBCs has been suggested as an indication of true subarachnoid hemorrhage, crenation can occur early, and this test is not reliable. Erythrophages. Erythrophages, which are macrophages that have engulfed RBCs, reliably attest to the presence of blood that has been in the CSF too long to be compatible with a traumatic tap unless an earlier lumbar puncture was performed introducing RBCs. However, cytology is needed to detect them, and they are rarely seen. Therefore, this test is too slow and insensitive to be of practical use.

Chapter 18

Although blood entering the CSF space activates the systemic hemostatic and fibrinolytic systems, and subarachnoid hemorrhage often causes elevation of the serum D-dimer, in clinical studies this test has not been adequately sensitive to screen for subarachnoid hemorrhage. Causes of xanthochromia other than pigments from blood in the CSF include the following:

Laboratory Evaluation

181

can vary greatly, so only rough guidelines can be suggested for differential diagnosis based on cell counts (Table 18-5).

Cytopathology Cytopathologic evaluation is useful to diagnose leptomeningeal or ependymal malignancy, usually carcinoma or lymphoma. This test is specific but insensitive. To optimize the sensitivity, a large volume of fluid should be sent to the cytopathology laboratory, and it should be processed immediately to avoid cell lysis or loss of characteristic morphologic features. In suspected cases, sometimes multiple samples must be analyzed before a diagnosis is confirmed. As noted earlier, because lymphomas usually produce monoclonal B cells, monoclonal antibody staining can help differentiate malignant from inflammatory lymphocytes when morphology does not.

Jaundice CSF protein greater than 150 mg/dL Certain drugs, such as rifampin Carotenoids in food faddists taking large dosages Melanin in meningeal melanomatosis Contamination with the cleansing iodine solution Cell Counts

CSF samples should be refrigerated and promptly analyzed to avoid systematic errors in cell counts. This is a real problem that must be circumvented in large hospitals where specimens are transported by messengers and often sit for long periods before analysis. Leukocytes (WBCs) begin to lyse within 1 hour of collection at room temperature. Most authors consider 5 or fewer mononuclear cells/mm3to be normal. In adults, more than 10 cells is clearly abnormal. In the case of a traumatic tap, the WBC differential count should be approximately proportional to the peripheral WBC differential count. A rough calculation allows for one WBC per 500 to 1500 RBCs; however, this calculation is very error-prone, and clinical judgment must enter into decision making. In normal CSF, almost all WBCs are mononuclear, mostly T lymphocytes. In inflammatory diseases, polymorphonuclear leukocyte and lymphocyte (again mainly T cells) numbers will rise. A predominance of polymorphonuclear cells suggests bacterial infection, early viral infection, or occasionally other infections, chemical meningitis, tumor, or infarction. Chronic infections, viral infections after the early phase, and noninfectious inflammatory disorders usually cause a rise in T lymphocytes. In leptomeningeal lymphoma, the lymphocytes typically are monoclonal B cells. Therefore, monoclonal antibody staining can help to differentiate lymphoma from inflammation. The numbers of cells

Glucose

Glucose enters the CSF by facilitated diffusion across endothelial cells mediated by a specific transporter. The CSF level depends on the serum level during the prior 4 hours or so and the rate of metabolism of glucose within the CSF. Therefore, a serum glucose level drawn within a few hours before the lumbar puncture should accompany any CSF sampling. When taken from the lumbar subarachnoid space, the normal CSF glucose is about 65% of the serum level. This ratio increases as sampling moves rostrally. When the serum glucose rises in diabetes mellitus, the CSF-toserum glucose ratio can fall to as low as 31%. In disease, the CSF glucose can be low as a result of increased metabolism by WBCs or increased glycolysis by the brain or as a result of decreased entry of glucose following from transporter inhibition. A low value always indicates some diffuse meningeal process. With a normal serum glucose, a CSF value of less than 50% of the serum value or less than 45 mg/dL usually indicates disease. Many infections, subarachnoid hemorrhage, chemical meningitis, noninfectious inflammatory diseases, and leptomeningeal malignancy can all lower the glucose level. Typically, the level is normal in viral infections, except herpes simplex virus, varicella-zoster virus, and mumps.

TAW 18-5. Cerebrospinal fluid Findings in Meningitis Origin

Cell bunts (cells/mmJ)

Glucose (mg/dL)

Rotein (mg/dL)

Normal Bacterial

55 >200cells (most >1000); PMN predominance Fewer; usually 5 to several hundred; lymph predominance <500; lymphs Increased

45-80 Low

20-45

>loo

Gram stain; latex agglutination;culture

Normal

el00

Low Low

100-500 >loo

Increased Increased Lymphocytes; neoplastic . cells . RBCs; may have increased WBCs
Normal or low Normal or low Low

Normal or mildly high Variable High

May have PMNs early, especially HSV, mumps, LCM; these organisms may also cause low glucose and protein up to about 200;PCR for HSV and CMV Glucose is almost always low; AFB; PCR May have PMN predominance; glucose is almost always low; with immune compromise the formula may be normal; cryptococcal antigen About 25% have low glucose when active About 10% have low glucose Cytology; monoclonal antibody typing

Low

Varies with RBC count

Normal or low

High

Viral Tuberculosis Fungal Syphilis Parameningeal Neoplastic SAH Sarcoidosis

bmments

Early WBC proportional to blood count; later WSC proportion rises with meningeal inflammation About half have low glucose; ACE has low sensitivity and specificity

Abbrewidions: ACE, angiotensin-convertingenzyme activity; AFB, add fast bacillus stain; CMV, cytomegalovirus; HSV, herpes simplex Virus; LCM, lymph+c polymerase chain reaction; PMN, polymorphonudearleukocytes; RBC, red blood cell; SAH, subarachnoid hemorrhage;WBC. white blood cell.

choriomeningitis; PCR

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Principles of Ambulatory Neurologyand the Approach to Clinical Problems H Principles of Diagnosis: Special Tests

Therefore, the glucose value is used clinically to help to differentiate viral and bacterial meningitis (Table 18-5). Certain diseases characteristically cause a low CSF glucose. These include tuberculosis, fungal meningitis, carcinomatous meningitis, and subarachnoid hemorrhage. In a significant proportion of cases of active neurosyphilis and parameningeal infection, the glucose also will be low.

Most CSF proteins are derived from the serum. A small fraction of them are synthesized in the CNS. Proteins exit by passing into the venous sinuses via the arachnoid villi. There is a rostral-caudal gradient of CSF protein concentration. In adults, approximate normal levels are 20 to 45 mg/dL in the lumbar subarachnoid space, 15 to 25 mg/dL in the cisterna magna, and 6 to 15 mg/dL in the ventricles. The total protein level is elevated in many diseases. Bacterial meningitis typically elevates the protein significantly, whereas viral meningitis usually does not; therefore, this also is used to differentiate these two diseases before culture information is available (Table 18-5). Mild to moderate elevations are common and nonspecific (Table 18-6). Great elevations (above 500 mg/dL) usually indicate spinal subarachnoid block, meningitis, arachnoiditis, or subarachnoid hemorrhage. Froin syndrome is a coagulation of CSF that occurs with elevations usually greater than 1000 mg/dL, as is seen in spinal subarachnoid block. Low CSF protein values may be seen in a few diseases (Table 18-7). Diseases that cause intrathecal synthesis of y-globulin may cause an elevation of y-globulin, IgG index, and oligoclonal bands. Normal CSF IgG is 5% to 12% of the total CSF protein. The IgG index can be used to identify intrathecal synthesis: IgG index =

I~GCSFfi~Gsemrn albCdF/albS'?IUm

The normal IgG index is 0.85 or less. A small volume of contaminating serum, as in a traumatic tap, can falsely elevate the IgG index. This requires about 0.2% serum or enough to allow 5000 to 10,000 RBCs/mm3. Oligoclonal bands are spikes of two or more clonal expansions of immunoglobulin found on CSF protein electrophoresis. Their presence suggests an immune-mediated

TABU18-6. Some Causes of Elevated Cerebrospinal Fluid Protein Infections Meningitis, tuberculosis, syphilis, human immunodeficiencyvirus, abscess of brain and epidural space Tumor Brain tumor, meningeal carcinoma or leukemia, neurofibroma, paraneoplastic syndromes of the nervous system Central demyelination Multiple sclerosis, acute demyelinatingencephalomyelitis Polyneuropathy Guillain-Barre syndrome, chronic inflammatory demyelinating neuropathy, diabetic polyneuropathy Cerebrovascular disease Infarction, hemorrhage Metabolic disease Hypothyroidism, uremia, diabetes mellitus with polyneuropathy Degenerative diseases of the nervous system Miscellaneous Central nervous system trauma, spinal subarachnoid block, arachnoiditis, noninfectious inflammatory disorders of the brain and meninges Data from Fishman RA: Cerebrospinal Fluid in Diseases of the Netvous System. 2nd Ed. p. 199. WB Saunders, Philadelphia, 1992.

TABLE 18-7. Some Causes of Low Cerebrospinal Fluid Protein Children less than 2 years After removal of large volumes of lumbar cerebrospinal fluid Cerebrospinal fluid leak Benign intracranial hypertension Water intoxication with increased intracranial pressure Hyperthyroidism Leukemia Data from Fishman RA: Cerebrospinal Fluid in Diseases of the Nervous System. 2nd Ed. p. 201. WB Saunders, Philadelphia, 1992.

CNS process. They are most commonly sought to give laboratory support to a diagnosis of multiple sclerosis. In definite multiple sclerosis, they are said to be present 83% to 94% of the time. The sensitivity is much lower when patients with probable and possible multiple sclerosis are included. Other diseases that result in intrathecal synthesis of immunoglobulin can cause oligoclonal bands. Almost all patients with subacute sclerosing panencephalitis have them. Many other CNS infections can cause them, including progressive rubella encephalitis, herpes simplex virus and other encephalitides, neurosyphilis, Lyme disease, and bacterial and viral meningitis. SUGGESTED READINGS Condemi JJ: Autoimmune diseases. JAMA 268:2883, 1992 Coull BM, Levine SR, Brey RL: The role of antiphospholipid antibodies in stroke. Neurol Clin 10125, 1992 Dalmau J, Graus F, Rosenblum MK et ak Anti-Hu-associated paraneoplastic encephalomyelitislsensoryneuronopathy: a clinical study of 71 patients. Medicine 71:59, 1992 Dalmau J, Posner JB: Paraneoplastic syndromes. Arch Neurol56405-408, 1999 Dressler F, Whalen JA, Reinhardt BN, Steere AC Western blotting in the serodiagnosis of Lyme disease. J Infect Dis 167:392, 1993 Fishman RA: Cerebrospinal Fluid in Diseases of the Nervous System. 2nd Ed. WB Saunders, Philadelphia, 1992 Hagen EC, Ballieux BEPB, van Es LA et ak Antineutrophilic cytoplasmic autoantibodies: a review of the antigens involved, the assays, and the clinical and possible pathogenetic consequences. Blood 81:1996, 1993 Harris EN, Chan JKH, Asherson RA: Thrombosis, recurrent fetal loss, and thrombocytopenia: predictive value of the anticardiolipin antibody test. Arch Intern Med 146:2153, 1986 Harris EN, Gharavi AE, Pate1 SP, Hughes GRV: Evaluation of the anticardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol68:215, 1987 Herndon RM, Brumback RA.The Cerebrospinal Fluid. Kluwer Academic, Boston, 1989 Hirsh J, Warkentin TE, Raschke R et al: Heparin and low-molecularweight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1 14:489!%510S, 1998 Jordan KG Modern neurosyphilis: a critical analysis. West J Med 149:47, 1988 Levine JS, Branch DW, Rauch J: The antiphospholipid syndrome. N Engl J Med 346752-763, 2002 Nachman RL, Silverstein R Hypercoagulable states. Ann Intern Med 119:819, 1993 Posner JB: Paraneoplastic syndromes. Neurol Clin 9919, 1991 Sigal LH: The polymerase chain reaction assay for Borrelia burgdorferi in the diagnosis of Lyme disease. Ann Intern Med 120520, 1994 Simon Rp: Neurosyphilis. Arch Neurol 42:606, 1985 Vermeulen M: Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry 52:826, 1989

Chapter 19

19

Genetic Testing for Neurologic Disorders

183

Genetic Testing for Neurologic Disorders Bruce R. Korf

The identification of genes responsible for disease has spawned a new diagnostic approach based on analysis of genetic mutations. This has led to major advances in medical practice, enabling more precise diagnoses and obviating more invasive tests for some genetic disorders. It has also made it possible to offer prenatal diagnosis and testing in advance of symptoms. Neurologists are already using some genetic tests in routine practice, and it is likely that this will increase, particularly as genes that contribute to common disorders come to light. The use of genetic tests is not without pitfalls, however. These include technical challenges, including the interpretation of both positive and negative results. There are also social and ethical concerns, particularly those that arise from predictive tests for disorders that cannot be prevented or treated, where testing may expose patients to anxiety and discrimination. The neurologist must be alert to these issues as genetic testing is increasingly incorporated into routine practice. This chapter reviews the indications for genetic testing of neurologic disorders, major approaches to testing, and counseling and ethical issues in genetic testing. INDICATIONS FOR GENETIC TESTING We define genetic testing as analysis of chromosomes, DNA, or RNA to identify a mutation that is associated with disease. There are many examples of conventional medical tests that can be used to diagnose genetic conditions. For example, hemoglobin electrophoresis can identify sickle hemoglobin, and cholesterol determination can diagnose familial hypercholesterolemia. For present purposes, however, these are not considered genetic tests. We also focus on detecting germ line mutations rather than somatic mutations such as those that occur in malignancy. One of the characteristics that distinguishes a genetic test from other kinds of diagnostic tests is that a genetic test can be performed using any source of tissue that includes germ line DNA. Most often this is peripheral blood, where nucleated white blood cells are a source of DNA. Cheek brushings provide another source of DNA, obtained easily and nontraumatically. In contrast, conventional medical tests usually entail access to tissue that is affected by the disease process. For neurologic disorders this means muscle or nerve biopsy or even brain biopsy. The promise of noninvasive testing therefore is one of the major attractions of a genetic test. Genetic testing also enables prenatal diagnosis of disorders that were previously impossible to detect until after birth and sometimes until after passage of many years. DNA can be obtained easily from the fetus by amniocentesis at 16 to 18 weeks of gestation or by chorionic villus sampling at 10 to 12 weeks. Another distinguishing characteristic of genetic testing is that it can be done at any time in life, in contrast to more phenotypically based tests, which can be performed only after the onset of signs or symptoms. This enables earlier diagnosis of those with early nondiagnostic symptoms and signs as well as prenatal and presymptomatic diagnosis of those known to be at risk. Genetic tests can be broadly divided into two groups: diagnostic tests and predictive tests. As the name implies, diagnostic tests are used to establish a diagnosis in a patient who is manifesting

signs or symptoms of disease. The test is used to determine whether a particular condition is the cause of these signs or symptoms or to exclude that condition as a cause. Here, it is fair to assume that the patient and physician are concerned about the possible cause and want to arrive at an answer. An example would be testing a young boy with muscle weakness for a dystrophin mutation to diagnose possible Duchenne muscular dystrophy. Establishing diagnosis in this case allows the family to be advised about the natural history of the disorder and management options. It also provides a basis for genetic counseling. Predictive tests are done on patients who are deemed to be at risk for a genetic disorder but at the time of testing do not manifest signs or symptoms. The risk may result from family history, ethnicity, or medical history. The results of the genetic test may modify the risk that the person will someday develop the condition, but unless the genetic trait displays complete penetrance, inheritance of the at-risk genotype does not make the phenotype inevitable. Also, the time of onset, specific symptoms, and degree of severity may not be predictable. Patients who are at risk for Huntington’s disease, for example, may learn that they will eventually develop the disorder if they live long enough, but the time of onset cannot be predicted. Determining a person’s ApoE genotype does not unequivocallypredict whether that patient will develop Alzheimer’s disease. The €4 allele is associated with an increased relative risk of Alzheimer disease, but the absolute risk to a person with this genotype may still be low. The distinction between diagnostic and predictive tests usually is a matter of timing. A patient with chorea may be tested for the huntingtin triplet repeat expansion as a diagnostic test, not a predictive test. Nevertheless, it is the use of genetic tests in asymptomatic patients to predict disease risks that has attracted the most concern from ethicists and from the public. In most cases, the disorder for which one is determined to be at risk cannot be prevented and may not be treatable. The patient therefore learns that he or she may (or may not) someday develop a serious medical condition but can do nothing to prevent that from occurring. This may lead to anxiety and could put the person at risk of loss of insurance or employment. We return to these and other ethical concerns later in this chapter. Despite these concerns, however, there are reasons that some might choose to undergo predictive testing. Many are tested in the hope that they will be found not to have inherited the disease gene for which they are at risk, accepting that the testing might reveal the opposite. Some would prefer to plan their lives for a time when their health might deteriorate. Predictive testing may be used for family planning purposes. Finally, as we come to better understand the pathogenesis of neurogenetic disorders, there is the hope that preventive or treatment strategies will be devised. This would make the medical utility of predictive testing more compelling. One additional application of genetic testing is in determining carrier status for recessive disorders. Carriers are not themselves at risk of developing the disorder but can transmit the gene to an offspring. For autosomal recessive traits, both parents would need to be carriers for a child to be at risk; for an X-linked recessive, a mother who is a carrier is at 50% risk of having an affected son.

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Principles of Diagnosis: Special Tests

Carrier testing may be offered to relatives of an affected person, such as female relatives of a boy with Duchenne muscular dystrophy. It is also offered to people who come from an ethnic group with a high frequency of carriers for a particular gene mutation (e.g., testing Ashkenazi Jews for carrier status of Tay-Sachs, Gaucher, or Niemann-Pick disease). APPROACHES TO GENETIC TESTING There are two major approaches to genetic testing: linkage analysis and direct mutation analysis. Linkage analysis involves tracking the chromosome region on which a gene mutation resides through a family to infer who has or has not inherited that region. The testing in this case is indirect. Direct mutation analysis provides a more definitive result but is not always possible. Linkage-Based Genetic Testing The principle of a linkage-based test is described in Figure 19-1. In this example, a family segregating a dominantly inherited disorder requests testing. The disease gene is known to be closely linked to two genetic markers, designated here “A” and ‘‘BY that flank the disease locus. Both “A” and “B” are polymorphic, meaning that variant forms of these genes exist and are common in the population. We designate the forms as “1” and “2” for gene “A” and “3” and “4” for gene “B.” The father has inherited the disease from his mother, along with the “1” allele for gene “A“ and the “3” allele for gene “B.” Therefore, we know that he will produce sperm cells with the disease gene together with the “1” and “3” alleles and the wild type (normal) gene together with the “2” and “4” alleles. His partner has only the “1” form of gene “A” and the “4”form of gene “B,” so we can easily follow which of the two chromosomes father passes on to his children. Any child who inherits “1” and “3” can be expected to inherit the disease allele, and a child who inherits “2” and “4”should not be affected. There is a possibility of ambiguity, or even diagnostic error, in this scheme, illustrated by the child in the middle. This child inherits “1” from father together with “4.” We know that father has “1” and “3” on the same chromosome, so we can infer that the “1” and “4”configuration is the result of a genetic recombination event. We cannot predict whether a child who inherits the recombinant chromosome will develop disease because we do not know whether the child did or did not inherit the disease gene. The use of flanking markers at least has revealed that recombination has occurred. If only “A” or “B” alone were used, the recombination event would have gone unnoticed and an erroneous diagnosis might have resulted. Frequency of recombination is a function of the distance of the marker gene from the disease gene; this allows estimation of the reliability of the test result, based on the probability of recombination. Obviously, it is a great advantage to use markers that are very closely linked to the gene of interest to minimize the chances for recombination. There are several other limitations to linkage-based testing. One is that the family must be “informative” for the analysis. This means that the two copies of the chromosome must be distinguishable in terms of marker genotypes in the parent (or parents) who carry the disease gene. One cannot always depend on the markers being informative in every family. (For example, if the father in this family had inherited a “1” allele from both parents, we would not be able to tell his two chromosomes apart at the “A” locus.) The specific alleles at the marker locus are not always

Recombination event

FIG. 19-1. Sample genetic linkage study.

associated with the disease gene in all families. A given allele, such as “1” in the example, will be common in the population; although marker “A” is always linked to the disease gene, it is just a matter of chance that allele “1” is present on the same chromosome with the disease gene in this particular family. Another limitation is that some disorders exhibit genetic heterogeneity, so that mutations at different gene loci can cause the same disease. Linkage analysis will not prove that the locus being tracked is the one that is responsible for the disease in a particular family. If it is not, diagnostic error is very likely. Such genetic heterogeneity exists for tuberous sclerosis, caused by genes on chromosomes 9 or 16 in different families. A linkage study that tracks chromosome 9 will not be helpful if the disorder in the family happens to be caused by mutation in the chromosome 16 gene. With these limitations it might seem that linkage analysis would not be the method of choice for any disorder. Indeed, if

Chapter 19 H Genetic Testing for Neurologic Disorders

direct mutation testing is feasible it is usually preferable. Linkage testing is most useful in disorders in which the disease gene has not yet been identified but has been mapped. It is also useful when there are technical obstacles to direct mutation analysis. For example, for very large genes it may be difficult to detect all possible mutations. An example is the dystrophin gene responsible for Duchenne muscular dystrophy. If a gene mutation cannot be found, linkage analysis remains useful for clinical purposes. An example is shown in Figure 19-2. One additional limitation inherent in linkage testing is the need to sample multiple members of the family. This can be timeconsuming and requires that relatives be available for testing and willing to cooperate. It should also be remembered that sometimes a linkage study will reveal that the stated father of a child in the family is not the biological father. This can raise sensitive issues that must be handled carefully. Direct Mutatlon Analysis

Direct mutation analysis requires that the disease gene has been identified and relies on technologies that permit mutations to be detected. The spectrum of mutations in different genes is highly diverse. The specific diagnostic approach therefore must be tailored to the types of mutations likely to be responsible for a particular trait. Some genetic disorders are characterized by a limited repertoire of pathogenetic mutations. The most extreme example is sickle cell anemia, always caused by the same substitution of valine for

Fetus 1

3 FIG. 19-2. Linkage study for Duchenne muscular dystrophy (DMD). Two markers are tested: 83/84 on one side of DMD and 123/124 on the other. Alleles are labeled "1," "2," and "3." The two affected boys inherit the "2" alleles for both loci from their mother. Their sister has likewise inherited these alleles and is therefore likely to be a carrier. However, the fetus has inherited the chromosome with the "1" and "3" alleles from his mother, which is the X chromosome inherited from her father, which does not carry a DMD mutation. The fetus therefore is unlikely to be affected, barring the possibility of double recombination.

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glutamic acid caused by an A to T change in the P-globin gene. Tay-Sachs disease is associated with a wider variety of mutation types, but three mutations make up the majority seen in the Ashkenazi population, where the mutation frequency is highest. These types of disorders lend themselves to straightforward diagnostic procedures aimed at detecting the most common mutations. In contrast, some disorders are associated with a large variety of mutation types that can be widely scattered across the gene. An example is neurofibromatosistype 1, where hundreds of mutations have been identified across the 60 exons of the NFl gene. In such cases it may not be practical to detect all possible mutations in a clinical test. The most extreme types of mutations are deletions of entire genes and often of entire groups of genes along a chromosome. There is a long history of study of chromosome abnormalities, ranging from trisomies of entire chromosomes to rearrangements that result in duplication or deletion of small chromosome segments. In the past several years a number of genetic syndromes have been delineated that are caused by deletions of very small chromosome regions, too small to see through the microscope with conventional staining. However, these microdeletions can be detected using fluorescence in situ hybridization, in which fluorescent-labeled DNA segments are hybridized to homologous sequences on the chromosome. Microdeletion syndromes produce complex phenotypes, probably because of loss of multiple contiguous genes on the chromosome. Mutations within single genes may interfere with expression of the gene product or may alter function of the protein. Many types of mutations may reduce levels of gene expression. These include deletions of all or part of a gene, changes in regulatory sequences that lead to reduced levels of transcription, and mutations that lead to premature termination of translation of the gene product. The latter include stop mutations, in which a single base change converts a sequence that encodes an amino acid to one that signals chain termination. It also includes frameshifts, deletions, or insertions of numbers of bases not equal to three, the number that makes up a codon that directs insertion of an amino acid. Mutations that upset the mechanism of removing introns and splicing together exons can also lead to premature termination of translation by inserting a nonsense sequence representing part of the intron into the final processed message or by deleting an exon from the message and juxtaposing two exons with different reading frames. Single base changes can also result in incorporation of an incorrect amino acid into a protein. Sometimes this results in loss of function of the protein if the new amino acid upsets secondary structure or substantially alters the physical properties of the protein. Other times there may be a gain of function, causing a protein to be active free from constraints of normal regulation. Sometimes this gain of function may be toxic to cells; other times it alters cellular function. A unique mutation class is found at the basis of several neurologic disorders. This is the triplet repeat expansion, in which a triplet of bases located within a gene is repeated multiple times, the exact number of repeats differing between individuals in the population. Increase in repeat number beyond a threshold disrupts the function of the gene, leading to a pathologic phenotype. Triplet repeat expansion underlies fragile X syndrome, Friedreich's ataxia, spinocerebellar ataxias, Huntington's disease, Kennedy's disease, and myotonic dystrophy. These disorders have in common the phenomenon of anticipation, in which age of

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onset decreases and severity increases as a trait is passed from generation to generation. This reflects the fact that larger repeat expansions are associated with more pronounced phenotypes, and larger expansions are prone to further expansion as germ cells are formed from one generation to the next. Various techniques are available to measure the size of repeat expansions and provide diagnostic or predictive testing and carrier detection for these disorders. Another distinctive type of mutation recognized in the recent past involves the phenomenon of genetic imprinting, in which some genes are not expressed from both the maternal and paternal copies. A number of clinical disorders, most notably Prader-Willi and Angelman’s syndromes, result from deletions or mutations involving imprinted genes. The particular phenotype in these disorders depends on which parent transmits the mutation. A variety of mutation detection technologies is used to identify specific mutation types. If the repertoire of mutations responsible for a disorder is limited, it may be possible to definitively detect the presence of a pathogenic mutation and diagnose or exclude a particular condition. If the repertoire of mutation is large, however, it may be difficult or impossible to detect all pathogenic changes. For smaller genes, direct DNA sequencing may be used, although even this may miss mutations that reside in regulatory sequences that flank a gene or within introns. For larger genes, there are techniques that allow large segments of a gene to be screened rapidly for the presence of a mutation, with follow-up by direct sequencing if evidence of a mutation is found. This kind of analysis is subject to two important pitfalls in interpreting results to which the clinician must be alert. First, as noted earlier, it is usually impossible to explore every base of a gene, its regulatory regions, and introns. Therefore, failure to find a mutation should not be taken as proof that no mutation is present. Second, many of the mutations found will be unique changes that have not been seen before. Some of these may not be pathogenic but rather could represent rare sequence variants of unknown significance. It is important to critically evaluate newly discovered mutations before concluding that they are pathogenic. Evidence of pathogenicity might include knowledge that the mutation segregates with the disease in a family, is not seen in unaffected people in the general population, or can be inferred to disrupt the structure or expression of the gene product significantly.

GENETIC COUNSELING AND ETHICAL ISSUES Genetic counseling has been defined as a communication process in which explanation is provided about the genetic contribution to a disorder, its natural history, the risk of recurrence, and the options available to deal with the disorder and the risk of genetic transmission. There are medical professionals who are specially trained to provide genetic counseling, including physicians or Ph.D.s trained in medical genetics, certified genetic counselors, or nurses with special training in genetics. The use and interpretation of genetic tests raise some specific issues that warrant special attention in the counseling process. These include Accurate interpretation of test results: As has been noted, there are many potential pitfalls in interpreting genetic test results. Most genetic tests have a high degree of analytical reliability, but there are many opportunities for misinterpretation. These include errors caused by genetic recombi-

Principles of Diagnosis: Special Tests

nation or genetic heterogeneity for a linkage-based test, or incomplete ascertainment of mutations or detection of benign variants in direct testing. The clinician must be alert to such pitfalls and must be prepared to explain them to patients or family members. Stigmatization: Patients who are found to carry specific mutations may be perceived as different by themselves, members of their families, or members of society. They may experience altered self-image or guilt, and relatives may blame them for carrying a gene that has led to disease in other members of the family. It is important to recognize these reactions and to be prepared to address them in the counseling process. Disorders associated with high risk of such reactions, such as Huntington’s disease, should be approached in a systematic manner with a well-organized process of counseling before and after genetic testing. Discrimination: Patients who are found to carry specific mutations that predict future disease may be at risk for loss of health or life insurance or employment discrimination. It is particularly important to respect the patient’s privacy. In some cases, patients may request that reports of genetic tests not be placed in the medical record. In some states, genetic privacy legislation has been enacted to protect the privacy of patients who have had genetic tests. Family relationships: Unlike many medical tests, genetic test results may have implications for many members of a family. Sometimes tests may reveal sensitive issues such as misattributed paternity. The privacy of individuals within the family must be respected and risks of discovery of information about others in the family discussed before testing. Research versus clinical testing: Most genetic tests are developed within research laboratories that are involved in discovering a gene and establishing its role in disease. Most such laboratories are not set up with the quality assurance mechanisms expected for clinical laboratories, yet for rare disorders they may be the only site where testing is available. National standards for oversight of genetic tests are being formulated. One principle is that clinical testing laboratories must be licensed under the Clinical Laboratory Improvement Amendments (CLIA). Clinicians who are seeking a laboratory where clinical testing can be performed for a specific disorder can consult the GeneTests database (www.genetests.org).

CONCLUSION Genetic testing is in its infancy, yet already it has had a major impact on the diagnosis and management of neurologic disorders. This includes the ability to provide more precise means of diagnosis, predictive testing, and prenatal diagnosis. With increasing knowledge of the human genome, it is likely that the domain of genetic testing will expand from attention to rare disorders to the diagnosis of more common and complex conditions. Technological advances are also likely to make it possible to screen large numbers of genes rapidly at low cost, enabling assessment for multiple genes that may contribute to risk. Clinicians increasingly must be alert to the principles of appropriate use and accurate interpretation of genetic tests and sensitive to the ethical issues raised by their application.

Chapter 20

Electrophysiology: Electroencephalographyand Evoked Potentials

SUGGESTED READINGS Benjamin CM, Adam S, Wiggins S et al: Proceed with care: direct predictive testing for Huntington disease. Am J Hum Genet 55:606617, 1994 Collins FS: Shattuck lecture: medical and societal consequences of the Human Genome Project. N Engl J Med 341(1):28-37, 1999 Korf B: Molecular diagnosis. N Engl J Med 332:1218-1220, 1499-1502, 1995 Korf B R Pitfalls in the interpretation of molecular diagnostic tests. J Clin Lab Anal 10(6):368-374, 1996

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McConnell LM, Koenig BA, Greely HT et al: Genetic testing and Alzheimer disease: recommendations of the Stanford Program in Genomics, Ethics, and Society. Genet Test 3(1):3-12, 1999 Olick RS Disclosing genetic information to family members. Do old paradigms fit the new medicine? N J Med 97( 1):43-46, 2000 Rosenberg RN: DNA-triplet repeats and neurologic disease. N Engl J Med 335( 16):1222-1224, 1996 Vnencak-Jones CL Molecular testing for inherited diseases. Am J Clin Pathol 112(1 Suppl 1):S19-S32, 1999 Wagstaff J: Genetics beyond Mendel. Understanding nontraditional inheritance patterns. Postgrad Med 108(3):131-138, 2000

Electrophysiology:Electroencephalography and Evoked Potentials

20

Edward B. Bromfield Even in the present age of sophisticated neuroimaging, the neurophysiologic techniques of electroencephalography (EEG) and evoked potentials (EP) can provide noninvasive and inexpensive means of obtaining information about neurologic function that is not otherwise available. Despite major advances in molecular biology and neurochemistry, the nervous system is still best considered as an electrical system; electrodiagnostic techniques are in this sense fundamental to an understanding of its function and dysfunction. From a clinical point of view, it is necessary to appreciate how these techniques complement the information obtained from history, physical examination, and other diagnostic studies. ~

ELECTROENCEPHALOGRAPHY Physiology and Anatomic Correlations

Routine EEG recordings summarize the electrical fields generated by large neuronal populations behaving in a synchronous manner; the physiologic correlates of the scalp EEG are thought to be excitatory and inhibitory postsynaptic potentials generated at the apical dendrites of cortical pyramidal cells. A single standard scalp electrode records activity from approximately 6 cmz of gyral surface. Cortical activity at the sides and depths of sulci, as well as at deeply located cortex such as the medial temporal or orbitofrontal regions, is less well represented. Nevertheless, a sufficiently large area of cortex is sampled to reflect many aspects of focal and global function. Furthermore, because cortical activity is affected in somewhat predictable ways by changes in other regions that are not directly accessed, including white matter, deep gray structures, and the brainstem, EEG can provide information about a wide variety of conditions. However, its utility is greatest for diseases that affect primarily cortical function, such as epilepsy.

Technique and Analysis Scalp EEG generally is recorded using metal cup electrodes filled with conducting gel or paste. Placement of electrodes on the head

was standardized in 1958 with the adoption of the International 10-20 System, which uses percentage measurements of distances between skull landmarks (Fig. 20-1). Newer nomenclature has been proposed mainly to include intermediate placements that allow many more than the 21 standard positions shown in Figure 20-1. The number of channels used for recording and display is, in theory, unlimited; in practice, paper tracings are made on machines with 16 to 21 channels, and digital systems often record 32 or more channels. Because of the low amplitude of scalp-recorded signals relative to electrical noise in the laboratory environment, a differential amplifier, which amplifies the difference between two inputs, is used. Therefore, each channel records the time-varying difference in electrical potential between two points. The arrangement on the page of the specific electrode pairs whose potential difference is displayed in each channel is called a montage. Although this arrangement is arbitrary, montages are devised to reflect a logical spatial approach that facilitates analysis. There are two main types of montages: referential and bipolar. In referential recording, the second input is the same for all channels. This arrangement is useful for certain types of analysis, but technical factors, particularly the impossibility of designating a truly inactive, artifact-free reference, limit its usefulness. In the other type of montage, called bipolar, a common reference electrode is not used; typically, pairs of adjacent electrodes are connected in chains such that the second input of one channel becomes the first input of the next (see Figs. 20-2 to 20-6). Some montages are better than others for displaying various normal and abnormal phenomena, and routine 20- to 30-minute studies usually make use of three to six different ones, including both the referential and bipolar types. Analysis of EEG depends on identifying the dominant frequencies and important transient electrical events over different regions during waking, drowsy, and sleeping states. Wave frequency is classified as a (8 to less than 14 Hz), p (14 Hz and greater), 8 (4 to less than 8 Hz), and 6 (less than 4 Hz). The normal adult waking EEG is characterized by posterior a-wave activity that attenuates on eye opening (Fig. 20-2). Lower-amplitude p-waves usually

Chapter 20

Electrophysiology: Electroencephalographyand Evoked Potentials

SUGGESTED READINGS Benjamin CM, Adam S, Wiggins S et al: Proceed with care: direct predictive testing for Huntington disease. Am J Hum Genet 55:606617, 1994 Collins FS: Shattuck lecture: medical and societal consequences of the Human Genome Project. N Engl J Med 341(1):28-37, 1999 Korf B: Molecular diagnosis. N Engl J Med 332:1218-1220, 1499-1502, 1995 Korf B R Pitfalls in the interpretation of molecular diagnostic tests. J Clin Lab Anal 10(6):368-374, 1996

187

McConnell LM, Koenig BA, Greely HT et al: Genetic testing and Alzheimer disease: recommendations of the Stanford Program in Genomics, Ethics, and Society. Genet Test 3(1):3-12, 1999 Olick RS Disclosing genetic information to family members. Do old paradigms fit the new medicine? N J Med 97( 1):43-46, 2000 Rosenberg RN: DNA-triplet repeats and neurologic disease. N Engl J Med 335( 16):1222-1224, 1996 Vnencak-Jones CL Molecular testing for inherited diseases. Am J Clin Pathol 112(1 Suppl 1):S19-S32, 1999 Wagstaff J: Genetics beyond Mendel. Understanding nontraditional inheritance patterns. Postgrad Med 108(3):131-138, 2000

Electrophysiology:Electroencephalography and Evoked Potentials

20

Edward B. Bromfield Even in the present age of sophisticated neuroimaging, the neurophysiologic techniques of electroencephalography (EEG) and evoked potentials (EP) can provide noninvasive and inexpensive means of obtaining information about neurologic function that is not otherwise available. Despite major advances in molecular biology and neurochemistry, the nervous system is still best considered as an electrical system; electrodiagnostic techniques are in this sense fundamental to an understanding of its function and dysfunction. From a clinical point of view, it is necessary to appreciate how these techniques complement the information obtained from history, physical examination, and other diagnostic studies. ~

ELECTROENCEPHALOGRAPHY Physiology and Anatomic Correlations

Routine EEG recordings summarize the electrical fields generated by large neuronal populations behaving in a synchronous manner; the physiologic correlates of the scalp EEG are thought to be excitatory and inhibitory postsynaptic potentials generated at the apical dendrites of cortical pyramidal cells. A single standard scalp electrode records activity from approximately 6 cmz of gyral surface. Cortical activity at the sides and depths of sulci, as well as at deeply located cortex such as the medial temporal or orbitofrontal regions, is less well represented. Nevertheless, a sufficiently large area of cortex is sampled to reflect many aspects of focal and global function. Furthermore, because cortical activity is affected in somewhat predictable ways by changes in other regions that are not directly accessed, including white matter, deep gray structures, and the brainstem, EEG can provide information about a wide variety of conditions. However, its utility is greatest for diseases that affect primarily cortical function, such as epilepsy.

Technique and Analysis Scalp EEG generally is recorded using metal cup electrodes filled with conducting gel or paste. Placement of electrodes on the head

was standardized in 1958 with the adoption of the International 10-20 System, which uses percentage measurements of distances between skull landmarks (Fig. 20-1). Newer nomenclature has been proposed mainly to include intermediate placements that allow many more than the 21 standard positions shown in Figure 20-1. The number of channels used for recording and display is, in theory, unlimited; in practice, paper tracings are made on machines with 16 to 21 channels, and digital systems often record 32 or more channels. Because of the low amplitude of scalp-recorded signals relative to electrical noise in the laboratory environment, a differential amplifier, which amplifies the difference between two inputs, is used. Therefore, each channel records the time-varying difference in electrical potential between two points. The arrangement on the page of the specific electrode pairs whose potential difference is displayed in each channel is called a montage. Although this arrangement is arbitrary, montages are devised to reflect a logical spatial approach that facilitates analysis. There are two main types of montages: referential and bipolar. In referential recording, the second input is the same for all channels. This arrangement is useful for certain types of analysis, but technical factors, particularly the impossibility of designating a truly inactive, artifact-free reference, limit its usefulness. In the other type of montage, called bipolar, a common reference electrode is not used; typically, pairs of adjacent electrodes are connected in chains such that the second input of one channel becomes the first input of the next (see Figs. 20-2 to 20-6). Some montages are better than others for displaying various normal and abnormal phenomena, and routine 20- to 30-minute studies usually make use of three to six different ones, including both the referential and bipolar types. Analysis of EEG depends on identifying the dominant frequencies and important transient electrical events over different regions during waking, drowsy, and sleeping states. Wave frequency is classified as a (8 to less than 14 Hz), p (14 Hz and greater), 8 (4 to less than 8 Hz), and 6 (less than 4 Hz). The normal adult waking EEG is characterized by posterior a-wave activity that attenuates on eye opening (Fig. 20-2). Lower-amplitude p-waves usually

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Principles of Diagnosis: Special Tests

NAS ION

INION FIG. 20-1. The International 10-20 System of electrode placement. A, earlobe or mastoid; C, central (near the central sulcus); F, frontal; Fp, frontopolar; 0, occipital; P, parietal; T, temporal. The numerical designation indicates left (odd), right (even), or midline (Z for zero) location, with higher numbers indicating greater distance from the midline. (From Aminoff MI: Electroencephalography:General Principles and Clinical Applications. p. 41. In: Electrodiagnosisin Clinical Neurology. 3rd Ed. Churchill Livingstone, New York, 1995, with permission.)

predominate anteriorly, intermixed with small amounts of lowerfrequency waves. p-Waves may be increased by certain drugs, especially sedatives (Fig. 20-3). Prominent 8- and &waves during the waking state in adults, particularly if asymmetric (Fig. 20-4), are abnormal. Normal stage 1 sleep is characterized by attenuation of a-wave and increased prominence of 0-wave frequencies. Characteristic sharp transients over the vertex are seen in late stage 1; stage 2 sleep is characterized by lower-voltage, rhythmic sleep spindles (Fig. 20-5), as well as K complexes, which resemble combinations of vertex waves and spindles. Stage 3 is defined by high-voltage 6-waves occurring during 20% to 50% of the analyzed segment, and stage 4 is characterized by the presence of 6-waves more than 50% of the time. EEG during rapid eye movement ( E M ) sleep resembles that of stage 1, but rapid horizontal eye movements and attenuation of muscle activity are also present. Neither slow wave sleep (stage 3 or 4) nor REM typically is recorded during a routine daytime study. Knowledge of the age and state of consciousness of the patient are needed in interpreting an EEG. Prenatal development, as manifested in the EEG of premature infants, is characterized by differentiation of the states of waking, active sleep, and quiet sleep (the latter two analogous to REM and non-REM sleep) and synchronization of the two hemispheres. Spindles first occur about 2 months after term, and a posterior waking rhythm of about 4 Hz occurs after approximately 3 months; frequency gradually increases to the a-wave range by 3 years and reaches adult frequencies at about 10 years. During childhood, slow waves in the waking state become less prominent, with 6-waves disappearing and 0-waves diminishing. EEG is stable through adolescence and maturity. In later adulthood, slower waves may again be normally

present, with even a small amount of &waves allowable in older adults, and the a-wave rhythm may also slow slightly. Characterization of normal and abnormal waveforms includes description of frequency, amplitude, contour (e.g., sharpness), rhythmicity, topographic distribution, polarity (surface positive versus surface negative), persistence, and reactivity. Some patterns are sufficiently distinct to have their own names (see Table 20-1). Indicators of cerebral dysfunction include a posterior rhythm that is too slow (relative to age-matched controls or a previous a-wave study) or marked left-right asymmetries of frequency or reactivity; amplitude is commonly higher over the right hemisphere, and right:left ratio can normally be as high as 2:1 or as low as 2:3. However, p-wave asymmetries should not exceed 2:3 in either direction; lower amplitude is an indicator of lateralized or localized cortical dysfunction. In the presence of a cranial defect, however, the high-frequency filtering effect of the skull is diminished, resulting in improved transmission and therefore higher amplitude of p-waves under the skull breach. The most common indicators of abnormal cerebral function are slow waves, with the degree of slowing proportional to the severity of dysfunction (e.g., &waves signify more severe dysfunction than &waves). Generalized slowing is the most common correlate of a diffuse encephalopathy, although a multifocal process can at times be indistinguishable. Localized slowing is of particular importance because it may in some circumstances be the only indication of a focal neurologic process. Structural lesions involving white matter typically correspond to areas of irregular slowing, whereas rhythmic slowing more often reflects involvement of deep midline structures or of both cortical and deep gray matter, as in metabolic processes.

Chapter 10

Electrophysiology: Electroencephalographyand Evoked Potentials

The interictal EEG correlate of a seizure tendency is the epileptiform discharge (Figs. 20-6 and 20-7), which may take the form of spikes, sharp waves, and spike-wave complexes. A splke is a transient electrical event that stands out from the background, has a sharp peak at the conventional paper speed of 30 mmhecond, and has a duration at its base of 20 to just under 70 msec. Because of the organization of cortical pyramidal cells, polarity as recorded at the cortical surface or scalp usually is negative. A sharp wave is similar but has a duration of 70 to 200 msec. A spike-wave complex is a spike immediately followed by a distinct €)-waveor, more commonly, a 8-wave; these often occur in rhythmic bursts. Variants include sharp-slow complexes and polyspike-wave or multiple-spike and slow-wave complexes. Distinguishing these interictal epileptiform discharges from normal or nonspecific phenomena is not always straightforward, however, and may depend on such characteristics as age and state of the patient as well as morphology, location, polarity, reactivity, amplitude, and context of the waveform. There are also distinct patterns, discussed in several of the “Suggested Readings,” that resemble single or repetitive discharges but correlate weakly, if at all, with a seizure tendency or other aspects of brain dysfunction. These include benign epileptiform transients of sleep (BETS, or small sharp spikes), rhythmic midtemporal €)-wavesof drowsiness (also called psychomotor variant), 14- and 6-Hz positive spikes,

6-Hz phantom spike-waves, and subclinical rhythmic EEG discharge of adults (SREDA). Finally, there are several distinctly abnormal patterns, often of a repetitive, periodic, or rhythmic nature. Periodic lateralized epileptiform discharges (PLEDs) are commonly seen in the setting of acute or subacute disturbances, such as strokes and inflammations, and, like sporadic localized sharp waves, are strongly associated with partial seizures. Bilateral insults may be manifested as bilateral independent or bisynchronous periodic discharges, with morphology and rate providing some etiologic information. Triphasic waves are a characteristic repetitive waveform that can resemble generalized sharp-slow complexes but occur in the context of metabolic encephalopathy rather than seizures. The burst suppression pattern, where periods of electrical silence alternate with bursts of mixed frequency activity, indicates severe underlying dysfunction. Transient rhythmic abnormal activity may represent an actual seizure, although an ictal recording during a routine study is unusual except in cases of status epilepticus. Clinical Uses

In contemporary practice, EEG is used primarily in cases of known or suspected epilepsy, more prolonged states of altered consciousness, or other instances of focally or globally impaired’ cerebral

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Principles of Ambulatory Neurology and the Approach to Clinical Problems rn Principles of Diagnosis: Special Tests

190

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FIG. 20-3. Excessive p-waves seen diffusely in patient on sedative medications.

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Chapter 10

Electrophysiology: Electroencephalography and Evoked Potentials

191

FIG. 20-5. Vertex wave and sleep spindle (arrow) during stage 2 sleep.

TABLE 20-1. Anatomic and Clinical Correlates of Common EEC Findings Findinn

Anatomic

Clinical

Slow background (bilateral) Asymmetric or unilateral slow background Widespread intermittent rhythmic &wave activity (usually anterior in adults, posterior in children) Persistent bilateral irregular slowing (especially 8) Irregular slowing, unilateral or focal

Diffuse or thalamocortical dysfunction lpsilateral diffuse or posterior dysfunction Deep and cortical gray matter

Encephalopathy (acute or chronic) Probable structural lesion Toxic metabolic encephalopathy; midline lesion; hydrocephalus; if unilateral, migraine, postictal state, or structural lesion More severe encephalopathy; bihemispheric or brainstem lesions Underlying structural lesion

Consistently asymmetric p or sleep spindles Sharp waves, spikes, or spike-wave complexes, focal or multifocal Spike-wave complexes, generalized

Diffuse, bihemispheric, or upper brainstem reticular dysfunction Focal subcortical dysfunction (slower and more persistent with increased dysfunction) Cortical dysfunction on side of lower amplitude, or skull or dural defect on opposite side Localized cortical irritability Diffuse cortical irritability

Periodic lateralized epileptiform discharges

Localized or hemispheric dysfunction with cortical irritability

Triphasic waves

Diffuse cortical and subcortical dysfunction

function. The most common scenario is that of an adult or child seen after a transient event that may have represented a seizure. The EEG result can contribute to clinical decision making in several ways: It can help to assess the probability that the event represented a seizure, and it can in some instances indicate the relative susceptibility of this patient to another seizure in the future. These probabilities are critical in deciding whether to treat the patient for presumed epilepsy. Furthermore, the type of interictal epileptiform activity present is important in identifying the underlying epilepsy syndrome (see Chapter 145), which can influence the choice of treatment. A staring spell, for example, can

Structural lesion or subdural collection on lower side; skull defect on higher side Partial epilepsy; focal or multifocal disturbance with seizure tendency Probable generalized epilepsy, either idiopathic (3 Hz or faster complexes, normal background), or symptomatic (slow rate, abnormal background) Acute or subacute process, often vascular or inflammatory (e.g., encephalitis), with seizure tendency; postictal or interictal in relation to serial seizures or status epilepticus Encephalopathy, especially hepatic, less commonlv uremic or postanoxic

be the manifestation of either a partial seizure of temporal lobe origin or an inherited tendency toward generalized absence seizures; in the first case, one would probably find temporal sharp waves or spikes, and in the second one would find 3-Hz generalized spike-wave complexes. When there are repeated or prolonged seizures, constituting status epilepticus, EEG is needed to guide therapy if motor manifestations are absent. In many cases of nonconvulsive status epilepticus (see Chapter 147), diagnosis would be impossible without EEG confirmation. The EEG can help in assessing severity, localization, and, in some cases, cause and prognosis of a wide variety of other

192

Principles of Ambulatoy Neurology and the Approach to Clinical Problems w

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Principles of Diagnosis: Special Tests

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FIG. 20-7. Generalized spike-wave complex with anterior predominance and slight right-greater-than-left asymmetry.

Chapter 20

Electrophysiology: Electroencephalographyand Evoked Potentials

conditions that affect cerebral function. In toxic or metabolic encephalopathies, the characteristic finding is diffuse slowing. Etiologic clues include excess fast activity in the case of sedative toxicity and triphasic waves in the case of hepatic encephalopathy. (If there is no evidence of the latter, uremia or hypoxia-ischemia should be considered.) More severe abnormalities, from burst suppression to continuously low voltage to electrocerebral inactivity, are most commonly seen after anoxia, although severe toxic or metabolic disturbances can also be the cause. The nonreactive “a-coma” pattern, in the most common setting of postanoxia, indicates a dismal prognosis but, like other patterns, may be less ominous if resulting from another cause. True electrocerebral inactivity, for which specific technical criteria have been adopted, can be a useful adjunct in the diagnosis of brain death as long as drug intoxication and hypothermia have been ruled out. In encephalopathy and coma, serial studies often are useful because EEG deterioration or improvement may precede clinical changes. Also worth noting is the use of EEG in suspected psychogenic coma, where a normal waking pattern with reactive posterior a rules out a cerebral cause. Alternatively, a normal background may be present in the locked-in syndrome caused by pontine pathology. EEG can also be very useful in diagnosing inflammatory and dementing conditions. Although findings in meningitis are similar to those of metabolic encephalopathies, encephalitis may be associated with focal or multifocal slowing as well as sharp waves or spikes. Herpes simplex encephalitis, in particular, is characteristically associated with unilateral or bilateral frontotemporal slowing, often with sharp waves or periodic complexes that may be synchronous or asynchronous between the hemispheres and recur at 1- to 5-second intervals; these changes may precede neuroimaging abnormalities. In the rare pediatric disease of subacute sclerosing panencephalitis, the EEG finding of slowly periodic (every 5 to 10 seconds) bursts of very high-voltage, bilateral slow and sharp waves is nearly pathognomonic. Creutzfeldt-Jakob disease in its middle and later phases typically shows simpler diphasic or triphasic, more rapidly repeated (every 0.5 to 1.5 second) periodic complexes. Senile dementia of the Alzheimer type, by contrast, usually is associated with background disorganization, showing increasing amounts of 8 and 6 as the condition progresses. Early in the disease, EEG may be normal, but a marked dissociation between clinical and electrographic findings may also suggest the diagnosis of pseudodementia secondary to depression. Vascular disease, including multi-infarct dementia, characteristically is associated with focal or multifocal slowing (Fig. 20-4), with or without loss of faster frequencies, depending on extent of cortical involvement. Localized sharp waves may be present and may be periodic in the acute or subacute stroke phase. An EEG performed during a hemispheric transient ischemic attack, when imaging may be negative, typically shows slowing over the involved area. Resolution on follow-up study can confirm the vascular nature of the process, although this does not rule out the possibility of a postictal deficit with associated slowing. Complicated migraine can show EEG findings identical to those of a stroke or transient ischemic attack, although rhythmic rather than irregular slowing may be more common in migraine. Between attacks, patients with migraine may have a variety of nonspecific abnormalities, including temporal 8 and sharp transients, which can be confused with those seen in patients with epilepsy. Use of EEG in patients with progressive focal lesions, such as tumors or abscesses, has been largely overtaken by neuroimaging, but EEG may still be useful in following more widespread changes that can result from radiation or medications, in assessing the role

193

of seizures in causing ictal or interictal functional impairment, or in showing progression of the underlying condition. The utility of EEG in psychiatric disorders, especially of computerized methods of display, remains controversial, but EEG is clearly helpful in ruling out neurologic causes of abnormal behavior. When combined with recording of other physiologic variables, EEG plays an integral role in the study of sleep disorders via polysomnography (see Chapter 150). The EEG Report: Contents and Tenninology

Many physicians, including some neurologists, view the EEG report as an arcane, jargon-laden document not worthy of detailed perusal and skip as quickly as possible to the “bottom line.” As with any laboratory test, the ordering clinician should specify the reason for the study, and the report should answer insofar as possible the specific question or questions asked. The accompanying detailed description is also important, however, and can provide clues about the usefulness of a particular study. The report should mention any special preparation or recording methods and then describe the dominant or important electrical activity noted in each of the waking, drowsy, and sleeping states, if represented. Description of the waking EEG usually uses the term background to refer to the dominant posterior rhythm, specifylng the frequency and approximate amplitude range. Description of the waking record may also include reference to P-frequencies, particularly as regards amount, amplitude, and symmetry. The description should next include any slower waves that are consistently seen, especially if abnormal based on age and state of the patient. Finally, any significant transient waveforms, specifically epileptiform discharges, should be described. If these are difficult to distinguish from normal or nonspecific phenomena alluded to earlier, the description should reflect this uncertainty. Description of the EEG recorded in drowsiness and sleep is similar, but the concept of a background is more nebulous. At the least, the report should note how any abnormal findings seen in the waking state evolve during subsequent states. Finally, activation procedures are described. In most cases these include hyperventilation for 3 to 4 minutes, which normally causes diffuse slowing but may bring out focal or epileptiform abnormalities, and intermittent photic (strobe light) stimulation, which is a general indicator of visual system function and in occasional patients precipitates epileptiform activity not noted under other conditions, or even a clinical seizure. Additional activation procedures may be tailored to the individual patient, particularly if clinical events are known to be precipitated by, for example, auditory stimuli, cognitive tasks, position changes, or anxiety. Each report should follow with a section summarizing the study. This begins with a global statement of whether it is normal or abnormal, perhaps including a modifier concerning degree of abnormality, and a list of the abnormal features. Most electroencephalographersprefer to call questionable findings normal rather than abnormal. This propensity makes clinical sense in the case of suspected epilepsy because a single EEG may be normal in approximately 50% of individuals with the condition, whereas a frankly abnormal EEG with definite epileptiform discharges may have a specificity greater than 95%. Finally, there should be an interpretation regarding the clinical implications of the findings, specifically in relation to the reason the EEG was requested. Comparisons with previous studies of the same patient and suggestions for future EEG studies can be useful. In the case of suspected epilepsy, although a single study is only about 50%

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Principles of Ambulatory Neurology and the Approach to Clinical Problems

sensitive, two more repeat recordings up to a total of three can increase the yield to 80% to 90%. An important part of the electroencephalographer’s art is wording the conclusion so as to answer the clinical question with the appropriate degree of confidence. Phrases such as “consistent with” or “suggestive of” may be frustrating for the clinician but do accurately represent the uncertainty of many clinical correlations. Although the evidence for dysfunction may be unequivocal, the cause of that dysfunction is rarely clear from the EEG alone. Table 20-1 shows the main types of EEG abnormalities with their anatomic and, where possible, etiologic correlates. More complete lists and discussions may be found in several excellent texts on electroencephalography.

Principles of Diagnosis: Special Tests

have been used over the past two decades. Most commonly, spectral analysis of waveforms recorded over several seconds is converted to a gray-scale or color map based on the amount of activity in various frequency bands at different sites. Although this method of data display can convey useful information, the information usually is apparent to an experienced reader on routine EEG and may be misleading if artifacts are not carefully screened out. Also, complex statistical issues render controversial the mapping profiles of various patient groups. Although some of the distinctions made by brain mapping may be valid on a population basis, their usefulness in diagnosing individual cases is debated. EVOKED POTENTIALS

Special Studies

This category includes both special patient preparation and special recording techniques, including electrode placements beyond those of the standard “10-20” system. The most important patient preparation techniques include sedation and sleep deprivation. These are particularly useful in evaluating seizures or suspected seizures, especially if the waking record shows no epileptiform discharges. Numerous studies have documented increased sensitivity of recordings that include drowsiness and stage 2 sleep, and some suggest an additional activating effect of sleep deprivation itself. It is unclear whether complete sleep deprivation is necessary. In children or uncooperative adults, sedation may be needed not just to record sleep but also to obtain a record sufficiently free of artifact to allow interpretation. It should be emphasized that neither sleep deprivation nor sedation is indicated when the purpose of the study is to evaluate encephalopathy, for which a fully awake recording provides the most reliable data. Special electrode placements are most often used to help detect or localize a seizure focus, especially when the mesial temporal lobe, not well sampled by standard electrodes, is suspected. Useful information is provided by anterior temporal or TUT2 electrodes, standard disc electrodes placed anteriorly and inferiorly to the standard midtemporal placements. Sphenoidal electrodes are thin wires introduced by means of a needle placed approximately 3 to 5 cm deep between the mandibular notch and the zygomatic arch, with the tips located near the foramen ovale. They must be inserted by a physician and are generally used only in long-term recordings. A simpler variant of these is the minisphenoidal electrode, a standard 1-cm needle electrode bent at the hub inserted at the same infrazygomatic location; surface electrodes at this site are also useful. Nasopharyngeal electrodes are uncomfortable, prone to artifact, and not clearly more sensitive than supplementary surface electrodes and so are rarely used. Additional techniques of EEG study include prolonged recordings with or without simultaneous video recording; these are especially useful in correlating specific clinical behaviors with EEG, thus demonstrating whether the behaviors have an epileptic basis. This is generally a reliable test for complex partial seizures, which are nearly always accompanied by some ictal or postictal EEG change. However, simple partial seizures, that is, with preserved consciousness, often are not detected on surface EEG recording. Also, artifacts produced by movement of the head and eyes can interfere with interpretation. Ambulatory studies, which generally are not accompanied by video recording, are particularly problematic in this regard. These long-term studies therefore must be interpreted by an experienced electroencephalographer. Computerized methods of EEG analysis, or brain mapping,

Evoked potentials used in clinical practice measure conduction along visual, auditory, or somatosensory pathways from the periphery to the central nervous system. Because the amplitude of these responses is small, generally less than that of the background EEG noise, routine use of these studies did not become possible until the advent of computer averaging techniques. Averaging results in a marked increase in signal-to-noise ratio because the evoked response is time-locked to the stimulus, whereas background noise occurs randomly. The smaller the evoked potential in relation to ongoing EEG activity, the greater the number of repetitions needed to visualize the signal. Clinically useful conclusions can be drawn from evoked potential studies even though the exact generators are not known in many instances. Electrodes placed close to the relevant nerve, tract, or cortical region can reveal the timing of impulse conduction in a straightforward manner. Because of specific characteristics of electrical fields generated by various sensory nuclei, however, even potentials generated by deep structures in the brainstem and elsewhere can be recorded by appropriately placed surface electrodes. In general, latency determinations are more reliable than amplitude changes; a readily identifiable but delayed peak is a strong indicator of slowed conduction, usually a consequence of demyelination; although a reliably decreased amplitude can reflect fewer involved axons producing the response, it is often difficult to exclude technical factors as an explanation for small or even absent peaks. For all evoked potential peaks, latencies are normally distributed in the general population. Therefore, “abnormal” prolongation of latencies must be statistically determined; in most laboratories, a cutoff of 2.5 or 3 standard deviations is used. By the stricter criterion, false positives would tend to occur less than 1% of the time; this degree of specificity is gained at the expense of some increase in the incidence of false negatives. Visual Evoked Potentials

Electrical responses to visual stimulation may be produced by neural elements in the retina (electroretinogram), but for neurologists the cortically generated visual evoked potentials (VEPs), recorded at the occiput, are of greatest use. These may be produced by a simple flash of light, but latency and waveform are highly dependent on patient and stimulus characteristics. In infants or other patients who cannot be instructed to attend to a specific stimulus, flash-induced VEPs can verify that the visual pathway from eye to brain is at least functioning, but they are insensitive to subtotal dysfunction. By far the most widely used method of visual testing is pattern-shift VEP, recorded in relation to abrupt reversal

Chapter 20

ElecArophysiology: Electroencephalographyand Evoked Potentials

of the light and dark squares of a checkerboard pattern, usually displayed on a video terminal. Generally, a rate of approximately two reversals per second is used for 100 to 200 stimuli. The normal response as recorded from the midoccipital region is a positive deflection approximately 100 msec after the stimulus, sometimes called the P100, or P1 (Fig. 20-8), At the usual check sizes, field sizes, and distances used, macular vision is important in generating this potential, and visual acuity must be at least 20/100 for a valid test. Because response can also be affected by such variables as ambient light, total luminance of the display, and degree of contrast between light and dark squares, it is important that each laboratory determine its own normal values. If an ophthalmic disorder can be ruled out, a prolonged latency of the major positive peak, either absolutely or in relation to the

N2

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contralateral eye, is highly specific for optic nerve or chiasmal disorder. This is the basis for the most common clinical uses of pattern-shift VEPs, particularly in documenting optic nerve impairment in suspected multiple sclerosis. This study is nearly 100% sensitive in known optic neuritis, even after clinical recovery. Perhaps more importantly, more than 50% of patients with multiple sclerosis without clinical optic nerve involvement have abnormal pattern-shift VEP, although the percentage probably is lower in those without a firm diagnosis. Another major use of pattern-shift VEP is in confirming psychogenic visual loss; this presupposes some patient cooperation, however, in that the patient must visually focus on the center of the checkerboard pattern during a sufficient number of stimuli. Unless fixation can be verified, therefore, an abnormal study is inconclusive in this context; a normal study, by contrast, argues strongly against an organic basis for major visual impairment, especiallyif monocular. Pattern-shift VEPs may be normal with postchiasmal abnormalities, rarely even in the case of cortical blindness. Hemifield pattern reversal stimulation may be used to investigate hemianopias, but is more difficult than full-field studies and less often used. Auditory Evoked Responses

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FIG. 20-8. Normal pattern-shift visual evoked potential. The major positive peak, also called P100, is labeled PI.

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Clinically used auditory evoked potentials are those generated by brainstem structures and therefore are often called brainstem auditory evoked responses (AERs). In contrast to the VEP, which is recorded immediately over its generator in the visual cortex, the brainstem AER is a series of far-field potentials recorded at the earlobe or mastoid linked to a vertex electrode. Using a broadband click stimulus, one can generally record at least five successive peaks, designated I to V (Fig. 20-9). Wave I, generated by the acoustic nerve, occurs approximately 2 msec after the stimulus, and the succeeding four peaks are approximately 1 msec apart; wave 111 is thought to be generated by the cochlear nucleus, and wave V is considered to reflect arrival of the signal at the inferior colliculus. Diencephalic and cortical auditory evoked potentials can also be recorded, but these are generally used only for research purposes. Because the latencies are so short, stimuli can be given

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FIG. 20-9. Normal left ear brainstem auditory evoked response (BAER). Peaks I, 111, and V are labeled. (Downward deflection to represent positive polarity is in keeping with EEG convention, but many laboratories reverse this for BAER studies.) Note stimulus artifact at onset of tracing.

Principles of Ambulatoy Neurology and the Approach to Clinical Problems H Principlesof Diagnosis: Special Tests

1%

rapidly, approximately 9 to 12 per second, but because the amplitudes are so small, 1000 to 4000 stimuli must be given. As with VEPs, latency of peaks is more informative than amplitude; absolute and especially interpeak latencies generally can distinguish between lesions affecting the acoustic nerve or cochlear apparatus and those affecting either the lower or upper brainstem. Audiography and other otolaryngologic studies can be helpful in more fully characterizing peripheral abnormalities suggested by brainstem AER. Because of the proximity of both peripheral and central structures subserving vestibular and auditory function, brainstem AERs may be helpful in assessing complaints of vertigo, diminished hearing, and tinnitus. Brainstem AERs remain a highly sensitive means of screening for acoustic neuromas and other infratentorial tumors, although this function has been largely

overtaken by advances in magnetic resonance imaging (MRI). In evaluating for possible multiple sclerosis, brainstem AER is less likely to reveal an asymptomatic (brainstem) lesion than VEP or somatosensory evoked potential. However, an abnormal brainstem AER in a patient with clinical involvement at a single site outside the brainstem can be highly suggestive of the diagnosis. Other uses of brainstem AERs include any condition where brainstem involvement, especially of the white matter, is suspected clinically, such as in the leukodystrophies. An advantage of brainstem AER is that this test does not require patient cooperation, as does pattern-shift VEP, and is generally resistant to the effects of anesthesia (unless hypothermia is produced). Therefore, reliable information can be obtained in unresponsive patients and in infants. In the latter case, agematched controls must be used because adult values are not

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5 15 25 35 ms 5 15 25 35 FIG. 20-10. Normal somatosensory evoked potentials elicited by stimulation of (A) right median and (B) left posterior tibia1 nerves. To eliminate stimulus artifact horizontal axis of display starts after time zero of stimulus presentation. Reference (second input to amplifier) is Fz unless othemvise noted. REP, right Erb's point; EP (also called Nq), Erb's point potential; C7 (also called N13), potential at seventh cervical spinous process; N1 (also called N20), major cortical negative peak recorded over C3', 2 cm posterior to C3 of 10-20 system; N1 on, onset of N1 peak; P1 (also called P23), cortical positive peak; L1, peak recorded at first lumbar spinous process (iliac crest reference); C7, peak recorded at seventh cenrical spinous process; P1 (also called P37), major cortical peak recorded at Cz', 2 cm posterior to Cz of 10-20 system.

Chapter 21 4 Electrophysiology: Newe Conduction Studies and Electromyography

reached until approximately age 2. A further use in infants is estimation of auditory threshold in those unable to cooperate with audiography. Somatosensoy Evoked Potentials

Stimulation of a peripheral nerve allows measurement of peak latencies at various sites between that stimulated and the sensory cortex. Use of mixed motor and sensory nerves, such as the median in the upper extremity (Fig. 20-1OA)and the posterior tibial (Fig. 20-10B)or peroneal in the lower extremity, produces a twitch response of the muscle innervated by the stimulated nerve, demonstrating adequacy of the stimulus; intensity does not have to be submaximal, as with compound muscle action potential testing. Recording sites generally include peripheral nerve or plexus, site of entrance into the spinal cord, one or more rostral spinal or brainstem locations, and the corresponding sensory cortex. Stimulus frequency is generally 4 to 7 Hz, with 500 to 2000 repetitions needed per trial. Somatosensory evoked potentials (SSEPs) are produced by the fastest conducting fibers, that is, those traveling in the posterior columns, and therefore may be insensitive to lesions affecting only spinothalamic or motor tracts in the spinal cord or brainstem. On the other hand, SSEPs test large areas of the nervous system; lower extremity studies in particular can screen for dysfunction along the entire length of the neuraxis. Approximately 80% of patients with multiple sclerosis have abnormal SSEPs, even if there is no clinical sensory loss, but the percentage is less than 50% among those in whom the diagnosis is not yet established. Lower extremity studies may be more sensitive than upper extremity but are more difficult to perform satisfactorily. SSEPs can be helpful in confirming an organic basis for otherwise unclear sensory complaints and often can help localize the site of the abnormality

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to peripheral nerve or plexus, spinal cord (cervical versus thoracolumbar), or brainstem+erebral hemisphere. Although interpeak latencies can be helpful, detection of a superimposed central abnormality in those with significant peripheral delay can be difficult. Finally, SSEPs can be useful in prognosis of nontraumatic coma, with several studies suggesting that preservation of unilateral and especially bilateral cortical responses to median nerve stimulation implies a more favorable prognosis. SUMMARY EEG and evoked potential studies provide noninvasive, inexpensive means of assessing physiologic function, thus complementing structural information obtained from neuroradiologic and other investigations. Although degree and location of abnormalities often can be assessed, specific causes cannot be determined by these tests alone, and results must be integrated with history, physical examination, and other laboratory studies. SUGGESTED READINGS Aminoff MJ: Electrodiagnosis in Clinical Neurology. 4th Ed. Churchill Livingstone, New York, 1999 Chiappa KH: Evoked Potentials in Clinical Medicine. 2nd Ed. Raven Press, New York, 1990 Ebersile JS, Pedley TA Current Practice of Clinical Electroencephalography. 3rd Ed. Raven Press, New York, 2002 Misulis KE: Spehlmann’s Evoked Potential Primer. 3rd Ed. ButterworthHeinemann, Boston, 2001 Niedermeyer E, Lopes da Silva F: Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th Ed. Lippincott, Williams & Wilkins, Baltimore, 1999

Electrophysiology: Nerve Conduction Studies and Electromyography Elizabeth M. Raynor and David C. Preston

The term electromyogruphy (EMG) is commonly used inclusively to refer to electrodiagnostic testing, which involves nerve conduction studies in addition to the needle electrode examination of muscle. These studies are used primarily in evaluating the peripheral nervous system, including both motor and sensory nerves as well as muscle and neuromuscular junction. When correlated with the clinical examination, they are a powerful tool for localizing and determining the extent, severity, approximate time course, and pathophysiology of a lesion. The importance of clinical correlation for planning the appropriate study and interpreting the results cannot be overemphasized. Thus, every electrophysiologic evaluation should be preceded by an appropriately tailored history and neurologic examination, and the results of the study should be viewed in light of the clinical picture.

~~

PHYSIOLOGIC VARIABLES Several physiologic variables may significantlyinfluence the results of nerve conduction studies and needle electromyography. Correct interpretation of electrophysiologic data depends on a full understanding of these and other external factors that affect the results. Age

Normal values for nerve conduction studies are age-dependent. Nerve conduction velocities, in particular, are related to the maturational stage of myelin. Myelination is incomplete at birth, and nerves continue to myelinate over the first few years. Nerve

Chapter 21 4 Electrophysiology: Newe Conduction Studies and Electromyography

reached until approximately age 2. A further use in infants is estimation of auditory threshold in those unable to cooperate with audiography. Somatosensoy Evoked Potentials

Stimulation of a peripheral nerve allows measurement of peak latencies at various sites between that stimulated and the sensory cortex. Use of mixed motor and sensory nerves, such as the median in the upper extremity (Fig. 20-1OA)and the posterior tibial (Fig. 20-10B)or peroneal in the lower extremity, produces a twitch response of the muscle innervated by the stimulated nerve, demonstrating adequacy of the stimulus; intensity does not have to be submaximal, as with compound muscle action potential testing. Recording sites generally include peripheral nerve or plexus, site of entrance into the spinal cord, one or more rostral spinal or brainstem locations, and the corresponding sensory cortex. Stimulus frequency is generally 4 to 7 Hz, with 500 to 2000 repetitions needed per trial. Somatosensory evoked potentials (SSEPs) are produced by the fastest conducting fibers, that is, those traveling in the posterior columns, and therefore may be insensitive to lesions affecting only spinothalamic or motor tracts in the spinal cord or brainstem. On the other hand, SSEPs test large areas of the nervous system; lower extremity studies in particular can screen for dysfunction along the entire length of the neuraxis. Approximately 80% of patients with multiple sclerosis have abnormal SSEPs, even if there is no clinical sensory loss, but the percentage is less than 50% among those in whom the diagnosis is not yet established. Lower extremity studies may be more sensitive than upper extremity but are more difficult to perform satisfactorily. SSEPs can be helpful in confirming an organic basis for otherwise unclear sensory complaints and often can help localize the site of the abnormality

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to peripheral nerve or plexus, spinal cord (cervical versus thoracolumbar), or brainstem+erebral hemisphere. Although interpeak latencies can be helpful, detection of a superimposed central abnormality in those with significant peripheral delay can be difficult. Finally, SSEPs can be useful in prognosis of nontraumatic coma, with several studies suggesting that preservation of unilateral and especially bilateral cortical responses to median nerve stimulation implies a more favorable prognosis. SUMMARY EEG and evoked potential studies provide noninvasive, inexpensive means of assessing physiologic function, thus complementing structural information obtained from neuroradiologic and other investigations. Although degree and location of abnormalities often can be assessed, specific causes cannot be determined by these tests alone, and results must be integrated with history, physical examination, and other laboratory studies. SUGGESTED READINGS Aminoff MJ: Electrodiagnosis in Clinical Neurology. 4th Ed. Churchill Livingstone, New York, 1999 Chiappa KH: Evoked Potentials in Clinical Medicine. 2nd Ed. Raven Press, New York, 1990 Ebersile JS, Pedley TA Current Practice of Clinical Electroencephalography. 3rd Ed. Raven Press, New York, 2002 Misulis KE: Spehlmann’s Evoked Potential Primer. 3rd Ed. ButterworthHeinemann, Boston, 2001 Niedermeyer E, Lopes da Silva F: Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 4th Ed. Lippincott, Williams & Wilkins, Baltimore, 1999

Electrophysiology: Nerve Conduction Studies and Electromyography Elizabeth M. Raynor and David C. Preston

The term electromyogruphy (EMG) is commonly used inclusively to refer to electrodiagnostic testing, which involves nerve conduction studies in addition to the needle electrode examination of muscle. These studies are used primarily in evaluating the peripheral nervous system, including both motor and sensory nerves as well as muscle and neuromuscular junction. When correlated with the clinical examination, they are a powerful tool for localizing and determining the extent, severity, approximate time course, and pathophysiology of a lesion. The importance of clinical correlation for planning the appropriate study and interpreting the results cannot be overemphasized. Thus, every electrophysiologic evaluation should be preceded by an appropriately tailored history and neurologic examination, and the results of the study should be viewed in light of the clinical picture.

~~

PHYSIOLOGIC VARIABLES Several physiologic variables may significantlyinfluence the results of nerve conduction studies and needle electromyography. Correct interpretation of electrophysiologic data depends on a full understanding of these and other external factors that affect the results. Age

Normal values for nerve conduction studies are age-dependent. Nerve conduction velocities, in particular, are related to the maturational stage of myelin. Myelination is incomplete at birth, and nerves continue to myelinate over the first few years. Nerve

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

conduction velocities in newborn infants are approximately 50% of normal adult values. Conduction velocity quickly increases after birth and reaches approximately 75% of adult normal values by 1 year of age. Complete myelination occurs between ages 3 and 5. Conduction velocity remains static throughout the adult years but tends to decrease slightly as the adult ages. This effect begins after age 20 and becomes more prominent after age 40. Overall, motor and sensory conduction velocities decrease by approximately 0.5 to 4 m/second/decade. Temperature

Nerve conduction studies are most significantly influenced by temperature. Nerve conduction velocity slows in direct proportion to a fall in temperature, at a rate of 1.5 to 2.0 m/second for each degree below 34OC. Similarly, distal latencies increase by approximately 0.3 msec per degree fall in temperature. Cooling also has a significant effect on compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) morphologies. For both, cooling results in a higher amplitude and longer duration potential. Lowering the temperature has a similar but less marked effect on motor unit action potentials (MUAPs) measured during the needle EMG. MUAP duration and amplitude increase with cooler temperatures, and the number of phases may also increase correspondingly. Height

Nerve conduction studies, particularly late responses (F responses and H reflexes), are influenced by the height of the patient. Taller people commonly have slower conduction velocities than shorter ones. This effect of nerve length is also reflected in the well-recognized finding that normal conduction velocities are slower in the lower extremities, where the limb is longer, than in the upper extremities. This translates into different normal values for conduction velocity in the upper and lower extremity, the latter being about 10 m/second slower. Two separate factors probably account for the effect of height or limb length on conduction velocity. First, nerves taper as they proceed distally. In general, the taller the person, the longer the limb and the more tapered the distal nerve. Because conduction velocity is directly proportional to nerve diameter, the more distally tapered nerves in taller people conduct more slowly. By the same reasoning, nerves in the leg conduct more slowly than those in the arm because of the longer limb length and more distal tapering. Second, and not as well appreciated, is the fact that limbs are cooler distally than proximally, and the legs are generally cooler than the arms. Therefore, conduction velocity slowing caused by cooling usually is more prominent in the legs than the arms. ANATOMY, PHYSIOLOGY, AND PATHOPHYSIOLOGY Anatomy and Physiology of Nerve and Muscle

The peripheral nervous system includes the motor, sensory, and autonomic neurons (i.e., anterior horn cells, dorsal root ganglia, parasympathetic nuclei in the brainstem and sacral spinal cord and sympathetic nuclei in the intermediolateral columns of the spinal cord, and sympathetic and parasympathetic ganglia); motor, sensory, and autonomic nerve fibers; neuromuscular junction; and muscle. The term motor unit refers to an anterior horn cell, its

Principles of Diagnosis: Special Tests

accompanying motor axon, and all the muscle fibers it innervates. The motor unit has great clinical importance. Nerve fibers are composed of axons of varying diameter, both myelinated and unmyelinated. In the sensory system, largediameter myelinated fibers are responsible for transmitting vibration and proprioceptive information, whereas small unmyelinated fibers transmit pain and temperature sense. Motor axons are myelinated fibers of mostly intermediate and large diameters. Myelin is composed of concentric spirals of Schwann cell membrane. For every myelinated fiber, successive segments are myelinated by single Schwann cells. Thus, the axonal membrane is exposed only distally near the neuromuscular junction and at the small uninsulated gaps between two adjacent Schwann cells, known as the nodes of Ranvier. In myelinated nerve, depolarization occurs by way of saltatory conduction, that is, with depolarization occurring only at each node of Ranvier and current jumping from node to node. Although more current is needed for saltatory conduction, much less nerve membrane is depolarized, less time is needed, and therefore conduction velocity dramatically increases. In contrast, unmyelinated fibers transmit impulses slowly by continuous propagation. Nerve conduction studies, both motor and sensory, provide information about myelinated axons of large and intermediate diameter. It is not possible to routinely measure the function of small unmyelinated fibers using current methods. Individual motor nerve fibers terminate via smaller twigs to multiple neuromuscular junctions, each of which is in direct contact with a single muscle fiber. Normally, when a motor neuron or its axon is activated (i.e., threshold for depolarization is reached), all the muscle fibers it innervates contract in a synchronous, all-or-none fashion. Pathologic Processes Affecting Peripheral Nerves

A number of different pathologic processes affect peripheral nerves, and the distribution of the lesions they produce may be generalized, focal, or multifocal, depending on the underlying cause. All neuropathic processes ultimately produce characteristic histologic and electrophysiologic abnormalities, which fall into three distinct categories discussed later in this chapter. In many instances, these abnormalities coexist in some combination, but one pathologic change usually is primary or predominant (Fig. 21-1). Axonal Degeneration. Often described as “dying back,” degeneration of the axon begins distally and proceeds proximally in the setting of toxic or other metabolic injury to the nerve. Mechanical injury to nerve or death of the parent neuron also results in axonal degeneration. Degeneration ultimately leads to denervation of muscle fibers associated with the motor unit. Examples include most toxic and metabolic neuropathies. Wallerian Degeneration. When a nerve is physically interrupted, the stump distal to the point of trauma degenerates. It usually takes 5 to 7 days to complete this process, after which the nerve is inexcitable. Before this time, the nerve can be stimulated normally distal to the site of injury. However, when the nerve is stimulated proximal to the lesion, the impulse is not conducted across the interrupted segment and may simulate a conduction block from demyelination. Examples include focal trauma to the nerve and ischemic injury to the nerve. Segmental Demyelination. Focal disruption in the myelin sheath often leads to denuded segments of nerve. Marked slowing of conduction velocity across these sites ensues because impulses

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199

NERVE CELL

AXON

fA

NODE OF RANVl E R ISCHWANN N T E [ -R . N O D 2 CELL NUCLEUS

NORMAL

WALL E R IAN DEGENERATION

SEGMENTAL DEMYELINATION

AXONAL DEGENERATION

FIG. 21-1. Normal and pathologic processes affecting peripheral nerves. (From Asbury AK, Johnson PC: Pathology of peripheral nerve. p. 5. In Bennington JL (ed): Major Problems in Pathology. Vol. 9. WB Saunders, Philadelphia, 1978, with permission.)

must travel along demyelinated segments in a continuous fashion. Conduction failure or block along a particular nerve fiber may occur if impulses cannot traverse the demyelinated segment. The important clinical consequence of conduction block is weakness. Examples of segmental demyelination include many of the common entrapment neuropathies (e.g., carpal tunnel syndrome), Charcot-Marie-Tooth polyneuropathy type I, and the acquired inflammatory demyelinating polyneuropathies (i.e., GuillainBarre syndrome and chronic inflammatory demyelinating polyneuropathy).

Pathologic Processes Affecting Muscle

The pathologic changes that affect muscle can be separated into two broad categories: neurogenic and myopathic. In general, these are accompanied by characteristic electromyographic abnormalities that allow fairly reliable distinction between them (Fig. 21-2). Neurogenic Processes. When any portion of the motor unit proximal to the muscle fiber degenerates, the muscle fiber ultimately becomes denervated. After such injury, denervation changes develop in muscles according to their proximity to the site of the lesion, earliest in the muscles nearest the lesion. Subsequent reinnervation of these muscle fibers occurs by collateral sprouting from the distal terminals of nearby healthy motor units. After reinnervation, the remaining fewer motor units have a larger number of muscle fibers than normal. Myopathic Processes. In primary disorders of muscle, motor neurons and their axons are intact, but the individual muscle fibers contributing to the motor unit degenerate. Consequently, each motor unit has a much smaller number of muscle fibers than previously. As opposed to the situation in neurogenic .disorders,

there is a normal complement of motor units with an abnormally reduced number of muscle fibers in each individual motor unit. NERVE CONDUCTION STUDIES Motor Nerve Conduction Studies To perform motor conduction studies, recording electrodes are placed on the skin overlying the belly of a muscle, and an inactive reference electrode is placed on a nearby tendon. The motor nerve innervating this muscle is stimulated with electrical current at low levels, increasing incrementally until the recorded response no longer gains amplitude. This supramaximal stimulation ensures that all the motor fibers belonging to the particular muscle have been depolarized. The recorded response is called a compound muscle action potential ( C W ) or M wave. It represents the summation of all muscle fiber action potentials activated by the stimulation of a motor nerve at a given site. Typical motor recordings from a normal subject are shown in Figure 21-3. There are several important parameters, which are discussed in the following subsections. Latency. Latency is the time, in milliseconds, from stimulation to the onset of the C W . The latency reflects the time needed to conduct the stimulus along the length of a nerve, transmit the neurotransmitter-mediated signal across the neuromuscular junction, and depolarize the muscle fiber membrane. It is a measure of the conduction time of the fastest-conducting fibers only. Distal latency is measured from the stimulation site closest to the muscle. Abnormal prolongation of distal latency reflects focal slowing across the segment, as in compressive neuropathies (e.g., carpal tunnel syndrome) or demyelinating neuropathies. Less significant prolongation occurs with axonal neuropathies.

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Principles of Diagnosis: Special Tests

axonal loss (typically less than 75% of the lower limit of normal) indicates segmental demyelination. Sensory Nerve Conduction Studies

\ \

“Myopathic”

4

FIG. 21-2. Normal, myopathic, and neuropathic motor units. Changes

in motor unit size and shape are accompanied by similar electromyographic changes. (From Young RR, Jarcho LW, Petajan JH: Laboratory aids in the diagnosis of neuromuscular disease. In Wintrobe MM (ed): Harrison’s Principles of Internal Medicine. 7th Ed. McCraw-Hill, New York, 1974, with permission.)

Amplitude. Amplitude is the height, in millivolts, of the

potential measured from baseline to peak. The CMAP amplitude reflects the number of muscle fibers activated by the stimulus at a particular site. Any disease process that reduces the number of axons or the number of muscle fibers that can be brought to action potential reduces the CMAP amplitude. Examples include axonal neuropathies, motor neuron disease, some myopathies, and neuromuscular junction disorders (e.g., botulism). Conduction Velocity. Conduction velocity is the speed, in meters per second, of nerve impulse conduction. For motor studies, a direct measure of conduction velocity along a nerve segment cannot be obtained simply by dividing the distance between stimulation site and recording site by the onset latency because the time for neuromuscular transmission and muscle membrane depolarization is included in the latency measurement. Therefore, two stimulation sites are used, and the distance between proximal and distal stimulation sites divided by the difference in latencies for the two sites gives a measure of conduction velocity along the nerve segment between them. Again, this value represents the conduction speed of the fastest-conducting fibers only. Mild slowing can occur in the setting of axonal loss with dropout of the fastest conducting fibers. Abnormal slowing of conduction velocity out of proportion to that expected from

In antidromic recordings, the recording electrodes are placed on the skin in an area of innervation of a single sensory nerve, and the nerve is stimulated supramaximally at a site proximal to the recording electrode. The recorded sensory nerve action potential (SNAP) is a summation of the individual action potentials of all the fibers activated. Because sensory nerves normally carry information from the periphery toward the sensory neuron, this setup is in the direction opposite to the natural movement of impulses along a sensory nerve. However, stimulation of a nerve creates a wave of depolarization that travels bidirectionally, allowing recording of sensory impulses distal or proximal to the stimulation site. In the latter situation, the recording technique is called orthodromic. An example of an antidromically recorded potential is shown in Figure 21-4. The parameters examined are as for motor nerves; however, several important differences should be noted. First, the latency measurement for sensory nerves directly reflects conduction time of the fastest-conducting fibers along a given segment because there is no neuromuscular transmission or muscle fiber activation time. Second, these potentials are smaller, with the amplitude usually measured in microvolts. Third, abnormalities in amplitude, latency, and velocity mirror those seen in motor fibers, given similar pathophysiology, with one important caveat: SNAP amplitudes are not affected by axonal or neuronal lesions proximal to the dorsal root ganglion. Axonal lesions proximal to the dorsal root ganglion cause degeneration up to the dorsal root ganglion cell, leaving the dorsal root ganglion and its peripheral axon intact and effectively disconnected from the spinal cord. Thus, if sensory loss is caused by a radiculopathy (i.e., proximal to the dorsal root ganglia), the recorded SNAP will be normal, no matter how severe the clinical deficit. Late Responses F Wave. With supramaximal stimulation of a motor nerve, the depolarizing wave is propagated bidirectionally, and the impulse traveling proximally reaches and activates a small number of anterior horn cells. The resulting action potential is then propagated down the motor nerve and creates a small potential of variable configuration occurring many milliseconds after the CMAP. The exact latency and configuration vary as the anterior horn cells involved in each F response vary from stimulation to stimulation. Figure 21-5 illustrates normal F wave recordings. The latency of this response measures conduction up and back down the length of the motor nerve from the point of stimulation to the recording site. It provides an indirect measure of conduction along the proximal portion of the motor nerve. The most commonly measured parameter is the minimum F wave latency. F Waves are most widely used in evaluating patients with demyelinating neuropathies in whom F wave latencies are prolonged because of demyelination in proximal nerve and root segments. H Reflex. Another late response, the H reflex, is otherwise unrelated to the F response. The H reflex is analogous to the ankle deep tendon reflex and is similarly mediated by the S1 root. Rather than a stretch stimulus, the stimulus is a submaximal electrical current that selectively activates IA afferent sensory fibers. The depolarizing wave travels up the sensory nerve, which activates a motor neuron, creating a reflex contraction of the muscle. The H

Chapter 21

A

Electrophysiology: Nerve Conduction Studies and Electrornyography

Stimulus Dirtalhttncy

Stimulus

Proximal Lsbmcy

FIG. 21-3. Motor nerve conduction study. Recording of the abductor pollicis brevis muscle and stimulating the median nerve (A) at the wrist and (B) at the antecubital fossa. The compound muscle action potential represents the summation of individual muscle fiber action potentials stimulated at each site. Amplitude is measured from baseline to peak. Latencies are measured from the stimulus to the onset of the potential and represent the fastest-conductingfibers. If distal and proximal sites are stimulated, conduction velocity between the two sites can be determined.

1 mree

Stimulus

D i s h Peak Latency Latency

FIG. 21-4. Sensory nerve action potential (SNAP). Recording over the second digit of the hand and stimulating the median nerve at the wrist (antidromic recording). The SNAP represents the summation of all individual sensory fiber action potentials. Amplitude is measured from baseline to peak. Latencies are measured from the stimulus to onset (representing the fastest fibers) and to peak Conduction velocity can be determined by dividing the distance between the stimulus and recording electrodes by the onset latency.

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20?

i 1 1

5. w c

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muscle and related nerves. In a routine examination, a small needle electrode is inserted into various muscles, and activity is observed in a number of sites within each muscle. Findings are observed during needle insertion, with the muscle at rest, and during voluntary contraction. The selection of muscles for study usually is made by the electromyographer based on the clinical question and the prior nerve conduction and EMG findings. Insertional Activity. Mechanical deformation of the muscle membrane by the needle normally causes brief discharges lasting less than 500 msec after needle movement ceases. Insertional activity increases in disorders that cause abnormal excitability of muscle membrane, most commonly in neurogenic disorders. Decreased insertional activity results from muscle fibrosis or fatty replacement, which may be present in long-standing muscle disorders such as dystrophies. SpontaneousActivity. Normal muscle is silent at rest, except when the needle is in the vicinity of the neuromuscular junction. Here, endplate activity normally may be recorded. This physiologic spontaneous activity is of little importance except that it may be mistaken for abnormal spontaneous activity.

I Motor Unit Potentials and Firing Pattern

I

With minimal voluntary contraction of the muscle, motor unit action potentials (MUAPs) are recorded. MUAPs are the summated action potentials of 10 to 20 muscle fibers derived from a single motor unit near the tip of the needle electrode. These complex potentials have a definable duration, amplitude, and number of phases. Normal values for MUAP parameters vary from one muscle to another and across different age groups. In addition to their configuration, MUAPs are characterized by their firing pattern. Although no pattern of abnormalities is pathognomonic of a specific disease process, it is usually possible to define MUAP abnormalities as neurogenic or myopathic. Figure 21-6 shows a normal MUAP and its parameters. Table 21-1 outlines changes in these parameters in neurogenic and myopathic lesions. The individual parameters of a MUAP are discussed in the following subsections.

I

I I

Stirrii

CMAPI

F Raspouw

FIG. 21-5. F Responses (10 rastered traces). Recording the abductor pollicis brevis muscle and stimulating the median nerve at the wrist. The F responses are late potentials that occur after the compound muscle action potential (CMAP) resulting from antidromic travel to the anterior horn cell in the spinal cord and back again. (Note the gain and sweep speed needed to measure the F responses and the resulting distortion of the CMAP potentials.) Each F response varies slightly in configuration and latency, representing a different population of motor fibers.

reflex typically is measured from the soleus muscle after stimulation of the tibia1 nerve at the knee. It is not readily obtainable from other sites in normal adults. Unilateral abnormalities indicate an S 1 radiculopathy. Bilateral abnormalities may represent bilateral S1 radiculopathies or, more commonly, peripheral neuropathy.

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ELECTROMYOCRAPHY Recording Methods and Normal Findings

1-

The electromyogram (EMG) is a recording of the electrical activity in muscle fiber membranes that provides information about the

I

I I

I

DuratioI

I

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FIG. 21-6. Motor unit action potential parameters.

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TABLE21-1. EMC Features of Neurogenic and Myopathic Disorders MUAP lesion

Insedonal Activity

Spontaneous AaiVity

Amplitude

Duration

Phases

Activation

Recruitment

Normal Normal High

Normal Normal Increased

Normal Normal Polyphasic

Normal Normal Normal

Reduced Reduced Reduced

Inflammatory Increased Fibs, PSWs, CRDs Low Short Polyphasic Low Short Polyphasic Noninflammatory Normal None Abbreviobbfls: MUAP, motor unit action potential; Fibs, fibrillations; PSWs, positive sharp waves; CRDs, complex repetitive discharges. 'May see Fibs and PSWs if ongoing denervation is occurring.

Normal Normal

Early Early

Neurogenic Denewation Acute (<3 wk) Subacute (3 wk-3 mo) Chronic reinnewation (3-6 mo)

Normal Increased Normal or increased

None

Fibs, PSWs None'

Myopathic

Amplitude. Amplitude is highly variable and depends primarily on the distance between the recording electrode and the actively firing muscle fibers. Only a small percentage of fibers in a given motor unit contribute to the MUAP amplitude. Those not in the immediate vicinity of the recording electrode tip are not recorded. Amplitude increases with proximity to the electrode and with increasing number or diameter of muscle fibers (as in neurogenic disorders). Amplitude decreases with increasing distance from the electrode and with decreasing number of muscle fibers (as in myopathies). Duration. The parameter of duration probably best reflects the size of the motor unit territory, that is, the number of muscle fibers innervated by a single motor unit. Duration increases in neurogenic disorders in which healthy motor units reinnervate denervated muscle fibers, consequently increasing their motor unit territories. Duration decreases in myopathic disorders because the number of muscle fibers per motor unit is less than normal. This parameter is more reliable than amplitude as a measure of abnormality because it is less dependent on needle placement. Phases. The number of phases is equal to the number of baseline crossings plus one (see Fig. 21-6). This parameter is a measure of the synchronicity of firing of the muscle fibers contributing to the CMAP. Normally, the number of phases is four or less; anything greater is considered polyphasic. Polyphasic potentials may occur normally in up to approximately 10% of motor units. Increased polyphasia occurs commonly in both neurogenic disorders with reinnervation and myopathic disorders. Firing Pattern. With voluntary contraction, force is generated by increasing the number of motor units firing (recruitment) and the firing frequency of the motor units present (activation). Normally, force is increased by both of these processes. When a muscle is first activated, one motor unit begins to fire at 4 to 5 Hz. As more force is generated, the firing rate increases to about 10 Hz. As force is increased further, a second motor unit begins to fire, and so forth. Motor units are recruited in an orderly arrangement according to their size, with the smaller motor units recruited first. The ability to recruit additional motor units is a peripheral process (i.e., the motor units must be present, not reduced by axonal loss or blocked from demyelination). Conversely, activation entails voluntary effort and depends on the central control of movement. Thus, activation may be abnormal in upper motor neuron lesions or with poor effort. If activation is poor enough, the firing rate will remain below that needed to recruit second and third motor units. Abnormal recruitment is distinct from abnormal activation and is

an important hallmark of neurogenic lesions. Abnormal recruitment is recognized by the inappropriate rapid firing of a reduced number of motor units. Characteristic changes in recruitment help differentiate neurogenic from myopathic lesions, as discussed in the next section. EMG Abnormalities Abnormal Spontaneous Discharges. Except for endplate activity, all spontaneous activity occurring with the muscle at rest is abnormal. A variety of different discharge patterns have been described. Table 21-2 outlines common abnormal EMG activity observed during rest. Figure 21-7 illustrates denervation potentials in the form of fibrillation potentials and positive sharp waves. Abnormal Motor Units (Neurogenic Versus Myopathic Lesions). Individual characteristics of the MUAP may be af-

fected similarly by these two types of lesions; however, the overall picture often defines an EMG abnormality as either neurogenic or myopathic. When the distinction is unclear, usually the recruitment pattern is of greatest relevance. Table 21-1 outlines the characteristicEMG features of neurogenic and myopathic lesions. Figure 21 -8 compares normal, neurogenic, and myopathic MUAPs. MYOPATHIC LESIONS. Myopathic MUAPs have a small amplitude and short duration and are highly polyphasic. Each motor unit has lost individual muscle fibers, so increasing force entails activation of more motor units than previously. There is no shortage of motor units, so recruitment occurs earlier than normal. NEUROGENIC LESIONS. The hallmark of neurogenic lesions is reduced recruitment. Because motor units have been lost, fewer are available for recruitment. The remaining motor units fire at an abnormally rapid rate in an effort to increase force. In severe lesions a single motor unit may fire at rates of 40 to 50 Hz. Changes associated with denervation and subsequent reinnervation occur over a predictable time course, so EMG findings depend on timing of the study in relationship to the lesion. Reduced recruitment is the only feature that is present acutely. Denervation is characterized by abnormal spontaneous activity. After reinnervation, motor units have high amplitude and long duration and are polyphasic. Time Course of Denewation and Reinnewation. After axonal injury, muscles become denervated according to their proximity to the injury. In a nerve root lesion, denervation is present (in the form of fibrillation potentials and positive sharp waves) in the related paraspinal muscles within 7 to 10 days, in the

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Tmrr 21-2. Characteristics of EMC Activity Recorded at Rest (Spontaneous Activity) Activity

Normal or Abnormal

Endplate activity

Normal

Fibrillations and positive sharp waves. Complex repetitive discharges (CRDs)

Abnormal Abnormal

Spontaneous repetitive discharge of grouped muscle fibers

Fasciculations

Abnormal

Spontaneous discharge of motor unit

Myotonia

Abnormal

Spontaneous repetitive discharge of muscle fibers

Myokymia

Abnormal

Repetitive grouped discharge of motor units

Flklp.tk.

Source

Associations

Miniature endplate potentials (neuromuscular junction) Spontaneous discharge of individual muscle fibers

Normal finding Neurogenic lesions with denervation Inflammatory myopathies Chronic neurogenic lesions with denervation Inflammatory myopathies (usually in chronic lesions) Lower motor neuron lesions (particularly of anterior horn cell) Radiculopathies Myotonic dystrophy Myotonia congenita, paramyotonia Inflammatory myopathies Acid maltase deficiency Radiation plexopathy Demyelinating neuropathy Compressive neuropathy

Podti*. W A

FIG. 21-7. Denervating potentials on EMC. When denenrated, individual muscle fibers spontaneously depolarize. They may take the form of fibrillation potentials (spike waveform) or positive waves (abrupt positive downward deflection followed by a slow negative phase). Although classically associated with neuropathic disease, they may also be seen in myopathies, especially inflammatory myopathies.

proximal limb muscles in 2 to 3 weeks, and in the distal limb muscles in 3 to 4 weeks. Reinnervation changes take approximately 3 to 6 months to develop. The presence of abundant fibrillation potentials in a muscle indicates ongoing axonal loss. One exception occurs after spinal surgical procedures; the paraspinal examination may continue to show denervation changes for years, which are nonspecific and do not necessarily imply ongoing root involvement.

ELECTRODIACNOSISOF COMMON NEUROMUSCULAR DISORDERS Compressive Neuropathies Median Neuropathy at the Wrist (Carpal Tunnel Syndrome).

When carpal tunnel syndrome is suspected, the goals are to localize the median neuropathy to the wrist and to rule out other diagnostic possibilities. The differential diagnosis includes more proximal median nerve compression, upper trunk brachial plex-

opathy, and C6 radiculopathy. The latter may co-occur with the carpal tunnel syndrome, creating a “double crush.” Characteristic findings from nerve conduction studies (NCSs) and EMG include the following:

NCS: There is focal slowing of median motor conduction across the carpal tunnel (i.e., wrist) segment. Distal motor latency may be prolonged. Sensory conduction velocity may be slowed across the wrist. Reduction in median SNAP or CMAP amplitudes implies axonal loss or distal conduction block. EMG: Ongoing denervation in the abductor pollicis brevis indicates significant, progressive axonal loss. Forearm muscles flexor carpi radialis and pronator teres (both derived from C6-7) are innervated by the median nerve quite proximal to its passing beneath the carpal tunnel; these should be screened to eliminate a possible double crush. Ulnar Neuropathy at the Elbow. When ulnar neuropathy at the elbow is suspected, the goals are to localize the ulnar lesion to

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205

by a distal predominance of axonal loss. The electrophysiologic findings in generalized sensorimotor neuropathy include the following: NCS: There are reductions of SNAP and CMAP amplitudes distally (i.e., lower extremity more than upper) with relative preservation of the conduction velocities (more than 75% of the lower limit of normal), even with marked reduction in amplitude. F Responses are normal or mildly prolonged, as are distal motor latencies. H Reflexes are symmetrically prolonged or absent, corresponding to the severity of the neuropathy. EMG: There are EMG signs of reinnervation that demonstrate a distal-to-proximal gradient of severity. Ongoing denervation with a similar distal predominance is present in more severe cases.

Normal

Neuropathic

Myopathic

FIG. 21-8. Motor unit action potentials (MUAPs) on EMG. An MUAP represents the depolarization of all muscle fibers within one motor unit (i.e., one anterior horn cell, its axon, and all muscle fibers connected to it). Most normal MUAPs are 5 to 15 msec in duration and have three phases. In neuropathic disease, MUAPs become large, long, and polyphasic, representing reinnenration. In myopathic disease, the MUAPs become smaller, briefer, and polyphasic as individual muscle fibers die out or become dysfunctional.

the elbow. The differential diagnosis includes lower trunk brachial plexopathy (e.g., neurogenic thoracic outlet syndrome) and C8-T1 radiculopathy. Characteristic findings include the following: NCS: There is focal slowing of conduction velocity across the elbow segment with or without conduction block. With the elbow flexed to 90 degrees, a drop-off in conduction velocity of more than 10 m/second is abnormal. The amplitude of the ulnar SNAP is reduced if there is axonal loss. EMG: There are signs of denervation and reinnervation in ulnar-innervated hand and forearm muscles. Median and radial innervated C8-Tl muscles are screened to rule out a C8 radiculopathy and lower trunk brachial plexopathy. Peroneal Neuropathy at the Knee. When evaluating suspected peroneal neuropathy at the knee, the goals are to localize the lesion to the peroneal nerve segment at the level of the fibular neck. The differential diagnosis includes sciatic nerve lesions, lumbosacral plexopathy, and L5 radiculopathy. Characteristic findings include the following:

NCS: There is reduced peroneal CMAP amplitude associated with abnormal slowing of motor conduction velocity across the fibular neck segment (drop-off of greater than 10 mhecond). If the superficial peroneal division is involved, SNAP amplitude is reduced. Tibial motor NCSs are normal. EMG: Denervation and reinnervation changes are present in peroneal innervated muscles of the lower leg. L5 muscles innervated by nerves other than the peroneal are screened to rule out a more proximal lesion.

Polyneuropathy In evaluating polyneuropathies by EMG, the goals are primarily to determine whether the neuropathy is axonal or demyelinating. Axonal Neuropathies. Axonal neuropathies are characterized

Demyelinating Neuropathies. Demyelinating neuropathies are characterized by segmental demyelination, which is best reflected in the NCS:

NCS: There is marked slowing of the conduction velocity to less than 75% of the lower limit of normal, which may be accompanied by prolongation of distal motor latencies, dispersion of the CMAP, and conduction block. Hereditary forms of demyelinating neuropathy do not characteristically demonstrate conduction block. SNAPS usually are slower and of lower amplitude. Marked reduction in CMAP amplitude indicates significant axonal loss or conduction block and implies a worse prognosis. F Wave latencies are markedly prolonged or unobtainable. EMG: Recruitment is reduced in proportion to the severity of weakness. Denervation may be present in severely affected nerves if there is secondary axonal degeneration. Radiculopathy When considering a possible radiculopathy, the goals are to localize the lesion to the nerve root (versus the plexus or nerve) and to determine its distribution (e.g., L4-L5, L5-Sl).

NCS: The C W amplitudes may be reduced if recorded from the appropriate myotomal territory. However, SNAPs recorded from an area of sensory loss are always normal in a lesion proximal to the dorsal root ganglion. EMG: There are denervation and reinnervation signs in the limb in the appropriate myotomal distribution. Additionally, paraspinal muscles show ongoing denervation (fibrillations) at the appropriate root level.

MYoPathY In myopathies, the nerve conduction studies usually are normal, although CMAP amplitudes may be reduced if there is significant distal involvement (e.g., myotonic dystrophy, inclusion body myositis). The EMG is characteristic and shows small-amplitude, short-duration MUAPs that are highly polyphasic and recruited early with minimal voluntary contraction. The interference pattern is full but of low amplitude. Ongoing denervation (fibrillations, positive sharp waves, and complex repetitive discharges) often is present in myopathies that are inflammatory or necrotic.

206

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Diagnosis: Special Tests

Motor Neuron Disease

In motor neuron disease, the anterior horn cell is the primary site of pathology. As in the case of nerve root lesions proximal to the dorsal root ganglion, the sensory system is normal on electrophysiologic testing in the case of motor neuron disease. However, in motor neuron disease, this normal sensory function parallels the preserved clinical function. NCS: Sensory nerve conduction studies are normal. CMAP amplitudes may be low or normal, with no significant slowing of conduction velocity. EMG: Ongoing denervation and reinnervation in multiple root distributions must be present in at least three of four body regions (i.e., bulbar, cervical, thoracic, lumbosacral) to diagnose a generalized motor neuron disorder.

TESTS OF NEUROMUSCULAR TRANSMISSION Repetitive Stimulation Studies Repetitive stimulation studies are the most common electrodiagnostic technique for evaluation of neuromuscular junction transmission disorders. When testing for neuromuscular junction transmission disorders (e.g., myasthenia gravis), the technique is similar to motor nerve conduction studies. Rather than a single supramaximal stimulus, trains of repetitive stimuli are delivered at a rate of 3 stimuli per second, with 6 to 10 stimuli in a train. For each train of stimuli, the CMAP amplitude of the first response is compared with that of the fourth or fifth response, and the percentage decrement is measured. Reproducible decrements greater than 10% are abnormal and are characteristic of a neuromuscular junction transmission disorder such as myasthenia gravis (Fig. 21-9). The sensitivity of the test is increased if performed after 1 minute of exercise, with the maximal decrement usually seen at 3 to 4 minutes after exercise. The greatest diagnostic yield is obtained if a weak muscle is examined. In patients with proximal weakness, the trapezius often is chosen for this reason. The presence of a decrement with 3-Hz repetitive nerve stimulation cannot differentiate between a presynaptic and postsynaptic neuromuscular junction transmission disorder. To make this distinction, fast repetitive nerve stimulation (i.e., 30 to 50 Hz) or exercise testing is needed. Patients with a presynaptic neuromuscular junction transmission disorder (e.g., Lambert-Eaton myasthenic syndrome [ LEMS]) demonstrate a marked increment (typically more than 200%) after fast repetitive nerve stimulation or 10 seconds of maximal voluntary contraction of the muscle. Although a decrement on repetitive nerve stimulation usually indicates a neuromuscular junction transmission disorder, exceptions do occur. Severe denervating diseases (e.g., amyotrophic lateral sclerosis), some metabolic myopathies, and myotonic

disorders may demonstrate abnormalities on repetitive nerve stimulation. Thus, repetitive nerve stimulation should never be performed in isolation; routine needle EMG is essential to exclude these other disorders. Single-Fiber Electromyography The specialized technique of single-fiber electromyography is highly sensitive for detecting neuromuscular transmission defects. Special expertise and equipment are needed, and the study may not be available at all centers. The electrode records simultaneously from a pair of single muscle fibers belonging to the same motor unit and measures the amount of variability between discharges, or jitter. Jitter reflects neuromuscular transmission time and is abnormally increased in disorders of neuromuscular transmission. Though highly sensitive, it is nonspecific and may be abnormal in neurogenic lesions. Electrodiagnosis of Common Disorders The electrodiagnostic approach varies widely depending on whether one is looking for a postsynaptic neuromuscular transmission disorder, as in myasthenia gravis, or a presynaptic disorder, as in LEMS. Myasthenia Cravis. In generalized myasthenia gravis, motor NCSs and EMGs usually are normal, although CMAP amplitudes may rarely be reduced and EMG may have a myopathic appearance. Repetitive stimulation studies usually show an abnormal decremental response to 3-Hz stimulation. The diagnostic yield is greater in those with obvious weakness; therefore, it may be helpful to withhold anticholinesterase medications before testing. Single-fiber EMG studies show abnormally increased jitter. Lambert-Eaton Myasthenic Syndrome (LEMS). When testing for LEMS, one usually can find abnormalities in any muscle examined. Routine motor nerve conduction studies often suggest the diagnosis because CMAP amplitudes are universally low. EMG may show myopathic changes or may be normal. Slow (3-Hz) repetitive nerve stimulation usually results in a decrement. However, as noted earlier, fast repetitive stimulation or exercise studies are needed looking for an abnormal increment or post-tetanic facilitation in the CMAP amplitude. Exercise testing is preferable to fast repetitive nerve stimulation unless a patient is unable to cooperate. The preferred method of electrodiagnosis involves recording a single CMAP before and after 10 seconds of maximal voluntary contraction. A dramatic increase in the recorded CMAP amplitude of 100% or more is diagnostic. Single-fiber EMG studies usually are not necessary for diagnosis. Botulism, another common presynaptic neuromuscular transmission disorder, has an electrophysiologic picture similar to LEMS.

FIG. 21-9. Repetitive nerve stimulation. In normal subjects, repetitive motor nerve stimulation at 3 Hz results in no

decrement of the compound muscle action potential. In disorders of neuromuscular transmission, decrements greater than 10% are typical. The figure shows abnormal decrement stimulating the ulnar nerve in a patient with myasthenia gravis.

Chapter 22

H Neuroimaging: Radiology, MRI, Magnetic Resonance Spectroscopy, PET, and SPECT

UTILITY AND LIMITATIONS OF ELECTRODIAGNOSTIC STUDIES A referring physician can improve the results obtained from electrodiagnostic testing in several ways. First, it is important to carefully select patients who are appropriately diagnosed by the tests performed in the EMG laboratory. Central or upper motor neuron disorders usually are not diagnosed by nerve conduction or EMG studies. Timing of the study in relation to injury is also important. Localization of nerve injuries may be difficult if studies are done before wallerian degeneration is complete (5 to 7 days), and the full extent of the lesion still may not be appreciated until denervation develops on EMG (3 to 6 weeks). The appropriate study is best determined by a clear clinical question, as in “question right carpal tunnel syndrome versus C6 radiculopathy,” as opposed to something vague, such as “arm pain.” Often, a brief capsule of the history and examination are all that is needed, as in “proximal weakness, arms and legs.” Finally, it is best to prepare patients for the study by letting them know what is involved and that it may be somewhat uncomfortable. Although electrodiagnostic testing is very valuable to the clinician and in some cases is diagnostic, findings can be abnormal

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but not clearly localizing. In those cases, the electromyographer reports the physiologic findings, and it is up to the clinician to interpret the results in light of the clinical picture. The EMG should always be considered an extension of, not a substitute for, the clinical evaluation.

SUGGESTED READINGS Brown WF: The Physiological and Technical Basis of Electromyography. Butterworth-Heinemann, Boston, 1984 Brown WF, Bolton C F Clinical Electromyography.2nd Ed. ButterworthHeinemann, Boston, 1993 Keesey J C AAEE Minimonograph #33: Electrodiagnostic approach to defects of neuromuscular transmission. Muscle Nerve 12:613, 1989 Kimura J: Electrodiagnosis in Diseases of Nerve and Muscle. 2nd Ed. FA Davis, Philadelphia, 1989 Oh SJ: Clinical Electromyography: Nerve Conduction Studies. 2nd Ed. Williams & Wilkins, Baltimore, 1993 Preston DC, Shapiro B E Electromyography and Neuromuscular Disorders. Butterworth-Heinemann, Boston, 1998 Sethi RK, Thompson L L The Electromyographer’s Handbook. 2nd Ed. Little, Brown, Boston, 1989

Neuroimaging:Radiology, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Positron Emission Tomography, and Single Photon Emission Computed Tomography Amir A. Zamani

Radiologic methods of investigating neurologic diseases have improved significantly in the past three decades. Noninvasive techniques have replaced many invasive procedures. These new techniques are far more accurate, much faster, and tolerated much better by patients.

COMPUTED TOMOGRAPHY Background and Technique The technology of computed tomography (CT) was a result of ingenious work by Hounsfield at the EM1 laboratory in England. The equipment became available for medical use in 1973, a year after Hounsfield announced the invention of “computerized axial transverse scanning” at the meeting of the British Institute of Radiology. With CT, the radiologic evaluation of neurologic disease changed forever. Before CT, available techniques included pneumoencephalography, ventriculography, gas myelography, angiography, and radionuclide scanning. These techniques were invasive, insensitive, or nonspecific. With CT, for the first time a diagnostic test offered noninvasive, accurate, and sensitive imaging of brain (and, a bit later, spine) disorders. Within a few years, CT scanning of the head and body became routine in many hospitals and imaging centers across the globe.

A short, simplified explanation of the CT physics is as follows. A collimated beam of x-ray photons enters the body (e.g., the head) and is attenuated as these photons interacting with the matter are absorbed. A detector on the opposite side of the head receives the attenuated beam and is connected to powerful computers. The x-ray source and the detector are coupled together and in the early scanners rotated about the head. Therefore, any point on a cross-section of the head is on the path of many beams and is seen from different vantage points. The computers calculate the attenuating ability of each point and, with other points put together, depict a two-dimensional picture of the slice. On this picture, contrast between adjacent tissues reflects their relative attenuation properties. Intravenous injection of contrast (an iodinated organic material) enhances the inherent absorptive differences and helps detect small lesions, such as vascular malformations and small metastases. Enhancement reflects the vascularity and the degree of blood-brain barrier breakdown of the lesion. However, contrast injection comes at a price: It adds a small risk to an otherwise safe procedure. Minor reactions include nausea and hives. More serious reactions include asthma, laryngeal edema, and anaphylaxis. Death is very rare (1 in 60,000 injections). Deterioration of renal function may be seen in patients with preexisting renal disease, especially diabetics. The radiation

Chapter 22

H Neuroimaging: Radiology, MRI, Magnetic Resonance Spectroscopy, PET, and SPECT

UTILITY AND LIMITATIONS OF ELECTRODIAGNOSTIC STUDIES A referring physician can improve the results obtained from electrodiagnostic testing in several ways. First, it is important to carefully select patients who are appropriately diagnosed by the tests performed in the EMG laboratory. Central or upper motor neuron disorders usually are not diagnosed by nerve conduction or EMG studies. Timing of the study in relation to injury is also important. Localization of nerve injuries may be difficult if studies are done before wallerian degeneration is complete (5 to 7 days), and the full extent of the lesion still may not be appreciated until denervation develops on EMG (3 to 6 weeks). The appropriate study is best determined by a clear clinical question, as in “question right carpal tunnel syndrome versus C6 radiculopathy,” as opposed to something vague, such as “arm pain.” Often, a brief capsule of the history and examination are all that is needed, as in “proximal weakness, arms and legs.” Finally, it is best to prepare patients for the study by letting them know what is involved and that it may be somewhat uncomfortable. Although electrodiagnostic testing is very valuable to the clinician and in some cases is diagnostic, findings can be abnormal

22

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but not clearly localizing. In those cases, the electromyographer reports the physiologic findings, and it is up to the clinician to interpret the results in light of the clinical picture. The EMG should always be considered an extension of, not a substitute for, the clinical evaluation.

SUGGESTED READINGS Brown WF: The Physiological and Technical Basis of Electromyography. Butterworth-Heinemann, Boston, 1984 Brown WF, Bolton C F Clinical Electromyography.2nd Ed. ButterworthHeinemann, Boston, 1993 Keesey J C AAEE Minimonograph #33: Electrodiagnostic approach to defects of neuromuscular transmission. Muscle Nerve 12:613, 1989 Kimura J: Electrodiagnosis in Diseases of Nerve and Muscle. 2nd Ed. FA Davis, Philadelphia, 1989 Oh SJ: Clinical Electromyography: Nerve Conduction Studies. 2nd Ed. Williams & Wilkins, Baltimore, 1993 Preston DC, Shapiro B E Electromyography and Neuromuscular Disorders. Butterworth-Heinemann, Boston, 1998 Sethi RK, Thompson L L The Electromyographer’s Handbook. 2nd Ed. Little, Brown, Boston, 1989

Neuroimaging:Radiology, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Positron Emission Tomography, and Single Photon Emission Computed Tomography Amir A. Zamani

Radiologic methods of investigating neurologic diseases have improved significantly in the past three decades. Noninvasive techniques have replaced many invasive procedures. These new techniques are far more accurate, much faster, and tolerated much better by patients.

COMPUTED TOMOGRAPHY Background and Technique The technology of computed tomography (CT) was a result of ingenious work by Hounsfield at the EM1 laboratory in England. The equipment became available for medical use in 1973, a year after Hounsfield announced the invention of “computerized axial transverse scanning” at the meeting of the British Institute of Radiology. With CT, the radiologic evaluation of neurologic disease changed forever. Before CT, available techniques included pneumoencephalography, ventriculography, gas myelography, angiography, and radionuclide scanning. These techniques were invasive, insensitive, or nonspecific. With CT, for the first time a diagnostic test offered noninvasive, accurate, and sensitive imaging of brain (and, a bit later, spine) disorders. Within a few years, CT scanning of the head and body became routine in many hospitals and imaging centers across the globe.

A short, simplified explanation of the CT physics is as follows. A collimated beam of x-ray photons enters the body (e.g., the head) and is attenuated as these photons interacting with the matter are absorbed. A detector on the opposite side of the head receives the attenuated beam and is connected to powerful computers. The x-ray source and the detector are coupled together and in the early scanners rotated about the head. Therefore, any point on a cross-section of the head is on the path of many beams and is seen from different vantage points. The computers calculate the attenuating ability of each point and, with other points put together, depict a two-dimensional picture of the slice. On this picture, contrast between adjacent tissues reflects their relative attenuation properties. Intravenous injection of contrast (an iodinated organic material) enhances the inherent absorptive differences and helps detect small lesions, such as vascular malformations and small metastases. Enhancement reflects the vascularity and the degree of blood-brain barrier breakdown of the lesion. However, contrast injection comes at a price: It adds a small risk to an otherwise safe procedure. Minor reactions include nausea and hives. More serious reactions include asthma, laryngeal edema, and anaphylaxis. Death is very rare (1 in 60,000 injections). Deterioration of renal function may be seen in patients with preexisting renal disease, especially diabetics. The radiation

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dosage received by the part being examined usually is quite small. In conventional CT a thin slice of the body is scanned, the gantry then moves to another slice, the x-ray generator is turned on, and that slice is scanned, and so on. In a new scanning technique called spiral or helical scanning, the gantry moves at a constant predetermined speed while the x-ray generator stays on. This way, a database of information is generated relating to the entire volume scanned. Such a database lends itself to easy reformation of images in multiple planes. A further refinement of the technique is afforded by multidetector technology. These newer techniques have led to successful CT angiography of neck and intracranial vessels and are very useful in multiplanar imaging of complex spinal pathology. Clinical Applications

One of the most important advantages of CT over older neuroradiologic tools is the possibility to repeat the examinations. This allows effective monitoring of pathologic processes (e.g., ventriculomegaly in patients with hydrocephalus, rebleed in patients with subarachnoid hemorrhage, or progression of a malignant glioma). CT is inexpensive, and there are hardly any contraindications. CT allows excellent assessment of bony structures and detects calcification with relative ease. Its sensitivity in detection of early hemorrhagic products makes it the ideal initial test in assessing patients with stroke even for inexperienced interpreters. This ease of interpretation is an important advantage of CT. Limitations of CT include poor visualization of the posterior cranial fossa, relative insensitivity to demyelinating processes, and the nonspecificity of many CT findings. Obtaining images in direct coronal and sagittal planes is difficult, although with newer techniques obtaining reformatted images in these planes is simple.

In patients with head trauma brain contusions, intracerebral hematomas, extra-axial hematomas, and calvarial fractures are easily identified. Midline shifts, subfalcine herniations, and signs of transtentorial herniation are easily detectable. With newer CT equipment, it is almost impossible to miss isodense subdural hematomas. Diagnosis of diffuse axonal injury is difficult with CT; in patients with sustained mental status change after head trauma, magnetic resonance imaging (MRI) of the brain is indicated. In unstable patients with head trauma and traumatic injuries of other organs, ease of monitoring vital functions during CT examinations and. the rapidity of the examinations are important advantages of CT. In patients who present with a cerebrovascular event, CT usually is the first radiologic test used. CT is very sensitive to subarachnoid hemorrhage (90%are detected in the first 24 hours) and intracerebral hemorrhage (Fig. 22-1). About 40% of bland infarcts are not seen in the first 24 hours. A brainstem or small cortical infarct may not be seen at all. Spiral CT angiography of intracranial and neck vessels is commonly used in conjunction with head CT to assess patency of the internal carotid artery in the neck and of the middle cerebral artery intracranially. Therapeutic decisions may be based on these CT angiography findings. Because at this early stage the extent of an infarct often is not visible, therapeutic decisions based on the size of involved territory rest primarily on clinical criteria. Here MRI has a clear advantage because diffusion-weighted MRI almost always shows the infarct. In addition, it is now possible to assess the ischemic territory at risk (ischemic penumbra) with perfusion MRI. A perfusion CT technique is being developed in some centers, and the initial experience has been promising. CT is a simple way to follow the clinical course of an infarct, especially cerebellar infarcts. These infarcts may develop edema and can cause compression of the

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A

FIG. 22-1. CT shows an intracranial hemorrhage. Blood is seen in (A) right frontal lobe, right sylvian fissure, and third and fourth ventricles and (B) lateral ventricles. There is hydrocephalus. This hemorrhage resulted from rupture of a berry aneulysm.

Chapter 22 W Neuroimaging: Radiology, MRI, Magnetic Resonance Spectroscopy, PET, and SPECT

brainstem, usually during the first 5 days. Also, hydrocephalus may develop as a result of fourth ventricular compression. CT scanning and MRI are the two competing tests in patients with intracranial tumors. CT is cheaper, more readily available, and more sensitive to calcification. Sometimes detection of calcification has significant diagnostic value (e.g., in craniopharyngiomas, meningiomas, and dermoids, and in nonneoplastic conditions such as aneurysms and cysticercosis). Because of its multiplanar capability and its capacity to provide metabolic and blood flow information, MRI is superior to CT in evaluating brain tumors. Some small posterior fossa tumors, such as intracanalicular vestibular schwannomas and small cerebellar metastases, can be missed with CT. Stereotactic localization for biopsy or for delivering focused radiation is an important use of CT in this field. In patients with meningitis, with few exceptions (tuberculous and syphilitic meningitis) CT usually does not show any abnormality. However, most intraparenchymal infections are well seen, and lesions caused by toxoplasmosis, aspergillosis, and mucormycosis are easily detected. The CT appearance often is nonspecific. Detection of lesions in herpes simplex encephalitis may lag up to 5 days behind the onset of symptoms. In patients with dementia, CT scanning is able to detect hydrocephalus, intracranial collections, and infarctions. An occasional brain tumor presenting with dementia will be detected as well. In some patients, the pattern of atrophy may suggest a specific degenerative disorder. Abdominal and pelvic CT scans are useful in patients presenting with lumbar or sacral plexopathies. Psoas abscesses, retroperitoneal hemorrhages, and abdominal and pelvic masses may be seen. In patients with brachial plexopathy, MRI is a better diagnostic test. However, radiologic tests often do not reveal any abnormality in plexopathies. In patients with herniated lumbar disc or lumbar stenosis, CT scanning is a useful test. Disc herniations, symptomatic or asymptomatic, can be detected easily. If a spinal tumor is suspected, MRI is a better test. MAGNETIC RESONANCE IMAGING Backgroundand Technique The phenomenon of nuclear magnetic resonance was discovered by Block and Purcell in 1946 and earned them the Nobel prize in 1951. For years, this technique was used in spectral analysis of small samples. Medical MRI is fairly new and owes its status today to the pioneering work of Damadian and Lauterbur. Widespread use of MRI would not have been possible if the medical profession had not been exposed to the CT experience earlier. The MRI technique uses a strong magnetic field (0.25 to 3 T). In this magnetic field, a small percentage of protons, being small magnets themselves, align along the magnetic field. External energy in the form of radio waves is added to the system. The protons absorbing this energy move to a higher and unstable energy status. As protons return to their initial, more stable energy level, the extra energy is given away in the form of a radio wave. An external antenna receives this signal. The location of the proton in the body is determined by adding three magnetic gradients in three orthogonal directions. Using Fourier transform applied to the signal, an image is produced. The speeds with which a sample becomes magnetized and a signal decays are related to T1 and T2 relaxation times of the sample. Every MR image has T 1 and T2 information; by changing imaging parameters, we can produce predominantly T1, predominantly T2, and intermediate (spin density) images. Cerebrospinal

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fluid is hypointense (dark) on T1- and hyperintense (bright) on T2-weighted images. Fat is hyperintense on T1-weighted images and becomes darker with increasing T2 weighting. Most brain lesions are hypointense on T1- and hyperintense on T2-weighted images. A rare earth element, gadolinium, is used in a chelated form as MR contrast. It is injected intravenously and remains, for the most part, intravascular. By shortening T1 relaxation times of lesions it enhances the inherent differences between the lesion and its surrounding tissue. Gadolinium is very well tolerated, and reactions and side effects are very rare. The most common adverse reactions are headache, coldness at the injection site, and nausea. Anaphylactic reactions are extremely rare. Caution should be exercised in patients with hemolytic anemia, in pregnant women, and in children less than 2 years old because safety of this drug in these patients has not been established. Conventional MRI techniques, such as spin echo, require a cooperative patient to lie still for a long time (5 to 15 minutes). It has been desirable to reduce the imaging time with MRI. Multiple faster imaging techniques have been developed recently. Two of these, fast spin echo and gradient echo imaging, are in widespread use. Ultrafast imaging with echo planar technique is the basis of some promising functional MRI techniques such as diffusionweighted imaging and perfusion imaging. In diffusion imaging, the minute, random, Brownian movements of molecules are measured. Restriction of diffusion is seen in a recent infarction, and diffusion-weighted imaging has had a tremendous impact in evaluating acute infarction. However, restriction of diffusion is not quite specific for infarction and can be seen in a variety of other disease entities. In perfusion imaging a bolus of the MR contrast agent gadolinium is injected intravenously, usually with a mechanical injector that delivers contrast at a fast and constant rate. As gadolinium enters the arteries and capillary bed of brain tissue, there is a reduction in MR signal with echo planar imaging. The scanner usually scans 10 to 15 slices of brain 30 to 40 times in a short time. This technique, which could not have been developed were it not for the speed of echo planar imaging, detects the signal decrease associated with the first pass of gadolinium through the brain. Postprocessing allows depiction of this signal change in a plot of intensity versus time. Other parameters such as time-topeak, regional cerebral blood volume, and even blood flow can be measured. Perfusion imaging is commonly used to evaluate infarctions and differentiate recurrent tumor from radiation necrosis. With conventional spin echo MRI, usually a volume of tissue is imaged simultaneously. Although unsaturated blood entering the lower portion of the volume gives a significantlyhigher signal than surrounding stationary tissues, this signal decays soon as blood moves up through the volume being imaged. With gradient echo technique each slice is acquired separately and the signal therefore does not decay. With a maximum-intensity projection technique, which allows only pixels with the highest signal to be used, this difference between moving blood and stationary tissue creates an MR angiogram. The preceding explanation describes the more popular timeof-flight technique. Another technique, phase contrast MR angiography (MRA), is used less frequently. It offers some advantages, such as the ability to depict direction of blood flow. MR spectroscopy (MRS), long used in chemistry labs, is now available as a medical imaging tool. MRS is based on chemical shifts. Because of minute magnetic fields generated by electrons orbiting about nuclei, the effective magnetic field experienced by these nuclei is not the same as the external magnetic field and is subject to the location and number of the adjacent electrons. The

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signals generated by these nuclei therefore are different and reflect the chemical structure of the substance. MRS is a noninvasive way of sampling living tissue, and hydrogen MRS is able to demonstrate peaks related to important metabolites such as N-acetyl aspartate (NAA),choline, creatine, glutamate-glutamine, myoinositol, and a host of other substances. Phosphorus and sodium MRS are becoming available to the medical community as higherstrength magnets become available. The most common use of MRS is to differentiate tumors from other similar-looking lesions (e.g., infarcts) and differentiate recurrent malignant brain tumors from radiation necrosis. Patients with intraorbital metallic foreign bodies, neurostimulators, and cochlear implants are excluded from MR examination. Significant strides have been made in making the newer aneurysm clips MR compatible. Imaging of a patient harboring an unknown aneurysm clip may be unsafe and is best avoided. An important cause of exclusion is a cardiac pacemaker. Although the use of MR has not been shown to be deleterious to the developing fetus, imaging of pregnant women in their first trimester of pregnancy is not recommended. A practical and common cause of exclusion is claustrophobia.

Clinical Applications MRI does not share many limitations of CT scanning. Images of the posterior fossa are very clear and almost free of artifacts. Obtaining images in direct coronal or sagittal planes is difficult with CT; newer CT generations can obtain reformatted images in these planes with ease, but these tasks take time. MRI can be obtained effortlessly in any plane. One of the greatest advantages of MRI is its ability to provide images of flowing blood. MRA has improved significantly in the past decade and is able to provide diagnostic-quality images of carotid bifurcations and intracranial vessels. The ability to obtain diffusion-weighted images, perfusion images, and spectroscopy along with conventional MRI has greatly enhanced the utility of MR in many clinical conditions from stroke to brain tumors.

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Principles of Diagnosis: Special Tests

The disadvantages of MR include relative insensitivity to small calcifications, poor delineation of bony structures, longer scanning times than CT, and expense. In addition, CT imaging and interpretation are easy to learn, whereas MR interpretation is more complex and takes more in-depth knowledge and effort. In patients with a cerebrovascular event, MRI with diffusionweighted images is able to reveal the extent of infarction early enough to be of use in acute therapeutic decision making (Fig. 22-2). Few infarctions are not seen on MRI obtained during the first few hours. These primarily include small infarcts less than 1 cm in size and, especially, small brainstem infarcts. Perfusion images may be able to reveal the uninfarcted territory at risk and help to direct intervention. MR spectroscopy may show a lactate peak and depressed NAA level. Concomitant MRA can assess extracranial and intracranial vessels. MRA with time-of-flight technique often overestimates and, less often, underestimates narrowing at the bifurcation. If Doppler ultrasonography and MRA concur, many centers do not require additional conventional angiography for a therapeutic decision. Very early cerebral hemorrhage is hard to differentiate from other lesions on conventional MRI and much easier to detect on CT scan. Gradient echo images are much more sensitive to hemorrhagic material and should be included whenever hemorrhage (or hemorrhagic material) is sought. The detection rate of subarachnoid hemorrhage was said to be at best 50% with conventional MR. The detection rate must be higher if gradient echo and fluid attenuated inversion recovery (FLAIR) images are used. Still, CT performs much better if subarachnoid hemorrhage is sought. However, MRI detects later products of hemorrhage (deoxyhemoglobin, methemoglobin, and hemosiderin) without difficulty. Subacute intracerebral hemorrhage can present with a confusing CT picture that may be difficult to differentiate from abscess and tumor. Diagnosis of subacute hemorrhage with MR is easy. The angiographically occult cerebrovascular malformation usually is a cavernous angioma; these lesions have characteristic MRI features. Because of signal loss associated with flowing blood, an arteriovenous malformation is easily seen with conventional

B

FIG. 22-2. (A) A right basal ganglionic infarct is seen on diffusion-weighted MRI. (B) The infarct is barely visible at this early stage on the TZ-weighted image.

Chapter 22 W Neuroimaging: Radiology, MRI, Magnetic Resonance Spectroscopy, PET, and SPEC3

21 1

C

FIG. 22-3. A brain tumor (glioblastoma multiforme) is seen on (A) a T2-weighted image and on (B) a contrast-enhanced T1-weighted image. Spectroscopy (C) demonstrates an elevated choline peak (chol), a decreased NAA peak, and a lactate

peak (Lac). MRI. MRA can be used to assess the arterial feeders and draining veins. Developmental venous anomalies are seen with relative ease on contrast-enhanced images. In patients with brain tumors, gadolinium-enhanced MRI is superior to contrast-enhanced CT, especially in demonstrating small extra-axial posterior fossa tumors and meningeal infiltration. By obtaining images in three orthogonal planes, MRI demonstrates the spatial relations of a tumor. This information helps the neurosurgeon choose the best possible approach to a deep lesion. The relationship of a tumor to a vital part of brain (e.g., somatosensory cortex) can be assessed with an MRI technique that is sensitive to increased blood flow as a result of activation of that part of the brain. Therefore, algorithms have been developed to localize somatosensory cortex, primary visual cortex, auditory cortex, and language areas with a technique known as the blood oxygen level-dependent technique (BOLD). Because of rapid turnover of membranes, most tumors demonstrate a large choline peak on MRS. There is diminution of the NAA peak, a marker of normal neuronal density (Fig. 22-3). After head trauma, a patient usually is studied by CT scanning. MRI examination may not be advisable because patients may be unstable or uncooperative. CT scanning also is more sensitive in detecting early hemorrhagic materials. MRI is able to detect all lesions secondary to trauma, especially if proper imaging sequences are used. MRI is clearly superior to CT in detecting diffuse axonal injury. Intracranial infections can be studied successfully with MRI, but a specific diagnosis may not be possible in many cases. For example, differentiating lesions caused by toxoplasmosis from those caused by other infections and lymphoma in patients with acquired immunodeficiency syndrome may not be possible from MRI findings alone. Meningeal involvement is easier to detect on MRI than CT. In herpes simplex encephalitis, the MRI changes (foci of increased intensity in temporal lobes and inferior frontal lobes) appear earlier (2 days vs. 3 to 5 days) than the changes on CT scans. MRI is more sensitive and more accurate in demonstrating the extent of the lesions. Brain abscesses caused by

pyogenic agents have a characteristic MRS picture (presence of cytosolic amino acids) that is not seen with other lesions. The necrotic center of a brain abscess typically is intense on diffusionweighted imaging. This finding may be helpful in differentiating brain abscesses from tumors. MRI is very sensitive to the changes seen in multiple sclerosis. In one study, 95% to 99% of patients had positive brain MRI (Fig. 22-4). A negative study of the brain does not exclude this diagnosis. Gadolinium-enhanced MRI reveals enhancement in active lesions. Serial MRI can be used to assess the disease burden and its changes with time or therapy. MRI abnormalities (increased T2 intensity in basal ganglia and thalami) have been reported in patients with Creutzfeldt-Jakob disease. Hydrocephalus, multiple infarcts, and mass lesions and collections can be seen or ruled out in patients with dementia. Abnormalities of iron deposition have been described in patients with Parkinson’s disease (excessive deposition of iron in putamina) and in Parkinson-like syndromes. In few other areas has MRI had more impact than in imaging of the spinal cord. Foci of demyelination, myelitis, traumatic lesions, syrinx, and tumors (Fig. 22-5) can be successfully demonstrated. By judicious use of imaging sequences, location of an extramedullary lesion (intradural vs. extradural) can be correctly appreciated, thus obviating myelography. Cord compression is no longer an indication for myelography. This can be assessed satisfactorily with MRI. PET AND SPECT

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide important functional and metabolic information, including regional cerebral blood flow and brain response to a variety of sensory stimuli. These techniques have also been used to study stroke, epilepsy, brain tumors, radiation necrosis, and a variety of psychiatric illnesses. Soon after a positron is emitted it collides with an electron. The two particles are lost in this encounter, and two photons

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Principles of Diagnosis: Special Tests

FIG. 22-4. A case of long-standing chronic multiple sclerosis is shown on these intermediate MR images. Foci of increased signal intensity are seen along the walls of the temporal and occipital horns. There is ventriculomegaly.

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B

FIG. 22-5. Multiple intradural spinal canal tumors (ependymomas) are seen on these MR images. (f?) The lesions show moderate enhancement. Note also the filling of the distal thecal sac with tumor. The patient had had an ependymoma of the posterior fossa in the past, and these spinal lesions represent leptomeningeal seeding.

Chapter 22

Neuroimaging: Radiology, MRI, Magnetic Resonance Spectroscopy, PET, and SPECT

(annihilation photons) are produced. PET is based on detection of these photons. Strong cameras with exquisite spatial resolution are needed. Recent advances in radiotracer technology, better scanners with high spatial resolution, and third-party reimbursement have led to the installation of many PET units in recent years. Perhaps the most important development has been commercial availability of the radiotracer "F-fluorodeoxyglucose. The distribution of this tracer in the brain is proportional to the regional metabolic activity in the brain. It also crosses the blood-brain barrier. In evaluating brain tumors, PET is very useful in choosing the most metabolically active part of a heterogeneous brain tumor for biopsy. It is also useful in the postoperative period for detecting residual or recurrent tumor because unlike CT and MRI, PET usually is unaffected by the postoperative changes. Combined PET and CT is another exciting new technology allowing simultaneous improved anatomic depiction and assessment of metabolic activity of a lesion. SPECT uses readily available pharmaceuticals and modified conventional nuclear medicine cameras. These advantages have facilitated widespread use of SPECT across the country. Today, SPECT is commonly used to differentiate radiation necrosis from recurrent brain tumors and to evaluate dementia and epilepsy. [99mTc]-Hexamethylpropyleneamine oxime SPECT can be used to give a semiquantitativemeasure of regional cerebral blood flow. Perfusion defects can be seen in acute stroke long before changes on CT scan can be appreciated. However, the spatial resolution of SPECT is far below that of CT and MRI.

CEREBRAL ANCIOCRAPHY AND SPINAL ANCIOCRAPHY Transfemoral cerebral angiography has become a much easier and safer test, mainly because of better digital imaging systems, better radiographic contrast agents, and smaller and better catheters, arterial sheaths, and guidewires. Most centers now perform these procedures on an outpatient basis, with the patients remaining in a nearby recovery room for 4 to 6 hours after the procedure. Currently, the most important indication for cerebral angiography is vascular disease. Angiography remains the gold standard in assessing atherosclerotic carotid bifurcation disease, although Doppler ultrasound, CT angiography, and MRA have drastically reduced the number of conventional catheter angiograms performed for this indication. Cerebral aneurysms, vascular malformations, and vasculitides are other indications. Better techniques, safer catheters, and faster imaging equipment have led to successful transcatheter endovascular therapy of a variety of cerebrovascular conditions, such as thrombolytic therapy of acute stroke and treatment of arteriovenous malformations and aneurysms. With availability of these techniques in most academic centers and many community hospitals, new paradigms are being considered in workup and treatment of these entities. Angiography is now rarely used to study brain tumors. The incidence of complications has diminished with newer, safer techniques. Still, permanent neurologic deficits occur rarely. Stroke as a result of angiography should not occur at a rate of more than 0.5% in good hands. Reversible deficits are perhaps two or three times more common. The most common local complication is groin hematoma. Spinal angiography is a much safer procedure than in the past. Its major indication is vascular malformations of the spinal canal. Assessment of vascular supply to a spinal tumor before surgery is

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another indication. As with cerebral angiography,safer procedures and better techniques have led to interventionaltherapy of some of these lesions. To diminish movement-generated artifacts during spinal angiography, these procedures often are performed under general anesthesia.

MYELOCRAPHY With widespread use of CT scans and MRI, the number of myelograms performed in the United States has decreased significantly. In patients suspected of harboring a cord tumor, myelography is rarely used. Cord tumors, whether extramedullary or intramedullary, are now studied with MRI. Most patients with lumbar or cervical disc disease or stenosis are now studied with CT scanning and MRI. In fact, CT scanning may be the most convenient and cheapest radiologic method to investigate patients with lumbar disc herniation. In complicated cases, to include some postoperative backs, in patients with suspected arachnoiditis, and in selected patients with cervical disc disease with equivocal MRI findings, myelography and postmyelography CT scan may be indicated. Patients who cannot undergo MR examination (those with pacemakers, aneurysm clips, or claustrophobia) are referred for myelography and postmyelogram CT. Safer aqueous contrast agents used in myelography (iohexol and iopamidol) are associated with fewer side effects. The most common adverse reactions are headache (20%), nausea, and vomiting. Back pain and leg pain may be accentuated during myelography, especially in patients with spinal stenosis. Confusion, restlessness, nightmares, and other neuropsychiatric side effects are now rare. Universal use of smaller lumbar puncture needles (25 G) and decreased dosage of contrast offer hope for further reductions in the incidence of complications. Contraindications to myelography are essentially the same as those to lumbar puncture, primarily increased intracranial pressure and coagulopathy.Patients with history of significant reaction to contrast material are excluded. Those with history of milder reactions in the past can be premedicated with steroids. In discography, a percutaneous needle is placed in the disc in question, and saline is injected into the disc, after which the patient's symptoms are compared with his or her spontaneous ones. This procedure has not received universal acceptance as a diagnostic test.

SUGGESTED READINGS Atlas: Magnetic Resonance Imaging of the Brain and Spine. 2nd Ed. Lippincott Williams & Wilkins, Philadelphia, 1996 Beauchamp NJ, Barker PB, Wang PY et ak Imaging of acute cerebral ischemia. Radiology 212: 307, 1999 Bradley WG MR appearance of hemorrhage in the brain. Radiology 189:15. 1993 Edelman RR, Warach S: Magnetic Resonance Imaging. N Engl J Med 328:708, 1993 Edelman RR, Warach S: Magnetic Resonance Imaging. N Engl J Med 328:785, 1993 Gentry L R Imaging of closed head injury. Radiology 191:1, 1994 Osborn A Diagnostic Neuroradiology. Mosby, St Louis, 1994 Rand SD, Prost R, Li SJ: Proton MR spectroscopy of the brain. Neuroimaging Clin N Am 9(2):379, 1999 Van Heertum RL, Drocea C, Ichise M et ak Single photon emission CT and positron emission tomography in the evaluation of neurological disease. Radio1 Clin North Am 391007, 2001

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23

Principles of Ambulatory Neurologyand the Approach to Clinical Problems H Principles of Diagnosis: Special Tests

Biopsy of the Brain Matthew P. Frosch and Umberto De Girolami

A brain biopsy is an important procedure that can contribute to neurologic diagnosis and influence therapy. This benefit must be balanced against the fact that sampling brain tissue carries the risk of neurologic disability. The clinical course, location and type of lesion, and information desired from the biopsy all help shape the decision to perform a biopsy. These factors also influence the manner in which the biopsy is handled. Once the decision to perform a brain biopsy has been reached, the neurologists, neurosurgeons, neuroradiologists, and neuropathologists should continue to interact. The pathologic interpretation of brain biopsies is beyond the scope of this chapter and is covered in detail in standard textbooks. This brief review is intended to offer some guidance regarding the general approach and evaluation of brain biopsies.

rn

a patient with multiple lesions, a biopsy of a single lesion provides information only about that lesion and may not be representative of the others. That is, different disease processes may be active in a given patient. This is an important issue in immunosuppressed patients, who may be affected simultaneously by multiple opportunistic infections. An erroneous diagnosis of a discrete mass lesion can be reached if tissue sampling is inadequate. For example, if necrotic tissue is obtained from the center of a ring-enhancing lesion, it will be impossible to distinguish between an associated high-grade neoplasm (either primary or metastatic) or an infectious process. Similarly, within glial tumors, the histologic grade can vary from one area of the lesion to another.

INTRAOPERATWE PATHOLOGIC INTERPRETATIONS TYPES OF BIOPSY The clinical setting, the patient’s medical condition, and the nature of the suspected pathologic process contribute to the selection of the biopsy method. Brain biopsies can be performed as open neurosurgical procedures with direct visualization of the tissue to be sampled or by stereotactic procedures. An open biopsy can allow additional resection, drainage, or other manipulation based on findings at the time of intraoperative pathologic consultation (frozen section). Thus, for metastatic lesions it is possible to resect the tumor nodule, and abscesses can be drained. Open biopsies are limited by the anatomic site of the lesion (e.g., excluding intrinsic brainstem lesions) and the underlying medical condition of the patient. In contrast, stereotacticbiopsies do not entail an extensive surgical procedure and can reach areas of the brain that are inaccessible to open biopsies. Recent advances in stereotactic neurosurgical techniques and more precise localization of lesions by computed tomography and magnetic resonance imaging have resulted in more widespread use of this method for brain biopsy. Although it may seem self-evident, it is worth stating that when a patient with a focal lesion needs a brain biopsy, the biopsy must be taken from the region of the lesion to maximize the likelihood of reaching a diagnosis. Stereotactic biopsies often are used for focal lesions that are defined by imaging studies; they are less useful in the context of diffuse or multifocal processes in which the larger sampling volume afforded by open biopsy increases the likelihood of obtaining a diagnostic specimen.

SAMPLING A major issue in interpreting brain biopsies is the adequacy of sampling. In any context, the biopsy must include the site of the suspected disease process. Thus, when one is attempting to provide histologic evidence of vasculitis, the biopsy sample must include adequate representation of meningeal and cortical vessels. Similarly, when a demyelinating process is suspected, as with progressive multifocal leukoencephalopathy, the specimen must contain white matter from the area of radiologic abnormality. At least as important as providing pathologic support for a suspected diagnosis, a brain biopsy helps exclude disease processes under consideration in the clinical differential diagnosis. Furthermore, in

Examination of brain biopsy tissue by neuropathologists during the course of a neurosurgical procedure is carried out routinely. The aims of this consultation include confirmation that lesional tissue has been biopsied, rendering of a preliminary histopathologic intraoperative diagnosis to provide information useful in surgical management, and proper triage of specimen handling for special studies. Gross and microscopic examination of the tissue and examination of radiologic studies and discussions with the neurosurgeons are always necessary to achieve these aims. The intraoperative histopathologic examination of tissue is most commonly performed in frozen sections. For this procedure, a portion of tissue-chosen to represent the biopsy adequately-is rapidly frozen in a mounting medium that solidifies in the cold. Sections approximately 8 to 12 micrometers thick are cut on a cryostat, picked up on glass slides, rapidly fixed in alcohol, and stained with a rapid hematoxylin and eosin (H&E) procedure. They may also be stained with an aniline dye and mounted in an aqueous medium. Frozen sections are also useful for detecting compounds that are partially soluble in the medium used to prepare standard histologic sections, such as lipid (with oil red 0 or Sudan black) and glycogen (with periodic acid-Schiff stain). The frozen section method has certain advantages. This method of diagnosis is well established around the world because the histopathologic changes and artifacts seen are similar to those of conventional tissue sections, so it is widely recognized as the standard of care. Frozen sections thus provide information about the histologic architecture of the lesion similar to that seen with permanent sections (Plate 23-1). Because the tissue used for frozen section analysis is routinely processed later for paraffin sections, the intraoperative diagnosis can be confirmed using the same piece of tissue that was previously used for the intraoperative frozen section. On the other hand, there are some drawbacks to the use of brain frozen sections. Frozen sections of brain are more difficult to perform than comparable sections on tissues from other regions of the body. The freezing process introduces artifacts: There is often poor nuclear detail in frozen sections, and paraffin sections prepared from tissue that was frozen usually show artifacts (e.g., clefts in the tissue, hyperchromatic or atypical nuclei). Important intraoperative complements to frozen sections are

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PLATE 23-1. Glioblastoma multiforme showing a densely cellular tumor with extensive pleomorphism and two of the architectural features characteristic of this high grade glioma: the presence of areas of necrosis surrounded by pseudopalisading of tumor cells and vascular cell proliferation. (H&E)

PLATE 23-2. Comparison of nuclear detail as seen with (A) frozen section and (B) smear prep. Both slides come from a suprasellar region tumor and contain two populations of cells: a small, benign-appearing lymphoid population and a larger, more pleomorphic population of germ cells. These findings, which are strikingly revealed on the smear preparation, are those of a germinoma. (H&E)

A

B

D

C

PLATE 233. Examples of smear preparations. (A) Elongated nuclei, delicate hairlike processes, and Rosenthal fibers are seen in a pilocytic astrocytoma. (B) Periiascular arrangement of processes ("perivascular pseudorosettes") are found in an ependymorna. (C) A well-defined syncytial cluster of cells is present in a rneningioma. (D) An abundant sheet of small, poorly differentiated cells characterize a medulloblastoma. (H&E)

C

D

E

PIATE 25-4. Examples of special studies. (A C B) Immunohistochemical marking of a lymphoma reveals that the tumor cells stain for a pan B-cell marker (Plate A) but not for a pan T-cell marker (Plate 6). (C) Methenamine silver stain reveals the presence of fungal forms within the debris of an abscess. (D) Toxoplasma organisms can be seen as both free tachyzoites and as bradyzoites within a pseudocyst (H&E). (E) lmmunohistochemistry for intermediate filament protein CFAP in a high-grade glioma shows staining of the tumor cells (the pale unstained islands of cells represent areas of vascular cell proliferation). (F) lmmunohistochemistry for JC virus antigen in a small lesion of progressive multifocal leukoencephalopathy shows the presence of numerous infected oligodendrocytes (counterstained with Lux01 Fast Blue/PAS).

F

PLATE 23-5. Stereotactic biopsy of the putamen from a patient with a rapidly progressive dementing illness. The biopsy shows the vacuolar change in the grey matter characteristic of Creutzfeldt-Jakob disease, with no changes present in the adjacent white matter. (H&E)

Chapter 23

the smear and touch preparations. These methods do not subject tissue to the trauma of freezing. Although these preparations do not yield information about the architecture of the lesion, they allow excellent demonstration of nuclear detail (Plate 23-2). The methods use extremely small amounts of tissue, so they can be performed in addition to the frozen section. Touch preparations are performed by applying a glass slide to the surface of the biopsy with a small amount of pressure, then rapidly fixing the slide and staining it in the usual manner. This method is helpful in examining poorly cohesive lesions, such as lymphomas, some carcinomas, and inflammatory lesions with areas of necrosis. To prepare smears, a small fragment of tissue is placed on the surface of the slide and then smeared rapidly against another slide in a manner similar to that used for preparing a thick blood smear. The slide is stained with H&E after rapid alcohol fixation. In addition to providing excellent nuclear detail, smear and touch preparations show individual cell morphology. Delicate processes of tumor cells, as seen in pilocytic astrocytomas, can be well visualized (Plate 23-3A), as can the perivascular arrangement of processes in ependymomas (Plate 23-3B). Similarly, the syncytial knots of cells from meningiomas (Plate 23-3C) and the cytologic features of medulloblastoma can be well seen (Plate 23-30). Because of their excellent preservation of nuclei, smear preparations can also be used to analyze DNA content (ploidy).

SPECIAL STUDIES At the time of intraoperative consultation, the neuropathologist and neurosurgeon make a number of decisions based on examination of the specimens. One critical decision regards the adequacy of the tissue sample. If the material provided is inadequate to allow a definitive diagnosis, this information must be conveyed to the neurosurgeon. Given the histologic appearance of the sampled tissue, the pathologist may initiate a variety of procedures. In general, biopsy tissue is fixed in 10% buffered formalin and processed by routine procedures. A variety of alternative or supplementary procedures can be followed, based on preliminary diagnoses from intraoperative consultation and clinical concerns. These special studies are intended to provide additional information and aid the pathologist in rendering a diagnosis. Some of the methods are considered briefly here. To diagnose processes involving lymphoid cells (either neoplastic or reactive) it is often useful to have access to the wide range of immunohistochemical procedures used by the hematopathologist, many of which work best on frozen tissue or material fixed with fixatives other than formalin (Plate 23-4A and B). Therefore, if such studies are considered, a portion of the specimen may be handled in this manner. When indicated, tissue should be frozen rapidly in liquid nitrogen or a dry ice and isopentane bath. Material prepared in this fashion can also be used for immunofluorescence studies in evaluating vasculitides. Similarly, special fixation is necessary if the tissue is to be used for electron microscopy, which may be helpful in cases of poorly differentiate? neoplasms, viral infections, and metabolic or storage diseases. Additional special handling may be necessary in metabolic or storage diseases because the “stored” material might be dissolved out of tissue during standard processing. Additional frozen sections and nonaqueous fixation and processing can preserve intracellular storage material. When a preoperative consideration or intraoperative consulta-

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tion has raised the possibility of an infectious process, microbiologic cultures (including viral, bacterial, and fungal cultures) are indicated. These may be complemented by stains for specific classes of organisms (Plate 23-4C), although some organisms can be seen with standard H&E staining (Plate 23-40). The past 20 years have seen the expansion of the role of immunohistochemical stains, especially in studying tumors. This method can provide various types of information. For example, it can confirm the glial nature of a lesion through immunoreactivity for the glial intermediate filament protein GFAP (Plate 23-4B) or reveal the nature of germ cells within a germinoma through immunoreactivity for placental alkaline phosphatase. With appropriate reagents, this method can also be useful in diagnosing infectious diseases (Plate 23-4F). Recent developments in the understanding of the molecular genetics of neoplasia and, in particular, of the genetic alterations found in primary central nervous system tumors has generated interest in additional studies of tumors. Specifically, samples of fresh sterile tumors can be submitted in some institutions for cytogenetic analysis. These can be performed either on direct preparations of cells (useful in highly proliferative neoplasms) or after short-term culture of tumor cells. The presence of certain chromosomal alterations can be characteristic of specific lesions (e.g., monosomy 22 in meningiomas) or predictive of natural history (e.g., role of aneuploidy in medulloblastomas or the relationship between loss of heterozygosity for l p and 19q and chemotherapy response in anaplastic oligodendrogliomas). There has also been an expansion in the use of polymerase chain reaction based (PCR) determinations of allelic loss or specific classes of mutations. Although these studies can be performed on fixed archival material, they are greatly facilitated by taking representative samples of lesional and nonlesional tissue for rapid freezing. In the absence of nonlesional material at the time of surgery, DNA prepared from the patient’s blood can be used for comparison purposes.

SPECIAL CONSIDERATIONS Unfixed biopsy tissue from all patients must be treated with universal precautions. However, in patients with known or highly suspected infection by certain pathogens, some additional considerations may be relevant. In many institutions, cryostats must be decontaminated after introduction of tissue from patients infected with hepatitis B virus, Mycobacterium tuberculosis, or HIV, in addition to regularly scheduled decontamination. For this reason, specimens from patients known to be infected by these agents are rarely processed for frozen section; they are either fixed promptly or evaluated by smear and touch preparations with the assistance of experts in the microbiology laboratory. When brain biopsies are performed for the purpose of confirming or excluding a spongiform encephalopathy, including Creutzfeldt-Jakob disease, certain additional precautions are observed because of the special nature of the infectious prion agent. Because this diagnosis must be based on excellent, artifact-free histologic preparation, frozen sections or smear preparations should never be performed. The biopsy is placed directly into formalin by the surgeon and allowed to fix. It is then fixed briefly in formic acid, followed by additional formalin fixation. This procedure provides adequate histologic detail (Plate 23-5), while resulting in near complete inactivation of the infectious agent.

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rn TABLE23-1. Entities Diagnosed by Brain Biopsy Focal lesions (mass lesions; some may be multifocal) Tumors Primary brain tumors Metastatictumors Lymphoma Germ cell tumors Pituitaly lesions Infections Bacterial abscesses Fungal infections (e.g., aspergillosis, candida, mucormycosis) Parasitic infections (e.g., toxoplasmosis) Viral infectionswith focal findings Herpes encephalitis Progressive multifocal leukoencephalopathy Other focal processes Multiple sclerosis (may rarely present as a mass lesion) Strokes with atypical features Vascular malformations Seizure foci cvsts Colloid cysts Arachnoid cysts Pineal region cysts Effects of prior treatment (radionecrosis)

Diffuse Processes

Meningitic processes Meningeal carcinomatosis Vasculitis Infections Sarcoidosis Infections Viral encephalitis Demyelinating diseases Acute disseminated encephalomyelitis Acute hemorrhagic leukoencephalitis Inflammatory, autoimmune processes (including paraneoplastic) Dementia Alzheimer's disease Other neurodegenerativediseases (e.g., Pick's disease, Lewy body disease) Creutzfeldt-Jakob disease Storage diseases (e.g., neuronal ceroid lipofuscinosis) Metabolic disorders

DIAGNOSTIC ISSUES The consideration of neuropathologic interpretation of brain biopsies is beyond the scope of this chapter; however, a few general comments are appropriate regarding the major categories of disease that are encountered (Table 23-1). A large proportion of brain biopsies are performed to determine whether a neoplasm is present. Depending on the institution involved and the pattern of neurosurgical referrals, there can be a wide range of ratios of primary and metastatic tumors. The neuropathologist often provides the essential information about the nature of a tumor and its histologic grade-information critical in patient care. Similarly, in cases of infectious diseases, the choice of antimicrobial therapy depends on the combination of microbiologic results and histologic interpretations. Patients with diseases that are

Principles of Diagnosis:Special Tests

ordinarily diagnosed without resort to surgery may sometimes come to brain biopsy because of an atypical clinical presentation (e.g., initial presentation of multiple sclerosis as a single lesion with moderate mass effect).

AREAS OF DIFFICULTY Although neuropathologic examination of biopsied brain tissue can be extremely important in guiding patient care, it is not an infallible technique and has several intrinsic difficulties. Some of these were considered earlier in the discussion of sampling effects. Apart from this and other technical issues, some histopathologic patterns, though distinctive, are not diagnostic. Therefore, a biopsy may show a pattern of reactive gliosis or increased numbers of astrocytes without indicating what has evoked the reaction. Similarly, the biopsy may demonstrate destructive lesions with evidence of tissue necrosis and inflammation and yet be nondiagnostic. Very small biopsies of tissue are also notoriously difficult to interpret. SUGGESTED READINGS Brown P, Wolff A, Gajdusek D C A simple and effective method for inactivating virus infectivity in formalin-fixed tissue samples from patients with Creutzfeldt-Jakob disease. Neurology 40:887, 1990 Burger PC, Scheithauer BW Tumors of the Central Nervous System. 3rd Set., Fax. 10. Armed Forces Institute of Pathology, Washington, DC, 1994 Burger PC, Scheithauer BW, Vogel FS: Surgical Pathology of the Nervous System and its Coverings. 4th Ed. Churchill Livingstone, New York, 2002 Chandrasoma PT, Apuzzo MLJ: Stereotactic Brain Biopsy. Igaku-Shoin, New York, 1997 Fletcher JA, Kozakewich HP, Hoffer FA et ak Diagnosticrelevance of clonal cytogenetic aberrations in malignant soft-tissue tumors. N Engl J Med 324:436, 1989 Folkerth RD: Smears and frozen sections in the intraoperativediagnosis of central nervous system lesions. Neurosurg Clin 5:1, 1994 Ganju V, Jenkins RB, O'Fallon JR et al: Prognostic factors in gliomas: a multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic and molecular markers. Cancer 74920, 1994 Graham D, Lantos P (eds): Greenfield's Neuropathology. 7th Ed. Arnold, New York, 2002 Hu DJ, Kane MA, Heymann DL Transmission of HIV, hepatitis B virus, and other bloodborne pathogens in health care settings: a review of risk factors and guidelines for prevention. Bull WHO 69623, 1991 Ino Y, Betensky RA, Zlatescu MC et al: Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clinical Cancer Res 72339-845, 2001 Moss TH, Louis D et al: Diagnostic Pathology of Nervous Ironside JW, System Tumors. Churchill Livingston, London, 2002 Kleihues P, Cavanee WK (eds): Pathology 8 Genetics of Tumors of the Central Nervous System. IARC Press, Lyon, 2000 WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies: Report of a WHO Consultation, Geneva, Switzerland, March 23-26 1999. World Health Organization, Geneva, 2000

Chapter 24

24

Biopsy of Netve and Muscle

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Biopsy of Nerve and Muscle Umberto De Girolami, Matthew P. Frosch, and Anthony A. Amato

Muscle and nerve biopsies can play an important role in evaluating neuromuscular disease. In this chapter, we address the indications for muscle and nerve biopsies, how to select the specific muscle or nerve to biopsy, and various aspects of specimen handling. Furthermore, we discuss the routine stains that are performed on muscle and nerve tissue, when to order special stains or studies on the tissue, and the normal and abnormal structure of muscle and nerve. Finally, we briefly take up the topic of the skin biopsy in evaluating patients with peripheral neuropathy. SKELETAL MUSCLE BIOPSY

Over the past 40 years there has been a growing recognition of the value of the muscle biopsy as a diagnostic tool in evaluating patients with muscle disease. An increasing range of methods of study has been applied to muscle biopsies, so that currently biopsies are studied through a combination of enzyme histochemistry, electron microscopy, and molecular biology. In spite (or because) of the advances in the laboratory, it remains all the more essential today to correlate the information obtained from the muscle biopsy with the clinical neurologic assessment and the electrophysiologicalfindings.

Indications for Muscle Biopsy Abnormalities detected by clinical examination and laboratory tests (e.g., elevated serum creatine kinase levels, myopathic electromyography)will suggest to the clinician that the patient has a disorder of muscle. However, these abnormalities often are nonspecific and do not reveal the exact cause of the underlying myopathy. Thus, muscle biopsies are extremely useful in the diagnosis of specific diseases of skeletal muscle. In our experience, muscle biopsies have greatest diagnostic utility when the patient manifests objective abnormalities on clinical examination, laboratory testing, or electromyography (EMG). Muscle biopsies generally are not useful in evaluating patients with subjective weakness, fatigue, or myalgias in the absence of objective abnormalities.

Techniques Either an open (minor surgical procedure) or closed (needle or punch) biopsy can be performed to obtain muscle tissue. Open muscle biopsies yield a larger sample of tissue, which can then be processed for light and electron microscopy, metabolic analysis (e.g., mitochondrial respiratory chain abnormalities or other enzyme activity measurements), and molecular studies (e.g., Western blot, direct genetic analysis). When muscle tissue is obtained with a needle biopsy, the procedure has the advantage of allowing the examination of multiple potentially affected muscles; it is also a less invasive procedure than an open muscle biopsy. The evaluation of a skeletal muscle biopsy specimen depends on careful selection of the site of the biopsy based on clinical and neurophysiologic data. Because the physician who requests the biopsy often is not the person who performs the surgery, communication between the two is essential to ensure that the

proper site is chosen. The muscle selected for biopsy should be mildly weak, preferably Medical Research Council (MRC) grade 4 or 5. If the muscle is too weak (i.e., MRC grade 3 or less), the tissue typically has end-stage damage, and it is often impossible to distinguish a myopathic process from severe neurogenic atrophy. In patients with little weakness on examination, electromyography can be helpful in selecting the muscle to biopsy. However, it is important to biopsy the muscle contralateral to the needle examination to avoid artifact from needle electromyography. Some clinicians use magnetic resonance imaging (MRI) and computed tomography (CT) imaging to help choose which muscle to biopsy. In our experience with adult patients, however, radiologic studies offer no benefit over the clinical and electrophysiologic examinations in determining the site of biopsy. The easiest muscle to biopsy, if clinically affected, is the biceps brachii. Other muscles that are commonly biopsied are the deltoid, triceps, and quadriceps. The peroneus brevis muscle is useful to biopsy along with the overlying superficial peroneal nerve in patients suspected of having vasculitis. We recommend avoiding the gastrocnemius muscle, if possible, because asymptomatic S1 radiculopathies or unrelated axonal polyneuropathies may give a false impression that the primary abnormality is a neurogenic process and therefore overshadow an underlying myopathy. Muscle biopsies usually are performed under local anesthesia except on very young children, who often need sedation. The biopsies should be taken with as little trauma as possible from the belly of the muscle and never from the tendinous insertion. Each specimen should be about 1 cm long and 0.5 cm wide. The specimens should be wrapped in moist gauze and placed in separate, labeled, sterile containers until they reach the laboratory. The laboratory should be notified before the surgery so that the tissue can be picked up directly from the operating room and processed immediately. A portion of the specimen is frozen for microscopy. We recommend obtaining two separate specimens for freezing and subsequent histochemistry because some processes can be multifocal. If patients complain of muscle pain, we recommend biopsy of a piece of the overlying fascia to look for evidence of fasciitis. Separate portions of the biopsy tissue are frozen in liquid nitrogen for biochemical analysis (e.g., for glycogen or lipid storage disorders, mitochondrial myopathies) as well as for Western blot or DNA analyses (e.g., in various forms of muscular dystrophy). The specimens for histochemistry are rapidly frozen in liquid nitrogen-cooled isopentane and carefully oriented to obtain transverse sections (or, if sufficient tissue is available, both transverse and longitudinal sections). Separate pieces of muscle are biopsied on a clamp or stretched out by suturing the muscle over a tongue blade to prevent the tissue from contracting. (Hypercontraction produces artifacts that render interpretation difficult by both light and electron microscopy.) This tissue is fixed in formalin for paraffin embedding and in glutaraldehyde and paraformaldehyde for plastic (resin) embedding for electron microscopy. Paraffin embedding allows the examination of a somewhat larger piece of tissue than that used for histochemistry and is especially useful in evaluating inflammatory

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Principles of Ambulatory Neurology and the Approach to Clinical Problems W

myopathies, vasculitides, and disorders that involve the connective tissue sheaths of muscle. The light microscopic evaluation of frozen sections stained with hematoxylin and eosin (H&E) and modified Gomori trichrome (GT) stains assesses the size, shape, and fiber type distribution of the muscle fibers and the supporting connective tissue and vasculature. Inflammatory and dystrophic changes are easily demonstrated with these stains. In addition, some specific abnormalities are well demonstrated with GT (e.g., ragged red fibers associated with mitochondrial myopathies, nemaline rods). Frozen sections are also processed with a panel of histochemical stains. Myofibrillar adenosine triphosphatase (ATPase) stains at alkaline and acid pH are used to distinguish the different muscle fiber types that are distributed randomly under normal circumstances (checkerboard pattern). Alterations of this random distribution occur when there is a clustering of fibers of the same histochemical type (fiber type grouping and group atrophy); these abnormalities indicate neurogenic processes. Specific histochemical reactions are used to evaluate glycogen content (periodic acid-Schiff [PAS] stain) and lipid (oil red 0 and Sudan black); these stains also allow fiber type discrimination. Oxidative enzyme stains (nicotinamide adenine dinucleotide [NADH] dehydrogenase, succinate dehydrogenase [ SDH], and cytochrome-c oxidase [COX]) are useful for identifying mitochondrial and intermyofibrillar network abnormalities. Loss of some enzyme activities associated with metabolic myopathies can be detected by specific staining protocols (e.g., myophosphorylase, phosphofructokinase, or myoadenylate deaminase). Amyloid deposition can be detected using Congo red, crystal violet, or immunostaining. Immunostaining techniques are of utmost importance in diagnosing specific muscular dystrophies (e.g., dystrophin staining for Duchenne and Becker muscular dystrophy, merosin staining for congenital muscular dystrophy, sarcoglycans and dysferlin for limb girdle muscular dystrophies, emerin for Emery-Dreifuss muscular dystrophy). Immunostaining is also useful in diagnosing inflammatory myopathies and vasculitis (e.g., stains for complement, membrane attack complex, immunoglobulins, appropriate lymphocyte markers). Electron microscopy evaluates the ultrastructural components of muscle fibers. Organelles have distinctive appearances in normal muscle tissue. In disease states, these organelles and membrane subcomponents show altered morphology. Although ultrastructural alterations in injured muscle often are not disease specific, significant insight into the pathogenesis of neuromuscular disorders has been gained using the combination of both light and electron microscopy. STRUCTURE OF NORMAL SKELETAL MUSCLE Skeletal muscles are composed of individual muscle fibers, which are multinucleated syncytia derived from numerous cells. The nuclei normally are located just beneath the plasma membrane (sarcolemma);they are slender, oval, and oriented parallel to the length of the fiber with evenly distributed chromatin and inconspicuous nucleoli. Internal nuclei are estimated to be found in no more than about 3% of normal adult fibers; they are more common in some pathologic conditions. Satellite cells, a reserve cell population, are located adjacent to the sarcolemma and are covered by basement membrane that encircles the entire muscle fiber. Almost the entire cytoplasm of the muscle fiber is filled with myofilaments, which form the contractile apparatus. A myofibril is

Principles of Diagnosis: Special Tests

composed of identical repeating units (sarcomeres) of interlaced, longitudinally directed thin filaments and thick filaments and perpendicularly disposed Z-bands. The T-tubule system, involved in calcium release during excitation, is an invagination of the sarcolemmal membrane into the interior of the cell that courses parallel to the Z-bands accompanied on each side by smooth endoplasmic reticulum. The adult muscle fiber is polygonal on transverse section; in infancy, fibers tend to be round, as are those of the extrinsic eye muscles and some facial and pharyngeal muscles in adults. The cross-sectional diameter of individual fibers varies depending on the specific muscle and its functional status. The functional unit of a muscle is a motor unit, which consists of multiple muscle fibers innervated by a single motor neuron. The number of fibers in a motor unit depends on the particular muscle being studied and on certain pathologic processes. The individual muscle fibers of a motor unit are randomly distributed throughout the cross-section of a normal muscle; this pattern is altered in some disease states. Two major types of fibers (type 1 and type 2) are recognized in muscle biopsies, and these correspond to some extent to the general physiologic subclassificationsof skeletal muscle cells (Fig. 24-1A and Table 24-1). Type 1 fibers are high in myoglobin, lipid stores, and oxidative enzymes and have many mitochondria; these features are consistent with their ability to perform tonic contraction. They stain dark with ATPase at pH 4.2 and light at pH 9.4. Type 2 fibers are rich in glycolytic enzymes and glycogen and are involved in rapid phasic contractions; they stain dark with ATPase at pH 9.4 and light at pH 4.2. The innervating motor neuron determines the type of an individual fiber; therefore, all fibers within a single motor unit are of the same type. Because these fibers are distributed randomly across the muscle, normal muscle shows a checkerboard pattern of alternating light and dark fibers, as demonstrated with ATPase and other of stains that distinguish fiber types. There is much variability in the relative abundance of type 1 and type 2 fiber types among different muscles. Muscle spindles are fusiform structures that respond to stretch in muscles and therefore have a role in maintaining tone. They consist of specialized muscle fibers (intrafusal fibers) and nerve fibers delimited by a multilayered connective tissue capsule. The connective tissue sheath of muscles include the endomysium, which surrounds individual muscle fibers; the perimysium, which groups muscle fibers into primary and secondary bundles (fasciculi); and the epimysium, which envelops single muscles or large groups of fibers.

W TABLE24-1.

Muscle Fiber Types

Characteristic

Twe 1

W e2

Action

Sustained force Weight-bearing NADH: dark staining ATPase pH 4.2: dark staining ATPase pH 9.4: light staining Abundant Scant Many mitochondria Wide Z-band Slow twitch Red Soleus (pigeon)

Sudden movements Purposeful motion NADH: light staining ATPase pH 4.2: light staining ATPase pH 9.4: dark staining Scant Abundant Few mitochondria Narrow Z-band Fast twitch White Pectoral (pigeon)

Enzyme content

Lipids Glycogen Ultrastructure Physiology Color Prototype

Chapter 24

REACTIONS TO INJURY

Muscle diseases are classified on histopathologic and etiologic grounds into three major categories: Neurogenic (denervation) atrophy: a pattern of muscle pathology resulting from interruption of innervation. Myopathies: inherited and acquired diseases characterized by abnormalities in the muscle fiber itself; they include dystrophies, congenital myopathies, inflammatory myopathies, metabolic myopathies, and toxic myopathies. Disorders of the neuromuscular junction: a small group of disorders in which the abnormality is limited to the neuromuscular junction; patients with these disorders have minimal structural alterations and are rarely biopsied. When axonal degeneration occurs, the muscle fibers within that motor unit lose their neural input and undergo denervation atrophy. Denervation of muscle leads to downregulation of myosin and actin synthesis, a resorption of myofibrils, and a decrease in the cell size while allowing the cell to survive. In cross-section, the atrophic fibers are smaller than normal and have a roughly triangular shape (angulated). There is also cytoskeletal reorganization of some muscle cells, which results in a rounded central zone of disorganized filaments (target fibers, best seen on NADH dehydrogenase staining). Reinnervation of muscle fibers may precede the regeneration of motor axons. Surviving axons from intact motor units can extend sprouts that will reinnervate the neighboring denervated muscle fibers. These newly incorporated muscle fibers assume the fiber type of their new parent motor unit. A group of adjoining fibers of the same histochemical type forms (fiber type grouping, Fig. 24-1B), and the normal checkerboard pattern of alternating light and dark fibers is lost. In chronic denervation, when these groups are denervated there is atrophy of the fibers of the type group (group atrophy, Fig. 24-1C). To be confident of the presence of

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fiber type grouping, we look for fibers of a given type entirely surrounded by fibers of the same histochemical type. In contrast to neurogenic atrophy, myopathic changes are abnormalities of the muscle fibers found in primary disorders of the muscle cell itself and represent a wide spectrum of histopathologic alterations. They include changes that result in fiber destruction with consequent regeneration and structural changes not leading directly to cell death but associated with fiber dysfunction. Segmental necrosis, destruction of a portion of a myocyte (Fig. 24-2A), can be followed by myophagocytosis as macrophages infiltrate the region. Myophagocytosis of necrotic muscle fibers is characteristic, though not pathognomonic, of inflammatory myopathies, but it may be a prominent component of any disorder with destruction of muscle fibers, such as toxic myopathies or dystrophies. Regeneration occurs as the peripherally located satellite cells proliferate and reconstitute the destroyed portion of the fiber. The regenerating muscle fiber has large internalized nuclei with prominent nucleoli, and the cytoplasm, laden with RNA, becomes basophilic. Other characteristics of myopathic injury include vacuolation, alterations in structural proteins or organelles, and accumulation of intracytoplasmic deposits (Fig. 24-2B). Whatever the cause, the loss of fibers observed in the end stages of severely or chronically injured muscle is associated with widespread interstitial deposition of collagen and fatty infiltration. Consequently, because it becomes impossible to determine the cause of the neuromuscular illness when studying end-stage muscle, it is crucial to avoid biopsy of clinically severely affected muscles. Individual myofiber hypertrophy occurs in response to increased load, either in the setting of exercise or in pathologic conditions in which other muscle fibers are injured. Large fibers may divide along a segment (muscle fiber splitting) so that, in cross-section, a single large fiber contains a cell membrane traversing its diameter, often with adjacent nuclei. The general category of diseases considered to be dystrophies

A0

C

FIG. 24-1. (A) Normal muscle showing checkerboard pattern of type 1 and type 2 fibers (ATPase enzyme histochemistry on frozen sections). (B) Denervation and reinnervation showing clustering of fibers of the same histochemical type and loss of checkerboard pattern (ATPase enzyme histochemistry on frozen sections). (C) End-stage denervation showing grouping of atrophic fibers (hematoxylin and eosin).

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Principles of Ambulatory Neurology and the Approach to Clinical Problems rn Principles of Diagnosis: Special Tests

A

B

FIG. 24-2. (A) Longitudinal section of paraffin-embedded muscle showing muscle fiber necrosis (hematoxylin and eosin). (6)Transverse section of paraffin-embedded muscle showing inflammatory infiltrates.

share some pathologic features while having widely varying clinical and genetic patterns. Overall, dystrophies are marked by the presence of degenerating and regenerating fibers, with the presence of variable amounts of inflammation and fibrosis. Although certain dystrophies have typical ancillary pathologic features (e.g., internalized nuclei in myotonic dystrophy, prominent inflammation in limb girdle dystrophies), the core of current diagnostic evaluation includes the use of immunostaining to evaluate for specific protein deficiencies as well as genetic assessment. Other types of structural alterations in the muscle fibers are seen in various disorders. These include those seen in the congenital myopathies, in which a variety of abnormalities in myofilament or organelle structure are evident, particularly by

electron microscopy. In the mitochondrial myopathies, there are alterations in mitochondrial organization, internal structure with the presence of paracrystalline inclusions, and number. Among the metabolic myopathies, lipid storage myopathies demonstrate abnormally numerous and misshapen lipid droplets, and certain metabolic myopathies show subsarcolemmal and intracytoplasmic vacuoles. Type-specific atrophy of muscle fibers occurs in a number of conditions. For example, type 2 fiber atrophy is seen in association with inactivity or disuse in a variety of clinical settings and with steroid treatment, and it may therefore be superimposed on another underlying process in a patient suffering from muscle pain that has resulted in decreased physical activity. Type 1 muscle fiber atrophy is seen in myotonic dystrophy.

Chapter 24

NERVE BIOPSY The basic work-up scheme that we follow for assessing a peripheral nerve biopsy combines the following attributes: Etiologic basis of the disorder: Is the process acquired or hereditary? Topography of the injury: Is the peripheral nervous system diffusely (polyneuropathy) or focally (mononeuropathy, single or multiple) involved? Chronology of pathologic process: Does the disease follow an acute, subacute, or chronic course? Underlying pathologic process: What pattern of injury is present (axonal degeneration, segmental demyelination, infection, vascular injury, or other process)? As is true for muscle biopsies, the interpretation of a nerve biopsy entails correlation of histologic changes with clinical information including the results of electrophysiologicinvestigations. lndlcations for Nerve Biopsy

The indications for nerve biopsies are more limited than those for muscle biopsies. In many instances, although abnormalities are present on the biopsy, tlie pathologic findings do not help to distinguish one form of peripheral neuropathy from another beyond what was already apparent from clinical examination, laboratory testing, and nerve conduction studies. A further limiting fact is that the removal of a segment of sensory nerve ordinarily is followed by permanent numbness in the corresponding cutaneous distribution. There can also be significant neuropathic pain in the distribution of the nerve for several months and potential for growth of painful neuromas. Evaluating patients for amyloid neuropathy or vasculitic neuropathy is an important indication for performing a nerve biopsy. Patients with vasculitic neuropathy usually have multiple mononeuropathies, but over time, when multiple nerves become involved so as to affect overlapping territories of distribution, the neuropathy may appear generalized and symmetric. Both motor and sensory involvement should be apparent clinically and electrophysiologically. Other indications for nerve biopsy include possible infectious processes (e.g., leprosy), autoimmune inflammatory conditions (e.g., sarcoidosis, perineuritis), and tumor infiltration (e.g., lymphoma, leukemia). A nerve biopsy may be needed to diagnose hereditary neuropathy when DNA testing is not available or is negative (e.g., in congenital hypomyelinating or demyelinating neuropathy, Charcot-Marie-Tooth disease type 4, hereditary sensory and autonomic neuropathy, giant axonal neuropathy, or polyglucosan body neuropathy). Most importantly, nerve biopsy usually is not of significant value in the majority of patients with otherwise cryptogenic, predominantly sensory polyneuropathy. Techniques

The nerve chosen for biopsy should be involved, both by clinical criteria and by nerve conduction studies. The sural is the nerve that is most often biopsied. Biopsy of this nerve causes only a limited area of sensory loss on the lateral aspect of the ankle and foot. The superficial peroneal nerve is particularly useful to biopsy because the underlying peroneus brevis muscle also can be biopsied through the same incision site, thereby increasing the diagnostic yield in cases of vasculitis. Biopsy of the superficial

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peroneal nerve causes numbness of the dorsum of the foot. If only the upper extremities are involved, the superficial radial nerve can be biopsied; however, this causes numbness of the dorsum of the hand, which is problematic for most patients. Regardless of which nerve is biopsied, it must be remembered that sampling a single distal sensory nerve may not be representative of focal disease processes elsewhere in the peripheral nervous system, especially in processes with predominant motor involvement. Nerve biopsies are performed under local anesthesia in adults; general anesthesia often is needed to obtain an adequate specimen from children. The laboratory must be contacted before the surgery so that the tissue can be picked up directly from the operating room and processed immediately. Local anesthetic should be injected into the nerve just proximal to the site of transection. At least a 2- to 3-cm-long section of nerve should be excised. It is important not to flood the nerve itself with anesthetic, to handle it very gently in transit, and to wrap it in salinemoistened gauze. A frozen section may be needed to confirm that peripheral nerve is present because sclerotic veins may mimic nerves. The biopsy is divided into several portions so that different types of studies can be performed. A portion is rapidly frozen in mounting medium for immunofluorescence studies; these studies can reveal the deposition of immunoglobulins or other inflammatory markers such as complement or fibrinogen. A second small fragment is snap frozen in liquid nitrogen for potential biochemical studies in cases of suspected metabolic disorder. The remainder of the tissue (the bulk of it) is stretched delicately on a cardboard strip or kept isometric with a clamp and fixed in glutaraldehyde or other fixatives (e.g., Karnovsky's fixative). From this tissue, material is embedded in plastic and processed for toluidine blue-stained semithin sections (1 pm) and thin sections for electron microscopy. These sections give the greatest morphologic information about the integrity of axons and myelin sheaths. Quantitative morphometric methods can be useful in detecting alterations in populations of fiber types, especially if adequate control samples are available. Other portions of this fixed material may be used for nerve teasing. With this method, individual myelinated fibers are separated from the nerve fascicles and lightly stained, allowing examination of the integrity and thickness of the myelin sheath and revealing alterations in internode length. Finally, but very importantly, routine paraffin embedding is performed on a portion of the aldehyde-fixed biopsy. These preparations are most useful in the setting of inflammatory, infiltrative, or infectious diseases. Thus from a single sural nerve biopsy, a wide spectrum of studies can be performed.

Structure of Normal Nerve The principal structural component of peripheral nerve is the nerve fiber, an axon with its Schwann cells and myelin sheath (Fig. 24-3). A nerve consists of numerous fibers that are grouped into fascicles by connective tissue sheaths. Myelinated and unmyelinated nerve fibers are intermingled across the fascicle. In sural nerve, myelinated fibers range from 2 to about 15 pm in diameter and have a bimodal distribution. Small myelinated axons, which average 4 pm, are about twice as numerous as the larger size population, which average 11 pm. Axons are myelinated in segments (internodes) separated by nodes of Ranvier. A single Schwann cell supplies the myelin sheath for each internode. The thickness of the myelin sheath is directly proportional to the

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A

B

FIG. 24-5. (A) Transverse section of normal sural nerve showing densely packed myelinated fibers of varying sizes and rim of perineurial layers (plastic-embedded 1ym-thick section stained with toluidine blue). (B) Electron micrograph of a transverse section through the internodal region of a single normal myelinated fiber with surrounding Schwann cell (bottom right) and several unmyelinated fibers (top and left).

diameter of the axon, and the larger the axon diameter, the longer the internodal distance. Unmyelinated axons are more numerous than myelinated axons and range in size from 0.2 to 3 pm. They occur in groups of 5 to 20, each group enveloped by a single Schwann cell. Each axon is invested by a region of Schwann cell membrane but without the specialized differentiation to form myelin. Schwann cells, regardless of their association with myelinated or unmyelinated fibers, have pale oval nuclei with an even chromatin distribution and an elongated bipolar cell body. By electron microscopy, Schwann cells, unlike fibroblasts, have a basement membrane. Peripheral axons contain organelles and cytoskeletal structures, including microfilaments, neurofilaments, microtubules, mitochondria, vesicles, smooth endoplasmic reticulum, and lysosomes. Dense-cored and coated vesicles are located in the nerve terminals. Protein synthesis does not occur in the axon, and axoplasmic flow delivers proteins and other substances synthesized in the perikaryon down the axon. A retrograde transport system serves as a feedback to the cell body. The connective tissue sheaths of peripheral nerve include the epineurium, which encloses the entire nerve; the perineurium, a multilayered, concentric connective tissue sheath that encloses each fascicle; and the endoneurium, which surrounds individual nerve fibers. The nerve microenvironment is regulated by the perineurial barrier formed by the tight junctions between the perineurial cells, the blood-nerve barrier, and the nervecerebrospinal fluid (CSF) barrier. Endoneurial capillaries derived from the vasa nervorum form tight junctions and establish the blood-nerve barrier. The blood-nerve barrier has been found to be less competent within nerve roots, dorsal root ganglia, and autonomic ganglia. The nerve-CSF barrier is formed by the tight junctions between the cells that form the outer layer of the arachnoid membrane. These cells fuse with the perineurium of the

roots and cranial nerves as they leave the subarachnoid space, and the motor and sensory fibers that travel separately within anterior and posterior roots intermingle within the mixed sensorimotor nerves that exit the spinal canal. Readons to Injury

Although disease processes of many kinds with differing pathogenic mechanisms may affect the peripheral nervous system, there are essentially two principal reactions to injury: segmental demyelination and axonal degeneration. These pathologic processes can also occur in combination. Segmental demyelination is the morphologic expression of dysfunction of the Schwann cell or damage to the myelin sheath. Because these disease processes typically affect some Schwann cells while sparing others, the process is characteristically variable (segmental) along the length of the nerve. The disintegrating myelin is phagocytosed by Schwann cells and macrophages. The denuded axon segment provides a stimulus for remyelination, and cells within the endoneurium remyelinate it, forming new myelinated internodes that are shorter and thinner than normal, features that are best seen with teased nerve preparations. With sequential episodes of demyelination and remyelination, there is an accumulation of tiers of Schwann cell processes around the axons. On transverse sections, these appear as concentric skeins of cell cytoplasm surrounding the axon, called onion bulbs (Fig. 24-4). Axonal degeneration is characterized by primary destruction of the axon, with secondary disintegration of its myelin sheath (Fig. 24-5). The damage to the axon may be caused by a discrete, localized event (e.g., trauma, ischemia) or by an underlying abnormality of the neuron (neuronopathy) or its axon (axonopathy). When axonal degeneration occurs as the result of transection,

Chapter 24

the distal portion of the fiber undergoes an acute process of disintegration (called Wallerian degeneration) characterized by breakdown and phagocytosis of the axon and its myelin sheath into fragments forming small oval compartments (myelin ovoids). In the slowly evolving neuronoparhies or axonopathies, evidence of myelin breakdown is scant because only a few fibers are degenerating at any given time. The proximal stumps of axons that have degenerated may develop new growth cones, which grow along the course of the degenerated axon. The presence of multiple, closely aggregated, thinly myelinated, small-caliber axons can be recognized as evidence of regeneration; these are called a regenerating cluster. This regrowth of axons is a slow process, on the order of 1 to 2 mm/day. Despite its slow pace, axonal regeneration accounts for some of the potential for functional recovery after peripheral axonal injury. In addition to these forms of pathologic reaction, which are specific to nerve, biopsies can reveal evidence of disease processes similar to those found in other organ systems. Thus, amyloid deposition can be found within nerve (e.g., amyloidosis). Vasculitis can be evidenced by infiltration of vessel walls by inflammatory cells, typically associated with evidence of axonal loss. Infiltration of the nerve by neoplastic or inflammatory cells can also be recognized.

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SKIN BIOPSY An increasing number of investigative studies are being published

on the utility of skin biopsies in evaluating peripheral neuropathy. Skin biopsies are most useful in patients with small-fiber neuropathies. Nerve conduction studies assess only the conduction of large myelinated nerve fibers, so nerve conduction study results are normal in patients with pure small-fiber neuropathies. Intraepidermal nerve fibers arise entirely from the dorsal root ganglia and are believed to represent the terminals of C and A nociceptors. The density of these nerve fibers may be lower in patients with small-fiber neuropathies in whom nerve conduction studies and routine nerve biopsies often are normal. Thus, skin biopsies allow an objective measurement of abnormality in patients with mainly subjective symptoms. Furthermore, the ease of the technique and ability to perform serial skin biopsies (in a manner not possible for nerve biopsies) may help to define the natural history of various neuropathies and to monitor response of the neuropathy to therapy. For this type of study, a punch biopsy of the skin in an affected region is performed and fixed in formalin. Appropriate immunohistochemical staining for nerve markers (e.g., protein gene product [PGP] 9.5) in thick sections reveals the small intraepidermal fibers. Morphometric methods are used to assess the number

B

A

FIG. 14-4. (A) Chronic and repeated segmental demyelination and remyelination in hereditary onion bulb neuropathy (Charcot-Marie-Tooth). Note decrease in the number of myelinated fibers, increase in endoneurial connective tissue, and numerous onion bulbs. (6) Electron micrograph of onion bulb showing myelinated axon surrounded by overlapping Schwann cell processes alternating with collagen fibers.

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C

D

FIG. 24-5. (A) Longitudinal section of paraffin-embedded nerve showing breakdown of myelinated fiber (Woelke stain for myelin). (B) Electron micrograph of axonal degeneration. Note disappearance of myelin and accumulation of filaments and organelles in the axon. Normal myelin sheath is shown at top. (C) Nerve teasing: normal fiber stains intensely black at the internode; node of Ranvier is located at clear zone between the two internodes. (0) Nerve teasing: axonal degeneration characterized by irregular beading and fragmentation of the myelin sheath and axon.

Chapter 25

and complexity of these nerves through parameters such as the linear density (number of fibers per millimeter of biopsy) or total length of intraepidermal nerve fibers. Similarly, immunostaining for vasoactive intestinal polypeptide, substance P, or calcitonin gene-related proteins can be used to measure the density of sudomotor axons innervating sweat glands, piloerector nerves to hair follicles, and nerves to small arterioles.

SUGGESTED READINGS

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King R Atlas of Peripheral Nerve Pathology. Arnold, London, 1999 Mendell JR, Kissel JT, Cornblath DR Diagnosis and Management of Peripheral Nerve Disorders. Oxford, New York, 2001 Midroni G, Bilbao JM: Biopsy Diagnosis of Peripheral Neuropathy. Butterworth-Heinemann, Boston, 1995 Ouvrier RA, McLeod JG, Pollard JD: Peripheral Neuropathy in Childhood. Raven Press, New York, 1990 Richardson EP Jr, De Girolami U Pathology of the Peripheral Nerve. WB Saunders, Philadelphia, 1995 Victor M, Ropper AH (eds): Adams and Victor’s Principles of Neurology. 7th Ed. McGraw-Hill, New York, 2001

Skeletal Muscle Biopsy Adams RD, Denny-Brown D, Pearson CM: Diseases of Muscle. A Study in Pathology. 2nd Ed. Harper & Row, New York, 1962 Carpenter S, Karpati G Pathology of Skeletal Muscle. 2nd Ed. Oxford University Press, New York, 2001 Dubowitz V, Brooke MH: Muscle Biopsy: A Modern Approach. WB Saunders, Philadelphia, 1973 Engel AG, Franzini-Armstrong C (eds): Myology. Basic and Clinical. WB Saunders, Philadelphia, 1994

Newe Biopsy Bouche P, Vallat J-M. Neuropathies Pkriphkriques. Doin, Paris, 1992 Dyck PJ, Thomas PK, Griffin JW et al: Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Ferreire G, Denef J-F, Rodriguez J, Guzzetta F: Morphometric studies of normal sural nerves in children. Muscle Nerve 8:697-704, 1985 Graham D, Lantos P (eds): Greenfield’s Neuropathology. 7th Ed. Arnold, New York, 2002

SECTION

Skin Biopsy Herrman DN, Griffin JW, Hauer P et ak Intraepidermal nerve fiber density, sural nerve morphometry and electrodiagnosis in peripheral neuropathies. Neurology 53:1634-1640, 1999 Holland NR, Crawford TO, Hauer P et ak Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol M47-59, 1998 Holland NR, Stocks NR, Hauer P et ak Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 48:708-711, 1997 McArthur JC, Stocks EA, Hauer P et ak Intraepidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 55: 1513-1520, 1998 Periquet MI, Novak V, Collins MP et ak Painful sensory neuropathy: prospective evaluation of painful feet using electrodiagnosis and skin biopsy. Neurology 53:1641-1647, 1999

4

PRINCIPLES OF TREATMENT

25

Pharmacology of Commonly Used Drugs Steven K. Feske

This chapter provides basic information about some of the drugs that are commonly used to treat neurologic diseases. The discussions here are general and selective in an attempt to target certain issues that repeatedly arise in the use of these drugs. Indications and further information about the use of a drug in a specific disease can be found in later chapters.

THROMBOEMBOLIC DISEASE AntlplateletAgenb Aspirin. Acetylsalicylic acid is the ester of acetic and salicylic acids. It irreversibly inhibits cyclo-oxygenase, the enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and thromboxanes. The major product of this metabolic pathway in

platelets is thromboxane, which promotes platelet adhesion. Because the platelet does not have the machinery to resynthesize cyclo-oxygenase, aspirin renders a platelet permanently deficient in thromboxane and hence poorly adherent. The major product of this metabolic pathway in endothelial cells is prostacyclin, which inhibits platelet adhesion. After irreversible inhibition of its cyclo-oxygenase by aspirin, an endothelial cell can replenish it if left unexposed to further aspirin. Aspirin is readily absorbed by the gastrointestinal (GI) tract; biotransformation occurs mainly in the liver. Aspirin and its inactive metabolites are excreted in the urine; alkaline pH promotes excretion of free salicylate by trapping the ionized form in the urine. Initial studies on the effect of aspirin in transient ischemic attacks used 1300 mg/day. Because low dosages offer a possible theoretical advantage-irreversibly inhib-

Chapter 25

and complexity of these nerves through parameters such as the linear density (number of fibers per millimeter of biopsy) or total length of intraepidermal nerve fibers. Similarly, immunostaining for vasoactive intestinal polypeptide, substance P, or calcitonin gene-related proteins can be used to measure the density of sudomotor axons innervating sweat glands, piloerector nerves to hair follicles, and nerves to small arterioles.

SUGGESTED READINGS

H

Pharmacology of Commonly Used Drugs

225

King R Atlas of Peripheral Nerve Pathology. Arnold, London, 1999 Mendell JR, Kissel JT, Cornblath DR Diagnosis and Management of Peripheral Nerve Disorders. Oxford, New York, 2001 Midroni G, Bilbao JM: Biopsy Diagnosis of Peripheral Neuropathy. Butterworth-Heinemann, Boston, 1995 Ouvrier RA, McLeod JG, Pollard JD: Peripheral Neuropathy in Childhood. Raven Press, New York, 1990 Richardson EP Jr, De Girolami U Pathology of the Peripheral Nerve. WB Saunders, Philadelphia, 1995 Victor M, Ropper AH (eds): Adams and Victor’s Principles of Neurology. 7th Ed. McGraw-Hill, New York, 2001

Skeletal Muscle Biopsy Adams RD, Denny-Brown D, Pearson CM: Diseases of Muscle. A Study in Pathology. 2nd Ed. Harper & Row, New York, 1962 Carpenter S, Karpati G Pathology of Skeletal Muscle. 2nd Ed. Oxford University Press, New York, 2001 Dubowitz V, Brooke MH: Muscle Biopsy: A Modern Approach. WB Saunders, Philadelphia, 1973 Engel AG, Franzini-Armstrong C (eds): Myology. Basic and Clinical. WB Saunders, Philadelphia, 1994

Newe Biopsy Bouche P, Vallat J-M. Neuropathies Pkriphkriques. Doin, Paris, 1992 Dyck PJ, Thomas PK, Griffin JW et al: Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Ferreire G, Denef J-F, Rodriguez J, Guzzetta F: Morphometric studies of normal sural nerves in children. Muscle Nerve 8:697-704, 1985 Graham D, Lantos P (eds): Greenfield’s Neuropathology. 7th Ed. Arnold, New York, 2002

SECTION

Skin Biopsy Herrman DN, Griffin JW, Hauer P et ak Intraepidermal nerve fiber density, sural nerve morphometry and electrodiagnosis in peripheral neuropathies. Neurology 53:1634-1640, 1999 Holland NR, Crawford TO, Hauer P et ak Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol M47-59, 1998 Holland NR, Stocks NR, Hauer P et ak Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 48:708-711, 1997 McArthur JC, Stocks EA, Hauer P et ak Intraepidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 55: 1513-1520, 1998 Periquet MI, Novak V, Collins MP et ak Painful sensory neuropathy: prospective evaluation of painful feet using electrodiagnosis and skin biopsy. Neurology 53:1641-1647, 1999

4

PRINCIPLES OF TREATMENT

25

Pharmacology of Commonly Used Drugs Steven K. Feske

This chapter provides basic information about some of the drugs that are commonly used to treat neurologic diseases. The discussions here are general and selective in an attempt to target certain issues that repeatedly arise in the use of these drugs. Indications and further information about the use of a drug in a specific disease can be found in later chapters.

THROMBOEMBOLIC DISEASE AntlplateletAgenb Aspirin. Acetylsalicylic acid is the ester of acetic and salicylic acids. It irreversibly inhibits cyclo-oxygenase, the enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and thromboxanes. The major product of this metabolic pathway in

platelets is thromboxane, which promotes platelet adhesion. Because the platelet does not have the machinery to resynthesize cyclo-oxygenase, aspirin renders a platelet permanently deficient in thromboxane and hence poorly adherent. The major product of this metabolic pathway in endothelial cells is prostacyclin, which inhibits platelet adhesion. After irreversible inhibition of its cyclo-oxygenase by aspirin, an endothelial cell can replenish it if left unexposed to further aspirin. Aspirin is readily absorbed by the gastrointestinal (GI) tract; biotransformation occurs mainly in the liver. Aspirin and its inactive metabolites are excreted in the urine; alkaline pH promotes excretion of free salicylate by trapping the ionized form in the urine. Initial studies on the effect of aspirin in transient ischemic attacks used 1300 mg/day. Because low dosages offer a possible theoretical advantage-irreversibly inhib-

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Ptinaples of Ambulatory Neurology and the Approach to Clinical Problems

iting platelet adhesion while allowing a return of prostacyclin production by the endothelium-and surely lower side effects, later studies have tested smaller dosages. It is now most common to use 325 mg/day for antiplatelet therapy, and even lower dosages have been shown to have clinical antithrombotic effects. Some patients may derive benefit from higher dosages. Details concerning its use in preventing thromboembolic disease are discussed in Chapter 42. The major side effects are GI symptoms and erosion with bleeding and other abnormal bleeding secondary to platelet dysfunction. The former can be minimized by the use of enteric-coated preparations. The antithrombotic effect can be assayed by the bleeding time, which is prolonged by aspirin. Clopidogrel. Ticlopidine and clopidogrel are thienopyridine derivatives that inhibit adenosine diphosphate-induced platelet aggregation. The efficacy of ticlopidine in lowering the risk of vascular events was established in two large studies, the Canadian American Ticlopidine Study and the Ticlopidine Aspirin Stroke Study in 1989. However, serious side effects, such as neutropenia, rash, and diarrhea, limited its use. Clopidogrel is a similar agent that has gained popularity because of its low side effect profile. In the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, clopidogrel was compared with aspirin for effectiveness in reducing risk of vascular events in patients with ischemic stroke, myocardial infarction, and peripheral arterial disease. This study showed a small increment of benefit over aspirin for the clustered endpoint of ischemic stroke, myocardial infarction, and vascular death. Patients whose qualifying event was a stroke were more likely to have a stroke as their endpoint event, and for these patients, the effect of clopidogrel was equivalent to aspirin (with a nonsignificant trend in favor of clopidogrel). Clopidogrel did not cause excessive bleeding, neutropenia, diarrhea, or rash. Based on these data, clopidogrel 75 mg daily has been added to the armamentarium of antiplatelet agents. Because aspirin and clopidogrel inhibit platelet function by different mechanisms, it is possible that their combined use will provide an additive effect. This hypothesis has been tested for ischemic heart disease in the recent Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. In this trial, clustered cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and stroke) and myocardial infarction were less likely in patients receiving both aspirin and clopidogrel than in patients receiving aspirin alone; there was a trend in favor of stroke prevention. This benefit was achieved at the expense of a higher risk of major systemic hemorrhage. The ongoing Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial is comparing the benefit of a combination of clopidogrel and aspirin with clopidogrel alone in preventing cerebrovascular and cardiovascular events in patients after stroke or transient ischemic attack. Dipyridamole. The mechanism of dipyridamole’s antiplatelet action is not clear, but it has several effects that decrease platelet activation: inhibition of cyclic nucleotide phosphodiesterase and of uptake of adenosine. Several studies in the 1980s and early 1990s testing the effect of dipyridamole for secondary stroke prevention produced conflicting results. Although the European Stroke Prevention Study showed a benefit of combined aspirin and dipyridamole, earlier studies had failed to show a benefit of combined therapy over aspirin alone. In the European Stroke Prevention Study 2, a combination of aspirin 25 mg twice a day and extended-release dipyridamole 200 mg twice a day was compared with these dosages of aspirin or dipyridamole alone and with placebo. The combination reduced the risk of recurrent

Principles of Treatment

stroke by 23% (absolute risk reduction 3% in 24 months) compared with aspirin, 24% (absolute risk reduction 3.3%) compared with dipyridamole alone, and 37% (absolute 5.4) compared with placebo. There was a slight early excess of headaches in patients receiving dipyridamole. This study has been criticized as providing too low an aspirin dosage in the aspirin group, but aspirin has been shown to be effective at dosages lower than 50 mg daily. Based on these data, combination extended-release dipyridamole with aspirin has also been added to the available antiplatelet agents used for secondary stroke prevention. Anticoagulants Heparin. Heparin is a large mucopolysaccharide polymer of repeating D-glucosamine-L-iduronicacid and D-glucosamhe-Dglucuronic acid disaccharide units. Commercially available heparin contains varying proportions of these disaccharides in polymers of various lengths. Heparin works through its interaction with the naturally occurring anticoagulants antithrombin 111 (AT 111) and heparin cofactor 11. AT 111 is a serine protease inhibitor (see Chapter 18 and Fig. 18-1) that irreversibly binds to the activated clotting factors XIIa, XIa, IXa, Xa, IIa (thrombin), and XIIIa. This complex formation inactivates these factors, especially factors Xa and thrombin, and inhibits thrombus formation. Heparin greatly accelerates the reaction of AT I11 with these factors. Because of its large molecular size and polarity, it is poorly absorbed through the GI tract, and it does not readily cross the placenta. It must be given intravenously or subcutaneously. Heparin is transformed by the liver into inactive metabolites, which are eliminated in the urine. The half-life increases with increasing dosages, and during continuous infusion, a steady state may not be reached for more than 48 hours. Large thrombi, as in pulmonary embolism, increase the clearance, decrease the halflife, and increase the dosages needed to achieve a given degree of anticoagulation. Low-dose heparin for prophylaxis against deep vein thrombosis usually is given subcutaneously at 5000 U twice daily, and this dosage usually has little, if any, effect on the partial thromboplastin time (PTT). For prophylaxis after a stroke or transient ischemic attack, full heparin anticoagulation usually is given by an infusion of approximately 1000 U/hour. No loading or a low-loading dosage of 500-1000 U probably decreases the risk of reperfusion hemorrhage (see Chapter 42). The PTT is checked in 6 to 8 hours, and the infusion is adjusted to maintain a PTT of 2 to 2.5 times the control value (about 50 to 80). Daily PTT values are measured to maintain the desired degree of anticoagulation. The use of heparin for stroke prevention is discussed in Chapter 42. The most common adverse effect is hemorrhage. Higher PTT values and large loading dosages have been associated with a higher risk of intracerebral hemorrhage after ischemic stroke. Other side effects include hypersensitivity and thrombocytopenia; the latter generally is caused by heparin-induced platelet aggregation. A more severe thrombocytopenia can result from the formation of antiplatelet antibodies, which can occasionally cause heparin-induced thrombosis. Therefore, all patients receiving fullor low-dose heparin should have serial platelet counts. Low-Molecular-Weight Heparins. Low-molecular-weight heparins are derived from unfractionated heparin by a process that results in heterogenous molecules with molecular weights between 1000 and 5000. These are approximately one third the size of standard heparin. The lower-molecular-weight fragments greatly reduce the inactivation of thrombin by antithrombin 111 because the smaller molecules cannot bind thrombin. The ability of the

Chapter 25

low-molecular-weight heparins to inactivate factor Xa is retained because this reaction only requires binding to antithrombin 111. The nonspecific binding to plasma proteins is reduced, leading to greater uniformity and predictability of response to a given dosage. Binding of macrophages and endothelial cells is reduced, increasing the plasma half-life. The incidence of heparin-induced thrombocytopenia is decreased, probably because of reduced binding to platelets and platelet factor 4. The stimulus for the development of osteoporosis is decreased, possibly because of the reduced binding to osteoblasts and osteoclast activation. These properties result in a more predictable dose-therapeutic response relationship with fewer side effects. This predictability allows fixed dosing schedules rather than dosing based on a monitored bioassay as with standard unfractionated heparin. When monitoring is needed, because the major effect is to inactivate factor Xa with little antithrombin activity, antifactor Xa activity is measured rather than aPTT, which is usually not affected (see Chapter 18). Low-molecular-weight heparins are renally excreted, and dosages must be reduced in patients with renal insufficiency, Warfarin. Warfarin sodium is a congener of dicumarol, which acts by interfering with post-translational modification in the liver of the vitamin K-dependent clotting factors I1 (prothrombin), VII, IX,and X. It also decreases the activity of the vitamin K-dependent proteins C and S, which interact to inhibit thrombosis (Fig. 18-1). Warfarin is well absorbed after an oral dose. It is almost totally bound to albumin. It is metabolized by the hepatic microsomal enzymes to inactive products and excreted in urine and stool. The degradation half-lives of the affected clotting factors differ. They are approximately 6, 24, 40, and 60 hours for factors VII, IX,X, and 11, respectively. The earliest anticoagulant effect in 8 to 12 hours is caused by depletion of factor VII. The peak effect is delayed by 2 to 4 days after the peak serum concentration and is caused by the depletion of factors X and 11. Usual practice is to start with the expected maintenance dosage of 2 to 5 mg/day or to give a loading dosage of 10 mg/day for 2 to 3 days and then lower the dosage to 5 mg/day when the international normalized ratio (INR) begins to rise. The dosage can then be adjusted, usually to 2 to 10 mg/day to achieve the desired INR (see Chapter 18). Recent recommendations have simplified the therapeutic goals for INR prolongation to 2 to 3 for all indications, except embolic prophylaxis in patients with a mechanical heart valve. These issues are discussed in Chapter 42. Because of the delay of peak effect, a dose should be expected to prolong the INR maximally in 2 to 3 days. Prothrombin checks and dosage adjustments should take this delay into account. Approximately weekly checks of the prothrombin should be followed until a stable dosage is found. Thereafter, periodic checking, approximately monthly, must continue as long as the patient is taking the drug because various drugs and conditions can alter the effect of a given dosage. The major side effect is hemorrhage. Higher prothrombin values, the addition of aspirin, and a tendency to fall correlate with an increased risk. A transient procoagulant effect with resultant thrombosis can occur early in therapy. This is because protein C, like factor VII, has a short half-life and is depleted before factors X and 11. This uncompensated early depletion of protein C may also be responsible for the skin necrosis that can rarely follow warfarin use. To prevent these potential early complications, many authors recommend overlapping the heparin with warfarin for 2 to 3 days after a therapeutic INR is achieved in cases necessitating acute anticoagulation.Vitamin K deficiency, alcoholism, hepatic disease, and hypermetabolic states increase the anticoagulant response to warfarin. A high intake of vitamin K-rich vegetables such as

Pharmacologyof Commonly Used Drugs

227

TABU25-1. Warfarin Drug Interactions Drugs that may enhance the anticoagulant effect Alcohol Allopurinol Cephalosporins Cimetidine Clofibrate Disulfiram Ethacrynic acid fluoxetine Heparin Lovastatin MAOlS

Metronidazole Paroxetine Pentoxifyiline Phenytoin Quinidine, quinine Salicylates Sertraline Tamoxifen Thyroid supplements TMP-SMZ Drugs that may inhibit the anticoagulant effect Antacids Antihistamines Barbiturates Carbamazepine Cholestyramine Corticosteroids Clutethimide Criseofulvin Haloperidol Nafcillin Oral contraceptives Paraldehyde Primidone Rifampin Trazodone Vitamin C Abbreviations: MAOls, monoamine oxidase inhibitors; TMP-SMZ, trimethoprimsulfamethoxazole.

broccoli and spinach, pregnancy, nephrotic syndrome, hypometabolic states, and hereditary resistance decrease the anticoagulant response. Warfarin has important interactions with many other commonly used drugs (Table 25-1). IMMUNE FUNCIION Several corticosteroids are used for different indications in many neurologic diseases. Dexamethasone, methylprednisolone, and prednisone, the most common choices, are congeners of cortisol, the primary endogenous glucocorticoid. Dexamethasone is fluorinated, which increases its potency. Corticosteroids act by forming a complex with an intracytoplasmic receptor. This complex enters the nucleus, where it binds to chromatin and alters RNA transcription and ultimately protein synthesis. This general basic mechanism is responsible for the many effects of corticosteroids on function. These effects include the stabilization of the blood-brain barrier and a decrease in the production of vasogenic edema, an inhibition of the inflammatory and immune responses by multiple effects on lymphocytes, macrophages, and immunoglobulins, and a lyric effect on neoplasms, especially lymphomas and myelomas. Dexamethasone and methylprednisolone are available in oral and injectable forms, and prednisone is given orally. They are protein bound by a specific binding protein, transcortin, and, at pharmacologic dosages, more importantly by

228

Principles of Ambulatory Neurology and the Approach to Clinical Problems

albumin. Prednisone is inactive and must be converted to prednisolone to have its effect; this conversion occurs rapidly in the liver. The corticosteroids are further metabolized in the liver and other tissues and excreted primarily in the urine. The dosages vary greatly with the indication and response. Potency equivalencies are shown in Table 25-2. Recommended dosages of dexamethasone for brain edema are given in Chapter 156 and for spinal cord compression in Chapter 174. For acute spinal cord trauma, an infusion of methylprednisolone has been recommended (Bracken et al. 1990). For multiple sclerosis, methylprednisolone is often used, as discussed in Chapter 44. Various regimens and dosages are used for steroid-responsive neuromuscular diseases. Although it is not possible to recommend a single regimen for all indications, it is perhaps helpful to emphasize some of the general principles of the proper use of chronic corticosteroids and to give an example of a reasonable tapering schedule that can be used as a model from which to deviate based on the clinical circumstances. Table 25-3 gives a conservative schedule for the slow tapering of high-dose prednisone. Many patients may tolerate a more rapid taper, and some will not need a maintenance dosage. When relapses occur on such a tapering schedule, it is usually necessary to raise the dosage to a level higher than the prior one on which the patient was stable and to slowly work back to the lower dosage. Therefore, it behooves the physician to remain cautious during prednisone tapering to avoid such setbacks, which may significantly increase the time spent on high dosages of medication. The many side effects of corticosteroids are well known. Acutely in large dosages, they may cause sodium and water retention, elevated blood pressure, glucose intolerance, GI bleeding, and an agitated confusional state. Chronically, they cause all of these problems and more, including a cushingoid appearance, osteoporosis, avascular necrosis, acneform and atrophic skin changes, cataracts, type 11 muscle fiber atrophy, potassium depletion, and susceptibility to

Principles of Treatment

opportunistic infections. In general, prednisone is safe for short-term use in pregnancy, such as in Bell's palsy. By accelerating the hepatic metabolism of the corticosteroids, the anticonvulsants phenobarbital, phenytoin, and carbamazepine may increase the dosages necessary to achieve a given effect. To minimize the side effects and possibly to increase the therapeutic effect, the entire daily dosage of corticosteroid should be given in the morning, and alternate-day regimens should be used when possible. All patients on chronic dosages should be counseled to follow a low-sodium, low-carbohydrate, high-protein diet and to avoid weight gain. Potassium should be supplemented by food choices or potassium chloride (KCI) supplements. H, blockers or antacids often are helpful to prevent GI side effects. Monitoring for the treatable side effects should be done with periodic urine or serum glucose measurements, serum K+, blood pressure, and stool hematests. To minimize osteoporosis, patients who are beginning a long-term course of corticosteroids should be given calcium and vitamin D supplements; postmenopausal women should consider hormonal replacement therapy, and all patients may benefit from weightbearing exercise. Bone mineral density should be followed, and some patients may benefit from more aggressive therapy with bisphosphonates or calcitonin. A detailed review of the prevention and treatment of steroid-induced osteoporosis has been published by the American College of Rheumatology (ACR Task Force 1996). When patients receiving chronic steroids become acutely ill, it is important to give them stress dosages of replacement corticosteroids (about 300 mg/day of cortisol or its equivalent) because the exogenous corticosteroids inhibit the hypothalamic-pituitaryadrenal axis. Patients with a history of tuberculosis or a positive PPD should receive isoniazid to prevent reactivation of tuberculosis. Pyridoxine 50 to 100 mg/day is given with isoniazid to prevent neuropathy.

Azathioprine W

TMLE 25-2. Relative Potencies and Equivalent Dosages

of Corticosteroids

Drug

Relative Antiinflammatory Potency

Equivalent Dosane l m d

1 4 5 25

20 5 4 0.75

Cortisol Prednisone Methylprednisolone Dexamethasone

Adapted from Haynes RC, Murad F: Adrenocorticotropichormone, p. 1475. In Cilman AC, Goodman LS, Rail MI: Goodman and Cilman's the PharmacologicalBasis of Therapeutics. Macmillan, New York 1985, with permission.

Azathioprine is a purine analogue, a derivative of mercaptopurine, that functions as an antimetabolite by virtue of its structural relationship to endogenous purines. Thus it decreases synthesis of adenine and guanine and hence of DNA. It impairs lymphocyte function and decreases the numbers of lymphocytes to cause its immunosuppressive effects. It is well absorbed orally and is also available for intravenous use. It is converted to 6-mercaptopurine and then to ribonucleotide thioinosinic acid, which is the active metabolite. This active metabolite and the unconverted azathioprine are converted to inactive metabolites in the liver and erythrocytes. Conversion by xanthine oxidase is one important pathway of inactivation. It is eliminated in the urine to an extent

TABU25-3. Slow Tapering Schedule for Alternate-Day Prednisone Treatment of Neuromuscular Diseasea High Day (mg)

low Day (mg)

Duration

100 100 100 100 100-70 70-40 40-20 15-10

100 100-1 0 10-0 0 0 0

3-4 wk 9 wk 2 wk 2-4 wk 18-24 wk 36-48 wk 8-16 mo Maintenance

Taper Method

Approximately 1 mg/kg daily starting dosage After 3-4 weeks, taper the alternate-day dosage by 10 mg/wk Slow the taper to 5 mg/wk for the last 2 weeks before stopping the alternate day's dose If no benefit by this time, consider alternative treatment Taper by 5 m g every 3-4 weeks Taper by 2.5 mg every 3-4 weeks months . TaDer bv 2.5 me everv 1-2~ 0 _ 0 e v e 4 3-4 months to 10-15 mg o n alternate days Taper b i 2.5 'Each day's dosage is given as a single morning dose. The starting dosage may be higher or lower, depending on the patienf's weight, The schedule tapers slowly, and a more rapid taper may be tolerated in many patients. Although many patients need a low maintenance dosage, some will be able to discontinuethe medication. Adapted from Dalakas M: Pharmacologic concerns of corticosteroids in the treatment of patientswith immune-related neuromusculardisordes, Neurol Clin 8:lOO. 1990, with permission.

mi

Chapter 25

adequate to cause accumulation in patients with renal insufficiency so that dosage reduction is necessary. In neuromuscular disease, it has been used largely for its steroid-sparing effects. That is, in patients needing large dosages of corticosteroids, its use may allow a reduction in the dosage of the steroids and thus in their side effects. The usual dosages are 1 to 3 mg/kg daily on a once- or twice-daily schedule. Onset of its therapeutic effect typically is delayed by 2 to 3 months. The major side effects are bone marrow suppression, with leukopenia and macrocytosis, and toxic hepatitis. Anemia, thrombocytopenia, and opportunistic infections are rare. Myelosuppression is dose-dependent and often reverses after reduction or temporary withdrawal of the drug. Other drugs that cause myelosuppression can potentiate this effect. Skin rash, GI complaints, and fever can also occur. Because it is metabolized by xanthine oxidase, the dosage must be markedly reduced (by about one fourth) when allopurinol is used at the same time. Periodic monitoring of complete blood count (CBC) and liver function tests is necessary throughout therapy.

Mycophenolate Mycophenolate mofetil is metabolized to mycophenolic acid, which inhibits purine synthesis by reversible inhibition of inosine monophosphate dehydrogenase. This is an enzyme in the de novo synthesis of guanine nucleotides. Because lymphocytes, unlike other cell lines, are dependent on the de novo synthetic pathway for purine synthesis, this effect selectively inhibits T- and B-lymphocyte proliferation and the formation of antibodies by B-lymphocytes. Mycophenolate has been shown to be effective in preventing transplanted organ rejection and other immunemediated diseases and, more recently, in the immunosuppressive therapy of neuromuscular disease, where it has been shown to promote functional improvement and steroid sparing. The usual dosage is 1 g twice daily. Occasionally, dosage reduction may be needed to minimize side effects. The major side effects are leukopenia and susceptibility to opportunistic infections; it may also cause diarrhea, abdominal pain, and nausea. It is thought to confer a lower risk of late malignancies than azathioprine and cyclophosphamide.

Cyclophosphamideis a nitrogen mustard alkylating agent. It binds to DNA, causing cross-linking. This disrupts cell division and other cell functions and is responsible for its cytotoxic effect. It decreases the production of anti-GM, antibodies in patients with multifocal motor neuropathy. It is well absorbed orally and is also available for intravenous use. It undergoes metabolic activation by hepatic microsomal enzymes. Inactivation also occurs in the liver. Inactive metabolites and unchanged drug are excreted by the kidney. It has found several uses in neurologic patients, including some cases of chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and isolated angiitis of the central nervous system (CNS). Some practitioners use it to treat multiple sclerosis. Many approaches to intravenous and oral treatment are taken. Several of these are discussed in the following chapters on specific diseases. For daily oral dosing, the usual starting dosage is a single 50-mg pill daily. This dosage can be increased by 50 mg/day every 3 to 4 weeks, if side effects allow, to the usual maintenance dosage of 100 to 150 mg daily (2 to 3 mg/kg/day). The dosage must be adjusted based on the white

Pharmacology of Commonly Used Drugs

229

blood cell (WBC) count. A usual approach is to follow the CBC weekly and maintain the WBC count between 3000 and 4000/mm3 and the ANC above 1500/mm3. (Occasionally, the desired therapeutic effect is achieved without leukopenia.) When counts fall below these levels, the medication should be held until the counts rise and then restarted at a lower dosage. The major side effects result from its cytotoxicity. Myelosuppression always occurs and must be closely followed. Nausea, vomiting, and alopecia may occur. The nausea and vomiting can be assuaged by taking the medication with meals or cold foods, although this may decrease absorption. Hemorrhagic cystitis results from contact of the toxic metabolite acrolein with the bladder mucosa. This risk can be diminished by maintaining increased urine flow with adequate fluid intake, but care must be taken to avoid water intoxication because cyclophosphamide can also promote renal water retention. If evidence of cystitis is found, the drug should be discontinued immediately. Infertility occurs in both men and women after exposure. Men may want to arrange for cryopreservation of sperm before treatment. Cyclophosphamide induces the potential to develop later malignancies, especially leukemia, lymphoma, and urologic carcinomas. This risk is thought to be significant after cumulative dosages exceeding 85 g, so it is important to maintain cumulative dosage records. Uncommon side effects include hepatotoxicity,pulmonary fibrosis, and opportunistic infections. In addition to the monitoring of CBCs mentioned earlier, urine analysis for evidence of hemorrhagic cystitis, urine cytologies for evidence of malignancy, and liver function tests should be followed periodically while the medication is in use.

Intravenous Immunoglobulin Human immunoglobulin is a pooled product of plasma containing a high concentration of y-globulins. Plasma is screened for alanine aminotransferase elevation and reactivity to hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus (HCV), anti-HCV, human immunodeficiency virus (HIV), and human T-cell lymphomdleukemia virus I before pooling. The product undergoes a fractionation process that decreases the viral burden. Some manufacturers have introduced an additional solvent detergent step to ensure further viral inactivation. The mechanism of action in autoimmune disease is not known. Possible mechanisms include downregulation of autoantibody production and the introduction of anti-idiotype antibodies in the foreign immunoglobulin. These large proteins must be administered intravenously. During the first week the levels fall as the immunoglobulins are redistributed between the intravascular and extravascular compartments. The elimination half-life is about 3 weeks but varies significantly between individuals. It has been given for various neuromuscular diseases with a proven or presumed immune pathogenesis, especially the Guillain-Barrk syndrome and myasthenia gravis. The dosage used by the Dutch Guillain-Barrk Study Group was 0.4 g/kg daily for 5 days. The past experience and indications for it in neurologic disease are discussed in Chapters 92, 103, and 205. Fever, chills, headache, urticaria, flushing, nausea, vomiting, chest tightness, shortness of breath, abdominal pain, arthralgias, and myalgias may be related to the infusion rate. Acute renal failure is an uncommon severe side effect. If the side effects are mild, the infusion can be halted temporarily and resumed after symptoms subside. Prophylaxis with aspirin, acetaminophen, and diphenhydramine may also be

250

Pnnciples of Ambulatory Neurology and the Approach to Clinical Problems W

Principles of Treatment

given. Those with IgA deficiency and known antibodies to IgA and those with a history of anaphylaxis or other severe reactions to intravenous immunoglobulins should not receive them. No cases of immunoglobulin-associated hepatitis B virus or HIV infection have been reported after widespread use. There have been some reported cases of associated HCV infection, although this risk is very low.

cited study. No differences in depression or suicide risk were found in this study. In animals given dosages higher than those used in the study, an abortifacient effect was found, and as with IFN-Plb, pregnant women are advised to discontinue therapy. Because of general risk with interferons, it is wise to monitor CBC, platelets, and liver function studies periodically during therapy.

Interferon-p,,

Glatiramer Acetate

Interferon-plb (IFN-P,b) is a serine-substituted, nonglycosylated recombinant IFN-P, an immunoregulatory cytokine. Its precise mechanism of action is not known; however, it seems to stimulate T-suppressor cell function, which is decreased in patients with progressive multiple sclerosis, to decrease T-helper activation, to inhibit the IFN-y-induced expression of class I1 major histocompatibility complex antigens on antigen-presenting cells, and to decrease production of IFN-y, which increases the T-cell-mediated inflammatory response in multiple sclerosis and promotes exacerbations. The Multiple Sclerosis Study Group compared placebo with 1.6 million international units (MIU) and 8 MIU every other day and found that IFN-Plb decreased exacerbation rates in relapsing-remitting multiple sclerosis in a dose-dependent manner at 2 and 3 years. At higher dosages it increased the number of patients who remained exacerbation-free for 2 years. The study showed no effect on disability scores in the 3 years of follow-up. Magnetic resonance imaging also showed fewer active scans, fewer new lesions, and a reduced burden of disease in the group receiving the higher dosage. IFN-Plb is approved for treating ambulatory patients with relapsing-remitting multiple sclerosis. The drug is given at a dosage of 8 MIU subcutaneously every other day. The major side effects include flulike symptoms, such as fever, chills, sweating, and myalgias, and inflammatory reactions at the injection site. Depression and suicidal ideation are possible side effects. One suicide and four suicide attempts occurred in the treatment groups (249 patients) in the cited study. It may have an abortifacient effect, and patients should be warned of this. Rarely there may be a reversible decrease in blood counts or an increase in liver function test results. It is recommended that the CBC, platelets, and liver functions be monitored periodically.

Glatiramer acetate (copolymer 1) is the acetate salt of the synthetic polypeptides of the four naturally occurring amino acids, L-alanine, L-glutamic acid, L-lysine, and L-tyrosine. It inhibits the cell-mediated immune response to myelin basic protein and possibly to other myelin antigens by a mechanism that has not been fully elucidated. It has been shown to inhibit T-cell activation. It is likely that cross-reactivity with myelin basic protein allows competition with myelin basic protein (MBP) for the major histocompatibility class I1 binding site responsible for antigen presentation. There is also limited evidence that it promotes the induction of antigen-specific suppressor cells. In a large clinical trial, patients with relapsing-remitting multiple sclerosis given glatiramer acetate 20 mg subcutaneously daily for 24 months had fewer relapses and better performance on disability rating scales than patients given placebo (Johnson et al. 1995). This effect was maintained in an extension of this study for 1 to 11 months. In a study of patients with chronic progressive multiple sclerosis, its effect showed only nonsignificant trends in favor of therapy (Bornstein et al. 1991). Glatiramer acetate is well tolerated. The most common side effect is local irritation at the injection site. Some patients develop an occasional systemic reaction characterized by flushing, chest tightness, palpitations, anxiety, and dyspnea. This reaction typically is brief, 30 seconds to 30 minutes, and self-limited. Based on these data, glatiramer acetate has been approved for use in patients with relapsing-remitting multiple sclerosis.

ACETYLCHOLINESTERASE INHIBITORS Table 25-4 summarizes information on acetylcholinesterase inhibitors.

Interferon-p, IFN-PI, is a natural human sequence, glycosylated recombinant IFN-P. Its precise mechanism of action is not known, but IFN-P clearly has favorable immunoregulatory effects. Like IFN-P,b, it appears to augment nonspecific suppressor T-cell function, to decrease T-helper activation, to inhibit interferon-y-induced class I1 major histocompatibility complex expression on antigenpresenting cells, to inhibit secretion of IFNy, and to induce interleukin- 10 gene transcription. In a large controlled trial (Jacobs et al. 1996) patients treated with 6.0 million units (30 pg) weekly intramuscularly for up to 2 years were compared with untreated patients. Treated patients accumulated less disability and had fewer exacerbations, and had fewer and a lower volume of gadolinium-enhancing lesions on magnetic resonance imaging, suggesting less disease activity. IFN-P,, is approved for use in patients with relapsing-remitting multiple sclerosis. It is given at a dosage of 30 pg (6 million units) intramuscularly once a week. As with other interferons, the major side effects are headache and flulike symptoms. These symptoms were mild and transient in the

Edrophonium is a rapid-onset, short-acting acetylcholinesterase inhibitor because of its reversible binding to acetylcholinesterase and its rapid elimination by the kidney. Its onset of action usually is within 30 seconds to 1 minute, and the effect lasts less than 10 minutes. It comes in vials of 1 mL containing 10 mg of medication. A test dose of 1 to 2 mg (0.1 to 0.2 mL) is given over about 30 seconds. If no adverse reaction occurs, the remaining 8 mg can be injected. Seybold (1986) and Daroff (1986) suggest a modified test with smaller incremental increases in the dosage. It is helpful to pretreat with 0.5 to 1.0 mg of intravenous atropine to prevent the muscarinic side effects. In addition to relieving discomfort, this helps to preserve patient blinding. The most important side effects are bradycardia and bronchospasm, and the testing physician must be prepared to respond with atropine and resuscitative measures to these problems should they arise. Caution should be taken in older adults. Patients with heart disease who might be expected to be sensitive to the cholinergic

Chapter 25

rn Pharmacology of Commonly Used Drugs

231

TABLE25-4. Acetylcholinesterase inhibitors D w

Route of Administration

Onset of Action Duration of Action

Edrophonium

IV

Neostigmine methylsulfate

IV SQ IM

Pyridostigmine bromide

IV SQ IM

Pyridostigmine bromide

PO

Neostigmine bromide

PO

20-30 s 2-4 min 20-30 min (IM)/ 2.5-4 h Rapid (minutes) 2-3 h 10-30 min 3.5-4.5 h 10-20 min

Dosage

Equivalence to Oral Pyridostigmine

2-1 0 mg 0.5 mg

120

2.0 mg

30

30- 1 20 mg

1

7.5-30 mg

4

3-4 h

Adapted from Johns TR: Summing up: the use of cholinesterase inhibitors. Semin Neurol 2:299, 1982, with permission.

effects on the heart and’patients with bronchospastic lung disease should not be tested with edrophonium.

The effect begins in 20 to 30 minutes, peaks in about 1 hour, and lasts for 3 to 4 hours. This provides a more prolonged period for diagnostic testing than does edrophonium.

Pyridostigmlne Pyridostigmine is a competitive inhibitor of acetylcholinesterase. It is a close congener of neostigmine, with fewer side effects, and has become the major anticholinesterase used for therapy in myasthenia gravis. It is available for oral and parented use. The usual starting dosage is 30 mg every 4 to 6 hours, with doses timed to achieve the greatest benefit at times of greatest need, such as 30 minutes before meals in patients with oropharyngeal weakness. The dosage is adjusted according to the symptoms. Most patients achieve maximum benefit at a dosage of 30 to 120 mg every 4 hours. Occasionally lower or higher dosages are necessary. To achieve the maximum benefit while minimizing the risk of overdose, it is best to keep the dosage low enough so that a definite improvement is detectable 30 to 45 minutes after a dose and there is some wearing-off effect before the next dose. Many patients can tolerate daytime-only dosing. For patients who have respiratory symptoms in the morning, extended-release tablets are available. These tablets can be broken into halves or fourths to titrate the dosage without sacrificing the delayed absorption. Absorption is erratic, however, and this preparation usually is not recommended for daytime use. Most side effects result from the increased effect at cholinergic receptors in the CNS, at smooth muscle, and at autonomic glands. Abdominal cramps, nausea, vomiting, and diarrhea are most common. Increased bronchial and oral secretions and wheezing occur less commonly and should warn the physician of possible cholinergic overdose. Loperamide, propantheline, glycopyrrolate, or diphenoxylatewith atropine can be used to minimize these side effects, but if the side effects are severe enough to necessitate their frequent use, treatments other than cholinesteraseinhibitors may be preferable. Enhanced vagal effects on the heart are uncommon, except with intravenous acetylcholinesterase inhibitors.

Neostigmine Like pyridostigmine, neostigmine is a competitive inhibitor of acetylcholinesterase. It is also available for oral and parented use. It has therapeutic and side effects similar to those of pyridostigmine, and because it may have a slightly higher incidence of side effects, its use has been largely replaced by pyridostigmine. An intramuscular injection of neostigmine has also been used as a diagnostic test. Neostigmine 0.04 mg/kg is given intramuscularly.

ANTIPARKINSON AGENTS Levodopa and Carbidopa Levodopa, an aromatic amino acid, is the metabolic precursor of dopamine. Carbidopa is an inhibitor of the aromatic amino acid decarboxylase, the enzyme that converts levodopa to dopamine. Dopamine does not cross the blood-brain barrier, so it is ineffective when given to patients with Parkinson’s disease. Levodopa does cross the blood-brain barrier and can be converted to dopamine in the striatum. However, levodopa is converted rapidly to dopamine by extracerebral tissues when given orally, necessitating large dosages and their attendant side effects to achieve significant CNS effects. Because carbidopa does not cross the blood-brain barrier, it prevents peripheral conversion to dopamine and thus allows more levodopa to enter the CNS at lower dosages and with fewer side effects. In the striatum levodopa must be taken up into the terminals of nigrostriatal neurons and decarboxylated to dopamine, which is then stored and released. Levodopa competes with other amino acids for absorption in the GI tract. Therefore, a high protein diet may significantlyimpair its absorption. It is excreted in the urine as dopamine and unconverted levodopa. The clinical use of levodopa-carbidopa is complex; this is discussed in Chapters 114-1 16. The major side effects are abnormal involuntary movements, confusion and other mental changes, and nausea and other GI symptoms. Early in Parkinson’s disease, the involuntary movements usually occur only at supratherapeutic dosages, whereas late in the disease, the abnormal movements may occur at the dosages needed for the therapeutic effect. Abrupt discontinuance of levodopa can result in a syndrome of severe muscle rigidity, fever, and elevated creatine kinase that resembles the neuroleptic malignant syndrome. The major drug interaction is with nonselective monoamine oxidase (MAO) inhibitors, and these drugs should not be given together. However, it is often given safely with the selective MAO-B inhibitor selegiline.

Selegiline Selegiline, L-deprenyl, is an irreversible MA0 inhibitor (MAOI). When given at the low dosages typically used for Parkinson’s disease, it is selective for MA0 type B, which is the primary MA0 in the brain that catalyzes the breakdown of catecholamine

232

Principles of Ambulatory Neurologyand the Approach to Clinical Problems

neurotransmitters. Selegiline may ameliorate symptoms of Parkinson’s disease by inhibiting the catabolism of striatal dopamine and therefore increasing the dopamine available to postsynaptic receptors. It has been hypothesized that it may also have a protective effect, that by decreasing oxidative catabolic reactions in the striatum, it may inhibit the generation of neurotoxic free radicals. This pathogenetic hypothesis for Parkinson’s disease has not been proven. The clinical effectiveness of selegiline for neuroprotection has been addressed by the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study (Parkinson Study Group 1989). The analysis for evidence of a neuroprotective effect was confounded by selegiline’s beneficial effect on parkinsonian symptoms. After absorption in the GI tract, selegiline is rapidly converted to the active metabolites N-desmethyldeprenyl, amphetamine, and methamphetamine. These metabolites have different half-lives and are excreted in the urine over several days. The usual dosage is 5 mg twice daily. The major side effects are the potential drug interactions. Because MA0 type A is the subtype primarily responsible for detoxifymg exogenous vasoactive amines as they enter the system through the GI tract, low dosages of selegiline usually do not lead to a hypertensive reaction to amine-containing foods, so at these dosages it is not necessary to enforce dietary restrictions as with nonselective MAOIs. However, at higher dosages the selectivity can be lost, and hypertensive crises can occur as with other MAOIs. Severe toxicity with stupor or agitation, fever, and rigidity have been reported when selegiline has been given with meperidine, as with meperidine and other MAOIs. Similar reactions may also occur when used in combination with fluoxetine and other serotonin reuptake inhibitors. Dopamine Agonists Bromocriptine. Bromocriptine is an ergot alkaloid derivative. It is a selective D, dopamine receptor agonist with mild D, antagonist effects. These effects confer symptomatic relief in some patients with parkinsonism. It is rapidly absorbed in the GI tract. It undergoes extensive first-pass conversion in the liver and is excreted largely in the bile and stool. The dosages are based on the clinical response. To minimize side effects, it should be started at low dosages of about 1.25 to 2.5 mg daily. The dosage is raised slowly, by about 1.25 mg each week, until the desired effect is achieved or side effects emerge. The usual dosages are in the range of 2.5 to 25 mg daily in divided doses. Higher dosages sometimes are used. The major side effects are orthostatic hypotension, nausea, vomiting, hepatitis, dyskinesias, dizziness, and various behavioral problems, including agitation, confusion, hallucinations, and psychosis. Distal paresthesias, livedo reticularis, and angina pectoris may occur as a result of the ergot properties. The effect of dopamine agonists may be inhibited by dopamine blockers, such as neuroleptics. Their effect may be enhanced by MAOIs and monoamine reuptake inhibitors. Pergolide. Pergolide, also an ergot derivative, is a D, dopamine receptor agonist and a weak D, agonist. Its indications are similar to those of bromocriptine. It is well absorbed by the GI tract. Multiple metabolites, some active, are excreted in the urine. It is 10 to 20 times more potent than bromocriptine and has a longer half-life. It should be started at low dosages, about 0.05 mg daily. Because of the prolonged half-life, the dosage should be raised slowly, and as with bromocriptine, small (about 0.1 to 0.15 mg) dosage increases should be made at intervals of a week or

Principlesof Treatment

more. Usual dosages are 1 to 5 mg daily divided into three doses. The side effects and drug interactions are similar to those of bromocriptine. Hepatotoxicity and pleural thickening can occur but are rare. Pramipexole. Pramipexole is a nonergot dopamine agonist with high affinity for D, and D, receptors. It has the same indications as other dopamine agonists. Because of a lower side effect profile, it has enjoyed wide use for these indications. It is rapidly absorbed in the GI tract, with no significant effect from food. It is excreted unchanged in the urine. It may cause drowsiness, dry mouth, and the other side effects common to dopamine agonists, such as dyskinesias, orthostatic hypotension, and hallucinations. To minimize side effects, it is recommended that the dosage be started low and slowly titrated to effect with weekly increases from 0.125 mg three times a day to a maximum dosage of 1.5 mg three times a day. The maintenance dosage must be lowered in the setting of renal insufficiency. Ropinirole. Like pramipexole, ropinirole is a nonergot dopamine agonist; it has high affinity for D, and D, receptors. It is rapidly absorbed by the GI tract without significant effect of food on absorption, although food my lessen nausea in some cases. There is a first-pass effect, and it is metabolized by the liver, primarily by the CYPlA2 system. Drugs that inhibit this enzyme, such as ciprofloxacin, can be expected to increase ropinirole levels. The side effect profile is similar to that of other dopamine agonists. To minimize side effects, it is recommend that it be started at a low dosage and titrated up to a beneficial effect with acceptable side effects. Dosing typically starts at 0.25 mg three times a day, with weekly increases by increments of 0.25 mg a day to 3 mg daily total dosage. After this, increments of 1.5 mg a day and then 3 mg a day may be used in the higher dosing ranges. The maximum tested dosage is 24 mg daily. Patients with hepatic insufficiency may be expected to need lower dosages. As with levodopa and other dopamine agonists, it should be withdrawn gradually to avoid a withdrawal syndrome resembling neuroleptic malignant syndrome with fever, muscle rigidity, autonomic overactivity, and confusion. Catechol-0-Methyltransferase Inhibitors

Catechol-0-methyltransferase (COMT) and MA0 are the major enzymes that break down monoamines. COMT inhibitors work by inhibiting the breakdown of levodopa and prolonging its effect. Tolcapone was released for adjunctive use with levodopacarbidopa in Parkinson’s disease with a wearing-off effect. However, because of the risk of fulminant hepatic failure and the frequent laboratory testing this entailed, its use has been limited. More recently a second COMT inhibitor, entacapone, was released. This agent has not been found to carry major hepatic risk, and it is finding clinical use. Although it does enter the CNS, entacapone’s known effect is peripheral. Its use in conjunction with levodopa-carbidopa results in more sustained plasma levels of levodopa and a longer-lasting clinical effect. It is indicated for adjunctive use with levodopa in patients with Parkinson’s disease and wearing-off symptoms. Dosages of 200 mg are recommended with each dose of levodopa-carbidopa up to eight doses a day. Caution must be observed in patients with hepatic insufficiency. Major side effects are those of excess levodopa, such as nausea, diarrhea, and dyskinesias. To avoid excess catecholamine response, it should not be used in patients taking nonspecific MAOIs, but it may be used in conjunction with selegiline, a selective MA0 type B

Chapter 25 rn Pharmacology of Commonly Used Drugs

inhibitor. Also, care must be taken to avoid excessive response when patients treated with COMT inhibitors are treated with any adrenergic drugs.

BEHAVIORAL NEUROLOGY AND PSYCHIATRY Acetylcholinesterase Inhibitors for Alzheimer's Disease Centrally active, reversible inhibitors of acetylcholinesteraseact by increasing the pool of acetylcholine available to postsynaptic receptors in the cerebral cortex and hippocampus. Tacrine, the first available agent, was shown to confer a modest benefit in early dementia, but frequent and serious side effects, anorexia, nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, confusion, and especially hepatotoxicity and the need for laboratory monitoring limited its use. Donepezil is a centrally active acetylcholinesterase inhibitor that is chemically distinct from tacrine and has been shown to confer sustained symptomatic benefit in patients with mild to moderate dementia from Alzheimer's disease. Clinical trials have shown sustained benefit up to a mean of 40 weeks. Because side effects (primarily nausea, vomiting, diarrhea, and agitation) have been mild at the recommended dosages of 5 to 10 mg daily, it has found wider use in clinical practice. Routine laboratory monitoring is not necessary with donepezil. Rivastigmine has been approved in the United States as a third central cholinesterase inhibitor for mild to moderate dementia of the Alzheimer type. Because of potentially severe GI side effects, nausea, vomiting, anorexia, and weight loss, it is recommended that rivastigmine be started at the subtherapeutic dosage of 1.5 mg twice daily and, if tolerated after 2 weeks, increased to 3 mg twice daily. The recommended therapeutic dosage is 6 to 12 mg daily (3 to 6 mg twice daily). Dosage increases to 4.5 or 6 mg twice a day may increase effectiveness, but they too should be done with careful monitoring for GI side effects for 2 weeks between dosage increments. If drug use is interrupted for more than a few days, it is recommended that it be resumed at the 1.5-mg twice-daily dosage and again slowly titrated as tolerated. Antidepressants Monoamine reuptake inhibitors are most often used in psychiatric practice to treat affective disorders. However, it behooves the

233

physician treating patients with neurologic disease to be familiar with these medications because they are useful in treating neurologic diseases such as neuropathic pain syndromes and headache, they are used as therapeutic trials in patients with possible depression presenting as pseudodementia, and many patients with neurologic complaints may be receiving these drugs for primary psychiatric illness. I will not discuss these agents here; however, they are compared according to several clinically relevant parameters in Table 25-5. Janicak et al. (1992) published an excellent discussion of the use of these drugs in psychiatric illness.

ANTIEPILEPTIC DRUGS Information on antiepileptic drugs is summarized in Table 25-6.

Phenytoin Phenytoin decreases ion flux through voltage-sensitive sodium channels in the resting state and during action potential generation. It also decreases calcium and potassium flux. This reduces the spread of excitation from epileptogenic foci. It is slowly and variably absorbed in the GI tract. It precipitates at the site of intramuscular injection and is slowly absorbed, so this route of administration is not recommended. It can be given intravenously. Phenytoin precipitates in glucose solutions, so it must be given in saline without glucose. After absorption or intravenous injection, it rapidly enters the brain. It is approximately 90% protein bound, mainly to albumin. Renal failure, liver disease, old age, pregnancy, and other conditions that lower the serum albumin decrease the ratio of bound to total phenytoin. It is transformed to inactive metabolites primarily by the hepatic microsomal enzymes. At low concentrations the inactivation is linear (first order), but at higher dosages the half-life increases with increasing dosage (zero order), probably because of saturation of the hepatic enzymes or inhibition of them by metabolites. This effect often is clinically relevant, with disproportionately great increases in the serum level after dosage increases in the higher dosage ranges. The inactive metabolites are eliminated in the stool and urine. At usual dosages, the half-life is about 22 hours. The dosages usually need not be adjusted for renal insufficiency, although the total level is lower for a given free level because of changes in the protein binding ratio as

rn TABU25-5. Adverse Effects of Commonly Used Antidepressants D w

Heterocyclics Amitriptyline lrniprarnine Doxepin Desipramine Nortriptyline Clomipramine Serotonin reuptake inhibitors fluoxetine Sertraline Paroxetine Triazolopyridines Trazodone Amino ketones Bupropion Triazolobenzodiazepines Alprazolam

otthortatic Hypotension

Cardii Conduction

H M M

M H

H H

M

L

H

L L L

M M M M

VL L L

N N N

VL N N

VL VL VL

H

VL

M

L

L

VL

VL

N

H

VL

VL

N

Sedation

Anticholineac

H M H L

M

M

H

Effcctr

AbbreviOtions: H, high; L, low; M, moderate; N, none; VL vely low. Adapted from Janicak ffi, Davis JM, Preskom SK, Ayd F): Principlesand Practice of F'sychopharmacotherapy.p. 272. Williams & Wilkins, Baltimore, 1993, with permission.

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Principles of Ambulatoy Neurology and the Approach to Clinical Problems

Principles of Treatment

TMLE 25-6. Selected Antiepileptic Drugs Drug

Half-life (hr)

Usual Dosage" (mu24 hr)

therapeutic level (Pp/mL)

Phenobarbital Phenytoin Primidone Carbamazepine

100 22 7-1 4 10-20

60-240 300 750- 1500 600-1000 (begin 100 bid)

15-40 10-20 5-1 2 6-1 2

50-60 500-1 500 Ethosuximide 1000-4000 (begin 15 mg/kg) 6-1 6 Valproic acid (divalproex) 18-50 0.5 mg tid, increase to 20 mg/day Clonazepam 5-7 900-3600 Cabapentin 22 (monotherapy) 50-1 00 Lamotrigine 6-8 1000-3000 Levetiracetam 21 400 Topiramate 63 100-600 Zonisamide 4-9 32-56 Tiagabine 'Optimal dosages and therapeutic levels may vary from the typical recommendationsin some patients.

noted earlier. The usual adult starting dosage is 300 mg daily. This can be given in a single daily dose or divided into two or three doses if GI upset is a problem. Dosage adjustments can then be based on the clinical response and serum levels. Intravenous phenytoin can be given in a loading dosage of about 18 mg/kg (about 1200 mg in a 70-kg patient), given no faster than 50 mg/minute with close monitoring of the cardiac rhythm and vital signs. Phenytoin has many side effects, although these usually do not prevent its use. Hirsutism can be a bothersome side effect, especially in women. Gingival hyperplasia is common and can be minimized by good dental hygiene. Hypersensitivity is not uncommon and can manifest as a mild pruritic rash or bullous eruptions (Stevens-Johnson syndrome), eosinophilia, hepatitis, interstitial nephritis, and fever. Lymphadenopathy resembling Hodgkin's disease, pseudolymphoma, can occur. Altered folate absorption and probably metabolism can cause folate depletion and megaloblastic anemia. Increased catabolism of vitamin K reduces the concentrations of vitamin K-dependent clotting factors. This can cause neonatal hemorrhage in the infant of a mother taking phenytoin. It can be prevented by the oral replacement of vitamin K in the last 2 weeks of pregnancy and by the administration of parenteral vitamin K to these newborns. Alteration of vitamin D metabolism and impairment of calcium absorption can cause osteopenia. GI symptoms are rarely limiting and can be lessened by dividing the dose and giving the medicine with food. With long-term use cerebellar degeneration and peripheral neuropathy may develop; however, these problems usually are not severe enough to be clinically significant. With overdoses and rapid intravenous use, cardiac arrhythmias can be serious side effects. Toxic levels are initially accompanied by high-amplitude gaze-evoked nystagmus (higher than roughly 20 pg/mL), by ataxia at higher levels (roughly 30 pg/mL), and finally by CNS depression (40 pg/mL). Cardiac toxicity can emerge in susceptible patients. Erythromycin, propoxyphene, and other drugs that inhibit hepatic microsomal enzymes can elevate phenytoin levels. Some of the many drug interactions are listed in Table 25-7. Total, free, and salivary levels of phenytoin have been used to monitor therapy. In most cases, optimal total levels are 10 to 20 pg/mL. When the protein binding is altered, as in renal failure and valproate therapy, so that the binding ratio is significantly less than 90%, lower total levels should be maintained. Free levels are not routinely measured, but they may help when problems arise. Therapeutic free levels are about 0.8 to 2.5 pg/mL. Salivary levels of phenytoin correlate well with free levels.

40- 100 50- 100 5-70 (rarely used)

Not used 0.5-3

Not used Not used Not used Not used

Available Preparations (mg) 30,60,100, syrup 30,50, 100, syrup 50,250, syrup 100,200, suspension of 100 mg/ 5 mL 250, syrup 125, 250, 500, sprinkles 0.5, 1.O, 2.0 100, 300,400, 600, 800, solution 25,100,150,200 250,500,750 25, 100,200 sprinkles 15,25 100 2, 4, 12, 16, 20

TABLE25-7. Phenytoin Drug Interactions Drugs that increase phenytoin levels Dicumarol Chloramphenicol Disulfiram lsoniazid Cimetidine Sulfonamides Drugs that lower the total and free phenytoin levels Carbamazepine Theophylline Phenobarbital (may occasionally raise level) Alcohol (may occasionally raise level) Drugs that lower the total level and increase the free fraction Valproate Phenylbutazone Sulfisoxazole Salicylates Drugs whose levels are lowered by phenytoin Carbamazepine Theophylline Oral contraceptives Corticosteroids

Phenobarbital Phenobarbital is a barbiturate sedative. It facilitates the inhibitory neurotransmitter action of y-aminobutyric acid (GABA) by allosteric modulation of its receptor. It is well absorbed orally and can also be given intravenously. It is 40% to 60% bound by plasma protein. It is largely transformed to inactive metabolites by hepatic microsomal enzymes. About 25% is excreted unchanged in the urine. The elimination half-life is about 100 hours. The typical adult maintenance dosage is about 1 to 4 mg/kg or 60 to 240 mg/day. Despite its long half-life, it is usually given on a twice-daily schedule to minimize sedation caused by large single doses. Intravenous loading with 10 to 20 mg/kg can be administered at a rate of up to 100 mg/minute with careful monitoring of the vital signs. Slow oral loading can be achieved by giving twice the expected maintenance dosage over the first 4 to 5 days of use. The major side effect is sedation. Usually tolerance develops to this side effect. Behavioral changes, especially irritability and hyperactivity in children and agitation and confusion in older adults, may occur. Like phenytoin it can impair vitamin K metabolism, causing neonatal hemorrhage; folate metabolism, causing megaloblastic anemia; and vitamin D metabolism, causing osteomalacia or osteoporosis. When given rapidly intravenously, it can cause

Chapter 25 W

hypotension, sedation, and respiratory depression, necessitating ventilatory assistance. This effect is greatly potentiated by the simultaneous use of benzodiazepines. It decreases the half-life of many drugs by inducing hepatic microsomal enzymes. Valproic acid raises the phenobarbital level by up to 40% by decreasing its inactivation. Therapeutic levels vary. Typical effective ranges are 15 to 40 pglmL.

Primidone Primidone is a congener of phenobarbital. Its mechanism is thought to be similar to that of phenobarbital. It is rapidly absorbed from the GI tract. It is metabolized by the liver to two active metabolites: phenobarbital and phenylethylmalonamide (PEMA). About 40% of the primidone is excreted unchanged in the urine. The half-life of primidone is about 7 to 14 hours; that of PEMA is about 16 hours. Phenobarbital’s half-life is about 100 hours. The active metabolites, especially phenobarbital, can accumulate with chronic use. The dosage usually is begun at 100 mglday and increased to 750 to 1500 mg/day. The daily dosage is divided to provide twice- or thrice-daily dosing. Many patients cannot tolerate primidone because of its common side effects. These include sedation, dizziness, nausea, and vomiting. Like phenytoin and phenobarbital, it can impair metabolism of vitamins K and D and folate. Its use carries with it the same potential drug interactions as does phenobarbital. Phenytoin increases the conversion to phenobarbital. Isoniazid decreases this conversion. When monitoring of levels is indicated, both phenobarbital and primidone levels should be measured. The typical therapeutic levels of primidone are 5 to 12 pg/mL.

Carbamazepine Carbamazepine has a tricyclic structure related to the tricyclic antidepressants. Like phenytoin it inhibits neuronal firing by blocking voltage-sensitive sodium channels. It is absorbed slowly and erratically by the GI tract. It is about 75% bound to plasma proteins. It is transformed by hepatic microsomal enzymes to an active epoxide metabolite whose serum concentration can reach 50% of the carbamazepine level and have significant anticonvulsant effect. The epoxide is further transformed to inactive metabolites that are excreted in the urine. The elimination half-life is about 10 to 20 hours during long-term therapy. At the onset of therapy the half-life is much longer; however, carbamazepine induces the hepatic microsomal enzymes that metabolize it (autoinduction), thereby shortening its own half-life with chronic use. The epoxide has a shorter half-life. Because of the long early half-life and the frequency of toxic symptoms even at low dosages at the beginning of treatment, it is best to start at a low dosage of about 100 mg twice a day. This dosage can be raised by 200 mg every 5 to 7 days to the desired maintenance dosage. This is usually in the range of 600 to 1200 mg daily, given in three to four divided doses. The most common side effects are dose-related vertigo, ataxia, nystagmus, nausea, and vomiting. It can cause an elevation in liver enzymes and the syndrome of inappropriate antidiuretic hormone with hyponatremia. The most serious side effects are agranulocytosisand aplastic anemia, but these are very rare. More commonly, mild leukopenia occurs. This may be transient, static, or progressive and typically responds to discontinuation of the drug. It is recommended that the medication be discontinued if the total WBC count falls below 3000 cells/mm3or the granulocyte count falls below 1500 cells/mm3. Most of its drug interactions

Pharmacology of Commonly Used Drugs

235

result from induction of hepatic microsomal enzymes by carbamazepine and other drugs. Phenytoin, phenobarbital, and primidone decrease carbamazepine levels. Carbamazepine decreases phenytoin and valproate levels and increases the conversion of primidone to phenobarbital. Erythromycin and propoxyphene inhibit the microsomal enzymes, causing a rise in carbamazepine levels. Therapeutic levels are usually 6 to 12 pg/mL. Periodic monitoring of sodium, CBC, and transaminases is recommended during chronic therapy.

Oxcarbazepine Oxcarbazepine is a heterocyclic agent structurally similar to carbamazepine. Oxcarbazepine appears to work through sodium channel blockade and possibly through voltage-gated calcium channel blockade as well. It is rapidly absorbed by the GI tract with no effect from food. It is metabolized in the liver to its active metabolite, the 10-monohydroxycompound (MHD). The half-life of the MHD metabolite is about 9 hours, and that of the parent, oxcarbazepine, is about 2 hours. Therefore, the major therapeutic effect is caused by the active metabolite. It is about 40% bound to plasma proteins. Oxcarbazepine is metabolized to MHD and inactive metabolites by the liver. A significant portion of the active MHD metabolite is excreted unchanged in the urine. Its coadministration with phenytoin may result in increased phenytoin levels at a given dosage. A similar though lesser effect occurs with phenobarbital. It does not induce its own metabolism as does carbamazepine. Agents that induce cytochrome p-450 enzymes may greatly decrease MHD levels. Oxcarbazepine has been shown to benefit patients with partial seizures. It is started at 300 mg twice daily, with increases of 300 mg daily to a target dosage of 600 mg twice daily. Dosages range from 600 to 2400 mg daily. Lower dosages are given to patients with renal insufficiency. Major side effects are headache, dizziness, fatigue, somnolence, and nausea. Because oxcarbazepine and MHD induce the CYP3A4 and CYP3A5 subgroups of p-450 enzymes, its use lowers the levels of dihydropyridine calcium antagonists and oral contraceptive agents.

Valprolc Add Valproic acid (VPA) is a simple branched-chain carboxylic acid. Sodium divalproex is a 1 :1 mixture of the acid and its sodium salt. VPA probably potentiates GABA-ergic inhibition, and it may have effects on both GABA-ergic systems and excitatory neurotransmitters. VPA is absorbed well by the GI tract, although absorption varies slightly with the formulation and is delayed by food. It is highly (90%) protein bound and displaces many other drugs from albumin binding sites. It is metabolized by the liver to inactive products. The half-life is from 6 to 16 hours. It is pushed to the lower end of this range by drugs, such as other antiepilepticdrugs, that induce hepatic microsomal enzymes. The initial dosage is 15 mg/kg/day, that is, about 1000 mglday in the average adult, usually divided into three or four daily doses. Dosages are then increased by 5 to 10 mg/kg/day (about 500 mg/day) at intervals of about a week to the effective dosage. The maximal dosage is about 60 mg/kg/day (about 4000 mglday). The major adverse effects are hepatic dysfunction and thrombocytopenia. Severe hepatic dysfunction with liver failure is uncommon; it usually occurs within the first 6 months of therapy and is more likely in younger children. Acute pancreatitis has also occurred. A dose-related and reversible elevation in liver function tests is more common. When

236

Rinciples of Ambulatoy Neurology and the Approach to Clinical Problems

mild this elevation may be addressed by lowering the dosage with close follow-up. Thrombocytopenia can occur as a result of decreased platelet production by the marrow or increased platelet destruction with antiplatelet antibodies. Impaired function of platelets in normal numbers may also occur and, depending on the cause, may respond to dosage reduction. More common but less severe side effects include nausea, vomiting, indigestion, and weight gain caused by increased appetite. An action tremor is common and may respond to dosage reduction. VPA decreases levels of carnitine and has many drug interactions. Because it is highly protein bound, it displaces many other drugs from plasma albumin, in most cases reducing the total level without significantly changing the free (active) level. The clinician must be aware of this effect when adjusting other agents, most importantly phenytoin. VPA inhibits the inactivation of phenobarbital and raises its level by about 40%. Phenobarbital dosages should be lowered accordinglywhen VPA is added. Other agents that induce hepatic microsomal enzymes will shorten the half-life and lower the levels of VPA. The published therapeutic range is 50 to 100 yg/mL. Levels significantly above this may be used in many patients. Liver function tests and CBC with platelets must be monitored closely in the first 6 months of therapy and periodically thereafter. When trying to achieve optimal dosing of phenytoin in combination with VPA, free drug levels may be helpful. Clonazepam

Clonazepam is a long-acting benzodiazepine that, like phenobarbital, acts by facilitating the action of GABA with its receptor. It is well absorbed by the GI tract and metabolized by the liver to other active and inactive metabolites. The half-life of the parent clonazepam is 18 to 50 hours. Elimination is by metabolism to inactive compounds and urinary excretion. The usual initial dosage is 0.5 mg two or three times a day. This dosage can be increased slowly to achieve the desired effect. Maximum recommended dosages are about 20 mg/day, although dosages much lower than this are usually used. The major adverse effect is CNS depression, which may lead to confusion, depression, and pseudodementia; it should be used with caution in older adults. Tolerance develops, and withdrawal can be difficult, causing CNS irritability. Rapid withdrawal can precipitate an acute withdrawal syndrome with seizures similar to that caused by withdrawal from alcohol and other benzodiazepines. The major drug interactions are a potentiation of the CNS depressant effects of other agents. Usual levels are 5 to 70 pg/mL; however, these are rarely used clinically, and the dosage is adjusted based on the therapeutic and adverse effects.

Ethosuximide is a succinimide. Although many physiologic and molecular effects of ethosuximide have been described, its mechanism of action as an antiepileptic agent remains unknown. It is well absorbed after an oral dose and is not significantlybound by plasma proteins. It is metabolized by hepatic microsomal enzymes to inactive metabolites; about 25% of the drug is excreted unchanged in the urine along with these metabolites. The half-life in adults is about 40 to 50 hours. In adults, the initial dosage is usually 250 mg twice a day. This may be increased by 250-mg increments weekly until the desired effect is achieved without excessive side effects. In adults, usual maintenance dosages range from 500 to 1500 mg/day given in three or four doses. GI

Principles of Treatment

symptoms are common: anorexia, nausea, vomiting, cramps, and diarrhea. CNS side effects may include drowsiness, irritability, and sleep disturbances. Bone marrow suppression may occur. Phenytoin levels may increase when ethosuximide is added. The therapeutic range is 40 to 100 yg/mL. Sore throat or fever should prompt an examination and check of the CBC and platelets. Cabapentin

Gabapentin is structurally related to GABA but, unlike GABA, readily crosses the blood-brain barrier. However, it does not seem to be an agonist of GABA receptors, and its mechanism is not known. It binds to a neuronal protein found only in the brain, and its antiepileptic efficacy is proportional to this binding. It is well absorbed by the GI tract and is not affected by food. It is not protein bound. It is not metabolized. Elimination follows linear kinetics at therapeutic dosages. It is eliminated by the kidney with a half-life of about 5 to 7 hours. Dosage adjustment is necessary with renal insufficiency. On the first day of the regimen 300 mg is administered, and on each of the next 2 days 300 mg is added until a starting dosage of 300 mg three times a day is reached. The usual therapeutic dosage is 900 to 1800 mg daily, although higher dosages, up to 3600 mg daily, have been well tolerated in clinical studies. The dosage should be raised above 900 to 1200 mg/day based on the clinical response. Rapid titration in 2 to 3 days has been well tolerated. The side effects have been mild in clinical studies: somnolence, dizziness, ataxia, fatigue, and headache have been the most prominent ones. No long-term data are available. It has no known significant interactions with other drugs and probably does not inhibit the effectivenessof contraceptives. No drug concentration, hematologic, or liver function monitoring is necessary. Lamotrigine

Lamotrigine is a phenyltriazine unrelated to other antiepileptic agents. Like phenytoin and carbamazepine, it acts on voltagesensitive sodium channels to inhibit neuronal firing. It also may reduce the release of the excitatory neurotransmitters glutamate and aspartate. By virtue of complementary mechanisms, lamotrigine and VPA may have a synergistic effect that benefits patients with intractable seizures. It is rapidly absorbed by the GI tract. It is about 55% bound to plasma proteins. It is metabolized by hepatic microsomal enzymes to inactive compounds. During monotherapy, the half-life is about 22 hours. In combination with phenytoin, carbamazepine, and phenobarbital, the half-life falls to 15 hours. With VPA the half-life of lamotrigine is prolonged to 59 hours, necessitating a downward adjustment in the dosage. The usual dosage is 50 to 100 mg daily, but dally dosages as high as 600 mg have been used. It is recommended that it be started with 25 mg at night and raised by 25 mg every 2 weeks to the effective dosage. It has a low toxicity, although serious rashes may occur. This risk of rash is greatest in the first 2 months of therapy and may be greater with coadministration of valproate or with rapid dosage increases. Other side effects include diplopia, drowsiness, dizziness, ataxia, headache, nausea, and vomiting. These are all dose-related and common with dosages greater than 100 mg/day. The main drug interactions are with other antiepileptic drugs. A severe disabling tremor has been reported in patients treated with a combination of lamotrigine and VPA. As noted earlier, VPA increases its half-life significantly, and drugs that induce hepatic microsomal enzymes shorten its half-life. It does not alter the

Chapter 25

metabolism of other antiepileptic drugs, except by raising the carbamazepine epoxide level by about 10%. Therapeutic trough levels are 0.5 to 3 pg/mL in most studies. No laboratory monitoring is necessary during maintenance. Levetiracetam

Levetiracetam is an antiepileptic agent in the pyrrolidone family, an analogue of piracetam. It is unrelated to other antiepileptic agents and has an unknown mechanism of action. A novel specific binding site for levetiracetam has been identified in the brain. In vitro, it has been shown to reverse inhibition by negative modulators of GABA-gated currents. It also has calcium channel blocking properties that may contribute to its antiepileptic effect. It appears to inhibit epileptiform burst firing and propagation of seizures. It is rapidly and completely absorbed by the GI tract. Peak levels are detected about 1 hour after an oral dose. It is minimally (10%) protein bound. The half-life is from 6 to 8 hours with normal renal function. It is largely excreted unchanged in the urine. A smaller proportion is converted to inactive metabolites, which are also excreted in the urine. Its metabolism does not depend on the cytochrome p-450 system. Elimination is linear within the therapeutic dosage range. It does not interact significantly with other antiepileptic agents, and it has few reported interactions with other drugs. At dosages between 1000 and 3000 mg daily, it has been shown to be effective as adjunctive therapy for intractable partial seizures. It is recommended that patients begin with 500 mg twice daily and that increases to 2000 and 3000 mg daily (also in twice daily dosages) be made as needed for seizure control after 2 weeks. Dosages must be reduced in patients with renal insufficiency. It is usually well tolerated. The most common side effects in clinical trials were somnolence, dizziness, asthenia, headache, and infection. No laboratory monitoring is recommended. Psychological, including psychotic, reactions have been rarely reported in patients taking levetiracetam, and it should be used with caution in patients prone to such events.

Topiramate is a sulfamated monosaccharide. Its mechanism of action is not fully understood, but it has multiple demonstrated effects that probably account for its antiepileptic activity: sodium channel blockade, potentiation of GABA inhibitory activity, and decreased activity of kainateIAMPA excitatory amino acid receptors. It is also a weak carbonic anhydrase inhibitor. It is rapidly absorbed by the GI tract without effects from food, and the peak concentration is reached about 2 hours after an oral dose. Protein binding is slight, 13% to 17%. Elimination is linear within the therapeutic dosage range, and serum half-life is approximately 21 hours in patients with normal renal function. It is mostly excreted unchanged in the urine, although hepatic metabolism plays a role in elimination, and clearance is decreased by hepatic dysfunction. Coadministration of topiramate has little effect on the concentration of other antiepileptic agents. Phenytoin and carbamazepine may significantly increase the level of topiramate achieved at a given dosage. It has been shown to be effective as adjunctive therapy in adults and children with partial seizures or primary generalized tonic-clonic seizures. The usual adult dosage is 400 mg daily, given in two divided doses of 200 mg. Dosages of 600 to 1000 have been studied, but it is not clear that dosage increases augment antiepileptic effect, and individual titration is recommended. It is recommended that the medication be started at 25 to 50 mg daily

W

Pharmacology of Commonly Used Drugs

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and titrated upward to an effective dosage. In clinical trial populations, 400 mg daily has been more effective than 200 mg daily. The maintenance dosage should be decreased in the setting of renal insufficiency. The most common side effects have been fatigue, somnolence, dizziness, and psychomotor slowing. Slow titration to the effective dosage is recommended to minimize side effects. Effects on liver functions and cell counts are uncommon, and laboratory monitoring is not recommended.

Zonisamide Zonisamide is a sulfonamide agent with antiepileptic activity. Its mechanism is not known, but it has several demonstrated effects that probably account for its antiepileptic activity. It inhibits flux in sodium and voltage-dependent calcium channels. It, too, is a weak carbonic anhydrase inhibitor. It is well absorbed by the GI tract, with peak levels 2 to 6 hours after an oral dose. Time to peak concentration is delayed by food. It binds avidly to erythrocytes. It is about 40% protein bound. Elimination is linear at dosages of 200 to 400 mg daily, but above 800 mg daily levels rise disproportionally, possibly because of saturation of erythrocyte binding. The plasma half-life is about 60 hours in patients with normal renal and hepatic function; elimination half-life from erythrocytes, where levels may be eight times plasma levels, is about 100 hours. Most of the drug is excreted as inactive metabolite and unchanged in the urine. It does not appear to affect the levels of other antiepileptic agents significantly. Cytochrome p-450 enzymes contribute to its metabolism, and enzyme-inducing agents, such as phenytoin, carbamazepine, and phenobarbital, shorten the elimination half-life to 1 to 1.5 days. It has been shown to be effective as adjunctive therapy in adults with partial seizures. It is recommended that dosage titration be taken slowly because its long half-life means that a steady state may not be reached before 2 weeks. It is started at 100 mg daily and then increased incrementally by 100 mg after a minimum of 2 weeks to effect or to dosages of 400 to 600 mg daily. Patients with renal and hepatic insufficiency may need slower titration and lower maintenance dosages. The most common side effects are somnolence, dizziness, and anorexia. No laboratory monitoring is recommended.

SUGGESTED READINGS American Academy of Neurology Quality Standards Subcommittee: Practice advisory on selection of patients with multiple sclerosis for treatment with Betaseron. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 441537, 1994 American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 39:1791-1801, 1996 Bornstein MB, Miller A, Slagle S et al: A placebo-controlled,double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 41:533-539, 1991 Bracken MB, Shepard MJ, Collins WF et ak A randomised, controlled trial of methylprednisolone or naloxone in the treatment of acute spinalcord injury. N Engl J Med 322:1405, 1990 Brodie MJ: Felbamate: a new antiepileptic drag. Lancet 341:1445, 1993 CAPRIE Steering Committee: A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 3481329-1339, 1996 Chadwick D Gabapentin. Lancet 343239, 1994 Chaudhry V, Cornblath DR, Griffin JWet ak Mycophenolate mofetil: a

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Principles of Ambulatory Neurologyand the Approach to Clinical Problems W

safe and promising immunosuppressant in neuromuscular diseases. Neurology 56:94-96, 2001 Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494-502, 2001 Dalakas M Pharmacologic concerns of corticosteroidsin the treatment of patients with immune-related neuromuscular disorders. Neurol Clin 8:93, 1990

Daroff RB: The office Tensilon test for ocular myasthenia gravis. Arch Neurol43:843, 1986

Davis KL, Thal LJ, Gamzu ER et al: A double-blind, placebo-controlled multi-center study of tacrine for Alzheimer’s disease. N Engl J Med 3221253, 1992

Diener H, Cuhna L, Forbes CD et al: European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 143:l-13, 1996 Farlow M, Gracon SI, Hershey LA et al: A controlled trial of tacrine in Alzheimer’s disease. JAMA 268:2523, 1992 Gent M, Easton JD, Hachinski VC et ak The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1:1215, 1989

Gilman AG, Goodman LS, Rall TW et ak Goodman and Gilman’s the Pharmacological Basis of Therapeutics. Macmillan, New York, 1985 Hass WK, Easton JD, Adams HP et ak A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 321:501, 1989 Hirsh J, Dalen JE, Anderson DR et al: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 114445S4698, 1998

IFNB Multiple Sclerosis Study Group: Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology

Principles of Treatment

JacobsLD, Cookfair DL, Rudick RA et ak Intramuscular interferonbeta-la for disease progression in relapsing multiple sclerosis. Ann Neurol 39:285-294, 1996

Janicak PG, Davis JM, Preskom SH, Ayd FJ: Principles and Practice of Psychopharmacotherapy.Williams & Wilkins, Baltimore, 1993 Johnson KP, Brooks BR, Cohen JA et ak Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase I11 multicenter, double-blind, placebo-controlled trial. Neurology 45:1268-1276, 1995 Johnson KP, Brooks BR, Cohen JA et al: Extended use of glatiramer acetate (Copaxone) is well-tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 50701-708, 1998

Management of Atherothrombosiswith Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH). Stroke 33:1733-1734, 2002 Parkinson Study Group: DATATOP a multicenter controlled clinical trial in early Parkinson’s disease. Arch Neurol 461052, 1989 Parkinson Study Group: Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 321:1364, 1989 Rogers SL, Friedhoff LT, the Donepezil Study Group: The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicenter, randomized, double-blind, placebo-controlled trial. Dementia 2293-303, 1996 Sanders DB, Scoppetta C: The treatment of patients with myasthenia gravis. Neurol Clin 12:343, 1994 Seybold M E The office Tensilon test for ocular myasthenia gravis. Arch Neurol 43:842, 1986 Watkins PB, Zimmerman HJ, Knapp MJ et al: Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 271:992, 1994

43:655, 1993

26

Therapeutic Plasma Exchange Richard 1. Benjamin and W Hallowell Churchill

RATIONALE Therapeutic plasma exchange (TPE) is a dramatic procedure with an intuitively simple rationale: If a plasma factor is the cause of disease, then its removal should be the cure. Evolving from the dubious historical practice of bloodletting, the removal of blood, separation of its formed elements, and their reinfusion with plasma replacement was suggested as a treatment for hyperviscosity as early as 1914 and accepted as standard therapy in 1960. However, it was only with the availability of modern apheresis machines, initially developed to facilitate the selective donation of blood components, that widespread therapeutic trials of plasma exchange have become feasible. Plasma exchange with either allogeneic plasma or, more commonly, human serum albumin in saline is by its very nature a nonspecific therapy. However, specificity may be derived from the delay with which a particular noxious agent is regenerated. In particular, antibodies, with their long half-lives (about 21 days), may remain depleted for prolonged periods after a short course of TPE. By this rationale, any autoimmune diseases with demonstrable autoantibodies became a legitimate subject for clinical trials, and just as bloodletting was advocated for a multitude of

rn

mysterious maladies, the availability of plasma exchange by apheresis rapidly found favor as the intervention of last resort in a variety of serious immune-mediated diseases. Several decades have passed, and plasma exchange has begun to find its proper niche in the medical armamentarium (Table 26-1). This process of validation has been instructive in itself. In practically every disease for which TPE has been advocated, initial case reports of dramatic efficacy in a small number of patients spurred interest and excitement. Thereafter, validation has been accomplished by several mechanisms. In some diseases, most notably myasthenia gravis, TPE became accepted medical practice by consensus without formal trial. In the 1986 Consensus Development Conference, TPE was endorsed as therapy for the short-term reduction of symptoms in myasthenia gravis based o n the rationale that autoantibodies play a major etiologic role and o n several uncontrolled, open clinical trials. For other diseases, a more conventional path was followed. In Guillain-Barre syndrome, benefit was demonstrated in a number of formal controlled trials. In thrombotic thrombocytopenic purpura, therapeutic efficacy was already assumed o n the basis of a decade of uncontrolled studies and then confirmed by controlled comparison of plasma infusion versus plasma replacement. In diseases

238

Principles of Ambulatory Neurologyand the Approach to Clinical Problems W

safe and promising immunosuppressant in neuromuscular diseases. Neurology 56:94-96, 2001 Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494-502, 2001 Dalakas M Pharmacologic concerns of corticosteroidsin the treatment of patients with immune-related neuromuscular disorders. Neurol Clin 8:93, 1990

Daroff RB: The office Tensilon test for ocular myasthenia gravis. Arch Neurol43:843, 1986

Davis KL, Thal LJ, Gamzu ER et al: A double-blind, placebo-controlled multi-center study of tacrine for Alzheimer’s disease. N Engl J Med 3221253, 1992

Diener H, Cuhna L, Forbes CD et al: European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 143:l-13, 1996 Farlow M, Gracon SI, Hershey LA et al: A controlled trial of tacrine in Alzheimer’s disease. JAMA 268:2523, 1992 Gent M, Easton JD, Hachinski VC et ak The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1:1215, 1989

Gilman AG, Goodman LS, Rall TW et ak Goodman and Gilman’s the Pharmacological Basis of Therapeutics. Macmillan, New York, 1985 Hass WK, Easton JD, Adams HP et ak A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 321:501, 1989 Hirsh J, Dalen JE, Anderson DR et al: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 114445S4698, 1998

IFNB Multiple Sclerosis Study Group: Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology

Principles of Treatment

JacobsLD, Cookfair DL, Rudick RA et ak Intramuscular interferonbeta-la for disease progression in relapsing multiple sclerosis. Ann Neurol 39:285-294, 1996

Janicak PG, Davis JM, Preskom SH, Ayd FJ: Principles and Practice of Psychopharmacotherapy.Williams & Wilkins, Baltimore, 1993 Johnson KP, Brooks BR, Cohen JA et ak Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase I11 multicenter, double-blind, placebo-controlled trial. Neurology 45:1268-1276, 1995 Johnson KP, Brooks BR, Cohen JA et al: Extended use of glatiramer acetate (Copaxone) is well-tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 50701-708, 1998

Management of Atherothrombosiswith Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH). Stroke 33:1733-1734, 2002 Parkinson Study Group: DATATOP a multicenter controlled clinical trial in early Parkinson’s disease. Arch Neurol 461052, 1989 Parkinson Study Group: Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 321:1364, 1989 Rogers SL, Friedhoff LT, the Donepezil Study Group: The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicenter, randomized, double-blind, placebo-controlled trial. Dementia 2293-303, 1996 Sanders DB, Scoppetta C: The treatment of patients with myasthenia gravis. Neurol Clin 12:343, 1994 Seybold M E The office Tensilon test for ocular myasthenia gravis. Arch Neurol 43:842, 1986 Watkins PB, Zimmerman HJ, Knapp MJ et al: Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 271:992, 1994

43:655, 1993

26

Therapeutic Plasma Exchange Richard 1. Benjamin and W Hallowell Churchill

RATIONALE Therapeutic plasma exchange (TPE) is a dramatic procedure with an intuitively simple rationale: If a plasma factor is the cause of disease, then its removal should be the cure. Evolving from the dubious historical practice of bloodletting, the removal of blood, separation of its formed elements, and their reinfusion with plasma replacement was suggested as a treatment for hyperviscosity as early as 1914 and accepted as standard therapy in 1960. However, it was only with the availability of modern apheresis machines, initially developed to facilitate the selective donation of blood components, that widespread therapeutic trials of plasma exchange have become feasible. Plasma exchange with either allogeneic plasma or, more commonly, human serum albumin in saline is by its very nature a nonspecific therapy. However, specificity may be derived from the delay with which a particular noxious agent is regenerated. In particular, antibodies, with their long half-lives (about 21 days), may remain depleted for prolonged periods after a short course of TPE. By this rationale, any autoimmune diseases with demonstrable autoantibodies became a legitimate subject for clinical trials, and just as bloodletting was advocated for a multitude of

rn

mysterious maladies, the availability of plasma exchange by apheresis rapidly found favor as the intervention of last resort in a variety of serious immune-mediated diseases. Several decades have passed, and plasma exchange has begun to find its proper niche in the medical armamentarium (Table 26-1). This process of validation has been instructive in itself. In practically every disease for which TPE has been advocated, initial case reports of dramatic efficacy in a small number of patients spurred interest and excitement. Thereafter, validation has been accomplished by several mechanisms. In some diseases, most notably myasthenia gravis, TPE became accepted medical practice by consensus without formal trial. In the 1986 Consensus Development Conference, TPE was endorsed as therapy for the short-term reduction of symptoms in myasthenia gravis based o n the rationale that autoantibodies play a major etiologic role and o n several uncontrolled, open clinical trials. For other diseases, a more conventional path was followed. In Guillain-Barre syndrome, benefit was demonstrated in a number of formal controlled trials. In thrombotic thrombocytopenic purpura, therapeutic efficacy was already assumed o n the basis of a decade of uncontrolled studies and then confirmed by controlled comparison of plasma infusion versus plasma replacement. In diseases

Chapter 26

Therapeutic Plasma Exchange

239

TAW 26-1. Indications for Therapeutic Plasma Exchange and Their Basis Randomized Trial

Consensus or Case Report

Possible but Not Proven

Guillain-Barre syndrome Chronic inflammatory demyelinating polyradiculopathy Peripheral neuropathy with monoclonal gammopathy of undetermined significance Thrombotic thrombocytopenic purpura

Myasthenia gravis Hyperviscosity Hemolytic uremic syndrome Cryoglobulinemia Familial hypercholesterolemia Post-transfusion purpura

Pemphigus Goodpasture's syndrome Autoimmune hemolytic anemia Cold agglutinin disease Antibody to coagulation factors Idiopathic thrombocytopenic purpura

such as polymyositis, dermatomyositis, and lupus nephritis, efficacy assumed on the basis of case studies was not confirmed by properly controlled clinical trials. The importance of properly designed studies is best illustrated by the use of plasma exchange in rheumatoid arthritis. Initial reports of effectiveness were popularized in the lay media and appeared to be confirmed by trials that did not include sham pheresis and blinded observation of outcome. When these controls were included, no clinical benefit was demonstrated despite significant differences in laboratory indices. The precedent has now been set: Although anecdotal reports are useful in directing attention to the potential of TPE in various diseases, full controlled trials, including sham TPE, are necessary before using this expensive, potentially harmful procedure as accepted practice in new applications. With these caveats, this chapter discusses the use of TPE in a limited number of neurologic diseases to illustrate the technical principles and potential complications inherent in this therapy. This serves as a basis for evaluating its role, potential or proven, in the many other neurologic conditions discussed in this book.

INDICATIONS The clinical impact of TPE can be summarized as fast, temporary, and expensive. TPE seldom induces disease remission by itself, and the ideal applications therefore are acute, self-limited disorders such as Guillain-Barre syndrome, or chronic disorders, such as myasthenia gravis, in which rapid short-term therapeutic effects are needed. To be considered in chronic diseases, TPE must be compared with less invasive and less expensive procedures. For example, a number of recent studies have focused on the use of intravenous y-globulin ( M g ) , which in selected situations may be efficacious. Nevertheless, neurologic diseases are the most common indications for TPE, constituting 89% of procedures in the recent report of Couriel and Weinstein (1994). Furthermore, the total number of TPE procedures and the proportion performed for neurologic indications appear to be increasing. The list of neurologic conditions for which TPE has shown benefit on occasion is long and is discussed in detail in the chapters concerning specific diseases; however, a few well-documented indications are illustrative. The benefit of TPE in Guillain-Barrk syndrome has been established in three large randomized trials that included more than 500 patients. Based on the rationale that humoral immunity may play an etiologic role in Guillain-Barrk syndrome, these studies show that TPE, begun early in the course of the disease, results in a decreased need for ventilatory assistance and more rapid improvement in muscular strength when compared with conservative therapy. Improvement was more marked in patients randomized to TPE within 1 week of clinical onset, although these patients may be more likely to relapse once TPE is stopped, presumably because of the regeneration of the putative toxic etiologic plasma factor. For this reason, it has been suggested that

if TPE is initiated in the first week of disease, it should be continued through the third week to decrease the likelihood of relapse. Randomized trials have compared the use of IVIg and TPE to treat Guillain-Barre syndrome. The study of van der Meche et al (1992) suggested a significantlybetter rate and degree of response in IVIg-treated patients, but observers noted that the TPE-treated patients in this trial fared no better than the controls (non-TPE) in prior North American trials. More recently, the Plasma Exchange/ Sandoglobulin Guillain-Barre Syndrome Trial Group showed in a multicenter, international trial of 383 patients that TPE and IVIg administered in the first 2 weeks after the onset of neurologic symptoms had equivalent efficacy. The combination of TPE followed by IVIg did not confer a significant advantage. In myasthenia gravis, an autoimmune disease usually associated with circulating antinicotinic acetylcholinereceptor antibodies and muscular weakness, there is a clear theoretical basis for trial of TPE, and there are many anecdotal reports of its efficacy. TPE generally effects a rapid (2 to 4 days) improvement in muscular strength, although maximal improvement may be delayed for several weeks. These effects are short-lived, and long-term remissions are not seen. The 1986 National Institute of Health (NIH) Consensus Conference recommended that TPE has a role in treating myasthenia, despite the fact that TPE has never been subjected to formal trial. TPE is recommended in acute exacerbations of myasthenia gravis (myasthenic crises), before and after thymectomy (in which TPE may reduce the need for postoperative ventilation), and during the introduction of more conventional anticholinergic and immunosuppressive therapy, when many patients experience a clinical deterioration. Although not a recommendation of the consensus conference, there are isolated reports of response to chronic TPE therapy in a minority of patients unresponsive to conventional therapy. A recent randomized trial compared TPE with M g in acute exacerbations of myasthenia gravis in 87 patients. The median time to the response endpoint in the TPE group was 9 days and 15 days in the IVIg group (P = .14). Although the study was not powered to discern a difference of this magnitude, these data may suggest a faster response in the TPE group. Chronic inflammatory demyelinating polyradiculopathy (CIDP) and disease-associatedpolyradiculopathies, both thought to be caused by poorly defined autoimmune processes, are ameliorated by TPE regimens. In particular, Dyck et al (1986) showed in a sham TPE controlled formal trial that a 3-week course of TPE led to significant improvement in nerve conduction studies, neurologic disability score, and motor function. These authors concluded that in some patients with CIDP, TPE has a clear ameliorating effect, but in others, no improvement is observed. Two studies have compared TPE with M g for CIDP. In an observer-blinded crossover study in 20 patients, Dyck et al (1994) found similar efficacy for both treatments. This was confirmed in a retrospective study of 33 patients reported by Choudhary and

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Principles of Ambulatory Neurology and the Approach to Clinical Problems rn Principles of Treatment

Hughes (1995), who noted that more side effects were seen with TPE than with IVIg. For TPE, published results have used schedules of one to three single-volume plasma exchange procedures per week for at least a month or until a clear plateau phase has been reached. Periodic retreatments have been tailored to the patient’s symptoms. TPE has been attempted in paraproteinemic peripheral neuropathy, including paraproteinemias associated with myeloma, lymphoma, amyloidosis, Waldenstrom’s macroglobulinemia, and monoclonal gammopathy of undetermined significance (MGUS). In these conditions, peripheral neuropathy may be caused by a variety of pathologic mechanisms, including ischemia, cryoglobulinemia, hyperviscosity, and direct attack on the myelin sheath by specific antibodies. Whatever the mechanism, the rationale for removing the paraprotein is strong; however, only limited trial results are available, and no clear recommendation on efficacy of TPE versus conventional cytotoxic therapy can be made, with the notable exception of the neuropathy associated with MGUS. Dyck et al. (1991) published results of a controlled trial of TPE versus sham TPE in patients with stable or worsening polyneuropathy with MGUS. A short course of TPE (six procedures over 3 weeks) produced a significant improvement in the neuropathy disability score, the weakness score, and the summed compound muscle action potential. On completion of the double-blind study, the sham-treated patients were crossed over to TPE and again showed significant improvement. In both arms of the study, patients with IgG or IgA gammopathy fared better than those with IgM gammopathy, and improvement was limited to 7 to 20 days. These findings support the use of TPE, with concomitant immunosuppressive therapy, in patients with debilitating neuropathy. By contrast with the aforementioned studies, in which TPE therapy was based on controlled trials or consensus, there are a number of conditions in which its use remains controversial. A good example is multiple sclerosis, for which large double-blind trials in both chronic progressive and acute relapsing multiple sclerosis both support and fail to support the use of TPE in conjunction with immunosuppressive agents. These studies place multiple sclerosis onto the long list of diseases for which anecdotal reports of improvement induced by TPE will continue to justify therapeutic trials when no other alternative is available or situations are particularly desperate. TECHNICAL ASPECCS

Whatever the indication, once the decision to treat a patient by TPE has been made, a series of further choices are necessary with respect to the site of venous access to be used, the type of plasmapheresis equipment needed, the nature of the anticoagulant and replacement fluid to be used, and the level of monitoring needed during the process. Excellent venous access is essential, inadequate access is a major barrier to TPE. Modern plasmapheresis equipment requires high blood flow rates of 40 to 100 mL/min, usually through two venous sites. Peripheral veins may be best suited for short courses of therapy, especially in the outpatient setting, but adequate peripheral access often is not available in obese patients or those with sclerosed peripheral veins. Furthermore, use of peripheral veins requires patient cooperation because hand squeezing often is needed to ensure adequate flow from antecubital veins. The alternative, a centrally placed large-bore multilumen venous catheter, offers high flow rates and convenience but exposes the patient to the risks inherent in placing and maintaining these lines.

These risks include potentially life-threatening problems such as catheter infection, hemorrhage, air embolism, and pneumothorax, as well as loss of access caused by thrombosis. Central pheresis catheters must be maintained meticulously to prevent infection. Patency may be maintained by filling with a small volume of heparin solution (e.g., 1.2 mL saline with 1,000 IU heparin) at the end of each procedure. Heparin in the lines, if accidentallyflushed into the patient rather than being withdrawn, can cause abnormal laboratory tests, heparin-induced thrombocytopenia, and occasional significant bleeding in patients with underlying coagulopathy. Notwithstanding these risks, central lines are more convenient for repeated procedures and are most suited to prolonged courses of TPE, especially in severely compromised patients in intensive care units. The choice of plasmapheresis equipment to be used usually is determined by availability. Modern machines all operate on one of three basic principles: continuous or discontinuous flow centrifugation or membrane filtration. Centrifugation methods offer the advantage that the same equipment may be used by the hematology services for white blood cell and platelet collection. Discontinuous centrifugation machines (e.g., Haemonetics 30, 30s,and V50, Haemonetics Inc., Braintree, MA) withdraw up to 350 mL blood per cycle, separate the cellular elements from plasma, and then return the former to the patient before starting the next cycle. Although this method has the advantage that a single venous access site may be used, it involves large changes in extracorporeal volume, which may not be tolerated in compromised patients. This problem can be minimized by using two vascular sites and infusing replacement fluid simultaneously with blood removal. Nevertheless, the high extracorporeal volume needed might still be a problem in severely anemic patients or those with cardiovascular instability, and such patients may need to be treated with repeated cycles of lower volume. By contrast, with continuous flow machines (e.g., Cobe Spectra, Cobe Laboratories Inc., Lakewood, CO; Fenwal CS3000, Baxter Health Care Corp., Deerfield, IL), blood flows at a constant rate from one venous site and is separated into components that are selectively recombined and reinfused via a second venous access site. These systems generally need lower extracorporeal volumes of 220 to 350 mL and are more efficient; indeed, there is suggestive evidence that continuous flow machines may offer marginally better clinical outcomes than discontinuous machines in Guillain-Barrk syndrome and multiple sclerosis, although the scientific basis for this observation is not clear. The third principle, plasma filtration, uses pressure over a selective membrane to separate plasma from cells and platelets. This process uses small extracorporealvolumes (less than 100 mL) and may be run on standard hemodialysis equipment; however, high blood flow rates (approximately 100 mL/min) via excellent venous access are needed. Furthermore, separation may become less than optimal because of changes in the selective properties of the membrane caused by adsorption of proteins, clotting, and the accumulation of partially rejected solutes adjacent to the membrane surface. This is particularly likely to be a problem in patients with polyclonal or monoclonal gammopathies. The filtration and continuous flow centrifugation machines have been further adapted to allow the selective removal of solutes by inline affinity columns or specific precipitation. In this manner, immune complexes, antibodies, bile acids, or lipoproteins may be selectively removed with reinfusion of the cleared plasma. These systems allow major savings on the costs of replacement fluids, and preliminary evidence, such as the increased levels of high-

Chapter 26 rn Therapeutic Plasma Exchange

density lipoprotein found after selective removal of low-density lipoprotein, may suggest the possibility of benefit; however, they have yet to justify their use with evidence of significant direct clinical improvement. Whichever type of plasmapheresis equipment is used, blood must be anticoagulated in the extracorporealcirculation, either by heparinization of the entire patient or, more commonly, by the addition of acid citrate dextrose at the proximal venous site. The amount of acid citrate dextrose added usually is specified by the plasmapheresis equipment manufacturer. In both cases, most of the anticoagulant is removed with the plasma; however, problems with residual anticoagulant are a common cause of complications in TPE and may necessitate reversal of anticoagulation. The volume and type of replacement fluid used may also affect the clinical outcome. Because the constant withdrawal and reinfusion of blood involves diluting the native plasma with the replacement fluid in vivo, total replacement is not feasible. A single exchange of one plasma volume theoretically removes 60% to 70% of native plasma, with larger proportional exchange necessitating exponentially increasing exchange volumes. Most programs therefore adopt strategies of 1 to 1.5 times plasma volume exchanges repeated regularly, thereby achieving more than 90% depletion of proteins such as immunoglobulins. This translates into a 2- to 4-L plasma exchange in an adult, using the empiric estimate of plasma volume in women at 40 mL/kg and in men at 45 mWkg. Although tables are available to determine plasma volume, most modern plasmapheresis machines are programmed to compute the optimum volume automatically based on the patient’s weight and hematocrit. However, clinical allowance must still be made for preexisting fluid shifts caused by the patient’s underlying condition. Plasma must be replaced by a similar colloid solution. Historically, fresh frozen plasma was the natural choice; however, a high incidence of allergic reactions and the risk of viral infections have now limited its use to diseases (e.g., thrombotic thrombocytopenic purpura) in which plasma has a direct beneficial effect. Synthetic plasma expanders have yet to gain popularity in this application because their short plasma half-life renders them unsuitable for sick patients undergoing repeated procedures. For these reasons, pasteurized human albumin diluted in saline is commonly used, providing maintenance of oncotic pressure, a minimal risk of infection, and a low incidence of side effects. However, albumin in saline does not replace coagulation factors and leads to a dilution coagulopathy, including hypofibrinogenemia, which persists for 24 to 48 hours after TPE. Consequently, TPE usually is scheduled every second day to minimize the effects of this acquired coagulopathy and to avoid the need for supplementary fresh frozen plasma, with its attendant risks of infection and allergy. The level of monitoring patients need when undergoing regular TPE varies according to the clinical situation. In all cases, a supervising physician must make the initial therapeutic plan and be readily available to manage any complications that emerge. At one extreme, severely compromised patients (e.g., severe GuillainBard syndrome) may need the cardiovascularand respiratory care of an intensive care unit, whereas patients with multiple sclerosis in remission may be treated as outpatients. At a minimum, a trained operator must be present throughout the procedure to monitor the patient’s vital signs and the plasmapheresis equipment’s operational status. A constant record of the fluid balance, anticoagulant use, and flow rates should be available to allow rapid

241

interpretation of adverse reactions. Routine assessments over a course of exchanges should include platelet counts, fibrinogen levels, and immunoglobulin levels because these factors are known to be depleted by TPE. Ultimately, those administering TPE must have a thorough familiarity with the complications commonly encountered during TPE and a sound knowledge of their management.

COMPLICATIONS Like those of any major medical procedure, the potential benefits of TPE must be weighed against the risks to the patient. These may vary from life threatening, necessitating immediate termination of the procedure, to mild, causing minimal interference. Indeed, recent surveys suggest that almost one half (40% to 49%) of all patients treated may demonstrate untoward effects at some point during their course of therapy, although these occur during a minority (4.8% to 17%) of individual exchange procedures. Most complications are mild to moderately severe and do not prevent the successful completion of a procedure; however, serious complications and even deaths have been reported. In general, TPE complications may be divided into common problems usually related to the nature of the replacement fluid or the anticoagulant and less common complications related to vascular access, hemostasis, cardiovascular stability, or the underlying disease process. Historically, the most common life-threatening reactions were caused by anaphylaxis in response to fresh frozen plasma, especially in IgA-deficient patients. Moreover, mild allergic reactions, including fever, chills, and urticarial rashes, were the most common mild complications (Table 26-2). These problems are dramatically reduced by the use of albumin in saline as replacement. In recent surveys, life-threatening or fatal reactions usually have related to the use of vascular access catheters. Although these are clearly necessary to allow repeated procedures with minimal discomfort to the patient, the threat of catheter-related bacteremia, hemothorax and pneumothorax, and hematomas is ever present. Indeed, anecdotal reports of venous catheters mistakenly placed in major arteries and at least one report of death relating to subclavian artery laceration during catheter placement demand consideration. Another rare but potentially serious complication relates to patients receiving angiotensin-convertingenzyme inhibitors. Statistical evidence shows that patients on these drugs are more likely to have unexplained episodes of flushing, hypotension, dyspnea, or bradycardia during apheresis, probably caused by interference with bradykinin metabolism. For this reason it is recommended that angiotensin converting enzyme inhibitors be stopped at least 24 hours before plasma exchange therapy. Less severe complications that warrant medical intervention but do not result in termination of the procedure include nausea, vomiting, vasovagal reactions, and hypotension. In these cases, positioning the patient, infusing 0.9% saline, and treating citrate toxicity usually allow the procedure to continue after a suitable delay. Reactions to citrate, the calcium-chelating anticoagulant used in most plasmapheresis machines, are now the single most common type of complication related to TPE (Table 26-2). This necessitatesroutine patient counseling about hypocalcemia and its common sequelae, including paraesthesias and muscle cramps. When symptoms occur, slowing the whole blood flow rate, adjusting the anticoagulant ratio, and administering oral calcium supplementation often are all that is needed; however, intravenous calcium supplementation administered in 5% dextrose water may

242

Principles of Ambulatory Neurology and the Approach to Clinical Problems H Principles of Treatment

TABLE 26-2. Incidence of Adverse Reactions with Therapeutic Plasma Exchange Complication Fever, chills, urticaria Muscle cramps, paresthesias Hypotension Nausea, vomiting, abdominal pain Headache Chest pain Cardiac arrhythmia Dyspnea, bronchospasm Convulsions Respiratory arrest Other Hypofibrinogenemia Percentage incidence Total number of procedures

Sutton et al(1989) (%) 3.7 2.5 2.3 1.5 1.2 0.2 0.1 0.1 0.04 0.04 0.8

-

12.5 5235

Couriel and Weinstein ( I 994) (46) 0.3 5.5 2.1 3.9

-

1.o 3.7 16.5 381

McLeod et a1 (1999) (%) 0.2

-a

1.o 1.7

-

0.3 0.2

-

1.4

-

4.8 3429

'This study excluded mild paresthesia and vasovagal events related to citrate toxicity.

be used. A less common reaction to citrate is metabolic alkalosis, especially in patients with renal failure who are unable to excrete the excess bicarbonate load generated by the hepatic metabolism of citrate. Such alkalosis may necessitate treatment with acetazolamide or, in severe cases, infusion of diluted hydrochloric acid through a dedicated central line. Hypofibrinogenemia caused by dilution with replacement fluid is another common finding after plasma exchange, although bleeding complications are rare. Nevertheless, it is important to monitor serum fibrinogen levels and to consider replacement therapy should concentrations fall below 50 mg/dL. This is especially true in patients with underlying hemostasis problems, including thrombocytopenia or after major surgery. Rarer mild complications related to the replacement fluid include metabolic defects such as hypomagnesemia, hypophosphatemia, and urticarid rashes caused by minor components of purified human serum albumin. Finally, one has to consider the spectrum of complications related to the underlying disease process. For example, patients with Guillain-Barre syndrome may be more prone to hypotensive episodes or those with thrombotic microangiopathies to bleeding problems.

CONCLUSION Plasma exchange sometimes is a startlingly effective and dramatic procedure in patients with otherwise untreatable disease. The nontrivial rate of complications in TPE demands intensive screening of patients before committing them to this hazardous and expensive therapy; nevertheless, the rarity of lifethreatening complications and the potential benefits in suitably selected patients argue strongly that it is a worthwhile procedure if performed by experienced personnel with appropriate monitoring.

SUGGESTED READING Abel JJ, Rowntree LG, Turner BB: Plasma removal with return of corpuscles (plasmapheresis). J Pharmacol Exp Ther 5:625-634, 1914 Burgstaler EA, Pineda AA: Plasma exchange versus affinity column for cholesterol reduction. J Clin Apheresis 769-74, 1992 Campion EW Desperate diseases and plasmapheresis. N Engl J Med 3261425-1427, 1992

Choudhary PP, Hughes RAC Long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathywith plasma exchange or intravenous immunoglobulin. Q J Med 88:493-502, 1995 Ciavarella D, Wuest D, Strauss RG et ak Management of neurological disorders. J Clin Apheresis 8:242-257, 1993 Consensus Conference: The utility of therapeutic plasmapheresis for neurological disorders. JAMA 2561333-1337, 1986 Couriel DC, Weinstein R Complicationsof therapeutic plasma exchange: a recent assessment. J Clin Apheresis 9:l-5, 1994 Domen RE, Kennedy MS, Jones LL, Senhauser DA Hemostatic imbalances produced by plasma exchange. Transfusion 24336339, 1984 Dwosh IL, Giles AR, Ford PM et al: Plasmapheresistherapy in rheumatoid arthritis: a controlled double blinded crossover trial. N Engl J Med 308:1124-1129, 1983

Dyck PJ, Daube J, O'Brien P et al: Plasma exchange in chronic demyelinating polyradiculoneuropathy. N Engl J Med 3 14:461465, 1986 Dyck PJ, Litchy WJ, Kratz KM et al: A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 36838-845, 1994 Dyck PJ, Low PA, Windebank AJ et ak Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med 325:1482-1486, 1991 French Cooperative Group on Plasma Exchange in Guillain-Barre Syndrome: Plasma exchange in Guillain-BarrC syndrome: one year followup. Ann Neurol 32:94-97, 1992 Gajdos P, Chevret S, Clair B et al: Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol 41:789-796, 1997 Grishaber JE, Cunningham MC, Rohret PA, Strauss RG Analysis of venous access for therapeutic plasma exchange in patients with neurological disease. J Clin Apheresis 7:119-123, 1992 Guillain-Barre Study Group: Plasmapheresis and acute Guillain-Barrk syndrome. Neurol 85:1096-1104, 1985 Huestis DW Mortality in therapeutic hemapheresis. Lancet 1:1043, 1983 Kornfeld P, Fox S, Maier K, Mahjoub M: Ten years experience with therapeutic apheresis in a community hospital. J Clin Apheresis 7:63-68, 1992

Lewis EJ, Hunsicker LS, Lan SP et ak A controlled trial of plasmapheresis therapy in severe lupus nephritis. N Engl J Med 3261373-1379, 1992 McKhann G, Griffen J, Cornblath D et al: Plasmapheresis and GuillainBarre syndrome: analysis of prognostic factors and the effect of plasmapheresis. Ann Neurol 23:347-353, 1988 McLeod BC, Sniecinski I, Ciavarella D et al: Frequency of immediate adverse effects associated with therapeutic apheresis. Transfusion 39~282-288, 1999

Miller FW, Leitman SF, Cronin ME et ak Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med 3261380-1384, 1992

Chapter 27 W

Moake JL TTP desperation, empiricism, progress. N Engl J Med 325426-428, 1992

Noseworthy JH, Vandervoort MK, Penman M et al: Cyclophosphamide and plasma exchange in multiple sclerosis. Lancet 337( 1):1540-1541, 1991

Rehabilitation of Neurologic Disability

243

Ropper AH, Albers JW, Addison R Limited relapse in Guillain-Barrk syndrome after plasma exchange. Arch Neurol45:314315, 1988 Samtleben W, Randerson DH, Blumenstein M et al: Membrane plasma exchange: principles and application techniques. J Clin Apheresis 2~163-169, 1984

Osterman PO, Fagius J, Lundemo G et al: Beneficial effects of plasma exchange in acute inflammatory polyradiculoneuropathy. Lancet (2):1296-1298, 1984

Owen HG, Brecher M E Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis. Transfusion 34891-894, 1994

Parker TS, Gordon BR, Saal SD et al: Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis. Proc Natl Acad Sci USA 83:777-781, 1986 Pearl RG, Rosenthal MM: Metabolic alkalosis due to plasmapheresis. Am J Med 79:391-393, 1985 Plasma ExchangelSandoglobulin Guillain-Barrk Syndrome Trial Group: Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barrk syndrome. Lancet 349: 225-230, 1997

Reimann PM, Mason P D Plasmapheresis: technique and complications. Int Care Med 163-10, 1990 Rock GA, Shumak KH, Buskard NA et al: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med

Schwab PJ, Fahey JL Treatment of Waldenstriim’s macroglobulinemia by plasmapheresis. N Engl J Med 263574579, 1960 Strauss RG Current status of hemapheresis in the United States. J Clin Apheresis 6 9 5 9 8 , 1991 Sutton DMC, Nair RC, Rock G et al: Complications of plasma exchange. Transfusion 293126127, 1989 Thornton CA, Griggs RC Plasma exchange and intravenous immunoglobulin treatment of neurological disease. Ann Neurol 8526G268, 1994

van der Meche FGA, Schmitz PIM, and the Dutch Guillain-Barrk Study Group: A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Bar6 syndrome. N Engl J Med 3261 123-1 129, 1992

Weinstein R Therapeutic apheresis in neurological disorders. J Clin Apheresis 15374128, 2000 Wood L, Jacobs P The effect of serial therapeutic plasmapheresis on platelet count, coagulation factors, plasma immunoglobulin, and complement levels. J Clin Apheresis 3:124-128, 1986 Ziselman EW, Bongiovanni MB, Wurzel HA: The complications of therapeutic plasma exchange. Vox Sang 46270-276, 1984

325:393-397, 1991

27

Rehabilitation of Neurologic Disability Me1 B. Glenn and Susan Biener Bergman

The development of a disabling neurologic condition can affect the patient’s medical health, mobility, self-care and independent living skills, vocational and recreational abilities, social roles, and psychological health. Each of these areas must be evaluated and then addressed in a coordinated team approach. The physician leading the rehabilitation effort must be trained to work as part of the team, not only tackling the medical aspects of neurologic disease but also treating the resulting impairments, disabilities, and psychosocial concerns. Residency training in physical medicine and rehabilitation specificallyaddresses these issues. However, some neurologists have spent much of their careers in a rehabilitation setting, and there has been a growing awareness among neurologists of rehabilitation issues. In recognition of the link between the two specialties, the American Board of Physical Medicine and Rehabilitation and the American Board of Psychiatry and Neurology have approved 5-year joint training that can lead to board certification in both specialties. Although traditionally the bulk of the initial rehabilitation after the onset of severe neurologic disability has been performed in an inpatient hospital setting, as health care has changed, rehabilitation has moved to a greater extent to the outpatient setting. The physician therefore is more likely to see a more disabled outpatient than in the past and must be prepared to address the more acute rehabilitation needs with a team-oriented outpatient approach. This chapter addresses some of the more

H common issues facing the clinician working with the neurologically disabled outpatient. MOTOR CONTROL Central Nervous System Disorders Spasticity is common with central nervous system (CNS) disease, and other motor problems may coexist with it, depending on the locus of injury. Spasticity often is prominent with spinal cord disease, stroke, cerebral palsy, traumatic brain injury, and hypoxic and other encephalopathies. With it are often seen weakness; primitive motor behaviors, such as the synergies, postural and labyrinthine reflexes, and prominent nociceptive reflexes (e.g., flexor spasms); and at times rigidity, dystonia, ataxia, and tremors. Proper treatment depends on a thorough inventory of the motor disturbances and an evaluation of their relative contribution to disability. What may be a problem at one time may be an asset at another, as in the use of spastic knee extensor muscles to aid in weight bearing or the use of spastic finger flexors to assist in grasping. A search for nociceptive influences is called for when spasticity or flexor spasms are severe or higher than baseline. Problems with the urinary tract, bowel, or skin are the most common contributors. Treating these exacerbating factors may reduce spasticity. Physical and occupational therapy play a primary role in

Chapter 27 W

Moake JL TTP desperation, empiricism, progress. N Engl J Med 325426-428, 1992

Noseworthy JH, Vandervoort MK, Penman M et al: Cyclophosphamide and plasma exchange in multiple sclerosis. Lancet 337( 1):1540-1541, 1991

Rehabilitation of Neurologic Disability

243

Ropper AH, Albers JW, Addison R Limited relapse in Guillain-Barrk syndrome after plasma exchange. Arch Neurol45:314315, 1988 Samtleben W, Randerson DH, Blumenstein M et al: Membrane plasma exchange: principles and application techniques. J Clin Apheresis 2~163-169, 1984

Osterman PO, Fagius J, Lundemo G et al: Beneficial effects of plasma exchange in acute inflammatory polyradiculoneuropathy. Lancet (2):1296-1298, 1984

Owen HG, Brecher M E Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis. Transfusion 34891-894, 1994

Parker TS, Gordon BR, Saal SD et al: Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis. Proc Natl Acad Sci USA 83:777-781, 1986 Pearl RG, Rosenthal MM: Metabolic alkalosis due to plasmapheresis. Am J Med 79:391-393, 1985 Plasma ExchangelSandoglobulin Guillain-Barrk Syndrome Trial Group: Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barrk syndrome. Lancet 349: 225-230, 1997

Reimann PM, Mason P D Plasmapheresis: technique and complications. Int Care Med 163-10, 1990 Rock GA, Shumak KH, Buskard NA et al: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med

Schwab PJ, Fahey JL Treatment of Waldenstriim’s macroglobulinemia by plasmapheresis. N Engl J Med 263574579, 1960 Strauss RG Current status of hemapheresis in the United States. J Clin Apheresis 6 9 5 9 8 , 1991 Sutton DMC, Nair RC, Rock G et al: Complications of plasma exchange. Transfusion 293126127, 1989 Thornton CA, Griggs RC Plasma exchange and intravenous immunoglobulin treatment of neurological disease. Ann Neurol 8526G268, 1994

van der Meche FGA, Schmitz PIM, and the Dutch Guillain-Barrk Study Group: A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Bar6 syndrome. N Engl J Med 3261 123-1 129, 1992

Weinstein R Therapeutic apheresis in neurological disorders. J Clin Apheresis 15374128, 2000 Wood L, Jacobs P The effect of serial therapeutic plasmapheresis on platelet count, coagulation factors, plasma immunoglobulin, and complement levels. J Clin Apheresis 3:124-128, 1986 Ziselman EW, Bongiovanni MB, Wurzel HA: The complications of therapeutic plasma exchange. Vox Sang 46270-276, 1984

325:393-397, 1991

27

Rehabilitation of Neurologic Disability Me1 B. Glenn and Susan Biener Bergman

The development of a disabling neurologic condition can affect the patient’s medical health, mobility, self-care and independent living skills, vocational and recreational abilities, social roles, and psychological health. Each of these areas must be evaluated and then addressed in a coordinated team approach. The physician leading the rehabilitation effort must be trained to work as part of the team, not only tackling the medical aspects of neurologic disease but also treating the resulting impairments, disabilities, and psychosocial concerns. Residency training in physical medicine and rehabilitation specificallyaddresses these issues. However, some neurologists have spent much of their careers in a rehabilitation setting, and there has been a growing awareness among neurologists of rehabilitation issues. In recognition of the link between the two specialties, the American Board of Physical Medicine and Rehabilitation and the American Board of Psychiatry and Neurology have approved 5-year joint training that can lead to board certification in both specialties. Although traditionally the bulk of the initial rehabilitation after the onset of severe neurologic disability has been performed in an inpatient hospital setting, as health care has changed, rehabilitation has moved to a greater extent to the outpatient setting. The physician therefore is more likely to see a more disabled outpatient than in the past and must be prepared to address the more acute rehabilitation needs with a team-oriented outpatient approach. This chapter addresses some of the more

H common issues facing the clinician working with the neurologically disabled outpatient. MOTOR CONTROL Central Nervous System Disorders Spasticity is common with central nervous system (CNS) disease, and other motor problems may coexist with it, depending on the locus of injury. Spasticity often is prominent with spinal cord disease, stroke, cerebral palsy, traumatic brain injury, and hypoxic and other encephalopathies. With it are often seen weakness; primitive motor behaviors, such as the synergies, postural and labyrinthine reflexes, and prominent nociceptive reflexes (e.g., flexor spasms); and at times rigidity, dystonia, ataxia, and tremors. Proper treatment depends on a thorough inventory of the motor disturbances and an evaluation of their relative contribution to disability. What may be a problem at one time may be an asset at another, as in the use of spastic knee extensor muscles to aid in weight bearing or the use of spastic finger flexors to assist in grasping. A search for nociceptive influences is called for when spasticity or flexor spasms are severe or higher than baseline. Problems with the urinary tract, bowel, or skin are the most common contributors. Treating these exacerbating factors may reduce spasticity. Physical and occupational therapy play a primary role in

244

Plinciples of Ambulatory Neurology and the Approach to Clinical Problems

treating many of the motor disorders seen with CNS disease. Range-of-motion (ROM) exercises with slow, sustained muscle stretch are pivotal in treating spasticity and other hypertonias. Patients and their caregivers should be taught to perform these exercises regularly to aid in the inhibition of increased muscle tone and to prevent contractures from developing or worsening. Therapists use a variety of other techniques to inhibit problematic hypertonia or reflex movements and to facilitate isolation of the controlled active movement when patterned movements tend to predominate. Proper positioning in bed or chairs is essential to this process. When these abnormal movements cannot be inhibited, therapists can help the patient learn to use them functionally. Strengthening exercises can be included when weakness is contributing to loss of motor control. Strengthening can also be used to decrease spasticity in the antagonist muscles. A variety of physical modalities often are useful as well. These include heat, cold, low-frequency vibration, electric stimulation of antagonists, high-frequency electrical stimulation of the hypertonic muscle, electromyographic biofeedback, and ultrasound. Casts or carefully fitted orthotic devices can help normalize muscle tone and movement control. They are most commonly used at the foot and ankle or the hand and wrist. Ankle-foot orthoses (AFOs) can assist in restoring a heel-toe gait by preventing excessive plantar flexion and inversion. Plastic orthoses can be made more restrictive to control more severe problems with hypertonia. Alternatively, they can be extensively customized to support critical areas of the foot, with customized footplates if necessary. Metal AFOs can be made with double-action ankle joints that allow adjustment of ankle position and its secondary effect on knee and hip positioning, which can then be readjusted as the patient’s motor control evolves. Medial or lateral straps can be used to control eversion and inversion. Children with spasticity and weakness at the knees and hips at times will need long-leg braces and pelvic bands, with the more proximal components gradually weaned as control improves. Patients and their assistants can be taught to use other equipment such as reachers, adapted splints, canes, crutches, walkers, wheelchairs, hospital beds, lifts, and other devices to improve activity of daily living (ADL) and mobility skills. Electronically based environmental control units can be used for more remote tasks, such as turning on radios and televisions or opening doors. Speaker phones can now follow voice commands, and voice-operated computers have evolved to become a practical alternative for some people. For those with speech impairments, a variety of augmentive communication devices are available. Medications can be useful when more conservative approaches are not adequately addressing the problem or are not practical. Muscle tone can be assessed using a scale such as the Ashworth or Modified Ashworth Scale, although such scales may not be sensitive or reliable enough to pick up the changes seen with medications. Response is best gauged by targeting specific functional or prefunctional goals and observing and discussing the response with the patient and therapists. Diazepam and other benzodiazepines are useful for spasticity, flexor spasms, and dystonic posturing. The usual dosage range of diazepam is from 4 to 60 mg/day. The proclivity of the benzodiazepines to cause sedation and impairment of attention and memory often precludes their use in those with supraspinal disease and older adults, who are most susceptible to these effects. Benzodiazepines should not be discontinued abruptly because withdrawal symptoms may occur. Baclofen tends to be somewhat less problematic with regard

Principles of Treatment

to cognitive side effects but often causes similar problems. Baclofen probably is more effective at addressing problematic flexor spasms than in decreasing hypertonia. It is generally started at 5 mg three times daily and increased gradually to 20 mg four times daily or the lowest dosage providing maximal benefit. Much higher dosages are sometimes used without adverse effect. It should not be discontinued abruptly because hallucinations can occur. Although it can be sedating, dantrolene sodium is the least likely to be so, which is an advantage for treating spasticity in patients with cerebral disorders. Dantrolene generally is started at 25 mg once or twice daily and gradually increased to as much as 100 mg four times daily. It occasionally causes hepatotoxicity and should be used only when liver function tests can be monitored. Because it affects hypertonia by inhibiting calcium release from the sarcoplasmic reticulum, it has a propensity to weaken muscles as well. This does not usually affect function except in areas where already weak muscles are strong enough to be useful but where the balance can easily be tipped. Clonidine has been used to treat spasticity and flexor spasms, but tizanidine, a central a,adrenergic agonist designed explicitly to treat increased muscle tone, is less likely to cause hypotension and dizziness. However, it is often sedating. It should be started at low dosages, such as 2 mg four times a day, and titrated gradually to as much as 36 mg/day. It is occasionally hepatotoxic, and liver function tests should be monitored. Gabapentin can be an effective agent for spasticity as well. Dosages of at least 1800 mg/day often are necessary. Gabapentin also must be increased gradually because of potential problems with sedation and dizziness. The treatment of parkinsonian rigidity is described in Chapter 114. Side effects and lack of the desired efficacy often limit the usefulness of medications in treating hypertonia, and more invasive approaches may be necessary. Chemical neurolysis with phenol or alcohol and neuromuscular blockade with botulinum toxin are both effective means of addressing spasticity by targeting a specific muscle or muscle group. The duration of effect of chemical neurolysis with phenol ranges from days to years but generally can be expected to be 6 months or more. Blocks can be performed at the level of the nerve root or plexus, the mixed sensorimotor peripheral nerve, or the motor nerve or branch. Although active function can be diminished in weak muscles or those in which hypertonia is being used to the patient’s advantage, with proper assessment before the block, this is not usually a problem. Only a small percentage of axons usually are affected by the block. When mixed sensorimotor nerves are lysed, dysesthesias can develop in the sensory distribution, but this typically lasts only a few weeks, and the level of pain generally is manageable. Rarely, the pain is severe or unremitting, in which case low-dose tricyclic antidepressants, a course of systemic corticosteroids, or ultimately a reblock at the same site usually relieves the pain. This issue can be avoided entirely by blocking motor branches only. Sensory loss is rare with chemical neurolysis of mixed sensorimotor nerves. Injecting botulinum toxin into the muscle can achieve a similar reduction in muscle tone, but the effect generally lasts for only 2 to 4 months. This can be an advantage or disadvantage, depending on the situation. The development of antibodies to botulinum toxin occasionally can render this treatment ineffective over time. There are now two subtypes, botulinum toxin A and B, available for intramuscular injection. Baclofen can also be delivered via an intrathecal pump with greater effect and avoidance of systemic side effects. The effectiveness of intrathecal baclofen has been demonstrated in patients

Chapter 27

with spinal cord pathology or spasticity caused by supraspinal lesions. The dosage can be titrated and programmed for the patient’s needs. Spasticity can also be diminished with radiofrequency dorsal rhizotomy. The procedure is effective for spasticity and usually lasts longer than chemical neurolysis. However, it can permanently impair sensation. Therefore, it is best reserved for those with complete sensory loss caused by spinal cord injury or for those with brain injury who are so physically incapacitated that they rely on others for ADLs, mobility, and skin care. It is not indicated for those whose major dysfunction or problem with care is being caused by dystonic posturing. Selective surgical dorsal rhizotomy generally does not cause impaired sensation and has been effectively used to diminish spasticity in children with cerebral palsy. It is a significantly more invasive procedure than radiofrequency rhizotomy. Dorsal column stimulation is used in some centers with reports of successful reduction of spasticity. It is rarely necessary to resort to other procedures with greater associated risks, such as myelotomy and intrathecal phenol injection, since the development of these approaches to problems with muscle tone. Orthopedic procedures can also contribute to hypertonia control. Musculotendinous transfers can be used to balance the tone about a joint but must be approached with great care because of the possibility of creating an imbalance on the antagonist side. Musculotendinous lengthening allows greater muscle stretch, particularly when contracture has developed in the context of spasticity. Lengthenings may need to be combined with other approaches so that the neurologic component is controlled as well. Ataxia can be an extremely disabling condition and is difficult to address. Occupational and physical therapists can help a patient to learn to stabilize an upper extremity proximally for more effective use of the distal extremity. Stabilizing devices can assist walking. However, functional motor control may improve only with numerous repetitions of the skill to be learned over weeks, months, and years. A variety of medications (e.g., P-adrenergic blockers, clonazepam, buspirone) have been reported to improve ataxia, although none has been proven to be consistently effective in well-controlled studies with large sample sizes. The pharmacologic management of other tremors and dyskinesias associated with CNS disorders is discussed in Chapter 125. Motor Unit Disorders

Muscle weakness is the sine qua non of the muscular dystrophies and often is a major issue in rehabilitating patients with motor neuron disease, peripheral neuropathy, or radiculopathy. The role of strengthening exercises in motor unit disorders has been controversial. In the early 197Os, the observation that some patients with, muscular dystrophy developed overwork weakness contributed to concern about the safety of active exercise. Indeed, overwork weakness may be the basis of postpolio syndrome. Numerous studies have demonstrated both the potential for the development of overwork weakness after heavy exercise and the safety and efficacy of submaximal resistance exercise, stopping well short of muscle fatigue. The latter can strengthen muscles in those with static disorders and retard the progression of weakness and maximize function in those with progressive disorders. Exercise plays a crucial role in treating radiculopathy. Pain can be reduced and further injury prevented by optimizing posture, flexibility, and strength in key areas. For example, when lumbosa-

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cral radiculopathy causes low back pain, strengthening exercises to the abdominals, paraspinals, and hip and knee extensors usually are prescribed as well as stretching exercises for the hamstrings, paraspinals, and other hip and pelvic muscles. For patients whose tolerance of land activities is limited, pool therapy offers an easily tolerated alternative. Proper body mechanics during basic and more strenuous ADLs help to prevent further injury. In entrapment neuropathies and cumulative trauma disorders, proper positioning, ergonomicallyoptimal workstations and tools, and strengthening of supporting musculature are most useful. Judicious use of nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen 600 mg four times daily) can help relieve pain so that exercise is better tolerated. The COX-2 inhibitors offer a powerful treatment alternative with a diminished risk of gastrointestinal bleeding, although they may be difficult to fund. Chronic pain can be treated effectively with low-dose tricyclic antidepressants (e.g., amitriptyline, starting at 10 mg at bedtime). Other useful classes of medications include local anesthetics, anticonvulsants, and certain antispasticity drugs, such as tizanidine. Narcotic analgesics may be helpful in certain settings. Transcutaneous electrical nerve stimulation may help control localized discomfort. Pain management is discussed in greater depth in Chapters 227 through 230. Progressive disorders, especially those that present in childhood, offer special challenges. Therapeutic goals include postponing loss of ambulation and enhancing independencein activitiesof daily living. ROM exercises help to retard the development of contractures. Normal ADLs or play should not be overlooked as a therapeutic regimen. They can provide submaximal active exercise, are easier to comply with than formal exercise sessions, and can have psychological benefit. Avoiding obesity also helps to maintain mobility. In the progressive disorders of childhood, as muscle weakness progresses, compensatory postures develop, facilitating the development of joint contractures. Together, weakness and contradures severely threaten mobility. Certain signs and symptoms herald the loss of ambulation, including falls, decreased active hip and knee extension, loss of stair climbing, decreased ROM in hips, knees, and ankles, and decreased cumulative standing and walking time per day. Hip and knee flexion contractures and ankle plantar flexion contractures should be monitored. Once these signs are noted, bracing should be initiated. Selection of the proper type of braces depends on the degree of weakness present. AFOs can relieve foot drop and reduce the stress on weakened hip girdle musculature. In patients with more severe hip weakness, lightweight knee-ankle-foot orthoses (UFOs) can be beneficial. Bracing can also be used to enhance safety and reduce pain and fatigue in neuropathies and radiculopathies. By normalizing gait patterns, energy consumption drops and injury to supporting muscles is minimized. Night splints to hold the neutral position can be used to reduce contractures and maintain ROM at the ankle in severe neuromuscular diseases. They can also reduce pain in entrapment neuropathies while facilitating resolution. Care must be taken to ensure proper fit and adequate padding to prevent skin breakdown. Contracture prevention is also important in the upper extremities. Wrist and finger deformities in progressive neuromuscular diseases can accelerate the loss of hand strength and function in the progressive neuromuscular diseases or severe neuropathies. For patients who can not ambulate safely, care must be taken in selecting the proper wheelchair. Instead of representing a loss, the

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right wheelchair can increase freedom and enable the patient to keep up with peers. However, in progressive disorders, moving to full-time wheelchair use can hasten the progression of scoliosis and respiratory muscle weakness, particularly in children. Therefore, proper positioning is vital. The patient should be comfortable and sit squarely on a firm but not rigid surface to prevent pelvic obliquity. A seatbelt offers additional safety and may prevent loss of positioning. Lateral supports and hip pads may help to maintain proper alignment of the trunk. Cushions and back supports can be adjusted to accommodate individual structural deformities and provide a stable seating surface. Custom-molded systems can be useful for those with deformities that are difficult to correct or accommodate. Overly rigid systems should be avoided; more compliant materials are better tolerated by fully sensate patients. Specific prescription considerations are well outlined by Brammell and Maloney. The choice of power chair control mechanisms depends on the degree of residual hand function. Adaptive equipment, ranging from the high-tech to the low-tech, can be very useful in prolonging independence with ADLs. Such equipment includes long-handled combs, brushes, and sponges; toilet paper holders, shoehorns, flexible shower hoses, tub transfer seats, elastic shoelaces, reaches, plate guards, built-up utensils, sandwich holders, and the like. Electronic equipment such as environmental control units and robotic devices may be helpful to augment function. Home modifications such as installment of ramps, widening of doorways, and elimination of architectural barriers can enhance independence. Contracture

Joint contracture is caused by shortening of muscles, tendons, ligaments, and joint capsules or by heterotopic ossification. Contractures are a common consequence of weakness, hypertonia, or hypotonia, and disuse. Passive, active, or active-assisted ROM exercises should be started as soon as possible after the onset of a disorder that results in one or more of these abnormalities to prevent contractures. Such exercises should be started as soon as possible to promote remediation if therapy begins after contractures have developed. Orthotics and other devices to control positioning often are essential to prevention. Hypertonia often must be addressed to prevent or remediate contractures. Serial casting or splinting is an effective method for regaining ROM once it has been lost. Traction is occasionally used but is often not practical. Surgical release or lengthening often is necessary when other approaches have failed. Contracture of nervous and vascular structures may limit the ability to lengthen soft tissues after long-standing contracture. Contractures are most easily reversed when they have recently developed but can usually be substantially corrected after months and sometimes even after years. Shoulder stiffness often develops in the hemiplegic patient after stroke, and this is often followed by shoulder-hand syndrome, which is believed to be a variant of regional pain syndrome (reflex sympathetic dystrophy). The joints of the hand become stiff, and flexion contractures begin to develop. Pain, edema, and vasomotor changes are prominent. The patient vigilantly protects the hand and may resist ROM exercises. The key to remediating this problem is to reduce edema and stiffness of the hand and stiffness of the shoulder. Edema is best controlled by elevation, edemareducing gloves, or graded wrapping of the fingers and hand, ROM exercises, and massage. Warm or cold packs to the hand and shoulder can make ROM movements less painful. A course of an

Principles of Treatment

NSAID may reduce pain and inflammation, although a short course of a corticosteroid is more likely to be effective for more severe shoulder-hand syndrome. A low dosage of a tricyclic antidepressant may also help to reduce pain. Other pharmacologic options include the anticonvulsants, particularly gabapentin. Stellate ganglion blocks may be necessary when other interventions have failed. If spasticity is causing pain and limiting ROM at the shoulder, nerve blocks to affect the shoulder adductors and internal rotators can be helpful. Neurogenic heterotopic ossification commonly occurs after a traumatic spinal cord injury (SCI) or severe traumatic brain injury (TBI) and occasionally can be seen with nontraumatic lesions of the CNS or peripheral nervous system. Often heralded by signs of a local inflammatory response, it occasionally causes significant disability in the patient with SCI but more commonly results in disability in the patient with severe TBI by causing pain and contracture at the shoulders, elbows, hips, and knees. The cause is uncertain, but trauma to the joint during ROM exercises or assisted transfers in the unconscious patient or patient with insensate extremities may lead to an interaction between undifferentiated mesenchymal cells and endogenous chemical mediators. Avoiding ROM exercises is not a satisfactory preventive measure in most instances because contracture will almost certainly develop if they are not done. Therapists must walk a fine line between contracture formation and the possibility of developing heterotopic ossification. Once ossification starts to form, ROM exercises generally are necessary to prevent ankylosis, although the severe pain caused by the presence of the heterotopic bone can be a limiting factor in the patient whose sensation is intact. Administering bisphosphonates such as disodium etidronate can effectively prevent hydroxyapatite crystal deposition on the bony matrix but does not prevent the osteoid. Once the medication is stopped, mineralization is likely to proceed. Although there may be some long-term benefit to using etidronate prophylactically for 3 to 6 months, this issue has not yet been studied sufficiently. NSAIDs have been studied for preventing postsurgical recurrence of heterotopic ossification but not as a prophylactic measure shortly after an injury. Ultimately, if heterotopic ossification results in limitation of ROM with functional consequences,surgical excision can be considered. However, recurrence is a common problem. To minimize this, the surgery usually is delayed until more than a year after the injury to allow the bone to mature. NSAIDs and radiotherapy appear to be effective approaches to prevent recurrence, although further studies are needed. In those with heterotopic ossification after TBI, the better the cognitive and motor function of the patient, the less likely recurrence seems to be. Participation in postoperative therapy is better as well. Scoliosis

Rapidly progressive spinal curvature is a significant source of morbidity in pediatric neuromuscular disease and is not uncommon in children with upper motor neuron dysfunction. If left untreated, curve progression can result in incapacitating deformities that can interfere with seating, worsen restrictive lung disease, and wreak havoc on body image. Until fairly recently, scoliosis was treated with various types of orthoses. Some may slow the course of progression, but none has effectively prevented progression. As survival has increased with mechanical ventilation, more aggressive surgical approaches have been tried. Timing of surgical intervention is critical to avoid both rapid increase in the magnitude of the curve and pulmonary complications. La Prade

Chapter 27 H Rehabilitationof Neurologic Disability

advocates offering surgery to patients whose curves approach 30 degrees and who have vital capacities of at least 30% the predicted value. Early surgical techniques such as Harrington rod instrumentation have given way to segmental spinal stabilization, which may not entail postoperative external immobilization. The curves must be considered in three dimensions, and the length of the fusion should be carefully calculated. RESPIRATORY INSUFFICIENCY In the late stages of progressive neuromuscular disorders and motor neuron disease, detection and treatment of respiratory insufficiency become the most pressing issues. Careful history taking may reveal symptoms of mild hypercarbia or hypoxemia, including anxiety, insomnia, morning headaches, somnolence, and nightmares. Pulmonary function testing in both sitting and supine positions may be helpful. Appropriate preventive measures include annual influenza vaccines and aggressive chest physical therapy for respiratory infections. Patients with high cervical SCI should receive these prophylactic therapies as well. Sleep apnea is common in patients with cervical SCI. Splaingard et al offer criteria for beginning mechanical ventilation in neuromuscular disease, including vital capacity below 25% predicted along with at least one of the following: P a , greater than 55 mm Hg Recurrent atelectasis or pneumonia Moderate dyspnea at rest Congestive heart failure They further suggest instituting nighttime ventilation on a semielective basis after careful discussion. Negative-pressure devices may be helpful at this stage. As the disease progresses further, daytime ventilation eventually will be needed. Tracheostomy may be necessary in the presence of upper airway obstruction. Technologic advances have allowed us to offer patients the opportunity to extend their lives significantly. However, before such treatment is started, some ethical issues must be addressed. Some argue that the quality of life once the patient becomes ventilator dependent is unacceptable. This argument is inconsistent with recent studies. Despite the fact that in Muscular Dystrophy Association clinics only one third of practitioners routinely prescribe respirators for patients developing respiratory failure, most respirator-dependent patients scored similarly to healthy controls in a recent life satisfaction survey. Despite decreased activity, patients can maintain their satisfaction with life. However, patients and families deserve to be fully informed about all aspects of living with a ventilator. Discussions with peers who have been through a similar experience may be helpful. The most beneficial approach to this problem is to discuss the options with the patient and family before respiratory failure becomes evident. This information should be repeated to be sure it is understood. The impact on family life, the ethical and legal difficulties involved in withdrawing support, and the fact that mechanical ventilation is not a cure should be emphasized. Ultimately, the decision belongs to the patient and family. The health care team can facilitate discussion of these issues. Counseling for the patient and the family can also help them sort out their feelings about death and dying. As society becomes more accepting of those with disabilities and as technology affords more effective devices, the length and quality of life for such patients will continue to improve. A

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well-managed patient can live significantly longer. With appropriate concern for psychological issues, this extended life can be satisfying. URINARY TRACT DYSFUNCTION Upper motor neuron disease can cause impairment of the urinary tract, resulting in incontinence, infection, stone formation, and the potential for renal insufficiency. Spinal cord lesions cause a hyperreflexic detrusor and the potential for detrusor-sphincter dyssynergia (simultaneous contraction of the detrusor and external or internal sphincters) and increased intravesical pressure. Increased intravesical pressure can result in bladder trabecdation and diverticula, vesicoureteral reflux, pyelonephritis, and hydronephrosis. When the bladder is not emptying properly, intermittent catheterization, aided by anticholinergic drugs if necessary, generally is the best approach but may not be practical because of motor impairment of the upper extremities, lack of availability of others to do catheterization, work schedules, or compliance problems. Indwelling catheters tend to encourage infection, stone formation, and urethral erosion and may be associated with an increased risk of carcinoma of the bladder. Suprapubic catheters avoid urethral problems and may be an acceptable choice. Surgical sphincterotomy or periodic application of phenol or botulinum toxin to the external urethral sphincter are other options that allow the use of an external drainage system without catheterization in the male. Some male patients can empty their bladders reasonably well and safely enough to use an external drainage system without the need for any procedures. Absorbent briefs may be necessary in some female patients. Diversion and bladder augmentation procedures are other alternatives for providing continence and greater ease of catheterization. However, the patient should understand the risks and should be encouraged to undergo yearly cystoscopy to screen for changes in the bladder lining. Measurement of voided volume and postvoid residual volume is a simple method for determining bladder capacity and assessing whether the patient with a neurologic disorder has a problem with storage or emptying. Urodynamic studies determine the dynamics of the detrusor and sphincters and measure the intravesical pressure. In patients with SCI, they should be obtained when increased voiding between intermittent catheterizations and lower postvoid volumes indicate that the transition from a hyporeflexic to hyperreflexic bladder is occurring. A cystometrogram is useful when reflux is suspected. Patients with potential for upper tract problems caused by increased intravesical pressure or reflw should have their upper tracts examined periodically with, for example, renal ultrasound and renal scan. Because detrusor-sphincter coordination is controlled at the pontine level, patients with intracranial lesions rarely develop detrusor-sphincter dyssynergia and therefore do not tend to have problems with increased intravesical pressure, reflux, and hydronephrosis. In such patients, the urodynamic study generally indicates that there is a hyperreflexic bladder that empties at low volumes without undue reflexive sphincter contraction. Urodynamic and upper tract studies are necessary only when repeated urinary tract infections occur or outlet obstruction is suspected. Lower motor neuron lesions result in a hyporeflexic detrusor with difficulty voiding and overflow leakage. This situation is best managed with intermittent catheterization, but if this is not practical, suprapubic catheters can be a reasonable alternative. If incontinence is primarily the result of inability to toilet oneself, then condom catheters and leg bags can be useful in male patients.

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Although indwelling urethral catheters may be a viable alternative for some female patients, they too often result in urethral dilation or breakdown. In addition, they promote urinary tract infection and stone formation. In male patients, indwelling urethral catheters often cause penile-scrota1 fistulas and abscesses. Incontinence briefs may be a necessary alternative if assistance is not available on a frequent enough basis. Symptomatic infections should be treated with antibiotics, but it is futile to attempt to treat persistent asymptomatic bacteriuria with course after course of antibiotics. Many patients with neurogenic bladders adapt to ongoing colonization with only occasional problems. Those who have vesicoureteral reflux, hydronephrosis, or urea-splitting organisms are at greater risk, and in such patients eradication of asymptomatic bacteriuria should at least be attempted. The best preventive approach remains bacteriostatic agents such as urinary acidifiers and optimal fluid intake. The value of continuous prophylactic antibiotic treatment is controversial.

BOWEL DYSFUNCTION Patients with lower and upper motor neuron lesions may experience constipation and bowel incontinence. A regular bowel program usually can minimize these problems. After adequately emptying a constipated gastrointestinal tract with laxatives and enemas if necessary, a regular daily or every-other-day suppository or digital stimulation combined with a fiber-rich diet and plenty of fluids is a good starting point. If this is unsuccessful, a stool softener-or, if the stool needs added bulk, psyllium hydrophilic mucilloid-can be added. A laxative such as senna can be given, timed so that its action coincides with the administration of the suppository or digital stimulation. Glycerin suppositories may suffice for some, whereas bisacodyl suppositories or minienemas may be needed for others. Attention should be paid to the bathroom equipment used by the patient to be sure that it fits correctly, is stable, and does not put too much pressure on the skin. If treatment proves difficult, rectodynamic studies, if available, can be used to identify anorectal dyssynergia, which can be treated with topical viscous lidocaine or prolonged anal stretch. If megarectum is diagnosed, high-volume enemas may be necessary. Colostomy should be reserved for those for whom all other approaches have failed.

Principles of Treatment

ety) for sexual dysfunction should be explored, as should the possibility of drug-induced, vascular, or endocrine causes. When needed, the patient should be referred for counseling by professionals experienced in working with the sexual concerns of people with disabilities. When nongenital sensorimotor dysfunction affects sexuality, these problems should be specifically addressed through physical and occupational therapy and the other approaches discussed earlier under “Motor Unit Disorders.” Speech and language issues should be treated by a speech and language pathologist who is aware of the sexual issues involved. Cognitive and behavioral issues can be explored with the assistance of a neuropsychologist who can work with the patient and significant other to develop strategies that will reduce the impact of these problems on the sexual relationship. The use of sexual aids such as vibrators should be discussed when relevant. Erectile dysfunction can be addressed with medications. The availability of oral sildenafil has revolutionized the treatment of sexual dysfunction, particularly after spinal cord injury. Sildenafil can successfully treat erectile dysfunction in men and decreased lubrication and arousal in women. When prescribing sildenafil, it is imperative to carefully review all medications the patient is taking. When sildenafil is taken with nitrate-containing agents, death can result from blood pressure and heart rhythm abnormalities. Other oral agents are being investigated. In addition, injectable vasoactive amines, externally applied vacuum pumps, and surgically implanted penile prostheses remain available. Risk-benefit ratios must be examined with all potential treatments. Higher erosion and infection rates must be considered in the population with SCI. These complications may be less of a problem with the inflatable prostheses than with the rigid type. Problems with vaginal lubrication can be treated with artificial lubricants. Conception generally is normal in women with SCI. Partners of men with SCI usually cannot conceive, in part because of ejaculatory dysfunction and in part because of spermatozoal dysfunction. However, electroejaculation and electrovibration techniques are improving, making conception more likely. Pregnancy, labor, and delivery can usually be brought to a good outcome in women with SCI, although further loss of mobility, skin breakdown, inability to detect labor, and autonomic dysreflexia are potential problems (see also Chapter 15).

AUTONOMIC DYSREFLEXIA SEXUAL FUNCTION

AU too often, health care professionals do not address, and may even avoid, discussion of sexuality with disabled patients. By taking a sexual history, the physician validates the legitimacy of the patient’s often unspoken concerns. Significant others should be brought into the discussion whenever possible. Although sexual dysfunction should be fully discussed, ultimately emphasis should also be placed on the patient’s abilities, whether physical or psychological in nature. In a sexual relationship, ownership of the problems should be placed on the couple as a unit and not solely on the person with the disability. Physicians can play an important role as counselors, providing correct information about neurogenic sexual dysfunction and the effects of motor, sensory, language, cognitive, and behavioral impairment on sexuality while offering approaches to address each of these areas. Sexually transmitted disease prevention, contraceptive needs, and child care should be discussed. Psychological causes (e.g., depression, anxi-

In addition to the hyperreflexia of the somatic and parasympathetically innervated systems noted earlier, patients with SCI above the level of the major sympathetic splanchnic outflow (T6 and above) commonly have hyperactive sympathetic reflexes. A noxious stimulus, usually from the bladder, bowel, or skin, initiates a sympathetic nervous system response that includes increased blood pressure, sweating, and piloerection. The spinal cord is isolated from the usual supraspinal control mechanisms, so the response goes unchecked. Vasodilation results in flushing of the face and neck and nasal and conjunctival congestion. Blood pressure can reach dangerous levels, resulting in intracerebral hemorrhage or seizures if the noxious stimulus is not removed. The patient usually experiences a pounding headache and, at times, chest pain. Most patients with SCI have been educated about this condition during their inpatient rehabilitation stay and alert uninformed caregivers or manage the problem themselves. The treatment is to identify the cause and eliminate it, if possible.

Chapter 27

Some of the common causes include a distended bladder, blocked catheter, urinary tract infection, urinary tract stones, constipation, pressure ulcer, ingrown toenail, tight clothing, and need for a change in position. An intra-abdominal disorder may occasionally be the culprit. While waiting for an infection to respond to treatment, intravesical lidocaine or pyridium may help to control blood pressure by decreasing bladder irritation and spasm and so decreasing afferent input into the reflex arc. Anticholinergic medications can similarly diminish nociceptive input by decreasing bladder irritability. If necessary, antihypertensives such as topical nitroglycerin or nifedipine can be used when the cause is elusive or temporarily unresolvable. Care must be taken to avoid hypotension when the condition resolves. Patients going for urinary tract or other procedures may need prophylactic medication or at least frequent monitoring of their blood pressure. Similar precautions must be taken for women anticipating labor and delivery. Autonomic dysreflexia must be distinguished from preeclampsia-eclampsia to prevent serious maternal morbidity.

COGNITIVE, PERCEPTUAL AND BEHAVIORAL DYSFUNCTION Supraspinal disorders often result in cognitive, language, perceptual, and behavioral impairment with adverse consequences for ADLs, other independent living, community, and vocational skills, and social interactions. These problems may reflect focal lesions, as seen after stroke, or diffuse injuries with superimposed focal lesions, such as those after TBI or anoxic encephalopathy. Those working with such patients must address these issues and any physical impairment that might be present. Neuropsychological evaluation can help to identify the core components of the cognitive disability so that strategies can be based on a thorough understanding of the deficits and the residual strengths of the patient. Language and cognitive treatments generally are designed to challenge the patient at a level at which success can be achieved with the support and structure provided by the therapist. Instruction and cues are intended to help the patient incorporate consistent strategies for overcoming or compensating for the deficit in question. It may be necessary to address core language, cognitive, and perceptual impairment as a starting point, but therapists should move toward working with the patient in a functional context as soon as is practical. It is important to address any sleep disturbances that may exacerbate cognitive impairment. Psychostimulant (e.g., methylphenidate, amphetamines, modafinil) and dopaminergic (e.g., amantadine) drugs can also be useful to address problems with arousal, initiation, and attention, as can the more adrenergic antidepressants (e.g., protriptyline). However, first any medical issues, such as infection or hydrocephalus, should be addressed. Medications that might be exacerbating these problems should be withdrawn, if possible. The treatment of behavioral disorders (e.g., disruptive and combative behaviors) should also be based on an evaluation of the underlying impairments contributing to the problem at hand. Premorbid conditions, such as frustration, depression, and anxiety in reaction to the disability or environment, and neuropsychological conditions can all contribute and must be addressed. Complex partial seizures may occasionally play a role. Those working with the patient must use planned behavioral interventions consistently. Underlying arousal, initiation, and attentional problems are common contributors to aggressive behavior and should be dealt with as noted earlier. If other approaches are not adequately

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effective, a wide variety of pharmacologic interventions can be used to assist in the treatment of aggressive and disruptive behaviors. Sedating or otherwise cognition-impairing drugs such as neuroleptics and benzodiazepines should be avoided unless they are necessary to control dangerous situations or there are specific indications for their use (e.g., psychosis, anxiety). Depression is common after the onset of severe disability. The support of family, peers, and staff, success during rehabilitation, and individual counseling can all be helpful. Cognitively impaired patients may be less able to benefit from these interventions. Medications should be used when depression interferes with the patient’s ability to participate in rehabilitation and other activities or when it is causing pain for extended periods of time.

POSTCONCUSSIONSYNDROME Despite terminology suggesting “mild” disability, patients with mild traumatic brain injury and postconcussion symptoms (headache, vertigo, forgetfulness, difficulty concentrating, fatigue) can be quite debilitated relative to their preinjury status. This can cause anxiety and depression for the significant minority who do not recover quickly. Persistent attention deficits and underarousal should be addressed as outlined earlier. Headaches may necessitate pharmacologic treatment and physical therapy for associated neck pain. Vertigo may improve with vestibular rehabilitation, and medications should be delayed if possible to allow the central nervous system to compensate. Counseling and medications often are needed for depression and anxiety, which along with pain and insomnia can exacerbate the cognitive sequelae (see also Chapter 17).

PSYCHOLOGICALADJUSTMENT AFTER NEUROLOGIC DISABILITY The development of a disability has a profound effect not only on the person with the disabilitybut also on the family and significant others. The disability may alter well-established roles. For example, the provider or nurturer must suddenly rely on others to a much greater extent, or the developing adolescent or young adult is suddenly thrust into a state of greater dependency than that from which he or she was struggling to emerge. Festering or latent interpersonal conflict may flare up. Even the most well-adjusted patient or family member will be placed under severe stress. The physician treating a patient with a neurologic disability should question the patient and family regarding adjustment issues, then counsel or refer for counseling if necessary. The stress felt by the patient and family may manifest itself as anger toward the physician or other rehabilitation team members. Despite the personal feelings that this may arouse in the treatment team, such a response should be approached sympathetically as a rehabilitation issue. At times, the patient or family may split the team into “allies” and “enemies.” As team leader, the physician must be aware of such dynamics to prevent discord among the team members. Other patients and family members may not outwardly express any signs of stress or may deal with stress by avoiding difficult situations as much as possible. These responses should be explored by the physician or other team members, such as the social worker or psychologist. Psychological adjustment after the disability is affected by society’s response to people with disabilities. The constant reminders of the limited access to services readily available to others can be daunting. The person with a disability should be

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encouraged to seek out peer support, if possible in the context of constructive political action. Consumer advocacy groups have had a substantial impact on legislation and funding for the needs of people with disabilities, and the process can be empowering to those involved.

SUGGESTED READINGS Biener Bergman S, Welner S L The disabled patient. In Carr PL, Freund KM, Somani S: The Medical Care of Women. WB Saunders, Philadelphia, 1995 Biener Bergman S, Yarkony GM, Stiens S A Medical complications. Self Directed Medical Knowledge Program. Spinal Cord Injury Rehabilitation. Arch Phys Med Rehabil78:3S, 1997. Braddom RL (ed): Physical Medicine and Rehabilitation. WB Saunders, Philadelphia, 1996 Brammell CA, Maloney FP Wheelchair prescriptions. In Maloney FP, Burks JS, Ringel SP (eds): Interdisciplinary Rehabilitation of Multiple Sclerosis and Neuromuscular Disorders. JB Lippincott, Philadelphia, 1985 Cawley MF, Yarkony GM, Biener Bergman S: Through the lifespan. Self Directed Medical Knowledge Program. Spinal Cord Injury Rehabilitation. Arch Phys Med Rehabil 78333, 1997 Cutter NC, Scott DD, Johnson JC, Whiteneck G: Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil81:164-169,2000 Delisa JA: Rehabilitation Medicine: Principles and Practice. Lippincott Williams & Wilkins, Philadelphia, 1998 Glenn MB, Elovic E Chemical denervation in the treatment of hypertonia and other motor disorders: phenol and botulinum toxin. J Head Trauma Rehabil 12(6):4042, 1997

Glenn MB, Whyte J (eds): The Practical Management of Spasticity in Children and Adults. Lea & Febiger, Philadelphia, 1990 Horn LJ, Zasler N D Medical Rehabilitation of Traumatic Brain Injury. Hanley & Belfus, Philadelphia, 1996 La Prade RF, Rowe D E The operative treatment of scoliosis in Duchenne muscular dystrophy. Orthop Rev 21:39, 1992 Monga M, Berie J, Rajaselcaran M Male infertility and erectile dysfunction in spinal cord injury: a review. Arch Phys Med Rehabil 80 (10):1331-1339, 1999

Rizzo M, Tranel D (eds): Head Injury and Postconcussive Syndrome. Churchill Livingstone, New York, 1996 Rosenthal M, Kreutzer JS, Griffith ER, Pentland B (eds): Rehabilitation of the Adult and Child with Traumatic Brain Injury. 3rd Ed. FA Davis, Philadelphia, 1999 Sipski ML, Rosen RC, Alexander CJ, Hamer RM: Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury. Urology 55(6):812-8 15, 2000 Splaingard ML, Frates RC, Harrison GM: Respiratory function in hereditary neuromuscular diseases: pathophysiologyand management. Curr Concepts Rehabil Med 2:3, 1985 Stiens SA, Biener Bergman S, Formal CS: Individual experience, personal adaptation, and social perspectives. Self Directed Medical Knowledge Program. Spinal Cord Injury Rehabilitation. Arch Phys Med Rehabil 78:3S, 1997

Stiens SA, Biener Bergman S, Goetz L L Neurogenic bowel dysfunction after spinal cord injury: clinical evaluation and rehabilitative management. Arch Phys Med Rehabil 78:3S, 1997 Varney NR, Roberts RJ (eds): The Evaluation and Treatment of Mild Traumatic Brain Injury. Erlbaum, Mahwah, NJ, 1999 Zasler N D Sexuality in neurologic disability: an overview. Sex Disabil 9~11-27, 1991

SECTION

1

GENERAL ASPECTS OF CEREBROVASCULAR DISEASE

28

Epidemiology and Stroke Risk Factors Tom J. Jeerakathil, and Philip A. Wolf

MORTALITY AND INCIDENCE OF STROKE Stroke, the most common life-threatening disease of the nervous system, accounts for half of all patients hospitalized for acute neurologic disease in the United States. Twenty percent of all cardiovascular disease (CVD) deaths are attributable to stroke, which ranks third as a leading cause of death in the United States, after heart disease and cancer. Although stroke is four times more likely to lead to disability than death, the American Heart Association estimates that in 1998 there were 158,448 deaths from stroke in the United States. Mortality data provide rates of stroke deaths according to age, gender, race, and geographic area and supply information on mortality trends over time. Although these death certificate data are crude, the large numbers of uniformly coded events provide a broad picture of stroke mortality (Fig. 28-1). Variation by Age, Gender and Race

Stroke mortality in the United States increases exponentially with age, approximately tripling in successive decades of life. Rates were approximately 50% higher overall in blacks than whites, and the greatest differences were seen in the younger ages, particularly below 65 years. In the National Health and Nutrition Examination Survey I

Epidemiologic Follow-up Study (NHEFS), age-adjusted mortality for blacks from stroke was 1.98 times that of whites. Of interest, 31% of excess mortality could be accounted for by six key risk factors for CVD. A further 38% of the excess deaths could be accounted for by family income. However, nearly one third (31%) of the excess black total mortality remained unexplained. When compared with whites, blacks had higher prevalence rates of hypertension and diabetes. They also had more intracerebral hemorrhage and less extracranial and large artery atherosclerotic disease than whites. Using National Vital Statistics’ death certificate data from 1995-1998 a recent report found that for ischemic stroke, intracerebral hematoma, and subarachnoid hemorrhage ( S A H ) , blacks, American Indians, and Alaskan Natives had higher death rates between ages 25-64 than whites. At older ages the death rates were similar. Hispanics, Asians, and Pacific Islanders had higher rates of intracerebral hemorrhage than whites between ages 25 and 64 but not at older ages. These results confirm earlier data from previous years, suggesting that much of the racial disparity in stroke mortality occurs at the younger ages. The epidemiology of stroke in blacks and Hispanics is being investigated with increased intensity in a number of multiracial populations in the United States. The Northern Manhattan Stroke Study has shown that compared with whites, blacks have a 2.4-fold higher stroke incidence and Caribbean Hispanics have a twofold

2

m e

Year

FIG. 28-1. Mortality from stroke in the United States, 1979 to 2000. Pop, population. (Data from Vital Statistics of the United States, National Center for Health Statistics.) 252

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z

8

Men

FIG. 28-2. Stroke incidence by race and ethnicity in the Northern Manhattan Stroke Study. (Adapted from Sacco RL, Boden-Albala B, Can R et al: Stroke incidence among whites, blacks, and Hispanics from the same community of northern Manhattan. Am 1 Epidemiol 147:260, 1998.)

higher incidence (Fig. 28-2). Hispanics are a heterogenous population with major groups originating from Mexico, the Caribbean basin, and South America. These groups may differ in regard to stroke incidence and mortality, but few data are available. Asians have a low rate of coronary heart disease (CHD) and a high prevalence of stroke. A high incidence and prevalence of stroke in Chinese were found in a survey of six mainland cities with rates that were comparable to those of native Japanese in Japan. The disparity between the stroke and CHD death rates, and presumably a similar disparity in incidence rates, is attributed to the high prevalence of hypertension and the low levels of blood lipids in Asians. Cerebrovascular disease was the most frequently certified cause of death in Japan during the three decades after World War 11, and the mechanism of stroke was most often thought to be intracerebral hemorrhage. In Japanese men in Hawaii and San Francisco, deaths attributed to stroke also were lower than those from CHD and cancer. It is now well established that infarction, not hemorrhage, is the most common stroke mechanism and accounts for two thirds of strokes in Japanese people, whether they live in Japan or Hawaii. However, hemorrhage does occur several times more often in Japanese than in U.S. whites or blacks. There is also a difference in the site of the atherosclerotic arterial disorder, with a predominance of intracranial disease in Japanese in contrast to the pattern in white Americans, where the extracranial arteries are the focus of the atherosclerotic process. Variation by Geographic Region

In the 1980s, the highest age-adjusted stroke mortality rates in the United States occurred in the South and the lowest rates in the

Northeast and the West (Fig. 28-3). The map of state-specific mortality rates in 1997 indicates that the highest rates were concentrated in the southeastern states: the “stroke belt.” These regional differences are apparent for each sex and racial group. These regional variations suggest an environmental basis for the variation in stroke mortality (and perhaps in stroke incidence). Mortality rates from stroke vary widely between countries (Fig. 28-4). Among 33 industrial countries, the United States had one of the lowest stroke death rates, whereas Eastern European countries and Portugal had substantially higher rates.

Secular Trends in Stroke Mortality Death rates for stroke in the United States have declined consistently since 1915. This decline occurred in all age groups, in all races and both sexes, and in all regions. The rate of decline up to 1968 averaged 1% per year. From 1972 to 1992 mortality rates for stroke decreased more than 60% in the United States. As seen in Fig. 28-1, stroke mortality rates declined between 1980 and 1989, as they had in the previous decade. Death rates fell in all age groups, in men and women, in blacks and whites, and in all regions of the United States. This remarkable recent decline was real and not an artifact of coding or death certification practices. Similar declines have also occurred in most other western industrial nations. This decline in death rates may have resulted from a decrease in stroke severity, improvements in the care of stroke patients, and perhaps a falling stroke incidence. More recently, there has been a plateau in this decline in mortality (Fig. 28-1). Given that age is a major predictor of stroke mortality, the aging of the populations of western countries may be counteracting other factors and threatens an increase in stroke mortality rates in years to come.

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FIG. 28-5. Age-adjusted death rates for stroke by state, US., 1995-1997. (From Morbidity and Mortality, Chartbook on Cardiovascular, Lung, and Blood Diseases, US. Department of Health and Human Senrices, May 2000, Fig. 3-55.)

Deaths per 100,000 population

FIG. 28-4. Death rates for stroke, age 35-74, by country and sex, 1999. (From American Heart Association: 2002 Heart and Stroke Statistical Update. American Heart Association, Dallas, 2001, with permission.)

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Incidence of Stroke Mortality statistics do not convey the degree of distress of stroke survivors and their families, whose lives are irrevocably altered. Cerebrovascular disease is a major problem; approximately 700,000 people sustained a new or recurrent stroke in 1998, and there are 4,500,000 survivors of stroke alive in the United States today, many of whom need chronic care. In older adults, the segment of the population where most stroke occurs, it is a major source of disability leading to institutionalization. In the Framingham Study, incidence of stroke was determined over 36 years of follow-up in 5070 men and women, ages 30 to 62, who were free of CVD at entry to the study in 1950. The population was examined every 2 years. After 36 years of follow-up, there were 693 cases of stroke and transient ischemic attack. The average annual incidence of all strokes combined increased with age and doubled in successive decades. Unlike myocardial infarction, where myocardial infarction rates are more than three times higher in men, stroke incidence is only 30% greater in men than women. Incidence of stroke has been reported in a number of other populations, and the same age-sex trends were seen.

RISK FACTORS FOR STROKE The term riskfactor was coined by William B. Kannel in one of the early Framingham Heart Study publications. That report identified, for the first time in a prospective epidemiologicstudy, certain factors predisposing to the development of CHD. Risk factors have been identified for stroke, and the relative magnitude of each has been determined. Because the pathologic processes underlying the various stroke types differ, it is reasonable to expect that risk factors for infarction differ from risk factors for hemorrhage. Furthermore, precursors of parenchymatous bleeding need not be identical to those for SAH. There is also reason to believe that risk factors for stroke caused by atherosclerosis of the carotid and

Epidemiology and Stroke Risk Factors

15s

vertebral arteries differ in their impact when compared with lacunar stroke. It is likely that the risk factor profile for embolic stroke will also be different. Nevertheless, certain predisposing factors, particularly elevated blood pressure, appear to be common to most stroke types. Although intravenous tissue plasminogen activator has been approved as a treatment for acute stroke, and intra-arterial therapies show promise, it seems likely that prevention will continue to be the most effective strategy in reducing the impact of cerebrovascular disease. Prevention is facilitated by an understanding of predisposing risk factors and diseases identified chiefly through prospective epidemiologic study. The relative impact of each of these risk factors has become clearer, and controlled clinical trials have demonstrated the effectiveness of modifymg a number of these risk factors for stroke prevention.

Atherogenic Host Factors Assessment of the importance of each of the major atherogenic risk factors was made specifically in the stroke type resulting most directly from the atherosclerotic process, atherothrombotic brain infarction. This category includes all ischemic stroke: large artery atherothrombosis,lacunar infarction, and infarct of undetermined cause, excluding cardiogenic embolism. The major host factors to consider are hypertension, systolic and diastolic blood pressure levels, blood lipids including serum cholesterol, diabetes, and fibrinogen. Hematocrit, obesity, serum proteins, and more recently homocysteine level have also been implicated. Hypertension. Hypertension is the chief risk factor for stroke. The age-adjusted relative risk of stroke among stage 2-3 hypertensives (higher than 160/100 mm Hg), compared with normotensives (<130/85), is 3.1 in men and 2.9 in women, and even stage 1 levels (levels between 140/90 and 159/99 mm Hg) carry a 50% higher stroke risk (Fig. 28-5). The impact of hypertension was seen in men and women and at all ages up to age 84 years.

FIG. 28-5. Incidence of atherothrombotic brain infarction (ABI) and hypertensive status, 36-year follow-up, the Framingham Study. (From Wolf PA: Cerebrovascular disease in the elderly. p. 130, Fig. 2. In Trexh DD, Aronow WS (eds.): Cardiovascular Disease in the Elderly Patient. Marcel Dekker, New York, 1987, with permission.)

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Although brain infarction incidence is higher in hypertensives, this categorical classification does not portray the strong relationship to the level of the blood pressure. Risk of stroke generally, and brain infarction specifically,is directly related to the level of the blood pressure throughout its range, with no critical value of pressure, systolic or diastolic, below which stroke does not occur. A substantial portion of stroke incidence is directly attributable to hypertension, and a portion of stroke in the population would be eliminated if hypertension were effectively treated. This portion, the population attributable fraction, was estimated to be 56.4%of strokes in men and 66.1% in women based on an analysis of 26-year follow-up of Framingham data. Systolic Versus Diastolic Pressure Level. Both systolic and diastolic blood pressure level are strongly and independently related to atherothrombotic brain infarction incidence, although the diastolic component has been thought to be of primary importance. Clinical trials of antihypertensive treatment and disease prevention, principally stroke, have used diastolic blood pressure as the basis for categorizing subjects. However, evidence of the ascendancy of diastolic blood pressure over systolic is lacking. Diastolic blood pressure, which is more difficult to measure accurately and varies within a narrower range than the systolic component, seems to provide no advantage in predicting the cardiovascular complications of hypertension. Among people with systolic blood pressures 160 mm Hg or higher, stroke risk does not increase with increasing levels of diastolic blood pressure. On the other hand, among people with diastolic hypertension, incidence of stroke increases steadily with level of systolic blood pressure. Isolated Systolic Hypertension. With advancing age, there is a disproportionate rise in systolic blood pressure, whereas the diastolic pressure levels off and then begins to decline. In older adults, this isolated elevation of systolic pressure becomes highly prevalent. Systolic pressure greater than or equal to 160 mm Hg with diastolic pressure less than 90 mm Hg occurs in 20% of men and 30% of women age 80 years and older. Elevated systolic blood pressure in the presence of normal diastolic levels in older adults results from decreased elasticity of the walls of the great arteries. Therefore, these isolated systolic pressure elevations were considered to be the consequence rather than a risk factor for CVD. However, it has been demonstrated in Framingham and in other epidemiologic studies that stroke and CVD incidence was significantly higher in people with isolated systolic hypertension. Risk was proportional to the level of systolic pressure even after diastolic pressure, age, and digital pulse wave configuration (an index of arterial rigidity) were taken into account. The Systolic Hypertension in the Elderly Program (SHEP Trial) and the Syst-Eur Trial each found a clear beneficial effect of systolic blood pressure reduction in older adults with isolated systolic hypertension and is discussed later in this chapter. It is apparent that even high normal blood pressure (130-140 mm Hg systolic) is associated with a higher incidence of CVD, including stroke and myocardial infarction, compared with optimal blood pressure (less than 120 mm Hg). In the Framingham study it was recently shown that subjects with high normal systolic blood pressure had a risk-factor-adjusted hazard ratio for developing CVD of 2.5 in women and 1.6 in men relative to those with optimal blood pressure. These and previous findings support the conclusion that stroke incidence increases in a linear manner with increasing blood pressure level, without evidence of a threshold effect.

Blood Lipids. The positive relationship between total serum cholesterol and incidence of CHD in men and women is well established. High-density lipoprotein (HDL) cholesterol has an inverse association and low-density lipoprotein (LDL) cholesterol has a direct relationship to CHD incidence. A significant impact on CHD incidence can be shown by blood lipids using the total/HDL cholesterol ratio up to age 80. These relationships do not apply to stroke generally or to brain infarction in particular, and a low total cholesterol level seems to predispose to parenchymatous hemorrhage. A meta-analysis consisting of 460,000 subjects with 46,000 strokes showed no significant association between total serum cholesterol and total stroke incidence. However, a relationship was found in the Honolulu Heart Study of Japanese men and in the Multiple Risk Factor Intervention Trial (MRFIT) screenees. In Honolulu, the level of total cholesterol measured years before was directly related to the incidence of thromboembolism. No such relationship existed, long or short term, between ischemic stroke and total or LDL cholesterol in Framingham, and there was no protective effect of HDL cholesterol. In MRFIT the incidence of death certificatediagnosed ischemic stroke was greater in those with the highest levels of serum total cholesterol obtained 6 years before. Furthermore, in a 1993 meta-analysis of cholesterollowering trials of drug treatment or lifestyle modification, the rate of myocardial infarction decreased but there was no significant benefit in stroke prevention in the treated groups. A surprisingly consistent finding has been the relationship between low total serum cholesterol and higher incidence of intracerebral hemorrhage. This finding was first noted among rural Japanese after World War 11. By Western standards, serum cholesterol levels were quite low, often below 160 mg/dL. An etiologic link has been suggested by the recent confirmation of this relationship in other Asian populations, in Hawaiian Japanese, and in Caucasian men in the United States. In 350,977 men aged 35 to 57 years screened for entry into the MRFIT Study, after 6 years of follow-up there were 83 deaths from intracerebral hemorrhage and 55 deaths from SAH. In the lowest serum cholesterol category, less than 160 mg/dL, the risk factor-adjusted relative risk of intracranial hemorrhage was 1.0 and relative risk at all higher levels of serum cholesterol was approximately 0.32 (Fig. 28-6). When deaths from intracranial hemorrhage were examined by entry diastolic blood pressure, the age-adjusted rate of death was significant only in people with pressures greater than 90 mm Hg. Death rates per 10,000 were 23.07 in the lowest serum cholesterol category (less than 160 mg/dL) and ranged from 3.09 to 4.83 in the four higher categories. The interaction of high diastolic blood pressure and low serum cholesterol in promoting intracerebral hemorrhage suggested to some investigators that very low serum cholesterol levels weaken the endothelium of intracerebral arteries, resulting in hemorrhagic stroke in the presence of hypertension. Other factors predisposing to intracerebral hemorrhage are high alcohol consumption, dietary protein deficiency, and a high intake of polyunsaturated fatty acids. These polyunsaturated fatty acids, both linoleic acid derived from vegetable oils and eicosapentaenoic acid from fish oil, reduce platelet aggregability and may thereby promote hemorrhage. Although the relationship between blood lipids and stroke is unclear, serum lipid levels have been directly related to extracranial carotid artery atherosclerosis and to extracranial carotid artery wall thickness. Atherosclerosis of the carotid artery, and the circle of Willis in autopsy studies, is directly related to levels of blood lipids. On the other hand, the relationship to stroke generally may

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FIG. 28-6. Ischemic stroke and intracerebral hemorrhage death rates in men with normal and elevated diastolic blood pressure (D6P) according to screening serum cholesterol level (Multiple Risk Factor lntelvention Trial screenees at 6-year follow-up). (From Wolf PA, Cobb JL, D’Agostino RB: Epidemiology of stroke. p. 16, Fig. 1-14. In Barnett HJM, Mohr JP, Stein BM, Yatsu FM (eds.): Stroke, Pathophysiology, Diagnosis, and Management. 2nd Ed. Churchill Livingstone, New York, 1992, with permission.)

be obscured by the differing influence of lipids on the varying vascular disorders underlying stroke. There is no apparent influence of lipids on lacunar infarcts or on strokes secondary to cerebral embolism. As discussed later in this chapter, although serum lipids have not been consistently established as a risk factor for stroke in observational studies, recent evidence from randomized trials indicates that treating high-risk groups with P-hydroxyP-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) reduces stroke incidence. Contrary to what might be expected based on observational data, these trials did not demonstrate an increase in intracerebral hemorrhage for subjects with lowered cholesterol from statin therapy. Diabetes. Diabetics have a higher susceptibility to atherosclerosis. Case control studies of stroke patients and prospective epidemiologic studies have confirmed the higher risk of ischemic stroke in diabetics, ranging from 1.8- to 3-fold. In the United States, between 1976 and 1980, a medical history of stroke was 2.5 to 4 times more common in diabetics than in people with normal glucose tolerance. In the Honolulu Heart Program, Japanese men living in Hawaii with diabetes had twice the risk of thromboembolic stroke of nondiabetics, independent of other risk factors. In a population-based cohort in Rancho Bernardo, diabetics had a relative risk of stroke that was 1.8 in men and 2.2 in women after adjusting for the effect of other pertinent risk factors. In Framingham, peripheral arterial disease with intermittent claudication occurred more than four times as often in diabetics. The coronary and cerebral arteries were affected but to a lesser extent. For brain infarction, the impact of glucose intolerance (i.e., physician-diagnoseddiabetes, glycosuria, or a blood sugar greater than 150 mg/100 mL) is greater in women than men and was significant as an independent contributor to incidence only in

older women. Overall, people with glucose intolerance have twice the risk of brain infarction as nondiabetics. Obesity. Obesity is associated with higher levels of blood pressure, blood glucose, and atherogenic serum lipids and for these reasons alone could be expected to increase stroke incidence. In the Framingham study, obesity, as expressed as a Metropolitan Relative Weight that is more than 30% above average, is a significant independent contributor to brain infarction incidence in men aged 35 to 64 and women 65 to 94 years. However, even in the other two age-sex groups, obesity exerts an adverse influence on health status that is probably mediated through elevated blood pressure, impaired glucose tolerance, and other mechanisms. In the Honolulu Heart Study obesity was identified as an independent factor related to stroke incidence. More recently, in the Nurses’ Health Study the risk of stroke was related to body mass index in women aged 30 to 55 after adjustment for stroke risk factors. In men aged 40 to 75 however, the Health Professionals’ Follow-up Study did not find a significant relationship between body mass index and stroke. Using another index of obesity, stroke risk was significantly higher in men in the highest quintile of waist-to-hip ratio (relative risk 2.33, 95% confidence interval [CI] 1.25-4.37), and the increased risk persisted after adjustment for body mass index, height, and other stroke risk factors. Therefore, the pattern of obesity has also been identified to be important. Central obesity manifested by abdominal fat deposition, rather than obesity involving the hips and thighs, has been related to the occurrence of atherosclerotic disease. There may be sex-related differences, with body mass index being of greater importance to women and waist-to-hip ratio being of greater importance to men. Family Histoy of Stroke. Although family history of stroke is perceived to be an important marker of stroke risk, definitive confirmation by epidemiologic study has been lacking. Maternal

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history of death from stroke, but not paternal, was found to be significantly related to stroke incidence in a cohort of Swedish men born in 1913. Other significant risk factors included hypertension, abdominal pattern of obesity, and fibrinogen level. Maternal history of fatal stroke was independently related to stroke even after these variables were taken into account. In Framingham, no relationship was found between a history of stroke death in parents and documented stroke in subjects. Verified stroke cases, nonfatal and fatal, in these cohort members were then related to the occurrence of stroke in their children (members of the Framingham Offspring Study cohort). In these analyses, both maternal and paternal stroke was associated with an approximately 1.5-fold higher risk of stroke even after other risk factors were taken into account. Thus, family history of stroke, so frequently mentioned and nearly universally acknowledged as a risk factor for stroke, has been only recently identified and documented by epidemiologic study. Fibrinogen, Coagulation Factors, and Inflammation. Elevated serum fibrinogen has been implicated in atherogenesis and in arterial thrombus formation. In prospective epidemiologic study there was a substantial and significant independent impact of fibrinogen on CVD incidence, including stroke. In a prospective study of 54-year-old Swedish men, fibrinogen in combination with elevated systolic blood pressure was found to be a potent risk factor for stroke. Fibrinogen level, measured on the tenth biennial examination in Framingham, was also significantly related to incidence of CVD, including stroke. However, fibrinogen was also positively associated with most of the major risk factors for stroke, including age, hypertension, hematocrit level, obesity, and diabetes. There were similar associations between fibrinogen level and subclinical atherosclerosis in the Cardiovascular Health Study (CHS). The only other clotting factor to have a significant relationship with atherosclerosis in the CHS was factor VIII. There is growing interest in the atherogenic and procoagulant effects of inflammation and in the relationship between inflammation, infection and CVD, including stroke. In the Framingham study subjects with increasing levels of C-reactive protein had a significantly higher risk of stroke after adjustment for other risk factors. Other studies have found relationships between Chlamydia pneumoniae antibody titers and future stroke risk. It remains to be seen whether inflammation and infection are important risk factors for stroke and whether they will be established as targets for preventive measures. Hyperhomocystinemia. Past and recent cross-sectional studies, retrospective case control studies, and a meta-analysis performed in 1995 have found elevated homocysteine to be a risk factor for stroke. This relationship has not been consistently present in recent prospective cohort studies. The British Regional Heart Study demonstrated a strong, graded, and independent relationship between homocysteine and risk of stroke over the course of a 13-year follow-up of men aged 40 to 59 years. The Framingham study also found a significant linear relationship, with subjects in the highest quartile of homocysteine concentration having 1.82 (95% CI 1.14 to 2.91) times the risk of stroke as those in the lowest quartile. However, the Atherosclerosis Risk in Communities Study, the Physicians’ Health Study, the Finnish Study, and the MRFIT study did not demonstrate the same relationship. There may be an increase in the risk of stroke with increasing levels of homocysteine. The risk may be strong, graded, and independent of other risk factors, but the relationship has not been entirely consistent across different cohort studies. The Vitamin Intervention for Stroke Prevention (VISP) trial is under

way to examine the effect of lowering elevated homocysteine with folic acid, B,,, and B, on risk of stroke, myocardial infarction, and death. In the interim, given the potential benefit and low possibility of adverse effects, treatment with folic acid, B,,, and B, might be considered for patients at high risk for stroke and coronary disease.

Heart Disease and Impaired Cardiac Function Cardiac disease and impaired cardiac function are common accompaniments and precursors of stroke. These cardiac contributors are disease states or organ dysfunctions and not risk factors. Although hypertension is the preeminent risk factor for stroke of all types, at each blood pressure level, people with impaired cardiac function have a significantly higher stroke risk. CVD is highly prevalent among stroke cases. In Framingham, after 36 years of follow-up of more than 600 stroke and transient ischemic attack cases, 80.8% of subjects were hypertensive, 32.7% had prior CHD, 14.5% had congestive heart failure, 14.5% had atrial fibrillation, and only 13.6% had none of these. Coronary Heart Disease. In Framingham, CHD was ascertained prospectively on biennial examination as well as by monitoring hospitalizations over 36 years of follow-up. Acute myocardial infarction predisposes to stroke, particularly in the days and weeks after the event. Stroke incidence has been clearly demonstrated to be reduced by aspirin or warfarin administered after an acute myocardial infarction. Among Q wave myocardial infarctions, anterior wall infarcts are more likely to lead to stroke than infarcts at other sites. The mechanism is presumed to be cerebral embolism from an intracardiac mural thrombus. Often, however, the mechanism of stroke in people with CHD is less apparent. People with uncomplicated angina pectoris, non-Q wave infarction, and clinically silent myocardial infarction also have a higher incidence of ischemic stroke. Recent data from Framingham suggest that silent, or unrecognized, myocardial infarction survivors had a 10-year incidence of stroke of 17.8% in men and 17.3% in women, an incidence not much lower than the 19.5% and 29.3% in men and women, respectively, that is seen after recognized myocardial infarction. Congestive Heart Failure. Congestive heart failure prevalence increases with age, from a low of 0.8% at ages 50 to 59 to 9.1% at 80 to 89 years, and is usually a consequence of hypertension and CHD. It predisposes to atrial fibrillation, which may precipitate or exacerbate congestive heart failure. However, even after the impact of atrial fibrillation, hypertension, and CHD are taken into account, congestive heart failure increases the risk of stroke more than fourfold. The hazard posed by congestive heart failure persists, despite the availability of many new drugs, although recent data from Framingham have shown increase in survival with congestive heart failure in recent years for both men and women. Because thrombus formation within the ventricular cavity may be the responsible mechanism of stroke, the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial is examining the use of warfarin anticoagulation to reduce stroke incidence in subjects with a reduced ejection fraction. Atrial Fibrillation. In association with rheumatic heart disease and mitral stenosis, atrial fibrillation has long been felt to predispose to stroke. Atrial fibrillation without valvular heart disease, previously considered to be innocuous, has been associated with more than a fivefold higher incidence of stroke. Atrial fibrillation is also a fairly common cardiac arrhythmia in older adults. In the Framingham study, atrial fibrillation prevalence

Chapter 28

more than doubled in successive decades to 8% at ages 80 to 89 years. Although 15% of strokes occurred in people with atrial fibrillation, the proportion of strokes associated with this arrhythmia increased steadily with age, reaching 36.2% for ages 80 to 89 years. There is clearly a powerful impact of atrial fibrillation on stroke incidence in older adults that is independent of cardiac disease and hypertension. The success of a series of clinical trials using warfarin to prevent stroke in atrial fibrillation has validated the independent importance of atrial fibrillation: nearly 70% risk reduction occurred without any specific measures to improve the associated cardiac conditions. Left Ventricular Hypertrophy by Electrocardiogram. Left ventricular hypertrophy by electrocardiogram (LVH by ECG) increases in prevalence with age and blood pressure. Risk of brain infarction was more than four times higher in men and six times higher in women with this abnormal ECG pattern. The increased risk persisted even after the influence of age and other pertinent risk factors was accounted for. EchocardiographicFactors. Using echocardiography, a number of structural changes have been identified that predispose to stroke. Several sources of emboli, aortic arch atheromata, and patent foramen ovale (PFO) have been identified and are discussed elsewhere in this section. Echocardiography has also identified structural changes that make an independent contribution to stroke incidence. These include mitral annular calcification, increased left atrial size, and increased left ventricular mass. Mitral annular calcification and increased left atrial size predispose to atrial fibrillation. However, each exerts an impact on stroke incidence that is independent of atrial fibrillation by mechanisms that are not entirely clear. Mitral valve prolapse, often cited in the past as a risk factor for stroke, has not held up as an important abnormality despite the high prevalence in the population. There has been conflicting evidence for the last 15 years as to whether PFO is a risk factor for stroke, particularly in young stroke sufferers or in people with no other likely cause of stroke (cryptogenic stroke). The Patent Foramen Ovale and Atrial Septal Aneurysm Study Group performed transesophageal echocardiography on 581 patients with cryptogenic stroke 18 to 55 years of age and followed them for a mean of 4 years. Almost all patients were treated with antiplatelet agents for most of the follow-up period. The risk of stroke in subjects with either PFO or atrial septal aneurysm (ASA) was quite low and not greater than that of subjects without PFO or ASA. The risk of stroke in subjects with both PFO and ASA was more than three times that of subjects without PFO or ASA. This study was limited by loss to follow-up at the 4-year mark, with only 10 of 51 subjects remaining in the PFO plus ASA subgroup. The Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) examined the risk of recurrent stroke in a subset of 630 subjects of the larger Warfarin-Aspirin in Recurrent Stroke Study (WARSS), 265 of whom had cryptogenic stroke at entry and 365 of whom had known stroke subtypes. All of these subjects underwent transesophageal echocardiography, and 203 had PFO. Subjects with cryptogenic stroke were more likely than those with known subtypes to have PFO (39.2% vs. 29.9%). The risk of recurrent stroke or death in the overall WARSS trial of 2206 patients was not significantly different for those treated with warfarin and those treated with aspirin. For the 203 subjects in the PICSS cohort with PFO, including cryptogenic and known stroke subtypes, the risk of recurrent stroke in those with PFO was not significantly different for those treated with aspirin (13.2%) or warfarin (17.4%). For the cryptogenic subgroup with PFO, the recurrence rate was lower

Epidemiology and Stroke Risk Factors

259

with warfarin (9.5%) than with aspirin (17.9%), but the difference was not significant. What is of interest is that for the cryptogenic subgroup without PFO, the results were almost identical to those with PFO, with a nonsignificantly lower risk for warfarin. This trend for a benefit of warfarin over aspirin in cryptogenic stroke was not present in the overall WARSS sample, in which the incidence of stroke was 15% with warfarin and 16.5% with aspirin. Neither the combination of PFO and ASA nor the size of the PFO affected stroke recurrence. These recent results suggest that the risk of recurrent stroke is quite low in people aged 18 to 55 with PFO alone who are on antiplatelet treatment. There may be a higher risk for people with a combination of PFO and ASA despite antiplatelet treatment, but this should be confirmed in other studies. There is no proven benefit of warfarin over aspirin in preventing stroke in subjects with PFO. Left ventricular mass (LVM-to-height ratio) determined by echocardiography offers a more sensitive and quantitative assessment of cardiac muscle hypertrophy than LVH by ECG. Recently, LVM as determined on M-mode echocardiography has been shown to be directly related to incidence of stroke. The hazard ratio for stroke and transient ischemic attack comparing the uppermost quartile with the lowest was 2.72 after adjusting for age, sex, and cardiovascular risk factors. There was a graded response, with a hazard ratio of 1.45 for each quartile increment of LVM-to-height ratio. Thus, echocardiography offers prognostic information beyond that provided by traditional risk factors.

Other Host Factors Migraine. The most extreme examples of the association between migraine and stroke occur in specific and rare disease syndromes. In the disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), migraine headache is associated with white matter disease, dementia, and subcortical strokes. Another syndrome of migraine and elevated stroke risk occurs in the primary antiphospholipid syndrome, in which migraine is associated with clearly elevated stroke risk and positive titers of antiphospholipid antibodies. Atypical migraine syndromes such as hemiplegic migraine are also a known cause of stroke and are quite rare. The relationship of stroke to the common migraine syndromes encompassing migraine with aura and migraine without aura has been investigated in several case control studies, the two largest of which are the Italian National Research Council Study Group on Stroke in the Young and a substudy of the World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Two large cohort studies have also examined the issue: the Physicians’ Health Study (PHS) and the National Health and Nutrition Examination Survey and Follow-up (NHANES I). Migraine was associated with a higher risk of ischemic stroke in all of the studies, with relative risk or odds ratios ranging from 2.0 to 3.8. The studies that distinguished between migraine with and without aura generally but not always found a higher risk for migraine with aura than for migraine without aura. The contribution of migraine to stroke risk decreases with increasing age, possibly suggesting that other stroke risk factors become more important with age. The WHO study and other case control studies have found in women with migraine under age 45 that the risk of stroke is increased greatly by smoking and the use of oral contraceptive agents.

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Most of these studies were limited by the lack of standardized criteria for the diagnosis of migraine, and some are further limited by a lack of confirmation of stroke events by medical record review. The degree of consensus suggests strongly that the associations may be real, but more prospective studies using standardized criteria for both the diagnosis of migraine and stroke events are needed. A particularly high-risk group are women with migraine who take oral contraceptive pills and who smoke. Given current knowledge, it seems prudent to encourage patients to avoid this combination of risk factors. Unruptured lntracranial Aneurysms. Unruptured intracranial aneurysms (UIAs) in patients with or without a history of SAH present a therapeutic dilemma in which the risk of future rupture must be weighed against the risks of surgical intervention. Anecdote and case series were the only evidence available to guide these decisions until the recent publication of the International Study of Unruptured Intracranial Aneurysms (ISHUA). In ISHUA a retrospective cohort was formed to examine the natural history of UIAs in subjects with and without a history of SAH, and a prospective cohort was formed to examine the morbidity and mortality of surgery for UIAs. In the retrospective cohort there were 727 subjects with UIAs and no history of SAH and 722 subjects with UIAs and a history of SAH from another aneurysm. For those with no history of previous SAH,aneurysm size was the major predictor of rupture. The rupture rate for aneurysms less than 10 mm in diameter was only 0.05% per year, compared with almost 1% per year for aneurysms more than 10 mm in diameter and 6% in the first year for giant aneurysms (more than 25 mm). Location was another major predictor, with posterior communicating, vertebrobasilar or posterior cerebral, and basilar tip aneurysms having a higher rate of rupture. For those with a history of SAH, aneurysms less than 10 mm in diameter had a rupture rate of 0.5% per year, 10 times higher than that of aneurysms of the same size in those without a history of SAH. Aneurysms more than 10 mm in diameter had a slightly higher hemorrhage rate of 0.65% per year. The only other clear predictor in this group was basilar tip location. For subjects without a history of SAH, the prospective component of ISHUA found the 30-day mortality rate for surgical treatment of UIAs to be 2.3%. Unliie previous studies, the ISHUA measured cognitive function as well as functional status to determine disability after surgery. Twelve percent of patients had cognitive or functional disability at 1 year after surgery. This suggests a high toll for surgery in these patients, who were for the most part neurologically normal before surgery.

W TMLE 28-1.

Some have raised the point that the ISHUA estimates of rupture rates are far lower than those reported in many large case series, suggesting that the retrospective sampling methods might have introduced bias and selected for subjects with a lower rate of rupture. Despite this possibility, the prospective findings of high surgical morbidity cannot be ignored. Given the controversy, strong recommendations cannot be made on the basis of the ISHUA findings alone. Current guidelines suggest that UIAs in those with a history of SAH or in those with symptoms from the aneurysm (i.e., severe headaches or mass effect) should be considered for surgery. Those with aneurysms more than 10 mm in diameter should also be considered for surgery. In the case of asymptomatic UIAs less than 10 mm in diameter an argument can be made for observation with repeat imaging to monitor for growth. If growth occurs or symptoms develop, surgery could be considered. Certain patient characteristics such as very young age, continued smoking, or high-risk angiographic features might argue in favor of surgery over observation even in the latter group. Environmental Factors Cigarette Smoking. Cigarette smoking, a powerful risk factor for myocardial infarction and sudden death, has been clearly linked to brain infarction and SAH (Table 28-1). A similar relationship between cigarette smoking and stroke has' been seen in Hawaiian Japanese men after 10 years of follow-up in the Honolulu Heart Study, where cigarette smoking made a significant independent contribution to cerebral infarction and intracranial hemorrhage risk. In the late 1970s, several studies of oral contraceptives and stroke in young women identified cigarette smoking as an important risk factor. Surprisingly, the association between cigarette smoking, oral contraceptives, and stroke was related primarily to SAH. In the Nurses' Health Study, in which a cohort of nearly 120,000 women was followed prospectively for 8 years for stroke development, there was a higher risk of SAH and thrombotic stroke in cigarette smokers. Relative risk of SAH showed a dose-response relationship ranging from 4-fold in light smokers to 9.8-fold in smokers of 25 or more cigarettes daily. Of note, in each smoking category the relative risk of SAH, whether or not other associated risk factors were taken into account, was twice as great as for thromboembolic stroke (Table 28-1). The association between cigarette smoking and SAH from aneurysm was also found in men (as well as women) in

Age-Adjusted Relative Risks of Stroke (Fatal and Nonfatal Combined) by Daily Number of Cigarettes Consumed Among Current Smokers NO. OF ClGlWmS SMOKE0 PER DAY AMONG CUlllrhl SMOKERS

Event Total stroke Subarachnoid hemorrhage Ischemic stroke Cerebral hemorrhane

Never Smoked

Former Smoker

Current Smoker

1-14

15-24

25-34

235

1 .OO 1 .OO

1.35 (0.98-1.85) 2.26 (1.16-4.42)

2.73 (2.18-3.41) 4.85 (2.90-8.1 1)

2.02 (1.29-3.14) 4.28 (1.88-9.77)

3.34 (2.38-4.70) 4.02 (1.90-8.54)

3.08 (1.94-4.87) 7.95 (3.50-18.07)

4.48(2.78-7.23) 10.22 (4.03-25.94)

1 .OO

1.27 (0.85-1.89)

2.53 (1.91-3.35)

1.83 (1.04-3.23)

3.57 (2.36-5.42)

2.73 (1.49-5.03)

3.97 (2.09-7.53)

1 .OO

1.24 (0.64-2.42)

1.24 (0.64-2.42)

1.68 (0.34-5.28)

2.53 (0.71-6.05)

1.41 (0.39-5.05)

Numbers in parentheses are 95% confidence intewals. Relative risk adjusted for age in 5-year intewals, follow-up period (1976-1978, 1978-1 980. 1980-1 982, 1982-1 984, 1984-1 986, or 1986-1 988). histoly of hypertension,diabetes, high cholesterol levels, body mass index past use of oral contraceptives, postmenopausal estrogen therapy, and age at starting smoking. Adapted from Kawachi 1, Coldik CA, Stampfer MJ:Smoking cessation and decreased risk of stroke in women. JAMA 269:233, 1993, Table 1, with permission.)

Chapter 28

Framingham and in New Zealand in case control analyses. In a case control study of 114 patients with SAH in a defined region in Finland, cigarette smokers were significantly more prevalent among cases than among matched controls. Relative risk of SAH in smokers, as compared with nonsmokers, was 2.7 in men and 3.0 in women. The authors suggested that smoking promoted a temporary increase in blood pressure, which, acting in concert with the metastatic emphysema effect, was responsible for SAH from cerebral aneurysm. No more reasonable hypothesis has been promulgated to explain this powerful relationship. In a population-based case control study in several counties in the Seattle, Washington, area, cigarette smoking was found to increase risk of SAH from aneurysm ninefold. The relationship of cigarette smoking to intracerebral hemorrhage has been recently shown in the Physicians’ Health Study: current smokers of 20 or more cigarettes per day had a multivariable adjusted relative risk of intracerebral hemorrhage of 2.06 (95% CI 1.08-3.96) in comparison with non-smokers. In a meta-analysis of 32 separate studies, including those cited earlier in this section, cigarette smoking was a significant independent contributor to stroke incidence in both sexes and at all ages and was associated with an approximately 50% higher risk overall when compared with nonsmokers. The risk of stroke generally, and of ischemic stroke specifically, rose as the number of cigarettes smoked per day increased in both men and women. Oral Contraceptives. A higher risk of stroke was reported in users of oral contraceptives, particularly in older women (i.e., above age 35), and predominantly in those with other cardiovascular risk factors, particularly hypertension and cigarette smoking. The relative risk of stroke was estimated to be five times higher in oral contraceptive users and former users, with risk concentrated in cigarette smokers above age 35. However, the mechanism of stroke in oral contraceptive users is unclear. Cerebral infarction is more likely to be caused by thrombotic disease than by atherosclerosis; it is known that clotting is enhanced by the oral contraceptive-induced increased platelet aggregability and by its alteration of clotting factors to favor thrombogenesis. In young women with unexplained ischemic stroke, use of oral contraceptives is presumed to be the cause of the infarct; however, stroke was attributed to oral contraceptive use in no more than 10% of a series of carefully studied patients. Although there have been few systematic investigations of oral contraceptives and stroke in the 1980s, in case control studies of stroke in oral contraceptive users conducted in the 1970s, thromboembolism was the type of stroke said to occur most often in oral contraceptive users. However, women in the case group often experienced transient episodes of neurologic dysfunction, transient ischemic attacks (TIAs), or stroke events categorized as having ill-defined and uncertain causes. Stroke risk was highest in women who took oral contraceptivescontaining higher levels of estrogen; the lower levels of estrogen in the newer oral contraceptive formulations seem to have substantially reduced the hazard, and former users have been thought to be at no increased risk of stroke. A recent meta-analysis included 16 studies published from 1960 to 1999 and addressed the relationship of oral contraceptive use and stroke. The overall relative risk of ischemic stroke across all preparations and study designs was 2.75 (95% CI 2.24 to 3.38). The relative risk in population-based studies of low-estrogen preparations controlling for both smoking and hypertension was 1.93 (95% CI 1.35 to 2.74). If these latter results are true, then low-dose oral contraceptive pills might lead to one stroke for every

H

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24,000 women treated, or 425 ischemic strokes in the United States each year. There are limitations of meta-analysis, and the results must be interpreted with caution, especially because many other studies did not find the same association between stroke and low-dose estradiol contraceptives. Of particular interest is the interaction between oral contraceptives, cigarette smoking, and SAH. Prospective observation of more than 40,000 women, half of whom were taking oral contraceptives, showed a higher risk of fatal SAH (not cerebral infarction) in women taking oral contraceptives. Risk was four times higher in cigarette smokers above age 35, with most cases confined to this group. Hormone ReplacementTherapy. Observational studies have shown either no influence of hormone replacement therapy (HRT) on stroke or a weak protective effect. The recent Women’s Estrogen for Stroke Trial (WEST) randomized 652 postmenopausal women aged 46 to 91 years to placebo or estradiol within 90 days of a TIA or nondisabling stroke. After a mean 2.7-year follow-up there was no difference in the outcome of nonfatal stroke or death. This was consistent with the sum of previous evidence suggesting that there is no effect of HRT on stroke incidence. However, the largest trial to date examining the issue of HRT and CVD was the Women’s Health Initiative Randomized Controlled Trial, which randomized 16,608 women to conjugated estrogens plus progesterone or placebo. The trial was stopped after 5.2 years because of a significant increase in breast cancer in the treatment group and because a global statistic indicated that the risks of treatment exceeded the benefit. Women taking HRT had a higher risk of stroke, with a relative risk of 1.41 (1.07 to 1.85). Despite a large body of observational evidence supporting a preventive effect of HRT on CHD, women on treatment also had a significantlyhigher risk of CHD. Pending further evidence to the contrary, HRT increases stroke and other negative outcomes and cannot be recommended as a measure to prevent CVD. Alcohol Consumption. As in myocardial infarction, the impact of alcohol consumption on stroke risk is related to the amount of alcohol consumed. Heavy alcohol use, either habitual daily heavy alcohol consumption or binge drinking, seems to be related to an increase in stroke and stroke deaths. Light or moderate alcohol consumption, on the other hand, is convincingly associated with a lower incidence of coronary heart disease, and recent evidence suggests moderate alcohol consumption may reduce the risk of stroke as well. Light and moderate alcohol use tends to raise the HDL cholesterol and may be associated with a reduction in CHD incidence, whereas high levels of alcohol intake are linked to hypertension and hypertriglyceridemiaand may thus be associated with an increased rate of CHD. Heavy alcohol consumption seems to increase the incidence of stroke, particularly parenchymatous hemorrhage. In a prospective study in Yugoslavia, heavy alcohol consumption was associated with higher stroke incidence, but the stroke subtype was not clearly determined. Higher incidence of intracerebral hemorrhage has been related to alcohol consumption in the Honolulu Heart Program, with a strong dose-response relationship. Increases in alcohol consumption were related to increasing levels of blood pressure and cigarette smoking and to lower serum cholesterol levels, all risk factors for intracerebral hemorrhage. However, even after taking these factors into account, heavy alcohol consumption was independently related to incidence of intracranial hemorrhage, both subarachnoid and intracerebral; no significant relationship was found between alcohol and thromboembolic stroke. Age-adjusted estimated relative risk of intracerebral hemorrhage

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Cerebrovascular Disease w General Aspects of Cerebrovascular Disease

for light drinkers ( 1 to 14 oz per month) as compared with nondrinkers was 2.1, for moderate drinkers (15 to 39 oz per month) it was 2.4, and for heavy drinkers (40 oz or more per month) it was 4.0. After adjustment was made for other associated risk factors, intracerebral hemorrhage was 2.0, 2.0, and 2.4 times more common, respectively, in these alcohol consumption categories. Data from the Framingham study also suggest an increased incidence of stroke with increased levels of alcohol use, but only in men. There are a number of mechanisms by which heavy alcohol consumption may predispose to and moderate alcohol consumption protect from stroke. Cigarette smoking is more common in heavy drinkers, and there is attendant hemoconcentration. Alcohol and cigarette smoking have been shown to increase both blood hematocrit and viscosity, and rebound thrombocytosis during abstinence has been observed. Cardiac rhythm disturbances, particularly atrial fibrillation, occur with alcohol intoxication, producing what has been called “holiday heart”. Acute alcohol intoxication has been named as a precipitating factor in stroke in young people, both in thrombotic stroke and in SAH. Physical Activity. Leisure time- and work-associated vigorous physical activity has been linked to lower CHD incidence. More physically active longshoremen had lower rates of myocardial infarction but had similar stroke incidence in comparison with less physically active peers. In a study of 17,000 former Harvard students, those who were more physically active had about half the risk of fatal CHD and one third the mortality rate of their least active fellow alumni. In recent years evidence has supported a protective effect of moderate physical activity on stroke incidence that is independent of other risk factors. In Framingham, physical activity in older adults, mean age 65 years, was associated with a lower stroke incidence than in the least active group in a sex-specific Cox proportional hazards model. For men the relative risk was 0.41 (95% CI 0.24 to 0.69, P = 0.0007) after takmg into account the effects of potential confounders. These included age, systolic blood pressure, serum cholesterol, glucose intolerance, vital capacity, body mass index, L W by ECG, atrial fibrillation, valvular heart disease, congestive heart failure, CHD, and occupation. However, there was no evidence of a protective effect of physical activity on risk of stroke in women. Furthermore, as is the case in CHD, there was no evidence that heavy levels of physical activity conferred any greater benefit than moderate levels. In a number of other population studies and in a series of case control studies, low levels of physical activity were associated with higher incidence of stroke. In 7735 men aged 40 to 59 there was a protective effect of high levels of physical activity on stroke incidence (Fig. 28-7). In the latter study there was a clear, graded inverse relationship between physical activity level and stroke incidence. An inverse relationship between level of physical activity and stroke in women was found in the Nurses’ Health Study of 72,488 women. Physical activity at baseline was related to stroke after 8 years of follow-up, and a graded protective effect was observed for increasing intensity and quantity of exercise. Physical activity exerts a beneficial influence on risk factors for atherosclerotic disease by reducing blood pressure and weight, reducing the pulse rate, raising the HDL and lowering the LDL cholesterol, improving glucose tolerance, and promoting a lifestyle conducive to dietary improvement and smoking cessation. Physical activity may now be added to the list of modifiable risk factors that can reduce stroke incidence.

FIG. 28-7. Physical activity and stroke, men 40-59 years of age. Age-adjusted rates of stroke according to physical activity. (Adapted from Wannamethee C, Shaper AC: Physical activity and stroke in British middle aged men. BMJ 304:598, 1992, with permission.)

Dietary Factors. Increased whole grain consumption was related to a lower risk of stroke in 75,521 women from the Nurses’ Health Study I. The relative risk of ischemic stroke in the highest quintile of grain consumption was 0.69 relative to the lowest quintile, adjusted for other stroke risk factors, supporting a preventive role for whole grains. In 1999, the Nurses’ Health Study and the Health Professionals’ Follow-up Study found that the relative risk of stroke was 0.69 (95% CI 0.52 to 0.92) for people with the highest quintile of fruit and vegetable intake relative to those with the lowest intake. The Nurses’ Health Study also investigated the relationship between omega-3 fatty acids and stroke. Subjects who consumed more than 5 servings of fish per week had an adjusted relative stroke risk of 0.38 times that of those who consumed less than one serving per month. Three recent studies examined the role of vitamins C or E levels in stroke prevention. The Shibata study followed a prospective cohort of 880 men and 1241 women for 20 years and found that the relative risk of stroke adjusted for all other risk factors was 0.71 in the subjects with the highest vitamin C levels relative to those with the lowest levels. The Health Professionals Follow-up Study also looked at this issue, administering food frequency questionnaires to 43,738 men, aged 40 to 75 years. After 8 years of follow-up there was no significant relationship between the frequency of consumption of vitamins C and E and the risk of stroke. In a randomized controlled clinical trial, the Heart Outcomes Prevention (HOPE) trial, 9,541 patients 55 years or older with CHD, stroke, peripheral vascular disease, or diabetes mellitus and one other risk factor received (in a 2 x 2 factorial design) vitamin E, ramipril, neither, or both. There was no benefit from vitamin E intake on the composite outcome of myocardial infarction, stroke, or vascular death. In summary, consumption of fruits and vegetables, whole grains, and omega-3 fatty acids in the form of fish reduces the risk of stroke. There is conflicting evidence regarding vitamin C, and there is no evidence that vitamin E prevents stroke.

Chapter 28 H Epidemiology and Stroke Risk Factors

STROKE PREVENTIONTHROUGH RISK FACTOR MANAGEMENT There has been rapid decline in death rates from stroke in the United States and in most other industrialized nations since 1968. In the United States this decline of more than 50% in mortality rates in a 20-year span supports the notion that modifiable environmental influences are operating in stroke and CVD occurrence. At least part of the decline results from a reduction in the severity of stroke that most attribute to improved detection and treatment of hypertension. Prevention of stroke, and perhaps stroke recurrence, has been shown to result from reductions in elevated blood pressure, cigarette smoking cessation, and warfarin anticoagulation in the presence of atrial fibrillation. It seems likely that prevention and treatment of predisposing cardiac diseases would help. Although elevated serum cholesterol has not been consistently identified as a risk factor for stroke, recent trials show a surprising level of stroke risk reduction in certain high-risk groups treated with HMG-CoA reductase inhibitors. The treatment of high-risk patients with angiotensin-converting enzyme (ACE) inhibitors has also been demonstrated by recent trials to decreasestroke risk. Of course, CHD is a major precursor of stroke and is the principal cause of death in stroke and TIA survivors, and for that reason CHD prevention is certainly worthwhile.

Hypertension Control and Stroke Prevention Based on a combined analysis of nine major prospective studies including 420,000 subjects with a mean 10-year follow-up, there was clear evidence of a graded relationship between diastolic pressure and stroke and CHD incidence. There was no threshold level below which risk gradients were flat. For every 7.5 mm Hg diastolic pressure increase there was a 46% increase in stroke incidence and a 29% increase in CHD. Relating these findings from prospective observational study to randomized trials of blood pressure reduction demonstrated that treatment prevented stroke. The findings should put to rest the concern that blood pressure reduction in hypertensive patients precipitates stroke. From a statistical analysis of 14 treatment trials with a total of 37,000 hypertensive subjects it was clear that blood pressure reduction in hypertensives reduced stroke incidence. There was an average diastolic blood pressure reduction of 5.8 mm Hg and a corresponding reduction in stroke incidence of 42%. This observed reduction in stroke closely approximated that expected on the basis of prospective observational studies. In these studies, the duration of blood pressure reduction was brief, from 2 to 5 years, suggesting interruption of a precipitating factor rather than interference with atherogenesis. Presumably, more prolonged blood pressure control would have both effects. Emphasis was placed on the diastolic component in almost all earlier treatment trials, although stroke risk is clearly no less directly related to systolic pressure levels. In older adults, in whom isolated elevation of the systolic pressure is common, treatment was thought to be ineffective in reducing pressure, hazardous in terms of side effects, and unwarranted on the basis of available epidemiologic data. In the SHEP trial, studying 4736 people above age 60 with systolic blood pressure levels above 160 mm Hg and diastolic pressures below 90 mm Hg, blood pressure reduction was associated with a 36% reduction in stroke and a 27% reduction in myocardial infarction and coronary death after 4.5 years of follow-up (Fig. 28-8). In the more recent Syst-Eur Trial in 2398 older adults

263

randomized to nitrendipine or placebo, a 10.1 mm Hg reduction in systolic blood pressure resulted in a 42% reduction in stroke and a 27% reduction in cardiovascular mortality. These findings have enormous importance because two thirds of all people with hypertension between the ages of 65 and 89 years have isolated systolic hypertension. The bulk of strokes occur in this age group. It is clear from the SHEP trial and from the European Working Party on Hypertension in the Elderly study that antihypertensive medication is well tolerated by older adults. SHEP demonstrated that pressure reduction was accomplished with relative ease, in approximately half of subjects pressure was controlled with chlorthalidone alone, and treatment was well tolerated, as evidenced by a 90% compliance rate in the active treatment group at 5 years. Observational studies indicate that stroke risk increases in a linear manner with increasing systolic and diastolic blood pressure. Clinical trials have addressed whether the converse is true: whether lowering blood pressure to increasingly lower levels results in additional stroke reduction. The Hypertension Optimal Treatment trial assigned 18,790 subjects to target diastolic blood pressures of less than 90 mm Hg, less than 85 mm Hg, and less than 80 mm Hg. In the overall study population there was no significant difference between the target groups in any of the endpoints, including stroke and cardiovascular mortality. However, the fact that the achieved blood pressures between the target groups were very similar (85.2 mm Hg, 83.2 mm Hg, and 81.1 mm Hg, respectively) and given an unexpectedly low event rate overall, it would have been very difficult to show a difference; therefore, the trial did not adequately address the issue. Looking at the risk of stroke as a function of achieved blood pressure, the trial demonstrated that the major benefit in stroke reduction and in preventing cardiovascular events occurs at a diastolic blood pressure of 85 mm Hg and a systolic blood pressure of 140 mm Hg, with little further risk reduction below these levels. An

FIG. 28-8. SHEP results: nonfatal events. CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction; RR, relative risk (From Wolf PA: Lewis A Conner lecture: Contributions of epidemiology to the prevention of stroke. Circulation 88:2471, 1993, Fig. 6, with permission.)

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General Aspects of Cerebrovascular Disease

The effectiveness of the newer classes of antihypertensive agents, calcium channel blockers and ACE inhibitors, compared with the traditional diuretics and P-blockers, was addressed in the Swedish Trial in Old Patients with Hypertension I1 and the randomized, open, masked-endpoint Nordic Diltiazem Study. The results of these trials would lead one to conclude that P-blockers and diuretics, long-acting calcium channel blockers, and ACE inhibitors have similar efficacy in stroke prevention, and the degree of benefit is related to the extent of blood pressure control achieved. The medications also have similar safety profiles, with earlier concerns regarding the safety of calcium channel blockers not being justified. However, with the publication of recent trials of newer ACE inhibitors and angiotensin receptor antagonists, the question has been raised as to whether these newer agents have an effect on stroke prevention out of proportion to their effect on blood pressure.

(PROGRESS) recruited 6105 hypertensive and nonhypertensive subjects with a history of stroke or TIA. This double-blind trial randomized subjects to either a perindopril-based treatment protocol or placebo. The perindopril-based treatment protocol allowed the use of the diuretic indapamide if the treating physician wanted more aggressive blood pressure control. In those assigned combination therapy, the blood pressure was 12.3 mm Hg systolic and 5.0 mm Hg diastolic lower than in those treated with placebo. In those assigned perindopril alone, blood pressure was 4.9 mm Hg systolic and 2.8 mm Hg diastolic lower than in those treated with placebo. After a mean follow-up of 3.9 years, those assigned perindopril treatment had a 28% lower incidence of all stroke and a 26% lower incidence of all major vascular events compared with those assigned placebo, with no significant difference in vascular death or overall death. Those assigned combination therapy had a significant 43% lower incidence of stroke compared with the placebo group; stroke incidence was a nonsignificant 5% lower for perindopril treatment alone in comparison with placebo. The degree of stroke risk reduction seems proportional to the degree of blood pressure reduction and is consistent with the magnitude of stroke reduction reported in previous trials of antihypertensive therapies for a similar reduction in blood pressure. The most recent trial of ACE inhibition in stroke prevention was the Losartan Intervention for Endpoint Reduction in Hypertension Study, which randomized 9193 patients with hypertension and LVH to the angiotensin I1 type 1 receptor antagonist losartan or to atenolol. After a mean follow-up of 4.8 years, the mean systolic blood pressure reduction was 30.2 mm Hg in the losartan group and 29.1 mm Hg in the atenolol group, and diastolic blood pressure reduction was 18.5 mm Hg in the losartan group and 19.2 in the atenolol group. Compared with the atenolol group, subjects on losartan therapy had a 13% lower rate of cardiovascular mortality, stroke, and myocardial infarction and an impressive 25% lower rate of stroke. Clearly the additional benefit of losartan over atenolol did not result from differences in systolic or diastolic blood pressure levels, which were quite similar between the two treatment arms. Treatment with ramipril or losartan produces a level of stroke risk reduction greater than that expected from the degree of blood pressure reduction alone. It does not seem that this incremental effect can be extrapolated to other ACE inhibitors, given that trials of the earlier ACE inhibitors lisinopril and enalapril and the more recent ACE inhibitor perindopril showed no similar incremental effects in stroke reduction beyond that expected on the basis of blood pressure reduction.

Newer ACE Inhibitors and Angiotensin Receptor Antagonists. The HOPE trial randomized 9297 subjects with CVD

The Effect of Antihypertensive Treatment in Recurrent Stroke. It has only recently been demonstrated that blood

(coronary artery disease, stroke, or peripheral vascular disease) or diabetes plus one other risk factor to 10 mg/day of ramipril or placebo. Although blood pressure in the ramipril group was reduced by an average of only 3 mm Hg systolic and 3 mm Hg diastolic by the end of the trial, there was a 26% lower rate of cardiovascular death, a 20% lower rate of myocardial infarction, and a 32% lower rate of stroke compared with placebo. This degree of risk reduction is not fully explained by the amount of blood pressure reduction, suggesting that ramipril's protective effect is mediated by other mechanisms. ACE inhibitors may have favorable effects on endothelial function, fibrinolysis, and smooth muscle proliferation. The Perindopril Protection Against Recurrent Stroke Study

pressure reduction in people who have already developed syrnptomatic cerebrovascular disease (stroke or TIA) will prevent recurrent events. The Post-Stroke Antihypertensive Treatment Study (PATS) trial demonstrated that moderate blood pressure reduction of 5 mm Hg systolic and 2 mm Hg diastolic with indapamide resulted in a rate of recurrent stroke or death 29% lower than that of placebo. The PROGRESS trial found a similar overall reduction of 28% in stroke events. With more aggressive blood pressure control, lowering blood pressure by 12.3 mm Hg systolic or 5 mm Hg diastolic, there was a 43% reduction in stroke. Even subjects who have already developed cerebrovascular disease should be considered candidates for stroke prevention through aggressive blood pressure control.

exception might be in diabetic patients. Although there was no difference for stroke alone, diabetics who were randomized to a diastolic blood pressure target of less than 80 mm Hg had less than half the risk of major cardiovascular events and one third the risk of cardiovascular mortality of those who were randomized to a diastolic blood pressure target of less than 90 mm Hg. Therefore, although the issue was not as clear for nondiabetics, diabetics seemed to benefit from a higher magnitude of blood pressure reduction. In both diabetics and nondiabetics blood pressure lowering to even as low as 120 mm Hg systolic and 70 mm Hg diastolic appears to be safe, with no significant increase in adverse outcomes at these levels. Further addressing the issue of blood pressure control in diabetics, investigators from the Syst-Eur Trial recently reported post hoc analyses of their data comparing the benefit in the 4203 nondiabetics with that of the 492 diabetics enrolled in the trial. The benefit of blood pressure control was more striking in the diabetic group, where overall mortality was reduced by 55%, mortality from CVD by 76%, all cardiovascular events by 69%, and risk of stroke by 73%. Also supportive of these results was the UK Prospective Diabetes Study Group Study, which showed that tight diastolic blood pressure control in diabetic older adults resulted in a 44% relative risk reduction in stroke compared with less stringent control. Because increased blood pressure is the most powerful risk factor for stroke and because the benefits of treatment occur so promptly, control of increased blood pressure, systolic as well as diastolic levels, is the cornerstone of stroke prevention. Diabetics stand to benefit most from antihypertensive therapy. Effectiveness of Various Classes of Antihypertensive Agents.

Chapter 28

b

W

Epidemiology and Stroke Risk Factors

265

k kctor

Me

66-76

cs(s

sl-stm,

ti#-,

>76

@or stroice or rM

FIG. 28-9. Efficacy of warfarin by risk category. Pooled analysis of atrial fibrillation trials. TIA, transient ischemic attack.

(Adapted from Risk factors for stroke and efficacy of antithrombotictherapy in atrial fibrillation, analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1454, 1994, Table 5, with permission.)

Preventing the Complications of Diabetes Despite the higher risk of stroke in diabetics, tight diabetic control in patients with type 1 and type 2 diabetes in the recent UK Prospective Diabetes Study Group and in the earlier Diabetes Control and Complications Trial was not found to decrease stroke incidence over 9 years of follow-up. Given that even tight diabetic control is not sufficient in this high-risk population to prevent cardiovascular events such as stroke, some of the focus has shifted to strategies to prevent the development of type 2 diabetes in the first place. One recent trial found that interventions aimed at reducing weight, decreasing total fat and saturated fat intake, and increasing physical activity reduced the risk of developing diabetes by 58%. As mentioned earlier, the combination of diabetes and hypertension is particularly dangerous in terms of elevated stroke risk, but diabetic subjects experience an even greater risk reduction from control of hypertension than nondiabetics. Therefore, aggressive blood pressure control in diabetic patients is a proven risk reduction strategy.

T d n g NonvalvularAtdal Fibrillationwith Warfarin It has been estimated that approximately 25% of people with nonrheumatic atrial fibrillation will sustain a stroke within 10 years. On the basis of clinical experience, it was suspected that chronic warfarin anticoagulation could prevent stroke recurrence in atrial fibrillation. However, warfarin anticoagulation carries a risk of hemorrhage, particularly intracranial hemorrhage. For

these reasons, clinicians were reluctant to prescribe warfarin, particularly in older adults with atrial fibrillation. However, in the past 10 years the benefit and safety of low-intensity Warfarin anticoagulation for stroke prevention in atrial fibrillation has been demonstrated by a series of randomized clinical trials. These trials have also validated the concept that it is the atrial fibrillation and not the associated cardiac conditions that is responsible for the increased stroke incidence in the presence of atrial fibrillation. Because treatment with warfarin has no effect on hypertension, CHD, or congestive heart failure, the anticoagulant action must be responsible for the benefit seen. When the data from the five primary prevention trials were pooled, there was a remarkable 68% reduction in the rate of stroke by warfarin anticoagulation. A more modest benefit of aspirin in stroke prevention was seen. In the Stroke Prevention in Atrial Fibrillation study (SPAF I1 trial), a 44% reduction was achieved with 325 mg per day of aspirin. The benefit of aspirin is not entirely clear, and there was no reduction of cardioembolic stroke in SPAF 11. Most of the effect was seen in the prevention of TIAs and mild ischemic events, and there was no benefit in those above age 75, where atrial fibrillation has its greatest impact. No benefit of aspirin was seen in the European Atrial Fibrillation Trial (EAFT). Factors that predisposed to stroke were identified from the pooled analysis by testing previously identified factors for the individual trials. The independent risk factors for stroke that were found included increasing age, previous stroke or TIA, history of hypertension, and diabetes (Fig. 28-9). The presence of one of these risk factors was associated with a higher incidence of stroke

266

CerebrovascularDisease

W

General Aspects of Cerebrovascular Disease

in each of the three age groups: less than 65, 65 to 74, and 75 years and older. In all but one of the categories, subjects with atrial fibrillation with or without associated risk factors warranted treatment with low-intensity warfarin anticoagulation. Subjects with atrial fibrillation less than 65 years old with no risk factors had a stroke risk of approximately 1% per year. These subjects, whose data have been extrapolated to include younger people with lone atrial fibrillation, appear to have such a low stroke risk that warfarin can be withheld (and aspirin 325 mg per day given). This dramatic reduction in stroke incidence by low-intensity warfarin anticoagulation was achieved with a 0.3% rate of intracranial hemorrhage and an overall major hemorrhage rate of 1.3%. Recurrent stroke in patients with atrial fibrillation was also strikingly reduced by warfarin. In the EAFT the 12% per year stroke rate in the placebo group was reduced to 4% in an intention-to-treat analysis, and there were no intracerebral hemorrhages in the warfarin group of 225 patients followed for 2.3 years. Of interest, there was no significant risk reduction from aspirin in this secondary prevention trial. Thus, with the exception of SPAF 11, where a high intensity of warfarin anticoagulation was used and was associated with an intracranial hemorrhage rate of 1.8% per year in subjects 75 years of age or older, the other five trials achieved a remarkably low rate of major hemorrhage. Bleeding risk with warfarin was significantly outweighed by the benefits of stroke prevention. Taken together, the five primary prevention trials of warfarin therapy resulted in intracranial hemorrhage rates of less than 0.3% per year. Warfarin for Preventing Recurrent Noncardioembolic Stroke

In patients with prior stroke and no cardioembolic source, warfarin sometimes is used in secondary prevention but with little evidence of efficacy in this situation. This issue was recently examined in the randomized, double-blinded, placebo-controlled Warfarin Aspirin Recurrent Stroke Study (WARSS) trial. This large, multicenter study showed no benefit of warfarin over aspirin in preventing recurrent stroke, with a hazard ratio for stroke of 1.13 (95% CI 0.92 to 1.38) for warfarin-treated subjects versus aspirin-treated subjects.

Physical Activity Promotion

As with cigarette smoking cessation, data from observational studies strongly suggest a beneficial role of moderate sustained physical activity in CVD prevention. No randomized clinical trial data are likely to appear that will bolster these data. Beneficial effects of increased vigor, feeling of well-being, and salutary effects on cardiovascular risk factors are compelling. It is clear that regular moderate physical activity should be an integral part of a lifestyle that will help to reduce the risk of stroke and other CVDs. Prevention and Treatment of Heart Disease Including Atrial Fibrillation

Because CHD, cardiac failure, and atrial fibrillation predispose to stroke, preventing these cardiovascular contributors can be anticipated to reduce incidence of stroke. On the basis of current knowledge of the epidemiology of cardiac failure, preventing obesity and treating hypertension may be beneficial. In addition to hypertension control and smoking cessation, CHD risk reduction measures include dietary or pharmacologic treatment to reduce elevated total and LDL cholesterol and to increase the HDL cholesterol fraction. Atrial fibrillation might best be prevented by preventing the appearance of the major precursor of atrial fibrillation, which is heart disease. HMC-CoA Reductase Inhibitors in Patients wlth Coronary Disease

Despite the lack of a relationship between blood lipid levels and ischemic stroke in cohort studies, a number of clinical trials performed in the last 7 years using the cholesterol-lowering (HMG-CoA reductase) inhibitors have demonstrated an impressive reduction in stroke incidence. The Cholesterol and Recurrent Events study investigated the efficacy of pravastatin treatment in patients presenting within 2 years after myocardial infarction and

1.4

1

Smoking Cessation

Based on data from the Nurses’ Health Study and from Framingham, it seems clear that stopping smoking is followed by a reduction in stroke risk in a remarkably short time (Fig. 28-10). Risk of CHD decreases by approximately 50% within 1 year of smoking cessation and reaches the level of those who never smoked within 5 years. In Framingham, in both men and women, risk of stroke in former cigarette smokers did not differ from that of people who never smoked by the end of 5 years. Clearly the axiom “It’s never too late to quit” holds true for stroke, as it does for CHD. The rapid reduction of the effect of cigarette smoking on CHD and stroke strongly suggests a precipitating effect of smoking on disease rather than an influence of promoting atherogenesis. An effect on endothelium and blood clotting might be the mechanism. In any case, it is certain that smoking cessation has been accepted as a proven way to reduce stroke risk promptly. Because smoking confers an increase in stroke risk of 40% in men and 60% in women, after all other pertinent risk factors have been taken into account, cessation may be expected to significantly reduce the risk of stroke.

0 ’ Current smoker

<2

2-4

5-9

210

Never smoker

Time since quitting smoking, years

FIG. 28-10. Smoking cessation and risk of stroke in women. Age-adjusted relative risks of total stroke in relation to time since stopping smoking. Current smoker was the reference category. Error bars represent 95% confidence intervals. (From Kawachi I, Colditz CA, Stampfer MJ et al: Smoking cessation and decreased risk of stroke in women. JAMA 269:234, 1993, Fig. 1, with permission.)

Chapter 28

Epidemiology and Stroke Risk Factors

267

FIG. 28-1 1. Probability of stroke during 10 years in women aged 70 years at two systolic blood pressure levels by impact of other risk factors. AF, atrial fibrillation; CICS, cigarette smoking; CVD, previously diagnosed coronaly heart disease, cardiac failure, or intermittent claudication; DM, diabetes mellitus; Hyp Rx, antihypertensive therapy; LVH-ECC, left ventricular hypertrophy by electrocardiogram. (From Wolf PA, D‘Agostino RB: Hypertension and risk of stroke: the influence of associated risk factors in the Framingham study. Hypertens Res 17(Suppl 1):585, 1994, Fig. 1, with permission.)

with normal or elevated cholesterol and found a reduction in stroke or TIA of 32%. The recent Long-Term Intervention with Pravastatin in Ischemic Disease study enrolled 9014 patients with myocardial infarction or unstable angina and cholesterol in the range 155 to 271 mg/dL and followed them for 6 years. There was a 23% lower incidence of nonhemorrhagic stroke in the pravastatin-treated group. The beneficial effect of HMG-CoA reductase inhibitors may not be limited to their lipid-lowering effects. They may stabilize the atherosclerotic plaque, improve endothelial function, and perhaps help to inhibit thrombosis.

ldentlfying High-Risk Candidates for Stroke Prevention Each physician can identify prime candidates for stroke among his or her asymptomatic patients. Control of elevated blood pressure, including isolated systolic hypertension, will definitely prevent stroke. Among asymptomatic people with borderline elevations of blood pressure, it would be helpful to ascertain which are at higher risk of stroke. Primary prevention of hypertension and control of mild blood pressure elevations, particularly in people at low risk of CVD, may be accomplishedwith hygienic measures. These include weight loss by calorie restriction, increase in dietary potassium, reduction in dietary sodium, moderation of alcohol consumption, and promotion of moderate physical activity. These measures can also be advocated for most people. People with higher blood pressure levels or those with a less benign risk factor profile probably need pharmacologic intervention for blood pressure control.

To select patients at greatest risk of developing CVD and stroke, a risk profile has been developed based on 36 years of follow-up data from Framingham. Using information collected during the course of a comprehensive medical history and conducting a physical examination, plus obtaining an ECG, a patient’s probability of stroke may be determined. Using a separate table for men and women, stroke probability is determined by a point system based on age, systolic blood pressure, antihypertensive therapy use, presence of diabetes, cigarette smoking, history of CVD (CHD or congestive heart failure), and ECG abnormalities (LVH or atrial fibrillation). It is apparent that in people at varying levels of blood pressure, probability of stroke varies across a wide range. Probability rises with increased systolic blood pressure (120 mm Hg and 180 mm Hg are shown), depending on the presence of other abnormalities in the risk profile (Fig. 28-11). Probability of stroke in the hypothetical 70-year-old woman depicted may be higher in the presence of multiple risk factor abnormalities at a systolic blood pressure of 120 mm Hg than at 180 mm Hg in the absence of such abnormalities. This quantitative determination of the probability of stroke, relative to what is average for a woman of this age, may help the patient (and the physician) more M y appreciate the patient’s risk level. The stroke risk profile will help the physician to identify borderline hypertensives warranting pharmacologic treatment by virtue of a higher probability of stroke. Clearly there are other situations not considered here when a patient can also be noted to be at elevated risk of stroke, including recent TIA, recent-onset atrial fibrillation, recent myocardial infarction, and cardiac surgery.

Cerebrovascular Disease rn General Aspects of Cerebrovascular Disease

268

SUGGESTED READINGS Collins R, Pet0 R, MacMahon S et a 1 Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 335827, 1990

Fisher C M The ascendancy of diastolic blood pressure over systolic. Lancet 2:1349-1350, 1985

Fletcher AE, Bulpitt CJ:How far should blood pressure be lowered?N Engl J Med 326251, 1992 JeerakathilTJ,Wolf PA Prevention of strokes. Curr Atheroscler Rep 3:321, 2001

Joint National Committee: The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 157:2413, 1997 Kawachi I, Colditz GA, Stampfer MJ et al: Smoking cessation and decreased risk of stroke in women. JAMA 269:232, 1993 Laupacis A Anticoagulants for atrial fibrillation. Lancet 342:1251, 1993

29

Mas JL, Arquizan C, Lamy C et al: Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 345:1740, 2001 Mohr J, Thompson JLP, Lazar RM et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 345:1444, 2001 Sacco RL, Boden-Albala B, Gan R et al: Stroke incidence among whites, blacks and Hispanics from the same community of northern Manhattan. Am J Epidemiol 147:260, 1998 SHEP Cooperative Research Group: Prevention of stroke by antihyperten-

sive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 265:3255, 1991 U.S. Department of Health and Human Services: Morbidity and Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institute of Health, Bethesda, MD, May 2000 Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB: Probability of stroke: a risk profile from the Framingham study. Stroke 22:312-318, 1991 Wolf PA Lewis A Conner lecture: Contributions of epidemiology to the prevention of stroke. Circulation 88:2471, 1993

Neurodiagnostic Testing Lawrence R. Wechsler, L. Dana Dew& and Viken L. Babikian

Evaluation of a patient with stroke begins with gathering a thorough medical history and conducting a detailed physical examination. From this information, the clinician attempts to determine localization of the ischemic insult and the mechanism of the event. Once these initial impressions are formulated, further evaluation using appropriate neurodiagnostic tests is planned to confirm or alter the original diagnosis. Ultimately, treatment decisions are based on knowledge of the pathophysiology and location of the stroke. Neurodiagnostic testing helps clarify each of these components. Many procedures have been developed or improved to aid in the clinical evaluation of cerebrovascular disease. For many years, angiography was performed by direct carotid puncture but was used sparingly until the transfemoral approach reduced complications. The use of ultrasound to evaluate the carotid arteries by Doppler, B-mode imaging, and duplex Doppler has grown steadily, and its efficacy has improved. Transcranial Doppler (TCD), magnetic resonance angiography ( M U ) , and computed tomography angiography (CTA) now provide a noninvasive evaluation of the intracranial circulation. Computed tomography (CT) and magnetic resonance imaging (MRI) techniques add a further dimension through imaging of physiology including cerebral blood flow (CBF) and metabolism. The challenge for the clinician is to select the appropriate tests

and sequence to clarify each clinical situation while minimizing time, cost, and risk to the patient. This requires the physician to have a basic understanding of the results generated by a test, its strengths and weaknesses, and any pitfalls in interpretation. This chapter briefly describes each of the tests commonly used to evaluate patients with cerebrovascular disease and helps the clinician to apply these tests intelligently to clinical vascular problems.

NONINVASIVECAROTID ARTERY EVALUATION In patients with stroke in the anterior circulation (carotid artery, middle cerebral artery, and anterior cerebral artery), evaluation focuses on possible sources of ischemia, including the carotid arteries and heart. Evaluation for carotid disease usually begins with a noninvasive vascular evaluation. Occasional patients with fluctuating signs or a crescendo pattern of transient ischemic attacks (TIAs) may warrant immediate angiography because significant carotid stenosis is almost certain, and rapid diagnosis is essential to prevent progression to stroke. However, most others with a single ischemic event or stable neurologic symptoms undergo noninvasive evaluation of the carotids as the initial test. Several different methods for ultrasound evaluation of the carotid arteries are available (Table 29-1).

a TABLE 19-1. Comparison of Various Modes of Carotid Imaging Mode

Continuous-waveDoppler B-mode ultrasound imaging Duplex Doppler Color-flow imaging

Doppler

Image

Expense

Accuracy

Advantage

Disadvantage

+

+ + +

+ ++ +++ ++++

+ + +++

No aliasing

++++

Site of maximal velocity easily found

No depth information Velocity change not detected Small jet of high velocity may be missed lnsonation angle alters reliability of color analvsis

-

+ +

Identifies nonstenotic plaque Corrects for angle of insonation

Cerebrovascular Disease rn General Aspects of Cerebrovascular Disease

268

SUGGESTED READINGS Collins R, Pet0 R, MacMahon S et a 1 Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 335827, 1990

Fisher C M The ascendancy of diastolic blood pressure over systolic. Lancet 2:1349-1350, 1985

Fletcher AE, Bulpitt CJ:How far should blood pressure be lowered?N Engl J Med 326251, 1992 JeerakathilTJ,Wolf PA Prevention of strokes. Curr Atheroscler Rep 3:321, 2001

Joint National Committee: The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 157:2413, 1997 Kawachi I, Colditz GA, Stampfer MJ et al: Smoking cessation and decreased risk of stroke in women. JAMA 269:232, 1993 Laupacis A Anticoagulants for atrial fibrillation. Lancet 342:1251, 1993

29

Mas JL, Arquizan C, Lamy C et al: Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 345:1740, 2001 Mohr J, Thompson JLP, Lazar RM et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 345:1444, 2001 Sacco RL, Boden-Albala B, Gan R et al: Stroke incidence among whites, blacks and Hispanics from the same community of northern Manhattan. Am J Epidemiol 147:260, 1998 SHEP Cooperative Research Group: Prevention of stroke by antihyperten-

sive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 265:3255, 1991 U.S. Department of Health and Human Services: Morbidity and Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institute of Health, Bethesda, MD, May 2000 Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB: Probability of stroke: a risk profile from the Framingham study. Stroke 22:312-318, 1991 Wolf PA Lewis A Conner lecture: Contributions of epidemiology to the prevention of stroke. Circulation 88:2471, 1993

Neurodiagnostic Testing Lawrence R. Wechsler, L. Dana Dew& and Viken L. Babikian

Evaluation of a patient with stroke begins with gathering a thorough medical history and conducting a detailed physical examination. From this information, the clinician attempts to determine localization of the ischemic insult and the mechanism of the event. Once these initial impressions are formulated, further evaluation using appropriate neurodiagnostic tests is planned to confirm or alter the original diagnosis. Ultimately, treatment decisions are based on knowledge of the pathophysiology and location of the stroke. Neurodiagnostic testing helps clarify each of these components. Many procedures have been developed or improved to aid in the clinical evaluation of cerebrovascular disease. For many years, angiography was performed by direct carotid puncture but was used sparingly until the transfemoral approach reduced complications. The use of ultrasound to evaluate the carotid arteries by Doppler, B-mode imaging, and duplex Doppler has grown steadily, and its efficacy has improved. Transcranial Doppler (TCD), magnetic resonance angiography ( M U ) , and computed tomography angiography (CTA) now provide a noninvasive evaluation of the intracranial circulation. Computed tomography (CT) and magnetic resonance imaging (MRI) techniques add a further dimension through imaging of physiology including cerebral blood flow (CBF) and metabolism. The challenge for the clinician is to select the appropriate tests

and sequence to clarify each clinical situation while minimizing time, cost, and risk to the patient. This requires the physician to have a basic understanding of the results generated by a test, its strengths and weaknesses, and any pitfalls in interpretation. This chapter briefly describes each of the tests commonly used to evaluate patients with cerebrovascular disease and helps the clinician to apply these tests intelligently to clinical vascular problems.

NONINVASIVECAROTID ARTERY EVALUATION In patients with stroke in the anterior circulation (carotid artery, middle cerebral artery, and anterior cerebral artery), evaluation focuses on possible sources of ischemia, including the carotid arteries and heart. Evaluation for carotid disease usually begins with a noninvasive vascular evaluation. Occasional patients with fluctuating signs or a crescendo pattern of transient ischemic attacks (TIAs) may warrant immediate angiography because significant carotid stenosis is almost certain, and rapid diagnosis is essential to prevent progression to stroke. However, most others with a single ischemic event or stable neurologic symptoms undergo noninvasive evaluation of the carotids as the initial test. Several different methods for ultrasound evaluation of the carotid arteries are available (Table 29-1).

a TABLE 19-1. Comparison of Various Modes of Carotid Imaging Mode

Continuous-waveDoppler B-mode ultrasound imaging Duplex Doppler Color-flow imaging

Doppler

Image

Expense

Accuracy

Advantage

Disadvantage

+

+ + +

+ ++ +++ ++++

+ + +++

No aliasing

++++

Site of maximal velocity easily found

No depth information Velocity change not detected Small jet of high velocity may be missed lnsonation angle alters reliability of color analvsis

-

+ +

Identifies nonstenotic plaque Corrects for angle of insonation

Chapter 29

Continuous Wave Doppler

Doppler evaluation of the carotid arteries is based on the reflection of ultrasound from red blood cells traveling through the carotid bifurcation. An ultrasound probe emits a signal that penetrates the skin and reflects from the flowing blood back to the probe. A receiving crystal within the probe then converts the signal into electric impulses. The frequency of the reflected signal is changed slightly from the emitted signal, and that change is directly proportional to the velocity at which the red blood cells are traveling. The faster the velocity, the greater the frequency shift. This relationship is known as the Doppler principle. The formula that describes the relationship between velocity and frequency shift is as follows:

where V = velocity; fo = emitted frequency, f = received frequency shift, c = constant, and 4 = angle of insonation. Continuous wave (CW) Doppler transducers include a separate transmitting and receiving crystal from which signals are continuously sent and received. Any reflectors in the path of the emitted signal are included in the received signal; therefore, two vessels in the same path cannot be distinguished. This method has an advantage, however, when the depth of a vessel is unknown because it is unlikely that a very deep artery or a small focal area of stenosis will be missed by CW Doppler. When an artery becomes narrowed, red blood cell velocity increases, allowing the same volume of blood to pass through the stenosis per unit of time. Therefore, increased velocity, reflected in increased frequency shift recorded by CW Doppler, indicates stenosis. The more severe the stenosis, the greater the velocity and therefore the frequency shift recorded by CW Doppler. Probe frequencies of 5 to 10 mHz are most commonly used for CW Doppler. Higher frequencies provide greater resolution but less penetration. The amount of frequency shift expected for any given velocity is greater the higher the probe frequency. Therefore, minor differences in degree of stenosis are distinguished more easily with a higher-frequency Doppler probe. Because the angle of insonation between the ultrasound beam and the artery is not known with CW Doppler, velocity cannot be calculated directly from frequency shift. However, assuming a constant angle, greater frequency shifts reflect higher velocities. The degree of stenosis indicated by a given frequency shift depends on the frequency of the probe. To interpret CW Doppler correctly, the frequency of the probe must be known. 8-Mode Ultrasound Imaging

Ultrasound imaging uses frequencies similar to those of CW Doppler but depends on signals reflected from interfaces between two structures of different acoustic impedance. An emitted ultrasound signal travels unimpeded through tissue until it reaches an interface between two acoustically dissimilar media. Some of the signal passes through the interface, but a component is reflected and detected by the original transducer. The strength of the reflected signal is proportional to the difference in acoustic impedance at the interface. Knowing the speed ultrasound travels in the tissue and time from emitted signal to reception of the reflected signal, the distance to the interface can be calculated. Each reflection is represented by a dot on a screen at the

NeurodiagnosticTesting

269

appropriate distance, and the intensity of the dot is proportional to the strength of the reflected signal. From information obtained by scanning a large area or sector, an image is reconstructed. Modern probes include an array of transducers that allow real time imaging by updating the image at a frequency fast enough to view continuous motion. As in CW Doppler, the resolution increases with higher transducer frequency, but tissue penetration is sacrificed. Therefore, a high-frequency imaging probe improves resolution but often cannot provide adequate images of deep arteries.

Duplex Doppler

The combination of B-mode imaging and Doppler evaluation is called duplex Doppler. In most cases, pulsed Doppler (PD) is used instead of CW Doppler. PD uses the same transducer to both emit and receive. A brief ultrasound signal is transmitted into the tissue. The transmitter is then turned off and the receiver opened for a short time. The timing of the receive cycle can be varied so that only signals reflected from a particular depth are received. Signals traveling shorter or longer distances reach the transducer but do not register because the receiver is not active at that time. The depth can be varied simply by changing the interval during which signals are received. Imaging and PD cycles alternate very rapidly, allowing simultaneous real-time imaging and Doppler analysis of a selected portion of the artery. Duplex Doppler provides several advantages over B-mode imaging or PD alone. Because the artery from which the Doppler signals are derived can be seen, the angle of insonation is measurable, and therefore velocity can be calculated directly from the PD information without making assumptions about the relationship between the probe and the artery. In addition, the Doppler window can be steered directly into the area that appears stenotic on the image. This ensures that areas of dense plaque are thoroughly investigated by PD. B-mode imaging provides excellent definition of the size, location, composition, and surface characteristics of plaque. However, it is difficult to accurately image a three-dimensional object in two dimensions. Multiple views through the area help reconstruct a three-dimensional picture, but a very small eccentric lumen often is difficult to assess even by the best ultrasonographers. Velocity generally does not increase until lumen diameter is narrowed by approximately 60%; therefore, no Doppler velocity changes are seen with minor stenoses. Spectral broadening, an increase in the number of different velocities present in the Doppler signal, sometimes reflects lesser degrees of stenosis, but B-mode imaging should be more accurate in estimating minor degrees of luminal narrowing. Beyond 60% stenosis, velocity increases rapidly with decreasing lumen size. This relationship is predictable (Fig. 29-1) and allows estimation of severe degrees of stenosis more accurately than by B-mode alone. The combination of the two in the form of duplex Doppler maximizes the definition of both the plaque and the degree of stenosis. Because the same transducer is alternately used for imaging and PD, there is a limit to the frequency that can be detected by these instruments. No such limit exists for CW Doppler. In addition, if the Doppler window is not placed in the critical area because of operator error or because the plaque causing stenosis is not well seen by imaging, the maximal stenosis may not be detected.

270

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1

General Aspects of Cerebrovascular Disease 1

1

)

96

I

84

I

I

16

64

% Decrease in cross-sectional

1

i

3

3.5

4

Lumen Diameter (mrn) FIG. 29-1. Relationship between residual lumen diameter or percentage stenosis and frequency shift measured by Doppler. (From Spencer MP, Reid JM: Quantitation of carotid stenosis with continuous-wave (C-W) Doppler ultrasound. Stroke 10:326, 1979,with permission.)

Color Flow Imaging

With color flow imaging, the velocity of blood flow recorded by Doppler is translated into a color scale, with red and blue indicating flow in one direction or the other and brightness of the color proportional to velocity. This is then superimposed on the B-mode image (Plate 29-1). Color flow imaging improves detection of short segments of high-grade stenosis or stenosis within hypoechoic plaque that may not be easily identified by B-mode imaging. The high-velocity flow is seen as a jet of bright color within the lumen. PD can then be directed to the area of maximal stenosis to record the highest velocity. Interpretatlon of Noninvasive Camtid Studies An experienced examiner with the highest-quality equipment can

achieve higher than 90% sensitivity and specificity for detecting more than 50% stenosis at the carotid bifurcation and accurately estimate the degree of stenosis within 10% to 20%. A typical report includes the peak systolic velocity recorded in the common internal and external carotid arteries on both sides, description of the amount of plaque, and the maximal stenosis observed by B-mode examination, usually based on an image obtained in the

transverse plane. Some laboratories also report the ratio of internal carotid to common carotid artery velocity. Values greater than 2 are considered abnormal. Information is obtained about the irregularity of the plaque surface and the characteristics of the plaque, such as homogeneous, nonhomogeneous, hypoechoic, or calcified (Fig. 29-2). It remains unclear whether these features of the plaque correlate with embolic potential or stroke risk. Highly stenotic plaques with ulceration are associated with a greater subsequent stroke risk than nonulcerated plaques, but it may be difficult to accurately identify ulceration by ultrasound. A smooth depression in a plaque or normal area of artery between two plaques sometimes mimics the appearance of an ulceration. Most clinicians rely on the degree of stenosis reported by carotid noninvasive testing for clinical decision making but apply information regarding irregularity or plaque characteristics with great caution. Peak velocities in the internal carotid artery (ICA) greater than 140 cmhecond using a 5-mHz Doppler probe are associated with diameter stenosis of at least 60%. Velocity continues to increase as the degree of stenosis increases. With severe stenosis (>75% diameter), end-diastolic velocity begins to rise (>125 cm/second; Fig. 29-3). Most reports classify diameter stenosis as less than 50%, 50% to 75%, 75% to 95%, more than !%yo, or occluded. This is usually based on the Doppler results but may be

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supported by the degree of stenosis seen on B-mode imaging. When there is a discrepancy between the B-mode and Doppler estimates of stenosis, the Doppler usually is more accurate for high degrees of stenosis and the B-mode image for minor degrees of narrowing. False negative results occasionally occur with carotid duplex, and the clinician should be aware of the possibility that a significant stenosis or occlusion may not be detected. If the report seems inconsistent with the clinical syndrome and there is a high index of suspicion of carotid disease, the quality of the ultrasound examination should be evaluated. In some patients, the presence of very deep arteries, a short and thick neck, or heavily calcified arteries limit the ability to visualize the vessel and detect a stenotic signal by Doppler. Angiography should be considered when there is doubt about the reliability of the ultrasound results. The ICA may be very tortuous and turn abruptly downward after takeoff from the common carotid artery. If the aberrant position is not identified, no ICA Doppler signal is detected, and the examiner

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may mistakenly diagnose carotid occlusion. Stenosis may be overlooked because of a short area of sudden narrowing with incomplete examination of this area by Doppler. However, when a high-velocity signal is found, signifjmg stenosis, this is rarely a false positive. Normal arteries should not produce high velocities in a focal segment. If angiography fails to confirm a stenosis in such cases, a web or kink may cause stenosis that cannot be seen on the views obtained by angiography. False negative studies also occur when the stenosis is beyond the first few centimeters of the ICA. This is seen with dissection, or when plaque begins high in the neck. False positive results may occur when an external carotid stenosis is mistaken for the ICA or when the angle of insonation is set incorrectly, falsely increasing the velocity calculation based on the frequency shift. If one of the arteries at the carotid bifurcation is occluded, it may be difficult to determine whether the remaining artery is the internal or external carotid artery. A well-trained examiner improves the overall accuracy of the test by knowing these pitfalls and avoiding errors

FIG. 29-2. B-mode ultrasound image of the carotid bifurcation demonstrating plaque in the internal carotid artery. ICA, internal carotid artery.

FIG. 29-3. Duplex Doppler examination of the same patient shown in Figure 29-2. The Doppler probe is directed to the area of stenosis, and the Doppler spectra recorded from this area are displayed below the image. Velocity is increased, with spectral broadening indicating a severe hemodynamic change. ICA, internal carotid artery.

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in the few cases where questions arise. In any noninvasive laboratory, quality assurance and ongoing correlations with angiographic results strengthen the ability of the physicians interpreting the study and establish the reliability of the laboratory on which other clinicians depend for proper evaluation of their patients.

Applications of Caratid Noninvasive Testing Stroke and T l k When a patient presents with a TIA or stroke, the major clinical concerns are the mechanism of the ischemic event and institution of appropriate therapy to prevent recurrence or progression of neurologic deficits. Severe carotid stenosis and recent carotid occlusion are associated with a substantial short-term stroke risk, and anticoagulation and carotid endarterectomy (CEA) are treatment options. Because of the high sensitivity and specificity of carotid noninvasive testing, this is an excellent screening test for significant carotid stenosis. If the study reveals greater than 70% diameter stenosis and symptoms are clearly attributable to the carotid circulation on the side of stenosis, CEA should be strongly considered. The risk of stroke in symptomatic patients reported in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) applies to a specific measurement of residual lumen diameter defined angiographically; at present, a similar threshold for carotid noninvasive studies has not been identified. Therefore, patients with stenosis by noninvasive testing in the 50% to 70% range should be considered for angiography to be certain they do not reach the 70% diameter stenosis threshold for consideration of CEA. Seventy percent diameter stenosis equates with 95% area stenosis; therefore, it is important to determine whether the results of carotid studies are reported as diameter or area stenosis. If this information is not included in the report, the ultrasonographer should be called to clarify this issue to properly assess the significance of the test results. Despite improvement in detection of very tight stenosis by color flow imaging, carotid noninvasive testing in any form cannot distinguish a near occlusion from complete occlusion with certainty. For this reason, when no Doppler signal is obtained from the ICA, most ultrasonographers report a near or complete carotid occlusion. Because patients are still at risk for stroke and CEA can be performed if a small residual lumen remains, patients with this pattern should undergo conventional angiography or CTA if they are candidates for CEA. Patients with multiple TIAs in the same vascular territory have an arterial lesion until proven otherwise. Although carotid noninvasive tests remain a good screen for the presence of significant carotid bifurcation disease, it is likely that angiography will be necessary regardless of the results to exclude tandem intracranial disease. Although the carotid studies may provide clues as to what to expect on angiography, in some cases noninvasive testing can be deferred and angiography performed as the initial test. Because of the small but finite risk of angiography, in some centers CEA is performed based on the results of noninvasive testing without the use of conventional angiography. This approach is controversial because the NASCET study that demonstrated the benefit of CEA for symptomatic stenosis depended on measurements obtained by angiography. Rather than relying on a single test, the combination of at least two studies such as ultrasound and MRA or CTA improves diagnostic accuracy when both confirm the presence of severe stenosis. If the tests give

discrepant results or indicate a stenosis of borderline significance, it is probably best to perform conventional angiography to be certain surgery is indicated. Vertebrobasilar Ischemia. Vertebrobasilar TIAs typically are not related to carotid disease, and carotid noninvasive testing is not always necessary. Carotid disease, even when significant, is incidental except for rare patients with unusual anomalies of the circle of Willis. Similarly, a typical lacunar stroke syndrome in a patient with appropriate risk factors for small vessel vascular disease need not always undergo noninvasive carotid testing. However, if there are any atypical features suggesting cortical involvement or the typical risk factors are absent, carotid noninvasive tests should be included in the stroke assessment. Syncope. Syncope has been reported in association with bilateral severe carotid stenosis or occlusion, but in most cases the carotid disease is known or previously suspected. Even when bilateral severe carotid disease is present, other causes of syncope, particularly cardiac causes, should be vigorously pursued. Mild or moderate degrees of carotid stenosis do not predispose to syncope. In the typical patient with syncope and no clear indication of carotid disease, the yield of carotid noninvasive testing is low and should not be considered an essential component of the evaluation. Asymptomatic Stenosis. There has been much debate about whether patients with asymptomatic carotid bruits should have carotid noninvasive testing. In some cases, finding stenosis by noninvasive tests leads to angiography and then CEA despite the asymptomatic state. Results from the Asymptomatic Carotid Atherosclerosis Study indicate a 55% relative reduction in ipsilateral stroke in asymptomatic patients with 60% or greater stenosis treated with CEA. These results apply to patients with reasonable surgical risks operated on by highly skilled surgeons, demonstrating a low surgical morbidity. Carotid bruits may not be a reliable indicator of significant carotid stenosis; therefore, carotid noninvasive testing may become a screening test for patients with risk factors for atherosclerotic carotid artery disease. Assessment of the degree of carotid stenosis in asymptomatic patients is helpful in long-term management even if immediate CEA is not considered. Rather than explaining TIAs to all patients with bruits and alarming many of them with little or no stenosis, noninvasive testing identifies those with high degrees of carotid stenosis who are at highest risk for stroke should a TIA occur. Because TIAs may not be recognized, it is useful to review with patients the possible symptoms of carotid TIAs and ask them to call or go to an emergency room if these symptoms occur. In some patients, carotid stenosis may be stable in serial studies performed over several years. In others, the degree of stenosis progresses between studies. When stenosis progresses to high levels (e.g., more than 80% diameter stenosis), prophylactic CEA might be more seriously considered, particularly in young patients who are excellent surgical candidates. ~~

TRANSCRANIAL DOPPLER Transcranial Doppler (TCD) takes advantage of relative areas of thinning of the skull or natural “windows” that allow penetration of ultrasound (Table 29-2). A transducer is positioned in these windows and directed toward the arteries at the base of the brain. The middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and terminal ICA are insonated from a temporal window located above the zygomatic arch and

PLATE 29-1. Color duplex image of the left carotid bifurcation in a patient with asymptomatic carotid artery stenosis.

PLATE 29-2. Transcranial color image of the intracranial circulation demonstrating middle cerebral artery, posterior communicating artery, distal internal carotid artery, and origin of posterior cerebral artery. (Courtesy of V. L Babikian, M.D.)

PUTE 29-3. Computed tomography (Cr) perfusion scan of a patient with a right middle cerebral artery territory stroke. Mean transit time (Mrr) is increased, and both cerebral blood flow (CBF) and cerebral blood volume (CBV) are decreased in the infarded territory.

PLATE 29-4. Xenon computed tomography in a pab'ent 6 hours after onset of a right hemisphere stroke. There is reduced cerebral blood flow in the right middle cerebral artery territory.

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TABLE20-2. Comparison of Transcranial Doppler Techniques

Mode

Doppler

Image

Expense

Accuracy

Advantage

Disadvantage

Transcranial Doppler Transcranial color duplex imaging

+ +

-

+ +++

++ +++

Rapid bedside examination Arteries more easily identified

No angle correction Equipment not as portable; need good window

+

anterior to the pinna. The vertebral arteries and basilar artery are approached from the occipital window along the midline below the occipital protuberance. The orbital window is accessed by placing the probe over the eye and pointing directly posterior to insonate the ICA siphon and ophthalmic artery. TCD uses a 2-mHz probe, in contrast to 5- to 10-mHz probes typically used for extracranial Doppler applications. The lower frequency allows a greater percentage of emitted ultrasound to pass through bone and reflect from moving red blood cells in the intracranial arteries. At higher transducer frequencies, the bone would absorb nearly all the ultrasound, and no reflected signal could be obtained. The velocity of blood flow is then determined from the frequency shift of the received signal according to the Doppler equation. Like carotid duplex, the velocity calculation depends on knowledge of the angle of insonation between the probe and the artery. Because velocity is proportional to cosine I$ of the angle of insonation, the calculated velocity would be within 15% of the true value, assuming the angle remains less than 30%. For most of the intracranial arteries, the angle of insonation is small, although it may occasionally exceed 30% when the artery is tortuous or displaced from its usual position by mass effect or edema. Arteries are identified from each window based on the position of the probe, the depth at which the signal is obtained, and the direction of blood flow. TCD instruments use a pulsed Doppler so that signals from varying depths can be discerned without overlap. The direction of blood flow is also distinguished so that two signals with flow in different directions can be displayed simultaneously. For example, from the temporal window, with the probe directed anteriorly and superiorly at a depth of 50 to 65 mm, flow toward the probe in the MCA is found. Increasing the depth to 70 to 75 mm places the focus of the ultrasound beam in the ACA with blood flow away from the probe. Directing the transducer more posteriorly, flow toward the probe appears in the proximal PCA at depths of 60 to 70 mm and away from the probe as the signal centers on the P2 segment of the PCA. Similar alterations in direction and depth differentiate the vertebral arteries from the basilar artery and the ICA siphon from the ophthalmic artery. lnterpretatlon of Transcranial Doppler A typical TCD report includes peak and mean velocities recorded from the MCAs, ACAs, PCAs, ICA siphons, ophthalmic arteries, vertebral arteries, and basilar artery. In some cases, pulsatility is also reported. The latter provides a measure of resistance in the distal arterial bed. Vasodilation caused by ischemia reduces pulsatility in the basal cerebral arteries. Increased pulsatility occasionally is seen with multiple distal emboli or raised intracranial pressure. Pulsatility is more variable than velocity and is used for interpretation only when clearly different in one arterial territory from all others. Stenosis of the intracranial arteries increases the peak and mean velocities above the normal range. This is determined by laboratory normals or published values for each artery. Abnormality usually is defined as velocities beyond 2.5 or 3 standard

deviations from the mean. Stenosis often produces an increased velocity in a focal segment of the artery with a sudden decrement in velocity beyond the stenosis (Fig. 29-4). The Stroke Outcome and Neuroimaging of Intracranial Atherosclerosis (SONIA) study, an investigation of the accuracy of TCD and MRA when compared with angiography, has used mean flow velocity cutpoints of 100 cmlsecond and 80 cmhecond for 50% stenosis of the MCA and basilar artery, respectively. Elevated velocities are not always caused by stenosis, however. Vasospasm also increases flow velocities, but the clinical context is different, and more than one artery usually is involved. Increased velocities also occur when an artery supplies collateral blood flow. For example, ACA velocity may be increased when the contralateral carotid artery is occluded and there is collateral blood flow to the hemisphere on the side of the occlusion across the anterior communicating artery (Fig. 29-5). In this setting, the increased velocity occurs in a more diffuse pattern throughout the course of the artery rather than the focal pattern characteristic of stenosis. In addition, other abnormalities such as reversed direction of blood flow in the ipsilateral ACA support collateral blood flow as the cause of increased velocity. Decreased velocity may occur in the MCA on the side of an extracranial carotid artery stenosis or occlusion but is rarely a significant finding when present in multiple intracranial arteries. The inability to find a signal from an artery suggests occlusion, but only if other arteries are easily found from the same window, ensuring that the absent signal is not caused by inadequate penetration of ultrasound through bone. Five to 10 percent of patients do not have an adequate temporal window, and a complete study cannot be obtained. Transcranial Color Duplex lmadng

Although the angle of insonation for most intracranial arteries is less than 30 degrees, direct determination of the position of the artery by B-mode ultrasound increases the reliability of this measurement and more precisely determines velocity. Transcranial color duplex imaging (TCDI) combines a B-mode image of the intracranial compartment with color flow imaging of the basal cerebral arteries (Plate 29-2). Because a low transducer frequency is used for TCDI (2 to 3 MHz), resolution is not optimal, but in most cases the major cerebral arteries can be identified. The Doppler is focused on the artery of interest, and velocities can be measured accurately after correction for the observed angle of insonation. Using this technique, velocities may be as much as 30% higher than those recorded with TCD alone, and the error in flow velocity measurement may be more substantial for intracranial stenoses. In addition to greater accuracy, TCDI shortens examination time and enhances test reproducibility. However, the failure rate is higher with TCDI because of the need for greater reflected signal. TCDI has limitations such as price of equipment and difficulty in imaging a sufficiently long segment of artery to obtain adequate Doppler recordings. The use of ultrasound contrast agents may expand the applicability of TCDI.

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Applications of Transcranial Doppler

lntracranial Stenosis. Intracranial atherosclerotic disease is detected in 5% to 10% of all patients who present to medical attention with a stroke and is more common in the African American and Asian populations. However, the risk of recurrent stroke after an ischemic event related to ICA siphon or MCA

stenosis is substantial, and detection of lesions facilitates treatment that may prevent further ischemic injury. Basilar artery and vertebral artery stenosis or occlusion can also be detected by TCD. In such cases, anticoagulation may be indicated. A velocity increase beyond the normal range in a segment of the intracranial artery with an abrupt decrement in velocity beyond the stenosis is the characteristic TCD pattern of stenosis

C

B

FIG. 29-4. (A) Transcranial Doppler from a patient with episodic dizziness and visual blurring demonstrating a focal increase in velocity in the middle panel with a decrease in velocity beyond this area (lower panel). (B) Corresponding lateral and (C) anteroposterior angiogram from the same patient showing stenosis in the distal vertebral or proximal basilar artery.

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A

B

FIG. 29-5.

(A) Transcranial Doppler recordings from both middle cerebral arteries (MCAs) and anterior cerebral arteries (ACAs) in a patient with severe extracranial carotid artery stenosis on the right. MCA velocity is reduced with blunting of the waveform on the side of the stenosis (top left). ACA velocity is increased contralateral to the extracranial stenosis (bottom right), with reversal of the normal direction of flow in the ACA ipsilateral to the stenosis (bottom left). (s) Recordings from the same patient after carotid endarterectomy. MCA velocity has increased with loss of the blunting on the operated side. ACA flow is now anterograde bilaterally with elevated velocities on the operated side.

(see Fig. 29-4). The extent of velocity elevation correlates with the degree of stenosis in the MCA, but this correlation is less precise for the basilar, vertebral arteries, and particularly the ACA. Sensitivity and specificity of TCD for detecting MCA stenosis is 80% to 90% or more in most studies. Limited data are available for other intracranial arteries, including the vertebrals and basilar artery, but sensitivity and specificity of more than 80% have been documented in a few small studies published to date. In the posterior circulation, a very short segment of stenosis in the

vertebral or proximal basilar artery may be overlooked because of the large sample volume used by most TCD instruments. In addition, the distal basilar artery is difficult to insonate consistently, and stenosis in this segment may not be detected. Despite these drawbacks, TCD provides an excellent screening tool for intracranial disease in patients with TIA or stroke. In the anterior circulation, intracranial stenosis can be detected without the need for angiography. Multiple ischemic events or stereotyped TIAs with normal extracranial carotid duplex studies should

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prompt a search for intracranial stenosis. Patients with TIAs or stroke attributable to the posterior circulation can be screened for significant large vessel stenosis with TCD. Many older adults present with vague symptoms of dizziness or visual disturbances for which vertebrobasilar ischemia is considered a possible cause. Rather than resorting to angiography, TCD evaluation identifies the few patients with significant stenosis who may benefit from medical treatment for stroke prevention. If basilar or vertebral artery stenosis is highly suspected based on the clinical presentation, MRA or CTA should be performed because of the possibility of a false negative TCD. The absence of a signal from one of the intracranial arteries is not always caused by occlusion. Technical factors such as a poor window or a tortuous artery may explain the inability to insonate an artery. Anomalies of the circle of Willis, such as an atretic A1 segment of the ACA or an atretic vertebral artery, may also mimic occlusion. MRA or CTA combined with TCD often provides more information about the intracranial circulation than either test alone. MRA suffers from artifacts caused by turbulent flow and tends to overestimate the degree of stenosis. Movement degrades the images, and claustrophobic reactions prevent some patients from completing the procedure. However, high-quality images identify arterial lesions accurately, whereas TCD provides velocity information to assess the hemodynamic significance of the stenosis. An absent signal by TCD or nonvisualization of an artery by MRA may be caused by technical artifacts, but when both tests are abnormal, occlusion is likely. In most patients with stroke or TIA, conventional angiography may be avoided if both studies are normal or both confirm an intracranial arterial stenosis or occlusion. Intracranial stenosis is not a rare complication of sickle cell disease. The ICA siphon (especially the supraclinoid segment), and the MCA and ACA proximal segments often are the site of severe stenoses. These lesions can be detected by TCD. In addition, when the time-averaged mean flow velocities in the distal ICA or proximal MCA are above 200 cm/second, transfusions reduce the risk of stroke. Monitoring in the Context of Acute Stroke. The introduction of thrombolysis during the first 6 hours after acute stroke has revolutionized the treatment of brain infarction and is a field of intense clinical and laboratory research. TCD assessment of patients who receive thrombolysis helps monitor the recanalization process, providing indirect evidence of clot breakup. Rapid recanalization is associated with short-term improvement. At some centers TCD monitoring has been successfully used to determine the need for continued or repeated thrombolysis. Some evidence suggests ultrasound at the frequency used for TCD may mechanically enhance thrombolysis, and clinical trials are currently in progress to investigate this possibility. Extracranial Carotid Artery Disease. TCD findings in patients with extracranial carotid artery disease reflect the distal hemodynamic effects of the carotid lesion. Therefore, changes do not usually occur until stenosis becomes severe or the artery is occluded. Velocity in the MCA ipsilateral to the stenosis may be less than in the contralateral side, and ipsilateral MCA pulsatility may be lower (see Fig. 29-5). A side-to-side difference in peak velocity of at least 25 cdsecond, when present, suggests a proximal ICA severe stenosis or occlusion. In addition, the contralateral ACA velocity may be increased and ipsilateral ACA flow direction reversed when there is collateral flow from the contralateral carotid across the anterior communicating artery.

Ophthalmic artery flow is reversed in some cases, reflecting flow via an external carotid-ophthalmic-ICAcollateral network, or this artery may be absent on the side of the extracranial lesion. If only one of these findings is present, the diagnosis is uncertain, but two or more abnormalities increase the likelihood of an extracranial carotid lesion. In most cases, however, extracranial stenosis or occlusion is identified by carotid duplex testing. TCD can rule out tandem lesions, and it is helpful in assessing the adequacy of collateral blood flow. If severe stenosis is found by carotid noninvasive procedures in a patient with minor stroke or TIA, CEA should be considered. With high-quality carotid duplex studies indicating more than 90% diameter stenosis, it is unlikely that angiography will demonstrate less than 50% diameter stenosis. MRA or CTA is then obtained to confirm the duplex finding. Angiography can be avoided in those with concordant ultrasound and MRA or CTA findings. Vasospasm. Despite treatment with calcium channel blockers, symptomatic vasospasm occurs in 10% to 20% of patients with subarachnoid hemorrhage from ruptured aneurysm. Vasospasm causes increased velocities in the basal cerebral vessels similar to stenosis caused by atherosclerosis. As vasospasm worsens, velocity increases. Therefore, TCD can be used to detect vasospasm before symptoms occur and to follow its course over time. Selection of patients at risk for ischemia based on steadily increasing velocities allows early treatment institution to prevent progression to infarction. Once therapy such as induced hypertension is started, vasospasm may be monitored by daily TCD studies. When velocities begin to decline, therapy may be discontinued (Fig. 29-6). TCD offers the advantage of convenient bedside testing that can be repeated at frequent intervals without risk to the patient. TCD detects MCA vasospasm with a sensitivity of 65% to 85% and specificity exceeding 95%, but as in atherosclerotic disease, corresponding figures are lower for other intracranial arteries. Elevated velocities may also occur with hyperemia, although this is much less common than vasospasm. Increased velocity in the submandibular ICA sometimes reflects hyperemia. The ratio of the MCA to submandibular ICA velocities is used as an index of hyperemia. Ratios greater than 3 usually indicate vasospasm. In rare cases, diffuse vasospasm in distal arteries beyond the basal cerebral vessels leads to infarction and clinical deterioration. This is not detected by TCD because only the proximal arteries can be insonated. When available, cerebral blood flow (CBF) studies complement TCD information. TCD reflects changes in the basal cerebral arteries, whereas CBF measures tissue perfusion. Distal vasospasm would be detected by reduced CBF despite normal TCD velocities. In asymptomatic patients with rapidly rising velocities, CBF may remain normal until vasospasm becomes severe. Once perfusion falls, ischemia probability is imminent. CBF measurement when velocities reach high levels (more than 300 cm/second systolic or 200 cmhecond mean) may better select those at high risk who would benefit from aggressive hypertension therapy. Systemic factors that alter TCD velocity must be considered when comparing serial studies in the same patient. Velocity is affected by age, and it varies with hematocrit and carbon dioxide changes. Medications may also directly modify velocity by changing the caliber of the basal cerebral arteries. Vasodilators such as nitroglycerin decrease velocity, assuming blood flow remains constant. In most ambulatory patients, these factors are not operative, but in critically ill patients with subarachnoid

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FIG. 29-6. Transcranial Doppler recording from the left middle cerebral artery (MU) in patient with symptomatic vasospasm after subarachnoid hemorrhage. Aphasia and right-hand weakness developed 10 days postoperatively and 13 days after the hemorrhage. Her symptoms resolved when blood pressure was raised. On day 16, MCA velocities remained elevated, and symptoms recurred when pressor therapy was tapered. Twenty-one days after the hemorrhage, velocities by transcranial Doppler had decreased, indicating less severe vasospasm. Her blood pressure was reduced without return of neurologic symptoms. On day 26, velocities in the MCA had returned to normal, and she remained asymptomatic. (From Wechsler LR, Ropper AH, Kistler JP: Transcranial Doppler in cerebrovascular disease. Stroke 17:905, 1986, with permission.)

hemorrhage, systemic factors must be monitored and considered in interpreting daily fluctuations in velocity. Embolus Detection. High-intensity transient signals within the Doppler spectrum signify small emboli traveling through the intracranial circulation. The detected emboli may be particulate (e.g., fibrin platelet) or gaseous (e.g., air) or represent cavitation caused by a mechanical disturbance such as a prosthetic valve. An audible thud is detected, and a characteristic high-intensity signal is superimposed on the normal TCD pattern (Fig. 29-7). High-intensity transient signals have been recorded in patients with atrial fibrillation, MCA stenosis, and fat embolism syndrome. They are particularly common distal to severe and symptomatic carotid stenosis. There is typically no immediate clinical correlate to a high-intensity transient signal; however, signals are detected more often in patients with recent symptoms of cerebral ischemia, and they occur with large vessel strokes more often than with lacunes. Preliminary data suggest that embolus monitoring can predict future cerebral ischemic events. Monitoring can also be useful during CEA and coronary artery bypass graft surgery. This technique has also been used to assess the effects of antithrombotic therapy.

FIG. 29-7. Transcranial Doppler recording from a patient with a

prosthetic valve demonstrating a high-intensity transient signal indicating embolic material in the middle cerebral artery.

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COMPUTED TOMOGRAPHY Creation of an image of the brain by CT scanning was a major breakthrough in evaluating neurologic disorders. It allowed examination of intracranial contents without the risks and discomfort inherent in pneumoencephalography or angiography. CT constructs an image from passage of x-rays through a thin section of the brain. A detector on the opposite side measures the number of emitted x-rays that are not scattered or absorbed by the tissue. Beams of x-rays pass through each area of the tissue slice from many different angles to create a map of tissue density. The brightness of each point in the tissue is mathematically represented by fast Fourier transformation, and the summed value from multiple projections is displayed on a cathode ray tube as relative brightness. Many advances in technology and design have resulted in improved resolution without excessivex-ray exposure. Scanning time continues to decrease, while image quality and information increase.

Applications of CT The use of CT to evaluate stroke dates back to 1973, when the first units were installed. It remains widely used for this purpose. With the development of MRI and the age of the cost-effective practice of medicine, it is important to recognize the advantages and disadvantages of CT compared with other modalities. In patients with stroke, CT often is the first study performed because it is likely to be the most readily available imaging procedure. It is rapid, requiring the patient to be still for only a short period of time, and provides information quickly. CT is the most important early imaging procedure when brain hemorrhage is suspected or must be ruled out before thrombolytic or anticoagulant therapy. It is now recognized that CT is often abnormal very early after the onset of stroke. CT is limited in the evaluation of lacunar strokes, which may not be evident on account of either their small size or their location in areas prone to generating artifacts, such as the pons. In general, CT does not visualize infarction well in the posterior fossa because of artifacts produced by the temporal bones. Arteriovenous malformations (AVMs) can be observed with CT if contrast is given, but small AVMs and cavernous angiomas may be missed. If contrast is necessary during CT evaluation, allergic reactions and renal disease can be limitations. Patients with iodine allergy should be premedicated if contrast CT must be performed, although MRI might be a safer alternative in such situations. Patients with renal compromise should be well hydrated before contrast administration. Again, if renal disease is severe, it might be advisable to perform MRI rather than contrast CT. The CT gantry is quite narrow and limited to the head; therefore claustrophobic reactions are far less likely than with MRI. CT scanning with modern scanners is accomplished in much less time than MRI, minimizing movement artifacts in agitated patients. Ischemic Stroke. Ischemic stroke appears as an area of hypodensity on CT. The shape and location of the region of hypodensity can help delineate the vascular territory involved and aid in the formulation of pathophysiology. Small, deep lesions suggest a lacunar stroke caused by small vessel disease. A wedge-shaped abnormality involving the cortex is characteristic of an embolic mechanism. Edema also appears as a region of hypointensity; therefore, early on, the area of infarction may appear larger than the actual territory of infarcted brain. However, CT is excellent for detecting changes caused bv mass effect. with

ventricular or cisternal compression, shift, or obliteration and displacement of midline structures. CT is more often readily available than newer modalities, and in the acute evaluation of the stroke patient, this is an important factor. However, CT in acute ischemic stroke often is normal, and detection of ischemic tissue can take at least 48 hours to become visible. Ischemic stroke will enhance after intravenous contrast administration from a few days to a few weeks after infarction. However, under most circumstances, performing enhanced CT on ischemic stroke is unnecessary and tends only to confuse matters; ischemic stroke may enhance irregularly or along the borders and give the appearance of abscess or tumor. The appearance of vessels on unenhanced and enhanced CT can sometimes be helpful in determining pathophysiology in ischemic stroke. Acute occlusive emboli can appear as cylindric hyperdensities in the basal cisterns and subarachnoid spaces. This has been noted most often in the MCA and has been called the hyperdense MCA sign (Fig. 29-8). Occasionally a small “dot” of hyperintensity is observed in the distal sylvian fissure representing clot in an MCA branch. Other early signs of ischemia may be observed as early as a few hours after the onset of stroke. Obscuration of the basal ganglia, loss of the insular ribbon, sulcal effacement, and early hypodensity are common in the setting of acute ischemia. Although these abnormalities occasionally reverse with reperfusion, in most cases these findings signify established infarction. This is particularly true for parenchymal hypodensity. In fact, evidence from some but

FIG. 29-8. Embolic occlusion of the middle cerebral artery after an internal carotid artery dissection. Thrombus is seen in the middle cerebral artery as a region of increased density in the stem of the artery /arrows).

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B

FIG. 29-9. (A). Computed tomography (Cr)angiogram of the carotid bifurcation. (B) CT angiogram of the basilar artery and

intracranial vertebral arteries.

not all thrombolytic trials suggests that a large area of hypodensity (greater than one third of the MCA territory) increases the risk of hemorrhage and fatal edema after thrombolytic therapy. Hemorrhagic Stroke. Intracranial hemorrhage on CT can be seen as a region of high density, either parenchymal, subarachnoid, intraventricular,subdural, or a combination of these. Unlike ischemic stroke, acute hemorrhage appears immediately and is very well delineated by CT and should be the first imaging evaluation when acute hemorrhage is suspected. Parenchymal hemorrhage can occur secondary to a variety of causes, such as hypertension, amyloid angiopathy, rupture of an AVM, cavernous angioma or aneurysm, hemorrhage into tumor, sympathomimetic drug effect, coagulopathy, and hemorrhagic conversion of ischemic stroke. The location and appearance of the hemorrhage on CT sometimes can help to determine the cause. A wellcircumscribed ball-shaped lobar hemorrhage or hemorrhage into the basal ganglia or cerebellum in a hypertensive patient probably is secondary to rupture of small penetrating vessels secondary to hypertensive damage. In a young, nonhypertensive person hemorrhage into a tumor or a vascular malformation must be considered. Occasionally, performing contrast CT in addition to plain CT may help to demonstrate tumor or vascular malformation; however, if the lesion is small, it may be engulfed by the hemorrhage and not be visible until a few months later, when the blood resolves. Hemorrhagic infarction often can be differentiated from other causes of parenchymal hemorrhage because of its inhomogeneous appearance and high density within a lowdensity, wedge-shaped infarct. Mass effect from hemorrhage and surrounding edema can be well delineated by CT. In addition, extension into the ventricles can be identified. Although this allows for some spontaneous drainage of blood out of the brain substance and with it some lessening of mass effect, extension of parenchymal blood into the ventricles usually is associated with a poorer prognosis. CT is the study of choice when acute subarachnoid hemorrhage is suspected. The distribution of blood in the basal cisterns or fissures often is helpful in discerning the location of the aneurysm. Anterior communicating artery aneurysms often rupture into the interhemispheric fissure with blood near the anterior perforated

substance and occasionally into the basal frontal lobe. MCA aneurysms often rupture primarily into the sylvian cisterns and sylvian fissure on the side of the aneurysm. Patients with hemorrhage from posterior communicating artery aneurysms have more blood posteriorly, near the posterior perforating substance, and near the ICA on the side of the aneurysm. Hemorrhage from aneurysm rupture in the posterior fossa is primarily into the posterior fossa cisterns. The thickness of blood and persistence of clot have been noted to correlate with the development of vasospasm. Subdural hematomas (SDHs) in the acute and subacute stages are well visualized on CT. However, in the later stages, a chronic SDH may be isointense to brain and be missed except for its mass effect. Bilateral SDH may also be difficult to identify, particularly in the isodense stage, because the mass effect from one side offsets the other, and the midline is not displaced. Absence of sulcal markings and inappropriately small ventricles may provide the only clues to the correct diagnosis. CTA and CT PerfusSon

In addition to the traditional information obtained by standard CT scanning, current CT technology enables imaging of the cerebral circulation (Fig. 29-9) and cerebral physiology (xenon CT and CT perfision). Studies have now verified the reliabilityof CTA in the evaluation of the patient with acute stroke. It is an accurate and safe method for evaluating arterial stenoses or occlusions in the vessels about the circle of Willis. In one study, two radiologists assessed the occlusion sites of the intracranial ICA, the basilar artery, and the MCA trunk with 100% sensitivity and specificity. Their evaluation was less certain in three patients with MCA branch occlusion. In making decisions in regard to thrombolytic therapy, this would be less essential anyway and would also be expected to be associated with better outcomes. Perfused blood volume images can be created at the scanning console from the images used to create the CTA. CTA source images are reformatted into slices and viewed at windows and levels typical for routine head CT. These images of the blood pool are more sensitive to the presence of infarcted brain tissue than

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unenhanced CT and correlate better with eventual infarct size. Perfusion studies are obtained by monitoring the first pass of a standard iodinated contrast agent through the cerebral vasculature. The contrast bolus causes a transient rise in attenuation proportional to the amount of tracer in a given region. Integration of data over the first pass of the contrast agent allows creation of maps of brain perfusion (Plate 29-3). Information can then be provided about cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) in a clinically feasible time frame. Xenon CT (Plate 29-4) has also been used to identify reversible brain ischemia in patients with acute stroke. Evidence suggests that a large area of low CBF (less than 8 cc/lOO g/minute) is associated with a high risk of hemorrhage and malignant cerebral edema. Areas of brain with CBF in the 10 to 20 cc/lOO g/minute range may be salvageablewith reperfusion therapies. Although further studies are needed, xenon CT and CT perfusion hold the promise of selecting the patients most likely to benefit from acute stroke therapy and those most likely to suffer complications.

MAGNETIC RESONANCE IMAGING MRI uses a magnetic field and radio waves to produce brain images. Rather than being an x-ray picture, MRI is based on different tissue responses to magnetic resonance. Magnetic resonance is defined as the enhanced absorption of energy occurring when the nuclei of atoms or molecules in an external magnetic field are exposed to radiofrequency energy at a specific frequency, called the Larmour or resonance frequency. In the production of an MRI, randomly oriented tissue nuclei are aligned by a powerful, uniform magnetic field. This alignment is then disrupted by properly tuned radiofrequency pulses. The nuclei recover their alignment by relaxation processes; tissue contrast develops as a result of the different rates at which nuclei realign with the magnetic field. The positions of nuclei are localized by the application of spatially dependent magnetic fields, called gradients. The signals are measured after a user-determined time has elapsed from the initial radiofrequency excitation. The signal is then transformed into an image by Fourier transformation. Several tissue-related factors affect the strength of the MR signal, including proton density, relaxation times, magnetic susceptibility, chemical shift, flow, and contrast agents. The most important factors are the relaxation times, TI and T2. Relaxation is the process by which the spins respond to the perturbing effects of the radiofrequency pulse. The duration of these processes, expressed by the T1 and T2 relaxation times, is dependent on certain physical and chemical characteristics of the tissues being imaged. Interpretation of Magnetic Resonance Imaging

Knowledge of the appearance of both normal brain elements and pathologic lesions on various scanning sequences is necessary to properly interpret MRI. Scanning sequences are designed to emphasize T1 or T2 characteristics of tissue. This depends on parameters called TE (echo time) and TA (repetition time). Short TE and TR enhance T1, whereas long TE and TR enhance T2. Gray and white matter, cerebrospinal fluid, and fat all have characteristic T1 and T2 appearances that help identify normal structures. Differential diagnosis of abnormalities depends on the T1 and T2 appearance in relation to known structures such as brain and cerebrospinal fluid, A typical MRI report usually includes a list of the scanning sequences performed as well as a description of any

abnormalities in terms of hyperintensity or hypointensity on TIand T2-weighted images. In some cases, injection of gadolinium shortens T1 in abnormal tissue and produces increased brightness on TI-weighted images. In addition to scanning sequences, magnet field strength also may alter the appearance of normal and abnormal brain tissues. High-field-strength ( 1.5 Tesla) magnets provide faster scanning times and improved signal-to-noise ratios. Lower field strengths (0.1 to 0.3 Tesla) allow mobile operation and reduce costs. Unfortunately, techniques such as MFU often are not possible with low field strength, limiting these instruments to routine scanning of the brain and spine. Applications of Magnetic Resonance Imaging

MRI is completely noninvasive, providing brain images without exposing the patient to x-radiation. The patient must lie very still for a longer period of time than for CT, although with newer developments the time required for acquiring data is becoming shorter. MRI cannot be performed on all patients. Pacemakers, metal implants, some mechanical valves, and aneurysm clips preclude MRI scanning. Claustrophobic reactions are common, although some low-field strength magnets have open gantries that are more easily tolerated. Movement degrades MRI images and renders the test less useful in agitated or poorly cooperative patients unless sedated. Gadolinium reactions occur but are rare. Ischemic Stroke. Because of the sensitivity of MRI for detecting early changes in brain water content, MRI is the most sensitive method for imaging the early infarction; ischemic changes are seen early because of water changes within cells that are usually the earliest morphologic signs of cell death. An increase in the bulk water content of tissue causes prolongation of both T1 and T2 relaxation times. Infarction therefore is visualized as an area of hypointensity on TI- and hyperintensity on T2-weighted studies (Fig. 29-10), with T2-weighted images being more sensitive. Diffusion-weighted MR imaging (DWI) is especially important in its ability to detect cerebral ischemia acutely and subacutely. With diffusion techniques, the MR image is sensitized to the random microscopic motion of water molecules in tissues. Symmetrical bipolar diffusion gradients impart and then reverse phase modulations of protons in tissues. Protons with restricted motion are rephased by the signal. High-field echo planar techniques typically are used to perform DWI; they are ultrafast and can obtain diffusion information in a rapid, clinically feasible time frame. An apparent diffusion coefficient (ADC) map can be calculated by obtaining images from at least two different levels of diffusion weighting, and these maps are specific for diffusion alterations. DWI is extremely sensitive for detecting early ischemia when imaging is obtained immediately after the onset of clinical symptoms. The pathophysiology is likely to involve the onset of cytotoxic edema with a net bulk motion of water from the free extracellular space to the restricted motion environment of the intracellular space. DWI can be very helpful in the acute evaluation of a stroke patient in helping to determine the cause of the stroke; this can be very important in making decisions in regard to the possible use of thrombolytic treatment. In patients who present a number of hours after a stroke, MRI with traditional techniques such as fluid-attenuated inversion recovery (FLAIR) fast spin echo typically would identify signal changes consistent with infarction. However, in a patient with a new small deep lesion and a lot of small vessel ischemic changes, or a new stroke with a history of multiple old strokes, the new lesion could

Chapter 29

blend in with the old changes and be missed. DWI can easily distinguish the new infarct from the old ones by the increased brightness of the recent lesion. Brain perfusion can be assessed with fast echo planar MR techniques that allow mapping of the first pass of a paramagnetic contrast agent, such as a gadolinium chelate, to provide measurements such a regional cerebral blood volume (rCBV), MTT, and mean time to enhance (MTE). Perfusion techniques are very helpful in the complete evaluation of a patient with acute and subacute stroke. The perfusion is a very sensitive measure of the tissue under ischemic insult. The vascular territory with decreased perfusion is often larger than the abnormality seen on DWI, the so-called perfusion-diffusion “mismatch.” Subtracting the volume of brain with restricted diffusion from the perfusion indicated volume of tissue under ischemic conditions yields the commonly accepted MR paradigm for tissue at risk for extension of infarction. This would imply that there is brain at risk for further infarction that may be spared by rapid reperfusion, possibly by thrombolytic therapy. Perfusion MR is also being used to evaluate patients with other neurologic conditions such as Alzheimer’s-type dementia, where decreased temporoparietal perfusion can be seen. Hemorrhagic Stroke. MRI characteristics of hemorrhage are determined primarily by the densities and paramagnetic qualities of hemoglobin and its breakdown products. For this reason, a hemorrhage changes its MRI characteristics as it undergoes degradation. MRI is excellent for staging the time of hemorrhage and for detecting old hemorrhage (Fig. 29-10). However, for the same reason, it is not as good for evaluating acute hemorrhage.

FIG. 29-1 0. Magnetic resonance image showing three intracerebral hemorrhages of different ages (arrows).

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Hyperacute hemorrhages, those less than 24 hours old, consist primarily of intracellular oxyhemoglobin that is isointense on both T1- and T2-weighted images. These hemorrhages therefore are difficult to detect. Sometimes they are slightly bright on T2-weighted images because of the similar intensities of intracellular oxyhemoglobin and water. Twenty-four to 48 hours after the hemorrhage, called acute hemorrhage, intracellular oxyhemoglobin has broken down into intracellular deoxyhemoglobin. This is nearly isointense on T1-weighted images, or it may have a slightly prolonged T1. Intracellular deoxyhemoglobin has a very short T2 relaxation time and appears black on T2-weighted images. There may be a rim of brightness on T2-weighted images because of the surrounding edema. This is also not an optimal time for MR detection of hemorrhage. CT is clearly better at this stage. However, recent observations have shown an improved performance of certain MRI techniques in the early detection of intracerebral hemorrhage. These have involved the inclusion of the echo planar T2* sequence known as susceptibility-weighted imaging, which in combination with T2-weighted images is capable of detecting parenchymal hemorrhage as early as 23 minutes from onset. From day 2 or 3 to weeks after the hemorrhage, intracellular deoxyhemoglobin is oxidized to intracellular methemoglobin, which has a short T1 phase and therefore is bright on TI-weighted images. This process begins at the periphery of a hematoma and gradually moves toward the center (Fig. 29-llA). With further degradation and lysis of red blood cells, methemoglobin is released into the extracellular space. Intracellular and extracellular methemoglobin are bright on T1-weighted images, although intracellular methemoglobin remains dark on T2-weighted images and becomes bright when it is released extracellularly. Therefore, in early subacute hemorrhages, intracellular methemoglobin appears bright on T1 and dark on T2. As time progresses, the hemorrhage appears bright on T1 and becomes bright on T2. Again, this process progresses from the periphery of the hematoma inward; therefore, at this stage, on T2 images one could see a bright periphery surrounding a dark center (Fig. 29-1 1B). Eventually, the hemorrhage appears bright on both TI- and T2-weighted images (Fig. 29-12A). Later, the blood products are further broken down into hemosiderin, which appears hypodense on both T1- and T2-weighted images. This is initially seen as a dark rim surrounding a bright center on T2-weighted studies (Fig. 29-12B). MRI is far superior to CT for identifjmg the site of old hemorrhage. Some hemosiderin remains even after all the hematoma has been resorbed, leaving a black slit on T2-weighted images. The basic appearance of hemorrhagic infarction on MRI is the same as previously described with CT (i.e., a lesion in a vascular distribution with inhomogeneous blood). The MRI characteristics of the blood are the same as previously outlined in MRI features of hematoma. Vascular Malformations. Flowing blood causes a loss of signal on MRI; therefore, vessels appear as dark voids on T1- and T2-weighted studies. These flow voids can be used to assess patency of a vessel on MRI (e.g., in looking for basilar occlusion). In A W s , a serpiginous tangle of vessels can be seen well on non-contrast-enhanced MRI (Fig. 29-13). With contrast, this becomes hyperintense, although contrast usually is not necessary when screening for the presence of AVMs. Increased signal in the cerebral veins or sinuses on routine MRI suggests sinus thrombosis (Fig. 29-14) and may be confirmed with magnetic resonance venography (MRV). MRI has been found to be much better than CT for detecting small, cryptic AVMs. Cavernous angiomas have a

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A

B

FIG. 29-1 1. (A) T1 -weighted and (B) T2-weighted magnetic resonance image of a subacute intracerebral hemorrhage (arrows).

distinct appearance on MRI. Because they tend to hemorrhage repetitively under low pressure, sometimes asymptomatically, they appear as a round, encapsulated-looking lesion, dark on T I - and T2-weighted images, and filled with or surrounded by hemosiderin (Figs. 29-15 and 16). Arterial Dissection. Dissection sometimes can be detected on plain MRI without conventional angiography or MRA. Clot can be seen in the vessel wall and has the characteristics of hematoma as outlined previously. Typically, the intramural thrombus shows

A

high intensity on axial T1-weighted images and remains white on T2-weighted images. This can be seen with axial sections through the head with intracranial dissection and axial cuts through the neck with extracranial dissection (Fig. 29- 17). MAGNETIC RESONANCE ANGIOGRAPHY MRA includes different evolving MRI techniques that can be used to directly image flow in arteries and veins, and cerebrospinal

B

FIG. 29-12. (A) T1-weighted and (B) T2-weighted magnetic resonance image of an intracerebral hemorrhage (arrows) age 3 months.

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FIG. 29-13. (A, B) Axial T2-weighted and (c 0) coronal T1-weighted magnetic resonance image showing flow voids in vessels of a frontal atteriovenous malformation (arrows).

fluid. The imaging techniques presently used include twodimensional time-of-flight (2D-TOF), three-dimensionaltime-offlight (3D-TOF), two-dimensional phase contrast (2D-PC), and three-dimensional phase contrast (3D-PC); each has advantages and disadvantages. A consensus has not been reached as to which technique should be used in a given application. In addition, it is very important that the one choosing the technique be completely aware of the clinical information and the purpose of the study. TOF techniques exploit the contrast between the high signal

intensity of inflowing, fully magnetized blood and the low signal intensity of saturated stationary tissue. During acquisitions, the imaging volume repeatedly experiences radiofrequencypulses that result in saturation of nonmoving spins. As fully magnetized flowing spins enter the imaging section or volume, there is greater signal intensity from the unsaturated spins than from the surrounding tissue, resulting in a difference in signal intensity between flowing blood and stationary tissue. The advantage of 2D-TOF is its sensitivity to slow flow, making it ideal for

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venography, to image the patency of dural venous sinuses or the venous outflow from an AVM. 3D-TOF has the advantages of short scan times and high spatial resolution. A disadvantage of the TOF technique is that thrombus or other short T1 substances may be confused with flow. MRA shows dropout of signal within a vessel when turbulence is present, secondary to a stenosis or tortuosity in a vessel. MRA is excellent for visualizing the carotid bifurcation in the neck and demonstrating ICA stenotic disease. However, because of turbulence caused by stenosis, MRA tends to overestimate the degree of

FIG. 29-1 4. T1-weighted magnetic resonance image showing bright signal in venous sinuses in patient with sinus thrombosis.

narrowing of the vessels. Extracranially, with a very tight, critical ICA stenosis, a region of total signal dropout may be seen, with reconstitution of flow above (Fig. 29-18). With complete occlusion, there is complete loss of signal from the occluded region extending caudally (Fig. 29-19A) and intracranially. This can be visualized as loss of signal in the carotid siphon (Fig. 29-19B). Critical ICA stenosis in the neck resulting in very slow flow past the stenosis can appear as an occlusion. Although MRA can actually be better than angiography for detecting slow flow above a critical stenosis, this can still be missed with MRA. Therefore, if CFA is considered, angiography with a trickle study should be performed. Carotid siphons are well visualized by MRA; however, because of the bends in the vessel, there may be dropout of signal that can be confusing when evaluating this region. The intracranial anterior circulation vessels are well seen when evaluating for regions of proximal stenosis. Tight MCA stenosis is seen as a narrowed vessel or region of signal dropout (Fig. 29-20). In the posterior circulation, the extracranial vertebral arteries are well visualized in the neck in the region between the origin and the portion of the vessel going through the bony vertebral foramina. MRA of the vertebral artery origins off the subclavian arteries usually is not adequate because of artifact from cardiac movement. Newer techniques are attempting to place receiving coils over this region to selectively image it, although this is not done routinely. The portion of the vertebral artery that bends around the rostral cervical vertebrae can be a problematic region for evaluation because of the sharp angulation and curvature of the artery. The intracranial vertebral arteries and the basilar artery are well visualized by MRA. Basilar stenosis appears as a region of signal dropout (Fig. 29-21A), which without specialized flow studies can be difficult to differentiate from occlusion. TCD ultrasound (Fig. 29-2 1B) or angiography (Fig. 29-21C) may be necessary for further clarification.

A

FIG. 29-15. (A) TI-weighted sagittal and (B) coronal magnetic resonance image of an upper midbrain cavernous angioma

(arrows).

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FIG. 29-16. (A) T1-weighted axial and (B) TZ-weighted coronal magnetic resonance image of a cavernous angioma in the medial left temporal lobe (arrows).

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FIG. 29-17. (A) Magnetic resonance image showing clot in the wall of the left internal carotid artery (ICA) caused by dissection. (B) Corresponding angiogram of the left ICA showing tapered narrowing characteristic of dissection.

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C

FIG. 29-18. (A) Magnetic resonance angiogram showing skip area in region of very tight ICA bifurcation stenosis (arrow) with reconstitution above. (8) MRA showing signal of flowing blood in carotid siphon above a tight ICA stenosis. (C) Angiogram corresponding to MRA in A.

Chapter 29

Depending on the MRA technique, flow in the posterior circulation, may be shown as an open vessel, no matter what the direction. Figure 29-22 outlines a major pitfall with MRA. This patient had severe bilateral intracranial vertebral disease with reversed flow in the basilar artery. The regions of vertebral disease were lost in the images between the extracranial study, which showed a very small right vertebral artery and a normal left vertebral artery, and the intracranial study, which did not demonstrate a right vertebral artery, but the

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left vertebral artery again appeared normal. On angiography, the right vertebral artery was occluded, the left was tightly stenotic in the intracranial portion, and the basilar artery filled retrograde via the carotids. TCD also demonstrated the reversal of flow in the basilar artery. M U techniques can be adapted to record the direction of flow in the vessels and eliminate these pitfalls. In addition, the extracranial and intracranial vessels can be viewed together, or images can be overlapped to avoid this problem.

A

B

FIG. 29-19. (A) Magnetic resonance angiogram (MRA) in internal carotid artery (ICA) occlusion. (13) MRA showing absence of signal indicating lack of flowing blood in carotid siphon above a complete ICA occlusion (arrow).

A

B

FIG. 29-20. (A) Magnetic resonance angiogram and (B) conventional angiogram of middle cerebral artery stenosis (arrow).

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A

C

B

FIG. 29-21. (A) Magnetic resonance angiogram in basilar stenosis showing region of complete signal dropout (arrow). (B) Transcranial Doppler recording from the same patient showing elevated velocities in the mid-basilar artery consistent with a region of stenosis. (C) Angiogram from the same patient showing basilar stenosis (arrow). Branch vessels such as the posterior-inferior cerebellar arteries, anterior-inferior cerebellar arteries, and superior cerebellar arteries often are well demonstrated on MRA. However, the smaller the vessel, the more likely that MRA will not detect it. MRA is not as good as angiography for evaluating small vessel occlusions or patterns suggestive of vasculitis.

Applications of Magndc Resonance Angiogrclphy Ischemic Stroke. In a patient with TIA or stroke attributable to ischemia in the distribution of the MCA or ACA, MRA may provide important information. It is probably not the optimal test for evaluating the carotid bifurcation because of the tendency to

Chapter 29 W

overestimate the degree of stenosis. Because recommendations regarding CEA in both symptomatic and asymptomatic patients depend on percentage stenosis, the most accurate measurement of lumen diameter should be obtained. Conventional angiography is preferred by most clinicians, although at some centers the combination of carotid duplex and MRA has replaced angiography if both studies coincide in indicating very severe stenosis. In a patient with TIA or stroke and no significant carotid disease by noninvasive carotid testing, intracranial disease should be suspected. This is particularly true when repeated stereotyped attacks occur in the absence of carotid bifurcation disease. MRA, similar to TCD, provides a noninvasive examination of the intracranial circulation. Narrowing of the carotid siphon or MCA can be identified, then further defined by TCD or contrast angiography.

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Negative study results obviate contrast angiography in most cases. Evaluation of vertebrobasilar TIAs or stroke may also include MRA. Similar to the anterior circulation, MRA provides a noninvasive screening test for stenosis in the vertebral and basilar arteries. Multiple stereotyped events or a stepwise progression of neurologic deficits not clearly attributable to a single branch of the basilar artery suggest large vessel disease in the posterior circulation. MRA allows rapid identification of stenosis (although the severity of stenosis may not be accurate) and may obviate conventional angiography or at least delay angiography until the patient’s clinical status stabilizes. Knowledge of the vascular anatomy early on facilitates decisions about management of blood pressure, use of antiplatelets or anticoagulants, and activity.

B

FIG. 29-22. (A) Magnetic resonance angiogram of extracranial vessels showing normal flow in the left vertebral artery (arrows) and small right vertebral artery. (13) Magnetic resonance image of the head showing normal-appearingflow in the left vertebral and basilar arteries. Illustration continued on following page

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C

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0ASlLAR FIG. 29-22. Continued(C) Angiogram showing tight left intracranialvertebral stenosis and (0) basilar artery filling retrograde from the carotid artery injection. (€1Transcranial Doppler recording showing elevated velocities in the left vertebral artery consistent with stenosis and reversed flow in the basilar artery (this patient also had a tight left ophthalmic artery stenosis). E

BASILAR

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Aneurysms and Artenovenous Malformations. With a sensitivity of !%%, MRA may be a useful screening test for intracranial aneurysms, if one is willing to accept some false negative studies for lesions less than 5 mm in diameter. In the setting of subarachnoid hemorrhage, angiography is necessary because even small aneurysms must be detected. AVMs that are seen as serpiginous flow voids on standard spin echo MRI can be better delineated by MRA, although contrast angiography remains the method of choice for definitive evaluation of intracranial aneurysms and AVMs.

Magnetic Resonance Venography MRV is excellent for visualizing the intracerebralveins and sinuses. It is particularly good when venous sinus thrombosis is suspected in that it is noninvasive, can be performed at the same time as the MRI, and can demonstrate the open vessels well. The occluded vessels are seen as absence of flow. MRV is helpful in identifying sagittal sinus thrombosis as the cause of chronic headaches and increased cerebrospinal fluid pressure (Fig. 29-23). Venous infarction appears on CT or MRI as a superficialcortical wedged-shaped

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abnormality, often with a prominent hemorrhagic component. When such lesions are seen, MRV is helpful to identify occlusion of a cortical vein or sinus without the need for contrast arteriography with venous imaging. MR Spectroscopy

MR spectroscopy allows noninvasive assessment of the chemistry of brain tissues. Single and multivoxel techniques are useful in evaluating focal brain lesions, especially when the disorder is not clear using other imaging techniques. MR spectroscopy imaging improves lesion characterization and assists in the differentiation of tumor from radiation necrosis, as well as from infection and infarct. Key metabolites in clinical proton MR spectroscopy include N-acetylaspartate (NAA), choline, and lactate. The concentration of NAA, a neuronal marker, is low in almost all focal brain lesions, including infarction, hemorrhage, neoplasm, and infection. Lactate is the end product of anaerobic glycolysis and is not typically present in a normal MR spectrum. It can be elevated in a number of conditions including hypoxia, infarction, hemorrhage, neoplasm, and infection, and lactate elevation is the hallmark of ischemia and infarction. Choline is a marker of membrane synthesis and is seen in high concentration in rapidly proliferating tissue such as the neonatal brain, as well as in brain neoplasms. It may be reduced in conditions such as infarction and hepatic encephalopathy.

CONTRAST ANGIOGRAPHY Contrast angiography remains the standard for optimally visualizing the cerebral and neck vessels. However, it is an invasive procedure with complications of stroke and bleeding as well as limitations such as dye allergy. In many situations, MRA or CTA has replaced contrast angiography. Angiography carries a comFIG. 29-24. Long, tapered narrowing of the extracranial internal carotid artery caused by dissection (arrow).

plication rate of 0.5% to 1%, whereas MRA or CTA presents almost no risk. Three-dimensional acquisitions by MRA or CTA allow multiple views of vascular anatomy. Contrast angiography typically obtains only two or three views, which may not optimally visualize the disorder. Angiography takes time and may delay appropriate therapy. However, when definitive information is needed about the status of the cerebral circulation, contrast angiography remains the test of choice.

Applidons of Contrast Angiography

FIG. 29-23. Magnetic resonance venography showing absence of flow in the superior and inferior sagittal sinuses.

Cerebrovascular Disease. Standard catheter angiography remains the optimal method for evaluating arterial lesions. Unlike MRA, contrast angiography is an actual anatomic diagram of the vessel. In the evaluation of extracranial vascular disease, angiography can differentiate between mild, moderate, or severe occlusive disease and shows regions of irregularity. It remains the method of choice for evaluating the aortic arch and the origins of the great vessels. In extracranial carotid dissection, angiography shows the well-described tapered stenosis or string sign (Fig. 29-24) and the telltale pouch.

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FIG. 29-25. Regions of the segmental narrowing presumed to be caused by vasospasm (arrows).

Angiography performed acutely after large vessel territory strokes often can be helpful in defining the pathophysiology of the stroke. It is excellent for identifjmg intracranial stenotic lesions and showing abrupt cutoff of vessels with embolic occlusion. If angiography is being performed to document embolic occlusion of a vessel, it is best performed within 48 hours of the ischemic event because emboli often break up via the body’s own thrombolytic mechanisms. Differentiating near occlusion of the carotid artery from total occlusion in symptomatic patients is important because those with near occlusion may be amenable to CEA.At present, neither MRA nor ultrasound reliably diagnoses total carotid occlusion. When either study suggests occlusion, contrast angiography should be pursued to definitively exclude a small residual lumen. The standard filming sequence should be extended to detect very slow antegrade flow. Technical improvements eventually may document the reliability of other techniques; however, until that time, contrast angiography should be performed unless other factors preclude carotid surgery. Aneurysm and Arteriovenous Malformations. Angiography remains an important tool for evaluating aneurysms and outlining AVMs with detail, showing feeding and draining vessels. For patients in whom surgery is being considered for either of these entities, angiography often is necessary. Angiography may be performed before evacuation of an intracerebral hematoma, in an attempt to demonstrate an aneurysm or AVM before surgery. Angiography demonstrates small vessels well and is the best imaging method available for outlining the beading of vessels seen

with vasculitis. However, vasculitis affecting only the very small penetrating vessels can be missed with angiography and can be diagnosed only with brain biopsy. Regions of segmental narrowing also occur in the absence of vasculitis and may be caused by reversible vasospasm (Fig. 29-25).

SUGGESTED READINGS Aaslid R, Markwalder TM, Nones H Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 57:769, 1982 Ackerman RH, Candia MR Assessment of the vascular substrate of ischemic brain disease. pp. 138-146. In Fisher M, Bogousslavsky J (eds): Current Review of Cerebrovascular Disease. Current Medicine, Philadelphia, 1993 Ackerstaff RGA, Moons KGM, van de Vlasakker CJW et al: Association of intraoperative transcranial Doppler monitoring variables with stroke from carotid endarterectomy. Stroke 31:1817,2000 Adams RJ, McKie VC, Hsu L et al: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 339:5, 1998 Alexandrov AV, Burgin WS, Demchuk AM et al: Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy. Circulation 103:2897,2001 Babikian VL, Wechsler L R Transcranial Doppler Ultrasonography. 2nd Ed. Butterworth Heinemann, Boston, 1999 Babikian VL, Wijman CAC, Hyde C et al: Cerebral microembolism and early recurrent cerebral or retinal ischemic events. Stroke 281314, 1997

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Barest GD, Sorenson AG, Gonzalez RG Magnetic resonance imaging of cerebral infarction. Top Magn Reson Imaging 9:199, 1998 Burtscher IM, Stahlberg F, Holtas S: Proton (1H) MR spectroscopy for routine diagnostic evaluation of brain lesions. Acta Radio1 38:953, 1997 Call GK, Fleming MC, Sealfon S et al: Reversible cerebral segmental vasoconstriction. Stroke 191159, 1988 Cenic A, Nabavi DG, Craen RA et ak Dynamic CT measurement of cerebral blood flow: a validation study. AJNR 2063, 1999 Eliasziw M, Streifler JY, Fox AJ et al: Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. Stroke 25:304, 1994 Estol CJ, DeWitt LD, Tettenborn B et ak Accuracy of transcranial Doppler in the vertebrobasilar circulation. Ann Neurol 28:225, 1990 Gacs G, Fox A, Barnett HJM, Vinuela F CT visualization of intracranial arterial thromboembolism. Stroke 14:756, 1983 Goldberg HI, Grossman RI, Gomori JM et al: Cervical internal carotid artery dissecting hemorrhage: diagnosis using MR. Radiology 158:157, 1986 Hennerici MG, Daffertshofer M Noninvasive vascular testing. pp. 121-137. In Fisher M, Bogousslavsky J (eds): Current Review of Cerebrovascular Disease. Current Medicine, Philadelphia, 1993 Huston J, Ehman RL: Comparison of time-of-flight and phase contrast MR neuroangiographic techniques. Radiographics 13:5, 1993 Knauth M, von Kummer R, Jansen 0 et ak Potential of CT angiography in acute ischemic stroke. AJNR 18:1001, 1997

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Ley-Pozo J, Ringelstein EB Noninvasive detection of occlusive disease of the carotid siphon and middle cerebral artery. Ann Neurol 28:640, 1990 Linfante I, Llinas RH, Caplan LR, Warach S MRI features of intracerebral hemorrhage within 2 hours from symptom onset. Stroke 302263,1999 Mattle HP, Kent KC, Edelman RR et al: Evaluation of the extracranial carotid arteries: correlation of magnetic resonance angiography, duplex ultrasonography, and conventional angiography. J Vasc Surg 13:838. 1991 Minematsu K, Fisher M, Li L, et al: Diffusion-weighted magnetic resonance imaging: rapid quantitative detection of focal brain ischemia. Neurology 42:235, 1992 North American Symptomatic Carotid Endarterectomy Trial (NASCET) collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 325:445, 1991 Ruggieri PM, Masaryk T, Ross JS Magnetic resonance angiography: cerebrovascular applications. Stroke 23:774, 1992 Schwartz RB, Jones KM, Chernoff DM et ak Common carotid artery bifurcation: evaluation with spiral CT. Radiology 185513, 1992 Shrier DA, Tanaka H, Numaguchi Y et al: CT angiography in the evaluation of acute stroke. AJNR 181011, 1997 Verro P, Tanenbaum LN, Borden NM et ak CT angiography in acute ischemic stroke: preliminary results. Stroke 33:276, 2002 Vora YY, Suarez-AlmazorM, Steinke DE et ak Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 44:1237, 1999

COMMON PATHOGENESES OF STROKE

30

Atherothrombotic Cerebral Infarction Carlos S. Kase and Conrad0 1. Estol

The mechanisms of ischemic and hemorrhagic stroke are multiple, in part reflecting the variability in size and location of the arteries involved. The chapters in this section present the pathogenetic mechanisms that underlie most cases of stroke. The frequency of these pathogeneses reflects the prevalence in the population of stroke risk factors, as discussed in Chapter 28, and is in turn reflected by the frequency of the different types of stroke. Table 30-1 lists the stroke subtypes and their frequencies as determined in the hospital-based Harvard Stroke Registry.

ATHEROGENESIS Atherothrombotic occlusion of cerebral arteries, also called large vessel disease, is most commonly the result of atheroma deposition in the vessel wall, often complicated by formation of fresh clot in an area of intimal disruption. The process of atheroma formation, which typically affects large and medium-size muscular arteries at branching points, involves the progressive deposition of fatty materials along with fibrous tissue in the subintimal region. Through a complex interaction of presumably injured endothelial

Chapter 30 W

Barest GD, Sorenson AG, Gonzalez RG Magnetic resonance imaging of cerebral infarction. Top Magn Reson Imaging 9:199, 1998 Burtscher IM, Stahlberg F, Holtas S: Proton (1H) MR spectroscopy for routine diagnostic evaluation of brain lesions. Acta Radio1 38:953, 1997 Call GK, Fleming MC, Sealfon S et al: Reversible cerebral segmental vasoconstriction. Stroke 191159, 1988 Cenic A, Nabavi DG, Craen RA et ak Dynamic CT measurement of cerebral blood flow: a validation study. AJNR 2063, 1999 Eliasziw M, Streifler JY, Fox AJ et al: Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. Stroke 25:304, 1994 Estol CJ, DeWitt LD, Tettenborn B et ak Accuracy of transcranial Doppler in the vertebrobasilar circulation. Ann Neurol 28:225, 1990 Gacs G, Fox A, Barnett HJM, Vinuela F CT visualization of intracranial arterial thromboembolism. Stroke 14:756, 1983 Goldberg HI, Grossman RI, Gomori JM et al: Cervical internal carotid artery dissecting hemorrhage: diagnosis using MR. Radiology 158:157, 1986 Hennerici MG, Daffertshofer M Noninvasive vascular testing. pp. 121-137. In Fisher M, Bogousslavsky J (eds): Current Review of Cerebrovascular Disease. Current Medicine, Philadelphia, 1993 Huston J, Ehman RL: Comparison of time-of-flight and phase contrast MR neuroangiographic techniques. Radiographics 13:5, 1993 Knauth M, von Kummer R, Jansen 0 et ak Potential of CT angiography in acute ischemic stroke. AJNR 18:1001, 1997

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Ley-Pozo J, Ringelstein EB Noninvasive detection of occlusive disease of the carotid siphon and middle cerebral artery. Ann Neurol 28:640, 1990 Linfante I, Llinas RH, Caplan LR, Warach S MRI features of intracerebral hemorrhage within 2 hours from symptom onset. Stroke 302263,1999 Mattle HP, Kent KC, Edelman RR et al: Evaluation of the extracranial carotid arteries: correlation of magnetic resonance angiography, duplex ultrasonography, and conventional angiography. J Vasc Surg 13:838. 1991 Minematsu K, Fisher M, Li L, et al: Diffusion-weighted magnetic resonance imaging: rapid quantitative detection of focal brain ischemia. Neurology 42:235, 1992 North American Symptomatic Carotid Endarterectomy Trial (NASCET) collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 325:445, 1991 Ruggieri PM, Masaryk T, Ross JS Magnetic resonance angiography: cerebrovascular applications. Stroke 23:774, 1992 Schwartz RB, Jones KM, Chernoff DM et ak Common carotid artery bifurcation: evaluation with spiral CT. Radiology 185513, 1992 Shrier DA, Tanaka H, Numaguchi Y et al: CT angiography in the evaluation of acute stroke. AJNR 181011, 1997 Verro P, Tanenbaum LN, Borden NM et ak CT angiography in acute ischemic stroke: preliminary results. Stroke 33:276, 2002 Vora YY, Suarez-AlmazorM, Steinke DE et ak Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 44:1237, 1999

COMMON PATHOGENESES OF STROKE

30

Atherothrombotic Cerebral Infarction Carlos S. Kase and Conrad0 1. Estol

The mechanisms of ischemic and hemorrhagic stroke are multiple, in part reflecting the variability in size and location of the arteries involved. The chapters in this section present the pathogenetic mechanisms that underlie most cases of stroke. The frequency of these pathogeneses reflects the prevalence in the population of stroke risk factors, as discussed in Chapter 28, and is in turn reflected by the frequency of the different types of stroke. Table 30-1 lists the stroke subtypes and their frequencies as determined in the hospital-based Harvard Stroke Registry.

ATHEROGENESIS Atherothrombotic occlusion of cerebral arteries, also called large vessel disease, is most commonly the result of atheroma deposition in the vessel wall, often complicated by formation of fresh clot in an area of intimal disruption. The process of atheroma formation, which typically affects large and medium-size muscular arteries at branching points, involves the progressive deposition of fatty materials along with fibrous tissue in the subintimal region. Through a complex interaction of presumably injured endothelial

294

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TABLE5 0 1 . Stroke Subtypes, Hospital-Based Series (n = 694) Subtype

No. Patients

46

233 34 Large artery thrombosis 131 19 Lacunar infarction 215 31 Embolism 70 10 lntracerebral hemorrhage 45 6 Subarachnoid hemorrhage From Mohr JP, Caplan LR Melski JW et al: The Harvard Cooperative Stroke Registry:a prospective registry. Neurology 28:754, 1978, with permission.

cells with macrophages, smooth muscle cells, and platelets, the arterial wall becomes the site where lipids, especially cholesterol, become deposited, at the same time triggering major changes in the smooth muscle cells in the arterial media. This process begins in the second decade of life and affects almost 70% of people by age 40. In this early stage of the disease, the artery undergoes a remodeling phenomenon in which lipids progressively thicken the arterial wall without affecting the arterial lumen. In advanced stages of this process encroachment of the lumen occurs. This new understanding of arterial disease has two major practical implications: Diagnostic methods that evaluate the arterial lumen (angiography) will not detect atherosclerotic changes before the stenotic stage, and treatment should focus on prevention, which should be initiated decades before the potential occurrence of events. The development of luminal stenosis secondary to enlargement of the atheromatous plaque is subject to individual variability and is thought to be accelerated by atherogenic risk factors such as hypertension, diabetes, hypercholesterolemia, and smoking, and by poorly understood local changes in the atheromatous plaque such as ulceration and subplaque hemorrhage. The resulting focal stenosis is the first event that eventuallyleads to symptoms in large vessel atheromatosis, either transient ischemic attacks (TIAs) or ischemic stroke.

availability of collateral blood flow that results in sparing of ischemic brain tissue. In patients with hemodynamically significant lesions such as complete arterial occlusion or severe stenosis, symptoms may be related to orthostatic changes, and they commonly occur upon arising in the morning. In the event of cerebral infarction occurring at the time of acute atherothrombosis, the stroke mechanism can be either distal embolization by clot that is dislodged from the stump of the fresh clot (generally thought to occur at the time of the acute thrombotic occlusion) or, less commonly, distal hemodynamic insufficiency resulting in infarction along the border zones of the major intracranial arteries that are branches of the involved proximal artery. For the ICA, these infarcts generally involve the MCA/ACA border zone along the anterior upper hemispheric convexity and the MCNPCA border zone in the posterior parietal-superior temporal convexity (Fig. 30-2). For the vertebral artery, the infarcts occur along the posterior edge of the cerebellar

ATHEROMA DISTRIBUTION AND MECHANISM OF SYMPTOMS The distribution of atherothrombosis in cerebral arteries favors the large proximal trunks at sites of bifurcation (Fig. 30- 1). These proximally located lesions can become symptomatic by several mechanisms: progressive lumen reduction to the point of compromising the distal cerebral flow, generally producing TIAs; deposition of thrombus on the plaque with embolization of thrombus fragments, resulting in the so-called artery-to-artery emboli that lodge in a distal branch of the affected artery; or in situ clot formation on an atheromatous plaque with total occlusion of the affected artery. The artery-to-artery embolic occlusions resulting from extracranial internal carotid artery (ICA) atheroma involve the main trunk or the divisions of the middle cerebral artery (MCA) more commonly than the anterior cerebral artery (ACA), whereas those of proximal vertebral artery or basilar artery origin affect the posterior cerebral artery (PCA) territory and less often the posterior and anterior inferior cerebellar arteries and the superior cerebellar arteries. A large enough clot could occlude the top of the basilar artery, causing ischemia in the territory of both PCAs, the midbrain, and the posterior thalamic region. On the other hand, complete arterial occlusion by fresh thrombus superimposed on atheroma can result in either cerebral infarction or-TIAs,-but this event can be fully asymptomatic because of the

FIG. 30-1. Frequency and severity of atherosclerotic lesions in the arterial celvicocerebral tree. (From Poirier 1, Gray F, Escourolle R: Manual of Basic Neuropathology. _. pp. 65-1 02. WB Saunders, Philadelphia, 1990. with permission.)

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A

@

B

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plaque. In this case, a small vessel infarction is the result of large vessel atheroma. Race has significant influence on atheroma location. Caucasians are more likely to suffer carotid artery stenosis at the bifurcation, whereas blacks and Asians are more prone to develop intracranial disease at the MCA stem, carotid siphon, and basilar artery, rarely presenting with extracranial carotid artery disease. Elderly Caucasian women also have a higher incidence of intracranial disease. Structural wall differences between intracranial and extracranial arteries explain that irregularities (such as ulcers) are common in extracranial plaques and very unusual in intracranial lesions.

CLINICAL PRESENTATION

C

E

D

@@

F

FIG. 30-2. Arterial border zones between anterior, middle, and posterior cerebral arteries. (A) Base of brain, (B) upper surface of hemispheres, (C) right lateral convexity, (0) left lateral convexity, (E) left medial view, (9right medial view. (From Mohr JP: Neurological complications of cardiac valvular disease and cardiac surgery including systemic hypotension. p. 143. In Vinken PJ, Bruyn CW (eds): Handbook of Clinical Neurology. North Holland Publishing, Amsterdam, 1979, with permission.)

hemisphere, in the posterior-inferior cerebellar artery to superior cerebellar artery border zone. For the proximal basilar artery, such infarcts can involve the PCNMCA border zone and, less commonly, the thalami bilaterally. Occasionally, unilateral infarcts in a border zone distribution can be caused by multiple small emboli that originate in a proximal stenotic artery. Isolated subcortical infarctions can be the result of atheroma in different arterial segments. A severe stenosis or occlusion at the carotid bifurcation may cause terminal territory ischemia in the lenticulostriate vessels. These small infarcts can present clinically with a pure motor hemiparesis mimicking small vessel disease if the appropriate studies are not performed. The large (20- to 40-mm) so-called striatocapsular infarction often is the result of an embolic artery-to-artery occlusion of the M1 segment of the MCA involving several penetrator vessels such as the medial and lateral lenticulostriate arteries simultaneously. Subcortical infarctions are the rule in young patients with carotid occlusion and good collateral circulation. These infarcts can also occur secondary to emboli originating in the heart and aorta. Other subcortical infarcts can be located in the territory supplied by the other deep arteries such as Heubner’s artery and the anterior choroidal, lenticulostriate, and polar arteries. Subcortical infarcts also occur after occlusion of the perforating medullary branches of the pial arteries of the cortical surface. In yet another scenario, when the atheroma in a large vessel invades the origin of a branching penetrator it is called a junctional

The clinical presentation in cerebral atherothrombosis varies depending on multiple factors, such as the location of the artery involved, the degree and progression rate of the arterial stenosis or occlusion, the availability of collateral blood flow, and probably the level and variations of systemic blood pressure. The latter three factors relate to the severity of the initial clinical deficit, whereas the location of the involved artery determines the specific stroke syndrome. Because the latter are presented in detail in Chapter 40, the discussion here is limited to the general clinical features of cerebral atherothrombosis that apply to this condition regardless of the location of the affected artery.

Transient Ischemic Attacks TIAs-brief episodes of fully reversible focal neurologic deficits-can occur in instances of atheromatosis of extracranial or intracranial arteries such as the ICA, vertebral artery, basilar artery, MCA, and PCA. The mechanism is thought to be either transient hemodynamic failure of hypoperfused distal branches of the affected artery or distal embolization of particulate material (thrombus) that after producing symptoms by blocking an intracranial artery is rapidly fragmented and pushed distally into the circulation, accounting for the rapid resolution of symptoms. The duration of TIAs is more often on the order of minutes than hours, and this factor relates to some extent to the mechanism of the TIAs; those lasting minutes are more commonly caused by hemodynamic factors, whereas those that last longer (hours) have features that favor an embolic mechanism; 50% of TIAs resolve within 1 hour and 90% within 4 hours. The risk of stroke is 5% within the first month after a TIA and 11.6% in the first year. This early occurrence of stroke events after TIA onset determines the recommendations for treating the patient with recent onset of TIAs. However, the risk for a particular patient can be assessed only if the specific cause of the TIA is identified with a thorough neurovascular, hematologic, and cardiac evaluation. Unusual Clinical Presentations. Although TIAs are by definition characterized by transient focal deficits or negative phenomena, an exception to the rule may be the occasional observation of transient positive phenomena in the setting of tight stenosis or occlusion of the appropriate artery. This includes the observation of transient repetitive clonic jerking of the contralateral arm or leg (limb shaking TIAs), without electroencephalographic changes or response to antiepileptic drugs to suggest a partial motor seizure, in instances of ICA stenosis or occlusion, and the occasional report of visual phenomena (flashing lights) in the hemifield contralateral to a stenotic or occluded PCA or in the eye ipsilateral to a stenotic or occluded ICA in an older adult

2%

Cerebrovascular Disease rn Common Pathogenesesof Stroke

without history of migraine headaches or previous episodes of hemianopsia or transient monocular blindness. These rare events probably correspond to cortical ischemia with irritative positive phenomena rather than the more common transient deficits of focal neurologic function that define TIAs. In the proper setting, which generally includes negative electroencephalographicexamination results for a seizure phenomenon and imaging procedures such as computed tomography (CT) and magnetic resonance imaging (MRI) that rule out a focal mass lesion or scar, TIAs should be considered in the differential diagnosis of these phenomena, and appropriate vascular studies aimed at detecting focal atherostenotic disease should follow. Clinical Significance. TIAs correlate with atheromatosis of the corresponding artery in 50% to almost 90% of cases, with some variability that depends on the clinical characteristics and vascular territory involved. As a result of this correlation, they are helpful in detecting symptomatic arterial stenosis and, most importantly, in preventing cerebral infarction, the most serious neurologic event that may follow the onset of TIAS. Correct recognition of carotid artery clinical presentations is crucial to d e h e symptomatic patients. Syncope, dizziness, vertigo, extremity numbness, and cognitive changes are common symptoms that are often erroneously attributed to carotid artery disease. It has been estimated that as many as 20% to 35% of patients with symptomatic ICA stenosis in the 70% to 79% through 90% to 99% range, respectively, develop ipsilateral hemispheric infarction within 24 months of TIA onset. The mortality of these patients with carotid stenosis is close to 6% per year and is related mostly to coronary artery disease. Every patient with TIAs should be considered for evaluation of myocardial perfusion, including those without cardiac symptoms. Patient Management. The need for hospital admission is most critical for patients with onset of TIAs within days, for those who have had repeated episodes over periods of days, and for patients who evidence appropriate focal neurologic deficits on examination despite reporting full subjective resolution of symptoms. The latter situation indicates the development of cerebral infarction, an event that may be documented in as many as 40% of patients when they are assessed with CT or MRI after TIA symptoms with full clinical resolution. Although unproven in a randomized uncontrolled trial, we recommend continuous intravenous heparin infusion after recent onset of TIAs, while further evaluation continues, on the (unproven) assumption that cerebral infarction can be averted by short-term in-hospital use of this medication during the period of highest stroke risk after TIA onset. The Trial of ORG 10172 in Acute Stroke Treatment (TOAST) study showed evidence of a benefit from intravenous anticoagulant treatment with a heparinoid in the subgroup of patients with large vessel disease. Heparin is used without an initial bolus, at a rate of 1000 U/hour, adjusting the infusion rate to maintain an activated partial thromboplastin time of 1.5 times control while monitoring hematocrit and stool guaiac for blood loss, and platelet counts for heparin-induced thrombocytopenia. The use of nomograms with a weight-adjusted heparin dosage results in fewer total complications,fewer mistakes in dosage adjustment, and less work for house staff. The indication of intravenous heparin in acute stroke has been questioned on the basis of negative or ambiguous results regarding a better outcome and lower mortality in most reported studies. Although these studies have confirmed an unequivocal benefit of early anticoagulation in preventing deep vein thrombosis and pulmonary embolism, they have also been associated with an increase in

hemorrhagic transformation of the ischemic stroke. However, inherent shortcomings in the design of these trials, such as the selection of appropriate candidates likely to benefit from anticoagulants, may have masked the potential benefits of anticoagulant treatment. The potential benefits of acute anticoagulation include decreased stroke recurrence, limitation of thrombus progression and anti-inflammatory effects mediated by inhibition of leukocyte rolling, blocking of selectins, decreased NO release, binding to macrophage antigen-1 (Mac-1), and a lesser increase in vascular cellular adhesion molecule 1 (VCAM-1). The controversy about the value of intravenous heparin for patients with acute ischemic stroke or TIA is not likely to be resolved with the currently available data. The prospective Rapid Anticoagulation Prevents Ischemic Damage (RAPID) trial is addressing this issue on a multicenter European trial currently in progress. Ischemic Stroke

Stroke as a result of atherothrombosis of a major arterial trunk can be caused by either distal embolization of thrombus (artery-toartery mechanism) or local thrombus formation with distal hemodynamic consequences. In the first instance, the clinical presentation is indistinguishable from that of intracranial embolism of other types, such as cardiogenic embolism, in which the type of onset and course reflect the sudden occlusion of a previously healthy intracranial artery by unstable particulate materials. The clinical features of cerebral embolism are discussed in Chapter 31. Atherothrombosis with hemodynamic ischemic stroke often presents as stroke during sleep, with the patient waking with the neurologic deficit. This type of onset is thought to relate to a propensity for clot formation during sleep as a result of changes in blood viscosity and coagulability, perhaps also facilitated by low blood pressure during sleep. In instances in which the onset of atherothrombotic stroke occurs during activity, a gradual progression of neurologic deficits is characteristic. Gradual, smooth progression or more commonly a stepwise course over minutes to hours is the rule. In the latter situation, a minimal focal neurologic deficit at onset, with initial stabilization,is followed by subsequent worsening and stabilization until a final, persistent level of dysfunction is reached. These steps in the early progression of atherothrombotic brain infarction can be related to lowering of blood pressure (including attempts at tightly controlling hypertension present on admission with a mild neurologic deficit), but in most instances they are unrelated to a detectable event, probably representing the gradual buildup of thrombus at the occlusion site. Another feature of the presentation of atherothrombotic stroke is the relative paucity of associated clinical findings at onset. These include a low figure of around 10% of headache and vomiting and a virtual absence of seizures at onset, features that distinguish this stroke subtype from cerebral embolism and, especially, the hemorrhagic stroke varieties. Seizures at onset are so rare that their presence in the setting of a progressive focal neurologic deficit (otherwise suggestive of atherothrombotic infarction) should raise the alternative diagnosis of brain tumor or abscess rather than cerebral infarction. It should be stressed that the effects of large vessel atherothrombosis include presentations with TIAs and ischemic stroke, as well as its potential for being a fully asymptomatic event. In the event of ICA occlusion, stroke, TIA, or a fully asymptomatic state can occur with similar frequencies of 37%, 30%, and 33%, respectively.

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LABORATORY DIAGNOSIS

TREATMENT

The diagnosis of stenosis or occlusion of large extracerebral and intracerebral arteries relies on a number of techniques that are being increasingly used to evaluate patients with TIAs or stroke and, to a lesser extent, in asymptomatic patients with suspected atherostenosis of those arteries. These tests are labeled as noninvasive when they rely on pulse, pressure measurements, neuroimaging (magnetic resonance angiography), or ultrasound techniques, in contradistinction to the invasive technique of contrast cerebral angiography. They are discussed in detail in Chapter 29. Our policy in using noninvasive diagnostic techniques is to obtain duplex ultrasound in all patients with suspected extracranial ICA and vertebral artery disease, along with transcranial Doppler (TCD) for evaluating intracranial arteries in those suspected of having atherostenosis or occlusion in the carotid or vertebrobasilar system. Duplex and TCD information complement each other, so both studies should be ordered together for full assessment of the cerebrovascular system. Carotid artery intimal media thickness measurement with B-mode ultrasound not only predicts coronary events but can also differentiate large vessel from small vessel disease, with a significantly higher intimal media thickness noted in the first group. Interpreting TCD results provides additional data on the presence and quality of collateral circulation. These ultrasound techniques are strongly operator dependent and have an overall accuracy of about 90% when performed in an experienced ultrasound laboratory. Magnetic resonance angiography may overestimate the degree of stenosis, but it is useful to compare results with ultrasound studies and define agreement between both techniques. For example, a stenotic lesion that allows some slow flow may appear normal on magnetic resonance angiography, masking the actual cause of symptoms. In this case, the velocity changes detected by TCD suggest the presence of a severe stenosis of the corresponding artery. Conventional catheter angiography should be reserved for patients with contradictory results between the ultrasound studies and magnetic resonance angiography. A critically stenotic carotid artery may be reported as occluded (false positive) by duplex, and the patient may miss the opportunity for an appropriate carotid endarterectomy. A “trickle” film is a special angiographic technique that can separate a “pinhole” lumen from a complete occlusion. We also favor conventional angiography to precisely delineate the intracranial and extracranial vascular anatomy in patients who will undergo carotid endarterectomy. For example, intracranial stenosis and aneurysms are readily detected with angiography. A 10% difference in the degree of stenosis may define the indication for surgery (e.g., in a patient with a symptomatic 60% stenosis), and it is unlikely that this magnitude of difference could be detected reliably with ultrasound. There is a 0.5% risk of stroke with catheter angiography, which is less than the at least 2% death and stroke risk associated with an incorrectly indicated endarterectomy. Helicoidal or spiral CT imaging, which involves the CT imaging of the affected artery after intravenous contrast injection, is a reliable new alternative to the aforementioned techniques. When large vessel atheromatous disease is confirmed, patients should undergo coronary artery evaluation to exclude coexisting pathology in this vascular bed. In some instances, large vessel disease may not be caused by atheroma, and the differential diagnosis should include dissection, hypercoagulable states, radiation, and fibromuscular dysplasia among other less common causes.

The general cerebrovascular disease notion that treatment should be specific to the mechanism, pathology, and etiology also applies to large vessel disease. Selection of different drugs with increasing treatment potency based on the severity of symptoms is likely to result in a therapeutic failure. The best treatment for a given patient is selected based on a thorough knowledge of the entire cerebrovascular system and potential cause of the vascular event. For example, symptomatic carotid artery stenosis greater than 70% is best treated with carotid endarterectomy. However, the treatment is different if the patient has an associated intraluminal thrombus or a tandem, severe, intracranial stenosis. A number of treatments for cerebral atherothrombosis have been added in recent years to the available therapeutic options, largely as a result of multicenter clinical trials. Among these, two major clinical trials (the North American Symptomatic Carotid Endarterectomy Trial [NASCET] and the European Carotid Surgery Trial [ECST] ) have established carotid endarterectomy as the treatment of choice for stroke prevention in patients with symptomatic (TIA or minor stroke) extracranial atherosclerosis of the ICA with stenosis of 70% or more. In both studies, the comparison between the randomized groups of medical and surgical therapy conclusively demonstrated a significantly lower frequency of stroke events in patients in the surgical group: In NASCET, after 24 months of follow-up, 26% of the medical group patients had a stroke ipsilaterally to the symptomatic ICA, whereas only 9% in the surgical group experienced this endpoint (17% absolute stroke risk reduction; Fig. 30-3). The benefit with surgery was increasingly superior by deciles ranging from 12% risk reduction for a 70% to 80% stenosis and 18% for 80% to 90% stenosis, to a 26% absolute risk reduction for 90% to 99% stenosis. Factors associated with higher surgical risk included, left endarterectomy, contralateral occlusion, ipsilateral lesion on CT, and irregular (“ulcerated”) plaque. One third of the complications were intraoperative and thromboembolic. The significant benefits reported in the original NASCET report persisted after 8 years of follow-up. In the ECST trial, the figures for ipsilateral stroke were 16.8% for the medical group and 10.3% for the surgical group after a follow-up of 33 months. The difference between the groups

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Month of Study FIG. 30-3. Survival curves of patients free of ipsilateral stroke in the surgical and medical groups. Difference significant ( p < .001) at 18 months of follow-up. (From North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl 1 Med 325:445, 1991, with permission.)

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was statistically significant in both trials. In the ECST, patients with symptomatic ICA stenosis of 30% or less were also included, and there was no demonstrated superiority of surgery over medical management. NASCET results for the 50% to 69% stenosis range were not as robust as those in the 70% to 99% group, so results in this lower stenosis subgroup should be interpreted with caution. In the moderate stenosis group (50% to 69% carotid stenosis) the 5-year incidence of stroke in surgical patients was 15.7% versus 22.2% in the medical treatment group. The absolute risk reduction (all stroke and all deaths) was 10.1%. This implies that twice as many patients with a 50% to 69% carotid stenosis should undergo endarterectomy to have a benefit of the magnitude observed in patients with greater than 70% stenosis. Women had a lesser degree of benefit with surgery than men. It is important to consider that the surgical risk of stroke and death in this group of patients was a remarkably low 2% and that an increase above this level would cancel the reported beneficial effects. In NASCET, patients with a stenosis of 50% or less had a stroke risk in follow-up that was not significantly different between the surgical and medical treatment groups. Approximately 40% to 50% of patients who undergo endarterectomy in North America are asymptomatic or have symptoms not attributable to the operated artery. The Asymptomatic Carotid Atherosclerosis Study (ACAS) trial showed a significant reduction in stroke and death rate from 11% in the medical treatment group to 5.1% in the surgical group over a projected 5-year follow-up period. A few caveats in interpreting this study include that results were reported at a projected 5-year follow-up period after only 2.7 years of actual follow-up, no increasing benefit by deciles, no significant reduction of major ipsilateral stroke, an absolute risk reduction of only 1.2% in favor of the surgical group, and a relative risk reduction of only 17% in women versus 66% in men. These issues and a low (2% per year) annual incidence of stroke in asymptomatic patients have led most experts to consider surgery mostly in patients with the most severe degrees of carotid stenosis (in the 80% or higher range of stenosis) or in those who show a substantial increase in the degree of stenosis in follow-up ultrasound studies. The Asymptomatic Carotid Surgery Trial (ACST), which is currently in progress and with the goal of including 3200 patients, will provide more precise data on the range of asymptomatic patients who are likely to benefit most from carotid endarterectomy. Angioplasty of the carotid artery is a new technique that has gained unexpected popularity. At present, the few randomized studies comparing angioplasty and carotid surgery have not shown a benefit favoring angioplasty; in fact, some have shown a greater risk of stroke with endovascular techniques. Thousands of patients who have undergone angioplasty have been reported in the literature with lower rates of complications than surgical patients. However, most of these series report asymptomatic patients with a wide spectrum of carotid lesions (including “irregularities” without stenosis and minor stenosis). The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) trial compared endovascular techniques with carotid endarterectomy in a prospective, randomized design. The 2 treatments had comparable rates of stroke/death at 30 days (5.9% for carotid endarterectomy, 6.4% for endovascular treatment), carotid endarterectomy had the expected higher rate of local complications such as neck hematoma and cranial neuropathy, and endovascular treatment has a higher frequency (14%) of recurrent stenosis at one year than carotid endarterectomy (4%). Until the results of the ongoing trials Carotid Revascularization Endarterectomy versus Stenting (CREST), and Stent-protected Percutaneous Angioplasty of the

Carotid versus Endarterectomy (SPACE), and others that are randomizing patients to endarterectomy and angioplasty are available, angioplasty should be considered only for patients who are not candidates for surgery (high risk of morbidity or mortality), those with radiation-induced stenosis, and those with contraindications for technical reasons (carotid bifurcation too high or too low, marked arterial tortuosity, and severe calcifications). In patients with carotid TIAs without a surgical lesion in the appropriate ICA and in those with vertebrobasilar TIAs, the currently recommended treatment for stroke prevention is with antiplatelet agents. The most commonly used agent is aspirin (acetylsalicylic acid [ASA]) because it has been shown to be superior to placebo in a number of clinical trials, which in aggregate have included more than 29,000 patients. A 25% relative risk reduction of stroke, myocardial infarction, and vascular death was demonstrated for aspirin in these studies. Its ideal dosage has not been determined yet, and the controversy over the use of high (975 to 1300 mg/day) or low (80 to 300 mg/day) ASA dosages continues. Most neurologists prescribe 325 mg of aspirin for secondary stroke prevention, although a lower dosage is reasonable for patients with gastrointestinal intolerance. In instances of ASA intolerance or failure of ASA to prevent stroke in TIA patients, a commonly used drug is clopidogrel, a thienopyridine derivative related to ticlopidine. Clopidogrel inhibits platelet aggregation induced by adenosine diphosphate and thus prevents activation of the glycoprotein IIb-IIIa complex. The dosage of clopidogrel is 75 mg per day, and its effect is more potent than that of ticlopidine. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, a secondary stroke prevention study comparing clopidogrel with 325 mg of aspirin that included almost 20.000 patients, showed a significant relative risk reduction of 8.7% in ischemic stroke, myocardial infarction, or vascular death favoring clopidogrel. Systemic and cerebral bleeding complications were more common in the aspirin group, and neutropenia incidence was similar in both groups. In comparison, for each 1000 patients treated in 1 year, aspirin prevents 19 and clopidogrel 24 major vascular events. Because of a substantially higher cost, clopidogrel should be reserved for patients who do not tolerate aspirin. Interestingly, both drugs may have an additive effect when used combined, and their use is under investigation in a controlled clinical trial of secondary stroke prevention (Management of Atherothrombosis with Clopidogrel in High-Risk Patients, or MATCH). Another antiplatelet agent, dipyridamole (a phosphodiesterase inhibitor), has also shown efficacy as it acts by inhibiting the binding of fibrinogen to the platelet wall as the first step leading to platelet aggregation. The European Stroke Prevention Study I1 (ESPS 11) was a large double-blind secondary stroke prevention trial that randomized patients to aspirin alone (25 mg twice daily), extended-release dipyridamole alone (200 mg twice daily), both drugs combined, or placebo. The patients who received a combination of aspirin and extended-release dipyridamole showed a 37% lower stroke risk and a 24% lower risk of stroke and death. This was highly significant compared with the effects of each drug individually and with placebo. Headache was the most common side effect of dipyridamole. The role of warfarin in treating TIAs is still unclear. In most situations in which surgical treatment is not an option, failure to prevent stroke with ASA or other platelet antiaggregants is followed by treatment with warfarin. However, the value of warfarin in this setting has not been properly evaluated in comparison with antiplatelet agents or in relation to its significant potential for producing life-threatening hemorrhagic complica-

Chapter 30 H

tions. In agreement with old opinion and practice, there is a suggested benefit of warfarin over ASA for stroke prevention in patients with TIAs caused by intracranial atherosclerotic disease in the carotid circulation (this is currently being evaluated in the National Institutes of Health-sponsored Warfarin-Aspirin for Symptomatic Intracranial Disease [WASID] trial). By extrapolating these data to the vertebrobasilar circulation, warfarin is generally favored over the antiplatelet agents for stroke prevention in patients with posterior circulation TIAs and documented (by magnetic resonance angiography or contrast angiography) atherosclerotic disease in that territory. If TIAs do not subside with anticoagulant treatment in the therapeutic range (international normalized ratio [INRI 2 to 3), antiplatelets could be added to the drug regimen, and if symptoms are still refractory, angioplasty of the affected segment could be attempted by an endovascular treatment team. Dissections in the posterior and carotid circulations can also be treated with anticoagulants following the rationale that intramural thrombus dislodgement through a ruptured intima is the likely (embolic) mechanism of most stroke events in instances of arterial dissection of neck vessels. After a few months, healing of the dissected artery is the rule when some flow persisted at the time of the original dissection, and anticoagulation can be discontinued. Instances of dissection leading to complete occlusion of the artery are not likely to recanalize. Intraluminal thrombus is another complication that can affect large arteries with or without stenosis. In these settings, anticoagulation is the preferred treatment until thrombus disappearance is confirmed with noninvasive studies. If thrombectomy is attempted, occlusion of the artery or intracranial embolization are common complications of the surgery. Patients with an intraluminal thrombus should be evaluated with a hypercoagulable battery. Bleeding risk with anticoagulants depends strongly on anticoagulation intensity. The INR should be used as the monitoring method and values maintained strictly between 2 and 3 (with the exception of patients with prosthetic cardiac valves, which may need a higher anticoagulation intensity). Excessive anticoagulation as reflected by high INR value and fluctuations of this parameter are the most important predictors for hemorrhagic complications. Age greater than 80, especially in patients with significant periventricular microangiopathy or leukoariosis, may also predict hemorrhage risk. The specific treatments discussed in this chapter should be added to the general measures that aim at improving cerebral oxygenation. Blood pressure should not be decreased abruptly unless it is higher than 230/120 mm Hg. Glucose levels should be in the normal range and solutions with dextrose avoided. Temperature elevations should be treated aggressively. The value of measures such as induced hypothermia is still undetermined, and it is under investigation in a controlled clinical trial. Hydration and fluid balance should be followed closely. Thirty percent of stroke patients are dehydrated on admission. Although the value of hemodilution has not been proven, crystalloid infusion decreases blood viscosity and improves cerebral perfusion. Decompressive craniotomy should be considered for selected patients with the “malignant” form of MCA infarction and cerebellar infarcts with edema. All patients with large vessel disease should be followed with the goal of primary and secondary stroke prevention. New risk factors for vascular disease such as homocysteine, C reactive protein, and lipoprotein (a) should be determined and treated. Cholesterol should be measured, and values outside the recommended ranges (total less than 200 mgldL, high-density lipoprotein greater than 40 mg/dL, low-density lipoprotein less than 100 mg/dL, triglycer-

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ides less than 180 mg/dL) should be treated with cholesterollowering agents. Smoking cessation should be encouraged; moderate alcohol consumption (less than 2 drinks per day) is acceptable, excess salt intake should be eliminated, blood pressure should be kept below 135/85 mm Hg for people of all ages, and a regular exercise program initiated. The use of perindopril, a blood pressure-lowering agent, should be considered even in patients without hypertension based on recent data (Perindopril Protection Against Recurrent Stroke Study [PROGRESS]) proving its efficacy in reducing stroke recurrence. Systematic monitoring and implementation of an effective program to control all these modifiable stroke risk factors will significantly reduce the incidence of vascular events.

SUGGESTED READINGS Adams HP Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke 332356, 2002 Albers GW, Easton JD, Sacco RL, Teal P Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 114683S, 1998 Barnett HJM, Wayne Taylor D, Eliasziw M et al: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 3391415, 1998 Benavente 0,Moher D, Pham B Carotid endarterectomy for asymptomatic carotid stenosk a meta-analysis. BMJ 3121477, 1998 CAFWE Steering Committee: A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 3481329,1996 CAVATAS Investigators:Endovascular versus surgical treatment in patients with carotid stenosis in the carotid and vertebral artery transluminal angioplasty study (CAVATAS): a randomized trial. Lancet 357: 1729, 2001

Castaigne P, Lhermitte F, Gaiter JC et al: Internal carotid artery occlusion: a study of 61 instances in 50 patients with post-mortem data. Brain 93:231, 1970

Chamorro A Immediate anticoagulation in acute focal brain ischemia revisited. Stroke 32:577, 2001 European Carotid Surgery Trialists’ Collaborative Group: MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 3321235, 1991

Fihn SD, Callahan CM, Marvin DC et al: The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 124970, 1996 Fisher CM, Ojemann R G A clinico-pathologic study of carotid endarterectomy plaques. Rev Neurol 142:573, 1986 Jonas S: Anticoagulant therapy in cerebrovascular disease: review and meta-analysis. Stroke 19:1043, 1988 Kappelle LJ, Eliasziw M, Fox AJ et al: Importance of intracranial atherosclerotic disease in patients with symptomatic stenosis of the internal carotid artery. Stroke 30282, 1999 Mohr JP, Caplan LR, Melski JWet al: The Harvard cooperative stroke registry: a prospective registry. Neurology 28:754, 1978 North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 325:445, 1991 Patron0 C Aspirin as an antiplatelet drug. N Engl J Med 3301287, 1994 PROGRESS: Randomised trial of perindopril based blood pressure lowering regimen among 6105 individuals with previous stroke or transient ischemic attack. Lancet 358:1033, 2001 Tatemichi TK, Young WL, Prohovnik I et al: Perfusion insufficiency in limb shaking transient ischemic attacks. Stroke 21:341, 1990 Taylor WD, Barnett HJM, Brian Haynes R et ak Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet 353:2179, 1999 Toth C, Voll C Validation of a weight based nomogram for the use of intravenous heparin in transient ischemic attacks and stroke. Stroke 33:670, 2002

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Cerebral Embolism Carlos S. Kase and Conrad0 1. Estol

Stroke caused by embolism is common and results from the sudden obstruction of a cerebral artery by particulate material that originates proximal to the occlusion site and is carried to it by the circulation. The sources of such material usually are located in the heart and the large vessels (aorta, carotid artery, vertebral artery; Table 31-1). This mechanism of ischemic stroke is characterized by a number of distinctive clinical and anatomic features that separate it from the atherothrombotic variety of brain infarction.

significantlydecrease this risk of embolization. Embolic fragments that are mechanically more stable include septic emboli originating in infected valvular vegetations in bacterial endocarditis, fibrocalcific materials from degenerated mitral or aortic valves, and cholesterol-fibrin emboli from denuded (ulcerated) aortic, carotid, or vertebral atheromatous plaques. Less often, mucinous emboli that originate in adenocarcinomas, fat emboli from long bone fractures or adipose tissue surgery, and intervertebral disc fragments have been reported as a cause of embolic stroke.

SOURCES OF EMBOLIC MATERIAL Embolic material may differ in type, size, and mechanical characteristics that in turn determine to some extent its behavior in the cerebral circulation. Embolic material of cardiac origin often is composed of fragments of thrombus that originate from either the left atrium or atrial appendage in instances of chronic atrial fibrillation with or without associated rheumatic valvular disease, or the left ventricle as a result of mural thrombus formation after recent or remote myocardial infarction (MI). In each instance, the embolic material is mechanically unstable at the site of final occlusion and is prone to spontaneous fragmentation or dissolution by the body’s fibrinolytic system, with eventual partial or complete reestablishment of the circulation at the site of the original occlusion. Other forms of unstable particulate material of cardiac origin include air bubbles or platelet aggregates formed during open-heart surgery under cardiopulmonary bypass. Careful positioning and release of clamps in an atheromatous aorta and new surgical techniques that avoid pump use during cardiac surgery TABLE31-1. Sources of Cerebral Embolism High-risk sources Mechanical prosthetic valve Mitral stenosis with atrial fibrillation Atrial fibrillation (other than lone atrial fibrillation) Left atrial-atrial appendage thrombus Sick sinus syndrome Recent myocardial infarction (<4 weeks) Left ventricular thrombus Dilated cardiomyopathy Akinetic left ventricular segment Atrial myxoma Infective endocarditis Medium-risk sources Mitral valve prolapse Mitral annulus calcification Mitral stenosis without atrial fibrillation Left atrial turbulence (smoke) Atrial septa1 aneurysm Patent foramen ovale Atrial flutter Lone atrial fibrillation Bioprosthetic cardiac valve Nonbacterial thrombotic endocarditis Congestive heart failure Hypokinetic left ventricular segment Myocardial infarction (A weeks, <6 months) From Adams HP, Bendixen BH, Kappelle U et al: Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 24:35, 1993, with permission.

Cardiac Sources Atrial Fibrillation. Chronic and paroxysmal atrial fibrillation in the setting of rheumatic heart disease results in a 17-fold higher risk of cerebral embolism than in control populations. Even nonrheumatic atrial fibrillation increases the risk of cerebral embolism five to six times, making atrial fibrillation the single most important cardiac risk factor for cerebral embolism, accounting for one of every six strokes. Atrial fibrillation is present in 16% of all ischemic strokes, but it has a causal role in the 10% that are associated with atrial thrombi. The prevalence of atrial fibrillation increases steadily with age, to approximately 15% in people older than 75 years, and it carries a risk of stroke of at least 5% per year in the absence of oral anticoagulanttreatment. Factors that increase the risk of systemic embolism (approximately 55% of cardiac emboli affect the brain) in patients with atrial fibrillation include recent conversion from paroxysmal to chronic atrial fibrillation, congestive heart failure, “spontaneous echo contrast” on transesophageal echocardiogram (TEE), advanced age, hypertension, previous stroke, left ventricular dysfunction, moderate to severe mitral regurgitation, and changes between atrial fibrillation and sinus rhythm as a result of electric or pharmacologic cardioversion. Myocardial Infarction. Recent MI, especially transmural and of the anterior wall, carries up to a 5% risk of cerebral embolism within the first 30 days, largely as a result of fresh mural thrombus formation. Factors that increase the embolic risk in this setting include concomitant atrial arrhythmias and congestive heart failure. An ejection fraction lower than 28% also increases the risk of stroke after MI. In the chronic state of a healed MI, a persistent risk of cerebral embolic events of 5% per year results from residual ventricular aneurysms or akinetic segments of the left ventricle, within which clot can occasionally be documented by TEE. Bacterial Endocarditis. Infected mitral or aortic valvular vegetations in bacterial endocarditis are a major source of cerebral embolism. Among the neurologic complications of bacterial endocarditis, cerebral embolism accounts for as many as 29%, a frequency that surpasses that of hemorrhagic stroke related to septic arteritis or mycotic aneurysm rupture. Emboli commonly present subacutely, mimicking an encephalopathy, rather than with the most typical acute and focal clinical manifestations. After an embolic infarction occurs, angiography should be obtained to rule out the secondary formation of an infectious (mycotic) aneurysm in the affected artery (Fig. 31-1). In the modern era of decreasing rheumatic heart disease but increasing use of intravas-

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A

B

C

FIG. 31-1. (A) CT scan with recent infarct in the left anterior cerebral artery (ACA) territory caused by septic embolism (urosepsis, positive blood cultures for enterococcus). (B,C) Contrast cerebral angiogram showing small infectious (“mycotic”) aneurysm of the left ACA (B, arrow), discovered after episode of subarachnoid hemorrhage (while on intravenous heparin after the initial presentation with left ACA embolic infarct). Patient had angiographically documented resolution of left ACA infectious aneurysm after 6 weeks of antibiotic treatment (C).

cular manipulations, illicit intravenous drugs, and immunosuppression, the most common responsible organisms in bacterial endocarditis have shifted from the low-virulence Streptococcus viridans to the more virulent Staphylococcus aureus and fungi. The general resistance of these more virulent organisms to antibiotic and antifungal agents results in an increased frequency of cerebral septic emboli and mortality, in comparison with infection with the Streptococcw species. Prosthetic Heart Valves. Mechanical heart valves carry a risk of cerebral embolism of about 3% per year, even in the presence of chronic oral anticoagulation. The embolic risk is higher with

mitral than with aortic valves, and it is potentiated by the concomitant occurrence of atrial fibrillation. In these patients, the international normalized ratio (INR) should be kept in the higher range of 3.5 to 4. The introduction of bioprosthetic valves with lower potential for clot formation, along with the routine use of anticoagulants (at times in association with antiplatelet agents), has dramatically reduced the frequency of this complication. Mitral Valve Prolapse. Recently defined strict echocardiographic criteria (leaflet bowing between 1.5 and 3 mm beyond the mitral annulus, significant myxomatous proliferation, elongation of the chordae) has shown a low prevalence of 2.4% of mitral valve

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prolapse in the general population. The presence of mitral valve prolapse is not more common among young patients with unexplained ischemic stroke than in control subjects. However, instances of embolic stroke in young patients with mitral valve prolapse and no other identifiable cause of stroke has been reported, especially in the setting of myxomatous degeneration with redundant leaflets and resulting insufficiency. Additional factors such as atrial fibrillation or infectious endocarditis may be necessary for cerebral embolism to occur in some patients with mitral valve prolapse. Patent Foramen Ovale and Interatrial Septa1 Aneurysm.

An

abnormal communication between the right and left atria via a patent foramen ovale is found in about 10% of the general asymptomatic population younger than 45 years. In patients with an otherwise unexplained ischemic stroke in the same age group, the prevalence of patent foramen ovale as detected by air contrast echocardiography with Valsalva maneuver rises significantly to 40% to 50%, suggesting that paradoxical embolism (of venous origin) through an abnormal right-left shunt is a potential source of embolic cerebral infarction. In addition, interatrial septal aneurysms, present in less than 5% of the general population and 28% of patients with stroke of undetermined cause, at times are associated with a patent foramen ovale and also carry a risk of cerebral embolism. Subjectswho have had a stroke in the setting of the combination of patent foramen ovale and atrial septal aneurysm have been recently identified as having a particularly high rate of ischemic stroke recurrence in comparison with poststroke patients with either condition in isolation. These data suggest that such high-risk subjects should be considered for treatment with agents stronger than aspirin because that agent failed to reduce their high rate of stroke recurrence. Potential mechanisms of cerebral embolism in the setting of interatrial abnormalities include thrombus formation in the right atrium, deep venous thrombosis (with paradoxical embolism), and atrial vulnerability. The latter implies the occurrence of transient atrial arrhythmias, including atrial fibrillation and flutter, predisposed by the presence of interatrial abnormalities. A larger patent foramen ovale, as measured by transesophageal echocardiography based on the number of agitated saline bubbles crossing to the left atrium (more than 20 bubbles), is more likely to be the cause of stroke than smaller interatrial communications. Atrial Myxoma. Atrial myxoma, a rare tumor of the left atrium and mitral valve, can be a source of multiple cerebral emboli, generally in the setting of systemic symptoms of malaise, fever, and weight loss. The tumor emboli may be associated with the development of cerebral aneurysms that in their multiplicity and peripheral location in the cerebral circulation resemble the “mycotic” aneurysms of infectious endocarditis. Miscellaneous Cardiac Sources. Calcified mitral and aortic valves result in a twofold greater risk of stroke. However, these are markers of carotid artery disease and atrial fibrillation and rarely are a direct cause of stroke. Mitral valve strands (Lambl’s excrescences) are thin fibrin filaments attached to the mitral and aortic valves that can be identified with TEE. Although an independent association with ischemic stroke has been shown, a lack of increased risk of recurrence has brought their causal relation with brain infarction into question. Nonbacterial (marantic) valvular vegetations with cerebral embolism have been found in patients with cancer, systemic lupus erythematosus and the antiphospholipid antibody syndrome.

Arterial Sources Arterial embolic sources lead to cerebral embolism by releasing particulate materials (generally thrombus, platelet-fibrin aggregates, or cholesterol-calcium particles) into distal arterial branches, generally intracranial, corresponding to the so-called artery-to-artery mechanism of embolism. Ulcerated Aortic Atheroma. As a mechanism of cerebral embolism, ulcerated aortic atheroma has been recognized recently in autopsy material and has been shown to be an independent predictor of stroke. TEE has allowed the visualization of extensive mobile thrombi protruding into the aortic lumen (Fig. 31-2). They are more common in the setting of advanced age, smoking, hypertension, diabetes, and mitral calcification. Embolization risk is greater in plaques between 4 and 5 mm in thickness and in those with mobile components on TEE, ulceration of 2mm or more, and with non-calcified hypoechoic features suggestive of superimposed thrombus. In patients without other detected embolic sources, the finding on TEE of aortic plaques with the above characteristics is considered the mechanism of cerebral embolism. Carotid Artery Atheroma. Cerebral embolism is assumed to be the stroke mechanism in instances of tight stenosis and acute occlusion of the extracranial internal carotid artery (ICA). The actual occurrence of distal embolism in patients with ulcerated carotid atheroma in the absence of significant stenosis is unclear. In the setting of acute ICA occlusion, the stroke mechanism has been inferred to be distal intracranial embolization in as many as two thirds of the cases, the remaining one third being on the basis of “distal insufficiency” with resulting border zone infarcts. A similar mechanism of distal embolization of fresh clot is thought to be the main cause of stroke in acute carotid artery dissection. In yet another situation, that of long-standing extracranial ICA occlusion with formation of a “stump,” presumed cerebral embolization has occurred as clot from the “stump” has traveled intracranially via the external carotid artery-ophthalmic artery collaterals to the intracranial ICA. However, fibrotic organization of the acute stump over 4 to 6 months after the occlusion makes embolization from this source in the chronic stage less likely. Vertebral Artery. The extracranialvertebral artery is prone to trauma in the area of the C1-C2 junction, where extreme head rotation and hyperextension after chiropractic neck manipulations, car and skiing accidents, voluntary neck “cracking” movements, and sneezing can lead to dissection. This in turn can produce occlusion of the vertebral artery and distal embolization, generally into the ipsilateral posterior-inferior cerebellar artery (PICA) but also into the basilar artery and its distal branches (superior cerebellar artery and posterior cerebral artery [PCA]). The origin of the vertebral arteries, a common site of atherosclerotic plaque formation, is commonly neglected during vascular evaluations with Doppler and neuroimaging. Stroke of Unknown Origin. In some patients the embolic source is not identified, and treatment decisions should be decided empirically, considering the patient’s clinical context. Emboli as small as 2 mm, which may be undetectable with current diagnostic technology, can occlude a division of the middle cerebral artery, causing a devastating deficit. Pathological studies with serial sections of the left atrial appendage have shown thrombus invisible to the eye located in the trabeculae carneae in instances of embolic stroke and atrial fibrillation.

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FIG. 31-2. Transesophageal echocardiogram of descending aorta (Ao), with ulcerated atheromatous plaque and atheromatousdebris and thrombus protrudinginto the aortic lumen (arrows). (Courtesy of Lisa k Mendes, MD, Department of Cardiology, Boston University Medical Center, Boston, MA.)

CONSEQUENCES OF EMBOLlZATlON OF INTRACRANIAL ARTERIES Depending on their size, embolic particles can obstruct intracranial arteries either proximally or at distal branch sites, thus leading to great variability in infarct sue and location. In addition, the absence of local disease of the obstructed artery may result in only transient occlusion. Even with established infarction, autopsy studies of cerebral embolism performed days after stroke onset may fail to disclose the arterial obstruction. This is further confirmed by angiography, which documents the appropriate occlusion in up to 75% of the cases if the study is performed within 48 hours of onset but in only 11% of patients if the study is delayed beyond that time. The transient character of some cerebral embolic occlusions is also responsible for another characteristic feature, hemorrhagic infarction, in contrast to the “pale” or “bland” infarct that characterizes atherothrombotic infarcts. Hemorrhagic infarction results from spontaneous fragmentation and lysis of the embolus and reperfusion bleeding of vessels in the area of ischemia. Abnormal permeability of hypoxically injured capillaries results in leakage of red blood cells into the infarcted parenchyma by diapedesis (rather than actual rupture of the vascular wall, as in parenchymal hemorrhage), with petechial hemorrhagic staining of the necrotic brain. Additionally, hemorrhagic infarction may result when bleeding occurs from collateral channels supplying the infarct, despite persistence of the embolic occlusion (Fig. 31-3). In both settings, the petechial staining of the already necrotic tissue usually has no clinical consequences because there is no added tissue damage or mass effect as a result of the hemorrhagic transformation. Hemorrhagic infarction is more often seen pathologically (in 50% to 70% of cases) than by computed tomography (CT, in 5% to 43% of cases), suggesting the relative

insensitivity of CT. Hemorrhagic infarct occurs after variable periods from the onset of the stroke, generally starting after at least 6 hours, reaching its peak by day 3 to 4, but may occur as late as 2 to 4 weeks after stroke onset if serial CT is performed. The occurrence of hemorrhagic infarction after cerebral embolism may affect management decisions. SITES OF OCCLUSION Cerebral embolism typically affects intracranial arteries. The larger extracranial ICA and vertebral artery are most susceptible to atherothrombotic occlusions (Fig. 31-4). Depending on the size of the embolus, the occlusion may affect a proximal artery at the circle of Willis or a more distal vessel, such as a division or a cortical branch. Intracranial branch occlusions are virtually diagnostic of embolism because atherothrombotic occlusions at these sites are rare and mostly seen in Asians, African Americans, and older Caucasians. Embolic particles have a predilection for certain intracranial vessels (Table 31-2), presumably reflecting the hemodynamics of the cerebral circulation and the patterns of angulation of the various branches off the main arterial trunks. The predominance of middle cerebral artery (MCA) embolic occlusions has been documented pathologically and angiographically as well as by the observed destination of particles released in the proximal circulation in the process of performing therapeutic embolization of arteriovenous malformations.

CLlNlCAL FEATURES Embolic occlusion typically produces a sudden focal neurologic deficit that is of maximal severity at its onset. The almost instantaneous character of a motor deficit often leads the patient

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to fall to the ground, not allowing time to sit down or hold onto a nearby source of support. The same features occur with the onset of aphasia or hemianopia, resulting in sudden speech dysfunction or “jargon” during conversation or inability to see to one side. This contrasts with the more gradual and progressive onset of the neurologic deficits in atherothrombotic and lacunar infarction and, to a lesser extent, in intracerebral hemorrhage. Rapid recovery from a major deficit, involvement of multiple independent arterial territories, and coexisting systemic emboli all suggest embolism as the cause of infarction. The focal deficits in cerebral embolism characteristicallyoccur during activity, in the awake state, and the presence of a deficit on awakening is unusual. Other clinical features that may accompany cerebral embolism include headache, seizures, and loss of consciousness. Although rare, these manifestations occur in embolism more often than in atherothrombotic infarction, with figures on the order of 10% for headache and 5% to 7% for seizures and loss of consciousness. The latter are thought to be caused by the sudden interruption of blood flow to a segment of the cerebral cortex as a result of the embolic cortical branch occlusion. The mechanism of the headache is less clear, but possible contributors are distention of the pain-sensitive artery by the impacted embolus and possibly vasodilation of arteries adjacent to the occlusion as potential sources of collateral flow. The latter mechanism is favored by reported instances of headache onset occurring at the time of resolution, rather than at the onset, of a focal neurologic deficit. The location of the headache is at times correlated with the site of arterial embolic occlusion: the temporal area in MCA stem occlusion, lateral retro-ocular in PCA occlusion, occipitocervical in vertebral artery

(VA) occlusion or dissection, and cervical or hemifacial in extracranial ICA occlusion or dissection. Patterns of Evolution of Naurologlc D e f k i b Caused

by Cerebral Embollsm The course that follows in the first hours after the “maximal from the onset” deficit is quite variable, with either stability, fluctuation, dramatic improvement, or, rarely, worsening. A fluctuating course after onset, the “nonsudden onset” of cerebral embolism, refers to deficits that occur suddenly, then improve rapidly, to be followed by recurrence of the same initial deficits or, more commonly, one that also reflects occlusion of a more distal branch in the same territory of the vessel involved initially. An example of this course results from embolic occlusion of the intracranial ICA, with sudden onset of a large hemispheric syndrome, with rapid improvement (presumably caused by effective distal collateral flow), followed by recurrence of a deficit indicative of distal MCA branch occlusion (such as aphasia). The latter is thought to result from migration of fragments of the original embolus into more distal branches in the MCA territory. A similar mechanism accounts for instances of sudden onset of a major hemispheric deficit that is followed by a dramatic improvement within hours of onset. This course, called “the spectacular shrinking deficit syndrome,” is often caused by embolic occlusion of the MCA stem with later spontaneous recanalization that may at times be suggested by the initial CT scan (Fig. 31-5). After a few hours of onset, the patient shows a remarkable improvement in neurologic function, with total or partial resolution of the hemiplegia, hemisensory defect, hemian-

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FIG. 51-3. (A) Embolic occlusion of the upper division of the middle cerebral artery (arrow), which did not reopen after treatment with rt-PA. (6) CT showing hemorrhagic infarction in the distal middle cerebral artery territory in the same patient. (From Garcia JH, Ho KL, Caccamo DV: lntracerebralhemorrhage:pathology of selected topics. pp. 49-72. In Kase CS, Caplan LR (eds): lntracerebral Hemorrhage. Butterworth-Heinemann, Boston, 1994, with permission.)

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IC

VA

161 cases) (25 cases) FIG. 31-4. Autopsy data of causes of cerebral infarction in the various vascular territories. Abbrevid’ons: ACA, anterior cerebral artery; BA, basilar artery; IC, internal carotid; MCA, middle cerebral artery; PCA, posterior cerebral artery; VA, vertebral artery. (From Poirier J, Gray F, Escourolle R: Manual of Basic Neuropathology. pp. 65-1 02. WB Saunders, Philadelphia, 1990, with permission.)

TMLE 31-2. lntracranial Arteries Affected in Cerebral Embolism (n = 148) MCA

PCA

Stem

UD

LD

ACA

Stem

Branch

Basilar

55 (37%)

48 (32%)

20 (1 3%)

1 (0.6%)

10 (7%)

3 (2%)

1 1 (7%)

Abbreviations: ACA, anterior cerebral artery; LD, lower division; MCA,middle cerebral artery; PC4, posterior cerebral artery; UD, upper division.

opia, and aphasia. Subsequent CT scans often show signs of infarction in the deep MCA (lenticulostriate) territory, at times along with a second, separate focus of infarction in one of the divisional territories of the MCA. In this and other scenarios, early angiography may help identify the subsequently vanishing embolus, confirming the embolic nature of the ischemic event. A deteriorating course after a cerebral embolism may reflect antegrade or retrograde clot extension from the initial site,

hemorrhagic transformation of the infarct, or cerebral edema with mass effect. Further clot extension at the site of the initial embolic occlusion can be demonstrated angiographically; its clinical manifestations are those of a gradual worsening of neurologic deficits, reflecting an enlarging area of ischemia superimposed on the abrupt and more limited initial deficit. Instances of neurologic deterioration after hemorrhagic transformation of the infarct are uncommon because most hemorrhagic infarctions do not add further to the initial neurologic

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deficits. However, on occasion a hemorrhage within the infarct (unlike a hemorrhagic infarction) may follow in the course of an otherwise uncomplicated embolic stroke and is most often associated with institution of anticoagulant or fibrinolytic treatment in the first few hours after stroke onset. Although such complications can also occur in the absence of treatments as part of the natural history of cerebral embolism, its frequency appears to be enhanced by the use of these agents, especially when used in combination. This suggests that a likely mechanism of this complication may be early reperfusion of the affected artery (generally the MCA stem) by the effect of the fibrinolytic agent, followed by hemorrhagic infarction or intracerebral hemorrhage caused by reflow of blood into an ischemic vascular bed with abnormally increased permeability. The severity of the latter process of extravasation may be enhanced by the concomitant use of anticoagulation or antiplatelet agents at the time of reperfusion. Cerebral edema may become symptomatic 24 to 72 hours after stroke onset, when most or all of the MCA territory, and occasionally the anterior cerebral artery (ACA) or PCA territories as well, is affected by the embolic infarction. This scenario is called malignant MCA infarction when it causes rapid deterioration of consciousness and progression of neurologic deficits. Mortality is close to 80%, and survival is associated with severe sequelae or a vegetative state. The clinical syndromes of cerebral embolism are varied, reflecting different sites of intracranial occlusions. They are discussed in detail in Chapter 39.

FIG. 31-5. Noncontrast CT scan with hyperdense middle cerebral artery (MCA) sign, representing clot in the MCA trunk (arrows).

LABORATORY DIAGNOSIS The laboratory diagnosis of cerebral embolism can be divided into the imaging documentation of the embolic occlusion and infarct topography by CT, magnetic resonance imaging (MRI), and angiography; and the documentation of a cardiac or vascular embolic source by ultrasound and angiographic techniques.

Imaging In the first hours after embolic infarction, both CT and MRI usually are negative for attenuation or signal changes in the parenchyma. However, noncontrast CT can document a hyperdensity consistent with clot in the area of the MCA stem in embolic occlusions (the hyperdense MCA sign; Fig. 31-5); the MRI correlate is absence of a flow void in the artery occluded by an embolus. CT scan shows the early signs of hypodensity in the parenchyma after about 6 to 12 hours from onset, and a well-established low-density area does not occur before 24 hours. In instances of early hemorrhagic transformation, the hyperdensity of hemorrhagic infarction may be documented earlier, but usually not before 6 hours after stroke onset. More subtle signs of early cerebral infarction can be detected after about 6 hours from onset. These include suggestions of obliteration of cortical sulci in MCA infarcts, representing early cerebral edema, and blurring of the gray-white matter distinction in the insular cortex area in MCA infarcts. CT perfusion studies are a recent development that allows earlier detection of infarction. Spiral CT angiography is a good alternative to magnetic resonance angiography, especially for evaluating extracranial carotid artery disease. MRI shows the parenchymal changes of infarction earlier than CT, generally after about 8 hours from onset. The changes occur first in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images as a bright signal in the area of infarction, followed by demonstration of infarction as low-signal changes in T1-weighted sequences. This test is also sensitive in showing the early changes of cerebral edema as mass effect causing obliteration of sulci and cisterns and as hyperintensity of the white more than the gray matter in the area of infarction. It is also accurate in detecting subtle hemorrhagic changes within the infarct. M N diffusion-weighted studies have become widely available to demonstrate the infarcted tissue within a few hours of ischemia onset. Perfusion MRI studies also reveal the entire vascular region affected by hypoperfusion and therefore at risk of infarction. The MRI diffusion-perfusionmismatch defines the penumbra territory (i.e., the cerebral tissue affected by ischemia in perfusion-weighted sequences but potentially salvageable, that is, not infarcted in diffusion-weighted sequences). A rapid and reliable detection of the penumbra is crucial to make decisions in acute stroke management. The therapeutic role that diffusion-perfusion images may have in the timing of thrombolysis administration is being actively evaluated. Contrast cerebral angiography can document embolic occlusions dependent on the time elapsed between stroke onset and the performance of the test. Its yield decreases dramatically (to about 17%) if the test is performed beyond 48 hours from onset, whereas it is high (about 75%) if performed within that period of time. This reflects the natural instability of embolic particles. The role of magnetic resonance angiography in detecting intracranial embolic occlusions is still evolving. This technique still has poor resolution for demonstrating occlusion of branches of intracranial arteries, although missing groups of branches may be apparent. Further-

Chapter 31

more, the degree of larger extracranial artery luminal stenosis or occlusion may be overestimated. It is expected that further refinements in technique will make it an alternative to conventional contrast angiography in the future.

Detection of Cardiac and Vascular Sources Many of the common cardiac sources of systemic embolism can be suspected or confirmed with clinical examination (cardiac auscultation) and routine laboratory data such as chest radiographs and electrocardiograms. Such studies will uncover instances of atrial fibrillation,sick sinus syndrome, valvular disease, recent or remote MI, and cardiomyopathy. The additional use of transthoracic echocardiography and especially TEE is indicated to confirm valvular disease (including mitral or aortic stenosis or insufficiency, mitral valve prolapse, vegetations in bacterial endocarditis, or nonbacterial thrombotic endocarditis), atrial myxoma, documentation of post-MI akinetic ventricular segments, ventricular aneurysms, mural thrombus, dilated cardiomyopathy with reduced ejection fraction, left atrial appendage thrombus, atrial septal aneurysm, and patent foramen ovale. The identification of spontaneous echo contrast in the dilated atria in atrial fibrillation correlates with embolic potential. An agitated saline (bubble contrast) study should be requested when investigating the possibility of atrial septal abnormalities because they may not be apparent with a transesophageal study without contrast techniques. Simultaneous transcranial Doppler monitoring will document the circulation of saline bubbles through the MCA window, confirming the presence of an interatrid foramen even in some cases where bubbles are not detected in the left atrium. The value of additional techniques, such as continuous (Holter) electrocardiographic monitoring, is low but helpful for the occasional detection of intermittent atrial arrhythmias (mainly atrial fibrillation). Patients who have been symptomatic with lightheadedness or presyncope or syncope should be further investigated for intermittent arrhythmias with potential for cerebral embolization. Although the finding of one of these sources of cardiac embolism is important in assigning a presumptive embolic cause to a stroke in the proper clinical setting, it does not always prove a cause-and-effect relationship. In approximately 17% of patients with a high-risk cardioembolic source such as atrial fibrillation, noninvasive techniques document a concomitant stenosis of more than 50% in the extracranial carotid artery appropriate to the location of the ischemic stroke. The investigation of vascular sources of systemic embolism (artery-to-artery) involves the study of extracranial arteries such as the carotid and VAs with ultrasound and angiography. In addition, the role of ulcerated atheroma with clot formation in the thoracic aorta can be investigated effectively with TEE. The techniques of vascular imaging are described in Chapter 29. Their application to the diagnostic evaluation of patients with suspected cerebral embolism aims at documenting a tightly stenotic proximal arterial lesion, with or without ulceration, appropriate to the intracranial occlusion. In the absence of a documented cardiac embolic source, such ultrasound findings should be considered the putative explanation for the embolic intracranial occlusion and managed accordingly. If management involves plans for treating a surgically correctable lesion, most surgeons require the confirmatory use of contrast angiography before performing surgery. The alternative of substituting contrast angiography with the combined information of Doppler ultrasound and magnetic resonance angiography of the extracranial circulation in presurgical assessment is being evaluated.

Cerebral Embolism

307

TREATMENT AND PREVENTION Acute Treatment Drug effectiveness depends on the composition of thromboembolic material, among other variables. Platelet emboli (white clots) tend to originate in rough arterial surfaces of fastmoving bloodstreams such as a nonstenotic ulcerated carotid artery, and respond best to antiplatelet drugs. Fibrin emboli (red clots) originate in slow-moving streams such as a stagnant left atrium and are best treated with anticoagulants. A highly stenotic lesion in the carotid bifurcation, for example, could generate both red and white clots, with important therapeutic implications. Therefore, knowing the different variables of the pathophysiology of stroke permits initiating a mechanismspecific therapy. Treating patients with an acute embolic stroke involves the principal issue of whether to use intravenous heparin anticoagulation to prevent recurrent embolism. In patients with a high-risk embolic source such as atrial fibrillation or rheumatic heart disease, the risk of reembolization was thought to be 1% per day, for a cumulative rate of about 10% in the first 2 weeks after stroke onset, although recent studies have shown a far lower rate of early recurrence. A decreased rate of thrombus progression, deep vein thrombosis, pulmonary embolism, and coronary syndromes support the use of heparin in stroke. Despite the publication of various randomized studies in the last few years, the use of anticoagulation is still controversial. None of these studies were designed or had enough patients in different stroke subcategories to assess treatment efficacy according to specific stroke origins. One study of ischemia from presumed arterial origin, Stroke Prevention in Reversible Ischemia Trial (SPIRIT), was terminated because of a significant bleeding rate secondary to a very high anticoagulation intensity (INR 3 to 4.5). A subanalysis of a study using a low-molecular-weight heparinoid, Trial of ORG 10172 in Aortic Stroke Treatment (TOAST), that was negative for the primary outcomes at 3 months revealed a benefit of anticoagulation treatment in patients with large vessel disease. Most recently, the results of Warfarin-Aspirin Recurrent Stroke Study (WARSS), in which 2206 patients were randomized to receive warfarin or aspirin to prevent recurrent stroke or death, did not show any significant difference between these two treatments. However, the subgroup of cryptogenic stroke was the only to show a nonstatistically significant benefit in favor of warfarin treatment. To reflect the shortcomings of study design, WARSS excluded 25% of patients with hemorrhages, 20% with atrial fibrillation, and 10% with a surgical carotid artery lesion. Among randomized patients, 56% had lacunar infarcts and 25% had strokes of undetermined origin, accounting for 80% of all treated patients. In a similar way in which a specific antibiotic is expected to be effective only in certain infections, anticoagulants probably are the best therapeutic option in conditions such as severe intracranial symptomatic arterial stenosis, hypercoagulable states, complex aortic plaques and high-risk cardiac sources, venous disease, and probably arterial dissections. To demonstrate a benefit of anticoagulation in cerebrovascular disease, a sufficiently large number of patients with the aforementioned disorders should be studied in randomized trials. The available studies have not proven that anticoagulation is not effective for specific stroke types but rather have confirmed the long-known, intuitive notion that anticoagulation is not effective for all types of ischemic cerebrovascular disease.

508

CerebrovascularDisease

Common Pathogenesesof Stroke

The risk of stroke recurrence has been the basis for the recommendation of early institution of heparin anticoagulation as a continuous intravenous infusion during the diagnostic work-up. Heparin generally is given without an initial bolus (because it often causes excessive prolongation of the activated partial thromboplastin time [aPTT] within the first 1 to 2 hours after administration) at a rate of 1,000 U/hour, adjusted to maintain an aPTT of 1.5 times control, generally corresponding to a value between 45 and 55 seconds. This treatment is maintained for several days while the stroke mechanism is evaluated. If the decision is made to treat the patient with long-term oral anticoagulants (warfarin), this is started, and when the dosage necessary to maintain an INR of 2 to 3 is reached, heparin is discontinued. If warfarin treatment is given directly without heparin, careful observation is recommended because a brief transient hypercoagulable state occurs over the first days of therapy. Treatment with heparin must be monitored closely to avoid intracranial or systemic bleeding and drug-induced thrombocytopenia. Intracranial hemorrhage is a potential but low-risk complication of continuous intravenous heparin infusion in patients with an acute embolic infarct. Heparin is contraindicated in patients with septic cerebral embolism because of the high propensity of septic emboli to produce necrosis of the arterial wall with potential hemorrhage. In the setting of nonseptic emboli, early heparin anticoagulation to prevent recurrent embolism is a safe treatment if the level of anticoagulation is not excessive and the patient does not have a massive infarct or uncontrolled hypertension (i.e,, a blood pressure more than 180/100 mm Hg). The presence of a CTdetected hemorrhagic infarction has been considered to contraindicate the use of anticoagulation because of the fear of promoting further hemorrhagic transformation or intracerebral hemorrhage by the anticoagulant effect. However, when the risk of recurrent embolism is great, as in patients with mechanical prosthetic heart valves or atrial fibrillation, heparin may be used safely in the presence of hemorrhagic infarction if excessive anticoagulation is avoided and blood pressure is monitored closely. Heparin-induced thrombocytopenia occurs in approximately 10% of patients treated. This complication takes two forms. Early thrombocytopenia (type I) occurs in the first 4 or 5 days of treatment and is generally mild (not reaching platelet counts below 50,000/mm3) and rarely associated with bleeding or thromboembolism. The platelet count usually recovers on its own, even without drug discontinuation. The cause is thought to be direct heparin-induced platelet aggregation. Late thrombocytopenia (type 11) occurs toward the end of the first or beginning of the second week of treatment and is serious (generally producing platelet counts below 50,000/mm3 and often below 10,000/mm3). It can be associated with hemorrhagic and especially thrombotic phenomena that can lead to stroke, MI, or limb loss secondary to gangrene. These vascular complications result from intravascular aggregates of platelets (the white clot syndrome). The mechanism of this serious form of heparin-induced thrombocytopenia is thought to be a immunoglobulin G (1gG)- and IgM-induced immune response. The identification of this potentially serious complication requires routine monitoring of platelet counts in patients treated with intravenous heparin. Other therapeutic modalities for acute cerebral embolism, such as thrombolytic and neuroprotector agents, are being evaluated (see Chapter 42). Thrombolytic agents can lyse embolic occlusions and restore critical cerebral perfusion. The use of intravenous rt-PA within 3 hours of an ischemic stroke was approved in 1996

after a National Institute of Neurological Disorders and Stroke (N1NDS)-sponsored randomized clinical trial report showed that treated patients were 30% more likely to have minimal or no disability at 3 months compared with patients who received placebo. Reports of patients treated in the community following the NINDS protocol have confirmed similar benefit and complication rates, although very few of all eligible candidates receive rt-PA in daily clinical practice. Two other studies (European Co-operative Aortic Stroke Study (ECASS I and ECASS 111) were done using a 6-hour window and two different rt-PA dosages. Both were negative in the intention-to-treat analysis and had only positive results in the post hoc analysis. Another study (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS]) with a 5-hour window was prematurely terminated after an interim analysis because it was unlikely that a beneficial effect could be demonstrated. An important finding of these studies was that early CT findings suggestive of ischemia (mass effect, hypodensity in more than one third of the MCA territory, blurring of the internal capsule, loss of gray-white matter differentiation, and sulcal effacement) predict the occurrence of bleeding complications after thrombolytic treatment. Strict restriction of treatment to the 3-hour window is strongly encouraged based on the study results. However, some patients treated within the first 3 hours have had major bleeding and some others, especially with vertebrobasilar territory ischemia, have been treated beyond the 3-hour frame without hemorrhagic complications. Thrombolysis can be achieved by systemic (intravenous) or intra-arterial administration, but as yet no direct comparison of these delivery modes has been done. Preliminary evidence suggests that intra-arterial delivery is more effective than intravenous delivery in producing recanalization, but this technique requires sophisticated facilities and trained personnel, which may limit accessibility and exceed the narrow time frame before ischemic tissue becomes irreversibly injured. Prolyse in Acute Cerebral Thromboembolism (PROACT 11) compared recombinant prourokinase (r-proUK) and heparin versus heparin alone, when r-proUK was administered intra-arterially into MCA stem occlusions within 6 hours of stroke onset in 180 patients. Neurologic recovery (15% absolute risk reduction) and recanalization rate were significantly greater in the r-proUK group. The median time to treatment was 5.3 hours, highlighting the complex, timeconsuming procedure that necessitated cerebral angiography to assess eligibility (followed by 120 minutes of intra-arterial drug treatment). Despite this positive clinical trial, intra-arterial thrombolytic therapy with r-proUK has not received U.S. Food and Drug Administration approval. The recurrence stroke rate in patients with inter-atrial septal abnormalities (patent foramen ovale, atrial septal aneurysm) remains ill defined. Anticoagulant therapy is an option, especially after stroke events in the setting of both patent foramen ovale and atrial septal aneurysm, but long-term treatment of young patients carries a significant cumulative bleeding risk. Surgery for closure of the inter-atrial defects has been performed with low complication rates but has not consistently prevented recurrence in patients older than 45 years. More recently, trans-catheter closure has become a simpler outpatient procedure, but mechanical failure has been reported, and long-term efficacy remains to be documented. No studies are available to define the best treatment for embolism caused by aortic atheroma. There is a valid concern about increasing the risk of cholesterol embolism by using anticoagulants in these patients, Available data from small clinical

Chapter 32

series support the value of warfarin anticoagulation for the prevention of recurrent stroke in this setting. Early extensive hemicraniectomy in selected patients (preferably non-dominant hemisphere lesions) at risk of malignant MCA infarction may prevent death and allow significant functional recovery by rapidly and effectively reducing ICP and increasing cerebral blood flow. Another group of agents, called neuroprotectors, have properties designed to limit the cascading toxic effects of the initial ischemic injury on the neuronal population at risk. These include calcium channel blockers, n-methyl-D-aspartate (NMDA) receptor antagonists, and free radical scavengers. Neuroprotective agents may limit the ischemic damage and, importantly, may provide additional time to initiate other treatments to restore arrested circulation, such as thrombolysis. However, clinical trials in patients with acute ischemic stroke have so far been negative, and no neuroprotective agents are currently available for clinical use. Primary Prevention Primary prevention is most effective in patients with cardiac conditions with high potential for embolization, such as mechanical prosthetic heart valves and atrial fibrillation. In patients with mechanical prosthetic heart valves, the rate of systemic embolization is dramatically reduced by the use of chronic oral (warfarin) anticoagulation. The protection conferred by this agent can be further enhanced by adding antiplatelet agents such as clopidogrel, dipyridamole, and aspirin. The recommended INR of 2.5 to 3.5 is higher than that used for other indications for warfarin use. The dosage of combined aspirin treatment is 325 mg/day. In patients with chronic atrial fibrillation who are neurologically intact at the onset of the prophylactic treatment, the use of chronic warfarin anticoagulation results in a dramatic overall reduction of 86% in the risk of cerebral embolic events. This effect has been documented in five clinical trials. These studies have shown a consistent beneficial effect of warfarin over placebo; a smaller benefit from aspirin over placebo in some studies (Stroke Prevention in Atrial Fibrillation [SPAF]) but not in others (AFASAK, BAATAF); a low rate of hemorrhagic complications when the PT and INR are tightly controlled, with PT values in the range of 1.25 times control; and a benefit of warfarin that applies to secondary stroke prevention as well (European Atrial Fibrillation Trial [EAFT]1. These data have clearly established the value of warfarin anticoagulation for primary and secondary stroke prevention in patients with chronic atrial fibrillation. A recent meta-analysis of all available studies showed that low-dose

32

Lacunar Infarction

309

warfarin did not add significant benefit to aspirin therapy and that, contrary to previous beliefs, patients older than 75 years with recurrent or chronic atrial fibrillation also benefit from warfarin anticoagulation. An INR of 2 is appropriate for primary prevention in older patients. The hemorrhagic risk in all anticoagulated patients is substantially reduced by careful monitoring of the INR. In case of stroke recurrence in anticoagulated patients with a low (less than 2.5) INR, adjusting therapy to an INR of up to 3.5 is preferable than adding an antiplatelet drug. Different reports have confirmed that warfarin treatment is dramatically underused in ideal candidates for anticoagulation in atrial fibrillation. As in the case of hypertension treatment, many patients with atrial fibrillation receive subtherapeutic dosages of anticoagulants.

SUGGESTED READINGS Albers GW, Amarenco P, Easton JD et al: Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 119:3OOS, 2001 Amarenco P, Cohen A, Tzourio C et al: Atheroscleroticdisease of the aortic arch and the risk of ischemic stroke. N Engl J Med 331:1474, 1994 Bogousslavsky J, Cachin D, Regli F et al: Cardiac sources of embolism and cerebral infarction: clinical consequences and vascular concomitants: the Lausanne Stroke Registry. Neurology 41:855, 1991 Caplan L R Brain embolism, revisited. Neurology 43:1281, 1993 Caplan LR, Hier DB, DCruz I: Cerebral embolism in the Michael Reese Stroke Registry. Stroke 14:530, 1983 Cerebral Embolism Task Force: Cardiogenic brain embolism. Arch Neurol 43:71, 1986

Dada-RomBn VG, Murphy SF, Nickerson NJ et al: Atherosclerosis of the ascending aorta is an independent predictor of long term neurologic events and mortality. J Am Coll Cardiol33:1308, 1999 Fisher CM, Adams RD: Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1092, 1951

Hacke W, Zeumer H, Ferbert A et ak Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 19:1216, 1988 Hart RG, Benavente 0, McBride R, Pearce LA:Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta analysis. Ann Intern Med 131:492, 1999 Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 17586, 1986 Mas JL, Arquizan C, Lamy C et al: Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 345:1740,2001 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581, 1995 Yatsu FM, Hart RG, Mohr JP, Grotta J C Anticoagulation of embolic strokes of cardiac origin: an update. Neurology 38:314, 1988

Lacunar Infarction Carlos S. Kase and Conrad0 1. Estol

Twenty percent of strokes are classified as lacunar infarctions (see Table 30-1). They represent areas of cerebral infarction measuring between a few millimeters and 1.5 cm, and they are also called penetrating artery disease or small vessel disease because affected vessels are the perforating branches of the main cerebral arteries,

w middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and basilar artery. These vessels measure between 40 and 400 pm (less than 0.5 mm) in diameter, and they supply deep hemispheric structures such as the basal ganglia, internal capsule, and thalamus, and portions of the

Chapter 32

series support the value of warfarin anticoagulation for the prevention of recurrent stroke in this setting. Early extensive hemicraniectomy in selected patients (preferably non-dominant hemisphere lesions) at risk of malignant MCA infarction may prevent death and allow significant functional recovery by rapidly and effectively reducing ICP and increasing cerebral blood flow. Another group of agents, called neuroprotectors, have properties designed to limit the cascading toxic effects of the initial ischemic injury on the neuronal population at risk. These include calcium channel blockers, n-methyl-D-aspartate (NMDA) receptor antagonists, and free radical scavengers. Neuroprotective agents may limit the ischemic damage and, importantly, may provide additional time to initiate other treatments to restore arrested circulation, such as thrombolysis. However, clinical trials in patients with acute ischemic stroke have so far been negative, and no neuroprotective agents are currently available for clinical use. Primary Prevention Primary prevention is most effective in patients with cardiac conditions with high potential for embolization, such as mechanical prosthetic heart valves and atrial fibrillation. In patients with mechanical prosthetic heart valves, the rate of systemic embolization is dramatically reduced by the use of chronic oral (warfarin) anticoagulation. The protection conferred by this agent can be further enhanced by adding antiplatelet agents such as clopidogrel, dipyridamole, and aspirin. The recommended INR of 2.5 to 3.5 is higher than that used for other indications for warfarin use. The dosage of combined aspirin treatment is 325 mg/day. In patients with chronic atrial fibrillation who are neurologically intact at the onset of the prophylactic treatment, the use of chronic warfarin anticoagulation results in a dramatic overall reduction of 86% in the risk of cerebral embolic events. This effect has been documented in five clinical trials. These studies have shown a consistent beneficial effect of warfarin over placebo; a smaller benefit from aspirin over placebo in some studies (Stroke Prevention in Atrial Fibrillation [SPAF]) but not in others (AFASAK, BAATAF); a low rate of hemorrhagic complications when the PT and INR are tightly controlled, with PT values in the range of 1.25 times control; and a benefit of warfarin that applies to secondary stroke prevention as well (European Atrial Fibrillation Trial [EAFT]1. These data have clearly established the value of warfarin anticoagulation for primary and secondary stroke prevention in patients with chronic atrial fibrillation. A recent meta-analysis of all available studies showed that low-dose

32

Lacunar Infarction

309

warfarin did not add significant benefit to aspirin therapy and that, contrary to previous beliefs, patients older than 75 years with recurrent or chronic atrial fibrillation also benefit from warfarin anticoagulation. An INR of 2 is appropriate for primary prevention in older patients. The hemorrhagic risk in all anticoagulated patients is substantially reduced by careful monitoring of the INR. In case of stroke recurrence in anticoagulated patients with a low (less than 2.5) INR, adjusting therapy to an INR of up to 3.5 is preferable than adding an antiplatelet drug. Different reports have confirmed that warfarin treatment is dramatically underused in ideal candidates for anticoagulation in atrial fibrillation. As in the case of hypertension treatment, many patients with atrial fibrillation receive subtherapeutic dosages of anticoagulants.

SUGGESTED READINGS Albers GW, Amarenco P, Easton JD et al: Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 119:3OOS, 2001 Amarenco P, Cohen A, Tzourio C et al: Atheroscleroticdisease of the aortic arch and the risk of ischemic stroke. N Engl J Med 331:1474, 1994 Bogousslavsky J, Cachin D, Regli F et al: Cardiac sources of embolism and cerebral infarction: clinical consequences and vascular concomitants: the Lausanne Stroke Registry. Neurology 41:855, 1991 Caplan L R Brain embolism, revisited. Neurology 43:1281, 1993 Caplan LR, Hier DB, DCruz I: Cerebral embolism in the Michael Reese Stroke Registry. Stroke 14:530, 1983 Cerebral Embolism Task Force: Cardiogenic brain embolism. Arch Neurol 43:71, 1986

Dada-RomBn VG, Murphy SF, Nickerson NJ et al: Atherosclerosis of the ascending aorta is an independent predictor of long term neurologic events and mortality. J Am Coll Cardiol33:1308, 1999 Fisher CM, Adams RD: Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1092, 1951

Hacke W, Zeumer H, Ferbert A et ak Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 19:1216, 1988 Hart RG, Benavente 0, McBride R, Pearce LA:Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta analysis. Ann Intern Med 131:492, 1999 Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 17586, 1986 Mas JL, Arquizan C, Lamy C et al: Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 345:1740,2001 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581, 1995 Yatsu FM, Hart RG, Mohr JP, Grotta J C Anticoagulation of embolic strokes of cardiac origin: an update. Neurology 38:314, 1988

Lacunar Infarction Carlos S. Kase and Conrad0 1. Estol

Twenty percent of strokes are classified as lacunar infarctions (see Table 30-1). They represent areas of cerebral infarction measuring between a few millimeters and 1.5 cm, and they are also called penetrating artery disease or small vessel disease because affected vessels are the perforating branches of the main cerebral arteries,

w middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and basilar artery. These vessels measure between 40 and 400 pm (less than 0.5 mm) in diameter, and they supply deep hemispheric structures such as the basal ganglia, internal capsule, and thalamus, and portions of the

310

CerebrovascularDisease H Common Pathogenesesof Stroke

brainstem such as the basis pontis. As a result of the small size and parenchymal location of the affected vessels, lacunar infarcts are, by definition, small and deep infarcts. Their common sites are the internal capsule (the posterior limb, genu, or less commonly, the anterior limb), the caudate nucleus, the basal ganglia (putamen, globus pallidus), the thalamus (rarely in combination with the internal capsule), the centrum semiovale and corona radiata, the basis pontis, and the cerebellum. PATHOGENESIS Llpohyalinosis In a number of landmark neuropathologic studies, Fisher defined the arterial abnormalities related to lacunar infarctions. Affected vessels were found to have an abnormality called lipohyalinosis, a process different from large vessel atheroma. This is a degenerative change caused by hypertension, which results in the deposit of a hyaline, amorphous substance within the arterial wall, at times progressing to occlusion of the lumen, causing a small ischemic infarct (lacune) (Fig. 32-1). Usually the obstructing lesion is along the course of the small vessel some distance from its origin. Hypertension was found in as many as 75% of patients with lacunar infarcts documented in the Harvard Stroke Registry. However, lacunar infarcts can also be the result of other mechanisms described in this chapter. In some patients the lipohyalinotic changes in the arterial wall progressively weaken the wall, leading to dilation and microaneurysm formation. Chronic hypertension results in hyalinization of the wall’s media, which progresses to involve the entire wall and is followed by diffuse fibrinoid degeneration. This lesion may express itself by a small lacunar infarct, or it may lead to the formation of a Charcot-Bouchard aneurysm, which may rupture and cause a hypertensive intracerebral hemorrhage.

Embolism Both the classic small lacunes and larger deep infarcts greater than 2 cm in diameter can be the result of small cardiac (rheumatic disease, nonbacterial endocarditis) or artery-to-artery (from the carotid or aorta or during cardiac catheterization) embolism. This notion is supported by the demonstration of lacunar infarcts at autopsy, in which the perforating artery leading to the lacune is free of disease in its wall, a finding highly suggestive of an embolic mechanism of occlusion, assuming disappearance of the original occluding embolus. However, the mere coexistence of a lacunar infarct with a proximal cardiac or vascular source of embolism does not necessarily establish a cause-and-effect relationship. In fact, significant carotid artery bifurcation disease is found in less than 5% of patients with lacunar infarcts, in contrast to 80% with cortical infarctions. Other clinical criteria, particularly the mode of onset and the course and clinical features of the neurologic deficit, must be considered in the diagnosis of the mechanism of a lacunar infarct.

Branch Artery Disease (Junctional Plaque and Microatheroma Mechanism) Mechanisms that affect the entire territory of a branch produce an infarct larger than the typical lacune and result from junctional plaques or microatheroma involving the penetrator at its origin. Caplan and Fisher called attention to lacunar infarcts, generally larger than the classic small lacunes, that were caused by occlusion

of penetrating branches at their origin from the parent vessels, producing a large swath of infarction. A plaque of atheroma in the MCA or the basilar artery could grow to involve the emerging penetrating artery, leading to its occlusion. Because these plaques affect the parent vessel and a penetrating artery simultaneously, they are also known as junctional plaques. Other possible mechanisms of occlusion involve the growth of microatheroma within the very origin or at different sites in the length of the penetrating vessel, with or without superimposed thrombus. A dissection in the wall of the parent vessel is another mechanism that can cause occlusion of the penetrator at its origin. CLINICAL FEATURES The mode of onset and course of lacunar infarcts differ from those of large vessel disease. Lacunar infarcts are preceded by transient ischemic attacks (TIAs) in 15% to 20% of cases, whereas at least 50% of atherothrombotic infarcts are preceded by TIAs. The following features characterize the TIAs of lacunar mechanism: They generally occur over shorter periods of time (2 to 5 days) before the onset of infarction, in comparison with weeks to months in cases of large artery atherothrombosis. TIAs from small vessel disease tend to occur in clusters, occasionally even several times a day (a so-called flurry of TIAs or “shotgun” TIAs), whereas large vessel TIAs usually present as recurrent isolated episodes. TIAs from small vessel ischemia are more stereotyped (e.g., weakness of the entire hemibody) than the more variable features of large vessel TIAs (transient monocular blindness, monoparesis, or dysphasia in the case of internal carotid artery [ICA] stenosis). The time of onset in lacunar infarcts (and atherothrombotic strokes) is equally distributed during sleep and activity, as opposed to embolism and intracranial hemorrhage, which almost always occur during the waking hours. The deficits caused by lacunar infarcts often have an insidious onset and a progressive course, in contrast with the sudden onset that characterizes embolism. Lacunar infarcts are the most commonly observed ischemic strokes that feature a gradually progressive course after onset. Headache, seizures, and mental status changes, which are common findings in cerebral embolism and intracranial hemorrhage, do not occur with lacunar infarcts. The absence of cognitive changes and seizures reflects the subcortical nature of lacunes, and the lack of headache presumably results from the absence of pain fibers in small parenchymal penetrating arteries. Absence of higher cognitive dysfunction (aphasia, neglect, anosognosia, and apraxia) strongly orients the diagnosis to the lacunar nature of the infarction. Also, cognitive dysfunction in embolic and large vessel disease infarctions predicts a decreased recovery potential, in contrast to patients with lacunar infarcts, who have high rates of recovery (close to 90% with no or minimal disability at 6 months), in part because of the absence of cognitive deficits.

Lacunar Syndromes The clinical syndromes related to lacunar infarcts have been described in detail since 1965 by Fisher, and they are discussed in detail in Chapter 42. There are approximately 50 possible lacunar syndromes, but the most common include pure motor hemipare-

Chapter 32 W

sis (the first syndrome identified), pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, and the dysarthria-clumsy hand syndrome. Multiple lacunar infarctions in the deep portions of the cerebral hemispheres cause the lacunar state (ttat lacunaire), characterized by a pseudobulbar syndrome with dysarthria, dysphagia, emotional lability, and a small-stepped gait (marche ri petits pas). Improved diagnosis and treatment of hypertension has

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decreased the number of lacunar infarcts observed in autopsy studies and has made the h t lacunaire a less common observation than in the past. Lacunar infarcts may also be incidental, asymptomatic findings in neuroimaging obtained for unrelated reasons. The Ctat cribli is a lacunar-like appearance of the brain secondary to dilatation of the perivascular Virchow-Robin space. Although these changes do not constitute true lacunar infarcts, it

A

B

FIG. 32-1. (A) Small parenchymal artery with lipohyalinosis (curved arrows, H&E, x45). (B) Multiple lacunar infarcts in the putamen (arrow), posterior limb of the internal capsule (double arrows), and thalami (curved arrows).

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is not clear whether this process is entirely benign, especially in regard to the development of cognitive dysfunction. Binswangefs Disease and Related Subcortlcal Degewrdons

The relationship between small vessel vasculopathy causing discrete lacunes and the more widespread cerebral white matter degeneration associated with progressive cognitive impairment and focal neurologic deficits (Binswanger’s encephalopathy) is unsettled. A variety of white matter lesions have been identified across the spectrum of the distinct, isolated, lacunar infarcts on one end and the more widespread small vessel involvement of Binswanger’s disease on the other (Table 32-1). These white matter changes reflect a microangiopathy and are reported on MRI as rims or caps of the lateral ventricles that, depending on severity, can range from limited areas of involvement to shadowing of the entire ventricular perimetry with peripheral confluent areas of white matter disease. This ventricular silhouetting should not be confused with transependymal reabsorption, in which cerebrospinal fluid is trapped in the periventricular region secondary to hydrocephalus. Unpredictably, some patients with periventricular microangiopathy may also have pontine rarefaction resembling the changes of central pontine myelinolysis. The cerebellar white matter is variably affected. Other patients may have associated mottling of the basal ganglia. Surprisingly, many patients with extensive white matter involvement are asymptomatic. Most are older than 60 years of age and have hypertension. The ready identification of white matter hypodensities on computed tomography (CT; i.e., leukoaraiosis) or high-signal lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) have led to correlation studies in both nondemented older patients and those with progressive dementia. Limited CT-neuropathologic observations in nondemented and demented patients with periventricular white matter hypodensities and presumed Binswanger’s encephalopathy have shown the triad of demyelination, axonal loss, and thickening of arteriolar walls. General cerebral atrophy, with ventricular enlargement, and multiple lacunes often are present. However, the CT findings alone do not reliably predict the presence of dementia because they are common in old patients with or without dementia who have hypertension and other vascular risk factors. The pathophysiology of these white matter changes relates to arteriolosclerosisof long medullary vessels that reach the periventricular regions arising from cortical areas. This deep territory becomes a border zone between the medullary arteries and the medial and lateral lenticulostriate vessels originating from the ACA and MCA trunks, respectively. The periventricular end of medullary vessels is affected by subadventitial collagen accumulation, but complete occlusion does not occur. Amyloid deposition occurs at the origin of medullary vessels but disappears as the vessel penetrates the cerebral hemisphere. Other age-related phenomena such as elongation, tortuosity, loops, and kinking of these vessels render the periventricular territory vulnerable to hypoperfusion and explain why aggressive blood pressure lowering may be detrimental. The frontal lobes, followed by the parietal, occipital, and temporal regions, are the most affected. In addition to arteriolosclerosis, hypertension contributes to white matter changes by causing plasma to transudate into the perivascular interstitiurn, where chronic edema results in gliosis and demyelination. These tissue changes do not constitute true infarcts but rather a transitional state between infarction and demyelination.

TMLE 32-1. Difference Between Lacunes and White Matter

Microangiopathy Clinical syndromes Diagnosis Vascular pathology Causes Treatment

Lacunes

Microangiopathy

Asymptomatic Classic lacunar Pseudobulbar Cr,MRI: focal Lipohyalinosis Atheroma Embolus Vascular risk factors

Asymptomatic Lower body parkinsonism Pseudobulbar 0, MRI: diffuse Arteriolosclerosis Amyloid Vascular risk factors Genetic Risk factor control Hemorrheology

Risk factor control Antiplatelets Anticoagulants? AbbreViOtions: Cr,computed tomography; MRI, magnetic resonance imaging.

The centrum semiovale and corona radiata can become involved, but the “U” arcuate fibers and corpus callosum are spared because they receive their blood supply from different sources. The occurrence of progressive cognitive impairment in association with multiple white matter lesions on neuroimaging has led to a differential diagnosis that includes Binswanger’s encephalopathy, congophilic angiopathy, normal pressure hydrocephalus, multiple sclerosis, acquired immunodeficiency syndrome, lymphoma, progressive multifocal leukoencephalopathy, radiation necrosis, gliomatosis cerebri, effects of chemotherapy, and other leukoencephalopathies. Small border zone infarcts may mimic white matter changes but can also be secondary to a surgically correctable carotid artery lesion, an intracranial stenosis, or multiple emboli. Often, the diagnosis of Binswanger’s disease is raised because of the neuroimaging findings in patients with progressive dementia. Whether this reflects chronic white matter ischemia from small penetrating arterial disease related to hypertension or to genetic or other pathogenetic factors is unclear. Binswanger’s disease as a single, independent pathologic entity has been questioned by many experts but is still considered the paradigmatic example of vascular dementia. The clinical course is marked by slow progression with significant fluctuations when compared with small vessel lacunar disease. Some patients have a steadily progressive course, and others suffer acute recurrences during the convalescent period from previous acute cerebrovascular episodes. Along the course of the disease, patients may show improvement of mental status and plateaus lasting several months. Motor dysfunction ensues before cognitive decline. The legs are affected out of proportion to the arms, leading to severe gait difficulties with broad base, short and shuffling steps, unstable turning, freezing, and festination resembling Parkinson’s disease. These limitations contrast with the ability of the patient to move the legs freely upon request while seated on a stretcher. Increased tone with paratonia in the arms and pseudobulbar findings are also present. Syncope is common. An apathetic, abulic state with emotional incontinence misleads the diagnosis to depression, and cognitive dysfunction, in early stages, affects construction with relative preservation of memory. Patients with multiple lacunes may develop a pseudobulbar state characterized by progressive bulbar dysfunction and, rarely, cognitive impairment, resulting from the cumulative effects of discrete lacunes from small penetrating arterial disease. Gait is severely limited, with a parkinsonian quality. These patients do not have the extensive white matter lesions and clinical findings characteristic of Binswanger’s disease, although distinguishing these conditions may be difficult.

Chapter 32

At least one genetic variant of white matter disease, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), has been identified in some familial clusterings. Patients are affected between the fourth and fifth decades, have history of migraine with aura, infarctions with onset on the fifth decade, and a high frequency of psychiatric disorders (mostly depression). Skin biopsy shows a granular arteriopathy with medial thickening and eosinophilic inclusions. Recent studies have localized the gene locus of CADASIL to chromosome 19q123. The diagnosis of Binswanger’s encephalopathy and related subcortical white matter conditions reflects our sharpened clinical observations and improved neuroimaging techniques, but their exact pathogenesis awaits further clarification from cliniconeuropathologic studies.

DIFFERENTIAL DIAGNOSIS The presence of a pure motor hemiparesis may be associated with isolated signs of visual neglect, dysphasia, or other cognitive deficits. This combination generally results from embolism to the MCA stem, leading to a deep, large striatocapsular and cortical infarct as shown by MRI or CT. These features reinforce the important clinical dictum that pure motor hemiparesis secondary to lacunar infarction should be diagnosed only in the presence of a deficit limited to the motor system. In addition, the presence of headache, seizures, mental status changes, an unusual distribution of weakness, and an absent history of hypertension should all raise the suspicion that the syndrome is not lacunar, prompting the use of further diagnostic testing. Rarely, a subdural hematoma, small parenchymal hemorrhage, tumor, or limited large artery cortical infarction may explain these imitators of pure motor hemiparesis. Because large and small artery disease share common risk factors, large vessel atherosclerosis of varying degrees can exist coincidentally in some patients with lacunar infarcts. This could lead to an unnecessary carotid endarterectomy if the physician is not familiar with the presentation of lacunar disease. On the other hand, patients with typical lacunar syndromes may have a small hemorrhage or cortical infarct, resulting in a limited deficit unrelated to penetrating artery disease. Hypertensive hemorrhages and lacunar infarcts have the common neuropathologic substrate of lipohyalinosis affecting small penetrating arteries, which occasionally may result in similar clinical signs such as pure motor hemiparesis or pure sensory stroke from a small capsular or thalamic hemorrhage, respectively. However, clinical differentiation is simple because the CT or MRI will readily document the hemorrhage. A severe stenosis of the ICA may cause hemodynamic insufficiency and ischemia in the MCA penetrator territory supplied by distal field lenticulostriate arteries, with resulting internal capsule infarction and pure motor hemiparesis. Extracranial ICA disease may be suspected if there is a history of carotid TIAs, or a carotid bruit. A duplex Doppler scan of the carotids, a contrast angiogram, or magnetic resonance angiography should be obtained to confirm the diagnosis and consider carotid endarterectomy.

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initial scan is negative, a later scan at 2 to 5 days may show the infarct (Fig. 32-2). MRI is superior to CT in detecting lacunar infarctions, especially in the brainstem, cerebellum, and thalamus (Fig. 32-3). In most patients with lacunar syndromes, especially pure motor hemiparesis, the lacune will be documented by CT or MRI. The use of diagnostic techniques to document cardiac or vascular embolic sources is necessary only in patients who present with an unclear history and clinical and imaging evidence of a lacunar infarction appropriate to the neurologic findings. Evaluation should include a search for both cardiac and vascular embolic sources, especially intracranial atherosclerotic disease. The latter is important in documenting branch syndromes (in the basilar artery, MCA) caused by atherosclerotic disease of the parent artery that gives rise to the involved perforators. This is being increasingly investigatedwith magnetic resonance angiography instead of contrast cerebral angiography to minimize the potential risks of cerebral angiography. Transcranial Doppler can reliably assess the intracranial circulation for the presence of stenotic lesions.

TREATMENT Excessive lowering of blood pressure in patients with lacunar infarction is a common mistake that can result in neurologic worsening. The blood pressure should be lowered only if it is consistently higher than 220 mm Hg systolic and 120 mm Hg diastolic on three successive measurements every 15 minutes. It is preferable not to decrease the blood pressure below 170/90during the first few days after stroke onset, and it should subsequently be slowly lowered to normal or near normotensive values over the

DIAGNOSIS The clinical history and findings on examination in most cases strongly suggest the diagnosis of a lacunar syndrome. Neuroimaging usually provides confirmation of the clinical suspicion; if the

FIG. 32-2. CT showing lacunar infarction in the posterior limb of the right internal capsule (arrows) 5 days after onset of left pure motor hemiparesis, after a normal CT scan on the day of onset.

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B

A

FIG. 32-5.

(A) T1-weighted MRI showing old lacunes in right thalamus, right caudate, and left putamen (arrows). (6) T2-weighted MRI showing lacune in right basis pontis (arrow). (Courtesy of Rita Bhatia, MD, Department of Radiology, Boston

University Medical Center, Boston, MA.) following 2 to 4 weeks. A study with the angiotensin-converting enzyme inhibitor perindopril has shown efficacy in decreasing the recurrence of stroke. This drug could be indicated with the double purpose of achieving secondary stroke prevention and controlling hypertension. Different studies have shown a decreased incidence of dementia in patients with strict blood pressure control. Aspirin (acetylsalicylicacid), 325 mg/day, is often given, more for reducing general cardiovascular effects than as a proven agent in preventing lacunar stroke progression or recurrence. Anticoagulation should be considered in branch artery disease when the parent vessel (large artery) shows significant narrowing and is not accessible to surgical correction. The Warfarin-Aspirin Recurrent Stroke Study (WARSS) randomized 2206 patients to receive warfarin or aspirin with the primary endpoints of reducing death and stroke recurrence. No significant difference in treatment results was detected between the warfarin and aspirin groups. There was a small, nonsignificant benefit of warfarin (8% risk reduction) in patients in the subcategory of cryptogenic stroke (25% of all patients). This subgroup is likely to represent patients with embolism or hypercoagulable states undetected during the diagnostic evaluation. Interestingly, 56% of patients in WARSS had a diagnosis of lacunar stroke, for which the use of anticoagulants to prevent recurrence is likely to be ineffective. Approximately 25% of patients with lacunar ischemia have a deteriorating course at onset, but anticoagulation has not been shown to alter this early progressive course. Patients with microangiopathy and impaired local microcirculation may benefit from improving hemorheologic factors such as thrombocytosis, polyglobulia, smoking, fibrinogen, and hyperlipidemia, with the aim of arresting progression of white matter disease. Patients with a pseudobulbar state should be considered for gastrostomy to prevent aspiration pneumonia. Severe sialorrhea

has recently been shown to improve significantly with botulinum toxin injection of the salivary glands. The recurrence rate of lacunar infarcts is low, and mortality at 1 year is lo%, generally because of cardiovascular complications. Rehabilitation with neurodevelopmental techniques should be encouraged in patients with lacunar syndromes because of their high likelihood of gaining independence. SUGGESTED READINGS Arboix A, Garcia-Eroles L, Massons J et al: Lacunar infarcts in patients aged 85 years and older. Acta Neurol Scand 101:25,2000 Caplan L R Binswanger’s disease revisited. Neurology 45:626, 1995 Ducros A, Nagy T, Alamowitch S et al: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval. Am J Hum Genet 58:171, 1996 Fisher CM: The arterial lesions underlying lacunes. Acta Neuropathol 12:1, 1969

Fisher CM: Lacunar infarcts: a review. Cerebrovasc Dis 1:311, 1991 Gerraty RP, Parsons MW, Barber PA et al: Examining the lacunar hypothesis with diffusion and perfusion magnetic resonance imaging. Stroke 33:2019, 2002 Lodder J, Bamford JM, Sandercock PA et al: Are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke 21:375, 1990 Longstreth WT Jr, Bernick C, Manolio TA et al: Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 55:1217, 1998 Miller V: Lacunar stroke: a reassessment. Arch Neurol 40129, 1983 Mohr J P Lacunes. Stroke 13:3, 1982 Nakamura K, Saku Y, Ibayashi S, Fujishima M Progressive motor deficits in lacunar infarction. Neurology 52:29, 1999 Toni D, Iweins F, von Kummer R et al: Identification of lacunar infarcts before thrombolysis in the ECASS I study. Neurology 54684, 2000

Chapter 33

33

lntracerebral Hemorrhage

315

Intracerebral Hemorrhage Carlos S. Kase and Conrad0 1. Estol

Intracerebral hemorrhage (ICH) results from direct bleeding into the substance of the brain, with local accumulation of blood and formation of a hematoma. Intracranial hemorrhage constitutes approximately 15% of all strokes, and its cause is hypertension in 50% to 70% of the cases. ICH accounts for 11% of all stroke deaths, it carries a mortality rate close to 50% (half of the deaths occur within the first 2 days), and only 20% of affected patients are independent at 6 months. The majority of these hemorrhages are located in the depth of the cerebral hemispheres (Table 33-1).

PATHOGENESIS Hypertension The pathogenesis of hypertensive ICH involves the rupture of small (50 to 300 pm in diameter) parenchymal perforating arteries (lenticulostriate, thalamogeniculate, paramedian basilar) as a result of hypertension-induced degenerative changes in their walls. These include the focal degenerative change of the vessel wall called lipohyalinosis, followed by fibrinoid necrosis and the formation of local outpouchings of the arterial wall, the so-called microaneurysms described by Charcot and Bouchard. There is still controversy as to which of these lesions causes the rupture of the arterial wall. Their pathogenic role in ICH is favored by their higher frequency in hypertensives in comparison with normotensives and by their preferential location to the areas of the brain in which ICH occurs most often (deep gray nuclei and subcortical white matter of the cerebral hemispheres). However, a history of chronic hypertension may not be present in up to 50% of patients with ICH. As an alternative mechanism, acute blood pressure elevations, even in young patients, can also cause perforating arteries to rupture. This could be the mechanism in eclampsiarelated hemorrhage, with use of sympathomimetic drugs, after carotid endarterectomy, or in patients who have acute pain related to trigeminal stimulation, called the “dental chair” hemorrhage. Once the arterial rupture has occurred, the period of actual bleeding into the brain parenchyma was thought to be brief (30 minutes or so). However, recent data derived from use of ultra-early serial computed tomographic (CT) scanning after ICH onset suggest that bleeding can proceed over periods of several hours. This results in the frequent observation of substantial increases in hematoma size associated with clinical deterioration after hours from onset. Hemorrhage eventually stops because of formation of a platelet plug that blocks the rupture site in the arterial wall, outside of which fibrin and red blood cells accumulate.

Nonhypertenshre Mechanisms A number of nonhypertensive mechanisms play a role in ICH (Table 33-2). Cerebral Amyloid Angiopathy. Cerebral amyloid angiopathy is a unique form of cerebral angiopathy with deposits of amyloid in the media and adventitia of small and medium-size arteries of the cerebral hemispheres. The affected arteries are those located in

the superficial layers of the cerebral cortex and the leptomeninges. Cerebral amyloid angiopathy affects up to 50% of people older than 70 years of age, in whom histopathologic features of Alzheimer’s disease often are found. However, hemorrhage from amyloid angiopathy accounts for only an estimated 10% of all ICHs. Pathologically, it is characterized by deposits of Congo red-positive material in the media and adventitia of cortical and leptomeningeal arteries, which show apple-green birefringence under polarized light. The ICHs occur in superficial, subcortical, or lobar locations because the angiopathy selectively affects arteries of the cortical surface and leptomeninges. An additional feature of cerebral amyloid angiopathy is a tendency to produce recurrent ICHs over periods of months or years, occasionally even leading to simultaneous acute hematomas in different brain locations but only exceptionally located in the basal ganglia and brainstem. In 50% of patients these hemorrhages can present clinically with transient episodes of tinghng, numbness, and less often weakness, simulating transient ischemic attacks. Patients with the apolipoprotein E epsilon 4 allele have hemorrhages at an average earlier age than patients without the allele. Also, patients with the allele may be more prone to suffer hemorrhages if treated with thrombolytics or anticoagulants. Gradient-echo magnetic resonance imaging (MRI) may show petechial hemorrhages or hemosiderin related to amyloid angiopathy, facilitating early detection of patients who may have a high bleeding risk.

W TAW 33-1.

Locations of lntracerebral Hemorrhage Location

46

33 Putamen Cerebral lobes 23 20 Thalamus 8 Cerebellum 7 Pons 9 Miscellaneous From Kase CS,Williams JP, Wyatt DA et al: lobar intracerebral hematomas: clinical and CT analysis of 22 cases. Neurology 32:1146, 1982, with permission.

TAW 33-2.Nonhypertensive Causes of lntracerebral

Hemorrhage Cerebral amyloid angiopathy Vascular malformations Anticoagulants Thrombolytic agents Brain tumors Sympathomimetic drugs Alcohol Vasculitis Cerebral infarction with hemorrhagic transformation Carotid endarterectomy Dural sinus thrombosis Delayed post-traumatic (“spat”) hemorrhage Infectious (herpes simplex, fungal) Neurosurgical (after evacuation of subdural hematoma or incomplete removal of an arteriovenous malformation) Eclampsia

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FIG. 33-1. T2-weighted sagittal MRI of cavernous angioma of the basal ganglia, showing mixed-signal central core with peripheral hypodense areas of hemosiderin deposition. (Courtesy of Rita Bhatia, MD, Department of Radiology, Boston University Medical Center, Boston, MA.)

Vascular Malformations. Previously unsuspected small vascular malformations, including arteriovenous malformations (AVMs), cavernous angiomas, and venous angiomas, can present as spontaneous ICH in adults. Their frequency in series of ICH varies between 4 and 8% of the cases. They are being increasingly diagnosed with the advent of CT scanning and MRI. AVMs appear as multiple vascular channels, often accompanied by calcification; cavernous angiomas have a characteristic aspect on the T2weighted MRI sequences, with a mixed-signal central core surrounded by a low-signal hemosiderin ring (Fig. 33-1); venous angiomas appear as a large, dilated venous channel that is connected to a series of smaller veins, the so-called caput medusae (Fig. 33-2). The risk of bleeding is highest in AVMs, lowest in venous angiomas, and intermediate in cavernous angiomas. Recent data suggest that venous angiomas have a negligible tendency to bleed, and when that occurs it is the result of rupture of an associated cavernous angioma. The hemorrhages produced by these lesions, especially those caused by AVMs, tend to occur more often in the subcortical white matter (rather than in the deep portions of the hemisphere), reflecting their usually more superficial location. Oral Anticoagulants. Oral anticoagulants (warfarin sodium, acenocoumarol) increase the risk of ICH 8 to 1 1 times. Some authors have linked these ICHs to the coexistence of hypertension, but a more consistent risk factor is an excessive prolongation of the prothrombin time or International Normalized Ratio (INR) beyond the therapeutic range. Widespread use of the INR as the method of choice for anticoagulation control has increased the safety of anticoagulant treatment. The hemorrhagic risk of patients treated with an INR lower than 3 is less than 0.5% per year and is greatest in the first few months of treatment. Clinically, these hemorrhages have some distinct features. A gradual and slow

progression of the neurologic deficit occurs in as many as 50% of the cases up to 48 hours after onset, suggesting a process of slow bleeding into the parenchyma (as opposed to the usually faster course of hypertensive ICH), possibly resulting from rupture of different type or size vessels than those affected in hypertensive ICH. The mortality rate from anticoagulant-related hemorrhages is 65%. Unconsciousness on admission and becoming unconscious before treatment are associated with the highest mortality rate. Upon diagnosis anticoagulation should be stopped and reversed with fresh frozen plasma, vitamin K, or coagulation factor concentrate. No significant difference has been detected among the different therapies for anticoagulation reversal. A common problem is the timing to restart anticoagulation in patients with atrial fibrillation, a mechanical heart valve, or severe intracranial stenosis complicated with ICH. The stroke risk reported for these patients while they are off anticoagulants has been reported to be between 3% in the first 2 weeks. The decision to resume therapy should be individualized based on the type of hemorrhage (volume, location), clinical manifestations, and indication for anticoagulant treatment. A period between 9 days and 2 weeks before resuming anticoagulation has been used safely in different series. Another therapeutic challenge occurs in patients with hemorrhagic conversion of an ischemic infarction. Hemorrhagic conversion refers to heterogenous blood mottling within the infarcted area without mass effect. A few anecdotal series have shown no clinical worsening of patients with hemorrhagic infarction receiving therapeutic dosages of anticoagulants. Moreover, in some patients complete reabsorption of the hemorrhagic component was confirmed with serial CTs in the course of full-dose

FIG. 33-2. MRI (T,-weighted) showing bilateral venous angiomas in the area of the 4th ventricle. The typical ”caput medusae” aspect is given by the small medullary veins that converge into the large veins near the 4th ventricle.

Chapter 33

anticoagulation. A distinction should be made between the aforementioned hemorrhagic conversion and ischemic infarctions complicated with frank hematomas that cause mass effect and extend beyond the limits of the infarct, causing clinical deterioration. In these patients anticoagulation should be discontinued. Thrombolytic Agents. Thrombolytic agents, which are extensively used to treat patients with acute myocardial infarction, have been associated with intracranial hemorrhage in approximately 0.5% of patients treated. ICH in this setting often is of lobar location and large size, the latter leading to high mortality rates (44%). Among the potential risk factors for this complication of thrombolysis, an excessive prolongation of the activated partial thromboplastin time from the concomitant use of intravenous heparin has been suggested. In other instances, a preexistent angiopathy with bleeding potential, such as cerebral amyloid angiopathy, has been identified at autopsy examination. This suggests that the choice of this form of therapy should be made carefully in older adults presenting with acute myocardial infarction to exclude those who may be at high risk of bleeding intracranially. In coronary artery disease, primary angioplasty is a safer therapy than thrombolysis for appropriate candidates. In cerebrovascular disease, the National Institute of Neurological Disease and Stroke (NINDS) rt-PA study showed that 6.4% of patients treated within 3 hours of an ischemic stroke had symptomatic cerebral hemorrhages compared with 0.6% in the placebo group. Studies with a 6-hour therapeutic window revealed that patients with early, subtle signs of cerebral ischemia on CT were at a higher risk for hemorrhagic complications. Strict compliance with the NINDS protocol and careful imaging evaluation to exclude patients with early signs of ischemia decreases the risk of thrombolysis. Recent data have suggested that hyperglycemia at hospital presentation may be a risk factor for ICH after intravenous and intra-arterial thrombolysis for acute ischemic stroke. Brain Tumors. Brain tumors are found in 2% to 10% of cases of ICH. Those likely to present as ICH are largely malignant, either primary (glioblastoma multiforme) or metastatic, the latter most commonly corresponding to bronchogenic carcinoma (low bleeding rate but leading cause because it is a very common metastatic source), melanoma, choriocarcinoma, or renal cell carcinoma. The sites of hemorrhage relate to the type of underlying tumor: Deep-seated white matter tumors such as glioblastoma multiforme produce deep hemispheric hemorrhages, whereas hemorrhages into metastatic tumors are more often corticosubcortical, reflecting the predilection of secondary tumors for the superficial portions of the cerebral hemispheres. Some benign tumors such as meningioma, oligodendroglioma, and pituitary adenomas may rarely cause ICH. Sympathomimetic Drugs. A number of sympathomimetic drugs have been implicated in causing ICH. These include the amphetamines, phenylpropanolamine, and cocaine. Hemorrhage has generally occurred shortly after use of the drug, within minutes to a few hours after exposure. The majority of the hematomas are lobar, with only occasional ones in the basal ganglia or thalamus. Transiently elevated blood pressure has been noted in approximately 50% of the reported cases, and angiographic changes of multifocal areas of arterial constriction and dilatation (“beading”) have been documented, raising the possibility of a drug-induced angiopathy as their cause. On rare occasions, this angiographic pattern has been shown histologically to correspond to a true drug-induced vasculitis, after use of either phenylpropanolamine or cocaine. Use of these drugs can also result in ischemic stroke.

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Vasculitis. Vasculitis affecting cerebral vessels is rare, in particular in the systemic vasculitides. Periarteritis nodosa, hypersensitivity vasculitis, Wegener’s granulomatosis, Behget’s disease, and Takayasu’s arteritis can present with intracerebral or subarachnoid hemorrhage. A primary cerebral form, isolated (or granulomatous) angiitis of the nervous system, which often leads to repeated episodes of ischemic infarction, can, on rare occasions, be the cause of episodes of ICH. In some instances, the ICH has been the first manifestation of the vasculitis. Hemorrhage in Young Patients. Rupture of an AVM is the leading cause (35%) of ICH in adults younger than 50 years, followed by hemorrhage of undetermined cause, hypertension, ruptured aneurysms, and drug abuse.

CLINICAL FEATURES The onset of ICH almost always occurs in the awake period, with a focal deficit that develops smoothly and steadily over seconds or minutes. The syndrome may cease to develop at any stage or continue to death in a few hours, the latter being frequently associated with CT scan documentation of progressive enlargement of the hematoma. This type of smooth onset is seen in approximately two thirds of the cases, whereas in the remainder it develops so rapidly that the deficit seems maximal at onset. None experience fluctuation or early resolution of the deficit. The risk of ICH is higher in patients older than 55 years, in men, in blacks and Asians, and in those who consume more than three alcoholic drinks per day. Headache can occur early and usually is intense, but up to 70% of patients may not have headache associated with ICH. A “deep group” that involves the basal ganglia, thalamus, pons, and cerebellum accounts for 75% to 90% of all ICHs, which are mostly related to hypertension (especially those in the pons). The other is the “superficial” or lobar group, which accounts for 10% to 25% of all ICHs and involves the frontal, temporal, occipital, and parietal lobes. Some of the lobar hemorrhages may have their origin in spreading basal ganglia or thalamic hemorrhages, and are more often related to alcohol intake. Mortality from ICH is best predicted by the combined evaluation of the Glasgow Coma Score, hematoma size, presence of intraventricular extension of bleeding, and blood pressure.

Putamlnal Hemorrhage The bleeding site in the putaminal variety of ICH is most commonly in the posterior half of the putamen (Fig. 33-3). From that area, the hemorrhage can spread into the centrum semiovale, the isthmus of the temporal lobe (along the course of the arcuate fasciculus), or across the internal capsule (often reaching the ventricular system). These patterns of extension of the hemorrhage result in further neurologic signs, and the larger hematomas eventually are accompanied by signs of intracranial hypertension. The rare instances in which the bleeding is small and remains confined to the posterior putamen can result in a surprisingly mild motor deficit, at times conforming to a “pure motor hemiparesis” syndrome. In the typical example of putaminal hemorrhage of moderate or large size, the patient develops a usually severe hemiparesis or hemiplegia affecting the arm, face, and leg, reflecting bleeding into the area of the internal capsule. This is accompanied by a hemisensory syndrome, hemianopia, and aphasia if the dominant hemisphere is affected. Unawareness of the deficit develops when the nondominant hemisphere is involved. The aphasia encoun-

318

Cerebrovascular Disease

Common Pathogeneses of Stroke

tered generally has been either slight or of the global variety; conduction aphasia is rare or nonexistent in this setting. Eye movement disorders feature conjugate horizontal gaze deviation toward the hematoma side when the hemiplegia is well developed, but eye movements often are normal when the hematoma is smaller, and the resulting hemiparesis is mild. More complex disorders of eye movements occur in the event of uncal herniation and midbrain compression. Pupillary size and reactivity to light

usually are normal unless uncal herniation with resultant thirdnerve palsy has occurred. Functional recovery often can be predicted by the degree of deficit present on examination. Patients with a dense hemiplegia show very little functional recovery, whereas those with only milder weakness may show complete resolution. Surgery to evacuate the hematoma generally is not done, except in some patients with large hematomas. Surgical intervention can lessen mortality, but functional prognosis remains poor.

Caudate Hemorrhage Hemorrhage into the head of the caudate nucleus is characterized by abrupt onset of headache and vomiting, often accompanied by decreased level of consciousness and neck stiffness, in a manner similar to subarachnoid hemorrhage from ruptured aneurysm. Focal neurologic deficits such as hemiparesis or gaze palsy are rare and transient. Cognitive and behavioral changes with agitation or abulia and memory dysfunction are common. Occasional patients develop signs of Horner’s syndrome ipsilateral to the hemorrhage. CT scan shows a hematoma in the head of the caudate nucleus, with extension into the adjacent lateral ventricle (Fig. 33-4), often associated with hydrocephalus. In cases with transient focal motor deficits, the hemorrhages tend to be larger, extending into the internal capsule and along the body of the caudate nucleus. Their outcome generally is benign, with progressive resolution of the clinical deficits and gradual reduction of ventricular size. Although it is often present at onset, hydrocephalus rarely necessitates surgical shunting. The main mechanism in primary caudate hemorrhage is hypertension, but ruptured anterior communicating aneurysm or parenchymal AVM must be ruled out by angiographic studies.

Thalamlc Hemorrhage FIG. 33-3. CT of large right putaminal hemorrhage with moderate

mass effect.

The hemorrhage that arises in the thalamus often enlarges and tracks laterally to involve the internal capsule, in addition to extending posterolaterally into the parietotemporal region or

FIG. 35-4. Left caudate nucleus hemorrhage with extension into the lateral ventricles.

Chapter 33

lntracerebral Hemorrhage

319

Lobar Hemorrhage

FIG. 55-5. CT of left thalamic hemorrhage with extension into the third and lateral ventricles.

downward into the midbrain (Fig. 33-5). Its location in the vicinity of the third ventricle often results in ventricular extension, at times with early obstructive hydrocephalus. The initial contralateral complete hemisensory syndrome and capsular hemiparesis or hemiplegia occurs immediately. If the hemorrhage enlarges laterally, conjugate horizontal gaze deviation toward the lesion occurs, but in rare instances a contralateral conjugate eye deviation (“wrong-way eyes”) is seen. As the hemorrhage spreads inferiorly and compresses the dorsal midbrain, ocular findings characteristicallyfeature upward gaze palsy with miotic unreactive pupils. Because of the upward gaze palsy, the ocular position at rest is one of conjugate downward deviation, sometimes associated with convergence. The sensory deficit often is of striking severity and widely distributed over the contralateral limbs and face, including the scalp, neck, and trunk. A thalamic pain syndrome can be the permanent sequela of the destructive lesion affecting the thalamus. An aphasia lasting several days is encountered in the smaller dominant hemisphere cases. It has been described as a fluctuating delirium-like state with disproportionate literal paraphasias. CT scan information on the size of the hematoma has useful prognostic significance: Hematomas larger than 3.3 cm often are fatal, whereas patients with hematomas smaller than 2.7 cm show significantly better survival rates. Because of the inaccessibilityof these hematomas, direct surgical evacuation is attempted rarely. It is possible that patients presenting with marked obstructive hydrocephalus at onset can benefit from ventriculostomy or cerebrospinal fluid shunting. In some instances, these surgical procedures have produced dramatic improvement in the clinical picture, and they may represent a useful therapy for selected cases of thalamic ICH.

Approximately one fourth of spontaneous ICHs occur in the subcortical white matter of the cerebral hemispheres (Fig. 33-6), predominantly in the parieto-occipital region. The hematoma develops at the junction of the gray and white matter, producing a globular mass that separates the two. At autopsy years later, the remnant of the hemorrhage appears as a shallow orange-stained cavity, called “slit hemorrhage.” The clinical manifestations depend on the location of the hematoma: hemiparesis predominating in the arm, behavioral changes and headache in frontal hemorrhages, sensorimotor deficit with visual field defect in parietal hematomas, homonymous hemianopsia with ipsilateral ocular pain in occipital hemorrhages, and Wernicke-type aphasia with preserved repetition (transcortical sensory aphasia) in dominant temporal lobe hematomas. The latter speech deficit is at times surprisingly evanescent. Seizures are more common in lobar hemorrhage than in other forms of ICH, reflecting the proximity of the lesion to the cerebral cortex. This variety of ICH often is of a nonhypertensive mechanism, suggesting that other causes such as occult vascular malformations, cerebral amyloid angiopathy, underlying tumors, and angiopathies related to drug use or abuse must be investigated once the lobar location of the ICH has been determined. Lobar ICHs generally show a less severe degree of disability in survivors and lower mortality (11%) than with other supratentorial sites of ICH (44%). Furthermore, they are accessible to surgical drainage and, if untreated, they may be fatal as a result of prominent pressure effects. If the CT scan shows that the hemorrhage is near the cortical surface, and if there is clinical deterioration and prominent mass effect on the CT, surgical evacuation should be considered.

FIG. 35-6. Right frontal lobar hemorrhage.

520

Cerebrovascular Disease

Common Pathogenesesof Stroke

tics of the hematomas on CT can be useful early predictors of clinical course: Patients with a benign, stable course tend to have hematomas smaller than 3 cm in diameter. Patients with abrupt onset and more severely depressed level of consciousness and tendency toward progressive deterioration show hematomas of 3 cm or more in diameter, associated with obstructive hydrocephalus and effacement of the quadrigeminal cistern. Surgical decompression is mandatory in the larger hemorrhages, but the results generally are poor if the patient has already reached a state of coma at the time of surgery. Therefore, it is important to operate early in instances of large cerebellar hemorrhages to prevent progressive brainstem dysfunction and coma. However, there have been reports of improvement after emergent decompression was performed in patients without brainstem reflexes, indicating that severe brainstem dysfunction from mass effect may be reversible. The smaller hematomas that show no associated hydrocephalus can be managed medically, but at the earliest indication of signs of brainstem dysfunction, surgery should be undertaken promptly. Pontlne Hemorrhage

FIG. 33-7. Left hemisphericcerebellar hemorrhagewith compression

of the fourth ventricle. Cerebellar Hemorrhage

Hemorrhage in the cerebellum represents 10% to 15% of intracerebral hematomas. The majority of the hemorrhages develop in the area of the dentate nucleus, spreading laterally into one hemisphere (Fig. 33-7) or superomedially to the midline of the superior vermis. The onset is sudden in 95% of cases, with prominent nausea, vomiting, dizziness, and inability to stand and walk. Headache occurs in 74%, but loss of consciousness at onset is rare (14%). Clinical examination shows limb or gait ataxia, peripheral facial palsy, and ipsilateral gaze palsy, a useful diagnostic triad. Hemiplegia and subhyaloid hemorrhages are extremely rare. Occasionally, small cerebellar hemorrhages present with pure vertigo, nausea and vomiting sometimes misdiagnosed as Meniere’s disease, acute labyrinthitis, or vestibular neuronitis. For this reason, one should maintain a high index of suspicion and perform a CT scan early in the course of the illness to assess the possibility of cerebellar hemorrhage. Cerebellar hemorrhage has a notorious tendency to produce sudden worsening in the patient’s condition after an initial benign course: 50% of patients presenting in an alert state on admission went on to develop sudden coma without first showing focal signs within 48 hours from onset in one series (Fig. 33-8). This course could not be related to reliable predictors on admission evaluation. Because surgical intervention has a low morbidity when performed in alert or obtunded patients and is usually associated with a satisfactory functional outcome, surgery is generally planned for cases diagnosed within the first 48 hours, particularly when signs of tegmental pontine involvement (ipsilateral horizontal gaze palsy, sixth-nerve palsy, facial palsy) are present. The characteris-

The most dramatic and least treatable of the hypertensive hemorrhages, pontine hemorrhage, produces the more uncommon syndromes. They usually affect the ventral pons, arising from bleeding from the paramedian penetrators, then extending into the rest of the basis pontis and tegmentum (Fig. 33-9). The larger hemorrhages can lead to deep coma within minutes of onset, usually in association with quadriplegia and decerebrate rigidity. In addition, reactive, small (“pinpoint”) pupils occur, along with a variety of ocular motility disorders, including ocular “bobbing,” unilateral or bilateral internuclear ophthalmoplegia,and unilateral or bilateral sixth-nerve palsy, all of which are replaced by bilateral horizontal ophthalmoplegia in the most severe cases. In addition, abnormal respiratory rhythms and hyperthermia are common. Large pontine hemorrhages are almost invariably fatal. Small

I 40

30

20

a

ui

c

10

Chapter 33

lntracerebral Hemorrhage

321

FIG. 33-9. Massive bilateral pontine hemorrhage with involvement of most of the basis and tegmentum, with extension into the fourth ventricle.

laterally placed hemorrhages in the pontine or midbrain tegmentum usually spare consciousness and produce an array of cranial nerve findings and lateralized weakness and ataxia. These smaller hematomas mimic syndromes of partial pontine ischemia such that CT scanning is necessary to separate hemorrhage from infarction. Prognosis is better in the unilateral than in the bilateral variety of pontine hemorrhage. Surgical intervention is not generally attempted.

Mesencephalic Hemorrhage The midbrain is a rare location for primary ICH; only 12 cases have been reported in the past 10 years. Six of these cases were caused by hypertension or AVMs; the rest of the patients were normotensive and without other risk factors for ICH. Their clinical presentation often involves the abrupt onset of headache and vomiting, with variable motor signs. The latter have been described primarily in unilateral hematomas and have corresponded to either contralateral hemiparesis or ipsilateral cerebellar ataxia, with a corresponding gait disturbance. The most common physical findings have reflected the tectal-tegmental location of the hemorrhages, leading to ocular signs that include paralysis of upward gaze, small unreactive pupils with preserved near reflex (i.e., light-near dissociation),and palpebral ptosis. One instance of a caudally placed tectal hemorrhage presented with bilateral fourth-nerve palsies and unilateral Homer’s syndrome. Hydrocephalus from aqueductal compression is commonly reported, in some instances necessitating ventricular shunting. In general, the prognosis has been good, with most patients surviving with persistent ocular and pupillary changes.

Medullary Hemorrhage Hemorrhage into the substance of the medulla oblongata is the least common form of ICH. It is at times seen as part of the caudal

extension of a pontine hemorrhage, but in its primary medullary form it has been reported in only 12 cases in the last 30 years. Its clinical presentation is highlighted by the sudden onset of features indicative of largely unilateral tegmental or basal medullary involvement, with vertigo, vomiting, gait imbalance, limb ataxia, and paresis of lower cranial nerves. Its findings on neurologic examination can be similar to those of Wallenberg’s lateral medullary syndrome, with the exception that medullary hemorrhage often presents with hemiparesis and hypoglossal nerve palsy, reflecting extension of the ICH ventrally and medially, respectively, away from the dorsolateral area.

DIAGNOSIS The diagnosis of ICH relies heavily on the imaging techniques of CT and MRI, which can diagnose the condition with 100% reliability. CT is particularly useful in establishing the diagnosis of ICH, as opposed to ischemic stroke, a distinction that is not always possible on clinical grounds alone, especially in instances of small hemorrhages that produce minimal signs of increased intracranial pressure (ICP). The advent of MRI has added to the diagnostic precision of brain imaging by providing useful data on the evolution of the ICH. These data derive from the paramagnetic properties of the hemoglobin contained in the hematoma, which undergoes predictable time-dependent biochemical changes, thus allowing precise timing of the duration of the ICH (Table 33-3). The initial study has traditionally been CT because of the notion that MRI does not show hemorrhage well in the first few hours; however, with the use of gradient-echo techniques, MRI can detect acute ICH as well as CT, and there is an increasing trend towards the use of this technique in the evaluation of acute ischemic stroke. MRI is unique as a second image to defining for amyloid angiopathy, cavernomas, and other vascular malformations. Magnetic resonance angiography has a high sensitivity to screen patients for AVMs and aneurysms, although catheter angiography

522 W TABLE 55-5.

Cerebrovascular Disease

Common Pathogeneses of Stroke

Hemoglobin and MRI Evolution in Hematoma HEMATOM

Stage

Time

Hb Form

Mametic Pro~crtv

51. T1

Hyperacute Acute Early subacute Late subacute Chronic

Hours Days Weeks Weeks-months Months-years

Oxyhemoglobin Deoxyhemoglobin Methemoglobin (intracellular) Methemoglobin (extracellular) Hemosiderin

Diamagnetic

= or 1 = or 1

Paramagnetic Paramagnetic Paramagnetic Paramagnetic

t tt

= or 1

51. R

t

11 1

tt

11

Hemosiderin Rim ISI.l.2l

ISI. l.2)

Edema

11 11 11

tt tt tt -

Abbreviations: Hb, hemoglobin; SI, signal intensity relative to normal gray matter; T1, T1-weighted sequences; T2, n-weighted sequences. From Dul K, Drayer B P CT and MR imaging of intracerebral hemorrhage. pp. 73-93. In Kase CS,Caplan LR (eds): lntracerebral Hemorrhage. Buttenworth-Heinemann,Boston, 1994, with permission.

may be necessary in some patients. To improve the yield in detecting a vascular anomaly, catheter angiography should be delayed a few days after the hemorrhage because mass effect from the extravasated blood may obliterate the underlying lesion during the first few days. The patients most likely to show vascular malformations with angiography are those younger than 45 years with lobar hemorrhages and patients with intraventricular hemorrhages. Patients with hypertension, those taking oral anticoagulants, alcoholics, and patients with thalamic or brainstem hemorrhages are unlikely to benefit from angiography.

COMPLlCATlONS Recent observations with early neuroimaging studies have shown that rebleeding within the first 24 hours is more common than previously thought and explains deterioration of patients with an initially moderate-size hemorrhage and a stable clinical condition. Early rebleeding is more severe in patients with coagulopathy, so a basic coagulation profile should be obtained in all patients and platelet transfusion given in those who have fewer than 70,000 platelets. Rebleeding months or years after the initial hemorrhage occurs in up to 5.3% of patients. This is usually secondary to a vascular malformation not diagnosed at the time of the presenting hemorrhagic episode or to hypertensive hemorrhages, for which the rebleeding risk can reach 10% per year when diastolic blood pressure values remain greater than 90 mm Hg. Hydrocephalus can cause rapid clinical deterioration and can be easily treated with cerebrospinal fluid drainage if promptly recognized. It is most common in patients with intraventricular hemorrhages and in thalamic and posterior fossa hemorrhages, which tend to extrinsicallycompress cerebrospinal fluid pathways. An intraventricular catheter placed contralaterally to the bloodflooded ventricle reduces the risk of clogging the draining system. The catheter also allows ICP monitoring and the possibility of instillation of thrombolytic drugs, which have been recently shown to improve survival by increasing intraventricular hematoma resolution. With large amounts of intraventricular blood the chances of a successful drainage are low and the patient’s prognosis is poor. Tissue edema and ischemic necrosis surrounding the hemorrhage also contribute to clinical deterioration. The genesis of edema is related not only to mass effect from the bleeding but also to perihemorrhagic changes in vascular permeability caused by edemogenic substances released from the clot. These

and other toxic substances generate edema and an inflammatory response that lead to delayed cellular death in experimental animal models.

MANAGEMENT Management of patients with ICH should be directed toward preserving remaining neurologic function and preventing deterioration caused by elevated ICP with resultant coma or death. These patients should be managed in a neurologic or neurosurgical intensive care unit, whether they are to be managed conservatively or are to receive preoperative or postoperative care. The patients should be kept at bed rest with the head elevated 30 degrees to reduce ICP by facilitating venous drainage. In patients with ICH who present with lethargy or in coma or who were initially alert and then deteriorated, an airway should be established, preferably with endotracheal intubation, and oxygenation to Po, of 100 to 150 mm Hg should be maintained. If the patient undergoes surgery, ventilation should be reversed slowly over a period of 2 to 3 days. ICP monitoring should be considered in patients with a Glasgow Score below 9. The management of increased ICP includes the use of hyperventilation (to produce hypocarbia of Pa, of 25 to 30 mm Hg, which effectively reduces ICP by producing cerebral vasoconstriction)and osmotic diuretics (mannitol) that reduce cerebral volume (and ICP) by causing a shift in water from the cerebral to the intravascular space. Mannitol also improves circulation by decreasing blood viscosity. Keeping osmolality between 310 and 320 is effective and safe. The ICP target should be less than 20 cm H,O. Euvolemia should be maintained with administration of 0.9% normal saline. The value of corticosteroids (e.g., dexamethasone)in improving outcome by reducing ICP has not been proven because their potential beneficial effects often are offset by their systemic complications. Electrolytes and osmolality should be controlled with special attention to sodium and the occurrence of the syndrome of inappropriate secretion of antidiuretic hormone. Many patients with ICH may present with markedly elevated blood pressure. It is often impossible to determine whether this represents an exacerbation of previously long-standing hypertension or is a reflex response to elevated ICP. In the presence of elevated ICP, excessive reductions of blood pressure in the setting of impaired cerebral autoregulation may substantially reduce cerebral blood flow and cause further deterioration because of added cerebral ischemia. This usually occurs when blood pressure is reduced below 80% of the admission’s mean arterial pressure. An acceptable goal is a mean arterial pressure of

Chapter 34

100 to 120 mm Hg, with special care to avoid abrupt blood pressure changes. Another important therapeutic issue in ICH relates to the choice of surgical or nonsurgical management. As a general rule, hemorrhages that are very large or small usually do not benefit from surgery. In most instances of supratentorial ICH, in particular in thalamic and putaminal locations, surgery may lower morbidity and mortality, but most patients remain severely disabled. The same is true for the primary brainstem (midbrain, pontine, and medullary) hemorrhages, despite the anecdotal reporting of successful surgical treatment in selected instances. The varieties of ICH that are often benefited by surgical intervention are the lobar and especially cerebellar locations. Six randomized studies with 414 patients and a meta-analysis failed to show a definite benefit in favor of surgery for supratentorial ICH. The timing of surgery appears crucial to limit the deleterious effects of early rebleeding and those from toxic substances released by the hematoma. A study comparing surgical and best medical treatment within 12 hours of diagnosis in supratentorial ICH showed only a modest benefit in mortality favoring surgery. The same research center designed a subsequent study limiting the surgical window to 4 hours from clinical onset. The median time to surgery was 3 hours. Six-month mortality was 36%, and the rebleeding rate was 40%, compared with 12% in the patients treated within the 12-hour window. The study was stopped, concluding that ultra-early evacuation exacerbated rebleeding. Another important conclusion from this study is that the patients with maximal removal of hematoma had the best outcome. Prior studies had shown that early removal of a hematoma was successful only if thorough hemostasis could be achieved by identification and ligation of the small bleeding perforator. Other scenarios in which surgery should be considered include evidence of herniation or rapid clinical deterioration; moderatesize hemorrhages in the nondominant hemisphere; hemorrhage in a young patient; hemorrhage caused by a defined surgicallyresectable lesion such as an AVM, cavernous angioma, or aneurysm; and persistently elevated ICP despite adequate medical treatment. Stereotactic surgical techniques and ultrasound-guided endoscopic hematoma evacuation have been used since the 1980s for superficialand deep hemorrhages. A limitation of these techniques

34

rn Subarachnoid Hemorrhage

323

is that it takes a long time to completely evacuate the clot. Some series of patients have shown benefit when stereotactic and endoscopic treatments are used in conjunction with injection of thrombolytics to liquefy the clot and facilitate a more complete aspiration of the hemorrhage. Their effectiveness should be defined with future randomized trials.

SUGGESTED READINGS Barinagarrementeria F, Cantu C Primary medullary hemorrhage: report of four cases and review of the literature. Stroke 25:1684, 1994 Broderick JP, Brott TG, Tomsick T et al: Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg 72: 195, 1990 Caplan LR Intracerebral hemorrhage revisited. Neurology 38:624, 1988 Kase CS, Furlan AJ, Wechsler LR et ak Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT I1 trial. Neurology 521603, 2001 Levine SR, Brust JCM, Futrell N et al: Cerebrovascular complications of the use of the "crack" form of alkaloidal cocaine. N Engl J Med 323699, 1990 Morgenstern LB, Demchuk AM, Kim DH et ak Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology 56:1294, 2001 Panagos PD, Jauch EC, Broderick J P Intracerebral hemorrhage. Emerg Med Clin North Am 20:631,2002 Prasad K, Browman G, Srivastava A et al: Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand 95:103, 1997 RaHdberg JA, Olsson JE, Raidberg C T Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment. Stroke 22:571, 1991 Schutz H, Bodeker FU-I,Damian M et al: Age-related spontaneous intracerebral hematoma in a German community. Stroke 21: 1412, 1990 Wijdicks EFM, Jack C R Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction. Stroke 24:554, 1993 Wijdicks EFM, Schievink WI, Brown RD et al. The dilemma of discontinuation of anticoagulation therapy for patients with intracranial hemorrhage and mechanical heart valves. Neurosurgery 42969, 1998 Woo D, Sauerbeck LR, Kissela BM et ak Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 33: 1190, 2002

Subarachnoid Hemorrhage Carlos S. Kase and Conrado 1. Estol

Many people's greatest fear is to have an aneurysm in the brain. The fear is justified considering the devastating effects of subarachnoid hemorrhage (SAH) secondary to aneurysmal rupture. Preventing S A H is difficult because of the lack of symptoms before aneurysmal rupture, and its treatment is associated with many obstacles related to the complications of S A H and the need for and timing of neurosurgical management.

MECHANISMS SAH is the result of bleeding from arteries and veins that are located close to the brain surface, with accumulation of blood in the basal cisterns and surrounding subarachnoid space. Trauma is the most common cause of S A H . Most (80%) nontraumatic SAHs are caused by rupture of congenital or berry aneurysms, which

Chapter 34

100 to 120 mm Hg, with special care to avoid abrupt blood pressure changes. Another important therapeutic issue in ICH relates to the choice of surgical or nonsurgical management. As a general rule, hemorrhages that are very large or small usually do not benefit from surgery. In most instances of supratentorial ICH, in particular in thalamic and putaminal locations, surgery may lower morbidity and mortality, but most patients remain severely disabled. The same is true for the primary brainstem (midbrain, pontine, and medullary) hemorrhages, despite the anecdotal reporting of successful surgical treatment in selected instances. The varieties of ICH that are often benefited by surgical intervention are the lobar and especially cerebellar locations. Six randomized studies with 414 patients and a meta-analysis failed to show a definite benefit in favor of surgery for supratentorial ICH. The timing of surgery appears crucial to limit the deleterious effects of early rebleeding and those from toxic substances released by the hematoma. A study comparing surgical and best medical treatment within 12 hours of diagnosis in supratentorial ICH showed only a modest benefit in mortality favoring surgery. The same research center designed a subsequent study limiting the surgical window to 4 hours from clinical onset. The median time to surgery was 3 hours. Six-month mortality was 36%, and the rebleeding rate was 40%, compared with 12% in the patients treated within the 12-hour window. The study was stopped, concluding that ultra-early evacuation exacerbated rebleeding. Another important conclusion from this study is that the patients with maximal removal of hematoma had the best outcome. Prior studies had shown that early removal of a hematoma was successful only if thorough hemostasis could be achieved by identification and ligation of the small bleeding perforator. Other scenarios in which surgery should be considered include evidence of herniation or rapid clinical deterioration; moderatesize hemorrhages in the nondominant hemisphere; hemorrhage in a young patient; hemorrhage caused by a defined surgicallyresectable lesion such as an AVM, cavernous angioma, or aneurysm; and persistently elevated ICP despite adequate medical treatment. Stereotactic surgical techniques and ultrasound-guided endoscopic hematoma evacuation have been used since the 1980s for superficialand deep hemorrhages. A limitation of these techniques

34

rn Subarachnoid Hemorrhage

323

is that it takes a long time to completely evacuate the clot. Some series of patients have shown benefit when stereotactic and endoscopic treatments are used in conjunction with injection of thrombolytics to liquefy the clot and facilitate a more complete aspiration of the hemorrhage. Their effectiveness should be defined with future randomized trials.

SUGGESTED READINGS Barinagarrementeria F, Cantu C Primary medullary hemorrhage: report of four cases and review of the literature. Stroke 25:1684, 1994 Broderick JP, Brott TG, Tomsick T et al: Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg 72: 195, 1990 Caplan LR Intracerebral hemorrhage revisited. Neurology 38:624, 1988 Kase CS, Furlan AJ, Wechsler LR et ak Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT I1 trial. Neurology 521603, 2001 Levine SR, Brust JCM, Futrell N et al: Cerebrovascular complications of the use of the "crack" form of alkaloidal cocaine. N Engl J Med 323699, 1990 Morgenstern LB, Demchuk AM, Kim DH et ak Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology 56:1294, 2001 Panagos PD, Jauch EC, Broderick J P Intracerebral hemorrhage. Emerg Med Clin North Am 20:631,2002 Prasad K, Browman G, Srivastava A et al: Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand 95:103, 1997 RaHdberg JA, Olsson JE, Raidberg C T Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment. Stroke 22:571, 1991 Schutz H, Bodeker FU-I,Damian M et al: Age-related spontaneous intracerebral hematoma in a German community. Stroke 21: 1412, 1990 Wijdicks EFM, Jack C R Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction. Stroke 24:554, 1993 Wijdicks EFM, Schievink WI, Brown RD et al. The dilemma of discontinuation of anticoagulation therapy for patients with intracranial hemorrhage and mechanical heart valves. Neurosurgery 42969, 1998 Woo D, Sauerbeck LR, Kissela BM et ak Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 33: 1190, 2002

Subarachnoid Hemorrhage Carlos S. Kase and Conrado 1. Estol

Many people's greatest fear is to have an aneurysm in the brain. The fear is justified considering the devastating effects of subarachnoid hemorrhage (SAH) secondary to aneurysmal rupture. Preventing S A H is difficult because of the lack of symptoms before aneurysmal rupture, and its treatment is associated with many obstacles related to the complications of S A H and the need for and timing of neurosurgical management.

MECHANISMS SAH is the result of bleeding from arteries and veins that are located close to the brain surface, with accumulation of blood in the basal cisterns and surrounding subarachnoid space. Trauma is the most common cause of S A H . Most (80%) nontraumatic SAHs are caused by rupture of congenital or berry aneurysms, which

314

Cerebrovascular Disease

rn

Common Pathogeneses of Stroke

(30%)

(30%)

FIG. 34-1. Frequency of aneurysms of the arteries of the circle of Willis. (From Crowell RM, Zervas NT: Management of intracranial aneurysm. Med Clin North Am 63:695-713, 1979, with permission.)

result from the effects of blood pressure on areas of congenitally malformed and weakened arterial walls, usually at bifurcation sites. Eighty-five percent of aneurysms are distributed in the carotid circulation (35% in the anterior communicating and anterior cerebral arteries, 30% in the internal carotid artery at the origin of the posterior communicating artery, and 20% in the middle cerebral artery [MCA]). The posterior circulation accounts for 15% of aneurysms, and the distribution is 10% at the top of the basilar artery and basilar-superior cerebellar artery junction and 5% in the vertebral artery (VA) at the origin of the posterior inferior cerebellar artery (Fig. 34-1). Other causes of aneurysms include dissection, and cardiac embolism (atrial myxoma and endocarditis). In up to 20% of patients the cause of SAH cannot be determined.

MiscellaneousCauses of Aneurysmal SAH Mycotic Aneurysms. These aneurysms are more appropriately called infectious or bacterial. Infected embolic material from cardiac valves with bacterial endocarditis causes an inflammation in the arterial wall with formation of a focal aneurysmal dilation of the vessel wall. The arteries affected usually are peripheral MCA or ACA branches (see Fig. 31-1).Mycotic aneurysms occur in 2% to 12% of patients with bacterial endocarditis and are multiple in 20% of patients. Therefore, angiography to rule out aneurysms is mandatory with symptoms of SAH or intracranial hemorrhage, and if an aneurysm is diagnosed, follow-up angiography is essential in planning management. Magnetic resonance angiography (MRA) is not adequate for the diagnosis or follow-up of mycotic aneurysms. In the proper clinical context, angiography should also be considered in some patients with bacterial endocar-

ditis and acute focal neurologic symptoms to rule out an infectious aneurysm even in the absence of confirmed intracranial hemorrhage. The treatment is intravenous antibiotics to promote vessel wall healing, and surgery is not encouraged because of vessel wall friability. However, there is controversy as to which of these treatment options is preferable. Angiography should be repeated after one, two, and four months after the diagnosis to assess the evolution of the aneurysm, which is generally toward resolution. It is generally agreed that patients who have a mycotic aneurysm that is more berry-like than fusiform in shape and, either did not disappear or became larger after an appropriate course of intravenous antibiotics, should be treated by surgical clipping of the aneurysm. Aneurysms may also result from embolization to distal MCA branches from atrial myxoma or from choriocarcinoma. They are similar to infectious aneurysms in their peripheral location in the cerebral circulation.

NonaneuysmalSubarachnoid Hemorrhage Not all SAHs are secondary to ruptured aneurysms. Pretruncal (formerly called perimesencephalic) hemorrhage is a condition with a good prognosis in which the SAH is almost exclusively limited to the subarachnoid space in front of the pons or midbrain. It accounts for 50% to 75% of all angiogram-negative SAH. The hemorrhage probably arises from capillary or venous bleeding in the pontomesencephalic region. The diagnostic criteria for pretruncal SAH allow only for accumulation of a minimal amount of blood adjacent to the sylvian fissure and in the occipital horns. The type of evolution is an uncomplicated clinical course with no risk of rebleeding and almost no incidence of vasospasm. Loss of consciousness and sentinel headache are exceptional. An

Chapter 34 w Subarachnoid Hemorrhage

angiogram should be obtained as part of the initial workup to rule out the alternative diagnosis of ruptured aneurysm of the top of the basilar artery. However, if the study is negative for aneurysm, a second angiogram is not indicated. Aggressive therapy (triple “H,” calcium channel blockers, anticonvulsants, surgery) is not necessary.

EPIDEMIOLOGY Intracranial hemorrhages account for approximately 15% of all strokes. SAH represents approximately one-third of these hemorrhages. In the United States, 30,000 aneurysmal hemorrhages occur each year. According to autopsy data, approximately 5% of the population harbor intracranial aneurysms. Death occurs in 15% of patients before arrival at the hospital, and more than 50% die within the first month. The main causes of mortality during the first 2 weeks are the direct effects of the initial hemorrhage, rebleeding, and vasospasm. Among the patients who survive, 50% are left with neurologic sequelae that prevent them from regaining employment, and only 30% have a good outcome.

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berry, or saccular aneurysms. Although their exact mechanism of origin has not been clearly defined, they probably develop during life in areas of congenitally malformed arteries. Others have proposed that aneurysms are lesions acquired during life that form in areas where the internal elastic lamina has suffered degenerative changes secondary to atherosclerosis.This theory also implies that coexisting medial defects, acquired or congenital, are necessary for aneurysm formation. Chronic hypertension and cigarette smoking are thought to be predisposing factors for aneurysmal growth. Fusiform or dolichoectatic aneurysms are elongated, tortuous, and dilated segments of arteries. These abnormal vessels often are associated with atherosclerotic changes in older adults with hypertension. In some patients, especially the young, these aneurysms may result from structural abnormalities in the vessel wall in the absence of atherosclerosis. Fusiform aneurysms can affect any of the main intracerebral vessels, but they are more common in the vertebrobasilar system. These aneurysms (especially those in the posterior circulation) often cause symptoms through either mass effect on adjacent structures or ischemia from embolic material dislodged from the wall, causing occlusion of distal branches.

PATHOGENESIS

CLINICAL FEATURES

Aneurysm is the abnormal dilation of an arterial segment. Because the tension in the wall increases proportionally to the vessel’s radius, the risk of arterial rupture is greater with increasing diameter of the aneurysm. This observation refutes the old notion that giant aneurysms are less likely to rupture than small ones; recent data suggest that giant aneurysms (greater than 2.5 cm; Fig. 34-2) have a high risk of rupture. They represent 3% to 5% of all intracranial aneurysms and are more common in women. They also carry a risk of ischemic infarction or transient ischemic attacks resulting from embolization of intra-aneurysmal thrombus into arteries distal to the aneurysm. These aneurysms can also present with mass effect, especially in the brainstem. The most common aneurysms are the so-called congenital,

Few symptoms in neurology have received as much attention as the headache of SAH. The most typical is that described as “the worst headache in the patient’s life,” but less severe headaches may represent slight leaking from aneurysms (which could even occur within the wall of the aneurysm without blood entering the subarachnoid space). The so-called sentinel headache, which is of sudden onset but transient, often is the prologue to the major episode of S A H and occurs in 50% of patients during the 3 weeks preceding the SAH. In one-third of patients, the site of the headache may help localize the aneurysm. However, some conditions with severe headache are not related to SAH, such as the “thunderclap headache,” the headache associated with arterial dissection, and benign orgasmic headache. Even in these latter situations, one cannot overemphasizethe importance of obtaining a cerebrospinal fluid (CSF) sample and computed tomographic (CT) scan to rule out SAH in questionable cases. Reasons for misdiagnosis of S A H include minimizing the diagnostic value of headache when it subsides spontaneously or with common analgesics, attributing the symptoms to a diagnosis of viral encephalitis, and treating the headache as trauma-induced in a patient whose primary event was an S A H with a subsequent fall. In about 30% of cases, the patient loses consciousness at the time of onset of S A H as a result of the sudden increase in intracranial pressure. Many patients regain consciousness after a few minutes or hours and remain obtunded. Coma may occur in patients with persistent elevation of intracranial pressure, with a large associated intracerebral hemorrhage, or with hydrocephalus. Neurologic examination may reveal a wide spectrum of signs, varying from normal to a deeply comatose patient with no brainstem function. Certain findings help localize the aneurysm, such as a third nerve palsy with a dilated pupil caused by an aneurysm of the internal carotid artery at the junction with the posterior communicating artery. Involvement of other cranial nerves can cause visual loss (optic nerve and chiasm), diplopia (sixth nerve), or facial pain (trigeminal nerve). Neck stiffness and a positive Brudzinski’s sign (hip and knee flexion upon flexing the patient’s neck) also are cardinal signs in patients with SAH. However, it is important to know that irritation of cervical roots

FIG. 54-2. Arteriogram with giant aneurysm of the left internal carotid artely. (Courtesy of Shripad Tilak, MD, Department of Radiology, Boston Medical Center, Boston, MA.)

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rn TABLE34-1. The Hunt-Hess Classification of SAH Grade.

Descrimtion

Unruptured aneurysm Asymptomatic or mild headache and slight nuchal rigidity la No acute meningeal or brain reaction but fixed neurological deficit 2 Cranial nerve palsy (i.e., third nerve palsy), moderate to severe headache, and nuchal rigidity 3 Mild focal deficit and lethargy or confusion Stupor, moderate to severe hemiparesis, and early decerebrate 4 riniditv 5 Deep coma, decerebrate rigidity, and moribund appearance ‘Add one grade for serious systemic disease and for severe vasospasm 0 1

by the subarachnoid blood can take a few hours to develop and that a supple neck on early examination does not exclude SAH. On funduscopic examination, subhyaloid hemorrhages are seen in 25% of patients. They are located in proximity to the optic disk and are caused by increased intracranial pressure interfering with the venous outflow from the eye. These hemorrhages appear to have a fluid level and result from accumulation of blood anterior to the retina. Subhyaloid hemorrhages may extend into the vitreous humor (Terson’s syndrome), and their presence is associated with a poor outcome from the SAH.

Systemic Diseases and lntracranialAneurysms Some systemic disorders are associated with an increased incidence of intracranial aneurysms. These include coarctation of the aorta, autosomal dominant polycystic kidney disease ( M U screening is favored in these patients because of their greater risk of renal failure from angiography), Marfan’s syndrome, fibromuscular dysplasia (with greater incidence of cerebral aneurysms in aortic, cervical, and intracranial locations than in the kidney), arteriovenous malformations, moyamoya disease, Ehlers-Danlos syndrome (type IV), and Rendu-Osler-Weber syndrome. The recognition of these disorders and their association with cerebral aneurysms may help in diagnosis at the asymptomatic, prerupture stage, allowing treatment before a potentially devastating S A H .

DIAGNOSIS The single most important issue in diagnosing SAH is a high index of suspicion for the condition. Up to 4% of patients evaluated in the emergency room for headache have SAH. Studies have shown that up to 25% of patients with SAH have been discharged home from emergency rooms with a diagnosis of benign headache. Misdiagnosis is common in patients with minor symptoms and a normal examination. Unfortunately, these undiagnosed patients with a “benign” initial presentation are the most likely to benefit from early treatment. In patients presenting with a sudden, severe headache (even if it is not the worst headache of their lives), a CT scan or lumbar puncture (LP) should be done.

Computed Tomography The first diagnostic step should be a noncontrast CT. Subarachnoid blood is seen in the majority of cases on the day of SAH (Fig. 34-3), but 4% of scans may show no blood in the subarachnoid spaces when bleeding has been slight. Also, the sensitivity of CT declines with time, to 90% after day 1,80% after day 5,50% after week 1, and 30% after week 2, with most CTs showing no subarachnoid blood after week 3. Thin (3-mm) cuts are necessary in the posterior fossa to avoid missing small blood accumulations and to help differentiate bone from blood, which have similar density. In patients with severe anemia (hematocrit lower than 20%), blood may become isodense with the parenchyma, limiting the diagnostic value of CT. Patient agitation is another source of

Grading Scales In dealing with a disease such as SAH, which has a varied prognosis and several serious complications, it is useful to classify patients in clinical subgroups that predict outcomes. This has led to the creation of several clinical scales. An additional value of these scales is for comparison of patients from different series to assess treatment strategies. The most widely used scale is that of Hunt and Hess, which grades the patient’s condition based on the presence of headache and other meningeal signs, mental status, and focal neurologic deficits (Table 34-1). Patients in grades 0 and 1 are candidates for early aneurysmal clipping (within the first 72 hours); grade 2 patients may also be considered for early surgery; grade 3 patients should be treated medically until an improvement to grade 1 or 2 occurs, making them candidates for surgery; patients in grades 4 and 5 have a poor prognosis, and they are usually not candidates for surgical treatment. However, in a retrospective analysis, some grade 4 and 5 patients had good outcomes, arguing for a more aggressive surgical approach in these groups.

FIG. 34-3. CT of acute subarachnoid hemorrhage showing diffuse distribution of blood in the basal cisterns and sylvian fissures. (Courtesy of Shripad Tilak, MD, Department of Radiology, Boston Medical Center, Boston, MA.)

Chapter 34

TABLE 34-2. Fisher's Grading System for Assessing the Amount of Blood in the Subarachnoid Space

in Patients with SAH Fisher

Group

Blood on CT

1 2 3 4

No subarachnoid blood Diffuse or vertical layers <1 mm thick Localized clot or vertical layer >1 mrn

lntracerebral or intraventricular clot with diffuse or no SAH

artifacts that compromise CT interpretation. Measurement of blood on CT in the grading system of Fisher has predictive value for the occurrence of vasospasm (Table 34-2). Contrast administration may show the aneurysm (especiallyif its diameter is greater than 10 mm) and most arteriovenous malformations. The CT distribution of the SAH can predict the location of the aneurysm in approximately 70% of cases: Greater accumulation of blood in the interhemispheric fissure suggests an anterior communicating artery aneurysm, blood in the sylvian fissure correlates with MCA aneurysm, and a lateralized SAH at the chiasmatic cistern suggests a posterior communicating artery aneurysm. Basilar artery aneurysms and the benign form of pretruncal SAH result in accumulation of blood in the entire suprasellar cistern, mimicking the distribution of blood from anterior circulation aneurysms. CT can also show parenchymal blood, which is often (in 20% to 40% of cases) associated with certain aneurysm sites; temporal lobe hemorrhage suggests a posterior communicating artery or MCA aneurysm rupture, and frontal lobe hemorrhage is associated with anterior cerebral artery or anterior communicating artery aneurysms. Intraventricular extension of blood (seen in 20% of patients) is associated with obstructive hydrocephalus if the third ventricle is involved; on the other hand, the pooling of blood in the occipital horns may reflect only the effect of gravity, and it has no prognostic value. An important nonhemorrhagic finding in CT is hydrocephalus. A baseline CT with normal ventricular size can be followed for the development of hydrocephalus, which at times may explain the onset of clinical deterioration in the absence of rebleeding.

Subarachnoid Hemorrhage

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a white background under good illumination. Another option is to perform a second LP one intervertebral level above the initial tap and if red blood cells are not found, then the first attempt can be considered traumatic. Timing of the lumbar Puncture. A false-negative result for CSF xanthochromia is possible if the CSF is analyzed too early after SAH. Pigments are released from the red blood cells no earlier than 2 hours after the bleeding; to be certain about absence of xanthochromia, the lumbar puncture should be delayed for 6 to 12 hours after the hemorrhage. In the event of a negative CT in a patient suspected of having an S A H , the lumbar puncture should be performed after at least 6 hours have elapsed from headache onset. It should be kept in mind that as these recommended waiting times elapse, the risk of early rebleeding increases (in one study the highest risk of rebleeding occurred in the first 6 hours after SAH); for this reason, while awaiting the diagnostic LP, patients must be treated as having SAH. Two weeks after an SAH, the LP is likely to be negative. Magnetic Resonance lmadng

Magnetic resonance imaging (MRI) is not a useful diagnostic tool in the first few hours after SAH because hemorrhages are isointense (i.e., not visible) because of the presence of deoxyhemoglobin and the absence of methemoglobin in the CSF. After the first few days, the presence of methemoglobin in the subarachnoid blood turns the subarachnoid space hyperintense on T1-weighted sequences. In the chronic stage, the accumulation of hemosiderin gives a hypointense signal to the subarachnoid space on both MRI sequences. MRI is also useful in detecting aneurysms and arteriovenous malformations, and it is the ideal imaging technique to visualize the true size of giant aneurysms, which is often underestimated in angiography in cases of partial intraluminal filling with thrombus. MRA is an appropriate screening method for patients with systemic diseases that predispose to aneurysm formation and for siblings in cases of familial aneurysms. MRA has a sensitivity of up to 90% in detecting aneurysms greater than 3 mm in diameter and an approximate false-positive rate of 15%. Transcranial Doppler

Lumbar Puncture

LP should be performed in every patient suspected of having SAH, including those with a clinical suspicion of S A H and a CT that is negative for the presence of blood in the subarachnoid space. LP can be useful in the diagnosis and follow-up of patients with SAH. Serial lumbar punctures may confirm improvement with progressive reabsorption of the blood in the subarachnoid space. In addition, if rebleeding is suspected, an increase in the amount of red blood cells may help confirm the diagnosis in the presence of equivocal CT results. When Is a Tap Traumatic? Approximately 20% of LPs are traumatic. The notion that a decreasing number of red blood cells in successive tubes supports the diagnosis of a traumatic puncture is correct but has too many exceptions to be a useful rule. The only reliable way to confirm SAH is to spin the tube with bloody CSF and examine the supernatant with a spectrophotometer to search for xanthochromia (dark yellow color), which reflects the presence of bilirubin and other pigments released by the prior occurrence of bleeding. When a spectrophotometeris not available,a less reliable method of assessing xanthochromia of the CSF supernatant is to compare it visually with a tube containing water or saline against

Transcranial Doppler (TCD) is an underused technology that can easily and accurately detect vasospasm in patients with SAH. It also has unique value for follow-up of vasospasm to guide treatment. The Lindegaard ratio is obtained from the middle cerebral and internal carotid arteries' mean velocities. With an MCA velocity between 150 and 200 cmhecond, the ratio is greater than 5 and is diagnostic of vasospasm. AndograPhY

In most cases, cerebral angiography provides information about the location and size of an aneurysm and the presence of vasospasm. In up to 15% of cases, the angiogram may appear negative, but this may result from an inadequate study without the special (oblique) views needed to locate an aneurysm. If an aneurysm is identified after first injecting the suspected artery, the other arteries should be surveyed to rule out multiple aneurysms, which are present in 20% to 25% of patients presenting with aneurysmal SAH. When multiple aneurysms are found on angiography, helpful hints that point to the one that bled include the largest aneurysm, the one closest to the greatest amount of

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subarachnoid blood, the one related to vessels that may be affected by vasospasm, and the one with an irregular shape. Both posterior-inferior cerebellar arteries must be imaged because 2% of aneurysms affect these arteries; in addition, filling through the anterior communicating artery is necessary to exclude aneurysms of this segment. Giant aneurysms may be missed on angiography when they are filled with thrombus. A comparison of angiography with MRI is useful in determining the presence of thrombus inside the aneurysm. Aneurysmal SAH with Negative Angiography. Angiography may be negative in cases of aneurysmal SAH for different reasons: The aneurysm may decrease in size or may be accompanied by spasm of its parent artery, resulting in poor filling and visualization; surrounding blood clots may exert mass effect that obliterates the aneurysm; blood in the neck of the aneurysm may clot, preventing dye from entering the aneurysmal sac; and bleeding may be secondary to an aneurysm that is too small to be visualized by angiography. An MRI or CT may reveal the source of bleeding in these patients. Most studies suggest that if aneurysms are not found after properly performed panangiography, the risk of recurrent bleeding or vasospasm is very low. If the initial angiogram is negative, we recommend repeat angiography after 10 to 15 days, and a third study should be considered a few weeks later if the index of suspicion remains high after two negative studies. A second angiogram is more likely to reveal an aneurysm in patients who had a large amount of blood on the initial CT scan. If clinically justified, a spinal MRI or angiography may show an arteriovenous malformation that presented as SAH. Young, nonhypertensive men are the patients most likely to have SAH with a negative angiogram.

COMPLlCAllONS Rebleeding The risk of rebleeding is greatest in the first few hours after the initial hemorrhage, and its actual frequency may be underestimated because of the difficulty in separating early rebleeding from the effects of the initial hemorrhage, especially in patients who are stuporous or have a high Hunt and Hess grade. The risk of rebleeding approaches 4% in the first day, decreasing to 1.5% per day during the next 2 weeks (20% in the first 2 weeks), reaching 50% in the first 6 months, and maintaining a plateau of 3% per year thereafter. Patients with a high Hunt and Hess grade on admission have higher rebleeding rates. The mortality rate from rebleeding can be as high as 90%. Vasospasm Vasospasm is sustained constriction of basal cerebral arteries, generally in the vicinities of the ruptured aneurysm, but sometimes it is widespread. Its main effect is ischemic cerebral infarction. Vasospasm uncommonly occurs earlier than the third day after SAH, has its peak frequency on day 7, and rarely occurs after day 17. This complication carries a 7% mortality and an even higher rate of permanent neurologic disability. The pathogenesis of vasospasm remains unsettled, It is in part the result of the vasoactive effects of various substances released into the subarachnoid space as a consequence of the SAH. These include prostaglandins, free radicals, epinephrine, and oxyhemoglobin. Although vasospasm usually is reversible, some of the vascular changes may be permanent, resulting in structural

changes in the arterial wall. Neuropathologic studies in the first few days of vasospasm have shown an inflammatory reaction in the adventitia, smooth muscle necrosis in the media with involvement of the elastic lamina, and swelling of intimal cells with an increase in the intercellular distance and loss of endothelial tight junctions. These changes are caused by a combination of stimuli that include the vasoactive substances, alteration of the endothelium-derived relaxing factor, and immunologically mediated phenomena. Vasospasm usually affects the vessels closest to the area of bleeding and is most severe in the presence of large clots in the subarachnoid space. It is present on angiography in 50% to 70% of patients in the first 2 weeks after SAH (Fig. 34-4), subsiding after about 3 to 4 weeks. However, angiographically identified vasospasm is clinically symptomatic in up to 30% of patients. The use of TCD has greatly facilitated the diagnosis and follow-up of vasospasm. This noninvasive technique can be repeated often and is easily performed at the bedside. Important limitations of this technique are that it is highly operator-dependent and that the transcranial windows may not be permeable to the ultrasound in about 10% of older adults. The clinical presentation of vasospasm usually is marked by a decrease in the level of consciousness and focal neurologic signs. Because ischemia is the clinical hallmark, patients may have any of the ischemic syndromes that relate to the arterial territory affected.

Hydrocephalus Hydrocephalus can be found in the first few hours after SAH, and its presence correlates with increasing age, hypertension, a large accumulation of subarachnoid blood, or aneurysms located in the posterior circulation. Subacute hydrocephalus occurs after the first week and chronic hydrocephalus after a few weeks or months. In the acute cases, CSF drainage can be life-saving, and shunt placement should be considered despite the fact that it may be associated with an increased risk of rebleeding. Seizures

Seizures occur in 25% of patients with SAH, usually in the early stages of the hemorrhage. In the absence of acute seizures, fewer than 5% of patients develop them later. There is no consensus on whether to give prophylactic anticonvulsants to patients with SAH, but, based on the potential for catastrophic aneurysmal rebleeding in the event of a seizure, their use is favored. An intravenous loading dose of phenytoin (17 mg/kg administered not faster than 50 mg/minute) followed by 300 mg/day is recommended. Phenobarbital, at a dosage of 90 to 120 mg/day, is an effective anticonvulsant and may also be useful as a mild sedative.

Hyponatremia Hyponatremia may produce an encephalopathy and can precipitate seizures, complicating the course of SAH. Determining the cause of hyponatremia in SAH may be difficult and presents a treatment dilemma. On one hand, it can result from the syndrome of inappropriate secretion of antidiuretic hormone, which improves with water restriction. On the other hand, hyponatremia after SAH is more often caused by sodium loss with hypovolemia (cerebral salt wasting syndrome), and treatment with water restriction may cause dehydration and worsen the ischemic effects

Chapter 34

rn Subarachnoid Hemorrhage

329

B

A

D C

FIG. 34-4. (A) Right carotid angiogram with marked spasm of the proximal anterior and middle cerebral arteries (arrows); note paucity of flow in the distal anterior cerebral artery branches. (B) Marked spasm in left anterior and middle cerebral arteries (arrows). (C) CT with infarction in the right middle cerebral artery (curved arrow) and left anterior cerebral artery (arrow) territories. (0)Large infarct in the right anterior cerebral artery territory.

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Common Pathogenesesof Stroke

of vasospasm. The distinction between these two conditions can be made with clinical (presence of dehydration or hypovolemia) and laboratory (serum and urinary sodium levels and osmolality) information, although values may be similar in both conditions. Depending on the degree of hyponatremia, treatment includes increased oral salt intake, intravenous normal saline, or, rarely, hypertonic saline. Usually, establishing normovolemia corrects the hyponatremia. A circulating digoxinlike substance or the atrial natriuretic factor may be related to the occurrence of hyponatremia in patients with SAH.

Cardiac Complications A number of electrocardiogram changes can occur in up to 90% of patients as a result of SAH. Changes in the ST segment and T wave (“waterfall Ts”), Q waves, sinus arrhythmia, and prolongation of the QT segment are common. Life-threateningtorsades de pointes, ventricular tachycardia, and ventricular fibrillation can also occur. Most arrhythmias are reversible, although myocardial ischemia from massive hypersympatheticdischarge can result in necrosis of myocardial fibers. The cause of this abnormal autonomic response is thought to be hypothalamic injury from the acute SAH. A few patients may develop a “stunned” myocardium with ventricular hypokinesis within the first week after S A H , followed by complete recovery.

TREATMENT General Medical Treatment The patient with SAH should always be admitted to an intensive care unit. The environment should be quiet, and absolute bed rest is essential. After 5 days, the patient is allowed to use a bedside commode. Stool softeners are prescribed routinely to prevent constipation and straining. Most management strategies depend on the patient’s initial condition. The most frequently used measures are regular recording of vital signs, neurologic checks, intake and output monitoring, daily laboratory tests (arterial blood gases and serum sodium level), intravenous fluids (0.45% saline and 59/0 dextrose in water at 100 mL/hour), nasal oxygen (some patients are intubated), cardiac monitoring, arterial and central lines, prophylactic anticonvulsants, antiemetics, dexamethasone, and analgesics (codeine) as needed. Treatment with volume expansion and hemodilution should be considered in patients at risk of vasospasm as determined by the Fisher’s grading scale or TCD velocities, even if they are in a good clinical state.

some carry a high risk of aneurysmal rupture if surgical clipping has not been performed in the first few days after the hemorrhage. The treatment modalities used to counteract the effects of vasospasm include the following:

Pharrnacologic agents. The partially cerebral-selectivevasodilator calcium channel blocker nimodipine in an oral dosage of 60 mg every 4 hours (started within 4 days of onset of SAH and continued for 21 days) has been effective in improving neurologic outcome. Although it has not been shown to reverse angiographic vasospasm, it may produce its beneficial effects through improvement in leptomeningeal collateral circulation, decreased platelet aggregation, increased red cell deformability, and a neuroprotective effect mediated by limitation of entry of calcium into neurons. Potential side effects include hypotension, renal failure, and pulmonary edema. Induced hypertension. The first step should be to produce volume expansion with colloids. Then, medications to increase blood pressure, such as dopamine in a 4 pg/kg/hour dosage or phenylephrine, can be administered.The aim is to reach a mean blood pressure of 140 mm Hg. This therapy carries a risk of aneurysmal rupture in nonoperated patients, in whom maximal systolic pressure should not exceed 160 mm Hg. Hernodilution. Using albumin or other colloids may improve circulation through the narrowed vessels. A hematocrit around 33 _+ 3% is ideal because it improves blood flow (via a decrease in blood viscosity) without compromising the oxygen-carrying capacity of the blood. An indwelling Foley catheter and an arterial line are necessary to monitor hypertensive, hemodilution, and hypervolemic therapies. Mechanical measures. In recent years, interventional neuroradiologic techniques have offered new treatment options for patients with aneurysmal SAH. Vasospasm may be mechanically reversed by introducing a balloon in the artery (in a way similar to that of coronary angioplasty) and then inflating it until vessel dilation is achieved. Angioplasty is particularly indicated for patients who fail to respond to the pharmacologic and rheologic measures just described. The simultaneous use of papaverine may help achieve dilation of distal vessels not reachable with the catheter. This procedure should be performed by experienced operators. With the use of the new, softer balloons, the risk of rupture of the angioplastied artery has declined.

AntMbrlnolytic Therapy Although antifibrinolytictherapy is effective in decreasing the risk of rebleeding, its use is not recommended because of several serious complications. hinocaproic acid and tranexamic acid are associated with an increased incidence of vasospasm and ischemic infarction, hydrocephalus, and other complications presumably related to a hypercoagulable state.

Vasospasm Vasospasm is the most important cause of death after SAH. Treatment of vasospasm is directed at augmenting blood flow in the affected areas. This goal can be achieved in several ways, but

The decision to perform surgery early (first 3 days) or late (after the tenth day) is controversial. The principal advantage of early clipping of the aneurysm is rebleeding prevention. The disadvantages include the surgical difficulties of operating on an acutely injured brain with the risk of rupturing the aneurysm or inducing vasospasm from surgical manipulation. However, advances in neuroanesthesia have improved the local surgical field, and the possibility of washing the subarachnoid space free of clot or even using thrombolytic agents to achieve this may reduce later vasospasm. Delayed surgery allows time for the patient to stabilizeclinically and for the brain to recover partially from the initial hemorrhage,

Chapter 34 H Subarachnoid Hemorrhage

but disastrous rebleeding may occur in the interim. Surgery is technically easier in the nonacute stage of SAH because there is better definition of anatomic landmarks and the aneurysm is less susceptible to rupture during the surgery. This controversy was partially resolved by the results of the Cooperative Study on the Timing of Aneurysm Surgery, which showed that early and delayed surgery are associated with similar mortality rates at 6 months. However, functional outcome was significantly better for the early surgery group. Other findings of this trial included poor results that occurred when surgery was performed between days 5 and 10 because of an increased frequency of vasospasm and cerebral infarction. Delayed surgery is indicated in patients with a poor clinical status (Hunt and Hess grade 4 or more), evidence of vasospasm on admission, active medical complications, giant aneurysms, or aneurysms of the top of the basilar artery. Early surgery with clipping of the aneurysm allows safe, aggressive treatment of vasospasm with induced hypertension and volume expansion. We favor early surgery in patients who present with a Hunt and Hess grade 1 or 2 and who have none of the contraindications described here. Surgery Versus EndovascularTreatment Aneurysms of the top of the basilar artery have a lower rate of complications with coiling, in comparison with the approximately 20% morbidity reported with surgery. Other aneurysms along the course of the basilar artery probably are best managed with endovascular treatment. However, aneurysms in the vertebral artery or posterior-inferior cerebellar artery and most in the anterior circulation can be clipped surgically with low complication rates. The exception is patients with a poor neurologic condition in whom a swollen, hyperemic brain limits appropriate exposure of the aneurysm. The recently completed ISAT (International Subarachnoid Aneurysm Trial) study included patients with predominantly anterior circulation and relatively small (93% were 10 mm or smaller in diameter) aneurysms who were randomized to surgical clipping or endovascular coiling. The long-term ( 1-year) outcome, measured as death or dependence, was significantly better in those patients treated with endovascular coiling. The results of this trial, although not necessarily applicable to the whole population of ruptured aneurysms, are likely to result in an increased use of endovascular treatment techniques.

UNRUPTURED ANEURYSM DETECTED INCIDENTALLY OR DURING EVALUATION OF A HIGH-RISK PATIENT A decision to treat an incidental, unruptured aneurysm surgically must weigh the natural history of the risk of rupture (and its consequences) against the surgical morbidity and mortality rates. For aneurysms less than 10 mm, the annual risk of rupture has been reported to range from 0% to 4%, and it is greater if the aneurysm is larger. Surgical treatment by experienced surgeons has been accomplished with a low mortality rate of 0% to 1%, and a morbidity rate of up to 14%. The surgical risks are greater with older age, larger aneurysms, and those located at the carotid bifurcation, with intermediate risks for MCA, ophthalmic artery, and anterior communicating artery aneurysms, and the lowest risk for internal carotid artery-posterior communicating aneurysms. A recent study showed that the rupture risk of an aneurysm

33 1

smaller than 10 mm is less than 0.05% per year, supporting a more conservative approach in these patients. However, the patient’s age at diagnosis is an important variable for decision analysis, and it would be reasonable to recommend surgery for a 20-year-old patient even if the aneurysm is 7 mm in diameter, whereas follow-up with MRA would be advised for the same size aneurysm in a 65-year-old person. On the other hand, surgery would be recommended for a 70-year-old person if the aneurysm is greater than 10 mm in diameter.

SUBARACHNOID HEMORRHAGE AND PREGNANCY Although previous opinions suggested an increased frequency of aneurysmal rupture in the third trimester, the rate probably is similar throughout pregnancy. Rupture is more common in multiparous women. The hypervolemia of pregnancy and the stress of delivery increase the risk of aneurysmal rupture. Decisions about treatment are made as in any other patient with SAH. CT and angiography should be performed using abdominal shielding to protect the fetus. If the patient is in favorable neurologic and general clinical condition, early surgery should be performed. Fetal maturation should be initiated on admission, especially if the episode occurs early in the third trimester. Cesarean section is performed with epidural anesthesia followed immediately by general anesthesia for aneurysm clipping. There is no strong evidence suggesting a better outcome with cesarean section than with vaginal delivery. The latter could be an option, using epidural anesthesia to reduce the risk of rebleeding. Earlier pregnancy with a nonviable fetus should not delay surgery, and clipping of the aneurysm should be done under general anesthesia, avoiding hypotension, with the mother in the lateral decubitus position to minimize the compromise of fetal circulation. There are no contraindications to the use of nimodipine to prevent vasospasm, although cautious fetal monitoring is advised to detect the fetal acidosis syndrome and myocardial depression. The physiologic volume expansion of pregnancy may help in limiting the ischemic effects of vasospasm. Unruptured aneurysms should be treated surgically if they are larger than 10 mm in diameter; otherwise, surgical clipping should take place after delivery.

SUGGESTED READINGS A d a m H P Calcium antagonists in the management of patients with aneurysmal subarachnoid hemorrhage: a review. Angiology 41:1010, 1990 Dias MS, Sekhar LN: Intracranial hemorrhage from aneurysms and

arteriovenous malformations during pregnancy and the puerperium. Neurosurgery 27:855, 1990 Edlow JA, Caplan L R Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 342:29, 2000 Fisher CM, Kistler JP, Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computed tomographic scanning. Neurosurgery 6:1, 1980 Haley EC, Kassell NF, Torner JC: The International Cooperative Study on the Timing of Aneurysm Surgery: the North American experience. Stroke 23:205, 1992 Hijdra A, van Gijn J, Nagelkerke NJD et ak Prediction of delayed cerebral ischemia, rebleeding and outcome after aneurysmal subarachnoid hemorrhage. Stroke 191250, 1988 International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. Lancet 360 1267, 2002

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Le Row PD, Elliot JP, Newell DW et al. The incidence of surgical complications is similar in good and poor grade patients undergoing repair of ruptured anterior circulation aneurysms: a retrospective review of 355 patients. Neurosurgery 38:887, 1996 Lindegaard KF, Nornes H, Bakke SJ et al: Cerebral vasospasm after subarachnoid hemorrhage investigated by means of transcranial Doppler ultrasound. Acta Neurochir 42:81, 1988 Rinkel GJE, Wijdicks EFM, Vermeulen M et ak Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow up study in 37 patients. Neurology 40:1130, 1990 The International Study Group of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms: risks of rupture and risks of surgical intervention. N Engl J Med 339:1725, I 998

35

van Crevel H, Habbema JDF, Braakman R Decision analysis of the management of incidental intracranial saccular aneurysms. Neurology 361335, 1986

Vermeulen M, van Gijn J: The diagnosis of subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry 53:365, 1990 Wiebers DO, Whisnant JP, OFallon WM: The natural history of unruptured intracranial aneurysms. N Engl J Med 304:696, 1981 Wijdicks EFM, Ropper AH, Hunnicutt EJ et ak Atrial natriuretic factor and salt wasting after aneurysmal subarachnoid hemorrhage. Stroke 22:1519, 1991

Wijdicks EFM, Schievink WI, Vermeulen M et al. Pretruncal nonaneurysma1 subarachnoid hemorrhage. Mayo Clin Proc 735'45, 1998 Wilkins RH: Attempts at prevention or treatment of intracranial arterial spasm: an update. Neurosurgery 18:808, 1986

Vascular Malformations Carlos S. Kase and Conrad0 1. Estol

Vascular malformations correspond to developmentally abnormal vessels that can be of different types, depending on their histologic configuration. The four main types of vascular malformations are arteriovenous malformations (AVMs), cavernous angiomas, venous angiomas, and telangiectasias.

ARTERIOVENOUS MALFORMATIONS AVMs are abnormal tangles of arteries and veins, with one or a group of feeding arteries that end in a central nidus, which drains, without interposed capillaries or brain parenchyma, into enlarged veins (that receive arterialized blood; Fig. 35-1). They are the second most common cause of subarachnoid hemorrhage and occur in a ratio of 1:lO with aneurysms. AVMs are also an important source of intracerebral hemorrhage, especially in patients with lobar or intraventricular hemorrhages. The mortality rate from the first hemorrhage (10%) is lower than that of aneurysmal subarachnoid hemorrhage, as is its morbidity rate (30% to 50%). Vasospasm does not occur after hemorrhages secondary to AVMs; they have a 1.5% to 3% per year bleeding risk, and rebleeding rates are lower than those for aneurysmal rupture. After the presenting hemorrhage, the rebleeding risk spreads evenly at 6% during the first year and plateaus at a 3% per year risk thereafter. Affected patients usually are younger (15 to 20 years) than those with aneurysms with an average age at presentation of 30 years for AVMs and a slight male preponderance. Seven percent of patients with AVMs have coexisting cerebral aneurysms, which are located in the feeding artery in two thirds of the patients. Small AVMs (less than 3 cm) have been found in some studies to have a worse course, with higher bleeding rates attributed to greater pressures in the feeding vessels.

Clinical Findings Hemorrhage is the most common presentation (50%) of AVMs, followed by seizures (25%) and focal neurologic signs secondary to mass effect with or without headaches (25%). Seizures are more common in patients diagnosed at a younger age and can also occur at the time of presentation of hemorrhage. However, the risk of hemorrhage in patients with seizures as the initial symptom is low. Seizures are thought to result in part from

electrical neuronal instability caused by partial focal ischemia, resulting from a steal phenomenon caused by blood shunting in the malformation. This same mechanism explains the occasional observation of ischemia leading to infarction in areas adjacent to an AVM. Headache is a common symptom but does not generally have the intensity described with aneurysmal rupture. It can be chronic and at times difficult to differentiate from migraine with aura, especially in patients with occipital AVMs and accompanying transient visual phenomena, particularly homonymous hemianopia. The prevailing practice is to suspect an AVM in young patients with hemicranial (migraine) headaches that are always located on the same side of the head, never on the opposite side. A bruit often is heard over the scalp with dural AVMs and occasionally with large superficial parenchymal malformations. An AVM located in the cerebellopontine angle may present with trigeminal neuralgia, various brainstem signs or symptoms that mimic an acoustic neuroma.

Diagnosis AVM diagnosis is greatly facilitated by the use of imaging techniques that depict not only the meningocerebral hemorrhage in instances of acute bleeding but also the malformation itself. Computed tomography (CT) scan often shows calcification in the area of the AVM, along with a serpiginous pattern of blood vessels, both arterial and venous, which is best depicted after intravenous contrast infusion. An even better definition of the AVM can be obtained with magnetic resonance imaging (MRI), which often shows the arterial and venous portions of the malformation as flow voids seen in T1-weighted images (Fig. 35-2). Visualizing the more specific characteristics of the malformation, in terms of the anatomy of feeding arteries and draining veins, that is essential to the surgical planning, still entails the use of contrast angiography. A four-vessel study injecting both vertebral and both carotid arteries is necessary to accurately define the complete AVM feeding and draining complex. Multiple imaging views are needed to identify potential aneurysms located in the feeders or in vessels distal to the AVM. Angiography also reveals areas of increased and decreased flow surrounding the AVM. An external carotid artery injection will serve surgical

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Le Row PD, Elliot JP, Newell DW et al. The incidence of surgical complications is similar in good and poor grade patients undergoing repair of ruptured anterior circulation aneurysms: a retrospective review of 355 patients. Neurosurgery 38:887, 1996 Lindegaard KF, Nornes H, Bakke SJ et al: Cerebral vasospasm after subarachnoid hemorrhage investigated by means of transcranial Doppler ultrasound. Acta Neurochir 42:81, 1988 Rinkel GJE, Wijdicks EFM, Vermeulen M et ak Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow up study in 37 patients. Neurology 40:1130, 1990 The International Study Group of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms: risks of rupture and risks of surgical intervention. N Engl J Med 339:1725, I 998

35

van Crevel H, Habbema JDF, Braakman R Decision analysis of the management of incidental intracranial saccular aneurysms. Neurology 361335, 1986

Vermeulen M, van Gijn J: The diagnosis of subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry 53:365, 1990 Wiebers DO, Whisnant JP, OFallon WM: The natural history of unruptured intracranial aneurysms. N Engl J Med 304:696, 1981 Wijdicks EFM, Ropper AH, Hunnicutt EJ et ak Atrial natriuretic factor and salt wasting after aneurysmal subarachnoid hemorrhage. Stroke 22:1519, 1991

Wijdicks EFM, Schievink WI, Vermeulen M et al. Pretruncal nonaneurysma1 subarachnoid hemorrhage. Mayo Clin Proc 735'45, 1998 Wilkins RH: Attempts at prevention or treatment of intracranial arterial spasm: an update. Neurosurgery 18:808, 1986

Vascular Malformations Carlos S. Kase and Conrad0 1. Estol

Vascular malformations correspond to developmentally abnormal vessels that can be of different types, depending on their histologic configuration. The four main types of vascular malformations are arteriovenous malformations (AVMs), cavernous angiomas, venous angiomas, and telangiectasias.

ARTERIOVENOUS MALFORMATIONS AVMs are abnormal tangles of arteries and veins, with one or a group of feeding arteries that end in a central nidus, which drains, without interposed capillaries or brain parenchyma, into enlarged veins (that receive arterialized blood; Fig. 35-1). They are the second most common cause of subarachnoid hemorrhage and occur in a ratio of 1:lO with aneurysms. AVMs are also an important source of intracerebral hemorrhage, especially in patients with lobar or intraventricular hemorrhages. The mortality rate from the first hemorrhage (10%) is lower than that of aneurysmal subarachnoid hemorrhage, as is its morbidity rate (30% to 50%). Vasospasm does not occur after hemorrhages secondary to AVMs; they have a 1.5% to 3% per year bleeding risk, and rebleeding rates are lower than those for aneurysmal rupture. After the presenting hemorrhage, the rebleeding risk spreads evenly at 6% during the first year and plateaus at a 3% per year risk thereafter. Affected patients usually are younger (15 to 20 years) than those with aneurysms with an average age at presentation of 30 years for AVMs and a slight male preponderance. Seven percent of patients with AVMs have coexisting cerebral aneurysms, which are located in the feeding artery in two thirds of the patients. Small AVMs (less than 3 cm) have been found in some studies to have a worse course, with higher bleeding rates attributed to greater pressures in the feeding vessels.

Clinical Findings Hemorrhage is the most common presentation (50%) of AVMs, followed by seizures (25%) and focal neurologic signs secondary to mass effect with or without headaches (25%). Seizures are more common in patients diagnosed at a younger age and can also occur at the time of presentation of hemorrhage. However, the risk of hemorrhage in patients with seizures as the initial symptom is low. Seizures are thought to result in part from

electrical neuronal instability caused by partial focal ischemia, resulting from a steal phenomenon caused by blood shunting in the malformation. This same mechanism explains the occasional observation of ischemia leading to infarction in areas adjacent to an AVM. Headache is a common symptom but does not generally have the intensity described with aneurysmal rupture. It can be chronic and at times difficult to differentiate from migraine with aura, especially in patients with occipital AVMs and accompanying transient visual phenomena, particularly homonymous hemianopia. The prevailing practice is to suspect an AVM in young patients with hemicranial (migraine) headaches that are always located on the same side of the head, never on the opposite side. A bruit often is heard over the scalp with dural AVMs and occasionally with large superficial parenchymal malformations. An AVM located in the cerebellopontine angle may present with trigeminal neuralgia, various brainstem signs or symptoms that mimic an acoustic neuroma.

Diagnosis AVM diagnosis is greatly facilitated by the use of imaging techniques that depict not only the meningocerebral hemorrhage in instances of acute bleeding but also the malformation itself. Computed tomography (CT) scan often shows calcification in the area of the AVM, along with a serpiginous pattern of blood vessels, both arterial and venous, which is best depicted after intravenous contrast infusion. An even better definition of the AVM can be obtained with magnetic resonance imaging (MRI), which often shows the arterial and venous portions of the malformation as flow voids seen in T1-weighted images (Fig. 35-2). Visualizing the more specific characteristics of the malformation, in terms of the anatomy of feeding arteries and draining veins, that is essential to the surgical planning, still entails the use of contrast angiography. A four-vessel study injecting both vertebral and both carotid arteries is necessary to accurately define the complete AVM feeding and draining complex. Multiple imaging views are needed to identify potential aneurysms located in the feeders or in vessels distal to the AVM. Angiography also reveals areas of increased and decreased flow surrounding the AVM. An external carotid artery injection will serve surgical

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Chapter 35 W Vascular Malformations

planning if dural feeders that could be injured in the initial approach are detected. Treatment

The conventional treatment for AVMs has been surgical resection. Ligation of feeding arteries, which carries the risk of brain infarction from ischemia, is limited to major arteries, followed by ligation of the draining veins. The nidus is then isolated from the brain parenchyma and excised en bloc using microsurgical

techniques. In the perioperative period, P-blockers are administered to decrease the risk of breakthrough bleeding when the small vessels left at the surgical site cannot handle the large volumes of blood previously flowing into the malformation. Classifications of AVMs using different variables have been developed to predict the risk of surgical intervention. The Spetzler-Martin grading system is the most popular and assigns a value from I to V according to AVM size, location in eloquent (e.g., language and sensorimotor areas, internal capsule, thalamus, brainstem) or noneloquent regions, and type of venous drainage (superficial only or deep;

A

C

B

FIG. 55-1. (A) Anteroposterior carotid angiogram showing AVM (arrow) fed by distal middle cerebral artery branches. (19) Lateral angiogram of large parietal AVM (arrow) fed by the middle cerebral artery. (C) Arterial phase angiogram with early draining of parietal AVM into the deep venous system and the transverse sinuses. (Courtesy of Shripad Tilak, MD, Department of Radiology, Boston University Medical Center, Boston, MA.)

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A

FIG. 35-2. (A) TI-weighted MRI showing large AVM as multiple flow voids in the right frontal lobe, along with prominent superficial venous channels (arrows). (6) T1-weighted MRI of same AVM in the coronal plane, showing markedly enlarged venous drainage channel in the cerebral surface (arrow) and an arterial feeder originating from the MCA trunk (curved arrow). (Courtesy of Rita Bhatia, MD, Department of Radiology, Boston University Medical Center, Boston, MA.)

TABU35-1.

Spetzler-Martin Grading System for AVMs Size

Small (<3 cm) Medium (3-6 cm) Large (>6 cm)

1 2 3

Eloquence of Adjacent Brain

Noneloquent Eloquent

0 1

Pattern of Venous Drainage

Superficial Deep

0 1

Table 35- 1). Grades I and I1 AVMs are rarely associated with major sequelae, grades 111 and IV have intermediate results, and grade V AVMs have a poor prognosis. In one report, complete excision of Spetzler-Martin grade I to IV AVMs was achieved with a 3.2% rate of major morbidity and 1.3% mortality. Interestingly,a substantial proportion of postoperative deficits were transient and had resolved or improved by 6 months after surgery. The same surgical group had no long-term morbidity and no mortality for AVMs smaller than 3 cm. Embolization techniques are rapidly evolving in the aneurysm and AVM field, although they have not yet replaced conventional surgery. In this technique, microcatheters are advanced to the feeding arteries and nidus to deliver in situ different types of embolic materials. In various series, the mortality rate ranges from 2% to 4%, and major morbidity is 5%. In some AVMs, embolization alone can completely obliterate the malformation; in others, embolization is used to decrease flow into the AVM before microsurgical resection or radiosurgical obliteration. The small,

usually cortical AVMs with one or two arterial feeders that could be completelyobliterated with embolization are more safely, easily, and cost-effectively removed with surgery. Therefore, as a general rule, most AVMs should be treated surgically or in combination with endovascular techniques because of the risk of incomplete occlusion or recanalization with embolization alone. Embolizations should not be repeated in an attempt to obliteratevessels that remain permeable after the first procedure. First, each endovascular treatment carries a significant risk, and available data suggest that because of the acutely induced hemodynamic changes, partially obliterated AVMs have a higher tendency to bleed. In large, high-flow AVMs, embolization as a first step may reduce flow intensity, thus decreasing the risk of perfusion breakthrough. If embolization were the sole treatment used, angiography should be repeated at 6 months to confirm persistent obliteration of the AVM. When the AVM has recanalized, further treatment is indicated because spontaneous occlusion is unlikely. Stereotactic radiosurgery (gamma-knife), developed over the last decade, is an effective method for treating AVMs less than 3 cm in size. Larger AVMs can also be treated with this technique, but the degree of obliteration decreases with increasing lesion size. It should be kept in mind that the obliterating process depends on proliferative endothelial changes, collagen deposition, and vascular wall fibrosis,which are progressive, and usually takes a few years to be completed (100% occlusion in 3 years for AVMs less than 4 cm3, 95% between 4 and 25 cm3, and 70% for those more than 25 cm3). Therefore, patients continue to be at risk of rebleeding during that period of time. In addition, radionecrosis of brain tissue adjacent to the AVM can result in cognitive deficits that are yet to be defined fully. Follow-up studies with MRI more than two decades after radiosurgical treatment have shown asymptomatic

Chapter 35

demyelination or gliosis, cyst formation, and increased T2 signal at the site of AVM treatment. Ideal lesions to treat with radiosurgery are those smaller than 3 cm, with a dense, compact nidus, that affect deep cerebral structures or eloquent brain regions. A commonly used approach is to reduce with embolization a 6-cm AVM to 3 cm, for example, and to then treat the smaller remnant with stereotactic radiosurgery. However, this rationale is likely to result in a treatment failure because small vessels may not be visualized with angiography after embolization, so the nidus that appears reduced actually is larger. Radiation probably will miss these angiographicallyoccult vessels, and the AVM will grow again after some time. Although different combinations of microsurgery, embolization techniques, and radiosurgery are indicated, depending on the lesion’s size and location, some general treatment guidelines are followed. Because most patients are previously healthy young people, we favor an aggressive approach with the goal of total surgical resection of the AVM once the patient has recovered from the initial effects of acute hemorrhage. In older patients and in those with severe deficits from the initial bleeding episode, conservative treatment is favored, with either radiotherapy or embolization techniques. Patients with seizures as the only manifestation of the AVM and those who are fully asymptomatic need to be individualized in terms of the need for treatment, based on the location, size, and anatomy of the AVM. Age is a crucial variable in treatment decisions because for a young patient the lifetime risk of hemorrhage may reach 80% (assuming a 3% annual risk of hemorrhage). If seizures are intractable, surgery should be considered, although AVM resection may not alter an established brain injury that is likely to remain as a seizure focus. Postoperative or intraoperative angiography in selected patients will confirm complete excision of the AVM. If resection has not been complete, a hemorrhagic risk will persist, and further surgery should be planned if the lesion is accessible. In cases of postsurgical deep AVM residua, stereotactic radiosurgery becomes an adequate option. Giant AVMs measuring more than 6 cm are best managed with clinical observation because surgical excision is invariably associated with severe sequelae or death. Patients harboring these giant AVMs can be reassured that they have a lower risk of bleeding than their smaller counterparts. The widespread availability of sophisticated neuroimaging techniques results in more frequent identification of patients with asymptomatic AVMs. These AVMs that are discovered in the absence of hemorrhage are thought to have a substantially lower risk of hemorrhage than those identified as a result of a bleeding episode (2.9% per year v. 11.3% per year). When the origin of the hemorrhage is not clear in patients with an AVM and a coexisting aneurysm, the latter is the likely cause of bleeding and should be operated first. If possible, both vascular malformations should be operated simultaneously.

Dural AVMs and Carotid-Cavernous fistulas These lesions are located in close proximity to the venous sinuses, especially the transverse and sigmoid sinuses. The feeding vessel is most commonly the occipital artery, although branches from the vertebral or carotid arteries can also be feeders. In an unknown number of patients, dural AVMs may be an acquired lesion reflecting revascularization as a result of a previous sinus thrombosis from trauma, infection, or surgery. In contrast to parenchymal AVMs, the dural types usually become symptomatic after age 40 and are more common in

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335

women. Because of their location, they often present with pulsatile tinnitus and an audible bruit (almost all patients), occipital bruit, headache, and visual disturbances. As with any other posterior fossa mass, they can cause papilledema. Their surgical treatment is difficult because of their tendency to bleed profusely. To limit this problem, presurgical embolization often is performed. Direct carotid-cavernousfistulas are an abnormal communication between the cavernous carotid artery and the cavernous sinus as a result of trauma or a ruptured carotid aneurysm. Indirect carotid cavernous fistulas result from abnormal connections between internal and external carotid artery branches and the cavernous sinus. The clinical manifestations are dominated by ocular findings with eye pain, progressive visual loss, diplopia, papilledema, proptosis, and chemosis. These findings are important criteria for treatment. Headache is a common, nonspecific finding. An audible bruit is often described by the patient. Because direct fistulas are high-flow lesions, very few occlude spontaneously. The treatment of choice is endovascular balloon occlusion within the fistula, preserving the carotid artery. In some cases, balloon occlusion of the internal carotid artery cannot be avoided.

Spinal AVMs These malformations merit separate mention because of the importance of their consideration in the differential diagnosis of subarachnoid hemorrhage. In the event of subarachnoid hemorrhage followed by negative angiography for cerebral aneurysm or AVM, a spinal AVM should be considered. Its typical presentation includes abrupt onset of severe back pain and myelopathy (may also cause radiculopathy), but they can also cause headache and other focal neurologic phenomena such as visual changes, ocular nerve palsies, seizures, and loss of consciousness. A slowly progressive spinal cord compression syndrome has also been recognized. Because they are potentially curable, spinal AVMs should always be considered with a high index of suspicion in the differential diagnosis of a progressive myelopathy. Spinal AVMs are classified according to the location of vessels in relation to the spinal cord. The most common type is the dural arteriovenous fistula located in lower thoracic cord with a predilection for men in the fifth and sixth decades. The other types of spinal AVMs (intramedullary, extramedullary, and perimedullary) affect young adults. Cervical and thoracic MRI images clearly depict the intraparenchymal component of abnormal vessels, hemorrhage if present, and the large-flow voids caused by the tortuous dilated veins that surround the spinal cord. Detailed identification of all vessels for surgical planning purposes should be done with conventional angiography. Selective injections of the vertebral, subclavian, and intercostal arteries may be necessary. Spinal AVMs can be successfully treated with microsurgery, endovascular therapy or a combination of both according to the specific type of AVM and angiographic findings. AVMs and Pregnancy

ICH from an AVM is the third most common nonobstetric cause of maternal death during pregnancy. Fifty percent of ICHs during pregnancy are caused by a ruptured AVM. The popular notion that pregnancy increases the risk of bleeding from an AVM probably is incorrect and derives from the fact that most AVMs bleed by age

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40, thus including women in their reproductive years. However, the increased blood volume of pregnancy, especially during the third trimester, a more active fibrinolytic system, and the increase in blood pressure and intracranial pressure of the peripartum period may increase the risk of AVM rupture, especially between the 20th week and the first few weeks postpartum. Pregnancy in a patient with a diagnosed AVM is a management dilemma because the natural history of these lesions is unknown. As is recommended for aneurysms, management guided by neurosurgical (and not obstetric) criteria should be undertaken if AVMs present with bleeding during pregnancy. A rebleeding rate that reaches 26% supports this aggressive approach. Hypotension and osmotic therapy should be limited or preferably avoided to prevent deleterious effects on the fetus. Depending on the anatomic characteristics of the lesion, the most appropriate treatment is selected. Partial treatments with embolization or radiosurgery started during pregnancy can be completed after delivery because no differences in maternal mortality rate have been documented between surgical and nonsurgical treatment. If emergent ICH evacuation is indicated and the fetus is mature, simultaneous neurosurgery and Cesarean section can be performed. Otherwise, surgery can be delayed until 2 months postpartum, when all hemodynamic parameters return to normal. Vaginal delivery is acceptable using epidural anesthesia, although some authors favor Cesarean section. CAVERNOUS ANCIOMAS (CAVERNOMAS) This lesion is characterized by groups of malformed vascular channels without arterial or venous structure, surrounded by connective tissue, without neural tissue in between them. Cavernous angiomas can be single, but in 50% of patients they are multiple, in which case familial incidence is highly likely. In the latter, they are often associated with epilepsy, and the responsible gene has been mapped to chromosome 7. Sporadic cavernomas may originate after brain radiation, at a surgical biopsy site, or from coalescence of telangiectases. Cavernomas can occur in any area of the brain and spinal cord, although they have a predilection for the pons. Their diagnosis is currently made routinely with MRI because of their highly characteristic pattern of a mixed-signal central core surrounded by a low-density hemosiderin ring in T2-weighted sequences (see Fig. 33-1). Clinically, cavernous angiomas present similarly to AWs, causing bleeding at a 1% per year rate, but with lower rebleeding and mortality rates. The exception is cavernomas located in the pons that can reach a rebleeding rate of 20% per year. Seizures and slowly progressive neurologic deficits can also occur, with the latter being a result of repeated episodes of small bleeding, often leading to a misdiagnosis of brain tumor or multiple sclerosis. Seizures are the most common clinical presentation in men, whereas hemorrhage at onset is more common in women. As with AVMs, cavernous angiomas carry a higher rate of re-bleeding (4.5% per year) after presenting with hemorrhage, in comparison with a rate of 0.6% per year when detected after presentations other than hemorrhage. Cavernous angiomas often are incidental findings after contrast CT or MRI. Low-grade gliomas and hemorrhagic metastases should be considered in the differential diagnosis of these images. Cavernomas are not detectable on angiography because of their small size and slow flow. Treatment often is surgical, with efforts to identify and excise the malformation that may not be easily detectable at the time of drainage of an intracerebral hematoma. Hemosiderin should be

meticulously removed in supratentorial cavernomas because it constitutes an epileptogenic focus. In up to 20% of patients cavernomas have an associated venous angioma that should not be touched at surgery. Treatment with the gamma-knife has shown conflicting results: recent series have shown a high rebleeding rate and radiation complications that outweigh the potential benefits of this treatment, while others suggested encouraging results for patients with "high risk" (for surgical resection) lesions. Modern microsurgical techniques with intraoperative neurophysiologic monitoring are allowing the removal of cavernous angiomas in areas of difficult surgical access, such as the pons and thalamus, where these lesions were deemed inoperable in the past. Clinical observation is appropriate in patient with multiple (familial) asymptomatic lesions or in those with a single minimally symptomatic cavernoma. VENOUS ANGIOMAS These lesions are formed by one or more enlarged veins that are most commonly an incidental CT or MRI finding. Angiography shows no abnormal vessels in the arterial and capillary phases, but a characteristic pattern of a cluster of abnormal veins (caput medusae) draining into a larger one in the venous phase of the angiogram is diagnostic of venous angioma. MRI can easily document venous angiomas by showing their characteristic pattern in TI- or T,-weighted sequences (see Fig. 33-2). Because they carry essentially no bleeding risk, they should not be treated. In the rare instances of bleeding associated with venous angiomas, it is now apparent that the cause is an associated cavernous angioma, not the venous angioma itself. In these instances, surgical therapy should be directed only at the cavernous angioma; removal or ligation of the venous angioma is contraindicated because it carries a high risk of postoperative venous hemorrhagic infarction. This is because venous angiomas, despite being malformed vessels, effectively perform the venous drainage in the area of the brain where they are located. TEIANGIECTASIAS These malformations are made of multiple enlarged blood vessels of capillary structure. They rarely cause neurologic deficits of brainstem origin, and they do not tend to bleed. They cannot be diagnosed with angiography because of their small size and slow flow, but they can sometimes be detected by MRI, although telangiectasias are most commonly diagnosed incidentally at autopsy. Occasionally, they are associated with cavernous angiomas in the same area of the brain, generally in the brainstem. Multiple telangiectasias occur as part of the Rendu-Osler-Weber, Sturge-Weber, ataxia-telangiectasia, and other congenital syndromes. Telangiectasias should not be treated. OCCULT VASCULAR MALFORMATIONS The term occult or cryptic refers to vascular malformations that are not identified with available neuroimaging techniques. Approximately 10% of all vascular malformations are not demonstrable despite appropriate use of all imaging modalities. Because angiography is the method with the greatest imaging resolution for vascular anomalies, the more specific term angiographically occult is also used. A few pitfalls during angiography that explain why malformations may not be seen include lack of late films to visualize a venous angioma, no external carotid artery injection,

Chapter 36 W

and a study during the acute stage of a large hemorrhage when mass effect may compress the abnormal vessels. Clinical presentation resembles that of vascular malformations in general, with a slight predominance of headache and seizures over hemorrhage. AVMs and cavernomas are the most common to present as angiographically occult vascular malformations. MRI is likely to show indirect signs with areas of hemosiderin surrounding a heterogeneous core of increased and decreased signal intensity. Surgery is indicated in patients with recurrent bleeding and intractable seizures.

SUGGESTED READINGS Caroscio JT, Brannan T, Budabin M et al: Subarachnoid hemorrhage secondary to spinal arteriovenous malformation and aneurysm. Arch Neurol 37:101, 1980 Gomori JM, Grossman RI, Goldberg HI et ak Occult cerebral vascular malformations: high-field MR imaging. Radiology 158:707, 1986 Hasegawa T, McInerney J, Kondziolka D et al: Long-term results after stereotactic radiosurgery for patients with cavernous malformations. Neurosurgery 5 0 1190, 2002 Heros RC, Korosue K, Diebold PM: Surgical excisions of cerebral arteriovenous malformations: late results. Neurosurgery 26:570, 1990

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Horton JC, Chambers WA, Lyons SL et al: Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations. Neurosurgery 27:867, 1990 Karlsson B, Kihlstrom L, Lindquist C et ak Radiosurgery for cavernous malformations. J Neurosurg 88:293, 1998 Kondziolka D, Lunsford LD, Kestle J R The natural history of cerebral cavernous malformations. J Neurosurg 83:820, 1995 Kondziolka D, Lunsford LD: The case for and against AVM radiosurgery. Clin Neurosurg 48:96, 2001 M a l i GM, Pearce JE, Ausman JL Dural arteriovenous malformations and intracranial hemorrhage. Neurosurgery 15:332, 1984 Ogilvy CS, Stieg PE, Awad I et ak Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke 32:1458, 2001 Rigamonti D, Hadley MN, Drayer BP et al: Cerebral cavernous malformations: incidence and familial occurrence. N Engl J Med 319343, 1988 Spetzler RF, Martin NA A proposed grading system for arteriovenous malformations. J Neurosurg 65:476, 1986 Steinberg GK, Fabrikant JI, Marks MP et al: Stereotactic heavy charged particle Bragg-peak radiation for intracranial arteriovenousmalformations. N Engl J Med 323:96, 1990 The Arteriovenous Malformation Study Group: Arteriovenous malformations of the brain in adults. N Engl J Med 340:1812, 1999

3 LESS COMMON CAUSES OF STROKE

36

Stroke in Young Adults Betsy B. Love and Jos6 Biller

Stroke is the third leading cause of death in the United States, accounting for 1 in 15 deaths in 1998. According to recent estimates, there are at least 700,000 new or recurrent strokes per year in the United States, with 150,000 deaths. Although the stroke death rate fell by 15% over the decade between 1988 and 1998, the actual number of strokes rose more than 5%. Stroke is the number-one cause of disability in adults. Stroke is defined by the World Health Organization as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death with no apparent cause other than of vascular origin.” Stroke in the young generally is classified as stroke occurring in people between 15 and 45 years of age. However, some studies have used an upper age limit of up to 50 years or have made further divisions that analyze those 31 years or older and those 30 years or younger separately. Strokes in young adults account for approximately 3% to 10% of all people with stroke. Stroke in the young is more common than once suspected. The incidence of stroke in this age group is higher than

that of multiple sclerosis among young women. This review is concerned with ischemic stroke in the young. The topics of coagulopathies, vasculitis, and subarachnoid and intracerebral hemorrhages are discussed elsewhere in this text. There are worldwide fluctuations in the incidence rates of stroke in the young. The average annual age-specific incidence of stroke in Rochester, Minnesota, among people less than 45 years of age is 5 to 10 per 100,000 annually. The ratio of hemorrhages to ischemic infarction in young adults depends on the population studied and the age groups included. A majority of the strokes in the young appear to be ischemic, although there is one report with a proportion of hemorrhages that was greater than that of infarctions. More important than any statistic is the potential for long-term disability and burden for the young person with stroke, families, and the community. The loss of full earning potential is incalculable for the individual and cumulatively enormous for society. Therefore, stroke prevention remains of paramount importance.

Chapter 36 W

and a study during the acute stage of a large hemorrhage when mass effect may compress the abnormal vessels. Clinical presentation resembles that of vascular malformations in general, with a slight predominance of headache and seizures over hemorrhage. AVMs and cavernomas are the most common to present as angiographically occult vascular malformations. MRI is likely to show indirect signs with areas of hemosiderin surrounding a heterogeneous core of increased and decreased signal intensity. Surgery is indicated in patients with recurrent bleeding and intractable seizures.

SUGGESTED READINGS Caroscio JT, Brannan T, Budabin M et al: Subarachnoid hemorrhage secondary to spinal arteriovenous malformation and aneurysm. Arch Neurol 37:101, 1980 Gomori JM, Grossman RI, Goldberg HI et ak Occult cerebral vascular malformations: high-field MR imaging. Radiology 158:707, 1986 Hasegawa T, McInerney J, Kondziolka D et al: Long-term results after stereotactic radiosurgery for patients with cavernous malformations. Neurosurgery 5 0 1190, 2002 Heros RC, Korosue K, Diebold PM: Surgical excisions of cerebral arteriovenous malformations: late results. Neurosurgery 26:570, 1990

SECTlON

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Horton JC, Chambers WA, Lyons SL et al: Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations. Neurosurgery 27:867, 1990 Karlsson B, Kihlstrom L, Lindquist C et ak Radiosurgery for cavernous malformations. J Neurosurg 88:293, 1998 Kondziolka D, Lunsford LD, Kestle J R The natural history of cerebral cavernous malformations. J Neurosurg 83:820, 1995 Kondziolka D, Lunsford LD: The case for and against AVM radiosurgery. Clin Neurosurg 48:96, 2001 M a l i GM, Pearce JE, Ausman JL Dural arteriovenous malformations and intracranial hemorrhage. Neurosurgery 15:332, 1984 Ogilvy CS, Stieg PE, Awad I et ak Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke 32:1458, 2001 Rigamonti D, Hadley MN, Drayer BP et al: Cerebral cavernous malformations: incidence and familial occurrence. N Engl J Med 319343, 1988 Spetzler RF, Martin NA A proposed grading system for arteriovenous malformations. J Neurosurg 65:476, 1986 Steinberg GK, Fabrikant JI, Marks MP et al: Stereotactic heavy charged particle Bragg-peak radiation for intracranial arteriovenousmalformations. N Engl J Med 323:96, 1990 The Arteriovenous Malformation Study Group: Arteriovenous malformations of the brain in adults. N Engl J Med 340:1812, 1999

3 LESS COMMON CAUSES OF STROKE

36

Stroke in Young Adults Betsy B. Love and Jos6 Biller

Stroke is the third leading cause of death in the United States, accounting for 1 in 15 deaths in 1998. According to recent estimates, there are at least 700,000 new or recurrent strokes per year in the United States, with 150,000 deaths. Although the stroke death rate fell by 15% over the decade between 1988 and 1998, the actual number of strokes rose more than 5%. Stroke is the number-one cause of disability in adults. Stroke is defined by the World Health Organization as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death with no apparent cause other than of vascular origin.” Stroke in the young generally is classified as stroke occurring in people between 15 and 45 years of age. However, some studies have used an upper age limit of up to 50 years or have made further divisions that analyze those 31 years or older and those 30 years or younger separately. Strokes in young adults account for approximately 3% to 10% of all people with stroke. Stroke in the young is more common than once suspected. The incidence of stroke in this age group is higher than

that of multiple sclerosis among young women. This review is concerned with ischemic stroke in the young. The topics of coagulopathies, vasculitis, and subarachnoid and intracerebral hemorrhages are discussed elsewhere in this text. There are worldwide fluctuations in the incidence rates of stroke in the young. The average annual age-specific incidence of stroke in Rochester, Minnesota, among people less than 45 years of age is 5 to 10 per 100,000 annually. The ratio of hemorrhages to ischemic infarction in young adults depends on the population studied and the age groups included. A majority of the strokes in the young appear to be ischemic, although there is one report with a proportion of hemorrhages that was greater than that of infarctions. More important than any statistic is the potential for long-term disability and burden for the young person with stroke, families, and the community. The loss of full earning potential is incalculable for the individual and cumulatively enormous for society. Therefore, stroke prevention remains of paramount importance.

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RISK FACTORS There are distinct differences in ischemic stroke causes and risk factor profiles in this age group when compared to older adults. There is a greater heterogeneity in the cause of stroke in the younger age groups. In older adults, atherosclerotic cerebrovascular disease is the most common cause of ischemic stroke, whereas the causes of ischemic stroke in the young are more diverse and challenging. Although there are more than 70 different causes or potential risk factors for stroke in young adults, ischemic stroke in young adults often results from nonatherosclerotic vasculopathies such as dissection and vasculitis, cardiac embolism, or prothrombotic states. Finally, the cause of stroke is undetermined in a substantially higher percentage of young patients (up to 40% in some series) than in older patients even after a complete diagnostic evaluation. There are also differences between the risk factor profiles for young patients with stroke and those of older adults with stroke. In one study, migraine and mitral valve prolapse were more common in the group less than 40 years of age, and there was a greater incidence of hypertension, diabetes mellitus, and lipid disorders in the group greater than 40 years of age. Strokes should not be thought of as cerebrovascular “accidents” because they usually strike high-risk groups and are preventable in many instances. Well-documented risk factors for stroke include old age, male sex, African American ethnicity, family history of stroke, hypertension, diabetes mellitus, dyslipidemia, heart disease, prior history of transient ischemic attack (TIA) or stroke, cigarette smoking, excessive alcohol intake, and high body mass index. The incidence of stroke increases dramatically with advancing age, and increasing age is a powerful risk factor for stroke. The majority of strokes occur in people older than 65, and the incidence of stroke doubles with each decade after the 35- to 44-year age group until the 75- to 84-year age group, with the greatest jump in risk occurring between ages 35 and 54. Because the prevalence of atherosclerosis increases with age, it is not surprising that atherosclerosis has been associated with stroke more often in young adults over 30 years of age than in those who are younger than 30 years. The prevalence of carotid artery stenosis or occlusion in young adults after a stroke is low. Men develop ischemic strokes at higher rates than women except in those older than 75 years and possibly in those younger than 30 years. Although the data have been conflicting in clinical series or population estimates, the male:female ratio tends to show a male predominance for infarct and hemorrhagic strokes in the young. Some have found that the incidence of ischemic stroke is higher in young women (less than 30 years) than in men. However, the overall incidence of stroke is very low among women of childbearing age, with an estimated annual incidence of 1 to 2.5 per 100,000 women. The rate of cerebral infarction is higher in African Americans than in Caucasians. The incidence of stroke is 6 per 100,000 whites aged 15 to 39 years and 38 per 100,000 among whites aged 40 to 44 years. The incidence is approximately 2.5 times higher in blacks. The incidence is 48.6 cases per 100,000 black women aged 40 to 44 years and 99.3 cases per 100,000 black men in the same age group. The rate of cerebral infarction is also estimated to be two times higher in Hispanics than in whites. Heredity seems to play a minor role in the pathogenesis of cerebral infarction. However, a higher risk is seen with a family history of stroke among first-degree relatives, with a mater-

nal history of death from stroke, and with a paternal or maternal history of stroke. In addition, there are a number of genetic causes of stroke. Some inherited diseases, such as the hereditary dyslipoproteinemias, predispose to accelerated atherosclerosis. Others are associated with nonatherosclerotic vasculopathies, including Ehlers-Danlos type IV syndrome, Marfan’s syndrome, and Rendu-Osler-Weber disease. Familial atrial myxomas, hereditary cardiomyopathies, and hereditary cardiac conduction defects are examples of inherited cardiac disorders that predispose to stroke. Deficiencies of proteins C and S, antithrombin 111 deficiency, platelet glycoprotein receptor IIIa polymorphism PIU, factor I1 G20210A mutant genotype, and activated protein C resistance are examples of inherited hematologic abnormalities that may be associated with ischemic stroke. Finally, rare inherited metabolic disorders that may cause stroke include the syndrome of mitochondria1 encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry’s disease, Menkes’ disease, Tangier disease, and homocystinuria. Hypertension is the most important modifiable risk factor for stroke. As blood pressure increases, the risk of cardiovascular events increases. At least 25% of the adult population has hypertension, defined as systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg. Blood pressure values between the 90th and 95th percentile are considered borderline or high normal. Hypertension predisposes to ischemic stroke by aggravating atherosclerosis and accelerating heart disease, multiplying the relative risk of stroke three to four times. Systolic blood pressure is a better predictor of stroke than diastolic blood pressure, and there is abundant evidence that treating hypertension reduces stroke incidence. Reduction of systolic blood pressure by 10 to 12 mm Hg or diastolic blood pressure by 5 to 6 mm Hg results in a 38% reduction in stroke incidence. Diabetes mellitus multiplies the risk of ischemic cerebrovascular disease two to four times. The potential mechanisms of stroke secondary to diabetes may result from cerebrovascular atherosclerosis, cardiac embolism, or hemorrheologic abnormalities. Hypercholesterolemia often is found in very young diabetic people. High low-density lipoprotein (LDL) cholesterol and low high-density lipoprotein (HDL) cholesterol are also well-established findings in adults with insulin-dependent diabetes mellitus. Hypertriglyceridemia may also be important. Mean arterial blood pressure is higher among patients with insulin-dependent diabetes mellitus with microvascular complications, but the excess stroke risk appears to be independent of age or blood pressure status. The presence of associated hypertension or hyperlipidemia adds further to the risk in this population. Atherosclerotic vascular disease occurs earlier and at a younger age among patients with diabetes. Diabetic patients with retinopathy and autonomic neuropathy appear to be at particularly high risk for ischemic stroke. High insulin levels increase the risk of atherosclerosis and may represent a pathogenic factor in cerebral small vessel disease. Hyperlipidemia seldom is an etiologic factor in the very young patient with stroke. High total serum cholesterol and high LDL concentration are correlated with atherosclerosis. Familial combined hyperlipidemia is the most frequently inherited (dominant inheritance) disorder of lipoprotein metabolism. Epidemiological studies suggest that patients with this disorder are at elevated risk for coronary atherosclerosis. Affected patients may manifest a type IIa, IIb, or type IV pattern, but often not until the second or third decade. A higher degree of suspicion is warranted, and first-degree relatives of all young stroke patients must be investigated. Signs of

Chapter 36

lipid deposition such as arcus cornealis, cutaneous, or Achilles tendon xanthomas should be sought on physical examination. Hypercholesterolemia also is an atherogenic risk factor. Adolescents with high blood cholesterol levels are also more likely to have hypercholesterolemia as adults than the general population. Although there is overwhelming evidence relating low levels of HDL cholesterol to coronary heart disease, the association with cerebrovascular disease is less clear. Source studies have shown a positive relationship between serum cholesterol levels and death resulting from nonhemorrhagic stroke. The relationship has not been consistent, however; possibly because different risks are associated with different lipoprotein subtypes. People with high serum lipoprotein(a) levels appear to have a higher risk of ischemic stroke. Administration of HMG-CoA reductase inhibitors has been shown to have beneficial effects on coronary and carotid atherosclerosis. Lipid-lowering agents may slow progression of intimal medial thickness and may cause a regression in plaque formation. Cardiac abnormalities, either congenital or acquired, account for up to one-third of stroke in young adults. Rheumatic valvular heart disease, prosthetic heart valves, paradoxical embolism, and dilated cardiomyopathy are the most common cardiac sources in young adults. Congenital heart disease, which is a significant stroke risk factor in children, may continue to pose an increased risk of stroke in young adults. Mitral valve prolapse is an uncommon cause of stroke in the young, with an estimated risk of 1 per 6000 per year. Arrhythmias such as nonvalvular atrial fibrillation (AF) are rare, but sick sinus syndrome should be considered because of its association with a variety of congenital and acquired heart diseases. Other risk factors include atrial septal defects, ventricular septal defects, and patent foramen ovale. Cigarette smoking is an independent risk factor for ischemic stroke in men and women of all ages. The risk of stroke in smokers is two to three times greater than in nonsmokers. It is a leading risk factor for carotid atherosclerosis in men. Cigarette smoking also increases the risk of ischemic stroke among women migraineurs on oral contraceptives. After approximately 5 years from smoking cessation, the stroke risk is reduced to that of never-smokers. Public education and attempts to decrease smoking in teenagers and young adults are important in stroke prevention in this age group. Alcohol is a leading killer of young adults. There is a J-shaped association between alcohol consumption and ischemic stroke; light to moderate daily amounts (up to 2 drinks per day) of alcohol evenly distributed throughout the week can decrease the risk by 20%, whereas heavy use can increase the risk by three times and lead to liver disease. Moderate alcohol intake may elevate HDL concentration. The use of illicit drugs increases the risk of stroke by as much as 6.5 times that of non-drug users. Among patients younger than 35 years, one series showed that drug abuse was the most commonly encountered risk factor for stroke, present in nearly one half of all patients, with an overall relative risk for stroke of 11.7. Obesity in childhood is a major public health problem and a risk factor for adult obesity. Obesity, particularly abdominal or truncal, is an important risk factor for cardiovascular disease in men and women of all ages. Obesity is sometimes associated with hypertension in children and with dyslipidemia in children and adolescents. However, obesity appears to be a risk factor for atherothrombotic brain infarction in older men and women. There is some evidence that moderate physical activity lowers

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stroke risk. This effect may result from a variety of factors, as exercise has been shown to be associated with reduced blood pressure, lower risk of cardiovascular disease, improved diabetes control, and lower body weight. Moderate physical exercise has been noted to reduce ischemic stroke risk. Patients who suffer TIAs are at greater risk than normal controls for stroke; the risk of stroke is about three times higher. Approximately 10% to 15% of those experiencing a stroke have TIAs before their stroke. Patients with hemispheric TIAs are at greater risk of ipsilateral stroke than patients with retinal TIAs. Patients with first-ever stroke are at greater risk of recurrent stroke, especially but not exclusively early after the first stroke. Those who suffer a recurrent stroke have a higher mortality than patients with first-ever stroke. If the recurrence is contralateral to the first stroke, prognosis for functional recovery is poor. Finally, several interesting observationshave been made regarding more unusual risk factors and stroke. A diurnal and seasonal variation of ischemic events has been noted. Lifestyle-associated activities may account for the weekend and holiday increase in the onset of brain infarction among young adults and women. Circadian changes in physical activity, catecholamine levels, blood pressure, blood viscosity, platelet aggregability, blood coagulability, and fibrinolytic activity may explain the circadian variations in onset of myocardial and cerebral infarction. Although an early morning peak has been identified for all subtypes of stroke, most clinical trials on the use of platelet antiaggregants or other antithrombotic agents do not take circadian variations into account. A history of recent infection, particularly of bacterial origin and within 1 week of the event, is also a risk factor for ischemic stroke in young as well as old patients. Sleep apnea is a significant cardiovascular and stroke risk factor that increases blood pressure and lowers arterial oxygenation while arterial carbon dioxide levels rise, leading to thrombosis. Habitual snoring increases the risk of stroke and adversely affects the outcome of patients admitted to hospital with stroke. The specific role of these risk factors among young patients with stroke is not clear. PRESENTATION OF STROKE IN YOUNG ADULTS The presentation of stroke in young patients is similar to that of older patients with stroke. Presenting signs and symptoms are outlined in Table 36- 1. Carotid distribution ischemia is suggested with monocular visual loss or aphasia. Vertebrobasilar distribution ischemia is suggested with binocular visual loss, vertigo, gait instability, balance difficulties, bilateral or alternating weakness or altered sensation, dysphagia, or diplopia. It is also possible to determine whether the ischemia involves cortical and/or subcorTAW 36-1. Symptoms Indicative of a Possible Stroke Visual loss (monocular, bilateral, or contralateral homonymous hemianopia) Hemiparesis (may be unilateral, bilateral, or shifting) Sensory loss (may be unilateral, bilateral, shifting, or crossed) Clumsiness (may be unilateral, bilateral, or shifting) Aphasia Dysarthria Vertigo Diplopia Dysphagia Ataxia Nausea or vomiting Symptoms may occur in combination. Isolated vertigo, diplopia, or dysphagia is not specific for diagnosing stroke.

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TABLE56-2. Differential Diagnosis of Ischemic Stroke in Young Adults lntracerebral hemorrhage lntracranial tumor Seizures Migraine Labyrinthine disorders Hypoglycemia Cerebral venous occlusive disease Cerebral abscess Syncope Hysteria Confusional states

tical structures. Patients with any degree of altered consciousness may have cortical or combined subcortical and cortical ischemia. The presence of loss of vision in one field or forced eye deviation usually implies cortical or combined cortical and subcortical ischemia. If the weakness or sensory loss affects the face, arm, and leg equally, a subcortical or brainstem localization is most likely. Severe dysarthria often indicates subcortical or combined cortical and subcortical ischemia. The major considerations in the differential diagnosis of stroke are listed in Table 36-2. It may be difficult based on the history alone to differentiate an ischemic stroke from an intracranial hemorrhage. Historical features that suggest a hemorrhage include an altered level of consciousness or a seizure at the onset, prominent nausea and vomiting, or a severe headache. However, people with an ischemic stroke can have headaches at onset in approximately 20% of cases. Patients with internal carotid artery dissection may present with pain involving the neck, ipsilateral head, or periorbital region. Patients with an intracranial tumor may present with symptoms resembling a stroke. However, symptoms with space-occupying lesions usually are gradual in onset, with an accumulation of deficits over time. A march of symptoms, particularly with associated involuntary motor activity, usually indicates focal seizure activity rather than a stroke. The presence of visual hallucinations or scintillating visual symptoms representing positive phenomena usually is more consistent with migraine than stroke. The presence of isolated vertigo often is more consistent with a labyrinthine disorder. Hypoglycemia, particularly in the diabetic patient, can present with transient paresis or aphasia with confusion and altered consciousness. Other conditions in the differential diagnosis include cerebral venous occlusive disease, cerebral abscess, syncope, confusional states, and hysteria. CAUSES OF STROKE IN THE YOUNG

It is useful to categorize the causes of stroke in the young into the following major groups: atherosclerotic cerebrovascular disease, nonatherosclerotic vasculopathies, cardioembolism, hematologic (prothrombotic states), other miscellaneous causes, and undetermined after a thorough investigation.

autopsy studies, has its onset in childhood and progresses further in adolescence and young adulthood. Atherothrombosis is multifactorial, with overlapping comorbidities and risk factors that are often additive. For example, hypertension often is associated with hyperlipidemia, hyperglycemia, elevated fibrinogen levels, excessive weight, and left ventricular hypertrophy on electrocardiogram. Patients with stroke caused by atherosclerosis may have large artery atherothrombosis or small vessel disease. Less than 30% of patients younger than 50 years of age have small artery and large artery atherosclerosis as a cause of stroke. In those less than 30 years old, atherosclerosis is not common as a cause of stroke. In one series, the percentage of patients between 16 and 30 years with atherosclerosis as a cause of stroke was only 2% of patients. In the same series, 7% of patients with stroke in the age group 31 to 45 years had atherosclerosis as a cause of infarction. Most young adults with atherosclerosis as a cause of infarction have the classic risk factors, such as hypertension, diabetes mellitus, cigarette smoking, and hyperlipidemia. Young people with atherosclerosis as a cause of cerebral infarction may have concomitant atherosclerosis in other vascular beds, such as the peripheral vascular system. The prevalence of concomitant coronary artery disease in this population has not been studied. Traditional stroke risk factors such as diabetes mellitus and tobacco use should be assessed diligently in the young patient with stroke. A small number of patients may have inherited conditions causing early and accelerated atherosclerosis, such as familial hypercholesterolemia, familial hypertriglyceridemia, or HDL deficiency states. A presumed atherosclerotic cerebral infarction in a very young patient warrants investigations for rare premature aging syndromes.

NonatheroscleroticVasculopathy A number of different nonatherosclerotic vasculopathies cause cerebral infarction in young adults (Table 36-3). Several of the more common causes of stroke in young adults in this category are discussed in this chapter. Vasculitis is discussed in Chapter 205. Moyamoya Disease. Moyamoya disease is a rare and progressive, occlusive, noninflammatory arteriopathy of undetermined cause. It is characterized by stenosis or occlusion of the distal intracranial internal carotid artery or the adjacent anterior, middle, or posterior arteries, along with the development of stereotypical collaterals (basal parenchymal, leptomeningeal, or dural). Pathologically, there is fibrocellular thickening of the intima, waving of the internal elastic lamina, and attenuation of the media. Elevated levels of fibroblastic growth factor (FGF) may play a role in its pathogenesis. Moyamoya disease is most common among the Japanese, Chinese, and Korean populations, but it has been reported in all ethnic groups. The disorder is seen in both children and adults. There is a bimodal age distribution, with a TABLE 56-5. Selected Nonatherosclerotic Vasculopathies

Associated with Stroke in the Young Atherosclerotic Cerebrovascular Disease

Atherosclerosis is a focal intimal disease of medium to large arteries including the aorta, coronary, and cerebral arteries. The earliest lesions are aortic fatty streaks, followed about a decade later by similar lesions in the coronary arteries. Although uncommon before age 40 years, atherosclerosis, as proven in

Cervicocephalicarterial dissections Traumatic cerebrovascular disease Moyamoya disease Fibromuscular dysplasia Vasculitis Migrainous infarction Radiation-inducedvasculoDathv

Chapter 36

peak in the first and fourth decades of life. A slight female preponderance of 1.8 to 1 has been noted. Approximately half of the affected patients present before 10 years of age. Although most cases are sporadic, a familial occurrence has been reported in approximately 10% of patients. Proposed criteria for the diagnosis of Moyamoya disease are stenosis or occlusion involving the region of the internal carotid artery bifurcation (Cl) and proximal portions of the anterior cerebral artery (Al) and middle cerebral arteries (Ml), presence of unusual netlike (“puff of smoke”) appearance of basal collateral arteries arising from the circle of Willis, and bilateral abnormalities. Occasionally, these abnormalities are found in association with a variety of other disease states, and the angiographic abnormality in those instances is called Moyamoya syndrome rather than Moyamoya disease. Clinical presentations in young adults with Moyamoya disease can include alternating hemiparesis, early morning headaches and nausea, seizures, involuntary (mostly choreiform) movements, intellectual decline, cerebral infarction, and intracranial hemorrhage. In adults, the most common symptoms are hemorrhagic, caused by subarachnoid, subependymal, or intraventricular hemorrhage. Ischemic strokes may be multiple and recurrent and predominantly involve the carotid circulation. The infarctions may be superficial or deep and often involve watershed territories. Routine hematologic, biochemical, and serologic investigations are unrevealing except for reports of elevated fibroblastic growth factor in the cerebrospinal fluid. The diagnosis is based on a distinct arteriographic appearance characterized by bilateral stenosis of the distal internal carotid arteries extending to the proximal anterior and middle cerebral arteries, with frequent involvement of the circle of Willis and development of an extensive collateral network at the base of the brain. The optimal treatment for Moyamoya disease has not been determined. Medical therapies that have been used include platelet antiaggregants, calcium channel blockers, corticosteroids, vasodilators, antifibrinolytics, and low-molecular-weight heparins. Numerous indirect or direct surgical revascularization techniques have been tried with good results in children and young adults with ischemic manifestations. Fibromuscular Dysplasia. Fibromuscular dysplasia (FMD) is a nonsegmental, noninflammatory, nonatheromatous angiopathy that is usually confined to the renal arteries but may also involve the cervicocephalic vessels. Its cause is unknown, but cigarette smoking may be a contributing factor. It is thought that FMD is usually inherited as an autosomal dominant trait. CervicocephalicFMD usually involves the extracranial internal carotid arteries at the level of the C1 and C2 vertebrae. FMD most commonly involves the extracranial internal carotid arteries, and involvement of the intracranial carotid or vertebrobasilar systems is rare. Typically, patients are women between 40 and 50 years. Symptoms of FMD are variable and include headaches, hemicrania, carotidynia, tinnitus, vertigo, amaurosis fugax, and Horner’s syndrome. Cerebrovascular complications arise from thromboembolism and may include TIAs or cerebral infarction. Cervicocephalic arterial dissections may also occur. There is also an increased frequency of intracranial aneurysms. Hypertension may be present because of concomitant renal FMD, but most patients remain asymptomatic. The diagnosis is made by cerebral arteriography, which usually shows a string-of-beads appearance. Unifocal or multifocal tubular stenosis is a less common finding. Although the optimal treatment of FMD has not been

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FIG. 36-1. Right carotid arteriogram demonstrates typical tapering stenotic appearance of the extracranial internal carotid artery consistent with arterial dissection.

determined, treatment usually involves medical therapy with platelet antiaggregants. Surgical intervention is seldom warranted. Percutaneous transluminal carotid angioplasty has been used successfully in some patients. Cervicocephalic Arterial Dissections. Cervicocephalic arterial dissections are an important cause of stroke in young adults. The extracranial internal carotid artery is the site of most dissections (Fig. 36-1). Vertebrobasilar and intracranial carotid artery dissection are less common. Spontaneous arterial dissection has been proposed as the most common cause of posterior circulation stroke in the young (Fig. 36-2). Cervicocephalic arterial dissections often are spontaneous. However, they have been reported after blunt or penetrating trauma and chiropractic manipulation. They have also been associated with fibromuscular dysplasia, Marfan’s syndrome, Ehlers-Danlos syndrome type IV, osteogenesis imperfecta type I, coarctation of the aorta, cystic medial necrosis, atherosclerosis, extreme vessel tortuosity, Moyamoya disease, pharyngeal infections, syphilitic arteritis, a-1 -antitrypsin deficiency, sympathomimetic drug abuse, and lentiginosis. Signs and symptoms associated with dissection of the cervicocephalic vessels are outlined in Table 36-4. Cervicocephalic arterial dissections should be considered in the differential diagnosis of TIAs or cerebral infarction in any young adult, particularly when traditional risk factors are absent. The diagnosis is based on arteriographic findings. High-resolution magnetic resonance imaging (MRI) and magnetic resonance angiography provide valuable noninvasive information and are increasingly replacing cerebral angiography in many centers. Treatment of cervicocephalic arterial dissections has included anticoagulation with intravenous unfractionated heparin followed by warfarin, but this is based on anecdotal evidence. Platelet antiaggregants are used by many physicians because of the lack of solid clinical data for the use of anticoagulants. Surgical correction has been used in selected patients who have not responded to medical therapy. Surgeries that have been used to treat cervicocephalic arterial dissections include proximal

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Less Common Causes of Stroke

ligation, trapping procedures, and extracranial-intracranialbypass procedures. Stents have been used successfully in some patients. The recurrence rate of cervicocephalic dissections is approximately 1% per year. The risk of recurrent dissections is higher in young patients and in those with a family history of arterial dissections. Migrainous Infarction and Other Vasospastic Disorders. Migraine is rare as a cause of cerebral infarction when one considers the high prevalence of migraine in the general population. To establish a diagnosis of migrainous infarction, the new International Headache Society classification requires that one or more migrainous aura symptoms must be present and not fully reversed within 7 days of onset or associated with neuroimaging confirmation of ischemic infarction. Migraine as a possible or probable cause of cerebral infarction in young adults accounts for 1% to 19% of strokes in series of young adults with cerebral infarction. Epidemiologic studies suggest a nonrandom association of both headache and migraine with stroke, particularly among young women. In a large Italian case-control study, this rare association was limited to women below age 35. The Physician's Health Study showed that physicians reporting migraine had higher risks of subsequent total stroke and ischemic stroke than those not reporting migraines. Cerebral infarctions caused by migraine usually are cortical and most commonly involve the distribution of the posterior cerebral artery. Once a possible migrainous infarction has occurred, it is probably best to discontinue and avoid P-blocking agents, triptans, and ergotamine. Although optimal management is not certain, a combination of a calcium channel blocker, such as verapamil, with aspirin may be used. Cerebral autosomal dominant arteriopathy with subcortical

A

infarcts and leukoencephalopathy (CADASIL) is a familial, nonatherosclerotic, nonamyloid arteriopathy characterized by recurrent subcortical ischemic strokes beginning in the third and fourth decades. Associated features often include pseudobulbar palsy, subcortical dementia, and early MRI abnormalities. The CADASIL gene has been identified as notch 3 on chromosome 19, allowing direct genotypic diagnostic testing for this condition. A subvariety of CADASIL with a high frequency of migraine is called cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and migraine (CADASILM). In this disorder, brain or skin biopsy characteristically demonstrates typical gran-

W TABLE 36-4. Signs and Symptoms of Extracranial

Cervicocephalic Arterial Dissection Extracranial Internal Carotid Artery

Hemicranial headache plus Hornet's syndrome Hemicranial headache plus delayed focal cerebral ischemia Pain (head, orbit, face, neck, scalp tenderness) Scintillations Subjective bruit Lightheadedness, tinnitus, syncope Hornet's syndrome Carotid transient ischemic attacks Cerebral infarction Lower cranial nerve palsies (XI!, X) Extracranial Vertebral Artery

Pain (occipital, posterior neck, mastoid, ears, shoulders) Vertebrobasilar transient ischemic attacks Variations of lateral or medial medullary infarction Cerebellar infarction Posterior cerebral artery distribution infarction

B

FIG. 36-2. A 30-year-old woman had severe occipital headaches after a normal delivery. Because of persistent headaches, MRI of the brain and base of the neck and four-vessel cerebral angiogram were obtained. (A) Left vertebral and (B) right vertebral arteriogram show multiple areas of caliber narrowing throughout the extracranial vertebral arteries, consistent with dissection.

Chapter 36 W

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C

D

F E

FIG. 36-2. Continued (C) Axial T1-weighted MRI image at the base of the neck shows crescentic signal hyperintensity (arrow) consistent with intramural hematoma of the right vertebral artery. Follow-up vertebral arteriography demonstrates complete resolution of the previously noted caliber abnormalities of the I& vertebral (0)and right vertebral (€) arteries. (fl Artist's rendition of the patient's position during delivery. The clinical and neuroimaging picture are consistent with postpartum bilateral simultaneous extracranial vertebral artery dissections.

ular osmiophilic material within the basement membrane of vascular smooth muscle cells (Fig. 36-3). Cardiac Embolism

Although nonvalvular AF and ischemic heart disease are the most common causes of cardioembolic stroke in older people, the causes in younger people with stroke are more diverse, and more unusual disorders must be considered. Potential sources of cerebral infarction of cardiac origin are listed in Table 36-5. In young patients with stroke, congenital heart disease, rheumatic heart disease, and infective endocarditis are among the most common cardiac disorders leading to embolic ischemic strokes. A number of cardiac diseases increase the risk of stroke. Among young patients with cerebral ischemia, one fifth to one

third are presumed to be caused by emboli of cardiac origin. Congenital heart disease is probably the most common cardiac disorder causing ischemic stroke in children, and there are often ongoing risks in the young adult population. Neurologic complications of congenital heart disease may be ischemic, hemorrhagic, hypoxic, or infectious or the result of cardiac surgery. Cerebral ischemia may result from systemic or paradoxical emboli, emboli occurring during cardiopulmonary bypass, or arterial or venous thromboses. Children with congenital heart disease and a low hemoglobin concentration are at special risk for arterial strokes; those with a high hematocrit are more likely to experience cerebral venous thrombosis. Right-to-left shunts can occur at the atrial level (e.g., atrial septal defect [ASD] with pulmonary hypertension), ventricular level (e.g., ventricular septal defect [VSD] with pulmonary

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FIG. 36-3. Leptomeningeal artery with extensive loss of smooth muscle layer and deposits of granular and diffuse Periodic Acid Schiff (PAS) positive material replacing the media in a patient with CADASIL. (Courtesy of Dr. Biagio Azzarelli, Indiana University School of Medicine)

hypertension), or at the arterial level (e.g., pulmonary arteriovenous fistula). ASD is one of the more common congenital heart diseases found in adults. ASDs are classified as secundum ASD, primum ASD, or sinus venoms defect, according to their location relative to the fossa ovalis. Right-to-left shunting provides an opportunity for passage of thrombi, which leads to paradoxical embolism. The most common defect in a patient with congenital heart disease is a VSD. A left-to-right shunt usually is present in those with VSD. In the patient with Eisenmenger's syndrome, there is a right-to-left shunt across the VSD. VSD (Roger's defect), atrioventricular septal defects, tetralogy of Fallot, and patent ductus arteriosus are among the most common cardiac abnormalities associated with Down syndrome. Patients with tetralogy of Fallot are cyanotic because of right-to-left shunting. Polycythemia and high hematocrit predispose to thrombotic complications, especially during illnesses associated with dehydration. The Fontan operation is one of the most common cardiac operations for children with congenital heart disease beyond the first year of life. Thromboembolic complications account both for morbidity and mortality after a modified Fontan procedure and may occur even months or years after surgery. Pulmonary arteriovenous fistulas are common in patients with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease), an autosomal dominant vascular dysplasia associated with a genetic defect at a locus on chromosome 9q34. Paradoxical embolism to the brain is also a potential complication of the intrapulmonary right-to-left shunt. Other central nervous system manifestations include intracranial hemorrhage and septic embolism leading to brain abscess. Common central nervous system lesions include arteriovenous malformations and fistulas, telangiectasias, and aneurysms. Cardiac valvular heart disease may result from rheumatic, prosthetic, myxomatous, inflammatory, infective, marantic, traumatic, degenerative, or congenital causes. Rheumatic fever is a common cause of acquired heart disease in children and young adults worldwide. It is the most common cause of mitral valve stenosis. Rheumatic AF increases the risk of stroke about 17-fold. Thromboembolism may be the first manifestation of mitral stenosis. The lifetime risk of systemic thromboembolism with

rheumatic mitral stenosis is 20%, and concomitant AF increases the risk of systemic thromboembolism. Approximately 4% of patients with congenital heart disease have aortic valve stenosis. A bicuspid aortic valve is a common congenital heart malformation, which affects men more commonly than women. It may remain asymptomatic throughout life unless there is associated coarctation of the aorta, or it may be discovered when a young person without apparent history of structural heart disease develops infective endocarditis. Cerebral embolism is a rare occurrence. There are two major types of prosthetic heart valves: mechanical and bioprosthetic. Mechanical valves have a substantial risk of thromboembolism, so lifetime anticoagulation is needed. Bioprosthetic heart valves carry a lower risk of thromboembolism than mechanical valves, but they are less durable. The rate of systemic thromboembolism in patients with mechanical heart valves receiving anticoagulant therapy is 4% per year in the mitral position and 2% per year in the aortic position. The frequency of thromboembolic complications is greater if there is associated AF. Mitral valve prolapse (MVP) is inherited in an autosomal dominant fashion and is often associated with a number of heritable disorders of connective tissue. Despite its high prevalence in the general population, MVP is an extremely rare cause of

TABLE36-5.Cardiac Sources of Cerebral Infarction Congenitalheart disease Ventricular septal defect Atrial septal defect Transposition of the great vessels Coarctation of the aorta Pulmonary stenosis Tetralogy of Fallot Eisenmenger's syndrome Truncus arteriosus with decreased flow Patent ductus arteriosus Endocardial cushion defect Hypoplastic left ventricle Ebstein's anomaly Pulmonary atresia Valvular heart diseose Congenital Rheumatic Prosthetic heart valves Mitral valve prolapse Calcific heart strands Mitral valve strands Giant Lamb1 excrescences Aneurysms of the sinus of Valsalva Infective endocarditis Nonbacterial thrombotic endocarditis Libman-Sacks endocarditis Cardiac arrhythmias Atrial fibrillation Supraventricular tachycardia Sick sinus syndrome Other cardiac causes lntracardiac defects (e.g., patent foramen ovale, atrial septal aneurysm) with paradoxical embolism Myocarditis Myocardial infarction Left ventricular aneurysm Cardiomyopathies lntracardiac tumors Cardiac procedures Extracorporeal procedures Extracorporeal membrane oxygenator Single chamber ventricular demand WI) pacing Catheter ablation techniques Kawasaki's disease Kearns-Savre svndrome

Chapter 36 W

embolic stroke. Most young adults with MVP and cerebral infarction have another cause of cerebral infarction. Infective endocarditis is a common complication in the patient with congenital or rheumatic heart disease. Native valve endocarditis, early or late prosthetic valve endocarditis, and infective endocarditis among intravenous drug users should be distinguished. Involvement of the central nervous system may be the most serious complication of infective endocarditis. Neurologic complications are common with infective endocarditis involving the left side of the heart. Mechanical valves carry a greater risk of early endocarditis, whereas bioprosthetic heart valves carry a greater risk of late endocarditis. Almost half of the neurologic complications are ischemic or hemorrhagic cerebrovascular events. The diagnosis should be suspected in any febrile stroke patient with an organic heart murmur. Helpful diagnostic clues include the presence of petechiae, splinter hemorrhages, Osler’s nodes, Janeway’s lesions, Roth’s spots on funduscopic examination, splenomegaly, and hematuria. Laboratory studies may show anemia, leukocytosis, elevated erythrocyte sedimentation rate, and positive blood cultures. The pathophysiologic mechanisms include septic embolization, mycotic aneurysm formation, and vasculitis. Infective endocarditis poses an embolic stroke risk of approximately 20%. The importance of appropriate stratification of infective endocarditis risk (i.e., low or no risk, moderate risk, or high risk) must be emphasized. Arteriography may be necessary to exclude mycotic aneurysms in the patient who develops focal neurologic signs. Libman-Sachs endocarditis of lupus erythematosus may be associated with stroke; findings resembling verrucous endocarditis of the mitral and aortic valves have been described in association with the antiphospholipid antibody syndrome. Marantic or nonbacterial thrombotic endocarditis, most often seen in association with mucin-producing carcinomas of the colon, pancreas, or lung, is an uncommon cause of stroke in young adults. This condition most commonly affects people older than 40 years. Because nonbacterial thrombotic endocarditis is common in terminally ill patients, it is often difficult to make a diagnosis. The presence of thrombophlebitis, early detection of ongoing intravascular coagulation, and dysfunction of major organ systems may suggest this diagnosis, especially in the presence of multiple embolic infarcts. AF is rare in young adults. An estimated 1 to 2 million Americans have chronic nonvalvular AF, a condition that is associated with a fivefold greater overall stroke incidence and a mortality rate about twice that of age- and sex-matched subjects without AF. The prevalence of AF increases with advancing age. The Framingham study found an incidence of 0.26% among men and 0.22% among women aged 25 to 34 years. AF may be associated with acute alcohol ingestion (“holiday heart syndrome”), hyperthyroidism, rheumatic heart disease, pericarditis, and cardiac surgery. When it occurs independently of any identifiable cause, it is called lone AF. Sick sinus syndrome (SSS) is also rare in young adults. The bradycardia-tachycardia syndrome, especially when complicated by AF, has the greatest risk of embolization. Patients with SSS may experience systemic embolism, even after pacemaker insertion. SSS may complicate a number of neuromuscular disorders. Complete heart block often is seen in association with KearnsSayre syndrome. Initially, there is a left anterior fascicular block and occasionally a right bundle branch block. Strokes may result from cardiac emboli. Strokes may complicate the course of cardiomyopathies.

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Primary cardiomyopathies (unrelated to valvular, ischemic, hypertensive, or inflammatory heart disease) may be dilated, restrictive, hypertrophic, or obliterative. Most patients with dilated cardiomyopathies present with symptoms of pulmonary venous congestion or cardiac arrhythmia. Some patients present with neurologic symptoms related to systemic embolization. Cardiomyopathy may also be present in several genetic neurologic and neurometabolic disorders such as neonatal and early infantile mitochondria1 disorders, Duchenne’s and Becker’s muscular dystrophy, myotonic dystrophy, carnitine palmitoyltransferase I1 deficiency, tyrosinemia type I, Friedreich’s ataxia, Refsum’s disease, Pompe’s disease, and the mucopolysaccharidoses. Cardiomyopathy may also be seen with hemochromatosis, endocardial fibroelastosis, and Loffler’s hypereosinophilic syndrome. Mitochondrial disorders are seldom associated with dilated cardiomyopathies; in most instances, patients have hypertrophic cardiomyopathies. Apical aneurysms may complicate Chagas’ cardiomyopathy; emboli may arise from the left or right heart chambers. Myocardial infarction is rare in young adults. Myocardial infarction may occur in the presence of congenital anomalies of the origin of the coronary arteries, calcific coronary arteriopathy of infancy, coronary artery dissection, ostial stenosis from primary disease of the aorta, medial calcificationwith fibroblastic proliferation of the intima, coronary emboli, childhood polyarteritis nodosa, mucocutaneous lymph node syndrome (Kawasaki’s syndrome), and Fabry’s disease. Acute myocardial infarction is complicated by cerebral embolism in 1% to 3% of cases. Atrial myxomas, the most common primary cardiac tumors, are rare in young adults. A majority of atrial myxomas are in the region of the fossa ovalis, and most protrude into the left atrium. They are sometimes familial and are more common in women. Presenting symptoms relate to systemic, obstructive, and embolic manifestations, such as low-grade fever, anemia, weight loss, and fainting spells. Most atrial myxomas are single, but multiple cardiac myxomas have been described and may be associated with lentiginosis, myxoid fibroadenomas of the breast, and cutaneous myxomas. Peripheral and cerebral aneurysms have also been diagnosed years after the initial embolic manifestations. Cardiac rhabdomyomas are closely associated with tuberous sclerosis. Most tumors are well circumscribed and intramural. Intracavitary pedunculated masses are rare. It is unusual to have systemic embolization. Patent foramen ovale (PFO) is present in 35% of people aged 1 to 29 years and in 25% of people aged 30 to 79 years. A PFO provides opportunity for right-to-left shunting during transient increases in the right atrial pressure above the left atrial pressure, reversing the interatrial gradient. Patients with PFO are more likely to have an unknown cause of stroke. In one study of the prevalence of PFO as detected by contrast echocardiography in 60 adults younger than 55 years of age, PFO was present in 40% of patients with stroke, compared with 10% in a control group. In patients with no identifiable cause of stroke, the prevalence was 54%. Stroke recurrence is uncommon in these patients. Atrial septal aneurysm (ASA) is an occult embolic cardiac source of cerebral ischemia. ASAs occur more often as an isolated abnormality than in association with other cardiac malformations. In a series of 36 patients with ASA, 28% had cerebrovascular events and 90% had interatrial shunting, suggesting paradoxical embolism as the mechanism for cerebral ischemia. Initial studies failed to correlate morphology and extent of ASA with embolic risk. More recently, however, it has been shown that patients with ASA, especially those with a greater than 10-mm excursion, are at

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greater risk of stroke. In addition, stroke recurrence after an initial presentation with stroke occurs more often with the combination of ASA and PFO than with either abnormality alone. PFO and ASA have also been associated with MVP. Patients suspected of having paradoxical embolism should be assessed for the possibility of an underlying May-Thurner syndrome. Thromboembolism can complicate cardiac surgery using cardiopulmonary bypass with deep hypothermia and cardiac arrest. Patients undergoing cardiac catheterization and a variety of cardiac surgical procedures including coronary artery bypass, percutaneous transluminal valvuloplasty and coronary angioplasty, intra-aortic balloon pump, ventricular assist devices, and cardiac transplantation are at risk for cerebral embolization. Strokes may also occur as a complication of the use of the extracorporeal membrane oxygenator. Thromboembolic complications may follow the Fontan procedure or its modifications (cavopulmonary anastomosis). Air embolism may complicate cardiopulmonary bypass surgery. Fat and air embolism may also follow manipulation of the heart and chest during surgery. An increased risk of perioperative stroke is seen with advanced age, prior stroke, severe atherosclerosis of the ascending aorta, history of congestive heart failure, postoperative AF, and cardiopulmonary bypass time greater than 2 hours. Prevention of cerebral and systemic embolism from cardiac sources with anticoagulant therapy is recommended for patients with acute myocardial infarction, AF, and prosthetic and rheumatic valvular heart disease. Anticoagulant therapy is also recommended in treating systemic embolism from a noninfective cardiac source. Prolonged parented bactericidal antibiotics are the mainstay of treatment of infective endocarditis; cardiac surgery for replacement of the infected valve may be needed in selected instances. Prophylaxis for endocarditis is recommended for patients with MVP and associated mitral regurgitation. Prompt surgical resection is indicated for patients with atrial myxomas. Selective surgical repair is indicated for major ASDs. Transcatheter techniques for closure of these defects have been proposed. The optimal management of paradoxical embolism associated with PFO andlor ASA is unknown. Hematologic (Prothrombotic) States

A number of conditions produce a prothrombotic state. These conditions are thoroughly discussed in Chapter 37. Other Miscellaneous Causes Oral Contraceptives. Oral contraceptives are used by more than 60 million women worldwide. Early epidemiologic studies demonstrating an increased risk for stroke in women who used oral contraceptives containing more than 50 mg of ethynyl estradiol led to a reduction of the estrogen and the progestogen contents of oral contraceptives and the subsequent withdrawal of the high-estrogen contraceptive pills from the market. Although there appears to be a small relative risk of stroke in healthy women using oral contraceptives, the relative risk of stroke increases particularly with a coexistent history of hypertension and cigarette smoking. However, progestogen-only pills are not associated with an increased risk of cerebral ischemia, and the newer agents that contain low-dose estrogen (less than 50 pg of ethinyl estradiol) have, in the aggregate, reduced the frequency of oral contraceptive-related cerebral infarction. Furthermore, recent population-based studies have shown that current users of

low-dose oral contraceptives have a risk of stroke (ischemic and hemorrhagic) similar to that of women who have never used oral contraceptives. Pregnancy. Although it is widely believed that the risk of ischemic stroke increases during pregnancy, the assertion of an excess risk of pregnancy-related stroke has been increasingly challenged. In a recent publication from a hospital-based registry studying the incidence and causes of stroke in young adults 15 through 44 years of age, the risk of cerebral infarction and hemorrhage was found to be increased only in the 6 weeks after delivery but not during pregnancy. The incidence of cerebral infarction in this study was 4.3 per 100,000 deliveries (95% confidence interval, 2.4%-7.1Yo). Interestingly, eclampsia was present in almost 50% of those with cerebral infarction. Although stroke in association with pregnancy is uncommon, it is a leading cause of maternal death. A number of changes that occur with pregnancy may predispose to stroke. There are a variety of hematologic effects including a hypercoagulable state; increased platelet adhesion; increased fibrinogen; increased factors VII, VIII, IX, and X; and decreased fibrinolysis, with reduced levels of available circulating plasminogen activator. There are also hemodynamic changes that occur with pregnancy, including an increase in blood volume, cardiac output, stroke volume, and heart rate. There may be a mild decrease in arterial blood pressure and decreased total peripheral and pulmonary vascular resistance. Postpartum or peripartum cerebral angiopathy is a poorly defined, somewhat nebulous reversible clinicoradiologic syndrome characterized by headache, vomiting, seizures, and occasional focal neurologic findings occurring in the puerperium. The neurologic deficits are at times the result of infarction, which tends to predominate in the posterior aspect of the cerebral hemispheres, leading to unilateral or bilateral visual field defects (Fig. 3 6 4 4 and B). Some patients have had a history of exposure to ergot derivatives or sympathomimetic agents, including bromocriptine, ergonovine, ergometrine maleate, or methylergonovine. Angiography reveals multisegmental arterial narrowings (Fig. 36-4C and D). Treatment includes' withdrawal of vasoactive substances. Clinical outcome usually is favorable. Reversible posterior leukoencephalopathy is a rare cause of altered sensorium and seizures that is in the differential diagnosis of focal neurologic disorders occurring in the puerperium. Clinically and radiographically, this syndrome is similar to hypertensive encephalopathy. The common symptoms and signs include headache, vomiting, seizures, confusion, cortical blindness, and other visual abnormalities and motor signs. Although there are many reported causes of reversible posterior leukoencephalopathy including thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, renovascular hypertension, glomerulonephritis, systemic lupus erythematosus, cyclosporine toxicity, erythropoietin administration, and baroreflex failure after carotid endarterectomy, puerperal eclampsia is one of the most common causes. The pathophysiology of this syndrome is unclear. Neuroimaging studies show edema without infarction involving the white matter in the posterior aspects of the cerebral hemispheres. However, other areas of the brain may be involved. Postpartum reversible posterior leukoencephalopathy appears to have a good prognosis, with resolution of the neurologic deficits over 2 weeks with treatment of elevated blood pressure in the eclamptic patient. Metabolic Disorders. Homocystinuria is an inborn error of amino acid metabolism that is inherited as an autosomal recessive trait and is an unusual cause of stroke. Patients with homocystinuria may display a marfanoid habitus, malar flush, livedo

Chapter 36 W

reticularis, high arched palate, ectopia lentis (downward lens dislocation), iridodonesis, myopia, glaucoma, optic atrophy, psychiatric abnormalities, mental retardation, spasticity, seizures, osteoporosis, scoliosis, genu valgus, rapidly progressive atherosclerotic vascular disease, and life-threatening arterial and venous thromboses. Three specific deficiencies responsible for homocystinuria have been identified cystathionine p synthase, homocysteine methyltransferase, and 5,lO-methylene tetrahydrofolate reductase deficiency. High homocysteine levels have potentially deleteriouseffects on endothelium, platelets, and smooth muscle cells. A tendency toward multiple infarctions and a higher rate of lesions typical of cerebral microangiopathy has been observed in patients with hyperhomocystinemia. Hyperhomocystinemia has been associated with an increased risk of stroke and thrombotic events in case-control studies. Cohorts with higher levels of homocysteine have increased rates of atherosclerosis, and there is an increase in risk of stroke with increasing total blood homocysteine concentration. The vascular occlusive events can occur at any age; a 25% risk of thromboembolism has been estimated by the end of the second decade. Elevated levels of homocysteine can be effectively reduced with the administration of folate, occasionally necessitating the addition of pyridoxine (vitamin B6), cobalamine (vitamin BJ, choline, or betaine. Conversely, serum folate concentrations less than 9.2 nmol/L have been associated with elevated plasma levels of homocysteine and the suggestion has been made that a low folate concentration may be a risk factor for ischemic stroke, particularly among African Americans. Fabry’s disease (angiokeratoma corporis diffusum) is an X-linked recessive disorder caused by a deficiency of the lysosomal

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enzyme a-galactosidase A. As a result of this deficiency, glycosphingolipids are deposited in cells, particularly in the vascular endothelium. Clinical manifestations include corneal opacifications and recurrent episodes of painful dysesthetic peripheral neuropathy, angiokeratomas of the skin, fever, abdominal pain, hypohidrosis and other manifestations of autonomic dysfunction, renal disease, hypertension secondary to renal involvement, cardiac conduction abnormalities, myocardial ischemia, and cardiomegaly. Stroke may occur in children and young adults because of either small or large vessel cerebrovascular disease, intracerebral hemorrhage, or aneurysms. Female carriers may be asymptomatic or may have mild disease. Tangier disease is a rare autosomal recessive disorder characterized by hyperplastic orange tonsils, hepatosplenomegaly, lymphadenopathy, neuropathy, premature atherosclerotic disease, low cholesterol levels, normal or elevated triglycerides, and HDL deficiency. Cardiovascular and cerebrovascular complications are believed to be related to the deposition of cholesterol esters. The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a nonmendelian, maternally transmitted syndrome with multiple system involvement. Mitochondrial encephalomyopathiesshould be suspected in patients with intractable seizures, recurrent strokes, lactic acidosis, or respiratory failure. Features of MELAS include a period of normal development followed by clinical changes that may include confusion, dementia, episodic vomiting, migraine-like headaches, and progressive hearing loss. Focal neurologic involvement may present as sudden, transient, or partially regressive attacks of hemiparesis, aphasia, hemianopia, ataxia, or cortical blindness. The episodes may be precipitated by a febrile illness. Other

A

B

FIG. 56-4. A 32-year-old woman developed severe headache, right hemiparesis, and a generalized seizure in the postpartum period, associated with cortical blindness. (A and 13) MRI 02-weighted and proton-density) showing bilateral acute occipital infarcts in the distribution of the posterior cerebral artery (arrows). //lustration continued on following page

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C

D

FIG. 36-4. Continued (C) Contrast angiogram showing multiple areas of arterial constriction in the posterior cerebral arteries (arrows). (0) Contrast angiogram with multiple areas of segmental constriction and dilation of distal branches of the right posterior cerebral artery (middle two arrows), lenticulostriate branches of the middle cerebral artery (middle arrow), and

middle cerebral artery trunk (lower arrow).

features may include lactic acidosis, short stature, muscle weakness, ragged red fibers, and exercise intolerance. The stroke-like episodes have a propensity for the posterior brain regions, may not conform to arterial territories, and occur before age 40 years. Treatment for MELAS has included coenzyme QlO, carnitine, vitamin C, riboflavin, and corticosteroids. Genetic Disorders. Marfan syndrome is an autosomal dominant inherited connective tissue disease associated with qualitative and quantitative defects of fibrillin. Affected patients have a variety of skeletal, ocular, and cardiovascular abnormalities. Marfan syndrome can have a number of features, including arachnodactyly, upward displacement of the lens, extreme limb length, joint laxity, pectus excavatum or carinatum, and aortic valvular insufficiency. Cardiovascular abnormalities that may be present include dilation of the aortic root, coarctation of the aorta, mitral valve prolapse, and mitral annulus calcification with regurgitation. Complications that may lead to cerebral ischemia include dissection of the ascending aorta caused by progressive

dilation of the aortic root, infective endocarditis, saccular intracranial aneurysms, or carotid artery dissections. Ehlers-Danlos syndrome is an autosomal dominant defect of collagen synthesis that causes hyperextensibility of the skin, hypermobile joints, and vascular fragility with bleeding diathesis. Arterial complications such as dissections, arteriovenous fistulas, and intracranial aneurysms have been reported with EhlersDanlos syndrome types I, 111, and IV,especially the last. Other cardiovascular abnormalities in patients with type IV EhlersDanlos syndrome include ventricular and atrial septal defects, aortic insufficiency, bicuspid aortic valve, mitral valve prolapse, and papillary muscle dysfunction. Arteriography can be risky in this population and should be avoided, if possible. Neurofibromatosis type 1 (NF1 or von Recklinghausen disease) is an autosomal dominant disorder with incomplete penetrance associated with a distinct chromosomal abnormality located on the long arm of chromosome 17. New mutations account for approximately half of the cases. NF1 can be associated with

Chapter 36

occlusive cerebrovasculardisease with extensive collateral channels in the basal ganglia and thalamus, resembling Moyamoya disease. Stroke in the very young may result from severe hypertension associated with NF1. Tuberous sclerosis (Bourneville’s or Pringle’s disease) is an autosomal dominant disease with cutaneous, visceral, ophthalmologic, and neurologic manifestations. Cerebral infarction may result from cardiac rhabdomyomas. Angiography may show features resembling Moyamoya disease. Miscellaneous Disorders. Susac syndrome is an occlusive arteriolar microangiopathyinvolving the brain, retina, and cochlea that occurs most often in young women. Although the cause is unknown, it has been attributed to an immune-mediated mechanism. Bilateral low-frequency sensorineural hearing loss results from cochlear infarcts. Arteriolar branch occlusions of the retina may occur and often are bilateral. MRI may demonstrate multifocal white and gray matter hyperintensities on T2-weighted images. Brain biopsy may show nonspecific periarteriolar chronic inflammatory cell infiltration with or without microinfarcts in both the gray and white matter. Treatment has included antithrombotics, calcium channel blockers, corticosteroids or other immunomodulators, intravenous immunoglobulins, plasmapheresis, and hyperbaric oxygen. Eales disease is a noninflammatory, vasoproliferative retinal perivasculitis characterized by repeated retinal and vitreous hemorrhages. It is more prevalent in the Middle East and the Indian subcontinent. Those affected are predominantly healthy young men. Although neurologic complications are rare, a few patients have developed ischemic strokes. Treatment with photocoagulation is effective in some patients. Undetermined

Despite a thorough investigation, up to 40% of strokes in young adults are of undetermined cause. A stroke should not be labeled as undetermined in cause unless a complete investigation has been performed. DIAGNOSIS Emergent Diagnostic Studies

Rapid diagnosis and treatment are important to maximize recovery and prevent the recurrence of stroke. Patients with an acute stroke should be admitted to the hospital for emergency evaluation and treatment, preferably in a stroke unit or intensive care unit where close medical and nursing observation is available. The goal of the diagnostic evaluation is to establish the diagnosis of ischemic cerebrovascular disease as a cause of the patient’s symptoms and to determine the underlying cause of the event. It is critical to diagnose and manage stroke within the first few hours. Emergent diagnostic laboratory studies that should be performed on all patients with ischemic stroke include a complete blood count with differential and platelet count, prothrombin time, partial thromboplastin time, plasma glucose level, blood urea nitrogen, serum creatinine, chest roentgenogram, and electrocardiography. If trauma is suspected, radiographic studies of the cervical spine and skull should be performed. Computed tomography (CT) of the brain without contrast is the emergent imaging study of choice in acute stroke to differentiate ischemic from hemorrhagic strokes. It is the recommended study before administration of thrombolytic therapy within 3 hours of symptom onset. MRI of the brain often provides different information

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from CT in patients with acute stroke. It is recommended for imaging of suspected brainstem infarcts, infarcts in the posterior and lower middle fossa, and small infarcts that are not visualized with CT. Diffusion-weightedMRI can detect ischemic brain tissue within the first 60 minutes after stroke onset. Diffusion-weighted imaging can be complemented with information obtained from perfusion-weighted imaging to delineate fairly accurately the areas of necrosis and surrounding ischemic and potentially salvageable tissue. The role of spiral CT angiography, magnetic resonance spectroscopy, single-photon emission computed tomography, and positron emission tomography in evaluating acute stroke patients remains uncertain. Subsequent Diagnostic Studies

Subsequent studies that should be considered include sedimentation rate, lipid analysis, syphilis serology, drug screen, and urinalysis. In some patients with ischemic stroke it is necessary to perform detailed hematologic testing to rule out hypercoagulable disorders. Tests that may be considered include: functional assay of antithrombin I11 level to evaluate for an antithrombin 111 deficiency; prothrombin G202 10A mutation; immunologic and functional assay of protein C and protein S; testing for resistance to activated protein C and factor V Leiden mutation; immunologic and functional assays of fibrinogen to evaluate for hyperfibrinogenemia or dysfibrinogenemia; plasminogen level to evaluate for hypoplasminogenemia or dysplasminogenemia; and anticardiolipin, antiphosphatidylethanolamine and antiphosphatidylserine antibodies with activated partial thromboplastin time 1:1 mix or kaolin clotting time and dilute Russel Viper Venom Time to evaluate for the antiphospholipid antibody syndrome and the presence of lupus anticoagulant.A number of other studies may be needed, and which tests are done is tailored to the individual situation. Cardiac investigations such as a two-dimensional echocardiogram and transesophageal echocardiography are advised in selected circumstances to evaluate for a cardiac embolic source. Transesophageal echocardiography is useful in young adults with stroke of unclear cause. Carotid Doppler ultrasonography is used as a noninvasive means of evaluating for stenosis or occlusion of the common and proximal portions of the internal and external carotid arteries. Cerebral angiography often is indicated in young adults with cerebral infarction because unusual causes, including nonatherosclerotic vasculopathies such as dissection and vasculitis, are much more common than in the older populations. Cerebral angiography should be used in any patient in whom there is no clearcut cause for cerebral infarction if its use would change management. Magnetic resonance angiography is recommended as an alternative method in patients who have a contraindication to conventional contrast angiography. It is not the recommended test for detecting vasculitis or ulcerative carotid artery disease. Magnetic resonance angiography has been useful in the detection and follow-up of vascular dissection. TREATMENT Medical and Neurologic Management

Medical and neurologic care should focus on preventing complications. A number of potential complications can arise after a stroke. During the first week after an acute cerebral infarction, the most common cause of deterioration is development of brain

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edema. One general clinical observation that can be made about young people with stroke is the seemingly greater tendency to develop symptoms associated with cerebral edema in the region of the cerebral infarction because of the relative lack of cortical atrophy that is often present in older patients. Patients may need antiedema agents or, in rare instances, surgical intervention in instances of nondominant hemispheric infarctions (usually associated with complete internal carotid territory infarctions), so monitoring is essential. In the second through fourth weeks, pneumonia is the most common cause of non-neurologic death. Other complications include seizures, cardiac arrhythmias, myocardial infarction, deep-vein thrombosis, electrolyte disturbances, decubitus ulcers, and urosepsis. Frequent neurologic checks are vital in the early recognition of neurologic changes associated with herniation, recurrent or progressive stroke, or complications such as seizures. In patients with stroke, the blood pressure should be monitored frequently or even continuously for the first 48 to 72 hours. It is not unusual for the blood pressure to be transiently elevated after a stroke. Within a few days, the blood pressure may return to prestroke levels. Whether transient elevations should be treated is controversial. It is important not to overtreat the blood pressure and cause hypotension. The most important objective is to maintain adequate cerebral blood flow in the presence of impaired autoregulation. If it is decided that urgent lowering of the blood pressure is indicated, intravenous labetalol can be given (e.g., 10 mg over 1 to 2 minutes, repeated or doubled every 10 to 20 minutes until the desired response has been achieved or a maximum dosage of 300 mg has been administered). Contraindications to the use of labetalol include congestive heart failure, asthma, or second- or third-degree heart block. Cardiac monitoring is recommended for the first 24 to 48 hours after stroke because of the high frequency of cardiac dysfunction associated with stroke. In approximately 3% of cases, concomitant cerebral and myocardial ischemia can occur. A variety of cardiac arrhythmias can complicate ischemic stroke. If ischemic electrocardiographic changes occur, serial creatine kinase, lactate dehydrogenase, or troponin isoenzymes are indicated. In the bedridden patient or in the patient with impaired oropharyngeal function, measures to prevent pulmonary complications are necessary. The mortality rate of pneumonia is as high as 25%. It is important to place a temporary enteral feeding tube if there is evidence of oropharyngeal dysfunction to minimize the risk of aspiration. Good pulmonary toilet is essential, including chest physical therapy, frequent turning, and volumetrics. Lower-extremitydeep-vein thrombosis in the hemiparetic limb is common if prophylaxis is not initiated. If there are no contraindications, low-dose subcutaneous heparin is used at a dosage of 5000 U twice a day. If heparin is contraindicated, intermittent pneumatic compression of the lower extremities is recommended. The patient’s nutritional status and fluid needs should be assessed. Patients with a large ischemic stroke may need a fluid restriction of two thirds of maintenance during the first few days. The patient’s swallowing function should be assessed before intake of fluid or food is initiated. Patients who have significant oropharyngeal dysfunction need parented or tube feeding. Seizures occur in a small percentage (less than 5%) of patients after an ischemic stroke. Anticonvulsant medications must be initiated if a seizure occurs. Indwelling catheters should be placed only if absolutely necessary and should be removed at the earliest possible time to

avoid urosepsis. The chronic use of an indwelling catheter should be limited to patients with incontinence or urinary retention that is refractory to other treatments. Pressure sores develop in approximately 15% of patients after a stroke. Steps to avoid this complication include inspecting and cleansing the skin, turning the patient frequently, using special mattresses and protective dressings, maintaining adequate nutritional status, and trying to improve the patient’s mobility. One of the most common causes of injury to the patient with a stroke is falling. The patient’s risk of falling should be assessed at regular intervals during the acute hospitalization. Measures should be instituted to minimize the risk of falls. Rehabilitation after stroke begins as soon as the diagnosis of stroke is established and as soon as any life-threatening neurologic or medical complications have been stabilized. Patients are screened to evaluate whether they are candidates for rehabilitation. The criteria used to make this decision, including the stroke survivor’s clinical and neurologic status and social and environmental factors, are complex. The available evidence on the effectiveness of rehabilitation suggests that rehabilitation is beneficial for some patients, but the superiority of a given type or the characteristics of patients most likely to benefit are not clear. Prosthetic devices, canes, or walkers should be used when appropriate.

Medical Management Several antiplatelet agents, including aspirin, ticlopidine, clopidogrel, and the combination of low-dose aspirin and slow-release dipyridamole are available for preventing stroke. Aspirin reduces the risk of stroke by approximately 20%. The dosage used has varied between 81 mg and 1300 mg per day. Evidence of the effectiveness of lower dosages of aspirin (81 or 325 mg) comes from the Aspirin in Carotid Endarterectomy (ACE) trial. In this trial, 2849 patients who were scheduled for carotid endarterectomy were randomly assigned to compare the benefits of low-dose aspirin (81 or 325 mg daily) with those of high-dose aspirin (650 or 1300 mg daily). At 3 months after surgery, the risk of stroke, myocardial infarction, or death was 6.2% in the low-dose aspirin group and 8.0% in the high-dose aspirin group. The side effects of aspirin are mainly gastrointestinal. Ticlopidine is an antiplatelet agent that exerts its effects by interfering with adenosine diphosphate-mediated platelet aggregation. It prolongs the bleeding time more than aspirin. Ticlopidine reduces the relative risk of all cardiovascular and cerebrovascular mortality, myocardial infarction, and stroke by 10% in comparison to aspirin. It is usually reserved for patients who are unable to tolerate aspirin because of allergy or gastrointestinal side effects or for patients who have recurrent cerebrovascular ischemia despite treatment with aspirin. The dosage is 250 mg twice a day with food. Side effects include neutropenia, rash, and diarrhea. A complete blood count with differential must be performed every 2 weeks for the first 3 months of therapy. The drug must be discontinued if the neutrophil count falls below 1200/mm3. Clopidogrel is a platelet adenosine diphosphate receptor antagonist. The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study assessed the relative efficacy of clopidogrel(75 mg daily) versus aspirin (325 mg daily) in reducing the incidence of ischemic stroke, myocardial infarction, and vascular death in 19,185 patients with previous ischemic stroke, recent myocardial infarction, or symptomatic atherosclerotic peripheral arterial disease. The results of this study showed that

Chapter 36 rn Stroke in Young Adults

clopidogrel was modestly more effective (8.7% relative risk reduction, p = .043) than aspirin in reducing the risk of the composite outcome cluster of ischemic stroke, myocardial infarction, or vascular death in patients with atherothrombotic disease. Overall, the tolerability of clopidogrel was excellent, with no higher incidence of neutropenia and a significantly lower incidence of gastrointestinal hemorrhage, indigestion, nausea, and vomiting than aspirin. The rate of diarrhea, rash, and pruritus with clopidogrel was higher than with aspirin. A recent report associated clopidogrel with thrombotic thrombocytopenic purpura (TTP) in 1 1 patients. How this observation will affect the clinical use of clopidogrel remains to be seen. Combinations of aspirin and clopidogrel are being tested for the secondary prevention of strokes in patients with TIA or stroke. Dipyridamole is a phosphodiesterase inhibitor that increases the levels of cyclic adenosine monophosphate and thereby diminishes platelet adhesion and possibly subsequent aggregation. It is still a matter of debate whether dipyridamole in combination with aspirin achieves any additional benefit over aspirin alone in patients with threatened stroke. The clinical efficacy of dipyridamole alone as a single agent is questionable. The European Stroke Prevention Study 2 randomized patients with prior stroke or TIA to treatment with aspirin alone (25 mg twice daily), modified release dipyridamole (200 mg twice daily), the two agents in combination, or placebo. The European Stroke Prevention Study 2 investigators concluded that both low-dose aspirin and high-dose dipyridamole in a modified release form alone were superior to placebo and that the combination was significantly superior to each drug alone. The European Stroke Prevention Study 2 investigators reported that dipyridamole had an additive effect when prescribed with aspirin. The Combination of aspirin 25 mg and dipyridamole 200 mg is now available for twice-daily dosing for secondary prevention of ischemic stroke and TIA. The combination appeared to have little additional benefit in preventing myocardial infarction or fatal stroke. Among the 25% of patients who withdrew from the study, most were in the dipyridamole and combination groups. The main side effects of dipyridamole are gastrointestinal distress, headache, and vasodilation. Heparin is a heterogeneous mixture of glycosaminoglycans that has anticoagulant properties. Heparin, in combination with small amounts of antithrombin I11 (heparin cofactor), inhibits thrombosis by inactivating factor X and inhibiting the conversion of prothrombin to thrombin. In addition, coagulation is further inhibited by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin is used acutely in selected patients after transient cerebral ischemia or cerebral infarction. At present, using or not using intravenous heparin to treat acute ischemic stroke or cardioembolic stroke is the physician’s preference because there are no definitive data about the safety and efficacy of intravenous heparin for these conditions. Intravenous heparin is given to some patients with nonseptic cardioembolic stroke to prevent recurrence, based on a small trial performed by the Cerebral Embolism Study Group. This study of 45 patients suggested that heparin might be useful, but the study was terminated prematurely because of a high rate of complications in the group that received delayed anticoagulation.The International Stroke Trial evaluated 19,333 patients who were randomized within 48 hours of stroke onset to receive 10,000 U or 25,000 U of heparin subcutaneously daily (compared to no heparin). There was no significant difference in the rate of death or recurrent ischemic or hemorrhagic stroke at 2 weeks (11.7% with heparin

351

and 12.0% without heparin). Patients receiving heparin had significantly fewer recurrent ischemic strokes at 2 weeks, but this was negated by a similar increase in hemorrhagic strokes. It should be noted that this trial used subcutaneous rather than intravenous heparin. Aggregate data from randomized and nonrandomized studies of the use of anticoagulants in stroke in evolution suggest that intravenous heparin reduces the rate of progression of cerebral infarction. However, some studies have not demonstrated a beneficial effect of intravenous heparin in these patients. Based on anecdotal evidence without the benefit of any statistically significant data, many physicians use intravenous heparin to prevent stroke recurrence in the setting of inherited or acquired hypercoagulable states, intraluminal arterial thrombus, extracranial cervicocephalic dissections, aseptic cerebral venous sinus thrombosis, and large vessel atherothrombosis and after embolic stroke in the setting of AF. If intravenous heparin is used, many physicians do not use a bolus and aim for a target activated partial thromboplastin time of 55 to 75 seconds or 1.5 to 2.0 times the control value. Warfarin is an anticoagulant that inhibits the vitamin K-dependent clotting factors 11, VII, IX, and X. It is usually reserved for use in patients who have a cardioembolic source of stroke and those who do not respond to antiplatelet agents. Warfarin is indicated for primary and secondary stroke prevention in patients with nonvalvular AE Patients with nonvalvular AF who are at high risk of stroke are treated with warfarin to maintain an International Normalized Ratio of 2.0 to 3.0. Patients who are less than 65 years old and have no other risk factors can be treated with aspirin, 325 mglday. Warfarin is also used in patients with AF and hyperthyroidism, after anterior wall myocardial infarction, after myocardial infarction with apical wall motion abnormalities or left ventricular thrombus, with mechanical prosthetic heart valves, and for 3 weeks before and 4 weeks after cardioversion for AF. Whether warfarin should be used to treat patients with symptomatic stenosis of a major artery is uncertain. A major trial (Warfarin-Aspirin Recurrent Stroke Study, or WARSS) compared the use of warfarin or aspirin for the prevention of recurrent stroke, and the results indicated no difference in efficacy of the two agents tested. An ongoing clinical trial (Warfarin Aspirin Symptomatic Intracranial Disease study, or WASID) is comparing these two agents for stroke prevention in patients with symptomatic stenosis of a major intracranial artery. Tissue plasminogen activator is indicated for the acute treatment of certain patients with ischemic stroke within 3 hours. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group showed that treatment with intravenous tissue plasminogen activator within 3 hours of onset of ischemic stroke improved clinical outcome (minimal or no disability on all four clinical assessment scales used) at 3 months. The study enrolled 624 patients. Cerebral angiography was not performed, so drug efficacy was assessed only by clinical outcome measures. Intravenous recombinant tissuetype plasminogen activator (0.9 mglkg, not to exceed 90 mg total, with 10% of the total dosage administered in a bolus given over 1 minute and the remainder of the infusion given intravenously over 1 hour) improved the proportion of patients with complete or near complete neurologic and functional recovery at 3 months by 11% to 14% (depending on the scale used) compared to placebo; the relative benefit was 30% to 50%. Subsequent assessment using a global statistic also demonstrated a sustained benefit of intravenous r-tPA at 6 and 12 months after the intervention in patients treated within 3 hours after onset of ischemic stroke symptoms. Additional prospective

352

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Less Common Causes of Stroke

randomized trials have not supported the use of intravenous rt-PA beyond 3 hours. The Second European-Australasian Acute Stroke Study investigators failed to confirm a statistical benefit for alteplase within 6 hours of ischemic stroke onset. The Prourokinase in Acute Cerebral Thromboembolism (PROACT) I1 trial with intra-arterial prourokinase given within 6 hours of ischemic stroke showed efficacy for improving outcome after ischemic stroke. Ancrod, a fibrinogen-depleting agent derived from Malaysian pit viper venom, was also shown to be beneficial for treating ischemic stroke when it was administered within 3 hours of stroke onset. Neither of these treatments has been approved by the U.S. Food and Drug Administration.

Stroke in young adults accounts for 3% to 10% of all patients with stroke. Diagnosis of the specific cause of stroke in young adults requires a knowledge of the numerous and diverse potential causes of cerebral ischemia in this age group compared to older adults with stroke. The emergent evaluation and treatment of stroke are similar for older and younger patients. Prognostic data indicate a nearly 4% annual mortality rate. Attention should be paid to preventing stroke recurrence in the young population.

Surgical Management

SUGGESTED READINGS

Carotid endarterectomy (CEA) is recommended for patients with symptomatic carotid stenosis of more than 70% as measured in the manner described by the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The European Carotid Surgery Trial (ECST) also showed a benefit from CEA compared with medical therapy in patients with mild carotid territory ischemic events associated with a diameter-reducing proximal internal carotid artery stenosis between 70% and 99%. It should be noted that a diameter-reducing stenosis of 70% to 99% by NASCET criteria is equivalent to a stenosis of 82% to 99% by ECST methodology; likewise, stenosis of 70% to 99% by ECST criteria is equivalent to a stenosis of 50% to 99% by NASCET criteria. For the benefit of CEA to occur, the surgery should have a low rate of morbidity and mortality. With a low surgical risk, carotid endarterectomy also provides a modest benefit in symptomatic patients with carotid artery stenosis of 50% to 69%, especially in those with hemispheric ischemia and no history of diabetes. Carotid endarterectomy provides no benefit if the stenosis is less than 50% (50% by NASCET criteria is equal to 75% stenosis by ECST criteria).

PROGNOSIS

Adams HP, Kappelle LJ, Biller J et a1 Ischemic stroke in young adults: experience in 329 patients enrolled in the Iowa Registry of Stroke in Young Adults. Arch Neurol 52:491, 1995 Andrew M Blood clots and strokes. A guide for parents and little folks. B.C. Decker Inc., London, 1998 Austin H, Chimowitz MI, Hill HA et al: Cryptogenic stroke in relation to genetic variation in clotting factors and other genetic polymorphisms among young men and women. Stroke 33:2762,2002 Biller J: Non-atherosclerotic vasculopathies. pp. 57-81. In Biller J (ed): Stroke in Children and Young Adults. Butterworth-Heinemann, Boston, 1994 Bogousslavsky J, Devuyst G, Nendaz M et ak Prevention of stroke recurrence with presumed paradoxical embolism. J Neurol 24471, 1997 Bogousslavsky J, Regli F Ischemic stroke in adults younger than 30 years of age: cause and prognosis. Arch NeurolM479, 1987 Garg BP, Bruno A, Biller J: Moyamoya disease and cerebral ischemia. pp. 489-499. In Batjer HH (ed): Cerebrovascular Disease. LippincottRaven, Philadelphia, 1997 Hinchey J, Chaves C, Appignani B et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334:494, 1996 Jacobs BS, Boden-Albala B, Lin IF, Sacco RL: Stroke in the young in the northern Manhattan stroke study. Stroke 33:2789, 2002 Musolino R, La Spina P, Granata A et al: Ischaemic stroke in young people: a prospective and long-term follow-up study. Cerebrovasc Dis 15:121,

In general, population-based data about the prognosis of ischemic stroke in young adults are lacking. One study followed 296 consecutive ischemic stroke patients aged 15 to 44 years and found that the mortality from vascular death was 1.7% and the incidence of vascular death, nonfatal myocardial infarction, o r recurrent stroke was 2.6% per year based on a mean follow-up time of 6 years. The mortality and the incidence of vascular death, nonfatal myocardial infarction, or recurrent stroke were twice as high among patients with large vessel disease. Prognosis is slightly better for the 16- to 30-year age group than for the 31- to 45-year age group. Mortality also is greater in those with a cardiac source of cerebral infarction. Another study of 330 patients with an average follow-up of 96 months found that the average annual mortality rate was higher during the first year (3.94%, 95% CI, 1.84%-6.04%) than in subsequent years. Myocardial infarctions occurred later, after the first year, with rates that were similar in patients with stroke and TIA at entry.

Pathan M, Kittner SJ: Pregnancy and stroke. Curr Neurol Neurosci Rep 3:27, 2003 Pezzini A, Del Zotto E, Magoni M et al: Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke 34:28, 2003 Pullicino P, Greenberg S, Trevisan M: Genetic stroke risk factors. Curr Opin Neurol 10:58, 1997 Schwartz SM, Petitti DB, Siscovick DS et al: Stroke and use of low dose oral contraceptives in young women: a pooled analysis of two US studies. Stroke 29:2277, 1998 Sharsar T, Lamy C, Mas J L Incidence and causes of stroke associated with pregnancy and puerperium: a study in public hospital of fle de France. Stroke 26:930, 1995 Williams LS, Garg BP, Cohen M et al: Subtypes of ischemic stroke in children and young adults. Neurology 49:1541, 1997 Zeiler K, Siostrzonek P, Lang W et al: Different risk factor profiles in young and elderly stroke patients with special reference to cardiac disorders. J Clin Epidemiol45:1383, 1992

CONCLUSION

2003

Chapter 37

37

Coagulation-Related Causes of Stroke

353

Coadation-Related Causes of Stroke v

Catherine Cho, Nalini Samuel, Luis D'olhaberriague, Lawrence M. Brass, and Steven R. Levine COAGULOPATHIES A wide variety of hematologic disorders underlie a proportion of all strokes. They have been implicated in about 5% of strokes, but they are a more common cause in young patients, in whom approximately 10% of cases are presumed to be caused by a coagulation disorder. Most of these are associated with a higher thrombotic tendency and a higher risk of ischemic stroke. Less commonly, a bleeding diathesis may predispose a patient to intracranial hemorrhage. Normal hemostasis is a delicate balance between the coagulation pathways and the vascular endothelial cells. Hypercoagulability may arise from deficiencies of factors inhibiting coagulation (e.g., antithrombin 111, protein C and protein S, plasminogen and plasminogen activator), elevated levels of factors promoting coagulation (e.g., factors V and VIII, fibrinogen, fibrin, thrombin, plasminogen activator inhibitor), and systemic states that are often associated with cerebrovascular complications (e.g., diabetes, hyperlipidemia, sepsis). Disorders of cellular blood elements can be associated with stroke (Table 37-1). Hypercoagulable states present more often with venous than arterial thrombosis. Venous occlusions account for only 1% to 4% of strokes. The yield of thrombophilia screens in the evaluation of venous thrombosis has increased from 10% to 15% to 25% to 30% since the discovery of the factor V Leiden and the prothrombin G20210A mutations. It is generally recommended to screen for these and other prothrombotic states in patients with cryptogenic embolic stroke, or even when there is another potential embolic source such as patent foramen ovale or atrial septal aneurysm, because the association of these disorders with ischemic stroke has been questioned by recent data (from the WARSS [WarfarinAspirin Recurrent Stroke Study] trial). The difficulty is in determining whether a thrombophilic disorder predisposed the patient to a stroke, whether it was coincidental, or whether the blood changes reflect an acute phase reaction. There are surprisingly few rigorous studies demonstrating an independent risk of specific coagulation disorders and the risk of arterial stroke. Coagulopathies can be inherited, acquired, or both. The most commonly investigated inherited coagulopathies in the clinical evaluation of patients with stroke are deficiencies of protein C, protein S, and antithrombin 111, as well as point mutations of factor V and the prothrombin gene. Protein C and protein S are both vitamin K-dependent cofactors. Protein C is activated by thrombin. It has lytic effects on activated factor VIII. A deficiency results in an enhanced tendency for thrombosis. The hereditary form has been reported in association with recurrent venous thrombosis, usually in children or young adults. Factor V point mutations result in activated protein C resistance. Factor V Leiden is the most common point mutation found in populations of European descent. This mutation is rare in Asians and Africans. Activated protein C resistance is linked with oral contraceptiveassociated venous thrombosis. The pathogenesis of the thrombotic disorders related to the prothrombin G20210A gene mutation is unclear. Accelerated thrombin formation is suspected once the coagulation cascade is initiated. This mutation is associated with

rn

cardiac disease and has been linked to stroke in the young and strokes of undetermined cause, especially venous sinus thrombosis in young women who use oral contraceptives. The antiphospholipid (aPL) syndrome, hyperhomocystinemia, dysplasminogenemia, high plasminogen activator inhibitor, dysfibrinogenemia, genetic polymorphisms of factor VII, and elevations in factors V and VIII have also been implicated in the pathogenesis of stroke. Some of the acquired hypercoagulable states involving coagulation factors include the aPL syndrome, hyperhomocystinemia, diffuse intravascular coagulation, thrombocythemia, pregnancy, malignancy, trauma, infection, obesity or stasis, nephrotic syndrome, liver disease, nutritional deficiencies, and medications. Hypertension and atrial fibrillation have also been associated with a hypercoagulable state via mechanisms related to the Virchow's triad. Acquired deficiencies of protein C, S, and antithrombin 111 are common in both acute and chronic medical diseases. Factor VIII is an acute phase reactant and can be elevated after a stroke. However, the factor VIIIC to fibrinogen ratio can distinguish between an intrinsically elevated level of factor VIII from a response to an acute illness. Often, the initial workup of a hypercoagulable state is initiated within a few days of a stroke. Most of the studies have to be repeated off anticoagulation 8 to 10 weeks after the stroke to establish the existence of thrombophilia. In selected patients under 50 years of age, with previous history of a thromboembolic event, family history of a clotting disorder, miscarriages, or the absence of other risk factors for stroke, ischemic stroke is more likely to be attributable to thrombophilia

N t a m 37-1. Disorders of Cellular Blood Elements Associated

with Cerebrovascular Disease

Erythrocytes

Functional changes Paroxysmal nocturnal hemoglobinuria Enhanced aggregability Altered number of red blood cells Increased: primary and secondary polycythemia Vera Decreased: anemia Leukocytes

Increased: leukemia (acute non-lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia) and lymphoma (Hodgkin's, non-Hodgkin's) Decreased: chronic familial cerebral vasculopathy Platelets

Disorders of aggregability Increased: Sticky platelet syndrome Decreased: Clanzmann's thrombasthenia, antiplatelet medications and drug effects, uremia, paraproteinemia Altered numbers Increased: essential thrornbocythemia,thrombocytosis Decreased: thrombocytopenia (thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura), alloimmune thrombocytopenic purpura, heparin-induced thrombocytopeniatypes I and II, hemolytic-uremicsyndrome, Wiscott-Aldrich syndrome Plasma Cells

Increasedplasma cells or protein: Waldenstrom's macroglobulinemia, myeloma, cryoglobulinemia

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Cerebrovascular Disease w

Less Common Causes of Stroke

than in the general population of stroke victims. Hypertension, diabetes, atherosclerosis, cardiac emboli, and arterial dissection still represent the majority of causes for stroke in the young; even in the presence of these mechanisms, studies of hypercoagulability often are recommended. The double hit theory presumes that in these patients, a thrombophilic disorder will lower their threshold for developing a stroke. In the absence of other risk factors, however, these patients may remain asymptomatic. Many women with a thrombotic event during pregnancy or oral contraceptive use have the prothrombin G20210A gene mutation, suggesting that screening for this mutation may be warranted in women who are contemplating pregnancy, oral contraceptive use, or hormone replacement. Coagulopathies are more prevalent in cerebral venous thrombosis than in arterial strokes. Patients typically present with headache, nuchal rigidity, papilledema, focal neurologic deficits, seizures, fever, and an altered mental status. Infection often is the trigger for these events. Coagulopathies that are risk factors for cerebral venous thrombosis include factor V Leiden, oral contraception, puerperium or pregnancy, dehydration, sepsis, aPL syndrome, malignancy, prothrombin gene mutation G20210A, and deficiencies of proteins C, S, and antithrombin 111. The trigger for an individual stroke associated with a coagulopathy usually is unknown, but surgery, trauma, pregnancy, oral contraceptives, and systemic illness have been postulated. New medications must also be suspected. COX-2 inhibitors may contribute to a prothrombotic state. Phenytoin interferes with vitamin B metabolism, resulting in hyperhomocystinemia. Therapy should be tailored to the individual case. For those with an acquired coagulopathy, treating the underlying condition may reverse the risk. Malignancies, especially much-producing adenocarcinomas, express tissue factors and may excrete cancer procoagulant A, which activates factor X. Malignancy-induced hypercoagulable states generally are treated with warfarin. However, subtherapeutic international normalized ratios (INRs) are associated with both increased thrombotic events and hemorrhage. In hereditary disease, especially with recurrent ischemic episodes or life-threatening events, warfarin often is recommended indefinitely. However, well-designed clinical trials confirming these trends and practices are lacking. Indiscriminate screening for thrombophilias in stroke patients has low yield and is not cost-effective. Pretest probabilities can be optimized by selecting tests based on patients’ histories, clinical presentations, and basic laboratory abnormalities. Bushnell et a1 (2001b) recently reviewed the literature selecting controlled studies of ischemic strokes and the prevalence of the factor V Leiden mutation or activated protein C resistance (APCR), the prothrombin G20210A gene mutation, deficiencies of antithrombin 111, protein C, protein S, and plasminogen, and the presence of anticardiolipin and aPL antibodies. All testing should be performed at least 2 months after the stroke. In hereditary coagulation defects (deficiency of protein C, protein S, antithrombin 111, plasminogen), the pretest probability in unselected patients is not known. Selected patients in whom testing is justified are those with a history of venous or arterial thrombosis before age 45, recurrent thrombosis without precipitating factors, thrombosis in an unusual location, warfarininduced skin necrosis, family history of thrombosis, thrombosis during pregnancy or oral contraceptive use, and resistance to heparin. Warfarin should be discontinued for 2 weeks, and heparin should be discontinued for at least 24 hours before testing for these coagulation disorders. Screening should use the func-

tional assays for protein C and protein S or antithrombin 111. If abnormalities are present, then quantitative tests are warranted. The abnormal results should be confirmed by repeating the tests weeks to months later. Testing also may have significance for family members. APCR was prevalent in 11% of ischemic strokes that occurred under age 50 and in 7% in all ages in one study. The prothrombin G20210A gene mutation was present in 6% of patients with strokes that occurred under age 50 and in 5% of all ages. A history of cerebral or venous thrombosis, thrombosis during pregnancy or oral contraceptive use, or family history of thrombosis increases the pretest probabilities. The patient should be off heparin for 24 hours and off warfarin for 2 weeks before testing. If the partial thromboplastin time-based assay for APCR is abnormal (PCAT-NR less than 0.85 or APCR ratio less than 2.1), then polymerase chain reaction testing for factor V Leiden or other factor V mutations should be pursued. The prothrombin gene mutation can be detected only by polymerase chain reaction testing. Hyperviscosity

Increased blood viscosity has been associated with decreased blood flow and a higher risk of ischemic stroke. This may result from diseases of red blood cell morphology or quantity. Macroglobulinemia (Waldenstrom’s disease) may produce a hyperviscosity state or a bleeding diathesis, leading to ischemic or hemorrhagic stroke, respectively. The recommended management is with plasmapheresis. In addition, multiple myeloma, particularly immunoglobulin A (IgA) myeloma, predisposes to a hyperviscosity state. Other causes of hyperviscosity syndrome are polycythemia Vera, cryoglobulinemia, and collagen vascular disorders. Treatment usually is directed at the underlying disorder. Phlebotomy may be useful if the hematocrit is extremely elevated. Other Hematologic Abnormalities

Although thrombophilic disorders are associated with venous more than with arterial occlusive disease, a large number of hematologic disorders are associated with an increased risk of arterial thrombosis. Platelet abnormalities, dysplasminogenemia, dysfibrinogenemia, and elevations in factors VII, VIII, and von Willebrand factor have all been associated with arterial thrombosis. The role of platelet abnormalities has been difficult to demonstrate in clinical studies because platelet function testing is technically difficult to perform, and even the process of venipuncture can activate platelets. Any process that damages the endothelium is associated with accelerated platelet activation. Most of the studies have been described in the cardiovascular literature. In 1996, a polymorphism of the glycoprotein IIb and IIIa receptor was described as an inherited risk factor for coronary artery disease. Despite the difficulties in diagnosing the disorders of platelets and coagulation, the importance of this group of disorders is likely to increase in the future. C-reactive protein is an emerging risk factor for cardiovascular events and a marker for inflammation. In the Framingham study, older adults with the highest quartile of C-reactive protein were at the greatest risk for cerebrovascular events (transient ischemic attacks and ischemic strokes). However, after adjustment for other vascular and stroke risk factors, the data were significant only in women. Aspirin may lower C-reactive protein levels. Multiple different types of malignancies have been associated with prothrombotic states. Several ways of inducing increased

Chapter 37

clotting have been identified in cancer patients: increased tissue factor VIIa (acute leukemias, stomach, ovary, kidney), cysteine protease Factor X (lung, prostate, colon, breast, kidney, leukemia), and mucin and sialic acid Factor X (lung, pancreas, gastrointestinal, ovary, prostate, renal cell). Furthermore, several chemotherapeutic agents used to treat cancer have been implicated in vascular and hematologic changes that could lead to thrombosis. Human immunodeficiency virus may also lead to altered hemostasis and both ischemic and hemorrhagic stroke. Generally, there is no established treatment for any of the thrombophilias associated with ischemic stroke, and their role is not sufficiently clearly identified in the pathogenesis of stroke to warrant screening. Many clinicians choose to anticoagulate these patients with warfarin (target INR 2 to 3) for either 6 to 12 months or indefinitely, although there are no data demonstrating efficacy of anticoagulation over other forms of antithrombotic therapy. aPL ANTIBODIES AND aPL SYNDROME The aPL antibodies are circulating immunoglobulins (IgG, IgM, and IgA isotypes) that bind anionic and neutral phospholipidcontaining moieties. The two most clinically studied and relevant aPL antibodies are the lupus anticoagulant and anticardiolipin antibodies. They are primarily acquired but can also be inherited. Several medications may be associated with drug-induced aPL (Table 37-2). aPL antibodies have been recognized since 1906 with the discovery of the Wassermann test for syphilis (syphilitic sera contains aPL). The term antiphospholipid syndrome was coined in the 1980s to categorize the distinct clinical and laboratory features associated with a hypercoagulable state and the presence of aPL antibodies. According to the International Consensus Statement on Preliminary Criteria for the Classification of the Antiphospholipid Syndrome, a diagnosis of aPL syndrome requires at least one of the clinical criteria and one of the laboratory criteria. The clinical criteria include the following: one or more clinical episodes or arterial, venous, or small-vesselthrombosis, occurring within any tissue or organ; or one or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation, one or more premature births of morphologically normal neonates at or before the 34th week of gestation, or three or more unexplained consecutive spontaneous abortions before the loth week of gestation. The laboratory criteria include the presence of anticardiolipin (aCL) IgG or Igh4 antibodies present at moderate or high levels in the blood on two or more occasions at least 6 weeks apart, or the presence of lupus anticoagulant (LA) antibodies detected in the blood on two or more occasions at least 6 weeks apart (according to the guidelines of the International Society on Thrombosis and Hemostasis). The principal clinical features include thrombotic events, both venous (most commonly deep-vein thrombosis) and arterial (most commonly ischemic stroke and transient ischemic attack),

TABU37-2. Medications Most Often Associated with DrugInduced Antiphospholipid Antibodies Phenothiazines (chlorpromazine) Hydralazine Procainamide Quinidine Phenytoin Valproic acid

Coagulation-Related Causes of Stroke

355

TABLE37-3. Features Associated with Antiphospholipid Antibodies and the Antiphospholipid Antibody Syndrome Clinical Arterial thrombosis Cerebral Ocular Peripheral Myocardial Dermal or digial Pulmonary Mesenteric Venous thrombosis Deep leg Hepatic (Budd-Chiari syndrome) Retinal Cerebral Adrenal Miscarriages Livedo reticularis Pulmonary hypertension Left-sided cardiac valvular lesions Verrucous endocarditis Libman-Sacks endocarditis Myxomatous mitral valve degeneration lntracardiacthrombi Chorea Laboratory

Prolonged activated partial thromboplastin time False-positive VDRL syphilis test Thrombocytopenia Hemolytic anemia Positive antinuclear antibody test Reduced C4

and left-sided cardiac valve lesions akin to verrucous or LibmanSacks endocarditis with fibrin-platelet deposits on the valvular surface. Other neurologic disturbances include migraine-like events and less commonly chorea and myelopathy. Miscarriages, adrenal thrombosis with orthostatic hypotension, pulmonary hypertension, and livedo reticularis are associated with the aPL syndrome (Table 37-3). Chronic ischemic damage often is overlooked because of its indolent clinical course. Other factors predisposing to a hypercoagulable state (i.e., oral contraceptive use) may unmask or stimulate the aPL syndrome. The syndrome can be acquired or inherited. Age at onset generally is younger than 50 years. Laboratory features include prolonged phospholipiddependent coagulation tests (activated partial thromboplastin time) as a sign of LA, thrombocytopenia, false-positive VDRL syphilis test result, IgG aCL antibodies, reduced complement C4, positive antinuclear antibody (usuallylow titer) test, and occasionally hemolytic anemia (Table 37-4). Antibodies to P,-glycoprotein 1, although not included in the laboratory criteria for the syndrome, are strongly associated with thrombotic events. The only laboratory abnormality in primary aPL syndrome may be a positive titer of aPL antibodies. aPL antibodies are seen in approximately 10% of first ischemic stroke patients and are an independent risk marker for first ischemic stroke. Many stroke patients have aPL antibodies but do not have the aPL syndrome. The aPLs are more common in younger stroke patients, and only the IgG isotype has been statistically linked to stroke in case-control studies. The IgM isotype may represent an acute phase reaction and can be seen after a variety of infections. The IgA isotype has been the least

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studied and has only anecdotal associations with stroke, GuillainBard syndrome, and myelopathy. The reasons for nonneurologists to screen patients for aPL include ischemic brain, eye, or spinal cord events or chorea without clear cause in a patient with recurrent thrombotic events and one or more clinical (systemic or neurologic) or laboratory features of aPL syndrome (Table 37-5). In one prospective study, patients with their first ischemic strokes under age 50 had a prevalence of aCL and LA of 21% and 8%, respectively. Idiopathic thrombocytopenia, multiple miscarriages, venous or arterial thrombosis, livedo reticularis, symptom onset at an early age (less than 45), sterile endocarditis with embolism (Libman-Sacks endocarditis), or suspicion of systemic lupus erythematosus (SLE) increased the pretest probabilities of positive titers of aCL or LA. Testing should be performed

TABLE37-4. Laboratory Diagnosis of Lupus Anticoagulant

Prolonged phospholipid-dependentcoagulation screening test Failure to correct with mixing studies Demonstrationof phospholipid specificity Studies Prothrombintime Activated partial thromboplastin time Tissue thromboplastin inhibition Platelet neutralization procedure Dilute phospholipid activated partial thromboplastin time Kaolin clotting time Russell viper venom time Dilute Russellviper venom time STACLOT LA@

in the absence of infection or inflammation. If there is low suspicion for aPL or SLE, a negative enzyme-linked immunosorbent assay is sufficient. Otherwise, confirmation testing in 6 to 8 weeks is needed regardless of the initial result. If available, testing for P,-glycoprotein 1 or other aPL antibodies (antiphosphatidylserine) may suggest the diagnosis. Because of the heterogeneity of testing available for LA, two tests should be negative before excluding a diagnosis of aPL. Abnormal results necessitate further mixing studies with normal plasma and confirmatory test depending on the method of screening. If confirmatory tests are abnormal, then platelet neutralization or hexagonal phase phospholipid testing should be done. Again, repeat testing in 6 to 8 weeks is warranted in cases where there is a high suspicion of aPL or SLE or if the initial screening is positive for LA. The mechanisms of the most common neurologic manifestations of aPL syndrome and transient ischemic attacks or stroke

TABLE 37-5. Screening for Antiphospholipid Antibodies (Anticardiolipin Antibodies and Lupus Anticoagulant) Any patient with ischemic symptoms in the brain or eye without a clear cause If one or more of the clinical or laboratory features are present to suggest antiphospholipid syndrome, even in the presence of known vascular risk factors Any patient with recurrent thrombosis

A

B

FIG. 37-1. (A) T2-weighted magnetic resonance image showing a perisylvian, chronic infarct (note lack of mass effect) in a young woman with antiphospholipid antibody syndrome. At the time, echocardiography did not reveal a specific abnormality. (6) Contralateral subcortical posterior cerebral artery infarct (arrowhead) in the same patient whose echocardiogram subsequently showed a noninfective vegetation of the mitral valve.

Chapter 37

probably are heterogeneous and include embolism from cardiac valve lesions (verrucous endocarditis, left-sided valve thickening and myxomatous degeneration, and intracardiac clot), a hypercoagulable state with in situ thrombosis, and a cerebral vascular endotheliopathy (Fig. 37-1). The aPL antibodies within the aPL syndrome, as opposed to aPL not associated with the syndrome, appear to need a cofactor for binding. This cofactor is P2glycoprotein 1, also called apolipoprotein H. This cofactor is a naturally occurring anticoagulant that inhibits the intrinsic coagulation pathway and the prothrombotic activity of platelets. Binding and subsequent alteration of the function of the cofactor therefore could lead to a prothrombotic state. Preliminary evidence suggests that aPLs are directed at the fifth repeating domain (C terminal) of the cofactor molecule and can inhibit prostaglandin I,, reduce protein C and protein S levels, and alter thrombomodulin binding. Also, aPL antibodies bind to activated platelets (not to normal, inactivated platelets). The ability of aPL antibodies to bind activated platelets appears to be directly related to the amount of phosphatidylserine exposure on the platelet membrane. Sera from patients with aPL antibodies and stroke have significantly higher IgG binding to human brain microvascular endothelium compared with stroke patients’ sera without aPL and sera from healthy controls. However, there is poor correlation between binding to brain endothelium and binding to aCL antibodies. The binding also is nonspecific, as similar binding to human umbilical vein cells has been demonstrated. There is no evidence for complement-mediated brain endothelium cytotoxicity. Another proposed mechanism is an oxidantmediated injury of the vascular endothelium promoted by antibodies to oxidized low-density lipoprotein. aCLs react with oxidized cardiolipins and may cross-react with oxidized lowdensity lipoprotein. The treatment of aPL syndrome remains empiric. The optimal therapy is unknown. Rational therapy has been hampered by the lack of precise understanding (probably because of multiple mechanisms) of how aPL antibodies lead to thrombosis. There have been no controlled treatment trials for neurologic disease in the aPL syndrome. Most treatment data come from studies of recurrent aborters with SLE. The Antiphospholipid Antibodies and Stroke Study Group recently completed a prospective study of first ischemic stroke associated with either aCL or LA. In patients without clear-cut evidence of cardiac disease or high-grade carotid stenosis, the presense of aPL antibodies (either aCL or LA) did not increase the risk of subsequent thrombo-occlusive events over the subsequent 2 years, and there was no treatment difference between aspirin (325 mg/day) and adjusted-dose warfarin (target INR 1.4 to 2.8) in preventing new thrombo-occlusive events in aPL antibody-positive stroke patients. Whether these data are generalizable to younger patients with the aF’L antibody syndrome is not known. Therapeutic options in these patients include antithrombotics and immune-based treatment. Antithrombotics include anticoagulants (warfarin [low versus high INRI, subcutaneous heparin, or low-molecular-weightheparin) and antiplatelet agents (aspirin, ticlopidine, and dipyridamole). Aspirin has been shown to provide some protection against thrombosis or thromboembolism in women with the aPL antibody syndrome and a history of pregnancy loss. In men with aCL antibodies, aspirin did not offer any protection against deep venous thrombosis and pulmonary embolism. Immune-based therapies include corticosteroids, immunosuppressants (azathioprine, cyclophosphamide, cyclosporine, hydroxychloroquine),intravenous immune globulin, plasmapheresis, and anti-idiotype antibodies.

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HOMOCYSTlNEMlA Homocystinemia is the sum of free and protein-bound homocysteine and homocysteinyl derivatives. In plasma, free homocysteine and cysteine-homocysteinemixed disullide account for about 20% of the total. The remainder is protein-bound homocysteine. Homocystinuria is a group of biochemical abnormalities, not a single disease entity. Several autosomal recessive enzyme deficiencies are associated with homocystinuria and an increased risk for cardiovascular disease and stroke. The proposed pathophysiologic mechanisms of vascular injury include peroxidation injury, proliferation of smooth muscle in vessels, monocytic chemotaxis, cytotoxicityand inflammation,increased clotting via expression of thrombomodulin and activation of protein C, inhibition of anticoagulation, impairment of endothelium-derived relaxation factor, and platelet aggregation. Homocysteine is at an important metabolic branch point. It is synthesized from methionine and metabolized via transsulfuration to cystathionine or methylated to form methionine (as part of the sulfur conservation cycle). Impaired conversion of homocysteine to cystathionine is caused by a deficiency of vitamin B, or cystathionine P-synthase, the most common enzymatic deficiency causing homocystinuria and increased plasma levels of homocysteine. The homozygous state has been associated with vascular disease and variable degrees of marfanoid (tall and thin) body type, lens dislocation, and mental retardation. Nearly every syndrome associated with atherosclerosis,including stroke, can be seen by early childhood. Although cystathionine P-synthase deficiency is inherited as an autosomal dominant trait, there appears to be genetic heterogeneity. This, along with nutritional status, may account for the wide variation in the age of onset and severity of the clinical syndrome. Recently, the heterozygous state and a variety of acquired disorders of methionine metabolism have been associated with an elevated risk of stroke (and cardiovasculardisease). Methylation of homocysteine depends on folate and vitamin B,,-containing enzymes. A deficiency of folate, vitamin B,,, or methylenetetrahydrofolate reductase (MTHFR) causes hyperhomocystinemia by decreased conversion of homocysteine to methionine. A gene for homocystinuria may be present in as many as 1 in 70 people. Whether MTHFR deficiency is associated with an elevated risk of stroke remains to be established. Over the last few years, more than 20 case-control and cross-sectional studies, which together included more than 2,000 patients, have consistently reported an association between higher blood levels of homocysteine and an elevated risk of vascular disease. For example, in the Physician’s Health Study, a plasma homocysteine level of just 12% over the upper limit of the normal range was associated with a 3.4-fold increase in the risk of myocardial infarction. The true upper limit of normal is not clear. A homocysteine level above 14 pmoVL has been used as the upper limit of normal, yet patients from the Framingham study with homocysteine levels between 11 and 14 KmollL were at higher risk for carotid stenosis. Modest elevations of homocysteine levels may also occur in up to a quarter of young patients with stroke. There is also evidence that elevated plasma homocysteine may be a risk factor for vascular disease in older adults. Elevated levels of homocysteine have also been associated with an increased likelihood of carotid atherosclerosisand greater degrees of carotid stenosis in older adults. This may be related to modest decreases in enzyme cofactors. One third to one half of those with low to

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normal serum vitamin B,, levels also have increased levels of homocysteine. How this combination of low B,, and increased homocysteine might contribute to vascular disease is still being evaluated. In pilot studies of older adults, 20% to 40% of those with cardiovascular disease also had increased levels of homocysteine and decreased levels of vitamin BIZ.Deficiencies of vitamin B, and folic acid may also result in an elevation in homocysteine levels. This may explain why patients with end-stage renal disease have accelerated atherosclerotic disease and very high levels of homocysteine. Phenytoin and methotrexate interfere with vitamin B metabolism and are also associated with elevated homocysteine levels. Several other conditions associated with elevated serum levels of homocysteine include hypothyroidism, psoriasis, hemolytic anemia, SLE, cigarette smoking, caffeine, and cyclosporine. A lowering of homocysteine levels has been associated with exercise, estrogens, and penicillamine. Measuring of serum homocysteine levels has become common in the evaluation of stroke patients. Genetic testing of patients for the heterozygote state is more difficult to perform, is expensive, and not widely available. The most commonly performed screening involves measuring homocystinemia in response to a methionine load. At present, testing is recommended only for those who have a normal vascular risk factor profile by routine testing, especiallyin young patients or in those with a strong family history of premature atherosclerosis. In the mid-1960s it was shown that treating patients with cystathionine P-synthase deficiency with pyridoxine could reduce plasma levels of methionine to normal and dramatically reduce homocysteine levels in plasma and urine. Not all of those with this enzyme deficiency responded. Responsiveness may be linked to the presence of residual activity of the mutant enzyme. It also appears that other forms of both inherited and acquired homocystinuria (and the elevated levels of homocysteine) may respond to dietary manipulation and treatment with folic acid, vitamin B,, or vitamin B,,. Dosages of 0.4 to 2.5 mg of folic acid can effectively reduce homocysteine levels. Currently, it is not entirely clear whether elevated homocysteine levels are an independent risk factor for vascular disease, or rather a laboratory feature that reflects other factors associated with stroke (sedentary lifestyle, dietary habits). The Vitamins to Prevent Stroke trial and the Vitamin Intervention for Stroke Prevention trial are already under way to investigate the value of vitamin supplementation in stroke prevention. Data from a recent coronary angioplasty study suggest that lowering serum homocysteine levels can reduce the rates of restenosis and need for revascularization procedures. Epidemiologic studies can first identify a potential risk factor, and then clinical trials are needed to demonstrate that control of the risk factor reduces the risk of subsequent events of interest. We are still at the primary stage of epidemiologic studies for many

coagulation factors, and not all studies have demonstrated consistent results. Because the association of a factor with stroke does not imply cause, causality of a hematologic condition in stroke may be better inferred if the hematologic alteration predates the stroke, the hematologic condition persists beyond the acute phase of the stroke, or it is detected in relatives of the patient.

SUGGESTED READINGS Bushnell CD, Goldstein LB: Diagnostic testing for coagulopathies in patients with ischemic stroke. Stroke 3 1:3067, 2000 Bushnell CD, Goldstein LB: Physician knowledge and practices in the evaluation of coagulopathies in stroke patients. Stroke 33:948, 2002 Bushnell CD, Siddiqi Z, Goldstein LB: Improving patient selection for coagulopathy testing in the setting of acute ischemic stroke. Neurology 521333, 2001a

Bushnell CD, Siddiqi, Morgenlander JC, Goldstein LB: Use of specialized coagulation testing in the evaluation of patients with acute ischemic stroke. Neurology 56624, 2001b Falk E, Zhou J, Moller J: Homocysteine and atherothrombosis. Lipids 36(Suppl):S3, 2001 Hankey GJ: Is homocysteine a causal and treatable risk factor for vascular diseases of the brain (cognitive impairment and stroke)?Ann Neurol 51:279, 2002 Hankey GJ, Eikelbomm JW, van B o c h e e r FM et al: Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 32:1793, 2001

Levine JS, Branch DW, Rauch J: The antiphospholipid syndrome. N Engl J Med 346:752, 2002 Rost NS, Wolf PA, Kase CS et al: Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack the Framingham Study. Stroke 32:2575,2001 Selhub J, Jacques PF et ak Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 322:286, 1995 Sen S, Oppenheimer SM, Lima J, Cohen B Risk factors for progression of aortic atheroma in stroke and transient ischemic attack patients. Stroke 33:930, 2002 Spence JD, Howard VJ, Chambless LE et al: Vitamin Intervention for Stroke Prevention (VISP) Trial: rationale and design. Neuroepidemiology 2016, 2001 Vermeer SE, van Dijk EJ, Koudstaal PH et al: Homocysteine, silent brain infarct, and white matter lesions: the Rotterdam Scan Study. Ann Neurol 51:285, 2002 The VITATOPS Trial Study Group: The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis 13:120, 2002 Wilson WA, Gharavi AE, Koike T et a 1 International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 42:1309, 1999

Chapter 38 rn Illicit Drugs and Stroke

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38 Illicit Drugs and Stroke Nalini Samuel, Luis D'Olhaberriague, Steven R. Levine, and Lawrence M. Brass ILLICIT DRUGS It is important to consider the use of illicit drugs as an unusual cause of stroke, particularly in the young. Various drugs can produce immediate and long-term effects on the vascular network that may predispose the patient to stroke (see Tables 36-1 and 36-2). Besides, drug users commonly develop an addictive lifestyle that includes the simultaneous use of different drugs and lack of hygienic habits, resulting in multiple infections. Parented drug users have an increased risk of bloodborne and other infections (infectious endocarditis, hepatitis, syphilis, and acquired immunodeficiency syndrome [AIDS] ) that also cause stroke. Cocaine

Cocaine, a local anesthetic, may be used as a recreational stimulant drug in the form of powder of cocaine hydrochloride for intranasal administration (snorting). Rectal, oral, vaginal, or sublingual administration is also used. Alkaloidal free base of cocaine, or crack, is inhaled or smoked. Crack has become the most popular form of cocaine because it has a higher power of addiction and is cheaper and easier to handle than cocaine hydrochloride. Since the introduction of crack in 1983, its use and its medical and neurologic complications have become epidemic. By 1982, 28% of people between 18 and 25 years had used cocaine, whereas in 1990, 34% of people between ages 15 and 44 years had used drugs, with cocaine being the predominant one. Since 1977, when Brust and Richter reported the first case of cocaine-related stroke, the number of reported cases remained below 10 per year until 1987, jumping from 0 in 1985 and 3 in 1986 to 29 in 1987. Since then, the number of cocaine-related strokes has increased dramatically. It is likely that the increasing number of reported cases reflects not only the spreading crack epidemic but also the greater cerebrovascular specificity and higher potency of this drug. The effects of cocaine include hypertension, central nervous system stimulation, and local anesthesia. Cocaine blocks reuptake of dopamine, serotonin, and norepinephrine and binds to dopamine transport protein at nerve terminals, thus blocking its presynaptic reuptake and increasing dopamine levels. It also blocks serotonin and norepinephrine reuptake. Dopaminergic effects include hypertension, tachycardia, and vasoconstriction. Cocaine intake results in marked increases in blood pressure, myocardial oxygen demand, and heart rate. Coronary blood flow, which increases in response to exercise, is decreased by cocaine intake. Therefore, cocaine simultaneously increases myocardial oxygen demand and decreases myocardial oxygen supply. These latter two effects of cocaine are potentiated by simultaneous tobacco smoking. In the cerebral arteries, enhanced sympathetic activity accompanied by hypertension could be a major factor for stroke via vasoconstriction and vasospasm. Increased perfusion pressure can give rise to hypertensive opening of the blood-brain barrier, which facilitates the entry of circulating catecholamines into the brain. Finally, cocaine has been shown to decrease acutely,

and on a long-term basis, cerebral metabolism, cerebral blood flow (CBF), and brain glucose metabolism. Single photon emission computed tomographic (SPECT) studies in former cocaine users found regions of hypoperfusion in frontal, periventricular, and temporal-parietal areas. Serotonergic effects include vasoconstriction on large and medium-sized cerebral arteries and increased platelet response to arachidonic acid with increased thromboxane production and platelet aggregation. A possible noradrenergic effect is a lack of increase in CBF in response to hypertension because norepinephrine increases cerebrovascular resistance. A direct inhibitory effect of cocaine in platelet aggregation has also been described. The mechanisms of cocaine-related stroke are multiple. Cocaine users often simultaneously use other potentially strokeinducing drugs, either voluntarily or because they are adulterants of cocaine. Cocaine-induced hemorrhagic strokes are associated in more than 50% of cases with arteriovenous malformations (AVMs) and aneurysms. Cocaine causes severe hypertension, which, together with increased cardiac output, can promote aneurysm or AVM rupture, thus causing hemorrhages (intracerebral hemorrhage [ICH] and subarachnoid hemorrhage [SAH]). Extreme hypertension may also cause primary ICH. After vasoconstriction, rapid reperfusion of previously ischemic brain tissue can also cause ICH. Vasoconstriction induced by increased monoamine activity, together with increased thrombotic activity as a result of a serotonin-induced rise in synthesis of thromboxane, may underlie some ischemic strokes. Vasospasm, either as a result of severe hypertension or related to S A H , is another possible cause of ischemic stroke (Fig. 38-1). Vasculitis has rarely caused cocaine-related ischemic stroke, which contrasts with a higher frequency of amphetamine-induced arteritis as a cause of ICH. Cocaine causes cardiac arrhythmia, cardiomyopathy, and myocardial infarction, with a potential risk of cardioembolic stroke. Parented cocaine users are at higher risk of infectious endocarditis. Cocaine-related stroke is an ailment of drug users, fetuses and newborns whose mothers use the drug, and pregnant women. Cocaine-related strokes affect mainly young people, with a male preponderance. Ischemic-including transient ischemic attacks and cerebral, retinal, and spinal cord infarcts-and hemorrhagic strokes occur with approximately equal frequency. However, there are clinically important differences, depending on the type of cocaine used. In cocaine hydrochloride users, hemorrhagic strokes are twice as common as ischemic strokes, whereas in alkaloidal cocaine users, ischemic and hemorrhagic strokes are equally likely. Aneurysms and AVMs are twice as common with cocaine hydrochloride stroke as with alkaloidal cocaine stroke. Concomitant alcohol use is more common in cocaine hydrochloride users than in alkaloidal cocaine users. Alcohol depresses the degradation of cocaine, and alcoholism is a risk factor for all types of stroke, especiallyhemorrhagic stroke. Finally, alkaloidal cocaine is related to a more rapid absorption of the drug and higher cocaine blood levels than with use of cocaine hydrochloride. Crack cocaine smokers are also more likely than cocaine hydrochloride intranasal users to escalate dosage. A proof of cocaine use can be obtained

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FIG. 38-1. Basilar artery narrowing (arrowhead) in a chronic intranasal cocaine user.

either by history taking or toxicologic screening. Cocaine, or its metabolite benzoylecgonine, can be detected from the urine of a novice user for up to 48 hours after intranasal use and for up to 3 weeks after chronic use. Anterior circulation ischemic strokes predominate over posterior circulation strokes. Small, deep infarcts and specific brainstem syndromes also occur. Hemorrhagic strokes are more often hemispheric, deep basal-ganglionic, or lobar and sometimes multiple. Angiographic findings include aneurysms, AVMs, branch stenosis or occlusions, beading, spasm, and very rarely vasculitis. Emboli rising from cardiomyopathies probably are an underrated cause of stroke in cocaine users who are prone to infectious endocarditis. Infectious endocarditis causes ischemic and hemorrhagic strokes, multiple microemboli presenting as toxic encephalopathy, meningitis, pyogenic arteritis, mycotic aneurysms, and SAH. Headache is the most common associated complaint in cocaine-related strokes and is more common than among unselected stroke patients. This serotonergic effect of cocaine on platelets may be related to these headaches. The prognosis for patients suffering from cocaine stroke is poor; one third of patients die, and another one third remain severely handicapped. Treatment does not differ from stroke from other causes, although there is some evidence that magnesium could ameliorate cocaine-induced cerebral vasospasm. Aneurysms and AVMs should be treated as needed. Mycotic aneurysms usually disappear after antimicrobial therapy, and their surgical clipping is rarely needed. In cocaine-induced central nervous system disorders other than stroke, seizures and status epilepticus may occur, with or without associated stroke, as a result of a decrease in seizure threshold. Drug intoxication is a common cause of status epilepticus. Animal studies demonstrated increased glucose metabolism in dopaminergic pathways after cocaine administration, and cocaine binding in humans is the highest in the

corpus striatum. Movement disorders related to cocaine include tremor, dystonia, myoclonus, chorea, tics, parkinsonism, akathisia, and neuroleptic malignant syndrome. Positron emission tomographic (PET) studies found decreased CBF, especially in frontal areas, in chronic users, even after detoxication, and computed tomographic (CT) studies demonstrated brain atrophy. Cognitive and behavioral deficits found in chronic users include impaired attention, concentration, new learning, memory, word production and visuomotor integration, euphoria, and psychotic behavior, especially paranoia.

Amphetamine and Psychostimulant Drugs Amphetamine, methamphetamine, and dextroamphetamine are powerful analeptics that are used because of their psychostimulant and appetite depressant effects. Two patterns of abuse exist. Truck drivers, homemakers, and students use oral preparations; drug addicts use intravenous administration. Nasal administration and concurrent intake of alcohol or other drugs are also common. Amphetamine and methamphetamine release cytoplasmic dopamine from the nerve terminals with general dopaminergic stimulation. There are also noradrenergic and serotonergic effects. Amphetamine induces tachycardia, hypertension, and increased respiratory rate, which can result in hypocapnia. Acute effects of amphetamine overdose include extreme hypertension, hyperpyrexia, coma, vascular collapse, and death. In extreme cases, neuropathologic examination shows diffuse brain edema without large infarctions or hemorrhages. Mechanisms underlying ICH include extreme hypertension, AVM rupture, and vasculitis. When these mechanisms are compared with those of cocaine-related hemorrhages, there are two main differences. AVMs in amphetamine users are uncommon, and amphetamine-induced vasculitis often is inferred radiologicallyor found at autopsy. Two different types of vasculitis

Chapter 38 rn Illicit Drugs and Stroke

have been described one that resembles polyarteritis nodosa and one that affects small arterioles and resembles hypersensitivity vasculitis. Ischemic strokes have also been related to vasospasm and endocarditis. Ischemic strokes and transient ischemic attacks are less common than hemorrhagic strokes after amphetamine use. The mean age of patients with ICHs was 25 years, and oral use of amphetamine followed by intravenous use was the most common route of administration. Lobar hemorrhages predominate over basal ganglionic hemorrhages. Angiography may be negative or show AVMs or a pattern of segmental areas of constriction, irregularity, and occasional fusiform dilation and beading suggestive of vasculitis. At times, the angiographic abnormalities are transient and disappear on a second examination. The clinical picture often is characterized by a paucity of focal signs despite large focal lesions. Oddly enough, signs of sympathetic overactivity generally are absent, but headache is common. Prognosis is poor, with the mortality rate ranging up to 20%. Amphetamineinduced central nervous system disorders other than stroke include restlessness, talkativeness, tremor, insomnia, psychomotor hyperactivity, psychotic behavior of paranoid schizophrenic type, seizures, and rhabdomyolysis.

Phenylpropanolamine Phenylpropanolamine (PPA) is a drug structurally related to amphetamine, though less potent. Its use is not under the Food and Drug Administration restrictions that apply to amphetamine, and it is found in over-the-counter medications, including nasal decongestants, cough and cold remedies, and appetite suppressants. Reported associations include hypertension, headache, seizures, psychiatric reactions, and ICH. Most of the reported hemorrhages are parenchymal, although SAH secondary to aneurysm rupture has also been described. Potential stroke mechanisms of hypertension and vasculitis have been reported. Some cases have been related to concomitant use of alcohol, caffeine, monoamine oxidase inhibitors, and cocaine. Cases have also been reported in the puerperium. Making a causal association between stroke and a common drug or risk factor is difficult. There are only a few dozen reported cases of stroke, but billions of doses of PPA are ingested each year worldwide. The issue of a potential association between PPA and intracranial hemorrhage was recently addressed in a case control study, which suggested a significantlyhigher risk of ICH in women who took the drug as an appetite suppressant. Although this conclusion was based on a small number of observations, the study led to the effective removal of this agent from over-thecounter preparations. Ephedrine and pseudoephedrine have been related to ICHs, phentermine and probably phendimetrazine to ischemic strokes, and methylphenidate to ischemic and hemorrhagic strokes.

Phencyclidineand LysergicAcid Diethylamide Phencyclidine (PCP, “angel dust”) was used legally as an animal immobilizing agent and illegally as an hallucinogen. PCP became very popular in the 1970s and was smoked, eaten, or injected. The mechanisms of action of PCP are not clear, although it enhances catecholamine and serotonin transmission and is a noncompetitive N-methyl D-aspartic acid antagonist. One to 5 mg of PCP induces euphoria, emotional lability, and a feeling of numbness; 5 to 15 mg causes confusion, decreased sensory perception, and

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body distortions; higher dosages produce psychosis, myoclonus, nystagmus, seizures, coma, and respiratory collapse. Hypertension, leading to hypertensive encephalopathy, can occur. A few cases of ICH and S A H , occasionally associated with aneurysms, and a single case of brainstem ischemia have been related to PCP use. Lysergic acid diethylamide has occasionally been related to ischemic strokes, sometimes with angiographic findings suggestive of vasculitis. Opiates and Barbiturates There are about half a miltion heroin abusers in the United States. Heroin usually is taken parenterally, so addicts have a higher risk of bloodborne and other infections (infectious endocarditis, hepatitis, syphilis, and AIDS). Violence, drug overdose, and AIDS are the most common causes of death in heroin addicts. Among the other medical complications of heroin users are ischemic and hemorrhagic strokes. Heroin overdose develops as a result of dosage miscalculation, suicide attempts, and circumstances that decrease drug tolerance (Addison’s disease, myxedema, liver disease, or pneumonia) and upon resuming the habit after a long period of withdrawal. Depressed consciousness with small, pinpoint pupils and respiratory depression are the hallmarks of heroin overdose. Patients surviving cardiorespiratoryarrest sometimes are left with residual anoxic encephalopathy. There are multiple mechanisms of strokes in heroin addicts. ICH and SAH are most often the result of mycotic aneurysm rupture in the setting of infectious endocarditis. Altered clotting caused by liver failure in the setting of hepatitis and malignant hypertension from heroin nephropathy are other causes of hemorrhagic strokes. Infectious endocarditis is the main cause of ischemic stroke in heroin addicts. Candida albicans and Staphylococcus aureus are the most common pathogens. Infectious endocarditis causes ischemic and hemorrhagic strokes, multiple microemboli presenting as toxic encephalopathy, meningitis, pyogenic arteritis, mycotic aneurysms, and SAH. A cerebral vasculitis has been described in some heroin-related infarcts. Elevated erythrocyte sedimentation rate, positive latex test, eosinophilia, and hypergammaglobulinemia suggest a possible immunologic mechanism. Delayed anoxic encephalopathy and bilateral globus pallidus infarction have been described in heroin addicts after cardiorespiratory arrest. An acute or subacute myelopathy has been reported in heroin users. Its pathogenesis is unknown, and some cases presented as an anterior spinal artery syndrome. Pentazocine and tripelennamine (“Ts and blues”) caused stroke in 3 of 13 patients with neurologic symptoms. The most likely mechanism was foreign body embolization. Barbiturates and other sedative drugs cause stroke as a result of overdose and decreased brain perfusion. Rarely, barbiturate abuse has been related to vasculitis or a Moyamoya pattern of intracranial arterial occlusions.

Alcohol Alcoholism affects 10.6 million adults in the United States, and about 20% of adolescents are problem drinkers. Alcohol intoxication is one of the two leading causes of status epilepticus. However, the relationships between alcohol and stroke are not clear. Coronary artery disease may be more prevalent in abstainers than in moderate drinkers, and some evidence suggests that internal

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carotid artery stenosis is related inversely with light to moderate alcohol intake. Light to moderate alcohol intake decreases low-density lipoprotein (LDL) cholesterol and increases highdensity lipoprotein (HDL) cholesterol, whereas heavy alcohol consumption increases triglyceride levels and blood pressure. The pattern of increased HDL and decreased LDL seems to protect from coronary artery arteriosclerosis; increased LDL (and intermediate-density lipoprotein) with decreased HDL are commonly found in patients with cerebral infarction. The impact of alcohol consumption on stroke risk depends on the study population, sex, race, alcohol dosage, alcoholism definition, presence of confounding factors (age, diabetes, and arterial hypertension), concomitant use of other drugs (tobacco and cocaine), and type of stroke (ischemic or hemorrhagic). Low to moderate alcohol consumption (5 to 25 g/day) is associated with a decreased relative risk of both myocardial and cerebral infarction and increased risk of SAH in women. Lifelong abstainers of both sexes appear to bear a higher risk of stroke. The likelihood of hospitalization for ischemic stroke, in both sexes and in whites as well as in blacks, was decreased in people who drank. People who consumed three or more drinks a day had a higher risk of hospitalization for ICH. Aging, hypertension, and black race are associated with a further increase in risk. Among men, the relative risk of stroke is greater in abstainers than in light drinkers (10 to 90 g of alcohol weekly), but heavy drinkers (300 g of alcohol or more weekly) have a four times greater increase in relative risk of stroke than abstainers. Several mechanisms might explain the different effects of different dosages of alcohol and differences in the risks of ischemic and hemorrhagic strokes. In humans, ethanol in small dosages produces cerebral vasodilation, and higher dosages induce cerebral vasoconstriction. Acute ethanol intoxication reduces the difference between carotid artery and jugular vein oxygen concentration, reflecting a reduced cerebral oxygen metabolism. Cardiac arrhythmias, especially atrial fibrillation, can result from underlying alcoholic cardiomyopathy or directly from alcohol-induced sympathetic stimulation in acute intoxication (“holiday heart”). Arterial hypertension results from both acute and chronic use. Acutely, alcohol decreases fibrinolytic activity, increases factor VIII and platelet activity, and shortens bleeding time. Ethanol consumption can also cause stroke by vasospasm and increased blood viscosity. Chronic alcoholic patients present with decreased levels of vitamin K-dependent clotting factors, increased fibrinolysis, and platelet abnormalities that are secondary to hepatic disease. Alcohol withdrawal has been related to both increased and decreased CBF. In conclusion, moderate alcohol consumption may decrease the risk of cerebral infarction, but the stroke risk is higher in heavy drinkers than in abstainers. Acute intoxication is related to an increased risk of both ischemic and hemorrhagic strokes. Chronic alcoholics have an increased risk of all types of stroke, especially the hemorrhagic subtypes. Tobacco

Tobacco smoking is an important risk factor for coronary artery disease. Although a few studies failed to prove a relationship between smoking and stroke, there is overwhelming evidence

linking smoking with increased risk of stroke. In the Nurses’ Health Study, smokers had a dose-dependent increased risk for both ischemic stroke and SAH. A role of smoking in causing ICH has been controversial because of conflicting results from different studies. Recent data from the Physicians’ Health Study suggested a higher risk of ICH in smokers, with an increased risk in proportion to the number of cigarettes smoked per day. Smoking cessation appears to decrease the previously increased risk, and in a Finnish study the observed declining incidence of stroke was attributed to the declining prevalence of smoking. There is an especially high risk of ischemic stroke and SAH in young women who smoke and use oral contraceptives. Oral contraceptives and smoking further potentiate each other in migraineurs. Among ischemic stroke subtypes, smoking is more common among noncardioembolic than cardioembolic stroke victims. Tobacco can induce stroke by multiple mechanisms. Tobacco smoking increases the risk of myocardial infarction, increases myocardial oxygen demand, and decreases myocardial oxygen supply. Concurrent use of cocaine potentiates the latter two effects of smoking. Smoking aggravates coronary artery disease, constricts coronary arteries, decreases HDL levels, raises systolic and diastolic blood pressure, increases heart rate, and can precipitate atrial fibrillation. Although smoking is not by itself a risk factor for hypertension, it accelerates its progression. Extracranial internal carotid artery stenosis seems to correlate in a dose-dependent fashion with smoking. CBF is decreased in smokers, and exsmokers show CBF values between those of smokers and nonsmokers. Tobacco smoking increases platelet reactivity and fibrinogen concentration and decreases prostacyclin formation. Chronic obstructive pulmonary disease is associated with increased hematocrit, which could further decrease CBF. Finally, lung cancer causes ICH as a result of bleeding into metastases and ischemic stroke from nonbacterial thrombotic endocarditis, tumor embolism, and disseminated intravascular coagulation.

SUGGESTED READINGS Berger K, Kase CS, Ajani U et al: Light-to-moderatealcohol consumption and the risk of stroke among U.S. male physicians. N Engl J Med 341:1557, 1999 Caplan L R Drugs. pp. 201-220. In Kase CS, Caplan LR (eds): Intracerebra1 Hemorrhage. Butterworth-Heinemann,Boston, 1994 Caplan LR, Thomas C, Banks G: Central nervous system complications of addiction to “T’s and blues.” Neurology 32:623, 1982 Green RM, Kelly KM, Gabrielsen T et al: Multiple intracerebral hemorrhages after smoking “crack” cocaine. Stroke 2 1:957, 1990 Kase CS, Kurth T,Berger K et ak Smoking and the risk of intracerebral hemorrhage in men [abstract]. Neurology 58(Suppl 3):A116, 2002 Kernan WN, Viscoli CM, Brass LM et ak Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 343:1826,2000 Levine SR, Brust JCM, Futrell N et al: Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 323:699, 1990 Rothrock JF, Rubenstein R, Lyden PD: Ischemic stroke associated with methamphetamine inhalation. Neurology 38:589, 1988 Rowley HA, Lowenstein DH, Rowbotham MC, Simon RP Thalamomesencephalic strokes after cocaine abuse. Neurology 39428, 1989 Tapia JF, Golden J A Case records of the Massachusetts General Hospital (Case 27-1993). N Engl J Med 329117, 1993

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CLINICAL FEATURES AND MANAGEMENT OF CEREBROVASCULAR DISEASE

39

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories Philip A. Teal

The clinical symptoms and signs of cerebrovascular disease are varied and, at first impression, may seem too heterogeneous and complex to classify by vascular territory. However, the goal of identifymg which artery is responsible for the patient’s symptoms is the very cornerstone of vascular diagnosis. Careful assessment of the clinical features often can help the physician clarify the affected vascular territory and even the specific artery. Differentiating large artery from small penetrating artery disease may help elucidate the underlying pathogenesis and guide diagnostic and management efforts. This chapter describes the common clinical vascular syndromes.

CAROTID TERRITORY Anatomy

Figure 39-1 illustrates the anatomy of the internal carotid artery (ICA) and its principal branches. Each ICA arises from the bifurcation of the common carotid artery and has a cervical (extracranial) and intracranial course. The right common carotid artery takes origin from the innominate artery, and the left common carotid artery usually arises directly from the aortic arch, although variations are common. The bifurcation of the common carotid artery into the external carotid artery and ICA occurs in the cervical region at approximately the level of the superior thyroid cartilage (C4 to C5), although individual variations, proximal or distal, are common. The location of the carotid bifurcation makes auscultation of bruits readily accessible. The external carotid artery is recognized by its several facial branches, which form important collateral channels when the circulation is compromised by occlusive lesions of the ICA or vertebral artery (VA). Anastomotic channels around and in the orbit may establish blood flow via the ophthalmic artery to the intracranial portion of the ICA when occlusion is at or just beyond the cervical bifurcation. The external carotid artery and the VA provide important reciprocal collaterals to each other in the presence of occlusive disease. The external carotid artery supplies branches that anastomose with the distal extracranialVA when the proximal, extracranial VA is occluded. Also, muscular branches of

the VA may reconstitute the external carotid artery in the presence of common carotid artery occlusion. The extracranial ICA, free of branches, extends from the bifurcation into the entrance of the petrous bone at the skull base. The intracranial ICA has three distinct segments: the petrosal, cavernous, and supraclinoid. The supraclinoid segment is the most important because of its several major branches. The first is the ophthalmic artery, which enters the orbit through the optic foramen and gives rise to several branches, including the important central retinal artery, which supplies the retina. The next branch is the posterior communicating artery, which joins the posterior cerebral artery (PCA) and, when fully developed, serves as an important conduit between the carotid (anterior) and vertebrobasilar (posterior) circulations. The anterior choroidal artery arises from the ICA just distal to the posterior communicating artery. The ICA then divides into its terminal branches, the anterior cerebral artery (ACA) and middle cerebral artery (MCA). The ACA supplies the upper medial surface of the hemisphere from the frontal pole to the posterior parietal area, extending over the convexity of the hemisphere to form an important anastornotic network with the distal branches of the MCA. The MCA supplies the entire lateral aspect of the hemisphere through several branches and is the largest extension of the terminating ICA.

Collateral Circulation

Several of the important collateral channels have already been described. These include connections between the external carotid artery and ICA via the orbital vessels; connections between the external carotid artery and VA; the circle of Willis, which connects the two intracranial carotid circulations via the anterior communicating artery; and the important carotid to vertebrobasilar connection through the posterior communicating artery. In addition, important leptomeningeal networks exist between the small terminal branches of the ACA and the MCA and PCA and MCA, providing border zone collaterals. All of these collateral channels provide critical safeguards to compensate for various extracranial and intracranial occlusive lesions (Fig. 39- 1).

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Clinical Features and Management of Cerebrovascular Disease

A

B

FIG. 39-1. Cerebral circulation showing the extracranial and intracranial course of the carotid artery and its principal

intracranial branches. Circled areas highlight important collateral pathways. (A) Lateral view. Transorbital anastomoses via the ophthalmic artery link the external and internal carotid arteries. The posterior communicating arteries connect the carotid and vertebrobasilar circulation. Muscular branches of the cervical arteries form extracranial anastomoses between the vertebral artery and the external carotid artery. (6)Anteroposterior view. The anterior communicating artery connects the right and left carotid circulations. Leptomeningeal anastomoses form important collateral pathways in the border zones between major arterial territories. ACA, anterior cerebral artery; M U , middle cerebral artery.

MANIFESTATIONS (PRESTROKE) OF INTERNAL CAROTID ARTERY DISEASE Two important prestroke manifestations of ICA disease are bruits and transient ischemic attacks (TIAs). The presence of a carotid bruit heard on auscultation may be an important sign of silent carotid artery disease or a reassuring corroboration of an occlusive lesion in the presence of symptoms. The carotid bruit, the sound of turbulent blood flow, suggesting an underlying stenosis, is best heard at the bifurcation area in the region of the superior thyroid cartilage to the angle of the mandible. Careful auscultation can almost always identify a bruit when severe stenosis is present. The quality of the bruit may vary and is not as predictive of underlying stenosis as the location at the bifurcation area. The bruit may be soft or loud, with a harsh or high-pitched quality. When the stenosis becomes critical or the artery occludes, the bruit may disappear or be absent from the start because of the reduced blood flow. A carotid bruit must be distinguished from other sounds that

may reflect conditions other than carotid stenosis, such as a radiated cardiac murmur, external carotid stenosis, nonstenosing lesions of the ICA, and venous sounds. Cardiac murmurs that radiate to the neck usually diminish in intensity the further they are from the heart, in contrast to bifurcation bruits, which are localized and remain constant or increase in intensity. Noncritical stenoses of the ICA may produce sounds of turbulent flow and may be difficult to differentiate from more severe stenosis without noninvasive testing. External carotid stenosis alone might produce a bifurcation area bruit. Its differentiation from ICA stenosis may be possible by detecting a diminished preauricular pulse from reduced flow in the ipsilateral superficial temporal artery compared with the normal side. Finally, venous sounds may confuse interpretation of neck bruits. However, venous sounds usually are heard low in the neck in the supraclavicular area. They may be obliterated by light compression of the external jugular vein or disappear in the supine position. All neck bruits, especially those suspected of reflecting ICA stenosis, should be investigated further with noninvasive carotid testing.

Chapter 39

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

In the presence of carotid occlusion, an ocular bruit may be heard with a stethoscope over the contralateral orbit in up to 25% of patients, at least during the early phase after occlusion. The ocular bruit is thought to reflect increased blood flow in the contralateral ICA. Sometimes an ocular bruit may be present with severe ipsilateral carotid siphon stenosis.

Carotid Territory TlAs TIAs are an important symptom of carotid artery disease and occur in 50% to 75% of patients with proven carotid stroke in retrospective series. TIAs are brief, reversible focal neurologic deficits that reflect temporary ischemia in a specific arterial territory. They last only minutes and must be differentiated from other common transient focal neurologic symptoms that reflect other mechanisms such as migraine, seizures, and isolated dizziness (vestibulopathy). TIAs may occur in any vascular territory but are broadly classified into carotid (anterior) and vertebrobasilar (posterior) circulation events. Carotid territory TIAs include transient monocular blindness (TMB) and transient hemispheric attacks (THAs), reflecting the principal target areas of the retina and hemisphere. Transient Monocular Blindness TMB is the occurrence of temporary monocular visual obscuration. It may take several forms in which the patients describe “a blur,” “a fog,” “a mist,” “a cloud,” or “Saran wrap,” affecting visual clarity in one eye. The classic form of a shade or curtain effect of visual loss, descending or ascending to obscure all or part of monocular vision, occurs in only a minority of patients. Positive visual phenomena such as sparkles, lights, or colors are uncommon and help to distinguish TMB from a migrainous event. TMB is brief in duration, lasting 1 to 5 minutes, usually less than 15 minutes. Patients may have a few episodes or hundreds over many months or even years before seeking medical evaluation. TMB occurs without other symptoms and, together with its brief duration, is often perceived by patient and physician as a benign, inconsequential event. Although TMB usually occurs without any obvious inciting stimulus, occasionally occurrence after standing up or after other position changes or reduction in blood pressure related to antihypertensive medications may precipitate the visual obscuration. Exposure to bright sunlight may provoke an episode of TMB in patients with severe carotid stenosis by the mechanism of retinal hypoperfusion with reduced resynthesis of visual pigments, stressed by the bright stimulus. The pathogenesis of TMB, when related to carotid disease, may reflect embolism into the retinal circulation from platelet-fibrin thrombi superimposed on extracranial ICA atheromatous disease or a hemodynamic effect from severe stenosis or occlusion. Chance observations of the ocular fundus during an attack of TMB in a small number of instances have documented embolic material traversing the retinal circulation. Usually, the embolus is grayish-white in appearance, reflecting platelet-fibrin material. Cholesterol emboli, also known as Hollenhorst plaques, named for the ophthalmologist who described them, are characterized by bright orange-gold birefringent crystals, but their relationship to TMB is unclear. Hollenhorst described these cholesterol crystals in patients with generalized cerebrovascular disease but found no association in a separate group of patients with TMB. They are often an incidental finding on funduscopic examination in

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patients with systemic atherosclerotic disease, and their principal importance is as a marker for generalized atherosclerosis. A poor prognosis related to a high mortality rate from cardiac death is associated with their discovery. The cholesterol emboli observed in the retinal circulation may arise from debris on a carotid atherosclerotic plaque or a more proximal atheroma from the aortic arch. Usually, no fundic abnormalities are seen during or after an attack of TMB, leading some to infer that embolic material has already passed from the retinal circulation. Undoubtedly, some attacks of TMB are caused by embolic material circulating through the retinal vasculature. Single or only a few attacks of TMB may be accounted for by this mechanism, but multiple, recurrent similar episodes of TMB over an extended period probably reflect retinal hypoperfusion from hemodynamic insufficiency related to carotid occlusive disease. Because the retinal circulation, like the hemisphere beyond, is a distal field of the carotid artery circulation, it is subject to hemodynamic effects in the presence of severe extracranial ICA stenosis or occlusion. A symptomatic low-perfusion state implies intermittent failure of collateral circulation. Conditions known to stress the delicate balance between adequate retinal perfusion and insufficiency include orthostatic blood pressure changes, hypotension induced by excessive antihypertensive medications, and exposure to bright light. Typically, patients with a hernodynamic mechanism may have many attacks over long periods without visual sequelae. The clinical features of such attacks often are similar or even identical (stereotyped) each time. The occurrence of TMB in an adult with known vascular risk factors carries a strong relationship to carotid artery occlusive disease in as many as 30% to 50% of patients. Other causes of retinal TIAs, such as cardiac origin embolism (as seen in chronic atrial fibrillation, for example) are distinctly less common than extracranial ICA stenosis. As expected, TMB also has a strong relationship to other manifestations of carotid occlusive disease. Patients may have a history of THAs, but, interestingly, these attacks do not occur simultaneously with TMB. The mechanisms for both types of attacks are similar, but factors sufficient to produce retinal ischemia seem to have little effect on the hemispheric circulation. A rare exception has been the report of simultaneous ocular and hemisphere infarction in a few patients with carotid disease, but this exception reinforces the general principle of nonsimultaneity. Patients with both eye and hemisphere attacks have a higher incidence of carotid disease than do patients with TMB alone. Patients with only TMB at the time of presentation have a lower 2-year stroke risk than do patients presenting with THAs. This conforms to clinical experience, which suggests that stroke seldom follows an attack of TMB alone until THAs occur. Benign Variants of TMB Young women and otherwise healthy adults younger than 45 years of age may have attacks of TMB with a benign course. These patients have no tendency toward generalized atherosclerosis, and carotid occlusive disease is not the underlying mechanism. Until recently, the actual mechanism was uncertain, but vasospasm of the retinal circulation, perhaps similar to a migrainous mechanism, has now been documented. Recognition of this benign variant is important to avoid unnecessary, costly, and potentially risky diagnostic procedures in search of the more common atherosclerotic causes of TMB.

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Cerebrovascular Disease rn Clinical Features and Management of Cerebrovascular Disease

Transient Hemispheric Attacks Transient ischemia that affects hemispheric function is the other common and important carotid TIA, called a THA. In general, hemispheric dysfunction is reflected by weakness numbness of part or all of the opposite side from the affected carotid artery. Speech may be involved when the dominant hemisphere is the target, and a behavioral alteration characterized by poor awareness of the deficit is common in nondominant hemispheric dysfunction. The latter affliction makes patients unreliable reporters of their own disability and often leads physicians astray in attempting to interpret their patients’ concocted symptoms. The most common symptoms experienced by the patient with carotid THAs are motor and sensory impairment of the contralateral limbs, followed by pure motor dysfunction, then pure sensory symptoms, and finally isolated dysphasia. Brachial paresis is the most consistent effect and may be the only symptom. It is common, as the sole manifestation of carotid occlusive disease, for the patient to describe suddenly dropping a utensil because of unexpected weakness. This specific deficit occurs presumably because of ischemia in the distal field of the carotid serving the suprasylvian motor area of arm function. THAs are brief in duration, usually lasting less than 15 minutes, with many only 1 to 10 minutes. Patients may have only one or many THAs, spanning weeks to months, but rarely for more than 1 year, before coming to medical attention. An unusual form of carotid THA called limb shaking involves movements of the contralateral limbs. The limb shaking tends to be recurrent, involuntary, irregular movements described as “shaking,” “trembling,” “twitching,” and “flapping.” When limb shaking is the initial manifestation of carotid insufficiency, its differentiation from focal epilepsy may be difficult. However, epilepsy is more stereotyped and rhythmic than typical limb shaking. When other types of carotid TIA are part of the patient’s history, then limb shaking may be more easily recognized as another ischemic manifestation. Limb-shaking TIAs are regularly associated with hemodynamically significant ICA stenosis or occlusion, presumably reflecting a motor instability. A few patients have been reported with bilateral carotid occlusive disease with limb shaking on both sides of the body, on different occasions. In a limited number of patients, carotid endarterectomy has abolished these limb-shaking spells. The pathogenesis of carotid THAs involves hemodynamic and embolic factors. Usually, patients with recurrent similar attacks have significant flow impairment from ICA stenosis or occlusion. In contrast, patients with only one or a few hemispheric attacks of different features may have an embolic mechanism affecting different MCA branches. Of course, both mechanisms and their effects may express themselves at different times in a patient. THAs associated with carotid stenosis of 70% or more carry a significant risk of subsequent stroke over a &year period, estimated to be approximately 26%, higher than TMB alone based on data from the North American Symptomatic Carotid Endarterectomy Trial.

OCULAR STROKE Extracranial carotid artery occlusive disease may present as ocular ischemia in the form of central retinal artery occlusion, retinal artery branch occlusion, or venous stasis retinopathy.

These and other ocular ischemic syndromes are discussed in Chapter 6.

CEREBRAL INFARCTION IN THE CAROTID TERRITORY Internal Carotid Artery Occlusive disease of the ICA may be asymptomatic or cause stroke of varying severity from mild to devastating, depending on the mechanisms of ischemia (whether hemodynamic or embolic), availability of collateral blood flow, and size and location of the resulting infarct. The evolution or tempo of the fixed neurologic deficit may take one of several forms. TIAs (ocular or hemispheric) may precede the stroke by days, weeks, or months. With this background, the patient may awaken one morning with minor arm-hand weakness and speech difficulty. This persists for several hours and may improve, only to worsen later the same day or over the next few days to a major hemisphere disturbance with aphasia and hemiplegia. This classic stepwise onset marks the process as atherothrombotic and implies a worsening hernodynamic condition with a final arterial-to-arterial embolic occlusion of the MCA stem or its branches. A stepwise onset with a less severe outcome may result from pure hemodynamic insufficiency and watershed infarction without intracranial embolism. Another scenario involves TIAs followed by a sudden, severe major hemispheric stroke, implying direct embolism to the MCA. Sometimes, with no history of preceding TIAs, the patient presents with a sudden partial or even complete MCA territory infarct as the first and only expression of his or her ICA disease, mimicking cardiac embolism. The absence of TIAs with a sudden, isolated embolic-type stroke may be questioned, but many patients do not report previous TIAs to the physician or family, and when the stroke occurs they are either unaware (nondominant hemisphere syndrome) or severely aphasic (dominant hemisphere) and unable to provide this history. The impact of the infarct usually involves the MCA territory, less commonly the ACA territory. One angiographic study of patients with symptomatic ICA occlusive disease found intracranial embolism to be the predominant mechanism for infarction in two thirds of patients studied, with a nonembolic, presumed low-perfusion state in one third. These two groups were further characterized by a high frequency of preceding TIAs and a milder clinical deficit in patients with a nonembolic mechanism. Infarctions resulting from these two mechanisms have a different hemisphere topography (Fig. 39-2A). The impact of the hemodynamic mechanism affects the suprasylvian area of the frontoparieta1 cortical convexity in the distal field of the carotid (MCA) supply. The resulting infarct lies high on the convexity and disproportionately affects motor function of the arm and hand, less so for the leg, with sparing of the face, which is situated lower in the sylvian area. Language abnormalities associated with these suprasylvian infarcts generally are not as severe as those with sylvian localizations and take the form of the transcortical aphasias characterized by the relative preservation of repetition. The embolic infarct pattern is a discrete hypodensity involving the cortex and underlying white matter, usually in the sylvian region (Fig. 39-2B). Embolism from the occlusive ICA atheroma often blocks the MCA stem or branches, but the ACA may also be involved, especially if the embolus occludes the top of the carotid, where both major arterial supplies arise. Because ICA territory strokes most often affect the MCA territory, distinguishing them from primary athero-occlusive disease of the MCA stem or cardiogenic

Chapter 39

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

embolism may not be possible on clinical grounds alone unless markers of previous carotid disease exist in the form of TMB. The majority of MCA occlusions result from embolism, either carotid or cardiac source. This fact makes it important to investigate for a carotid source when MCA territory infarction is present, even if obvious cardiac embologenic disease is present, because both mechanisms may coexist. ~~

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and anterior parietal regions in a sylvian-suprasylvian distribution; the inferior division supplies the temporoposterior parietal region. The functional anatomy underlying these vascular territories leads to specific neurologic deficits. Occlusions of individual branches of the superior and inferior division usually are caused by embolism and result in partial clinical syndromes, depending on the vessel and brain location affected.

~~

MIDDLE CEREBRAL ARTERY TERRITORY

The MCA and its branches supply the largest portion of the cerebral hemisphere, including the deep basal ganglia-internal capsular area and lateral surface of the hemisphere. The MCA territory accounts for the most common stroke syndromes because of its large blood supply and susceptibility to occlusion.

Pathogenesis of MCA Territory Stroke

The most common cause of MCA occlusion is embolism from either a cardiac or artery-to-artery source from extracranial ICA atherosclerosis. Primary atherosclerosis may produce a focal stenosis or occlusion of the MCA stem, but overall it is an uncommon cause of occlusion compared with embolism.

Anatomy

The most common anatomic pattern is the MCA originating as a stem from the terminal ICA, which then divides into a superior and inferior division, from which approximately 12 branches arise to supply the lateral aspect of each hemisphere. The lenticulostriate arteries (LSAs), small vessels that originate from the MCA stem, or less often the superior division, are end arteries supplying the putamen, part of the internal capsule, and caudate nucleus (Fig. 39-3). Either the superior or inferior divisions may be individually blocked by embolism, resulting in a restricted cortical territory infarct. The superior division territory supplies the lateral frontal

Clinical Features MCA Stem. Table 39-1 illustrates the computed tomographic (CT) patterns and attendant clinical deficits for MCA territory infarcts. The maximal neurologic syndrome, well known to the clinician, results from a large infarct involving the deep territory and cortical surface produced by occlusion of the MCA stem proximal to the take-off of the LSAs. The principal clinical signs include hemiplegia of face, arm, and leg; head and eye deviation to the affected hemisphere; hemisensory loss; homonymous hemianopsia; and global aphasia (dominant hemisphere) or neglect (nondominant hemisphere). The neurologic outcome associated

A

B

FIG. 39-2. (A) Computed tomographic scan of a patient with a watershed infarction, showing low attenuation along the anterior and posterior border zones caused by low perfusion, resulting from a carotid artery occlusion. (B) Computed tomographic scan of a patient with an embolic infarction shows a discrete area of low attenuation in the territory of the superior division of the middle cerebral artery.

Cerebrovascular Disease H Clinical Features and Management of Cerebrovascular Disease

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Superior Division of MCA PrerolanY

I)

Posterior Temporal A.

Inferior Division of MCA

A

[In'.

Carotid A. B

FIG. 39-3. Anatomy of the middle cerebral artery (MCA). (A) Lateral view showing the most common vascular pattern with cortical branches arising from superior and inferior divisions. (B) Anteroposterior view showing the lenticulostriate arteries originating from the stem of the M U . ACA, anterior cerebral artery.

TABLE 39-1. Middle Cerebral Artery Territory Infarct Patterns and Clinical Features Computed Tomography

Motor

Sensory

Visual

language

Behavior

MCA stem complete territory

Hemiplegia; F+A+L Head and eye deviation

Hemianesthesia

Homonymous hemianopsia

Global aphasia

Neglect (ND > D)

MCA superior division

Hemiparesis; F+A>L Head and eye deviation

Hemianesthesia; F+A>L

Motor aphasia (Broca's) (D)

Neglect (ND)

MCA inferior division

Minimal weakness

Rapidly resolving hemisensory

Sensory aphasia (Wernicke's) (D)

Behavioral disturbances Constructional apraxia, delirium (ND)

Arterial Territory

-

Homonymous hemianopsia or upper . . quadrant . anopsia

Abbreviations: A, arm; D,dominant hemisphere; F, face; MCA, middle cerebral artery; ND, nondominant hemisphere.

with MCA stem occlusion produces an unacceptably severe deficit, although rarely a benign outcome has been noted in patients with effective collaterals who have had a progressive occlusive lesion, allowing time for compensatory collaterals to develop. MCA Penetrator Territory. The LSAs arise from the MCA stem and consist of a medial and lateral group of vessels. Occlusion of one or more of these penetrators results in a small, deep infarct in the striatocapsular area. The resulting neurologic deficit usually is a pure motor hemiparesis from the capsular infarct. The prognosis for functional recovery is excellent.

MCA Divisions. The clinical syndrome associated with superior division occlusion results from infarction of the anterior sylvian and suprasylvian part of the hemisphere involving the frontoparietal region (Fig. 39-4). The deep penetrating territory of the LSAs is spared because the superior division originates distal to their origin. Motor deficits predominate in superior division territory infarction. Hemiparesis follows the distribution of face and arm, which are more affected than the leg. Head and eye deviation is common. The hemisensory loss follows the pattern of the motor deficit, with the face and arm more affected than the leg.

Chapter 39

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

An expressive-type (Broca’s) aphasia results in the dominant

hemisphere and neglect in the nondominant hemisphere. The inferior division clinical syndrome results from infarction in the temporoparietal area and usually is below the sylvian fissure (Fig. 39-4). Here, motor deficits are overshadowed by a predominantly fading hemisensory loss and either homonymous hemianopsia or inferior quadrantanopsia related to injury of the optic radiation deep to this region. A receptive-type (Wernicke’s) aphasia occurs in the dominant hemisphere, and behavioral disturbances of agitation and constructional apraxia result from the nondominant hemisphere. MCA Branches. Individual branches or combinations of two or more branch occlusions of the superior or inferior division result in restrictive clinical signs referable to the focal brain region and its functional anatomy (Fig. 39-3).

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ANTERIOR CEREBRAL ARTERY Anatomy

The ACA and its cortical branches supply the anterior and medial aspects of each cerebral hemisphere except for the most posterior portion supplied by the PCA (Fig. 39-5). Deep branches, including Heubner’s artery, supply the anterior limb of the internal capsule and part of the head of the caudate nucleus. The anterior communicating artery, which is a critical conduit of the circle of Willis, joins both ACAs in the midline. The cortical branches of the ACA supply the medial orbital surface of the frontal lobe, the frontal pole, the supplementary motor area, and the motorsensory cortex supplying the foot, leg, and urinary bladder. Branches also supply the corpus callosum. The leptomeningeal branches of the ACA course over the convexity of the hemisphere to form the important border zone anastomoses with the distal branches of the MCA from the lateral surface of the hemisphere. Variations of ACA anatomy are common, and often both ACAs are supplied from one carotid circulation because of an atretic or absent proximal (A-1) segment. Pathogenesis of ACA Territory Stroke

Occlusive disease of the ACA usually results from embolism of a carotid or cardiac origin. Intrinsic athero-occlusive disease of the ACA, like the MCA, is uncommon. Bilateral ACA territory infarcts usually are caused by vasospasm following rupture of a saccular aneurysm of the anterior communicating artery. Ischemic stroke in the territory of an ACA is uncommon compared with stroke in the MCA territory, accounting for approximately 5% of all anterior circulation infarcts. Clinical Features

FIG. 39-4. Surface anatomy and functional correlates of terriiorial infarctions of superior and inferior divisions of the middle cerebral artery (MCA).

The principal clinical features of ACA territory infarction include motor and sensory dysfunction of the contralateral foot and leg. The proximal arm may also be weak, but the face and hand usually are spared. Sensory loss, confined to the foot and leg, is mild and involves two-point discrimination, localization,

FIG. 39-5. Cortical branches of the anterior and posterior cerebral arteries on the medial surface of the cerebral hemisphere.

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Clinical Features and Management of Cerebrovascular Disease

stereognosis, and position sense. Pain and temperature sense are less affected. The distribution of the weakness and sensory loss, which disproportionately affects the leg and proximal rather than distal arm, with the face spared, stamps the process as ACA territory in contrast to MCA distribution deficits, which heavily affect the lower face, arm, and hand but less often the leg. This distribution presumably reflects the cortical localization of foot and leg, located superiorly and medially in the hemisphere. With bilateral ACA territory infarcts, the patient may have a paraparesis mimicking a spinal cord syndrome. Another feature is abulia, a behavioral alteration characterized by lack of volition and spontaneity. Abulia is a profound state of reduced responsiveness to verbal and environmental stimuli in an otherwise alert patient. Soft, whispering speech and delayed and laconic responses to questions are common. Abulia reflects injury to the anterior and medial frontal cortex. It may result from only unilateral ACA territory infarction or from bilateral infarcts that produce a more profound state of unresponsiveness. Aphasia does not occur but can be mistakenly suggested by the behavioral alterations and tendency for echolalia. Dyspraxia of the left limbs for verbal and tactile stimuli may result from a presumed disconnection syndrome when the corpus callosum is involved in the infarct. Urinary incontinence may occur, with unilateral or bilateral lesions reflecting involvement of the paracentral lobule. Heubner’s arteries include two to four arteries that arise from the proximal ACA and supply part of the caudate nucleus, anterior limb of the internal capsule, and anterior part of the putamen. The clinical features resulting from Heubner arterial territory infarction include dysarthria and behavioral-cognitive deficits such as abulia, neglect, and aphasia. ANTERIOR CHOROIDAL ARTERY Anatomy and Pathogenesis The anterior choroidal artery is a small vessel that originates from the internal carotid artery a few millimeters distal to the origin of the posterior communicating artery. It supplies branches to the optic tract. As it courses posteriorly, it gives off branches to the medial aspect of the temporal lobe, cerebral peduncle, and thalamus. Branches supply the lateral geniculate body and posterior half of the posterior limb of the internal capsule. The vessel terminates in the choroid plexus. Stroke in the territory of anterior choroidal artery is uncommon but can be recognized by the topography of the CT infarct encompassing the deeper territories of the hemisphere (Fig. 39-6). The most common stroke mechanism is small vessel disease in patients with hypertension and diabetes. Cardiac embolism may also account for some cases of infarction.

Clinical Features The most consistent clinical features are hemiparesis and hemisensory loss from infarction of the posterior limb of the internal capsule and homonymous visual field defects from ischemia to the optic radiations or lateral geniculate body. The absence of higher cortical dysfunction in a patient with hemiparesis, hemisensory loss, and hemianopsia reflects the large subcortical extent of the infarct and helps differentiate anterior choroidal artery territory stroke from large infarcts in the MCA territory.

FIG. 39-6. Computed tomographic appearance of an anterior choroidal artery infarction showing an area of low attenuation in the posterior limb of the internal capsule and lateral geniculate body (arrow).

VERTEBROBASIUR TERRITORY The vertebrobasilar (VB) circulation supplies the brainstem, cerebellum, and, through the PCA, the medial temporal lobe, thalamus, and visual centers, including the primary visual (calcarine) cortex. Physicians have traditionally viewed the VB circulation as somehow uniquely different from the carotid or anterior circulation. The clinical symptoms often are confusing to the physician, and the stroke mechanisms are thought to be mysterious. Often, the patient’s symptoms, which are not readily consistent with carotid ischemia, are casually labeled VB insufficiency, and without further diagnostic effort, anticoagulants are prescribed. This attitude, in contrast to the efforts made to clarify carotid territory ischemia, reflects in part the perceived absence of surgical treatment such as carotid endarterectomy, the puzzling array of symptoms and signs, and a poor understanding of the pathophysiology of VB stroke. Earlier attempts to understand VB ischemia by Mayo Clinic clinicians led to the term VB insuficiency and treatment with warfarin anticoagulation, based on favorable results in small, uncontrolled studies that lacked angiographic clarification of the underlying vascular disease. This approach has unfortunately persisted despite new information that has emerged from neurodiagnostic techniques and detailed clinical studies of various VB syndromes. As Caplan et al (1992) pointed out in comparing the VB with the carotid circulation, “Consider two arterial systems. They are located only a few inches apart, have the same anatomic constitutions, and, except for size, cannot be easily distinguished from each other grossly or under a microscope. They are exposed to the same blood, the same cardiac output, and the same blood pressure. Would you expect that diseases of the two systems would be very different? The answer is a resounding no.” We now know that the two circulations are more similar than different in terms of stroke risk factors, mechanisms of ischemia

Chapter 39 W

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

(primary atherosclerosis, artery-to-artery embolism, cardiac origin embolism, and all other common mechanisms of VB territory ischemia), and potential treatments. Even the unusual conditions of dissection, vasculitis, and fibromuscular hyperplasia occur in the VB circulation. An understanding of the clinicopathologic features of the VB circulation should help eliminate the double standard in our approach to these problems and enable the clinician to approach VB vascular disease with the same confidence as in the carotid territory. Anatomy Figure 39-7 illustrates the anatomy of the VB circulation. The two VAs arise extracranially from the subclavian arteries and join at the pontomedullary junction to form the single basilar artery. The basilar artery lies on the ventral surface of the pons and, at the pontomesencephalic junction, divides into the two PCAs. The two VAs usually are not equal in size. The dominant, larger VA often is the left one. One VA may be absent or atretic or

371

terminate at the posterior inferior cerebellar artery (PICA) without joining to form the basilar artery. The VAs have four segments; the first segment includes the origin of the VA from the subclavian artery to its entrance in the transverse foramen of the cervical vertebra at the level of C6 or C5. The second segment is entirely within the bony canal of the transverse foramina from its entrance to C2. The third segment is the portion with a tortuous route emerging from C2 and coursing posteriorly and laterally, circling the posterior arch of C1, and passing between the atlas and occiput. The fourth segment is the intracranial portion that pierces the dura mater to enter the foramen magnum. Its long extracranial course, bony encasement, and tortuous exit make the VA susceptible to traumatic injury, a common cause of stroke. The PICA is the largest branch of the VA, originating a few millimeters above the foramen magnum, approximately 1.5 an below the origin of the basilar artery. The PICA supplies the posterior inferior cerebellar hemispheres and provides a branch to the dorsal medullary area. Direct branches from the VA, just

ACA

,

Vertebral A'rteries FIG. 39-7. Anatomy of the vertebrobasilar circulation. (A) Lateral view showing the origin and extracranial course of the left vertebral artery, the basilar artery, and its major branches. (B) Anteroposterior view showing the merging of the vertebral arteries to form the basilar artery and their principal branches. ACA, anterior cerebral artery; AICA, anterior inferior cerebellar artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery.

B

372

Cerebrovascular Disease H Clinical Features and Management of Cerebrovascular Disease

distal to the origin of PICA, are the major supply to the lateral medullary region. Near the confluence of the two VAs that form the basilar artery, small branches form the anterior spinal artery, which courses caudally to supply a major portion of the anterior spinal cord. The largest branches of the basilar artery are the paired cerebellar arteries, the anterior inferior cerebellar artery (AICA), and superior cerebellar artery (SCA). The AKA originates at approximately the midbasilar level and supplies the anterior inferior aspect of each cerebellar hemisphere. The AICA and PICA may provide important anastomotic pathways to compensate for occlusive disease in the proximal basilar artery. The internal auditory artery usually is a branch of AICA but may arise directly from the basilar artery. The SCA originates in the rostral basilar just proximal to its bifurcation into the PCAs. The SCA supplies the superior surface of the cerebellum and part of the rostral lateral pontine tegmentum. The basilar artery then usually bifurcates into the two PCAs unless one or, uncommonly, in both PCAs arise directly from the ICA. The other group of vessels arising from the basilar are the penetrating arteries, which supply the medial and lateral pons and part of the midbrain. This paramedium group consists of 7 to 10 vessels arising from the posterior wall of the basilar artery and supplies the basal and tegmental pons on either side of the midline. Another group, the short lateral circumferential arteries, numbering five to seven arteries, supplies the more lateral pontine base and lateral tegmentum. VERTEBRAL ARTERY Pathogenesisof VA Territory Stroke Disease of the VA is a common cause of brainstem and cerebellar stroke. The consequences of VA occlusion are variable and, like other vascular territories, depend on the pathogenesis, occurrence of local embolism to distal sites, and availability of effective collateral channels. Unilateral VA occlusion, especially in its extracranial segments, may be well tolerated without symptoms because of effective collaterals and patency of the other VA. On the other hand, distal embolism to the basilar artery or its branches can lead to disastrous consequences. One reason why extracranial disease is so well tolerated is the abundance of collateral circulation, leading to reconstitution of the more distal VA (Fig. 39- 1A). The external carotid artery may effectively reestablish antegrade VA flow via the occipital branch to the VA. Also, muscular branches of the deep cervical and ascending cervical arteries and thyrocervical trunk may reconstitute the distal VA when proximal VA occlusion is present. Increasingly, it has been recognized that extracranial VA occlusive disease, like carotid artery disease, can serve as a source for distal embolism into the basilar artery or its branches and lead to stroke. The extracranial VA is also susceptible to traumatic injury because of its encasement in the bony part of the cervical canal. Either spontaneously or after minor trauma from neck manipulation, the VA may be injured, and dissection with luminal compromise and clot embolization may occur. This is a common cause of stroke, especially in young patients without other vascular risk factors. Intracranial VA occlusive disease results from atheromatous disease and is a common cause of stroke. It is the usual cause of lateral medullary and cerebellar infarction. When occlusion is associated with thrombus propagation or local embolism, the

basilar artery may be swept into the occlusive process, leading to a major pontine infarct. CIinicaI

Extracranial VA occlusive disease usually is well tolerated unless distal embolism occurs. These effects are discussed with the specific arterial syndromes that follow. The best-known extracranial VA vascular problem is the subclavian steal syndrome. This results from subclavian atherostenosis but affects the VB circulation (Fig. 39-8). Subclavian stenosis just proximal to the origin of the left VA impairs antegrade flow and creates a low-pressure system in the VA. Because the subclavian also supplies the arm circulation, the pulse is reduced or absent, and exercise of the limb may precipitate the diversion of blood out of the intracranial circulation from the right VA and basilar artery into the low-pressure left VA system. With angiographic visualization, the contrast is seen filling the right VA antegrade and then flows retrograde down into the left VA instead of continuing into the intracranial basilar circulation. In effect, blood is diverted from the basilar circulation by the pressure differential in the left VA as a result of the subclavian occlusive lesion. The clinical effects of subclavian steal are inversely related to the prominent acclaim associated with this vascular condition. That is, it is a benign syndrome in relation to brainstem ischemic effects. Neurologic symptoms usually are transient and may include episodic posterior headache, dizziness, loss of balance, and double vision. Stroke is rare. Symptoms in the ischemic arm are common, and patients complain of fatigue, tiredness, cramping, or coldness. The left subclavian artery is more often affected than the right subclavian, and a bruit caused by the stenosis may be heard along the subclavian artery. lntracranial VA The lateral medullary syndrome is the most common stroke associated with intracranial VA occlusive disease. In approximately 20% of patients, associated cerebellar infarcts are present as a result of compromise of the PICA circulation, which is in close proximity to the VA occlusive process. More often, the infarct is limited to a small wedge of tissue in the dorsal lateral medulla, resulting from occlusion of direct VA branches that supply this area (Fig. 39-9). Table 39-2 lists the typical symptoms and signs of lateral medullary infarction. Although initial disability may be severe, by 6 months recovery is excellent. Magnetic resonance imaging (MRI) may show the infarct, but CT rarely delineates this small area of the medulla because of reduced sensitivity and artifacts from adjacent bony structures. CEREBELLAR INFARCTION Cerebellar infarction usually is caused by atheromatous disease of the parent VA or basilar artery or embolism to one of the long circumferential cerebellar arteries (PICA, AICA, or SCA). The cerebellar infarct may be limited to the cerebellum or may be part of a larger syndrome that includes other brainstem structures, as in the lateral medullary syndrome. The clinical diagnosis of cerebellar infarct often is confused with the more benign medical condition of peripheral vestibulopathy because dizziness and vertigo, with accompanying vomiting, are a prominent part of the cerebellar syndromes, mimicking an isolated vestibular dysfunction. Differentiation is critical because the pathogenesis, treat-

Chapter 39 H Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

373

Int.

Ext.

Innominate A

/

Aorta

FIG. 59-8. Subclavian steal with right-to-left vertebrovertebral crossover flow caused by a proximal stenosis of the left subclavian artery.

ment, and prognosis are different. Often, neuroimaging (CT or MFU) may be necessary to differentiate and clarify the clinical picture, The clinical features may help differentiate the cerebellar vascular territory (Table 39-3). Posterior Inferior Cerebellar Artery

PICA territory infarcts are the most common of the cerebellar strokes and generally produce the largest infarcts. The pathogeneses of PICA territory infarcts are equally divided between intracranial VA athero-occlusive disease and embolism from a cardiac or proximal arterial source. The most common clinical features include sudden spinning dizziness, gait ataxia, and posterior headache. Nausea and vomiting are a regular accompaniment. Appendicular dysfunction on the side of the infarct usually is present. If only the medial PICA branch is involved, the midline vermis may be most affected, producing gait ataxia. If the lateral PICA branch is affected, then the infarct lies laterdy in

the cerebellar hemisphere, and lateropulsion,veering to the side of the infarct when walking or standing, is common. In larger PICA territory infarcts, mass effect compromising brainstem structures, obstructive hydrocephalus from compression of the fourth ventricle, and herniation through the foramen magnum may jeopardize life. Other signs accompanying these seriously ill patients include reduced level of consciousness, ipsilateral face paresis, decreased corneal response, and a Babinski sign, indicating a progressive mass effect. If medical measures fail to reverse the process, urgent ventricular drainage and surgical evacuation of the necrotic cerebellar tissue may be life-saving measures. Once the acute phase has passed, functional recovery generally is good with some rehabilitation effort. Anterior Inferior Cerebellar Artery

AKA territory infarcts are commonly accompanied by other brainstem signs from involvement of nearby structures in the

314

Cerebrovascular Disease rn Clinical Features and Management of CerebrovascularDisease

pons. The reason is that the offending obstructive lesion usually originated in the adjacent basilar artery and affected the AICA circulation in the limited number of patients studied. The cerebellar component of the infarct usually is smaller than those caused by PICA and SCA occlusion and, by itself, has a favorable course. The brainstem signs usually produce maximal involvement at the midpontine level, extending from the midline to the lateral margin, The signs are similar to the lateral medullary syndrome with the addition of peripheral involvement of the seventh (facial) cranial nerve and eighth cranial nerve (ipsilateral hearing impairment) but sparing of cranial nerves IX and X.

TABLE39-3.Cerebellar Infarction: Vascular Territory and Clinical Features Vascular Territow PICA AlCA

SCA

Superior Cerebellar Artery Occlusion of the SCA often is caused by embolism, which blocks the rostral basilar artery and includes the SCA territory; occasion-

Clinical Features Vertigo, ataxia, vomiting, lateropulsion, headache, delayed coma (large infarction) Dysmetria (ipsilateral), crossed syndrome-ipsilateral Horner, facial palsy, deafness, lateral gaze palsy, contralateral temperature and pain loss Ataxia, unilateral limb dysmetria, dysarthria, nystagmus; headache and vertigo less common; Horner's syndrome, contralateral pain and temperature loss, and fourth nerve palsy may be seen; rostral basilar artery syndrome or coma, often with tetraplegia, mav occur ~~~-

Associated Infarcts

* Lateral medulla syndrome

Lateral pons, middle cerebellar peduncle

* Midbrain, tha-

lamic, occipitotemporal lobes

-I

\

Abbreviations: AICA, anterior inferior cerebellar artery; PICA, posterior inferior cerebellar artery; SCA. superior cerebellar artery.

I

Medullary Arteries

PIC

S p i n a l A.

\

PICA

V e r t e b r a l A.

I FIG. 39-9. Vascular anatomy of the vertebrobasilar junction. Small branches arising directly from the distal vertebral artery supply the lateral medulla. AKA, anterior inferior cerebellar artery; PICA, posterior inferior cerebellar artery.

FIG. 39-10. Angiogram showing an abrupt occlusion of the superior cerebellar artery (arrow) caused by a cardiac embolus. TABLE59-2. Lateral Medullary Syndrome lpsilateral to the lesion Facial pain Decreased facial pain and temperature sensation Decreased corneal sensation Horner's syndrome Dysphagia, hoarseness, and decreased gag reflex caused by paralysis of palate, pharynx, and larynx (nucleus arnbiguus) lpsilateral cerebellar signs Contralateral to the lesion Decreased pain and temperature on trunk and extremities Nonlateralized features Vertigo, nausea, and vomiting (caused by involvement of vestibular nuclei) Nystagmus, usually greatest to side of lesion; gait ataxia

ally, isolated SCA embolic occlusion occurs, as seen in Figure 3-10 in a patient with mitral stenosis. Gait and limb ataxia and dysarthria are the most prominent signs; vertigo and headache are less common than in PICA territory infarcts. Because the penetrating short circumferential branches of the SCA supply the upper pontine and midbrain tegmentum, other signs often are present. Horner's syndrome, contralateral pain, and temperature impairment of the face and limbs, contralateral fourth cranial nerve paresis, and ipsilateral involuntary movements have all been recorded.

Chapter 39

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

BASllAR ARTERY The early reports of basilar artery occlusive disease were based on autopsy material and naturally portrayed a dismal outcome. In fact, the deficits associated with basilar artery occlusion were viewed as incompatible with life or as so devastating as to be unacceptable for functional recovery. We now know that basilar artery occlusion can encompass a spectrum of neurologic dysfunction, which is minor in some patients and life threatening in others. In between these extremes, a variety of disability may occur. This is similar to the effects of large artery disease in the anterior carotid arterial territory. The critical factors influencing outcome relate to the mechanisms of the vascular disease, the availability of effective collatera l ~ and , the size and distribution of the resulting infarct. In a survey of the New England Medical Center stroke registry, all 20 patients with angiographically proven basilar artery occlusion collected over a 5-year period survived with varying disability, many with a surprisingly good functional outcome. The diagnosis of basilar artery occlusion has been enhanced by modern neurovascular techniques such as angiography, MRI and magnetic resonance angiography, and transcranial Doppler ultrasound so

that an accurate and more representative population of patients can be assessed. Pathogenesis of Basllar Artery Territory Stroke Occlusive lesions of the basilar artery usually affect the proximal, middle, or distal segments of the artery, although the mechanisms differ for each site; the proximal and midportions are susceptible to atherothrombosis, and the more distal basilar artery is most often affected by embolism. Basilar artery stenosis, from atherosclerosis, usually precedes the occluding atherothrombotic lesion and may involve any segment of the artery with approximately equal frequency (Fig. 39-11). The common belief that the proximal basilar is most susceptible to focal stenosis is not borne out by a review of available reports based on autopsy and angiographic series. Early recognition of basilar artery disease at the stage of TIAs may allow treatment to prevent the full-blown deficits that may be associated with complete occlusion. In our own series of nine patients with basilar artery stenosis, TIAs were the common initial presentation, occurring in six patients. The TIAs preceded stroke except in two patients whose only clinical manifestation was TIAs.

FIG. 39-1 1. Angiograms showing focal atherostenosis occurring in the proximl, middle, and distal segments of the basilar artery (arrows).

375

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Cerebrovascular Disease rn Clinical Features and Management of Cerebrovascular Disease

Seven patients had brainstem stroke; in four, it was preceded by TIAs. The TIA features included two or more of the following symptoms: dizziness, diplopia, perioral numbness, dysphagia, weakness, or loss of consciousness. The complete clinical picture of basilar artery occlusion depends on the distribution and extent of brainstem infarction. Several variations in VB anatomy may complicate the final result. For example, if only one VA supplies the basilar artery because the other is hypoplastic, is occluded, or ends as a PICA, then occlusion of the dominant VA may act as a primary basilar occlusion (so-called basilarization of the VA; Fig. 39-12). Bilateral intracra-

I

Basilar A.*-

.A I C A .PICA

Left Vertebral A.

FIG. 39-12. The basilar artery may be supplied by a single vertebral artery as a result of congenital or acquired vascular anomalies, as shown in the circle. Stenosis of the dominant or solitaryvertebralartery may result in severe compromise of basilar artery perfusion. AICA, anterior inferior cerebellar artery; P a , posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery.

nial VA occlusions may produce an effect similar to isolated proximal or middle basilar artery occlusion. TIAs often precede basilar artery occlusion in up to 50% of patients. The tempo of stroke onset is variable and depends on the mechanism. In embolism to the basilar apex, the onset is abrupt with a maximal deficit, as in other embolic syndromes. If atherothrombosis is the mechanism, a subacute and stepwise onset is typical, as in carotid occlusive disease. For example, a patient may have TIAs over days to weeks followed by a partial deficit involving slurred speech, gaze paresis, and hemiparesis. This may stabilize or even improve for hours, up to a few days, only to be followed by progression to include bilateral weakness, ophthalmoplegia, hemianopsia, and impaired consciousness. Often, the process may abate at any point in the course. The full picture usually evolves over 2 to 5 days. The distribution of brainstem infarction is variable. The pons is the principal target area of maximal injury with proximal and middle basilar artery segmental occlusion (Fig. 39-13). The infarct often is bilateral but asymmetrical and usually affects the basis pontis and medial tegmentum, producing bilateral weakness or paralysis, with extension to the tegmentum, cranial nerve palsies and pseudobulbar effects such as dysarthria and dysphagia may be present. If the infarct involves part of the midbrain tegmentum, an array of oculomotor abnormalities is common, including bilateral ptosis and partial or complete ophthalmoplegia. When the infarct is extensive and involves the pontine base and tegmentum bilaterally, limb weakness, bulbar paralysis, and extraocular palsies occur. The patient may be alert but unable to move except for eye blinking. This alert but immobile state is called the locked-in syndrome. Top-of-the-Basilar Syndrome

When embolism blocks the rostra1 basilar artery, the resulting infarct involves penetrating branches from the basilar apex,

PCA

Superior cerebellar artery Basilar artery

@ D

FIG. 39-13. Bilateral infarction of the pons (shaded areas) caused by basilar artery occlusion. (A) Midbrain, (B) upper pons, (C) lower pons, (0)medulla.

Chapter 39

Cardinal Clinical Features of Ischemic Cerebrovascular Disease in Relation to Vascular Territories

377

FIG. 39-14. Computed tomographic scans showing low-density areas of infarction in the midbrain and both medial thalami in a patient with an embolic stroke resulting in a top-of-the-basilar syndrome (arrows).

posterior communicating artery, and PCA and may include the SCA territory in the infarct as well. The infarct usually is bilateral but asymmetrical, involving the midbrain, thalamus, and medial temporal lobe and the occipital territory of the cortical branches of the PCA (Fig. 39-14). Behavioral and visual and oculomotor disturbancespredominate, with weakness absent or minor. Abnormalities in alertness with excessive sleeplike behavior are common from bilateral medial thalamic involvement. If awake, the patient may be abulic, lacking in spontaneity. Depending on the extent of midbrain infarction, paralysis of voluntary vertical and downgaze may be impaired, with relative sparing of vertical movements with reflex maneuvers. Conversion nystagmus, bilateral ptosis, and lid retraction also occur if the medial midbrain tegmentum is affected. If the occlusive process extends into one or both PCAs, then unilateral or bilateral hernianopic defects that produce cortical blindness occur. Cortical visual disturbances include Balint’s syndrome (absence of voluntary eye movements, optic ataxia in coordinating visuomotor function, and asimultagnosia). Sometimes patients are poorly aware of their blindness or actively refute its existence (Anton’s syndrome), attempting to perform as a normally sighted person with disastrous consequences.

ments. Double vision, unilateral or bilateral internuclear ophthalmoplegia, paresthesias, and other cranial nerve abnormalities occur. POSTERIOR CEREBRAL ARTERY Anatomy The PCAs arise at the pontomesencephalic junction from the termination of the basilar artery in 70% of patients; of the remainder, one or sometimes both PCAs may originate from the ICA from a large posterior communicating artery. The PCAs course around the cerebral peduncles and give off penetrating branches to the midbrain and thalamus. The branches to the thalamus include the thalmoperferants, thalmogeniculates, and posterior choroidal arteries. After circling the peduncle in the ambient cistern, the artery divides into its cortex-supplying branches; these include the anterior and posterior temporal branches, which supply the medial and lateral surfaces of the temporal lobe, respectively; the parietal-occipital artery, which supplies the deep white matter of the occipital lobe; and the medial placed calcarine artery, which supplies the primary visual cortex (Fig. 39-15).

Basilar Artery Penetrator Territory

Small paramedian and short circumferentialarteries arise from the posterior wall of the basilar artery and supply the paramedian and lateral pontine regions. A variety of clinical signs may occur, depending on the extent and exact location of the infarct. Pure motor hemiparesis with dysarthria and ataxia are the most common features associated with occlusive disease of these small vessels. Despite the common occurrence of these small pontine infarcts, the spectrum of clinical features has not been fully defined to date. Although the basis pontis is a favorite site for these infarcts, the pontine tegmentum often is also involved, producing various cranial nerve dysfunctions, especially involving eye move-

Pathogenesisof PCA Stroke

Occlusion of the cortical branches of the PCA usually is caused by embolism, either cardiac in origin or from a more proximal VB source. Intrinsic atheromatous disease of the PCA stem, similar to its MCA stem counterpart, is not as common as embolism. The rarity of PCA stem stenosis was documented in our identification of only six symptomatic patients in a 7’-year review of angiographic records at New England Medical Center (Fig. 39-16). The stenosis occurs at the more proximal (perimesencephalic)segment of the artery as it courses around the midbrain.

Cerebrovascular Disease W

378

Clinical Features and Management of Cerebrovascular Disease

Clinical TIAs may be associated with PCA disease if the primary lesion is atherostenosis. In our series of PCA stenosis, transient hemianoptic visual disturbances and paresthetic sensory symptoms were common and contrasted with MCA stem stenosis, in which motor and speech TIAs predominate. The most common and consistent feature of PCA territory infarction is a hemianopsia. It is usually congruous, spares macular (central) vision, and reflects unilateral infarction of the calcarine visual cortex. The visual defect may be limited to a superior quadrantanopsia if the hsiform and lingual gyri below the calcarine fissure are the principal target of infarction or an inferior quandrantanopsia if the upper bank (cuneus) of the calcarine cortex is primarily affected. Superior quadrantanopsia is more common than inferior visual field defects. Hemianopsia may be the only clinical sign. Approximately three fourths of patients are aware of their hemivisual field defect but may not recognize that it involves both eyes. They quickly adjust by turning their head or adjusting visual materials to compensate for their awareness of unilateral visual impairment. This clear awareness by the patient helps distinguish visual fields loss in the PCA territory from loss in the MCA territory in which infarction of the parietal lobe leaves the patient invariably unaware. Sensory abnormalities are also part of PCA territory infarction, and together with hemianopsia mark the localization as PCA territory. Sensory symptoms result from ventral posterolateral thalamic infarction supplied by the small branches of the thalamogeniculate pedicle. The patient complains of a dysesthetic feeling involving all or part of the contralateral face, limbs, and body, described as a prickly, cold, warm, or tingling sensation. Usually, the complaints exceed any abnormalities found on examination, which tends to be negative. This pure sensory stroke, when it occurs in isolation, reflects a small infarct in the distribution of the thalamic penetrating branches. If the infarct is

i

Posterior Temporal A

.I'/

'

Thalamoaenicutate A . Anterior /Temporal A .

,.

/\

/

'Posterior Corn rn u n icat ing A ,

Thalamoperforant A . Basilar A .

FIG. 39-16. Angiogram showing a stenosis of the proximal stem of the left posterior cerebral artery (arrow).

larger, as a result of multiple branch occlusions, then objective findings on examination usually are present. Other interesting cognitive abnormalities may occur with large-territory PCA infarcts. If the medial temporal lobe in the dominant hemisphere is affected, a severe but temporary amnestic syndrome may occur. Rarely does memory impairment last longer than a few months, if that long. Recent and immediate memory functions are most affected, and patients may attempt to fill-in for their absent memories with fabrications (confabulation). With large infarcts involving the visual cortex and surrounding deep visual association territory, several classic syndromes may result: Alexia without agraphia. In this striking syndrome, patients are able to write correctly and legibly but cannot read their own production or other lexical material. Sometimes, individual words may be read, but sentence material is impaired. Visual color naming may be abnormal in the presence of intact color matching and the ability to recite color names for familiar objects. Amnestic dysnomia. Patients are unable to name common objects and have difficulty producing proper names in spontaneous speech but can describe the function and nature of objects. Visual agnosia. Patients are unable to name objects at sight but may copy objects correctly and name them when presented by other input modalities such as touch, sound, or description. Bilateral lesions in the parietal-occipital territory produce even more spectacular behavior abnormalities.

Chapter 40

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Differential Diagnosis of the Major Stroke Subtypes

379

Prosopugnosia. When lesions involve the temporal occipital areas (lower banks of the calcarine fissure) bilaterally, patients may be unable to recognize and name familiar faces. B a h t ’ s syndrome. In bilateral parietal-occipital lesions, patients may be unable to move their eyes voluntarily, although reflex eye movements are normal (psychic paralysis of gaze); to coordinate visuomotor performance, so it appears the patient is ataxic in reaching for objects (optic ataxia); and to assess a picture in its totality instead focusing on detailed aspects without seeing the meaning of the picture (asimultagnosia). Anton’s syndrome. Cortical blindness from bilateral occipital lesions leaves patients with poor awareness or active denial of their blindness. In this extraordinary syndrome, patients deny their blindness and attempt to perform as a sighted person, walking into objects and then making excuses for their clumsiness.

Anderson DC, Kappelle LJ, Eliasziw M et al: Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 331963, 2002 Barnett HJM, Gunton RW, Eliasziw M et ak The causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA

Usually, motoy function is preserved in PCA territory infarcts except for the uncommon occurrence of midbrain peduncular lesions that may produce a hemiparesis. The predominance of visual and sensory symptoms, including higher cortical behavioral abnormalities, is the hallmark of PCA territory infarction. This helps distinguish PCA territory infarcts from those in the MCA territory, in which motor and speech disturbances predominate.

2000 Kase CS, Norrving B, Levine SR et ak Cerebellar infarction. Clinical and anatomic observations in 66 cases. Stroke 2476, 1993 Pessin MS, Duncan GW, Mohr JP, Poskanzer D C Clinical and angiographic features of carotid transient ischemic attacks. N Engl J Med 296:358, 1977 Streifler JY, Eliasziw M, Benavente OR, et al. The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. Arch Neurol 52:246-249, 1995 Wong KS, Gao S , Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-

SUGGESTED READINGS Amarenco P The spectrum of cerebellar infarctions. Neurology 41:973, 1991

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283:1429, 2000

Caplan L R Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 39: 1246, 1989 Caplan LR, Pessin MS, Mohr J P Vertebrobasilar occlusive disease. p. 443. In Barnett HJM, Stein BM, Mohr JP, Yatsu FM (eds): Stroke: Pathophysiology, Diagnosis, and Management, 2nd Ed. Churchill Livingstone, New York, 1992 Fisher CM: Observations of the fundus oculi in transient monocular blindness. Neurology 9333, 1959 Fisher CM: Occlusion of the internal carotid artery. Arch Neurol Psychiatry 69:346, 1951 Helgason C, Caplan LR, Goodwin J, Hedges T Anterior choroidal artery territory infarction. Arch Neurol 43:681, 1986 Johnston SC, Gress DR, Browner WS, Sidney S: Short-term prognosis after emergency department diagnosis of TIA. JAMA 2842901,

weighted imaging and microemboli monitoring study. Ann Neurol 52:74-81, 2002

Differential Diagnosis of the Major Stroke Subtypes Louis R. Caplan

Effective treatment of patients with cerebrovascular disease depends on accurate diagnosis. An outpatient ambulatory setting offers the physician advantages and disadvantages over inpatient encounters in caring for patients with cerebrovascular disease, and different issues may arise. The office allows more privacy, room, time, and freedom from distractions. The patient and any accompanying friends or family can be interviewed behind closed doors and at more leisure than in the usual hospital room. Somehow, seeing the patient and significant others in their usual attire adds an insight into their character that is not gotten from seeing the patient in hospital uniform. The hospital environment is more anxiety producing; the decision to place the patient in the hospital itself implies serious illness. Hospital routines and the many personnel are hard to adapt to, and patients lose their autonomy. However, the physician can return to see the hospitalized patient as often as feasible and has several opportunities to ask questions of the patient and examine, instruct, and interact with the patient. In the outpatient setting, the doctor has a limited amount of time to arrive at a

diagnosis and plan. A revisit may be needed to revise the diagnosis and management plan. In the outpatient setting, the decision of whether to hospitalize a patient with cerebrovascular disease often is central. In ambulatory patients, the key questions are as follows. What is the diagnosis (what and where are the vascular and brain lesions)? What tests should be ordered, and how soon? What treatment should be prescribed? What instructions and explanations should be given to the patient? These decisions must be made quickly, directly after the outpatient encounter. This section focuses on the first two issues: making the diagnosis and planning the evaluation of a patient suspected of having cerebrovascular disease.

GENERAL STRATEGIES, RULES, AND AIMS OF DIAGNOSIS A few general strategies help the physician arrive at an accurate stroke diagnosis. To treat the patient who has had

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379

Prosopugnosia. When lesions involve the temporal occipital areas (lower banks of the calcarine fissure) bilaterally, patients may be unable to recognize and name familiar faces. B a h t ’ s syndrome. In bilateral parietal-occipital lesions, patients may be unable to move their eyes voluntarily, although reflex eye movements are normal (psychic paralysis of gaze); to coordinate visuomotor performance, so it appears the patient is ataxic in reaching for objects (optic ataxia); and to assess a picture in its totality instead focusing on detailed aspects without seeing the meaning of the picture (asimultagnosia). Anton’s syndrome. Cortical blindness from bilateral occipital lesions leaves patients with poor awareness or active denial of their blindness. In this extraordinary syndrome, patients deny their blindness and attempt to perform as a sighted person, walking into objects and then making excuses for their clumsiness.

Anderson DC, Kappelle LJ, Eliasziw M et al: Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 331963, 2002 Barnett HJM, Gunton RW, Eliasziw M et ak The causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA

Usually, motoy function is preserved in PCA territory infarcts except for the uncommon occurrence of midbrain peduncular lesions that may produce a hemiparesis. The predominance of visual and sensory symptoms, including higher cortical behavioral abnormalities, is the hallmark of PCA territory infarction. This helps distinguish PCA territory infarcts from those in the MCA territory, in which motor and speech disturbances predominate.

2000 Kase CS, Norrving B, Levine SR et ak Cerebellar infarction. Clinical and anatomic observations in 66 cases. Stroke 2476, 1993 Pessin MS, Duncan GW, Mohr JP, Poskanzer D C Clinical and angiographic features of carotid transient ischemic attacks. N Engl J Med 296:358, 1977 Streifler JY, Eliasziw M, Benavente OR, et al. The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. Arch Neurol 52:246-249, 1995 Wong KS, Gao S , Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-

SUGGESTED READINGS Amarenco P The spectrum of cerebellar infarctions. Neurology 41:973, 1991

40

283:1429, 2000

Caplan L R Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 39: 1246, 1989 Caplan LR, Pessin MS, Mohr J P Vertebrobasilar occlusive disease. p. 443. In Barnett HJM, Stein BM, Mohr JP, Yatsu FM (eds): Stroke: Pathophysiology, Diagnosis, and Management, 2nd Ed. Churchill Livingstone, New York, 1992 Fisher CM: Observations of the fundus oculi in transient monocular blindness. Neurology 9333, 1959 Fisher CM: Occlusion of the internal carotid artery. Arch Neurol Psychiatry 69:346, 1951 Helgason C, Caplan LR, Goodwin J, Hedges T Anterior choroidal artery territory infarction. Arch Neurol 43:681, 1986 Johnston SC, Gress DR, Browner WS, Sidney S: Short-term prognosis after emergency department diagnosis of TIA. JAMA 2842901,

weighted imaging and microemboli monitoring study. Ann Neurol 52:74-81, 2002

Differential Diagnosis of the Major Stroke Subtypes Louis R. Caplan

Effective treatment of patients with cerebrovascular disease depends on accurate diagnosis. An outpatient ambulatory setting offers the physician advantages and disadvantages over inpatient encounters in caring for patients with cerebrovascular disease, and different issues may arise. The office allows more privacy, room, time, and freedom from distractions. The patient and any accompanying friends or family can be interviewed behind closed doors and at more leisure than in the usual hospital room. Somehow, seeing the patient and significant others in their usual attire adds an insight into their character that is not gotten from seeing the patient in hospital uniform. The hospital environment is more anxiety producing; the decision to place the patient in the hospital itself implies serious illness. Hospital routines and the many personnel are hard to adapt to, and patients lose their autonomy. However, the physician can return to see the hospitalized patient as often as feasible and has several opportunities to ask questions of the patient and examine, instruct, and interact with the patient. In the outpatient setting, the doctor has a limited amount of time to arrive at a

diagnosis and plan. A revisit may be needed to revise the diagnosis and management plan. In the outpatient setting, the decision of whether to hospitalize a patient with cerebrovascular disease often is central. In ambulatory patients, the key questions are as follows. What is the diagnosis (what and where are the vascular and brain lesions)? What tests should be ordered, and how soon? What treatment should be prescribed? What instructions and explanations should be given to the patient? These decisions must be made quickly, directly after the outpatient encounter. This section focuses on the first two issues: making the diagnosis and planning the evaluation of a patient suspected of having cerebrovascular disease.

GENERAL STRATEGIES, RULES, AND AIMS OF DIAGNOSIS A few general strategies help the physician arrive at an accurate stroke diagnosis. To treat the patient who has had

3ao

Cerebrovascular Disease W Clinical Features and Management of Cerebrovascular Disease

ICH Hemorrhage< sbH

-_...

/Thrombosis Inhemia~Embolism

‘

Large artery ewtracranlal& lntracranlalmluaive disease Small penetrating artery disease Aorta ~~~rterial

Systemic hypoperfusion

FIG. 40-1. Differential diagnostic considerations in major stroke. ICH, intracerebrai hemorrhage; SAH, subarachnoid hemorrhage.

W TMLE 40-1. Data Used for the What Diagnosis

Ecology; Demography and medical conditions known in the past or recognized now (e.g., age, race, sex, hypertension,angina pectoris, diabetes, hypercholesterolemia,rheumatic heart disease) Past cerebrovascular events: Transient ischemic attacks and past strokes (distribution, nature, and cause) Activity at onset of cerebrovascular event Course: Maximal at outset, fluctuating from normal to abnormal, stepwise, gradually progressive, or with rapid improvement Associated symptoms: Headache, vomiting, loss of consciousness, or seizures Neuroimaging:Computed tomography or magnetic resonance imaging

a stroke effectively, the physician would like to know the following: The stroke mechanism (ischemic or hemorrhagic and their subtypes). Figure 40-1 shows a diagnostic tree that lists the major differential diagnostic considerations. The nature, location, and severity of the causative cardiac, cerebrovascular, and hematologic lesions. The pathophysiology of the vascular lesion that caused the brain injury (hemorrhage, hypoperfusion, or embolism). The nature and function of the key cellular and serologic blood components and any disorder of coagulation. The state of the brain, whether normal, infarcted, or injured but recoverable. Modern diagnostic methods can yield most of this information. In most circumstances, the testing can be performed safely and quickly on an ambulatory basis if the pace and severity of the symptoms and signs permit. Rule 1. The diagnostic encounter should be hypothesis driven. The physician aims to know what disease process is occurring and where the lesion is, both in the nervous system and in the cardiovascular bed. Initially, it is important to let the patient tell the story uninterrupted. This offers great insight into the patient’s intelligence, language, and organizing skills, and concerns. As the patient tells his or her story, aided by any accompanying family members or significant others, the physician should begin to generate what and where hypotheses and to test them actively as the history is taken. Tables 40- 1 and 40-2 contain lists of the types of information used to arrive at what and where diagnoses. The patient’s sex, age, and past illnesses are known and can give the first clues. For example, suppose the patient is a hypertensive older man who developed a slight left hemiplegia 4 days ago. Hypertension raises the possibility of intracerebral hemorrhage (ICH). His age also favors some types of hemorrhage (e.g., amyloid angiopathy or minor trauma). Alternatively, the hypertension might have caused penetrating artery disease (the cause of

lacunar infarcts) or accelerated the development of large-artery extracranial and intracranial atherosclerosis. Already there are three hypotheses about the stroke type. Then, as the course of development of the deficit is pursued, the physician decides whether the patient’s and family’s account of the early symptoms and their subsequent course favors one of these hypotheses or suggests a different possibility. This process of generating and testing what hypotheses should continue throughout the patient encounter. At the same time, the physician also should be thinking about where diagnosis, the localization of the lesion in the nervous system and the arteries that supply these regions. The patient’s description of what is or was wrong should generate anatomic hypotheses. Full awareness of a left hemiparesis by the patient makes a subcortical or brainstem locus more likely than a frontal or parietal lobe cortical lesion. If a homonymous visual field defect is present, the lesion must be supratentorial and posteriorly located in the contralateral cerebral hemisphere. An arm monoparesis or a great discrepancy in the degree of weakness in the patient’s face, arm, hand, and leg suggests a cortical, paracentral localization. As the history taking proceeds, physicians should construct a mental picture of the location of the lesion. Rule 2. The diagnosis should be attacked vigorously and sequentially during each part of the encounter. Much hinges on the completeness and accuracy of the diagnosis. Go after the diagnosis tenaciously, first during the history, then during the general and neurologic examinations, and then during each step of the laboratory and imaging evaluations. Rule 3. The diagnosis should be considered using probabilities. The likelihood of a given diagnosis affects the evaluation. After the history, it is useful to list possible what and where diagnoses with their likely probabilities. Table 40-3 is an example of such a list in a patient with a left hemiparesis. Rule 4 . Be sure to consider and exclude diagnoses of serious conditions necessitating special management even if they are not high on the probability list. Subdural hematomas are not common causes of transient ischemic attacks (TIAs), but missing the diagnosis could have serious consequences. Similarly, hypoglycemia is not a very common cause of hemiplegia, but making the diagnosis drastically alters diagnostic strategies and management. The general and neurologic examinations should be planned ahead of time. What features could be found during the examination that would clarify the stroke mechanism and the pathologic anatomy? For example, in a patient with left hemiparesis, visual field testing, tests for neglect, drawing and copying, somatosensory testing, and careful cranial nerve examination should allow more precise localization. Clearly, the neck should be auscultated with a stethoscope for carotid and vertebral artery bruits, and a careful cardiac and peripheral vascular examination is warranted. Are there any signs of systemic bleeding or head injury? At times, the examination uncovers findings completely unsuspected from the history. For example, the patient with left

TABLE 40-2. Data Used for Where Diagnosis Neurologic symptoms described by patient Neurologic signs found on neurologic examination Vascular examination Brain neuroimaging:CT and MRI Vascular diagnostic tests: Ultrasound (extracranial and intracranial), MRA. CTA, standard angiography Abbreviations: Cr, computed tomography; CTA, computed tomography angiography; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging.

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TABU40-3. Weighting of Risk Factors

Hypertension Severe hypertension Coronary artery disease Claudication Atrial fibrillation Sick sinus syndrome Valvular heart disease Diabetes Bleeding diathesis Hyperlipidemia Cancer Old age Black or Asian origin

Thrombosis

Lacunae

++ +++ +++ +++

+++ +

+++

+ + ++ +

+++ +++ +

hemiparesis might have additional right-sided weakness and a bilateral Babinski sign or nystagmus suggesting a brainstem (pontine) localization or an enlarged nodular liver that may indicate metastatic disease. As the examination proceeds, the physician should continue to weigh what and where hypotheses and their probabilities. After the history and general and neurologic examinations, the laboratory and imaging evaluation should be planned to test the existing hypotheses. Ordinarily a brain imaging test, either computed tomography (CT) or magnetic resonance imaging (MRI), is the first test in a patient who has had a stroke or has neurologic signs. The presence of a hemorrhage dictates a battery of tests that are different than if the process were ischemic. Some blood testing should be performed in most patients, including hemoglobin, hematocrit, white blood cell count, platelet count, prothrombin time, and activated partial thromboplastin time (aPTT). Vascular diagnostic tests and cardiac testing usually are optimally planned after the results of imaging and blood tests are known. When the imaging laboratory is distant from the office, the physician may have to order vascular imaging to be performed concurrent with brain imaging.

DEMOGRAPHICSAND PAST ILLNESSES Age, sex, race, family history, and the patient’s medical history strongly affect the probability of the various stroke mechanisms. Some illnesses heavily favor only one mechanism (e.g., rheumatic mitral stenosis with atrial fibrillation strongly suggests cardiac origin embolism). Others, such as hypertension, can predispose to a number of possibilities. Factors such as race and sex affect the likelihood of particular vascular occlusive lesions. In general, white men have more extracranial occlusive disease of the internal carotid artery (ICA) and vertebral artery origins in the neck; women, blacks, and Asians have more intracranial large-artery occlusive disease. Blacks and Asians have a higher frequency of ICH. Table 40-3 estimates the relative weights attributable to the various risk factors. Risk factors also help the physician assess the chances of future vascular disease: stroke, coronary artery disease, and peripheral vascular occlusive disease. These risk factors should be identified and discussed with the patient and family before they leave the office. Table 40-4 lists the key modifiable risk factors.

Embolism

++ ++ + ++++ ++ +++ + + ++

lntracerebral Hemorrhage

Subarachnoid Hemorrhage

++ ++++

+ ++

++++ + + ++

+ + -

TABU40-4. Modifiable Stroke Risk Factors Smoking Hypertension Diabetes Polycythemia Thrombocytosis Obesity Physical inactivity Excess alcohol use Use of high-dose estrogen oral contraceptives Use of amphetamines, cocaine, and other sympathomimeticdrugs

PASTANDRECENTCEREBROVASCULAREVENTS A history of a stroke or TIA can yield important clues to the present cerebrovascular event. As arteries gradually occlude, there are often brief periods of intermittent reduced distal blood flow and embolization of white platelet-fibrin aggregates, red fibrindependent clots, and plaque material into the intracranial branches supplied by that artery. In the Harvard Stroke Registry, about 50% of patients with large-artery occlusive lesions and one fourth of patients with penetrating artery disease had preceding TIAs in the same vascular territory as their stroke. In large-artery lesions (e.g., the ICA in the neck), the attacks are spread over a long interval and often are heterogeneous, with, for example, transient monocular blindness in one attack, hand and face numbness in a second attack, and aphasia with hand weakness in a third spell. In penetrating artery disease, attacks usually, but not always, occur during a shorter time span and closer to the time of the stroke. Lacunar TIAs often are similar in their features and reflect the subcortical blood supply (e.g., tingling on the left side of the body in each attack usually is caused by disease of a thalamogeniculate branch artery supplying the lateral thalamus). Patients whose present stroke is a small deep infarction caused by penetrating artery or branch atheromatous disease often have had past lacunar strokes in different regions. Similarly, patients with emboli originating from the heart often have also had prior embolic strokes or unrecognized brain infarcts in other vascular territories. These past lacunes and embolic brain infarcts may be detectable clinically but sometimes are evident only on CT and MRI. Patients with lobar ICHs may have had other smaller hemorrhages detectable by susceptibility-weighted(T2, also called gradient-echo) MRI images. The nature of the prior attacks or recent TIAs as revealed by history, examination, or imaging provides a clue to the nature of

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the present event. Unfortunately, most people are nafve about the workings of their bodies, especially their nervous systems. A patient may attribute temporary hand numbness and weakness to a local lesion in the limb and may not think of reporting it. Similarly, most patients are unlikely to report having white sparkles in the left visual field 10 days ago, thinking it a symptom for the eye doctor. To elicit the history of prior TIAs or strokes, the physician must tenaciously ask and reask about specific functions (“Has your foot or leg ever gone temporarily limp?” “Has your vision ever faded temporarily in one eye?” “Has your speech failed you or come out garbled, slurred, or wrong?” and so forth). Family members may remember such spells that the patient did not recognize or recall. The patient may not recall symptoms the first time the questions are asked but may remember the events later. For example, a patient with transient monocular blindness when questioned about loss of vision on at least three occasions always gave a negative response. The day after he said “no” for the third time, he spontaneously said, “Doc, now I remember. About a week ago I was in line at the food store, and my left eye went gray for about a minute. The clerk said that I must have gotten a speck of dirt in the eye. Because it went away, I didn’t make much of it.”

had to limp with my left leg. When I called my daughter, my words were slurred. I lay down again, but this time, when I tried to get up, I couldn’t use my left side at all.” This fluctuating pattern of the development of the deficit is characteristic of a thrombotic stroke, in which the deficit is caused by occlusion of a feeding artery with distal hy-poperfusion. In her case, the symptoms fit the pattern of a pure motor hemiparesis, probably caused by penetrating artery or branch atheromatous disease. ACTIVITY AT ONSET OF STROKE OR TIA

Most strokes and TIAs occur during activities of daily living. Emboli can be precipitated by coughing or sneezing, suddenly rising from bed during the night to go to the bathroom, or sexual intercourse (especially paradoxical emboli). SAH and ICH can be precipitated by intercourse or emotional stress. In patients with large-artery occlusive disease, standing or rising after bending can precipitate brief ischemic attacks. Vigorous turning or stretching of the neck can cause extracranial arterial dissections. Always ask what the patient was doing before and during the attack. Was there any unusual or vigorous physical activity or emotional duress in the minutes, hours, or days before the attack?

COURSE OF STROKE DEVELOPMENT

Each stroke subtype has its usual common signature of development and evolution. Emboli most often (in more than 80% of the cases) occur suddenly and create deficits that are maximal immediately. Patients suddenly slump with a hemiplegia. In contrast, ICHs grow gradually over minutes to hours, and the signs gradually increase. If the hematoma becomes large, then headache, vomiting, and decreased consciousness ensue after the initial signs of focal brain dysfunction. Subarachnoid hemorrhage (SAH) also begins suddenly, but the blood released into the cerebrospinal fluid under arterial pressure causes severe headache, vomiting, and transient interruption in posture or activities. Unlike in ICH, focal symptoms of brain dysfunction usually are not present at the outset. In patients with large-artery occlusive disease, fluctuations in the symptoms and signs are characteristic, with stepwise increases in deficits, temporary improvements or return to normal function, and the gradual but erratic progression of symptoms and signs during a few days. These fluctuations and changes are presumed to be caused by changes in the systemic circulation affecting collateral blood flow and propagation and embolization of thrombi distally into downstream branches. Transcranial Doppler monitoring has shown that microemboli are common in patients with occlusive disease of large arteries. Decreased perfusion in these arteries impedes washout of these microemboli. Few patients can give a completely accurate account of the development of symptoms. Those with right hemisphere frontal and parietal lobe strokes may not recognize any deficit. Again, family and friends can supply useful data. Have the patient walk through the events before and after the stroke began. A patient reported that she gradually developed a left-sided paralysis that morning. When she described the events in more detail she said, “At the breakfast table, my left hand and arm went weak and clumsy, and I dropped the coffee cup from my hand. I went upstairs to my bedroom, and I walked OK on the stairs. I rested for a half hour, and then when I came downstairs my hand was all right. I cleaned the room without trouble. An hour later, my hand and arm went weak again. This time I stumbled on the steps and

ACCOMPANYING SYMPTOMS

Headache, loss of consciousness, vomiting, and seizures all provide clues to the cause of the stroke. Headaches, unusual for the patient before the stroke, may signify large-artery occlusive disease or recent elevation in blood pressure. Headache at stroke onset is invariable in SAH and sometimes occurs in brain embolism. In ICH, headache usually follows the onset of other symptoms and signs. Figure 40-2 shows the relationship of headache and vomiting to types of stroke in the Michael Reese and University of Illinois stroke registries. Vomiting is very common near the onset of SAH and is common in large supratentorial and infratentorial ICHs. Vomiting is also common in patients with cerebellar and medullary infarcts. Seizures are slightly more common in patients with embolic infarcts and lobar ICHs than in patients with other stroke subtypes. Loss of consciousness is common in patients with SAH, large ICHs, and brainstem infarcts that affect the tegmentum bilaterally. LABORATORY AND IMAGING EVALUATION

After completing the history and examination and constructing a list of what and where differential diagnoses, the physician is ready to plan the investigations. In some cases, the patient has already had some investigations. It is best to obtain the history and examine the patient before reviewing such accompanying information. Clearly, the nature and speed of the evaluation depend on the circumstances. Acute Stroke

In the case of acute stroke, a hospital admission is almost always in order. CT or MRI and blood screening tests should be ordered as the patient is admitted. Subsequent testing depends on the results of imaging and blood tests. The exception might be a patient with a clear-cut lacunar infarct who prefers to stay at home and can be managed by the family there. Such a patient would have risk factors for a lacune, especially hypertension or diabetes, and a

Chapter 40

c

c

Differential Diagnosis of the Major Stroke Subtypes

383

80-

Q)

f

n 200 .

Is

Subtype FIG. 40-2. Headache and vomiting frequencies by stroke subtypes. ICH, intracerebral hemorrhage; IS, ischemic stroke (embolic and thrombotic); SAH, subarachnoid hemorrhage. (From Corelick PB, Hier DB, Caplan LR, Langenberg P: Headache

in acute cerebrovascular disease. Neurology 36:1445, 1986, with permission.)

typical clinical picture of a lacunar syndrome with nondisabling signs, such as pure motor stroke, pure sensory stroke, dysarthria with minor arm clumsiness, and pure dysarthria. In that patient, an MFU before sending the patient home would help confirm the diagnosis and rule out the presence of unexpected lesions. If the scan shows a small deep infarct that explains the clinical findings, then the diagnosis is clear. If the MRI or CT shows old lacunes and no cortical infarct, then the diagnosis of lacunar infarction is still highly probable. If a cortical infarct or small hemorrhage is found, then further diagnostic testing, usually in the hospital, is warranted.

Remote Stroke

If the patient has a remote stroke (i.e., a stroke more than 1 week old), a scan brought with the patient (or a reliable report of the films by a neuroradiologist) should suffice to tell whether the lesion was a hemorrhage or an infarct and its location. If it was a hemorrhage, the site, size, and pattern of spread should be evident. If the problem was ischemic, the scan might show the infarct or have only slight or nondiagnostic abnormalities. If the studies are old, inadequate, or nondiagnostic, then a new scan (optimally an MRI) should be ordered.

An angioma or arteriovenous malformation may be evident from

the films. If such a lesion is present and potentially resectable, then angiography may be in order. If the patient is hypertensive and the ICH is in a typical site for a hypertensive hematoma (putamen, caudate, thalamus, cerebellum, or pons), then antihypertensive therapy is indicated without the need for other evaluation except blood screening. Ordinarily, all patients should have a platelet count, prothrombin time, and aPTT. An inquiry about the use of drugs (cocaine, diet pills, or methamphetamine) and medicines (especially warfarin) is important. The location of the hemorrhage might suggest a contusion caused by trauma. If the scan suggests SAH or an aneurysm is seen, then admission for SAH management, including the performance of cerebral angiography, is indicated.

Infarction

If the lesion is a small, deep infarct and the patient has hypertension or diabetes and compatible clinical findings, then blood testing usually is sufficient (complete blood cell count, platelet count, and fibrinogen level). If the scan shows a cortical lesion or any lesion unlikely to represent a lacune, then usually a triad of blood screening tests (complete blood cell count, platelet count, prothrombin time, aPTT, and serum calcium), cardiac tests (electrocardiography and echocardiography), and noninvasive vascular tests (extracranial and intracranial ultrasound or magnetic resonance angiography [MRA] or CT angiography [CTA]) should be ordered. The localization of the ischemia determinesthe main vessels to be studied. If the lesion is in the right cerebral hemisphere, then a carotid duplex and color flow Doppler of the ICA in the neck and transcranial Doppler of the anterior circulation arteries would be indicated. Alternatively, an MRA or CTA examination of the ICA and its tributaries could be performed. If the lesion is in the posterior circulation, then a duplex and color flow Doppler examination of the vertebral arteries in the neck, a continuous wave Doppler insonation of the upper neck in the region of the atlas loop (V,) portion of the vertebral artery to determine the direction of flow in this area, and a transcranial Doppler using a suboccipital window to insonate the intracranial vertebral arteries and basilar artery should be performed. Alternatively, head and neck MRA or CTA could be done with attention to the vertebrobasilar arteries. In patients who will undergo MRI, an accompanying MRA can be done while the patient is still in the magnet after reviewing the preliminary results of the MRI so that the vascular study can be adequately planned. TlAs in the Absence of a Stroke

What if the patient had one or more TIAs and not a stroke? If the evaluation can be performed urgently (that day), then outpatient preliminary testing is an option. If the nature or frequency of the attacks is very worrisome, then hospital admission is prudent. Usually, a scan (CT or MRI) and ultrasound or MRA are scheduled concurrently. Blood screening, as described earlier, is also done. If the pattern of the clinical findings or the scan suggests large-artery occlusive disease (TIAs in the same vascular territory), then

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Clinical Features and Management of Cerebrovascular Disease

cardiac testing can be postponed until the results of ultrasound or MRA are available. If there is only one attack or there were attacks in a number of vascular territories, especially if there is clinical evidence of cardiac disease, then cardiac testing is scheduled first or concurrently with noninvasive vascular testing. When the clinical localization is unclear, a review of the scan is necessary before deciding on the order and nature of the cardiac and vascular testing.

SUGGESTED READINGS Bogousslavsky J, Caplan LR (eds):Stroke Syndromes. 2nd Ed. Cambridge University Press, Cambridge, UK, 2001 Caplan L R Caplan’s Stroke: A Clinical Approach. 3rd Ed. ButterworthHeinemann, Boston, 2000 Caplan L R Cerebrovascular disease (stroke). p. 1957. In Stein J (ed): Internal Medicine. 3rd Ed. Little, Brown, Boston, 1990 Caplan L R Diagnosis and treatment of ischemic stroke. JAMA 266:2413, 1991

41

Caplan L R Intracranial branch atheromatous disease: a neglected, under-studied, and under-used concept. Neurology 39:1246, 1989 Caplan L R Posterior Circulation Disease. Clinical Findings, Diagnosis, and Management. Blackwell Science, Boston, 1996 Caplan L R Stroke neuroimaging: evaluation of a recent stroke patient. J Neuroimaging 3:48, 1993 Caplan L R TIAs: We need to return to the question “What is wrong with Mr Jones?” Neurology 39:791, 1988 Caplan LR, Gorelick PB, Hier DB: Race, sex, and occlusive cerebrovascular disease: a review. Stroke 17:649, 1986 Caplan LR, Hollander J: The Effective Clinical Neurologist. 2nd Ed. Butterworth Heinemann, Boston, 2001 Caplan LR, Hurst JW, Chimowitz MI: Clinical Neurocardiology. Marcel Dekker, New York, 1999 Chimowitz MI, Logigian EL, Caplan L R The accuracy of bedside neurological diagnosis. Ann Neurol 28:78, 1990 Gorelick PB, Hier DB, Caplan LR, Langenberg P: Headache in acute cerebrovascular disease. Neurology 3 6 1445, 1986 Kase CS, Caplan L R Intracerebral Hemorrhage. Butterworth-Heinemann, Boston, 1994

Common Vascular Problems in Office Practice Marc 1. Chimowitz, Daryl W. Thompson,Anthony 1. Furlan, and Ajay K. Arora

Internists and neurologists evaluate patients with a wide variety of cerebrovascular problems. In this chapter, we discuss selected cerebrovascular disorders seen in office practice and focus on their diagnosis and management.

CAROTID BRUITS AND ASYMPTOMATIC CAROTID STENOSIS Clinical Detection and Prognosis Carotid bruits are detected in 4% to 5% of the population aged 48 to 80 years and are associated with internal carotid artery stenosis in 50% of cases. Other causes of carotid bruits include increased venous flow, external carotid artery stenosis, and transmitted cardiac murmur. Localized bruits just below the angle of the jaw correlate best with underlying internal carotid artery stenosis, especially those with a diastolic component; the longer the bruit, the tighter the stenosis. Bruit loudness does not reliably predict the presence or severity of internal carotid stenosis; loud bruits may be heard with increased venous flow, whereas preocclusive internal carotid stenosis may produce a very soft bruit. Venous noises usually are low-pitched rumbles that are continuous through diastole and often change with body position or Valsalva. Cardiac murmurs are loudest below the clavicle and fade away as one auscultates up the neck. Subclavian bruits are loudest in the supraclavicular fossa or at the base of the neck and may disappear with light supraclavicular compression. Bruits from cervical vertebral artery stenosis are uncommon but can occasionally be heard in the posterior neck triangle. The absence of a carotid bruit does not rule out the diagnosis of carotid occlusive disease; for example, a bruit may not be heard if there is low flow through a tight stenosis or if the internal carotid artery is occluded. In the latter case, a contralateral orbital bruit may be heard because of increased flow through the contralateral internal carotid artery.

Patients with asymptomatic carotid bruits have a slightly elevated risk of stroke. The annual risk of unheralded stroke (i.e., stroke without preceding transient ischemic attack [ TIA] ) in these patients is 1.5% to 4%, but many of these strokes occur contralateral to the side of the bruit and are related to other mechanisms of stroke, such as penetrating artery disease or cardioembolism.

Evaluation and Treatment of Patients with Asymptomatic Carotid Bruit Most centers use duplex (Doppler and B-mode) carotid ultrasound as the initial screening test in a patient with a carotid bruit. In laboratories with good quality assurance, carotid ultrasound has a sensitivity of 85% and a specificity of 90% for detecting carotid occlusive disease. Magnetic resonance angiography (MRA) has emerged as an alternative to duplex ultrasound. MRA is easier to read than ultrasound and provides a picture of the carotid artery based on blood flow characteristics. The sensitivity and specificity of MRA are equal to or superior than those of ultrasound but are lower than those of contrast angiography for detecting high-grade carotid stenosis. MRA and ultrasound tend to overestimate the degree of stenosis and often cannot distinguish subtotal from complete carotid artery occlusion. The most effective treatment for patients with asymptomatic carotid stenosis remains controversial. Although the Asymptomatic Carotid Atherosclerosis Study (ACAS) showed that endarterectomy offers a statistically significant benefit in patients with asymptomatic carotid stenosis of 60% or more, the absolute risk reduction from endarterectomy was very modest (only 1%). In that trial patients with asymptomatic carotid stenosis of 60% or more were randomized to best medical therapy (aspirin and risk factor modification) or endarterectomy and best medical therapy. Kaplan-Meier projections showed that the risk of stroke over 5

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cardiac testing can be postponed until the results of ultrasound or MRA are available. If there is only one attack or there were attacks in a number of vascular territories, especially if there is clinical evidence of cardiac disease, then cardiac testing is scheduled first or concurrently with noninvasive vascular testing. When the clinical localization is unclear, a review of the scan is necessary before deciding on the order and nature of the cardiac and vascular testing.

SUGGESTED READINGS Bogousslavsky J, Caplan LR (eds):Stroke Syndromes. 2nd Ed. Cambridge University Press, Cambridge, UK, 2001 Caplan L R Caplan’s Stroke: A Clinical Approach. 3rd Ed. ButterworthHeinemann, Boston, 2000 Caplan L R Cerebrovascular disease (stroke). p. 1957. In Stein J (ed): Internal Medicine. 3rd Ed. Little, Brown, Boston, 1990 Caplan L R Diagnosis and treatment of ischemic stroke. JAMA 266:2413, 1991

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Caplan L R Intracranial branch atheromatous disease: a neglected, under-studied, and under-used concept. Neurology 39:1246, 1989 Caplan L R Posterior Circulation Disease. Clinical Findings, Diagnosis, and Management. Blackwell Science, Boston, 1996 Caplan L R Stroke neuroimaging: evaluation of a recent stroke patient. J Neuroimaging 3:48, 1993 Caplan L R TIAs: We need to return to the question “What is wrong with Mr Jones?” Neurology 39:791, 1988 Caplan LR, Gorelick PB, Hier DB: Race, sex, and occlusive cerebrovascular disease: a review. Stroke 17:649, 1986 Caplan LR, Hollander J: The Effective Clinical Neurologist. 2nd Ed. Butterworth Heinemann, Boston, 2001 Caplan LR, Hurst JW, Chimowitz MI: Clinical Neurocardiology. Marcel Dekker, New York, 1999 Chimowitz MI, Logigian EL, Caplan L R The accuracy of bedside neurological diagnosis. Ann Neurol 28:78, 1990 Gorelick PB, Hier DB, Caplan LR, Langenberg P: Headache in acute cerebrovascular disease. Neurology 3 6 1445, 1986 Kase CS, Caplan L R Intracerebral Hemorrhage. Butterworth-Heinemann, Boston, 1994

Common Vascular Problems in Office Practice Marc 1. Chimowitz, Daryl W. Thompson,Anthony 1. Furlan, and Ajay K. Arora

Internists and neurologists evaluate patients with a wide variety of cerebrovascular problems. In this chapter, we discuss selected cerebrovascular disorders seen in office practice and focus on their diagnosis and management.

CAROTID BRUITS AND ASYMPTOMATIC CAROTID STENOSIS Clinical Detection and Prognosis Carotid bruits are detected in 4% to 5% of the population aged 48 to 80 years and are associated with internal carotid artery stenosis in 50% of cases. Other causes of carotid bruits include increased venous flow, external carotid artery stenosis, and transmitted cardiac murmur. Localized bruits just below the angle of the jaw correlate best with underlying internal carotid artery stenosis, especially those with a diastolic component; the longer the bruit, the tighter the stenosis. Bruit loudness does not reliably predict the presence or severity of internal carotid stenosis; loud bruits may be heard with increased venous flow, whereas preocclusive internal carotid stenosis may produce a very soft bruit. Venous noises usually are low-pitched rumbles that are continuous through diastole and often change with body position or Valsalva. Cardiac murmurs are loudest below the clavicle and fade away as one auscultates up the neck. Subclavian bruits are loudest in the supraclavicular fossa or at the base of the neck and may disappear with light supraclavicular compression. Bruits from cervical vertebral artery stenosis are uncommon but can occasionally be heard in the posterior neck triangle. The absence of a carotid bruit does not rule out the diagnosis of carotid occlusive disease; for example, a bruit may not be heard if there is low flow through a tight stenosis or if the internal carotid artery is occluded. In the latter case, a contralateral orbital bruit may be heard because of increased flow through the contralateral internal carotid artery.

Patients with asymptomatic carotid bruits have a slightly elevated risk of stroke. The annual risk of unheralded stroke (i.e., stroke without preceding transient ischemic attack [ TIA] ) in these patients is 1.5% to 4%, but many of these strokes occur contralateral to the side of the bruit and are related to other mechanisms of stroke, such as penetrating artery disease or cardioembolism.

Evaluation and Treatment of Patients with Asymptomatic Carotid Bruit Most centers use duplex (Doppler and B-mode) carotid ultrasound as the initial screening test in a patient with a carotid bruit. In laboratories with good quality assurance, carotid ultrasound has a sensitivity of 85% and a specificity of 90% for detecting carotid occlusive disease. Magnetic resonance angiography (MRA) has emerged as an alternative to duplex ultrasound. MRA is easier to read than ultrasound and provides a picture of the carotid artery based on blood flow characteristics. The sensitivity and specificity of MRA are equal to or superior than those of ultrasound but are lower than those of contrast angiography for detecting high-grade carotid stenosis. MRA and ultrasound tend to overestimate the degree of stenosis and often cannot distinguish subtotal from complete carotid artery occlusion. The most effective treatment for patients with asymptomatic carotid stenosis remains controversial. Although the Asymptomatic Carotid Atherosclerosis Study (ACAS) showed that endarterectomy offers a statistically significant benefit in patients with asymptomatic carotid stenosis of 60% or more, the absolute risk reduction from endarterectomy was very modest (only 1%). In that trial patients with asymptomatic carotid stenosis of 60% or more were randomized to best medical therapy (aspirin and risk factor modification) or endarterectomy and best medical therapy. Kaplan-Meier projections showed that the risk of stroke over 5

Chapter 41 H Common Vascular Problems in Office Practice

years was 5.1% for patients treated surgicallyand 11% for patients treated medically only. This represents a relative risk reduction of 55% and an absolute risk reduction of 5.9% over 5 years. This implies that 17 patients (100/5.9) with asymptomatic carotid stenosis of 60% or more would need to undergo endarterectomy to prevent one stroke over 5 years. Our experience is that when patients are presented these data (i.e., 89% chance of being stroke-free at 5 years if treated medically versus 95% chance of being stroke free at 5 years if treated surgically), most of them opt for medical therapy.

BRAIN SPELLS Internists and neurologists often encounter patients with recurrent episodic neurologic symptoms (i.e., brain spells). The differential diagnosis of brain spells includes TIA, migraine, seizure, metabolic derangements (e.g., hypoglycemia), presyncope, and a psychogenic disorder. To determine the cause of the patient’s spells, it is useful to separate nonfocal from focal spells; the former are rarely caused by cerebrovascular occlusive disease, whereas the latter may be. Excluded from this discussion are psychogenic spells, the manifestations of which are myriad. Nonfocal Spells Isolated Dizziness. Dizziness is a nonspecific term used by patients to describe a variety of different symptoms. A detailed history usually enables the physician to ascertain whether the patient is referring to lightheadedness or faintness, unsteadiness or imbalance, or true vertigo (subjective sense of self or environmental rotatory motion). Faintness or lightheadedness is rarely neurologic in origin. The causes are myriad and include anemia, volume depletion, postural hypotension, vasovagal disorders, dysautonomia, arrhythmias, hyperventilation, panic attacks, and other anxiety disorders. Unsteadiness or imbalance also has many possible causes (disease of cerebellum and its connections, vestibular disease, posterior column dysfunction, peripheral neuropathy). From a cerebrovascular point of view, the most common cause of acute isolated unsteadiness or imbalance (ataxia) is cerebellar infarction or hemorrhage. Vertigo can be caused by peripheral or central vestibular dysfunction. Postural aggravation suggests a peripheral cause. Other associated features help distinguish peripheral from central vertigo. For example, the coexistence of deafness or tinnitus suggests that the vertigo is of peripheral origin. The presence of diplopia, dysarthria, or sensory or motor dysfunction indicates a central origin. Both peripheral and central vertigo can be associated with nausea, vomiting, and gait ataxia. Vertebrobasilar occlusive disease should always be considered in the differential diagnosis of vertigo. Patients with vertebrobasilar disease often present with recurrent stereotypical spells of vertigo, diplopia, dysarthria, perioral numbness, and ataxia. Episodes of isolated vertigo that occur over several months are rarely caused by vertebrobasilar disease and usually are the result of a peripheral vestibular disorder. Syncope. Syncope is the loss of consciousness and postural tone that occurs as a result of globally diminished blood flow to the brain. It is invariably caused by disorders that cause low cardiac output (eg., aortic stenosis, heart block, ventricular arrhythmia, vasovagal syncope, orthostatic hypotension). Occasionally, patients with vertebrobasilar occlusive disease may lose conscious-

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ness because of ischemia to the reticular activating system in the brain stem; however, these patients invariably have associated brainstem symptoms and signs before losing or upon regaining consciousness. The diagnostic evaluation of syncope should focus on the cardiovascular system. Diagnostic tests to consider include an electrocardiogram (ECG), Holter monitoring (although it has a low diagnostic yield), electrophysiologic studies, a tilt table test, and autonomic testing. Neurologic testing should include an electroencephalogram (EEG) if a generalized seizure cannot be ruled out by the history. Carotid imaging is not indicated unless the patient has associated slurred speech, monocular visual loss, or hemiparesis before losing or upon regaining consciousness. The prognosis of patients with syncope depends on the results of the cardiac evaluation. Patients with a serious cardiac cause of syncope (e.g., ventricular arrhythmia associated with poor left ventricular function) are at high risk of sudden death, whereas those without a cardiac or other identifiable cause have a more benign outcome.

Focal Brain Spells Transient Ischemic Attacks. The differential diagnosis of transient focal neurologic spells includes seizures, migraine, transient global amnesia, and TIAs. TIAs are acute focal neurologic deficits caused by cerebral ischemia that, by definition, clear within 24 hours. However, most TIAs last only a few minutes. Typically with TIAs, the deficit is maximal at onset, and there is no march of symptoms, altered awareness, or clonic motor activity. TIAs associated with carotid occlusive disease usually consist of episodes of transient monocular blindness (amaurosis fugax), dysarthria or dysphasia, and hemiparesis involving the hand and face predominantly. Rare TIAs in patients with high-grade carotid occlusive disease include transient monocular blindness upon exposure to bright light, and focal clonic limb shaking (limbshaking TIAs) that may mimic focal seizures. TIAs associated with vertebrobasilar occlusive disease consist of episodes of visual loss of both eyes, diplopia, dysarthria, vertigo, ataxia, perioral numbness, hemiparesis, and quadriparesis. Focal Seizures (Simple Partial Seizures). Focal seizures that manifest as motor, sensory, or speech disturbancesmay be difficult to distinguish from TIAs. Motor or sensory symptoms that march over seconds up or down one side of the body suggest a focal seizure rather than a TIA. Clonic limb shaking usually is caused by a seizure but may also be a rare manifestation of a TIA. The cause of the limb shaking in this setting is hypoperfusion of the cerebral cortex caused by high-grade carotid stenosis or occlusion. Migraine. TIA may also be difficult to distinguish from migraine. Headache is not always a distinguishing feature because TIA can be associated with head pain in up to 40% of patients, and migrainous neurologic symptoms may be unaccompanied by headache (acephalgic migraine). Carotid distribution ischemia typically causes fiontotemporal head pain, whereas vertebrobasilar ischemia causes occipital head pain. The mechanism is probably related to collateral arteries dilating in response to ischemia. Visual symptoms may be a prominent feature of both disorders. Whereas a scintillating scotoma is highly suggestive of a migrainous event, a retinal or occipital embolus may cause a similar phenomenon. Similarly, transient monocular blindness points to ischemia in the carotid distribution, but migraine may produce retinal dysfunction that mimics amaurosis fugax. The visual aura of a migraine

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tends to spread across the visual field over the course of a few minutes, usually has positive features such as motion or color, and is generally followed by a headache. The headache of cerebral ischemia has a more variable time relationship to the neurologic symptoms. Rarely, weakness of the limbs or facial muscles on one side of the body occurs as a migrainous aura. Migraine weakness generally lasts 20 to 30 minutes and, again, often has a spreading evolution over minutes. Attacks of migraine with hemiparesis sometimes are familial (hemiplegic migraine). Aphasia can also occur as the aura of migraine, further complicating the distinction from TIA. The syndrome of basilar artery migraine has many features in common with vertebrobasilar ischemia. Each may manifest as disturbances of consciousness, vision, equilibrium, and motor and sensory function. Occasionally migraine disappears for years only to reemerge in later life to be easily confused with TIAs. The 70-year-old patient may have completely forgotten the menstrual headaches she had at age 20 with identical visual scintillations now mimicking vertebrobasilar insufficiency. Fisher calls such attacks transient migrainous accompaniments, and they are not rare in any large practice. TIAs cannot be distinguished from migrainous events based on a single feature of either disorder. They are clinical diagnoses requiring several features to be present to suggest one or the other. Features suggesting cerebral ischemia include multiple risk factors for vascular disease, age greater than 60 years, and previous ischemic events. Features suggesting migraine include recurrent attacks of headache, a family history of migraine, onset of headaches before 40 years of age, scintillating scotoma, and the marching onset of neurologic symptoms. Transient Global Amnesia (TGA). TGA is characterized by the abrupt onset of severe anterograde amnesia without disturbance of consciousness, focal neurologic symptoms, or epileptic features, which resolves within 24 hours. Most patients are middle-aged or older adults. The cause is uncertain, but growing evidence suggests that it is most often related to migraine. In some cases, TGA may result from thromboembolic vertebrobasilar occlusive disease or complex partial seizures. Patients usually only have a single attack, but occasionally the attacks may recur over several years. If the clinical presentation is typical, expensive and invasive tests (e.g., brain MRI, angiography) should be avoided because they are invariably normal and may pose a risk to the patient.

region of the Sylvian fissure. Involvement of the dominant hemisphere produces the neurologic syndrome of Wernicke’s aphasia, hemianopia, and agitation, which is readily recognized as having a vascular cause. The mirror image infarct in the nondominant hemisphere produces a syndrome of confusion, agitation, hemianopia, and poor drawing and copying, which may be misinterpreted as having a psychiatric cause because of the prominent behavioral abnormalities. We have seen patients with nondominant inferior division MCA infarction who were admitted to the psychiatry service with a diagnosis of delirium (Fig. 41-1). Recognition of the hemianopia is critical for preventing this error, but its detection may be difficult in a markedly agitated patient.

Dominant Hemisphere Infarction Occlusion of the superior division of the MCA in the dominant hemisphere produces Broca’s aphasia that is usually associated with hemiparesis. This syndrome is readily recognized as having a vascular cause. Occasionally, a Broca-type aphasia may be the only manifestation of an infarct in this territory, and a vascular cause should be suspected because of the sudden onset of the aphasia. Infarction of the entire territory supplied by the inferior division of the MCA in the dominant hemisphere produces Wernicke’s aphasia, hemianopia, and agitation. This syndrome can also be seen with lobar hemorrhages in the temporal lobe and after traumatic brain injury. Smaller, discrete cortical infarcts in the territory supplied by the inferior division of the MCA produce subtypes of aphasia that are not associated with visual or behavioral abnormalities. These subtypes include conduction aphasia, pure word deafness, and alexia with agraphia. These

INOBVIOUS STROKE The acute onset of hemiparesis is the archetypal presentation of stroke. The diagnostic challenge in patients with this presentation is not to recognize that the cause is vascular but rather to establish the specific cause of stroke (e.g., large artery occlusive disease, penetrating artery disease, or cardioembolism). In patients with stroke that is not manifested by hemiparesis (stroke without paralysis), it may be difficult to recognize that the cause of the patient’s neurologic presentation is vascular. This is particularly true when the cardinal feature of the patient’s presentation is a behavioral abnormality. Awareness of the stroke syndromes described in this section should prevent physicians from attributing these presentations to nonvascular causes. NondominantTemporoparietal Infarction Occlusion of the inferior division of the middle cerebral artery (MCA) causes infarction of the temporal and parietal lobes in the

FIG. 41-1. A 67-year-old man admitted to the psychiatry service with delirium. CT showed a wedge-shaped cortical infarct in the territory supplied by the inferior division of the right middle cerebral artely.

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presentations usually are recognized as having a vascular cause because of the sudden onset of the deficit. Occasionally, Alzheimer’s disease may present with aphasia, but the onset is always more gradual if an accurate history is obtained. Patients with pure word dearness, a rare aphasic syndrome characterized by impaired auditory comprehension with normal reading comprehension, usually report that they cannot hear, which may lead to the incorrect diagnosis of an otological problem. This error can be avoided by showing that the patient hears auditory stimuli (e.g., is able to count the number of times hands are clapped or a bell rings) but has impaired auditory comprehension. Most occlusions of the superior or inferior divisions of the MCA or their branches are caused by an embolus from the heart or carotid artery and less commonly by intrinsic atherosclerosis.

Occipital Infarction The cardinal sign in patients with an occipital infarct caused by occlusion of the posterior cerebral artery (PCA) is a contralateral, congruous homonymous hemianopia or quadrantanopia. Visual loss usually is recognized immediately by the patient when the lesion involves the dominant hemisphere; however, the patient often reports that the visual loss involves the contralateral eye only. This may lead the unsuspecting physician to a diagnosis of ocular pathology rather than occipital infarction. Careful visual field testing of each eye separately will uncover the homonymous hemianopia and lead to the correct diagnosis. Patients with infarction of the dominant occipital lobe may have other signs such as alexia without agraphia, hemiachromatopsia, dysnomia, and memory loss (the latter two signs imply associated medial temporal lobe involvement) that help to clarify the diagnosis. When the nondominant occipital lobe is infarcted, patients may not recognize their visual loss because of inattention to the contralateral hemifield. This type of infarction is sometimes recognized only when these patients undergo a routine examination by an ophthalmologist. In some cases of nondominant occipital infarction, agitation may be a prominent feature that brings the patient to medical attention. Detection of the homonymous hemianopia leads to the correct diagnosis. As with MCA division infarcts, most PCA territory infarcts are caused by an embolus from the heart or vertebral or basilar arteries. Bilateral occipital infarction causes cortical blindness that is often denied by the patient (Anton’s syndrome). This usually occurs in the setting of a hypotensive event (e.g., cardiac arrest) or occlusion of the top of the basilar artery. Associated signs may include agitation, confusion, and memory disturbance (from associated bilateral medial temporal infarctions).

Caudate and Medial Thalamic Infarcts Infarction of the caudate nucleus without extension into the adjacent anterior limb of the internal capsule often causes isolated cognitive and behavioral abnormalities. These abnormalities may include abulia, agitation and hyperactivity, contralateral neglect (right caudate), and language abnormalities (left caudate). Lipohyalinotic or atherosclerotic occlusion of Heubner’s artery, a branch of the anterior cerebral artery (ACA), or a medial striate artery that arises from the proximal ACA or MCA is the usual cause of infarction. The acute onset of these neurobehavioral abnormalities should suggest the possibility of a vascular cause, especially in a patient with vascular risk factors. Thalamic infarction is readily recognized when a patient

FIG. 41-2. A 47-year-old man presented with acute confusion and memory disturbance. MRI showed a left medial thalamic infarct.

presents with acute hemisensory loss involving face, arm, leg, and torso. An infarct in the ventroposterolateral thalamic nucleus caused by occlusion of a thalamogeniculate artery is responsible for this syndrome. Less commonly, thalamic infarction may involve the paramedian thalamic nuclei (intralaminar nuclei, dorsomedial nuclei) that are supplied by the thalamoperforating arteries. Patients with these infarcts usually present with cognitive and behavioral abnormalities such as confusion, memory disturbance, hemineglect (nondominant), aphasia (dominant), and somnolence (Fig. 41-2). SEIZURES AND RELATION TO STROKE Seizures After Stroke

Seizures have been recognized as a complication of stroke since 1864, when Hughlings Jackson described a patient with partial seizures after cerebral infarction. Subsequently, studies have clarified the frequency of seizures after stroke and the risk factors for developing seizures. The percentage of patients who have at least one seizure within 2 years of stroke is 4.4% to 8.4%. Onset of the initial seizure is within the first week of stroke in 33% to 65% of patients and within 1 year in 73% to 90%. Only 2% of initial seizures occur more than 2 years after stroke. Lobar hemorrhages are associated with the highest rate of seizures (12% to 15%), followed by subarachnoid hemorrhage (8.5%) and cortical infarction (6.5% to 8%). Small subcortical infarcts are rarely associated with seizures. In patients with ischemic stroke, early studies suggested that cardioembolism was particularly associated with a

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high rate of seizures; however, more recent studies have shown that other mechanisms of ischemic stroke (e.g., artery-to-artery embolism, low flow from high-grade stenosis) are associated with similar rates of seizures. Simple partial (56%) or complex partial (24%) seizures account for 80% of seizures after stroke. The epileptic phenomenology typically reflects the site of cerebral injury (e.g., focal motor seizure with infarction of the precentral gyrus, complex partial seizures with medial temporal infarction). Status epilepticus occurs in only 8% of initial seizures after stroke and usually involves partial seizures only (epilepsia partialis continua). Most studies show that initial seizures occurring more than 2 weeks after stroke are associated with a high rate of multiple, recurrent seizures (i.e., epilepsy); however, the risk of epilepsy after early poststroke seizures (i.e., seizures within 2 weeks of stroke) has long been debated. Whereas initial studies suggested that the long-term risk of epilepsy was only 6% after early poststroke seizures, more recent studies have shown epilepsy rates of 22% to 32% during a mean follow-up of 26 to 30 months. In one study by Kilpatrick et al. of consecutive patients with ischemic or hemorrhagic stroke, epilepsy rates were compared in 31 patients with early poststroke seizures and 31 patients without early seizures who were matched for age and stroke mechanism. The epilepsy rate over 26 months in the group with early seizures was 32%, compared with 10% in patients without early seizures ( p < .05). Risk factors that have predicted multiple, recurrent seizures after an initial poststroke seizure are hemorrhagic stroke (superficial or deep), large cortical infarcts, and periodic lateralized epileptiform discharges (PLEDs) or diffuse slowing on EEG. Anticonvulsant therapy usually is very successful in controlling poststroke epilepsy. Because most of these seizures are simple partial or complex partial with occasional secondary generalization, monotherapy (e.g., phenytoin, carbamazepine, oxcarbazepine) is sufficient to control seizures in 90% of these patients. In a few intractable cases polytherapy may be necessary. Although some physicians use anticonvulsants routinely in all patients with acute hemorrhagic or ischemic stroke, the low overall rate of seizures after stroke (4.4% to 8.4%) argues against this approach. Our current practice is to initiate an anticonvulsant once a seizure occurs because of the high rate of recurrence. A baseline EEG is useful to determine whether PLEDs are present because this finding may influence a later decision to continue or discontinue anticonvulsant therapy. We prescribe anticonvulsant monotherapy to control the seizures without causing drug toxicity, and once the patient has been seizure-free for at least 18 months, we discuss the option of tapering the anticonvulsant. A repeat EEG may be helpful in making that decision. Factors that would argue against tapering the anticonvulsants are the presence of PLEDs or diffuse slowing on the baseline EEG, persistent spikes on a recent EEG, hemorrhagic stroke, a large cortical infarct, or if the patient’s occupation involves driving or working with moving machinery. Seizures After Carotid Endarterectomy

Seizures occur in approximately 1% of patients within 2 to 13 days of carotid endarterectomy. The seizures invariably are focal motor seizures contralateral to the side of the endarterectomy, which occasionally become generalized. These seizures are caused by either hyperperfusion injury after endarterectomy or infarction occurring during the procedure. In the former case, postoperative hypertension and failure of autoregulation ipsilateral to carotid

endarterectomy result in hyperperfusion of the ipsilateral hemisphere. This may manifest as ipsilateral headache, contralateral motor seizures, and occasionally intracerebral hemorrhage. Brain imaging shows patchy cerebral edema and occasionally hemorrhage ipsilateral to the side of the carotid endarterectomy. Transcranial Doppler ultrasound shows markedly elevated ipsilatera1 middle cerebral artery blood flow velocities. With judicious management of blood pressure, the headache and focal brain edema usually resolve within 2 weeks. Anecdotal data suggest that the long-term risk of recurrent seizures in patients who have an initial seizure related to postendarterectomy hyperperfusion is low. These patients typically have not needed long-term anticonvulsants, whereas patients with seizures related to stroke during endarterectomy have a higher rate of recurrent seizures and therefore need long-term anticonvulsant therapy. OCULAR STROKE The retina and optic nerve may be the primary targets for certain cerebrovascular disorders. Branches of the ophthalmic artery supply both these ocular structures: The central retinal artery supplies the retina, and the posterior ciliary artery supplies the optic nerve. These two branches of the ophthalmic artery are affected by different vascular disorders. Retinal Ischemia

The most common cause of retinal ischemia is carotid occlusive disease followed by other sources of embolism (e.g., the heart, aortic arch) and, rarely, hyperviscosity states (e.g., polycythemia Vera). The mechanism of retinal ischemia in patients with carotid disease is either embolism to the central retinal artery or its branches or hypoperfusion of the retina caused by high-grade carotid stenosis or carotid occlusion. Transient retinal ischemia is manifested by transient monocular blindness (amaurosis fugax), which is classically but uncommonly described by patients as a “shade being pulled down” over the eye. It is more common for patients to describe fuzzy, blurred, or cloudy vision in the eye. When evaluating patients with a complaint of transient monocular visual loss, it is important to ask them whether they covered one eye and then the other eye to verify that the visual loss was monocular. Patients with homonymous hemianopia (e.g., from occipital ischemia), who do not cover one eye at a time to test their vision, often complain of monocular visual loss in the eye corresponding to the side of the hemianopia. Clues to the mechanism of transient retinal ischemia may be obtained from the history. Sector or altitudinal field cuts with a horizontal meridian suggest embolism to the retina, whereas slow monocular dimming of vision, like a camera shutter, suggests hypoperfusion. A variant of this symptom is monocular visual dimming upon exposure to bright light, related to retinal hypoperfusion from ipsilateral carotid artery occlusion or critical stenosis. The ophthalmoscopic examination may reveal other clues to the mechanism of ischemia. Hollenhorst plaques, which are yellowish, refractile retinal emboli composed of cholesterol flakes, suggest an arterial source of embolism. Platelet fibrin emboli, which are large and chalk-white and lodge in the central retinal artery over the disk head, may arise from a heart valve or complex carotid plaque. Septic emboli (Roth‘s spots), which appear as whitish cores surrounded by hemorrhage, suggest endocarditis.

Chapter 41

Prolonged occlusion of the central retinal artery causes permanent damage to the retina. Central retinal artery occlusion usually causes total blindness that is usually painless. The pupil may fail to react because of diffuse retinal ischemia. The retina becomes pale and edematous, and the retinal vessels narrow. The optic disk becomes pale, but the fovea retains its color and stands out as a cherry red spot. Occasionally the actual embolus may be seen. Occlusion of a branch of the central retinal artery causes a segmental retinal infarct and visual loss in the form of a large scotoma. Although some studies suggest a low correlation between central retinal artery occlusion and ipsilateral carotid occlusive disease, more recent studies show a higher correlation. We suggest that all patients with central retinal artery occlusion undergo duplex carotid ultrasound to rule out carotid occlusive disease. If the carotid ultrasound is unrevealing, echocardiography should be performed to rule out a cardiac source of embolism. A less recognized cause of retinal ischemia is venous stasis retinopathy (VSR).VSR is caused by chronic retinal hypoperfusion usually from internal carotid artery occlusion. VSR appears similar to diabetic retinopathy with dot and blot hemorrhages and cotton wool patches; they are distinguished by the fact that VSR usually is unilateral. Eventually VSR may lead to neovascular glaucoma and blindness unless the hypoperfusion is reversed. In this setting, if a stenotic external carotid artery is supplying blood flow to the orbit, external carotid endarterectomy should be considered. On the other hand, if blood flow to the eye is largely from limited collateral flow from the contralateral hemisphere through the anterior communicating artery, ipsilateral extracranial-intracranialbypass surgery may be considered.

Optic Nerve Ischemia Anterior ischemic optic neuropathy (AION) usually is caused by processes that involve the posterior ciliary arteries. The most common of these are mechanical restriction of flow in these vessels in patients with small optic cups, intrinsic atherosclerosis and temporal arteritis. Rarely, optic nerve ischemia may be caused by sudden, severe hypotension. Carotid stenosis is rarely associated with AION. Patients with AION present with unilateral visual loss that is maximal in the temporal field or in an inferior altitudinal pattern. An afferent pupillary defect is invariably present and ophthalmoscopy shows a pale, swollen disc that is frequently associated with flame hemorrhages around the disc. In patients with AION there is a high risk of recurrence in the contralateral eye. Ischemia of the optic nerve may rarely involve the posterior portion of the nerve. We have seen patients who, on awakening from major surgery that is associated with severe blood loss, complain of monocular blindness. The examination initially shows an afferent pupillary defect but no abnormality of the disk. In time,.optic atrophy develops.

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patients with cerebrovascular disease (particularly carotid stenosis), this is not true for asymptomatic CAD. Frequency of Asymptomatic CAD in Patients with TIA or Stroke

The frequency of abnormal cardiac stress tests in patients presenting with TIA or stroke and no symptoms of CAD is 28% to 40%. There are limited data on the comparative frequency of asymptomatic CAD in patients with different vascular causes of TIA or stroke (e.g., carotid artery disease, intracranial atherosclerotic disease, cardioembolism, or penetrating artery disease [small vessel disease]). Because CAD is invariably caused by atherosclerosis, it is likely that subtypes of stroke that are related to underlying atherosclerosis (e.g., carotid, vertebral, or intracranial atherostenosis) are associated with a higher risk of CAD than nonatherosclerotic subtypes of stroke. Support for this notion was provided by a study that compared the frequency of abnormal cardiac stress tests in 30 patients with atherosclerosis of a major cerebral artery (i.e., cervical carotid artery or a major intracranial artery) with that in 39 patients with other causes of cerebral ischemia (penetrating artery disease, cardioembolism, cryptogenic stroke). AU 69 patients in the study presented with TIAs or ischemic stroke and no overt CAD. The rate of abnormal stress tests was 15 of 30 (50%) in patients with atherosclerotic stenosis of a cervical carotid or major intracranial artery and 9 of 39 (23%) in patients with other causes of stroke

( p = .04). Other studies have also shown a high rate (up to 60%) of asymptomatic CAD in patients with carotid stenosis. In one study, coronary angiography was performed on 200 patients without symptoms of CAD, most of whom presented with carotid bruits: Eighty patients (40%) had severe CAD defined by more than 70% stenosis of at least one coronary artery, 93 patients (46%) had mild or moderate CAD, and only 27 patients (14%) had normal coronary arteries. Prognosis of Asymptomatic CAD in Patients with Cerebrovascular Disease

Although the risk of MI within 30 days of carotid endarterectomy in patients without a history of CAD is low (1% to 2%), the long-term cardiac prognosis in these patients is far from benign. Studies suggest that the annual risk of MI in these patients is 3% to 8%, with older adults at particularly high risk. There are limited data on the cardiac prognosis of patients with stroke from penetrating artery disease or atrial fibrillation. However, available data suggest that the risk of MI in patients with these subtypes of stroke and no history of CAD is low (i.e., 0.5% to 1.5% per year). Treatment of Asymptomatic CAD

UNDERLYING CORONARY DISEASE I N PATIENTS WITH STROKE

Because stroke and myocardial infarction (MI) share common risk factors and pathologic mechanisms, it is not surprising that population studies and stroke therapy trials have consistently shown that coronary artery disease (CAD) is a major cause of death in patients with cerebrovasculardisease. Although strategies have evolved for evaluating and treating symptomatic CAD in

Although patients with carotid stenosis have a high frequency of asymptomatic CAD and are at high risk of major cardiac events during long-term follow-up, studies have not been performed to evaluate optimal treatment for asymptomatic CAD in these patients. Limited data on the treatment of asymptomatic CAD in noncerebrovascular patients suggest that anti-anginal medical therapy (e.g., P-blockers) and revascularization are effective for preventing major cardiac events in these patients, particularly if they have silent myocardial ischemia detected by ambulatory ECG.

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An Approach to Manadng Asymptomatic CAD En Patients with Carotid Stenosis

In view of the low rate of cardiac complications in the periendarterectomy period in patients without a history of CAD (1% to 2%), the low positive predictive value of cardiac stress tests for predicting perioperative MI, and the current emphasis on cost containment in medical care, recent guidelines from an American College of Cardiology and American Heart Association (ACC/ AHA) task force do not recommend routine cardiac stress testing in patients without a history of CAD who are undergoing carotid endarterectomy. The ACC/AHA recommendations, which focus on the preoperative management of CAD in patients undergoing vascular surgery, do not address the long-term management of asymptomatic CAD in patients with carotid stenosis. Given the high annual risk of major cardiac events in these patients and mounting evidence that treating silent myocardial ischemia improves cardiac outcome, screening for asymptomatic CAD in patients with carotid stenosis should be considered. What should the cardiac evaluation and treatment of these patients entail? A definitive answer is not possible until a randomized study has clearly established the value of screening for CAD and treating asymptomatic CAD in this population. Until such a study is performed, the following approach may be appropriate based on currently available data: Patients with carotid stenosis and no history of CAD who are at high risk of major cardiac events (e.g., diabetics, patients with coexistent intracranial occlusive disease or peripheral vascular disease, smokers, patients with a strong family history of CAD) should undergo a provocative test for myocardial ischemia. The most commonly used provocative tests for myocardial ischemia are exercise ECG, myocardial perfusion imaging study, or dobutamine stress echocardiography. Patients with abnormal screening studies should be referred to a cardiologist. These patients should be considered for ambulatory ECG monitoring to detect episodes of silent myocardial ischemia because the presence of silent ischemia may be the most important predictor of cardiac events in these patients. When the noninvasive cardiac studies suggest severe underlying CAD (e.g., patients with a large reversible perfusion defect on a myocardial perfusion imaging study and episodes of silent ischemia on 24-hour ambulatory ECG), the patient should be considered for coronary angiography. Based on currently available data, patients with severe multivessel or left main disease should be considered for bypass surgery, especially if they have episodes of silent myocardial ischemia. Patients with less extensive disease (e.g., isolated proximal disease of the left anterior descending artery) should be treated with angioplasty. For asymptomatic CAD that is not

amenable to revascularization, medical therapy (P-blockers, antithrombotic therapy) should be instituted, especially in patients with silent myocardial ischemia. Regardless of whether revascularization or medical therapy is used to treat asymptomatic CAD, an essential component of the treatment plan must include aggressive management of vascular risk factors (hypertension, diabetes, smoking, and hyperlipidemia). Recent studies have focused on the importance of lipid-lowering therapy in patients at high risk of myocardial infarction. SUGGESTED READINGS Babikian V, Wijman CA, Koleini B et al: Retinal ischemia and embolism: etiologies and outcomes based on a prospective study. Cerebrovasc Dis 12:108, 2001 Bentes C, Pimentel J, Ferro JM: Epileptic seizures following subcortical infarcts. Cerebrovasc Dis 12:331, 2001 Bogousslavsky J, Regli F, Uske A Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 38:837, 1988 Caplan LR, Kelly CS, Kase CS et al: Infarcts of the inferior division of the right middle cerebral artery: mirror image of Wernicke’s aphasia. Neurology 36:1015, 1986 Chimowitz MI, Poole RM, Starling MR et ak Frequency and severity of asymptomatic coronary disease in patients with different causes of stroke. Stroke 28:941, 1997 Davies RF, Goldberg AD, Forman S et al: Asymptomatic cardiac ischemia pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization. Circulation 95:2037, 1997 Eagle KA,Brundage BH, Chaitman BR et ak Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery. Circulation 93: 1278, 1996 Executive Committee for the Asymptomatic Carotid Atherosclerosis Study: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 273:1421, 1995 Fisher CM Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci 7:9, 1980 Huber R, Aschoff AJ, Ludolph AC, Riepe M W Transient global amnesia: evidence against vascular ischemic etiology from diffusion weighted imaging. J Neurol 249:1520, 2002 Kilpatrick CJ, Davis SM, Hopper JL, Rossiter S C Early seizures after acute stroke: risk of late seizures. Arch Neurol 49:509, 1992 Romano JG, Babikian VL, Wijman CA, Hedges TR Retinal ischemia in aortic arch atheromatous disease. J Neuroophthalmol 18:237, 1998 Sandok BA, Whisant JP, Furlan AJ, Mickell J L Carotid artery bruits: prevalence survey and differential diagnosis. Mayo Clin Proc 57227, 1982 Wijman CA, Wolf PA, Kase CS et al: Migrainous visual accompaniments are not rare in late life: the Framingham Study. Stroke 29:1539, 1998

Chapter 42

42

Current Treatment Strategies for Ischemic Stroke

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Current Treatment Strategies for Ischemic Stroke H. Christian Schumacher, Randall S. Marshall, and J. P. Mohr

ANTIPLATELET THERAPY Inhibition of platelet aggregation is the main treatment strategy in most patients with ischemic stroke for secondary stroke prevention. Several drugs are available and are discussed in more detail in this chapter.

Aspirin therapy has been widely used in stroke prevention because of its ease of administration, its documented prophylactic effect in coronary artery disease, and the perception by physicians and the public as a benign treatment. Aspirin irreversibly inhibits platelet cyclooxygenase, the essential enzyme for synthesis of thromboxane A,. Thromboxane A, is a potent vasoconstrictor and platelet activator that causes platelet aggregation. More than 10 randomized placebo-controlled trials of aspirin after transient ischemic attacks (TIAs) or minor strokes have been completed. Most showed a significant risk reduction of recurrent stroke and cardiovascular death with aspirin. The results of the aspirin trials, combined with the decline in stroke incidence over the past few decades, have led statisticiansto calculate that modern clinical trials of stroke prevention may need approximately 1,000 patients enrolled and followed for an average of 5 years to detect a 50% difference at a significance level of P < .05.Smaller studies may conclude benefit when none exists or overlook a true benefit. All four of the largest clinical trials (the British, European, French, and Canadian) found some degree of benefit, ranging from 20% reduction in stroke and vascular death in the British trial, to 50% reduction in stroke and stroke death in the French trial. Two slightly smaller trials (the Danish and the Swedish) found no benefit. The Danish study used an acetylsalicylic acid (ASA) dosage of 50 to 75 mglday, and the Swedish study entered only patients who had suffered major strokes. Differences found in other studies are of uncertain significance. A lack of benefit in women, reported in the British and Canadian studies, may have resulted from a lack of statistical power because the risk of stroke and stroke recurrence is lower for women. The optimum dosage of aspirin remains controversial.A Dutch trial for stroke prevention after TIA, using calcium salicylates, showed no difference between 30 mglday and 283 mglday. The British trial found no difference between 300 mglday and 1300 mglday, but the meaning of the data has been disputed. Patients in the Stroke Prevention in Atrial Fibrillation (SPAF) trial benefited from ASA 325 mglday in the setting of atrial fibrillation only, not in the setting of TIA or prior stroke. Consequently, it remains unsettled whether ultra-low-dose aspirin or aspirin in dosages as high as 1300 mglday is associated with slight, wide, or no major differences in rates of first or recurrent stroke. The only source of agreement is that the higher dosages produce more gastrointestinal side effects.

For some time it remained unclear when to start aspirin after an ischemic stroke. The major concern was that early treatment might increase the risk of symptomatic hemorrhagic conversion, thus increasing morbidity and mortality. In the past, most patients started aspirin treatment within 2 to 3 months after an ischemic stroke. Recent studies examining early treatment of ischemic stroke patients brought important information to this topic. The first study to examine the effect of early aspirin treatment (300 mg) in acute ischemic stroke was the Multicenter Acute Stroke Trial-Italy (MAST-I), published in 1996. MAST-I randomized 153 patients to aspirin, 156 patients to aspirin plus IV streptokinase, and 156 patients to neither aspirin nor streptokinase treatment. Both drugs were given within 6 hours after stroke onset. This small study demonstrated no benefit of aspirin treatment over placebo in reducing mortality at day 10 and disability at 6 months after stroke. Two large randomized trials published in 1997, the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST), examined the effects of early aspirin treatment started within 48 hours after stroke onset. IST randomized 19,435 patients to either aspirin (300 mg daily) or no aspirin treatment. At 14 days, there was a significant reduction in the likelihood of death or nonfatal recurrent stroke, corresponding to 11 fewer per 1,000 cases in favor of aspirin. There was no significant excess of hemorrhagic stroke but a significant excess of 5 transfused or fatal extracranial hemorrhage per 1,000 patients allocated to aspirin. At 6 months, aspirin prevented 10 deaths or nonfatal recurrent strokes per 1,000 cases, although this effect was not statistically significant. CAST randomized 21,106 patients to either aspirin (160 mg four times daily) or no aspirin treatment. For the scheduled outcome period (i.e., in hospital up to 4 weeks) there was a significant reduction of death or nonfatal stroke in favor of aspirin, correspondingto 7 fewer cases per 1,000 patients allocated to aspirin. In CAST there was a nonsignificant excess of hemorrhagic stroke and a significant excess of 3 transfused or fatal extracranial hemorrhage per 1,000 patients treated with aspirin. Both IST and CAST included 771 patients with hemorrhagic strokes who were randomized before a computed tomography (CT) scan was performed. A post hoc analysis of that subgroup did not provide evidence of harm in patients treated with aspirin. In summary, IST and CAST established the modest but definite net reduction of early death and nonfatal strokes with aspirin use. A combined analysis of IST, CAST, and MAST-I reveals that early aspirin treatment within 48 hours after stroke onset results in 13 fewer dead or dependent subjects per 1,000 treated.

Thienopyridlnes The thienopyridine derivatives ticlopidine and clopidogrel are antiplatelet drugs that act through a mechanism different from aspirin. Whereas aspirin inhibits cyclooxygenase and thromboxane

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levels, thus reducing adenosine diphosphate (ADP) levels in thrombocytes, the thienopyridines directly irreversibly inhibit the binding of ADP on its platelet receptor. ADP binding is necessary for activation of the glycoprotein IIb/IIIa receptor, the binding site for fibrinogen, which is a necessary step prior to platelet aggregation. Ticlopidine

Ticlopidine has been used outside the United States for more than 20 years and was approved by the U.S. Food and Drug Administration in 1994. Its maximum antiplatelet action is at a dosage of 500 mg/day, it reaches maximum effect at 3 to 5 days, and its effects last the lifetime of the platelets. Adverse side effects include gastrointestinal disturbance in 20% of patients, which may resolve with temporary dosage reduction; rash in 10%; neutropenia in 2.4%; and severe neutropenia in 0.8%. Neutropenia is seen in the first few months and is reversible after drug discontinuation. Significant hemorrhage occurs in less than 1% of patients, and gastrointestinal bleeding is less likely in patients taking 500 mg of ticlopidine than 1300 mg of ASA. Two large clinical trials found a benefit of ticlopidine over ASA and placebo in preventing vascular events. The CanadianAmerican Ticlopidine Study randomized 1,053 patients with recent noncardioembolic stroke to receive ticlopidine 250 mg twice a day or placebo. Intention-to-treat analysis found a 23% risk reduction for the treatment group. Fifty-two percent of patients in the ticlopidine group and 40% of those in the placebo group discontinued treatment. Relative reduction in stroke or stroke death was found on secondary analysis to be 33.5%. Ticlopidine proved equally effective in men and women. The Ticlopidine-Aspirin Stroke Study randomized 3,069 patients to ticlopidine 250 mg twice a day or aspirin 650 mg twice a day. The study consisted of patients with TIAs, transient monocular blindness, or minor stroke; the average follow-up period was 2.3 years. In their intention-to-treat analysis, these investigators showed a 12% reduction in stroke or stroke death with ticlopidine. Twenty-one percent of the ticlopidine group and 14.5% of the aspirin group discontinued the drug. For those who can tolerate the medicine, ticlopidine appears to have a slight advantage over aspirin and a definite advantage over placebo in secondary stroke prevention. The main disadvantage of ticlopidine is a 0.8% risk for agranulocytosis, necessitating weekly blood examinations for the first 18 weeks of treatment and extensive counseling of the patients on symptoms of agranulocytosis. In addition, post-marketing experience with this agent disclosed multiple reports of TTP (thrombotic thrombocytopenic purpura), leading to its virtual disappearance from the current antiplatelet options. Clopidogrel

Clopidogrel is chemically closely related to ticlopidine. However, it has a more potent antiplatelet action and fewer side effects. Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation. It irreversibly inhibits the binding of ADP to its membrane receptors. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, 6,431 patients with recent noncardioembolic ischemic stroke, 6,302 patients with recent myocardial infarction, and 6,452 patients with symptomatic peripheral arterial disease were randomized to either clopidogrel

(75 mg) or aspirin (325 mg). The primary outcome was the reduction in the composite outcome cluster of ischemic stroke, myocardial infarction, or vascular death. Overall, there was a small but significant relative risk reduction of 8.7% for the primary endpoint in favor of clopidogrel. However, this resulted primarily from the relative risk reduction of 23.8% for the primary endpoint in the subgroup of patients with symptomatic peripheral artery disease. In the subgroup with recent stroke, clopidogrel had a nonsignificant relative risk reduction of 7.3%. This means that in patients with recent stroke clopidogrel seems to be equivalent to aspirin in preventing stroke, myocardial infarction, and vascular death. Overall for the whole study population, the proportion of intracranial hemorrhage in both treatment groups was low, and there was no statistically significant difference between clopidogrel and aspirin (0.35% vs. 0.49%). However, intracranial hemorrhage rates may be different in the subgroup of stroke patients compared with the two other subgroups, and CAPRIE does not provide hemorrhage rates for each subgroup alone. Patients assigned to clopidogrel reported statistically significantly lower occurrence of gastrointestinal bleeding events compared with aspirin (1.99% vs. 2.66%) but more cutaneous rashes (6.02% vs. 4.61%). One major disadvantage of clopidogrel is high treatment cost. For that reason, clopidogrel usually is prescribed for patients who cannot tolerate aspirin or who have peripheral arterial occlusive disease, the subgroup of CAPRIE with the highest benefit from clopidogrel. Instances of TTP have also been reported with the use of clopidogrel, but the frequency of this serious complication seems to be lower than with ticlopidine. Combination of Antiplatelet Agents for Stroke Prevention Aspirin and Dipyridamole. The European Stroke Prevention Study 2 (ESPS-2) examined the effect of a combination of aspirin with extended-release dipyridamole for secondary stroke prevention. Like aspirin, dipyridamole is a platelet-inhibiting agent, although its exact mode of action is not fully understood. Dipyridamole may work by increasing platelet cyclic-3’,5’adenosine monophosphate concentrations by inhibiting phosphodiesterase. ESPS-2 was conducted based on the assumption that dipyridamole might add to the antiplatelet activity of aspirin. Patients included in ESPS-2 had suffered either a TIA or a completed stroke within the preceding 3 months. In this randomized study, 1,650 patients were assigned to a combination of 25 mg aspirin and 200 mg extended-release dipyridamole twice daily, 1,649 patients to aspirin 25 mg alone twice daily, 1,654 patients to 200 mg extended-release dipyridamole alone twice daily, and 1,649 patients to placebo. The study analyzed three primary endpoints: stroke, death, and stroke and death combined. For this trial, stroke event rates at 2 years were 15.8% for placebo, 13.2% for extended-release dipyridamole, 12.9% for aspirin, and 9.9% for the combination. The overall difference in stroke recurrence rates among the four groups was statistically significant. When compared with placebo, the relative risk reduction for recurrent stroke was 18.1% for aspirin alone, 16.3% for dipyridamole alone, and 37.0% for the combination. Compared with aspirin, the relative risk reduction was 23.1% for the combination. This translates into the prevention of an additional 33 recurrent strokes per 1,000 treated patients during a 2-year treatment period by the combination of aspirin and extended-release dipyridamole over aspirin alone.

Chapter 42

Early in the treatment, approximately 8% of patients assigned to dipyridamole or the combination discontinued the medication because of headaches, and 7% discontinued because of gastrointestinal events. Overall, the most common side effects of the combination of aspirin and dipyridamole were headache (39.2%), dyspepsia (18.4%), abdominal pain (17.5%), nausea (16%), and diarrhea ( 12.7%).Moderate to severe bleeding complications were seen more often in the aspirin-assigned treatment arms (8.2% for aspirin, 8.7% for dipyridamole plus aspirin) than in those treated with dipyridamole alone (4.7%) or placebo (4.5%). Moderate to severe or fatal hemorrhages occurred more often in the aspirincontaining treatment arms (aspirin alone, 3.2%; combination, 3.6%) than in those treated with dipyridamole alone (1.5%) or placebo (1.3%). However, there was no statistically significant difference in mortality between the four treatment arms. ESPS-2 has been criticized because of the very low aspirin dosage used and the assumption that a higher aspirin dosage may have produced a greater reduction in stroke recurrence rates. Furthermore, compliance was confirmed in only 84% of the patients assigned to aspirin. Overall, ESPS-2 confirmed the benefit of aspirin 50 mg daily for secondary stroke prevention. Additionally, ESPS-2 established the superiority of the combination of low-dose aspirin with extended-release dipyridamole over low-dose aspirin alone for stroke recurrence. Aspirin and Clopidogrel. Another widely used treatment regimen is the combination of aspirin (75 to 325 mg daily) and clopidogrel (75 mg daily). Because aspirin and clopidogrel inhibit different pathways of platelet activation, there is a potential synergy between these antiplatelet agents. There is evidence from animal and ex vivo platelet studies confirming that synergy. The available data on this Combination are from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. Patients were included in the trial if they had unstable angina or acute myocardial infarction without ST segment elevation. In this trial, 6,259 patients were randomized to a combination of clopidogrel and aspirin and 6,303 patients to a combination of placebo and aspirin for 3 to 12 months. In the clopidogrel arm, patients were loaded with 300 mg and received 75 mg daily thereafter. Aspirin dosage varied between 75 mg and 325 mg daily at the discretion of the treating physician. The primary study outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke. The combination of clopidogrel and aspirin significantly reduced the proportion of patients experiencing the primary outcome event compared with aspirin alone (9.3% vs. 11.4%). Major bleeding complications were more common in the combination group (3.7% vs. 2.7%). The proportion of hemorrhagic strokes during follow-up was very low, and there was no difference between the two treatment groups (0.1% vs. 0.1%). The data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial are not applicable to secondary prevention after stroke, as the population studied included patients who were symptomatic with coronary artery disease, not stroke or TIA. The ongoing Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial is aimed at assessing efficacy and safety of the combination of aspirin with clopidogrel. In this study 7,600 patients with recent ischemic stroke or transient ischemic attacks who have at least one additional risk factor (prior

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ischemic stroke, myocardial infarction, symptomatic peripheral artery disease, or diabetes) will be randomized to either clopidogrel(75 mg daily) plus placebo or clopidogrel(75 mg daily) plus aspirin (81 to 325 mg daily). The primary objective is to evaluate whether the combination of clopidogrel and aspirin is superior to clopidogrel alone in preventing new ischemic cerebrovascular and cardiovascular events. The study will also provide data on safety of the combination over clopidogrel alone. Until the results of this study are published, the combination of clopidogrel and aspirin should be used cautiously and cannot be recommended as a standard treatment.

ANTICOAGULATION Hepadn The administration of heparin for acute ischemic stroke has a long tradition. It was first administered to stroke patients in 1941 and gained more widespread use in the 1950s. Over the years, there has been a profound controversy among neurologists over heparin use in acute stroke. Several randomized and controlled trials designed and conducted in the past 15 years have brought some insight into its therapeutic value for that indication. However, this topic is confounded by different heparin types used (unfractionated heparin vs. low-molecular-weight heparin), mode of administration (intravenous vs. subcutaneous), and timing of administration after stroke onset (immediate vs. delayed). The rationale for the therapeutic use of heparin or heparinoids in patients with acute ischemic stroke is threefold: Impairment of thrombogenesis. Anticoagulation with intravenous or subcutaneous heparin is not intended to dissohe a thrombus but to impair the thrombogenesis created by the clotting cascade. The antithrombotic effects of heparin are mediated largely through its interaction with antithrombin 111that acceleratesits ability to inactivate factors IIa, Xa, and IXa. Heparin is thought to prevent propagation of intraarterial thrombi. Intravenous unfractionated heparin has a measurable anti-inflammatory effect, and this may contribute to the presumed antithrombotic effect. The antiinflammatory effect seems to be associated with lower levels of circulating tissue factor and monocyte procoagulant activity, as has been shown in patients with unstable angina treated with heparin. These effects are more pronounced for unfractionated heparin than for low-molecular-weightheparin. Theoretically%early heparin administration therefore may result in a smaller infarct size and less leukocyte accumulation, as has been demonstrated in animal experiments. However, clinical proof of this concept in randomized trials is still lacking. Prevention of recurrent stroke. Patients with ischemic stroke are at risk for early stroke recurrence. Recurrent stroke adds to the morbidity and may negatively affect overall survival. There is clinical evidence from randomized trials (IST) that anticoagulation prevents early recurrent stroke, but unfortunately it increases the risk of cerebral and extracerebral major hemorrhagic complications. Prevention of deep vein thrombosis and pulmonary embolism. Deep vein thrombosis occurs in up to 50% of patients after hemiplegic stroke by lZ5I fibrinogen screening. Most of the deep vein thromboses are clinically asymptomatic, and two

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thirds of them are located below the knee. In immobilized stroke patients, deep vein thrombosis develops during the first week after stroke and may cause early fatal or nonfatal pulmonary embolism. Pulmonary embolism accounts for up to 25% of early deaths after stroke and is most common between the second and forth week after stroke. Heparin and heparinoids prevent deep vein thrombosis in immobilized stroke patients.

Intravenous Unfradonated Heparin Data supporting the general use of intravenous unfractionated heparin in acute stroke are lacking. Considering the decades-long experience with heparin, one might assume that heparin’s utility has been settled. However, this is not the case. Only a few clinical trials in the CT era evaluated the effect of heparin anticoagulation in acute stroke treatment. A study by Duke et al (1986) used unfractionated intravenous heparin for 7 days in patients within 48 hours after ischemic stroke onset. Patients had to be conscious, and they had to have only partial motor deficits. They were excluded if a cardiac source of emboli was suspected or if they showed progression of stroke within the hour before randomization. This trial assigned 112 patients to heparin, with dosage adjusted to maintain the activated thromboplastin time between 50 and 70 seconds, and 113 patients to placebo. At the end of the treatment period, the number of patients who improved was statisticallysimilar for the heparin and placebo groups (26.6% vs. 24.3%). Furthermore, neither the proportion of patients with stroke progression (17% in the heparin group versus 19.5% in the placebo group) nor the death rate (1.8% versus 0.9%) was statistically different. The results from the second Prolyse in Acute Cerebral Thromboembolism Trial (PROACT 11) give some insight into the risk of hemorrhage in patients treated with intravenous low-dose heparin. The aim of PROACT I1 was to determine the clinical efficacy and safety of intra-arterial recombinant prourokinase (r-proUK) in patients with acute stroke of less than 6 hours’ duration caused by middle cerebral artery (MCA) occlusion. In PROACT I1 all patients received a 2,000-U bolus and a 500-U/hour infusion of intravenous heparin for 4 hours beginning at the time of angiography. After 4 hours all antithrombotic treatment was held for 24 hours. The trial randomized 180 patients to either 9 mg intra-arterial r-proUK plus low-dose intravenous heparin or control (low-dose intravenous heparin alone) in a ratio of 2:l. A total of 162 patients were treated as randomized 108 patients received r-proUK plus IV heparin and 54 patients received heparin alone. After the 2-hour treatment period, angiography demonstrated total recanalization of the occluded MCA in only 2% and partial recanalization of the occluded MCA in another 16% of the control patients. In the same group, symptomatic intracranial hemorrhage at 24 hours occurred in 2% of the patients. These data suggest that intravenous low-dose heparin given for 4 hours and started within 6 hours after stroke is not effective in recanalizing an occluded MCA and carries a slight risk of early symptomatic hemorrhage within 24 hours. In summary, the benefit of early treatment with intravenous unfractionated heparin in acute ischemic stroke remains unresolved, and there is no reliable evidence from randomized, placebo-controlled trials to support its routine use. At present, the multicenter Rapid Anticoagulation Prevents Ischemic Damage (RAPID) trial is being conducted in Europe and awaits completion. In this study, 1,400 patients will be allocated within 12 hours

from onset of stroke to weight-adjusted intravenous unfractionated heparin or aspirin (160 to 325 mg).

Intravenous Low-Molecular-Weight Heparin There are several different low-molecular-weight heparins. In contrast to unfractionated heparin, low-molecular-weight heparins inhibit thrombin as well as coagulation factor Xa, so their anticoagulant potency can be measured by their anti-factor Xa activity. The efficacy and safety of intravenous low-molecular-weight heparin in stroke patients were evaluated in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). In this randomized, placebo-controlled, double-blind, multicenter trial, 638 patients were assigned to danaparoid sodium within 24 hours of stroke onset and 634 patients to placebo. Active treatment was initiated by an intravenous bolus of danaparoid followed by a continuous infusion for 7 days. The infusion rate was adjusted after 24 hours to maintain the anti-factor Xa activity at 0.6 to 0.8 anti-factor Xa UlmL. The study endpoint was favorable outcome at 3 months after stroke, defined as a score of I or I1 on the Glasgow Outcome Scale and a score of 12 to 20 on the modified Barthel Index. No difference in the outcome event rates was found between the two treatment arms. At 7 days, 59.2% of patients assigned to danaparoid and 54.3% of patients assigned to placebo had a favorable outcome. The favorable outcome rates at 3 months after stroke were 75.2% and 73.7% for danaparoid and placebo, respectively. In TOAST about 10% of the patients deteriorated within 7 days, and the deterioration rates were similar in the danaparoid and placebo treatment arms. There was a trend for more symptomatic hemorrhagic transformations of ischemic strokes in the danaparoid-allocated patients than in the placebo group (1.4% vs. 0.4%), but it was not statistically significant. However, danaparoid-allocated patients had significantly more serious extracerebral bleeding events than those in the placebo group (4.1% vs. 1.1%). At 7 days, recurrent stroke rates were similar in danaparoid- and placebo-treated patients (1.1% vs. 1.3%). At 3 months, there was no difference in mortality between the two treatment arms (danaparoid, 6.5%; placebo, 6.1%). In the subgroup analyses, there were two interesting observations: Patients with stroke secondary to large artery atherosclerosis seemed to benefit from danaparoid At 3 months patients treated with danaparoid had a higher rate of favorable outcome than those treated with placebo (68.1% vs. 54.7%). Symptomatic deep vein thromboses were significantly less common in danaparoid-allocated patients than in the placebo group at the end of the observation period (0.31% vs. 1.6%). In summary, TOAST demonstrated no efficacy of intravenous low-molecular-weight heparin in improving outcomes at 3 months after stroke.

Subcutaneous Unfractionated Heparin The efficacy and safety of subcutaneous unfractionated heparin in stroke patients has been evaluated in the International Stroke Trial (IST). In this randomized, open label study, 2,430 patients were allocated to unfractionated heparin 12,500 IU SC twice daily in combination with aspirin 300 mg daily; 2,432 patients to unfractionated heparin 5,000 IU SC twice daily in combination

Chapter 42 rn Current Treatment Strategiesfor Ischemic Stroke

with aspirin 300 mg daily; 4,858 patients to aspirin 300 mg daily alone; 2,429 patients to unfractionated heparin 12,500 IU SC twice daily alone; 2,429 patients to heparin 5,000 IU SC twice daily alone; and 4,860 patients to no heparin and no aspirin. Treatment was initiated within 48 hours of stroke onset. The 9,716 heparin-allocated patients had significantly fewer recurrent ischemic strokes within 14 days compared with the 9,717 no-heparin patients (2.9% vs. 3.8%), corresponding to an absolute risk reduction of 9 recurrent ischemic strokes per 1,000. However, this benefit was completely offset by a similar-sized increase in hemorrhagic stroke (1.2%vs. 0.4%), corresponding to an increase in absolute risk of 8 hemorrhagic strokes per 1,000 patients. Among the heparin-allocated patients there were fewer deaths within 14 days (9.0% vs. 9.3%), corresponding to an absolute reduction of 3 deaths per 1,000 patients, but this was not statisticallysignificant. Overall at 14 days, there was no significant difference in the combined outcome of nonfatal stroke (recurrent ischemic or hemorrhagic) or death (1 1.7% vs. 12.0%). The subgroup analysis of IST reveals some interesting points: 1. The 1,557 heparin-allocated patients with atrial fibrillation had significantly fewer recurrent ischemic strokes within 14 days than the 1,612 no-heparin patients with atrial fibrillation (2.8% vs. 4.9%), corresponding to an absolute risk reduction of 21 recurrent ischemic strokes per 1,000. This benefit was offset by an increase in hemorrhagic stroke (2.1%vs. 0.4%),corresponding to an absolute increase in risk of 16 hemorrhagic strokes per 1,000. Overall, in patients with atrial fibrillation heparin resulted in a reduction in the number of nonfatal strokes (recurrent ischemic or hemorrhagic) or deaths at day 14 ( 19.1%vs. 20.7%), corresponding to a nonsignificant absolute risk reduction of 16 per 1,000. 2. There was a clear increase in adverse hemorrhagic outcome events with the higher heparin dosage. The 4,856 patients allocated to medium-dosage heparin (12,500 UI SC twice

daily) experienced more transfusions or fatal extracranial hemorrhages (2.0% vs. 0.6%) and more hemorrhagic strokes (1.8% vs. 0.7%) than the 4,860 patients allocated to low-dose heparin (5,000 IU SC twice daily). There was also no reduction of recurrent ischemic strokes in the medium-dose compared with the low-dose heparin treatment group (3.2% vs. 2.6%). Overall, the risk of recurrent nonfatal stroke or death at day 14 was significantly higher in the medium-dose than in the low-dose heparin treatment group (12.6% vs. 10.8%), corresponding to an increase of combined outcome events of 17 per 1,000. The analysis of outcome events at 6 months in IST revealed similar results for the whole group and the subgroups. IST has been criticized for its open label design and for the large number of patients (one-third) who received treatment before a cranial CT was done to rule out a primary intracerebral hemorrhage. From a pharmacologic point of view, the choice of a fixed-dose heparin regimen may have seriously affected hemorrhagic complication rate: In most patients a standard dosage of 12,500 IU heparin SC has minimal effect on coagulation, but in some patients clotting times are significantly prolonged. IST provides no coagulation data, and it remains unclear to what extent patients with hemorrhagic complications actually had a prolonged clotting time compared with patients with no hemorrhagic events during follow-up. It also remains unclear whether the reported hemorrhagic strokes were actually symptomatic or just asymptomatic

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hemorrhagic conversions of ischemic strokes visualized on cranial CT. The mode of heparin administration may also be important. At least 24 hours must elapse after subcutaneous injection of heparin before stable anticoagulant effects are achieved. Another major limitation of IST is that the authors fail to report outcome results on patients treated exclusively with heparin. Subcutaneous Low-Molecular-Weight Heparin

The first trial to examine the efficacy of subcutaneously administered low-molecular-weight heparin in treating ischemic stroke was the Fraxiparin Ischemic Stroke Study (FISS). FISS was a randomized, double-blind, placebo-controlled trial comparing two dosages of nadroparin with placebo. FISS randomized 102 patients to high-dose nadroparin (4100 anti-factor Xa units SC twice daily), 101 patients to low-dose nadroparin (4100 antifactor Xa units SC daily), and 105 patients to placebo. Patients were assigned to one of the treatment arms within 48 hours after stroke onset and received treatment for 10 days. At the end of the 10-day treatment period, there was no statistically significant differencein the rates of death between the three treatment groups (high-dose group, 6.9%; low-dose group, 7.9%; placebo, 7.6%). There was a trend for higher complication rates in the placebo group, but this was not statistically significant (high-dose group, 16.7%; low-dose group, 16.3%; placebo, 24.8%) and a trend for lower stroke recurrence rates in the heparin-allocated patients (high-dose, 1 .O%; low-dose, 2.0%; placebo, 4.8%). The primary study outcome was poor outcome, defined as either death from any cause or dependency in daily activities at 6 months after randomization. At 6 months, patients allocated to heparin were less likely to have a poor outcome (dead or dependent) compared with the placebo group (high-dose, 45.0%; low-dose, 51.5%; placebo, 64.8%).A surprising finding of FISS is that there was no significant difference in major intracranial and extracranial bleeding complications in patients allocated to heparin, irrespective of the dosage. This finding is not consistent with other studies using low-molecular-weight heparin and remains unexplained. The second trial studying the safety and efficacy of subcutaneously administered low-molecular-weightheparin in patients with moderate to severe stroke was the Tinzaparin in Acute Ischemic Stroke Trial (TAIST). This was a randomized, double-blind, aspirin-controlled trial comparing two dosages of tinzaparin with aspirin. In this study 487 patients received high-dose tinzaparin (175 anti-Xa IU/kg SC daily), 508 patients low-dose tinzaparin (100 anti-Xa IU/kg SC daily), and 491 patients aspirin (300 mg daily). Patients were assigned to one of the treatment arms within 48 hours after stroke onset and received treatment for up to 10 days. The primary outcome measure was independence, determined by a modified Rankin score of 0 to 2. The proportion of patients deteriorating during a 15-day postrandomization period was similar in the three treatment groups (high-dose tinzaparin, 12.1%; medium-dose tinzaparin, 11.9%; aspirin, 11.9%), and there was no difference in the proportions of recurrent strokes (high-dose tinzaparin, 3.3%; medium-dose tinzaparin, 4.7%; aspirin, 3.1%). For the same period, patients allocated to tinzaparin were more likely to suffer a symptomatic intracranial hemorrhage (high-dose tinzaparin, 1 N o ; medium-dose tinzaparin, 0.6%; aspirin, 0.2%) but were less likely to suffer from venous thromboembolism (high-dose tinzaparin, 0.4%; mediumdose tinzaparin, 1.2%; aspirin, 2.6%). However, the proportion of patients who returned to independence at 6 months was similar in the three treatment groups (high-dose tinzaparin, 41.5%;

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medium-dose tinzaparin, 42.4%; aspirin, 42.5%), as was the proportion of deaths (high-dose tinzaparin, 14.6%; medium-dose tinzaparin, 14.2%; aspirin, 14.9%). No treatment effect of tinzaparin was found across different stroke subtypes and causes. The prevention of recurrent stroke in patients with atrial fibrillation was specifically evaluated in the Heparin in Acute Embolic Stroke Trial (HAEST), a double-blind, randomized, aspirin-controlled trial. In this trial 224 patients were allocated to the low-molecular-weight heparin dalteparin ( 100 IUlkg SC twice daily) and 225 patients to aspirin (160 mg daily). Patients were assigned to one of the treatment arms within 30 hours after stroke onset and received treatment for 10 days. The primary outcome measure was recurrent stroke during the first 14 days. At 14 days, the frequency of recurrent stroke was similar between the two treatment groups (dalteparin, 8.5%; aspirin, 7.5%). There was a nonsignificant trend to more symptomatic cerebral hemorrhages in the dalteparin-allocated group than in the aspirin group (2.7% vs. 1.8%). There was an insignificant association between dalteparin and a higher rate of stroke progression within the first 48 hours (10.7% vs. 7.6%) and more deaths after 14 days (9.4% vs. 7.1%). At 3 months, no difference in the proportions of patients dependent or dead was seen (dalteparin, 63,0%; aspirin, 64.0%). Although not designed to assess efficacy, the Therapy of Patients with Acute Stroke (TOPAS) trial adds some interesting information to the use of low-molecular-weight heparins for acute ischemic stroke. This trial randomized patients within 12 hours after stroke onset to one of four treatment groups of subcutaneous certoparin: 99 patients received of 3,000 U daily, 102 patients 3,000 U twice daily, 103 patients 5,000 U twice daily, and 100 patients 8,000 U twice daily. A dosage of 3,000 U certoparin daily corresponds to the prophylactic dosage used to prevent thromboembolic complications after abdominal or hip operations, and a dosage of 8,000 U twice daily corresponds to the dosage used to treat deep vein thrombosis. The treatment period ranged from 12 to 16 days after randomization. This trial contained no aspirin or placebo control group, so the efficacy of certoparin could not be determined. The primary study outcome was the proportion of patients with a favorable outcome at 3 months after randomization. Favorable outcome was defined as 90 or more points in the Barthel index, which corresponds to independent functioning in the activities of daily living. During the active treatment period of 12 to 16 days, recurrent strokes or transient ischemic attacks occurred in similar proportions in the four treatment groups, ranging from 3.9% to 5.8%. Severe bleeding complications were more common in the highest-dose group (9%), and in the three lower-dose groups they occurred in 1% to 3% of the patients. Deep vein thrombosis or pulmonary embolism occurred in only 1 patient during the treatment period. At 3 months, there was no statistically significant difference in the proportion of patients with a favorable functional outcome, ranging from 56.3% to 63.3%. Summary: Heparin Treatment for Ischemic Stroke At present there is insufficient evidence to support the emergency use of any form of heparin in the setting of an acute stroke. Heparin seems to prevent recurrent stroke, but this occurs at the price of more frequent intracranial hemorrhage. There is no evidence that heparin arrests neurologic worsening during the treatment period, reduces short- or long-term mortality, or improves outcomes. The only indication for heparin treatment in

acute stroke patients is the prevention or treatment of deep vein thrombosis or pulmonary thromboembolism or as a bridge to oral anticoagulation when cardioembolic stroke is identified.

LONG-TERM ANTICOAGULATION FOR STROKE PREVENTION Oral Anticoagulation to Prevent Cardioembolic Stroke Oral anticoagulation with warfarin has a long history in clinical practice and has become standard treatment in patients with rheumatic mitral stenosis and prosthetic valves. It has never been subjected to rigorous clinical trials for those conditions and is not likely to undergo such trials in the near future. Large epidemiologic studies, for which the Framingham study is a model, have established high risk of stroke in patients with cardiac disease. The highest risk was seen in patients with atrial fibrillation in combination with valvular disease. The overall risk of stroke in patients with chronic atrial fibrillation is 5% per year. With the decline in incidence of rheumatic heart disease and rising uncertainty of the best management for nonvalvular atrial fibrillation, such patients have been considered suitable for such clinical trials. Six prospective, randomized trials have now proved there is a benefit in long-term anticoagulation and a low risk of serious complications. The six studies are the Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation Study (AFASAK); SPAF; the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF); the Canadian Atrial Fibrillation Anticoagulation (CAFA) trial; the Veterans’ Administration Stroke Prevention in Nonrheumatic Atrial Fibrillation trial; and the European Atrial Fibrillation Trial (EAFT). Overall, patients on warfarin had a 64% reduction in stroke risk in an intention-to-treat analysis and an 83% reduction in an on-treatment analysis. Patients with strokes in the warfarin groups were no more likely to have hemorrhagic than ischemic strokes. The rate of major bleeding was nearly identical for the warfarin and control groups at about 2%; minor bleeding was three times more likely in the warfarin group. The design of the studies varied slightly. All six studies excluded highest-risk cardiac patients: those with recent embolic events, recent myocardial infarction and significant congestive heart failure, or cardiomyopathy. SPAF excluded patients with lone atrial fibrillation, randomizing them to aspirin or placebo groups only because of a low stroke risk of less than 0.5% per year. AFASAK excluded patients with paroxysmal atrial fibrillation for the same reason. The level of anticoagulation differed slightly. AFASAK and EAFT used a prothrombin time of 1.5 to 2.0 times control, SPAF a prothrombin time of 1.3 to 1.8 times control, and CAFA, the Veterans’ Administration Stroke Prevention in Nonrheumatic Atrial Fibrillation trial and BAATAF a prothrombin time of approximately 1.2 to 1.5 times control. For the control groups AFASAK used ASA 75 mg/day or placebo, SPAF and EAFT used 325 mg/day or placebo, and BAATAF allowed ASA or no treatment to be used, at the discretion of the investigators. The AFASAK study randomized 1,007 patients over a 2-year period. The unblinded warfarin group showed an incidence rate of 2% per year of stroke or systemic thromboembolism, compared with a 5.5% incidence rate in the ASA and placebo arms. Three of the five stroke patients in the warfarin group had strokes when they were off warfarin. Nonfatal bleeding occurred in 6% of the warfarin group (43% of these patients were found to have inflammatory or malignant disease) as compared with 1% in the

Chapter 42

control groups. A drawback of this study was that 38% of patients in the warfarin group dropped out, mostly because of the inconvenience of frequent blood draws. The SPAF study randomized 1,330 patients and was terminated early at a mean follow-up period of 1.3 years. The incidence of stroke or systemic embolism was 2.3% in the warfarin group, 3.6% in the ASA group, and 7.4% in the placebo group. In this study as well, four of six patients with ischemic stroke in the warfarin group had strokes off therapy. Major bleeding complications were comparable in the warfarin, ASA, and placebo groups at 1.5%, 1.4%, and 1.6%, respectively. Of the 420 patients randomized in the BAATAF study, who were followed for an average of 2.2 years, ischemic stroke occurred in the warfarin group at a rate of 0.41% per year and in the control group at 2.98% per year, for a risk reduction of 86%. The two strokes in the warfarin group occurred at prothrombin times of less than 1.2. Among the strokes in the control group, 8 of 13 occurred in patients taking aspirin. The death rate in the warfarin group was 2.25% and in the control group 5.97%. Two fatal hemorrhages occurred, one presumed intracerebral hemorrhage (ICH) in the warfarin group and a pulmonary hemorrhage in the control group. Minor bleeding occurred in 38 patients in the warfarin group and in 21 patients in the control group. The CAFA trial was altered midway because of the superior benefit conferred by warfarin in the AFASAK and SPAF trials. Patients were then allowed open label access to warfarin. The results from the study were then reported in an efficacy analysis in which endpoint events occurring more than 28 days after stopping therapy were not counted. A risk reduction of 52% was counted among the 378 patients randomized in the trial. The Veterans’ Administration Stroke Prevention in Nonrheumatic Atrial Fibrillation trial randomized 525 men to receive warfarin or placebo. This trial was the only one among the six to fully blind the warfarin assessment. A 12-hour cutoff was used to distinguish TIA from stroke. A 79% risk reduction was found for the warfarin group before the trial was terminated. Of the six trials discussed here, only the EAFT addressed secondary stroke prevention. In this study, 1,007 patients with TIA or minor ischemic stroke were randomized to receive open label warfarin, aspirin 300 mg/day, or placebo. During the mean follow-up period of 2.3 years, 8% in the anticoagulation group reached an endpoint of stroke, myocardial infarction, systemic embolism, or death related to any vascular disease. By contrast, 17% in the placebo group reached these endpoints. The relative risk reduction for stroke alone was 66%. Warfarin was also found to be much more effective when compared with the aspirin group (relative risk = .60; 95% confidence interval = 0.41 to 0.87). Oral Anticoagulation for Preventing Noncardioembollc Stroke

Until recently, warfarin treatment was considered for patients with noncardioembolic stroke if they failed antithrombotic treatment with antiplatelet agents. Two trials examined safety and efficacy of long-term anticoagulation for secondary stroke prevention. The first study is the Stroke Prevention in Reversible Ischemia Trial (SPIRIT). In SPIRIT, patients with a recent transient ischemic attack or minor stroke of presumed arterial origin were randomized to either aspirin (30 mg daily) or oral anticoagulation (international normalized ratio [INRI of 3.0 to 4.5). This range of oral anticoagulation had previously been well tolerated in cardiac

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patients, and the SPIRIT trialists assumed that the same would apply to ischemic stroke patients; this proved to be wrong. The primary measure of outcome was the composite event “death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or non-fatal major bleeding complications.” A total of 665 patients were allocated to aspirin and 651 patients to oral anticoagulation. During a mean follow-up of 14 months, there was a statistically significantly higher rate of the primary outcome in the anticoagdated group than in the aspirin group (12.4% vs. 5.4%). This result was attributed to a higher proportion of major bleeding complications (mostly ICH) in the anticoagulated versus aspirin group (4.2% vs. 0.9%). Mortality from major bleeding complications was also higher in the anticoagulated group than in the aspirin group (2.6% vs. 0.2%). Therefore, the safety monitoring committee stopped this study prematurely. The second study is the Warfarin Aspirin Recurrent Stroke Study (WARSS). WARSS examined whether warfarin is superior to aspirin in preventing recurrent stroke in patients with a prior noncardioembolic ischemic stroke. This multicenter, randomized, double-blind trial assigned 1,103 patients to warfarin (at a dosage adjusted to produce an INR of 1.4 to 2.8) and 1,103 patients to aspirin (325 mg daily). The primary endpoint was recurrent stroke or death from any cause. The follow-up rate after the scheduled 24 months was 98.5%. At that point, 17.8% of patients assigned to warfarin and 16.0% of patients assigned to aspirin reached the primary endpoint, a difference that was statistically nonsignificant. The rates of major hemorrhagic complications were low and similar in the treatment groups (warfarin, 2.22 per 100 patientyears; aspirin, 1.49 per 100 patient-years). There was also no difference in outcome for different types of prior stroke (i.e., lacunar, cryptogenic, or large artery stroke). Overall, warfarin treatment is not superior to aspirin for secondary stroke prevention in patients with noncardioembolic stroke. However, in the dosage range tested, warfarin seems to be as safe as aspirin treatment. An interesting finding of WARSS is that warfarin exerts its therapeutic effect at an INR of 1.5, with little additive effect above that value. This finding replicates the treatment effect of warfarin for cardioembolic stroke prevention in SPAF-3. A trial is under way to assess the safety and efficacy of chronic anticoagulation for secondary stroke prevention in patients with noncardioembolic stroke, the European/Australian Stroke Prevention in Reversible Ischemia Trial. This study aims to randomize 4,500 patients between oral anticoagulation (dosage adjusted to an INR of 2.0 and 3.0), the combination of dipyridamole (400 mg daily) plus aspirin (in any dosage between 30 and 325 mg), and aspirin alone (in any dosage between 30 and 325 mg). The primary outcome event is a composite event of vascular death, stroke, myocardial infarction, or major bleeding complication. Long-Term Anticoagulation for Symptomatic lntracranlal Atherosclerosis

Although WARSS showed no benefit of warfarin over aspirin in the secondary prevention of large artery strokes, it was not specifically designed to answer that question. Data from a specifically designed trial for this patient group are lacking. Treatment recommendations therefore are based on the results of two retrospective studies examining the effect of anticoagulation over antiplatelet therapy for intracranial atherosclerosis. The pilot study Warfarin Versus Aspirin for Symptomatic Intracranial Disease analyzed a series of symptomatic patients with

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angiographically proven intracranial stenosis of at least 50%. This retrospective, multicenter study compared major vascular outcomes (vascular death and stroke) in 88 patients treated with warfarin and 63 patients treated with aspirin. The rates of major vascular events were 18.1 per 100 patient-years of follow-up in the aspirin group (stroke rate, 10.4/100 patient-years; myocardial infarction or sudden death rate, 7.7/100 patient-years) and were statistically higher when compared with 8.4 per 100 patient-years of follow-up in the warfarin group (stroke rate, 3.6/100 patientyears; myocardial infarction or sudden death rate, 4.8/100 patient-years). In a recent retrospective study from Stanford University, of 52 patients with symptomatic intracranial atherosclerosis, 29 (56%) failed antithrombotic therapy (antiplatelet agents in 55%, warfarin in 31%, or heparin in 14%). The median time to recurrent TIA, stroke, or death was only 36 days (95% confidence interval 13 to 59). Among patients who failed antithrombotic therapy, the subsequent rate of stroke or death was extremely high (45% per year). Both studies suggest that patients with symptomatic intracranial atherosclerosis are at a high risk for recurrent stroke or death, and many stroke neurologists still treat that patient group with warfarin after failure of antiplatelet agents. At present two randomized trials are specifically evaluating different antithrombotic treatments for secondary stroke prevention in intracranial atherosclerosis. The prospective Warfarin-Aspirin for Symptomatic Intracranial Disease (WASID) trial is a randomized, doubleblind, clinical trial in which 806 patients with TIA or minor stroke from an angiographically proven stenosis (50% to 99%) of a major intracranial artery were randomized to warfarin (INR 2-3) or aspirin (1,300 mg/day). The main aim of the study was to determine whether warfarin is superior to aspirin for preventing ischemic stroke or death in those patients. The Aspirin Versus Anticoagulants in Symptomatic Intracranial Stenosis study is a randomized, multicenter, open trial designed to compare the efficacy and safety of aspirin (300 mg/day) and warfarin (adjusted to an INR of 2 to 3) in the secondary prevention of ischemic stroke, other vascular events, and major hemorrhagic complications among patients with transient ischemic attack or cerebral infarction attributable to MCA stenosis. Both studies await completion. Until the results of these studies are available, anticoagulation with warfarin for intracranial atherosclerosis is an option, especially after WARSS demonstrated a similar safety compared with aspirin at a dosage adjusted to an INR of 1.4 to 2.8.

Long-Term Anticoagulation for Secondary Stroke Prevention in Patients with Patent Foramen Ovale Numerous retrospective studies have found an association between cryptogenic stroke and the presence of a patent foramen ovale (PFO). Treatment recommendations for that condition include anticoagulation with warfarin and either operative or percutaneous endovascular closure of the foramen ovale for secondary stroke prevention. The recently published PFO in Cryptogenic Stroke Study (PICSS), a substudy of WARSS, revealed important information on anticoagulation in stroke patients with a PFO. PICSS randomized 312 patients to warfarin and 318 patients to aspirin. Of these, 265 patients experienced cryptogenic stroke and 365 experienced a known stroke subtype. PFO was demonstrated by transesophageal echocardiography in 203 patients. Endpoints were recurrent stroke or death at 2 years. At 2 years’ follow-up, there was no statistically significant difference in

the primary outcome between the patient group with a PFO and the patient group without a PFO for the whole study population (14.8% vs. 15.4%), and for the subset with a cryptogenic stroke (14.3% vs. 12.7%). PICSS was also unable to demonstrate any statistically significant difference in the proportion of the primary event rates with increasing size of the PFO or with the presence of an associated atrial septa1 aneurysm. However, the most important result is that patients with a PFO assigned to warfarin had similar proportion of primary event rates after 2 years’ follow-up compared with patients assigned to aspirin (16.5% vs. 13.2%). In summary, the results of PICSS do not support routine anticoagulation in stroke patients with a PFO. However, there may be some patients with PFO in whom anticoagulation seems appropriate (i.e., patients with recurrent stroke while on aspirin, documented deep vein thrombosis, and right-to-left shunt).

Summary of Chronic Anticoagulation in Stroke Patients Chronic anticoagulation is established for secondary stroke prevention in cardiogenic ischemic stroke. In patients with prosthetic valves, an INR of 3.0 to 4.0 should be the goal. In patients with atrial fibrillation an INR of 2.0 to 3.0 is recommended for primary and secondary stroke prevention. Low-dose anticoagulation (INR 1.5 to 2.8) for noncardioembolic stroke of any type and in patients with a PFO offers no more benefit than aspirin. The value of anticoagulation in patients with intracranial atherosclerosis remains to be established.

STATINS Statins are potent cholesterol-lowering agents that act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Large placebo-controlled, randomized trials have shown that statin treatment reduces acute coronary events. Three randomized trials have established the beneficial effect of statins on secondary stroke risk reduction in patients with symptomatic coronary artery disease. The first secondary prevention study suggesting a possible benefit of statins for stroke prevention was the Scandinavian Simvastatin Survival Study. In this study, patients with coronary artery disease were randomized to either simvastatin (10 to 40 mg daily) or placebo. Patients had either high or average cholesterol levels at study entry. In a post hoc analysis, there was a significant relative risk reduction for stroke and TIAs of 28% in favor of simvastatin. However, after TIAs were excluded from the analysis, there was only a nonsignificant risk reduction for stroke of 23% favoring simvastatin over placebo. The second study assessing the effect of a statin in secondary prevention is the Cholesterol and Recurrent Events (CARE) trial. This study included patients with a cholesterol level less than 240 mg/dL and past myocardial infarction 3 to 20 months before randomization. A total of 2,081 patients were randomized to pravastatin (40 mg daily) and 2,078 patients to placebo. The number of patients suffering from stroke during a median 5-year follow-up was low (pravastatin, 2.5%; placebo, 3.7%), but this translates into a significant stroke risk reduction of 32% favoring pravastatin over placebo. Although the difference is not statistically significant because of the low numbers in each category, all subtypes of ischemic stroke were lower in the pravastatin group, and there was no higher risk of hemorrhagic stroke in patients treated with pravastatin. There was a trend for higher relative stroke risk reduction in patients treated with pravastatin and high

Chapter 42 H Current Treatment Strategiesfor Ischemic Stroke

total cholesterol (more than 209 mg/dL), high LDL cholesterol (more than 137 mg/dL), high LDL to HDL cholesterol ratio (3.7 or higher), and high triglycerides (144 mg/dL or more) compared with patients allocated to placebo. There was no statistically significant effect favoring pravastatin over placebo in patients with normal levels of cholesterol (209 mg/dL or less), low LDL cholesterol (137 mg/dL or less), low LDL to HDL cholesterol ratio (less than 3.7), and low triglycerides (less than 144 mg/dL). The third and last published secondary prevention study using statins is the Long-term Intervention with Pravastatin and Ischemic Disease (LIPID) study. This study randomized 4,512 patients to pravastatin (40 mg daily) and 4,502 patients to placebo. To be included in the study, patients had to have myocardial infarction or unstable angina within 3 to 36 months before randomization, cholesterol levels of 155 to 271 mg/dL, and a fasting triglyceride level less than 455 mg/dL. As in the CARE study, during the mean follow-up period of 6 years, the proportion of patients suffering from strokes was low (pravastatin, 3.7%; placebo, 4.5%), but again these proportions correspond to a relative stroke risk reduction of 19% favoring pravastatin over placebo. Although the difference is not statistically significant because of the low numbers in each category, all subtypes of ischemic stroke were lower in the pravastatin group. There was a statistically nonsignificantly higher proportion of hemorrhagic stroke in patients assigned to pravastatin than in patients assigned to placebo (0.4% vs. 0.2%). In conclusion, statins reduce stroke event rates in patients with symptomatic coronary artery disease by approximately 20% to 30%. However, all published studies have been performed in patients with heart disease. Currently there is little information regarding the role of statins in recurrent stroke prevention, and trials are under way to answer that question. One of them is the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. This study will assess the effect of aggressive lipid lowering in secondary stroke prevention in patients after an ischemic stroke. This 5-year, randomized, double-blind, placebocontrolled trial plans to enroll 4,200 patients with previous stroke or transient ischemic attacks and low-density lipoprotein cholesterol between 100 mg/dL (2.6 mmol/L) and 190 mg/dL (4.9 mmolh). Patients are assigned to either atorvastatin (80 mg daily) or placebo. The primary study outcome is the time from randomization to first occurrence of a fatal or nonfatal stroke. Until the results of the ongoing studies are available, statins should be used in stroke patients with high cholesterol. The situation in patients with normal cholesterol profile is less clear, and no general recommendation can be given at this time.

ANTIHYPERTENSIVES AND ANCIOTENSIN-CONVERTING ENZYME INHIBITORS Numerous studies have demonstrated that blood pressure levels are directly and continuously associated with the initial occurrence of ischemic stroke or ICH. Controlling high blood pressure therefore is an important intervention for primary stroke prevention. However, most neurologists usually have to make antihypertensive treatment decisions in patients who have suffered a TIA or stroke. Measuring blood pressure is an essential part of the evaluation of every stroke patient, and adequate treatment of hypertension is an important part of secondary stroke prevention. In contrast to the numerous studies on blood pressure treatment for primary stroke prevention, there are far fewer studies examining its effect and safety for secondary stroke prevention.

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The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) is the largest study specifically examining the effect of blood pressure lowering for secondary stroke prevention in patients with symptomatic cerebrovascular disease. To qualify for the trial, patients had to have suffered an ischemic or hemorrhagic stroke or transient ischemic attack within 5 years before randomization. All patients were subjected to a 4-week run-in period on active trial medication and subsequently switched to placebo or active treatment. Preexisting antihypertensive treatment was continued in all patients. Active treatment consisted of the angiotensin-converting enzyme (ACE) inhibitor perindopril(4 mg daily) and in 58% of all cases also the diuretic indapamide (2 to 2.5 mg daily). A total of 3,051 patients were allocated to active treatment and 3,054 patients to placebo. The primary study outcome was fatal or nonfatal stroke. After a mean follow-up of 3.9 years, patients allocated to active treatment had a significantly lower stroke event rate compared with controls (10% vs. 14%), corresponding to a relative risk reduction of 28%. The annual stroke event rate was lower in the active treatment group than in the control group (2.7% vs. 3.8%). This effect in favor of the active treatment group was seen in both ischemic and hemorrhagic strokes. During follow-up, fewer patients suffered a major vascular event (combined vascular death, nonfatal myocardial infarction, and nonfatal stroke) in the active treatment arm (15% vs. 20%). However, there was no difference in mortality between the two treatment groups (10.1% vs. 10.4%). The combination of perindopril and indapamide reduced statistically significantly the mean blood pressure by 12/5 mm Hg compared with placebo and was more effective for secondary stroke prevention than perindopril alone, which reduced the mean blood pressure only by 513 mm Hg. Interestingly, these treatment effects were similar for hypertensive and nonhypertensive participants. It remains unclear from PROGRESS whether the treatment effect was caused by the reduction of blood pressure alone or whether there is an additional treatment class effect of the ACE inhibitor used. The effect in nonhypertensive patients suggests an effect beyond blood pressure reduction. Overall, in PROGRESS one stroke could be prevented among every 14 patients treated with the combination of perindopril and indapamide for 5 years. However, a significant portion of patients was unable to tolerate the active treatment: 14% of all patients withdrew from the trial during the 4-week run-in period before actual randomization, mostly because of side effects of the active treatment drugs. In other words, one in seven eligible patients was unable to tolerate the study drugs. The Heart Outcomes Prevention Evaluation (HOPE) trial was a double-blind, randomized trial with a two-by-two factorial design in which participants were randomized to receive up to 10 mg of the ACE inhibitor ramipril, 400 IU of vitamin E, both, or matching placebos. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular cause. The study did not reveal any treatment benefit of vitamin E over placebo, and this part of the study will not be further discussed in this section. Overall, 4,645 patients were allocated to ramipril and 4,652 patients to placebo. There was a statistically nonsignificant reduction in blood pressure on average by 3.8 mm Hg systolic and 2.8 mm Hg diastolic in the ramipril group and by 0.66 mm Hg systolic and 1.1 mm Hg diastolic in the placebo group. After a mean follow-up period of 5 years, there was a significantly lower rate of the primary outcome in patients allocated to ramipril than in controls (14.0% vs. 17.8%). This was true for all individual outcome events included in the primary outcome definition (myocardial infarction, 9.9% vs. 12.3%; stroke, 3.4% vs. 4.9%;

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cardiovascular death, 6.1% vs. 8.1%). No difference in noncardiovascular deaths was seen between the two treatment groups. Statistically significantly fewer patients in the ramipril group than in the placebo group had an ischemic stroke (2.2% vs. 3.4%). There was a trend toward fewer nonischemic strokes (hemorrhagic or uncertain cause) in the ramipril group than in controls, which did not reach statistical significance (1.1% vs. 1.4%). As in PROGRESS, these effects were seen regardless of the baseline blood pressure. Although adequate blood pressure reduction is beneficial for secondary stroke prevention in general, there are situations in which blood pressure reduction may have catastrophic consequences. These situations are as follows. In the acute stage of an ischemic stroke, vigorous blood pressure reduction may further decrease cerebral perfusion and therefore should be avoided. In most stroke centers antihypertensive treatment is withheld the first 3 days after an acute ischemic stroke. Although there is no general recommendation about the ideal blood pressure range during the acute phase, most stroke neurologists believe that the blood pressure should be maintained in the range of 140 to 180 mm Hg systolic pressure to ensure adequate cerebral perfusion. Some even recommend raising the blood pressure with vasopressors, even in normotensive stroke patients, to improve cerebral perfusion. Blood pressure reduction after an acute ischemic stroke may be deleterious in patients with high-grade extracranial or intracranial stenoses. Therefore, blood pressure reduction should be initiated only if hemodynamically significant stenoses of the cerebral vasculature have been ruled out by noninvasive or invasive methods. In patients with long-standing cerebral microangiopathy or widespread ischemic cerebral damage, rapid reduction of blood pressure may produce an encephalopathic clinical picture because of the adaptation of the cerebral vasculature to a higher threshold. Generally, blood pressure reduction in patients in the acute phase after a stroke is not a medical emergency and should be performed with caution in the stable phase after stroke to avoid adverse events. The results from PROGRESS and the HOPE trial suggest that ACE inhibitors may also be beneficial in normotensive patients at high risk for stroke. SURGICAL INTERVENTION Carotid endarterectomy was introduced in 1954. Although efficacy was unproven in the early years, the operation grew in popularity from 15,000 in 1971 to 105,000 in 1985. After the 1985 trial that suggested that the extracranial-intracranial bypass procedure was ineffective, a series of randomized clinical trials was initiated to assess the efficacy of endarterectomy. Three large multicenter trials addressed the question of operating in the setting of symptomatic carotid artery disease. Results from these trials demonstrated a 10% to 18% absolute reduction in stroke risk for endarterectomy in high-grade (greater than 70%) stenosis. Endarterectomy for symptomatic patients with moderate stenosis and with asymptomatic carotid stenosis confers a lesser degree of benefit. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) drew data from 50 centers in the United States and Canada, randomizing patients to surgery and best medical therapy (mostly ASA 1300 mg/day) or medical therapy alone. The patients were stratified to 30% to 49%, 50% to 69%, or 70% to 99% stenosis documented by angiogram. After 659 patients had been randomized in the high-grade stenosis group-half the

number projected as necessary to prove a 10% risk reduction-the study was terminated because of a dramatic therapeutic benefit favoring surgery. The cumulative risk of ipsilateral stroke at 2 years was found to be 9% in the surgical group and 26% in the medical group, for a risk reduction of 17%. The cumulative risk of major or fatal ipsilateral stroke was 2.5% in the surgical group and 13.1% in the medical group. The risk of all strokes was 12.6% versus 27.6% and the risk of death or major stroke was 8% versus 18.1% for the surgical and medical groups, respectively. Average perioperative morbidity and mortality for all involved centers was 5.8%. Perioperative incidence of major stroke or death was 2.1%. For the group with 50% to 69% stenosis, 5-year rates of ipsilateral stroke were 15.7% among those treated surgically and 22.2% among the medically treated patients. Patients with stenosis less than 50% did not benefit from endarterectomy. Another multicenter trial, the Veterans Administration study, randomized 189 patients with greater than 50% internal carotid artery (ICA) stenosis to surgical plus medical therapy (ASA 325 mg) or medical therapy alone and found similar results. At a mean follow-up of 11.9 months, crescendo TIAs and stroke were found in 7.7% of patients in the surgical group and 19.4% in the medical group, for a risk reduction of 11.7%. Patients with greater than 70% stenosis showed a risk reduction of 17.7%. Perioperative morbidity and mortality in this study was 5.5%. The largest, longest-running trial was the European Carotid Surgery Trial (ECST), which also found a striking benefit of surgical intervention for high-grade carotid stenosis among the 25 18 patients they recruited. Their comparison groups were surgery plus aspirin versus aspirin alone. The high-grade stenosis (greater than 70%) portion was terminated for this trial after a 9.3% risk reduction was noted for stroke or death in less than 30 days and a 9.6% reduction in stroke or death at 3 years. This study also showed moderate surgical benefit for patients with symptomatic stenosis greater than 50% and none for lesser stenosis. The challenge of what to do with asymptomatic carotid artery disease has been addressed by three randomized trials. Overall, the evidence favors surgery; however, gender and severity of stenosis remain contentious issues. Asymptomatic bruits are present in 4% to 5% of the general population aged 45 to 80, but the reported risk of carotid stenosis without symptoms has varied widely in the literature. Often quoted is a small study of 50 patients with greater than 50% stenosis: Stroke occurred in 4.5% and TIAs in 16.5%. At the other extreme is a study of patients with asymptomatic stenotic carotid arteries contralateral to operated symptomatic arteries, and no strokes occurred in a 20-year follow-up period. Nonuniformity of definitions and follow-up contributes to the problem in defining risk. Radiographic evidence of prior strokes may be found in 15% to 20% of all stroke patients presenting with their “first” acute stroke. An older multicenter trial of asymptomatic carotid stenosis, Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin, randomized 410 patients to surgery and medical therapy (ASA 330 mg, dipyridamole 75 mg) or surgery alone. Those with more than 90% stenosis were excluded. Their endpoints were stroke or death. Patients were removed from the study and operated on if a TIA occurred in the ipsilateral territory, if more than 90% stenosis developed, or if there was more than 50% bilateral disease. These investigators observed no difference between the two groups; however, the exclusion of patients with more severe arterial disease and the small number of participants left the issue unresolved. A Veterans Administration trial of asymptomatic patients

Chapter 42

with greater than 50% carotid stenosis randomized 444 men to receive either 1,300 mg of aspirin daily or aspirin therapy plus carotid endarterectomy. The rate of perioperative stroke or death, including angiographic complications, was 4.7% in the surgical group. Neurologic endpoints, which included fatal and nonfatal stroke, TIAs, and transient monocular blindness, were found in 12.8% of patients in the surgical group and in 24.5% in the medical group, for a relative risk reduction of 51%, favoring surgery. However, eliminating transient neurologic events from the analysis made the differences between the two groups nonsignificant. Furthermore, when only ipsilateral events were considered, the difference between surgery and medical therapy disappeared also. The Asymptomatic Carotid Atherosclerosis Study (ACAS) fared slightly better in defining a benefit for surgery, at least for men. In this study, 40 U.S. centers randomized 1,644 patients with greater than 60% ICA stenosis to receive either best medical therapy (usually an antiplatelet agent and aggressive management of modifiable risk factors) or best medical therapy plus endarterectomy. The aggregate risk of any stroke or death in the perioperative period was 2.3%. After a mean follow-up period of 2.7 years, the Kaplan-Meier projections from an intention-to-treat analysis showed the incidence of any stroke or death over 5 years to be 5.1% for the endarterectomy group versus 11.0% for patients treated with medical therapy alone over the same period. The relative risk reduction conferred by surgery therefore was 55% (95% confidence interval = 23 to 73). Explanations for a fourfold difference in the relative risk reduction for men and women in this study (69% vs. 16%) await further analysis. Although the two asymptomatic carotid stenosis studies appear to support the use of surgical intervention, it remains up to the individual clinician to assess the risk and benefit in a given patient. Advancing stenosis appears to increase risk. Supplementary laboratory data may help assess the significance of a carotid stenosis. Regional cerebral blood flow measurements may show low-flow areas and areas of decreased vasoreactivity after CO, inhalation. The existence of adequate collaterals may be inferred by the reestablishment of low resistance flow in the common carotid artery on duplex Doppler (external carotid artery to ophthalmic to ICA collateral) or a reversal of flow in the anterior cerebral artery on transcranial Doppler (collateral via the anterior communicating artery). An alternative to surgical endarterectomy is carotid angioplasty and stenting, which has proved to be effective and safe for patients with restenosis of the carotid artery after endarterectomy or radiation-induced stenosis or for patients who have other surgical contraindications to endarterectomy such as a surgically inaccessible stenosis or medical contraindications to surgery. Rapidly developing technical advances in this field continue to improve the safety and efficacy of the endovascular approach. However, outcome assessments at any given time are therefore difficult. Whether carotid stenting will prove as durable and effective as endarterectomy for stroke prevention in uncomplicated carotid stenosis is the subject of ongoing controlled clinical trials. For patients with complete occlusion of the ICA, positron emission tomography may identify areas of "misery perfusion" in the ICA territory representing tissue at risk that could be better perfused after operation. Extracranial-intracranial bypass for patients with symptomatic ICA occlusion and positron emission tomography evidence of perfusion failure is currently being retested as a surgical intervention to reduce stroke risk. Unlike the 1985 extracranial-intracranial bypass trial that failed to show a

w Current Treatment Strategies for Ischemic Stroke

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beneficial effect that outweighed the surgical risk, the Carotid Occlusion Surgery Study will randomize only symptomatic ICA occlusion patients who demonstrate hemodynamic failure by ipsilateral increased oxygen extraction fraction on positron emission tomography.

HYPERACUTE TREATMENT OF STROKE Important treatment decisions in acute stroke depend on the individual clinical presentation. The primary aims of acute stroke treatment are to stabilize the patient's condition, reduce the amount of ischemic brain damage, and prevent secondary complications or reinfarction. Current treatment strategies focus on early treatment, such as systemic or intraarterial thrombolysis. However, at present in the United States, as in other countries, only 1% to 2% of acute ischemic stroke patients are actually treated with any form of thrombolysis. This is mostly because of low awareness among patients and their family members regarding stroke symptoms and the need to present rapidly at an emergency room, but it also results from delays in the diagnosis of acute stroke by physicians. Community-based education efforts have been launched to remedy this situation. A rapid evaluation of the stroke patient as soon as he or she arrives into the emergency room is imperative to obtain the information needed for any acute stroke treatment and placement. Table 42-1 lists such a protocol for the initial assessment of stroke patients.

Intravenous Thrombolysis Early trials with thrombolytic agents, including urokinase and streptokinase, failed to show better outcomes for patients with acute stroke, predominantly because of high rates of symptomatic intracranial hemorrhage. Better results have been achieved with recombinant tissue plasminogen activator (rtPA), although clinical trials indicate rather narrow parameters within which IV throm-

TMLE 42-1. Emergency Department Protocol for the Initial Management of Acute Stroke 1. Obtain vital signs (temperature, pulse, blood pressure, oxygen satura-

tion) and start monitoring every 5 to 15 min, depending on the clinical situation. 2. Begin continuous cardiac and oxygen saturation monitoring. 3. Ensure adequate aiway and respiratory status: a. lntubate and initiate mechanical ventilation if necessary. b. Otherwise, begin oxygen at 2 L per minute via nasal cannula. 4. IV access: start IV 0.9 normal saline at 50 mL/hr; saline lock in opposite arm. 5. Obtain an emergent electrocardiogram. 6. Perform laboratory studies: a. Serum glucose (may be done at bedside). b. Complete blood count with platelet count. c Chemistry profile. including cardiac enzymes. d. Coagulation studies (prothrombin time, activated thromboplastin time). e. Urine pregnancy test for women of childbearing age. f. Urine toxicology screen. g. Stool guaiac in patients with suspected or known gastrointestinal bleeding sources. 7. Measure or estimate patient's weight. 8. Order emergent computed tomography without contrast 9. Obtain exact date and time of stroke onset or time patient last seemed normal. 10. Do not give antiplatelet agents or anticoagulants to potential thrombolytic therapy patients. Modifiedfrom Hickenbottom SL, Barsan WG: Acute ischemic stroke therapy. Neurol Clin 19:379.2000.

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bolysis may work. The National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous rtPA demonstrated improved outcomes in patients who received treatment within 3 hours of stroke onset. Part I of the trial (291 patients) assessed changes in neurologic deficits at 24 hours after stroke onset. Part I1 (333 patients) used a combination of four outcome measures to assess functional recovery at 3 months. Safety results combining data from parts I and I1 showed that symptomatic ICH was significantly higher in the rtPA group (6.4%) than in the control group (0.6%) but was significantly lower than the 18% to 20% present in the early streptokinase trials. Symptomatic ICH occurred in patients who were more severely affected by stroke at baseline or whose baseline CT scan showed early signs of infarction. Mortality was no higher in the treatment arm. In part I, the 24-hour outcome was not significantly better in the treatment group. However, part I1 showed that in the rtPA group there was a 12% greater number of patients who had minimal or no disability at 3 months than in the placebo group. Overall, the result of the NINDS acute stroke trial translates into an additional 160 independent survivors per 1,000 patients treated with rtPA. A second acute stroke trial of IV rtPA, the European Cooperative Acute Stroke Study (ECASS), examined a longer time window of up to 6 hours after stroke onset. This trial initially also used a higher dosage of IV rtPA than the NINDS trial and suffered from a symptomatic ICH incidence as high as that of the early streptokinase trials. A revision of this trial replicated the lower NINDS rtPA dosage (0.9 mg per kg) and showed fewer hemorrhages. Most patients in this study were treated after 3 hours, however, and the trial showed no benefit for rtPA. Once the Food and Drug Administration approved rtPA for a 3-hour time window, ATLANTIS, a third rtPA trial with a 5-hour time window, modified its original protocol to examine the 3- to 5-hour time window specifically. The study was terminated early because of a lack of eflicacy for outcome at 24 hours or at 3 months for the window beyond 3 hours. Subsequent phase IV trials, which are designed to test the highly controlled phase I11 trial protocols in the real world, showed that IV rtPA could be administered safely in nonacademic centers with similar outcomes despite a higher rate of protocol violations and symptomatic hemorrhage. The inclusion and exclusion criteria for rtPA treatment in acute ischemic stroke are shown in Table 42-2. According to established guidelines, patient evaluation (including medical history, physical examination, CT, and laboratory examination) should be complete within 45 minutes, and rtPA should be administered within 60 minutes after the patient’s arrival in the emergency room. In extremely well-organized acute stroke centers the door-to-needle time can be as low as 20 minutes, and up to 15% to 20% of all acute ischemic stroke patients can be treated with rtPA. Such short evaluation times entail strict organization, which can be achieved only by specialized stroke teams acting within each hospital and in close cooperation with the emergency medical services as soon as they transport the patient from the field into the hospital. The treatment protocol for systemic thrombolysis and blood pressure control during thrombolysis is shown in Table 42-3. Over the last few years, much experience has been obtained in the use of rtPA, and some observations may result in future revisions of current treatment guidelines. For example, in a recent analysis from Foothill Medical Center University of Calgary, Canada, 57 patients presenting within 3 hours after stroke onset demonstrated rapid improvement of their symptoms and therefore received no rtPA. However, 25 of these patients (43%) died during admission or were dependent at discharge. Therefore, some stroke centers

W TABLE 42-2. Eligibility Criteria for Treating Ischemic

Stroke

with Intravenous rtPA Inclusion criteria

Exclusion criteria Medical history

Clinical examination

Laboratory examination

Age 21 8 yr Clinical diagnosis of ischemic stroke with clear sympto; onset within 3 hr No evidence of hemorrhage on noncontrast computed tomography Prior intraaanial hemorrhage, no time limit History of intracranial neoplasm, or vascular malformation (aneurysm, arteriovenous, or cavernous malformation) Stroke or major head trauma within the previous 3 mo Major surgery or biopsy of parenchymal organ within the preceding 14 d Gastrointestinal or urinary bleeding within the preceding 21 d Recent myocardial infarction History of known hereditary or acquired abnormal hemostasis Current use of oral anticoagulants with an international normalized ratio >1.5 Use of heparin in the previous 48 hr with prolonged partial thromboplastin time Neurologic signs that are improving rapidly Isolated mild neurologic deficits, such as isolated mild ataxia, dysarthria, or sensory loss alone Systolic blood pressure >185 mm Hg, diastolic blood pressure >110 mm Hg, or aggressive therapy needed to control blood pressure Platelet count <10O,ooO/pL International normalized ratio >1.5 or prothrombin time > I 5 s Blood glucose <50 mg/dL (2.7 mmol/L) or >400 mg/dL (22.2 mmol/L) Positive guaiac stool test

Data adapted from the National Institute of Neurological Disordersand Stroke (NINDS) rt-PA Stroke Study Group: Tissue plasminogen activator for acute-ischemic stroke. N Engl J Med 333:1581,1995.

administer rtPA to rapidly improving patients if their neurologic deficit at treatment onset is still moderately severe. In the same study from the University of Calgary, in 41 patients presenting within 3 hours the stroke syndrome was considered too mild and rtPA was not given. Of these, 7 patients (17%) either died during admission or were dependent at discharge. At present, most centers exclude patients with mild strokes from systemic thrombolysis. Large efforts have been undertaken to identify high-risk patients for major hemorrhagic complications, specifically ICH, using clinical and neuroimaging data. Predictive factors for symptomatic ICH found in several studies are severe neurologic syndrome at treatment onset, signs of a large infarct on baseline cranial CT, hyperglycemia at baseline, and advanced age. With more widespread use of IV thrombolysis, more risk factors for symptomatic ICH will be established, and treatment protocols may be changed in the future.

lntradrterial Thrombolysis A breakthrough occurred with intra-arterial thrombolysis. The PROACT Study was a multicenter effort to determine whether administering an intra-arterial thrombolytic agent-in this case pro-urokinase (pro-UK)-could improve 3-month functional outcomes in patients with acute MCA territory stroke. The time window for this study was 6 hours. One hundred eighty patients were randomized to receive intra-arterial pro-UK or placebo. Symptomatic hemorrhage occurred in 10% of the treatment group

Chapter 42 H Current Treatment Strategiesfor Ischemic Stroke

and 2% of the control group. Mortality at 90 days was no higher in the treatment group, however. The primary outcome measure showed that 40% of patients treated with intra-arterial thrombolysis had minimal or no disability at 3 months, compared with 25% in the control group. Perhaps the most important outcome was that the mean time to treatment was 5.3 hours, suggesting that intra-arterial thrombolysis can extend the acute stroke treatment window beyond what appeared to be an immutable time limit of 3 hours. In the United States, pro-urokinase is not yet available in the market and intra-arterial thrombolysis is performed with rtPA. However, intra-arterial rtPA has never been examined in a randomized trial, and this treatment is not approved by the Food and Drug Administration. A small trial of combined IV and intra-arterial thrombolysis within 3 hours failed to show improvements at 7 days or 3 months, but the approach may be tested further because there did not appear to be increased symptomatic ICH in patients treated in this way. Newer endovascular techniques that include mechanical manipulation of the thrombus and angioplasty of the artery containing the thrombus also await further development and outcomes of clinical trials.

403

NEUROPROTECTION More than 49 neuroprotective drugs have been tested in acute stroke patients. The aim of neuroprotective drugs is to salvage ischemic tissue, reduce infarct size, prolong the time window for revascularization, and minimize reperfusion injury and inflammation. Despite encouraging results in animal models of ischemic stroke, none of the drugs tested in clinical trials proved to be effective. Besides the heterogeneity of stroke patients compared with animal models of stroke, treatment initiation delay after stroke onset seems to be an important factor to account for these negative results. The initial enthusiasm for neuroprotective agents has been replaced by some pessimism. However, new clinical trials are under way combining neuroprotective agents with thrombolysis. The use of modern neuroimaging in the acute stroke evaluation (i.e., perfusion and diffusion-weighted imaging) may be helpful in characterizing patients who still have salvageable brain tissue. Testing neuroprotective agents in these patient groups may result in a positive finding. At present, no neuroprotective agent can be recommended for acute stroke treatment outside clinical trials.

RECOMMENDATIONS FOR MANAGING STROKE TABLE42-3. Treatment Protocol for Systemic Thrornbolysis A. Thrombolysisa

1. Obtain informed consent from patient or family (if required by institution or local laws). 2. Calculate the dosage of rtPA as 0.9 mg/kg body weight. Do not exceed a total dosage of 90 mg, even in very adipose patients. 3. Give 10% of total dosage of rtPA over 1 min as a bolus. 4. Start IV infusion of the remaining 90% of total dosage to infuse over 1 hr. 5. Maintain systolic blood pressure <185 mm Hg and diastolic blood pressure 230 mm Hg or diastolic blood pressure is 121-1 40 mm Hg for two or more readings 5-1 0 min apart, a. Give intravenous labetalol 10 mg over 1-2 min. The dosage may be repeated or doubled every 10 min up to a total dosage of 150 mg. b. Monitor blood pressure every 15 min during labetalol treatment and observe for development of hypotension. c. If no satisfactory response is seen, infuse sodium nitroprusside at a dosage of 0.5-1 .O pg& body weight/minute, preferably using continuous arterial monitoring. 4. If diastolic blood pressure is >140mm Hg for two or more readings 5-10 min apart, a. Infuse sodium nitroprusside at a dosage of 0.5-10.0 pg/kg body weight/min, preferably using continuous arterial monitoring. Data adapted from the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study. T h e National Institute of Neurological Disorders and Stroke (NINOS) &PA Stroke Study Group: Tissue plasminogen activator for acuteixhemic stroke. N Engl J Med 333:1581, 1995.

bBrott T et al: Hypertensionand its treatment in the NINDS a-PA stroke trial. 1504,1998.

Stroke 29:

From the outset of the encounter with an acute stroke patient, the conscientious clinician must collect sufficient data to make informed and timely management decisions. Settling the diagnosis of stroke subtype is no longer pro forma but can help predict likely outcome and direct therapy. From the history, TIAs, hypertension, glucose level, cardiac disease, and stroke subtype predict recurrence. Particular attention should be paid to indicators of cardioembolic sources, such as recent myocardial infarction, arrhythmias, or congestive heart failure. Headache suggests subarachnoid bleeding in the absence of focal signs, but the combination of headache and focal signs suggests ICM rather than ischemic stroke. Pain in the neck, side of face, teeth or jaw, or retro-orbital area may indicate vertebral or carotid artery dissection, even without a history of neck trauma. The physical examination can give an impression of the size and a fair estimate of the location of the infarct and thus guide the urgency of subsequent management steps. Hemiparesis and forced gaze deviation suggest a large hemispheral or critical brainstem lesion, particularly if accompanied by decreased level of consciousness, whereas hemiparesis involving face, arm, and leg in an alert patient suggests a small, deep lesion involving a confluence of motor fibers. When isolated, behavioral abnormalities such as aphasia or hemineglect without a gaze preference suggest smaller hemispheral lesions. General examination may reveal a carotid bruit, and physical examination and an electrocardiogram may reveal an arrhythmia or signs of cardiomyopathy or congestive heart failure. Magnetic resonance imaging (MRI) should identify all but the smallest lesions and is superior to CT for brainstem and small, deep lacunar infarcts. Either technology may miss an infarct within the first several hours of onset. Data collected should suggest stroke origin. From 15% to 30% of strokes are embolic from a cardiac source such as atrial fibrillation or valvular disease. Although 5% to 6% of patients may have a fluctuating course, the classic clinical presentation of cardioembolic stroke is of sudden deficit, maximal at onset. Syndromes more likely to be embolic include hemianopia without hemiparesis, pure Wernicke’s aphasia, and ideomotor apraxia. CT and MRI that show a single cortical

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branch territory infarct also is consistent with an embolic source because atheroma rarely extends out onto the surface vessels, although the source of the inferred embolus may not be readily apparent even after full evaluation. Main stem branch occlusions are also often embolic, but local atherostenosis is a possibility in such a setting as well. One difficult pitfall on initial CT is the deep-lying lucency involving the internal capsule and basal ganglia of some 2 to 3 cm in size, apparently sparing cortex, which can be labeled as a large lacune. Often such instances are also of embolic origin, involving several lenticulostriate branches of the MCA from temporary occlusion of the middle cerebral stem, followed by rapid collateralization from anterior or posterior cerebral branches or recanalization of the occlusion with distal migration of the embolus. A right-to-left shunt, usually a PFO, can be inferred when transcranial Doppler shows microbubbles in the intracranial vessels after injection of 10 mL of agitated saline in the antecubital vein, and contrast transesophageal or standard transthoracic echocardiography usually can find the defect in the cardiac atrial wall. Holter monitoring may infer a cardiac emboligenic source by documenting atrial fibrillation. In 15% of cases, severe large vessel atherosclerosis is present and seems to be responsible for the stroke. It is best appreciated when there is severe extracranial internal carotid stenosis or occlusion, and the distal field lesion is imaged on CT scan or MRI as an infarct high over the convexity, spreading caudally from the border zone between arterial territories. The most common clinical profile of this type of infarct is fractional arm weakness (shoulder different from hand). Male sex, hypertension, and diabetes mellitus appear significantly more often in this group than in patients with cardioembolic stroke. Although the standard angiogram most reliably demonstrates large vessel stenosis, when it is severe enough to be of hemodynamic significance, duplex Doppler usually readily delineates the severity of the internal carotid stenosis and shows high-velocity, turbulent flow. Intracranial ICA stenosis may produce detectable high resistance flow on Doppler examinations of the extracranial carotid. Transcranial Doppler often shows dampened pulsatility in the ipsilateral middle cerebral artery. Duplex Doppler, in combination with magnetic resonance angiography, is rapidly becoming a reliable alternative to the more invasive traditional contrast angiogram. Cerebral blood flow measurements with xenon CT, single photon emission computed tomography (SPECT), and regional cerebral blood flow techniques are also being used to evaluate regional hypoperfusion. In perhaps 15% of all strokes, large vessel atherosclerosis with less than hemodynamic stenosis (less than 80% occluded or with an ulcerated plaque) occurs in the absence of a cardioembolic source, and the cause as an artery-to-artery embolus is inferred. Embolic fragments may arise from atherosclerotic lesions in the ICA, the basilar artery, intracranial large vessels, the proximal stump of an occluded carotid, or the distal tail of a thrombus in an occluded ICA. Distinguishing intra-arterial embolism from possible cardioembolic cause may be difficult; however, the former usually produces a smaller cortical infarct, and the latter is more often associated with an abnormal initial CT scan. Small, deep lesions in the subcortical white matter, the thalamus, the basal ganglia, or the pons accompanied by an appropriate clinical syndrome suggest lacunar disease, accounting for 15% to 20% of all stroke. Arteriolar wall lipohyalinosis, microatheroma, or even microemboli may produce the disorder. Early studies described only a handful of classic syndromes, but case reports have expanded the number to more than 70. Positive scans in the capsule, adjacent corona radiata,

thalamus, or pons have been reported for clumsy hand dysarthria, ataxic hemiparesis, and hemiballism; pure sensory syndromes have been associated with small thalamic lesions. CT scanning is positive in only half of lacunar strokes, with MRI increasing the yield somewhat. Larger lacunes are more often symptomatic. Hypertension is the risk factor most associated with lacunar infarction. Despite efforts to arrive at a diagnosis, the cause of infarction in up to 40% of cases remains undetermined. This may result from an inability to perform appropriate laboratory studies because of the patient’s advanced age or comorbidity or because of unwillingness on the part of the physician or patient. It may also result from improper timing of tests, such as an angiogram performed after an embolus has cleared or a CT scan or MRI performed before the infarction appears. In a majority of these cases, however, appropriate testing done at the proper time produces normal or ambiguous findings. Some of these cases may be explained by hypercoagulable states from protein C, free protein S, fibrinogen, lupus anticoagulant, or anticardiolipin antibody abnormalities. Paradoxical emboli through a PFO may explain other cases. Migraine, meningitis, dissection, arteritis, or inherited metabolic abnormality may explain rare cases. Rather than force a classification into one of the four established categories, we recommend maintaining the classification of infarct of undetermined cause (or cryptogenic infarction) until a definite cause can be established.

SUMMARY OF CURRENT PRACTICE All patients with suspected stroke should be evaluated in an emergency room within 3 hours. If the patient meets inclusion and has no exclusion criteria for IV tPA, systemic thrombolysis should be administered. If the patient has an ischemic stroke diagnosed between 3 and 6 hours and meets inclusion criteria for thrombolysis, intraarterial rtPA should be considered if an experienced interventionist is available to perform the intracranial arterial catheterization. Currently, beyond 6 hours after an ischemic stroke thrombolysis cannot be recommended, although in some institutions cases of vertebrobasilar acute occlusion are considered for intraarterial thrombolysis as late as 8 to 12 hours after stroke onset. Investigation of stroke cause should focus first on cardioembolic sources and large vessel atherothrombosis. Transthoracic echocardiography, carotid duplex Doppler sonography, and transcranial Doppler sonography should be performed. Magnetic resonance angiography and transesophageal echocardiography may deliver a diagnosis when the aforementioned studies are inconclusive. Patients with recent myocardial infarction, atrial fibrillation, valvular disease, or intracardiac thrombus should be orally anticoagulated for at least 1 year. The prothrombin time should be kept at 1.5 to 3.0 times control (INR = 2.0 to 3.0). If there is atrial fibrillation, warfarin should be continued indefinitely if reliable monitoring is available. If the ischemic stroke is large and disabling, there is greater risk of hemorrhagic transformation; brain imaging should be repeated 48 to 72 hours after stroke onset and anticoagulation started only if hemorrhagic conversion has not occurred. If the clinical and imaging diagnosis is intracranial hemorrhage, anticoagulants and antiplatelet agents should not be given. Subcutaneous heparin should be given to immobilized stroke patients to prevent deep vein thrombosis and pulmonary embolism.

Chapter 42

If the stroke is small, the heart is normal, and a duplex Doppler sonogram shows significant carotid stenosis (greater than 70%), prophylactic endarterectomy should be undertaken as soon as possible. For patients with a lesser degrees of stenosis, Doppler monitoring should be undertaken at intervals of 6 or 12 months to document those whose stenosis increasesto more than 70%, which qualifies them for surgery. Patients in whom asymptomaticcarotid stenosis greater than 60% is identified can be considered for endarterectomy if the operation can be performed at a center where the perioperative morbidity and mortality is less than 3%. If no cardioembolic source or operable carotid stenosis is identified and the patient is not considered at risk for hemorrhage, antiplatelet treatment with one antiplatelet agent (aspirin, aspirindipyridamole combination, clopidogrel) should be prescribed as chronic outpatient therapy. Control of cardiovascular risk factors is essential for secondary stroke prevention and should be attempted in every patient. Statins or ACE inhibitors may be prescribed in appropriate patient groups.

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SUGGESTED READINGS

Coull BM, Williams LS, Goldstein LB et al: Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Stroke 33:1934, 2002 Gladstone DJ, Black SE, Hakim AM: Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33:2123, 2002 Gorelick P B Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke 33:862, 2002 Hankey GJ, Sudlow CL, Dunbabin D W Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials. Stroke 31:1779,2000 Hess DC, Demchuk AM, Brass LM, Yatsu F M HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention. Neurology 54790, 2000 Howard PA Guidelines for stroke prevention in patients with atrial fibrillation. Drugs 58:997, 1999 Lenz TL, Hilleman D E Aggrenox: a fixed-dose combination of aspirin and dipyridamole. Ann Pharmacother 341283, 2000 Leys D, Deplanque D, Mounier-Vehier C et al: Stroke prevention: management of modifiable vascular risk factors. J Neurol 249507,

Adams HP: Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke 332356, 2002 Albers GW: Advances in intravenous thrombolytic therapy for treatment of acute stroke. Neurology 57(5 Suppl 2):S77, 2001 Bednar MM, Gross CE: Antiplatelet therapy in acute cerebral ischemia. Stroke 30:887, 1999 Bungard TJ, Shuaib A, Tsuyuki R T Stroke prophylaxis in nonvalvular atrial fibrillation. Curr Opin Neurol 14:59, 2001

2002 Mohr JP, Thompson JL, Lazar RM et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 345:1444, 2001 National Institute of Neurological Disorders rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581, 1995 Sacco RL: Extracranial carotid stenosis. N Engl J Med 345:1113, 2001

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IMMUNE-MEDIATED DISEASE

43

Pathophysiology and Clinical Features of Multiple Sclerosis Loren A. Rolak

Multiple sclerosis (MS) is the most common disabling neurologic disease of young people, afflicting at least a quarter of a million Americans. The symptoms of MS result from recurrent attacks of inflammation in the central nervous system (CNS), and there is very strong but circumstantial evidence that it is an autoimmune disorder. The target of the immune attack is myelin, the lipoprotein sheath that surrounds the axons and provides extremely efficient insulation, which enhances nerve conduction. The white matter of the brain takes its name from the glistening white appearance of this lipid wrapping and contains most of the tracts, pathways, and axonal projections of the CNS; the gray matter contains primarily the cell bodies of the neurons themselves. Inflammation and damage to the myelin (which is made by cells called oligodendrocytes) interrupt nerve conduction and thus nerve function, thereby producing the symptoms of MS.

PATHOPHYSIOLOCY No one knows how MS is acquired, and the pathophysiology of the disease remains poorly understood. Patients are not born with MS, so some environmental factor must act on genetically susceptible individuals to produce the disease, but the nature of that factor (such as whether it is a virus) remains elusive. The most consistent and plausible explanation postulates that macrophages present myelin antigens to appropriate T cells, thereby activating the T cells to proliferate. They then cross the blood-brain barrier through interactions with intercellular adhesion molecules, and once inside the CNS they release cytokines that both damage myelin and perpetuate the immune response. The details of this process, including the nature of the triggering antigen, are still subject to speculation. There is nevertheless strong evidence that MS is a T cell-mediated autoimmune attack on CNS myelin. There is also damage to the underlying axon, which can lead to irreversible disability. Among the unanswered questions is whether multiple sclerosis is a single disease. It may be that different antigens are involved in different patients, different T cells are activated, or the specific mechanisms of cell damage are different. The clinical picture of focal areas of demyelination producing relapsing symptoms could arise from a variety of diverse immunologic mechanisms.

EPIDEMIOLOGY MS favors women over men by a ratio of nearly 2 to 1 and strikes most often between ages 20 and 40, with a peak at age 30. 408

Caucasians are especially vulnerable, particularly those of northern European extraction and those living in northern latitudes, where the incidence of the disease is highest, but the “melting pot” of America is so intermixed and geographically mobile that these epidemiologic features provide little useful information to the clinician. Though clearly not inherited in any direct fashion, it tends to cluster slightly within families; there is a 1to 3 percent risk of developing MS if a parent or sibling has the disease and a 25 percent concordance among monozygotic twins.

CLINICAL FEATURES Variability and diversity characterize the symptoms and presentation of MS. Almost every neurologic complaint has been traced to MS at one time or another, and a comprehensive account of its clinical features can become nothing more than a mere recitation of a positive neurologic review of systems. The most common symptoms are as follows: Weakness or numbness in one or more limbs w Optic neuritis: painful loss of vision in one eye w Tremor and ataxic gait, caused by cerebellar dysfunction Double vision, dysarthria, or vertigo, caused by brainstem dysfunction w Bowel or bladder dysfunction w Fatigue Some symptoms, reflecting primarily gray matter damage, occur so rarely that their appearance casts doubt on the diagnosis of MS; they include the following: Dementia, lethargy, or other altered mental status w Aphasia w Seizures, syncope, or loss of consciousness Pain w Dystonia, chorea, or other involuntary movements Muscle atrophy or fasciculations Most symptoms of MS are focal, representing the inflammation of a specific tract or pathway within the CNS, such as monocular visual loss from optic neuritis, weakness or numbness in one or more limbs caused by damage to the spinal cord, or ataxia and tremors caused by lesions in the cerebellar pathways. Diffuse, nonfocal symptoms, such as dementia, confusion, syncope, and vague dizziness, are less common. An exception to this rule is fatigue, an overwhelming sense of exhaustion and lassitude that often accompanies focal symptoms of MS.

Chapter 43

Most symptoms develop abruptly, within minutes or hours. These exacerbations or “attacks” of MS typically last 6 to 8 weeks from onset to recovery and can involve multiple areas of the CNS simultaneously, producing a polysymptomatic presentation. Resolution often is complete. Attacks strike approximately every 14 to 16 months (or about 0.7 attacks per year). This pattern of symptoms is referred to as relapsing-remitting MS. In many patients, over a span of 5 to 10 years, the attacks begin more indolently, persist more chronically, and remit less completely, transforming into a pattern of steady deterioration rather than episodic flares. This is then referred to as secondary progressive MS. The pathophysiologic mechanism causing this transformation to a more chronic progressive disease is unknown, but it has implications for therapy because most of the drugs that suppress MS attacks seem useless against secondary progressive disease. PROGNOSIS MS is seldom fatal, and the life expectancy is shortened only by months; concerns about prognosis center primarily on the quality of life and prospects for disability. Most patients and clinicians harbor an unfounded view of MS as a relentlessly progressive, inevitably disabling disease. In fact, 15 years after the onset of MS, 20 percent of patients are bedridden or institutionalized, another 20 percent need a wheelchair, crutches, or a cane to ambulate, but 60 percent are ambulatory without assistance and may have little deficit at all. Probably one third of all patients with MS go through life without persistent disability and with only intermittent, transient episodes of symptoms. The following factors predict a good prognosis in MS

w Young age at outset Sensory symptoms at onset (numbness, paresthesias, visual loss) Rapid resolution of initial symptoms Benign course during the first 5 years A patient who has accumulated little disability after 5 to 7 years is unlikely ever to do so.

DIAGNOSIS MS is one of the most difficult of all diseases to diagnose because of the bewildering number of symptoms it causes and the multiple ways in which they can present. The typical patient with MS is a young woman with abrupt, focal neurologic symptoms occurring discretely or in combinations, lasting weeks to months and then resolving, with new or recurrent symptoms developing months to years later. A definite diagnosis may be difficult, or indeed impossible, when the situation is not typical, that is, when the patient is older, when symptoms are strictly progressive, or when there has been only one episode of neurologic dysfunction. Tests can buttress the clinical diagnosis of MS, but no laboratory hdings are specific for MS, and all have pitfalls that limit their usefulness. Magnetic resonance imaging (MRI) is a highly sensitive but disappointingly nonspecific technique for visualizing the inflammatory lesions of MS, which appear as multiple, irregular, confluent areas of increased signal intensity, ranging in size from 0.5 to 3.0 cm, scattered deep within the brain, especially around the ventricles. Nearly 90 percent of patients with definite MS have abnormal MRI scans, and various analyses show that MRI of the

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Pathophysiology and Clinical Features of Multiple Sclerosis

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head should be the first test performed to evaluate suspected MS. A major disadvantage of MRI remains its lack of specificity because many conditions mimic MS on MRI. Although it is a sensitive, noninvasive technique, it is also nonspecific and often detects “abnormalities” in patients without clear pathology, thus inappropriately labeling many patients with the diagnosis of MS. The use of MRI takes great expertise, and overdiagnosis of MS based on MRI changes is too common. Abnormalities in the cerebrospinal fluid (CSF) are sufficiently common and characteristic to make CSF analysis accurate for diagnosing MS. Spinal fluid protein and white blood cell counts occasionally are mildly elevated, but the most useful findings are immunologic changes, including an increase in the immunoglobulin G level and synthesis rate. Immunoglobulins in the spinal fluid, presumably reflecting an underlying autoimmune activation, appear as distinct oligoclonal bands when electrophoresed. The pattern formed by these bands varies from patient to patient, but they are present in some form in nearly 90 percent of all patients with MS, and other diseases that produce similar banding are seldom mistaken for MS. The major obstacle to the use of CSF to diagnose MS is the reluctance of patients to undergo lumbar puncture. Evoked potentials play a limited but occasionally useful role in diagnosing MS. Evoked potentials measure conduction along specific CNS pathways by recording the electroencephalographic response to visual, auditory, or sensory (electrical) stimulation; a slowing in conduction is presumed to reflect inflammation and demyelination in that pathway, thus detecting an asymptomatic or subclinical MS lesion. The sensitivity and specificity of these techniques do not approach those of the MRI or CSF, but they can often reveal unsuspected lesions or confirm an organic basis for vague complaints and thereby heighten the probability of MS. The following is a nonexhaustive list of diseases that often mimic M S Hysteria and somatization disorders Postviral demyelination (acute disseminated encephalomyelitis) Vasculitis affecting the CNS (either primarily or secondary to other conditions, such as lupus erythematosus, Sjogren’s syndrome, or polyarteritis nodosa) Spinocerebellar degenerations Spirochetal infections: Lyme disease or syphilis Sarcoidosis Retroviral infections: human acquired immune deficiency syndrome T cell lymphotrophic virus-1 Stroke in the young Inherited white matter diseases (leukodystrophies) Tumors: metastases, lymphoma Syringomyelia A diagnosis of definite MS can be made by fulfillingcertain clinical criteria: The patient must have two separate CNS lesions. w The symptoms must have occurred in two or more separate episodes. w The symptoms must involve the white matter, not the gray matter. The neurologic examination must show objective abnormalities. w The patient must be between ages 10 and 50, but preferably between 20 and 40.

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The Datient must have no other disease accounting for the symptoms. If all clinical criteria are not met, a diagnosis of definite MS can still be made using laboratory support. There are many pitfalls and nuances in diagnosing MS. Because of the implications of this diagnosis for future disability, employability, insurance, and early treatment options, the diagnosis criteria undergo frequent revisions. Ultimately, physicians often use their own judgment when diagnosing MS rather than relying on predetermined criteria.

French-Constant C Pathogenesis of multiple sclerosis. Lancet 343:271, 1994 McDonald WI, Compston A, Edan G et al: Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of MS. Ann Neurol 50121-127,2001 Reingold S C Advances in the understanding and treatment of multiple sclerosis. J Neuroimmunol 44:221, 1993 Rolak L Multiple sclerosis. pp. 107-132. In Rolak L, Harati Y (eds): Neuroimmunology for the Clinician. Butterworth-Heinemann, Boston, 1997

SUGGESTED READINGS Confavreux C, Vukusic S, Moreau T,Adeleine P Relapses and progression of disability in multiple sclerosis. N Engl J Med 343:1430-1438, 2000

44

Immunotherapy of Multiple Sclerosis Loren A. Rolak

ACUTE THERAPY Acute relapses of multiple sclerosis (MS) are conventionally treated with steroids. A landmark in the history of MS was the first modern treatment trial using a prospective, randomized, doubleblind, placebo-controlled design to test the efficacy of a therapeutic intervention for MS: adrenocorticotropic hormone (ACTH). This trial, published in 1970, showed that steroids in the form of ACTH mitigate the acute relapse of MS, and steroids in one form or another have been standard therapy since. There has never been a good follow-up study to determine the true effectiveness of steroids; the optimum dosage, route of administration, or duration of treatment; or the most appropriate indications for their use. Steroid treatments have become a traditional, accepted standard of practice when new neurologic symptoms appear, and there is a universal sense that they shorten symptoms, enhance well-being, and provide many benefits in an acute relapse, despite a paucity of scientific proof of their effectiveness. A standard regimen for an acute attack of MS uses intravenous methylprednisolone, 1 glday for 3 days. Lower dosages have also been used over 5 or even 7 days, sometimes (but not always) followed by a tapering dosage of oral steroids. Steroids alter the immune system, enhance conduction of action potentials along axons, seal the blood-brain barrier, reduce inflammation and swelling, and have other properties potentially beneficial against MS. However, steroids probably do not alter the fundamental pathology of MS to any significant degree, and they seem ineffective in altering the natural history of MS or preventing ultimate disability.

CHRONIC THERAPY Five drugs are currently approved by the U.S. Food and Drug Administration (FDA) as disease-modifymg agents that alter the natural history of MS. These drugs are p-interferon-la (Avonex and Rebif), P-interferon-lb (Betaseron), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone). The FDA approval for

these medications is based on their use with certain clinical patterns of MS, and much of the research on their effectivenesshas been done on these specific subpopulations of patients with MS. In practice, then, the treatment of MS depends on identifymg the clinical pattern of MS and then choosing appropriate therapy. Avonex is a preparation of recombinant human p-interferon-la administered in a dosage of 6 million U intramuscularly once a week. Betaseron is a recombinant preparation of P-interferon-lb, which differs from Avonex in some minor aspects of an amino acid substitution and less glycosylation, administered in a higher dosage of 12 million U subcutaneously every other day. Rebif is a p-interferon-la preparation identical to Avonex but administered in a dosage of 12 million U subcutaneously three times a week. Copaxone is a polypeptide composed of four amino acids that shares many antigenic similarities to myelin-basic protein and appears to alter the immune response to myelin. It is a subcutaneous preparation given daily. Novantrone is a longestablished cancer chemotherapeutic drug, effective primarily for lymphomas and leukemias, with broad immune-altering properties, which can delay the progression of MS when administered in a dosage of 12 mg/m’ intravenously once every 3 months. Such periodic treatments can continue only until a cumulative dosage of 100 to 140 mg has been given, at which point the potential for irreversible cardiac toxicity precludes further administration.

Relapsing-Remitting MS The most common clinical pattern of MS, especially early in the course of the disease, at the time when the diagnosis is first made, is of sudden neurologic symptoms developing within hours or days (relapses) followed by a gradual recovery back to normal over the next few weeks or months (remissions). Although MRI data suggest that MS often is a constantly simmering and active disease, it usually produces only a few distinct clinical relapses, often only one or two per year. Avonex, Rebif, Betaseron, and Copaxone are all approved for patients with relapsing-remitting MS, and all are about equally effective, reducing the number of relapses by

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The Datient must have no other disease accounting for the symptoms. If all clinical criteria are not met, a diagnosis of definite MS can still be made using laboratory support. There are many pitfalls and nuances in diagnosing MS. Because of the implications of this diagnosis for future disability, employability, insurance, and early treatment options, the diagnosis criteria undergo frequent revisions. Ultimately, physicians often use their own judgment when diagnosing MS rather than relying on predetermined criteria.

French-Constant C Pathogenesis of multiple sclerosis. Lancet 343:271, 1994 McDonald WI, Compston A, Edan G et al: Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of MS. Ann Neurol 50121-127,2001 Reingold S C Advances in the understanding and treatment of multiple sclerosis. J Neuroimmunol 44:221, 1993 Rolak L Multiple sclerosis. pp. 107-132. In Rolak L, Harati Y (eds): Neuroimmunology for the Clinician. Butterworth-Heinemann, Boston, 1997

SUGGESTED READINGS Confavreux C, Vukusic S, Moreau T,Adeleine P Relapses and progression of disability in multiple sclerosis. N Engl J Med 343:1430-1438, 2000

44

Immunotherapy of Multiple Sclerosis Loren A. Rolak

ACUTE THERAPY Acute relapses of multiple sclerosis (MS) are conventionally treated with steroids. A landmark in the history of MS was the first modern treatment trial using a prospective, randomized, doubleblind, placebo-controlled design to test the efficacy of a therapeutic intervention for MS: adrenocorticotropic hormone (ACTH). This trial, published in 1970, showed that steroids in the form of ACTH mitigate the acute relapse of MS, and steroids in one form or another have been standard therapy since. There has never been a good follow-up study to determine the true effectiveness of steroids; the optimum dosage, route of administration, or duration of treatment; or the most appropriate indications for their use. Steroid treatments have become a traditional, accepted standard of practice when new neurologic symptoms appear, and there is a universal sense that they shorten symptoms, enhance well-being, and provide many benefits in an acute relapse, despite a paucity of scientific proof of their effectiveness. A standard regimen for an acute attack of MS uses intravenous methylprednisolone, 1 glday for 3 days. Lower dosages have also been used over 5 or even 7 days, sometimes (but not always) followed by a tapering dosage of oral steroids. Steroids alter the immune system, enhance conduction of action potentials along axons, seal the blood-brain barrier, reduce inflammation and swelling, and have other properties potentially beneficial against MS. However, steroids probably do not alter the fundamental pathology of MS to any significant degree, and they seem ineffective in altering the natural history of MS or preventing ultimate disability.

CHRONIC THERAPY Five drugs are currently approved by the U.S. Food and Drug Administration (FDA) as disease-modifymg agents that alter the natural history of MS. These drugs are p-interferon-la (Avonex and Rebif), P-interferon-lb (Betaseron), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone). The FDA approval for

these medications is based on their use with certain clinical patterns of MS, and much of the research on their effectivenesshas been done on these specific subpopulations of patients with MS. In practice, then, the treatment of MS depends on identifymg the clinical pattern of MS and then choosing appropriate therapy. Avonex is a preparation of recombinant human p-interferon-la administered in a dosage of 6 million U intramuscularly once a week. Betaseron is a recombinant preparation of P-interferon-lb, which differs from Avonex in some minor aspects of an amino acid substitution and less glycosylation, administered in a higher dosage of 12 million U subcutaneously every other day. Rebif is a p-interferon-la preparation identical to Avonex but administered in a dosage of 12 million U subcutaneously three times a week. Copaxone is a polypeptide composed of four amino acids that shares many antigenic similarities to myelin-basic protein and appears to alter the immune response to myelin. It is a subcutaneous preparation given daily. Novantrone is a longestablished cancer chemotherapeutic drug, effective primarily for lymphomas and leukemias, with broad immune-altering properties, which can delay the progression of MS when administered in a dosage of 12 mg/m’ intravenously once every 3 months. Such periodic treatments can continue only until a cumulative dosage of 100 to 140 mg has been given, at which point the potential for irreversible cardiac toxicity precludes further administration.

Relapsing-Remitting MS The most common clinical pattern of MS, especially early in the course of the disease, at the time when the diagnosis is first made, is of sudden neurologic symptoms developing within hours or days (relapses) followed by a gradual recovery back to normal over the next few weeks or months (remissions). Although MRI data suggest that MS often is a constantly simmering and active disease, it usually produces only a few distinct clinical relapses, often only one or two per year. Avonex, Rebif, Betaseron, and Copaxone are all approved for patients with relapsing-remitting MS, and all are about equally effective, reducing the number of relapses by

Chapter 44 rn immunotherapyof Multiple Sclerosis

approximately 30%. When clinical attacks do occur, they are also less disabling and less prolonged. Although there are minor differences in the clinical features of these drugs, there is little head-to-head data available, none of it compelling, and these four drugs can be considered approximately equal in appropriateness for treatment. Therapeutic decisions often are made based on convenience of dosage (daily, every other day, or weekly), route of administration (subcutaneous or intramuscular), side effects (which are more common with Avonex, Rebif, and Betaseron and include flulike reactions of malaise and fever and myalgias with occasional local skin reactions), or concern for neutralizing antibodies (which develop against the interferons after 6 to 12 months in 2% to 30% of patients). AU these medications should be considered prophylactic or preventive strategies designed to minimize future attacks rather than restorative therapies to recover lost function. Patients therefore should anticipate long-term administration. Extrapolating from their effects on reducing relapses and stabilizing MFU changes, it is presumed that these drugs will delay the accumulation of neurologic deficits and so will postpone permanent disability. However, there is little scientific data about how much, if any, long-term benefit will accrue from their use. MonosymptomaticDisease

Many patients who suffer an isolated monosymptomatic episode of demyelination, such as optic neuritis or transverse myelitis, ultimately develop a second inflammatory demyelinating event in the central nervous system and so will be diagnosed as having MS. This is particularly true if MRI scanning of the brain at the time of the initial demyelinating event reveals white matter changes characteristic of MS. Therefore, patients with a single episode of demyelination and such an MRI scan are widely presumed to have MS already (even though most rigid diagnostic criteria would classify these patients as not yet proven to have MS). In these monosymptomatic patients, early treatment with Avonex delays the onset of a second lesion by approximately a year. Although such a small delay is not likely to have a major impact on a lifelong disease, such patients should be considered for therapy. It is likely that Betaseron and Copaxone would have similar delaying effects. Secondary Progressive M S

In the majority of patients with MS, their disease begins with distinct relapses and remissions, but over time the onset of symptoms becomes less abrupt and more gradual, the remissions become less complete, and the clinical picture thus shifts into one of slowly and gradually progressing symptoms without much

41 1

recovery. This pattern of secondary progressive MS develops in more than half of all patients, although it may take 10 years or more to appear. Such patients have less intense MRI activity in addition to a more indolent clinical course. For these patients there is little evidence that Avonex, Rebif, Betaseron, or Copaxone provides much benefit. Some studies suggest that high dosages of interferons can slow progression in some patients, so such treatment is an option, but these results have been difficult to replicate. The only drug FDA approved specifically for secondary progressive MS is mitoxantrone (Novantrone). In a series of careful trials, done primarily in Europe, the drug slowed the secondary progression of MS by up to 50% in selected patients. Its primary acute toxicity is alopecia, fatigue, nausea, and bone marrow suppression, including risk of infection. Its long-term toxicity is dominated by damage to cardiac muscle, with an incidence of congestive heart failure of approximately 1 in 500 when cumulative dosages exceeding 100 mg/m2 are received. Primary Progressive MS

Some patients never experience a relapse or a remission of MS symptoms; rather, they have slowly progressive disease from the onset. This is the most disabling form of MS, but fortunately it afflicts only about 10% of patients. It is also the form of the disease most refractory to treatment. Such patients generally are older (in their 40s or later) and have primarily spinal cord symptoms such as spastic paraparesis, bowel and bladder difficulties, and gait abnormalities. Although clinicians cannot be faulted for trying to aid their patients by initiating one of these medications, there is no good evidence for their effectiveness in this setting. For these patients (as indeed for all forms of MS), significant benefits often can be obtained with symptomatic management, as discussed in a previous chapter.

SUGGESTED READINGS Burks JS, Johnson KF’, eds: Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. Demos, New York, 2000 Compston A, e d McAlpine’s Multiple Sclerosis. 3rd Ed. Churchill Livingstone, London, 1998 Dhib-JalibutS: Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 58( Suppl 4):53-59, 2002 Hawkins CP, Wolinsky JS, eds: Principles of Treatments in Multiple Sclerosis. Butterworth, Heinemann, Boston, 2000 Polman CH, Uitdehaag D M Drug treatment of multiple sclerosis. BMJ 321:490-494,2000 Rolak LA: Multiple sclerosis treatment 2001. Neurol Clin 19107-118, 2001

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Multiple Sclerosis:Management of Disease Complications Lael A. Stone

The treatment of multiple sclerosis (MS) often is divided into two broad categories: therapy directed against the disease process itself and therapy directed toward mitigating the damage that has already been done. Someday there may be a third category, that of remyelinating therapy, but there are no known effective therapies to put in such a category. Therefore, this chapter briefly reviews pharmacologic and other forms of therapy that reduce or eliminate symptoms of MS but have no known significant effect on the course of disease or pathophysiology. Not all symptoms in patients with MS are caused by their MS. One of the difficulties faced by any patient with a chronic illness is physicians may label all complaints as caused by their chronic illness, without consideration of other processes. Although the manifestations of MS are rightly called protean, MS patients often go back and forth between their neurologist and their general practitioner to seek help for a problem. A few common conditions that lead to this type of difficulty in MS patients are cervical and lumbar spondylosis with and without foraminal or cord compromise, headaches of all sorts, uterine prolapse, and carpal tunnel syndrome. Some complaints such as fatigue often are multifactorial, and consideration of medical, neurologic, and psychiatric and psychosocial factors is needed to reduce the symptoms. The most common symptoms of MS are listed in Table 45-1. Less common symptoms that are seen as a direct result of MS lesions are listed in Table 45-2. VISUAL SYMPTOMS Decreased visual acuity, double vision, visual field cuts, unstable or moving vision, and unusual responses to visual stimuli may all be found in patients with MS. Although visual symptoms may be some of the most disabling for a patient with MS, there are very few areas in which a neurologist can alleviate this type of symptom. An important contribution for the neurologist is in recognizing the symptoms and providing follow-up education so that the patients understand their difficulty and do not feel that they are “going crazy” for having these difficulties. A second important contribution is to make appropriate referrals to low-vision resources, neuro-ophthalmologists, or even driver’s TABU45-1. Symptoms of

MS

Visual symptoms Sensory symptoms (including pain) Dizziness, vertigo, or fainting Fatigue Bladder dysfunction Bowel dysfunction Sexual dysfunction Increased tone (spasticity) Weakness Tremor Cognitive deficits Depression or euphoria Speech difficulties Swallowing difficulties

TABLE 45-2. Less Common Symptoms That May Be Caused

by MS Seizures Psychosis Hearing loss Respiratory compromise Movement disorders other than tremor (e.n., &tonic spasms)

rehabilitation services, which may offer more concrete assistance. An exception is the management of acute optic neuritis, which is universally recognized as signaling a relapse of MS. Although the majority of MS neurologists and neuro-ophthalmologists would treat this type of relapse as described in Chapter 46,most general ophthalmologists are reluctant to treat and thus are fatalistic about the outcome. Although the majority of patients with optic neuritis recover significantly, if a decrease in visual acuity results from the optic neuritis, it may be difficult for the patient to compensate. In addition, the attack is evidence of ongoing disease activity, which should increase the neurologist’s level of therapeutic aggressiveness. Finally, treatment with high-dose methylprednisolone can be very effective in managing the severe eye pain, headache, and pain on eye movement that may accompany the optic neuritis, especially if it is bilateral. Double vision may be eliminated by the prescription of prism lenses once it is clear that this is a lasting phenomenon. It is quite common for this symptom to worsen with heat and exercise and even emotional stress. Gabapentin, carbamazepine, or the benzodiazepams, particularly clonazepam, may be useful in managing nystagmus, but this symptom often is resistant to pharmacotherapy. A subtype of nystagmus, periodic alternating nystagmus, may respond to baclofen. Many patients with MS complain of another visual phenomenon, that of dizziness or unsteadiness when driving or walking down a supermarket aisle. This last symptom is felt to be the result of lesions in the parietal lobe processing systems. SENSORY SYMPTOMS The sensory symptoms in MS may be classed broadly in two categories: lack of sensation and abnormal sensation. The absence of sensation in a limb puts the patient with MS at the same risk of injury as a diabetic who has lost sensation through neuropathy, and these patients and their caregivers must be taught to prevent injury with resultant infection, burns, and pressure sores. The abnormal sensations may be further subdivided into constant or intermittent (e.g., paroxysmal) and may range in discomfort level from merely annoying to extremely painful. The first step in reducing the abnormal sensation is to ascertain with certainty that the cause is purely MS. Although pharmacotherapy for conditions such as radiculopathy or diabetic neuropathy overlaps that for central pain, physical or medical therapy may also be needed in the later conditions and may not be as

Chapter 45

useful in treating symptoms caused purely by MS. Unfortunately, patients with MS still hear that MS does not cause pain, but some patients with MS do experience central pain caused by MS lesions. Cervical cord lesions are particularly troublesome with regard to pain syndromes. A variety of treatments for abnormal sensations are listed in Table 45-3. The mainstays for the pharmacotherapy of a variety of painful conditions is currently gabapentin (Neurontin). Some practitioners prescribe this medication in a very gradually increasing dosage, using the 100-mg capsules at bedtime and increasing the dosage every three nights. Other practitioners start dosing throughout the day, 100 to 300 mg three times a day from the beginning. A few patients with MS will benefit from more than 2700 mg/day. Some benefit from doses spread over four rather than three times a day. Venlafaxine (Effexor) (particularly the long acting form) can be extremely effective for cord lesion pain although may require some persistence on the part of the patient due to the side effects of headache, nausea, and drowsiness during the adjustment period. Older medications such as carbamazepine, phenytoin, nortriptyline, and baclofen still have a role in pain management as well. A common paroxysmal pain syndrome is trigeminal neuralgia, which may certainly be a symptom of MS or may occur as a result of vascular compression in a patient with MS. Pharmacotherapy remains the mainstay, although ablation may be needed in some cases. Bandlike sensations around the body are a common complaint of patients with spinal cord lesions from any cause. In addition to the usual pharmacotherapy for this type of dysesthesia, relief of constipation often relieves the pain as well. Low back pain that is not related to spondylosis or radiculopathy in a patient with MS may be the result of biomechanical abnormalities of gait. This chronic back soreness may respond well to the use of assistive devices such as an ankle foot orthosis (AFO), a cane, or a walker in addition to physical therapy and nonsteroidal medications. Although acupuncture may have a growing role in pain management, its use in central pain, as is found in MS, is controversial. Psychosocial issues may have a significant effect on pain and should also be addressed through appropriate referrals.

DIZZINESS, VERTIGO, OR NEAR FAINTING Dizziness is as frustrating to the neurologist as to the patient. Sometimes the cause, such as medication or benign positional vertigo caused by otolith misalignment, is clear. Unfortunately, the symptom may be difficult to label and thus to treat. Sometimes a patient travels back and forth from neurologist to otorhinolaryngologist with no diminution of symptoms. The standard pharmacotherapy for dizziness, which involves a spinning sensation, in

W

TABLE45-3. Treatments for Abnormal Sensations

Eliminate cause, if not MS Neuropathic pain agents Anticonvulsants: gabapentin, carbamazepine, phenytoin, tiagabine Antidepressants: venlafaxine, bupropion hydrochloride, selective serotonin reuptake inhibitors Tricyclic antidepressants: amitriptyline, nortriptyline Nonsteroidals Long-acting narcotics or intrathecal narcotics as a last resort Biofeedback and other behavioral therapies Treatment of coexisting depression Radiosurgical or surgical ablation of medically unresponsive trigeminal neuralgia Physical therapy or massage Ice packs or, for some patients, heat packs

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MS includes meclizine, diazepam, clonazepam, and scopolamine patches (if not contraindicated). Lightheadedness with or without true fainting may respond to an increase in fluid intake (because many patients with MS and bladder problems seem to be chronically dehydrated), increase in salt intake (if not medically contraindicated), or fludrocortisone (Florinef). Some patients may respond to the agent used in cases of autonomic failure, midodrine hydrochloride.

FATIGUE Although fatigue certainly is a symptom of MS, other contributing factors also must be considered. Because the population that suffers from MS also has a high rate of thyroid disease and anemia, many practitioners begin any investigation into the complaint of fatigue with a complete blood count and thyroid-stimulating hormone screening blood work. B12 levels may be decreased as well, particularly in patients on acid lowering agents. Obtaining a good sleep history, including the amount and quality of the sleep, often is helpful in managing fatigue in patients with MS. Disordered sleep may result from MS-related issues such as depression, bladder problems, or spasticity. Sleep disorders such as sleep apnea or gastroesophageal reflux also are common in patients with MS. Some patients simply do not sleep enough because of lifestyle decisions such as staying up late to watch TV or read or sleeping with their dogs or cats. An increase in physical activity may both deepen nighttime sleep and increase daytime stamina. Sometimes a great deal of counseling and education by the neurologist or physical therapist is needed to find the right type of physical activity for the patient with MS. Some occupational therapists are also skilled in helping patients make the most of the energy that they have by modifying how and when they perform activities to maximize efficiency. Though extremely useful for the management of fatigue in MS, medications should be a last resort. Amantadine has been shown in placebo-controlled trials to be useful for managing fatigue. Some patients are sensitive to this medication and need only 100 mg in the morning. All patients should be counseled to take their second dose (if there is one) far from bedtime (i.e., around 1 or 2 PM) so as not to induce insomnia. The selective serotonin reuptake inhibitors (SSRIs), particularly citalopram, which has a quick time to action, may be quite useful in patients less than 55 years old and may even be useful when the clinical signs of depression are minimal. Older patients may respond better to the heterocyclic antidepressants (nefazodone, trazodone), begun at very low dosages. Although stimulant medications such as pemoline have not shown efficacy in MS clinical trials, some practitioners and patients find them useful, although periodic liver function monitoring is needed with this agent. Occasional patients benefit from the use of nonsteroidal medications such as aspirin or acetaminophen, presumably to lower body temperature. The newest antifatigue medication in MS is modafinil, which can be helpful in selected patients. They must be counseled to eat breakfast when taking the drug, and a few patients have had worsening of mania or depression while using this medication.

BLADDER DYSFUNCTION Although many patients with MS develop bladder difficulties, the first step in management is to ascertain whether the problem is mechanical or neurologic. Many women may experience cough and sneeze incontinence or dribbling caused by childbirth injuries

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coupled with weight gain. This type of problem may be lessened by weight loss, Kegel exercises, or collagen injections. Male patients may have coexisting prostate problems. Patients of either gender can be susceptible to caffeine-induced bladder irritability, which increases frequency and urgency. Neurologic bladder problems in MS generally are divided into three categories: flaccid, dyssynergic, and hyperactive (spastic). In some geographic areas patients with MS are best served by a combination of neurologic and neurourologic physicians, whereas in other areas urogynecologists serve many of the same functions. Mild bladder dysfunction may be managed by timed voiding, avoidance of bladder irritants, and techniques such as double voiding. The medications oxybutynin and tolterodine may be safely used in patients with postvoid residuals, evaluated by catheterization or bladder scanning, of less than 100 mL. The newer preparations seem to cause less difficulty with dry mouth and constipation than the older medications. However, all patients should be warned about the possibility of urinary retention even with a normal postvoid residual. Imipramine and propantheline also continue to have a role in bladder management, particularly at bedtime. Some practitioners also prescribe desmopressin acetate at bedtime to slow the renal production of urine and thus allow patients to get a fuller night’s sleep, although this medication should be used with caution. For patients with significant bladder dyssynergia, intermittent catheterization may be the best way to reduce the occurrence of infection and overflow incontinence. Sometimes the hardest part of recommending intermittent catheterization is to sell the patient on the benefits. Many patients are nearly housebound because of their incontinence or plan their lives around the location of bathrooms. These patients benefit greatly from catheterization three to four times daily, which restores their freedom. Closedcatheter systems may be useful in patients on intermittent catheterization who experience frequent urinary tract infections. Although at first blush surgical intervention by placing a new stoma in the abdomen, with or without bladder augmentation, may seem extreme, selected patients benefit greatly, with increased independence and decreased infection risk. Injection of Botulism toxin into the sphincter has been tried for DSD with mixed results. Urinary infections should be looked for and treated aggressively in all patients with MS because of the potential for triggering an exacerbation. Many patients with MS will show no clinical signs of a urinary infection, and therefore the threshold for screening for infection should be low. BOWEL DYSFUNCTION Improved bowel function may improve other symptoms in MS, perhaps through feedback loops. Symptoms that are particularly likely to improve with constipation management are bandlike sensations, spasticity, and bladder symptoms. A few patients also experience back pain with constipation. Bowel incontinence is almost always masked constipation and should be managed first by placing a patient on a modified bowel program. Increased fluids and fiber and a specific time for bowel evacuation usually are the first steps. Lactulose and pramipexole (Mirapex) may be needed when stool softeners and fiber and fluid are not enough. While plain lactulose may be difficult to tolerate, it can be flavored by the pharmacist and is available in crystalline form as well. It is well to remember the patient’s genetic risk of colon cancer in managing constipation.

SEXUAL DYSFUNCTION Many physicians and patients are uncomfortable discussing sexual dysfunction. Various mechanical aids and medications are available to assist men in achieving and maintaining erections. Because trazodone has a well-described side effect of priapism, some male and female patients request this drug for enhancing sexual activity. Sildenafil citrate has been of limited benefit in women, although some drugs are supposedly in development for women. Decreased libido is common in patients with MS and may be a result of fatigue and depression as well as decreased self-esteem. SPASTICITY Patients with upper motor neuron dysfunction often experience troublesome increases in muscle tone. Many practitioners use a three-pronged approach of exercise, bowel management, and medications. Almost all patients with MS should be on a maintenance program of stretching, which particularly benefits those who have increases in tone. Medications that are useful for managing spasticity are baclofen, tizanidine, and diazepam. Some patients find sedation a problem on all medications, particularly tizanidine. Tizanidine is particularly useful for painful nighttime leg spasms. Patients should be counseled about the potential for reduction in walking ability with the decrease in stiffness, and in general they should be allowed some latitude in titrating their own dosing and timing of the medications. When no further medication can be used orally (maximum dose of 100 mglday for baclofen, 32 mglday for tizanidine), intrathecal pump placement may be contemplated in some patients. This route is most commonly used in wheelchair-bound patients whose spasticity or spasms inhibit sitting or hygiene. Although some pumps may be programmed for variable rates of medication administration, titrating and adjusting the medication in ambulatory patients can be difficult. Lidocaine or narcotics may be added to intrathecal baclofen pumps as well, but again the titration is complicated. WEAKNESS Patients with MS often experience weakness. Some of their weakness is permanent, but gentle exercise and physical therapy can be helpful in many patients. The use of appropriate assistive devices such as ankle-foot orthoses, canes, and walkers is useful in preventing further injury. Most patients with MS find that a four-wheeled walker with handbrakes is more useful than the type of walker that must be lifted with each step. Some of these also have baskets and seats, which allow conservation of energy, another important goal in managing weakness. Drug treatment is limited 4-aminopyridine or fampridine is an experimental medication that can improve the stamina and strength of some patients with MS. Unfortunately, it has been difficult to prove this in clinical trials, and the medication carries a high risk of seizures because of its effect on potassium channels. TREMOR Patients with MS may experience many types of tremor; the most difficult to manage and most disabling is cerebellar tremor. Some patients have a limited response to clonazepam, starting in dosages of 0.5 mg once a day, increasing to two or three times a day. Sedation limits the usefulness of this agent, however. Although

Chapter 45

isoniazid in dosages of 900 to 1200 mg/day has shown benefit in several studies, most practitioners are too concerned about the hepatic and peripheral nerve toxicities to use this agent. A few patients benefit from agents that are useful in essential tremor such as propranolol (up to 160 mg a day) and primidone (in doses of 250 mg twice a day). Some practitioners use ondansetron for cerebellar tremor with reasonable results, but the drug is prohibitively expensive. Certain centers are trying deep brain stimulation to reduce tremors in MS, but the results are variable and may be short lived or require frequent adjustment. Occasionally patients can gain independence in activities of daily life with wrist weights and weighted utensils.

COGNITIVE DEFICITS Patients and neurologists have underestimated the extent and variability of cognitive impairment. Assessing neuropsychological function often entails testing by neuropsychologists who are familiar with the deficits caused by MS. In our center, we offer two screening methods: a 45-minute battery by our health psychologists, who also interview the patients with a particular view to psychosocial issues, and a 4- to 5-hour battery addressing various cognitive functions but looking less closely at psychosocial issues. Some patients need both types to fully assess their status. We perform cognitive testing at our center for various reasons, including concern for the patient and family, education of the patient and family, and disability planning and application process. Planners, lists, and cueing devices may help keep some patients with MS on track. Treating underlying issues of fatigue, depression, and sleep disorders may improve functioning as well. Donepezil has been reported to improve cognitive function slightly in MS, and a multicenter trial is under way to address this agent’s usefulness.

MOOD DISORDERS Depression is very common in patients with MS. Sometimes the MS is the tip of the iceberg in people’s lives, but it is what pushes them to finally seek help for long-standing mental health issues. Some patients respond to counseling alone, but many others need medication and counseling together. The SSRIs are the most commonly prescribed, with citalopram and sertraline the most popular. All the SSRIs may cause sexual dysfunction, although citalopram is the least likely to cause this side effect. Hair loss, diarrhea, and precipitation of mania are seen on rare occasions in patients with MS on these agents. Although bupropion hydrochloride was initially avoided in all patients with neurologic disorders because of the increased risk of seizures, the long-acting preparation generally is safe and well tolerated in patients with MS. This agent may be particularly useful for chronically depressed patients. Venlafaxine can be used in patients with coexisting pain with good benefit, although the blood pressure must be monitored for hypertension. Older adults may find the heterocyclics such as

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trazodone or nefazodone most useful, particularly if they are titrated slowly.

SWALLOWNG PROBLEMS Swallowing problems in patients with MS must be differentiated from esophageal problems. Patients with esophageal problems generally point to the sticking point at the bottom of the neck and top of the sternum. A proper swallowing study with a skilled speech therapist can help distinguish and manage these problems. Sometimes it is necessary to remind patients to always eat in an upright position and to take small bites and chew slowly. GERD may also be a problem in disturbing sleep. Patients should also be warned not to eat less than 1 hour before nap or bedtime.

SUGGESTED READINGS Branas P, Jordon R, Fry-Smith A et al: Treatment for fatigue in multiple sclerosis: a rapid and systematic review. Health Techno1 Assess 4(27):141, 2000

Clanet MG, Brassat D The management of multiple sclerosis patients. Curr Opin Neurol 13(3):263-270, 2000 Cooper ZR, Rose S: Fecal incontinence: a clinical approach. Mt Sinai J Med 67(2):96-105, 2000

Gallien P, Robineau S: Sensory-motor and genito-sphincter dysfunctions in multiple sclerosis. Biomed Pharmacother 53(8):38&385, 1999 Huntley A, Ernst E Complementary and alternative therapies for treating multiple sclerosis symptoms: a systematic review. complementary Ther Med 8(2):97-105,2000 Kamensek J: Continuous intrathecal baclofen infusions. An introduction and overview. Axone 20(3):67-72, 1999 KO KO C Effectiveness of rehabilitation for multiple sclerosis. Clin Rehabil 13(Suppl 1):3341, 1999

LaBan MM, Martin T, Pechur J, Sarnacki S: Physical and occupational therapy in the treatment of patients with multiple sclerosis. Phys Med Rehabil Clin North Am 9(3):603414, 1998 Leary SM, Thompson AJ: Current management of multiple sclerosis. Int J Clin Pract 54(3):161-169, 2000 Litwiller SE, Frohman EM, Zimmern P E Multiple sclerosis and the urologist [published erratum appears in J Urol 162(1):172, 19991. J Urol 161(3):743-757, 1999 Merson RM, Rolnick MI: Speech-language pathology and dysphagia in multiple sclerosis. Phys Med Rehabil Clin North Am 9(3):631-641, 1998 Metz LM, Patten SB, McGowan D Symptomatic therapies of multiple sclerosis. Biomed Pharmacother 53(8):371-379, 1999 Minden S L Mood disorders in multiple sclerosis: diagnosis and treatment. J Neurovirol 6(Suppl 2):S16O-S167, 2000 Moulin D E Pain in central and peripheral demyelinating disorders. Neurol Clin 16(4):889-898, 1998 Rashid TM, Hollander J B Multiple sclerosis and the neurogenic bladder. Phys Med Rehabil Clin North Am 9(3):615429, 1998 Rosenblum D, Saffir M: Therapeutic and symptomatic treatment of multiple sclerosis. Phys Med Rehabil Clin North Am 9(3):587-601, 1998 Shakespeare DT, Young CA, Boggild MD: Antispasticity agents for MS. [Rev] Cochrane Database Syst Rev 4CD001332, 2000

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Immune-Mediated Disease

Optic Neuritis Daniel M. Jacobson

Optic neuritis is a group of disorders that have in common inflammation of the optic nerve and loss of vision on the basis of optic nerve dysfunction. Although a variety of specific entities may produce inflammation, infection, or, more commonly, demyelination of the optic nerve and the syndrome of optic neuritis (Table 46-l), it usually occurs either as an isolated presentation (called isolated, idiopathic, monosymptomatic, or demyelinating optic neuritis) or in association with multiple sclerosis (MS). It is one of the most common causes of optic neuropathy, especially in adults younger than 45 years. In practice, establishing the diagnosis of optic neuritis requires primarily clinical skills, not neurodiagnostic tests. Although no treatment clearly offers better recovery of vision than the natural history of spontaneous, and usually good, improvement, there are ways to reduce the risk of developing MS for patients presenting with an isolated attack of optic neuritis. CLINICAL PROFILE, HISTORY, AND PHYSICAL EXAMINATION The majority of patients with idiopathic optic neuritis are between the ages of 15 and 45 years. Women are affected slightly more frequently than are men. In adults, idiopathic optic neuritis usually is a unilateral disorder. For patients with idiopathic optic neuritis, three key features of the history support the diagnosis: 1. Tempo of visual loss and recovery. Most patients experience either sudden onset of visual loss or insidious awareness of a nonspecific change in vision. Loss of vision gradually progresses over the next week or so before stabilization occurs. Progression of symptoms beyond 2 weeks is distinctly uncommon and should raise suspicion of another mechanism of optic neuropathy, such as compression or infiltration of the optic

TABLE46-1. Causes of Optic Neuritis Idiopathic (neurologically isolated, demyelinating, monosymptomatic) Multiple sclerosis Devic's syndrome Acute disseminated encephalomyelitis Postviral Mononucleosis (Epstein-Barr virus) Varicella zoster (chicken pox) Cytomegalovirus Mumps Measles Postvaccination Sphenoethmoid sinusitis Other infectious disorders Syphilis (Treponemupollidurn) Lyme disease (Borrelio burgdorferi) Cat scratch disease (Bartonello henselue) Toxoplasmosis Systemic vasculitides and granulomatous disorders Systemic lupus erythematosus Sjogren's syndrome Autoimmune optic neuropathy Sarcoidosis Wegenef s granulomatosis Juxtapapillary inflammatory chorioretinopathies

nerve. After a few weeks of stable visual impairment, most patients experience gradual improvement of sight over the next several weeks. Sudden visual loss that does not progress or resolve is more characteristic of ischemic injury of the optic nerve. Quality of the visual loss. If specifically queried, most affected patients report dimness of vision, a washed-out appearance of colors (color desaturation), and blank regions (scotomas) in their visual field. Though not specific for optic neuritis, these qualities of visual loss taken together are more suggestive of optic nerve injury than of dysfunction of the retina or an ocular cause of visual loss. Presence and quality of pain. Most patients experience a variably intense, dull, and achy pain behind the eye or around the globe. When the eye is still, there is little or no pain. When the eye is rotated, the pain appears or is exacerbated. The globe may be tender to touch. Pain may occur a few days before, at the same time of, or a few days after visual loss. It usually resolves after a week or two. The presence of pain is so characteristic of optic neuritis that the diagnosis should be questioned in patients without it. Persistent or progressive pain suggests the presence of an alternative condition, such as a mass lesion compressing the optic nerve or infection (e.g., aspergillosis) or granulomatous process (e.g., sarcoidosis) infiltrating it. The physical examination, though nonspecific, serves three purposes for helping to establish the diagnosis of optic neuritis and treating the affected patient. First, it provides signs that localize loss of vision to the optic nerve. Second, certain features of the examination are characteristic of optic neuritis. Third, it provides a baseline assessment that can be followed over time to determine whether the optic nerve function is improving, worsening, or remaining stable. There are three commonly measured subjective tests of optic nerve function (visual acuity, color vision, and visual fields) and two objective signs of optic neuropathy (identification of a relative afferent pupillary defect and ophthalmoscopic inspection of the optic disk). The degree of impairment of visual acuity is variable. Visual acuity may not be affected if the papillomacular bundle of optic nerve fibers, those that transmit visual information from the fovea, are spared by the inflammatory process. On the other hand, patients with extreme injury of the optic nerve may not be able to perceive light. Typically, however, the level of visual acuity impairment ranges between 20/40 and 20/200. Comparing color vision between the affected and fellow eye is another important test of optic nerve function. Most patients with optic neuritis report that colors appear faded in their affected eye, whereas most patients with comparable loss of vision caused by disease of the retina or a cataract do not report a similar degree of dyschromatopsia. This simple office test usually is reliable for screening for dyschromatopsia: Ask the patient to compare the color quality of a small red object using one eye at a time. The red top of a bottle of ophthalmic dilating drops or some other small handheld red object serves this purpose well. Dimness of vision, a subjective sign of optic neuropathy, can be similarly assessed by

Chapter 46

asking the patient to compare the relative intensity of a handheld light viewed with one eye at a time. Testing the field of vision using formal perimetry reveals scotomas and other patterns of visual field loss that reflect injury of the optic nerve fiber bundles in most patients. The most common patterns of visual field loss include central scotomas and arcuate defects. Identification of certain patterns of visual field loss, such as a nasal or temporal defect that lines up along the vertical meridian, should raise concern that some other lesion of the anterior visual pathway, such as mass lesion, is compressing the optic chiasm or tract. A relative afferent pupillary defect, detected during the swinging flashlight test, is expected in the affected eye of all patients with optic neuritis and is an objective sign of optic neuropathy. Accordingly, it is the most important sign to seek when evaluating a patient with unilateral visual loss. If one is not present, consider an ocular cause of visual loss (e.g., vitreous hemorrhage), disorder of the retina, or factitious visual loss. When optic disk edema is present, as in roughly one third of affected patients, the disorder is called papillitis. When the initial appearance of the optic disk is normal, the disorder is called retrobulbar neuritis. Although a normal optic disk is certainly compatible with optic neuritis, other causes of retrobulbar optic neuropathy (e.g., compressive lesion) should be considered in atypical cases. The assistance of an ophthalmologist is recommended in many cases because they have the training and equipment to measure and interpret these parameters of visual loss. Additionally, they can inspect the eye for signs of an alternative ocular cause of visual loss. Optic neuritis in young children often is different in certain features than that of adults. It usually presents with bilateral papillitis and often is a postinfectious (viral) disorder. Accordingly, the risk of developing MS in children is generally less than when optic neuritis presents in adulthood. DIAGNOSTIC EVALUATION Optic neuritis is a classic neurologic disorder in which the diagnosis is established primarily through the history and physical examination. Given the typical patient profile outlined in this chapter, there is generally no need to obtain additional neurodiagnostic tests, including magnetic resonance imaging (MRI), to confirm the diagnosis or to identify some other neurologic disorder mimicking optic neuritis in most patients. For example, MRI of the brain identified only 2 of 457 (0.4%) patients originally enrolled in the Optic Neuritis Treatment Trial (ONTT) with an alternative lesion. In one patient, a pituitary tumor was identified on an initial MRI. In the other patient, the presence of persistent pain and worsening vision, features highly atypical of optic neuritis, prompted a second MRI 1 month after enrollment that identified an aneurysm. There is one useful role for a brain MRI in the diagnostic evaluation of a patient with suspected optic neuritis. MRI identifies abnormal brain lesions consistent with those seen in patients with established MS in roughly 50% to 80% of patients with neurologically isolated optic neuritis. Identifylng such changes in a patient with an optic neuropathy of undefined mechanism would support optic neuritis as the underlying cause. In summary, brain MRI generally is not indicated for the diagnosis of typical optic neuritis. It may help in the rare circumstance in which the history and neuro-ophthalmologic

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examination are too nonspecific to assign a diagnosis of demyelinating optic neuritis based on clinical criteria alone. But brain MRI probably should be obtained in patients with optic neuritis for prognostic reasons because therapeutic interventions now exist to delay the development of MS in those with abnormal imaging results. MRI of the orbits, using special techniques to suppress the orbital fat signal and performed after contrast administration, reveals abnormal enhancement of the involved optic nerve in most patients with acute optic neuritis (Fig. 46-1). This is a nonspecific radiographic sign that can be seen in other disorders, including those that infiltrate the optic nerve such as leptomeningeal metastases, fungal infections, and sarcoidosis. The length of involved optic nerve is highly variable but often longer than 1 cm. The intraorbital, intracranial, or both segments of the optic nerve may enhance. Although some evidence suggests that a worse prognosis for visual recovery is associated with longer lesions or involvement of the intracanalicular segment of the optic nerve, sufficient variability exists that this generality is not clinically useful for patient counseling. The abnormal enhancement resolves over time coincident with improvement of vision. Although orbital MRI generally is not needed to diagnose optic neuritis in patients with good clinical support of that diagnosis, it should be obtained in patients with atypical features. The following imaging findings, if present, should suggest an alternative diagnosis:

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Thickening, tortuosity, or lumpy-bumpy borders of the optic nerve (suggestive of infiltration of the optic nerve, especially by malignancy) Significant enhancement of the optic nerve sheath more than the optic nerve (suggestive of a leptomeningeal infectious, inflammatory, or neoplastic process) Enhancement of the orbital fat or other orbital structures (suggestive of neoplastic infiltration or orbital pseudotumor) Contiguous involvement of the optic nerve and chiasm (suggestive of an optic nerve tumor)

Visual evoked potentials (VEPs) often are obtained to confirm acute optic neuritis in a patient with suspicious symptoms. But a carefully performed swinging flashlight test to identify a relative afferent pupillary defect is just as sensitive, far less expensive, and a more objective measure of optic neuropathy. If the region of optic nerve fiber bundle injury lies outside of the papillomacular bundle, as may occur in optic neuritis, the VEP may be normal although a relative afferent pupillary defect still exists. Abnormal VEPs are not specific for optic neuritis and may occur with other disorders that injure the afferent visual pathway, including diseases of the retina that affect the macula and other optic neuropathies, such as those caused by compressive or infiltrative lesions. Visual evoked potentials may help confirm the presence of optic neuropathy in a patient with recovered optic neuritis whose vision has returned back to normal because they remain abnormal in the majority of such cases. There is little diagnostic role for evaluating cerebrospinal fluid (CSF) in patients with suspected optic neuritis. In the ONNT, CSF was analyzed in roughly one third of the enrolled patients and did not identify an alternative diagnosis in any case. Mild CSF lymphocytic pleocytosis and elevation of total protein concentration are found in only about 33% and 10% of patients with isolated optic neuritis, respectively. These are nonspecific changes and can be seen in a variety of inflammatory and infectious disorders that affect the leptomeninges of the brain diffusely. A cell count higher

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Immune-MediatedDisease than 25 leukocytes/mL or total protein concentration greater than 70 mg/mL should suggest an alternative diagnosis. Oligoclonal bands are present in roughly 50% of patients with neurologically isolated optic neuritis. Although nonspecific, their presence supports a demyelinating mechanism of optic neuropathy in a patient with an ambiguous history and neuro-ophthalmologic examination, similar to the implication of finding abnormal MRI lesions of the brain in a patient with suspected optic neuritis. What is the appropriate workup for a patient with suspected optic neuritis? The history and neuro-ophthalmologic examination are the most powerful tools used to determine whether the presentation is typical, in which case no further neurodiagnostic tests are necessary in most cases, or whether atypical features (Table 46-2) exist that warrant additional tests to identify a different mechanism of optic neuropathy or cause of visual loss. A carefully performed review of systems must be obtained to seek symptoms that would suggest the presence of one of the specific causes of optic neuritis (Table 46-1) or prior relapsing and remitting neurologic symptoms that might suggest the presence of MS.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of optic neuritis (Table 46-3) includes disorders that cause rapid monocular loss of vision in young adults, with or without eye pain. Because the optic disk may appear swollen or normal, other causes of unilateral disk edema and retrobulbar optic neuropathies are included in this list. Finally, other non-optic nerve causes of monocular visual loss must be

A

w TABLE46-2. Red Flags That Suggest the Presence of a Disorder Other Than Optic Neuritis Feature

Alternative Consideration

Atypical Symptoms

Sudden awareness of visual loss No pain Prominent positive visual symptoms No dimness, color desaturation, scotomas Metamorphopsia, micropsia, macropsia

Preexisting compressive or infiltrative* lesions Retina disease or other optic neuropathy Retina disease Retina or ocular disease Maculopathy

Atypical Signs

Optic disk pallor at acute presentation No optic disk edema

B

FIG. 46-1. Typical-appearing orbital magnetic resonance images using a fat saturation technique after intravenous administration of contrast in a 26-year-old woman with right-sided optic neuritis. (Top) Axial image demonstrating marked enhancement of the intraorbital segment of the right optic nerve (thick black arrow) and, less dramatically, of the intracranial nerve segment (thin black arrow). @ottom) Coronal image at the midlevel of the orbit, demonstrating marked enhancement of the right optic nerve (black arrow).

Florid optic disk edema Exudates around optic disk or macula No relative afferent pupillaly defect No loss of color vision Normal central visual field Enlarged blind spot

Preexisting optic neuropathy Other retrobulbar optic neuropathies or ocular diseases Infiltrative optic neuropathies* Infectious optic neuropathy or neuroretinitis Nonoptic neuropathy Retina disease Retina disease Retina disease

Atypical Clinical Course

Progression of visual loss beyond 2 weeks No improvement of vision after 2 months Corticosteroid responsiveness or dependency

Compressive or infiltrative* optic neuropathy Compressive or infiltrative* optic neuropathy Compressive or infiltrative* optic neuropathy

*Including chronic infections (e.g., fungal), tumors (eg, lymphoma or glioma), and granulomatous disorders (e.g., sarcoidosis).

Chapter 46 H Optic Neuritis W TABLE 46-3.

Differential Diagnosis of Optic Neuritis

Causes of unilateral disk edema Neuroretinitis Optic perineuritis Leber's hereditary optic neuropathy Anterior ischemic optic neuropathy Diabetic papillopathy Central retinal vein occlusion Papillophlebitis Asymmetric papilledema Infiltrative lesions* Paraneoplasticoptic neuropathy Causes of unilateral retrobulbar optic neuropathy Mass (compressive) lesions Infiltrative lesions* Paraneoplasticoptic neuropathy Causes of non-optic nerve monocular visual loss Acute maculopathies (e.g., central serous maculopathy) Occult outer retinopathies (e.g., acute zonal occult outer retinopathy) Factitious visual loss 'Including chronic infections (eg, fungal), tumors (e.g., lymphoma or glioma), and granulomatous disorders (e.g.. sarcoidosis).

considered. The entities included in the differential diagnosis of optic neuritis generally are not associated with the typical relapsing and remitting profile seen with optic neuritis. Certain red flags-atypical features of optic neuritis-should trigger concern that one of these disorders is present (Table 46-2). TREATMENT The bottom line is that currently there is no specific treatment for optic neuritis that is better than the generally good visual recovery that occurs spontaneously in most patients. In the ONTT, 457 patients with acute optic neuritis were randomly assigned to receive oral prednisone (1 mg/kg/day) for 14 days, intravenous methylprednisolone (250 mg, four times daily) for 3 days followed by oral prednisone (1 mg/kg) for 11 days, or oral placebo for 14 days. Although visual function recovered slightly faster in the group receiving intravenous methylprednisolone than in those receiving placebo, there was no significant difference between the two groups in visual acuity, color vision, visual fields, or contrast sensitivity when assessed at 1 year after the acute attack. Most of the benefit of methylprednisolone occurred during the first 2 weeks, so that by 2 months, there was little difference between the two groups. The decision whether to use intravenous methylprednisolone must be determined on an individual basis, balancing the small benefit of faster recovery against the potential side effects of such treatment and absence of ultimate therapeutic efficacy. Oral prednisone was no better than placebo. More importantly, as discussed in the next section, the rate of recurrent attacks of optic neuritis was significantly higher in the group that received oral prednisone. Accordingly, not only is oral prednisone in the dosage prescribed in the ONTT ineffective for treating acute optic neuritis, but it may also be harmful. PROGNOSIS The prognosis for spontaneous recovery of vision in patients with optic neuritis is good. In most patients, recovery of vision usually starts within 3 weeks from the acute attack, and the majority of improvement is realized in the first month or two. It should be expected that most patients will demonstrate some improvement in vision. If not, consider an alternative optic neuropathy, such as a compressive or infiltrative lesion. By 6 months, most patients

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recover visual acuity to a level of 20/30 or better. The degree of visual loss at onset may predict the visual outcome, although this is not always a reliable rule for an individual patient. Even patients whose initial visual acuity is so poor that they cannot detect light usually experience improvement, many times nearly back to normal. Most patients, even those with excellent recovery of vision, still are aware of annoying, although usually not disabling, persistent symptoms reflecting residual optic nerve injury. Commonly reported symptoms include color desaturation, dimness, impaired depth perception, and loss of ability to discriminate fine contrast. Roughly 50% of patients with recovered optic neuritis experience brief spells of blurring, dimming, or loss of vision in their affected eye, called Uhthoffs symptom. These events often are precipitated by physical exertion (e.g., mowing the lawn), exposure to a warm environment (e.g., hot shower), or fatigue. They last several minutes to an hour. Patients should be reassured that these are not recurrent bouts of optic neuritis and will not harm their eye. Between 15% and 35% of patients experience a recurrent event in their previously affected or unaffected eye. It remains a matter of debate whether recurrences fulfill the criteria of dissemination in space necessary to satisfy the clinical definition of MS. However, there are patients who experience multiple bouts of recurrent optic neuritis yet have no clinical or paraclinical (i.e., abnormal brain MRI or CSF) evidence of generalized cerebral demyelination who should not be labeled as having MS. One disturbing finding of the ONTT was the significantly higher rate of recurrent bouts of optic neuritis that occurred in the group of patients randomized to oral prednisone. Although the explanation of this remains unclear, it forces the recommendation that oral prednisone, at the dosage prescribed in the ONTT ( 1 mg/kg/day for 14 days), is contraindicated in patients with typical optic neuritis. RELATlONSHlP TO MS AND WAYS TO REDUCE THE RISK OF CONVERSION Patients with neurologically isolated optic neuritis cannot be diagnosed with MS because, by definition, they have not demonstrated that they have a disorder characterized by clinical events disseminated in time and space. But, in retrospect, idiopathic optic neuritis often is the first manifestation of MS. Of the prospectively followed cohort of patients enrolled in the ONTT who did not have probable or definite MS, 30% developed MS in the 5 years after enrollment. In some studies that followed patients for longer periods after optic neuritis, the proportion who developed MS was even higher. Patients with isolated optic neuritis can be arbitrarily categorized into two groups depending on whether their risk of developing MS is high or low. The most reliable prognostic tool for assigning such risk is the presence or absence of abnormal MRI brain lesions thought to represent demyelinating plaques. In the ONTT, 51% of patients with three or more MRI lesions developed MS within 5 years from the time they first experienced optic neuritis, whereas only 16% of patients with normal MRI developed MS during the same time. Although the presence of CSF oligoclonal bands also is predictive of the development of MS in patients presenting with isolated optic neuritis, in most patients this variable does not add to the prognostic information available from brain MRI data. Two recently completed multicenter, randomized, prospective treatment trials have identified interventions that can reduce the

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risk of developing MS in patients with isolated optic neuritis who are at high risk of converting based o n abnormal brain MRI. In the ONTT, patients in the intravenous methylprednisolone group developed definite MS at about half the rate as did those in the placebo group. Unfortunately, the protective effect of the intravenous methylprednisolone treatment regimen on delaying the development of MS wore off sometime between 2 and 3 years after administration, at which point the risk of developing MS reverted to its previous rate. In patients with normal brain MRI or nonspecific lesions not characteristic of MS, the rate of conversion to MS was so low that a benefit could not be demonstrated using intravenous methylprednisolone. More recently, the results of the Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) provided even more compelling data that intervention for patients with optic neuritis and abnormal MRI delays conversion to MS. In the CHAMPS, 383 patients with an acute attack of isolated optic neuritis or transverse myelitis or one involving the brainstem or cerebellum who had two or more clinically silent MRIdemyelinating lesions first received intravenous methylprednisolone 1 g daily for 3 days followed by an oral taper of prednisone. Patients were not enrolled if they had experienced a previous event consistent with demyelination. The patients were then randomized to receive either a weekly intramuscular injection of interferon beta-la (Avonex) 30 pg or placebo. The cumulative probability of developing clinically definite MS was significantly lower in the group receiving active treatment than in the group receiving placebo. Based on the results of these two studies, it is rational to obtain brain MRI in patients with isolated optic neuritis to categorize their relative risk of developing MS and to treat those with lesions consistent with demyelination (i.e., high risk) with intravenous methylprednisolone followed by a tapering course of oral prednisone and then weekly intramuscular injections of interferon beta-la. The benefit of such a protocol must be tempered by the additional cost burden and side effects of the treatments. Accordingly, the decision to use such a protocol must be made on an individual basis.

Beck RW, Cleary PA, Backlund JC, for the Optic Neuritis Study Group: The course of visual recovery after optic neuritis. Experience of the optic neuritis treatment trial. Ophthalmology 101:1771-1778, 1994 Beck RW, Cleary PA, Trobe JD et al: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 329:1764-1769, 1993 Briex PA, Ciccarelli 0, ORiordan JI, et al: A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158-164,2002 Celasia GG, Kaufman DI, Brigell M et al: Optic neuritis: a prospective study. Neurology 40:919-923, 1990 CHAMPS Study Group: Interferon Beta-la for optic neuritis patients at high risk for multiple sclerosis. Am J Ophthalmol 132:463-471,2001 Cox TA, Thompson HS, Hayreh SS, Snyder J E Visual evoked potential and pupillary signs. A comparison in optic nerve disease. Arch Ophthalmol 1001603-1607, 1982 Jacobs LD, Beck RW, Simon JH et al: Intramuscular interferon beta-la therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 343:898-904, 2000 Jacobson DM: Optic neuritis. pp. 133-154. In: Rolak LA, Harati Y (eds): Neuro-immunology for the Clinician. Butterworth-Heinemann, Boston, 1997 Nikoskelainen E Symptoms, signs and early course of optic neuritis. Acta Ophthalmol 53:254-271, 1975 Optic Neuritis Study Group: The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 109:1673-1678, 1991 Optic Neuritis Study Group: The 5-year risk of MS after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Neurology 49:14041413, 1997 Perkin GD, Rose F C Symptoms at presentation. pp 32-42. In: Optic Neuritis and Its Differential Diagnosis. Oxford University Press, Oxford, England, 1979 Perkin GD, Rose F C Visual signs at presentation. pp 43-73. In: Optic Neuritis and Its Differential Diagnosis Oxford. Oxford University Press, Oxford, England, 1979 Rolak LA, Beck RW, Paty DW et al: Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial. Neurology 46:368-372, 1996 Youl BD, Turano G, Miller DH et al: The pathophysiology of acute optic neuritis. An association of gadolinium leakage with clinical and electrophysiologicaldeficits. Brain 114:2437-2450, 1991

SUGGESTED READINGS Beck RW, Cleary PA, Anderson MM et al: A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326:581-588, 1992

47

Transverse Myelitis Loren A. Rolak

Transverse myelitis is a syndrome of acute inflammation cutting across the spinal cord, usually producing weakness, numbness, and bowel and bladder dysfunction. It equally afflicts all ages and both sexes in all parts of the world. Most cases presumably represent an autoimmune inflammation and demyelination of the spinal cord, similar to an attack of multiple sclerosis (MS) o r acute disseminated encephalomyelitis, but the syndrome can be pro-

duced by a direct viral infection of the cord, as a paraneoplastic remote effect of cancer, or other cause.

CLINICAL FEATURES Transverse myelitis has a dramatic presentation, with the rapid onset of symptoms over several hours to a few days. Nearly one

Acute Disseminated Encephalomyelitis

Chapter 48

48

423

Acute Disseminated Encephalomvelitis Aljoeson Walker and William R. Tyor

Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease. However, it tends to follow a monophasic course when compared with multiple sclerosis, which is also a demyelinating disease. It is also called parainfectious, postinfectious, or postvaccinial encephalomyelitis because of its association with infectious illnesses and vaccines (Table 48-l), and in its most aggressive form it is called acute hemorrhagic leukoencephalitis. The bestcharacterized relationship of ADEM with infectious disease is with measles infection; before the introduction of measles vaccine, this was a common association, occurring in 1:400 to 1:lOOO measles cases. Development of ADEM following other infections, including rubella, mumps, herpes viruses, influenza, Lyme disease, and mycoplasma, has also been described (Table 48-1). ADEM associated with rabies vaccines prepared from animal brain is well known, and early studies involving the injection of rabbit brain into monkeys led to our current concept of the autoimmune nature of this disease and the development of the first animal model of experimental allergic encephalomyelitis. Other vaccines that have been linked with occasional cases of ADEM include smallpox, pertussis, influenza, rubella, diphtheria, and measles. However, in many cases the relationship between ADEM and infectious disease or vaccination is not clear, and therefore these represent idiopathic events.

TABLE 48-2. Clinical Features of Acute Disseminated

Encephalomyelitis Demographics and initial symptoms Any age, but unusual before 10 years Usually follows infection or vaccination by 1 to 3 weeks May be several days of fever, chills, and malaise Possible neurologic manifestations (uniphasic) Abrupt onset of seizures with rapid progression to coma Subacute onset evolving over days Headache, fever, nausea, vomiting, meningismus Progression to delirium Sensory abnormalities, hemiparesis, paraparesis Ataxia, visual disturbances, cranial nerve signs Bladder or bowel dysfunction Involuntary movements, myoclonus Behavioral and cognitive disturbances Increased intracranial pressure More chronic course developing over weeks

deterioration to coma, or they may evolve over a period of days involving primarily white matter in the cerebral hemispheres, optic nerves, brainstem, cerebellum, and spinal cord. Signs include encephalopathy, hemiparesis, cranial nerve palsies, visual dysfunction, ataxia, and myelopathy (i.e., paraparesis and sphincter dysfunction). However, signs referable to gray matter involvement are not uncommon and consist of movement disorders such as choreoathetosis, seizures, and myoclonus. There also may be signs of increased intracranial pressure.

CLINICAL PRESENTATION

Typically, the onset of ADEM begins 1 to 3 weeks after an infection or immunization and may affect all ages, although it is uncommon in children under 10 years old. In some patients, a prodrome of fever, malaise, and myalgia occurs for several days before the onset of focal or multifocal neurologic deficits (Table 48-2). Symptoms may develop abruptly, with seizures and rapid TMLE 48-1. Parainfectious and Postvaccinal Agents

Associated with Acute Disseminated Encephalomyelitis Infections Viral Coxsackie Epstein-Barr Herpes zoster Herpes simplex Influenza Measles Mumps Rubella Bacterial Borrelia burgdorferi Legionellapneumophila Leptospira Vaccinations Diphtheria Influenza Measles Pertussis Rabies Rubella Vaccinia

PROGNOSIS

Generally, deficits peak within several days and begin to resolve, but occasionally a protracted course lasting weeks and, rarely, months is observed. It should be emphasized that ADEM is a uniphasic disease, and this important feature helps distinguish it from multiple sclerosis, which can also cause abrupt, multifocal neurologic deficits. Relapses that can be considered manifestations of ADEM and not of multiple sclerosis are rare. The mortality rate for ADEM has been estimated as high as 30%, but complete recovery occurs in at least half of the patients. Rapid onset with severe manifestations leads to a poor prognosis. DIAGNOSIS No laboratory abnormality is pathognomonic for ADEM, but there are common findings (Table 48-3). Cerebrospinal fluid (CSF) pressure may be elevated, and the CSF may demonstrate moderate leukocytosis (fewer than 100 cells/pL, usually mononuclear cells) and a modest increase in protein (less than 100 mg/dL). However, infrequently the CSF is normal. Occasionally the CSF shows an increased immunoglobulin G (IgG) index and oligoclonal bands, although increased myelin basic protein occurs in a larger proportion of patients, especially in ADEM after measles infection or Semple vaccination (inactivated rabies prepared from sheep brain). Computed tomography (CT) scans reveal multifocal hypodense lesions, usually in the white matter, which may enhance with contrast. Magnetic resonance imaging (MRI) is more sensitive and demonstrates areas of increased intensity on T2-

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TABLE 48-3.Magnetic Resonance Imaging and Cerebrospinal

Fluid Findings in Acute Disseminated Encephalomyelitis Cerebrospinal fluid Pressure May be elevated Cell count Usually between 5 and 100 white cells/mL Predominantly polymorphonuclear early and mononuclear later Chemistries Glucose normal Protein usually between 45 and 100 mg/dL Other Myelin basic protein may be elevated Immunoglobulin G index may be elevated Oligoclonal bands may be present Magnetic resonance imaging Multifocal areas of increased T2-weighted intensity, usually in the white matter

weighted scan or FLAIR, mainly in the white matter. The electroencephalogram often is abnormal but nonspecific, displaying generalized, multifocal, or focal slowing. Systemic findings can include an increased erythrocyte sedimentation rate and mild proteinuria. The most important differential diagnosis of ADEM is multiple sclerosis, and the clinical, laboratory, and pathologic similarities of these two diseases have long been appreciated. It is often impossible, using any criteria, to separate ADEM from a single, first attack of multiple sclerosis. The diagnosis of multiple sclerosis is clear when multifocal neurologic signs relapse and remit, but the discrimination between ADEM and multiple sclerosis is difficult when neurologic deficits do not relapse, remain static, or progress slowly over months. Distinguishing between these diseases often must await the passage of time, even years. Other diagnostic considerations include viral encephalitis, tumor, meningitis, cerebrovascular disease, endocarditis with cerebral embolization, intracranial abscess, intracranial hemorrhage, central nervous system vasculitis, and central nervous system sarcoidosis. TREATMENT There are no controlled trials of corticosteroids in ADEM. Based on the similarities of ADEM with multiple sclerosis and the likelihood that they are autoimmune diseases, as well as numerous anecdotal reports of the beneficial effects of steroids, intravenous methylprednisolone followed by prednisone is recommended (Table 48-4). Normally, 1 g methylprednisolone administered intravenously in 500 mL normal saline over 2 hours is given for 3 days, followed by prednisone, 60 to 80 mg ( 1 mg/kg) taken orally for 7 days and then tapered rapidly over the next 10 days. In severe or refractory cases, intravenous steroids may be given for longer periods, or more vigorous immunosuppression such as with cyclophosphamide or azathioprine should be considered. However, data on these types of prolonged or intense immunotherapy are deficient. Information about the efficacy of other treatments, such as plasmapheresis, is also lacking. A recent report described two patients who were treated with intravenous immunoglobulin (IV Ig). Deterioration of their neurologic condition occurred during treatment with intravenous methylprednisolone. However, subsequent administration of N Ig appeared to promote dramatic improvement. Therefore, IV Ig appears to be a viable alternative when there is no benefit from steroids. When intracranial pressure

is significantly elevated, it may be necessary to administer mannitol, reverse Trendelenburg position, hyperventilation, and even surgical placement of intracranial pressure monitoring and decompression. Some complications of ADEM can be ameliorated (Table 48-4). Seizures usually are well controlled with the standard recommended dosages of phenytoin, carbamazepine, or phenobarbital. Awareness of bladder dysfunction and its treatment is important to help prevent further complications of urinary tract infection and potential sepsis. Bowel dysfunction, usually seen as constipation, is also a common complication, especially in patients who are bedridden. Decubitus ulcers, thrombophlebitis, contractures, and peripheral nerve compression often afflict bedridden patients. Atelectasis and pneumonia may develop, so respiratory care is important. Occasionally, patients with ADEM become dysphagic and need special diets or tube feeding. Dysesthetic pain may develop and can be improved with nonsteroidal anti-inflammatory drugs, tricyclic agents such as amitriptyline, or anticonvulsants such as carbamazepine. Spasticity is a common complication and may necessitate treatment with baclofen, diazepam, and physical therapy. Physical therapy is useful early for passive range of motion and later for more active exercises. Occupational therapy also is an important adjunct, especially in patients with persistent deficits in activities of daily living. Use of social services and vocational rehabilitation ultimately may be necessary. Most patients with ADEM recover significantly, but many have residual deficits that often necessitate continued care and support. Mild depression is to be expected and occasionally necessitates treatment with antidepressants or mental health referral. Mention should be given to the recently reported results of the trial of interferon beta-la in patients at high risk for the development of multiple sclerosis. These patients essentially had ADEM with at least three significant lesions, consistent with demyelinating disease, on MRI of the brain. Therefore, they were at high risk for developing a second episode of demyelinating disease (i.e., multiple sclerosis). They were randomized to receive either interferon beta-la (30 pg IM once a week) or placebo. This treatment significantly delayed the onset of their second demyelinating episode; therefore, treatment with interferon beta- la should be considered in patients with ADEM who have at least 3 characteristic lesions on MRI. TABLE48-4.General Guidelines for Therapy of Acute

Disseminated Encephalomyelitis Immunosuppression Intravenous methylprednisolone 1 &day for 3 days If no response, consider prolonged IV steroids or other immunosuppressive therapy Then prednisone 60 mg/day for 1 week followed by a rapid taper Supportive care Prevention of complications in bedridden patients Decubitus ulcers Thrombophlebitis Contractures Bowel dysfunction Atelectasis Symptomatic therapy Seizures Bladder dysfunction Dysphagia Pain Spasticity Depression Physical and occupational therapy

Chapter 49

Approach to the Patient with Central Nervous System Infection

SUGGESTED READINGS Jacobs LD, Beck RW, sirnonJH et al: Intramuscularinterferon beta-la therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898, 2000 Johnson RT: Viral infections of the nervous system. Lippincott-Raven Press, Philadelphia, 1998 Miller HG, Gibbons J L Acute disseminated encephalomyelitis and acute disseminated sclerosis: results of treatment with ACTH. BMJ 2:1345, 1953

SECTION

425

Sriram S, Steinman L Postinfectious and postvaccinal encephalomyelitis. Neurol Clin North Am 2:341, 1984 Tyor WR: Postinfectious encephalomyelitisand transverse myelitis. p. 155. In: Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Disease. 4th Ed. Mosby, St. Louis, 1993 Ziegler DK: Acute disseminated encephalitis: some therapeutic and diagnostic considerations. Arch Neurol 23:476, 1966

2 INFECTIOUS DISEASES

49

Approach to the Patient with Central Nervous System Infection J. Douglas Lee and Kurt Reed

When a patient is thought to have an infection of the central nervous system (CNS), considering the disease features in a sequential manner can limit the differential diagnosis and thereby expedite specific diagnosis and treatment. The steps consist of defining the clinical syndrome being evaluated, the medical characteristics of the affected patient, and the circumstances in which the disease was contracted and obtaining appropriate laboratory and imaging data,

DELINEATING THE CLINICAL SYNDROME The primary CNS infections include meningitis, encephalitis, myelitis, abscess, radiculopathy, and combinations of these. Each of these can exist in an acute to chronic spectrum. Acute disease usually is caused by viral or bacterial infections, and chronic disease usually is caused by granulomatous disease, syphilis, or less common infections. The spectrum of organisms ranges from prions to parasites. Meningitis in the acute form presents with an altered level of consciousness and fever or hypothermia as the most consistent features. Headache is combined in many cases with evidence of meningeal irritation (stiff neck), and the diagnosis of meningitis is confirmed by finding significant cerebrospinal fluid (CSF) pleocytosis. The duration of illness spans hours to days before presentation. The cause usually is viral or readily culturable bacterial infections, although rickettsial disease, syphilis, Lyme borreliosis, Listeria rnonocytogenes, leptospirosis, and noninfectious diseases can cause this syndrome. Chronic meningitis (more than 4 weeks’ duration) often causes a degree of encephalitis as well, producing lethargy and confusion.

The meningeal inflammation may produce cranial nerve palsies, and the CSF pleocytosis is mononuclear. Causes include granulomatous diseases, tumor, sarcoid, and syphilis, but many cases are idiopathic. Encephalitis of the acute type presents with the rapid onset of cortical dysfunction and fever, with a modest CSF pleocytosis. Common causes include viruses, especially herpes viruses, enteroviruses, human immunodeficiency virus (HIV), and mumps. Chronic encephalitis presenting as dementia usually is not of infectious origin, but syphdis and immunodeficiency-associated infections should be excluded, as should the conditions responsible for chronic meningitis. Myelitis often is associated with encephalitis and has a similar infectious disease differential diagnosis. It may present as transverse myelitis or as ascending disease with motor (poliomyelitis syndrome) or mixed sensory and motor findings. Mechanical cord compression, including that caused by abscesses or tumor, must be excluded as a first priority in cases consistent with a single level of cord dysfunction. Space-occupyinglesions, such as brain abscesses or the lesions of toxoplasmosis in acquired immune deficiency syndrome (AIDS), usually are accompanied by headache, altered mental status, and focal or lateralized signs indicating an intracranial site of involvement. Seizures are common. In the spinal canal the presentation is one of transverse myelitis. Radiculopathy, with evidence of sensory and motor dysfunction in a radicular distribution, usually is mechanical, but varicella-zoster virus, herpes simplex virus, and Lyme borreliosis may be responsible. Nonradicular neuropathy may be caused by Guillain-Barrk syndrome, diphtheria, or botulism.

Chapter 49

Approach to the Patient with Central Nervous System Infection

SUGGESTED READINGS Jacobs LD, Beck RW, sirnonJH et al: Intramuscularinterferon beta-la therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898, 2000 Johnson RT: Viral infections of the nervous system. Lippincott-Raven Press, Philadelphia, 1998 Miller HG, Gibbons J L Acute disseminated encephalomyelitis and acute disseminated sclerosis: results of treatment with ACTH. BMJ 2:1345, 1953

SECTION

425

Sriram S, Steinman L Postinfectious and postvaccinal encephalomyelitis. Neurol Clin North Am 2:341, 1984 Tyor WR: Postinfectious encephalomyelitisand transverse myelitis. p. 155. In: Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Disease. 4th Ed. Mosby, St. Louis, 1993 Ziegler DK: Acute disseminated encephalitis: some therapeutic and diagnostic considerations. Arch Neurol 23:476, 1966

2 INFECTIOUS DISEASES

49

Approach to the Patient with Central Nervous System Infection J. Douglas Lee and Kurt Reed

When a patient is thought to have an infection of the central nervous system (CNS), considering the disease features in a sequential manner can limit the differential diagnosis and thereby expedite specific diagnosis and treatment. The steps consist of defining the clinical syndrome being evaluated, the medical characteristics of the affected patient, and the circumstances in which the disease was contracted and obtaining appropriate laboratory and imaging data,

DELINEATING THE CLINICAL SYNDROME The primary CNS infections include meningitis, encephalitis, myelitis, abscess, radiculopathy, and combinations of these. Each of these can exist in an acute to chronic spectrum. Acute disease usually is caused by viral or bacterial infections, and chronic disease usually is caused by granulomatous disease, syphilis, or less common infections. The spectrum of organisms ranges from prions to parasites. Meningitis in the acute form presents with an altered level of consciousness and fever or hypothermia as the most consistent features. Headache is combined in many cases with evidence of meningeal irritation (stiff neck), and the diagnosis of meningitis is confirmed by finding significant cerebrospinal fluid (CSF) pleocytosis. The duration of illness spans hours to days before presentation. The cause usually is viral or readily culturable bacterial infections, although rickettsial disease, syphilis, Lyme borreliosis, Listeria rnonocytogenes, leptospirosis, and noninfectious diseases can cause this syndrome. Chronic meningitis (more than 4 weeks’ duration) often causes a degree of encephalitis as well, producing lethargy and confusion.

The meningeal inflammation may produce cranial nerve palsies, and the CSF pleocytosis is mononuclear. Causes include granulomatous diseases, tumor, sarcoid, and syphilis, but many cases are idiopathic. Encephalitis of the acute type presents with the rapid onset of cortical dysfunction and fever, with a modest CSF pleocytosis. Common causes include viruses, especially herpes viruses, enteroviruses, human immunodeficiency virus (HIV), and mumps. Chronic encephalitis presenting as dementia usually is not of infectious origin, but syphdis and immunodeficiency-associated infections should be excluded, as should the conditions responsible for chronic meningitis. Myelitis often is associated with encephalitis and has a similar infectious disease differential diagnosis. It may present as transverse myelitis or as ascending disease with motor (poliomyelitis syndrome) or mixed sensory and motor findings. Mechanical cord compression, including that caused by abscesses or tumor, must be excluded as a first priority in cases consistent with a single level of cord dysfunction. Space-occupyinglesions, such as brain abscesses or the lesions of toxoplasmosis in acquired immune deficiency syndrome (AIDS), usually are accompanied by headache, altered mental status, and focal or lateralized signs indicating an intracranial site of involvement. Seizures are common. In the spinal canal the presentation is one of transverse myelitis. Radiculopathy, with evidence of sensory and motor dysfunction in a radicular distribution, usually is mechanical, but varicella-zoster virus, herpes simplex virus, and Lyme borreliosis may be responsible. Nonradicular neuropathy may be caused by Guillain-Barrk syndrome, diphtheria, or botulism.

426

Immune and Infectious Disease W

Infectious Diseases

Involvement of multiple sites (e.g., meningitis with radiculopathy, or cranial neuritis and encephalopathy, or myelopathy with chronic encephalitis) in the acute state suggests a systemic viral or bacterial infection, syphilitic disease, Lyme borreliosis, or postinfectious phenomena. In the chronic state, neoplastic meningitis, syphilis, granulomatous disease, or other noninfectious causes are possible. MEDICAL CHARACTERISTICS OF THE AFFECTED PATIENT Immune Status The immune status of the patient may be the most important piece of epidemiologic information. Patients with antibody deficiency or dysfunction are predisposed to infections with encapsulated bacteria such as Neisseria meningitidis, Streptococcus pneumoniae, and Haernophilus influenzae, which are major causes of meningitis. Patients with agammaglobulinemia rarely develop chronic enteroviral encephalitis. Deficiencies of the terminal components of the complement pathway predispose to Neisseria infections, and patients with a family history of these infections or a recurrent history of Neisseria infections should be evaluated for these deficiencies. Patients with impaired inflammatory responses (e.g., chronic steroid use) or deficient cell-mediated immunity are particularly prone to intracellular infections such as fungal, mycobacterial, Listeria, and herpetic infection. In the presence of advanced AIDS all of these infections are considered, but reactivation toxoplasmosis, tuberculosis, progressive multifocal leukoencephalopathy, cryptococcosis and other fungal infections, syphilis, and HIV dementia deserve special consideration. Associated Diseases A number of medical conditions predispose to specific neurologic infections. Patients with chronic sinus or mastoid infection are predisposed to brain abscess, as are patients with chronic suppurative pulmonary infections (bronchiectasis and lung abscess), dental sepsis, endocarditis, or intracardiac or intrapulmonary right-to-left shunts. Coexisting pneumonitis should raise the question of nocardiosis, tuberculosis, histoplasmosis, blastomycosis, or coccidioidomycosis in patients with CNS disease. Chronic or recurrent uveitis may indicate the existence of systemic lupus erythematosus (SLE), toxoplasmosis, Behget syndrome, sarcoidosis, leprosy, or Vogt-Koyanagi-Harada (VKH) syndrome. Skin depigmentation is also seen in VKH and in other autoimmune diseases. Neoplastic disease may cause carcinomatous meningitis or space-occupying lesions, mimicking chronic meningitis or abscess, respectively. Certain drugs are known to cause sterile meningitis (sulfamethoxazole-trimethoprim,nonsteroidal antiinflammatory drugs [NSAIDs], and azathioprine), as can connective tissue diseases (SLE, Behget syndrome, vasculitis, and sarcoidosis). Surgical or traumatic damage to the meninges predisposes to skin flora, gram-negative rod and staphylococcal meningitis, and, if associated with mucosal surfaces, pneumococcal or “normal respiratory flora” meningitis.

insects, untreated water, or standing water. Epidemics of bacterial CNS diseases are rare with the exception of meningococcal disease in closed populations such as in barrack living. The distribution of cases in time and place (family, work, school, or community at large) and history of animal or insect exposure (Table 49-1) may indicate the nature of transmission (airborne, arthropod vector) and thus the origin. Although a patient who is the first in a viral epidemic often is treated for bacterial disease, after the first few cases information from the laboratory allows less aggressive treatment of subsequent cases. Geography If the patient recently has traveled internationally, diseases uncommon in the United States should be considered. These include viral encephalitis, tick-borne encephalitis, malaria, typhus, trypanosomiasis, schistosomiasis, rabies, and brucellosis. Current information and advisories are available at www.cdc.gov/travel, where one can search by geographic area. Vocational and Avocational Exposures Vocational and avocational exposures relate mainly to zoonotic diseases. People who spend much of their time outdoors are at particular risk of Lyme disease (borreliosis), rickettsial diseases, and other arthropod-borne illnesses. Animal handlers are at risk for the zoonoses described earlier. On occasion living or working

TABLE49-1. Partial List of Exposure Histories and CNS Infections Exposure

Aaent Twe

Disease

Mosquito

Arboviruses (worldwide) Malaria Arboviruses Rickettsia Borrelia burgdorferi Rickettsia Afipia felis Bartonella Rickettsia Herpes B virus Toxoplasma Rabies virus A. felis Bartonella Coxiella burnetii Lymphocytic choriomeningitis virus Brucella Rabies virus C. burnetii Leptospira Rabies virus Brucella Leptospira Rabies virus Brucella Leptospira Rabies virus C. burnetii Brucella Leptospira Rabies virus

Encephalitis Cerebral malaria Encephalitis Spotted fevers, typhus Lyme disease Scrub typhus Cat scratch disease Cat scratch disease Scrub typhus Encephalitis Toxoplasmosis Rabies Cat scratch disease Cat scratch disease Q fever Meningoencephalitis

Toxocara canis Rabies virus

Meningoencephalitis Rabies

Ticks fleas and lice Mites Monkeys Cats

Mice Cattle Rodents Horses Swine Goats and sheep

CIRCUMSTANCES OF THE INFECTION Epidemic or Sporadic When other patients appear to have the same condition during the same time period (an epidemic), a virus is the usual cause. Seasonality is also a factor, particularly for diseases for which risk is related to recreational activities or environmental exposure to

Skunks, foxes, dogs, and other carnivores

Doas Bat;

Chronic meningitis Rabies Q fever Meningoencephalitis Rabies Chronic meningitis Encephalitis Rabies Chronic meningitis Encephalitis Rabies Q fever Chronic meningitis Encephalitis Rabies

Chapter 49

in crowded, poorly ventilated areas has resulted in epidemics, particularly of Neisseria.

LABORATORY DATA Blood Tests Of the routine available laboratory tests, the complete blood count may indicate chronicity of disease or underlying hematologic disease. Leukopenia or absence of leukocytosis may indicate severe sepsis, viral or granulomatous causes, connective tissue disease, or a noninfectious cause. Lymphocytosis, particularly atypical lymphocytosis, suggests a viral cause but may be present in toxoplasmosis and other intracellular infections. Thrombocytopenia may indicate sepsis, disseminated intravascular coagulation underlying marrow disease, or an autoimmune disease. Hyperglobulinemia suggests either a chronic inflammatory disorder (HIV, chronic infection, or connective tissue disease) or a plasma cell or lymphocytic disorder with possible antibody deficiency or dysfunction. Abnormalities of liver or renal function imply a multisystem disease and indicate the need to search for disseminated infections (viral, spirochetal, rickettsial, Whipple’s disease, or granulomatous infections), as well as noninfectious causes. Spinal Fluid EvaluatSon Examination of the CSF is simple and usually the single most valuable laboratory test available. In all diseases the range of values for any CSF test value is very large, and much overlap exists, but some guidelines are useful. The CSF white blood cell counts and differential must be interpreted with caution. In general, infections of the parenchyma and parameningeal foci of infection result in a less intense pleocytosis, a tendency toward mononuclear pleocytosis, and lower protein levels than does meningitis. Cell counts in bacterial meningitis tend to be higher (1000 to 5000/mm3) than in viral infection (100 to 1000/mm3), but there are many exceptions. Although bacterial meningitis usually has a neutrophilic pleocytosis (above 85%), in partially treated bacterial infections the differential may shift toward the right. Viral meningitis (especially mumps) may also present with a neutrophilic pleocytosis before changing to a lymphocytosis after a day or so. The presence of eosinophils (rare) suggests allergic or parasitic disease but may be seen with tuberculosis, fungal infections, and lymphoma. Large numbers of red blood cells in the CSF, if not caused by a traumatic tap, suggest subarachnoid bleed, herpes encephalitis, or another necrotizing process. The presence of elevated protein is expected in all CNS infections, but very high levels (more than 400 mg/dL) with few cells suggest neoplasm. Proteins of 100 to 400 mg/dL are typical of bacterial meningitis, whereas levels usually are lower in viral meningitis. In chronic infections or inflammation the CSF y-globulin levels may be high relative to albumin, suggesting intracompartmental antibody production. Glucose in bacterial meningitis usually is less than 35 mg/dL but normal in viral infections and parenchymal infections. Numerous exceptions to this rule are seen.

Approach to the Patient with Central Nervous System Infection

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and bacterial pathogens may be present in low concentrations (e.g., Cryptococcus and Mycobacterium tuberculosis), it is important to provide at least several milliliters of CSF to the laboratory. If unusual pathogens (e.g., Leprospiru or Borrelia) are a consideration, consultation with the laboratory will allow the most appropriate methods of detection to be used. Blood cultures should be done in all cases of suspected acute meningitis. During community outbreaks of meningitis, the agent should be fully identified from at least the first patients identified in the epidemic and the results forwarded to public health officials. Serologic Tests Serologic studies to detect organism-specific antibodies may complement microbiologic results. For fastidious organisms or those that are not cultivable in most laboratories, diagnosis may depend on serologic testing (such as syphilis, borreliosis, many viruses, rickettsia, mycoplasma, protozoa, and parasites). A few infections may be diagnosed using a single serum specimen (syphilis, brucellosis, HIV, human T-cell leukemidlymphoma virus-I), but when any serology is negative, paired serum samples drawn 2 or more weeks apart, in the acute and convalescent stages of illness, are more sensitive and specific. In advanced AIDS, comparable states of immunosuppression, and hypogammaglobulinemia, negative serologies may remain negative because of the patient’s inability to produce antibody. Detection of localized antibody production in the CNS (organism-specific CNS antibody index) is possible for many organisms. These tests are not well standardized. Because interpretive criteria generally originate in the laboratory that performs the test, consultation with the reference laboratory is recommended to ensure proper interpretation of the results. Antigen Tests Antigen detection in the CSF is the rapid diagnostic method of choice for cryptococcal infection. Patients with AIDS and cryptococcal infection have positive serum cryptococcal antigen more often than do patients without HIV. Detection of bacterial antigens in CSF, serum, or urine should not be used routinely, but this test plays a role in the patient with partially treated meningitis. Molecular Diagnosis There is increasing use of molecular methods to provide rapid and specific diagnosis of CNS infections. In the case of suspected herpes simplex virus infection, polymerase chain reaction of CSF is of proven value and can allow prompt initiation of life-saving therapy. Similar amplification technology is available for the diagnosis of enteroviral as well as an increasing number of other viral and bacterial pathogens. Use of these tests generally is not helpful unless there are significant leukocyte and protein abnormalities in the CSF. The current costs of these tests prohibit the effective use of them in a shotgun approach. New organism-specific tests will continue to become available, so consultation with the reference laboratory is recommended when difficult cases are encountered.

Microbiologic Tests

Imaging Studies

Recovery of the etiologic agent in culture provides a definitive diagnosis and should always be attempted when infection is a consideration and CSF has been obtained. Because some fungal

Imaging studies (CT scan or MRI) are indicated if spaceoccupying lesions or hydrocephalus are suspected or if knowledge of the extent and location of the inflammatory process is needed

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for diagnosis or planning of biopsies. If imaging is needed in a setting; that is compatible with acute meningitis and a lumbar puncture is deemed inadvisable, then empirical therapy must be used, pending imaging and lumbar puncture. If images cannot be obtained immediately, empirical therapy is unlikely to obscure the diagnosis because blood cultures often are positive, the CSF will not be sterilized immediately, and CSF antigen tests often are positive.

50

SUGGESTED READINGS Mitchell PS, Espy MI, Smith TF et al: Laboratory diagnosis of central nervous system infections with herpes simplex virus by PCR performed with cerebral spinal fluid. J Clin Microbiol35:2873-2877, 1997 Tang YW, Ebbs JR Tau KR et al: Effective use of polymerase chain reaction for diagnosis of central nervous system infections. Clin Infect Dis 29:803-806, 1999

Bacterial Meningitis Thomas P. Giordano, Steven J. Spindel, and Richard L. Harris

Bacterial meningitis in adults is a serious infection that results in severe morbidity and mortality. The annual incidence of bacterial meningitis in the United States is about 3 per 100,000people, or approximately 8500 cases. Despite recent medical advances, the mortality from bacterial meningitis remains between 10% and 35%, and neurologic sequelae are still a significant complication.

EPIDEMIOLOGY Causes of acute bacterial meningitis can be divided into community-acquired and nosocomial. Approximately one half of all community-acquired infections in adults are caused by Streptococcus pneumoniae and Neisseria rneningitidis (Table 50- 1). Other organisms causing meningitis are Listeria monocytogenes, streptococci, Staphylococcus aureus, and Haernophilus influenzae type B. Until recently, H. influenzae contributed a significant portion of community-acquired meningitis, especially in younger age groups. However, the incidence of H. influenzae invasive disease has declined by more than 90% since the advent of conjugated H. influenzae type B vaccine in 1988. Nosocomial episodes of meningitis are defined as those that occur while the patient is hospitalized (typically more than 48 hours after admission) or within 1 week after discharge. The proportion of meningitis that is nosocomially acquired has risen significantly over the past three decades, increasing from 28% in

TAW 50-1. Causative Organisms in Adult Bacterial Meningitis Ornanism

S. pneumoniae N. meningitidis Other streptococci L monocytogenes S. aureus Cram-negative bacilli (not H. influenzae)

H. influenzae Mixed infection Anaerobes Enterococci Coagulase-negative staphylococci

CommunityAcquired (%)

Nosocomial (%)

38-48 14-15 7-1 2 6-1 1 5-9 4-5

5 <1 7 3 10 39

3-4 1-2 0- 1 0- 1 0

3 7 1 3 8

(Data modified from Durand MI., Calderwood SB. Weber DJ et al: Acute bacterial meningitis in adults. N Engl J Med 328(1):21-28, 1993; and Aronin SI, Peduui P, Quagliarello VJ: Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 129(11):862-869, 1998.)

rn

the 1960s to 48% in the 1980s because of advancing medical technology in neurosurgical techniques and the care of trauma patients. Most cases of nosocomial meningitis occur in patients after recent neurosurgery, placement of a neurosurgical device, or head trauma. Nosocomial meningitis without antecedent neurosurgical procedures or trauma is rare but occurs in patients who have contiguous or extracranial sites of infection and are otherwise debilitated. The majority of cases of nosocomial meningitis are caused by gram-negative bacilli (other than H. inpuenzae), staphylococci, and streptococci. The overall incidence and proportion of meningitis caused by gram-negative bacilli (other than H. influenzae) and staphylococci has increased primarily because of these factors. The incidence of infection of ventricular shunts, ventriculostomies, intracranial pressure (ICP) monitors, or cerebrospinal fluid (CSF) reservoirs varies but averages 5% to 15%. The risk of infection is proportional to the amount of time the device is externalized and, with ICP monitors, increases when in place for 72 hours or more. CSF reservoirs and shunts usually become infected within 1 to 2 months of placement. Staphylococci and gram-negative bacilli account for up to 50% and 25% of these infections, respectively. Nosocomial meningitis can occur in almost one fifth of patients with head trauma and up to 50% of patients with head trauma and a CSF leak. CSF leaks are most frequently associated with patients who have a basilar skull fracture. Pathogens associated with meningitis caused by basilar skull fractures often reflect nasopharyngeal colonization and so are similar to those in community-acquired infection (S. pneumoniae, N.rneningitidis, H. influenzae).

PATHOPHYSIOLOGY Bacteria that invade the CSF and cause meningitis have several virulence factors. They must be able to colonize the nasopharynx, penetrate into and survive in the bloodstream, and breach the blood-brain barrier to enter the CSF. In the CSF, there are few if any host immune defenses. The lack of complement-mediated or humoral immunity enables the bacteria to replicate with ease. Resultant damage in the central nervous system (CNS) probably is caused by the local production of cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor. Cytokines are stimulated by bacterial cell wall components such as lipoteichoic acid of S. pneurnoniae and lipopolysaccharide of gram-negative bacteria. These cytokines directly and indirectly initiate a cascade of immune responses that allow leukocytes to adhere to endothelial

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for diagnosis or planning of biopsies. If imaging is needed in a setting; that is compatible with acute meningitis and a lumbar puncture is deemed inadvisable, then empirical therapy must be used, pending imaging and lumbar puncture. If images cannot be obtained immediately, empirical therapy is unlikely to obscure the diagnosis because blood cultures often are positive, the CSF will not be sterilized immediately, and CSF antigen tests often are positive.

50

SUGGESTED READINGS Mitchell PS, Espy MI, Smith TF et al: Laboratory diagnosis of central nervous system infections with herpes simplex virus by PCR performed with cerebral spinal fluid. J Clin Microbiol35:2873-2877, 1997 Tang YW, Ebbs JR Tau KR et al: Effective use of polymerase chain reaction for diagnosis of central nervous system infections. Clin Infect Dis 29:803-806, 1999

Bacterial Meningitis Thomas P. Giordano, Steven J. Spindel, and Richard L. Harris

Bacterial meningitis in adults is a serious infection that results in severe morbidity and mortality. The annual incidence of bacterial meningitis in the United States is about 3 per 100,000people, or approximately 8500 cases. Despite recent medical advances, the mortality from bacterial meningitis remains between 10% and 35%, and neurologic sequelae are still a significant complication.

EPIDEMIOLOGY Causes of acute bacterial meningitis can be divided into community-acquired and nosocomial. Approximately one half of all community-acquired infections in adults are caused by Streptococcus pneumoniae and Neisseria rneningitidis (Table 50- 1). Other organisms causing meningitis are Listeria monocytogenes, streptococci, Staphylococcus aureus, and Haernophilus influenzae type B. Until recently, H. influenzae contributed a significant portion of community-acquired meningitis, especially in younger age groups. However, the incidence of H. influenzae invasive disease has declined by more than 90% since the advent of conjugated H. influenzae type B vaccine in 1988. Nosocomial episodes of meningitis are defined as those that occur while the patient is hospitalized (typically more than 48 hours after admission) or within 1 week after discharge. The proportion of meningitis that is nosocomially acquired has risen significantly over the past three decades, increasing from 28% in

TAW 50-1. Causative Organisms in Adult Bacterial Meningitis Ornanism

S. pneumoniae N. meningitidis Other streptococci L monocytogenes S. aureus Cram-negative bacilli (not H. influenzae)

H. influenzae Mixed infection Anaerobes Enterococci Coagulase-negative staphylococci

CommunityAcquired (%)

Nosocomial (%)

38-48 14-15 7-1 2 6-1 1 5-9 4-5

5 <1 7 3 10 39

3-4 1-2 0- 1 0- 1 0

3 7 1 3 8

(Data modified from Durand MI., Calderwood SB. Weber DJ et al: Acute bacterial meningitis in adults. N Engl J Med 328(1):21-28, 1993; and Aronin SI, Peduui P, Quagliarello VJ: Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 129(11):862-869, 1998.)

rn

the 1960s to 48% in the 1980s because of advancing medical technology in neurosurgical techniques and the care of trauma patients. Most cases of nosocomial meningitis occur in patients after recent neurosurgery, placement of a neurosurgical device, or head trauma. Nosocomial meningitis without antecedent neurosurgical procedures or trauma is rare but occurs in patients who have contiguous or extracranial sites of infection and are otherwise debilitated. The majority of cases of nosocomial meningitis are caused by gram-negative bacilli (other than H. inpuenzae), staphylococci, and streptococci. The overall incidence and proportion of meningitis caused by gram-negative bacilli (other than H. influenzae) and staphylococci has increased primarily because of these factors. The incidence of infection of ventricular shunts, ventriculostomies, intracranial pressure (ICP) monitors, or cerebrospinal fluid (CSF) reservoirs varies but averages 5% to 15%. The risk of infection is proportional to the amount of time the device is externalized and, with ICP monitors, increases when in place for 72 hours or more. CSF reservoirs and shunts usually become infected within 1 to 2 months of placement. Staphylococci and gram-negative bacilli account for up to 50% and 25% of these infections, respectively. Nosocomial meningitis can occur in almost one fifth of patients with head trauma and up to 50% of patients with head trauma and a CSF leak. CSF leaks are most frequently associated with patients who have a basilar skull fracture. Pathogens associated with meningitis caused by basilar skull fractures often reflect nasopharyngeal colonization and so are similar to those in community-acquired infection (S. pneumoniae, N.rneningitidis, H. influenzae).

PATHOPHYSIOLOGY Bacteria that invade the CSF and cause meningitis have several virulence factors. They must be able to colonize the nasopharynx, penetrate into and survive in the bloodstream, and breach the blood-brain barrier to enter the CSF. In the CSF, there are few if any host immune defenses. The lack of complement-mediated or humoral immunity enables the bacteria to replicate with ease. Resultant damage in the central nervous system (CNS) probably is caused by the local production of cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor. Cytokines are stimulated by bacterial cell wall components such as lipoteichoic acid of S. pneurnoniae and lipopolysaccharide of gram-negative bacteria. These cytokines directly and indirectly initiate a cascade of immune responses that allow leukocytes to adhere to endothelial

Chapter 50

cells in the cerebral vasculature and migrate into the CSF. Intercellular junctions become leaky, and albumin exudes into the CSF. Locally released cytokines cause cells to swell, and CSF outflow is slowed. The resultant brain edema, increased intracranial pressure, and altered cerebral blood flow may result in severe consequences such as ischemic brain damage, seizures, cranial nerve injuries, and herniation. Meningitis after head trauma is initiated when organisms colonizing the nasopharynx or the skin are directly introduced into the CSF. Basilar skull fractures allow organisms from the sinuses, ear canal, and mastoid air cells to enter the CSF. Meningitis caused by ventricular shunts and ventriculostomies most commonly occurs as infection progresses in a retrograde fashion from the distal end. Other routes of infection for shunts include skin or wound breakdown, hematogenous seeding, and contamination of the surgical device at the time of placement.

PATHOGENS The pneumococcus is the most common cause of bacterial meningitis in adults, accounting for one third to one half of all cases. Pneumococcal meningitis occurs in the late fall and winter, and outbreaks are associated with overcrowded conditions. S. pneumoniae is also the most common organism associated with CSF leaks and represents the most common cause of recurrent episodes of bacterial meningitis. Pneumonia is seen in one fourth of cases, and concomitant disease such as sinusitis, mastoiditis, or otitis often is present. Pneumococcal meningitis is seen in all age groups but has an increased incidence at the extremes of age (less than 2 or more than 60 years of age) and in patients with underlying medical disorders. Predisposing factors include alcoholism, cirrhosis, sickle cell anemia, asplenia, thalassemia, multiple myeloma, chronic lymphocytic leukemia, and immunoglobulin deficiencies. Meningococcal meningitis is caused by serogroups A, B, C, Y, and W135 of N.meningitidis. The overwhelming majority of cases of meningococcal meningitis in the United States are sporadic, and epidemic outbreaks are very rare, but such outbreaks remain common in developing areas of the world. Groups B, C, and Y account for most of the sporadic cases of meningitis in the United States. In epidemics, groups A and C are more likely to be found. Meningococcal meningitis follows seasonal trends, occurring in the winter and early spring. It afflicts mostly children and young adults. Its peak incidence occurs in infants less than 4 months of age, with half of the cases occurring in infants less than 2 years old. Only 10% of cases occur in patients more than 45 years old unless an epidemic is in progress. Nasopharyngeal carriage of virulent strains is found in 20% to 40% of young adults and contacts, although in epidemics this can approach 90%. Patients with primary terminal complement deficiencies ( C X 9 ) are at greater risk for invasive neisserial diseases including meningitis but have lower mortality rates from these diseases than the general population. Other diseases that impair humoral immunity or complement function, such as the nephrotic syndrome, multiple myeloma, systemic lupus erythematosus, and hepatic failure, increase the risk for meningococcal meningitis. Meningitis caused by H. influenme usually is caused by serotype B, with less than 15% being non-type B. In the northern United States there is a biphasic incidence pattern peaking in the spring and the fall. There has been a dramatic change in the epidemiology of all H. influenme disease since the introduction of conjugated vaccines and earlier vaccination schedules since 1988.

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429

H. influenzae once was the most common cause of meningitis in children up to age 6, and 80% of these cases occurred in children less than 2 years old. Only 5% of cases occurred in adolescents between ages 10 and 18. Since the use of the new vaccines, the incidence of H. influenzae disease has decreased by almost 95% in children under age 5 , and H. influenzae is now an uncommon cause of meningitis. It is an even rarer pathogen in adults, but more than half of these patients have a risk factor such as a CSF leak, head trauma, or contiguous infection (e.g., otitis or sinusitis). Additional risk factors include immunodeficiencies such as alcoholism, hypogammaglobulinemia, diabetes mellitus, asplenia, and HIV infection. L. monocytogenes causes meningitis primarily in neonates and occasionally in adults. It can occur in otherwise healthy patients but remains a leading cause of bacterial meningitis in immunocompromised hosts. Patients at risk include alcoholics, diabetics, pregnant women, patients on corticosteroids, patients with liver failure or iron overload, patients with HIV infection, renal transplant recipients, and neutropenic patients. Infections usually occur in the summer and early fall. Meningitis results from bacteremia, the source of which is presumed to be the gastrointestinal tract. L. monocytogenes is a P-hemolytic gram-positive bacillus, so a laboratory report of diphtheroids or P-hemolytic streptococci would prompt suspicion of possible Listeria meningitis. The physician must work closely with the microbiology laboratory to assist in the diagnosis of this disease. Various streptococci including viridans streptococci and groups A, B, D, and G can cause meningitis in older adults and are associated with pneumonia, endocarditis, or brain abscess. Underlying diseases in susceptible patients include diabetes mellitus, cancer, alcohol abuse, hepatic failure, renal failure, and corticosteroid use. The frequency of meningitis caused by gram-negative bacilli other than H. influenzae increased from 11% to 24%between 1962 and 1988. Gram-negative bacilli are an uncommon cause of community-acquired meningitis (less than 5%); however, they are a constant and significant source of nosocomial meningitis (40%). Half of the cases occur in postneurosurgical patients, and one third occur after head trauma. The remainder occur in neutropenic patients and other immunocompromised hosts such as those with acquired immunodeficiency syndrome (AIDS), cirrhosis, and diabetes mellitus. Gram-negative bacillary meningitis occurs primarily in patients over age 60. Escherichia coli and Klebsiellu pneumoniae are the most common causes, accounting for three fourths of meningitis caused by gram-negative organisms. Other pathogens include Pseudomonas aeruginosa, Proteus, Enterobacter, Acinetobacter, and Serratia. Staphylococcus aureus and the coagulase-negative staphylococci account for the majority of ventricular shunt infections and also cause meningitis in patients who have suffered head trauma and needed invasive neurosurgical procedures. Communityacquired cases of S. aureus meningitis are uncommon (approximately 5%). Most of these patients have extracranial sources of infection such as endocarditis or skin and soft tissue infections that seed the meninges hematogenously. One half of patients have underlying diabetes mellitus, cancer, renal failure, alcoholism, or other immunodeficiencies. The coagulase-negative staphylococci do not cause meningitis in the absence of invasive procedures into the CNS. Less common causes of meningitis include enterococci, anaerobes, nocardia, diphtheroids, and mixed infection. Enterococcal meningitis usually occurs in the severely debilitated patient with

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multiple medical conditions or another focus of enterococcal infection. Anaerobic meningitis is associated with trauma or a contiguous focus of infection, such as otitis, sinusitis, or a soft tissue abscess. Nocardial meningitis is rare and is associated with underlying malignancy or other immunocompromised state in 75% of cases. Diphtheroids cause meningitis only in patients with CNS shunts or a history of other invasive procedures. Spinal fluid cultures yielding mixed flora should alert the clinician to the presence of a contiguous site of infection, unsuspected trauma, or malignancy that has damaged the barriers between the CNS and the rest of the body.

CLINICAL MANIFESTATIONS Approximately 95% of patients with meningitis have fever, 80% have meningismus, and 70% have altered mental status. Most patients have a headache. The classic triad of fever, meningismus, and cognitive dysfunction occurs in about two thirds of patients with bacterial meningitis. In addition, about 25% of patients have focal neurologic findings (such as cranial nerve palsies, hemiparesis, aphasia, or visual field deficits), and 20% have a rash. Other common symptoms are nausea, vomiting, rigors, sweats, weakness, myalgias, and photophobia. Confusion, lethargy, obtundation, and coma represent the range of mental status changes that can occur. Seizures are seen in up to one third of patients. Papilledema is a rare finding and, if present, raises the suspicion of an intracranial mass or abscess. Pneumococcal meningitis is more likely to cause altered mental status and focal neurologic defects than meningitis caused by other pathogens. A petechial rash of the extremities is associated with meningococcemia in about 50% of cases but can be seen with other infections, such as pneumococci, staphylococci, or H. influenme, especially in asplenic patients. Echovirus and rickettsiae also cause similar rashes. Atypical skin rashes such as purpuric changes and maculopapular lesions can also be seen. Older adults may present with very subtle signs and symptoms, and confusion is the most common presenting symptom. Nuchal rigidity is less common in older adults, appearing in only about one half of patients. However, these patients may have neck stiffness caused by other diseases, and often a lumbar puncture must be performed in a febrile older adult with neck stiffness and altered mental status to rule out meningitis. Neutropenic patients can also present with mild and nonspecific signs and symptoms because of their inability to mount an inflammatory response. The clinical manifestations of meningitis in patients who have suffered head trauma or have undergone neurosurgery are similar to those with community-acquired meningitis. However, because the patient’s underlying condition can mimic or obscure meningeal symptoms, the diagnosis can be difficult. Rhinorrhea or otorrhea may be indicative of a CSF leak, which can occur in patients with basilar skull fractures. Patients with intraventricular shunt infections may exhibit fewer meningeal signs because infection is limited primarily to the ventricles. Signs and symptoms such as headache, nausea, vomiting, and mental status changes probably result from shunt malfunction rather than infection itself. Fever may be absent. There may be associated clinical findings from bacteremia or peritonitis because of infection at the distal end of the ventricular shunt.

DIAGNOSIS The suspicion of bacterial meningitis is a medical emergency, and it is critical that the diagnosis be made urgently because infection can be rapidly progressive and fatal. Empirical antimicrobial therapy should be initiated as soon as possible, preferably once CSF and blood cultures have been obtained. As long as focal neurologic findings and papilledema are absent, a lumbar puncture should be performed immediately. If papilledema or focal neurologic deficits are present, an intracranial mass or abscess should be excluded by a computed tomography (CT) scan. Before performing an imaging study, the clinician should obtain blood cultures from these patients and administer antibiotics. Further management and refinement of antibiotics can be performed after the Gram stain of the CSF and other laboratory data become available. A difficult and often controversial situation arises when lumbar puncture has not been or cannot be performed but meningitis is highly suspected. We recommend obtaining blood cultures immediately and initiating empirical therapy. The etiologic agent still is likely to be identified via the blood cultures (positive in 50%), in cultures of CSF obtained after antibiotics are given, or by latex agglutination tests. Studies of the CSF in bacterial meningitis typically reveal a white blood cell (WBC) count greater than 1000/mm3, neutrophil predominance, glucose less than 40 mg/dL or less than 50% of the serum glucose, and protein greater than 100 mg/dL (Table 50-2). It is important to remember that any or all of the CSF studies may be normal in up to 30% of cases of bacterial meningitis. The differential white blood cell count demonstrates a predominance of neutrophils, although lymphocytosis occurs in 14% of cases (especially in meningitis caused by L. rnonocytogenes or in patients with partially treated meningitis of any cause). Hypoglycorrhachia occurs in 50% to 70% of patients, and almost all have elevated protein levels. Normal ventricular fluid has slightly higher glucose and lower protein concentrations than lumbar CSF, which should be taken into account when evaluating ventricular CSF. Organisms are seen on Gram stain in 60% to 90% of culture-positive cases, and the yield can be improved with cytospin preparations of the CSF. The most common error on CSF analysis is the misidentification of L. rnonocytogenes as pneumococci. Cultures are positive in at least 70% of patients with bacterial meningitis. Prior antibiotics usually have little effect on initial CSF findings, but they can convert the pleocytosis to a lymphocytic predominance, decrease the yield of CSF Gram stains to 40% to 60%, and also decrease the yield of CSF cultures by one third. The opening pressure is elevated in 75% or more patients (above 140 to 200 mm H,O), although extremely high values (e.g., higher than 600 mm H,O) should suggest an intracranial mass or communicating hydrocephalus. Rapid diagnostic tests such as counterimmunoelectrophoresis

TABU50-2. Typical Findings in Normal and Infected

Cerebrospinal Fluid Normal

Bacterial Meningitis

White blood cells (per mm’) Pleocytosis

<5 >85%

> 1000 Average 85% neutrophils

Glucose (rng/dL) CSF:serum glucose ratio Protein (mg/dL)

45-60 0.6 10-60

lymphocytes

<40 <0.5

>loo

Chapter 50

(CIE) and latex agglutination are available for most bacterial pathogens. They have good specificity, but sensitivities are highly variable and dependent on the methods used. It is important to realize that the diagnosis of meningitis should not be excluded by a negative test. Rapid tests can detect nonviable bacteria and can be helpful, especially in patients who receive antibiotics before obtaining CSF for cultures. CIE and latex agglutination tests can be obtained for H. inj7uenzae type B, S. pneurnoniae, group B streptococci, E. coli K, staphylococci, and N. meningitidis groups A, C, Y, and W135. Tests to detect nuclear material based on the polymerase chain reaction are in development. In addition, preliminary clinical data suggest that serum procalcitonin levels may aid in rapidly distinguishing bacterial from nonbacterial meningitis. In patients with suspected nosocomial meningitis without continuous access to the CSF, imaging to rule out raised ICP before lumbar puncture is warranted because of the high likelihood of raised ICP after neurosurgery or trauma. In those with continuous access, CSF may be obtained directly. It may be more difficult to diagnose meningitis in patients after trauma or neurosurgery because of the underlying CSF changes and pleocytosis that occur in these conditions. However, a neutrophilic pleocytosis usually is present, and the WBC to red blood cell ratio in the CSF should be higher than CSF values after trauma or neurosurgery. Nevertheless, the diagnosis of meningitis ultimately may be based on culture results. In meningitis caused by CSF leaks, radiographic imaging can detect clues such as basilar skull fractures or opacification of sinuses. Nuclear medicine tests such as radionuclide cisternography are sensitive but nonspecific for the site of CSF leaks. The best test to detect the site of CSF leakage is a CT scan with CSF contrast enhancement with metrizamide. These tests should not be performed acutely but rather after the infection has been suppressed. When a ventricular shunt infection or ventriculitis is suspected, the CSF should be sampled from the ventricle because CSF obtained from the lumbar area may not accurately reflect the presence of infection. CSF glucose often is normal, and the WBC count may be normal or increased in these cases. CT scans may demonstrate the route by which meningeal infection has been introduced, such as erosive lesions, septic emboli, or abscesses. Other findings may include meningeal enhancement, ventriculomegaly, hydrocephalus, infarctions, cavernous sinus thrombosis, and subdural effusions or empyemas.

TREATMENT Antimicrobial agents for treating bacterial meningitis must be able to penetrate the blood-brain barrier into the CSF and attain high bactericidal concentrations in the CSF. Empirical therapy can be based on the age, clinical syndrome, and the risk factors of the host. The necessity for urgent treatment often dictates that an antibiotic be started before the causative agent can be identified definitively. A reasonable empirical therapeutic regimen for community-acquired meningitis in adults must take into account the growing rate of penicillin-resistant pneumococci and should therefore include vancomycin and cefiriaxone (or cefotaxime), which cover pneumococci and meningococci. If the patient is more than 50 years old or has impaired cellular immunity (because of steroids, HIV infection, or other immunocompromising agents or conditions, including alcoholism), ampicillin should

Bacterial Meningitis

43 1

w TMLE 50-3. Adult Dosages of Antibiotics Used for Bacterial Meningitis Antibiotic

Dosage and Interval

Amikacin

15 mg/kg/day IV in two or three divided doses ? 5-1 0 mg IT q12-24h to keep CSF levels 2-1 0 pJmL 2 g IV q4h 2 g IV q6-8h 2 g IV q8h 2 g IV q4h 2 g IV q8h 2-3 g IV ql2h 1-1.5 g IV q6h 5 mg/kJday IV in two or three divided doses ? 4 mg IT ql2-24h to keep CSF levels 2-10 pJmL 1-2 g IV q8h 2-3 g IV q4h 4 million U IV q4h 3-4 g IV q4-6h 600 mg PO or IV qd 10 mJkg IV q8h 1 g IV ql2h k 5-20 mg IT q24-48h to keep CSF levels >10 pg/mL

Ampicillin Aztreonam Cefepime Cefotaxime Ceftazidime Ceftriaxone Chloramphenicol Gentamicin or tobramycin Meropenem Nafcillin or oxacillin Penicillin G* Piperacillin Rifampin Trimethoprim-sulfamethoxazolet Vancomycin+

*If penicillin is unavailable, use ampicillin. tDosage based on trimethoprim component *Higher or more frequent dosages may be needed to give adequate CSF levels. Abbrevid'ons: IT, intrathecal (or intraventricular).

be added for L. rnonocytogenes. An empiric regimen for nosocomid meningitis should include vancomycin for gram-positive bacteria (including methicillin-resistant S. aureus and coagulasenegative staphylococci) and ceftazidime, cefepime, or meropenem for nosocomial gram-negative bacilli. (Recommended dosages for these antimicrobials are listed in Table 50-3.) Once the identification and susceptibility of the organism are confirmed, antibiotic treatment can be tailored for the specific cause (Table 50-4). Duration of therapy is traditionally 10 to 14 days for most organisms. Gram-negative meningitis should be treated for at least 21 days or until 10 days after a negative CSF culture. Third-generation cephalosporins are the treatment of choice, and systemic aminoglycosides can also be added (amikacin has better CSF penetration than gentamicin or tobramycin). Piperacillin, meropenem, or trimethoprim-sulfamethoxazolecan be substituted for cephalosporins if resistant organisms are suspected. Imipenemcilastatin should not be used because of the high rate of seizures observed when used in patients with meningitis. Intraventricular or intrathecal aminoglycosides may be added in these cases or when the patient is not responding, especially if antibiotic concentrations in the CSF are low. Experimental animal data and case reports suggest that fluoroquinolones may be an acceptable alternative in certain situations, but other options should be tried before resorting to a quinolone. Treating infections associated with neurosurgical devices may be difficult. Intravenous antibiotics alone are successful in only one fourth of patients, and the addition of intrathecal or intraventricular antibiotics increases the success rate to 40%. This outcome can be improved further to 75% by the immediate removal of the shunt, which acts as a nidus of persistent infection. Delayed replacement of the shunt is advised if possible. CSF leaks should be repaired if recurrent infection occurs or the leak does not spontaneously cease within 1 month. Antibiotic-resistant organisms are an emerging problem. About 33% of pneumococcal strains isolated in the United States are

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penicillin resistant. These isolates are identified by the oxacillin disk diffusion method, and a zone less than 20 mm around the oxacillin disk represents penicillin resistance. Pneumococcal strains can possess either intermediate (minimum inhibitory concentration [MIC] between 0.1 and 1.0 pg/mL) or high-level penicillin resistance (MIC greater than 1.0 pg/mL). Strains with intermediate-level resistance to penicillin may also be cephalosporin-resistant,and MICs for ceftriaxone and cefotaxime should be checked (by standard broth dilution methods). If there is any penicillin resistance (MIC greater than 0.1 pg/mL) but susceptibility to ceftriaxone (MIC less than 0.5 pg/mL), ceftriaxone alone may be used. If the pneumococcus has any penicillin resistance and ceftriaxone resistance, then combination therapy with ceftriaxone and either vancomycin or rifampin is recommended; the ceftriaxone is useful because synergy has been observed in this circumstance. The penetration of vancomycin into the CSF is very unpredictable, and higher or more frequent doses of vancomycin are needed for treatment. CSF levels of vancomycin should be monitored, and if they are low the dosage of vancomycin can be adjusted. Intrathecal vancomycin administration can also be used to achieve bactericidal CSF concentrations. Resistance to ampicillin by H. influenzae has been increasing, with p-lactamase producing strains responsible for up to one third of all cases of H. influenzae meningitis. There are also penicillin-resistant strains of N. meningitidis with low-affinity penicillin-binding proteins that have been reported, predominantly in Europe. Therefore, extended spectrum cephalosporins are the drugs of choice for both of these organisms until the susceptibility patterns of the strain can be established. Therapeutic choices can be confusing in the patient claiming an allergy to penicillin. Many people carry the label of penicillin allergy, but only a small minority have life-threatening reactions. A careful history should be obtained of the allergic reaction, and if it is not consistent with an anaphylactic or immediate type I allergy (i.e., immunoglobulin E-mediated and resulting in anaphylaxis, angioedema, or hives), penicillin or a cephalosporin can be used. If no history can be obtained, we recommend the use of cephalosporins, given the low risk:benefit ratio of using these W

antibiotics for a life-threatening meningitis. Intravenous desensitization or skin testing should be considered for patients with allergy before a preferred regimen is abandoned. An alternative antibiotic regimen must be administered promptly while one investigates these options. There has been intensive investigation of the use of adjunctive anti-inflammatory measures to prevent much of the sequelae of meningitis. Antibiotics cause rapid bacterial killing, cell lysis, and the release of cell wall components that have inflammatory properties. There is speculation that antibiotics with less bacteriolytic properties may decrease these severe effects (e.g., new carbapenems). In children with H. influenzae meningitis, corticosteroids have been determined to decrease morbidity such as sensorineural hearing loss, ataxia, and hemiparesis. However, there are no good studies of the adjunctive use of corticosteroids in adults, and experimental data indicate that dexamethasone may decrease vancomycin penetration into the CSF. Nonetheless, some experts currently recommend the use of dexamethasone (4 mg IV every 12 hours for 2 days) in adults with meningitis when bacterial loads are high (e.g., when the Gram stain is positive) or with an elevated opening pressure or other evidence of cerebral edema and increased intracranial pressure. If dexamethasone is to be administered to a patient with severe pneumococcal meningitis, it should be given before or within 2 hours after antibiotics if possible. Antibiotic administration should not be delayed to accommodate steroid administration. If dexamethasone is given, the addition of rifampin can be considered.

OUTCOME Bacterial meningitis was associated with a 25% case fatality rate in a large series of adult community-acquired and nosocomial bacterial meningitis at Massachusetts General Hospital during a 27-year period (1962-1988). Mortality associated with meningitis caused by S. pneumoniae, N. meningitidis, and H. influenzae was 28%, lo%, and 11%, respectively. Mortality caused by gramnegative bacteria was markedly higher (36%). Risk factors found to increase mortality were age (older than 60), obtunded mental

TABLE 50-4. Antimicrobial Therapy for Adult Bacterial Meningitis

-

..

Omanism

Risk Factors and Clinical Svndrome

TheraDv

S. pneumoniae

Community-acquired,CSF leak, recurrent meningitis

PCN-sensitive: penicillin C or ampicillin PCN intermediate resistance and CTX sensitive: cD( PCN high resistance or CTX resistance: vancomycin CTX rifampin k IT vancomycin* Severe PCN allergyt: vancomycin rifampin PCN-sensitive: penicillin C or ampicillin PCN-resistant: CTX Severe PCN allergy: chloramphenicol P-Lactamase-negative: ampicillin P-Lactamase-positive: CTX Severe PCN allergy: chloramphenicolor aztreonam Penicillin C or ampicillin Severe PCN allergy: trimethoprim-sulfamethoxazole Cefepime or ceftazidime or meropenem or aztreonam or piperacillin If Pseudomonasaeruginosa, add IV aminoglycosides k IT or intraventricularaminoglycosides Penicillin C or ampicillin + IV aminoglycosides MSSA: nafcillin or oxacillin MRSA: vancomycin IT vancomycin f rifampin Vancomycin IT vancomycin rifampin

+

*

N. meningitidis

Community-acquired,contact to meningitis case

H. influenzae

Community-acquired, basilar skull fracture, day-care exposure, sinusitis, otitis

L. monocytogenes

Community-acquired,age >50 years, immunocompromised Age s50 years, nosocomial infection, postneurosurgety

Cram-negative bacilli (other than H. influenzae) Streptococci S. aureus

+

Endocarditis Post-trauma, neurosurgery, shunt placement, endocarditis, other site of infection Coagulase-negative staphyShunt placement, ventriculostomy, post-trauma, neulococci rosurgety *Intrathecaladministration if CSF concentrations are persistently low or patient is not clinically responding. tPCN Allergy: Use vancomycin as an alternative only in the setting of a histon/ of anaphylaxis; CTX may still be safe (see text). Abbreviations: cD(,ceftriaxone (or cefotaxime);MRSA, methicillin resistant 5. oureus; MSSA, rnethicillinsensitive 5. oureus; PCN, penicillin.

*

+

+

Chapter 50

Bacterial Meningitis

453

TABLE 50-5. Recommendations for Prophylaxis of Meningitis Organism

Prophylaxis

Alternatives and Comments

N. rneningitjdis

Rifarnpin 600 mg PO bid for 2 days Rifarnpin 10 rng/kg/dose (up to 600 rng) for children

H. influenzae

Rifarnpin 600 mg PO qd for 4 days Rifarnpin 20 mg/kg/dose (up to 600 rng) qd for 4 days for children

Minocycline (100 rng PO bid for 5 days) for adults Ciprofloxacin (500 rng PO single dose) for adults Ofloxacin (400 rng PO single dose) for adults Ceftriaxone (250 rng adult/l25 rng children IM single dose) Azithrornycin (500 mg PO single dose) for adults Rifarnpin recommended, ceftriaxone (250 rng adult/l25 rng children IM single dose) is alternative Day-care prophylaxis if children <2 years old with 225 contact hours per week or 22 cases in 60 days

status upon admission, and seizure onset within 24 hours of admission. In an active surveillance study involving more than 10 million adults and children in 22 U.S. counties in 1995, community-acquired meningitis caused by five major pathogens had an overall case fatality rate of 14%. Pathogen-specific rates were 21% for S. pneumoniae, 15% for Listeria, 7% for group B streptococci, 6% for H. influenzae, and 3% for N. meningitides. In a prospectively validated model, adverse clinical outcome from community-acquired meningitis in adults (death or neurologic deficit at discharge) was best predicted by three factors at presentation: hypotension, altered mental status, and seizures. Overall mortality was 27%, and adverse clinical outcome varied from 9% in those with no factors to 57% in those with two or three factors. Furthermore, an adverse outcome was more likely if any of these factors developed while the patient was being evaluated, before antibiotic administration. More than 50% of adults with meningitis caused by S. pneumoniae have long-term neurologic sequelae.

capsular polysaccharide vaccine for serogroups A, C, Y,and W135 of N. meningitides is available. Of note, serogroup B, which is responsible for about one third of cases in the United States, is not represented in the vaccine. The vaccine’s primary use is in outbreak or epidemic settings. The efficacy of the vaccine in an outbreak in Texas was 85%. Recently, the U.S. Public Health Service has recommended that first-year college students living in dormitories receive this vaccine because that population is at higher risk for disease than the general population. The vaccine should be considered for travelers to an endemic area (including sub-Saharan Africa), pilgrims to Saudi Arabia, active alcoholics, and patients with a terminal complement deficiency or asplenia. Data on the efficacy of the polysaccharide vaccine for pneumococcus are not as convincing, but the vaccine is recommended for older adults and immunocompromised patients. A new conjugated vaccine for S. pneumoniae reduced the incidence of invasive pneumococcal disease in children; its effects in adults and meningitis in particular remain to be seen. A conjugated vaccine against N. meningitides is also promising.

PROPHYLAXIS In documented cases of N. meningitidis, close family, household, and intimate contacts, classmates, and day-care attendees should be treated with prophylaxis immediately after exposure to prevent infection (Table 50-5). Transmission to health care workers is very rare and occurs via direct contact with respiratory secretions. Treatment is indicated only for health care workers with intensive close contact (e.g., cardiopulmonary resuscitation or exposure to respiratory secretions). Prophylaxis should be given to children of all ages and adults in the household or day care setting because colonized persons can serve as a reservoir for infection of susceptible children. Prophylaxis should be prescribed when there are susceptible children who have had contact with the index case in the prior week. Studies of the efficacy of prophylactic antibiotics in patients with CSF leaks have yielded conflicting results. None of these were well-controlled prospective trials, so no clear-cut current recommendations can be given. VACCINES

Unfortunately, the success of the haemophilus vaccine has not yet been reproduced for other pathogens. In the United States, a

SUGGESTED READINGS Aronin SI, Peduzzi P, Quagliarello VJ: Community-acquiredmeningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 129(11):862-869, 1998 Durand ML, Calderwood SB, Weber DJ et al: Acute bacterial meningitis in adults. N Engl J Med 328(1):21-28, 1993 Moellering RC, Schaad UB, eds: Bacterial meningitis. Infect Dis Clin North Am 13:3, 1999 Quagliarello VJ, Scheld WM: Treatment of bacterial meningitis. N Engl J Med 336( 10):708-716, 1997 Taylor JP et ak Efficacy of meningococcal vaccine Rosenstein N, Levine 0, and barriers to vaccination. JAMA 279(6):435-439, 1998 Schuchat A, Robinson K, Wenger JD et al: Bacterial meningitis in the United States in 1995. N Engl J Med 337( 14):97&976, 1997 Tunkel AR, Scheld WM: Acute meningitis. pp. 959-997. In Mandell GL, Bennett JE, D o h R (eds): Principles and Practices of Infectious Diseases. 5th Ed. Churchill Livingstone, New York, 2000 Wenger JD, Hightower AW, Facklam PR et al: Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. J Infect Dis 162(6):1316-1323, 1990

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51

Immune and Infectious Disease W

Infectious Diseases

Brain and Spinal Abscess A

Loren A. Rolak Bacteria seldom cause abscesses within the parenchyma of the brain, and when they do it usually is as a complication of an infection elsewhere in the body. Although rare, brain abscesses produce devastating consequences, so their detection and treatment are urgent medical matters.

rn TABLE51-2. Most Common Presenting Symptoms of a Brain Abscess Symptom

EPIDEMIOLOGY Although one fourth of all brain abscesses occur in previously healthy patients with no predisposing infections or medical complications, most arise as the result of either local extension or hematogenous spread of infection by pyogenic bacteria in other locations. Table 51-1 shows the most common sites of underlying infections and the organisms most likely to cause brain abscesses in each setting. In the brain, at least half of abscesses contain two or more pathogenic bacteria, which often complicates diagnosis and treatment. Approximately 75% of patients have only a solitary abscess, especially patients in whom the abscess arises from a perimeningeal infection or other contiguous site. Most patients with multiple abscesses have a hematogenous source of infections, such as endocarditis, or have an underlying immune deficiency, including acquired immunodeficiency syndrome (AIDS). CLINICAL FEATURES Although brain abscesses obviously represent a pyogenic infection, most do not present with the features of an infection; fever, nuchal rigidity, and elevated peripheral white blood cell (WBC) count are rare. Even the spinal fluid is usually normal. Instead, the usual presentation is of a mass lesion, with clinical features reflecting the subacute onset of a progressively enlarging space-occupying lesion. Table 51-2 shows the most common presenting symptoms rn TABLE51-1. Causes of Brain Abscesses Underlying Infection (%)

Common Pathogens

Otitis or mastoiditis (1 5)

Gram-negative bacilli Streptococcus Bacteroides 5treptococcus Bacteroides Staphylococcusaureus 5treptococcus Bacteroides Haemophilusinfluenzae S. aureus Cram-negative bacilli Streptococcus Streptococcus Mixed flora Nocardia Streptococcus S. aureus S. aureus Streptococcus Bacteroides Toxoplasmagondii Nocardia Aspergillus Candida

Dental infections (1 5) Sinusitis (20)

Head wound or neurosurgery (5) Pulmonary infection (15) Endocarditis (5) Idiopathic or unknown (25) Acquired immunodeficiency syndrome (or other immune deficiency)

Frequency (96)

Headache Focal deficit Altered mental status Seizures Fever Increased intracranial pressure (vomiting, papilledema) Nuchal riniditv

1-

75 65 60

40 30 20 20

51-3. Formation of a Brain Abscess

Stage

Time (days)

Process

Early cerebritis

1-3

Late cerebritis

4-9

Capsule formation

10-14

Acute inflammation Polymorphonuclear Infiltration Necrotic center Fibroblast activity Edema New vessel formation Mature collagen capsule

of a brain abscess, with focal deficits, seizures (often focal), and increased intracranial pressure dominating the picture. The onset of symptoms generally is subacute and gradual, evolving over 2 weeks or more, as the infection progresses from a localized cerebritis to a focal, well-encapsulated abscess with a necrotic center and well-defined capsule (Table 51-3). DIAGNOSIS Imaging of the brain, with either magnetic resonance imaging (MRI) or computed tomography (CT) scanning, provides the key to the diagnosis of abscesses. Surgical biopsy, guided by the imaging, usually is needed for a definitive diagnosis. Paradoxically, many standard tests for infections provide little useful information in patients with brain abscesses. Cultures of the blood and the spinal fluid seldom yield the causative organisms. For this reason, as well as the fact that lumbar punctures may carry a risk of neurologic deterioration in patients with increased intracranial pressure from a brain abscess, a spinal tap is seldom indicated for diagnosing brain abscesses. Very little information exists on the value of serologic or immunologic methods of identifying the pathogens responsible for the abscess, such as counterimmunoelectrophoresis and other techniques, but their utility probably is limited. Both CT and MRI are accurate for detecting abscesses, showing a focal lesion with a necrotic center and an enhancing ring (the collagen capsule) surrounding it, generating edema and mass effect (Fig. 51-1). This appearance can be definitive in the proper clinical setting, but an identical radiographic appearance may be produced by certain tumors (especially metastases) and even occasional ischemic infarctions, resolving hematomas, and radiation necrosis. Therefore, to provide greater diagnostic certainty

Chapter 51

FIG. 51-1. CT scan with contrast enhancement from a 68-year-old man with a bacterial abscess (of unknown cause) in the left frontal lobe. The scan shows the necrotic abscess surrounded by an enhancing capsule, with edema and mass effect.

and to obtain exact identification of the causative organisms, a biopsy usually is needed. When brain imaging shows changes compatible with an abscess, further diagnostic testing often should include a chest radiograph, blood cultures, electrocardiogram, and echocardiography. The physical examination should focus particular attention on the sinuses, teeth, ears, and lungs (for pulmonary AVMs),and all patients should have their human immunodeficiency virus (HIV) status determined. Brain abscesses can seldom be diagnosed or treated successfully without surgical intervention. In most cases, a stereotactic CT-guided needle aspiration should be performed to confirm the diagnosis and culture the responsible bacteria. More than 90% of patients have positive bacterial cultures in this setting.

TREATMENT Ideal treatment consists of antibiotics tailored to the specific organisms obtained from the abscess. In most cases, such specific cultures can be obtained through surgical intervention. However, if surgery is not possible or if the surgical specimen proves sterile (which occurs in up to 20% of cases in some series, although the yield generally is excellent), or if empirical therapy must be started before a definitive diagnosis, either because of the seriousness of the patient’s medical condition or because of anticipated delays in further management, then the initial antibiotic regimen necessarily is less precise. Many abscesses contain multiple organisms, so empirical therapy must include broad-spectrum coverage. Streptococci, common organisms in many abscesses, respond well to penicillin, which is also an effective agent against most grampositive organisms and many anaerobes. Metronidazole has an

Brain and Spinal Abscess

435

excellent action against bacteroids and penetrates abscess walls well. The third-generation cephalosporins provide good coverage against gram-negative bacteria and so should also be included in an empirical regimen for brain abscesses. A suggested empirical therapy for brain abscesses is penicillin G 4 million U IV every 4 hours plus ceftriaxone 4 g IV every 12 hours plus metronidazole 500 mg IV every 6 hours. Surgery greatly facilitates brain abscess management. In addition to biopsy and culture for diagnosis, draining the abscess almost always accelerates healing and recovery. This generally can be accomplished stereotactically, and repeated drainage can be performed if necessary. Definitive surgical excision of an abscess is seldom necessary; it is a major surgical procedure with significant morbidity and mortality, abscesses are not always localized in easily resected areas, and drainage alone usually leads to adequate clinical recovery. Complete excision therefore is generally reserved for lesions that do not respond to stereotactic drainage plus antibiotic treatment. Nonsurgical management of brain abscesses has been effective in some cases. However, such treatment is seldom successful for large abscesses (larger than 3 cm) and certainly is much more difficult than treatment aided by surgical drainage. Therapy with antibiotics alone usually is recommended only if multiple abscesses are present, making surgical drainage too difficult, or if the patient is otherwise an unacceptable surgical candidate because of underlying medical complications or other factors. Even with surgical drainage, antibiotic therapy generally must continue for at least 6 weeks. Repeated MRI or CT scan can effectively document the response to treatment, but therapy need not continue until the scans are entirely normal because complete radiographic resolution always lags behind successful treatment, often by many months. Despite the frequent presence of edema and mass effect, the concomitant use of steroids is not advised for abscesses. Steroids often delay healing and impair antibiotic effectiveness by solidifjmg the abscess capsule and inhibiting drug penetration across the blood-brain barrier. In the modern era of neuroimaging and sophisticated antibiotics, the mortality from brain abscesses has declined to approximately 20%, from a greater than 80% mortality in the preantibiotic era. Nevertheless, as many as 50% of survivors suffer permanent neurologic sequelae from the abscess. Focal neurologic findings may persist, depending on the location of the abscess. Permanent seizures often complicate brain abscesses, and as many as 50% of patients experience seizures after successful treatment of their infection. Fortunately, conventional anticonvulsant therapy, such as with phenytoin or carbamazepine, generally successfully suppresses these seizures. SPINAL EPIDURAL ABSCESS In the spine, bacterial abscesses seldom involve the substance of the cord itself but rather tend to arise in the epidural space, between the dura that surrounds the spinal cord and the bony vertebral bodies themselves. Like brain abscesses, these lesions often arise in patients with underlying infections, especially osteomyelitis of the vertebral bodies; intravenous drug abuse also is a particular risk factor for the development of spinal epidural abscesses. Also analogously with brain abscesses, these lesions seldom present as an infection, and fever or elevated peripheral WBC counts seldom appear. Rather, the presentation usually takes the form of an acute spinal cord compression from the mass effect, resembling cord compression from a metastatic neoplasm. Pain at

436

Immune and Infectious Disease

Infectious Diseases

the level of the abscess almost always is present, followed by signs of spinal cord compression, including paralysis, a sensory level, and loss of bowel and bladder function. Most abscesses arise in the thoracic or lumbar region and develop subacutely over days or even weeks. Diagnostically, lumbar puncture and examination of the CSF almost never yields a specific diagnosis and may dangerously spread the infection. Instead, diagnostic testing should begin with spinal imaging, by MRI if possible. MRI accurately detects the abscess, which then guides definitive decompression and drainage of the abscess. Urgent surgical decompression is almost always indicated. Culture of surgical specimens provides a definitive diagnosis and accurate identification of the causative organisms in almost all cases. Empirical antibiotic therapy, pending the final culture results, should be directed at coverage for Staphylococcus aureus and streptococci, which account for 75% to 90% of all cases. Gram-negative aerobes cause almost all other cases (especially in intravenous drug users), so an appropriate regimen would be

52

vancomycin 1 g every 8 hours or nafcillin 2 g every 4 hours plus a third-generation cephalosporin such as ceftriaxone 4 g every 12 hours. Intravenous antibiotics must be continued for 4 to 8 weeks. Neurologic recovery is excellent if spinal cord damage is minimal at the time of presentation and decompression but is very poor if paraparesis or paralysis has been present longer than 48 hours.

SUGGESTED READINGS Davis LE, Baldwin NG: Brain abscess. Curr Treat Opt Neurol 1:157-166, 1999 Mathisen GE, Johnson J P Brain abscess. Clin Infect Dis 25:763-781, 1997 Sandhu FS, Dillon W P Spinal epidural abscess: evaluation with contrastenhanced MR imaging. AJR 158:45, 1992 Wheeler D, Keiser P, Rigamonti D, Keay S: Medical management of spinal epidural abscesses: case report and review. Clin Infect Dis 15:22, 1992 Yan SY, Zhao CS: Review of 140 patients with brain abscess. Surg Neurol 39:290-296, 1993

Tuberculosis Clifford C. Dacso

Mycobacteria cause a broad repertoire of human disease. In the nervous system, the most important of the mycobacteria are Mycobacterium tuberculosis and Mycobacteriurn leprae. Nontuberculous mycobacteria, historically known as atypical mycobacteria or mycobacteria other than tuberculosis (MOTT), have also been implicated in nervous system disease, but only rarely. Mycobacteria share the characteristic of producing surface lipids that render them acid-fast, meaning that they cannot be decolorized by acid alcohol after staining. Although some other organisms (such as Nocardia) sometimes are acid-fast, most organisms with this staining characteristic are mycobacteria. Mycobacteria generally are slow-growing, and in the laboratory they need supplemented media and a 5% to 10% C 0 2 atmosphere. EPIDEMIOLOGY Tuberculosis syndromes are caused either by M. tuberculosis or M. bovis, but because the latter has been largely eradicated in cattle in the United States, domestic tuberculosis is almost always M. tuberculosis. The incidence of tuberculosis infection in the United States is approximately 9 cases per 100,000. Developing countries have an incidence approximately 15 times that in the United States. Nationally, tuberculosis showed a progressive decline after systematic surveillance was introduced in 1953, but this decline reversed in the early 1990s, coincident with the spread of the human immunodeficiency virus (HIV) and increased immigration from endemic areas. Increased efforts to control, particularly in institutions, and directly observed therapy seem to have been effective in the latter half of decade. Despite the changes in pulmonary tuberculosis, extrapulmonary and nervous system tuberculosis rates have remained constant. Tuberculous meningitis remains rare. Of the 3438 cases of extrapulmonary tuberculosis reported in the United States in 1999, 171 were tuberculous meningitis.

CLINICAL FEATURES Tuberculosis infection usually begins as a respiratory infection, after which the bacilli are ingested by macrophages and carried to lymph nodes and then are disseminated hematogenously throughout the body. In 90% or more of patients, the primary pulmonary focus heals, as do the disseminated lesions, forming granulomas and often calcifjmg. These sites may serve as foci for later reactivation, however. Tuberculous infection of the central nervous system (CNS) may develop after reactivation from such a distant site, although the most common pathogenesis is not from direct hematogenous seeding but rather from rupture of an adjacent focus of tuberculosis, called a tubercle. Organisms are widely disseminated throughout the CNS and, under the appropriate host conditions, may proliferate. Conditions of immunosuppression, such as waning cellular immunity of age, corticosteroids or other immunosuppressing drugs, or trauma, promote tuberculosis reactivation. Tuberculous meningitis has a broad and protean range of presentations. It is best thought of as a chronic meningitis with gradual onset, although it may present abruptly, mimicking acute bacterial meningitis. An acute onset of symptoms cannot rule out tuberculosis as the cause of meningitis. Nevertheless, the most typical picture is a gradual headache and confusion, often with little or no fever. Personality changes also are common as the disease progresses. A more insidious form of CNS tuberculosis is even more chronic, with personality changes occurring over months to years. Tuberculous meningitis generally also causes signs and symptoms characteristic of a chronic basilar meningitis. As a consequence, cranial nerve abnormalities are common. The inflammation often begins to involve blood vessels as well, producing a secondary vasculitis and subsequent strokes. These are often major

436

Immune and Infectious Disease

Infectious Diseases

the level of the abscess almost always is present, followed by signs of spinal cord compression, including paralysis, a sensory level, and loss of bowel and bladder function. Most abscesses arise in the thoracic or lumbar region and develop subacutely over days or even weeks. Diagnostically, lumbar puncture and examination of the CSF almost never yields a specific diagnosis and may dangerously spread the infection. Instead, diagnostic testing should begin with spinal imaging, by MRI if possible. MRI accurately detects the abscess, which then guides definitive decompression and drainage of the abscess. Urgent surgical decompression is almost always indicated. Culture of surgical specimens provides a definitive diagnosis and accurate identification of the causative organisms in almost all cases. Empirical antibiotic therapy, pending the final culture results, should be directed at coverage for Staphylococcus aureus and streptococci, which account for 75% to 90% of all cases. Gram-negative aerobes cause almost all other cases (especially in intravenous drug users), so an appropriate regimen would be

52

vancomycin 1 g every 8 hours or nafcillin 2 g every 4 hours plus a third-generation cephalosporin such as ceftriaxone 4 g every 12 hours. Intravenous antibiotics must be continued for 4 to 8 weeks. Neurologic recovery is excellent if spinal cord damage is minimal at the time of presentation and decompression but is very poor if paraparesis or paralysis has been present longer than 48 hours.

SUGGESTED READINGS Davis LE, Baldwin NG: Brain abscess. Curr Treat Opt Neurol 1:157-166, 1999 Mathisen GE, Johnson J P Brain abscess. Clin Infect Dis 25:763-781, 1997 Sandhu FS, Dillon W P Spinal epidural abscess: evaluation with contrastenhanced MR imaging. AJR 158:45, 1992 Wheeler D, Keiser P, Rigamonti D, Keay S: Medical management of spinal epidural abscesses: case report and review. Clin Infect Dis 15:22, 1992 Yan SY, Zhao CS: Review of 140 patients with brain abscess. Surg Neurol 39:290-296, 1993

Tuberculosis Clifford C. Dacso

Mycobacteria cause a broad repertoire of human disease. In the nervous system, the most important of the mycobacteria are Mycobacterium tuberculosis and Mycobacteriurn leprae. Nontuberculous mycobacteria, historically known as atypical mycobacteria or mycobacteria other than tuberculosis (MOTT), have also been implicated in nervous system disease, but only rarely. Mycobacteria share the characteristic of producing surface lipids that render them acid-fast, meaning that they cannot be decolorized by acid alcohol after staining. Although some other organisms (such as Nocardia) sometimes are acid-fast, most organisms with this staining characteristic are mycobacteria. Mycobacteria generally are slow-growing, and in the laboratory they need supplemented media and a 5% to 10% C 0 2 atmosphere. EPIDEMIOLOGY Tuberculosis syndromes are caused either by M. tuberculosis or M. bovis, but because the latter has been largely eradicated in cattle in the United States, domestic tuberculosis is almost always M. tuberculosis. The incidence of tuberculosis infection in the United States is approximately 9 cases per 100,000. Developing countries have an incidence approximately 15 times that in the United States. Nationally, tuberculosis showed a progressive decline after systematic surveillance was introduced in 1953, but this decline reversed in the early 1990s, coincident with the spread of the human immunodeficiency virus (HIV) and increased immigration from endemic areas. Increased efforts to control, particularly in institutions, and directly observed therapy seem to have been effective in the latter half of decade. Despite the changes in pulmonary tuberculosis, extrapulmonary and nervous system tuberculosis rates have remained constant. Tuberculous meningitis remains rare. Of the 3438 cases of extrapulmonary tuberculosis reported in the United States in 1999, 171 were tuberculous meningitis.

CLINICAL FEATURES Tuberculosis infection usually begins as a respiratory infection, after which the bacilli are ingested by macrophages and carried to lymph nodes and then are disseminated hematogenously throughout the body. In 90% or more of patients, the primary pulmonary focus heals, as do the disseminated lesions, forming granulomas and often calcifjmg. These sites may serve as foci for later reactivation, however. Tuberculous infection of the central nervous system (CNS) may develop after reactivation from such a distant site, although the most common pathogenesis is not from direct hematogenous seeding but rather from rupture of an adjacent focus of tuberculosis, called a tubercle. Organisms are widely disseminated throughout the CNS and, under the appropriate host conditions, may proliferate. Conditions of immunosuppression, such as waning cellular immunity of age, corticosteroids or other immunosuppressing drugs, or trauma, promote tuberculosis reactivation. Tuberculous meningitis has a broad and protean range of presentations. It is best thought of as a chronic meningitis with gradual onset, although it may present abruptly, mimicking acute bacterial meningitis. An acute onset of symptoms cannot rule out tuberculosis as the cause of meningitis. Nevertheless, the most typical picture is a gradual headache and confusion, often with little or no fever. Personality changes also are common as the disease progresses. A more insidious form of CNS tuberculosis is even more chronic, with personality changes occurring over months to years. Tuberculous meningitis generally also causes signs and symptoms characteristic of a chronic basilar meningitis. As a consequence, cranial nerve abnormalities are common. The inflammation often begins to involve blood vessels as well, producing a secondary vasculitis and subsequent strokes. These are often major

Chapter 52

w TABLE 52-1. Staging of Tuberculous Meningitis Stage

Mental Status

Signs

1 2 3

Conscious, alert Confused Comatose

Meningismus, nonfocal examination Cranial nerve involvement, hemiparesis Dense hemiplegia or paraplegia

infarcts, resulting in severe hemiparesis. The inflammation and exudate at the base of the brain may lead to another major complication, hydrocephalus. This can be sufficiently severe to cause increased intracranial pressure and herniation. Table 52-1 shows the staging of tuberculous meningitis. A patient's recovery depends on the stage at which therapy is instituted. Untreated, tuberculous meningitis usually is fatal within weeks.

DIAGNOSIS Although most patients have extrameningeal tuberculosis, and a chest radiograph can be diagnostically useful, failure to find other organs involved with the disease cannot exclude tuberculosis as the cause of meningitis. In the urban setting, social ills, alcoholism, acquired immunodeficiency syndrome, homelessness, and drug use are frequent concomitants, and diagnostic suspicion should be higher in these patients. The diagnosis of tuberculous meningitis often rests on finding compatible signs and symptoms in a suitable clinical situation. Fungal meningitis Sarcoidosis w Lyme disease Borreliosis w Syphilis w Parameningeal focus of infection w Brain abscess w Toxoplasmosis w Carcinomatous meningitis 1Partially treated pyogenic meningitis Peripheral blood tests often are normal, including the complete blood count. Hyponatremia may be seen as a result of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that develops in as many as 30% of patients with tuberculous meningitis. A positive purified protein derivative (tuberculin) test is useful, although a negative one occurs in as many as one third of cases. The imaging modalities of magnetic resonance imaging (MRI) or computed tomography (CT) scanning can be extremely helpful in the diagnosis and treatment of patients with tuberculous meningitis. The CT scan usually can demonstrate (and follow) the major features of tuberculous meningitis, including basilar inflammation, cerebral infarction and edema, tuberculomas, and hydrocephalus. Spinal fluid examination is the cornerstone of the diagnosis of tuberculous meningitis. Almost all patients have a substantial lymphocytic pleocytosis. Hypoglycorrhachia is seen in the majority of cases and can be useful in distinguishing tuberculosis from other causes of chronic basilar meningitis. Although the protein usually is elevated in the spinal fluid, a normal protein does not rule out the disease. The key to diagnosing tuberculous meningitis is the demonstration of acid-fast bacilli. To find the organisms, the

Tuberculosis

437

importance of large-volume taps done repeatedly cannot be overemphasized. Culture of these slow-growing bacilli is not useful because of the length of time a culture may take. The polymerase chain reaction test, despite relative lack of standardization, offers hope of a more accurate and rapid diagnosis. Polymerase chain reaction seems very suited for CNS tuberculosis because of the paucity of organisms in this disease.

TREATMENT Therapy for tuberculous meningitis should consist of three drugs, although resistant organisms necessitate more, as shown in Table 52-2. Isoniazid and pyrazinamide most reliably penetrate the CNS. Corticosteroids generally are added when there are focal neurologic signs (stages 2 and 3), cerebral edema, elevated intracranial pressure, spinal fluid block, or deteriorating mental status. Some authors also recommend steroids when there is involvement of the optic nerve. Surgery is reserved for patients with hydrocephalus or those whose increased intracranial pressure has not responded to corticosteroids and repeated lumbar puncture. Treatment success is related to the clinical stage at which treatment is begun (Table 52-1). Patients in stage 1 have almost no mortality, whereas 40% to 60% of patients in stage 3 die despite aggressive treatment. Because of the time needed to isolate the organism and the time duration of the disease, therapy usually is started empirically.

TUBERCULOMA Tuberculomas are space-occupying lesions resulting from the containment of the inflammatory process in metastatic tuberculosis. Tuberculomas are more common in developing countries, particularly in children. In the United States, tuberculomas are seen most frequently in the setting of acquired immunodeficiency syndrome. Presenting signs of tuberculomas depend on the site of the lesion. When adjacent to the arachnoid they may rupture, causing arachnoiditis. In the brain, tuberculomas present as mass lesions, often with seizures. In the spinal cord, tuberculomas may cause cord compression and spinal fluid block; combined surgery and chemotherapy should be instituted for these cases. Fewer than one third of patients have signs of tuberculosis elsewhere, as contrasted with tuberculous meningitis. CT scans are very useful in the diagnosis. Early tuberculomas show edema and low-density or isodense lesions. As the lesions progress, they become hyperdense, with ring enhancement. Medical treatment is preferable to surgery, which is reserved for lesions in critical locations or for diagnosis. Steroids are useful if cerebral edema causes symptoms. TAME 52-2. Therapy for Tuberculous Meningitis* Antituberculous therapy should consist of the following three drugs given once daily for 9 months lsoniazid 10 mg/kg Rifampin 600 mg Pyrazinamide 25 to 35 mg/kg Prednisone 60 to 80 mg daily for 1 to 2 weeks should be added in severe cases. 'When resistant organisms are suspected, multidrug regimens are needed.

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SUGGESTED READINGS Centers for Disease Control and Prevention: Reported Tuberculosis in the United States, 1999. August 2000 ~ ~LE,vRastogi i ~KR,Lambert LC et Tuberc~ous meningitis in the southwest United States: a community based study. Neurology 43:1775, 1993 Garcia-Monco J C Central nervous system tuberculosis. Neurol Clin 17:737-759, 1999

53

Kaneko K, Onodera 0, Miyatake T et ak Rapid diagnosis of tuberculous meningitis by polymerase chain reaction (PCR). Neurology 401617, 1990

Kennedy DH, Fallon RJ: Tuberculous meningitis. JAh4A 241:64, 1979 Leonard JM, Des Prez RM: Tuberculous meningitis. Infect Dis Clin North Am 4:769, 1990

Leprosy Yadollah Harati and Steven Lovitt

Leprosy (Hansen’s disease) is a chronic, infectious, granulomatous disease caused by the intracellular acid-fast bacillus Mycobacterium Zeprue. It is primarily a disease of peripheral nerves, but the skin, eyes, upper respiratory tract mucosa, muscles, bones, and testes may also be affected. The spectrum of clinical and pathologic manifestations depends on the immune status of the infected patient. Only a small portion of any given population is susceptible to M. leprae. Despite a very low transmission rate and available medical treatment, a significant stigma is still associated with the disease. Until recently, the estimated number of patients with leprosy around the world was about 10 to 12 million, but recent estimates by the World Health Organization (WHO) indicate that this number has fallen from 5.1 million in 1987 to 640,000 at the beginning of 2000. This steady decline is attributed to the introduction of multidrug therapy against leprosy in 1982 by the WHO. The infection occurs in nearly all countries, but it is found primarily in the Indian subcontinent, sub-Saharan Africa, and southeast Asia. Three countries alone-India, Indonesia, and Myanmar-account for 70% of the estimated cases. In the United States there have been up to 350 new cases reported every year for the past 20 years, many of which have been acquired in other countries. There are about 6000 active cases in the United States, mostly in the states bordering the Gulf of Mexico, (Louisiana, Florida, and Texas) but also in Hawaii. Because almost all states in the United States have reported at least a few cases of leprosy, there are 10 Hansen’s disease clinics around the country funded by the U.S. Public Health Services. The Hansen’s Disease Center in Baton Rouge, Louisiana, is the sole focus of centralized care for leprosy in the United States. When a patient with leprosy is encountered it is advisable to contact the experienced staff of this center for information on the latest therapeutic regimen and advice. Their telephone number is (225) 756-3791.

EPIDEMIOLOGY Although close human contact has been traditionally accepted as the mode of infection with M. Zeprae, the precise modes of transmission have not been established. A major portal of entry may be the respiratory tract: The nasal secretions of those with lepromatous leprosy may contain up to 2 x lo8 M . Zeprue in a single nose blow. Other possibilities, such as inoculation via the skin, gastrointestinal transmission, or insect bite, have been

considered but not proven. As many as 70% and no fewer than 50% of patients with leprosy have no history of contact with another known patient with leprosy. Nonhuman sources of infection, such as infected wild armadillos (Daypus novemeinctus), have been suggested as the source of leprosy in these patients. Armadillos are common in the southwestern portion of the United States, where they are sometimes handled, hunted, skinned, and eaten. Approximately 5% to 10% of wild armadillos in Louisiana and eastern Texas have leprosy. Leprosy has also been discovered in the sooty mangabey, a New World monkey. The reason for the greater susceptibility of some people to the disease is not known; there is no strong support for genetic, racial, ethnic, or nutritional factors.

CLINICAL FEATURES Few diseases present as many different clinical and pathologic presentations as leprosy. Traditionally, it has been considered a spectrum of disease, distinguished by the immunologic response to the infection: At one end of the spectrum is tuberculoid (TT); at the other end of the spectrum, lepromatous (LL); and in the middle, borderline (BB). The borderline type may be further divided into borderline tuberculoid (BT), midborderline (BB), and borderline lepromatous (BL). A minor form, called indeterminate leprosy, is a nascent stage of the disease in which the clinical and histopathologic destiny of the disease is uncertain. However, the WHO Expert Committee on Leprosy uses a different classification scheme for patients with leprosy. Patients are classified into three groups: paucibacillary single-lesion leprosy (one skin lesion), paucibacillary (two to five skin lesions), and multibacillary (more than five skin lesions). Although the traditional classification scheme is more widely known, the WHO classification was designed, in part, to simplify the diagnostic criteria to facilitate reaching more patients with leprosy. A practicing physician may encounter a patient with leprosy when there is evidence of peripheral nerve lesions affecting cutaneous nerves, single or multiple motor sensory nerves, or nerves of the distal lower limbs. M. leprae reproduces maximally between 27OC and 30OC; this explains the tendency of M. Zeprae to grow in cooler areas of the body (i.e., pinnae of the ears, the extensor surfaces of the limbs, the face, or the buttocks). The patchy cutaneous sensory deficits are more commonly seen in these areas; they do not usually involve the warmer areas of the skin such as the palms of the hands and soles of the feet, inguinal

430

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Infectious Diseases

SUGGESTED READINGS Centers for Disease Control and Prevention: Reported Tuberculosis in the United States, 1999. August 2000 ~ ~LE,vRastogi i ~KR,Lambert LC et Tuberc~ous meningitis in the southwest United States: a community based study. Neurology 43:1775, 1993 Garcia-Monco J C Central nervous system tuberculosis. Neurol Clin 17:737-759, 1999

53

Kaneko K, Onodera 0, Miyatake T et ak Rapid diagnosis of tuberculous meningitis by polymerase chain reaction (PCR). Neurology 401617, 1990

Kennedy DH, Fallon RJ: Tuberculous meningitis. JAh4A 241:64, 1979 Leonard JM, Des Prez RM: Tuberculous meningitis. Infect Dis Clin North Am 4:769, 1990

Leprosy Yadollah Harati and Steven Lovitt

Leprosy (Hansen’s disease) is a chronic, infectious, granulomatous disease caused by the intracellular acid-fast bacillus Mycobacterium Zeprue. It is primarily a disease of peripheral nerves, but the skin, eyes, upper respiratory tract mucosa, muscles, bones, and testes may also be affected. The spectrum of clinical and pathologic manifestations depends on the immune status of the infected patient. Only a small portion of any given population is susceptible to M. leprae. Despite a very low transmission rate and available medical treatment, a significant stigma is still associated with the disease. Until recently, the estimated number of patients with leprosy around the world was about 10 to 12 million, but recent estimates by the World Health Organization (WHO) indicate that this number has fallen from 5.1 million in 1987 to 640,000 at the beginning of 2000. This steady decline is attributed to the introduction of multidrug therapy against leprosy in 1982 by the WHO. The infection occurs in nearly all countries, but it is found primarily in the Indian subcontinent, sub-Saharan Africa, and southeast Asia. Three countries alone-India, Indonesia, and Myanmar-account for 70% of the estimated cases. In the United States there have been up to 350 new cases reported every year for the past 20 years, many of which have been acquired in other countries. There are about 6000 active cases in the United States, mostly in the states bordering the Gulf of Mexico, (Louisiana, Florida, and Texas) but also in Hawaii. Because almost all states in the United States have reported at least a few cases of leprosy, there are 10 Hansen’s disease clinics around the country funded by the U.S. Public Health Services. The Hansen’s Disease Center in Baton Rouge, Louisiana, is the sole focus of centralized care for leprosy in the United States. When a patient with leprosy is encountered it is advisable to contact the experienced staff of this center for information on the latest therapeutic regimen and advice. Their telephone number is (225) 756-3791.

EPIDEMIOLOGY Although close human contact has been traditionally accepted as the mode of infection with M. Zeprae, the precise modes of transmission have not been established. A major portal of entry may be the respiratory tract: The nasal secretions of those with lepromatous leprosy may contain up to 2 x lo8 M . Zeprue in a single nose blow. Other possibilities, such as inoculation via the skin, gastrointestinal transmission, or insect bite, have been

considered but not proven. As many as 70% and no fewer than 50% of patients with leprosy have no history of contact with another known patient with leprosy. Nonhuman sources of infection, such as infected wild armadillos (Daypus novemeinctus), have been suggested as the source of leprosy in these patients. Armadillos are common in the southwestern portion of the United States, where they are sometimes handled, hunted, skinned, and eaten. Approximately 5% to 10% of wild armadillos in Louisiana and eastern Texas have leprosy. Leprosy has also been discovered in the sooty mangabey, a New World monkey. The reason for the greater susceptibility of some people to the disease is not known; there is no strong support for genetic, racial, ethnic, or nutritional factors.

CLINICAL FEATURES Few diseases present as many different clinical and pathologic presentations as leprosy. Traditionally, it has been considered a spectrum of disease, distinguished by the immunologic response to the infection: At one end of the spectrum is tuberculoid (TT); at the other end of the spectrum, lepromatous (LL); and in the middle, borderline (BB). The borderline type may be further divided into borderline tuberculoid (BT), midborderline (BB), and borderline lepromatous (BL). A minor form, called indeterminate leprosy, is a nascent stage of the disease in which the clinical and histopathologic destiny of the disease is uncertain. However, the WHO Expert Committee on Leprosy uses a different classification scheme for patients with leprosy. Patients are classified into three groups: paucibacillary single-lesion leprosy (one skin lesion), paucibacillary (two to five skin lesions), and multibacillary (more than five skin lesions). Although the traditional classification scheme is more widely known, the WHO classification was designed, in part, to simplify the diagnostic criteria to facilitate reaching more patients with leprosy. A practicing physician may encounter a patient with leprosy when there is evidence of peripheral nerve lesions affecting cutaneous nerves, single or multiple motor sensory nerves, or nerves of the distal lower limbs. M. leprae reproduces maximally between 27OC and 30OC; this explains the tendency of M. Zeprae to grow in cooler areas of the body (i.e., pinnae of the ears, the extensor surfaces of the limbs, the face, or the buttocks). The patchy cutaneous sensory deficits are more commonly seen in these areas; they do not usually involve the warmer areas of the skin such as the palms of the hands and soles of the feet, inguinal

Chapter 53

areas, intergluteal fold, perineum, axillae, or scalp. The involved areas have decreased temperature and pain sensation, but position and vibration sensations are normal. Because the pattern of sensory loss is caused by intracutaneous nerve involvement, it does not follow the pattern of any peripheral nerve or nerve root distribution. This, along with intact muscle stretch reflexes resulting from preservation of deep and warmer intramuscular nerves, should raise the possibility of leprosy. The preservation of reflexes remains the most helpful sign in differentiating all forms of leprosy with nerve involvement from other polyneuropathies. The evolution, pattern, and extent of the sensory involvement and subsequent motor weakness are determined by the type of leprosy. Sensory loss, whether patchy or diffuse, precedes paralysis in all types of leprosy. Tuberculoid leprosy is the most common and localized form of the disease, characterized by a vigorous immune response to M. leprue. Patients with this form of leprosy are likely to seek medical attention early in the disease process and be seen by a neurologist. Characteristically, there are one or several asymmetrically distributed hypopigmented, hypoesthetic, and analgesic skin lesions, with firmly papulated borders. The involved areas are also anhidrotic and eventually lose hair. Cutaneous nerves adjacent to lesions often are enlarged, and nearby peripheral nerves often are palpable. The most commonly enlarged nerves are the greater auricular, the ulnar above the elbow, the peroneal at the fibular bone head, and the posterior tibial nerve. The enlarged ulnar nerve extends 10 to 12 cm proximal to the olecranon groove area. The involved nerves usually display slowed nerve conduction from the earliest stage, often resulting in single or multiple mononeuropathies. However, in other neuropathies with enlarged nerves (e.g., amyloidosis, hypertrophic neuropathies, Refsum’s disease) there is typically widespread areflexia and distal symmetric deficits, allowing the differentiation from leprosy. Patients with tuberculoid leprosy are immunocompetent and mount an intense tissue reaction at the site of entry into nerve of M. leprue, preventing the bacilli from multiplying. However, the vigorous immune response against the microorganism results in the nerve damage at the outset. Nerve biopsy shows few (if any) organisms, even in the face of complete nerve destruction by profound tissue proliferation. In contrast to tuberculoid leprosy, the poor immune response of patients with lepromatous leprosy permits unchecked bacillary proliferation and hernatogenous dissemination. These patients do not present to the physician early in their disease process because there are no early signs of nerve involvement, and the patient is not likely to notice early dermal lesions. The patients are highly infectious, however. The two symptoms that usually cause the patient to seek medical attention are nasal stuffiness and pedal edema. Because of the absence of tissue reaction, including little intraneural macrophage invasion, there is minimal early nerve damage despite massive bacillary invasion of Schwann cells. The loss of nerve function is gradual, as opposed to the rapid nerve destruction seen in tuberculoid leprosy and many borderline forms. Loss of sensation in limbs in advanced neuropathies leads to repeated injuries and ulcerations of the feet and hands. Because of the deeper and warmer location of autonomic nerves and gangha, prominent clinical autonomic dysfunction is not seen. Biopsy or smear of skin, cutaneous nerves, and nasal mucosa reveals rampant acid-fast bacilli infiltration. Borderline cases have a variable combination of clinical, bacteriologic, histologic, and immunologic abnormalities of the two polar types. They usually downgrade toward lepromatous leprosy if not treated. Nerve involvement is variable with either

Leprosy

439

asymmetric nerve involvement in upgrading disease or symmetric neuropathy when disease is downgrading to the lepromatous pole. In certain borderline cases, a prolonged mononeuropathy multiplex phase may occur before the appearance of s k i n lesions, leading to misdiagnosis if peripheral nerve enlargement is not detected by palpation. It should be remembered that, in the absence of sensory loss, leprosy should not be diagnosed. In leprosy, deep tendon reflexes and position and vibration sense usually are preserved, proximal muscle wasting and weakness are uncommon, and pyramidal tract signs are not observed. LEPROSY REACTIONS Aside from the slow progressive illness, several specific reactions occur during treatment that may be associated with sudden deterioration of neurologic function. The first type of reaction, known as the reversal reaction (type 1 reaction), occurs in borderline leprosy, causing a sudden exacerbation of the existing lesions. Acute neurologic deficit and severe pain may follow treatment with chemotherapy and are thought to be caused by the sudden increase in the cell-mediated immunity response to M. leprue. The second type, known as erythema nodosum leprosum (ENL), or type 2 reaction, occurs in about 50% of patients with lepromatous leprosy after several months of therapy and is characterized by fever, malaise, generalized lymphadenopathy, hepatosplenomegaly, and arthritis. Erythematous subcutaneous nodules can occur, and acute painful neuritis may also develop. The reaction presumably results from an acute hypersensitivity reaction precipitated by the release of antigens from dead mycobacteria. Leprosy reactions and the acute neuritis must be recognized early and treated immediately.Corticosteroidsare most commonly used. If untreated, the neurologic deficits may remain permanent. DIAGNOSIS A definitive diagnosis is best made by the demonstration of acid-fast bacilli in skin or peripheral nerve biopsies, although organisms may be difficult to detect in tuberculoid disease. Detection of antibody against leprosy (phenolic glycolipid 1) is extremely specific, but is also insensitive in polar tuberculoid disease.

TREATMENT Leprosy should be treated under the auspices of an infectious disease specialist. State and local health departments should be notified for the purpose of locating and evaluating contacts as well as assisting with the treatment. It is important that family members and other intimate contacts be examined both clinically and electrophysiologically. The WHO recommends administering monthly doses of rifampicin 600 mg and clofazimine 300 mg along with daily doses of dapsone 100 mg and clofazamine 50 mg for patients with multibacillary leprosy. Patients who are unable to tolerate clofazamine may instead take monthly doses of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg (ROM) for 24 months. Patients with paucibalillary leprosy with two to five skin lesions are treated with dapsone 100 mg daily and monthly doses of rifampicin 600 mg for 6 months. One dose of ROM therapy is recommended for patients with single-lesion paucibacillary lep-

440

Immune and Infectious Disease rn Infectious Diseases

rosy; in this subgroup, a large multicenter double-blind study showed equal efficacy of ROM therapy and the 6-month WHO treatment for multilesion paucibacillary leprosy. Other medications may also be used in treatment and may be considered if the treatments just described cannot be tolerated. Leprosy reactions must be treated promptly. Corticosteroids (60 to 80 mg prednisone/day), thalidomide, and clofazimine are the major drugs used. The effect of thalidomide is rapid (2 to 3 days) and impressive. However, its exact mechanism of action in treating leprosy reactions is unknown. Surgical intervention when nerve compression is present is of significant value. Because of the complexity and chronicity of the disease, optimum patient care includes the cooperation and skills of many health providers including internist, neurologist, orthopedic surgeon, neurosurgeon, ophthalmologist, rehabilitation specialist, occupational therapist, and social worker.

54

SUGGESTED READINGS Altman A, Amato A Lepromatous neuropathy. J Clin Neuromusc Dis 1:68, 1999

Black LA, West BC, Lary CH, Todd IV Jr: Environmental nonhuman sources of leprosy. Rev Infect Dis 9:562, 1987 Haimanot RT, Melaku Z Leprosy. Curr Opin Neurol 13(3):317,2000 Harati Y,Kolimas R Infectious peripheral neuropathies. Curr Neurol8:37, 1988

Jakeman P, Smith WCS: Thalidomide in leprosy reaction. Lancet 343:432, 1994

Koch H P Thalidomide and congeners as anti-inflammatory agents. Prog Med Chem 22:165, 1985 Meyer WM, Marty AM: Current concepts in the pathogenesis of leprosy. Drugs 412332, 1991 Van Brake1 WH: Peripheral neuropathy in leprosy and its consequences. Lepr Rev 71(Suppl S):146, 2000

Brucellosis Clifford C. Dacso

Brucellosis is a zoonosis caused by Brucella species. Brucellosis sometimes is called undulant fever because of the waxing and waning course of the chronic disease. David Bruce identified the causative organism, a small gram-negative coccobacillus, from the spleen of a patient in 1886. The disease sometimes is called Malta fever because of the extensive work done on characterizing the illness by the Mediterranean Fever Commission at the beginning of the 20th century. Traditionally, there are six Brucella speciesrecent abortus, suis, melitensis, canis, ovis, and neotomae-but genetic studies show that all brucellae probably are from a single species, Brucella melitensis. Because of the variety of the clinical presentation and host specificity, however, the older names have been retained and continue to be used in the literature. EPIDEMIOLOGY Brucellae exist in nature in a broad variety of animals and locations. Humans usually become ill when they ingest milk or milk products contaminated with brucellae. Mucosal and respiratory inoculation are other important routes of acquisition, as is direct contact through breaks in the integument. Laboratory exposures have also been reported, and people who have frequent animal contact, such as slaughterhouse (abattoir) workers and veterinarians, have a higher risk of brucellosis. CLINICAL FEATURES Brucellosis has a broad repertoire of clinical manifestations by virtue of its chronicity and its ability to infect a large number of organ systems. The onset of illness is usually within weeks of exposure and often is insidious, with headache, backache, myalgias, malaise, and low-grade fever. There are few physical findings, however. If left untreated, brucellosis often becomes chronic with multiple areas of focal infection. Organs involved include the heart, liver, lungs, musculoskeletal system, skin, and other reticuloendothelial tissue-bearing organs. Brucellosis is considered

in the differential diagnosis of conditions that are difficult to diagnose, such as fever of unknown origin, suppurative arthritis, osteomyelitis, and culture-negative endocarditis. Descriptions of clinical brucellosis often use the phrase “protean manifestations.” NEUROLOGIC MANIFESTATIONS Brucellosis affects the central nervous system (CNS) in 2% to 6% of reported cases, but because the symptoms of neurobrucellosis are as nonspecific as headache and depression, the actual incidence probably is higher. Neurobrucellosis can be the presenting symptom of systemic brucella infection, or it can occur later in the disease. Although data are not specific on psychiatric complications, depression is said to be more common with brucellosis than with other chronic infections. Headache is another common symptom, although meningismus is seen in only one half of the patients. Cerebrovascular complications, including mycotic aneurysms and strokes, have been reported in rare cases, as have optic neuritis and cranial neuropathy. DIAGNOSIS A high degree of clinical suspicion is needed in diagnosing

neurobrucellosis. Although both culture and serology may be diagnostic, neither alone is usually sufficient. The complete evaluation of suspected neurobrucellosis should include lumbar puncture with culture, serum and cerebrospinal fluid (CSF) brucella serology, and blood culture. Neurobrucellosis usually presents with a CSF mononuclear pleocytosis, hypoglycorrhachia, and increased protein. Bone marrow culture can be useful, particularly in chronic cases. Because of the predilection of the organism for blood vessels and the incidence of mycotic aneurysm, thrombosis, and hemorrhage, CNS imaging may be useful in evaluating selected cases, particularly in patients presenting with a focal neurologic examination.

440

Immune and Infectious Disease rn Infectious Diseases

rosy; in this subgroup, a large multicenter double-blind study showed equal efficacy of ROM therapy and the 6-month WHO treatment for multilesion paucibacillary leprosy. Other medications may also be used in treatment and may be considered if the treatments just described cannot be tolerated. Leprosy reactions must be treated promptly. Corticosteroids (60 to 80 mg prednisone/day), thalidomide, and clofazimine are the major drugs used. The effect of thalidomide is rapid (2 to 3 days) and impressive. However, its exact mechanism of action in treating leprosy reactions is unknown. Surgical intervention when nerve compression is present is of significant value. Because of the complexity and chronicity of the disease, optimum patient care includes the cooperation and skills of many health providers including internist, neurologist, orthopedic surgeon, neurosurgeon, ophthalmologist, rehabilitation specialist, occupational therapist, and social worker.

54

SUGGESTED READINGS Altman A, Amato A Lepromatous neuropathy. J Clin Neuromusc Dis 1:68, 1999

Black LA, West BC, Lary CH, Todd IV Jr: Environmental nonhuman sources of leprosy. Rev Infect Dis 9:562, 1987 Haimanot RT, Melaku Z Leprosy. Curr Opin Neurol 13(3):317,2000 Harati Y,Kolimas R Infectious peripheral neuropathies. Curr Neurol8:37, 1988

Jakeman P, Smith WCS: Thalidomide in leprosy reaction. Lancet 343:432, 1994

Koch H P Thalidomide and congeners as anti-inflammatory agents. Prog Med Chem 22:165, 1985 Meyer WM, Marty AM: Current concepts in the pathogenesis of leprosy. Drugs 412332, 1991 Van Brake1 WH: Peripheral neuropathy in leprosy and its consequences. Lepr Rev 71(Suppl S):146, 2000

Brucellosis Clifford C. Dacso

Brucellosis is a zoonosis caused by Brucella species. Brucellosis sometimes is called undulant fever because of the waxing and waning course of the chronic disease. David Bruce identified the causative organism, a small gram-negative coccobacillus, from the spleen of a patient in 1886. The disease sometimes is called Malta fever because of the extensive work done on characterizing the illness by the Mediterranean Fever Commission at the beginning of the 20th century. Traditionally, there are six Brucella speciesrecent abortus, suis, melitensis, canis, ovis, and neotomae-but genetic studies show that all brucellae probably are from a single species, Brucella melitensis. Because of the variety of the clinical presentation and host specificity, however, the older names have been retained and continue to be used in the literature. EPIDEMIOLOGY Brucellae exist in nature in a broad variety of animals and locations. Humans usually become ill when they ingest milk or milk products contaminated with brucellae. Mucosal and respiratory inoculation are other important routes of acquisition, as is direct contact through breaks in the integument. Laboratory exposures have also been reported, and people who have frequent animal contact, such as slaughterhouse (abattoir) workers and veterinarians, have a higher risk of brucellosis. CLINICAL FEATURES Brucellosis has a broad repertoire of clinical manifestations by virtue of its chronicity and its ability to infect a large number of organ systems. The onset of illness is usually within weeks of exposure and often is insidious, with headache, backache, myalgias, malaise, and low-grade fever. There are few physical findings, however. If left untreated, brucellosis often becomes chronic with multiple areas of focal infection. Organs involved include the heart, liver, lungs, musculoskeletal system, skin, and other reticuloendothelial tissue-bearing organs. Brucellosis is considered

in the differential diagnosis of conditions that are difficult to diagnose, such as fever of unknown origin, suppurative arthritis, osteomyelitis, and culture-negative endocarditis. Descriptions of clinical brucellosis often use the phrase “protean manifestations.” NEUROLOGIC MANIFESTATIONS Brucellosis affects the central nervous system (CNS) in 2% to 6% of reported cases, but because the symptoms of neurobrucellosis are as nonspecific as headache and depression, the actual incidence probably is higher. Neurobrucellosis can be the presenting symptom of systemic brucella infection, or it can occur later in the disease. Although data are not specific on psychiatric complications, depression is said to be more common with brucellosis than with other chronic infections. Headache is another common symptom, although meningismus is seen in only one half of the patients. Cerebrovascular complications, including mycotic aneurysms and strokes, have been reported in rare cases, as have optic neuritis and cranial neuropathy. DIAGNOSIS A high degree of clinical suspicion is needed in diagnosing

neurobrucellosis. Although both culture and serology may be diagnostic, neither alone is usually sufficient. The complete evaluation of suspected neurobrucellosis should include lumbar puncture with culture, serum and cerebrospinal fluid (CSF) brucella serology, and blood culture. Neurobrucellosis usually presents with a CSF mononuclear pleocytosis, hypoglycorrhachia, and increased protein. Bone marrow culture can be useful, particularly in chronic cases. Because of the predilection of the organism for blood vessels and the incidence of mycotic aneurysm, thrombosis, and hemorrhage, CNS imaging may be useful in evaluating selected cases, particularly in patients presenting with a focal neurologic examination.

Chapter 55

TREATMENT Neurobrucellosis treatment involves first the treatment of the systemic disease with doxycycline (100 mg twice a day) and either oral rifampin (900 mg/day) or parented streptomycin (15 mg/kg IM). The combination with streptomycin is thought to be better when spondylitis is present, but there are no prospective studies comparing regimens for neurobrucellosis. Many authorities feel that additional drugs should be used if there is neurologic involvement, and a combination of doxycycline, streptomycin, rifampin, and trimethoprim-sulfamethoxazole(480/2400 mglday) for 2 to 4 months has been suggested. (Streptomycin usually is given only for the first 2 or 3 weeks because of toxicity.) Although third-generation cephalosporins achieve good CNS penetration, their efficacy against brucellae is variable, and in vitro susceptibilities should be confirmed before their use. Corticosteroids have been used in neurobrucellosis, but their

55

Legionellosis

441

efficacy has not been demonstrated by trials. Dexamethasone is speculated to be beneficial in neurobrucellosis, particularly if initiated before antimicrobial chemotherapy. When treatment is initiated early in the course of neurobrucellosis, the outcome generally is good.

SUGGESTED READINGS Cohenero JD, Reguera JM, Martos F et ak Complications associated with Brucella melitensis infection: a study of 530 cases. Medicine 75:195211, 1996

McClean DR, Russell N, Khan My: Neurobrucellosis: clinical and therapeutic features. Clin Infect Dis 15:582, 1992 Mousa AM, Bahar RH, Araj GF et ak Neurological complications of brucella spondylitis. Acta Neurol Scand 81:16, 1990 Mousa AM, Koshy TS, Araj GF et ak Brucella meningitis: presentation, diagnosis, and treatment. J Med 60:873, 1986

Legionellosis Clifford C. Dacso

Legionellosis is the collective name of clinical syndromes produced by the family Legionellaceae, a group of gram-negative aerobic intracellular bacilli. Although there are more than 30 species in this family, most of the clinical illness is produced by Legionella pneumophila. EPIDEMIOLOGY Legionellae are ubiquitous aquatic organisms that thrive in artificial reservoirs such as air conditioning cooling towers and water distribution systems. Aerosolization and inhalation of contaminated water is a major mode of transmission. Patients with chronic lung disease, airway compromise, and immunosuppression are more likely to develop clinical manifestations of Legionella infection. The preponderance of clinical disease caused by legionellae occurs in the lung.

NEUROLOGIC MANIFESTATIONS Neurologic manifestations are common concomitants of Legionnaire’s disease. Headache is very common. Abnormal mentation occurs in up to 30% of infected patients, including lethargy, confusion, delirium, and hallucinations and is out of proportion to any hypoxia present. This has no prognostic significance and tends to resolve with the illness. Other neurologic conditions such as peripheral neuropathy (primarily motor), chorea, seizures, sixth nerve palsies, and brain abscess have been reported, but their incidence is iinknown and in some cases their relationship to legionellosis is speculative. Cerebellar dysfunction, including ataxia and dysarthria, is a particularly prominent complication and may persist as a permanent residual.

DIAGNOSIS CLINICAL MANIFESTATIONS Clinical legionellosis can present in two ways: Legionnaire’s disease and Pontiac fever. Pontiac fever is a self-limited illness characterized by flulike symptoms, cough, and headache. Although seroconversion to legionellae occurs, there is no pulmonary parenchymal disease, and complete recovery occurs without any more than supportive treatment. Legionnaire’s disease is the name given to pulmonary and multisystem disease. Onset of the disease usually follows inoculation by 2 days to 2 weeks. Flulike symptoms are prominent early, followed by pulmonary symptoms of nonproductive cough and chest pain. Gastrointestinal symptoms of diarrhea, nausea, and abdominal pain are common, as are constitutional symptoms of fever, headache, malaise, and myalgias. In fact, in one study diarrhea was the only symptom that was significantly different from other community-acquired pneumonias.

Legionellosis should be suspected clinically in patients with an acute febrile pneumonia with a nonproductive cough, diarrhea, and altered mental status. The electroencephalogram is abnormal (diffusely slow) in 40% of patients, and the cerebrospinal fluid is abnormal (mildly elevated protein and pleocytosis) in 20%. Despite their ubiquity, legionellae are difficult to cultivate in vitro. Using special media, legionellae have been recovered from respiratory secretions, pleural fluid, abscesses, blood, and wounds. Direct fluorescent antibody tests can give a rapid diagnosis and should be performed on the appropriate specimen when legionellosis is suspected, but tests are positive in only 50% of cases. Although serodiagnosis is possible, its use requires the demonstration of an antibody rise, which may take months. A combination of all these test methods gives the best yield. Polymerase chain reaction has been studied in legionellosis diagnosis but has not been shown to be superior to culture.

Chapter 55

TREATMENT Neurobrucellosis treatment involves first the treatment of the systemic disease with doxycycline (100 mg twice a day) and either oral rifampin (900 mg/day) or parented streptomycin (15 mg/kg IM). The combination with streptomycin is thought to be better when spondylitis is present, but there are no prospective studies comparing regimens for neurobrucellosis. Many authorities feel that additional drugs should be used if there is neurologic involvement, and a combination of doxycycline, streptomycin, rifampin, and trimethoprim-sulfamethoxazole(480/2400 mglday) for 2 to 4 months has been suggested. (Streptomycin usually is given only for the first 2 or 3 weeks because of toxicity.) Although third-generation cephalosporins achieve good CNS penetration, their efficacy against brucellae is variable, and in vitro susceptibilities should be confirmed before their use. Corticosteroids have been used in neurobrucellosis, but their

55

Legionellosis

441

efficacy has not been demonstrated by trials. Dexamethasone is speculated to be beneficial in neurobrucellosis, particularly if initiated before antimicrobial chemotherapy. When treatment is initiated early in the course of neurobrucellosis, the outcome generally is good.

SUGGESTED READINGS Cohenero JD, Reguera JM, Martos F et ak Complications associated with Brucella melitensis infection: a study of 530 cases. Medicine 75:195211, 1996

McClean DR, Russell N, Khan My: Neurobrucellosis: clinical and therapeutic features. Clin Infect Dis 15:582, 1992 Mousa AM, Bahar RH, Araj GF et ak Neurological complications of brucella spondylitis. Acta Neurol Scand 81:16, 1990 Mousa AM, Koshy TS, Araj GF et ak Brucella meningitis: presentation, diagnosis, and treatment. J Med 60:873, 1986

Legionellosis Clifford C. Dacso

Legionellosis is the collective name of clinical syndromes produced by the family Legionellaceae, a group of gram-negative aerobic intracellular bacilli. Although there are more than 30 species in this family, most of the clinical illness is produced by Legionella pneumophila. EPIDEMIOLOGY Legionellae are ubiquitous aquatic organisms that thrive in artificial reservoirs such as air conditioning cooling towers and water distribution systems. Aerosolization and inhalation of contaminated water is a major mode of transmission. Patients with chronic lung disease, airway compromise, and immunosuppression are more likely to develop clinical manifestations of Legionella infection. The preponderance of clinical disease caused by legionellae occurs in the lung.

NEUROLOGIC MANIFESTATIONS Neurologic manifestations are common concomitants of Legionnaire’s disease. Headache is very common. Abnormal mentation occurs in up to 30% of infected patients, including lethargy, confusion, delirium, and hallucinations and is out of proportion to any hypoxia present. This has no prognostic significance and tends to resolve with the illness. Other neurologic conditions such as peripheral neuropathy (primarily motor), chorea, seizures, sixth nerve palsies, and brain abscess have been reported, but their incidence is iinknown and in some cases their relationship to legionellosis is speculative. Cerebellar dysfunction, including ataxia and dysarthria, is a particularly prominent complication and may persist as a permanent residual.

DIAGNOSIS CLINICAL MANIFESTATIONS Clinical legionellosis can present in two ways: Legionnaire’s disease and Pontiac fever. Pontiac fever is a self-limited illness characterized by flulike symptoms, cough, and headache. Although seroconversion to legionellae occurs, there is no pulmonary parenchymal disease, and complete recovery occurs without any more than supportive treatment. Legionnaire’s disease is the name given to pulmonary and multisystem disease. Onset of the disease usually follows inoculation by 2 days to 2 weeks. Flulike symptoms are prominent early, followed by pulmonary symptoms of nonproductive cough and chest pain. Gastrointestinal symptoms of diarrhea, nausea, and abdominal pain are common, as are constitutional symptoms of fever, headache, malaise, and myalgias. In fact, in one study diarrhea was the only symptom that was significantly different from other community-acquired pneumonias.

Legionellosis should be suspected clinically in patients with an acute febrile pneumonia with a nonproductive cough, diarrhea, and altered mental status. The electroencephalogram is abnormal (diffusely slow) in 40% of patients, and the cerebrospinal fluid is abnormal (mildly elevated protein and pleocytosis) in 20%. Despite their ubiquity, legionellae are difficult to cultivate in vitro. Using special media, legionellae have been recovered from respiratory secretions, pleural fluid, abscesses, blood, and wounds. Direct fluorescent antibody tests can give a rapid diagnosis and should be performed on the appropriate specimen when legionellosis is suspected, but tests are positive in only 50% of cases. Although serodiagnosis is possible, its use requires the demonstration of an antibody rise, which may take months. A combination of all these test methods gives the best yield. Polymerase chain reaction has been studied in legionellosis diagnosis but has not been shown to be superior to culture.

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TREATMENT Erythromycin has been the cornerstone of treatment of legionellosis. Of the macrolide class, the newer agents, particularly azithromycin, are emerging as the drugs of choice along with quinolones. Quinolone antibiotics and rifampin have in vitro activity against legionellae. It is reasonable to combine azithromycin with rifampin when central nervous system disease is suspected. Similarly, quinolones have been used successfully in Legionnaire’s disease unresponsive to erythromycin. Legionella pneumonia is fatal in 15% of those who are infected, but the rate is 25% to 80% if the patient is immunosuppressed.

56

However, when it occurs recovery is usually complete. There are case reports of peripheral neuropathy associated with legionellosis persisting for months.

SUGGESTED READINGS Bernstein JM: Treatment of community-acquired pneumonia: IDSA guidelines. Chest 115:9-13, 1999 Johnson JD, Raff MJ, Van Arsdall J A Neurologic manifestations of Legionnaire’s disease. Medicine 63:303, 1984 Nguyen MN: Legionellosis. Infect Dis Clin North Am 5:561, 1991

Tetanus Clifton L. Gooch

The fearsome effects of tetanus were well known long before contemporary immunization programs. Despite widespread immunization in the United States, however, cases of tetanus continue to appear. Approximately 100 cases are reported nationwide each year, with mortality rates of 30% despite aggressive therapy. Inadequately immunized patients (up to 10% of the U.S. population) constitute most cases. High-risk groups include those over 50 years old, African Americans from the rural South, and intravenous drug abusers, especially heroin addicts. In developing countries lacking adequate immunization programs, tetanus is a common cause of death, with an estimated 500,000 cases per year internationally and a mortality rate of 45%.

incubation period ranges from 1 day to several months. Once established, the organisms begin to produce tetanospasmin, an extremely powerful toxin. Tetanospasmin then undergoes retrograde axonal transport via local nerves to the central nervous system, where it interferes with the release of inhibitory neurotransmitters such as y-aminobutyric acid (GABA), diversely affecting the spinal cord, brainstem, cerebral cortex, and hypothalamus. Resultant disinhibition of motor systems and altered sympathetic nervous system function ultimately result in increased muscle contraction, rigidity, reflex spasms, and autonomic dysfunction. Restricted local symptoms may be the first manifestation, but if the toxin disseminates by hematogenous, lymphatic, and intra-axonal spread, generalized symptoms may appear.

EPIDEMIOLOGY The causative bacteria, Clostridium tetuni, may exist as a spore in topsoil, clothing, and dust for long periods. It is strictly anaerobic and must enter its host through a contaminated wound for successful infection and subsequent production of its pathogenic toxin, tetanospasmin. Approximately 70% of cases are associated with acute trauma, and although puncture wounds are classically associated with tetanus, lacerations are an equally likely cause. Potential causes of tetanus are as follows: Puncture wound Laceration Otitis media Corneal abrasion Intramuscular injection Foreign body injuries Dental manipulation Cutaneous ulcerations Burns Abortions Pregnancy and delivery Gastrointestinal or genitourinary surgery Neonatal tetanus may also be caused by infection of the umbilical stump. From 5% to 10% of cases have no identifiable antecedents. After contamination, germination and local infection cause clinical disease in an average of 3 to 21 days, although the

CLINICAL FEATURES Tetanus may be classified clinically as generalized, local, cephalic, or neonatal (Table 56- 1). Unfortunately, generalized tetanus is the most common form of the disease. Some patients report headache, rn TABLE56-1. Clinical Types of Tetanus Clinical Type

Symptoms

Prognosis

Generalized

Trismus, generalized rigidity, risus sardonicus, painful tetanic spasms, opisthotonus, dysphagia, laryngeal and pharyngeal spasm, autonomic dysfunction (labile hypertension, arrhythmias, etc.) Localized muscular stiffness, superimposed localized spasm, isolated limb rigidity Facial and ocular muscle weakness, localized spasm, early trismus Follows umbilical cord contamination by 7 to 10 days, poor feeding, irritability, then opisthotonus and generalized tetanic spasms

30% mortality, significant secondary morbidity

Local

Cephalic Neonatal

Good, < I % mortality, but may generalize Guarded, more likely to generalize Very poor

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TREATMENT Erythromycin has been the cornerstone of treatment of legionellosis. Of the macrolide class, the newer agents, particularly azithromycin, are emerging as the drugs of choice along with quinolones. Quinolone antibiotics and rifampin have in vitro activity against legionellae. It is reasonable to combine azithromycin with rifampin when central nervous system disease is suspected. Similarly, quinolones have been used successfully in Legionnaire’s disease unresponsive to erythromycin. Legionella pneumonia is fatal in 15% of those who are infected, but the rate is 25% to 80% if the patient is immunosuppressed.

56

However, when it occurs recovery is usually complete. There are case reports of peripheral neuropathy associated with legionellosis persisting for months.

SUGGESTED READINGS Bernstein JM: Treatment of community-acquired pneumonia: IDSA guidelines. Chest 115:9-13, 1999 Johnson JD, Raff MJ, Van Arsdall J A Neurologic manifestations of Legionnaire’s disease. Medicine 63:303, 1984 Nguyen MN: Legionellosis. Infect Dis Clin North Am 5:561, 1991

Tetanus Clifton L. Gooch

The fearsome effects of tetanus were well known long before contemporary immunization programs. Despite widespread immunization in the United States, however, cases of tetanus continue to appear. Approximately 100 cases are reported nationwide each year, with mortality rates of 30% despite aggressive therapy. Inadequately immunized patients (up to 10% of the U.S. population) constitute most cases. High-risk groups include those over 50 years old, African Americans from the rural South, and intravenous drug abusers, especially heroin addicts. In developing countries lacking adequate immunization programs, tetanus is a common cause of death, with an estimated 500,000 cases per year internationally and a mortality rate of 45%.

incubation period ranges from 1 day to several months. Once established, the organisms begin to produce tetanospasmin, an extremely powerful toxin. Tetanospasmin then undergoes retrograde axonal transport via local nerves to the central nervous system, where it interferes with the release of inhibitory neurotransmitters such as y-aminobutyric acid (GABA), diversely affecting the spinal cord, brainstem, cerebral cortex, and hypothalamus. Resultant disinhibition of motor systems and altered sympathetic nervous system function ultimately result in increased muscle contraction, rigidity, reflex spasms, and autonomic dysfunction. Restricted local symptoms may be the first manifestation, but if the toxin disseminates by hematogenous, lymphatic, and intra-axonal spread, generalized symptoms may appear.

EPIDEMIOLOGY The causative bacteria, Clostridium tetuni, may exist as a spore in topsoil, clothing, and dust for long periods. It is strictly anaerobic and must enter its host through a contaminated wound for successful infection and subsequent production of its pathogenic toxin, tetanospasmin. Approximately 70% of cases are associated with acute trauma, and although puncture wounds are classically associated with tetanus, lacerations are an equally likely cause. Potential causes of tetanus are as follows: Puncture wound Laceration Otitis media Corneal abrasion Intramuscular injection Foreign body injuries Dental manipulation Cutaneous ulcerations Burns Abortions Pregnancy and delivery Gastrointestinal or genitourinary surgery Neonatal tetanus may also be caused by infection of the umbilical stump. From 5% to 10% of cases have no identifiable antecedents. After contamination, germination and local infection cause clinical disease in an average of 3 to 21 days, although the

CLINICAL FEATURES Tetanus may be classified clinically as generalized, local, cephalic, or neonatal (Table 56- 1). Unfortunately, generalized tetanus is the most common form of the disease. Some patients report headache, rn TABLE56-1. Clinical Types of Tetanus Clinical Type

Symptoms

Prognosis

Generalized

Trismus, generalized rigidity, risus sardonicus, painful tetanic spasms, opisthotonus, dysphagia, laryngeal and pharyngeal spasm, autonomic dysfunction (labile hypertension, arrhythmias, etc.) Localized muscular stiffness, superimposed localized spasm, isolated limb rigidity Facial and ocular muscle weakness, localized spasm, early trismus Follows umbilical cord contamination by 7 to 10 days, poor feeding, irritability, then opisthotonus and generalized tetanic spasms

30% mortality, significant secondary morbidity

Local

Cephalic Neonatal

Good, < I % mortality, but may generalize Guarded, more likely to generalize Very poor

Chapter 56

low-grade fever, and irritability early, but jaw stiffness with subsequent difficulty opening the mouth (trismus or “lockjaw”) usually is the presenting symptom. Sequential spread to other facial, bulbar, neck, axial, and limb muscles then ensues, culminating in generalized rigidity. The patient’s extremities may be firmly extended, with persistent contraction of the facial muscles and lip retraction, producing risus sardonicus (a sardonic smile). With further progression, torturous generalized tonic spasms begin. These consist of severely painful episodes of arching of the back with extension of the legs (opisthotonus), adduction and flexion of the arms, and flexion of the fists over the chest. These spasms may occur in response to minor emotional or visual stimuli and can be violent enough to cause tendon detachments and long bone and vertebral fractures. Consciousness is not impaired. In addition to the excruciating pain of these tetanic spasms, involvement of the pharyngeal, laryngeal, and diaphragm musculature may precipitate aspiration or death by suffocation. Further dangers appear with sympathetic nervous system involvement. Tachycardia may herald this complication, which can include arrhythmias, bradycardia, and sinus arrest. Labile hypertension, refractory hypotension, excessive sweating, and fever may also be encountered. If the patient survives the initial phase of the illness, recovery may be prolonged. Spasms typically improve after 2 weeks and slowly resolve over 3 to 4 weeks, with resolution of all symptoms over 1 to 2 months, provided secondary complications do not occur. Rehabilitation may take several more months. Local tetanus appears as progressively increasing muscular stiffness (eventually becoming continuous) in the vicinity of a local trauma or surgical site, with intermittent superimposed spasms that, like generalized tetanic spasms, may be induced by a number of different stimuli. It is more common in the extremities and may cause significant rigidity of the affected limb. Typically it persists for weeks to months, then gradually resolves without sequela. Patients in this category have a good prognosis, with less than 1% mortality, and usually recover completely if they do not progress to the generalized form. Cephalic tetanus typically follows injury of the face and head and may appear after otitis media. Symptoms may occur after 1 to 2 days, most often as weakness of the facial and ocular muscles with later localized tetanic spasm. Trismus also may be an early sign. This variety is more likely to progress to generalized disease, although a nonprogressive cephalic form may occur. Neonatal tetanus usually appears after umbilical cord contamination in the first 7 to 10 days after delivery, most commonly in underdeveloped regions with poor maternal immunization and nonsterile delivery environments. Poor feeding and irritability quickly give way to diffuse rigidity, opisthotonus, and intermittent generalized spasms with minimal stimulation. The prognosis for recovery is very poor.

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TREATMENT Prevention The most effective and simple way to eliminate tetanus is through appropriate immunization. Primary immunization (Table 56-2) can be achieved in infancy with diphtheria, tetanus, and pertussis (DTP) vaccines administered at 2,4,6, and 15 months of age, with a booster at 4 to 6 years of age and every 10 years thereafter. If immunization is not achieved in infancy, patients less than 7 years old may receive DTP vaccination on the following schedule: initial dose, second dose 4 to 8 weeks after the first, third dose 4 to 8 weeks after the second, fourth dose 6 to 12 weeks after the third, and booster dose at 4 to 6 years old and every 10 years thereafter. Unimmunized patients older than 7 years should receive three injections of tetanus and diphtheria (Td) on the following schedule: initial dose, second dose 4 weeks after the first, third dose 6 months after the second, and every 10 years thereafter. Unimmunized pregnant patients should receive two injections of Td during the last two trimesters, at least 1 month apart, and every 10 years thereafter. Vaccination should not be attempted during the first trimester. Tetanus vaccination is well tolerated and is contraindicated only by a history of anaphylaxis or other adverse reaction after vaccination, although these are rarely encountered. After acute injury, appropriate wound care, including debridement, irrigation, and indicated antibiotics, are paramount. Further treatment depends on the nature of the wound. In tetanusprone wounds (older than 6 hours, infected, contaminated, or ischemic) in patients with an incomplete or unclear immunization history, human tetanus immune globulin (HTIG) 250 U should be administered intramuscularly, followed by completion of the primary immunization schedule described earlier. Patients with such wounds and a clear history of complete immunization with adsorbed tetanus vaccine do not need HTIG but should receive a

TAW 56-2. Primary Tetanus Immunization Patient

Vaccine

Schedule

Infant

DTP

Less than 7 yean

DTP

Four doses 2 months of age, 4 months of age, 6 months of age, and 15 months of age Booster 4 to 6 years, every 10 years thereafter Four doses Primary vaccination Second dose 6 to 12 weeks after the

first

More than 7 years

Td

Pregnant

Td

DIAGNOSIS The diagnosis of tetanus is a clinical one, based on the features just described. Serum antibody levels greater than 0.01 IU/mL make the diagnosis less probable but do not exclude it. Wound cultures may be negative. The differential diagnosis includes other conditions, most of them noninfectious, which produce severe muscle spasms, such as strychnine poisoning, black widow spider bite, dystonia associated with neuroleptic use, rabies, hysteria, and the stiff person syndrome.

Tetanus

Third dose 6 to 12 weeks after the second Fourth dose 6 to 12 weeks after the third Booster 4 to 6 yean old Every 10 years thereafter Three doses Primary vaccination Second dose 4 weeks after the first Third dose 6 months after the second Booster Every 10 years thereafter Two doses During second and third trimester only, at least 4 months apart Booster Every 10 yean thereafter

Abbreviations: DTP, diphtheria, tetanus, and pertussis; Td, tetanus and diphtheria. (Data from Croleau, C: Tetanus. Emerg Med Clin North Am 10551, 1992.)

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booster (Td in patients older than 7 years, DTP in patients younger than 7 years) if their last booster was more than 5 years ago. Pregnant patients in the first trimester with a history of full immunization may receive HTIG without risk to the fetus. Second- and third-trimester patients may receive routine boosters as indicated. For more minor clean wounds, nonimmunized patients do not need HTIG but should begin the appropriate vaccination schedule immediately. Immunized patients without a booster in the last 10 years should receive a booster vaccination. Acute! Treatment

Patients diagnosed with tetanus should be admitted to the intensive care unit for close observation. A single dose of HTIG, 3000 to 10,000 U, should be given intramuscularly in an attempt to neutralize the toxin. Appropriate wound care followed by antibiotic administration to eradicate the infection is the next step, and procaine penicillin 10 to 12 million U IV or IM daily in divided doses for 10 days is the therapy of choice. For the penicillinallergic patient, clindamycin 150 to 300 mg every 6 hours, erythromycin 500 mg PO every 6 hours, or tetracycline 500 mg PO or IV every 6 hours for 10 days is an acceptable alternative. The patient should be maintained in as dark and quiet an environment as possible. Mild tetanus without tetanic spasms may be treated with diazepam 2 to 10 mg IV every 4 to 12 hours or phenobarbital 50 to 100 mg every 3 to 6 hours, titrated to response. Dantrolene may also be effective. More severe tetanus with tetanic spasms necessitates tracheostomy because of the danger of associated laryngospasm, and mechanical ventilation is needed before more intensive pharmacotherapy is instituted because all recommended therapies may cause significant respiratory depression. Benzodiazepines are the most effective agents for treating tetanic spasms, and diazepam, at high dosages of 40 to 120 mglday IV in divided doses every 2 to 8 hours, is recommended. Alternatively, phenobarbital or short-acting barbiturates such as pentobarbital (initially given in dosages of 50 to 200 mg IM every 2 to 8 hours, titrated to response) in combination with chlorpromazine 200 to 300 mg/day may be used. Tachyphylaxis from chlorpromazine and worsening muscle spasm may limit this

approach, however. Barbiturates and diazepam in combination may cause cardiac arrest and should be used with great care. Severe rigidity and spasms refractory to the these drugs should be treated with neuromuscular blockade, which can be instituted with succinylcholine and maintained with pancuronium with continuation of heavy sedation to minimize patient discomfort. Alternative use of higher-dose intravenous dantrolene (140 mg bolus, followed by 1 mg/kg IV every 4 hours, with ultimate conversion to 100 mg PO every 4 hours) has been reported to be an effective substitute for neuromuscular paralysis in a few severe cases. Autonomic dysfunction does not reliably respond to medical therapy, but treatment of labile hypertension may be attempted with intravenous morphine in 5- to 30-mg infusions over 30 minutes, repeated every 2 to 8 hours. General principles regarding care of the debilitated critically ill patient should be closely observed, with particular attention to nutritional needs and the prevention of decubitus ulcers, gastric ulcers, and deep vein thrombosis. Tetanus is a horrible affliction and, once contracted, carries a high risk of death. It is preventable, however, and physicians should be attentive to the immunization status of their patients and take every opportunity to provide them with the protection our modern era has made available.

SUGGESTED READINGS Farrar JJ, Yen LM, Cook T et al: Tetanus. J Neurol Neurosurg Psychiatry 69:292, 2000 Groleau G: Tetanus. Emerg Med Clin North Am 10:351, 1992 Kefer M: Tetanus. Am J Emerg Med 10:445, 1992 Tidyrnan M, Prichard JG, Deamer RL, Mac N: Adjunctive use of dantrolene in severe tetanus. Anesth Analg 64538, 1985 Walsh TM: Diseases of nerve and muscle. p. 358. In Samuels MA (ed): Manual of Neurology. 4th Ed. Little, Brown, Boston, 1991 Weinstein L Current concepts: tetanus. N Engl J Med 289:1293, 1973 Wright DK, Lalloo UG, Nayiager S, Govender P: Autonomic nervous system dysfunction in severe tetanus: current perspectives. Crit Care Med 17:371, 1989

SECTION

3 SPIROCHETAL INFECTIONS

57

Neurosyphilis J. Douglas Lee

Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. At the time of primary infection, the spirochetes replicate at the site of inoculation and within 3 weeks create a painless chancre. This chancre may last 2 to 8 weeks, or longer in patients infected with human immunodeficiency virus (HIV). Within several weeks of the primary chancre, a spirochetemia produces the second stage of syphilis, and it is at this stage that spirochetes invade the central nervous system (CNS) in one third of patients. Although acute syphilitic meningitis may occur (1% to 3% of patients), neurologic symptoms usually are absent at this stage. Secondary syphilis is self-limited in the normal host and is followed by a latent period of chronic infection that may last months, years, or a lifetime (Table 57-1). In 30% of untreated patients, tertiary syphilis subsequently appears, and it is these tertiary manifestations that are of major concern to the neurologist (Table 57-2). CLINICAL FEATURES OF NEUROSYPHILIS

In the secondary stage, 1% to 2% of all patients with syphilis show evidence of acute aseptic meningitis or meningoencephalitis, usually with evidence of syphilis in other organ systems, particularly the skin. Clinical manifestations may also include cranial neuropathies, particularly cranial nerve VIII. Tertiary syphilis generally produces three patterns of neurologic involvement, all based on obliterative endarteritis causing neuronal loss. Although it is important to remember that there are few neurologic entities that syphilis cannot mimic, typical syndromes are as follows:

Meningovascular syphilis. This is a chronic syphilitic meningitis associated with arteritis and occlusion of blood vessels producing cerebral infarctions. The clinical picture may be TABLE57-1. Stages of Syphilis Stage

lime from Infection

Neurologic Manifestations

Primary Secondary

0-4 weeks 4-8 weeks

Latent Tertiary

8 weeks-lifetime 5-1 0 years

None Acute syphilitic meningitis or asymptomatic meningitis None Meningovasculitis General paresis Tabes dorsalis Optic atrophy, otitis Cummas Cardiovascular

15-20 years 25-30 years

TABLE 57-2. Neurologic Manifestations of Tertiary Syphilis Meningovascular Strokes Chronic meningitis General paresis Dementia Personality change Irregular (Argyll-Robertson) pupils Tabes dorsalis Numbness in feet and legs (position and deep pain) Lightning pains in legs Other Optic neuritis or atrophy Asymmetric sensorineural hearina loss or dizziness

that of a chronic meningitis, or a dementia, but most patients present with a stroke syndrome. This usually occurs 5 to 10 years after primary infection. Parenchymal syphilis: general paresis. Fifteen to twenty years after primary infection, a chronic low-grade encephalitis producing neuropsychiatric abnormalities and dementia may occur. Pupillary changes are common. Parenchymal syphilis: tabes dorsalis. In this syndrome, the dorsal columns of the spinal cord and the proprioceptive pathways are preferentially involved, creating a sensory ataxia with painful paresthesias; loss of deep pain, position and temperature sensation in the legs; and, in the end stage, Charcot joints. Optic atrophy and Argyll-Robertson pupils may also occur. Parenchymal syphilis: cranial nerve disease. This can involve any cranial nerve, but the optic and the VIII nerve are most commonly involved. Optic atrophy, unexplained pupillary reflexes, asymmetric tinnitus, or asymmetric sensorineural hearing loss suggests syphilis. Although these are characteristic, it must be understood that neurosyphilis has been called “the great imitator” for good reason. Because it can mimic almost any neurologic disease, it must be suspected in a wide variety CNS diseases and in any patient with a history of positive syphilis serology whether or not treatment has been received. DIAGNOSIS OF NEUROSYPHILIS

Patients with any neurologic problem consistent with syphilis should be evaluated for neurosyphilis. To confirm a clinical suspicion of active neurosyphilis, a patient should have both 445

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serologic abnormalities indicating the presence of syphilis and characteristic spinal fluid changes. Confirmation of neurosyphilis requires a reactive specific treponemal serology in the cerebrospinal fluid (CSF), such as fluorescent treponema antibody (FTAABS) or T. pallidum hemagglutination assay (TPHA). The activity or status of the neurosyphilis is indicated by the CSF parameters, the CSF Venereal Disease Research Laboratories (VDRL) test if positive, and the level of antitreponemal antibody production in the CNS. The greater the evidence of active infection, the greater the certainty that the signs or symptoms are caused by this infection. For some patients the significance of a positive serology is uncertain, but because of the treatable nature of this disease, some patients need treatment when the diagnosis is not definite. An example is the patient with a positive syphilis serum serology and with nervous system disease consistent with syphilis but normal CSF findings. It is very important that patients in these situations understand the uncertainty of the diagnosis. Antibody Testing There are two types of serologic tests for syphilis: treponemal and nontreponemal. The nontreponemal or reagin tests quantitatively measure a patient's antibody response to cardiolipin-lecithincholesterol antigens. These tests include the VDRL serology and the rapid plasma reagin (RPR) serology. These antibodies are reliably produced during primary and secondary stages of infection with Treponema pallidurn, very soon after the chancre occurs, but may be falsely negative in late syphilis. These tests may be performed on CSF or serum samples. The treponemal tests detect antibodies in serum or CSF specifically directed toward treponemal antigens. These are very specific, with very few false positives or negatives. These tests include the FTA-ABS and the microhemagglutinin assay for antibodies to rl: pallidum (MHA-TP). Neurosyphilis is unlikely with a negative serum treponemal antibody test, and a definite diagnosis of neurosyphilis generally should not be made if these antibodies are absent in the CSF. Although the nontreponemal tests can be used for diagnostic screening in the secondary stage, specific treponemal tests are needed to screen for late syphilis and to determine the significance of positive nontreponemal test results. False-positive serum nontreponemal tests are not uncommon. A false-positive result is defined as a positive nontreponemal serology and a negative treponemal antibody test. Because of false positives and false negatives, treponemal and nontreponemal tests should be used together. The VDRL or RF'R on blood or CSF should not be used alone to screen for neurosyphilis. Serial determinations of CSF VDRL or RPR after treatment provide a reliable monitor of the adequacy of therapy in cases possessing these antibodies. The specific treponemal tests (FTA, MHA-TP) remain positive even after the disease has been treated successfully and are useful for determining the effectiveness of therapy only if declines in intrathecal antibody production can be documented using sequential CSF FTA or TPHA antibody indices over several years. This is rarely needed. CSF Analysis and Disease Activity

In patients with serologic evidence of syphilis, the presence of neurosyphilis can be determined only by CSF analysis. The CSF should be examined in all patients with suspected neurosyphilis. If

adequacy of prior treatment is uncertain, if relapse is suspected, or if the CSF has not been evaluated, lumbar puncture is necessary. Although active neurosyphilis probably can occur with normal spinal fluid, there is usually a pleocytosis (5 to 200 cells/mm3) or elevated protein (usually less than 200 mg/100 mL). In addition there should be a one or more positive CSF serologies (treponemal or nontreponemal). In neurosyphilis, the CSF VDRL or RPR tests usually are negative, but when positive they suggest active neurosyphilis. Intrathecal production of antitreponemal antibodies can be measured and is expressed as an index. A high index indicates that antibody is being produced at a higher rate in the CNS than outside the CNS, indicating the presence of neurosyphilis. An antibody index usually is not needed but may assist in distinguishing active from inactive disease. Although not part of the diagnostic criteria for syphilis, most patients have elevated immunoglobulin G (IgG) levels in the spinal fluid, with oligoclonal bands. A diagnosis of neurosyphilis is made when there is serologic evidence of CNS invasion by treponemes (positive CSF TPHA or FTA). The activity of the process can be assessed by the extent of CSF abnormalities and a CSF VDRL titer when positive. In troublesome cases a CSF antibody index may be helpful. It is important to recognize that no single serology is perfect and that there will be patients with evidence of syphilis and neurologic disease in whom the relationship between the two is uncertain because the diagnosis of neurosyphilis is uncertain or the neurosyphilis appears quiescent. In these cases treatment for syphilis or consultation with a syphilis expert is recommended. NEUROSYPHILIS WITH HIV INFECTION

In patients with acquired immune deficiency syndrome (AIDS), neurosyphilis usually is more virulent because of the impaired immune response. This allows the disease in all stages to progress more rapidly and particularly alters the secondary stage of syphilis, when the CNS is invaded by the spirochete. This usually subclinical infection often produces significant symptoms in the HIV-infected patient. Acute syphilitic meningitis is especially common at this stage. Because of impaired immune response, atypical manifestations may appear, including severe necrotizing brain and spinal cord lesions. The diagnosis of neurosyphilis often is more difficult because impaired immune responses may affect serum and CSF serologic tests. HIV infection itself often produces spinal fluid changes of pleocytosis and elevated protein, which can mimic changes seen in syphilis. HIV may also cause dementia, myelopathy, and other symptoms and signs consistent with neurosyphilis. Thus, the clinical, serologic, and CSF values needed to diagnose syphilis may be altered. In patients with AIDS who are suspected of having neurosyphilis, blood and spinal fluid should be examined, and treatment is recommended for HIV-positive patients in whom there is any evidence of neurosyphilis. THERAPY

Any patient who has definite or possible neurosyphilis should be treated. Particularly in low-prevalence areas, patients will be seen who have minimal CNS disease and conflicting or minimally abnormal laboratory studies (e.g., unilateral cranial nerve VIII disease, normal CSF, and a positive serum FTA only). Whether neurosyphilis is the cause of the symptoms is uncertain. These

Chapter 58

patients should be treated, recognizing the limitations of biologic tests in producing a definite diagnosis and recognizing the potential harm in missing a diagnosis. The patient should be informed of the uncertainty of the diagnosis and the rationale for treatment to minimize legal, social, and emotional consequences. All follow-up should be undertaken for these patients as for definite cases. High-dose intravenous penicillin is the drug of choice for treatment of neurosyphilis. Patients should receive intravenous aqueous crystalline penicillin G in a dosage of 4 million U every 4 hours for 10 to 14 days. Traditional intramuscular therapy of 2.4 million U benzathine penicillin a week does not achieve reliably bacteriocidal concentrations of penicillin in the nervous system. Patients who claim to be allergic to penicillin often are not and should be evaluated with skin testing and chart reviews to confirm the existence of the allergic response because penicillin is considered to be the best therapy. There are a variety of other antibiotic regimens, but there are not good studies to prove equivalency to penicillin. Penicillin desensitization should be considered if necessary. Antibiotic regimens for tertiary syphilis are as follows: W W W W W

Penicillin G 4 million U every 4 hours x 10 to 14 days (recommended) Procaine penicillin 2.4 million U IM per day x 10 to 14 days with probenecid 500 mg PO 4 times a day Doxycycline 200 mg PO twice a day x 21 days Ceftriaxone 2 g IM per day x 14 days Amoxicillin 3 g plus probenecid 1 g twice a day x 15 days

Adequate antibiotic therapy for neurosyphilis should arrest the progression of clinical signs and symptoms but will not reverse

58

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existing neurologic damage. The spinal fluid should return toward normal and should be reexamined at 3- to 6-month intervals after treatment to verify a return to normal of the previously observed abnormalities. The cell counts should be normal by 6 months and the protein within 2 years. If not, retreatment should be considered. After therapy, the CSF VDRL test should be followed until it is negative or has declined to a low and stable titer. A rebound in any parameter suggests recurrence and necessitates an additional full course of antibiotic therapy. This is particularly a problem in patients with HIV, in whom treatment failures are more common. In the case of a relapse of neurologic disease, if the CSF VDRL initially was negative and CSF abnormalities were trivial, obtaining a CSF antitreponemal antibody index may be done to determine whether active syphilis is present. SUGGESTED READINGS 1998 guidelines for treatment of sexually transmitted diseases. MMWR 47(RR-1), January 23, 1998 Davis LE, Schmitt Clinical significance of cerebrospinal fluid tests for neurosyphilis. Ann Neurol 2550, 1989 Hart G Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 104368, 1986 Hook EW, Marra CM Acquired syphilis in adults. N Engl J Med 326:1060, 1992 Musher DM, Hamill RJ, Baughn RE: Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 113:872, 1990 Simon Rp: Neurosyphilis. Neurology 44:2228, 1994 Wolters EC Treatment of neurosyphilis. Clin Neuropharmacol 1 0 143, 1987

L m e Disease Lauren 9. Krupp

Lyme disease is a major infectious disease in the United States resulting from a bacterial infection caused by the tickborne spirochete Borrelia burgdorferi. The disease can affect multiple systems, and clinical features range in severity from a mild transient constitutional illness to a more severe and chronic condition with rheumatologic, neurologic, and cardiac complications. Major target organs of the infection include the skin, joints, heart, and nervous system. The neurologic consequences of this infection are varied and multiple. Some are certainly a direct consequence of nervous system infection, whereas others may be secondary to the host’s immune reaction. The classic description of neuralgia, neuritis, and chronic lymphocytic meningitis associated with this disorder occurred in 1941 when Bannwarth reported on a series of patients with radicular pain, aseptic meningitis, and involvement of the peripheral and cranial nerves. In subsequent decades, European authors recognized that this syndrome consisted of dermatologic features and symptoms of meningoradiculoneuritis. Often a preceding tick bite was recalled. Wider recognition of the disorder came later in the mid-1970s when Steere and colleagues described an unusual outbreak of arthritis among children in Lyme, Connecticut. This outbreak was associated with a skin rash in 25%

of patients and in 21% was preceded by a tick bite. By the end of the decade, the illness was called Lyme disease. In 1982, a unique spirochete was recovered from a deer tick and named Borrelia burgdorferi after its discoverer. This spirochete was subsequently identified as the etiologic agent for Lyme disease. The term Lyme disease replaces former labels of “Bannwarth syndrome,” “Garin-Bujadoux disease,” and “tickborne meningoencephalitis.” In Europe, neurologic Lyme disease still is often called neuroborreliosis. EPIDEMIOLOGY Lyme disease is the leading tickborne disease in Europe and the United States. Since 1982, when the Centers for Disease Control and Prevention (CDC) established a national surveillance for the infection, the number of reported cases has risen sharply. Approximately 15,000 cases are reported each year, and the infection is endemic in more than 15 states. The areas of the United States in which the disorder occurs most commonly are in the Northeast from Maine to Maryland, in the Midwest including Wisconsin and Minnesota, and in the West in northern California and Oregon. Epidemiologic surveys document spread of the tick

Chapter 58

patients should be treated, recognizing the limitations of biologic tests in producing a definite diagnosis and recognizing the potential harm in missing a diagnosis. The patient should be informed of the uncertainty of the diagnosis and the rationale for treatment to minimize legal, social, and emotional consequences. All follow-up should be undertaken for these patients as for definite cases. High-dose intravenous penicillin is the drug of choice for treatment of neurosyphilis. Patients should receive intravenous aqueous crystalline penicillin G in a dosage of 4 million U every 4 hours for 10 to 14 days. Traditional intramuscular therapy of 2.4 million U benzathine penicillin a week does not achieve reliably bacteriocidal concentrations of penicillin in the nervous system. Patients who claim to be allergic to penicillin often are not and should be evaluated with skin testing and chart reviews to confirm the existence of the allergic response because penicillin is considered to be the best therapy. There are a variety of other antibiotic regimens, but there are not good studies to prove equivalency to penicillin. Penicillin desensitization should be considered if necessary. Antibiotic regimens for tertiary syphilis are as follows: W W W W W

Penicillin G 4 million U every 4 hours x 10 to 14 days (recommended) Procaine penicillin 2.4 million U IM per day x 10 to 14 days with probenecid 500 mg PO 4 times a day Doxycycline 200 mg PO twice a day x 21 days Ceftriaxone 2 g IM per day x 14 days Amoxicillin 3 g plus probenecid 1 g twice a day x 15 days

Adequate antibiotic therapy for neurosyphilis should arrest the progression of clinical signs and symptoms but will not reverse

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existing neurologic damage. The spinal fluid should return toward normal and should be reexamined at 3- to 6-month intervals after treatment to verify a return to normal of the previously observed abnormalities. The cell counts should be normal by 6 months and the protein within 2 years. If not, retreatment should be considered. After therapy, the CSF VDRL test should be followed until it is negative or has declined to a low and stable titer. A rebound in any parameter suggests recurrence and necessitates an additional full course of antibiotic therapy. This is particularly a problem in patients with HIV, in whom treatment failures are more common. In the case of a relapse of neurologic disease, if the CSF VDRL initially was negative and CSF abnormalities were trivial, obtaining a CSF antitreponemal antibody index may be done to determine whether active syphilis is present. SUGGESTED READINGS 1998 guidelines for treatment of sexually transmitted diseases. MMWR 47(RR-1), January 23, 1998 Davis LE, Schmitt Clinical significance of cerebrospinal fluid tests for neurosyphilis. Ann Neurol 2550, 1989 Hart G Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 104368, 1986 Hook EW, Marra CM Acquired syphilis in adults. N Engl J Med 326:1060, 1992 Musher DM, Hamill RJ, Baughn RE: Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 113:872, 1990 Simon Rp: Neurosyphilis. Neurology 44:2228, 1994 Wolters EC Treatment of neurosyphilis. Clin Neuropharmacol 1 0 143, 1987

L m e Disease Lauren 9. Krupp

Lyme disease is a major infectious disease in the United States resulting from a bacterial infection caused by the tickborne spirochete Borrelia burgdorferi. The disease can affect multiple systems, and clinical features range in severity from a mild transient constitutional illness to a more severe and chronic condition with rheumatologic, neurologic, and cardiac complications. Major target organs of the infection include the skin, joints, heart, and nervous system. The neurologic consequences of this infection are varied and multiple. Some are certainly a direct consequence of nervous system infection, whereas others may be secondary to the host’s immune reaction. The classic description of neuralgia, neuritis, and chronic lymphocytic meningitis associated with this disorder occurred in 1941 when Bannwarth reported on a series of patients with radicular pain, aseptic meningitis, and involvement of the peripheral and cranial nerves. In subsequent decades, European authors recognized that this syndrome consisted of dermatologic features and symptoms of meningoradiculoneuritis. Often a preceding tick bite was recalled. Wider recognition of the disorder came later in the mid-1970s when Steere and colleagues described an unusual outbreak of arthritis among children in Lyme, Connecticut. This outbreak was associated with a skin rash in 25%

of patients and in 21% was preceded by a tick bite. By the end of the decade, the illness was called Lyme disease. In 1982, a unique spirochete was recovered from a deer tick and named Borrelia burgdorferi after its discoverer. This spirochete was subsequently identified as the etiologic agent for Lyme disease. The term Lyme disease replaces former labels of “Bannwarth syndrome,” “Garin-Bujadoux disease,” and “tickborne meningoencephalitis.” In Europe, neurologic Lyme disease still is often called neuroborreliosis. EPIDEMIOLOGY Lyme disease is the leading tickborne disease in Europe and the United States. Since 1982, when the Centers for Disease Control and Prevention (CDC) established a national surveillance for the infection, the number of reported cases has risen sharply. Approximately 15,000 cases are reported each year, and the infection is endemic in more than 15 states. The areas of the United States in which the disorder occurs most commonly are in the Northeast from Maine to Maryland, in the Midwest including Wisconsin and Minnesota, and in the West in northern California and Oregon. Epidemiologic surveys document spread of the tick

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vector and increased tick infection rates within endemic areas. States with the highest incidence are New York, Connecticut, New Jersey, Pennsylvania, &ode Island, Massachusetts, Maryland, Minnesota, and California. In Europe, Lyme disease occurs most often in Scandinavia, Germany, Austria, Slovenia, and Sweden. The causative agent of Lyme disease consists of three distinct species: B. burgdorferi (which characterizes the strain type found in the United States), Borrelia afzelli, and Borrelia garinii. The two latter strains are responsible for the majority of infections found in Europe. The Borrelia species shares some features with other spirochetal agents, such as those that produce syphilis, leptospirosis, and relapsing fever. Spirochetes first infect locally and involve the skin or entry site, then produce a spirochetemia and disseminate throughout the body. Later, chronic organ infection can occur. The Borrelia species is very difficult to grow in culture, often making the laboratory diagnosis of the infection difficult. In the United States B. burgdojeri infects several different tick species, each unique to a specific geographic area. Ticks commonly feed on wildlife, such as deer or field mice. When a human serving as an incidental host is bitten by an infected tick, the disease may be transmitted.

rn TAILE 58-1. Lyme Disease Stages Localized Unifocal erythema migrans flulike illness Disseminated Multifocal erythema migrans Cardiac conduction abnormalities Hepatitis Arthritis Lymphocytic meningitis Headachewithout meningitis Cranial neuropathy Radiculitis Chronic Arthritis and arthralgia Encephalomyelitis Encephalopathy Chronic neuropathy Entrapment neuropathies Post-treatment and remote effects Fatigue Cognitive difficulty Fibromyalgia Sleep disturbance Headache Arthralaia

CLINICAL FEATURES The CDC has established clinically useful guidelines for diagnosing Lyme disease. A case is defined as a person with the erythema migrans rash or a person with at least one late objective manifestation and laboratory confirmation of infection. Erythema migrans is a pathognomonic marker that appears 1 to 30 days after infection as a patch that expands centrifugally from 5 to 42 cm. It may be multiple, has central clearing, and is absent from soles and palms. The rash lasts for days to weeks. Histologic tests show a superficial and deep perivascular interstitial plasma cell infiltrate; spirochetes may be present at the periphery. Objective late systemic manifestations of Lyme disease include any of the following when an alternative explanation is not found musculoskeletal (recurrent brief attacks of objective joint swelling in one or a few joints, sometimes followed by chronic arthritis), cardiac (acute onset high-grade atrioventricular conduction defect that resolves in days to weeks and sometimes is associated with myocarditis), or neurologic (cranial neuritis, particularly unilateral or bilateral facial palsy, radiculoneuropathy, or, rarely, encephalomyelitis if associated with intrathecal B. burgdorferi antibody production). Although the CDC criteria are helpful, rigid adherence to the case definition is likely to exclude some true cases of Lyme disease. Lyme disease has been divided into localized (early or acute), disseminated, and later (chronic) stages (Table 58-1). Although specific syndromes are more common in particular stages of the infection, a great deal of overlap exists in the time course of clinical manifestations. In general, disseminated neurologic syndromes such as lymphocytic meningitis, facial nerve palsy, severe encephalitides, and painful radiculitis occur within weeks to months of infection. Patients with long-standing, chronic disease commonly have encephalopathy of mild to moderate severity, peripheral neuropathy, or both. After resolution of the infection, many patients suffer from persistent remote effects such as fatigue, myalgia, and headache.

rn TABLE 58-2. Peripheral Nervous System Manifestations Multifocal axonal neuropathy Painful radiculitis Cuillain-Barre-like neuropathy Mononeuritis multiplex Chronic mild sensorimotor neuropathy Facial nerve palsy Entrapment neuropathy Carpal tunnel syndrome Myositis

Peripheral Nerve and Muscle The specific PNS disorders of Lyme disease are listed in Table 58-2. Paresthesias and radiculopathy of varying severity often are associated with Lyme disease. An intense radicular pain may develop in the dermatologic distribution of either the arthropod bite or the rash. The peripheral neuropathy usually is milder, of the axonal type (causing atrophy and denervation but without much slowing of nerve conduction velocities), and usually affects the lower extremities. Patients with PNS involvement often experience meningeal symptoms and cerebrospinal fluid (CSF) abnormalities. Thoracic sensory radiculitis, mononeuritis multiplex, and brachial plexitis associated with meningeal involvement are well documented. Another neuropathy common to Lyme disease is entrapment neuropathy, particularly carpal tunnel syndrome. Much rarer are cases of polyradicular motor neuropathy suggestive of GuillainBarre syndrome (GBS). The presence of CSF pleocytosis distinguishes these cases from classic GBS, and often the neuropathy is axonal as opposed to the demyelinating radiculopathy with slowed conduction times in GBS. Myositis and polymyositis have also been noted in Lyme disease but are uncommon. Cranial Nerve

NEUROLOGIC CLINICAL SYNDROMES Both the central nervous system (CNS) and peripheral nervous system (PNS) can be involved in Lyme disease.

The seventh (facial) nerve is commonly affected in Lyme disease, with an incidence as high as 10% of patients with disseminated infection. Bilateral facial nerve palsy may occur. Damage may

Chapter 58

develop as part of a peripheral nerve process or as part of a basal meningitis. Cranial nerves 111, IV, V, VI, and VIII can be affected by Lyme disease, and Lyme disease has occasionally been associated with optic neuritis. A few cases of recurrent laryngeal nerve abnormalities have occurred, but the lowest cranial nerves otherwise seem to be spared. In a particularly dramatic case, cared for by the author, an older adult without a known history of tick bite presented with a VI nerve partial paresis, followed by painful radiculopathy, and approximately 2 weeks later laryngeal paralysis developed. All findings resolved after antibiotic therapy. Central Nervous System A large number of different CNS syndromes have been associated with Lyme disease, but a causal relationship is compelling in only a few. The main syndromes are shown in Table 58-3 and include meningitis, encephalitis, encephalomyelitis, and encephalopathy. The hallmark of neurologic Lyme disease is meningitis. This occurs during the early disseminated phase and may vary from a mild illness to, less often, a severe meningoencephalitis. Headache is common in 50% to 89% of cases and sometimes persists after treatment. Fever may occur but often is absent. Many patients (20% to 50%) with meningeal symptoms experience memory and concentration difficulty, mood disturbance, disrupted sleep, and, in more severe cases, obtundation and stupor. Approximately half of all patients with meningitis have cranial neuropathy, and a third have radiculoneuropathy. Systemic symptoms include weight loss, profound fatigue, and myalgia. The CSF generally reveals pleocytosis, elevated immunoglobulin G (IgG), and intrathecal antibody production to B. burgdorferi or other evidence of B. burgdorferi CNS invasion such as borrelial antigens or DNA. Encephalomyelitis and encephalitis are much less common than meningitis but can occur. Patients with myelitis present with spastic paraparesis and an inflammatory lesion visualized on MRI within the spinal cord. Other clinical presentations, which occasionally mimic mass lesions, include hemiparesis, ataxia, stupor, aphasia, apraxia, psychosis, and dementia. Hearing loss and headache are common accompanying problems. Seizures are rare. Varying degrees of cognitive impairment may be present. An acute or subacute monophasic illness is the usual time course. In untreated patients, a relapsing-remitting or progressive course spanning months to years is possible. More common, less severe symptoms include confusion, irritability, and lethargy. In some patients, a mild to moderate encephalopathy with noninflammatory CSF is present. Patients with intrathecal antibody produce may be more severely affected. Memory difficulties, word-finding difficulty, and other deficits have been confirmed with neuropsychological testing and often improve after antibiotic therapy. In a subset of patients, however, complaints of cognitive dysfunction persist. Although a variety of other neurologic manifestations of Lyme TABLE 58-3. Central Nervous System Manifestations Lymphocytic meningitis With secondary cranial neuropathies Focal encephalitis or encephalomyelitis Severe, with focal findings Mild, with encephalopathy Encephalopathy Usually mild, occasionally moderate to severe, associated headache, fatigue, and malaise common

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disease have been reported, including vasculitis, movement disorders, and dementia, many of these syndromes occurred in patients lacking CSF abnormalities or measurement of anti-B. burgdorferi antibody in the CSF. Therefore, their relationship to the disease requires further study. Post-treatment Lyme Manifestationsand Remote Effects

Remote effects of Lyme disease include symptoms that persist months after vigorous antibiotic therapy (Table 58-1). The most common persistent symptoms are fatigue, confusion, cognitive loss, arthralgia, myalgia, and headache. Many patients with Lyme disease experience mild to moderate depressive symptoms, as occurs with other chronic medical disorders. Psychosis and severe anxiety disorder have been observed in rare cases of Lyme disease. In some instances, inadequate initial treatment leads to continued symptoms. For other cases, the initial therapy may have been adequate, and the recovery period takes longer than expected. In most of these cases the electroencephalogram (EEG) or magnetic resonance imaging (MRI) is normal or nonspecific. For the patient who fails to make a good recovery over time, evaluation for other disorders may be revealing. DIAGNOSIS The diagnosis of Lyme disease rests heavily on the clinical presentation. However, because many patients have no recollection of the tick bite or may lack the pathognomonic erythema migrans rash, the diagnosis is aided by laboratory testing. Unfortunately, laboratory diagnosis is not infallible and has three major areas of difficulty: The diagnostic methods that are most accurate and specific (either culture or visualization of B. burgdorferi) are too insensitive and too slow for practical application. Thus, diagnosis relies on indirect means, such as detection of an antibody response. However, because of the nature of the immunologic response, early in the illness (within the first few weeks after exposure) many infected patients are not seropositive in even the best clinical laboratories. There are many different commercial diagnostic assays for detecting antibodies to B. burgdorferi. Most have failed the standards established by the CDC because of lack of standardization, reliability, and sensitivity. Some cross-reactivity develops between autoantibodies or antibodies to other inflammatory conditions and those directed against B. burgdorferi. Also, people exposed to the organism may remain asymptomatic and never develop a clinical infection. Therefore, in areas where Lyme is endemic, physicians may inappropriately use a low or borderline Lyme test as a basis for treatment while ignoring the absence of a supporting clinical history. To deal with each of these problems effectively, the strengths and limitations of the different diagnostic methods available for this infection must be understood.

Successful growth of B. burgdorferi has been achieved using special media, but in only 10% of meningitis cases is the organism recovered from CSF. In most reports, the yield for recovering the

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organism from blood is even lower, ranging from 1.3% to 5%. Similarly, identification of B. burgdorferi in tissue has a very low yield because the organisms are very sparse.

Antibody Assay Measurement of anti-B. burgdorferi antibodies in the blood, currently the most useful diagnostic test for Lyme disease, entails a two-step approach. There must be positivity by the enzymelinked immunosorbent assay (ELISA); in experienced and reliable laboratories, up to 93% of infected patients are seropositive. Furthermore, there must be a positive Western blot interpreted according to the criteria of the CDC. For acute infection (less than 1 month duration), the Western blot must be positive for an IgM response, with positive defined as presence of two of the following three bands: 23,39,41 kDa. For patients with disease of more than 1 month duration, there must be a positive IgG Western blot as defined by the presence of at least 5 of the following 10 bands: 18, 23, 28, 30, 39, 41, 45, 48, 66, and 93 kDa. The problem of false-negative results is particular to the early phase of the infection. In suspected seronegative Lyme cases the antibody test should be repeated in 4 weeks. Occasionally, antibiotics may abrogate the antibody response in an infected patient so that the ELISA is falsely negative. False-positive results can occur in patients who had past infection and have failed to clear their antibody response or in patients with other conditions such as bacterial endocarditis. To test for CNS infection, both serum and CSF analyses must be obtained and antibody from both compartments measured and compared. A CSF:serum antibody titer ratio greater than 1 indicates intrathecal synthesis. The presence of intrathecal antibody synthesis is the only laboratory marker currently recognized by the CDC for diagnosing active CNS infection. In cases of meningitis, the relationship between the organism that has invaded the CNS and the resultant neurologic syndrome is straightforward. On the other hand, the relationship of some of the neurologic complaints in Lyme disease still is not well understood. Although encephalopathy associated with Lyme disease and intrathecal antibody synthesis should be considered secondary to active infection and treated with antibiotic therapy, in encephalopathy cases with normal CSF, the treatment response and relationship of the neurologic findings to the infection are less clear.

W

Ancillary Tests The CSF may be abnormal in patients with radicular syndromes, facial palsy, other cranial neuropathies, or CNS disorders. Most often the CSF shows a lymphocytic pleocytosis. Oligoclonal bands in the CSF are rare but may be present. Protein elevation may occur but usually is mild. Whereas patients with meningitis and radiculitis often have intrathecal production of specific antibodies to B. burgdorferi, those with mild axonal neuropathy or entrapment neuropathy generally lack a CSF pleocytosis or evidence of intrathecal antibody synthesis. Electrophysiologic studies in patients with PNS syndromes are normal or show an axonal neuropathy. In some patients with encephalitis, the EEG reveals focal or generalized slowing, but more often the EEG is normal. When the MRI is abnormal, the findings are typical of an inflammatory process. Singular or multiple punctate lesions on T2-weighted images involving the subcortical white matter are most common. Lesions may also appear in the brainstem, thalamus, periventricular areas, and rarely the corpus callosum. In summary, most patients suspected of having neurologic Lyme disease need a CSF examination and blood work. Antibody testing in the serum must include both ELISA and Western blot testing. Diseases to exclude in the blood include other spirochetal infections, collagen vascular diseases, and disorders that might lead to false-positive serology. In special cases, additional studies including EEG, electromyography, MRI, and neuropsychological testing will be helpful.

TREATMENT Choosing the appropriate antibiotic therapy for patients with Lyme disease depends on correctly identifymg their clinical syndromes (Table 58-4). Choosing antibiotics with good CSF penetration is important. Patients with early localized disease, such as erythema migrans and flulike symptoms respond well to oral antibiotics, which shorten the course of the skin infection and reduce the frequency of later syndromes. The standard treatments are doxycycline 100 mg twice daily for 2 1 days or amoxicillin 500 mg three times daily for 21 days. In cases of allergy to these two options, cefuroxime axetil 125 mg in two divided doses for 21 days is a successful treatment. Certain neurologic complications also respond well to oral

TABLE58-4. Antibiotic Therapy for Lyrne Disease

Route

Indications

Antibiotic

Oral therapy

Localized (early) infection: erythema migrans rash with or without flulike symptoms such as fatigue, malaise, and mild concentration difficulty Early disseminated infection without CSF abnormalities (i.e., facial nerve palsy) Disseminated (late) infection: cranial neuropathy, radiculopathy, neuropathy, and radiculitis without CSF abnormalities

Intravenous therapy

Meningitis, encephalitis, encephalomyelitis, cranial neuritis, facial nerve palsy, or radiculitis with CSF abnormalities; severe encephalopathy or documented progressive cognitive loss and evidence of systemic Lyme borreliosis Systemic disseminated late disease: cardiac pericarditis or conduction block, arthritis, multifocal erythema migrans, and acrodermatitis chronica atrophicans

Amoxicillin 500 mg qid x 3-4 weeks Doxycycline 100 mg bid x 3 weeks Amoxicillin 500 mg tid x 3 weeks For patients allergic to tetracyclines and penicillin: cefuroxime axetil 125 mg bid x 3 weeks Doxycycline 100 mg bid x 3 weeks Amoxicillin 500 mg tid x 3 weeks For patients allergic to tetracyclines and penicillin: cefuroxime axetil 125 mg bid x 3 weeks Ceftriaxone, 2 g daily x 3-4 weeks Of

Cefotaxime, 2 g tid x 3-4 weeks Of

In cases of cephalosporin or penicillin allergy, an alternative

is high-dose doxycycline 200 mg bid

Chapter 59

therapy. For patients with mild symptoms of peripheral neuropathy or entrapment neuropathy and no evidence of intrathecal antibody synthesis, oral antibiotic therapy is effective. Some patients treated for symptoms of radicular pain, vertigo, or leg weakness who lack CSF abnormalities improve with high-dose oral doxycycline. On the other hand, many patients need parenteral treatment for these syndromes. If there is evidence of CNS involvement, such as CSF pleocytosis, protein elevation, intrathecal antibody synthesis, or signs of meningitis, parenteral therapy is indicated. Patients with meningitis, meningoencephalitis, encephalitis, or severe encephalopathy need parenteral antibiotics. The preferred agents are either ceftriaxone 2 g once daily or cefotaxime 2 g three times a day. Both antibiotics cross the blood-brain barrier readily and yield CSF levels that exceed the mean inhibitory concentration for the spirochete. A practical advantage of ceftriaxone is its long half-life, allowing once-daily administration. In many circumstances, this can be done in the home by a visiting nurse. A problem with ceftriaxone is the possibility of developing pseudomembranous colitis and gallbladder disease. Pseudomembranous colitis can be avoided with a diet supplement of active yogurt or acidophilus. However, patients with gastrointestinal histories must be followed closely. A Jarisch-Herxheimer reaction occurs in 10% to 20% of parenteral antibiotic-treated cases, usually within the first 24 hours of treatment. It is best managed with anti-inflammatory agents. In most cases steroids are best avoided; they may interfere with therapy and increase treatment failures. Patients who are allergic to penicillin often can be treated with ceftriaxone or cefotaxime, but the clinician should proceed cautiously. An alternative is high-dose oral doxycycline (200 mg twice a day). Occasionallypatients given oral therapy develop late neurologic syndromes. Parented treatment is also indicated in these cases. Most patients respond to these regimens. In rare instances, relapse may occur. In such cases reevaluation is appropriate, and it is imperative to distinguish persistent symptoms that are not antibiotic-responsive from genuine treatment failure in which additional antibiotic therapy is appropriate. Finally, reinfection can occur and necessitates retreatment. In highly endemic areas or in people with occupations that place them at high risk (e.g., landscaper, park ranger), reinfection is not unusual. Treatment response should be determined by the clinical response, not by serum serology. Many adequately treated patients have persistently elevated serum Lyme titers for months and, rarely, years after treatment. Therefore, following the Lyme titer alone is not a reliable treatment guide. On the other hand, patients

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with severe CNS syndromes who are not responding after several weeks of parenteral therapy should have repeat CSF examinations. If the CSF shows persistent pleocytosis or elevated protein, then an additional 2 or 3 weeks of parenteral therapy is advised. Prophylactic treatment of deer tick bites depends on whether the potential exposure occurred in a highly endemic area and whether the tick was removed within 24 hours. In cases where prophylactic treatment is considered, a single 200-mg dose of doxycycline administered within 72 hours of the tick bite prevents the development of Lyme disease. There is now a vaccine for Lyme disease that should be considered for people who live in or visit high-risk areas and have frequent exposure to the tick vector. For protection, it is advised that vaccination be delivered three times over a 12-month period; booster injections may be necessary after 1 or more years. Management of persistent symptoms that fail to resolve 6 or more months after adequate antibiotic therapy can be very difficult. Although the relationship between remote effects or post-treatment syndromes to continued infection is still under investigation, recently completed clinical trials for persistent post-treatment symptoms have not demonstrated a significant benefit for repeat courses of antibiotic therapy over placebo. Therefore, in the post-treatment seropositive patient with encephalopathy, fatigue, myalgia, or neuropathic pain and normal CSF, repeated courses of IV antibiotic therapy usually are not helpful and may be associated with serious adverse events. Symptomatic management with therapies directed specifically at pain, fatigue, or mood disturbance is safer and more likely to be effective. Lyme disease is an infection whose neurologic complications may range from the cranial nerves to the PNS and CNS. Fortunately, the majority of patients with neurologic complications respond extremely well to antibiotic treatment.

SUGGESTED READINGS Coyle PK Neurologic complications of Lyme disease. Rheum Dis Clin North Am 19:993, 1993 Gaudino EA, Coyle PK, Krupp LB: Post-Lyme syndrome and chronic fatigue syndrome: neuropsychiatric similarities and differences. Arch Neurol 541372-1376, 1997 Klempner MS et al: Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345235-92,2001 Nadelman RB,Wormser GP Lyme borreliosis. Lancet 352567465, 1998 Re& L R Lyme disease and the nervous system. Thieme, New York, 1991 Steere AC Lyme disease. N Engl J Med 345:115-125, 2001

Leptospirosis Patrick f.Nolan

Leptospirosis is an uncommon systemic infectious disease in which meningitis is a common feature, caused by a spirochete of the genus Leptospiru. A worldwide zoonotic disease, leptospirosis is transmitted and propagated among wild and domestic animals, with humans considered accidental, "dead-end" hosts. L. interro-

rn gans is the only species that causes disease in humans. There are more than 170 serotypes of L. interroguns, which is a finely coiled, motile spirochete, 0.1 pm in width by 6 to 20 pm in length, with a characteristic bent, hooked end.

Chapter 59

therapy. For patients with mild symptoms of peripheral neuropathy or entrapment neuropathy and no evidence of intrathecal antibody synthesis, oral antibiotic therapy is effective. Some patients treated for symptoms of radicular pain, vertigo, or leg weakness who lack CSF abnormalities improve with high-dose oral doxycycline. On the other hand, many patients need parenteral treatment for these syndromes. If there is evidence of CNS involvement, such as CSF pleocytosis, protein elevation, intrathecal antibody synthesis, or signs of meningitis, parenteral therapy is indicated. Patients with meningitis, meningoencephalitis, encephalitis, or severe encephalopathy need parenteral antibiotics. The preferred agents are either ceftriaxone 2 g once daily or cefotaxime 2 g three times a day. Both antibiotics cross the blood-brain barrier readily and yield CSF levels that exceed the mean inhibitory concentration for the spirochete. A practical advantage of ceftriaxone is its long half-life, allowing once-daily administration. In many circumstances, this can be done in the home by a visiting nurse. A problem with ceftriaxone is the possibility of developing pseudomembranous colitis and gallbladder disease. Pseudomembranous colitis can be avoided with a diet supplement of active yogurt or acidophilus. However, patients with gastrointestinal histories must be followed closely. A Jarisch-Herxheimer reaction occurs in 10% to 20% of parenteral antibiotic-treated cases, usually within the first 24 hours of treatment. It is best managed with anti-inflammatory agents. In most cases steroids are best avoided; they may interfere with therapy and increase treatment failures. Patients who are allergic to penicillin often can be treated with ceftriaxone or cefotaxime, but the clinician should proceed cautiously. An alternative is high-dose oral doxycycline (200 mg twice a day). Occasionallypatients given oral therapy develop late neurologic syndromes. Parented treatment is also indicated in these cases. Most patients respond to these regimens. In rare instances, relapse may occur. In such cases reevaluation is appropriate, and it is imperative to distinguish persistent symptoms that are not antibiotic-responsive from genuine treatment failure in which additional antibiotic therapy is appropriate. Finally, reinfection can occur and necessitates retreatment. In highly endemic areas or in people with occupations that place them at high risk (e.g., landscaper, park ranger), reinfection is not unusual. Treatment response should be determined by the clinical response, not by serum serology. Many adequately treated patients have persistently elevated serum Lyme titers for months and, rarely, years after treatment. Therefore, following the Lyme titer alone is not a reliable treatment guide. On the other hand, patients

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451

with severe CNS syndromes who are not responding after several weeks of parenteral therapy should have repeat CSF examinations. If the CSF shows persistent pleocytosis or elevated protein, then an additional 2 or 3 weeks of parenteral therapy is advised. Prophylactic treatment of deer tick bites depends on whether the potential exposure occurred in a highly endemic area and whether the tick was removed within 24 hours. In cases where prophylactic treatment is considered, a single 200-mg dose of doxycycline administered within 72 hours of the tick bite prevents the development of Lyme disease. There is now a vaccine for Lyme disease that should be considered for people who live in or visit high-risk areas and have frequent exposure to the tick vector. For protection, it is advised that vaccination be delivered three times over a 12-month period; booster injections may be necessary after 1 or more years. Management of persistent symptoms that fail to resolve 6 or more months after adequate antibiotic therapy can be very difficult. Although the relationship between remote effects or post-treatment syndromes to continued infection is still under investigation, recently completed clinical trials for persistent post-treatment symptoms have not demonstrated a significant benefit for repeat courses of antibiotic therapy over placebo. Therefore, in the post-treatment seropositive patient with encephalopathy, fatigue, myalgia, or neuropathic pain and normal CSF, repeated courses of IV antibiotic therapy usually are not helpful and may be associated with serious adverse events. Symptomatic management with therapies directed specifically at pain, fatigue, or mood disturbance is safer and more likely to be effective. Lyme disease is an infection whose neurologic complications may range from the cranial nerves to the PNS and CNS. Fortunately, the majority of patients with neurologic complications respond extremely well to antibiotic treatment.

SUGGESTED READINGS Coyle PK Neurologic complications of Lyme disease. Rheum Dis Clin North Am 19:993, 1993 Gaudino EA, Coyle PK, Krupp LB: Post-Lyme syndrome and chronic fatigue syndrome: neuropsychiatric similarities and differences. Arch Neurol 541372-1376, 1997 Klempner MS et al: Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345235-92,2001 Nadelman RB,Wormser GP Lyme borreliosis. Lancet 352567465, 1998 Re& L R Lyme disease and the nervous system. Thieme, New York, 1991 Steere AC Lyme disease. N Engl J Med 345:115-125, 2001

Leptospirosis Patrick f.Nolan

Leptospirosis is an uncommon systemic infectious disease in which meningitis is a common feature, caused by a spirochete of the genus Leptospiru. A worldwide zoonotic disease, leptospirosis is transmitted and propagated among wild and domestic animals, with humans considered accidental, "dead-end" hosts. L. interro-

rn gans is the only species that causes disease in humans. There are more than 170 serotypes of L. interroguns, which is a finely coiled, motile spirochete, 0.1 pm in width by 6 to 20 pm in length, with a characteristic bent, hooked end.

452

Immune and Infectious Disease H Spirochetal Infections

EPIDEMIOLOGY Leptospirosis is reported about 100 times per year in the United States, with a seasonal predilection for the summer and early fall. It has most often affected males with occupational or recreational exposure to animals. Traditionally, sewer workers, miners, and fish workers, work characterized by exposure to rats, represented most cases. Now more cases are seen in farmers, veterinarians, abattoir workers, campers, swimmers, canoeists, and kayakers. In the United States, dogs, livestock, rodents, wild mammals, and cats are the most prevalent animal exposures. Rats are the classic enzootic reservoir and are the most common disease source worldwide. Poor sanitary conditions such as rat-infested urban dwellings, homes where pet dogs share close proximity to humans and exhibit urinary incontinence, and recreational activities in inland, stagnant waters where infected animals have urinated are common epidemiologic associations. Part of the difficulty in the control of this zoonosis lies in the fact that a symbiotic relationship can occur in the animal host whereby a healthy-appearing animal can harbor the spirochete in the renal tubules and excrete live and contagious microorganisms in the urine for prolonged periods. Even fully vaccinated pet dogs have been known to transmit disease in this fashion.

CLINICAL FEATURES The coiled spirochete penetrates intact mucous membranes and abraded skin. Cuts or abrasions of the skin or a history of immersion or splash that may contaminate the mucous membranes of the eyes or nasopharynx are pertinent historical findings. From the mucocutaneous site of infection, the spirochete enters the bloodstream and disseminates to every organ system, including the central nervous system, eye, liver, and kidney. Tissue injury occurs by an unknown mechanism, but vasculitis usually is a prominent feature; nonspecific inflammatory changes occur most commonly in the liver and kidney but can be widespread. Most cases are subclinical, and therefore the disease is felt to be largely underreported. Infections associated with clinical disease sometimes follow a biphasic course. Although most often a monophasic illness, this biphasic paradigm is helpful in thinking about the pathogenesis of the disease. After an incubation period of 7 to 12 days, a flulike illness ensues associated with fever, headache, and myalgia. Often this has an abrupt onset. The headache is intense and may be associated with photophobia. A relative bradycardia has been described. During this phase, spirochetes can be found circulating in the blood, cerebrospinal fluid (CSF), and most tissues. Myofibrils with cytoplasmic vacuoles and a mild polymorphonuclear infiltration can be demonstrated histologically in the muscles during this period of often intense myalgia. Toward the end of the first week, there may be improvement, and the patient may actually become afebrile for a few days. The second phase is characterized by the disappearance of spirochetes from the bloodstream, cerebrospinal fluid, and organs, and the presence of circulating antibody. Cultures of the blood and CSF usually are negative, and cultivation of leptospires usually can be made only from the urine. This second “immune” or “leptospiruric” phase is thought to be mediated by circulating immune complexes and is manifested clinically by lymphadenopathy, a skin rash, meningitis, hepatitis, nephritis, and uveitis. Conjunctival suffusion is particularly characteristic and can be a

clue to this disease. This may be associated with photophobia, ocular pain, and a conjunctival hemorrhage. About 90% of cases are mild and without jaundice (“anicteric leptospirosis”). About 10% of the time a severe course with jaundice and renal failure unfolds in a syndrome known as Weil’s disease. This was first described by Weil in 1886 and was called “acute febrile icterus” in Osler’s textbook. Fever, severe headache often uncontrolled by analgesics, and a mild delirium are characteristic. Nausea, vomiting, and abdominal pain are common, and splenomegaly occurs in 15% to 25% of patients. Abnormal urinalysis is described in 70% of cases. Myocarditis can be one feature of the immune phase inflammatory process, and a fatal hemorrhagic myocarditis with cardiogenic shock has been described. The fullblown syndrome of renal and hepatic failure, bleeding diathesis, vascular collapse, and coma has a 5% to 10% mortality rate. During the second, leptospiruric phase, an aseptic meningitis can be demonstrated on CSF examination in 50% to 90% of patients, usually with a mononuclear pleocytosis of less than 500 cells. Typically, the CSF protein is moderately elevated and the glucose normal, in a picture resembling viral meningitis. There have been reports of both neutrophilic pleocytosis and hypoglycorrhachia, however. Leptospires can no longer be isolated, and the meningitis may be caused by secondary immune reactions. The meningitis seldom persists more than a few days and is never fatal. Although aseptic meningitis is the most common neurologic manifestation, peripheral neuropathy, flaccid paraplegia, and mononeuritis multiplex have been reported in the medical literature. DIAGNOSIS The differential diagnosis includes the causes of fever associated with a multisystem disease or, in severe cases, icteric multisystem disease. Staphylococcus aureus, group A streptococci, and Neisseria meningitides can mimic the acute, undifferentiated fever. Viral aseptic meningitis or toxin exposure could also be considered in the differential diagnosis. With a history of zoonotic exposure, Brucella, tularemia, plaque, and rickettsial infections such as Q fever and Rocky Mountain spotted fever could all reasonably be considered with leptospirosis. The severe icteric form can mimic obstructive jaundice or viral hepatitis. The presence of fever, zoonotic exposure, the conjunction of hepatic and renal abnormalities, and elevated creatine kinase (reflecting the prominence of muscle involvement) can be good clinical clues to the diagnosis. Culture requires a special semisolid medium, and it may take up to 8 weeks, although growth usually appears 6 to 10 days after inoculation. Diagnosis is most often confirmed serologically. Agglutinins begin to appear in the second week of the illness and generally peak in the third or fourth week. A microscopic slide agglutination method uses killed antigen pooled from the most common serotypes and often is used as a screening test. A fourfold rise in titer in an appropriate clinical setting is diagnostic. The microscopic agglutination test uses live antigen and is more specific, although cross-reactions still make serotyping problematic. Culture is the only reliable way to identify the infecting serotype but is most useful for epidemiologic purposes. TREATMENT Treatment with tetracycline or doxycycline instituted within the first 2 to 4 days of anicteric disease has been shown to shorten the course of illness. Because of the inherent delay in diagnosis, an

Chapter 60 W Fungal Infections

early index of suspicion for leptospirosis and empirical treatment are most appropriate. Doxycycline 100 mg PO or IV twice daily is the recommended dosage. Penicillin G, even when given late in severe icteric disease, can also attenuate the severity and shorten the course. Penicillin G 1.5 million units IV every 6 hours should be given in these cases. Cefotaxime and erythromycin have experimental support for use in situations such as allergy to penicillin or tetracycline. The duration of treatment is 5 to 7 days. Despite early use of appropriate antibiotics, some patients have died. Early suspicion, appropriate antibiotic therapy, and meticulous intensive care offer the best chance to lessen the 5% to 10% mortality rate in severe disease.

SECTION

453

SUGGESTED READINGS

Edwards GA, Domm BM: Human leptospirosis. Medicine 39:117, 1960 Kreisberg RA: An abundance of options. N Engl J Med 329:413, 1993 Levett PN, Branch SL, Whittington CU et al: Two methods for rapid serological diagnosis of acute leptospirosis. Clin Diagn Lab Immunol 8~349-351,2001

Sperber SJ, Schleupner CJ: Leptospirosis: a forgotten cause of aseptic meningitis and multisystem febrile illness. South Med J 82:1285, 1989 Westblom TU, Everett ED, Satalowich M: Leptospirosis: a 10-year experience. Missouri Med 83:744, 1986

4

FUNGAL AND PARASITIC INFECTIONS

60

Fungal Infections Temple W. Williams, Jr.

Fungi are nonphotosynthetic eukaryotic microorganisms that typically grow as a mass of branching filaments (hyphae) known as a mycelium. Some fungi grow only in the yeast form. Most pathogenic fungi are dimorphic: The mycelial phase occurs in nature, and conversion to the yeast phase occurs at body temperature. Unlike the vast armies of bacterial and viral pathogens, only a few fungi cause human disease, and often only in immunocompromised patients. However, most fungi that cause systemic disease can also affect the central nervous system (CNS). The incidence of fungal infections of the CNS has dramatically increased because of the ever-increasing number of immunosuppressed patients with cancer, transplanted organs, or acquired immunodeficiency syndrome (AIDS). The clinical manifestations of fungal CNS infection vary widely and include meningitis, meningoencephalitis, and abscesses of the brain and spinal cord. The clinical presentation of fungal meningitis or encephalitis in patients without AIDS typically is subacute to chronic and includes symptoms and signs suggestive of meningeal inflammation and, eventually, basilar meningitis with cranial nerve abnormalities. Symptoms and signs include headache, fever, malaise, nausea, vomiting, mental status changes, signs of meningeal inflammation (nuchal rigidity, Kernig and Brudzinski signs), visual changes or photophobia, and seizures. In contrast, patients with AIDS and fungal meningitis often present with a new headache or fever as their only clue to the cause of a nonspecific deterioration. Other physical findings often are absent; meningismus occurs in less than one third of patients. As many as 15% of patients with AIDS and fungal meningitis may

have no CNS symptoms or signs, so a high degree of suspicion must be maintained in these patients, and the threshold for diagnostic lumbar punctures must be much lower than in patients with normal immune systems. The most common fungal pathogens that cause CNS infection are Cryptococcus neoformans and Coccidioides immitis. Many other fungi are less common but potential CNS pathogens, including Histoplasma capsulatum, Blastomyces dermatitidis, Candida species, Sporothrix schenckii, the Mucoraceae, and some exotic molds (Table 60-1). Successful treatment of fungal infections of the CNS depends on early diagnosis and early institution of appropriate therapy. Also important to a successful outcome is the underlying immune status of the patient; patients with AIDS pose the most difficult challenge therapeutically. CRYPTOCOCCOSIS Cryptococcus neoformans has always been the most common cause of fungal meningitis. Before the AIDS epidemic, more than 50% of patients with cryptococcal meningitis had a serious underlying disease, often with altered cell-mediated immunity. Some underlying conditions predisposing to the development of cryptococcal meningitis are as follows: W W

AIDS Lymphoproliferative malignancies Organ transplant recipients

Chapter 60 W Fungal Infections

early index of suspicion for leptospirosis and empirical treatment are most appropriate. Doxycycline 100 mg PO or IV twice daily is the recommended dosage. Penicillin G, even when given late in severe icteric disease, can also attenuate the severity and shorten the course. Penicillin G 1.5 million units IV every 6 hours should be given in these cases. Cefotaxime and erythromycin have experimental support for use in situations such as allergy to penicillin or tetracycline. The duration of treatment is 5 to 7 days. Despite early use of appropriate antibiotics, some patients have died. Early suspicion, appropriate antibiotic therapy, and meticulous intensive care offer the best chance to lessen the 5% to 10% mortality rate in severe disease.

SECTION

453

SUGGESTED READINGS

Edwards GA, Domm BM: Human leptospirosis. Medicine 39:117, 1960 Kreisberg RA: An abundance of options. N Engl J Med 329:413, 1993 Levett PN, Branch SL, Whittington CU et al: Two methods for rapid serological diagnosis of acute leptospirosis. Clin Diagn Lab Immunol 8~349-351,2001

Sperber SJ, Schleupner CJ: Leptospirosis: a forgotten cause of aseptic meningitis and multisystem febrile illness. South Med J 82:1285, 1989 Westblom TU, Everett ED, Satalowich M: Leptospirosis: a 10-year experience. Missouri Med 83:744, 1986

4

FUNGAL AND PARASITIC INFECTIONS

60

Fungal Infections Temple W. Williams, Jr.

Fungi are nonphotosynthetic eukaryotic microorganisms that typically grow as a mass of branching filaments (hyphae) known as a mycelium. Some fungi grow only in the yeast form. Most pathogenic fungi are dimorphic: The mycelial phase occurs in nature, and conversion to the yeast phase occurs at body temperature. Unlike the vast armies of bacterial and viral pathogens, only a few fungi cause human disease, and often only in immunocompromised patients. However, most fungi that cause systemic disease can also affect the central nervous system (CNS). The incidence of fungal infections of the CNS has dramatically increased because of the ever-increasing number of immunosuppressed patients with cancer, transplanted organs, or acquired immunodeficiency syndrome (AIDS). The clinical manifestations of fungal CNS infection vary widely and include meningitis, meningoencephalitis, and abscesses of the brain and spinal cord. The clinical presentation of fungal meningitis or encephalitis in patients without AIDS typically is subacute to chronic and includes symptoms and signs suggestive of meningeal inflammation and, eventually, basilar meningitis with cranial nerve abnormalities. Symptoms and signs include headache, fever, malaise, nausea, vomiting, mental status changes, signs of meningeal inflammation (nuchal rigidity, Kernig and Brudzinski signs), visual changes or photophobia, and seizures. In contrast, patients with AIDS and fungal meningitis often present with a new headache or fever as their only clue to the cause of a nonspecific deterioration. Other physical findings often are absent; meningismus occurs in less than one third of patients. As many as 15% of patients with AIDS and fungal meningitis may

have no CNS symptoms or signs, so a high degree of suspicion must be maintained in these patients, and the threshold for diagnostic lumbar punctures must be much lower than in patients with normal immune systems. The most common fungal pathogens that cause CNS infection are Cryptococcus neoformans and Coccidioides immitis. Many other fungi are less common but potential CNS pathogens, including Histoplasma capsulatum, Blastomyces dermatitidis, Candida species, Sporothrix schenckii, the Mucoraceae, and some exotic molds (Table 60-1). Successful treatment of fungal infections of the CNS depends on early diagnosis and early institution of appropriate therapy. Also important to a successful outcome is the underlying immune status of the patient; patients with AIDS pose the most difficult challenge therapeutically. CRYPTOCOCCOSIS Cryptococcus neoformans has always been the most common cause of fungal meningitis. Before the AIDS epidemic, more than 50% of patients with cryptococcal meningitis had a serious underlying disease, often with altered cell-mediated immunity. Some underlying conditions predisposing to the development of cryptococcal meningitis are as follows: W W

AIDS Lymphoproliferative malignancies Organ transplant recipients

454

Immune and Infectious Disease

Fungal and Parasitic Infections

TABU 60-1. Diagnosis of Fungal Meningitis Omanism

Initial Infection

Distribution in America

India Ink

Antigen or Antibody Tests in CSF

Antigen or Antibody Tests in Serum

CSF Cultures

Cryptococcosis

Pulmonary

Widespread

+

Yes, antigen

Yes, antigen

+, often within 1

Coccidioidomycosis

Pulmonary

Southwest

-

Pulmonary

-

Blastomycosis

Pulmonary

Candidosis

Commensals, norma1 flora Skin wound, pulmonary

Ohio and Mississippi river valleys Southeastern and Great Lakes Widespread

Yes, comp fix antibody Yes

+, but may take

Histoplasmosis

Yes, comp fix antibody Yes, occasionally

Widespread

Sporotrichosis

week

weeks

+, but may take weeks

-

No

Yes

-

No

Yes

-

Yes

?

+, but difficult +, often high colony count +, but difficult

Symbols: +, positive;-, negative.

H

H H

Corticosteroid therapy Diabetes mellitus Sarcoidosis

In recent years, most cases of cryptococcosis occur in patients with AIDS; 10% to 15% eventually are infected. C. neoformans is linked to pigeons and pigeon droppings, which form a fertile medium for growth of the fungus, which is found worldwide. The route of infection is pulmonary, but the primary infection often is asymptomatic or passed off as a cold or flulike illness. There is invasion of the lung, however, and hematogenous spread of the yeast to the brain as well as to other organs, including the kidney and the prostate gland. The neurotropism of this organism is an essential feature of the infection and accounts for its preeminence as the leading cause of fungal CNS infection. The CNS infection usually manifests as meningitis or meningoencephalitis but rarely as an isolated granulomatous lesion (cryptococcoma). The pathogenic strains of C. neoformans typically have a large polysaccharide capsule surrounding the yeast. This capsule is antiphagocytic and accounts for the very minimal inflammatory response in infected tissues. This polysaccharide is shed into cerebrospinal fluid (CSF) and body tissues, and its detection forms the basis for the cryptococcal antigen test. The capsule also is the basis for the India ink preparation, in which the carbon black particles of the ink are displaced away from the red cell-sized yeast by the large polysaccharide capsule (Fig. 60- 1). Cryptococcal meningitis typically is a subacute to chronic illness except in patients with AIDS, where it may present as an acute fulminant infection. Most patients appear after days to weeks of headache; fever is not constant but often present. Other manifestations include nausea, vomiting, altered mental status, malaise, meningeal signs, papilledema, visual changes, photophobia, and seizures or focal neurologic deficits. As many as 10% of patients with cryptococcal meningitis have no neurologic symptoms or signs and are discovered by serologic tests or lumbar puncture performed as a part of an evaluation for fever. Specific diagnosis should depend on a positive culture from CSF. The CSF in patients with fungal meningitis, including cryptococcal meningitis, usually is grossly clear but has a lymphocytic pleocytosis, low glucose (often very low; range, 5 to 10 mg/dL) and an elevated protein level. These CSF parameters may be normal, however, in patients with AIDS, although they more often have an elevated opening pressure. India ink preparations of spun CSF sediment should be positive in half the patients without AIDS and in three fourths of the patients with AIDS. In

patients with AIDS, the large number of organisms often allows a positive India ink preparation using unspun CSF and allows a presumptive diagnosis pending culture results. C. neoformans is easy to grow and often can be grown and identified on culture within the first week. In patients with a negative India ink preparation, a presumptive diagnosis can be made by detection of cryptococcal antigen by latex agglutination or enzyme immunoassay techniques in CSF or serum. This is a highly sensitive and specific test and is readily available. The antigen is positive in CSF in 95% to 99% of infected patients with AIDS and in serum in 90% to 95%. The very rare negative CSF antigen tests in patients with subsequently positive CSF cultures are attributed to infection with a rare nonencapsulated strain of C. neoformans var gattii. False-positive tests in the CSF usually are caused by a positive rheumatoid factor, chronic lymphocytic leukemia with cerebral involvement, or disseminated Trichosporon beigelii infection, but such false-positive titers rarely are higher than a 1:4 dilution. Although a positive culture of CSF provides the definitive diagnosis, the organism can also be grown from urine, bone marrow, and from blood when cultured using the lysis centrifugation method. Therefore, the initial clue to the possibility of

FIG. 60-1. India ink preparation in the CSF, showing the encapsulated cryptococcal organism. Arrowheads indicate red blood cells; arrows, C. neoforrnans.

Chapter 60

cryptococcalsepsis and meningitis may come from a positive urine or blood culture obtained during a fever evaluation. Treatment for cryptococcal meningitis traditionally has been systemic amphotericin B, with or without 5-fluorocytosine (5FC), used early in the course in acutely ill patients. In the patient with AIDS and chronic meningitis who is not moribund or acutely and fulminantly ill, the practical approach still is the regimen for administering intravenous amphotericin B: On day 1, the patient receives a test dose of 5 mg amphotericin B in 50 mL D5W infused over 1 hour, with vital signs checked every 15 minutes; 4 hours later, the dosage is increased to 10 mg in 100 mL D5W over 1 hour, with 15-minute vital signs recorded; and 4 hours later, the dosage is further increased to 25 mg in 250 mL D5W over 2 hours; on day 2, the maximum dosage is given as 50 mg in 500 mL D5W over 2 hours. This dosage of 50 mg daily is repeated until creatinine is 3.0 mg/dL or more or blood urea nitrogen (BUN) is more than 50 mg/dL; then the same dosage is given every other day. Treatment should be continued for a minimum of 6 weeks or until 1 g amphotericin B has been given after the first negative CSF culture was obtained. The CSF should be recultured at 0.5 g, 1.0 g, 2.0 g, and 3.0 g of amphotericin B administration. The most common side effects of amphotericin B are as follows, in order of frequency:

w Increased BUN and creatinine Fever and chills w Nausea, vomiting, and anorexia w Local phlebitis Hypokalemia and hypomagnesemia Anemia Headache w Bronchospasm w Hypotension w Anaphylaxis Treatment of these side effects may include an antiemetic and meperidine 25 to 50 mg IV slowly for severe chills. A central line may be useful in the patient with poor peripheral venous access and in the patient who elects to complete treatment at home. In most patients, the symptomatic reactions actually decrease as the daily dosage is increased. If the reactions persist with each dose, pretreatment may be necessary with a nonsteroidal antiinflammatory agent orally or parenterally or a small dose of hydrocortisone (25 to 50 mg) IV just before the start of the amphotericin B infusion. Another major toxic effect of amphotericin B treatment is a usually reversible rise in BUN and serum creatinine. The dosage regimen should be modified based on this side effect, and BUN and serum creatinine must be monitored twice weekly until stable and then once weekly during the course of treatment. The BUN and creatinine should return to the pretreatment level if the total dosage of amphotericin B does not exceed 3.5 g in a lifetime. New lipid formulations of amphotericin B are extremely expensive and need not be used in the routine clinical situation. However, in patients with preexisting renal insufficiency (serum creatinines greater than 2.5 mg/dL), a lipid formulation of amphotericin B can be used as initial therapy. The lipid-based formulations can also be used in patients who are truly intolerant of or whose infection is refractory to treatment with conventional amphotericin B. Price probably will determine which liposomal preparation is on a patient’s formulary. Additional toxic effects include a drop in serum potassium and magnesium and a drop in hemoglobin and hematocrit. The serum potassium and magnesium may drop precipitously and should be

Fungal Infections

455

monitored along with the BUN and serum creatinine, and replacements should be given as indicated. The drop in hemoglobin and hematocrit probably will be much slower and does not necessitate treatment unless the patient becomes symptomatic or has a coexisting medical condition that would be made critically worse by the anemia, in which case treatment consists of blood transfusions. Once the amphotericin is discontinued, the hemoglobin and hematocrit return to the pretreatment levels without specific iron or vitamin therapy. Iron and B,, or folate treatment is not effective because this is a direct toxic effect of the amphotericin B on the bone marrow. Intrathecal administration of amphotericin B probably is not useful in treating cryptococcal meningitis. Other ancillary treatment measures in the patient without AIDS include the addition of 5FC given orally or by nasogastric tube in a dosage of 100 mg/kg/day in the patient who is moribund or critically ill when the diagnosis is established. The 5FC can be initiated in full dosage while simultaneously building up to the full daily dosage of amphotericin B. This combination may lead to more rapid sterilization of the CSF and is believed by some to be superior to amphotericin B alone in the treatment of patients without AIDS. However, once the BUN and serum creatinine start to rise, the serum levels of 5FC rise, and bone marrow or hepatic toxicity may occur. It is necessary to stop the 5FC at this point or monitor levels and keep them under 100 yg/mL, ideally in the range of 40 to 60 pg/mL (draw levels 2 hours after a dose) if it is essential to continue the drug because of the severity of the illness. Liver function tests and complete blood counts should be performed weekly during this course of treatment. If possible, continue the flucytosine for the first 2 weeks of amphotericin B treatment. Then switch to oral fluconazole 400 mg/day for an additional 8 to 10 weeks. An alternative regimen in the HIV-negative patient is amphotericin B plus flucytosine 100 mg/kg/day for 6 to 10 weeks if the combination is well tolerated. In patients with AIDS and cryptococcal meningitis, no therapeutic regimen is curative. The best method for initial treatment, and then long-term suppression to prevent relapse, is amphotericin B for at least 2 weeks combined with flucytosine 100 mg/kg given in four divided doses per day. After this 2-week course of therapy, fluconazole in a dosage of 400 mglday should be started and continued until CSF cultures are sterile or a minimum of 8 weeks even if cultures are sterile before that point. After the cultures are sterile, maintenance lifelong suppressive treatment is begun and consists of fluconazole 200 to 400 mg/day or itraconazole 200 mg twice a day or amphotericin B 50 mg one to three times a week. The primary objective is to prevent relapse of infection. A critical point is that the CSF culture must be negative before switching to the long-term suppressive or maintenance therapy in patients with AIDS. In this patient population, repeat lumbar puncture probably should be performed at 2 and 4 weeks of treatment, then monthly until cultures are negative and the patient can be switched to maintenance therapy. New recommendations for treatment and maintenance regimens in patients with AIDS may emerge as trials are completed and published. COCClDlOlDOMYCOSlS Coccidioides immitis is the etiologic agent of coccidioidomycosis and is the second most common pathogen in fungal meningitis. In contrast to C. neoforrnans, which exists only in the yeast form, C.

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irnrnitis is a dimorphic fungus, growing as a mold in nature and converting to a pathogenic yeast when inhaled into the lung at body temperature. This fungus is limited in its geographic distribution to the semiarid regions of the southwestern United States, Mexico, and areas of Central and South America between latitudes 40 degrees north and 40 degrees south. This endemic region is marked by the growth of the creosote bush. Infection with this fungus occurs when a susceptible person inhales the mold (arthroconidia) form of the fungus while traveling in or residing in the endemic area. A primary pulmonary infection occurs when the mold phase converts to the yeast phase at body temperature. There is then invasion of the lung by the yeast phase, with spread to the hilar nodes and systemic hematogenous spread throughout the body, including the brain and meninges. In hosts with normal immune systems, this primary pulmonary illness with hematogenous dissemination may manifest as a cold or flulike illness and usually is self-limited without specific treatment. Once infected, African Americans, Filipinos, Native Americans, patients with AIDS, and pregnant women have a higher risk of progressive disseminated disease and a higher mortality. Coccidioidal meningitis is the most severe form of disseminated disease and probably is incurable even in patients with normal immune systems. In African Americans, Filipinos, Native Americans, and patients with AIDS, the presentation often is that of an acute meningitis occurring within 3 months of the primary infection, with multiple other organs involved as well. In whites without AIDS, the presentation is more often that of chronic meningitis occurring long after the primary infection, with a protracted course and periods of spontaneous remission of symptoms. This is particularly common in nonpregnant white women, in whom the CNS alone is infected and there is a predilection for the meninges, in contrast to cryptococcal meningitis, where involvement of the brain is extensive. The clinical presentation of acute or chronic meningitis may include headache, varying degrees of fever, altered mental status, nausea, vomiting, and seizures. Signs of meningeal irritation usually are absent in the chronic form, but hydrocephalus or focal neurologic deficits may be found. The diagnosis is established by growth of the organism from CSF. This is much more difficult in coccidioidomycosis than in cryptococcosis because the colony count of yeast in the CSF is much lower. The diagnosis should be considered in any patient with a lymphocytic pleocytosis in the CSF and a very low CSF glucose level, with or without an elevated CSF protein level. Once cryptococcus has been excluded by a negative India ink preparation and a negative cryptococcal antigen in the CSF and serum, the differential diagnosis should turn to coccidioidomycosis and tuberculosis. A careful travel history and a history of exposure to tuberculosis becomes very helpful at this point. A presumptive diagnosis can be established by a positive test for complement-fixing antibodies in the CSF for coccidioidomycosis. This is a very sensitive (75% to 95%) and specific test in patients with CNS coccidioidomycosis. To corroborate this etiologic diagnosis, a repeat lumbar puncture with removal of a large volume (50 to 60 mL) of CSF for culture may be necessary. Cultures of C. irnrnitis may take several weeks, so treatment can be started based on the presumptive diagnosis established by the positive complement fixation test on CSF. Serum antibody titers are useful in the immunocompetent patient in establishing an early diagnosis of disseminated disease, but it is important to establish the presence or absence of CNS infection by specific

serologic tests and cultures of CSF because the treatments for meningitis and disseminated coccidioidomycosis without meningitis are different. Patients with immunodeficiency states, including AIDS, may fail to develop complement-fixing antibodies in serum or CSF, but their CSF cultures are more likely to be positive because of more aggressive infection. Therapy for coccidioidal meningitis includes prolonged treatment with fluconazole and intrathecal amphotericin B. Oral fluconazole is given in a dosage of 400 to 800 mg/day. Intrathecal amphotericin B can be administered by cisternal tap or via an Ommaya reservoir, which can be inserted surgically with direct access to a lateral ventricle. If the patient has noncommunicating hydrocephalus and needs a shunt, a combination apparatus with Ommaya reservoir and shunt can be inserted. Intrathecal amphotericin B is irritating, so the dosages must be very low. Therapy should begin with 0.01 mg given into the cisternal CSF or lateral ventricle via an Ommaya reservoir. If this is tolerated, increase the dosage to 0.05 mg, then 0.1 mg, then 0.2 mg, working up by 0.1 mg per dose until the side effects are intolerable, then reduce the dosage to the maximum tolerable level. This tolerable dosage probably will be in the 0.5 to 1.5 mg range, although some patients may tolerate as much as 5 mg per dose. Once the maintenance dosage has been reached, therapy can continue with alternate days of intrathecal amphotericin B. Combination fluconazole and intrathecal amphotericin B therapy should be continued until the CSF culture and complement fixation titer are negative or until the latter levels off at 1:2 or 1:4. At that point, long-term suppression with oral fluconazole 400 mg/day alone or intrathecal maintenance therapy alone can be continued and the interval of treatments reduced over time to the minimum dosage needed to keep the CSF complement fixation titer negative or stable at its low level, which may consist of one to three intrathecal doses per week. This suppressive maintenance therapy must be continued indefinitely to prevent relapse. The new triazole itraconazole also shows promise in treating coccidioidal meningitis. It is given in a dosage of 400 to 600 mg/day orally and shows benefits in patients without AIDS. Clinical trials are under way to better define the best treatment of coccidioidal meningitis in patients with or without AIDS.

HISTOPLASMOSIS

Histoplasma capsulaturn is the etiologic agent of histoplasmosis. It is a thermal dimorphic fungus found commonly in the Ohio and Mississippi river valleys. Like C. irnrnitis, H. capsulaturn grows as a mold in nature, and the primary infection results from inhalation of the mold. Once in the lung, the mold converts to the yeast phase, which invades the lung and spreads hematogenously. Most patients with progressive histoplasmosis have widespread infection of the reticuloendothelial system. Central nervous system involvement is rare in the patient without AIDS. When it does occur, it usually presents as chronic meningitis, and the CSF reveals a lymphocytic pleocytosis (with or without elevated CSF protein) and low CSF glucose, sometimes very low (in the 5 to 10 mg/dL range). In patients with AIDS, disseminated disease and meningitis are more common and can result from primary exposure or reactivation of a quiescent focus. Therefore, a history of recent travel in the endemic area is not critical in suspecting the diagnosis if the patient has ever lived in the endemic regions. In patients with AIDS, CNS manifestations can be subclinical or can range from frank acute meningitis to acute confusional states to a picture of single or multiple space-occupying lesions.

Chapter 60

The diagnosis is established by a positive CSF culture. As in coccidioidal meningitis, the colony count of fungi in CSF may be very low. To compensate for this, large volumes of CSF should be cultured if initial cultures are negative. H. capsulatum can be very slow-growing, and the cultures must be held for a full 6 to 8 weeks before being reported as negative. A presumptive diagnosis can be established by positive complement fixation antibody titers to yeast phase and mycelial phase antigens in CSF. Unfortunately, these are not as sensitive or specific as the similar serologic tests in the CSF in coccidioidal meningitis. Patients with AIDS often do not demonstrate an antibody response. There is a new radioimmunoassay for H. capsulatum polysaccharide antigen (HPA), which seems more specific but still not very sensitive, being present in only a quarter of patients without AIDS with culture-proven meningitis. This test is being evaluated at present. Treatment of histoplasma meningitis in the patient without AIDS is parenteral amphotericin B in a total dosage of 2.0 to 2.5 g followed by oral fluconazole 800 mg daily for an additional 9 to 12 months. In patients with AIDS, the initial intensive course of amphotericin B can be stopped at 1.0 to 1.5 g if the clinical response is adequate. However, relapse will occur, and maintenance therapy must be continued with parenteral amphotericin B 50 mg once or twice weekly or fluconazole 800 mglday given orally. If successful, this maintenance therapy should be continued indefinitely in the patient with AIDS.

Fungal Infections

457

patients with disseminated blastomycosis. Therefore, there is no proven treatment regimen to recommend in this situation. The treatment regimen recommended for patients with AIDS and histoplasma meningitis should be effective.

CANDIDOSIS Candida species number more than 80, but only 10 or so species are proven pathogens. Most are commensals and part of the normal flora of the gastrointestinal tract. Tissue invasion is associated with altered host defenses. The organism can reach the bloodstream from the gut, from the urinary tract, or by infection of a venous or arterial line. Dissemination is hematogenous, and CNS infection usually is part of widespread disseminated disease. The clinical picture mirrors the disseminated nature of the infection, with fever and headache being common complaints and meningismus being a common sign. The CSF reveals a lymphocytic pleocytosis, elevated protein level, and normal to low glucose levels. The colony count of yeast often is high, so a Gram stain of CSF sediment is positive in half the patients, and the cultures rapidly become positive. Diagnosis is established by a positive culture. Serologic tests are being evaluated. Treatment for candidal meningitis is the same as for cryptococcal meningitis in the patient with or without AIDS. Therapy of candida meningitis associated with neurosurgical procedures must include removal of infected prosthetic materials and avascular foreign bodies.

BLASTOMYCOSIS Blastomyces dermatitidis is the etiologic agent in North American blastomycosis. This is another thermal dimorphic fungus found principally in North America, particularly in the southeastern United States and in the Mississippi, Ohio, and St. Lawrence river areas as well as around the Great Lakes. It grows as a mold in nature, and the primary infection is in the lungs. There is conversion of the mold to the yeast phase at body temperature and then invasion of the lung and hematogenous seeding. CNS infection can result from this seeding or by direct extension, as from osteomyelitis of the spine. CNS blastomycosis is extremely rare and usually is a late manifestation of disseminated disease. It can present in three clinical patterns: focal pyogranulomas, spinal abscess secondary to extension of an epidural abscess, or as an exudative or chronic meningitis. Focal neurologic deficits may be present if the presentation is with a mass lesion of a pyogranuloma. The patient with meningitis may present with headache, fever, lethargy, or altered mental status and a stiff neck. Back pain and signs of cord compression accompany the epidural abscess form. In any case, the CSF reveals an elevated cell count, but this fungus can elicit a pyogenic response so the differential count can be mixed rather than the lymphocytic pleocytosis typical of most fungal infections. The CSF protein usually is elevated, and the glucose level is low. Serologic tests for blastomycosis are notoriously poor, so they cannot be relied on to help make a presumptive diagnosis. The diagnosis is established by culture of the spinal fluid and, again, large volumes should be cultured to compensate for the low colony count of the yeast in the CSF if initial fungal cultures are negative in routine small-volume samples of CSF. Treatment in the patient without AIDS consists of parented amphotericin B in a total dosage of 2.0 to 2.5 g. h o l e s should not be used for primary treatment of CNS blastomycosis. Blastomycosis is rare in patients with AIDS, and meningitis is rare in

SPOROTRICHOSIS Sporothrix schenckii is the etiologic agent of sporotrichosis. This is another thermal dimorphic fungus. It grows in nature as a mold, often in association with sphagnum moss. Its usual presentation is as a cutaneous or subcutaneous infection after a puncture wound or abrasion of the skin. Spread is via lymphatics. If not recognized and treated, the lymphatic drainage can lead to hematogenous dissemination to the CNS. CNS involvement is very rare and usually presents as a chronic meningitis: Headache is the most common symptom, followed by altered mental status and fever. The CSF reveals a lymphocytic pleocytosis with elevated protein level and normal to low glucose levels. The colony count is low, so culture of a large volume of CSF may be necessary to establish the diagnosis. A presumptive diagnosis can be established by detecting antibody to S. schenckii in the CSF by latex agglutination or enzyme immunoassay. Treatment in the patient without AIDS is parenteral amphotericin B in a total dosage of 2.0 to 2.5 g. In patients with AIDS a regimen of parented amphotericin B, as described earlier, followed by lifelong suppressive itraconazole 200 mg twice a day or fluconazole 800 mglday seems appropriate, but data are lacking at present because of the paucity of cases.

OTHER FUNGAL INFECTIONS Other fungi cause CNS infections, but the clinical picture is more often that of a mass lesion with blood vessel invasion and infarction, or focal parenchymal lesions, rather than meningitis. The common pathogens producing this form of CNS disease include the molds, Aspergillus species, and the zygomycetes,which cause mucormycosis. Mucormycosis usually is caused by R. arrhizus or R. oryzae molds in the zygomycete class. It is ubiquitous and usually

458

Immune and Infectious Disease rn Fungal and Parasitic Infections

incapable of infection except in patients with serious underlying diseases, including diabetes mellitus. Unlike yeasts, molds may grow fulminantly, as a mass lesion, or produce a cerebritis that involves arteries and veins and leads to vascular infarctions. Rhinocerebral mucormycosis often presents with diplopia, face pain, and nasal stuffiness arising from inflammation and necrosis of the nose and orbit. The mass erodes the skull and sinuses, picking off cranial nerves, and then invades intracranially, causing coma and death within days or weeks. Fever and headache are common, as is an abnormal CSF, showing mild pleocytosis and elevated protein. Computed tomography scans or magnetic resonance imaging shows characteristic sinus opacification and bony erosion, and cerebral involvement is seen as a nonspecific mass lesion or cerebral infarcts. Confirmation of the diagnosis usually entails biopsy. Treatment for these pathogens often includes extensive surgical debridement of the craniofacial lesions or the brain masses, plus appropriate chemotherapy of intravenous amphotericin B. This infection justifies the initial use of a liposomal amphotericin B. A team approach including neurosurgical and infection disease consultation is recommended because mortality rates exceed 90%.

61

SUGGESTED READINGS Chapman SW et al: Practice guidelines for the management of patients with blastomycosis. Clin Infect Dis 30:679-683, 2000 Dismukes W E Introduction to antifungal drugs. Clin Infect Dis 30: 653-657, 2000 Galgiani JN et al: Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis 30:658461, 2000 Kauffman CA, Hajjeh R, Chapman SW: Practice guidelines in the management of patients with sporotrichosis. Clin Infect Dis 3 0 684-687, 2000 Mandell GL Jr, Bennett JE, D o h R (eds): Principles and Practice of Infectious Diseases. 5th Ed. Churchill Livingstone, New York, 2000 Rex JH et al: Practice guidelines for the treatment of candidiasis. Clin Infect Dis 30:662478, 2000 Saag MS et al: Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 30:710-718, 2000 Stevens DA et al: Practice guidelines for diseases caused by aspergillus. Clin Infect Dis 30696-709, 2000 Wheat J et a1 Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 30:688-695, 2000

Cysticercosis Richard M. Armstrong

Neurocysticercosis is one of the most common parasitic infections affecting the nervous system. It results from the encystation of the larval form of the pork tapeworm Tuenia solium in the brain parenchyma, the ventricular system, or the meninges.

Neurocysticercosis is endemic in many regions of the world and is most common where there is a high rate of infestation in pigs. It is a significant problem among immigrants to the United States. The actual prevalence is not known, but autopsy series in Mexico indicate that up to 3.6% of the population may be infected.

EPIDEMIOLOGY Tapeworms, or cestodes, are segmented worms that attach to the intestinal mucosa with their head, or scolex, which contains sucking disks and hooks. Behind the scolex form the ribbon-like segments, or proglottids, each of which contains several thousand eggs. The pork tapeworm generally has 1000 proglottids and extends up to 3 m in length. When the proglottids are shed into the feces, the eggs are infective and, if ingested by a human, will develop into larval oncospheres that penetrate the gut wall, enter the bloodstream, and disseminate throughout the body, with a predilection for the central nervous system (CNS). The larvae may then develop into a cyst containing a scolex, which is known as a cysticercus. In this sequence of events, the infected person is acting as an intermediate host for the parasite. The pig also functions as an intermediate host for T. solium and is crucial to the continued presence of the disease in endemic areas. Humans can also function as the primary or definitive host when they harbor the adult T. solium worm in the small intestine. Ingestion of cysts, usually in infected pork, results in colonization of the small intestine when the scolex, released from the ingested cyst, affixes to the gut wall and proceeds to mature into an adult worm with numerous proglottid segments. Usually only a single worm is present in the lumen of the small bowel, and the host is asymptomatic, possibly harboring a worm for many years. Fecally contaminated foodstuffs are then ingested by humans (autoinfection) or other intermediate hosts, usually the pig.

CLINICAL FEATURES Humans, the primary hosts of T. solium, usually are asymptomatic when infected. However, when infected by the larval stage they function as intermediate hosts and may be symptomatic with fever and headache as the larvae invade the tissues. Once the cysts are established in the tissues they may remain viable for many years, be well tolerated by the host, and persist without clinical manifestations. Neurocysticercosis may become symptomatic up to 30 years after infection. Neurologic symptoms usually result either from the local inflammatory response induced by the parasite or from the mass effect of the space-occupying lesion. After implantation, the cyst consists of a thin-walled sac that contains the scolex attached to the cyst wall. In this vesicular stage the parasite elicits little response from the host. If they remain small and few in number, they may persist in the brain parenchyma through a long asymptomatic phase. Computed tomography (CT) scans and magnetic resonance imaging (MRI) show circumscribed hypodense lesions without associated enhancement or edema. Eventually, the cyst begins to undergo degenerative changes and enters into a colloidal phase. The vesicular liquid takes on a gelatinous-colloidal character, and the cyst wall thickens. This change elicits an inflammatory host response, and radiologically the cyst and surrounding edema are enhanced by contrast media. The degenerating cyst then enters a nodular granular phase in

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Immune and Infectious Disease rn Fungal and Parasitic Infections

incapable of infection except in patients with serious underlying diseases, including diabetes mellitus. Unlike yeasts, molds may grow fulminantly, as a mass lesion, or produce a cerebritis that involves arteries and veins and leads to vascular infarctions. Rhinocerebral mucormycosis often presents with diplopia, face pain, and nasal stuffiness arising from inflammation and necrosis of the nose and orbit. The mass erodes the skull and sinuses, picking off cranial nerves, and then invades intracranially, causing coma and death within days or weeks. Fever and headache are common, as is an abnormal CSF, showing mild pleocytosis and elevated protein. Computed tomography scans or magnetic resonance imaging shows characteristic sinus opacification and bony erosion, and cerebral involvement is seen as a nonspecific mass lesion or cerebral infarcts. Confirmation of the diagnosis usually entails biopsy. Treatment for these pathogens often includes extensive surgical debridement of the craniofacial lesions or the brain masses, plus appropriate chemotherapy of intravenous amphotericin B. This infection justifies the initial use of a liposomal amphotericin B. A team approach including neurosurgical and infection disease consultation is recommended because mortality rates exceed 90%.

61

SUGGESTED READINGS Chapman SW et al: Practice guidelines for the management of patients with blastomycosis. Clin Infect Dis 30:679-683, 2000 Dismukes W E Introduction to antifungal drugs. Clin Infect Dis 30: 653-657, 2000 Galgiani JN et al: Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis 30:658461, 2000 Kauffman CA, Hajjeh R, Chapman SW: Practice guidelines in the management of patients with sporotrichosis. Clin Infect Dis 3 0 684-687, 2000 Mandell GL Jr, Bennett JE, D o h R (eds): Principles and Practice of Infectious Diseases. 5th Ed. Churchill Livingstone, New York, 2000 Rex JH et al: Practice guidelines for the treatment of candidiasis. Clin Infect Dis 30:662478, 2000 Saag MS et al: Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 30:710-718, 2000 Stevens DA et al: Practice guidelines for diseases caused by aspergillus. Clin Infect Dis 30696-709, 2000 Wheat J et a1 Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 30:688-695, 2000

Cysticercosis Richard M. Armstrong

Neurocysticercosis is one of the most common parasitic infections affecting the nervous system. It results from the encystation of the larval form of the pork tapeworm Tuenia solium in the brain parenchyma, the ventricular system, or the meninges.

Neurocysticercosis is endemic in many regions of the world and is most common where there is a high rate of infestation in pigs. It is a significant problem among immigrants to the United States. The actual prevalence is not known, but autopsy series in Mexico indicate that up to 3.6% of the population may be infected.

EPIDEMIOLOGY Tapeworms, or cestodes, are segmented worms that attach to the intestinal mucosa with their head, or scolex, which contains sucking disks and hooks. Behind the scolex form the ribbon-like segments, or proglottids, each of which contains several thousand eggs. The pork tapeworm generally has 1000 proglottids and extends up to 3 m in length. When the proglottids are shed into the feces, the eggs are infective and, if ingested by a human, will develop into larval oncospheres that penetrate the gut wall, enter the bloodstream, and disseminate throughout the body, with a predilection for the central nervous system (CNS). The larvae may then develop into a cyst containing a scolex, which is known as a cysticercus. In this sequence of events, the infected person is acting as an intermediate host for the parasite. The pig also functions as an intermediate host for T. solium and is crucial to the continued presence of the disease in endemic areas. Humans can also function as the primary or definitive host when they harbor the adult T. solium worm in the small intestine. Ingestion of cysts, usually in infected pork, results in colonization of the small intestine when the scolex, released from the ingested cyst, affixes to the gut wall and proceeds to mature into an adult worm with numerous proglottid segments. Usually only a single worm is present in the lumen of the small bowel, and the host is asymptomatic, possibly harboring a worm for many years. Fecally contaminated foodstuffs are then ingested by humans (autoinfection) or other intermediate hosts, usually the pig.

CLINICAL FEATURES Humans, the primary hosts of T. solium, usually are asymptomatic when infected. However, when infected by the larval stage they function as intermediate hosts and may be symptomatic with fever and headache as the larvae invade the tissues. Once the cysts are established in the tissues they may remain viable for many years, be well tolerated by the host, and persist without clinical manifestations. Neurocysticercosis may become symptomatic up to 30 years after infection. Neurologic symptoms usually result either from the local inflammatory response induced by the parasite or from the mass effect of the space-occupying lesion. After implantation, the cyst consists of a thin-walled sac that contains the scolex attached to the cyst wall. In this vesicular stage the parasite elicits little response from the host. If they remain small and few in number, they may persist in the brain parenchyma through a long asymptomatic phase. Computed tomography (CT) scans and magnetic resonance imaging (MRI) show circumscribed hypodense lesions without associated enhancement or edema. Eventually, the cyst begins to undergo degenerative changes and enters into a colloidal phase. The vesicular liquid takes on a gelatinous-colloidal character, and the cyst wall thickens. This change elicits an inflammatory host response, and radiologically the cyst and surrounding edema are enhanced by contrast media. The degenerating cyst then enters a nodular granular phase in

Chapter 61

which the vesicle shrinks and its contents become semisolid. It is progressively replaced by granulomatous tissue, and on CT scan it appears as a hypodense area with irregular borders and surrounding edema. With contrast media enhancement, small, rounded hyperdensities are seen. Finally, the lesion retracts further and becomes a calcified, inactive mass. Small parenchymal cysts may remain asymptomatic until they begin to degenerate and the host mounts an inflammatory response. This inflammation, with edema, may then act as an

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Cysticercosis

irritative focus, and seizures may develop. If the cyst size or number is large, there may be mass effect with resulting headache and focal neurologic signs. If there is diffuse involvement with multiple reacting lesions, the clinical picture may be that of an acute encephalitis. Seizures and headaches are the most common presenting clinical features. The seizures often are focal in onset. Less commonly, there may be nausea, vomiting, papilledema, meningeal irritation, altered mental status, and other signs of increased intracranial pressure. Cranial nerve palsies, focal neurologic

A

B

C

FIG. 61-1. (A) TZ-weighted MRI scan showing an active cyst at the gray-white matter junction in the right cerebral hemisphere. (6) The same lesion on gadolinium-enhanced T I imaging, showing the characteristic enhancement and surrounding edema. This T1 technique also shows a small, nonenhancing punctate lesion (arrow), which is an old, degenerated, inactive cyst. (C) Contrast-enhanced T1 -weighted MRI 7 weeks after adequate therapy with praziquantel, showing shrinkage, resolution of edema, and loss of enhancement. The old, inactive lesion is unchanged. (Courtesy of 1. Douglas Lee, MD, and Lawrence Hutchins, MD, The Marshfield Clinic, Marshfield, Wl.)

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Immune and Infectious Disease W Fungal and Parasitic Infections

deficits from cerebral lesions, ataxia, and signs of cord compression may also present or occur during the course of the disease. Meningeal inflammation, in reaction to neurocysticercosis, may result in vascular occlusion and infarction. Cysts may develop within the ventricles and cause obstructive hydrocephalus as a result of their anatomic location, not because of degenerative changes or host reactions. However, the latter may occur, and the resulting inflammatory response may also produce an obstructive hydrocephalus and signs of meningeal irritation. In the spinal canal, meningeal lesions can produce cord compression. The cervical region is most commonly involved. Meningeal cysts may have a mass effect by themselves or by the inflammatory response they elicit in the meninges, which may result in vessel occlusion and infarction of the cord. Intramedullary cysts also occur within the spinal cord. Ocular cysticercosis is rare but can occur. Extraocular, intraorbital, subretinal, conjunctival, and palpebral lesions have all been reported. Many patients have involvement of multiple anatomic sites and present with various combinations of symptoms and syndromes. The clinical manifestations reflect the number, size, variability, or biologic status of the parasite and the host response to the parasite. MFU and CT studies are informative in defining location and the biologic status of the cysts.

examination. CT scanning and MRI also allows definition of cysts in the ventricular and arachnoid spaces. It is not uncommon for the CT or MRI studies to show multiple lesions in various phases of evolution.

TREATMENT Figure 6 1-2 shows an algorithm for treating neurocysticercosis. Praziquantel and albendazole are the most commonly used anticysticercal drugs, with albendazole probably superior in reducing the total number of cysts. Praziquantel usually is given in a dosage of 50 mg/kg/day in three divided doses for 12 to 14 days. The regimen for albendazole is 15 mg/kg/day in three doses for 8 days. If only calcified lesions are seen on CT and the CSF is normal, then no anticysticercal treatment is needed. Active cysts in a symptomatic patient should be treated with either praziquantel or, preferably, albendazole, both of which are effective against viable and degenerating cysts.

DIAGNOSIS Headaches and seizures are the primary presenting features, and neurocysticercosis should be considered in the differential diagnosis of any patient who has a history of exposure in an endemic area. Neurocysticercosis is the most common identified cause of adult seizures in Mexico and also accounts for a significant proportion of cases of hydrocephalus or intracranial masses. Calcified, palpable subcutaneous or intramuscular nodules are found in fewer than 5% of patients in modern series. Peripheral blood eosinophilia is inconstant. Cerebrospinal fluid (CSF) analysis is normal in approximately two thirds of cases, but in one third there may be a pleocytosis of polymorphonuclear or lymphocytic cells and an associated increase of protein. Occasionally, eosinophils may be seen in the CSF. Serologic and CSF tests to detect antibodies are available. The enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunoelectrotransfer blot (EITB) can be useful in confirming the diagnosis. The EITB has a specificity of 100% and a sensitivity greater than 93% in the serum and approximately 80% in the CSF. The ELISA is less sensitive in the serum and CSF. These tests are not readily available in all areas, and for the present they are used as confirmatory rather than diagnostic tests. ELISA and EITB are more sensitive and specific than the earlier techniques of complement fixation, immunoprecipitation, and other tests to detect antibody and antigen. CT and MRI studies are informative in diagnosing neurocysticercosis (Fig. 61- 1). The appearance of typical lesions, combined with a history and physical examination that are consistent with cysticercosis, allows the diagnosis to be made with a high degree of confidence. Cysts in the vesicular stage are seen as low-density, rounded lesions without associated contrast media enhancement or edema. Once degeneration begins, the cysts appear as hypodense or isodense rounded lesions with ring or nodular enhancement and adjacent edema. End-stage neurocysticercosis may appear as small calcifications at multiple sites but predominantly at the gray-white junction. These are best seen by CT

4

4

-1.

4

Arachnoiditis

Vasculitis and encephalitis

Granulomas or clacifications

Basal fibrosis

-

4

-1.

Symptomatic treatment bp., antiepileptic dNgs

With hydrocephalus

~

V

Ventricular shunt

1

Steroids or Immunosuppressants

4 Praziquantel (50 mg/kg/day for 2 weeks)

I I

lntraventricular cyst

I Ventricular shunt

Remission

I I

lntraocular

Confirmation by myelography or spinal CT

Confirmation by contrasted CT ventriculography

Surgical extirpation

FIG. 61-2. Algorithm for treating neurocysticercosis. (From Johnson RT: Neurocysticercosis in Current Therapy in Neurologic Disease. 2nd Ed. Mosby, St. Louis, 1992, with permission.)

Chapter 62

During treatment, parenchymal lesions that have been tolerated asymptomatically may begin to undergo degeneration and activate an inflammatory host response, which results in edema. If the lesion is large, there may be mass effect and compromise of adjacent neurons, producing neurologic deficits. The lesion may also act as an irritative focus, which produces seizures. Druginduced death of cysticerci may thus result in an increased inflammatory response analogous to the Herxheimer response. Clinically, this may be manifest as increased intracranial pressure, meningeal irritation, or general malaise. Some authorities recommend the concomitant administration of corticosteroids (prednisone or dexamethasone), but this may decrease significantly the bioavailability of praziquantel. If the lesion load is not great and there is little or no meningeal involvement, then it is appropriate to treat without corticosteroids and to monitor the patient for the first few days of treatment adding corticosteroids if there is a significant reaction. Nonsteroidal anti-inflammatory drugs may be used as an alternative to steroids. If recurrent seizures occur, they can usually be managed effectively with phenytoin or carbamazepine in the usual therapeutic dosages. There is some suggestion that anticonvulsants may decrease the bioavailability of the anticysticercal agents, but this is probably not significant in most cases. Imaging studies should be repeated 3 months after treatment to assess the efficacy of the treatment by documenting a decrease in size and number of cysts. Occasionally, complications necessitate surgical treatment of neurocysticercosis. Intraventricular cysts may cause obstructive hydrocephalus, for which early surgical intervention is indicated. Shunting may be needed acutely to treat the hydrocephalus, and, if

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possible, the cyst should be removed. Ventricular shunting and brain decompression may also be needed to manage cases of acute fulminant cysticercosis encephalitis. Cysts may develop in the meninges around the spinal cord or within the cord, and these, too, should be treated surgically. Anticysticercal agents, anticonvulsants, and corticosteroids, when appropriate, should be used concomitantly. Neurocysticercosis can be prevented by cooking pork properly and implementing appropriate sanitary practices. Carriers of the adult worm should be treated. Handwashing by food handlers and eliminating contaminated foods for pigs have been effective in developed countries.

SUGGESTED READINGS Alarcon F, Hidalgo F, Moncayo J et al: Cerebral cysticercosis and stroke. Stroke 23:224, 1992 DelBrutto OH: Medical treatment of cysticercosis: effective. Arch Neurol 52:102, 1995 DelBrutto OH, Santibanez R, Noboa CA et ak Epilepsy due to neurocysticercosis: analysis of 203 patients. Neurology 42:389, 1992 Kramer L D Medical treatment of cysticercosis: ineffective. Arch Neurol 52:101, 1995 Pretell EJ, Garcia HH, Custodio N et al: Short regimen of praziquantel in the treatment of single brain enhancing lesions. Clin Neurol Neurosurg 102:215-218, 2000 Scharf D: Neurocysticercosis: 238 cases from a California hospital. Arch Neurol 45:777, 1988 Thyanagui OM, Jardim E Therapy for neurocysticercosis: comparison between albendazole and praziquantel. Arch Neurol49:290, 1992

Trichinosis Yadollah Harati and Steven Lovitt

Human trichinosis, the best-known parasitic infection of muscles, is caused by nematodes of the species Trichinellu spirulis. It develops after the ingestion of raw or incompletely cooked infected pork, bear, horse, or walrus meat containing viable cysts of the parasite. Trichinosis has been documented in 39 countries of North and South America, Europe, and Africa. Its prevalence is higher in ethnic groups with a culinary preference for raw or inadequately cooked pork products, including people of Laotian, Cambodian, German, Italian, and Polish descent; several recent outbreaks of trichinosis among southeast Asian refugees in the United States have also been reported. With the ease of world travel and heightened immigration, the likelihood that a practicing physician in the United States will encounter patients with trichinosis has significantly increased, and the diagnosis should be considered in any patient presenting with fever, myalgias, periorbital edema, and eosinophilia.

EPIDEMIOLOGY Approximately 28 million people worldwide are infected with this parasite, but most are asymptomatic or minimally symptomatic and thus do not come to medical attention. The annual incidence

of trichinosis in the United States has steadily declined; only 206 cases were reported to the Centers for Disease Control and Prevention from 1987 to 1990. There is no gender difference in reported cases; about 60% of patients are between ages 20 and 50. The highest number of cases come from the northeastern and mid-Atlantic states, which reflects both higher rates of infection among swine in these areas and a higher concentration of ethnic groups with culinary preference for raw or lightly cooked pork. Pork and pork products, especially sausage, account for 75% of all human Trichinellu infection; nonpork products including game animals, bear, and walrus meat account for 13%, and in 12% of patients the source is undetermined. Ground beef contaminated by pork (e.g., in a meat grinder) is a common source of non-pork-induced disease. Although in suspected cases of trichinosis a detailed dietary and travel history is important, failure to elicit a history of raw pork consumption does not exclude the diagnosis. Travelers to Mexico, Asia, and Africa make up 65% of reported cases of travel-associated trichinosis in the United States; this percentage appears to be increasing in parallel with an increase in the total number of travelers to high-risk countries. Trichinosis should be suspected in any person with eosinophilia returning from abroad.

Chapter 62

During treatment, parenchymal lesions that have been tolerated asymptomatically may begin to undergo degeneration and activate an inflammatory host response, which results in edema. If the lesion is large, there may be mass effect and compromise of adjacent neurons, producing neurologic deficits. The lesion may also act as an irritative focus, which produces seizures. Druginduced death of cysticerci may thus result in an increased inflammatory response analogous to the Herxheimer response. Clinically, this may be manifest as increased intracranial pressure, meningeal irritation, or general malaise. Some authorities recommend the concomitant administration of corticosteroids (prednisone or dexamethasone), but this may decrease significantly the bioavailability of praziquantel. If the lesion load is not great and there is little or no meningeal involvement, then it is appropriate to treat without corticosteroids and to monitor the patient for the first few days of treatment adding corticosteroids if there is a significant reaction. Nonsteroidal anti-inflammatory drugs may be used as an alternative to steroids. If recurrent seizures occur, they can usually be managed effectively with phenytoin or carbamazepine in the usual therapeutic dosages. There is some suggestion that anticonvulsants may decrease the bioavailability of the anticysticercal agents, but this is probably not significant in most cases. Imaging studies should be repeated 3 months after treatment to assess the efficacy of the treatment by documenting a decrease in size and number of cysts. Occasionally, complications necessitate surgical treatment of neurocysticercosis. Intraventricular cysts may cause obstructive hydrocephalus, for which early surgical intervention is indicated. Shunting may be needed acutely to treat the hydrocephalus, and, if

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possible, the cyst should be removed. Ventricular shunting and brain decompression may also be needed to manage cases of acute fulminant cysticercosis encephalitis. Cysts may develop in the meninges around the spinal cord or within the cord, and these, too, should be treated surgically. Anticysticercal agents, anticonvulsants, and corticosteroids, when appropriate, should be used concomitantly. Neurocysticercosis can be prevented by cooking pork properly and implementing appropriate sanitary practices. Carriers of the adult worm should be treated. Handwashing by food handlers and eliminating contaminated foods for pigs have been effective in developed countries.

SUGGESTED READINGS Alarcon F, Hidalgo F, Moncayo J et al: Cerebral cysticercosis and stroke. Stroke 23:224, 1992 DelBrutto OH: Medical treatment of cysticercosis: effective. Arch Neurol 52:102, 1995 DelBrutto OH, Santibanez R, Noboa CA et ak Epilepsy due to neurocysticercosis: analysis of 203 patients. Neurology 42:389, 1992 Kramer L D Medical treatment of cysticercosis: ineffective. Arch Neurol 52:101, 1995 Pretell EJ, Garcia HH, Custodio N et al: Short regimen of praziquantel in the treatment of single brain enhancing lesions. Clin Neurol Neurosurg 102:215-218, 2000 Scharf D: Neurocysticercosis: 238 cases from a California hospital. Arch Neurol 45:777, 1988 Thyanagui OM, Jardim E Therapy for neurocysticercosis: comparison between albendazole and praziquantel. Arch Neurol49:290, 1992

Trichinosis Yadollah Harati and Steven Lovitt

Human trichinosis, the best-known parasitic infection of muscles, is caused by nematodes of the species Trichinellu spirulis. It develops after the ingestion of raw or incompletely cooked infected pork, bear, horse, or walrus meat containing viable cysts of the parasite. Trichinosis has been documented in 39 countries of North and South America, Europe, and Africa. Its prevalence is higher in ethnic groups with a culinary preference for raw or inadequately cooked pork products, including people of Laotian, Cambodian, German, Italian, and Polish descent; several recent outbreaks of trichinosis among southeast Asian refugees in the United States have also been reported. With the ease of world travel and heightened immigration, the likelihood that a practicing physician in the United States will encounter patients with trichinosis has significantly increased, and the diagnosis should be considered in any patient presenting with fever, myalgias, periorbital edema, and eosinophilia.

EPIDEMIOLOGY Approximately 28 million people worldwide are infected with this parasite, but most are asymptomatic or minimally symptomatic and thus do not come to medical attention. The annual incidence

of trichinosis in the United States has steadily declined; only 206 cases were reported to the Centers for Disease Control and Prevention from 1987 to 1990. There is no gender difference in reported cases; about 60% of patients are between ages 20 and 50. The highest number of cases come from the northeastern and mid-Atlantic states, which reflects both higher rates of infection among swine in these areas and a higher concentration of ethnic groups with culinary preference for raw or lightly cooked pork. Pork and pork products, especially sausage, account for 75% of all human Trichinellu infection; nonpork products including game animals, bear, and walrus meat account for 13%, and in 12% of patients the source is undetermined. Ground beef contaminated by pork (e.g., in a meat grinder) is a common source of non-pork-induced disease. Although in suspected cases of trichinosis a detailed dietary and travel history is important, failure to elicit a history of raw pork consumption does not exclude the diagnosis. Travelers to Mexico, Asia, and Africa make up 65% of reported cases of travel-associated trichinosis in the United States; this percentage appears to be increasing in parallel with an increase in the total number of travelers to high-risk countries. Trichinosis should be suspected in any person with eosinophilia returning from abroad.

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Enactment of several federal and state laws prohibiting the feeding of non-heat-treated garbage to swine has all but eliminated commercial pork products as a cause of trichinosis. However, the noncommercial sources of pork-for example, from wild animals and small farms not using modern hog management and slaughter practices-are emerging as an important source of human trichinosis in the United States. Case reporting of trichinosis consistently increases from December through March, probably as a result of homemade pork products eaten during the holiday season.

ness, malaise, and elevated serum CK levels, may result in diagnostic confusion with polymyositis (or dermatomyositis if skin rash is also present). However, in trichinosis the pain is more severe than polymyositis, and pain in the jaws, neck, and back may be prominent. Involvement of extraocular muscles, intercostal muscles, and the diaphragm also are more common in trichinosis. Electromyography in both conditions demonstrates myopathic features and fibrillation potentials. In this setting, the presence of eosinophilia, other systemic symptoms, and the travel and culinary history become the critical diagnostic clues.

CLINICAL FEATURES

DIAGNOSIS

After the ingestion of contaminated meat, the encysted larva is digested by stomach and proximal intestinal enzymes, leading to liberation of the organism in the upper small bowel. The released larvae burrow into the mucosa of the small intestine and after 24 to 36 hours develop into mating male and female adult worms. Each female worm then produces up to 1500 new larva during her lifetime of 2 to 5 weeks. The progeny larva penetrate through the mucosa of the small intestine, gaining access to the lymphatic and venous circulation and disseminate widely, especially to striated muscles. The muscles most commonly invaded, in order of frequency, are as follows: diaphragm, extraocular, tongue, pharyngeal, jaw, intercostal, neck, back, abdominal, and limb muscles. Immature larva reaching striated muscles will encyst, but larva reaching nonstriated muscles or other tissues do not encyst and may continue to migrate, resulting in marked inflammation and tissue necrosis. This process usually is self-limited but may result in severe multiorgan pathology, chronic sequela, or even death. The muscle cystic structures may begin to calcify as early as 6 months after the initial infection. However, as in animals, the larva may remain viable within cysts for several years. The clinical symptoms of trichinosis arise from successive phases of parasitic enteric invasion, larval migration, and tissue encystment. When muscle invasion involves less than 10 larvae per gram of muscle, no symptoms may arise, but infection of 50 to 100 larvae per gram can produce severe symptoms. Most infections are asymptomatic and are not recognized clinically. During the first week of infection, when larval invasion of the gut occurs, transient diarrhea, abdominal pain, nausea, or vomiting may occur. During the second week after infection, when larval migration and muscle invasion begin, local and systemic hypersensitivity reactions occur. Fever, chills, headache, periorbital and facial edema, subconjunctival, retinal, and nailbed hemorrhage, macular, petechial or urticaria1 skin rash, hoarseness, cough and dyspnea, dysphagia, and hypereosinophilia develop. When infection is severe and hypereosinophilia exceeds 4000/mm3, a cardioneurologic syndrome consisting of diffuse and focal encephalopathy (microinfarcts or focal cerebritis), hypodensities on brain computed tomography (CT) scan, diffuse ischemic or focal myocarditis with tachyarrhythmia, heart failure, and creatine kinase (CK-MB) isoenzyme elevation may occur. The myocarditis initially may manifest as tachycardia or chest pain and may mimic acute myocardial infarction. Electrocardiographic evidence of myocardial involvement may be found in up to 75% of patients with trichinosis. Most fatalities of trichinosis are caused by myocarditis, pneumonitis, or encephalitis and occur in the third to ninth week of the disease. Upon larval invasion and encystment of muscles at the end of the first week, pain and tenderness develop, particularly of proximal muscles. This symptom, along with generalized weak-

Confirmation of the diagnosis often is accomplished by serologic testing or muscle biopsy. Serologic testing is simple, highly sensitive, and specific. However, antibodies to I: spiralis are not detected until 3 weeks or more after the onset of infection, although ultimately significant antibody titers develop in about 95% of patients. Available serologic tests include rapid screening counterimmunoelectrophoresis, enzyme-linked immunosorbent assay (ELISA), passive hemagglutination, and indirect immunofluorescence. The bentonite flocculation test is most widely used; a titer of 1:5 or greater is considered positive, although a fourfold rise in the titer is more convincing. The test may be repeated in 4 to 6 weeks to determine a rise in the titer. An elevated titer may persist for many months. The quickest way to establish the diagnosis during the muscle phase of the illness is to find Trichinellu larva within the striated muscles. An open muscle biopsy to obtain at least 1 g of muscle is required. The highest yield of larvae is near the tendon insertion of the muscle. An inflammatory infiltrate-mainly eosinophils and neutrophils, with fewer lymphocytes, plasma cells, and other mononuclear cells-is seen around parasite-containing muscle fibers and in the interstitium. When larvae are not observed because of a sampling error, such an inflammatory reaction to larvae may be the only pathologic abnormality present. If the biopsy is obtained 3 or 4 weeks after the infection, encapsulation or even calcification of the capsule may be seen. Plain films may reveal nodular calcificationswithin the muscle and can be useful as both a supportive study and in selecting which muscle to biopsy. The differential diagnosis of trichinosis, which is a disease with multisystem involvement, is extensive:

W

Polymyositis Dermatomyositis Viral syndromes: influenza, gastroenteritis, exanthems Periarteritis Sepsis: pneumonitis, meningitis, typhoid Allergic phenomena Encephalitis

Trichinosis should be considered in patients who present with fever and myalgias, especially if they show allergic phenomena such as periorbital edema and eosinophilia. Patients should be thoroughly questioned about their consumption of pork and wild animal meat and asked whether other people became ill after a common meal.

PROGNOSIS Most mildly infected patients recover uneventfully with supportive care consisting of bed rest, analgesics, and antipyretics. In prospective studies of patients who had severe acute trichinosis

Chapter 63

10 years earlier, 60% have shown lingering symptoms of muscle pain, burning eyes, and decreased stress tolerance; 56% had impaired muscle strength; 55% had conjunctivitis; and 32% had impaired coordination. More than one third of patients continued to have detectable immunoglobulin G antibodies to T spiralis 10 years later. However, soft tissue radiographs, brain magnetic resonance imaging, or muscle biopsy failed to show calcified residual larva. The cause of these persistent symptoms remains unknown but may suggest “chronic trichinosis” or persevering immune reaction.

TREATMENT As soon as the disease is suspected, it is advisable to treat the patient with menzimidazole compounds such as thiabendazole 25 mg/kg twice a day (maximum 3.0 g/day) for 5 to 7 days to remove intestinal larva and worms. The drug is ineffective against Trichinella in the muscle. However, mebendazole, a carbamate derivative of thiabendazole, has been shown to be active against both the invasive phase and the encystment of infection at a dosage of 400 mg PO three times a day for 10 days. The drug is better tolerated than thiabendazole. (Another effective drug, albendazole, is not currently licensed by the Food and Drug Administration for use in the United States.) Because a Herxheimer-like reaction may result from the simultaneous disintegration of many larvae after antihelminthic therapy, corticosteroids (prednisone 40 to 60 mg PO for 5 to 10 days) usually are given. Severe trichinosis should be treated with antihelminthic drugs as well as high-dose corticosteroids orally or intravenously (methylprednisolone 250 to 500 mg/day).

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adequate. The pork should be cooked until it is no longer pink. Freezing at -15OC (home freezers) for 3 weeks or at -32°C for 24 hours is also effective in eliminating larvae. Smoking, salting, or drying meat does not prevent Trichinella infection. Trichinella of arctic meat (walrus or bear) are most resistant and may remain viable despite freezing.

SUGGESTED READINGS Appleyard GD, Gajadhar AA: A review of trichinellosis in people and wildlife in Canada. Can J Public Health 91(4):293, 2000 Bailey TM, Schantz PM: Trends in the incidence and transmissionpatterns of human trichinellosis in the United States, 1982-1986. Rev Infect Dis 12:5, 1990 Compton IS, Celum CL, Lee C et ak Trichinosis with ventilatory failure and persistent myocarditis. Clin Infect Dis 16:500, 1993 Fourstie V, Douceron H, Brugieres P et al: Neurotrichinosis. Brain 116603, 1993 Harms G, Binz P, Feldmeier H et al: Trichinosis: a prospective controlled study of patients ten years after acute infection. Clin Infect Dis 17:637, 1993 Herrera R, Varela E, Morales G et al: Dermatomyositis-like syndrome caused by trichinosis: report of two cases. J Rheumatol 12:782, 1985 Kociecka W Trichinellosis: human disease, diagnosis, and treatment. Vet Parasit01 93(3-4):365, 2000 Landry SM, Kiser D, Overby T et al: Trichinosis: common source outbreak related to commercial pork. South Med 185:428, 1992 McAuley JB, Michelson MK, Hightower AW et al: A trichinosis outbreak among southeast Asian refugees. Am J Epidemiol 135:1404, 1992 McAuley JB,Michelson MK, Schantz PM: Trichinellainfection in travelers. J Infect Dis 164:1013, 1991

PREVENTION Prevention of trichinosis is possible by thorough cooking of infected meat; a temperature of 58.3”C throughout the meat is

63

Toxodasmosis Bradley K. Evans

The intracellular parasite Tomplasma gondii infects a wide variety of organisms, organs, and cells. Although cats are the definitive hosts, T. gondii can infect humans and other animals. In humans, central nervous system (CNS) involvement is common. Three neurologic syndromes are commonly recognized congenital toxoplasmosis (which is not discussed in this chapter), meningoencephalitis associated with a mononucleosis-like syndrome, and CNS toxoplasmosis (sometimes called toxoplasmic encephalitis) in patients infected with the human immunodeficiency virus (HIV).

fecal material or bradyzoites (tissue cysts) in undercooked meat. These transform into invasive tachyzoites. Tachyzoites penetrate into cells and multiply. The cells later rupture, and new tachyzoites spew forth. A primary infection becomes latent when tachyzoites, for whatever reason, revert to bradyzoites. Bradyzoites may be the source of future trouble because they are still viable and could change yet once again into tachyzoites. This is known as reactivation.

EPIDEMIOLOGY

CLINICAL FEATURES

According to serologic surveys, 25% to 75% of adults in the community have had a primary infection with T gondii. Humans become infected because they eat material that is contaminated by animal feces or because they eat undercooked meat, commonly pork or lamb. Digestion releases cysts, which are either oocysts in

Primary infection usually does not cause symptoms in children and adults. When patients do have symptoms, they have fever, fatigue, malaise, myalgias, and pharyngitis. Examination may show cervical lymphadenopathy and a fine maculopapular rash. Physicians generally assume that these patients have mononucle-

Chapter 63

10 years earlier, 60% have shown lingering symptoms of muscle pain, burning eyes, and decreased stress tolerance; 56% had impaired muscle strength; 55% had conjunctivitis; and 32% had impaired coordination. More than one third of patients continued to have detectable immunoglobulin G antibodies to T spiralis 10 years later. However, soft tissue radiographs, brain magnetic resonance imaging, or muscle biopsy failed to show calcified residual larva. The cause of these persistent symptoms remains unknown but may suggest “chronic trichinosis” or persevering immune reaction.

TREATMENT As soon as the disease is suspected, it is advisable to treat the patient with menzimidazole compounds such as thiabendazole 25 mg/kg twice a day (maximum 3.0 g/day) for 5 to 7 days to remove intestinal larva and worms. The drug is ineffective against Trichinella in the muscle. However, mebendazole, a carbamate derivative of thiabendazole, has been shown to be active against both the invasive phase and the encystment of infection at a dosage of 400 mg PO three times a day for 10 days. The drug is better tolerated than thiabendazole. (Another effective drug, albendazole, is not currently licensed by the Food and Drug Administration for use in the United States.) Because a Herxheimer-like reaction may result from the simultaneous disintegration of many larvae after antihelminthic therapy, corticosteroids (prednisone 40 to 60 mg PO for 5 to 10 days) usually are given. Severe trichinosis should be treated with antihelminthic drugs as well as high-dose corticosteroids orally or intravenously (methylprednisolone 250 to 500 mg/day).

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adequate. The pork should be cooked until it is no longer pink. Freezing at -15OC (home freezers) for 3 weeks or at -32°C for 24 hours is also effective in eliminating larvae. Smoking, salting, or drying meat does not prevent Trichinella infection. Trichinella of arctic meat (walrus or bear) are most resistant and may remain viable despite freezing.

SUGGESTED READINGS Appleyard GD, Gajadhar AA: A review of trichinellosis in people and wildlife in Canada. Can J Public Health 91(4):293, 2000 Bailey TM, Schantz PM: Trends in the incidence and transmissionpatterns of human trichinellosis in the United States, 1982-1986. Rev Infect Dis 12:5, 1990 Compton IS, Celum CL, Lee C et ak Trichinosis with ventilatory failure and persistent myocarditis. Clin Infect Dis 16:500, 1993 Fourstie V, Douceron H, Brugieres P et al: Neurotrichinosis. Brain 116603, 1993 Harms G, Binz P, Feldmeier H et al: Trichinosis: a prospective controlled study of patients ten years after acute infection. Clin Infect Dis 17:637, 1993 Herrera R, Varela E, Morales G et al: Dermatomyositis-like syndrome caused by trichinosis: report of two cases. J Rheumatol 12:782, 1985 Kociecka W Trichinellosis: human disease, diagnosis, and treatment. Vet Parasit01 93(3-4):365, 2000 Landry SM, Kiser D, Overby T et al: Trichinosis: common source outbreak related to commercial pork. South Med 185:428, 1992 McAuley JB, Michelson MK, Hightower AW et al: A trichinosis outbreak among southeast Asian refugees. Am J Epidemiol 135:1404, 1992 McAuley JB,Michelson MK, Schantz PM: Trichinellainfection in travelers. J Infect Dis 164:1013, 1991

PREVENTION Prevention of trichinosis is possible by thorough cooking of infected meat; a temperature of 58.3”C throughout the meat is

63

Toxodasmosis Bradley K. Evans

The intracellular parasite Tomplasma gondii infects a wide variety of organisms, organs, and cells. Although cats are the definitive hosts, T. gondii can infect humans and other animals. In humans, central nervous system (CNS) involvement is common. Three neurologic syndromes are commonly recognized congenital toxoplasmosis (which is not discussed in this chapter), meningoencephalitis associated with a mononucleosis-like syndrome, and CNS toxoplasmosis (sometimes called toxoplasmic encephalitis) in patients infected with the human immunodeficiency virus (HIV).

fecal material or bradyzoites (tissue cysts) in undercooked meat. These transform into invasive tachyzoites. Tachyzoites penetrate into cells and multiply. The cells later rupture, and new tachyzoites spew forth. A primary infection becomes latent when tachyzoites, for whatever reason, revert to bradyzoites. Bradyzoites may be the source of future trouble because they are still viable and could change yet once again into tachyzoites. This is known as reactivation.

EPIDEMIOLOGY

CLINICAL FEATURES

According to serologic surveys, 25% to 75% of adults in the community have had a primary infection with T gondii. Humans become infected because they eat material that is contaminated by animal feces or because they eat undercooked meat, commonly pork or lamb. Digestion releases cysts, which are either oocysts in

Primary infection usually does not cause symptoms in children and adults. When patients do have symptoms, they have fever, fatigue, malaise, myalgias, and pharyngitis. Examination may show cervical lymphadenopathy and a fine maculopapular rash. Physicians generally assume that these patients have mononucle-

464

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osis and never diagnose toxoplasma infection unless immunoglobulin M (IgM) and immunoglobulin G (IgG) antitoxoplasma antibodies are requested. Patients often need symptomatic treatment only. Of patients with a mononucleosis-like illness, about one in five have a headache, mental confusion, and abnormal cerebrospinal fluid (CSF) findings (mild elevation in white cell count, generally less than 50/mm3), indicating that they have meningoencephalitis. Their toxoplasma infection must be treated with pyrimethamine and the sulfonamides. CNS toxoplasmosis is an illness seen in HIV-infected patients. Almost always, the CD4 count is less than 200/pL,usually less than lOO/pL. These patients have acquired immunodeficiency syndrome (AIDS). Symptoms of CNS toxoplasmosis evolve over a few days. Occasional patients have rapid onset, mimicking a stroke, and others have a gradual onset, mimicking a brain tumor. Common symptoms at the onset are headache (70%), altered mental status (60%), fever (50%), seizures (33%), and focal neurologic deficits (60%). Focal signs and symptoms ultimately are seen in most patients. In patients with AIDS, focal signs and symptoms are diagnostic clues. Eighty-five percent of patients with CNS toxoplasmosis have IgG antitoxoplasma antibodies (antibody-positive), indicating that they have had a past, primary infection. For the remaining 15% who are antibody-negative, either they have had a prior primary infection with poor antibody response or they have a primary infection. In the patient with AIDS, CNS toxoplasmosis is the most common cause of a focal brain lesion. At least 10% of HIVinfected patients have CNS toxoplasmosis during the course of their illness. This risk jumps to 33% if the patient is antibodypositive. The risk is markedly reduced in patients who are known to be antibody-negative. NEUROIMAGING Head computed tomography (CT) and head magnetic resonance imaging (MRI) are key tests. MRI is more sensitive than CT in showing the lesions. There are four cardinal neuroimaging findings that, in the right clinical setting, are highly suggestive of CNS toxoplasmosis: First, there are multiple lesions (if an MRI shows only a single lesion, alternative diagnoses should be considered carefully); second, the lesions are preferentially located in the basal ganglia and gray-white junctions of the cerebrum; third, the lesions have a mass effect; fourth, they enhance (Fig. 63-1). These four findings are not absolutely diagnostic of CNS toxoplasmosis; similar findings can be seen, for instance, in primary CNS lymphoma. Some patients may even have both conditions. It is not known at present whether newer scanning modalities (positron emission tomography and single photon emission computed tomography) will be clinically useful in diagnosing and treating patients with CNS toxoplasmosis. DIAGNOSIS Diagnosis of CNS toxoplasmosis usually is made presumptively, without tissue confirmation. Clinicians use information from history and examination, results of HIV and CD4 testing if available, results of antitoxoplasma antibody tests if available, and neuroimaging findings. Often, clinicians must reevaluate prior decisions based on a day-to-day review of information. There is no defined decision tree for this situation.

In a patient with AIDS who is antibody-positive and who has a typical clinical syndrome and typical findings on neuroimaging studies, antitoxoplasma therapy is begun as a therapeutic trial. Improvement-within 2 weeks clinically and within 4 weeks by neuroimaging studies-then confirms the diagnosis. For patients who do not meet these criteria because they have atypical syndromes, their CD4 count is greater than 200/pL, their neuroimaging findings are unusual, they are antibody-negative, or they are already on antibiotics with antitoxoplasma effects, the clinician should consider early brain biopsy for a definitive diagnosis. Also, one should consider brain biopsy for diagnosis if there is clinical worsening after 1 week of antitoxoplasma treatment, failure to improve 14 days after initiating treatment, or worsening of an individual lesion by neuroimaging criteria. Even a brain biopsy may not provide a definitive diagnosis because there is intense inflammation, making tachyzoites difficult to find (bradyzoites, in themselves, are not diagnostic). Sometimes, tachyzoites are not found and the inflammation is misidentified as CNS lymphoma or viral encephalitis. The greatest tachyzoite yield is found if the surgeon does an open rather than a stereotactic biopsy and if the pathologist immunostains for tachyzoites. The usefulness of polymerase chain reaction in diagnosis is unknown. In considering the differential diagnosis, one should remember that a patient may have multiple concurrent CNS disease processes. The following list of alternatives should be considered in patients with AIDS

w Primary CNS lymphoma w Progressive multifocal leukoencephalopathy w Infectious abscesses (bacterial, tuberculous, fungal) W Brain metastases H Herpes simplex encephalitis HIV encephalitis CNS lymphoma is the main alternative diagnosis. Symptoms can evolve fairly rapidly over 1 or 2 weeks. Patients often have focal neurologic symptoms and signs and similar neuroimaging findings. Primary CNS lymphoma is common in patients with AIDS (about 2% of patients with AIDS develop CNS lymphoma). The diagnosis of CNS lymphoma usually is made by stereotactic biopsy (because patients with this tumor do worse after open biopsy with resection). CNS lymphoma may temporarily “melt away” if the patient has been treated with corticosteroids. If a clinician is conducting a therapeutic trial with a combination of corticosteroids and antitoxoplasma therapy in a patient thought to have CNS toxoplasmosis or CNS lymphoma, it will be difficult to interpret the implications of any improvement that may occur. Brain metastases, fungal or tuberculous abscesses, and multiple bacterial abscesses associated with acute endocarditis can also mimic CNS toxoplasmosis. These diagnoses often are initially considered if the patient is HIV-positive. Viral encephalitis, HIV encephalitis, and progressive multifocal leukoencephalopathy can also produce abnormalities on neuroimaging studies in patients with AIDS but do not usually produce the combination of acute onset, focal neurologic findings, and multiple enhancing lesions with mass effect. Finally, in patients with AIDS, about 20% of brain biopsies performed to evaluate focal brain lesions are nondiagnostic. PREVENTION AND TREATMENT Although CNS toxoplasmosis represents reactivation of a latent infection, it may still be important to advise HIV-infected patients to minimize activities that could cause a primary infection.

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A

C

FIG. 63-1. An immunocompromised patient with toxoplasmosis. (A) T2-weighted MRI of the brain showing a large lesion at the gray-white junction of the cerebrum of the right frontal lobe, with a mass effect. Two smaller lesions are seen in the left hemisphere. (6) TI-weighted MRI of the same patient after infusion of gadolinium, showing the characteristic enhancement of toxoplasmosis. (C) T2-weighted MRI of the same patient 4 weeks after treatment with high-dose pyrimethamine, sulfadiazine, and leucovorin, showing substantial resolution of the lesions. (Courtesy of J. Douglas Lee, MD, and Lawrence Hutchins, MD, the Marshfield Clinic.)

Trimethoprim-sulfamethoxazole (often used anyhow to prevent Pneurnocystis carinii pneumonia) is effective in preventing toxoplasmosis reactivation. Primary treatment with high-dose pyrimethamine (typically, 200 mg initially, then 50 to 100 mg/day), sulfadiazine (4g initially, then 1 to 2 g four times daily), and folinic acid (leucovorin, 10 to 15 mg/day) is begun. Pyrimethamine is associated with bone marrow toxicity and sulfadiazine with rash and crystal-induced renal dysfunction. Up to 40% of patients therefore do not tolerate this treatment. As an alternative to sulfadiazine, clindamycin or azithromycin can be used. Clinical improvement should occur within 10 to 14 days, and radiologic improvement should be seen within 2 to 4 weeks. Corticosteroids are best avoided if possible.

After 6 weeks of primary treatment with high-dose pyrimethamine, sulfadiazine, and leucovorin, patients continue lifelong maintenance therapy with the same drugs but at about half the dosage of primary treatment. Without maintenance therapy, nearly all patients relapse. Even if patients are prescribed and take maintenance therapy, up to 25% relapse. A patient in relapse needs retreatment with high-dose therapy. It is not clear whether patients with new seizures or new headaches but without worsening on neuroimaging studies should be considered to be in relapse, but empirical retreatment often is advised. If patients are not already on highly active antiretroviral therapy (combination therapy often abbreviated HAART) for HIV infection, most clinicians start these medicines after patients are stable and on maintenance therapy.

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W

Viral Infections

SUGGESTED READINGS Carr A, Tindall B, Brew BJ et ak Low dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 117106, 1992 Jacobson JM, Haher R, Remington J et ak Dose-escalation, phase 1/11

study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 15:583, 2001 TOXOPlasmic encephalitis in Luft Haher R, Korzun AH et patients with the acquired immunodeficiencysyndrome. N Engl J Med BJi

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VIRAL INFECTIONS

64

Viral Meningitis and Encephalitis Stephen B. Greenberg

Many viruses can invade the central nervous system (CNS). Viral CNS infections (often called aseptic meningitis) may be asymptomatic or associated with only mild symptoms, but they can occasionally cause severe meningitis or encephalitis. The diagnostic criteria for the acute aseptic meningitis syndrome are as follows: H W

Signs and symptoms of acute meningeal irritation Mononuclear cell predominance in cerebrospinal fluid (CSF) Absence of detectable bacteria in the CSF Absence of parameningeal or systemic illness Brief and benign illness

The diagnostic criterion for encephalitis is alteration of consciousness or focal neurologic findings with evidence of meningeal inflammation. Therefore, the term meningoencephalitis may be appropriate in many cases. An estimated 8000 to 12,000 cases of acute aseptic meningitis occur annually in the United States. Approximately 1000 to 2000 cases of encephalitis are reported annually to the Centers for Disease Control. Viral causes of meningoencephalitis are numerous, but clinical signs and symptoms alone usually cannot establish a specific diagnosis. However, new laboratory methods are becoming available that will aid in rapid and specific identification of viral agents and will lead to new knowledge of the epidemiology of these viral infections. PATHOGENESIS Entry and replication of the viruses that cause meningitis and encephalitis occur extraneurally. Most viruses reach the CNS by the hematogenous route. Viruses may invade the CNS through the choroid plexus or by direct penetration of the endothelium of cerebral blood vessels. Nonhematogenous routes of transmission also exist; these routes may be important in the pathogenesis of rabies or adult-onset herpes simplex encephalitis (HSE). In these

cases, the virus may infect the brain by retrograde travel along axons in the spinal cord or the brain. With viral replication in neural cells, cell death or dysfunction results. The extent of the neuronal damage may contribute to the clinical severity of viral meningoencephalitis. In viral meningitis, activated T cells and monocytes are found in the CSF. Proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) levels are high in the CSF of patients with viral meningitis but not in patients with bacterial meningitis. Interleukin-10 (IL-10) and transforming growth factor-P (TGF-P) are present in the CSF of patients with viral meningitis and may have an anti-inflammatory effect. These cytokines are thought to be produced locally in the brain. Recruitment of blood monocytes into the CSF may result from the effects of chemokines such as macrophage inflammatory protein-a (MIP-a), RANTES, IL-8, and growth related oncogene-a (GRO-a). EPIDEMIOLOGY When the viral causes of acute aseptic meningitis syndrome were first reported in the 1960s, most infections were caused by enteroviruses or mumps, with a few cases secondary to lymphocytic choriomeningitis (LCM), herpes simplex virus (HSV), or arboviruses. Although the spread of human immunodeficiency virus (HIV) and increased vaccine usage has led to a change in common causes, enteroviruses and arboviruses still account for the majority of viral aseptic meningitis and encephalitis (Tables 64-1 and 64-2). Viral meningitis or encephalitis can occur either sporadically or epidemically. Enteroviruses and arboviruses are most often the agents in epidemics, whereas HSV-1 is the most common cause of sporadic cases of encephalitis in the United States. Less common causes of encephalitis are the herpes viruses (Epstein-Barr virus [EBV], cytomegalovirus [CMV], varicella-zoster virus [VZV]), measles, and rabies (Table 64-1).

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SUGGESTED READINGS Carr A, Tindall B, Brew BJ et ak Low dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 117106, 1992 Jacobson JM, Haher R, Remington J et ak Dose-escalation, phase 1/11

study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 15:583, 2001 TOXOPlasmic encephalitis in Luft Haher R, Korzun AH et patients with the acquired immunodeficiencysyndrome. N Engl J Med BJi

329995, 1993

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VIRAL INFECTIONS

64

Viral Meningitis and Encephalitis Stephen B. Greenberg

Many viruses can invade the central nervous system (CNS). Viral CNS infections (often called aseptic meningitis) may be asymptomatic or associated with only mild symptoms, but they can occasionally cause severe meningitis or encephalitis. The diagnostic criteria for the acute aseptic meningitis syndrome are as follows: H W

Signs and symptoms of acute meningeal irritation Mononuclear cell predominance in cerebrospinal fluid (CSF) Absence of detectable bacteria in the CSF Absence of parameningeal or systemic illness Brief and benign illness

The diagnostic criterion for encephalitis is alteration of consciousness or focal neurologic findings with evidence of meningeal inflammation. Therefore, the term meningoencephalitis may be appropriate in many cases. An estimated 8000 to 12,000 cases of acute aseptic meningitis occur annually in the United States. Approximately 1000 to 2000 cases of encephalitis are reported annually to the Centers for Disease Control. Viral causes of meningoencephalitis are numerous, but clinical signs and symptoms alone usually cannot establish a specific diagnosis. However, new laboratory methods are becoming available that will aid in rapid and specific identification of viral agents and will lead to new knowledge of the epidemiology of these viral infections. PATHOGENESIS Entry and replication of the viruses that cause meningitis and encephalitis occur extraneurally. Most viruses reach the CNS by the hematogenous route. Viruses may invade the CNS through the choroid plexus or by direct penetration of the endothelium of cerebral blood vessels. Nonhematogenous routes of transmission also exist; these routes may be important in the pathogenesis of rabies or adult-onset herpes simplex encephalitis (HSE). In these

cases, the virus may infect the brain by retrograde travel along axons in the spinal cord or the brain. With viral replication in neural cells, cell death or dysfunction results. The extent of the neuronal damage may contribute to the clinical severity of viral meningoencephalitis. In viral meningitis, activated T cells and monocytes are found in the CSF. Proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) levels are high in the CSF of patients with viral meningitis but not in patients with bacterial meningitis. Interleukin-10 (IL-10) and transforming growth factor-P (TGF-P) are present in the CSF of patients with viral meningitis and may have an anti-inflammatory effect. These cytokines are thought to be produced locally in the brain. Recruitment of blood monocytes into the CSF may result from the effects of chemokines such as macrophage inflammatory protein-a (MIP-a), RANTES, IL-8, and growth related oncogene-a (GRO-a). EPIDEMIOLOGY When the viral causes of acute aseptic meningitis syndrome were first reported in the 1960s, most infections were caused by enteroviruses or mumps, with a few cases secondary to lymphocytic choriomeningitis (LCM), herpes simplex virus (HSV), or arboviruses. Although the spread of human immunodeficiency virus (HIV) and increased vaccine usage has led to a change in common causes, enteroviruses and arboviruses still account for the majority of viral aseptic meningitis and encephalitis (Tables 64-1 and 64-2). Viral meningitis or encephalitis can occur either sporadically or epidemically. Enteroviruses and arboviruses are most often the agents in epidemics, whereas HSV-1 is the most common cause of sporadic cases of encephalitis in the United States. Less common causes of encephalitis are the herpes viruses (Epstein-Barr virus [EBV], cytomegalovirus [CMV], varicella-zoster virus [VZV]), measles, and rabies (Table 64-1).

Chapter 64

Of the many factors influencing the epidemiology of acute aseptic meningitis syndrome or viral encephalitis, the most important for determining the cause are the patient’s age, immunocompetence, geographic location, and the season. Certain viral infections occur worldwide, infect humans of all ages, and display little or no seasonal variation; others are specific to season and geographic area, especially those caused by insectborne viruses (Table 64-3). Typical clinical findings with enteroviral infections are myocarditis and pleurodynia, which can cause epidemics, espe-

H TABLE64-1.

Viruses Causing Aseptic Meningitis Syndrome or Encephalitis Meningitis

HNS

Encephalitis

Adenoviruses Arboviruses +++ +++ Coronaviruses Cytomegalovirus + Enteroviruses + -+ + +++ Epstein-Barrvirus + Herpes simplex type 1 + ++ Herpes simplex type 2 +++ Human immunodeficiency virus + Influenza Lymphocytic choriomeningitis + Measles + + Mumps + + Parainfluenza virus + Rabies + Rotavirus Rubella Varicella zoster virus + Symbols: + + +. comrnon/sporadic or epidemic; + +, commonlsporadic; +, uncommon; -, rarely reported.

-

-

H TABU 64-2. Classification of the Most Common Viruses

Causing Epidemic Aseptic Meningitis or Encephalitis Enterovirus (gastrointestinal spread) Poliovirus Coxsackievirus Echovirus Arbovirus (arthropod-borne [insect] spread) Eastern equine encephalitis Western equine encephalitis Venezuelan equine encephalitis St. Louis encephalitis California encephalitis

H TABLE64-3.Epidemiology

H

Viral Meningitis and Encephalitis

467

cially in the summer and fall. Acute HIV infection should be considered in high-risk populations and often presents with a mononucleosis syndrome. Contact with rodents often is an indication of possible infection with LCM, and patients with HSV-2 often have primary genital lesions. Mumps, although less common since the widespread use of vaccines, can have associated parotitis. Focal neurologic deficits are seen with HSE, although there is no seasonality. The characteristic rash of VZV is seen with this infection, and encephalitis in children often is manifested by cerebellar ataxia. The mononucleosis syndrome can be seen in patients with EBV- or CMV-associated encephalitis. A history of mosquito bite may be helpful in detecting the common arbovirusassociated encephalitides. Adenovirus may have preceding respiratory symptoms. Rabies characteristically is associated with an animal bite, although many cases have occurred where this history is lacking. CLINICAL FEATURES AND DIAGNOSIS The clinical features of meningitis or encephalitis range from mild febrile illnesses associated with headache to severe illnesses associated with convulsions, coma, and death. Usual signs and symptoms of aseptic meningitis are fever, headache, vomiting, photophobia, and stiff neck. Usual signs and symptoms of encephalitis include altered consciousness, seizures, and focal deficits. These clinical features are so universal and so nonspecific that diagnosis of the precise virus causing the infection is seldom possible. There are also few diagnostically specific laboratory tests. In most cases, a complete blood count is normal. Opening pressure of the CSF usually is elevated. The CSF white blood cell counts range from a few cells to more than 1000 cells/mL. Early on, neutrophils may be present, but after 48 hours lymphocytes predominate. A moderately elevated protein level often is found. Glucose concentration usually is normal, but cases of mumps or HSV have been associated with hypoglycorrhachia. Gram stain is negative. In all patients with presumed viral meningitis or encephalitis, an acute serum should be obtained for serologic studies and CSF sent for virus culture. Isolation of virus from the CSF may be possible in many viral infections (Table 64-4), especially the enteroviruses. Throat washings and stool specimens may be positive in some viral infections, but one should be cautious in interpreting positive cultures outside of the CNS because they may reflect chronic or previous infection rather than the acute episode. In the case of serum, whether the patient recovers or continues to

of Viral Meningoencephalitis

Anent

TvDical Clinical Findinm or Historv

Season and Eiidemiolonv

Summer and fall; epidemic and sporadic Myocarditis, pleurodynia, rash No seasonality; sporadic High-risk populations, mononucleosis symptoms Winter; sporadic Contact with rodents Spring and summer; sporadic Parotitis No seasonality; sporadic Focal neurologic deficits No seasonality; sporadic Primary genital lesions No seasonality; sporadic Characteristic rash, cerebellar ataxia No seasonality; sporadic Mononucleosis syndrome, immunosuppressed No seasonality Fowl neurologic Summer; epidemic Mosquito-borne, seizures Summer; epidemic Mosquito-borne, syndrome of inappropriatesecretion of antidiuretic hormone Summer; epidemic North Central states, seizures Bunyaviridae (California) No seasonality; sporadic Prior respiratory symptoms Adenovirus No seasonah: sporadic Historv of animal bite: hvdroohobia Rabies (From Creenberg 5:viral infections. In Kelley WN (ed): Textbook of Internal Medicine. 2nd Ed. JB Lippincott, Philadelphia, 1992, with permission.)

Enteroviruses Human immunodeficiencyvirus Lymphocytic choriomeningitis Mumps Herpes simplex type 1 Herpes simplex type 2 Varicella-zoster virus Epstein-Barr virus/cytomegalovirus Human herpesvirus 6 Togaviridae (eastern or western equine) flaviviridae (St. Louis)

468

Immune and Infectious Disease

Viral Infections

significant sequelae have been reported in agammaglobulinemic patients with enteroviruses. In a few of these cases, treatment by intravenous and intrathecal immunoglobulin has been beneficial.

TABLE64-4. Viral Diagnosis of Aseptic Meningitis Syndrome

and Encephalitis WNS

Adenovirus Arboviruses Coronaviruses Cytomegalovirus Enteroviruses Epstein-Barr virus Herpes simplex type 1 Herpes simplex type 2 Human herpesvirus 6 Human immunodeficiency virus Influenza Lymphocytic choriomeningitis Measles Mumps Parainfluenza Rabies Rotavirus Rubella Varicella zoster virus

Tissue Culture

Antigen Detection

Serology

+++ ++ + +++ +++ + +++ +++ ++ ++ ++ + ++ + +++ + + ++ +++

+ + + +++ + + ++ +-+ +++ ++ + + + ++ ++ +++ + ++

+++ +++ + +++ ++ +++ +++ + -+ + +++ +++ ++ +++ ++ + ++ +++ +++ +++

Symbols: +, method not available or research laboratory only; + +, method available in specialized reference laboratories; + + +, method used in most virology laboratories.

be ill over several weeks, if virus cultures are negative, a convalescent serum should be obtained and both the acute and convalescent samples tested for antibody titers. An exception is arbovirus encephalitis, in which a single high titer in an acute phase serum may be diagnostic. Newer techniques are available for detecting many viruses using immunofluorescence, polymerase chain reaction (PCR), and enzyme immunoassay. These newer techniques, although not readily available, will soon provide the clinician with more rapid and specific diagnosis of viral meningitis and encephalitis.

SPECIFIC VIRUSES THAT CAUSE MENINGITIS OR ENCEPHALITIS Enteroviruses Enteroviruses cause more than 80% of identified cases of the aseptic meningitis syndrome. These viruses appear to be transmitted by the fecal-oral route. Infections occur worldwide and year-round but peak during the summer, are more common in young infants and children than in adults, and may occur sporadically or epidemically. Only a few types are common, although many serotypes may cause aseptic meningitis or encephalitis. The clinical presentation of the infections includes fever, malaise, nausea, vomiting, pharyngitis, signs of meningeal irritation, and occasionally a maculopapular rash. Infants may not present with these typical signs and symptoms, often showing only irritability or a change in behavior. Clues to identifying an enterovirus meningitis or encephalitis are time of year (summer), presence of other cases in the community, presence of exanthems, mild pericarditis or conjunctivitis, or pleurodynia. Most laboratory tests are not helpful. Initially, the CSF may show a polymorphonuclear predominance, but in approximately 66% of cases there is a shift to lymphocytes in the CSF during the first 6 to 48 hours. In approximately 15% of cases the CSF shows low glucose levels. Diagnosis can be most readily made by culturing the CSF for virus. Newer tests of the CSF for PCR detecting viral RNA appear to be more sensitive than culture. Treatment is supportive and, although late sequelae have been reported, most patients recover uneventfully. However,

Arboviruses The arboviruses that infect humans in the United States include western equine encephalitis (WEE), eastern equine (EEE), Venezuelan equine encephalitis (VEE), St. Louis encephalitis (SLE), and California encephalitis (CE). There are marked geographic differences between these agents: WEE extends from the West Coast to the Midwestern and Southern United States, EEE extends from the Atlantic coast to the Gulf Coast, VEE is found in the Southern states, SLE is widely distributed among many states, and CE is found in the Eastern and north central United States. West Nile virus, a flavivirus, has recently caused an epidemic of encephalitis and dengue-like illness in the Northeastern United States. This previously unrecognized airborne disease in the Western Hemisphere may be an emerging infectious disease in the coming years. Deaths have been reported for all the arboviruses, especially in very young children and older adults. Mosquitos and birds are the animal hosts for WEE, EEE, and SLE. Clinically, there are few clues to identifylng an arbovirus encephalitis. Diagnosis of these infections is based on serologic tests because these viruses are not easily cultured. A presumptive diagnosis may be made with a high titer in an acute phase serum sample. Treatment is supportive because no specific antiviral agent is effective. Severe neurologic sequelae have been reported in many patients with SLE and EEE but are rare in patients with VEE and CE. Herpes Simplex Type 1 and Type 2 HSE presents with altered levels of consciousness and either focal or diffuse neurologic signs and symptoms, especially hallucinations, personality change, and headache. Focal or generalized seizures occur in approximately 50% of all cases. Electroencephalography (EEG) may show a periodic spike-slow wave activity in the temporal lobe, and computed tomography (CT) scans or magnetic resonance imaging (MRI) may show contrast enhancement and mass effect, especially in the frontotemporal areas of the brain. In many patients, CSF shows a lymphocytic pleocytosis and red blood cells. Rarely is HSV-1 cultured from CSF in patients with HSE, and diagnosis is based on detection of the virus by brain biopsy or, more recently, by amplification of HSV DNA in the CSF of patients by PCR. CSF PCR analysis is accepted in place of brain biopsy for diagnosis of HSE. Acyclovir, when added to basic supportive management and treatment of increased intracranial pressure, has been shown to reduce the morbidity and mortality of severe cases of HSE. Acyclovir 10 mg/kg should be given every 8 hours for 2 weeks. It is most effective in patients begun on therapy before coma. HSV-2 can cause aseptic meningitis. Evidence of acute genital tract infection with HSV-2 often is found at the time of the neurologic infection. Although the genital disease tends to recur, the meningitis seldom relapses.

Other Viruses Acute HIV infection has been associated with the aseptic meningitis syndrome. Often, the diagnosis can be made only by detection of p24 antigen in the CSF or viral RNA levels because

Chapter 65

Herpes Simplex Encephalitis

469

late conversion of enzyme-linked immunosorbent assay and Western blot serologic tests occurs several weeks later. Patients with high-risk behavior should be suspected of having acute HIV meningitis. Less common causes of meningoencephalitis include LCM and the group of other herpesviruses such as CMV, EBV, and VZV. Each of these viruses can be diagnosed using a combination of serologies and virus cultures. Laboratory diagnosis of EBV CMV, VZV, and JC virus infection of the CNS by PCR analysis has excellent specificity and very good sensitivity. No specific epidemiology is associated with these viruses, except for the exposure to animals in LCM and the appehance of the typical chicken pox or shingles lesions in patients with VZV meningoencephalitis.

meningitis has increased in adults in recent years, and it may occur as an isolated finding separate from pulmonary or disseminated infection. A lymphocyte predominance appears in the spinal fluid, and the protein levels range from 100 to 500 mg/dL. The CSF glucose level often is below 40 mg/dL in half the patients, and only in 10% to 40% of patients are there acid-fast bacilli on microscopic examination of the CSF. Although ring-enhancing or other inflammatory lesions may be demonstrated on CT or MRI scans, these are not always present and not specific to tuberculosis. Thus, in some cases it may be necessary to initiate empirical therapy when clinical suspicion and laboratory data suggest possible tuberculous meningitis.

DIFFERENTIAL DIAGNOSIS

TREATMENT

There are many nonviral causes of meningitis and encephalitis, which can be confused clinically with viral infections. Such nonviral causes include the following:

If the initial CSF findings are compatible with viral meningitis or encephalitis, treatment consists of close observation and supportive therapy. Specific antiviral therapy for the patient with aseptic meningitis is available for herpes simplex viral infections.

Leptospirosis (Weil’s disease) Tuberculosis Toxoplasmosis Rocky Mountain spotted fever Mycoplasma infection Lyme disease Syphilis Cryptococcosis Histoplasmosis Cysticercosis Systemic lupus erythematosus Granulomatous angiitis Uveomeningoencephalitis (Vogt-Koyanagi-Harada syndrome) Behget’s disease Whipple’s disease Sarcoidosis Mollaret’s disease The differentiationof viral from nonviral causes of meningitis and encephalitis is important because there is effective treatment for bacteria, spirochetes, Rickettsia, Mycoplasma, fungi, and protozoa. In addition, noninfectious causes such as collagen vascular disease, sarcoidosis, and tumor have also been reported to give a similar picture. Tuberculous meningitis is one of the most serious mimics of viral meningitis or encephalitis. The incidence of tuberculous

65

SUGGESTED READINGS Bale JF: Viral encephalitis. Med Clin North Am 7725, 1993 Chesky M, Scalco R, Failace L et ak Polymerase chain reaction for the laboratory diagnosis of aseptic meningitis and encephalitis. Arq Neuropsiquiatr 58:836, 2000 Devetag FC, Boscariolo L Cytomegalovirus meningoencephalitis with paroxysmal course in immunocompetent adults: a new nosographical entity. Clinical, diagnostic and therapeutic correlations, and pathogenetic hypothesis. Eur Neurol 44:242, 2000 Gubler DJ, Campbell GL, Nasci R et ak West Nile virus in the United States: guidelines for detection, prevention, and control. Viral Immuno1 13:469, 2000 Rantalaiho T, Farkkila M, Vaheri A, Koskiniemi M: Acute encephalitis from 1967 to 1991. J Neurol Sci 184169, 2001 Read SJ, Kurtz J BLaboratory diagnosis of common viral infections of the central nervous system by using a single multiplex PCR screening assay. J Clin Microbiol371352, 1999 Rotbart HA: Viral meningitis. Semin Neurol20277, 2000 Spanos A, Harrell FE Jr, Durack D T Differential diagnosis of acute meningitis: an analysis of the predictive value of initial observations. JAMA 262:2700, 1989 Taiiber MG, Moser B: Cytokines and chemokines in meningeal inflammation: biology and clinical implications. Clin Infect Dis 28:1, 1999 Tsai T F Arboviral infections in the United States. Infect Dis Clin North Am 5:73, 1991

Herpes Simplex Encephalitis Percy N. Karanjia

The herpes simplex family of viruses is a group of ubiquitous, complex, double-stranded DNA viruses that are responsible for a variety of acute infections of the central nervous system (CNS). These include herpes simplex encephalitis (HSE), meningitis, myelitis, and radiculitis. Herpes simplex type I (HSV-1) is responsible for most cases of HSE, and herpes simplex type I1 (HSV-2) is the usual agent for herpetic myelitis and radiculitis in

adults and for neonatal HSE. Both agents have been implicated in aseptic meningitis. Primary infection with HSV-1 is presumed to occur in childhood or early adulthood, resulting in gingivostomatitis and, uncommonly, keratitis or skin lesions. Antibodies to HSV-1 are detectable in at least 75% of the world’s population by adolescence. HSV-1 is transmitted most commonly in saliva, and HSV-2

Chapter 65

Herpes Simplex Encephalitis

469

late conversion of enzyme-linked immunosorbent assay and Western blot serologic tests occurs several weeks later. Patients with high-risk behavior should be suspected of having acute HIV meningitis. Less common causes of meningoencephalitis include LCM and the group of other herpesviruses such as CMV, EBV, and VZV. Each of these viruses can be diagnosed using a combination of serologies and virus cultures. Laboratory diagnosis of EBV CMV, VZV, and JC virus infection of the CNS by PCR analysis has excellent specificity and very good sensitivity. No specific epidemiology is associated with these viruses, except for the exposure to animals in LCM and the appehance of the typical chicken pox or shingles lesions in patients with VZV meningoencephalitis.

meningitis has increased in adults in recent years, and it may occur as an isolated finding separate from pulmonary or disseminated infection. A lymphocyte predominance appears in the spinal fluid, and the protein levels range from 100 to 500 mg/dL. The CSF glucose level often is below 40 mg/dL in half the patients, and only in 10% to 40% of patients are there acid-fast bacilli on microscopic examination of the CSF. Although ring-enhancing or other inflammatory lesions may be demonstrated on CT or MRI scans, these are not always present and not specific to tuberculosis. Thus, in some cases it may be necessary to initiate empirical therapy when clinical suspicion and laboratory data suggest possible tuberculous meningitis.

DIFFERENTIAL DIAGNOSIS

TREATMENT

There are many nonviral causes of meningitis and encephalitis, which can be confused clinically with viral infections. Such nonviral causes include the following:

If the initial CSF findings are compatible with viral meningitis or encephalitis, treatment consists of close observation and supportive therapy. Specific antiviral therapy for the patient with aseptic meningitis is available for herpes simplex viral infections.

Leptospirosis (Weil’s disease) Tuberculosis Toxoplasmosis Rocky Mountain spotted fever Mycoplasma infection Lyme disease Syphilis Cryptococcosis Histoplasmosis Cysticercosis Systemic lupus erythematosus Granulomatous angiitis Uveomeningoencephalitis (Vogt-Koyanagi-Harada syndrome) Behget’s disease Whipple’s disease Sarcoidosis Mollaret’s disease The differentiationof viral from nonviral causes of meningitis and encephalitis is important because there is effective treatment for bacteria, spirochetes, Rickettsia, Mycoplasma, fungi, and protozoa. In addition, noninfectious causes such as collagen vascular disease, sarcoidosis, and tumor have also been reported to give a similar picture. Tuberculous meningitis is one of the most serious mimics of viral meningitis or encephalitis. The incidence of tuberculous

65

SUGGESTED READINGS Bale JF: Viral encephalitis. Med Clin North Am 7725, 1993 Chesky M, Scalco R, Failace L et ak Polymerase chain reaction for the laboratory diagnosis of aseptic meningitis and encephalitis. Arq Neuropsiquiatr 58:836, 2000 Devetag FC, Boscariolo L Cytomegalovirus meningoencephalitis with paroxysmal course in immunocompetent adults: a new nosographical entity. Clinical, diagnostic and therapeutic correlations, and pathogenetic hypothesis. Eur Neurol 44:242, 2000 Gubler DJ, Campbell GL, Nasci R et ak West Nile virus in the United States: guidelines for detection, prevention, and control. Viral Immuno1 13:469, 2000 Rantalaiho T, Farkkila M, Vaheri A, Koskiniemi M: Acute encephalitis from 1967 to 1991. J Neurol Sci 184169, 2001 Read SJ, Kurtz J BLaboratory diagnosis of common viral infections of the central nervous system by using a single multiplex PCR screening assay. J Clin Microbiol371352, 1999 Rotbart HA: Viral meningitis. Semin Neurol20277, 2000 Spanos A, Harrell FE Jr, Durack D T Differential diagnosis of acute meningitis: an analysis of the predictive value of initial observations. JAMA 262:2700, 1989 Taiiber MG, Moser B: Cytokines and chemokines in meningeal inflammation: biology and clinical implications. Clin Infect Dis 28:1, 1999 Tsai T F Arboviral infections in the United States. Infect Dis Clin North Am 5:73, 1991

Herpes Simplex Encephalitis Percy N. Karanjia

The herpes simplex family of viruses is a group of ubiquitous, complex, double-stranded DNA viruses that are responsible for a variety of acute infections of the central nervous system (CNS). These include herpes simplex encephalitis (HSE), meningitis, myelitis, and radiculitis. Herpes simplex type I (HSV-1) is responsible for most cases of HSE, and herpes simplex type I1 (HSV-2) is the usual agent for herpetic myelitis and radiculitis in

adults and for neonatal HSE. Both agents have been implicated in aseptic meningitis. Primary infection with HSV-1 is presumed to occur in childhood or early adulthood, resulting in gingivostomatitis and, uncommonly, keratitis or skin lesions. Antibodies to HSV-1 are detectable in at least 75% of the world’s population by adolescence. HSV-1 is transmitted most commonly in saliva, and HSV-2

410

Immune and Infectious Disease

Viral Infections

is transmitted by genital contact. Primary CNS involvement is uncommon. After replication in epithelial tissue, HSV is believed to be transported to neurons by retrograde axoplasmic transport, where it remains latent. At autopsy, HSV has been detected in trigeminal, dorsal root, and autonomic ganglia. Host factors for reactivation of the virus have not been identified; the disease has been described in those with acquired immunodeficiency syndrome, but it is not common in this population. On reactivation, the virus may be transmitted to the periphery by orthograde axoplasmic transport, resulting in common herpes labialis. In rare instances, HSV may be transported to the orbitofrontal and temporal lobes of the brain by the olfactory nerves or dural branches of the trigeminal nerves; the result is a severe, necrotizing, hemorrhagic encephalitis that is often fatal.

should alert the clinician to the diagnosis. Headaches and fever (101’F to 104’F), evolving over a few days, are the usual initial symptoms, sometimes preceded by a mild flulike illness. Occasionally, the onset of the disease may be subacute or even chronic. There is nothing about the headache that differentiates it from less severe illnesses. Alteration of consciousness occurs invariably, ranging from a minor clouding of consciousness to coma. Subtle

W

Percentage of Patients

Symptoms

Change in consciousness Fever Change in personality Headache Seizures Autonomic changes Aphasia Amnesia Hallucinations

EPIDEMIOLOGY HSE constitutes approximately 10% to 20% of all cases of acute encephalitis. It shows no seasonal or geographic preference and is equally prevalent in both men and women. The disease occurs at all ages, although most adult cases are seen in patients over 50 years.

TABLE 65-1. Clinical Features of HSE

W

95 90 85 80 65 60 50 25 20

TABLE 65-2. Initial CSF Findings in HSE

CLINICAL FEATURES

Opening pressure White blood cells

No clinical features are pathognomonic for HSE (Table 65-1). However, the virus shows a predilection for the temporal and orbitofrontal lobes, resulting in a characteristic clinical picture that

Red blood cells Protein Glucose

Typical

Atypical

Elevated Lymphocytes

Normal Neutrophils Acellular Absent >I00mg/dL Low

50-1 00 WBC/mm3

Present 50-1 00 mg/dL

Normal

HF 70 W

.

U

V

~

FIG. 65-1. EEG showing PLEDs over the right temporal area (especially in leads 1-4,9, and 10) in a 26-year-old woman with HSE, seizures, and confusion. The background is slow and disorganized.

Chapter 65

Herpes Simplex Encephalitis

47 1

changes in personality, agitation, or frank psychosis are common. Partial or generalized seizures are common and may be difficult to control; status epilepticus may occur. Focal neurologic signs evolve over the next few days in approximately 50% of patients, of which language disorders and hemiparesis are the most common. Hallucinations of an olfactory and gustatory type or autonomic dysfunction caused by orbitofrontal involvement, and memory loss caused by temporal lobe involvement are characteristic, the latter usually being a striking late feature. On rare occasions a brainstem encephalitis occurs. The course of the untreated illness progresses over several days or weeks in the majority of patients, with severe cerebral edema leading to brain herniation and death.

DIAGNOSIS The diagnosis of HSE is urgent because the virus multiplies rapidly, and the prognosis depends on the stage of the patient when a treatment is begun. Although focal findings reflecting frontal and temporal lobe damage are characteristic, no clinical features reliably differentiate HSE from other forms of encephalitis. Laboratory tests that are useful in the diagnosis include cerebrospinal fluid (CSF) examination, electroencephalogram (EEG), computed tomography (CT) scanning, and magnetic resonance imaging (MRI). These tests are not specific for HSE but can be obtained readily in most community settings and, when taken in the context of an appropriate clinical picture, are highly suggestive of the diagnosis. Firm confirmation of the diagnosis requires brain biopsy or serologic evidence in the CSF. In most cases the CSF is abnormal (Table 65-2). The opening pressure often is raised. The leukocyte count is 50 to 100 cells/mm3 with lymphocytes generally predominant, although neutrophils may sometimes dominate early in the illness. Red blood cells often are present (40% or more), and some xanthochromia may be seen, which substantiates the necrotic nature of the virus and helps distinguish HSE from most other viral encephalitides. The protein level is moderately elevated-50 to 100 mg/dL early in the illness-but may be very high as the disease progresses and may remain elevated for several months. The glucose level usually is normal but is moderately depressed in 25% of cases. Mumps and varicella are other encephalitides that may show a low CSF glucose. Immunodiagnostic techniques using the polymerase chain reaction (PCR) to amplify viral DNA are highly sensitive and specific for HSV and should be obtained whenever possible. The clinician should be aware that both false-positive and falsenegative results may occur. About 95% of spinal taps performed within 1 to 2 days of symptom onset demonstrate a positive PCR. Serial examinations therefore are suggested only if the diagnosis is strongly suspected and the initial PCR is negative. Preliminary results are available in about 8 hours, but confirmation takes longer. The PCR may remain positive in the CSF for up to 5 days after acyclovir treatment is instituted. Tests to detect viral antigen in the CSF and intrathecal synthesis of HSV immunoglobulin G are also used in the diagnosis. Serum antibody analysis is of little use in the diagnosis because the general population has a very high prevalence of HSV antibodies, and a rise in titer may occur with a variety of non-HSV illnesses. Conversely, a fourfold rise in HSV antibodies in the CSF has a sensitivity and specificity of about 80%. If the patient fails to improve clinically, or if the initial CSF shows a predominance of neutrophils with a low glucose level, a repeat lumbar puncture must be performed to exclude bacterial

FIG. 65-2. Postcontrast T1 -weighted MRI scan showing typical enhancement of the parenchyma and cortical ribbon in the right temporal lobe in a 70-year-old woman with HSE.

infection. If there are no atypical features, the lumbar puncture should not be repeated because the CSF takes several weeks to normalize, and a worsening CSF profile with a rise in white blood cell count and protein may be seen despite clinical improvement, which may be misleading. The EEG is abnormal in about 85% of patients, with periodic, predominantly lateralized sharp or spike activity known as periodic lateralized epileptiform discharges (PLEDs) superimposed on a disorganized slow background localized over one or both temporal or frontal areas (Fig. 65-1). This EEG picture in a patient with encephalitis is very suggestive of the diagnosis. The CT scan may be normal early in the illness but 5 or 6 days later may show low attenuation lesions in one or both anterior and mesial temporal lobes or orbitofrontal lobes in 60% of patients. Areas of patchy hemorrhage are common; mass effect is common. The lesions show contrast enhancement caused by disruption of the blood-brain barrier after the first week. MRI is the imaging procedure of choice in HSE. It is more sensitive than CT in the early detection of HSE because it detects smaller quantities of edema, shows axial and coronal views, and is less susceptible to artifacts. MRI may show unilateral or bilateral abnormalities of the mesial temporal and orbitofrontal cortices even when the CT scan is normal. The T2-weighted images show signal hyperintensity in the temporal or orbitofrontal lobes (Fig. 65-2). Contrast enhancement of the parenchyma and cortical

472

Immune and Infectious Disease rn Viral Infections

ribbon is common. Methemoglobin, as evidence of hemorrhage, is also common. Radionuclide scans show increased uptake of the tracer over the temporal and frontal lobes but are rarely performed today because they give no useful additional information. The value of single photon emission tomography in HSE is unclear. Brain biopsy provides a definitive diagnosis in most cases if it is taken from an affected area. Because the disease is often asymmetrical, stereotactic biopsy under radiologic control is desirable. The material should be sent for histopathology, electron microscopy, immunologic studies, and cultures for viruses, bacteria, and fungi. Microscopically, areas of necrosis, hemorrhage, and polymorphonuclear infiltrates are seen in the more severely affected areas. Eosinophilic intranuclear inclusions (Cowdry A bodies) are seen in neurons and glial cells and are characteristic but are also seen with varicella-zoster, cytomegalovirus, and measles. Unfortunately, there is controversy regarding who should have a brain biopsy. The fear is that other treatable diseases masquerading as HSE may be missed because only 40% of patients undergoing a biopsy for HSE in early studies actually had the

disease. However, with the availability of MRI and the PCR in CSF, the likelihood of diagnostic errors has greatly diminished. Brain biopsy is not a benign procedure, despite the reported low complication rates (0% to 3%). Serious complications include hemorrhage and increased brain swelling, leading to herniation. Valuable time may also be lost before treatment is begun if one awaits a biopsy. Therefore, a biopsy should be reserved for the patient who has an atypical clinical, radiologic, or laboratory picture, who cannot undergo further testing, or who has not shown the anticipated clinical response to treatment. Immunosuppressed patients pose a different problem because they are known to harbor unusual illnesses; in this group, early biopsy is generally favored. The differential diagnosis of HSE includes other viral encephalitides, bacterial infections including tuberculosis, fungal infections, Q fever, and brain abscess. Cerebral infarction, tumors, and acute disseminated encephalomyelitis are other conditions that must be considered. The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes can masquerade as an atypical, recurrent form of HSE. Headache Fever Seizures Stupor Focal signs

Suspect HSE MRI/CT

Typical temporal lobe lesion

Edema

No edema

Normal

Atypical

Start acyclovir

Biopsy

1

I

t

Begin acyclovir

Begin acyclovir

1

1

Lower ICP

EEG

No PLEDS

1

Biopsy ~

Diagnostic of HSE

J

Acyclovir x 14 days

Typical

PLEDS

pntinus1

Continue

7

J.

A

1

EEWLP

Typical

J

Repeat imaging

Atypical Atypical

Biopsy

acyclovir

t

Improvement

No improvement

I

I

I

Continue

Biopsy

Treat accordingly

I

I

A FIG. 65-3. Algorithm for management of suspected HSE.

J.

Atypical

J

Biopsy

Chapter 66

Once the diagnosis of HSE is clinically suspected, the following procedures must be performed emergently (Fig. 65-3): Neuroimaging of the head, preferably by MRI. If this shows the typical temporofrontal lesion and no mass effect, proceed with lumbar puncture (LP) and send CSF for cell count, protein, glucose, cultures for bacteria, mycobacteria, cryptococcal antigen, and fungi. If mass effect is demonstrated on brain imaging, do not perform an LP. Instead, reduce intracranial pressure (ICP) with a 20-mg bolus of dexamethasone administered intravenously, followed by 4 mg every 4 hours. If the mass effect produces a midline shift of more than 3 mm, or if the patient continues to deteriorate or is comatose, admit the patient to the intensive care unit, intubate, and hyperventilate (to a Pco, of 28 to 30 mm Hg). Use a bolus of intravenous mannitol (50 to 100 g) if the imaging suggests incipient herniation, and alert the neurosurgeon. Obtain an open biopsy with brain decompression at the earliest possibility. If the CSF results are atypical, repeat the LP and proceed with a brain biopsy. Obtain an EEG. If the EEG is characteristic, proceed with acyclovir therapy and wait to see whether a clinical response occurs in the next 72 to 96 hours.

473

General management includes close attention to details of fluid and electrolyte balance as well as renal function. Frequent checks of neurologic function looking for signs of raised ICP, such as yawning, progressive drowsiness, pupillary asymmetry, and rise in blood pressure while pulse rate decreases, must be obtained. A neurologist or neurosurgeon must be informed immediately if there is any clinical deterioration.

PROGNOSIS HSE carries a mortality rate of 70% if untreated. Therapy with acyclovir decreases the mortality rate to 15% to 20%, but with vidarabine the mortality rate is 50%. Memory disturbance, altered personality, hemiparesis, and seizures are common sequelae, occurring in 50% or more of acyclovir-treated survivors. Despite the disability, many are able to return to near-normal lives. The prognosis is worse in older adults, in the immunocompromised, and in the patient who is comatose upon presentation. Relapse rarely occurs in the adequately treated patient. Should this happen, restart acyclovir at a higher dosage (15 mg/kg every 8 hours) for a longer time (3 weeks).

SUGGESTED READINGS

TREATMENT As soon as the diagnosis is suspected, even while definitive test

results are pending, start acyclovir, 10 mg/kg IV every 8 hours. After confirmation of HSE, acyclovir therapy should be continued for 2 weeks. Use vidarabine (15 mg/kg/day) intravenously if acyclovir cannot be administered for any reason. Unfortunately, vidarabine is neither as effective an agent as acyclovir nor as safe because it is insoluble and large volumes of fluid must be administered. Start anticonvulsants if seizures occur. Because seizures often are multiple, intravenous loading with fosphenytoin, 18 mg/kg given slowly over 30 minutes, followed the next day by 5 mg/kg/ day, is the fastest way to attain adequate anticonvulsant coverage. Status epilepticus, when it occurs, must be treated aggressively.

66

rn Varicella-ZosterVirus Infection

Aurelius E Herpes simplex encephalitis: early diagnosis and immune activation in the acute stage and during long-term follow-up. Scand J

Infect Dis (Suppl) 89:3, 1993 Domingues RB, Fink MCD, Tsanclis AMC et ak Diagnosis of herpes simplex encephalitis by magnetic resonance imaging and polymerase chain reaction assay of cerebrospinal fluid. J Neurol Sci 157:148, 1998

McGraith N, Anderson NE, Croxson MC et ak Herpes simplex encephalitis treated with acyclovir:diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 63:321, 1997 Whitley RJ: Herpes simplex virus infections of the central nervous system.

Drugs 42406, 1991 Whitley RJ, Cobbs CJ, Alford CA Jr et ak Diseases that mimic herpes simplex encephalitis: diagnosis, presentation and outcome. NIAID CollaborativeAntiviral Study Group. JAMA 262:234, 1989

Varicella-Zoster Virus Infection Yadollah Harati and Steven Lovitt

Primary infection by the highly contagious varicella-zoster virus (VZV), a DNA virus, produces chicken pox (varicella), described first in the ninth century A.D. by the Persian physician Rhazes. After the initial infection, the virus, in keeping with its nature as a herpes virus, becomes latent in multiple sensory ganglia for decades. (It appears that VZV ascends to sensory ganglia from the skin lesions of varicella.) The subsequent and delayed reactivation of VZV may cause many neurologic manifestations, such as Herpes zoster (shingles) Postherpetic neuralgia

W

W

Postherpetic dermatomal anesthesia Cranial neuropathies: cranial nerves VII, VIII (Ramsay-Hunt syndrome); 111, IV,VI (ophthalmoplegia); 11, V, IX,X Motor neuropathies Radiculopathies Diaphragmatic paralysis Myelitis Meningoencephalitis Cerebral vasculopathy Myositis Cystitis and urinary retention Colonic pseudo-obstruction (Ogilvie syndrome)

Chapter 66

Once the diagnosis of HSE is clinically suspected, the following procedures must be performed emergently (Fig. 65-3): Neuroimaging of the head, preferably by MRI. If this shows the typical temporofrontal lesion and no mass effect, proceed with lumbar puncture (LP) and send CSF for cell count, protein, glucose, cultures for bacteria, mycobacteria, cryptococcal antigen, and fungi. If mass effect is demonstrated on brain imaging, do not perform an LP. Instead, reduce intracranial pressure (ICP) with a 20-mg bolus of dexamethasone administered intravenously, followed by 4 mg every 4 hours. If the mass effect produces a midline shift of more than 3 mm, or if the patient continues to deteriorate or is comatose, admit the patient to the intensive care unit, intubate, and hyperventilate (to a Pco, of 28 to 30 mm Hg). Use a bolus of intravenous mannitol (50 to 100 g) if the imaging suggests incipient herniation, and alert the neurosurgeon. Obtain an open biopsy with brain decompression at the earliest possibility. If the CSF results are atypical, repeat the LP and proceed with a brain biopsy. Obtain an EEG. If the EEG is characteristic, proceed with acyclovir therapy and wait to see whether a clinical response occurs in the next 72 to 96 hours.

473

General management includes close attention to details of fluid and electrolyte balance as well as renal function. Frequent checks of neurologic function looking for signs of raised ICP, such as yawning, progressive drowsiness, pupillary asymmetry, and rise in blood pressure while pulse rate decreases, must be obtained. A neurologist or neurosurgeon must be informed immediately if there is any clinical deterioration.

PROGNOSIS HSE carries a mortality rate of 70% if untreated. Therapy with acyclovir decreases the mortality rate to 15% to 20%, but with vidarabine the mortality rate is 50%. Memory disturbance, altered personality, hemiparesis, and seizures are common sequelae, occurring in 50% or more of acyclovir-treated survivors. Despite the disability, many are able to return to near-normal lives. The prognosis is worse in older adults, in the immunocompromised, and in the patient who is comatose upon presentation. Relapse rarely occurs in the adequately treated patient. Should this happen, restart acyclovir at a higher dosage (15 mg/kg every 8 hours) for a longer time (3 weeks).

SUGGESTED READINGS

TREATMENT As soon as the diagnosis is suspected, even while definitive test

results are pending, start acyclovir, 10 mg/kg IV every 8 hours. After confirmation of HSE, acyclovir therapy should be continued for 2 weeks. Use vidarabine (15 mg/kg/day) intravenously if acyclovir cannot be administered for any reason. Unfortunately, vidarabine is neither as effective an agent as acyclovir nor as safe because it is insoluble and large volumes of fluid must be administered. Start anticonvulsants if seizures occur. Because seizures often are multiple, intravenous loading with fosphenytoin, 18 mg/kg given slowly over 30 minutes, followed the next day by 5 mg/kg/ day, is the fastest way to attain adequate anticonvulsant coverage. Status epilepticus, when it occurs, must be treated aggressively.

66

rn Varicella-ZosterVirus Infection

Aurelius E Herpes simplex encephalitis: early diagnosis and immune activation in the acute stage and during long-term follow-up. Scand J

Infect Dis (Suppl) 89:3, 1993 Domingues RB, Fink MCD, Tsanclis AMC et ak Diagnosis of herpes simplex encephalitis by magnetic resonance imaging and polymerase chain reaction assay of cerebrospinal fluid. J Neurol Sci 157:148, 1998

McGraith N, Anderson NE, Croxson MC et ak Herpes simplex encephalitis treated with acyclovir:diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 63:321, 1997 Whitley RJ: Herpes simplex virus infections of the central nervous system.

Drugs 42406, 1991 Whitley RJ, Cobbs CJ, Alford CA Jr et ak Diseases that mimic herpes simplex encephalitis: diagnosis, presentation and outcome. NIAID CollaborativeAntiviral Study Group. JAMA 262:234, 1989

Varicella-Zoster Virus Infection Yadollah Harati and Steven Lovitt

Primary infection by the highly contagious varicella-zoster virus (VZV), a DNA virus, produces chicken pox (varicella), described first in the ninth century A.D. by the Persian physician Rhazes. After the initial infection, the virus, in keeping with its nature as a herpes virus, becomes latent in multiple sensory ganglia for decades. (It appears that VZV ascends to sensory ganglia from the skin lesions of varicella.) The subsequent and delayed reactivation of VZV may cause many neurologic manifestations, such as Herpes zoster (shingles) Postherpetic neuralgia

W

W

Postherpetic dermatomal anesthesia Cranial neuropathies: cranial nerves VII, VIII (Ramsay-Hunt syndrome); 111, IV,VI (ophthalmoplegia); 11, V, IX,X Motor neuropathies Radiculopathies Diaphragmatic paralysis Myelitis Meningoencephalitis Cerebral vasculopathy Myositis Cystitis and urinary retention Colonic pseudo-obstruction (Ogilvie syndrome)

474

Immune and Infectious Disease W

Viral Infections

Herpes zoster (shingles), the most common neurologic complication, has been recognized from antiquity as a creeping eruption (herpes, Greek, “to creep”) that girdles the body (zoster, Greek, “girdle, belt”); from this characteristic feature the common name shingles is derived (n’ngulurn,Latin, “a girdle”). Exactly why and by what mechanism the virus remains latent for so long, what reawakens it from latency, and why such reactivation occurs infrequently when compared with herpes virus infection, is not clear.

EPIDEMIOLOGY Unlike varicella, herpes zoster is a sporadic disease occurring at all ages but mainly among older adults. The disease is uncommon in children, constant in frequency between 20 and 50 years of age (2.5 cases per 1000 annually), and thereafter doubles its incidence each decade. The cumulative risk of zoster, if one lives to age 80, is about 15%. The recurrence of herpes zoster infection, unlike herpes simplex, is uncommon, and only about 2% of patients experience a second episode. There is often no apparent provoking factor, but well-known predisposing factors include immunosuppression by cytotoxic drugs, corticosteroid treatment, radiation therapy, acquired immunodeficiency syndrome (AIDS), organ transplantation, systemic disorders such as systemic lupus erythematosus (SLE), and, in particular, malignancies. In particular, the association with lymphomas and leukemia is very close. In one series, 7.9% of 303 patients with lymphoma and leukemia developed zoster, and of these 40% had Hodgkin’s disease. The association between malignancy and the risk of developing zoster should not lead to the converse notion that patients with zoster are more likely to have underlying malignancy. Population-based studies have disproved this assumption, thereby obviating thorough evaluation of otherwise healthy patients with zoster to search for an underlying malignancy. Immunosuppression predisposes the patient to spread of the virus beyond the dermatome and sensory ganglia and into the central nervous system or systemically. In human immunodeficiency virus (HIV) infection, one of the most common causes of immunodeficiency in recent years, the incidence of herpes virus is seven times greater than that of the general population. Diagnosis of disseminated zoster in a young, previously healthy patient should be an indication for HIV testing. CLINICAL FEATURES

The first sign of herpes zoster often is a gradual onset of unilateral hyperesthesia or paresthesia of the affected dermatome. This is soon followed by dermatomal pain of variable intensity. During this phase, which usually lasts about 1 or 2 days but may be prolonged up to 21 days, the pain may be misdiagnosed as myocardial infarction, pleurisy, appendicitis, ovarian cyst, herniated intervertebral disk, thrombophlebitis, duodenal ulcer, cholecystitis, or thoracoabdominal diabetic neuropathy, depending on the dermatome involved. However, the zoster pain usually is associated with pruritus and hypersensitivity of the involved dermatome to touch. The dermatomes most commonly involved are from T3 to L3, with T5 and T6 having the highest affliction (about 60%). The ophthalmic division of the trigeminal nerve is the most frequently affected cranial nerve (about 15%). In approximately 5% of patients fever, headache, mild stiff neck, regional adenopathy, and nausea may coincide with the painful

phase and precede the development of rash, but these symptoms do not seem to be correlated with the likelihood of any complications, including postherpetic neuralgia. The rash usually appears as erythematous macules, papules, and then vesicular eruptions in a beltlike distribution following one or, rarely, multiple sensory dermatomes. They become turbid and begin to crust within 5 to 10 days and occasionally become pustular or hemorrhagic, often with superficial necrosis. The crusts usually fall off in 2 to 3 weeks, commonly leaving scars and increased or decreased pigmentation with or without skin anesthesia. Weakness and denervation of intercostal and abdominal muscles, which may pass unnoticed, sometimes develop. In the immunocompromised host, especially a patient with AIDS, this time course may become protracted, and a picture of chronic zoster emerges. Dissemination reflects a viremia and can be arbitrarily defined as the appearance of more than 20 lesions outside the primary and adjacent dermatomes. In about one half of patients with disseminated lesions, other neurologic complications (listed earlier in this chapter), visceral involvement (particularly pneumonitis), and ocular involvement contribute to the morbidity and mortality. Even with aggressive antiviral therapy, the mortality rate in such patients is in the range of 4% to 15%. Involvement of the ophthalmic branch of the trigeminal nerve may be complicated by local spread, causing eye damage, cranial nerve palsies, meningoencephalitis, postherpetic neuralgia, and delayed cerebral angitis and cerebral infarction. Ocular damage occurs in nearly 50% of such patients, especially when it affects the nasociliary nerve branch (supplying sensation to the eyeball and the tip of the nose), resulting in corneal scarring and inflammation. The presence of the vesicles at the end of the nose (Hutchinson sign) indicates involvement of this branch and should prompt ophthalmologic consultation. In addition to retinal vasculitis, necrotizing retinitis, and arterial sheathing, optic neuritis and retrobulbar neuritis may occur. Untreated patients have an extremely poor prognosis, and retinal detachment resulting from retinal holes may subsequently develop. About 64% of patients with retinal necrosis become legally blind. The clinical triad of eruption on the ear and within the ear canal, hearing impairment, and ipsilateral facial paralysis, described by J. Ramsay Hunt, may extend to other areas, including the second and third cervical root, oral and nasopharyngeal region. The earliest otologic symptom usually is unilateral pain in the ear, and before the development of any objective finding, the diagnosis may be difficult to secure. Tinnitus, vertigo, nausea, often incapacitating gait unsteadiness, and occasionally a Mhihrel i e syndrome may develop. With the appearance of the rash and facial palsy the diagnosis becomes clear. The facial weakness in Ramsay Hunt syndrome is more severe than Bell’s palsy and, when complete, recovers less frequently. Hearing deficit may be partial or total, and often there is reduced speech discrimination. Ramsay Hunt syndrome is believed to result from herpetic inflammation of the geniculate ganglion, the somatic sensory locus of the facial nerve. Involvement of peripheral motor nerves or nerve roots resulting in paralysis varies from 0.5% to 31% and is more common in older adults and in association with malignancies. Motor weakness nearly always follows the cutaneous lesions, the time interval between the two commonly being no more than 2 to 3 weeks. Within hours or days the weakness reaches its peak level with no further progression or spread to other muscles. Involvement of upper extremities, especially C5-C6 segments, occurs

Chapter 66

twice as often as in lower extremities. In patients with a motor neuropathy of the limbs, about 50% to 70% have complete functional recovery. When the phrenic nerve is involved with herpes zoster, paralysis of the hemidiaphragm occurs. A neurogenic bladder caused by involvement of motor or sensory nerves innervating the bladder or sacral segments of the spinal cord can develop after cutaneus eruption in sacral dermatomes. Gastrointestinal visceral motor complications manifesting as paralytic ileus, colonic pseudo-obstruction (Ogilvie syndrome), or localized colonic spasm may occur after lumbar and sacral segment involvement. Although the prognosis of this manifestation of herpes zoster generally is good, its recognition is extremely difficult when the preceding cutaneous eruptions are not reported or noticed. Myelitis, of variable extent, occurs in less than 1% of cases of herpes zoster and results from direct viral invasion of the spinal cord from dorsal root ganglia. It usually follows the rash of thoracic dermatomes by a few days or up to 10 weeks. However, it can precede the rash and cause diagnostic difficulties, necessitating imaging and myelographic studies to exclude other causes. Prominent weakness and back pain may be present, but a sensory level occurs in less than half of patients. The cerebrospinal fluid (CSF) examination usually discloses mononuclear pleocytosis, elevated protein, and normal glucose levels. At least three types of brain involvement may complicate herpes zoster: diffuse encephalitis, focal parenchymal infection, and vasculitis. Older adults and immunodeficient patients may present with acute encephalitis a few days after the cutaneous rash. The clinical picture is that of an acute or subacute delirium accompanied by CSF pleocytosis, with few focal features. Again, the encephalitis may precede the skin eruption, creating diagnostic difficulties. At the onset of encephalitis fever is common, and headache, nuchal rigidity, and ataxia are also common. The electroencephalogram shows diffuse slow-wave activity, and about 10% of patients have seizures. In 94% of patients with clinical encephalitis, VZV antibody, measured by indirect membrane immunofluorescence, is present in the CSF at a titer of 1:2 or more. Most patients with encephalitis recover if other complications of the disease do not intervene. Focal encephalitis is seen in immunosuppressed patients and resembles progressive multifocal leukoencephalopathy, with cerebral lesions mainly involving the white matter. Its onset may be temporally remote from the cutaneous rash or occur without the presence of skin eruption. It may be associated with vasculopathy and focal infarction. Brain biopsy may be needed for accurate diagnosis. Cowdry type A intranuclear inclusions on microscopic examination and visualization of herpes virus nucleocapsids by electron microscopy confirm the diagnosis. Delayed cerebral vasculitis involving the internal carotid artery or its major branches, resulting in a catastrophic onset of hemiplegia, may occur after ophthalmic division zoster. The delay between the rash and onset of cerebral dysfunction varies from none to as long as 6 months, with a mean interval of 7 weeks. The syndrome results from direct viral invasion of the arterial wall by viral spread from the infected ganghon or a delayed granulomatous reaction. POSTHERPETIC NEURALGIA The syndrome of postherpetic neuralgia (PHN) is defined solely by the persistence of pain after herpes zoster. A conservative definition is when pain in the affected region lasts longer than 3

Varicella-Zoster Virus Infection

475

months after crusting of the skin lesions. PHN occurs in about 10% to 15% of all patients with herpes zoster and is the most feared complication of this condition. The incidence of PHN progressively increases to more than 60% in patients over age 60. However, the symptoms gradually disappear in most and are still present at 6 months in only 13% of those older than 60. In some patients, however, PHN persists for years or even a lifetime. PHN is more common after ophthalmic herpes zoster than it is after spinal segment involvement. The more severe the initial herpes zoster involvement, the greater the likelihood of the pain becoming chronic. Pain usually is described as a constant nagging, burning, aching, tearing, and itching on which may be superimposed shocks and jabs. Many patients describe “tenderness” (allodynia) even with light contact with clothing or hyperpathia superimposed on the continuous component of the pain. The misery of patients is such that PHN is known in Danish as Helvedesild, meaning “hell-fire.’’ The differential diagnosis of PHN should not be difficult. Almost all patients describe the acute episode of herpes zoster and manifest pigmentary changes in the skin. However, the diagnosis of PHN after herpes zoster in the absence of skin rash, known as zoster sine herpete, is difficult to establish. The existence of this form of herpes zoster has been questioned, but recent studies demonstrating VZV DNA in the CSF of several patients tends to support this syndrome as a clinical variant of PHN. However, the diagnosis must be made only after other causes of radiculopathy, such as nerve compression and diabetic thoracoabdominal neuropathy, are excluded. TREATMENT Treatment of individual patients must take into account their background risk for particular complications (Table 66- 1). In some young immunocompetent patients with uncomplicated truncal or limb herpes zoster, the usual analgesics such as aspirin, local compresses such as calamine lotion, or local anestheticcontaining creams may be sufficient to reduce the intensity of pain. In older patients, amitriptyline and fluphenazine, alone or in combination, are useful. When the zoster appears to be complicated or herpes ophthalmicus or Ramsay Hunt syndrome has developed, it is prudent to start early treatment with oral antiviral agents such as acyclovir, 600 to 800 mg five times per day for 10 days, or famciclovir 500 to 750 mg three times a day. Although there has been no controlled clinical trial of antiviral therapy in cases of myelitis, encephalitis, or cerebrovascular diseases, in such cases it is best to administer acyclovir intravenously because of its superior bioavailability to the oral form. In herpes ophthalmicus, when acyclovir is started within 7 days after the rash, the incidence of corneal ulceration and uveitis is diminished, but that of PHN is not altered. Similar treatments, when given to immunocompetent and immunocompromised patients with truncal zoster, result in a slightly faster relief from pain and shorter healing time of lesions but has no significant effect on PHN. Valacyclovir and famciclovir have been shown to be as effective as or more effective than acyclovir in treating acute herpes zoster and have a more convenient dosing schedule. They also have a modest effect on shortening the duration of PHN. Famciclovir, a prodrug of penciclovir, is readily absorbed after oral administration. Penciclovir is similar to acyclovir in terms of structure, spectrum of activity, and mechanism of action. Famciclovir, when given at a dosage of 500 mg or 750 mg three times

416

Immune and Infectious Disease rn Viral Infections

TABU66-1. Treatment of Acute Herpes Zoster Young, immunocompetent, uncomplicated zoster Nonopioid analgesics Local anesthetic creams Supportive care Young, immunocompetent, with cephalic zoster Analgesics Local anesthetic creams Antidepressants Oral antiviral (famciclovir or acyclovir) Young, immunocompetent, complicated zoster (encephalitis, myelitis, vasculitis) Analgesics Local anesthetic creams Antidepressants Intravenous acyclovir Corticosteroids Elderly, immunocompetent, spinal or limb zoster Analgesics Local anesthetic creams Antidepressants with or without carbarnazepine Short-course oral corticosteroid for very severe pain Elderly, immunocompetent, cephalic zoster Analgesics Local anesthetic creams Antidepressants with or without carbamazepine Oral antivirals (famciclovir or acyclovir) Corticosteroids Any age, immunocompromised,with or without complications Analgesics Topical anesthetics Antidepressants with or without carbamazepine intravenous acyclovir

daily to immunocompetent patients with zoster, results in a modest improvement in cutaneus healing and shortens the duration of PHN to nearly half if no treatment was given. In comparison with acyclovir, the primary advantages of famciclovir are the more convenient dosing schedule and perhaps its ability to shorten the duration of PHN. Valacyclovir, the L-valyl ester of acyclovir, is converted rapidly to acyclovir after oral administration. Like famciclovir it is absorbed significantly better than acyclovir when taken orally, and fewer daily doses are needed. When compared with patients taking acyclovir, immunocompetent patients over 50 years old have 1 or 2 weeks less herpetic pain. The valacyclovir dosage is 1 g orally three times per day for 7 days. Metabolism of acyclovir, famciclovir, and valacyclovir is altered in patients with renal insufficiency, and the dosages of these medications should be lowered accordingly. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have been reported in patients with advanced HIV infection, allogenic bone marrow transplantation, and renal transplantation. All three viral agents may also cause malaise, diarrhea, nausea, vomiting, confusion, somnolence, headache, and paresthesias. Patients of any age who are immunocompromised, including those with cancer, cephalic zoster, or any complications of zoster, should be treated promptly, preferably within 24 hours of onset, with intravenous acyclovir to prevent systemic spread. The recommended intravenous dosage is 5 to 10 mg/kg infused every 8 hours for 5 days. However, it is not known whether such a regimen will reduce the outcome of motor weakness or zosterassociated cerebral vasculitis. In acyclovir-resistant patients with VZV infection, foscarnet 40 mg/kg intravenouslyevery 8 hours for 7 to 14 days is recommended. The drug is more expensive and generally less well tolerated than acyclovir, and controlled rates of infusion in large volumes of fluid are necessary. The place of corticosteroids in treating acute herpes zoster

remains uncertain. Randomized, double-blind trials of acyclovir for 7 or 21 days, with or without prednisone 40 mg/day, showed no additional benefit from steroid therapy in the rate of PHN, although steroids did seem to reduce the pain during the first 3 days of therapy when the inflammation was at its maximum. Conversely, in a randomized, prospective trial, only 1.6% of 255 patients with acute zoster who received epidural bupivacaine and methylprednisolone complained of pain after 1 year of follow-up, compared with 22.2% of the 345 patients who received intravenous acyclovir and prednisolone. Although these results are striking, until the results of confirmatory studies become available, the use of systemic and epidural corticosteroids and antiviral agents should be reserved for older immunocompetent patients with severe herpes zoster pain or for complicated zoster (e.g., encephalitis, myelitis, or vasculitis) in combination with antiviral drugs. Although dissemination after steroid use in immunocompetent patients has been observed anecdotally, it has not been observed in several controlled studies, suggesting that the therapy is safe in otherwise healthy patients. Treatments such as subcutaneous injections of local anesthetics, peripheral nerve block, paravertebral or epidural block, and sympathetic block, although anecdotally and empirically effective, cannot be recommended for routine use. PHN Treatment

Treating PHN is a formidable task (Table 66-2). Amitriptyline or nortriptyline are effective in pain relief in 44% to 67% of patients with PHN, an effect that is independent of the antidepressant properties of the drugs. The dosage can be gradually increased (10 mg/day at bedtime) until pain relief or a maximum dosage of 150 mg/day is reached. Gabapentin and specific 5-hydroxytryptamine (5HT) reuptake blockers (e.g., fluoxetine, paroxetine, and citalopram), which are safer in older adults and lack cardiovascular toxicity, may prove effective and should be tried if amitriptyline and nortriptyline are of no benefit or cause side effects. The addition of carbamazepine may alleviate shooting and jabbing pains. If these treatments are not successful or pain relief is only partial, a transcutaneous electrical nerve stimulation (TENS) unit along with physical therapy may prove helpful. However, in most patients the beneficial effect of TENS declines with time. Infiltration of lidocaine into painfully sensitive skin may result in TABLE66-2. Treatments Use for Postherpetic Neuralgia Nonpharmacologic Support and education Physical therapy Transcutaneous electrical nerve stimulation Cognitive and behavioral therapy Pharmacologic Topical anesthetics Antidepressants Anticonvulsants (carbamazepine, phenytoins, gabapentin) Topical capsaicin Lidocaine analogues (mexiletine) Intravenous or intrathecal lidocaine lntrathecal corticosteroids Opioids Surgical Sympathectomy Dorsal root entry zone lesions Dorsal column and brainstem stimulation Various nerve blocks Clyoanalgesia

Chapter 67 H CytomegalovirusInfection

temporary (a few hours to days) but significant improvement. Local applications of topical lidocaine (5% or 10% in cream, ointment, gel, or patches) have been effective in isolation and in combination with other therapies. Capsaicin cream, a substance P depleter, applied three times per day, results in modest pain relief after several days of application. Patients who do not respond to these therapeutic modalities may be given an oral lidocaine analogue, mexiletine, at a dosage of 150 mg two or three times a day, to be increased to a total of 600 mg daily. Gastrointestinal and central nervous system side effects of mexiletine may prohibit its use. Those with more severe and long-term PHN may benefit from intravenous lidocaine (5 mg/kg), resulting in pain relief comparable to intravenous morphine. However, the beneficial effect usually is short lasting. Intrathecal medications may also be of benefit; 91% of 89 patients who received intrathecal lidocaine and methylprednisolone had good to excellent pain relief, compared with 15% and 4% in lidocaine only and control groups. Opioids, used intravenously or orally, may result in substantial relief and should not be withheld from patients with severe PHN for fear of addiction liability, tolerance, or safety. Clinical experience in managing cancer pain and chronic nonmalignant pain indicates that addiction and tolerance to opioid analgesics are not relevant treatment complications. Upward titration of slowrelease oral morphine or oxycodone results in good to excellent pain control without significant effects on cognition. However, this treatment should be reserved for patients proven refractory to all other pharmacologic therapies.

67

477

Several invasive and surgical treatments have been used to treat PHN. Acupuncture, nerve block, dorsal column and brain stimulation, dorsal root entry zone operation, ganglionectomy, sympathetic block, and cryoanalgesia are ineffective or provide only transient relief at much greater risk of morbidity. Only patients who are truly refractory to all other treatment modalities should be considered for ablative surgeries.

SUGGESTED READINGS Anonymous: Varicella-zoster virus infection: new insights into pathogenesis and postherpetic neuralgia. Ann Neurol 35S1, 1994 Galer B: Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch results of an enriched enrollment study. Pain 80:533-538, 1999 Gilden DH, Wright RR, Schneck SA et al: Zoster sine herpete, a clinical variant. Ann Neurol 35:530, 1994 Hirschmann yV: Herpes zoster. Semin Neurol 12:322, 1992 Kotani N Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 34331514-1519,2000 Pasqualucci A Prevention of post-herpetic neuralgia: acyclovir and prednisolone versus epidural local anesthetic and methylprednisolone. Acta Anaesthesiol Scand M.910-918, 2000 Rowbotham M: Treatment of postherpetic neuralgia. Semin Dermatol 11:218, 1992

Straus SE, Ostrove JM, Inchauspe G et al: Varicella-zoster infection. Ann Intern Med 108:221, 1988 Watson CPN Postherpetic neuralgia. Neurol Clin 7:231, 1989

Cytomegalovirus Infection Diana L. Rodriguez

Cytomegalovirus (CMV) is a ubiquitous agent that commonly infects people of all ages, geographic locations, and socioeconomic and cultural backgrounds. Human CMV is a species-specific, double-stranded DNA herpesvirus that is widely disseminated in nature and is capable of remaining latent in the host. Most CMV infections are subclinical; however, clinical illness may range from mild to fatal.

EPIDEMIOLOGY CMV infections occur worldwide and are influenced by many factors, including age, geographic location, cultural and socioeconomic status, and child-rearing practices. CMV is the most common cause of congenital and perinatal viral infections throughout the world. The incidence is not seasonal, and there is no sexual predilection. CMV may be acquired congenitally, perinatally, or postnatally, with postnatal acquisition being highest in early childhood, adolescence, and during the childbearing years. Approximately 1% of all newborns are congenitally infected with CMV; the incidence is highest in populations with low standards of living. Infection of the fetus may occur via primary (newly acquired) or recurrent (reactivated) maternal CMV infection. Although most newborns congenitally infected with CMV are likely to be asymptomatic, symptoms and sequelae are much

more common in infants whose mothers experienced a primary, rather than a recurrent, CMV infection during pregnancy. Perinatal infections are much more prevalent than congenital infections because of more potential exposure via the mother’s cervicovaginal secretions, urine, saliva, and breast milk. The usual incubation period for perinatal infection is 5 to 6 weeks. Children not congenitally or perinatally infected with CMV may be infected during toddler or preschool years. Infection is influenced by day-care attendance and low socioeconomic status of the family. In developing countries and in lower socioeconomic populations, more than 80% of children acquire CMV infection by age 3 years, and almost all people have been infected by adulthood. CMV infection in adolescents and adults also varies according to geographic location and socioeconomic status. CMV infection increases in adolescence, presumably because of the more intimate physical contact that occurs in that age group; it may result from sexual transmission. It appears to be more prevalent in nonwhite races. CMV infection may be conferred via other routes, such as bone marrow and organ transplantation, blood transfusion, and very rarely by nonintimate person-to-person contact. It is the most common debilitating and dangerous viral infection in immunosuppressed bone marrow and organ transplantation recipients and in patients with acquired immunodeficiency syndrome (AIDS). An active infection with CMV occurs in almost all such patients

Chapter 67 H CytomegalovirusInfection

temporary (a few hours to days) but significant improvement. Local applications of topical lidocaine (5% or 10% in cream, ointment, gel, or patches) have been effective in isolation and in combination with other therapies. Capsaicin cream, a substance P depleter, applied three times per day, results in modest pain relief after several days of application. Patients who do not respond to these therapeutic modalities may be given an oral lidocaine analogue, mexiletine, at a dosage of 150 mg two or three times a day, to be increased to a total of 600 mg daily. Gastrointestinal and central nervous system side effects of mexiletine may prohibit its use. Those with more severe and long-term PHN may benefit from intravenous lidocaine (5 mg/kg), resulting in pain relief comparable to intravenous morphine. However, the beneficial effect usually is short lasting. Intrathecal medications may also be of benefit; 91% of 89 patients who received intrathecal lidocaine and methylprednisolone had good to excellent pain relief, compared with 15% and 4% in lidocaine only and control groups. Opioids, used intravenously or orally, may result in substantial relief and should not be withheld from patients with severe PHN for fear of addiction liability, tolerance, or safety. Clinical experience in managing cancer pain and chronic nonmalignant pain indicates that addiction and tolerance to opioid analgesics are not relevant treatment complications. Upward titration of slowrelease oral morphine or oxycodone results in good to excellent pain control without significant effects on cognition. However, this treatment should be reserved for patients proven refractory to all other pharmacologic therapies.

67

477

Several invasive and surgical treatments have been used to treat PHN. Acupuncture, nerve block, dorsal column and brain stimulation, dorsal root entry zone operation, ganglionectomy, sympathetic block, and cryoanalgesia are ineffective or provide only transient relief at much greater risk of morbidity. Only patients who are truly refractory to all other treatment modalities should be considered for ablative surgeries.

SUGGESTED READINGS Anonymous: Varicella-zoster virus infection: new insights into pathogenesis and postherpetic neuralgia. Ann Neurol 35S1, 1994 Galer B: Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch results of an enriched enrollment study. Pain 80:533-538, 1999 Gilden DH, Wright RR, Schneck SA et al: Zoster sine herpete, a clinical variant. Ann Neurol 35:530, 1994 Hirschmann yV: Herpes zoster. Semin Neurol 12:322, 1992 Kotani N Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 34331514-1519,2000 Pasqualucci A Prevention of post-herpetic neuralgia: acyclovir and prednisolone versus epidural local anesthetic and methylprednisolone. Acta Anaesthesiol Scand M.910-918, 2000 Rowbotham M: Treatment of postherpetic neuralgia. Semin Dermatol 11:218, 1992

Straus SE, Ostrove JM, Inchauspe G et al: Varicella-zoster infection. Ann Intern Med 108:221, 1988 Watson CPN Postherpetic neuralgia. Neurol Clin 7:231, 1989

Cytomegalovirus Infection Diana L. Rodriguez

Cytomegalovirus (CMV) is a ubiquitous agent that commonly infects people of all ages, geographic locations, and socioeconomic and cultural backgrounds. Human CMV is a species-specific, double-stranded DNA herpesvirus that is widely disseminated in nature and is capable of remaining latent in the host. Most CMV infections are subclinical; however, clinical illness may range from mild to fatal.

EPIDEMIOLOGY CMV infections occur worldwide and are influenced by many factors, including age, geographic location, cultural and socioeconomic status, and child-rearing practices. CMV is the most common cause of congenital and perinatal viral infections throughout the world. The incidence is not seasonal, and there is no sexual predilection. CMV may be acquired congenitally, perinatally, or postnatally, with postnatal acquisition being highest in early childhood, adolescence, and during the childbearing years. Approximately 1% of all newborns are congenitally infected with CMV; the incidence is highest in populations with low standards of living. Infection of the fetus may occur via primary (newly acquired) or recurrent (reactivated) maternal CMV infection. Although most newborns congenitally infected with CMV are likely to be asymptomatic, symptoms and sequelae are much

more common in infants whose mothers experienced a primary, rather than a recurrent, CMV infection during pregnancy. Perinatal infections are much more prevalent than congenital infections because of more potential exposure via the mother’s cervicovaginal secretions, urine, saliva, and breast milk. The usual incubation period for perinatal infection is 5 to 6 weeks. Children not congenitally or perinatally infected with CMV may be infected during toddler or preschool years. Infection is influenced by day-care attendance and low socioeconomic status of the family. In developing countries and in lower socioeconomic populations, more than 80% of children acquire CMV infection by age 3 years, and almost all people have been infected by adulthood. CMV infection in adolescents and adults also varies according to geographic location and socioeconomic status. CMV infection increases in adolescence, presumably because of the more intimate physical contact that occurs in that age group; it may result from sexual transmission. It appears to be more prevalent in nonwhite races. CMV infection may be conferred via other routes, such as bone marrow and organ transplantation, blood transfusion, and very rarely by nonintimate person-to-person contact. It is the most common debilitating and dangerous viral infection in immunosuppressed bone marrow and organ transplantation recipients and in patients with acquired immunodeficiency syndrome (AIDS). An active infection with CMV occurs in almost all such patients

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and usually becomes apparent clinically and virologically about 30 to 90 days after transplantation. Although reactivation, reinfection, and primary CMV infections all can produce symptoms in immunosuppressed transplant recipients, primary CMV infections are much more likely to be severe.

CLINICAL FEATURES Although most CMV infections are asymptomatic, they can range from minor to severe or even fatal. Common manifestations of CMV infection may include a mononucleosis syndrome or an interstitial pneumonitis. Less commonly, the virus may cause congenital or acquired chorioretinitis, hepatitis, various gastrointestinal illnesses, myocarditis, endocrinopathies, genitourinary system infections, or any of several neurologic illnesses, especially in immunosuppressed patients. CMV-induced mononucleosis can occur as a primary infection in both immunocompetent and immunocompromised patients, as well as a reactivation infection in immunocompromised patients. Although it may be seen at any age, it most commonly occurs in young adults 20 to 40 years old. It is characterized by very pronounced malaise and fever that may last 1 to 4 weeks, peripheral lymphocytosis with atypical lymphocytes, and mild elevation of liver enzymes. Pharyngitis, splenomegaly, and the production of heterophil antibodies are not as common in CMVinduced infectious mononucleosis as they are in the Epstein-Barr virus (EBV)-induced mononucleosis syndrome. Complications are rare, but may include Guillain-Barrk syndrome and meningoencephalitis. Interstitial pneumonitis caused by CMV is a common and serious infection in immunosuppressed children and adults, especially in organ transplantation patients and in those with AIDS. It is characterized by fever and dry, nonproductive cough, which then progresses to respiratory distress with dyspnea, retractions, wheezing, and hypoxia. Its mortality rate in transplant recipients is close to 90%. Radiographically, it is a diffuse, interstitial infiltrate.

NEUROLOGIC MANIFESTATIONS The most significant neurologic illnesses caused by CMV are as follows: W W

W W W W

Congenital CMV infection Meningoencephalitis Retinitis pigmentosa or chorioretinitis Transverse myelitis Polyneuritis Illnesses in immunosuppressed patients Encephalitis Myeloradiculitis Mononeuritis multiplex Peripheral neuropathy

Prenatal transmission of CMV to the fetus occurs by way of maternal viremia and transplacental passage of the virus, perhaps within virus-infected leukocytes. Symptomatic patients are infected during the second or third trimester of pregnancy, in contrast to rubella infections, which are felt to occur during the first trimester. Each year, approximately 30,000 to 40,000 babies are born with congenital CMV infection. Of these, 5% to 10% have typical cytomegalic inclusion disease (CID) (Table 67- l ) ,

TABLE 67-1. Clinical Manifestations of Congenital

Cytomegalic Inclusion Disease Swptom

Deafness Hepatomegaly Splenomegaly Jaundice Intrauterine growth retardation Petechiae, purpura Cataracts Microcephaly Microphthalmia Retinopathy Cerebral calcifications Congenital heart disease Glaucoma Pneumonia

Percentage of Patients 90

70 70 64

63 57 50 40 18 18 17

5 3 3

Modified from Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases, p. 931. WB Saunders, Philadelphia, 1991, with permission.

another 5% have atypical involvement, and 90% have no clinical manifestations at birth. Neurologic sequelae and/or deafness occur in up to 90% of infants who are symptomatic at birth. Approximately 6% of children asymptomatic at birth with congenital CMV will have deafness, psychomotor retardation, microcephaly, or chorioretinitis as sequelae at follow-up. Involvement of the central nervous system (CNS) produces the most severe sequelae of the disease. The most common ophthalmologic findings include optic atrophy, strabismus, and chorioretinitis. The chorioretinitis cannot be differentiated from that caused by congenital toxoplasmosis, either in appearance or in location on the retina (Fig. 67-1). Microcephaly is another common CNS manifestation. It may not be present at birth, but it may become apparent by 1 year of age or later. When associated with cerebral calcifications, microcephaly carries a high probability of psychomotor retardation. The cerebral calcifications typically are periventricular in distribution, a pattern that may also be observed in congenital toxoplasmosis (Fig. 67-2). Other cerebral lesions include microgyria and other cortical malformations, cerebellar aplasia, subdural effusions, polycystic encephalomalacia, porencephaly, and calcifications of cerebral arteries. Hydrocephalus, which may be progressive, may also rarely be seen. Meningoencephalitis caused by CMV is rare. It may occur as a complication of CMV mononucleosis, secondary to a primary infection in an immunocompetent patient, or as a primary or recurrent infection in an immunosuppressed patient. Symptoms include headache, photophobia, nuchal rigidity, memory deficits, and inability to concentrate. In addition to the encephalopathic findings, cranial nerve palsies, nystagmus, and ataxia may be observed; otherwise, the neurologic examination generally is nonfocal. Cranial magnetic resonance imaging may reveal an increased periventricular signal on T2-weighted images (the chief clue to CMV encephalitis), enlarged ventricles, or both. The cerebrospinal fluid (CSF) reveals a mild mononuclear pleocytosis and slightly elevated protein content. Although CMV is rarely isolated from the CSF or brain parenchyma, neuropathologic findings of intranuclear inclusions and microglial nodules are characteristic. CMV DNA may be detected in the CSF using polymerase chain reaction (PCR) assays. CMV may also cause an acquired chorioretinitis, especially in immunosuppressed patients such as bone marrow transplant recipients and in patients with AIDS. It probably occurs secondary

Chapter 67

Cytornegalovirus Infection

479

FIG. 67-1. CMV chorioretinitis. (Courtesy of Richard A. Lewis, MD, Baylor College of Medicine, Houston, Texas.)

FIG. 67-2. Computed tomography scan showing peiventricular calcifications in a patient with congenital CMV infection. (Courtesy of Gail Dernmler, MD, Baylor College of Medicine, Houston, Texas.)

to hematogenous spread of the virus to the retina. The appearance of the hnduscopic and congenital CMV chorioretinitis is similar. Because CMV retinitis can progress to complete blindness if the macula is involved, immunosuppressed patients should receive regular ophthalmologic evaluations for early diagnosis and therapy. The other important CNS disease produced by CMV is transverse myelitis. Although this syndrome of acute spinal cord inflammation results in most cases from demyelination and autoimmune phenomena, it can arise from viral infections including, albeit rarely, CMV. The virus can also invade the peripheral nervous system. It is associated with a polyradiculopathy and a painful peripheral neuropathy in patients with AIDS and with Guillain-BarrC syndrome in immunocompetent patients. Bell's palsy has been noted in a pregnant woman during a primary CMV infection. CMV infection is one of the most common opportunistic infections in patients with AIDS; indeed, approximately 50% of these patients may show evidence of CNS CMV infection at postmortem examination. It has been reported to cause encephalitis, myeloradiculitis or polyradiculomyelopathy, mononeuritis multiplex, and polyneuropathy. A peculiar polyradiculomyelopathy, especially lumbosacral, has been associated with CMV infection. It is a rapidly progressing syndrome occurring in about 1% of patients with AIDS, characterized by low back pain, subacute ascending motor weakness and paresthesias, areflexia, sphincter disturbance, and progressive flaccid paraparesis. On occasion, magnetic resonance imaging with gadolinium may reveal enhancing thickened and clumped nerve roots of the cauda equina. The CSF findings are uncharacteristic of a viral infection and usually demonstrate a neutrophilic CSF pleocytosis with an elevated protein content and low glucose levels. Electrophysiologic studies typically demonstrate features of neuroPathY associated with varying degrees of demyelination.

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There have been several reports of patients with AIDS who have developed a mononeuritis multiplex made up of multifocal subacute sensorimotor neuropathies in whom CMV has been found in the peripheral nerve. Involvement has been patchy and symmetrical, as confirmed by electrophysiology. Cranial nerves occasionally have been affected, notably the recurrent laryngeal nerve. The CSF usually is normal, although polymorphonuclear pleocytosis may occur. Peripheral nerve biopsy demonstrates multiple foci of endoneurial necrosis with CMV inclusions in Schwann cells. DIAGNOSIS Infection with CMV, whether congenital or acquired in adulthood, can only absolutely be established by isolation of the virus from urine, saliva, CSF, sexual body fluids, breast milk, or blood, together with a fourfold or greater rise in antibody titers. Techniques for detecting antibody to make the diagnosis include immunofluorescence, demonstration of complement-fixing or neutralizing antibody, or enzyme-linked immunosorbent assay. Unfortunately, these serologic techniques are difficult to interpret because antibody elevations may not be detectable for up to 4 weeks after the primary infection, and titers often remain high for years afterward. The advent of PCR for CMV DNA has greatly facilitated the diagnosis of CMV infections. It has become the diagnostic method of choice. There is a 6% false-positive rate for this test. It is both sensitive and specific in diagnosing CNS infection; however, it may be positive in patients with minimal disease and in those with active, severe CNS disease. To help distinguish between the two, quantitation of CMV genomes in CSF is useful. A negative CSF PCR for CMV DNA virtually eliminates CMV as the cause of the disease. TREATMENT Therapy with ganciclovir, foscarnet, or a combination of both has been used in patients with CMV neurologic disease. Ganciclovir, previously called 9-(1,3-dihydroxy-2-propoxy-methyl)guanine (DHPG), was the first antiviral compound licensed specifically for the treatment of life-threatening and sight-threatening infections with CMV. This agent acts by inhibiting replication of viral DNA polymerase; ganciclovir must be metabolized to the triphosphate form intracellularly to effect this inhibition. Ganciclovir is virostatic and therefore suppresses active infection but does not produce a cure. CSF concentration of the drug usually is 25% to 70% of the plasma concentration. Ganciclovir is indicated for the treatment of CMV retinitis in immunocompromised patients, CMV meningoencephalitis, and CMV polyradiculomyelitis. Ther-

apeutic trials of ganciclovir in newborns with evidence of CNS involvement are in progress. Ganciclovir treatment usually is given in two phases: induction and maintenance. The usual dosage for induction in patients with normal renal function is 5 mg/kg IV every 12 hours for 2 to 3 weeks. Following induction, IV maintenance treatment of 5 mglkglday given 5 to 7 days of the week is necessary for many patients who remain immunosuppressed, especially patients with AIDS. If the disease progresses on maintenance therapy, then another course of the induction treatment should be considered. Oral ganciclovir may be used for CMV retinitis in immunocompromised patients, including patients with AIDS, once ganciclovir maintenance has been achieved provided the retinitis is stable. Alternatively, the combination of oral ganciclovir and an intraocular ganciclovir implant has been found to be efficacious in adults and adolescents with CMV retinitis. Important side effects include bone marrow suppression with neutropenia, anemia, and thrombocytopenia. Foscarnet (trisodium phosphonoformate) is a compound that inhibits the DNA polymerase of human herpes viruses, including CMV. It is also active against human immunodeficiency virus (HIV). It has been used in patients with AIDS who have CMV encephalomyelitis, CMV retinitis, and polyradiculomyelopathy.As with ganciclovir, foscarnet treatment is given as induction and then maintenance therapy. Induction therapy for patients with normal renal function is administered intravenously as 60 mglkg every 8 hours for 2 to 3 weeks, depending on the patient’s response. Following induction, maintenance therapy of 90 to 120 mglkglday intravenously is administered. If the disease progresses, the patient may be retreated with the induction and maintenance phases again or with a combination of ganciclovir and foscarnet. Foscarnet is very nephrotoxic; the majority of patients experience some decrease in renal function in response to its administration. It also may cause electrolyte abnormalities as well as anemia and leukopenia. Therefore, these parameters should be closely monitored during administration. SUGGESTED READINGS Alford CA, Stagno S, Pass RF, Britt WJ: Congenital and perinatal cytomegalovirus infections. Rev Infect Dis 12:745, 1990 Bale JF Jr: Human cytomegalovirusinfection and disorders of the nervous system. Arch Neurol 41:310, 1984 Drew WL: Cytomegalovirus infection in patients with AIDS. J Infect Dis 158:449, 1998 Menkes JH: Textbook of Child Neurology. 5th Ed. Lea & Febiger, Philadelphia, 1995 Pruitt A Neurologic emergencies. Neurol Clin 162, 1998 Swainman K F Pediatric Neurology, Principles and Practices. 2nd Ed. Mosby, St Louis, 1993

Chapter 68

68

Epstein-Barr Virus Infection

481

Epstein-Barr Virus Infection Clifford C. Dacso

The Epstein-Barr virus (EBV) is one of the herpes viruses that infect humans. Other members of this group include herpes simplex types I and 11, varicella-zoster virus, cytomegalovirus, human herpes virus types 6, 7, and 8, and simian herpes B virus (Herpes sirniae). The latter is primarily an infection of nonhuman primates, with humans as accidental hosts. Herpes viruses share some common characteristics. They all produce viral latency, meaning that the viral genetic material is integrated into that of the host. However, this does not mean that the virus is completely dormant because there is production and display of virus antigens of EBV on host cell surfaces. EBV is different from other human herpes viruses in that it has several distinct antigens that do not cross-react. These antigens provide unique serologic markers for EBV activity. Herpes viruses contain double-stranded DNA. EBV DNA can exist in a circular form called the EBV episome, and replication of this form by host DNA polymerase plays a role in the persistence of EBV infections. Viral transmission usually is either by direct transfusion of infected material or by mucosal exposure. EPIDEMIOLOGY EBV is a ubiquitous infector of humans. It was initially described as a virus associated with Burkitt's lymphoma, and its etiologic role in the pathogenesis of infectious mononucleosis has since become clear. Much like the other herpes viruses, EBV persists in human tissues and is shed for long periods after the acute infection. Because the major mode of transmission of EBV is salivary and respiratory secretions, the prolonged shedding of the virus provides ample opportunity for transmission. Although EBV can be transmitted by blood transfusion, the oropharyngeal route is the major one. As with cytomegalovirus, the acquisition of the infection occurs at a younger age in lower socioeconomic groups. The incidence of primary infection with EBV coincides with the beginning of social activity in adolescents, during which there is exposure to oropharyngeal secretions. About 90% of adults have serologic evidence of exposure to the virus. CLINICAL FEATURES After an incubation period of 4 to 8 weeks, infectious mononucleosis usually begins insidiously. It has a fairly stereotyped repertoire of signs and symptoms. Fever, pharyngitis, and anterior or posterior cervical lymphadenopathy are almost universal findings. Splenomegaly and hepatomegaly are common. These features of the acute infection resolve within 5 to 14 days, but the malaise of mononucleosis may persist for months and delay the return to school or work. Although neurologic manifestations of EBV infection occur in only 1% of patients, they can be the presenting signs and symptoms and can be quite severe. Neurologic manifestations of infectious mononucleosis have been recognized for many years, well before the etiologic agent was identified. Infectious mononucleosis may present as meningitis or en-

cephalitis. When this occurs, examination of the CSF shows a lymphocytic pleocytosis, sometimes even with atypical lymphocytes seen in the smear. Symptoms often develop abruptly and become quite severe, but recovery without complications is the most common outcome of EBV meningitis in the immunocompetent host. EBV meningoencephalitis usually is indistinguishable from other diffuse viral encephalitides; however, involvement of the cerebellum seems to be more prominent. Because of the rarity of this condition, the incidence of cerebellitis is difficult to ascertain, but it can be a striking, albeit transient complication. Other neurologic conditions that have been associated with EBV infection are as follows: H

H H H H H

Encephalitis Meningitis Meningoencephalitis Bell's palsy Other cranial nerve palsies Transverse myelitis Brachial plexopathy Mononeuritis multiplex Seizures Demyelinating disease Optic neuritis Guillain-Barr6 syndrome B-cell lymphoma Transient global amnesia Psychosis

Again, because of the rarity of neurologic complications of EBV, most of the data about these conditions exist in case report form, often as a serologic finding of acute infection in patients presenting with a neurologic symptom. However, at least two conditions, Guillain-BarrC syndrome and central nervous system demyelination, apparently can occur as a result of EBV infection directly, without signs of infectious mononucleosis and often without positive antibodies. Although the rare deaths that occur with infectious mononucleosis usually result from neurologic complications, most damage to the nervous system resolves completely, leaving no sequelae. Persistent deficits are rare. In the setting of the acquired immunodeficiency syndrome (AIDS), EBV is a very common infecting agent. B-Cell lymphomas in the central nervous system have been associated with EBV infection in patients with AIDS and in those receiving immunosuppressive agents over a long period of time, such as after organ transplantation. This malignancy is resistant to therapy.

DIAGNOSIS Nonspecific laboratory abnormalities abound in EBV infection. Mild transaminase elevation is very common, and cryoglobulinemia to a greater or lesser extent is almost universal. Circulating atypical lymphocytes are seen in almost all cases but are not pathognomonic because other virus infections, hematologic ma-

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lignancies, and toxoplasmosis can also produce atypical lymphocytes in the peripheral blood smear. The laboratory diagnosis of EBV infection rests on the demonstration of the serologic response. Antibodies reactive with sheep red blood cells (heterophil) are manifestations of the polyclonal immunoglobulin production that occur during EBV infection and may even mediate some of the complications of infectious mononucleosis. The heterophil antibody test is positive in more than 90% of patients. These antibodies are checked by using the highly accurate and reproducible Monospot test. Although the Monospot test is positive in the preponderance of cases and false positives are rare, the appearance of heterophil antibodies in the course of the disease is variable. Therefore, EBV infection should not be ruled out on the basis of a single negative Monospot. Antibodies to the viral capsid antigen (VCA) can be demonstrated and immunoglobulin G (IgG) differentiated from IgM. IgG antibody rises early in clinical disease and persists for life, but IgM antibody does not persist. For this reason, Igh4 VCA antibody is diagnostic of acute disease. Although the data are preliminary, the polymerase chain reaction holds out hope for rapid diagnosis of EBV disease in the central nervous system. A syndrome consisting of unusually abrupt-onset fatigue and lassitude, variously coupled with low-grade fever, myalgias, arthralgias, lymphadenopathy, and evanescent rashes, has been reported sporadically for at least the last 100 years. At one time this “chronic fatigue syndrome” was thought to represent chronic infection with EBV, based on rising antibody titers to EBV early antigens. When examined closely, it became evident that there is no consistent association, either virologically or epidemiologically, between chronic fatigue syndrome and EBV. However, a large number of clinicians and patients still insist on this association.

69

Despite the lack of correlation with EBV, chronic fatigue syndrome is debilitating and responds poorly to therapy. However, it appears to be self-limited.

TREATMENT Specific antiviral treatment effective in vivo is not yet available; however, many agents can be shown to decrease viral replication in vitro. For the rare severe manifestations of EBV, including impending airway closure, some have recommended a rapidly tapering course of corticosteroids. Because most of the EBV complications are self-limited, including the neurologic manifestations, this intervention is seldom needed.

SUGGESTED READINGS Bray PF, Culp KW, McFarlin DE et al: Demyelinating disease after neurologically complicated primary Epstein-Barr virus infection. Neurology 42:278, 1992 Buchwald D: Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. J Med Virol 50:25-30, 1996 Grose C, Henle W, Henle G et ak Epstein-Barr virus infections in acute neurological disease. N Engl J Med 292:392. 1975 Holmes GP, Kaplan JE, Gantz NM et ak Chronic fatigue syndrome: a working case definition. Ann Intern Med 108387, 1988 Ito H, Sayama S, Kie S et al: Antineuronal antibodies in acute cerebellar ataxia following Epstein-Barr virus infection. Neurology 4 4 1506, 1994 Silverstein A, Steinberg G , Nathanson M: Nervous system involvement in infectious mononucleosis. Arch Neurol 6:353, 1972 Tsutsumi H: Epstein-Barr virus infection and neurological disorders in children: detection of Epstein-Barr virus genomes in the cerebrospinal fluid by polymerase chain reaction technique, abstracted in English. No To Hattatsu 25:135, 1993

Poliomyelitis Clifton L. Gooch

Although the dread inspired by the polio epidemics of the 1950s, which left an estimated 250,000 to 300,000 survivors with paralysis, has been largely forgotten by recent generations, poliomyelitis remains a significant threat in underdeveloped countries with inadequate immunization programs. Because of immigration, imported cases continue to appear in the United States, and vaccine-associated paralytic polio, though rare, is a well-documented risk. Recurrent weakness in polio survivors (the postpolio syndrome) is a late complication in approximately 25% of cases and has been reported with increasing frequency over the last decade. Although considered eradicated for the present in many developed countries, polio epidemics recur when vaccination standards fall. Even in the United States, despite aggressive vaccination, some communities are poorly immunized (with survey documentation of inadequate immunization in 50% of children younger than 2 years), providing unprotected populations for the reappearance of polio. The polioviruses are single-stranded RNA viruses belonging to the enterovirus subgroup of the picornaviruses. They are spread by

fecal-oral contamination, surviving in sewage or contaminated water for prolonged periods. Once ingested, the virus enters the lymphatic tissue in the ileum and pharynx and disseminates locally by lymphatic, followed by hematogenous, spread. The infection may then enter the central nervous system (CNS), possibly through defects in the blood-brain barrier, where it prominently affects the motor nerves (anterior horn cells) or brainstem motor nuclei. These lesions are responsible for the areflexic weakness that is the hallmark of the disease as well as the bulbar weakness and, depending on distribution, may impair respiratory muscle function. Thalamic and reticular formation involvement may rarely precipitate autonomic instability. EPIDEMIOLOGY Before the development of effective immunization, polio epidemics occurred primarily in northern, temperate countries with excellent sanitation. Populations living under less sanitary conditions are more likely to be exposed to endemic polio in early

482

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lignancies, and toxoplasmosis can also produce atypical lymphocytes in the peripheral blood smear. The laboratory diagnosis of EBV infection rests on the demonstration of the serologic response. Antibodies reactive with sheep red blood cells (heterophil) are manifestations of the polyclonal immunoglobulin production that occur during EBV infection and may even mediate some of the complications of infectious mononucleosis. The heterophil antibody test is positive in more than 90% of patients. These antibodies are checked by using the highly accurate and reproducible Monospot test. Although the Monospot test is positive in the preponderance of cases and false positives are rare, the appearance of heterophil antibodies in the course of the disease is variable. Therefore, EBV infection should not be ruled out on the basis of a single negative Monospot. Antibodies to the viral capsid antigen (VCA) can be demonstrated and immunoglobulin G (IgG) differentiated from IgM. IgG antibody rises early in clinical disease and persists for life, but IgM antibody does not persist. For this reason, Igh4 VCA antibody is diagnostic of acute disease. Although the data are preliminary, the polymerase chain reaction holds out hope for rapid diagnosis of EBV disease in the central nervous system. A syndrome consisting of unusually abrupt-onset fatigue and lassitude, variously coupled with low-grade fever, myalgias, arthralgias, lymphadenopathy, and evanescent rashes, has been reported sporadically for at least the last 100 years. At one time this “chronic fatigue syndrome” was thought to represent chronic infection with EBV, based on rising antibody titers to EBV early antigens. When examined closely, it became evident that there is no consistent association, either virologically or epidemiologically, between chronic fatigue syndrome and EBV. However, a large number of clinicians and patients still insist on this association.

69

Despite the lack of correlation with EBV, chronic fatigue syndrome is debilitating and responds poorly to therapy. However, it appears to be self-limited.

TREATMENT Specific antiviral treatment effective in vivo is not yet available; however, many agents can be shown to decrease viral replication in vitro. For the rare severe manifestations of EBV, including impending airway closure, some have recommended a rapidly tapering course of corticosteroids. Because most of the EBV complications are self-limited, including the neurologic manifestations, this intervention is seldom needed.

SUGGESTED READINGS Bray PF, Culp KW, McFarlin DE et al: Demyelinating disease after neurologically complicated primary Epstein-Barr virus infection. Neurology 42:278, 1992 Buchwald D: Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. J Med Virol 50:25-30, 1996 Grose C, Henle W, Henle G et ak Epstein-Barr virus infections in acute neurological disease. N Engl J Med 292:392. 1975 Holmes GP, Kaplan JE, Gantz NM et ak Chronic fatigue syndrome: a working case definition. Ann Intern Med 108387, 1988 Ito H, Sayama S, Kie S et al: Antineuronal antibodies in acute cerebellar ataxia following Epstein-Barr virus infection. Neurology 4 4 1506, 1994 Silverstein A, Steinberg G , Nathanson M: Nervous system involvement in infectious mononucleosis. Arch Neurol 6:353, 1972 Tsutsumi H: Epstein-Barr virus infection and neurological disorders in children: detection of Epstein-Barr virus genomes in the cerebrospinal fluid by polymerase chain reaction technique, abstracted in English. No To Hattatsu 25:135, 1993

Poliomyelitis Clifton L. Gooch

Although the dread inspired by the polio epidemics of the 1950s, which left an estimated 250,000 to 300,000 survivors with paralysis, has been largely forgotten by recent generations, poliomyelitis remains a significant threat in underdeveloped countries with inadequate immunization programs. Because of immigration, imported cases continue to appear in the United States, and vaccine-associated paralytic polio, though rare, is a well-documented risk. Recurrent weakness in polio survivors (the postpolio syndrome) is a late complication in approximately 25% of cases and has been reported with increasing frequency over the last decade. Although considered eradicated for the present in many developed countries, polio epidemics recur when vaccination standards fall. Even in the United States, despite aggressive vaccination, some communities are poorly immunized (with survey documentation of inadequate immunization in 50% of children younger than 2 years), providing unprotected populations for the reappearance of polio. The polioviruses are single-stranded RNA viruses belonging to the enterovirus subgroup of the picornaviruses. They are spread by

fecal-oral contamination, surviving in sewage or contaminated water for prolonged periods. Once ingested, the virus enters the lymphatic tissue in the ileum and pharynx and disseminates locally by lymphatic, followed by hematogenous, spread. The infection may then enter the central nervous system (CNS), possibly through defects in the blood-brain barrier, where it prominently affects the motor nerves (anterior horn cells) or brainstem motor nuclei. These lesions are responsible for the areflexic weakness that is the hallmark of the disease as well as the bulbar weakness and, depending on distribution, may impair respiratory muscle function. Thalamic and reticular formation involvement may rarely precipitate autonomic instability. EPIDEMIOLOGY Before the development of effective immunization, polio epidemics occurred primarily in northern, temperate countries with excellent sanitation. Populations living under less sanitary conditions are more likely to be exposed to endemic polio in early

Chapter 69 rn Poliomyelitis

infancy, usually while still protected from severe disease by maternal antibodies, and thus may develop lifelong immunity. In the absence of immunization, more sanitary conditions prevent such early exposure, creating large groups highly susceptible to the virus and setting the stage for recurrent epidemics. These typically occur in late summer and affect predominantly children older than 6 months, adolescents, and young adults. Older patients, when affected, are more likely to have severe disease. CLINICAL FEATURES Clinically, poliovirus infection can be divided into four types: subclinical infection, abortive poliomyelitis, nonparalytic poliomyelitis with aseptic meningitis, and paralytic poliomyelitis (Table 69-1). The incubation period after ingestion of the virus typically is 1 to 2 weeks but may range from 4 days to 5 weeks. Dissemination and viremia cause no symptoms in 90% of cases (subclinical infection). Malaise, fever, headaches, sore throat, cough, diarrhea, nausea, and vomiting are prominent in the remaining 10%. In this group with clinically apparent infections, most patients have selflimited symptoms that resolve after 2 or 3 days, without recurrence (abortive poliomyelitis). Only 2% of infections progress to the CNS. These patients report persistence of their systemic symptoms, or recurrence 2 to 10 days after apparent recovery, accompanied by constant headache and painful neck stiffness caused by meningeal irritation. Cerebrospinal fluid (CSF) analysis demonstrates an early leukocytosis (25 to 500 cells/mm3) with neutrophilic predominance in the first few days, superseded by lymphocytic predominance. Normal glucose and mildly to moderately elevated protein (usually less than 150 mg/dL) are also present. These symptoms usually resolve without sequels in 7 to 14 days (nonparalytic poliomyelitis with aseptic meningitis). Unfortunately, 0.1% to 1% of infections invade the motor system after CNS penetration, resulting in paralytic poliomyelitis. These patients complain of back and hamstring stiffness, spasm, and muscle tenderness in addition to the above-mentioned symptoms. The onset of weakness and paralysis follows closely, occurring during or after resolution of the fever and 3 to 5 days after the onset of CNS symptoms (although it may range from a presenting symptom of nervous system involvement to late appearance 2 or 3 weeks into the illness). Weakness progresses rapidly over hours to days, with coarse fasciculations early and atrophy starting in 1 to 3 weeks. Asymmetric onset is common, and the lower extremities are more often affected, especially in children under 5 years. Associated arm weakness and bilateral lower extremity weakness are more common in older children and

W

183

adolescents, whereas young adults are most at risk for quadriplegia. Although hyperreflexia may be present in some cases initially, diminution and loss of deep tendon reflexes ultimately occurs, often as an early finding. Muscles of the trunk and thorax, including the muscles of respiration, may also be affected. Bulbar involvement complicates 10% to 15% of cases, most commonly affecting the tenth cranial nerve and causing paralysis of the pharyngeal musculature. Laryngeal weakness may also develop. Facial palsies are less likely, although facial diplegia may sometimes appear. Urinary bladder muscle dysfunction is a common complication in adults. Myocarditis, autonomic dysfunction with hypertension, acute cerebellar ataxia, and transverse myelitis are less common accompaniments. Approximately 15% to 30% of adults and 2% to 5% of children with paralytic disease die, and patients with bulbar disease and respiratory involvement are at the greatest risk. Mortality peaks in the first week of paralysis, chiefly from respiratory failure caused by depression of the respiratory centers and by destruction of the motor neurons supplying the intercostal and diaphragm muscles. Other causes of death include aspiration caused by bulbar weakness and disturbed control of vascular tone. Strength may begin to recover within the first month after onset, and maximal recovery usually occurs by 6 to 9 months. Approximately one third of patients have significant permanent weakness. Appropriate care is essential to minimize musculoskeletal deformities such as scoliosis, subluxations, and joint dislocations and equinovarus deformities. Weakness typically remains stable after infection, but 25% to 30% of paretic patients develop a progressive weakness, sometimes involving previously asymptomatic muscles, approximately 25 to 35 years after infection. This condition, called the postpolio syndrome, advances extremely slowly, with an average decline in strength of 1% per year. Its cause remains controversial, but it does not appear to cause significant additional paralysis in most cases. DIAGNOSIS The diagnosis of polio is made in the appropriate clinical setting and can be supported by the isolation of viruses from the throat, stool, and CSF. Virus grown in tissue culture systems should enable identification of enterovirus in 3 to 4 days, with specification of poliovirus in 10 to 11 days. Submitting all these specimens is highly important because CSF cultures alone are rarely positive. Acute and convalescent serum antibody titers to the three pathogenic types of poliovirus can also be measured, with a fourfold increase considered diagnostic of acute infection.

TABLE69-1. Clinical Types of Poliovirus Infection

Clinical T w e

Percentage of Total

Subclinical Abortive (4 days-5 weeks postexposure)

90 8

Nonparalyticwith aseptic meningitis (2-10 days after abortive illness)

1.98

Paralytic (3-5 days after onset of CNS symptoms)

0.02

Features

Prognosis

No symptoms

Excellent Excellent

Malaise, fever, headache, sore throat, cough, diarrhea, nausea, and vomiting Malaise, fever, sore throat, cough, diarrhea, nausea and vomiting, severe headache, meningismus, CSF pleocytosis, elevated protein Muscular stiffness, spasm (early), resolution of fever, coarse fasciculations, focal weakness, urinary bladder dysfunction, respiratory failure, rare bulbar weakness (pharyngeal, facial), rare autonomic dysfunction

Good, with small chance of progression

15%~-30% mortalii; 33% of survivors with

permanent weakness

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Immune and Infectious Disease rn Viral Infections

Because neurologic symptoms often develop after (or in the absence of) systemic symptoms, paralytic polio seldom presents with clinical features of an infection. Instead, the differential diagnosis of polio includes other conditions that cause rapid, flaccid paralysis: W W W W W

Guillain-Barre syndrome Transverse myelitis Botulism Heavy metal poisoning Tick paralysis

TREATMENT

Therapy is supportive. Patients should be hospitalized when they manifest signs of nervous system infection. Early muscle and meningeal pain may respond to hot packs and analgesics. Close attention to early signs of respiratory insufficiency such as increasing restlessness and anxiety is critical, and serial vital capacities should be monitored and mechanical ventilation instituted when measurements fall below 50% of predicted values. Tracheostomy may be necessary because of excessive secretions in bulbar and spinal disease. Bladder paralysis typically is transient, lasting only a few days, and may be treated with bethanechol, 5 to 10 mg PO or 2.5 to 5 mg SQ as needed to induce voiding, although some patients nevertheless may need catheterization. Constipation, secondary to abdominal muscle weakness, should be treated with enemas. Appropriate positioning of weak limbs with splints, boards, and sandbags as well as early physical therapy is critical to minimize deformity, but surgical correction of specific abnormalities may be needed in some cases and should be performed by an experienced orthopedic surgeon.

Prevention Because antiviral medications are not effective in treating poliomyelitis, vaccination remains the best means of controlling this disease. Both the live, attenuated, oral polio vaccine (OPV, or Sabin vaccine) and the formalin inactivated polio vaccine (IPV, or Salk vaccine) protect against all three antigenic types of poliovirus. OPV provides greater intestinal immunity and the advantage of herd immunity (caused by transfer of the virus from the inoculated patients to their contacts) and is the recommended regimen in the United States. Because of the risk, though extremely low, of paralytic disease after inoculation with the live attenuated vaccine (1 in 550,000 after the first dose and 1 per 12.3 million after subsequent doses), OPV should not be given to patients whose are immunocompromised. One way to reduce the risk of vaccine associated poliomyelitis is sequential vaccination with inactivated polio vaccination (enhanced immunogenicity inactivated polio vaccine, or eIPV), followed by vaccination with OPV. Although this method induces high levels of immunity, a reduction of vaccine-associated paralytic disease with this approach has yet to be definitively demonstrated. Other complications of oral poliovirus vaccination have also been reported including headache, fever, vomiting, meningitis, encephalitis, facial paralysis, transverse myelitis, and Guillain-Barre syndrome. Current U.S. Centers for Disease Control and Prevention

vaccination recommendations include either OPV or eIPV at 2,4, and 12 to 18 months and again at 4 to 6 years, or a combined schedule of eIPV at 2 and 4 months followed by OPV at 12 to 18 months and 4 to 6 years. In immunocompromised patients, only eIPV is recommended. Adult immunization usually is not recommended in the United States but may be needed for travel to endemic regions. Unvaccinated adults whose children are receiving OPV, as well as health care workers who may be exposed to polio, should receive the eIPV. Because immunity may not be maintained indefinitely with eIPV, further adult inoculations may be necessary. Patients with a history of streptomycin or neomycin allergy should not receive eIPV. The oral vaccine must be handled specially before administration and must be stored and shipped frozen and, after thawing, must be refrigerated at temperatures less than 10°C or it may lose its potency; it must be discarded if refrigerated for more than 30 days. Since the poliomyelitis eradication program was instituted in 1988, the number of countries reporting new infections has declined from 100 to 53, and the number of infected continents has decreased from 5 to 2, corresponding to a 90% reduction in the worldwide incidence of polio. Eradication is most challenging in South Asia and Africa, where ongoing social unrest and poor health infrastructure are impeding progress. Although progress toward the global elimination of polio continues, our increasingly mobile international community ensures that a future polio outbreak will remain possible until the last patient is immunized and the last host clear of disease. Current information about the progress of the worldwide polio eradication program and additional helpful information about the infection can be found on the World Health Organization’s official polio site: www.po1ioeradication.org.

SUGGESTED READINGS Agree JC, Rodriguez AA, Tafel JA Late effects of polio: critical review of the literature on neuromuscular function. Arch Phys Med Rehabil 172:923, 1991 Centers for Disease Control: Polio: what you need to know. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 1992 Centers for Disease Control and Prevention: Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule with an activated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee of Immunization Practices (ACIP). MMWR 46(RR-3):12, 1997 Centers for Disease Control and Prevention: Recommended childhood immunization schedule: United States. Recommendations of the Advisory Committee of Immunization Practices (ACIP). MMWR 48:12, 1999 Foege WH: Eradication of polio in the Americas. JAh4A 270:1857, 1993 Munsat TM: Poliomyelitis: new problems with an old disease. N Engl J Med 324:1206, 1991 Nkowane BM, Wassilak SGF, Orenstein WA et al: Vaccine-associated paralytic poliomyelitis: United States: 1973 through 1984. JAMA 257:1335, 1987 Patriarca PA Polio outbreaks: a tale of torment. Lancet 344:630, 1994 Ramlow J, Alexander M,LaPorte R et al: Epidemiology of the post-polio syndrome. A m J Epidemiol 136769, 1992

Chapter 70 rn Measles and Subacute Sclerosing Panencephalitis

70

48s

Measles and Subacute Sclerosing Panencephalitis Diana L. Rodriguez

Measles, or rubeola, is caused by an RNA virus that produces a fever, cough, coryza, conjunctivitis, and an erythematous maculopapular confluent rash. There is a pathognomonic enanthem comprised of Koplik spots located on the buccal surface of the cheeks. Complications caused by measles infection are numerous and affect many organ systems, including the central nervous system (CNS). Fortunately, in 1963 the measles vaccine became available, and its administration led to a dramatic reduction in epidemic measles and its complications.

EPIDEMIOLOGY Measles is primarily a disease of children. In the prevaccine era, the highest rate of occurrence was in children 5 to 10 years old, but since the introduction of the vaccine, half of all cases now occur in adolescents and young adults. In many developing countries, measles is the most important cause of death from ages 1 through 5 years and accounts for 1 to 2 million deaths per year worldwide.

CLINICAL FEATURES Measles is a highly contagious disease characterized by three stages: 1. An incubation stage of approximately 10 to 14 days with few, if

any, symptoms 2. A prodromal or catarrhal stage of approximately 3 to 5 days with Koplik spots, mild to moderate fever, mild conjunctivitis, coryza, and progressively worsening, brassy cough 3. A final or exanthem stage with a maculopapular rash erupting from head to toe, accompanied by high fever Measles is spread via the respiratory route and is most contagious during the prodromal period, or catarrhal stage of illness. Patients should be considered contagious from 1 to 2 days before the onset of symptoms (3 to 5 days before the rash) to at least 7 days after the onset of the rash. Patients with subacute sclerosingpanencephalitis (SSPE), a complication of measles, are not infectious. In typical measles, the exanthem occurs at about the peak of the respiratory symptoms. The duration of the rash usually is 6 to 7 days. During the exanthem phase, the fever usually peaks on the second or third day and then declines over a 24-hour period. Fever that persists after the third or fourth day of exanthem usually is an indication of a complication. Other manifestations during this period may include pharyngitis, localized or generalized lymphadenopathy, diarrhea, vomiting, laryngitis, croup, and abdominal pain.

encephalitis), and SSPE (or Dawson’s encephalitis). Other less common CNS complications include a Guillain-Barrk syndrome, cerebral thrombophlebitis, and retrobulbar neuritis.

Parafnfectious Encephalomyelitis Parainfectious encephalomyelitis (a type of acute disseminated encephalomyelitis) is a demyelinating illness that occurs more often in association with measles infection than with other exanthematous illnesses, complicating approximately 1 in 800 to 2000 measles cases. Although the encephalitis may be mild, the mortality rate is 10% to 20%, and a similar percentage suffer persistent neurologic sequelae. Prevention of this neurologic complication of measles alone provides sufficient justification for immunization against the disease. The encephalomyelitic syndrome may precede the rash, but, characteristically, the rash is fading and other symptoms are improving when the patient suddenly experiences a recrudescence of fever, convulsions, stupor, and deepening coma. Other less common manifestations include hemiplegia, cerebellar disease, and occasionally a transverse myelitis or other signs of spinal cord involvement. Choreoathetotic movements occur infrequently. In many cases the syndrome is much less severe, and the patient suffers a transient encephalitic illness with abrupt recurrence of fever, headaches, irritability, listlessness, lethargy, confusion, and signs of meningeal irritation. In immunocompromised patients, the syndrome may be fatal. Ultimately, there appears to be no correlation between the severity of the rash and the subsequent encephalomyeliticsyndrome nor between the severity of the illness and the neurologic prognosis. Long-term sequelae of parainfectious measles encephalitis may include various degrees of retardation, epilepsy, deafness, a syndrome of postencephalitic hyperkinesia, and hemiplegia or paraplegia. The occurrence of neurologic sequelae does not correlate with the severity of the initial symptoms. Similar CNS complications may occur after measles immunization but only with an incidence of approximately 1.68/1,000,000 vaccine doses. Fever and rash develop 7 to 12 days after immunization, followed by lethargy, irritability, and possibly seizures (which are usually febrile seizures). The mechanisms responsible for the neurologic syndromes are controversial. Recent investigations have failed to isolate measles virus or to demonstrate measles virus RNA or other viral antigens in the brains of most affected patients. These findings have led to the hypothesis that the illness may be autoimmune and that viral invasion of the CNS is unnecessary. Acute Measles Encephalitis of the Delayed Type

NEUROLOGIC COMPLICATIONS The neurologic complications and sequelae of measles infection are not rare. Neurologic manifestations of a primary measles infection most frequently include a parainfectious encephalitis/ encephalomyelitis (also known as acute measles encephalitis), acute measles encephalitis of the delayed type (or subacute measles

A unique measles encephalitis that occurs in immunosuppressed patients is sometimes called acute measles encephalitis of the delayed type (or subacute measles encephalitis). Although the symptoms vary, the illness appears to be different from either the acute parainfectious encephalitis that occurs in patients without known immunodeficiencies or the chronic picture of

486

Immune and Infectious Disease

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SSPE. The incubation period has varied between 5 weeks and 6 months. Convulsions often are the initial symptom, and they are a prominent aspect of the illness. The seizures may be focal, unilateral, or continuous localized clonic activity (epilepsia partialis continua). Other findings include hemiplegia, stupor, coma, hypertonia, and slurred speech. Most cases have been fatal, and the duration of illness has been from 1 week to 2 months. Investigators have isolated measles virus from the brains of patients with this illness. The lesions are similar to those of SSPE except that the inflammatory changes are lacking. In a sense, this subacute measles encephalitis is an opportunistic infection of the brain in an immunodeficient patient. The interval between exposure and onset of neurologic disease, the rapid subsequent course, and the paucity of immunoglobulin M (IgM) antibodies may help to distinguish this subacute measles encephalitis from both parainfectious encephalitis and SSPE.

SUBACUTE SCLEROSING PANENCEPHALITIS A more delayed form of measles encephalitis is SSPE, a progressive inflammatory disease of the CNS caused by a persistent, aberrant measles virus infection. The risk of SSPE in children who previously had natural measles is between 0.6 and 2.2 per 100,000 infections, with a mean latency to onset of SSPE of 7 to 12 years. In contrast to natural measles, the risk of SSPE after measles immunization is about 1 per 1 million. In vaccinees who develop SSPE, the mean incubation period is approximately 3 to 7 years. SSPE affects mainly children and adolescents and rarely occurs beyond the age of 18 years, with a usual age of onset between 5 and 15 years. Typically, there is a history of primary measles infection at a very early age, often before age 2 years. It is more common in rural than urban populations, and it appears to be five times more common in males than in females. The National SSPE Registry, which was established to monitor cases after the introduction of the measles vaccine in 1964, continues to record 10 to 20 new cases each year (some of which may be vaccine-induced). SSPE has been divided into four clinical stages. Stage I (0% to 30% disability) involves impairment of intellectual functions, especially behavior and learning. There is slowing of mental processes and behavioral reactions. This stage may be missed because of its insidious onset and progression. It may last a few weeks to a few years. Stage I1 (30%to 55% disability) is marked by seizure activity and progression of the dementia. Rhythmic myoclonic jerks are the characteristic finding, occurring at 5- to 15-second intervals, initially involving the head and then the trunk and limbs. These rhythmic myoclonic jerks are the unique hallmark of SSPE. They do not occur in sleep, nor do they impair consciousness. Also seen in Stage I1 is a decrease in spontaneous movement and speech, although comprehension remains intact. Stage 11 lasts approximately 1 month to 1 year. Stage 111 (55% to 80% disability) is marked by further loss of cortical function, hyperthermia, difficulty swallowing, drooling, choreoathetoid movements, decorticate or decerebrate posturing, more extrapyramidal and pyramidal symptoms, disappearance of the characteristic involuntary movements, and alteration of consciousness. Half of these patients have ophthalmologic abnormalities such as optic atrophy, papilledema, or a focal chorioretinitis that can affect the periphery or the macula with subsequent visual loss. Stage 111 lasts approximately 3 to 18 months. The patient with stage IV disease (end stage and 80% disability to death) is mute and quadriplegic. This stage may last from 1 to 6 years. Remissions in SSPE have been described, but the patients

ultimately succumb to the illness. The length of survival seems to depend on the age of onset; younger patients tend to survive longer than older patients. Most patients die 1 to 3 years after the onset of the illness, although survival for as long as 16 years has been described. There are no reliable clinical or laboratory indicators that predict length of survival. Death usually is a result of loss of central control mechanisms for temperature, respiratory and cardiac functions, or is caused by secondary infection. The pathogenesis of SSPE is not entirely understood, but seems to involve an alteration of the virus as it infects the CNS, allowing it to escape immune surveillance. There appears to be an abnormality in the synthesis of the matrix (M) protein, a polypeptide, which is important in the assembly of the viral nucleocapsid; however, the full complement of genetic material needed to code for all proteins, including the M protein, is present and functional. Patients with SSPE therefore lack antibody to the M protein even though they have high titers of antibody to other measles virus polypeptides. In addition, most patients who develop SSPE had their acute measles infection at a very young age, which suggests that immature or altered immunity may play a role.

DIAGNOSIS The diagnosis of measles usually is made from the typical clinical picture; laboratory confirmation is rarely needed. During the prodromal stage, multinucleated giant cells can be demonstrated in smears of the nasal mucosa. Koplik spots on the buccal mucosa, which are pathognomonic for measles, may also be noted during the prodromal stage. Virus can be isolated if necessary in tissue culture. Finally, diagnostic rises (a fourfold increase) in antibody titer can be demonstrated between acute and convalescent sera. Interestingly, Gibbs and associates noted that 51% of 680 patients with measles without clinical evidence of encephalitis had abnormal electroencephalograms (EEGs) during acute or immediate postacute illness. The diagnosis of measles postinfectious encephalomyelitis usually is suggested by the history of preceding measles infection and the ensuing encephalomyelitic picture. The cerebrospinal fluid (CSF) usually shows a lymphocytic pleocytosis and increased protein content. Magnetic resonance imaging (MRI) may reveal areas of demyelination. Measles encephalitis of the delayed type, compared with SSPE, has a short interval between exposure and onset of neurologic disease and a subsequent rapid course. The CSF may be normal (as occurs in approximately one third of patients), but it usually reveals a mild mononuclear pleocytosis with slightly elevated protein. There may be no increase in measles antibody titers. The detection of measles RNA in CSF by polymerase chain reaction can aid in the diagnosis of subacute measles encephalitis; however, this study is not routinely available. The diagnosis can be confirmed only by brain biopsy, which reveals the measles virus. Pathologically, brain lesions are similar to those of SSPE except that the inflammatory changes are lacking. Cranial MRI findings are nonspecific. The characteristic clinical and laboratory features of SSPE are progressive dementia, myoclonic movements, a typical EEG pattern, elevated immunoglobulin G (IgG) and oligoclonal bands in the CSF, and very high titers of antimeasles antibody in the serum and CSF. Characteristic, although not pathognomonic, of SSPE is an EEG pattern of periodic paroxysmal bursts seen in stage I1 disease (Fig. 70-1). These consist of 2- to 3-second high-voltage diphasic activity occurring at 5- to 8-second intervals, often associated with spike discharges. They occur in approxi-

Chapter 70

T5A1

EMG

Measles and Subacute Sclerosing Panencephalitis

487

1 # * &-.-*.-'

-./ I SOW 1n c

FIG. 70-1. EEC showing the periodic paroxysmal bursts with accompanying myoclonus seen in SSPE.

FIG. 70-2. Light microscopy demonstration of an eosinophilic intranuclear inclusion (arrow) and reactive gliosis in SSPE. (Courtesy of Marvin A. Fishman, MD, Baylor College of Medicine, Houston, Texas.)

mately 80% of patients with SSPE, sometimes several years before the clinical onset of myoclonus. The CSF in SSPE often is abnormal. The CSF IgG, most of which is directed against the measles virus, rises to levels greater than 20% of the total protein. Oligoclonal banding is observed, and an excessive number of plasmacytes are found in the CSF. High antimeasles antibody titers in serum and CSF confirm the diagnosis of SSPE. Other tests that help corroborate the diagnosis are MRI and brain biopsy. Imaging studies obtained during early stages of SSPE demonstrate small ventricles with obliteration of hemispheric sulci and fissures. With a prolonged course, they

reflect changes consistent with demyelination and atrophy of gray and white matter. A brain biopsy may be performed if the diagnosis is uncertain. In SSPE, the pathologic process represents a subacute encephalitis accompanied by demyelination. Light microscopy reveals inflammatory lesions of the gray and white matter, including demyelination, intranuclear and intracytoplasmic inclusion bodies of neurons and glial cells (Cowdry A and Cowdry B bodies), inflammatory cells, and gliosis (Fig. 70-2). Electron microscopy reveals intracellular inclusions that can be shown to contain measles virus nucleocapsids.

488

Immune and Infectious Disease

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TREATMENT Treatment of the typical case of self-limited measles is supportive. Recent data suggest that supplementation with vitamin A during the measles infection may reduce its morbidity and mortality. Likewise, the treatment of measles encephalomyelitis and acute measles encephalitis of the delayed type is also symptomatic and supportive. Neither y-globulins nor corticosteroids offer benefit or prevent the development of sequelae. Seizures should be controlled aggressively. There is no proven effective treatment for SSPE, although case reports of the use of inosiplex and intrathecal a-interferon suggest a possible beneficial effect. Despite these hopeful treatments, the cornerstone of care is still supportive: airway protection, nutrition, prevention of contractures and decubiti, and monitoring for and treating secondary infections. Seizures are difficult to control in these patients, but carbamazepine, valproic acid, diazepam, and primidone may be useful in controlling myoclonic, generalized, and psychomotor seizures.

Budka H, Urbanits S, Liberski PP Subacute measles virus encephalitis: a new and fatal opportunistic infection in a patient with AIDS. Neurology 46:2, 1996 Gazzola P, Cocito L, Capello E Subacute measles encephalitis in a young man immunosuppressed for ankylosing spondylitis. Neurology 52:5, 1999 Grattan-Smith PJ, Procopis PG, Wise A, Grigor WG Serious neurological complications of measles: a continuing preventable problem. Med J Aust 143:385, 1985 Lyon G, Ponsot G, Lebon P Acute measles encephalitisof the delayed type. Ann Neurol2:322, 1977 Menkes JH: Textbook of Child Neurology. 5th Ed. Lea & Febiger, Philadelphia, 1995 Park S, Kohl S: Subacute sclerosing panencephalitis in an identical twin. Pediatrics 1046, 1999 Swaiman KF: Pediatric Neurology:Principles and Practice. 2nd Ed. Mosby, St. Louis, 1993

~

SUGGESTED READINGS Aarli JA Nervous complications of measles. Eur Neurol 12:79, 1974 Behrman RE: Nelson Textbook of Pediatrics. 16th Ed. WB Saunders, Philadelphia, 2000

71

Progressive Mdtifocal Leukoencephalopathy Bradley K. Evans

Progressive multifocal leukoencephalopathy (PML), a rare disease of brain white matter, occurs in immunosuppressed patients, particularly those with acquired immunodeficiency syndrome (AIDS). JC virus, a small, circular, double-stranded DNA virus in the papovavirus family, is the causative agent. In patients with PML, JC virus infects oligodendrogliocytes. Dysfunction and death of these cells leads to demyelination, causing the symptoms of PML.

EPIDEMIOLOGY Most people have been exposed in childhood to the virus. Because some people intermittently excrete the virus in urine, it is assumed that JC virus can establish a latent infection in kidney and perhaps in other tissues as well. Reactivation of a latent JC virus infection in brain or other tissue leads to PML. Compared with JC virus in kidney, however, the JC virus in PML lesions has multiple mutations. These mutations may be important in conferring the qualities needed to produce clinical disease. Currently, more than half of patients with PML have AIDS. Because of this association, human immunodeficiency virus (HIV) testing is indicated in all patients diagnosed with PML. In HN-infected patients, the risk of developing PML during the course of their illness is approximately 2% to 5%. Although PML often is the first manifestation of HIV infection, the CD4 count in patients with AIDS and PML is very low, typically less than 50/mm3. Other causes of immunosuppression associated with PML are lymphocytic malignancies (e.g., chronic lymphocytic

leukemia and Hodgkin’s disease), organ transplantations, corticosteroid therapy, and cancer chemotherapy.

CLINICAL FEATURES PML usually progresses indolently over several weeks. Sometimes the onset seems to be more precipitous, particularly if the lesion is in a clinically vital area of the brain. Typically, PML causes one or more focal brain lesions, usually arising at the gray-white junction and later spreading into adjacent white matter. Lesions can affect the cerebral hemispheres, the cerebellum, or the brainstem, and they produce symptoms depending on their location. Typical early symptoms are hemiparesis, hemianopsia, and ataxia. Besides these signs of a focal brain lesion, which are present in approximately 75% of patients, PML may produce altered mental status (about 50% of patients), particularly late in the illness, when the lesions are multiple and large. Fever and headache are uncommon, probably no more common than in other patients with AIDS. Seizures are slightly more common in patients with AIDS and PML (10% to 20% of patients). As patients progress, they develop progressive vision loss and motor dysfunction, dementia, and incontinence.

DIAGNOSIS Blood tests seldom aid in the diagnosis. Some patients with PML may have a high cerebrospinal fluid myelin basic protein level, reflecting intense myelin breakdown, but this is a nonspecific

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TREATMENT Treatment of the typical case of self-limited measles is supportive. Recent data suggest that supplementation with vitamin A during the measles infection may reduce its morbidity and mortality. Likewise, the treatment of measles encephalomyelitis and acute measles encephalitis of the delayed type is also symptomatic and supportive. Neither y-globulins nor corticosteroids offer benefit or prevent the development of sequelae. Seizures should be controlled aggressively. There is no proven effective treatment for SSPE, although case reports of the use of inosiplex and intrathecal a-interferon suggest a possible beneficial effect. Despite these hopeful treatments, the cornerstone of care is still supportive: airway protection, nutrition, prevention of contractures and decubiti, and monitoring for and treating secondary infections. Seizures are difficult to control in these patients, but carbamazepine, valproic acid, diazepam, and primidone may be useful in controlling myoclonic, generalized, and psychomotor seizures.

Budka H, Urbanits S, Liberski PP Subacute measles virus encephalitis: a new and fatal opportunistic infection in a patient with AIDS. Neurology 46:2, 1996 Gazzola P, Cocito L, Capello E Subacute measles encephalitis in a young man immunosuppressed for ankylosing spondylitis. Neurology 52:5, 1999 Grattan-Smith PJ, Procopis PG, Wise A, Grigor WG Serious neurological complications of measles: a continuing preventable problem. Med J Aust 143:385, 1985 Lyon G, Ponsot G, Lebon P Acute measles encephalitisof the delayed type. Ann Neurol2:322, 1977 Menkes JH: Textbook of Child Neurology. 5th Ed. Lea & Febiger, Philadelphia, 1995 Park S, Kohl S: Subacute sclerosing panencephalitis in an identical twin. Pediatrics 1046, 1999 Swaiman KF: Pediatric Neurology:Principles and Practice. 2nd Ed. Mosby, St. Louis, 1993

~

SUGGESTED READINGS Aarli JA Nervous complications of measles. Eur Neurol 12:79, 1974 Behrman RE: Nelson Textbook of Pediatrics. 16th Ed. WB Saunders, Philadelphia, 2000

71

Progressive Mdtifocal Leukoencephalopathy Bradley K. Evans

Progressive multifocal leukoencephalopathy (PML), a rare disease of brain white matter, occurs in immunosuppressed patients, particularly those with acquired immunodeficiency syndrome (AIDS). JC virus, a small, circular, double-stranded DNA virus in the papovavirus family, is the causative agent. In patients with PML, JC virus infects oligodendrogliocytes. Dysfunction and death of these cells leads to demyelination, causing the symptoms of PML.

EPIDEMIOLOGY Most people have been exposed in childhood to the virus. Because some people intermittently excrete the virus in urine, it is assumed that JC virus can establish a latent infection in kidney and perhaps in other tissues as well. Reactivation of a latent JC virus infection in brain or other tissue leads to PML. Compared with JC virus in kidney, however, the JC virus in PML lesions has multiple mutations. These mutations may be important in conferring the qualities needed to produce clinical disease. Currently, more than half of patients with PML have AIDS. Because of this association, human immunodeficiency virus (HIV) testing is indicated in all patients diagnosed with PML. In HN-infected patients, the risk of developing PML during the course of their illness is approximately 2% to 5%. Although PML often is the first manifestation of HIV infection, the CD4 count in patients with AIDS and PML is very low, typically less than 50/mm3. Other causes of immunosuppression associated with PML are lymphocytic malignancies (e.g., chronic lymphocytic

leukemia and Hodgkin’s disease), organ transplantations, corticosteroid therapy, and cancer chemotherapy.

CLINICAL FEATURES PML usually progresses indolently over several weeks. Sometimes the onset seems to be more precipitous, particularly if the lesion is in a clinically vital area of the brain. Typically, PML causes one or more focal brain lesions, usually arising at the gray-white junction and later spreading into adjacent white matter. Lesions can affect the cerebral hemispheres, the cerebellum, or the brainstem, and they produce symptoms depending on their location. Typical early symptoms are hemiparesis, hemianopsia, and ataxia. Besides these signs of a focal brain lesion, which are present in approximately 75% of patients, PML may produce altered mental status (about 50% of patients), particularly late in the illness, when the lesions are multiple and large. Fever and headache are uncommon, probably no more common than in other patients with AIDS. Seizures are slightly more common in patients with AIDS and PML (10% to 20% of patients). As patients progress, they develop progressive vision loss and motor dysfunction, dementia, and incontinence.

DIAGNOSIS Blood tests seldom aid in the diagnosis. Some patients with PML may have a high cerebrospinal fluid myelin basic protein level, reflecting intense myelin breakdown, but this is a nonspecific

Chapter 71

finding. Routine spinal fluid tests usually are normal. However, JC virus polymerase chain reaction (PCR) on spinal fluid can be a helpful test. The false-positive rate is about 10% and the false-negative rate about 30%. PCR can be quantified, and this can be prognostically helpful because patients with high viral loads do worse than those with low viral loads. Neuroimaging, particularly head magnetic resonance imaging (MRI), is the key test in this disorder. The MRI shows one or more hyperintense lesions on T2-weighted imaging. These lesions do not have mass effect and do not generally enhance. The lesions are focal, in contrast to AIDS-dementia complex, in which the MRI shows diffuse changes in both cerebral hemispheres. Head computed tomography (CT) is less sensitive than the head MRI (rarely, head MRI may be normal in patients with PML). In patients with PML, head CT typically shows one or more hypolucent lesions, without mass effect and without enhancement (Fig. 71- 1). These neuroimaging findings, although highly suggestive of PML, are not diagnostic: Focal virus encephalitis caused by cytomegalovirus(CMV) infection or herpes zoster can produce an identical radiologic picture. Thus, the keys to the diagnosis are recognition of the patient’s immunosuppressed state and proper interpretation of the MRI. In an immunosuppressed patient with a typical clinical picture and neuroimaging findings, the diagnosis may be made presumptively, without tissue confirmation. This occurs particularly if the patient is too ill to undergo a biopsy, if lesions are in areas difficult to biopsy, or if vigorous treatment is not contemplated. Definitive diagnosis is by brain biopsy, usually done stereotactically. Because biopsies from patients with PML can be misread as a demyelinating plaque, an astrocytoma, or viral encephalitis, pathologists must stain and examine tissue from these biopsies carefully. By light microscopy, PML produces demyelination, giant astrocytes that have bizarre nuclei or are multinucleate (mimicking cell changes seen in astrocytomas), and oligodendroglial cells with intranuclear inclusions that can be eosinophilic or basophilic. These inclusions are crystalline masses of viral particles, which immunostain for JC virus. Immunostaining definitely identifies the inclusions as JC virus and not CMV or the varicella-zoster virus.

489

Progressive Multifocal Leukoencephalopathy

In HIV-infected patients, the differential diagnosis of PML is central nervous system (CNS) toxoplasmosis, CNS lymphoma, AIDS-dementia complex, focal viral encephalitis, and multiple concomitant brain diseases. CNS toxoplasmosis and CNS lymphoma are more rapid illnesses, often progressing over a few days to weeks. Seizures, altered mental status, and headache are more common in these two illnesses than in PML, and neuroimaging in these conditions shows lesions with mass effect and enhancement. AIDS-dementia complex presents with altered mental status and no focal findings. CMV and herpes zoster can cause focal encephalitis that can mimic PML clinically, radiologically, and pathologically. Finally, it is important to remember that 20% of patients with AIDS and focal lesions by head CT or MRI have nondiagnostic brain biopsies. If a patient is not recognized as being immunosuppressed,PML may be mistaken for ischemic stroke, multiple sclerosis, a leukodystrophy, or a low-grade glioma.

TREATMENT PML progresses inexorably to death in nearly all patients. The average survival is 4 months in patients with AIDS and 9 months in patients with other types of immune suppression. In 2% to 5% of patients, the disease may “burn out.” The chance that this will happen probably is greater in patients who have inflammatory changes on brain biopsy (reflecting an active immune response) and in patients who have mild and reversible immune suppression. In patients with AIDS, treatment with highly active antiretroviral therapy may reverse immune suppression and lead to resolution of symptoms and signs of PML. No specific, effective treatment for PML is known. Because JC virus can be grown in cell culture, possible treatments for PML can first be tested in the laboratory. Cytosine arabinoside, in cell culture at dosages achievable therapeutically, successfully inhibits JC virus replication, but cytosine arabinoside was an ineffective treatment in a large placebo study. Other specific therapies, such as interferon-a and cidofovir, are in clinical trials.

A

B

FIG. 71-1. (A) Contrast-enhanced CT scan of the head of an irnrnunocornprornised patient with PML In both occipital lobes there are patchy hypolucent lesions, without mass effect and without enhancement. (6) T2-weighted MRI scan of the same patient showing the characteristic findings in PML of focal, hyperintense lesions without mass effect.

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Immune and Infectious Disease W Viral Infections

SUGGESTED READINGS Berger JR: AIDS and the nervous system. p. 757. In Aminoff M (ed): Neurology and General Medicine. Churchill Livingstone, New York, 1995 Brew BJ: Progressivemultifocal leukoencephalopathy.Chapter 13. In Brew BJ: HIV Neurology. Oxford University Press, New York, 2001 Cinque P, Scarpelhi P, Vago L et al: Diagnosis of central nervous system

72

complications in HIV infected patients: cerebrospinal fluid analysisby polymerase chain reaction. AIDS 11:1, 1997 Clifford D, Yiannoutsos C, Glicksman M et al: HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 52:623, 1999 Tornatore C, Berger JR, Houff SA et ak Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy.Ann Neurol 3 1:454, 1992

Rabies Patrick E. Nolan

Rabies is an ancient, almost uniformly fatal infectious disease in which the clinical manifestations are distinctly neurologic, most often causing an encephalitis. It is caused by an RNA virus of the rhabdovirus family and is primarily a disease of animals, with most human infections developing after an animal bite. Although rabies claims fewer than a dozen victims in America each year, more than 1 million Americans are bitten by animals annually, making at least the specter of infection a common health problem.

EPIDEMIOLOGY Because it is a zoonotic disease, the frequency of occurrence is directly related to the animal reservoir in a given locale. In developing countries, the primary reservoir is domestic dogs and cats. Except on the Texas/Mexico border, there is essentially no endemic domestic rabies in the United States, and most cases of human rabies are imported by patients exposed to dogs or cats in foreign countries. The few exposures occurring in the United States usually involve wild carnivores, with only 10% traced to domestic animals infected by the endemic wildlife reservoir. The main responsible species is the skunk, and less common sources are racoons, foxes, wolves, and bats. Bats are an insidious source in that most infections retrospectively identified by isolation of bat-associated strains occur in patients who cannot recall any exposure to bats. An important rule regarding the implicated species is that an unprovoked attack by any animal is cause for concern. (Bites or scratches that occur while petting or feeding animals are considered provoked in most circumstances.) Among domestic animals, cats are implicated more often than dogs because of the tighter controls and regulations of rabies vaccination in dogs and the more independent and predatory nature of cats. Animal saliva and central nervous system tissue are considered the only infectious material when determining what constitutes an exposure. Dried secretions and blood, feces, and urine are not considered contagious. An animal bite with a break in the skin and contamination of the wound with rabid saliva is the most efficient route of transmission. Nonbite exposures rarely transmit infection, but high-risk animal contamination of an open wound or mucous membrane warrants intervention. Aerosolization of virus in bat-infested caves and transplantation of infected human tissue, especially corneas, have been the most efficient nonbite exposures. Simple contact such as petting a rabid animal does not constitute a significant exposure. The risk of infections to humans after

significant exposure to a rabid animal is variable: 5% to 80% after a bite and 0.1% to 1% after a scratch.

CLINICAL FEATURES After infection, the rabies virus is sequestered at the local site of the bite or wound and probably replicates as an intracellular infection of local skeletal muscle cells. This partially explains the long incubation period of 30 to 90 days (and occasionally more than a year) in humans. (The incubation period in domestic animals is only 3 to 5 days and is the basis for holding animals for observation in questionable cases of transmission.) Spread occurs out of the muscles by way of peripheral nerves back to the spinal ganglia and central nervous system, where the virus appears most concentrated in the gray matter of the limbic system and lower brain. Subsequently, the virus may spread outward via autonomic nerves to almost every organ system, including the salivary glands, which can transmit the virus through infected saliva. The clinical manifestations of rabies include the prodrome, the acute neurologic period or second phase, and the final phase of coma and death. The prodrome lasts 1 to 4 days and is very nonspecific, with low-grade fever, malaise, gastrointestinal upset, cough, and headache. In 50% to 80% of patients, pain, paresthesias, or pruritus develops at the site of the bite. Subtle neurologic changes herald the second phase, with confusion and anxiety progressing to agitation, combativeness, and excessive motor activity. Aggressive behavior with a waxing and waning pattern may occur with intervals of normal mental status. Hallucinations are common. Vocal paralysis, hyperreflexia, and ataxia paint a distinctive picture of the acute neurologic phase. Muscle contractions with jerking movements and facial grimacing are characteristic, with contractures of the pharynx and larynx occurring with attempts to swallow liquids. Hydrophobia refers to episodes of uncontrolled muscle spasm, lasting 1 to 5 minutes. precipitated by attempts to drink water. Choking, gagging, hypersalivation, diplopia, optic neuritis, and facial palsies are further evidence of brainstem and cranial nerve dysfunction. Such brainstem involvement helps distinguish rabies from other viral encephalitides and accounts for its fulminantly fatal course. This presentation characterizes approximately 80% of cases and is called classic or furious rabies. The remaining 20% of patients may manifest so-called paralytic rabies. In this presentation, an ascending paralysis, either symmetrical or asymmetrical, is the predominant presentation.

490

Immune and Infectious Disease W Viral Infections

SUGGESTED READINGS Berger JR: AIDS and the nervous system. p. 757. In Aminoff M (ed): Neurology and General Medicine. Churchill Livingstone, New York, 1995 Brew BJ: Progressivemultifocal leukoencephalopathy.Chapter 13. In Brew BJ: HIV Neurology. Oxford University Press, New York, 2001 Cinque P, Scarpelhi P, Vago L et al: Diagnosis of central nervous system

72

complications in HIV infected patients: cerebrospinal fluid analysisby polymerase chain reaction. AIDS 11:1, 1997 Clifford D, Yiannoutsos C, Glicksman M et al: HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 52:623, 1999 Tornatore C, Berger JR, Houff SA et ak Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy.Ann Neurol 3 1:454, 1992

Rabies Patrick E. Nolan

Rabies is an ancient, almost uniformly fatal infectious disease in which the clinical manifestations are distinctly neurologic, most often causing an encephalitis. It is caused by an RNA virus of the rhabdovirus family and is primarily a disease of animals, with most human infections developing after an animal bite. Although rabies claims fewer than a dozen victims in America each year, more than 1 million Americans are bitten by animals annually, making at least the specter of infection a common health problem.

EPIDEMIOLOGY Because it is a zoonotic disease, the frequency of occurrence is directly related to the animal reservoir in a given locale. In developing countries, the primary reservoir is domestic dogs and cats. Except on the Texas/Mexico border, there is essentially no endemic domestic rabies in the United States, and most cases of human rabies are imported by patients exposed to dogs or cats in foreign countries. The few exposures occurring in the United States usually involve wild carnivores, with only 10% traced to domestic animals infected by the endemic wildlife reservoir. The main responsible species is the skunk, and less common sources are racoons, foxes, wolves, and bats. Bats are an insidious source in that most infections retrospectively identified by isolation of bat-associated strains occur in patients who cannot recall any exposure to bats. An important rule regarding the implicated species is that an unprovoked attack by any animal is cause for concern. (Bites or scratches that occur while petting or feeding animals are considered provoked in most circumstances.) Among domestic animals, cats are implicated more often than dogs because of the tighter controls and regulations of rabies vaccination in dogs and the more independent and predatory nature of cats. Animal saliva and central nervous system tissue are considered the only infectious material when determining what constitutes an exposure. Dried secretions and blood, feces, and urine are not considered contagious. An animal bite with a break in the skin and contamination of the wound with rabid saliva is the most efficient route of transmission. Nonbite exposures rarely transmit infection, but high-risk animal contamination of an open wound or mucous membrane warrants intervention. Aerosolization of virus in bat-infested caves and transplantation of infected human tissue, especially corneas, have been the most efficient nonbite exposures. Simple contact such as petting a rabid animal does not constitute a significant exposure. The risk of infections to humans after

significant exposure to a rabid animal is variable: 5% to 80% after a bite and 0.1% to 1% after a scratch.

CLINICAL FEATURES After infection, the rabies virus is sequestered at the local site of the bite or wound and probably replicates as an intracellular infection of local skeletal muscle cells. This partially explains the long incubation period of 30 to 90 days (and occasionally more than a year) in humans. (The incubation period in domestic animals is only 3 to 5 days and is the basis for holding animals for observation in questionable cases of transmission.) Spread occurs out of the muscles by way of peripheral nerves back to the spinal ganglia and central nervous system, where the virus appears most concentrated in the gray matter of the limbic system and lower brain. Subsequently, the virus may spread outward via autonomic nerves to almost every organ system, including the salivary glands, which can transmit the virus through infected saliva. The clinical manifestations of rabies include the prodrome, the acute neurologic period or second phase, and the final phase of coma and death. The prodrome lasts 1 to 4 days and is very nonspecific, with low-grade fever, malaise, gastrointestinal upset, cough, and headache. In 50% to 80% of patients, pain, paresthesias, or pruritus develops at the site of the bite. Subtle neurologic changes herald the second phase, with confusion and anxiety progressing to agitation, combativeness, and excessive motor activity. Aggressive behavior with a waxing and waning pattern may occur with intervals of normal mental status. Hallucinations are common. Vocal paralysis, hyperreflexia, and ataxia paint a distinctive picture of the acute neurologic phase. Muscle contractions with jerking movements and facial grimacing are characteristic, with contractures of the pharynx and larynx occurring with attempts to swallow liquids. Hydrophobia refers to episodes of uncontrolled muscle spasm, lasting 1 to 5 minutes. precipitated by attempts to drink water. Choking, gagging, hypersalivation, diplopia, optic neuritis, and facial palsies are further evidence of brainstem and cranial nerve dysfunction. Such brainstem involvement helps distinguish rabies from other viral encephalitides and accounts for its fulminantly fatal course. This presentation characterizes approximately 80% of cases and is called classic or furious rabies. The remaining 20% of patients may manifest so-called paralytic rabies. In this presentation, an ascending paralysis, either symmetrical or asymmetrical, is the predominant presentation.

Chapter72 W

This may mimic Guillain-Barre syndrome. For unclear reasons, paralytic rabies is more common after exposure to bats. It may also complicate the more primitive neural tissue-derived rabies vaccines still used in some developing countries. The final phase is characterized by autonomic instability, dysrhythmias, coma, and death from a brainstem respiratory center damage. Survival after the onset of neurologic symptoms is only 4 to 20 days. Only three survivors have been reported from clinical human rabies, and these patients received partial passive and active immunization before onset of symptoms. DIAGNOSIS

The differential diagnosis includes the spectrum of unexplained encephalitis. Botulism, cerebral malaria, epilepsy, metabolic encephalopathy, illicit drug effect, rabies hysteria, rickettsial disease, stroke, tetanus, and arboviral encephalitis might all be considered, depending on the clinical presentation. The diagnosis can be confirmed by viral isolation from the saliva or cerebrospinal fluid (CSF), but this takes a minimum of 6 days. Rabies antibody levels can be detected in the serum or CSF but occasionally are negative early in the illness. Direct fluorescent

Rabies

antibody staining for antigen detection on saliva, a corneal impression, or a skin biopsy from the nape of the neck has a diagnostic sensitivityof 50% to 90% and a diagnostic specificity of almost 100%. This test usually is positive before antibody formation and probably is the best test available. Brain biopsy specimens demonstrating the characteristic cytoplasmic inclusion bodies known as Negri bodies may help confirm the diagnosis. TREATMENT

Determining when to treat after a possible exposure can be difficult, and the algorithm in Figure 72-1 provides some broad guidance. Treatment consists of a triadic approach with local wound care, passive immunoglobulin administration, and active immunization with rabies vaccine, all vitally important. The only clinical failures have been related to failure to properly perform all three steps in this approach: Local wound care consists of a thorough and vigorous cleaning of the wound with soap and water. This can significantly reduce the risk in superficial wounds, as has been appreci-

Is rabies known or suspected in that species in that area?

Yes

/

No

No treatment

Was the animal captured for quarantine?

Treat for rabies Does the animal have evidence of rabies (clinical illness or fluorescent antibody staining of the brain)?

Treat for rabies

491

No treatment

FIG. 72-1. Treatment algorithm for a person bitten or licked on an open wound by a possibly rabid animal.

492

Immune and infectious Disease

Viral Infections

ated since the time of Celsius in A.D. 100, when he recommended excising and cauterizing the wound. Quaternary ammonium compounds such as benzalkonium chloride may also be used as cleansers. Tetanus toxoid often is used as well. Passive immunization is accomplished using human rabies immunoglobulin (HRIG). Administration of 200 IU/kg of HRIG at the time of exposure offers antibody protection during the initial 2-week period before the active vaccine has elicited an antibody response. One-half of this dosage is infiltrated into the wound, and the other half is injected intramuscularly at a site different from the vaccine and with a syringe that is not used for the vaccine. Active immunization is provided by the human diploid cell vaccine (HDCV), administered in five 1-mL intramuscular doses on days 1 , 3 , 7 , 14, and 28. These doses should always be injected in the deltoid muscle, as failures have occurred with gluteal injections. Note that veterinarians and others with a high risk of exposure to the rabies virus may consider preexposure prophylaxis. The

73

preferred regimen uses three intramuscular injections of HDCV on days 1, 7, and 28. A neutralizing antibody titer should be checked after vaccination. Local and state health departments are good resources when a question arises regarding decisions of preexposure or postexposure prophylaxis. The Division of Viral and Rickettsial Diseases at the Centers for Disease Control and Prevention in Atlanta is also available for rabies advice, at (404) 639-1075 during working hours or (404) 639-2888 after hours.

SUGGESTED READINGS Baer GM, Fishbein DB: Rabies postexposure prophylaxis. N Engl J Med 3161270, 1987. Corden TE, Kazmierczak JJ: Rabies prevention. WMJ 99:47-50, 2000 Fishbein DB, Robinson L E Rabies. N Engl J Med 329:1632, 1993 Hoff GL, Mellon GF, Thomas MC, Geidinghagen DH: Bats, cats and rabies in an urban community. South Med J 86:1115, 1993 Rosenthal KE, Thornton GF: The ten most common questions about rabies. Infect Dis Clin Pract 3:44, 1993

Lymphocytic Choriomeningitis Clifford C. Dacso

Lymphocytic choriomeningitis (LCM) virus is a member of the Arenavirus family of pleomorphic single-stranded RNA viruses. All arenaviruses exist in a rodent reservoir, and humans are accidental hosts. Other members of the group include the Old World species such as Lassa virus and the Tacaribe virus complex. Like the others in its class, LCM virus produces asymptomatic infections in rodents but can be devastating in humans. EPIDEMIOLOGY LCM virus is ubiquitous in European and American mice. There is no reason to suspect that the virus is not present in other parts of the world, although it has not been definitively identified. Infection is more common in the autumn and winter when infected mice escape the cold and appears to be related to contact with infected mouse urine. Laboratory workers who handle hamsters and mice are particularly at risk. Transmission is by direct inoculation or aerosol, although the route of transmission is not clear in many cases. Infections are isolated, not epidemic, and human-to-human transmission has not been reported. CLINICAL FEATURES After infection, two separate syndromes of LCM may appear (Table 73-1). The first is an influenza-like syndrome, with arthralgias, pharyngitis, and orchitis beginning a few days after infection and lasting 3 to 10 days. Liver enzymes may rise slightly, and a chest radiograph may show basilar pneumonitis. Meningitis usually appears 2 to 3 weeks after inoculation. Typically, the acute viral illness appears first, followed by meningitis in 2 weeks. Fever, headache, and pharynnitis . , - are prominent signs. Relapse is common within a few days or weeks I

after apparent recovery. In mice, the meningitis, when it occurs, is attributed not to the direct infection but rather to a cell-mediated immune reaction. This reaction may contribute to the pathogenesis of the disease in humans also, although virus has been recovered from the spinal fluid of infected patients. DIAGNOSIS The peripheral blood usually shows mildly elevated liver enzymes, neutropenia, and thrombocytopenia. The cerebrospinal fluid has a lymphocytic pleocytosis with a few hundred cells per microliter. As opposed to several other viral meningitides, LCM infection shows hypoglycorrhachia in a quarter of cases. Although the virus can be isolated from the spinal fluid, it is a dangerous procedure and should be performed only in laboratories equipped to handle arenaviruses. The diagnosis is commonly made by direct immunofluorescence of cells in the cerebrospinal fluid or by serologic response using enzyme-linked immunosorbent assay or radioimmunoassay. With the exception of specific

TABLE 73-1. Signs and Symptoms of Lymphocytic Choriomeningitis infection Sign or Symptom

Fever and chills Malaise, weakness Retro-orbital headache Photophobia Anorexia, nausea Pharyngitis Vomitinn DysesthGsia

Frequency (96)

75-1 00 50-75 50-75 50-75 50-75 25-50 25-50 25-50

492

Immune and infectious Disease

Viral Infections

ated since the time of Celsius in A.D. 100, when he recommended excising and cauterizing the wound. Quaternary ammonium compounds such as benzalkonium chloride may also be used as cleansers. Tetanus toxoid often is used as well. Passive immunization is accomplished using human rabies immunoglobulin (HRIG). Administration of 200 IU/kg of HRIG at the time of exposure offers antibody protection during the initial 2-week period before the active vaccine has elicited an antibody response. One-half of this dosage is infiltrated into the wound, and the other half is injected intramuscularly at a site different from the vaccine and with a syringe that is not used for the vaccine. Active immunization is provided by the human diploid cell vaccine (HDCV), administered in five 1-mL intramuscular doses on days 1 , 3 , 7 , 14, and 28. These doses should always be injected in the deltoid muscle, as failures have occurred with gluteal injections. Note that veterinarians and others with a high risk of exposure to the rabies virus may consider preexposure prophylaxis. The

73

preferred regimen uses three intramuscular injections of HDCV on days 1, 7, and 28. A neutralizing antibody titer should be checked after vaccination. Local and state health departments are good resources when a question arises regarding decisions of preexposure or postexposure prophylaxis. The Division of Viral and Rickettsial Diseases at the Centers for Disease Control and Prevention in Atlanta is also available for rabies advice, at (404) 639-1075 during working hours or (404) 639-2888 after hours.

SUGGESTED READINGS Baer GM, Fishbein DB: Rabies postexposure prophylaxis. N Engl J Med 3161270, 1987. Corden TE, Kazmierczak JJ: Rabies prevention. WMJ 99:47-50, 2000 Fishbein DB, Robinson L E Rabies. N Engl J Med 329:1632, 1993 Hoff GL, Mellon GF, Thomas MC, Geidinghagen DH: Bats, cats and rabies in an urban community. South Med J 86:1115, 1993 Rosenthal KE, Thornton GF: The ten most common questions about rabies. Infect Dis Clin Pract 3:44, 1993

Lymphocytic Choriomeningitis Clifford C. Dacso

Lymphocytic choriomeningitis (LCM) virus is a member of the Arenavirus family of pleomorphic single-stranded RNA viruses. All arenaviruses exist in a rodent reservoir, and humans are accidental hosts. Other members of the group include the Old World species such as Lassa virus and the Tacaribe virus complex. Like the others in its class, LCM virus produces asymptomatic infections in rodents but can be devastating in humans. EPIDEMIOLOGY LCM virus is ubiquitous in European and American mice. There is no reason to suspect that the virus is not present in other parts of the world, although it has not been definitively identified. Infection is more common in the autumn and winter when infected mice escape the cold and appears to be related to contact with infected mouse urine. Laboratory workers who handle hamsters and mice are particularly at risk. Transmission is by direct inoculation or aerosol, although the route of transmission is not clear in many cases. Infections are isolated, not epidemic, and human-to-human transmission has not been reported. CLINICAL FEATURES After infection, two separate syndromes of LCM may appear (Table 73-1). The first is an influenza-like syndrome, with arthralgias, pharyngitis, and orchitis beginning a few days after infection and lasting 3 to 10 days. Liver enzymes may rise slightly, and a chest radiograph may show basilar pneumonitis. Meningitis usually appears 2 to 3 weeks after inoculation. Typically, the acute viral illness appears first, followed by meningitis in 2 weeks. Fever, headache, and pharynnitis . , - are prominent signs. Relapse is common within a few days or weeks I

after apparent recovery. In mice, the meningitis, when it occurs, is attributed not to the direct infection but rather to a cell-mediated immune reaction. This reaction may contribute to the pathogenesis of the disease in humans also, although virus has been recovered from the spinal fluid of infected patients. DIAGNOSIS The peripheral blood usually shows mildly elevated liver enzymes, neutropenia, and thrombocytopenia. The cerebrospinal fluid has a lymphocytic pleocytosis with a few hundred cells per microliter. As opposed to several other viral meningitides, LCM infection shows hypoglycorrhachia in a quarter of cases. Although the virus can be isolated from the spinal fluid, it is a dangerous procedure and should be performed only in laboratories equipped to handle arenaviruses. The diagnosis is commonly made by direct immunofluorescence of cells in the cerebrospinal fluid or by serologic response using enzyme-linked immunosorbent assay or radioimmunoassay. With the exception of specific

TABLE 73-1. Signs and Symptoms of Lymphocytic Choriomeningitis infection Sign or Symptom

Fever and chills Malaise, weakness Retro-orbital headache Photophobia Anorexia, nausea Pharyngitis Vomitinn DysesthGsia

Frequency (96)

75-1 00 50-75 50-75 50-75 50-75 25-50 25-50 25-50

Chapter 74 W Rubella

serology, the disease often is indistinguishable from other viral encephalitides.

TREATMENT There is no effective treatment for LCM, although recovery from meningitis is almost universal. On the rare occasions when encephalitis supervenes, residual neurologic deficits can be seen in a quarter of the patients.

SUGGESTED READINGS

493

Borrow P, Oldstone MB: Mechanism of lymphocytic choriomeningitis virus entry into cells. Virology 198:1, 1994 Hammer SM, Connolly KJ: Viral aseptic meningitis in the United States: clinical features, viral etiologies, and differential diagnosis. Curr Clin Top Infect Dis 12:1, 1992 Jahrling PB, Peters CJ: Lymphocytic choriomeningitis virus: a neglected pathogen of man. Arch Pathol Lab Med 116486, 1992 Stephensen CB, Blount SR, Lanford RE et ak Prevalence of serum antibodies against lymphocytic choriomeningitis virus in selected populations from two U.S. cities. J Med Virol 38:27, 1992 Turkovic B, Ljubicic M: ELSA and indirect immunofluorescence in the diagnosis of LCM virus infections. Acta Virol 36576, 1992

Barton L L Lymphocytic choriomeningitis virus: pediatric pathogen and fetal teratogen. Pediatr Infect Dis J 1854C541, 1999

74

Rubella Diana L. Rodriguez

Rubella is caused by an RNA virus. Except in cases of congenital infection, the virus usually causes a mild exanthematous, infectious illness with low morbidity and mortality rates. Before the introduction of the rubella vaccine in 1969, children were the most commonly affected, but now most cases appear in adolescents and young adults. In 1941, Australian ophthalmologist Gregg reported congenital defects in babies of mothers who had rubella during early pregnancy. This led to the recognition of the congenital rubella syndrome (CRS), a postnatal manifestation of a prenatally acquired infection. Neurologic damage may complicate CRS or adult acquired disease.

EPIDEMIOLOGY Rubella occurs worldwide. Epidemics occur every 6 to 9 years and pandemics every 10 to 30 years. The last worldwide pandemic occurred from 1962 to 1964. During this time in the United States, there were 12.5 million cases of acquired rubella. There were also 11,000 fetal deaths, and 20,000 infants were born with defects consistent with CRS, 2100 of whom died. Since the introduction of routine vaccination during infancy, rubella activity has decreased by 99%. In recent years, however, rubella outbreaks have occurred in prisons, colleges and universities, hospitals, and among office workers. In community epidemics, attack rates in susceptible people are estimated to range from 50% to 90%. Humans are the only natural host for rubella. It is spread by the respiratory route, and infected people shed large concentrations of the virus from the nose and throat. Rubella occurs seasonally, mostly in the winter and spring. In adults, more cases of rubella are reported in women than in men, but this finding may be more related to concern about CRS than to a true difference on the basis of sex.

CLINICAL FEATURES Postnatally acquired rubella infection generally is a very benign, exanthemous infection, and symptoms typically are more pronounced in adults than in children. The incubation period usually is 14 to 21 days. In children, there are typically no prodromal

symptoms; the first symptom usually is the rash. In older people, however, the rash usually is preceded by 1 to 5 days of prodromal symptoms, which may include low-grade fever, headache, malaise, anorexia, mild conjunctivitis and eye pain, coryza, pharyngitis, cough, and tender lymphadenopathy (suboccipital, postauricular, or cervical nodes). An enanthem (Forchheimer spots) consisting of small, red macules on the soft palate occasionally precedes or accompanies the rash. Once the exanthem becomes apparent, the prodromal symptoms subside. The characteristic rash is pruritic, appears erythematous and maculopapular, and lasts 1 to 5 days or longer. In contrast to the measles exanthem, the rash usually is less coppery and pinker in appearance and heals with desquamation or brownish discoloration. The duration of illness in uncomplicated rubella is variable. Most patients would continue normal activity if the rash were not present, In general, full return to normal activity occurs within 3 days. Treatment is symptomatic.

NEUROLOGIC COMPLICATIONS Neurologic sequelae of rubella infection are uncommon; a conservative estimate of the complication rate is approximately 1 in 5000 to 6000 cases. They usually take the form of CRS in children or an encephalitis or encephalomyelitis from acquired infections in both children and adults.

Congenital Rubella Syndrome CRS is a multisystem disease characterized by intrauterine growth retardation, cataracts, chorioretinitis, congenital heart disease, sensorineural deafness, hepatosplenomegaly, jaundice, anemia, thrombocytopenia, and rash. Approximately 5% to 25% of women of childbearing age do not have rubella antibodies and therefore are at risk for primary infection. Transplacental transmission of the infection occurs via maternal viremia. Although as many as two thirds of proven congenitally infected infants may be asymptomatic at birth, almost 75% of them

Chapter 74 W Rubella

serology, the disease often is indistinguishable from other viral encephalitides.

TREATMENT There is no effective treatment for LCM, although recovery from meningitis is almost universal. On the rare occasions when encephalitis supervenes, residual neurologic deficits can be seen in a quarter of the patients.

SUGGESTED READINGS

493

Borrow P, Oldstone MB: Mechanism of lymphocytic choriomeningitis virus entry into cells. Virology 198:1, 1994 Hammer SM, Connolly KJ: Viral aseptic meningitis in the United States: clinical features, viral etiologies, and differential diagnosis. Curr Clin Top Infect Dis 12:1, 1992 Jahrling PB, Peters CJ: Lymphocytic choriomeningitis virus: a neglected pathogen of man. Arch Pathol Lab Med 116486, 1992 Stephensen CB, Blount SR, Lanford RE et ak Prevalence of serum antibodies against lymphocytic choriomeningitis virus in selected populations from two U.S. cities. J Med Virol 38:27, 1992 Turkovic B, Ljubicic M: ELSA and indirect immunofluorescence in the diagnosis of LCM virus infections. Acta Virol 36576, 1992

Barton L L Lymphocytic choriomeningitis virus: pediatric pathogen and fetal teratogen. Pediatr Infect Dis J 1854C541, 1999

74

Rubella Diana L. Rodriguez

Rubella is caused by an RNA virus. Except in cases of congenital infection, the virus usually causes a mild exanthematous, infectious illness with low morbidity and mortality rates. Before the introduction of the rubella vaccine in 1969, children were the most commonly affected, but now most cases appear in adolescents and young adults. In 1941, Australian ophthalmologist Gregg reported congenital defects in babies of mothers who had rubella during early pregnancy. This led to the recognition of the congenital rubella syndrome (CRS), a postnatal manifestation of a prenatally acquired infection. Neurologic damage may complicate CRS or adult acquired disease.

EPIDEMIOLOGY Rubella occurs worldwide. Epidemics occur every 6 to 9 years and pandemics every 10 to 30 years. The last worldwide pandemic occurred from 1962 to 1964. During this time in the United States, there were 12.5 million cases of acquired rubella. There were also 11,000 fetal deaths, and 20,000 infants were born with defects consistent with CRS, 2100 of whom died. Since the introduction of routine vaccination during infancy, rubella activity has decreased by 99%. In recent years, however, rubella outbreaks have occurred in prisons, colleges and universities, hospitals, and among office workers. In community epidemics, attack rates in susceptible people are estimated to range from 50% to 90%. Humans are the only natural host for rubella. It is spread by the respiratory route, and infected people shed large concentrations of the virus from the nose and throat. Rubella occurs seasonally, mostly in the winter and spring. In adults, more cases of rubella are reported in women than in men, but this finding may be more related to concern about CRS than to a true difference on the basis of sex.

CLINICAL FEATURES Postnatally acquired rubella infection generally is a very benign, exanthemous infection, and symptoms typically are more pronounced in adults than in children. The incubation period usually is 14 to 21 days. In children, there are typically no prodromal

symptoms; the first symptom usually is the rash. In older people, however, the rash usually is preceded by 1 to 5 days of prodromal symptoms, which may include low-grade fever, headache, malaise, anorexia, mild conjunctivitis and eye pain, coryza, pharyngitis, cough, and tender lymphadenopathy (suboccipital, postauricular, or cervical nodes). An enanthem (Forchheimer spots) consisting of small, red macules on the soft palate occasionally precedes or accompanies the rash. Once the exanthem becomes apparent, the prodromal symptoms subside. The characteristic rash is pruritic, appears erythematous and maculopapular, and lasts 1 to 5 days or longer. In contrast to the measles exanthem, the rash usually is less coppery and pinker in appearance and heals with desquamation or brownish discoloration. The duration of illness in uncomplicated rubella is variable. Most patients would continue normal activity if the rash were not present, In general, full return to normal activity occurs within 3 days. Treatment is symptomatic.

NEUROLOGIC COMPLICATIONS Neurologic sequelae of rubella infection are uncommon; a conservative estimate of the complication rate is approximately 1 in 5000 to 6000 cases. They usually take the form of CRS in children or an encephalitis or encephalomyelitis from acquired infections in both children and adults.

Congenital Rubella Syndrome CRS is a multisystem disease characterized by intrauterine growth retardation, cataracts, chorioretinitis, congenital heart disease, sensorineural deafness, hepatosplenomegaly, jaundice, anemia, thrombocytopenia, and rash. Approximately 5% to 25% of women of childbearing age do not have rubella antibodies and therefore are at risk for primary infection. Transplacental transmission of the infection occurs via maternal viremia. Although as many as two thirds of proven congenitally infected infants may be asymptomatic at birth, almost 75% of them

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develop long-term sequelae within the first 5 years of life. Clinical manifestations, when present, often are very apparent (Table 74-1). Growth retardation is apparent at birth. Eye findings are common and include cataracts (usually present at birth), pigmentary or "salt-and-pepper'' retinopathy (Fig. 74-1), microphthalmia (usually unilateral), and congenital glaucoma. Sensorineural hearing loss, which is most often bilateral, is another very common finding; some degree of hearing loss is noted in almost all patients. Cardiac findings may be a cause of early infant morbidity and mortality and include myocarditis and a variety of structural anomalies. Central nervous system manifestations in congenitally infected infants are pervasive. Signs and symptoms may occur at birth or become apparent as the child grows and matures. Ten to 20 percent of congenitally infected infants have active meningoencephalitis at birth. Findings may include a large, full, or bulging anterior fontanel, irritability, hypotonia, seizures (usually not observed until after the neonatal period), lethargy, disturbances of tone, and head retraction with arching of the back. The seizures, which may occur in 25% of infected infants, are most commonly minor motor seizures or abrupt vasomotor changes. Cerebrospinal fluid (CSF) examination reveals an elevated protein content and a mild pleocytosis; rubella virus often can be isolated from the CSF. By 1 to 4 months of age, affected children may demonstrate irritability, restlessness, vasomotor instability, photophobia, opisthotonic posturing, and developmental delay. Remarkably, however, between 6 and 12 months of age, approximately one half of these infants appear to improve and acquire developmental milestones. Later neurologic disease, such as mental and motor retardation, can be related to the severity and persistence of the initial meningoencephalitis. Active central nervous system infection has been demonstrated for 1 year or more, and rubella virus has been isolated from the CSF as long as 18 months after birth. Behavior disorders often are seen in children with deafness but cannot always be associated with a preceding meningoencephalitis. Reactive behavior disorders and infantile autism may occur. Children with CRS and generalized growth retardation but a proportionally small head size often have normal intelligence. In contrast, the prognosis for mental development in a child with true microcephaly is poor.

Acquired Adult Rubella Rubella can be associated with postinfectious encephalitis and/or myelitis. Postrubella encephalomyelitis tends to be a more severe but shorter illness than measles postinfectious encephalitis and is an acute demyelinating, possibly autoimmune disease with

W

TABU74-1. Manifestations of Congenital Rubella Syndrome Manifestation

Percent

Deafness 67 Heart disease 48 Psychomotor retardation 45 Chorioretinitis 39 22 Thrombocytopenia 15 Bilateral cataracts 13 Unilateral cataracts 12 Spasticity 3 Glaucoma Modified from Cooper LT,Ziring PR, Ockerse AB et al: Rubella: clinical manifestations and management. Am J Dis Child 118:18, 1969, with permission.

FIG. 74-1. Rubella "salt-and-pepper" retinopathy. (Courtesy of Dr. Richard A. Lewis, Baylor College of Medicine, Houston, Tx)

numerous foci of demyelination (surrounding small- and medium-sized vessels) throughout the brain and spinal cord. The onset of the encephalomyelitic syndrome most often occurs 2 to 4 days after the appearance of rash, but occasionally rash and neurologic symptoms occur at the same time; in other instances, the appearance of encephalitis is delayed as much as 1 week after the onset of illness. Typically, the rash is fading and other symptoms are improving when the patient suddenly develops a recrudescence of fever, headache, neck stiffness, convulsions, stupor, and deepening coma. Coma and seizures are more common than in measles encephalitis and carry a poor prognosis. Other less common manifestations include hemiplegia and evidence of cerebellar disease (such as ataxia) and occasionally spinal cord disease. With spinal cord involvement, there may be partial or complete paraplegia or quadriplegia, diminution or loss of reflexes, sensory impairment, and varying degrees of paralysis of bladder and bowel. Myoclonic movements or choreoathetosis may be observed. The mortality rate for rubella encephalomyelitis is approximately 20% and most patients die early in the course of the illness, usually in the first 3 days. Despite the gravity of the illness, recovery usually is complete, with most cases returning to baseline neurologic function in approximately 2 weeks. Another grave illness associated with rubella is a progressive rubella panencephalitis syndrome, which is now rare; no new cases have been reported in the last decade. Four to 14 years after either a congenital or acquired rubella infection, patients developed a progressive, insidious dementia, often associated with seizures. Clumsiness of gait was an early symptom, followed by frank ataxia of gait and then of the limbs. Death usually occurred 3 to 8 years after the onset of new neurologic symptoms. Thus, it appears that rubella virus infection, acquired in utero or in the postnatal period, may persist in the nervous system for years before rekindling a chronic active infection. Finally, other less common entities previously associated with rubella infection bear mentioning. These include transverse myelitis, carotid artery thrombosis, optic neuritis, polyradiculopathy, polyneuropathy (such as carpal tunnel syndrome), and Guillain-Barre syndrome. Most of these manifestations occur within 1 to 2 weeks after rubella infection. Finally, rubella vaccine has been associated with

Chapter 75 N HIV Infection and Diseases of the Brain

polyneuropathy and myeloradiculoneuritis; however, no causal relationship with the rubella vaccine has been established.

DIAGNOSIS Diagnosis of congenital rubella infection at birth can be accomplished by isolating the virus in culture from the nasopharynx, urine, stool, bu@ coat of the blood, or CSF or by the demonstration of an elevated immunoglobulin M (I@) level at birth identified as specific rubella antibody. Between 6 to 12 months of age, a persistently elevated IgG titer is considered presumptive evidence of a congenital rubella infection in an unimmunized infant without a history of postnatal rubella. After one year of age, the diagnosis of congenital rubella infection in children is quite difficult because viral isolation by culture is usually not successful and because serologic testing is usually not diagnostic. Retrospective diagnosis of congenital rubella infection in older children may be suggested by administration of the rubella vaccine. In seronegative children with congenital rubella, only 10% respond with a rise in titer of hemagglutinationinhibition antibodies, as opposed to 98% of nonimmune normal children. Postnatally acquired disease can be diagnosed by viral isolation from nasal or throat specimens, by a significant change in hemagglutination-inhibition anbitodies (classically,the most standard diagnostic test), by enzyme-linked immunosorbent assay values or neutralizing antibody titers, or by the demonstration of specific IgM rubella antibody in a single serum sample. In rubella postinfectious encephalomyelitis, cranial magnetic resonance imaging (MRI) may reveal single or multiple areas of demyelination, which may enhance. CSF examination usually reveals a mild pleocytosis (20 to 100 celldmm), with most cells being lymphocytes. The protein content is normal or slightly elevated, and the glucose concentration is normal. In the progressive panencephalitis syndrome, cranial MRI may reveal diffuse brain atrophy. The CSF shows a mild increase in cells

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(lymphocytes), a modest elevation of protein, and a marked increase in the proportion of y-globulin (35% to 52% of total protein), which assumes an oligoclonal pattern when analyzed by agarose gel electrophoresis. The CSF and serum rubella antibody titers are elevated. Electroencephalograms have shown consistent abnormalities consisting of high-voltage slow-wave activity without the periodicity characteristic of subacute sclerosing panencephalitis. Pathologic examination of the brain has shown a widespread, progressive subacute panencephalitis, mainly affecting the white matter. No inclusion-bearing cells have been seen.

TREATMENT Unfortunately, no specific treatment exists for CRS or progressive rubella panencephalitis syndrome. High-dose steroids have been tried for postrubella encephalomyelitis, as with other forms of postinfectious immune-mediated inflammatory syndromes, but their value is unclear. Care is primarily supportive in these cases. Isoprinosine and other antiviral agents have not been found to be effective.

SUGGESTED READINGS Connolly JH, Hutchinson WM, Allen N et ak Carotid artery thrombosis, encephalitis, myelitis and optic neuritis associated with rubella virus infections. Brain 98:583, 1975 Kuroda Y: Progressive rubella panencephalitis. Nippon Rinsho 55(4):922925, 1997 Menkes JH: Textbook of Child Neurology. 4th Ed. Lea & Febiger, Philadelphia, 1990 Swaiman KF Pediatric Neurology, Principles and Practice. 2nd Ed. Mosby, St Louis, 1993

Townsend JJ, Baringer JR, Wolinsky JS et al: Progressive rubella panencephalitis. N Engl J Med 292990, 1975 Wolinsky JS, Berg BO, Maitland CJ: Progressive rubella panencephalitis. Arch Neurol 33:722, 1976

HIV Infection and Diseases of the Brain Bradley K. Evans

Human immunodeficiency virus (HIV) is an RNA virus. When it infects a cell, its RNA enters the cell and is reverse transcribed to DNA. Reverse transcription is the step of infection affected by the therapeutic agents zidovudine (AZT), zalcitabine (dideoxycytosine), didanosine (dideoxyinosine), and most other drugs currently available for treating HIV infection. After HIV RNA is reverse transcribed to DNA, some of this DNA is inserted into the cell's genome. From the safety of the cell's nucleus, the DNA can produce viruses and virus-related material until the cell dies. The strategy of the HIV virus is to control the production of viruses very carefully so that the cell survives for a long time. This is a slow virus infection. One important viral protein made by an infected cell is gp160, a large protein that extends through the cell's plasma membrane. In the course of normal processing, gp160 is cleaved to gp120 and gp41. These two proteins provide a way for HIV to infect cells and

thus are a key step in the pathogenesis of infection. The larger protein, gp120, binds to a helper T lymphocyte and monocyte cell surface protein called CD4; the smaller one, gp41, is responsible for the fusion of lipid membranes that allows the viral RNA to enter cells. Many H N vaccine candidates are variants of the gp160 or gp120 proteins. HIV TESTING

Common diagnostic tests for H N infection are the HIV antibody test and the p24 antigen test. The HIV antibody test is sensitive and specific for HIV infection. It actually refers to two tests: an enzyme-linked immunosorbent assay (ELISA), which, if positive, is followed by a Western blot. The ELISA alone has many false-positive results. The Western blot is technically difficult to perform, making it unfeasible to do routinely. In the Western blot,

Chapter 75 N HIV Infection and Diseases of the Brain

polyneuropathy and myeloradiculoneuritis; however, no causal relationship with the rubella vaccine has been established.

DIAGNOSIS Diagnosis of congenital rubella infection at birth can be accomplished by isolating the virus in culture from the nasopharynx, urine, stool, bu@ coat of the blood, or CSF or by the demonstration of an elevated immunoglobulin M (I@) level at birth identified as specific rubella antibody. Between 6 to 12 months of age, a persistently elevated IgG titer is considered presumptive evidence of a congenital rubella infection in an unimmunized infant without a history of postnatal rubella. After one year of age, the diagnosis of congenital rubella infection in children is quite difficult because viral isolation by culture is usually not successful and because serologic testing is usually not diagnostic. Retrospective diagnosis of congenital rubella infection in older children may be suggested by administration of the rubella vaccine. In seronegative children with congenital rubella, only 10% respond with a rise in titer of hemagglutinationinhibition antibodies, as opposed to 98% of nonimmune normal children. Postnatally acquired disease can be diagnosed by viral isolation from nasal or throat specimens, by a significant change in hemagglutination-inhibition anbitodies (classically,the most standard diagnostic test), by enzyme-linked immunosorbent assay values or neutralizing antibody titers, or by the demonstration of specific IgM rubella antibody in a single serum sample. In rubella postinfectious encephalomyelitis, cranial magnetic resonance imaging (MRI) may reveal single or multiple areas of demyelination, which may enhance. CSF examination usually reveals a mild pleocytosis (20 to 100 celldmm), with most cells being lymphocytes. The protein content is normal or slightly elevated, and the glucose concentration is normal. In the progressive panencephalitis syndrome, cranial MRI may reveal diffuse brain atrophy. The CSF shows a mild increase in cells

75

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(lymphocytes), a modest elevation of protein, and a marked increase in the proportion of y-globulin (35% to 52% of total protein), which assumes an oligoclonal pattern when analyzed by agarose gel electrophoresis. The CSF and serum rubella antibody titers are elevated. Electroencephalograms have shown consistent abnormalities consisting of high-voltage slow-wave activity without the periodicity characteristic of subacute sclerosing panencephalitis. Pathologic examination of the brain has shown a widespread, progressive subacute panencephalitis, mainly affecting the white matter. No inclusion-bearing cells have been seen.

TREATMENT Unfortunately, no specific treatment exists for CRS or progressive rubella panencephalitis syndrome. High-dose steroids have been tried for postrubella encephalomyelitis, as with other forms of postinfectious immune-mediated inflammatory syndromes, but their value is unclear. Care is primarily supportive in these cases. Isoprinosine and other antiviral agents have not been found to be effective.

SUGGESTED READINGS Connolly JH, Hutchinson WM, Allen N et ak Carotid artery thrombosis, encephalitis, myelitis and optic neuritis associated with rubella virus infections. Brain 98:583, 1975 Kuroda Y: Progressive rubella panencephalitis. Nippon Rinsho 55(4):922925, 1997 Menkes JH: Textbook of Child Neurology. 4th Ed. Lea & Febiger, Philadelphia, 1990 Swaiman KF Pediatric Neurology, Principles and Practice. 2nd Ed. Mosby, St Louis, 1993

Townsend JJ, Baringer JR, Wolinsky JS et al: Progressive rubella panencephalitis. N Engl J Med 292990, 1975 Wolinsky JS, Berg BO, Maitland CJ: Progressive rubella panencephalitis. Arch Neurol 33:722, 1976

HIV Infection and Diseases of the Brain Bradley K. Evans

Human immunodeficiency virus (HIV) is an RNA virus. When it infects a cell, its RNA enters the cell and is reverse transcribed to DNA. Reverse transcription is the step of infection affected by the therapeutic agents zidovudine (AZT), zalcitabine (dideoxycytosine), didanosine (dideoxyinosine), and most other drugs currently available for treating HIV infection. After HIV RNA is reverse transcribed to DNA, some of this DNA is inserted into the cell's genome. From the safety of the cell's nucleus, the DNA can produce viruses and virus-related material until the cell dies. The strategy of the HIV virus is to control the production of viruses very carefully so that the cell survives for a long time. This is a slow virus infection. One important viral protein made by an infected cell is gp160, a large protein that extends through the cell's plasma membrane. In the course of normal processing, gp160 is cleaved to gp120 and gp41. These two proteins provide a way for HIV to infect cells and

thus are a key step in the pathogenesis of infection. The larger protein, gp120, binds to a helper T lymphocyte and monocyte cell surface protein called CD4; the smaller one, gp41, is responsible for the fusion of lipid membranes that allows the viral RNA to enter cells. Many H N vaccine candidates are variants of the gp160 or gp120 proteins. HIV TESTING

Common diagnostic tests for H N infection are the HIV antibody test and the p24 antigen test. The HIV antibody test is sensitive and specific for HIV infection. It actually refers to two tests: an enzyme-linked immunosorbent assay (ELISA), which, if positive, is followed by a Western blot. The ELISA alone has many false-positive results. The Western blot is technically difficult to perform, making it unfeasible to do routinely. In the Western blot,

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many problems of interpretation can arise. If the patient’s serum contains antibodies to normal cell proteins, the Western blot may show abnormal bands that can be mistaken for bands caused by anti-HIV antibodies. A major problem with all HIV antibody tests is that anti-HIV antibodies may not appear in the serum for a highly variable period of time after the initial infection, typically weeks to a few months. This period of HIV infection, in which a patient is infected but anti-HIV antibodies cannot be detected, is popularly called the window. Diagnosis during the window period may entail repeating the HIV antibody test a few months later or using a diagnostic test that relies on detection of HIV antigens instead of antibody. The common HIV antigen tested for is p24. This is a viral protein contained in infected cells, in viral particles, and sometimes free in serum. The p24 antigen is detectable only in very early or very late infections, when antigen exceeds the amount of antibody. Most of the time, in HIV-infected patients, p24 antigen is negative because antibody is in excess. The p24 antigen test’s practical usefulness is limited to diagnosis of HIV infection during the window period. The CD4 count is an enumeration of peripherally circulating lymphocytes that express the CD4 antigen on their surface. Functionally, these are T-helper cells. In normal, uninfected people, the CD4 count usually is 500 to 1600 cells/mm3. Early in HIV infection, the CD4 count often transiently drops, and then, late in infection, the CD4 count reliably decreases, reflecting the inexorable depletion of T-helper lymphocytes by HIV infection. A low CD4 count correlates highly with impaired immune function; that is, patients with opportunistic infections almost always have a CD4 count less than 200/mm3. Recently, the CD4 count has become accepted as a surrogate marker for gauging the severity of HIV infection. In an HIV-infected patient, a CD4 count less than 200/mm3, by itself, indicates full-blown acquired immunodeficiency syndrome (AIDS). Serial CD4 counts are used to monitor the success of treatment with antiretroviral drugs; a sudden decrease in the CD4 count may prompt a change in antiretroviral therapy. However, the CD4 count can fluctuate in response to factors other than HIV infection. For example, other viral infections can result in fewer circulating CD4 cells. Comparing the CD4 count with the CD4/CD8 ratio (the ratio of T-helper cells to T-suppressor and T-cytotoxic cells) often is helpful in interpreting a low CD4 count. With HIV infection, the CD4 count and the CD4/CD8 ratio decrease in tandem (in AIDS, typically less than 200/mm3 and less than 0.2, respectively); other causes of a low CD4 count usually are also associated with a decreased number of CD8-positive lymphocytes, leaving the CD4/CD8 ratio in its normal range (0.5 to 2.0). Other tests, such as viral culture, virus quantitation in plasma, acidified p24 antigen test, polyethylene glycol precipitation, and various polymerase chain reaction techniques are, at the moment, research tools only. One or more of these tests, or variations of them, may eventually replace either the HIV antibody test or the CD4 count because of the problems discussed in this chapter. Table 75-1 lists the central nervous system (CNS) diseases that are commonly associated with HIV infection and AIDS.

HIV MENlNCOENCEPHALmS Even at the time of primary infection, HIV is present in the brain of most patients. By the time of AIDS, the virus titer in the brain is higher than in any other organ. However, most patients with HIV infection have no neurologic complaints, and most have a

TABLE 75-1. HIV Infection and Diseases of the Central Nervous System HIV meningoencephalitis AIDS dementia complex Parenchymal infections Toxoplasmosis Progressive multifocal leukoencephalopathy Focal encephalitis Syphilitic gumma Tuberculoma Cryptococcoma Nocardial abscess Central nervous system lymphoma Ischemic stroke Meningeal infections Acute meningitis Chronic meningitis Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome.

normal neurologic examination and unremarkable neuroimaging. Even when the patient is asymptomatic, however, the cerebrospinal fluid (CSF) may show a range of abnormalities: a pleocytosis of up to 50 mononuclear cells/mm3, a protein level up to 100 mg/mL, oligoclonal bands, and, sometimes, hypoglycorrhachia. These CSF abnormalities may be present at any time during infection. In fact, CSF pleocytosis becomes less common as the illness progresses. Any time during the illness, but particularly at 1 month after primary infection, patients may have a mononucleosis-like illness that may present with any combination of headache, meningismus, fever, altered mental status, and isolated cranial nerve palsies. Investigation shows only a CSF lymphocytic pleocytosis. The diagnosis may be complicated because the HIV antibody test may not become positive for weeks or a few months after this illness. Treatment is symptomatic.

AIDS DEMENTIA COMPLEX This illness is also called HIV encephalitis, HIV dementia, and HIV-associated cognitive/motor complex. The diagnosis of AIDS dementia complex (ADC) is an AIDS-defining illness. Although sometimes the patient’s CD4 count is as high as 500/mm3, ADC is more common the lower the CD4 count is. ADC is the most common neurologic diagnosis in patients with AIDS. The pathophysiology of ADC is not known, but some pathologic and laboratory data, and a complicated chain of reasoning, implicate excitotoxicity as a possible mechanism. In the white matter of the cerebral hemispheres of patients with ADC, there are microglial nodules. These are collections of microglial cells and monocytes, both cell types infected with HIV. Multinucleated giant cells may also be seen in the white matter of patients with severe ADC. These cells are thought to be the result of fusion of infected cells with adjacent cells, perhaps mediated by gp41 on the surface of the infected cells. The severity of dementia correlates with the number of microglial nodules and the presence of multinucleated giant cells, and these are the only brain cells definitely known to be infected with HIV. These infected cells release gp120 and cytokines, which can induce an astroglial enzyme, indolamine-2,3-dioxygenase.This is the key enzyme in the synthesis of an N-methyl D-aspartic acid (NMDA) receptor agonist, quinolinic acid. Quinolinic acid is elevated in the CSF of patients with ADC. In certain neurons, excessive NMDA agonist activity causes intracellular calcium to rise and the neurons to die (excitotoxicity). In fact, there are fewer neurons in the cerebral

Chapter 75

cortices of patients with AIDS than in uninfected controls, supporting the idea that excitotoxicity may play a role in the pathophysiology of ADC.

Clinical Manifestations Common early complaints are memory problems, slowed thinking, and apathy. The usual memory tasks (three-object recall, serial sevens, and spelling words backward) usually are performed accurately. Patients have difficulty with verbal fluency tests (e.g., name as many fruits as possible in 30 seconds; as a general rule, the ability to name 10 or more fruits in 30 seconds is normal, 5 to 9 is mildly impaired, and 0 to 4 is consistent with moderate or severe dementia). Complex motor tasks (grooved pegboard, trailmaking, and timed walking) also are performed slowly. Patients may have an unsteady gait, sometimes severe enough to suggest that the patient has vacuolar myelopathy. Besides this common presentation of mental slowness, patients may present with fulminant psychosis. These patients have grossly disturbed thinking, often with extreme agitation, sexual impulsivity, and violence. In the late stages of ADC, patients become apathetic, withdrawn, and eventually quadriparetic and bedridden. Patients do not necessarily progress inexorably to the late stage. A patient’s clinical condition can fluctuate remarkably over weeks or months, sometimes because of changes in treatment, sometimes for no apparent reason. In ADC, head magnetic resonance imaging shows cerebral atrophy and deep white matter hyperintensities on T2-weighted images. The hyperintensities are “fluffy” and symmetrical in the cerebral hemispheres. There is no mass effect and no enhancement. These white matter changes are characteristic, but not diagnostic, of ADC. Head computed tomography may be normal

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or show faint white matter abnormalities and may also reveal striking atrophy (Fig. 75-1). A lumbar puncture is often performed, primarily to exclude other conditions. In patients with ADC, as with all HIV-infected patients, the CSF may show pleocytosis, elevated protein, or hypoglycorrhachia. The CSF also shows higher amounts of P-microglobulin and neopterin, which correlate with the severity of ADC. Neopterin and P-microglobulin are proteins released by activated immune cells. CSF quinolinic acid is also elevated in ADC.

Diagnosisand Differential Diagnosis ADC is considered a diagnosis of exclusion. The differential diagnosis of ADC is psychiatric illness (e.g., depression and mania), systemic illness, a side effect of a medication, disease of the brain parenchyma other than ADC, chronic meningitis, malnutrition, and vitamin deficiencies. Two vitamin deficiencies, thiamine deficiency and cyanocobalamin deficiency, are important to consider. Thiamine deficiency is a treatable cause of altered mental status. Patients with AIDS may develop thiamine deficiency if they are alcoholic or if they have esophagitis, pancreatitis, or other gastrointestinal disease. Patients who do not eat may become thiamine deficient within a couple of weeks. These patients develop “quiet” confusion and motor incoordination that may be mistaken for ADC. Nystagmus and poor short-term memory are important neurologic signs of possible thiamine deficiency, but thiamine should be given to any malnourished patient thought to have ADC, whether these neurologic signs are present or not. Vitamin B,, deficiency may also cause mild mental confusion and gait abnormalities similar to those seen in ADC. Patients with subacute combined degeneration have impaired vibration sensa-

A

B

FIG. 75-1. (A) Computed tomography (0scan of a 31-year-old man with AIDS dementia complex, showing mild diffuse atrophy. (6) CT scan done only 6 weeks later, showing a marked increase in the amount of atrophy. (Courtesy of Susan Weathers, MD, Baylor College of Medicine, Houston, Texas.)

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tion in the lower extremities and a Romberg sign. A low serum cyanocobalamin level confirms the diagnosis.

Treatment ADC is treated with AZT. The current recommendation is that high dosages (at least 1000 mg/day) be used. Improvement may be delayed for weeks to a few months after starting treatment. AZT not only treats ADC but also prevents its development. Other antiretroviral agents have not been well studied, but they seem to be less effective than AZT. Other possible treatments of ADC-memantine (an NMDA receptor antagonist) and nimodipine (a calcium channel blocker)-are now in clinical trials. They are based on the idea that excitotoxicity is involved in the pathophysiology of ADC.

OTHER PARENCHYMAL BRAIN DISEASES The three most common diseases affecting the brain parenchyma are CNS toxoplasmosis (see Chapter 63), CNS lymphoma, and progressive multifocal leukoencephalopathy (PML; see Chapter 71). Other parenchymal brain diseases are neurosyphilitic gummas, tuberculomas, cryptococcomas, nocardial brain abscesses, or focal encephalitides caused by cytomegalovirus, varicella-zoster virus, or herpes simplex virus type 1. This category also includes ischemic and embolic strokes. Ischemic strokes may be caused by vasculitis due to Treponema pallidurn, varicella-zoster virus, hepatitis B virus, or HIV. Any of these diseases might present primarily with altered mental status and mimic ADC. Seizures, headaches, papilledema, and focal or lateralizing findings on neurologic examination are indications that the patient may have a parenchymal brain disease. Neuroimaging studies usually are abnormal, showing focal or multifocal disease, sometimes with mass effect and enhancement. CNS toxoplasmosis and CNS lymphoma cause multifocal lesions with mass effect and enhancement; these are not seen with PML. The other parenchymal diseases cause variable amounts of mass effect and enhancement. Cryptococcomas usually are multiple, cystic, and located in the basal ganglia (Fig. 75-2). Lumbar puncture is contraindicated when neuroimaging studies show a large mass effect. Diagnosis may entail brain biopsy, but brain biopsy is nondiagnostic in at least 20% of patients. In addition, brain biopsy itself involves risk to the patient. It is sometimes better to treat mass lesions of the brain presumptively, without tissue confirmation of the diagnosis, and follow the success of treatment by clinical examination and serial neuroimaging studies. This approach is widely accepted for CNS toxoplasmosis, when the patient has positive serologic findings and multiple mass lesions in the brain. CNS toxoplasmosis and PML treatments are considered in separate chapters. CNS lymphoma is treated with chemotherapy and cranial irradiation. The other diseases are treated as they are in patients who are not HIV infected, except one has to remember that higher dosages and longer courses of acute treatment may be needed and that maintenance therapy may be necessary.

MENINGITIS IN HIV-INFECTED PATIENTS Among diseases that primarily affect the meninges, common presenting signs are fever, cranial nerve palsies, seizures, strokes

FIG. 75-2. CT scan of a patient with AIDS, showing multiple, cystic cryptococcomas located primarily in the basal ganglia. (Courtesy of Michael Hillman, MD, and Lawrence Hutchins, MD, The Marshfield

Clinic.) caused by vasculitis or venous thrombosis, and elevated intracranial pressure (caused by obstructive hydrocephalus, nonobstructive hydrocephalus, or diffuse cerebral edema). Acute meningitis is not common in patients with AIDS, surprisingly. The most common causative organisms are Streptococcus pneumoniae, Salmonella, and Listeria monocytogenes. Listeria causes a more subacute meningitis, with a lymphocytic pleocytosis. By Gram stain, Listeria organisms may be mistaken for diphtheroids. T. pallidum may occasionally cause acute meningitis and a polymorphonuclear pleocytosis. Patients with a gramnegative meningitis may have disseminated strongyloidiasis; fresh feces, sputum, and CSF should be specifically examined for the motile larvae of Strongyloides stercoralis. Treatment of these infections is the same as for patients who are not HIV infected. Chronic meningitis is most commonly caused by Cryptococcus neoformans, but Mycobacterium tuberculosis, 'I: pallidurn, lymphoma, Histoplasma capsulatum, Coccidioides immitis, L. rnonocytogenes, cytomegalovirus, herpes zoster, and herpes simplex type 2 can also cause CSF lymphocytic pleocytosis. Only 25% of patients with AIDS and cryptococcal meningitis have meningeal signs. Some patients have normal CSF cell counts, protein, and glucose. Diagnostic tests are serum cryptococcal antigen (positive in 90% to 99% of patients with AIDS and cryptococcal meningitis), blood fungal culture, CSF cryptococcal antigen, India ink examination of CSF, and CSF fungal culture. Rheumatoid factor can cause a false-positive cryptococcal antigen test result unless the CSF or serum is specifically pretreated to eliminate this possibility. Cryptococcal antigen tests can also be falsely negative in the presence of extremely high titers of antigen

(prozone phenomenon). Serial dilutions should be done to show positivity at higher titers. Treatment of cryptococcal meningitis in patients with AIDS includes acute treatment and maintenance therapy. In patients treated with fluconazole as maintenance therapy, there is a 3% relapse rate within the first 3 months. Neurosyphilis in HIV-infected patients presents special problems in diagnosis and treatment. Neurosyphilis may present at any stage of HIV infection. Interpretation of CSF studies in HIVinfected patients is complicated by the fact that many of these patients have a CSF pleocytosis caused by the HIV infection. Serologic tests for syphilis and the specific antitreponemal tests (such as FTA-Abs) rely on the patient producing antibody, but antibody production may be impaired in patients with AIDS. These serologic tests also may show a prozone phenomenon, that is, a positive test is seen only at high titers, when serial dilutions are done. The polymerase chain reaction test for syphilis is, so far, experimental. Early versions of this test show a lack of sensitivity for syphilis. The usual treatment of early syphilis is associated with a high

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HIV Infection and Diseases of the Brain

Chapter 75

rate of failure in HIV-infected patients. Failure often manifests as neurosyphilis, particularly meningitis and strokes. High-dose intravenous penicillin G treatment for neurosyphilis may also be associated with a high rate of treatment failure. Because of these diagnostic and treatment problems in HIV-infected patients, because syphilis can be clinically evident at any stage of HIV infection, and because HIV and syphilis are sexually transmitted diseases, it is recommended that all patients diagnosed with syphilis have HIV testing, and all patients with HIV have testing for syphilis.

PROBLEMS IN DIAGNOSIS Mental confusion and headaches in an HIV-infected patient can be caused by a bewildering variety of diseases. By the history and examination alone, it is often not possible to reach a definite diagnosis. For the most common diseases, that is, ADC, CNS toxoplasmosis, CNS lymphoma, PML, and cryptococcal meningitis, there is great overlap in their clinical features (Table 75-2).

TABU 75-2. Human Immunodeficiency Virus Infection and the Central Nervous System" Disease

Percentageb

-

None ADC CNS toxo CNS lymph PML

Cryptorneningitis

Onset

Varies

33 10 2 2 10

Altered Mental status 1%)

Headache

Focal Signs

1%)

1%)

Seizures 1%)

0 100 75 75 50 25

20 20 50 50 20 75

0 0 75 75 95 10

2 2 25 25 10 10

-

Days

Days-weeks Weeks-months Weeks

Other

1%)

Fever 50%, (+) serology >95 Fever 75%, (+) serum CRAG

Abbreviations: ADC = acquired immunodefiaency syndrome dementia complex; CNS lymph = CNS lymphoma; CNS toxo = CNS toxoplasmosis; CRAG = cryptococcal antigen; PML = progressive multifocal leukoencephalopathy. 'Percentages are approximate. bPercentage of patients who will develop the disease.

Neuro Hx & Px

Focal or multifocal parenchymal brain disease

/

Neuroimaging ------,

I

Nonfocal

CD4 count? 1 c 200 or unknown

CD4 > 2OO/mm3

1

Biopsy or treat empirically

I

Lumbar puncture

/ \ Diagnostic

I

Probable meningeal disease

Nondiagnostic

\

Treat likely diagnosis without lumbar puncture

Probable ADC I

Treat Treat FIG. 75-3. Approach to the diagnosis of patients with HIV infection and central nervous system symptoms. Hx, history; Px, physical examination.

500

Immune and Infectious Disease

Viral Infections

”HIBGIA”: Sometimes Useful in Diagnosis One principle sometimes helpful in diagnosis is called “HIBGIA” (“Had it before, got it again”). This refers to the fact that disease recurrence is common in patients with AIDS because of failure of acute therapy, failure of maintenance therapy, or failure to take maintenance therapy. By this principle, if a patient had a disease, particularly an infectious disease, and now has new neurologic complaints, then it is likely that the patient has recurrence of the disease. For example, if a patient was previously treated for syphilis and now has neurologic complaints, then neurosyphilis is a primary consideration as a diagnosis.

with every lumbar puncture to be able to evaluate a low CSF glucose level. Even when one or more of these abnormalities are present, it still may not be possible to reach a definite diagnosis.

An Approach to Clinical Diagnosis The diagnostic strategy shown in Figure 75-3 is suggested. The neuroimaging study itself, and not just the report of the study, should be reviewed by the clinician.

SUGGESTED READINGS Lumbar Puncture in Patients with AIDS The lumbar puncture can be hazardous in HIV-infected patients. Such patients may have parenchymal brain disease with mass effect and be asymptomatic or largely asymptomatic. For that reason, neuroimaging should be done first, before the lumbar puncture, in all HIV-infected patients. For patients with a large amount of mass effect, lumbar puncture is contraindicated. The CSF can be difficult to interpret in HIV-infected patients, and careful thought should be given to what information is needed from the lumbar puncture. An opening pressure should be obtained every time because many CNS diseases in patients with AIDS are complicated by elevated intracranial pressure. An elevated CSF white cell count (more than 5/mm3) is seen in 25% of HIV-infected patients undergoing a diagnostic lumbar puncture, an elevated CSF protein level (more than 50 mg/dL) in 50%, and hypoglycorrhachia in 10%. Because hypoglycorrhachia is so common, a concomitant blood glucose level should be obtained

76

Berger J R AIDS and the nervous system. pp. 743-762. In Aminoff M (ed): Neurology and General Medicine. 3rd ed. Churchill-Livingstone, Philadelphia, 2001 Gordon SM, Eaton ME, George R et al: The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med 331:14691473, 1994 Hollander H, McGuire D, Burack J H Diagnostic lumbar puncture in HIV-infected patients: analysis of 138 cases. Am J Med 96:223-228, 1994 Sidtis JJ, Gatsonis, Price RW et al: Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. Ann Neurol 33:343-349, 1993 Simpson DM, Tagliati M: Neurologic manifestations of HIV infection (Review). Ann Intern Med 121:769-785, 1994 Worley JM, Price RW. Management of neurologic complications of HIV-1 infection and AIDS. pp. 193-217. In Sande MA, Volberding PA (eds): The Medical Management of AIDS. 3rd Ed. WB Saunders, Philadelphia, 1992

HIV Infection and Diseases of the Spinal Cord, Nerve Roots, Peripheral Nerves, and Muscle Bradley K. Evans

In patients with acquired immunodeficiency syndrome (AIDS), three common reasons for neurologic consultation are gait instability, painful feet, and urinary retention with inability to walk. These are usually caused by disease of the spinal cord (vacuolar myelopathy), peripheral nerves (distal sensory polyneuropathy), and nerve roots (cytomegalovirus [CMV] polyradiculitis), respectively. In addition to these common syndromes, human immunodeficiency virus (HIV)-infected patients can also develop other neuropathies and myopathies. VACUOLAR MYELOPATHY Vacuolar myelopathy is the most common cause of walking problems in HIV-infected patients. Patients tend to have a CD4 count less than 200/mm3, but the CD4 count may occasionally be as high as 500/mm3. Vacuolar myelopathy is a unique spinal cord syndrome, seen only in HIV-infected patients. Despite this strong

association with HIV infection, the exact pathophysiology is not known. There is no effective treatment. Over several months, walking deteriorates, and patients eventually need gait assistance and sometimes a wheelchair. Clinical Manifestations Symptoms begin with gait instability, which is slowly progressive over several weeks. The upper extremities are not affected. Some patients notice proximal weakness, but there is no urinary incontinence, except perhaps in the latest stages of the illness. Neurologic abnormalities are confined to the lower extremities and are symmetrical. The gait is wide-based and unsteady. Patients are unable to tandem walk, but they do not have a Romberg sign. Patients have proximal weakness, brisk reflexes, and bilateral Babinski toe signs. Sensation, including vibration sensation, is normal or nearly normal.

500

Immune and Infectious Disease

Viral Infections

”HIBGIA”: Sometimes Useful in Diagnosis One principle sometimes helpful in diagnosis is called “HIBGIA” (“Had it before, got it again”). This refers to the fact that disease recurrence is common in patients with AIDS because of failure of acute therapy, failure of maintenance therapy, or failure to take maintenance therapy. By this principle, if a patient had a disease, particularly an infectious disease, and now has new neurologic complaints, then it is likely that the patient has recurrence of the disease. For example, if a patient was previously treated for syphilis and now has neurologic complaints, then neurosyphilis is a primary consideration as a diagnosis.

with every lumbar puncture to be able to evaluate a low CSF glucose level. Even when one or more of these abnormalities are present, it still may not be possible to reach a definite diagnosis.

An Approach to Clinical Diagnosis The diagnostic strategy shown in Figure 75-3 is suggested. The neuroimaging study itself, and not just the report of the study, should be reviewed by the clinician.

SUGGESTED READINGS Lumbar Puncture in Patients with AIDS The lumbar puncture can be hazardous in HIV-infected patients. Such patients may have parenchymal brain disease with mass effect and be asymptomatic or largely asymptomatic. For that reason, neuroimaging should be done first, before the lumbar puncture, in all HIV-infected patients. For patients with a large amount of mass effect, lumbar puncture is contraindicated. The CSF can be difficult to interpret in HIV-infected patients, and careful thought should be given to what information is needed from the lumbar puncture. An opening pressure should be obtained every time because many CNS diseases in patients with AIDS are complicated by elevated intracranial pressure. An elevated CSF white cell count (more than 5/mm3) is seen in 25% of HIV-infected patients undergoing a diagnostic lumbar puncture, an elevated CSF protein level (more than 50 mg/dL) in 50%, and hypoglycorrhachia in 10%. Because hypoglycorrhachia is so common, a concomitant blood glucose level should be obtained

76

Berger J R AIDS and the nervous system. pp. 743-762. In Aminoff M (ed): Neurology and General Medicine. 3rd ed. Churchill-Livingstone, Philadelphia, 2001 Gordon SM, Eaton ME, George R et al: The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med 331:14691473, 1994 Hollander H, McGuire D, Burack J H Diagnostic lumbar puncture in HIV-infected patients: analysis of 138 cases. Am J Med 96:223-228, 1994 Sidtis JJ, Gatsonis, Price RW et al: Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. Ann Neurol 33:343-349, 1993 Simpson DM, Tagliati M: Neurologic manifestations of HIV infection (Review). Ann Intern Med 121:769-785, 1994 Worley JM, Price RW. Management of neurologic complications of HIV-1 infection and AIDS. pp. 193-217. In Sande MA, Volberding PA (eds): The Medical Management of AIDS. 3rd Ed. WB Saunders, Philadelphia, 1992

HIV Infection and Diseases of the Spinal Cord, Nerve Roots, Peripheral Nerves, and Muscle Bradley K. Evans

In patients with acquired immunodeficiency syndrome (AIDS), three common reasons for neurologic consultation are gait instability, painful feet, and urinary retention with inability to walk. These are usually caused by disease of the spinal cord (vacuolar myelopathy), peripheral nerves (distal sensory polyneuropathy), and nerve roots (cytomegalovirus [CMV] polyradiculitis), respectively. In addition to these common syndromes, human immunodeficiency virus (HIV)-infected patients can also develop other neuropathies and myopathies. VACUOLAR MYELOPATHY Vacuolar myelopathy is the most common cause of walking problems in HIV-infected patients. Patients tend to have a CD4 count less than 200/mm3, but the CD4 count may occasionally be as high as 500/mm3. Vacuolar myelopathy is a unique spinal cord syndrome, seen only in HIV-infected patients. Despite this strong

association with HIV infection, the exact pathophysiology is not known. There is no effective treatment. Over several months, walking deteriorates, and patients eventually need gait assistance and sometimes a wheelchair. Clinical Manifestations Symptoms begin with gait instability, which is slowly progressive over several weeks. The upper extremities are not affected. Some patients notice proximal weakness, but there is no urinary incontinence, except perhaps in the latest stages of the illness. Neurologic abnormalities are confined to the lower extremities and are symmetrical. The gait is wide-based and unsteady. Patients are unable to tandem walk, but they do not have a Romberg sign. Patients have proximal weakness, brisk reflexes, and bilateral Babinski toe signs. Sensation, including vibration sensation, is normal or nearly normal.

Chapter 76

W

HIV Infectionand Diseases of the Spinal Cord, Nerve Roots, Peripheral Netves, and Muscle

Neuroimaging is unremarkable. The cerebrospinal fluid (CSF) may show mild pleocytosis, slightly elevated protein level, and, sometimes, a slight hypoglycorrhachia, but these CSF findings are nonspecific and usually are not helpful in the diagnosis. Diagnosis and Differential Diagnosis This clinical pattern is sufficiently distinctive to be virtually diagnostic, and any patient with these clinical findings should be suspected of being HIV infected. Somewhat similar clinical pictures can be seen in spinal cord compression, subacute combined degeneration, and cervical stenosis. Patients with spinal cord compression usually present more acutely with walking problems. They may have back pain and tenderness, urinary incontinence, or asymmetrical findings suggesting a partial Brown-Skquard syndrome. A patient with any one of these findings should undergo neuroimaging of the spinal canal. Lymphoma is the most common cause of spinal cord compression in patients with AIDS, and neuroimaging may also be indicated in patients with lymphoma who have typical findings of vacuolar myelopathy. HIV-infected patients have an increased risk of developing vitamin B,, deficiency. Macrocytosis and pancytopenia, typical clues to this diagnosis, may either be absent or wrongly attributed to HIV infection or its treatment. Because vitamin B,, deficiency is treatable, a serum vitamin B,, level should be done in all patients suspected of having vacuolar myelopathy. Although patients with subacute combined degeneration have a similar gait instability, they also have marked loss of vibration sensation and the Romberg sign, which are not seen in vacuolar myelopathy. Subacute combined degeneration and vacuolar myelopathy are very similar pathologically. Therefore, it seemed that vacuolar myelopathy might be the result of abnormal vitamin B,, metabolism in these patients (despite their normal serum vitamin B,, levels). Further study has shown that plasma and urinary homocysteine and methylmalonic acid values are normal in these patients and that cyanocobalamin, L-methionine, or a combination of the two is not an effective treatment for vacuolar myelopathy. Some HIV-infected patients who were already receiving adequate cyanocobalamin treatment for vitamin B,, deficiency have developed vacuolar myelopathy. The pathogenesis of vacuolar myelopathy therefore remains unknown. Cervical stenosis may also mimic vacuolar myelopathy. Patients with cervical stenosis tend to have distal, not proximal, lower extremity weakness. Neuroimaging tests establish the diagnosis of cervical stenosis. Because most patients with vacuolar myelopathy have proximal weakness, physicians may diagnostically consider a treatable myopathy or neuropathy. Sometimes, a patient has an elevated serum creatine kinase level or other evidence of a myopathy or has electrodiagnostic findings suggesting a concomitant neuropathy, but even in these patients, treatment of the myopathy or neuropathy usually does not improve walking. DISTAL SENSORY, SYMMETRICAL POLYNEUROPATHY Distal sensory, symmetrical polyneuropathy (DSP) is common in patients with AIDS, particularly in those with very low CD4 counts. DSP is an axonal, “dying-back” polyneuropathy, with pathologic changes not only in the distal peripheral nerve but also in the fasciculus gracilis in the cervical spinal cord. It is assumed

501

that HIV itself causes DSP, but how it does is not known. Why some patients with AIDS-about 30%-have DSP but others do not also is unknown. Clinical Manifestations Patients with DSP have dysesthesias in their feet. They may suffer pain, burning, coldness, aching, or just uncomfortable feelings, and walking is painful. They may present in a wheelchair with a primary complaint of “inability to walk.” There may be no neurologic abnormalities, or patients may have a “stocking” loss of light touch and pinprick sensations. Pain sensation remains intact. If there is sensory loss, it does not extend much above the ankles. Ankle jerks often are lost. Clinical abnormalities progress either very slowly or not at all. Patients developing signs of a more severe neuropathy (such as weakness in the lower extremities or any neurologic abnormality in the upper extremities) do not have DSP but another type of peripheral neuropathy. In DSP, electrodiagnostic tests, if they are done, are normal or show only mild distal denervation changes. Diagnosis and Differential Diagnosis Any mild peripheral neuropathy can cause complaints and neurologic findings similar to those of DSP. For instance, diabetes mellitus and alcoholism, the most common causes of peripheral neuropathies, often produce neuropathies in HIV-infected patients, too. Medications can cause a peripheral neuropathy, which, in its early stages, can mimic DSP. In HIV-infected patients, the most commonly implicated drugs are zalcitabine (dideoxycytosine or ddC) vincristine, and isoniazid. The neuropathy caused by ddC is not only dose related but also dependent on individual susceptibility. However, it is not possible to predict who will develop a neuropathy from ddC. Treatment consists of stopping the drug, but the neuropathy may continue to worsen (or “coast”) for up to 8 weeks after ddC is stopped. The neuropathy of vincristine is also related both to dosage and to individual susceptibility.For some of these patients, vincristine neuropathy may be extremely severe, resembling Guillain-Barrk syndrome. Isoniazid neuropathy can vary from a mild peripheral neuropathy to a fulminant syndrome of encephalopathy and diffuse weakness. Patients with a preexisting neuropathy who are malnourished and alcoholic are particularly susceptible. Pyridoxine (vitamin B6) 100 mg/day, given with isoniazid, helps prevent neuropathy and does not diminish isoniazid’s antimycobacterial actions. Preventive treatment with pyridoxine is important because for serious tuberculous infections there may be no practical alternative to isoniazid, even when a patient develops a neuropathy. Treatment In general, treatment of DSP is symptomatic; however, there is an ongoing clinical trial of nerve growth factor treatment to see whether this will directly improve the neuropathy. As far as symptomatic treatment for DSP is concerned, amitriptyline is most commonly prescribed, usually beginning at 25 mg at bedtime and increasing to 100 to 150 mg at bedtime. Its side effects are mental confusion, orthostatic hypotension, and urinary retention.

502

Immune and Infectious Disease

Viral Infections

Mexiletine, clonazepam, and capsaicin cream are useful alternatives to amitriptyline for some patients. Opiates are also effective. CYTOMECALOVIRUS POLYRADlCULlTlS This syndrome occurs exclusively in patients with AIDS, usually when the CD4 count is less than 50/mm3. In fact, many patients are being treated for a CMV infection elsewhere in the body at the time this illness begins. Clinical Manifestations The first complaint is either inability to walk or urinary retention. Symptoms progress over a few days to a couple of weeks, so patients may develop both problems. In addition to these primary complaints, about half of patients have superficial pain and dysesthesias in the pelvic girdle area. In the full-blown syndrome, patients have severe proximal weakness, loss of sensation in a bathing-trunk distribution, loss of knee jerks, and a large, flaccid urinary bladder. Diagnosis and Differential Diagnosis If diagnosed early, this is a treatable condition. Suspicion of CMV polyradiculitis should arise if the patient has an extremely low CD4 count, known CMV infection elsewhere in the body, rapid onset of proximal weakness, urinary retention, pain and dysesthesias of the proximal lower extremities, or any combination of these findings. The diagnostic test is a lumbar puncture. The CSF shows a polymorphonuclear pleocytosis (usually more than 100/mm3) and hypoglycorrhachia. About half of the time, CMV can be cultured from the CSF. Because neurosyphilis, human T-cell lymphotrophic virus type I, and lymphomatous meningitis can rarely cause a similar polyradiculitis, it is important to do diagnostic tests for these conditions. Other neurodiagnostic tests are only inconsistently helpful. Lumbar magnetic resonance imaging may or may not show contrast enhancement, suggesting inflammation of the meninges and nerve roots. Electromyogram may show denervation changes proximally, but it may not because of the acuteness of the illness.

Untreated, a patient with CMV polyradiculitis becomes bedridden, with urinary retention. With early treatment, urinary bladder function and ability to walk can return. Treatment is high-dose ganciclovir. Patients with negative CSF culture for CMV are just as likely to respond as are those with positive cultures. If the patient is already receiving high-dose ganciclovir, foscarnet is added. Whether glucocorticoids are beneficial is not known. INFLAMMATORY DEMYELINATINC POLYNEUROPATHIES The inflammatory demyelinating polyneuropathies include Guillain-Barre syndrome (or acute inflammatory demyelinating polyneuropathy) and chronic inflammatory demyelinating polyneuropathy (CIDP). These neuropathies tend to occur in the early or middle stages of the illness, often when the patient is not known to be HIV-infected. The neuropathy is identical to that of Guillain-Barre syndrome and CIDP occurring in patients who are

not HIV infected. In HIV-infected patients, the CSF may show a pleocytosis; CSF pleocytosis is unusual in patients who are not HIV infected and therefore is a valuable clue that the patient might have an HIV infection. Diagnosis of HIV infection in inflammatory demyelinating neuropathies requires specific HIV testing. The HIV antibody test may be falsely normal early in the infection, when inflammatory demyelinating neuropathies often occur. Either a p24 antigen test or repeat HIV antibody test in 2 to 6 months is needed for diagnosis in this situation. Whether or not the neuropathy is associated with HIV infection, treatment options are the same: glucocorticoids (for CIDP), plasmapheresis, and y-globulin. MONONEURITIS MULTIPLEX This is a poorly understood condition, which is rare. Patients notice localized pain or sensory loss and focal weakness. If symptoms begin in a single nerve distribution, the condition may initially be misdiagnosed as a compression neuropathy. Later, neurologic deficits indicate involvement of multiple individual nerves. Sometimes localization points to brachial or lumbar plexus lesions. Although this syndrome is vasculitic, the cause or causes are not known, but HIV, CMV, and hepatitis B virus have been implicated. Reportedly, mononeuritis multiplex early in the course of HIV infection may spontaneously remit, whereas mononeuritis multiplex in patients with low CD4 counts tends to progress. With progression, mononeuritis multiplex becomes symmetrical and clinically resembles a generalized polyneuropathy. There is no recognized treatment for mononeuritis multiplex in HIV-infected patients. Case reports suggest that ganciclovir may be effective for some patients with mononeuritis multiplex and low CD4 counts. MYOPATHIES In patients with AIDS, weakness is most commonly caused by malnutrition and concurrent illness. Proximal weakness is more commonly seen with vacuolar myelopathy than with myopathy. Although patients with vacuolar myelopathy and CMV polyradiculitis have proximal weakness, the upper extremities are spared, and there are other neurologic findings in the lower extremities that point to the correct diagnosis. In patients with a clinically important myopathy, the serum creatine kinase level is nearly always elevated. Therefore, this test is useful as a simple screening test for patients with AIDS and unexplained proximal weakness. Serum creatine kinase elevations occur in patients with AIDS who do not have a myopathy, so a high creatine kinase value alone, even in a patient with proximal weakness, is not diagnostic of a myopathy. In patients with AIDS and myopathy, electromyography shows brief, low-amplitude muscle potentials and helps confirm the diagnosis. There are three myopathic syndromes in HIV-infected patients: HIV wasting syndrome, inflammatory myopathy, and mitochondrial myopathy. Patients with the HIV wasting syndrome, which is common, have loss of gluteal mass (“saggy butt syndrome”). This may be caused by a myopathy, but it is usually unaccompanied by any weakness that the patient notices. Inflammatory myopathy can occur anytime during the course of HIV infection, but it is rare. Patients complain of proximal weakness involving the upper and lower extremities. There are no sensory abnormalities. Muscle stretch reflexes usually are dimin-

Chapter 77

ished in proportion to the weakness. The immune pathophysiology of this inflammatory myopathy is not known; HIV is not

found in muscle fibers. It is treated with glucocorticoids (e.g., prednisone 60 mg/day). HIV-infected patients may also have changes in their muscle biopsies consistent with a mitochondrial myopathy (ragged-red fibers). The mitochondrial changes presumably reflect direct muscle toxicity of zidovudine, which inhibits mitochondrial DNA polymerase in vitro. This myopathy is more common in patients who have taken high dosages (e.g., more than 1000 mg/day) of zidovudine for more than 6 months. Now that lower daily dosages of zidovudine are commonly used, this myopathy is rarely a clinical problem. The treatment is to decrease or eliminate zidovudine. On muscle biopsy, a patient with AIDS and a myopathy may have multiple abnormalities: inflammation, ragged-red fibers, and rod (or nemaline) bodies. The presence of all these changes makes it difficult to know what therapy to recommend. Either glucocorticoid treatment or decreasing zidovudine can be tried first.

77

HTLV-I Infection

SO5

SUGGESTED READINGS Berger J R AIDS and the nervous system. pp. 743-762. In Aminoff M (ed): Neurology and General Medicine. 3rd Ed. Churchill Livingstone, Philadelphia, 2001 Dalakas M, Illa I, Pezeshkpour GH et ak Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322:1098-1105, 1990 Simpson DM, Tagliati M: Neurologic manifestations of HIV infection. Ann Intern Med 121:769-785, 1994 So YT, Olney FUC Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome: experience in 23 patients. Ann Neurol 3553-58, 1994 Worley JM, Price RW Management of neurologic complications of HIV-1 infection and AIDS. pp. 193-217. In Sande MA, Volberding PA (eds): The Medical Management of AIDS. 3rd Ed. WB Saunders, Philadelphia, 1992

HTLV-I Infection Robert R. McKendall

The discovery of human T-cell lymphotrophic virus type I (HTLV-I) and its linkage to an unusual leukemia and chronic myelopathy is an extraordinary story of modern-day medical scientific investigation. In 1980, Poeisz and his collaborators isolated a retrovirus from fresh lymphocytes of an American patient with cutaneous T-cell lymphoma. This was the first human retrovirus isolated, and it was called HTLV-I. A worldwide search for links between hematologic malignancies and human retroviruses ensued. In Martinique, neurologist Jean Claude Vernant noted a patient with tropical spastic paraparesis (TSP) who had serum antibodies to HTLV-I. He had a group of 25 patients with TSP tested for serum HTLV-I antibodies, and 78% were positive. This was the first link of TSP with HTLV-I. Independently, Mitsuhiro Osame observed multilobulated flower lymphocytes in the blood and cerebrospinal fluid (CSF) of some Japanese patients with spastic paraparesis. These cells were similar to the leukemic cells of adult T-cell lymphoma. Osame’s patients were shown to have serum and CSF antibodies to HTLV-I, and he reported on a new clinical entity, which he named HTLV-I-associated myelopathy (HAM). Soon, the DNA from HAM cell lines was shown to be identical to DNA from adult T-cell leukemia cell lines. Finally, based on seroepidemiologic, clinical,

pathologic, and viral isolation similarities, HAM and TSP were shown to be the same disease, caused by the retrovirus responsible for adult T-cell lymphoma (HTLV-I). In recent years, HTLV-I virus has been linked to uveitis and infective dermatitis of children. Other conditions less well proven but linked to the virus include interstitial cystitis, persistent prostatitis, polymyositis, arthropathy, and Sjogren’s syndrome. ______

EPIDEMIOLOGY Seroepidemiologic studies have expanded the known HTLV-I endemic areas far beyond the original descriptions in Japan and the Caribbean. Endemic regions exist in Central America, South America (Columbia, Venezuela, Peru, Bolivia, and Brazil), and Africa (Uganda, Ivory Coast, Tanzania, and Zaire). The virus remains rare in Europe and Australia. In North America, seropositive people have been found in Canada, the United States, and Mexico. The prevalence rate in U.S. volunteer blood donors is 0.025%. Most cases of HAM/TSP in the United States have occurred in immigrants, patients who had sexual partners from endemic areas, or blood transfusion recipients or in association with intravenous drug abuse. Endemic

Chapter 77

ished in proportion to the weakness. The immune pathophysiology of this inflammatory myopathy is not known; HIV is not

found in muscle fibers. It is treated with glucocorticoids (e.g., prednisone 60 mg/day). HIV-infected patients may also have changes in their muscle biopsies consistent with a mitochondrial myopathy (ragged-red fibers). The mitochondrial changes presumably reflect direct muscle toxicity of zidovudine, which inhibits mitochondrial DNA polymerase in vitro. This myopathy is more common in patients who have taken high dosages (e.g., more than 1000 mg/day) of zidovudine for more than 6 months. Now that lower daily dosages of zidovudine are commonly used, this myopathy is rarely a clinical problem. The treatment is to decrease or eliminate zidovudine. On muscle biopsy, a patient with AIDS and a myopathy may have multiple abnormalities: inflammation, ragged-red fibers, and rod (or nemaline) bodies. The presence of all these changes makes it difficult to know what therapy to recommend. Either glucocorticoid treatment or decreasing zidovudine can be tried first.

77

HTLV-I Infection

SO5

SUGGESTED READINGS Berger J R AIDS and the nervous system. pp. 743-762. In Aminoff M (ed): Neurology and General Medicine. 3rd Ed. Churchill Livingstone, Philadelphia, 2001 Dalakas M, Illa I, Pezeshkpour GH et ak Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322:1098-1105, 1990 Simpson DM, Tagliati M: Neurologic manifestations of HIV infection. Ann Intern Med 121:769-785, 1994 So YT, Olney FUC Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome: experience in 23 patients. Ann Neurol 3553-58, 1994 Worley JM, Price RW Management of neurologic complications of HIV-1 infection and AIDS. pp. 193-217. In Sande MA, Volberding PA (eds): The Medical Management of AIDS. 3rd Ed. WB Saunders, Philadelphia, 1992

HTLV-I Infection Robert R. McKendall

The discovery of human T-cell lymphotrophic virus type I (HTLV-I) and its linkage to an unusual leukemia and chronic myelopathy is an extraordinary story of modern-day medical scientific investigation. In 1980, Poeisz and his collaborators isolated a retrovirus from fresh lymphocytes of an American patient with cutaneous T-cell lymphoma. This was the first human retrovirus isolated, and it was called HTLV-I. A worldwide search for links between hematologic malignancies and human retroviruses ensued. In Martinique, neurologist Jean Claude Vernant noted a patient with tropical spastic paraparesis (TSP) who had serum antibodies to HTLV-I. He had a group of 25 patients with TSP tested for serum HTLV-I antibodies, and 78% were positive. This was the first link of TSP with HTLV-I. Independently, Mitsuhiro Osame observed multilobulated flower lymphocytes in the blood and cerebrospinal fluid (CSF) of some Japanese patients with spastic paraparesis. These cells were similar to the leukemic cells of adult T-cell lymphoma. Osame’s patients were shown to have serum and CSF antibodies to HTLV-I, and he reported on a new clinical entity, which he named HTLV-I-associated myelopathy (HAM). Soon, the DNA from HAM cell lines was shown to be identical to DNA from adult T-cell leukemia cell lines. Finally, based on seroepidemiologic, clinical,

pathologic, and viral isolation similarities, HAM and TSP were shown to be the same disease, caused by the retrovirus responsible for adult T-cell lymphoma (HTLV-I). In recent years, HTLV-I virus has been linked to uveitis and infective dermatitis of children. Other conditions less well proven but linked to the virus include interstitial cystitis, persistent prostatitis, polymyositis, arthropathy, and Sjogren’s syndrome. ______

EPIDEMIOLOGY Seroepidemiologic studies have expanded the known HTLV-I endemic areas far beyond the original descriptions in Japan and the Caribbean. Endemic regions exist in Central America, South America (Columbia, Venezuela, Peru, Bolivia, and Brazil), and Africa (Uganda, Ivory Coast, Tanzania, and Zaire). The virus remains rare in Europe and Australia. In North America, seropositive people have been found in Canada, the United States, and Mexico. The prevalence rate in U.S. volunteer blood donors is 0.025%. Most cases of HAM/TSP in the United States have occurred in immigrants, patients who had sexual partners from endemic areas, or blood transfusion recipients or in association with intravenous drug abuse. Endemic

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infection in the United States has been well documented or is highly likely in Texas, North Carolina, Alabama, South Carolina, New York, Alaska, and Florida. Overall epidemiologic studies of HAM frequency and seropositivity rates have estimated that seropositive people have a 1% risk of developing adult T-cell lymphoma or HAM/TSP.

CLINICAL FEATURES Progressive leg weakness, spasticity, and urinary symptoms are the hallmarks of this disease. Back pain is less consistent. Patients often complain of difficulty walking rather than leg weakness; stiffness is the most common complaint. Foot dragging, falling, and difficulty running are other symptoms, and some impairment of ambulation is present in 60% to 80% of patients. Urinary retention, urgency, and incontinence are common, though not as primary presenting complaints. Impotence and constipation occur less often. Sensory disturbances are occasional and usually mild. Paresthesias occur in 25% to 33% of cases, and sensory cord levels are present in only 10% to 25% of cases. Cranial nerves usually are not impaired, although nystagmus and diplopia occur in 8%, and transient seventh nerve paralysis has been reported. Intention tremor, dysmetria, deafness, and retrobulbar neuropathy are other rare features. On neurologic examination, the findings reflect involvement primarily of the pyramidal tracts (motor), with lesser involvement of the posterior columns (proprioception). Weakness is primarily proximal, in the iliopsoas and gluteus medius. The legs are uniformly involved, and the arms are weak in up to 33% of patients. Hyperreflexia with or without clonus is present in 100% of patients, and upgoing Babinski signs are present in more than 90% of patients. A jaw jerk is present in 12% to 33% of patients in the larger series. The gait exhibits mild scissoring and an awkward stiffness. About 50% need a cane or other gait appliance. The diminished vibration sensation and proprioception in the feet and toes are mild. Involvement of touch and pain fibers is uncommon (6% to 10%). Brain magnetic resonance imaging (MRI), electroencephalography (EEG), and pathologic evaluation have shown that the disease clearly involves widespread areas of the nervous system; however, clinical symptoms of involvement outside the spinal cord are not often prominent. The onset and course are highly variable; most patients (75%) have an insidious course progressing over months to years. About 10% to 20% of cases progress to severe gait impairment over 1 to 3 months. Rarely, a more acute onset simulating a transverse myelopathy or even a vascular event has been observed. The disease usually begins with asymmetric leg weakness and stiffness. Over months, the other leg becomes involved. Mild paresthesias may develop, and the patient may begin to notice jumping or jerking of one or both legs caused by spasticity. Backache may then develop as the spasticity becomes more pronounced. Occasional urinary incontinence or difficulty starting the urine stream develops. When the patient notes interference with ambulation or athletic activities, medical attention is sought.

DIAGNOSIS Laboratory Studies Table 77- 1 summarizes the laboratory findings in HAM/TSP. The leukocyte count is normal, but blood smears may show flower lymphocytes, named for their multilobulated nuclei, which are morphologically similar to adult T-cell lymphoma cells. These cells are 1% of the leukocytes and must be searched for carefully. They

TABLE 77-1. Laboratory Features in Human

T-cell

Lymphotrophic Virus-Associated Myelopathy and Tropical Spastic Paraparesis Serum Flower lymphocytes Hypergammaglobulinemia (IgC and IgA) Oligoclonal bands Antibodies to gag, env, and tax viral proteins Venereal Disease Research Laboratories test positive Increased CD4+4B4+ (helper/inducer) T cells Normal CD4+2H2+(suppressor/inducer) T cells Elevation of circulating adhesion glycoprotein clCAM-1 Cerebrospinal fluid Glucose level normal Protein variably elevated Mononuclear pleocytosis Flower lymphocytes Oligoclonal bands Elevated IgG synthesis rate Anti-HTLV-I-specific antibodies by ELlSA and Western blot Elevated neopterin level Tumor necrosis factor-a detectable in mononuclear cells Elevated IL-1 Elevated IL-6 Elevated interferon-y Not all findings are present in all

patients

may also be present in the CSF, and they are pathognomonic of HTLV-I infection. Flower lymphocytes are CD4+ CD10+, indicating activated T-helper cells. Hypergammaglobulinemia (immunoglobulin [Ig] G and IgA) and serum oligoclonal bands may be important diagnostic clues. Most patients are seropositive for HTLV-I by enzyme-linked immunosorbent assay and Western blot. Interestingly, abnormal tests for syphilis and Lyme disease are common in both serum and CSF.

Cerebrospinal Fluid Abnormalities Routine CSF analysis may be normal or may show various abnormalities. The glucose level is uniformly normal. Protein is elevated in up to 40% of patients, ranging from 50 to 210 mg/dL. Cell counts are elevated in up to 57% of patients, the rise consisting of all mononuclear cells. Flower lymphocytes appear in 12% to 100% of cases. Elevated intrathecal production of IgG, as measured by oligoclonal IgG bands, IgG index, or CSF IgG synthesis rate, occurs in 21% to 85% of patients. The specificity of most of the antibody is unknown, but some of the IgG bands contain antibody to the viral gag protein p24.

Imaging The imaging study of choice for both spinal cord and brain evaluation is MRI. The spinal cord often shows atrophy and high-intensity T2-weighted lesions, which are diffuse in the cervical and thoracic cord (Fig. 77-1). The incidence of MRI abnormalities in the brain ranges from 25% to 80%. Lesions appear in subcortical, deep cerebral, and periventricular areas (Fig. 77-2). The periventricular lesions usually are contiguous with the lateral ventricles, often near the posterior horn, and usually appear as large confluent areas. The subcortical and deep lesions usually are small and multifocal.

Electroencephalographyand Evoked Potentials Diffuse EEG abnormalities occur in 64% of patients, and delays in visual, brainstem auditory, and somatosensory-evoked potentials

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SO5

have been described. However, these studies are nonspecific and not particularly useful diagnostically.

Differential Diagnosis A presumptive diagnosis of HTLV-I myelopathy entails a compatible clinical presentation of progressive or mildly relapsing and remitting myelopathy, a CSF with a low-grade inflammatory and immunoglobulin profile, MRI showing spinal cord atrophy or diffuse T2-weighted bright abnormalities, presence of Western blot-confirmed HTLV-I-specific antibodies in the serum or CSF, and exclusion of other causes, including cord compression, multiple sclerosis, vitamin B,, deficiency, human immunodeficiency virus infection, and Lyme disease. The presumptive diagnosis is strengthened by residence in a high-seroprevalence endemic area, by transfusion exposure, and by a history of intravenous drug abuse. Finding one of the associated systemic diseases commonly accompanying HTLV-I may also be helpful, including pulmonary alveolitis, arthritis not attributable to other causes, uveitis, persistent prostatitis, cystitis, infective dermatitis, and polymyositis. Pulmonary bronchoalveolitis may be detected as a persistent or fluctuating infiltrate on chest radiography. In addition to the findings listed earlier, a definitive diagnosis entails demonstration of virus or viral genes in CSF cells by isolation or polymerase chain reaction, evidence of intrathecal synthesis of specific HTLV-I antibody by comparison of Western blots run with serum and CSF at equal IgG concentrations, or presence of unexplained serum hypergammaglobulinemia or serum oligoclonal bands. Without at least one of the latter three findings, a diagnosis of HTLV-I myelopathy is only presumptive and is especially likely to be wrong in patients from areas of low seroprevalence. Multiple sclerosis would be more likely in those instances.

FIG. 77-1. Spinal cord MRI in a 64-year-old woman with myelopathy and HTLV-I virologically proved to be in cerebrospinal fluid cells. Transverse cut at T8 shows a small spinal cord in a spinal canal that appears large because of the loss in diameter of the spinal cord.

FIG. 77-2. Brain MRI abnormalities in a 53-yearsld black man with virologically proven HTLV-I-associated myelopathy and bilateral lower extremity weakness and urinary hesitation. Multiple areas of high signal intensity clustered in the left medial cerebrum on a T2-weighted scan.

PATHOGENESIS

The pathogenesis of HAM/TSP is incompletely understood. Only 0.25% to 7% of infected patients develop the disease. Several findings distinguish carriers from disease-affected patients and have been used as the basis for some of the therapeutic strategies discussed in this chapter. Afflicted patients have a proviral load in CD4+ cells that is 10 times higher than in carriers and have very high blood levels of CD8+ cytotoxic T lymphocytes (CTLs) that are virus specific. Most of these are directed against HTLV-I-tax gene products, p27x and p40x. In the active early phase of disease (2 to 5 years) the spinal cord shows an inflammatory pathology made up of CD4+ and CD8+ cells as well as B cells and macrophages. Later the inflammation decreases substantially and is made up mostly of CD8+ cells. Three hypotheses describe mechanisms that could contribute to central nervous system (CNS) demyelination and injury. First, infected CD4+ T cells migrate to the CNS and infect resident cells, which are then killed by tax-specific CD8+ CTLs. Second, infected CD4+ cells, which are known to become autoproliferative through virally induced interleukin-2 (IL-2) and IL-2R expression, undergo dramatic clonal expansion producing forbidden antiself clones or antiviral clones capable of cross-reacting through molecular mimicry with self CNS antigens after they migrate to the CNS. The third proposed mechanism is bystander damage, in which interferon-a (IFN-@-secreting HTLV-I-infected CD4+ T cells and their recognition by virusspecific CD8+ T cells in the CNS induce microglia to secrete TNF-a and other cytokines that may be toxic for myelin. Many therapeutic strategies have been directed at reducing proviral load, limiting clonal expansion of infected CD4+ T cells, or reducing the numbers of effector responses of anti-tax CTLs.

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PREVENTIONAND TREATMENT Prevention involves four major areas: blood transfusions, sexual transmission, breast feeding, and vaccine development. The rare instances of seronegativeHAM/TSP indicate that transmission by blood cannot be completely eliminated. Strong public health educational programs and marital counseling are needed to promote condom use and to warn seropositive mothers of the risk of transmission by breastfeeding.Vaccines would be cost-effective, at least in high-prevalence endemic areas, but currently no vaccines are in trials. Several treatment approaches are in development, but most have not been subjected to placebo-controlled, blinded trials, so the results must be interpreted cautiously. Oral prednisolone has been the most extensively tried treatment. It was reported to induce improvement over 6 months in the first Japanese reports, but improvement was not maintained after a 2-year follow-up period. There are other reports of continued improvement in a few patients treated with prednisone. Systemic natural human IFN-a was administered to 48 Japanese patients with HAM/TSP for 28 days in a double-blind trial randomized across three dosage levels. Patients treated with the highest dosage (3.0 MU) had statistically significant improvement in motor and urinary function compared with patients treated with 0.3 MU. In an open trial, 6.0 MU natural human IFN-a was administered to seven Japanese HAM patients for 22 weeks and resulted in sustained improvement in 5 (70%). In an open trial, pentoxifylline was associated with increased CSF levels of IL-4 and IL-10, which correlated with clinical improvement in 6 of 12 patients. An open trial with anti-IL-2R monoclonal antibody resulted in dramatic reduction of infected CD4 peripheral blood lymphocytes (PBLs) and viral load in nine patients, three of whom had improvement in their ambulation index. However this treatment also eliminates noninfected CD4 cells, which express IL-2R as a consequence of activation. Heparin has been used based on its ability to inhibit migration of activated T cells into the CNS and to inhibit induction of autoimmune diseases such as experimental allergic encephalomyelitis. Danazol, an anabolic steroid, has been used in two open trials, with modest success. Plasmapheresis has been used in small trials, usually with other immunologic therapies, and it should be tried in the patient who does not respond to steroids or IFN-a; however, the improvement seen with plasmapheresis may not be maintained.

HTLV-I reverse transcriptase is an essential enzyme for viral replication. Some reverse transcriptase-inhibiting drugs used to treat human immunodeficiency virus are also active against HTLV-I virus and were used with the rationale of reducing proviral burden. Results of treatment with zidovudine at dosages of 0.5 to 1 glday have been mixed and largely disappointing. However, lamivudine treatment in an open trial of five patients was shown to cause a 90% reduction of viral DNA in peripheral blood mononuclear cells (PBMC). In one patient, who had recent-onset disease, there was a fall in virus-specific CTLs and clinical improvement, which was not detailed. Supportive therapy of spasticity and urinary sphincter disturbances can be very helpful. Administration of baclofen, a-adrenergic medications, and anticholinergic medications is similar to that of myelopathies of other causes. The practitioner is well advised to cautiously interpret failed or unsustained responses seen in some trials. Small patient numbers, inadequate empirical dosing, too brief a duration of treatment, and inclusion of patients with burned-out late phase disease make it difficult to interpret these failures.

SUGGESTED READINGS Izumo S, Goto I, Itoyama Y et ak Interferon-a is effective in HTLV-Iassociated myelopathy: a multicenter, randomized, double-blind, controlled trial. Neurology 46:1016-1021, 1996 McKendall RR: HTLV-1 diseases. pp. 737-772. In McKendd RR,Stroop WG (eds): Handbook of Neurovirology. Marcel Dekker, New York, 1994 Nakagawa M, Izumo S, Ijichi S et ak HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings. J Neurovirol 1:50-61, 1995 Nakagawa M, Nakahara K, Maruyama Y et ak Therapeutic trials in 200 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. J Neurovirol 2:345-355, 1996 Roman GC Tropical spastic paraparesis and HTLV-1 myelitis. pp. 525542. In McKendall RR (ed): Handbook of Clinical Neurology. Vol56. Elsevier, Amsterdam, 1989 Roman GC, Vernant JC, Osame M (eds): HTLV-1 and the Nervous System. Alan R. Liss, New York, 1989 Taylor G P Pathogenesis and treatment of HTLV-I-associated myelopathy. Sex Transm Infect 74:316-322, 1998

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Chronic and Recurrent Noninfectious Meningitis Elizabeth A. Sekul, Ahmed Sadek, and Tetsuo Ashizawa

Chronic meningitis is defined as cerebrospinal fluid (CSF) pleocytosis for more than 4 weeks in association with clinical signs of meningitis such as headache, fever, and neck stiffness. Recurrent meningitis implies cellular clearing from the CSF between episodes. Chronic or recurrent lymphocytic meningitis can present a diagnostic challenge, particularly when it is the initial manifestation of multisystem disease. The underlying disease processes that can present with these meningitides are varied, but they can be classified into several categories. Infectious causes, particularly viral, fungal, rickettsial, tubercular, and syphilitic, probably are the most common cause and should be aggressively sought via direct culture, polymerase chain reaction (PCR) assays, antibody titers, and antigen presence (such as VDRL). Parameningeal foci of infection such as mastoiditis can also produce a picture of chronic CSF pleocytosis. Noninfectious causes of chronic or recurrent meningitis include a group of less common disorders (Table 78-1). Because the infectious causes are discussed elsewhere, the focus of this chapter is on the noninfectious causes of chronic and recurrent meningitis, including the vasculitides (which are also discussed in detail in other chapters).

MOLLARET'S MENINGITIS Mollaret's meningitis is a form of recurrent meningitis marked by episodic attacks of fever and myalgia, associated with the signs and symptoms of meningeal irritation. No other organ systems are involved. The attacks are self-limited, resolving without sequelae in 2 to 7 days. Other than the signs of meningeal irritation, the TAW 78-1. Noninfectious Causes of Chronic or Recurrent Meningitis Mollaret's meningitis BehGet's disease Vogt-Koyanagi-Harada syndrome Cranulomatous disease Sarcoidosis Wegenef s granulomatosis Lymphomatoid granulomatosis Primary angiitis of the central nervous system Other autoimmune vasculiides Systemic lupus erythematosus Sjogren's syndrome Systemic necrotizing vasculitides Drug-induced meningitis Meningeal carcinomatosis Spinal arachnoiditis Migraine

1

neurologic examination during the attacks usually is normal; however, seizures, facial nerve palsies, anisocoria, and positive Babinski signs have been reported. The disease duration averages from 3 to 5 years, with the longest reported duration being 28 years. The meningeal attacks are of variable intensity and frequency. Little has been published about ethnic or gender predilections of Mollaret's meningitis. It is generally believed that it commonly afflicts middle-aged subjects with no gender or racial preponderance. Although it is rare in children, patients as young as 1 year old have been reported. In Mollaret's meningitis, the CSF cell count ranges from 200 cells/mm3 to thousands of cells, which are predominantly lymphocytes, with few polymorphonuclear cells and distinguishing endothelial cells intermixed. This endothelial cell is the histologic hallmark of Mollaret's meningitis; however, they are not pathognomonic. They are mononuclear cells of the monocyte lineage with irregular and poorly differentiated nuclear and cytoplasmic membranes. They are present only during the first few days of the attack and then degenerate into lytic or ghostlike cells before they clear completely. The CSF protein is mildly elevated, and the glucose level is normal to slightly low. Oligoclonal bands may be present. The CSF returns to normal within 1 week of the attacks, and between attacks the CSF is normal. The laboratory findings outside the CSF are nonspecific, such as an elevated erythrocyte sedimentation rate or peripheral eosinophilia. The cause of Mollaret's meningitis is unknown, but it is felt to be autoimmune or allergic in nature. No microorganisms have been identified. However, in some cases herpes simplex type 2 DNA has been detected by PCR assay in the CSF during the acute illness, suggesting that this virus may play a major role in the pathogenesis. Because of the self-limited nature of this disease and lack of sequelae, treatment usually is symptomatic. Steroids may reduce the duration of the episode. Prophylactic therapy is controversial. Both prednisone and acyclovir have been reported to be effective prophylaxis. However, the unpredictability of the disease makes treatment efficacy in Mollaret's meningitis difficult to assess. BEH@"'S D I S m E

BehCet's disease is a multisystem disorder that causes aseptic chronic recurrent meningitis, sometimes as a presenting feature, and is also characterized by the classic triad of recurrent oral ulceration, genital ulcerations, and eye inflammation. The disease, though global, is much more common in Japan, the Middle East, and the Mediterranean countries, where its prevalence can reach 507

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10 per ~00,000population. One study in the United States showed a prevalence of 0.3 per 100,000 population. Men are affected two to three times more often than women. Familial cases have been observed. This may be caused by an association with HLA-B5, particularly B51, which has been noted in the Mediterranean populations. However, this association is not as strong in the Western populations. The cause is unknown but probably is autoimmune in nature, mediated by a combination of factors involving immune dysregulation. Several reports suggest that the disease may be triggered by an infectious agent. Streptococcal and herpes infections have been the most widely studied, and results have been promising but not conclusive. Overall, no infectious agent has been reproducibly isolated in Behqet’s disease. The primary pathologic finding is a leukoblastic vasculitis, possibly directed at the vasa vasorum. In addition, musculocutaneous lesions show mononuclear infiltrates of the dermis and epidermis. In the central nervous system (CNS), inflammation, necrosis, gliosis, and variable degrees of demyelination can be seen. Hypercoagulability, probably caused by increased platelet aggregation, decreased prostacyclin synthesis, and decreased fibrinolytic activity also occurs in Behqet’s disease and increases morbidity. Because no combination of historical or laboratory findings is specific for Behqet’s disease, the diagnosis remains clinical. According to the clinical diagnostic criteria established in 1990 by the International Study Group for Behqet’s Disease, the diagnosis depends on the presence of oral ulcerations and two of the following: genital ulcerations, typical defined eye lesions, typical defined skin lesions, or a positive pathergy test. These oral lesions are aphthous or herpetiform ulcerations, which typically heal within several days without scarring and recur at least three times in one 12-month period. They may be very painful. The recurrent genital lesions consist of pustules or painful ulcerations that may scar. Ocular manifestations, which may lead to blindness within 5 years, include retinal vasculitis, hypopyon, and iritis, resulting from anterior uveitis, and in late-stage optic atrophy and secondary glaucoma. The recurrent skin lesions include erythema nodosum, nonpruritic pseudofolliculitis, and subcutaneous thrombophlebitis. A positive pathergy test is 90% specific but only approximately 60% sensitive for Behqet’s disease. BehCet’s disease is a protean disease affecting many systems, including neurologic, musculoskeletal, gastrointestinal, and cardiovascular. Arthritis is reported in 50% of patients and is typically nonmigrating, nonerosive, and oligoarticular, involving large joints. Gastrointestinal manifestations such as constipation, diarrhea, abdominal pain, and vomiting are common (50%). Cardiovascular disease is seen in approximately one third of patients. Thrombotic complications with venous occlusions more so than arterial occlusions can cause thrombotic complications. Arterial aneurysms, including aortic aneurysms, have been reported in conjunction with Behqet’s disease. Neurologic involvement occurs in up to 30% of patients, usually within 5 years of disease presentation; in 5%, it may be the initial presentation. The intermittency of the neurologic features is one of the most characteristic findings. Because of the frequency and severity of neurologic involvement, the term neuro-Beh&s disease was coined in the literature. The mortality rate associated with neuro-Behqet’s disease has been reported as high as 50% with most deaths occurring within 1 year of neurologic symptom onset. However, with improved treatment modalities, mortality rates as low as 13% have been reported. Any portion of the neuraxis may be involved, and neurologic complications can vary from one

relapse to the next. Three common patterns of central neurologic involvement are noted a brainstem syndrome affecting many cranial nerves, a meningoencephalitis syndrome, and an organic confusional state. Meningoencephalitis can occur in up to 12% as the presenting neurologic picture and can vary from uncomplicated aseptic meningitis to a fulminant and fatal meningoencephalomyelitis. Typically, fever, headache, meningismus, and CSF pleocytosis are present. Cerebral infarctions caused by meningeal vessel involvement may occur. The organic confusional state may lead to severe dementia, personality changes, or delirium. CSF pleocytosis may accompany the psychiatric symptoms; however, clinical findings of meningeal irritation usually are absent. In acute meningitis, cell count may exceed 500 cells/mm3, but in chronic manifestations, 60 cells or less usually are noted. Although these cells usually are lymphocytes, polymorphonuclear cells may be seen. The total protein level is normal or slightly elevated. The CSF glucose level in the active stages typically is normal. CSF immunoglobulin G (IgG) and IgA levels are increased with IgA oligoclonal bands but not IgG. The presence of these bands may be used to monitor disease activity. Serum laboratory findings in Behqet’s disease are nonspecific but suggestive of an inflammatory reaction. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) may show signs of infarction or edema and are useful in distinguishing neuroBehqet’s from multiple sclerosis, which also may present with relapsing and remitting course, and from tumors and abscesses. Treatment of Behqet’s disease has been difficult to evaluate because of the relapsing nature of the disease. Both local and systemic treatment are advocated. Topical steroids for oral, genital, and ocular lesions are recommended. Oral ulcers may also respond to topical tetracycline. Corticosteroids remain the mainstay of systemic treatment and are used alone or in conjunction with other immunosuppressants, such as azathioprine or chlorambucil. Prednisone (20 to 100 mglday or 1mglkglday) may be needed to control the ocular and neurologic manifestations. Methylprednisolone 1000 mglday IV for 3 days with or without a prednisone taper has also been efficacious. Other drugs tried in BehCet’s disease include azathioprine, cyclophosphamide, cyclosporine, colchicines, thalidomide, levamisole, a-interferons, and dapsone. Colchicine (1 to 1.5 mg per day) is reported to be effective in treating mucocutaneous symptoms. Plasmapheresis in acute situations has been helpful in some patients. When vaso-occlusive disease occurs, steroids alone are not sufficient, and a combination of immunosuppressant agents and antiplatelet agents should be used.

VOCT-KOYANACI-HARADA SYNDROME Another uveomeningoencephalic syndrome that may be difficult to differentiate from Behqet’s disease is Vogt-Koyanagi-Harada syndrome (VKH). It is more common in pigmented races, particularly Hispanics and Asians. Its onset typically is later than that of Behqet’s disease, peaking in incidence in the fourth to fifth decade. Women are slightly more commonly affected than men. Unlike Behqet’s disease, in which the blood vessels are affected, the cause of VKH appears to be an autoimmune reaction to melanocytes. Melanocytes are located in the skin, uvea and retinal choroid, membranes of the inner ear, and leptomeninges, particularly at the base of the cerebrum, thus accounting for the particular limited pattern of involvement seen in this syndrome. MART-1, a self-antigen expressed on melanocytes and the retina, may be the target antigen. Other candidate antigen proteins

Chapter 78

include tyrosinase-related protein 1 and 2. Genetic predisposition with human leukocyte antigen (HLA) subtypes has been described. HLA-DR4 seems to be the most prevalent subtype in patients with VKH. However, some reports suggest that HLADRBl subtype correlates to the chronicity of the disease. In VKH, the ocular findings usually are more pronounced than the otologic or neurologic manifestations, although involvement of the latter is a rather constant feature. In the early active stage, the ophthalmologic involvement consists of bilateral uveitis and choroidal inflammation, which may result in retinal detachment. In the recovery stage, the retina has a characteristic sunset glow appearance caused by depigmentation. Later ocular findings consist of cataracts, glaucoma, and globe atrophy. In the early active phase, the meningeal involvement may lead to encephalopathy, seizure, myelopathy, or other focal signs. In some cases, the meningitis is subclinical. CSF lymphocytic pleocytosis ranges from less than 20 to 500 cells/mm3. Elevated CSF protein level, averaging 49 mg/dL in one series, occurs in approximately 50% of patients. Opening CSF pressure usually is normal. CSF immunoglobulins have been studied in only a few patients, with occasional elevations of CSF IgG noted. Melaninladen macrophages within the CSF may also occur early in the disease. Other manifestations of VKH include dysacousia with hearing loss and tinnitus, alopecia, poliosis (whitening of the eyebrows and lashes), and vitiligo. Unlike in Behget’s disease, the cutaneous involvement is not ulcerative but rather characterized by depigmentation. The treatment of VKH consists of systemic and local corticosteroid administration. Treatment generally is monitored by ophthalmologic parameters, and patients should be under the care of an ophthalmologist for this. Few studies using other immunosuppressants have been done; their efficacy remains to be proved.

SARCOIDOSIS The prevalence of sarcoidosis in the United States is 10 to 40 per 100,000. It is more common in women than in men and appears to be 10 to 20 times more common in blacks than in whites. The peak age of onset is 25 to 30 years of age, and it is rare below age 15 years. The cause of sarcoidosis is unknown. It is probably an antigen-driven disease because the response to the Kveim antigen has been universal. However, the antigen responsible remains unknown. An infectious cause has been studied extensively, particularly with Myobacterium as the likely candidate antigen, but results via cultures and PCR studies have not been conclusive. A recent report from Japan suggests that propionibacteria genome was detected in the sarcoid lymph nodes, but whether it is the cause has not been determined. Sarcoidosis is responsible for multiple neurologic presentations, including aseptic chronic or recurrent meningitis. Symptomatic neurosarcoidosis occurs in 4% to 14% of patients, usually within the first 2 years of disease onset, and may be the presenting feature. Spontaneous remissions occur in approximately two thirds of patients with neurologic involvement, whereas one third show a progressive course. The shorter the history and the younger the patient, the more likely is the resolution of symptoms. The most common CNS involvement in sarcoidosis is the granulomatous infiltration of the meninges, particularly at the base of the skull. This causes cranial nerve entrapments and subsequent palsies, most commonly of the facial nerve. Facial nerve palsies occur in approximately 50% of those who develop other CNS manifestations. Ocular involvement occurs in 30% of patients with neurosarcoidosis, ranging from

Chronic and Recurrent Noninfectious Meningitis

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iriditis and uveitis to papilledema as a result of meningeal involvement of the casing of the optic nerve and subsequent swelling. Meningeal involvement can occur in all regions of the CNS and may lead to obstructive hydrocephalus caused by scarring. Involvement over the surface of the brain may act as seizure focus or, if generalized, may present with clinical meningitis. Rarely, space-occupying parenchymal lesions caused by granulomas may occur. Focal involvement of the arachnoid or dura of the spinal cord is unusual but can occur, presenting as transverse myelitis. Involvement of the hypothalamic-pituitary axis is not uncommon, and diabetes insipidus is the most common result. The peripheral nervous system is involved in up to 50% of patients, in a pattern varying from symmetricalpolyneuropathyto mononeuritis multiplex. In these patients, CSF pleocytosis tends to be slight, and the CSF protein is higher, as opposed to that in patients with CNS disease, but glucose level is normal. Myopathy clinically occurs in up to 50% of patients with sarcoid; however, granulomas often are found on muscle biopsy even in asymptomatic patients. The CSF findings in neurosarcoidosis show an elevated cell count, usually less than 100 mononuclear cells/mm3, and an increased protein level, up to 200 mg/dL. Approximately one half of the patients have elevated CSF IgG levels, derived mostly from serum. Rarely, oligoclonal bands are present. A low CSF glucose level may be present, especially when obvious meningeal involvement signs are found. Patients with isolated hypothalamic or pituitary involvement may have normal CSF. CSF angiotensinconverting enzyme (ACE) levels are elevated in approximately 50% of patients with neurosarcoidosis and only 8% of patients with systemic sarcoid. However, this is not specific because the CSF ACE level may also be elevated with tumors or bacterial meningitis. The diagnosis of sarcoidosis is based on the histologic findings of noncaseating granulomas containing large epithelial cells. There is no necrosis in the granulomas. Variable numbers of giant cells are present, of either the Langerhans or foreign body type. Clinically, sarcoidosis is suspected by hilar adenopathy on chest radiograph. Additional suspicion is aroused by demonstrated impairment of the delayed-type skin hypersensitivity response to appropriate antigenic stimulation. Other immunologic alterations include elevation of serum immunoglobulins, particularly IgG, and a positive response to the Kveim-Siltzbach antigen, derived from sarcoidosis-involved lymph node. In approximately 75% of patients with sarcoidosis, a nodule showing the histologic changes resembling sarcoidosis occurs when this antigen is injected intradermally. Approximately 90% of symptoms improve with steroid therapy, although treatment often must continue for months. Oral steroids usually are adequate, such as prednisone 60 to 80 mg/day, with slow switch to alternate-day therapy and then a gradual taper, monitoring for recurrent disease. Several reports suggest that cyclosporine (4 to 6 mg/kg/day) may be helpful in refractory neurosarcoidosis. Other immunosuppressive agents are of possible, unproven benefit.

WECENER‘S CRANULOMATOSIS Wegener’s granulomatosis is a systemic disease characterized by necrotizing granulomata and vasculitis affecting predominantly the medium and small vessels. Typical features of Wegener’s

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granulomatosis include granulomatous lesions of the upper and lower respiratory tract, focal segmental glomerulopathy, and necrotizing vasculitis. Approximately 90% of patients present with symptoms related to the upper or lower airway. The incidence of Wegener’s granulomatosis in the United States is approximately 1:30,000. Its peak incidence is in the fourth or fifth decade, with a mean age of 41 years. Its cause is also unknown. Neurologic involvement occurs in up to 30% of patients with Wegener’s granulomatosis and can include aseptic chronic meningitis similar to that seen in sarcoidosis, with granulomatosis in the basilar meninges. However, vascular involvement of the meninges can also occur. CSF may reveal lymphocytosis and elevated protein levels, particularly with meningeal involvement. Mononeuritis multiplex is a common neurologic complication occurring in approximately 15% of patients. Wegener’s granulomatosis can be recognized clinically by the presence of upper and lower respiratory tract lesions, although pathologic diagnosis (biopsy) is mandatory. Basic laboratory tests are unrevealing. Erythrocyte sedimentation rate may be elevated, particularly during periods of active disease. Recently a high specificity for antineutrophil cytoplasmic antibody (c-ANCA) positivity during active disease and Wegener’s granulomatosis has been noted. Recognition of Wegener’s disease is important because it is universally fatal if left untreated, with an average survival of 5 months. However, a remission rate of more than 90% has been reported with immunosuppressive treatment using cyclophosphamide. LYMPHOMATOIDCRANULOMATOSIS Another systemic granulomatosis very similar to Wegener’s granulomatosis is lymphomatoid granulomatosis. Again, the lungs are primarily involved, but unlike Wegener’s granulomatosis, the upper respiratory tract usually is spared. Neurologic manifestations occur in approximately 30% of cases. The most common CNS finding is necrotizing inflammatory masses in the brain parenchyma; however, the meninges often are involved, resulting in multiple cranial nerve palsies, encephalopathy, or radiculopathy with a picture of aseptic chronic meningitis. The cause of lymphomatoid granulomatosis is unknown. It appears to be a mixture of granulomatosis and lymphoproliferative disorders. It progresses to lymphoma in approximately 13% of patients. No consistent laboratory abnormalities are typical. However, in contrast to Wegener’s granulomatosis, leukopenia is very common. The CSF is abnormal in up to 50% of patients with findings similar to those of sarcoidosis and Wegener’s granulomatosis, except that mononuclear cells seen are chiefly reticular cells with some plasma cells and lymphocytes. These cells simulate those found in meningeal lymphoma and other diffuse meningeal neoplasms. Diagnosis is based on the clinical presentation and tissue histology. Treatment is with prednisone and cyclophosphamide.

affected slightly more often than women, and the illness may occur at any age. The disease is very unusual in children. The mortality rate may exceed 85%. PACNS may involve the entire neuraxis, but it predominantly affects the intracranial structures. It is usually asymmetrical in distribution and at times may be remarkably focal. It most commonly involves the small vessels of the leptomeninges; however, larger vessels are involved in up to one third of cases. Clinically, PACNS is subacute in onset. It presents with headache and mental status changes, which progress to confusion and disorientation followed by lethargy and focal signs. Focal or generalized seizures occur in approximately one fourth of patients. Cerebral edema may occur and often is massive. Among untreated people, 90% eventually develop focal CNS signs. The electroencephalogram is abnormal in 80% of patients, most often showing generalized or focal slowing. The erythrocyte sedimentation rate is elevated in approximately 70%, usually in the low range and rarely exceeding 100 mm/hour. Tests for autoantibodies such as antinuclear antibody are consistently negative. CSF abnormalities are seen in 80% of patients. An elevated opening pressure is frequent. The protein concentration is elevated in 80% of patients, with a mean of 160 mg/dL, and the CSF IgG level is elevated in some patients. CSF lymphocytic pleocytosis is noted in approximately two thirds of patients with up to 250 cell/mm3. Some erythrocytes (less than 1000/mm3) may also be seen in one third of patients. CT and MRI studies show patchy areas of ischemia and edema. Angiography is normal in many patients; however, the remaining patients show arterial beading, aneurysms, or arterial branch occlusions. Leptomeningeal biopsy is the most useful method to establish the diagnosis. Histologic findings include angiitis, segmental intimal proliferation, vascular narrowing, and intensive inflammatory infiltrates with granulomas consisting of lymphocytes, plasma cells, multinuclear cells, and fibrinoid necrosis. However, because of the focal nature of the disease, a negative biopsy does not preclude the diagnosis. The mean duration from onset of the symptoms to death is 6 months in untreated patients. Corticosteroids with another immunosuppressant, particularly cyclophosphamide, are the treatment of choice. OTHER AUTOIMMUNE VASCULITIDES Systemic Lupus Erythematosus Neurologic involvement can be documented in 25% to 75% of patients with systemic lupus erythematosus (SLE) at some point in their disease. Psychiatric symptoms or seizures are the most common complications and sometimes are accompanied by CSF lymphocytic pleocytosis. However, clinical aseptic meningitis is rare in SLE, especially as a presenting manifestation. Aseptic meningitis has also been reported in SLE in association with elevated serum antiphospholipid antibodies.

Sjogren’s Syndrome ISOLATED CENTRAL NERVOUS SYSTEM ANGllTlS The fourth noninfectious granulomatous disease that affects the meninges and can present as aseptic chronic meningitis is isolated or primary angiitis of the CNS (PACNS). It is a rare granulomatous vasculitis of unknown cause that is limited largely to the CNS. The incidence of isolated CNS vasculitis is low, but the exact incidence is unknown. It accounts for only a small fraction of dementias, encephalopathies, strokes, and myelopathies. Men are

Sjogren’s syndrome is characterized by keratoconjunctivitis sicca, xerostomia, and connective tissue disorder (usually rheumatoid arthritis). It is associated with anti-SSa and anti-SSb antibodies, which are autoantibodies to extractable components of nuclear cytoplasm. Peripheral nerve involvement is far more common than CNS involvement. However, CNS abnormalities occur in 20% of patients in some series and may mimic multiple sclerosis, with abnormal CSF findings and multiple lesions on MRI. A

Chapter 78

recurrent aseptic meningoencephalitis has also been noted. When present, CNS involvement is associated with cutaneous signs of vasculitis in more than 70% of patients, which in turn is highly correlated with anti-SSa antibodies. The CSF shows an elevated IgG index in nearly 100% of patients with Sjogren’s syndrome and CNS disease. Systemic Necrotizing Vasculiides

Polyarteritis nodosa, Churg-Straws syndrome, temporal arteritis, Takayasu’s arteritis, and drug abuse-associated vasculitis can also involve the meningeal blood vessels. Approximately 20% of patients with these diseases may have clinical or laboratory evidence of aseptic meningitis at some time during their illness. Aseptic meningitis has similarly been reported in other systemic vasculitidessuch as mixed connective tissue disease and Kawasaki’s d’isease. DRUG-INDUCED ASEPTIC MENINGITIS

Aseptic meningitis can also occur as a reaction to a wide variety of drugs taken systemically (Table 78-2). Whether this results from a direct toxic effect from diffusion of the drug across the bloodbrain barrier or from a hypersensitivity reaction of the cerebral blood vessels is unknown. Aseptic meningitis caused by nonsteroidal anti-inflammatory drugs occurs primarily in patients with connective tissue disorders, especially those with SLE and mixed connective tissue disease. Clinically, patients develop the classic signs of meningitis, usually including fever. In most cases, this reaction occurs within hours to 1 day of exposure and is reproducible upon reexposure to the offending agent. CSF studies in general show lymphocyte-predominant pleocytosis unless the fluid was collected early in the course, at which time polymorphonuclear cells may predominate. Eosinophils may also be present. The CSF protein level is mildly elevated, and glucose concentration is normal in most patients. Generally, the symptoms resolve without sequelae, and only supportive therapy is needed. On the first exposure, of course, a full evaluation for other causes of aseptic meningitis usually is warranted. Similar self-limiting aseptic meningitis may be seen in patients who receive a large intravenous dose of y-globulins. MENINGEAL CARCINOMATOSIS

Meningeal carcinomatosis commonly presents with headache, cranial nerve signs, back pain, focal weakness, or seizure. Unlike in most other chronic meningitides, nerve roots, including the cauda equina, often are involved with carcinomatous meningitis. This type of meningitis must be distinguished from the remote effects of cancer, toxicity of treatment, or infections. Malignant meningeal involvement can occur as a primary diffuse infiltration, from either CNS lymphoma or meningeal gliomatosis, or as an extension from a primary brain tumor such as a glioblastoma, astrocytoma, or medulloblastoma. However, a metastasis may also cause meningeal carcinomatosis, most commonly with breast cancer, lung cancer, melanoma, leukemia, and lymphoma. CSF pressure generally is elevated except in the early stages of the disease. The CSF protein level may be normal but usually is elevated. Cell counts typically are elevated but may be normal in up to one third of patients. Large-volume samples or multiple CSF samples may need to be examined cytologically before the malignant cells can be identified. However, the presence of

Chronic and Recurrent Noninfectious Meningitis

51 1

TABLE78-2. Drugs and Chemicals Associated with Aseptic Meningitis Antimicrobial drugs Sulfonamides Trirnethoprim Sulfasalazine Cephalosporin Ciprofloxacin lsoniazid Penicillin Antineoplastics (systemic use) Cytosine arabinoside Corticosteroids Methylprednisolone acetate Hydrocortisone sodium succinate Nonsteroidal anti-inflammatory drugs Diclofenac Ibuprofen Naproxen Sulindac Tolmetin Ketoprofen Salicylates Piroxicam lntrathecal drugs Antineoplastics Cytosine arabinoside Methotrexate Antimicrobials Baclofen Steroids Spinal anesthesia lntrathecal diagnostic agents Radiologic contrast media lophendylate Metrizarnide Radiolabeled albumin Miscellaneousdrugs hathioprine Carbamazepine Famotidine Intravenous immune globulin Murornonab CD-3 Phenazopyridine Pyrazinarnide Ranitidine Vaccines Polio Measles, mumps, and rubella Hepatitis B

malignant cells is not specific for direct meningeal involvement because they are often found in the CSF when brain tumors, particularly involving the ventricular wall or cortex, are present. Hypoglycorrhachia generally reflects diffuse meningeal involvement rather than localized disease. In some cases, cisternal puncture may have a higher yield when the basilar meninges are involved. Elevated CSF immunoglobulins and abnormal CSF IgG index and oligoclonal bands often are present. Tumor markers, such as vasopressin, carcinoembryonicantigen, adrenocorticotropin, lactic dehydrogenase, and P-glucuronidase may also be helpful. MRI or myelography may show thickened, nodular nerve roots or epidural tumors. Meningeal contrast enhancement on MRI or CT is sensitive but not specific for diffuse carcinomatosis. Treatment depends on the tumor type.

SPINAL ARACHNOlDmS Spinal arachnoiditis can be acute, subacute, or chronic. Chronic spinal arachnoiditis can cause chronic CSF lymphocytic pleocytosis and should be considered a variant of chronic meningitis. It

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usually follows intrathecal injection of a foreign substance, such as contrast material, antibiotics, or anesthetic agents. However, prolapse of vertebral disc, spinal injury or surgery, and infections have been implicated. The presence of blood in the CSF increases the likelihood of developing arachnoiditis. The CSF pleocytosis generally is lymphocytic, but in acute cases following recent foreign substance administration, polynuclear cells may predominate, and a mild eosinophilia may develop. The CSF protein level is elevated to a variable degree. Chronic adhesive arachnoiditis is confirmed by MRI or myelography. Treatment is surgical but not always effective; the arachnoiditis may recur.

MIGRAINES Migraine headaches may be another cause of recurrent CSF lymphocytic pleocytosis. In general, CSF pleocytosis is uncommon in severe but uncomplicated migraines but can occur with elevated cell counts in the range of 15 to 100 cell/mm3. However, patients with complicated or hemiplegic migraines have a higher frequency of CSF abnormalities, with cell count up to 300 cells/mm3 and minor elevation in protein levels.

OTHER CAUSES Recurrent aseptic meningitis can also occur as a result of intermittent leakage of cystic contents from a craniopharyngioma, dermoid cyst, epidermoid cyst, teratoma, or malignant glioma. Cerebral MRI is helpful in establishing the cause of the meningitis in such cases. Patients with familial Mediterranean fever have also been reported to have recurrent aseptic meningitis. One in 2000 subjects who received mumps vaccination have developed aseptic meningitis in Japan and Germany.

means including PCR is necessary in most cases. CSF pleocytosis, protein levels, glucose levels, and immunoglobulin studies are mostly nonspecific. Recognition of systemic manifestations of the baseline diseases that cause aseptic meningitis therefore is often crucial. Various laboratory tests, such as viral titers and other serologic tests, arteriography, CT, MFU, and specific PCR studies may provide important clues for a correct diagnosis. Pathologic diagnosis is sometimes needed, particularly for the granulomatous diseases. Prognosis is variable, ranging from a self-limited benign course to a fatal outcome, depending on the cause. Treatment also depends on the underlying disease. Chronic or recurrent aseptic meningitis often becomes a challenge for physicians and necessitates thorough clinical investigations.

SUGGESTED READINGS Fishman RA: CSF findings in diseases of the nervous system. p. 253. In Fishman RA (ed): Cerebrospinal Fluid in Disease of the Nervous System. 2nd Ed. WB Saunders, Philadelphia, 1992 Frederics JAM, Bruyn G W Mollaret’s meningitis. p. 627. In McKendall RR (ed): Handbook of Clinical Neurology. 56th Ed. Elsevier, New York, 1989 International Study Group for Behget’s Disease: Criteria for diagnosis of Behget’s disease. Lancet 335:1078, 1990 Iomata H, Kato M: Vogt-Koyanagi-Harada disease. p. 611. In McKendall RR (ed):Handbook of Clinical Neurology. 56th Ed. Elsevier, New York, 1989

JainK K Drug-Induced Neurological Disorders. 2nd Ed. Hogrefe & Huber, Gottingen, 2000

Shannon KM, Goetz CG: Connective tissue disease and the central nervous system. p. 389. In Aminoff MJ (ed): Neurology in General Medicine. 2nd Ed. Churchill Livingstone, New York, 1995 Silberberg DH: Sarcoidosis of the nervous system. p. 701. In Aminoff MJ (ed): Neurology in General Medicine. 2nd Ed. Churchill Livingstone, New York, 1995

CONCLUSION

Stratigos AJ, Laskaris G, Stratigos J D Behqet’s disease. Semin Neurol

The causes of culture-negative chronic or recurrent meningitis are diverse, and the diagnosis often is difficult to make, particularly early in the disease process. Exclusion of infectious causes by other

Tucker T, Ellner JJ: Chronic meningitis. p. 188. In Tyler KL, Martin JB (eds): Infectious Disease of the Central Nervous System. FA Davis, Philadelphia, 1993

79

12:346, 1992

Prion Diseases Eugene Lai

The prion diseases are sometimes called transmissible spongiform encephalopathies or transmissible cerebral amyloidoses. They encompass several diseases affecting humans and animals; the human prion diseases include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker(GSS)syndrome, kuru, and fatal familial insomnia (FFI; Table 79-1). The unique feature common to these disorders is the sharing of a similar pathogenesis that involves the aberrant metabolism of the prion protein. The term prion was introduced in 1982 by Stanley Prusiner to mean small, proteinaceous infectious particles that resist inactivation by procedures that modify nucleic acids. Recent advances in the molecular biology of prions revealed that a gene located at the short arm of human chromosome 20 codes for the prion protein. It codes for a normal host protein, but the function of the prion

protein has not yet been identified. In human prion diseases, an abnormal form of this protein, which becomes proteinase resistant, accumulates in the brain. These diseases may be sporadic, dominantly inherited, or acquired by transmission. The prion protein, which contains no nucleic acids (DNA or RNA), can produce disease after injection into animals, thus fulfilling its definition as an infectious agent composed purely of protein.

CREUTZFELDT-JAKOB DISEASE CJD is a rare central nervous system disorder characterized by a relentlessly progressive course and an invariably fatal outcome. It constitutes about 75% of all the human prion diseases. Sporadic, familial, and iatrogenic forms of CJD have been described.

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usually follows intrathecal injection of a foreign substance, such as contrast material, antibiotics, or anesthetic agents. However, prolapse of vertebral disc, spinal injury or surgery, and infections have been implicated. The presence of blood in the CSF increases the likelihood of developing arachnoiditis. The CSF pleocytosis generally is lymphocytic, but in acute cases following recent foreign substance administration, polynuclear cells may predominate, and a mild eosinophilia may develop. The CSF protein level is elevated to a variable degree. Chronic adhesive arachnoiditis is confirmed by MRI or myelography. Treatment is surgical but not always effective; the arachnoiditis may recur.

MIGRAINES Migraine headaches may be another cause of recurrent CSF lymphocytic pleocytosis. In general, CSF pleocytosis is uncommon in severe but uncomplicated migraines but can occur with elevated cell counts in the range of 15 to 100 cell/mm3. However, patients with complicated or hemiplegic migraines have a higher frequency of CSF abnormalities, with cell count up to 300 cells/mm3 and minor elevation in protein levels.

OTHER CAUSES Recurrent aseptic meningitis can also occur as a result of intermittent leakage of cystic contents from a craniopharyngioma, dermoid cyst, epidermoid cyst, teratoma, or malignant glioma. Cerebral MRI is helpful in establishing the cause of the meningitis in such cases. Patients with familial Mediterranean fever have also been reported to have recurrent aseptic meningitis. One in 2000 subjects who received mumps vaccination have developed aseptic meningitis in Japan and Germany.

means including PCR is necessary in most cases. CSF pleocytosis, protein levels, glucose levels, and immunoglobulin studies are mostly nonspecific. Recognition of systemic manifestations of the baseline diseases that cause aseptic meningitis therefore is often crucial. Various laboratory tests, such as viral titers and other serologic tests, arteriography, CT, MFU, and specific PCR studies may provide important clues for a correct diagnosis. Pathologic diagnosis is sometimes needed, particularly for the granulomatous diseases. Prognosis is variable, ranging from a self-limited benign course to a fatal outcome, depending on the cause. Treatment also depends on the underlying disease. Chronic or recurrent aseptic meningitis often becomes a challenge for physicians and necessitates thorough clinical investigations.

SUGGESTED READINGS Fishman RA: CSF findings in diseases of the nervous system. p. 253. In Fishman RA (ed): Cerebrospinal Fluid in Disease of the Nervous System. 2nd Ed. WB Saunders, Philadelphia, 1992 Frederics JAM, Bruyn G W Mollaret’s meningitis. p. 627. In McKendall RR (ed): Handbook of Clinical Neurology. 56th Ed. Elsevier, New York, 1989 International Study Group for Behget’s Disease: Criteria for diagnosis of Behget’s disease. Lancet 335:1078, 1990 Iomata H, Kato M: Vogt-Koyanagi-Harada disease. p. 611. In McKendall RR (ed):Handbook of Clinical Neurology. 56th Ed. Elsevier, New York, 1989

JainK K Drug-Induced Neurological Disorders. 2nd Ed. Hogrefe & Huber, Gottingen, 2000

Shannon KM, Goetz CG: Connective tissue disease and the central nervous system. p. 389. In Aminoff MJ (ed): Neurology in General Medicine. 2nd Ed. Churchill Livingstone, New York, 1995 Silberberg DH: Sarcoidosis of the nervous system. p. 701. In Aminoff MJ (ed): Neurology in General Medicine. 2nd Ed. Churchill Livingstone, New York, 1995

CONCLUSION

Stratigos AJ, Laskaris G, Stratigos J D Behqet’s disease. Semin Neurol

The causes of culture-negative chronic or recurrent meningitis are diverse, and the diagnosis often is difficult to make, particularly early in the disease process. Exclusion of infectious causes by other

Tucker T, Ellner JJ: Chronic meningitis. p. 188. In Tyler KL, Martin JB (eds): Infectious Disease of the Central Nervous System. FA Davis, Philadelphia, 1993

79

12:346, 1992

Prion Diseases Eugene Lai

The prion diseases are sometimes called transmissible spongiform encephalopathies or transmissible cerebral amyloidoses. They encompass several diseases affecting humans and animals; the human prion diseases include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker(GSS)syndrome, kuru, and fatal familial insomnia (FFI; Table 79-1). The unique feature common to these disorders is the sharing of a similar pathogenesis that involves the aberrant metabolism of the prion protein. The term prion was introduced in 1982 by Stanley Prusiner to mean small, proteinaceous infectious particles that resist inactivation by procedures that modify nucleic acids. Recent advances in the molecular biology of prions revealed that a gene located at the short arm of human chromosome 20 codes for the prion protein. It codes for a normal host protein, but the function of the prion

protein has not yet been identified. In human prion diseases, an abnormal form of this protein, which becomes proteinase resistant, accumulates in the brain. These diseases may be sporadic, dominantly inherited, or acquired by transmission. The prion protein, which contains no nucleic acids (DNA or RNA), can produce disease after injection into animals, thus fulfilling its definition as an infectious agent composed purely of protein.

CREUTZFELDT-JAKOB DISEASE CJD is a rare central nervous system disorder characterized by a relentlessly progressive course and an invariably fatal outcome. It constitutes about 75% of all the human prion diseases. Sporadic, familial, and iatrogenic forms of CJD have been described.

Chapter 79

TABU 79-1. The Human Prion Diseases Disease

Etiolonv

Creutzfeldt-Jakob Sporadic Familial Iatrogenic New variant Cerstmann-Straussler-Scheinker Kuru Fatal familial insomnia

Unknown Prion mutation Transmission Transmission Prion mutation Transmission Prion mutation

Prion Diseases

513

new variant CJD has been identified in Europe in the last 10 years. It has affected more than 80 people and is thought to be linked to the consumption of beef from cattle that contracted bovine spongiform encephalopathy (or mad cow disease). These patients have a number of distinctive features compared with those of classic CJD, including a young age at disease onset, a slower clinical course, the presence of early psychiatric and sensory symptoms, and the finding of widespread protein clumps or plaques on neuropathologic examination.

Diagnosis Clinical Features CJD usually occurs in late middle age, but its range can extend from 16 to 82 years. Both sexes are affected equally. The clinical manifestations encompass almost the entire nervous system and may be confusing in the early stages of the disease (Table 79-2). Approximately one third of patients present with mental deterioration that includes memory loss, behavioral abnormalities, and confusion; another third of patients have only physical complaints, most often cerebellar ataxia or visual disturbance; and the final third of patients present with a mixture of both mental and physical symptoms; More than one fourth of the patients report prodromal symptoms, consisting of fatigue, disturbance of sleep patterns or appetite, anxiety, or weight loss that may last for several weeks. As a rule, the disease progresses rapidly, and symptoms advance within weeks. Memory decline usually progresses to profound and global intellectual deficits, often with prominent grasp, glabellar, palmomental, and snout reflexes. Movement disorders, such as cerebellar ataxia, tremor, dysarthria, hypokinesia, rigidity, or choreoathetoid movements, may become pronounced. Myoclonus, often provoked by sensory stimuli, usually appears in midcourse of the disease. Pyramidal tract involvement is also common, as manifested by hyperreflexia, extensor plantar reflexes (Babinski signs), and clonus. Visual complaints include hallucinations, diplopia, dimming or blurring of vision, and visual distortions that may evolve into cortical blindness. The patient continues to deteriorate to mutism, complete helplessness, and a vegetative existence. The disease typically ends in death from respiratory or systemic infections, usually within 1 year of onset. Only 5% to 10% of patients may have clinical courses of more than 2 years.

The routine analysis of cerebrospinal fluid (CSF) usually is unremarkable, but an immunoassay for detecting the 14-3-3 protein in CSF is useful for confirming the diagnosis. However, a negative test does not rule out CJD. Though typically normal, a computed tomography scan of the head may show nonspecific cerebral atrophy. Magnetic resonance imaging (MRI) of the brain, especially using diffusion-weighted imaging (DWI) , may allow earlier and noninvasive diagnosis of CJD (Fig. 79-1). Areas of bright signal abnormalities on DWI correlate well with areas of the most severe and characteristic neuropathologic changes in CJD, typically in the basal gangha and deeper cortical layers. The electroencephalogram (EEG) is helpful diagnostically if it shows the characteristic abnormality. It is often normal early in the course of illness. In later stages, it may show generalized slow wave activity or background disorganization that progresses to a typical pattern of periodic (1 or 2 cycles/second) sharp waves against a slow background or, in some cases, to episodic burst suppression with high-voltage activity. A clinical triad of dementia, myoclonus, and the characteristic EEG pattern is highly indicative of CJD. The diagnosis can be confirmed by finding the typical light microscopy spongiform vacuolar changes in brain tissue during brain biopsy. Immunohistochemistry or Western blot analysis with antibodies against the prion protein further improves the specificity of the diagnosis. Differential diagnosis should include progressive neurodegenerative diseases such as Alzheimer’s disease, severe parkinsonism, and cerebellar degeneration. Acquired immunodeficiency syndrome, cerebrovascular disease, drug toxicities, central nervous system neoplasm or infection, acute exacerbation of multiple sclerosis, and acute psychosis should also be ruled out.

Pathology Epidemiology and Causes The disease occurs in adults throughout the world, with an annual incidence of 0.5 to 2.0 cases per 1 million population. Sporadic CJD constitutes most cases. Its exact cause is unknown but has been hypothesized to involve a somatic mutation of the prion gene that causes a spontaneous conformational conversion of the normal host prion protein to an abnormal form. A small proportion of the cases, varying from 5% to 15%, according to various reports, are familial and may arise from a germ line mutation in the prion protein gene. Familial CJD has been found to be prevalent among Libyan Jews. The disease is also transmissible, as demonstrated in cases of iatrogenic CJD. Human-tohuman transmission has occurred inadvertently during corneal and cadaveric dura mater transplantation and during the use of contaminated brain electrodes. A few cases have also resulted from treatment with growth hormone prepared from pooled human cadaveric pituitary glands. No transmission of the disease by casual contact or between family members has been reported. A

The pathological abnormalities in CJD are confined to the central nervous system. There is degeneration and disappearance of

TABLE 79-2. Clinical Characteristics of Creutzfeldt-Jakob

Disease (Percentage of Patients with Symptoms and Signs) SvmDtomr and Sims

Mental deterioration Memory loss Higher cortical functions Behavioral abnormalities Involuntary movements Myoclonus Cerebellar ataxia Pyramidal weakness or hyperreflexia Extrapyramidal rigidity Periodic EEC Visual or oculomotor disturbance

At Onset

69 48 16 29 4 1

33 2 0.5 0 19

Durinn Course 100 100

73 57 91

78 71 62 56 60 42

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specimens should be disposed of as biohazard waste after decontamination.

GERSTMANN-STRjiUSSLER-SCHEINKER SYNDROME GSS syndrome is a rare neurodegenerative disease that has an apparent autosomal dominant pattern of inheritance. There are approximately 30 known families with GSS in various parts of the world, including the Americas, Europe, and Japan. The clinical features are dominated by cerebellar ataxia, pyramidal signs, and dementia. The average age of onset is 40 years, and the average duration is about 5 years, with a range of 1 to 11 years. Its neuropathology is characterized by extensive multicentric prioncontaining amyloid plaques and spongiform change in the gray matter of the cortex. Mutations in the protein coding region of the prion protein gene that result in amino acid substitutions have been found in several kindreds.

KURU

Kuru is a disease of historic interest only. It is restricted to the Fore tribe of Papua New Guinea and is transmitted by ritual cannibalistic practices during the care of the dead. Patients present with progressive emotional lability, mental slowing, and movement disorders, such as ataxia, tremor, and rigidity, that progress to mutism and vegetative state. Death occurs within 1 year of symptom onset. Kuru has largely disappeared as a result of the cessation of the practice of cannibalism. FIGURE 79-1. Diffusion-weighted MRI of the brain showing bright signal in the basal ganglia characteristic of Creutzfeldt-Jakob disease.

FATAL FAMILIAL INSOMNIA

neurons and their processes together with widespread hypertrophy and proliferation of astrocytes. These changes result in microscopic vacuolation and spongy appearance of the gray matter, particularly the cerebral cortex, hence the term spongiforrn encephalopathy In 5% to 20% of cases, prion immunopositive amyloid plaques have been observed. The white matter usually is preserved, and inflammatory reactions are absent.

FFI is a progressive autosomal dominant disease with subacute onset that is characterized by untreatable insomnia, dysautonomia, motor disturbance, and severe selective atrophy of thalamic nuclei. Several Italian families have been studied, and FFI is also linked to a mutation in the prion protein gene.

SELECTED READINGS Management

No effective treatment is available, and the disease is uniformly fatal. In view of the transmissibility of the disease iatrogenically, certain precautions should be taken in the medical care and handling of materials from the patients. It should be noted that because of the low and limited infectivity of the responsible agent, affected patients present minimal risks to caretakers, and the handling of blood and tissue specimens is not dangerous if appropriate precautions are taken. Isolation of patient is not necessary. Casual skin contacts are allowed, and hand washing with ordinary soap afterwards is recommended. Gloves should be worn when handling blood, body fluids, and tissues, and accidental skin exposure to these samples should be washed with a 1:lO dilution of sodium hypochlorite (household bleach). Contaminated surgical and pathologic instruments can be cleaned by steam autoclaving at 132°C and 15-lb/in2 pressure for 1 hour or by immersing for 1 hour in 5% sodium hypochlorite. Laboratory

Brown P, Gibbs CJ, Rodgers-Johnson P et al: Human spongiform encephalopathy: the National Institute of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35:513-529, 1994 Hsich G, Kenney K. Gibbs CJ et a1 The 14-3-3 brain protein in cerebrospinal fluid as a marker for the transmissible spongiform encephalopathies. N Engl J Med 335:924-930, 1996 Lantos P L From slow virus to prion: a review of transmissible spongiform encephalopathies. Histopathology 20:1-1 1, 1992 Mittal S, Farmer P, Kalina P et al: Correlation of diffusion-weighted

magnetic resonance imaging with neuropathology in CreutzfeldtJakob disease. Arch Neurol 59:128-134, 2002 Poser S, Mollenhauer B, Kraubeta A et al: How to improve the clinical diagnosis of Creutzfeldt-Jakobdisease. Brain 122:2345-2351, 1999 Prusiner SB, Hsiao K K Human prion diseases. Ann Neurol 35:385-395, 1994

Webb RM, Leech RW, Brumback RA: Spongiform encephalopathies: the physician’s responsibility. South Med J 83:141-145, 1990 Weihl CC, Roos Rp: Creutzfeldt-Jakobdisease, new variant CreutzfeldtJakob disease, and bovine spongiform encephalopathy. Neurol Clin 17~835-859, 1999

Chapter 80

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Rickettsial Infections of the Nervous System J. Douglas Lee

Rickettsiae are obligate intracellular, small, gram-negative pleomorphic bacilli that normally cause infection in rodents and other mammals; humans are incidental hosts. The rickettsiae can be grouped as typhus, spotted fevers (Rocky Mountain spotted fever [RMSF]), Q fever, and Ehrlichia. Until recently, Bartonella (formerly Rochalimaea) was also included in this group. Typhus and RMSF, which cause central nervous system (CNS) involvement in almost all infected humans, and Q fever, which does so on occasion, are discussed here. Although these diseases are uncommon, they remain a diagnostic consideration in both rural and urban settings. Each year, 1000 cases of RMSF and somewhat fewer cases of typhus and Q fever are reported in the United States. These diseases undoubtedly are underreported because of a lack of consideration of the diagnosis. PATHOPHYSIOLOGY The organisms of typhus and the spotted fevers selectively infect vascular endothelial cells, producing microvasculitis with inflammation, vascular permeability, local hemorrhage, thrombosis, luminal obstruction, and microinfarction. This is more intense in RMSF than in typhus infections. Because systemic vessels are involved diffusely, a characteristic rash appears in most patients. The rash and the various CNS syndromes dominate the clinical picture; the word typhus is derived from the Greek word for “hazy” or “smoky,” referring to the delirium characteristic of the disease. In the CNS, perivascular glial nodules are almost always present and are considered pathognomonic of rickettsial infection. These are accumulations of enlarged endothelial cells, lymphocytes, and macrophages that contain the organisms, which appear 1 to 2 weeks after the illness. In contrast, the organism of Q fever, Coxiella burnetii, has no such predilection for endothelium, and vasculitis is not seen, so the frequency of CNS involvement (meningitis) is less and the clinical picture usually is characterized by fever with atypical pneumonia and abnormal liver enzyme levels but no rash. ~

CLINICAL PRESENTATION The presentation is related to the type of pathology involved. Patients with RMSF or typhus have an abrupt onset of fever, chills, headache, myalgia, and arthralgia. Restlessness, irritability, confusion, and lethargy are usual, often with photophobia and stiff neck. This picture of an acute severe meningitis may develop within hours and may precede the rash. Other neurologic signs are generally nonfocal but may include increased reflexes and Babinski signs, spasticity, and movement disorders, especially athetosis. Cranial nerve involvement can include facial weakness, gaze palsies, nystagmus, and dysphagia. Eye findings are common, including papilledema, retinal fasciculitis, and uveitis. In a small percentage of patients, transverse myelitis may develop, including paraplegia or quadriplegia and a neurogenic bladder. Seizures are common. Within 1 week, most patients have a petechial rash,

which on occasion becomes confluent. When the rash is accompanied by disseminated intravascular coagulation, it rarely may cause skin or extremity gangrene. Before antibiotic therapy, cases of full-blown encephalitis and delirium had an 80% mortality rate. Patients with Q fever most often have a febrile pneumonia but with few pulmonary symptoms. Headache and constitutional and gastrointestinal symptoms are common, but rash is not a feature. A small number of patients develop meningitis, with headache, nuchal rigidity, and confusion. Some also develop a chronic disease, such as hepatitis, endocarditis, or osteomyelitis. In endemic areas, seroprevalence in the population is high, and undiagnosed Q fever is common. LABORATORY ABNORMALKIES The leukocyte count usually is normal or low, with a left shift. Thrombocytopenia is common, as is mild prolongation of the prothrombin time. Disseminated intravascular coagulation is not commonly documented. In typhus and spotted fevers, as in multisystem vasculitides, abnormalities of the liver and muscle enzymes are common, with the degree of abnormality related to the level of overall illness. Hypoalbuminemia, hypocalcemia, and hyponatremia are also frequent. The cerebrospinal fluid in RMSF often shows a modest mononuclear pleocytosis with normal glucose and elevated protein levels; in typhus and Q fever, the cerebrospinal fluid usually is normal. Imaging results usually are normal. The electroencephalogram in most cases shows diffuse slowing. In Q fever, liver enzyme abnormalities are prominent, as are chest radiographic findings; muscle enzyme and fluid electrolyte abnormalities are less common. DIAGNOSIS The diagnosis of rickettsial infections is clinical, with confirmation by serology during convalescence. Proteus agglutinins (Well-Felix reaction) are commonly present but are nonspecific, insensitive, and delayed (up to 14 days after the onset of symptoms) and so should not be relied upon. Specific rickettsial antibodies may be detected after they develop later in the illness, and it is useful to freeze serum during the acute phase of the illness to allow testing of paired sera later. Some laboratories offer direct immunofluorescent staining to demonstrate the organism in tissue such as skin biopsies. The most important disease to differentiate in the febrile patient with rash is meningococcemia. Counterimmunoelectrophoresis and latex agglutination, in addition to routine cultures, may help make this differentiation. TREATMENT A tetracycline is the treatment for rickettsial infections in adults. Doxycycline 100 mg twice a day or tetracycline 500 mg four times a day is adequate. In children younger than 8 years old and those

516

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w

Other Infections and Mimicken

TABLE80-1. Rickettsial Diseases of Humans: Differential Features sevew (treated mortality)

Disease

Organism

Ceonrarhv

Vector or Route

Reservoir

Rash’

RMSP

R. rickettsii

Western hemisphere

Dog tick

lick

Extremities to trunkd

Severe (4%-8Vo)

Epidemic typhus

R. prowazekii

Wood tick Louse feces

Severe (4%)‘

R. typhi

Flea

Human Flying squirrel Rodents

Trunk

Murine typhus

C. burnetii

Inhalation‘

Numerous mammals

Trunk to extremities None

Moderate (1%-4%)

Q fever

Eastern/SE U.S. Worldwide Eastern U.S.’ Worldwide Southern U.S. Worldwide

Moderate (uncommon)

“ash may be absent in any of these but is usually present. bMortality rate depends on preexisting disease and severity. It is likely that subclinical disease is common, and significant neurologic disease is a poor prognostic indicator. ‘Similar spotted fevers exist with different rickettsiae, vectors, and vertebrate hosts on various continents. dNinety percent of patients. eRare disease in United States. Hardy organisms inhaled from residua of infected placental tissue of wild or farm animals or domestic pets. ‘Brill-Zinsser disease or recrudescent typhus is seen in patients from endemic areas years after immigration. Disease is mild.

allergic to tetracycline, chloramphenicol 50 mg/kg/day in four equally divided doses is effective (maximum dosage 4 g/day). Drugs should be administered for 3 days after the patient becomes afebrile, usually about 7 to 10 days total. The fatality rate in typhus and RMSF remains close to 5%, with patients in the oldest age groups faring the worst.

SPECIFIC INFECTIONS The clinical diagnosis of specific rickettsia1 infections is based on the geographic area of exposure, potential vector exposure, and the distribution and spread of the rash (Table 80-1). Diseases with tick

81

vectors cluster in seasons and around activities allowing tick attachment. Diagnosis confirmation is by serology in most cases.

SUGGESTED READINGS Kirk JL, Fine DP, Sexton DJ, Muchmore H G Rocky Mountain spotted fever: a clinical review. Medicine 69:3545, 1990 Marrie TJ: Rikettsial infections of the central nervous system. Semin Neurol 12:213, 1992 Saah AJ, Marne TJ, Dumler JS, Walker DH: Rickettsial diseases, pp. 1719-1741. In Mandell G (ed): Principles and Practice of Infectious Diseases. 4th Ed. Churchill Livingstone, New York, 1992

Mycoplasma Infections Steven J. Spindel

The normal human oropharynx and genital tract are colonized by a class of bacteria that lack a cell wall, called Mollicutes, which includes the mycoplasmas and ureaplasmas. These are the smallest known free-living organisms. A few of these agents can cause diseases in humans and have central nervous system (CNS) manifestations, including Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum. M. pneumoniae is a bacterial organism that is responsible for pharyngitis, bronchitis, and pneumonia in children and young adults. Nervous system disease has been well recognized in association with this organism, and neurologic manifestations are the most common extrapulmonary symptoms in patients with M. pneumoniae, especially in children.

outbreaks of respiratory infection have been observed to occur in 4- to 7-year cycles in crowded conditions such as schools, colleges, and military institutions. CNS manifestations occur in 7% to 10% of patients hospitalized with infection caused by M. pneumoniae. Neurologic involvement is reported mainly in the pediatric populations, probably because of the greater frequency of the organism in children and young adults. Similarly, the trend for nervous system disease is to manifest in younger patients, although it is an unusual pathogen of encephalitis in infants younger than 1 year old. Much like pulmonary disease, M. pneumoniae infections of the CNS show no gender preference and occur more often in the late summer and fall.

CLINICAL FEATURES EPIDEMIOLOGY M. pneumoniae-associated CNS disease was originally observed during epidemic outbreaks of “primary atypical pneumonia” in the 1940s, when the organism’s identity was not yet known. Transmission occurs via contaminated respiratory droplets, and the incubation period ranges from 16 to 32 days. Epidemic

Usually, M. pneumoniae causes an acute tracheobronchial pneumonia with fever, sore throat, and a severe cough, which may be difficult to distinguish, by clinical or radiographic criteria, from many other causes of pneumonia. The pulmonary disease generally runs its course in 2 to 4 weeks. M. pneumoniae can cause a primary infection of the CNS and

516

Immune and Infectious Disease

w

Other Infections and Mimicken

TABLE80-1. Rickettsial Diseases of Humans: Differential Features sevew (treated mortality)

Disease

Organism

Ceonrarhv

Vector or Route

Reservoir

Rash’

RMSP

R. rickettsii

Western hemisphere

Dog tick

lick

Extremities to trunkd

Severe (4%-8Vo)

Epidemic typhus

R. prowazekii

Wood tick Louse feces

Severe (4%)‘

R. typhi

Flea

Human Flying squirrel Rodents

Trunk

Murine typhus

C. burnetii

Inhalation‘

Numerous mammals

Trunk to extremities None

Moderate (1%-4%)

Q fever

Eastern/SE U.S. Worldwide Eastern U.S.’ Worldwide Southern U.S. Worldwide

Moderate (uncommon)

“ash may be absent in any of these but is usually present. bMortality rate depends on preexisting disease and severity. It is likely that subclinical disease is common, and significant neurologic disease is a poor prognostic indicator. ‘Similar spotted fevers exist with different rickettsiae, vectors, and vertebrate hosts on various continents. dNinety percent of patients. eRare disease in United States. Hardy organisms inhaled from residua of infected placental tissue of wild or farm animals or domestic pets. ‘Brill-Zinsser disease or recrudescent typhus is seen in patients from endemic areas years after immigration. Disease is mild.

allergic to tetracycline, chloramphenicol 50 mg/kg/day in four equally divided doses is effective (maximum dosage 4 g/day). Drugs should be administered for 3 days after the patient becomes afebrile, usually about 7 to 10 days total. The fatality rate in typhus and RMSF remains close to 5%, with patients in the oldest age groups faring the worst.

SPECIFIC INFECTIONS The clinical diagnosis of specific rickettsia1 infections is based on the geographic area of exposure, potential vector exposure, and the distribution and spread of the rash (Table 80-1). Diseases with tick

81

vectors cluster in seasons and around activities allowing tick attachment. Diagnosis confirmation is by serology in most cases.

SUGGESTED READINGS Kirk JL, Fine DP, Sexton DJ, Muchmore H G Rocky Mountain spotted fever: a clinical review. Medicine 69:3545, 1990 Marrie TJ: Rikettsial infections of the central nervous system. Semin Neurol 12:213, 1992 Saah AJ, Marne TJ, Dumler JS, Walker DH: Rickettsial diseases, pp. 1719-1741. In Mandell G (ed): Principles and Practice of Infectious Diseases. 4th Ed. Churchill Livingstone, New York, 1992

Mycoplasma Infections Steven J. Spindel

The normal human oropharynx and genital tract are colonized by a class of bacteria that lack a cell wall, called Mollicutes, which includes the mycoplasmas and ureaplasmas. These are the smallest known free-living organisms. A few of these agents can cause diseases in humans and have central nervous system (CNS) manifestations, including Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum. M. pneumoniae is a bacterial organism that is responsible for pharyngitis, bronchitis, and pneumonia in children and young adults. Nervous system disease has been well recognized in association with this organism, and neurologic manifestations are the most common extrapulmonary symptoms in patients with M. pneumoniae, especially in children.

outbreaks of respiratory infection have been observed to occur in 4- to 7-year cycles in crowded conditions such as schools, colleges, and military institutions. CNS manifestations occur in 7% to 10% of patients hospitalized with infection caused by M. pneumoniae. Neurologic involvement is reported mainly in the pediatric populations, probably because of the greater frequency of the organism in children and young adults. Similarly, the trend for nervous system disease is to manifest in younger patients, although it is an unusual pathogen of encephalitis in infants younger than 1 year old. Much like pulmonary disease, M. pneumoniae infections of the CNS show no gender preference and occur more often in the late summer and fall.

CLINICAL FEATURES EPIDEMIOLOGY M. pneumoniae-associated CNS disease was originally observed during epidemic outbreaks of “primary atypical pneumonia” in the 1940s, when the organism’s identity was not yet known. Transmission occurs via contaminated respiratory droplets, and the incubation period ranges from 16 to 32 days. Epidemic

Usually, M. pneumoniae causes an acute tracheobronchial pneumonia with fever, sore throat, and a severe cough, which may be difficult to distinguish, by clinical or radiographic criteria, from many other causes of pneumonia. The pulmonary disease generally runs its course in 2 to 4 weeks. M. pneumoniae can cause a primary infection of the CNS and

Chapter 81

neurologic manifestations as a complication of pulmonary infection. The organism has been isolated from the cerebrospinal fluid (CSF), providing evidence that invasion of the CNS does occur and that M. pneumoniae can directly cause neurologic disease. Some investigatorsbelieve that other mechanisms are also at work because of the inability to detect the presence of M. pneumoniae in the CSF or brain tissue in several reported cases with CNS disease. An autoimmune process has been postulated whereby antibodies are produced against brain tissue in response to the infecting organism. Other theories include the production of a neurotoxin or a vasculitis affecting the CNS. Other Mycoplasma species have been shown in experimental animal models to produce CNS injury by these mechanisms, although they have not been demonstrated with M. pneumoniae. Postmortem examination of the brain occasionally reveals edema, hemorrhage, perivascular inflammatory infiltrates, microthrombi, and demyelination. Up to 20% of patients with neurologic symptoms have no associated pulmonary disease, a situation especially likely to occur in children. In patients who have antecedent respiratory symptoms, the average time to the onset of neurologic symptoms is 10 days (range 3 to 30 days). Symptoms then develop abruptly, often peaking in less than 24 hours (Table 81-1). Neurologic complications include the following: Encephalitis Meningitis Hydrocephalus Psychosis Myelitis Polyradiculitis Encephalitis and meningoencephalitis are the most common manifestation of CNS disease in M. pneumoniae infection. Encephalitis can be diffuse or focal and often affects the cerebellum (producing ataxia) and the pons (producing cranial nerve damage). Most patients have fever and meningeal symptoms, including headache, nausea, vomiting, and neck stiffness. Other clinical manifestations such as seizures, altered mental status, lethargy, ataxia, and focal neurologic defects (such as hemiparesis) are more commonly seen with encephalitis. Spinal cord involvement usually presents as transverse myelitis. Cranial nerve palsies also occur, and the facial nerve is most frequently affected. M. pneumoniae has also been associated with approximately 5% of patients with Guillain-Barrk syndrome. A significant number of patients also suffer damage in other organ systems (e.g., heart, liver, and bone marrow). TAW 81-1. Signs and Symptoms of Mycoplasma-Associated Encephalitis Signs and Symptoms Meningeal signs/symptoms Temp >39OC Convulsions Unconsciousness Somnolence Ataxia Ocular findings Respiratory symptoms Carditis

4b of Patients 78 53 46 35 42 20 15 38 6

Adapted from KoshkiniemiM: CNS manifestations associated with Mycoplama pneumoniae infections:summary of cases at the University of Helsinki and review. Clin Infect Dis 17(suppl. 1):552, 1993, with permission.

Mycoplasma Infections

517

Mortality and morbidity rates approach 10% and 23%, respectively, in some series. The time interval between respiratory symptoms and neurologic complications does not seem to affect the prognosis. Residual neurologic deficits occur more often after cases of encephalitis or polyradiculitis than after meningitis; in most published case series, meningitis results in very few or no neurologic complications or deaths. The neurologic sequelae of encephalitis include mental retardation, seizures, choreoathetosis, decreased visual acuity, and movement disorders.

DIAGNOSIS The CSF appears normal in up to 60% of cases. When pleocytosis is present, mononuclear cells predominate (55% to 75%). CSF glucose values are almost always normal, and the protein level is normal to high. The opening pressure may be normal or slightly elevated. Electroencephalographic abnormalities are noted in three-quarters of patients but usually reveal only diffuse, nonspecific slowing of limited diagnostic value. Brain imaging studies (such as computed tomography or magnetic resonance imaging) are normal or show mild diffuse edema. The primary diagnosis of M. pneumoniae-associated CNS disease often is made on clinical grounds and serologies. Serum complement fixation titers are the best available diagnostic test. A fourfold rise from acute to convalescent (obtained 7 to 21 days later) is diagnostic for M. pneumoniae. A single high titer of 1:32 or more also suggests the diagnosis. Titers begin to rise 1 week after the onset of infection and peak at 3 to 4 weeks. This test has good specificity (which rises with an increase in the titer), but the sensitivity is only approximately 50%. Complement fixation titers of the CSF are nonspecific because of cross-reactivity with antigens normally present in the CSF. Cold agglutinins for M. pneumoniae are positive in 30% to 50% of patients with pulmonary disease. A high titer of cold agglutinins, that is, more than 1 :128, can be very suggestive for M. pneumoniae. Bedside cold agglutinins are positive at titers of more than 1 :64, and, when present, this finding supports the diagnosis. However, a negative test does not exclude the presence of M. pneumoniae, and a low titer is nonspecific because other conditions can cause a weakly positive test (viruses, other causes of atypical pneumonias, collagen vascular disease, and myeloma). The peripheral leukocyte count may be normal or mildly elevated. Cultures for M. pneumoniae are slow growing, and the organism requires a special medium containing yeast and supplemental nutrients. These cultures are not routinely performed, and the physician with a clinical suspicion of M. pneumoniae should notify the microbiology laboratory so that these specific cultures can be done. There are also species-specific RNA probes available to demonstrate M. pneumoniae in sputum, pharyngeal swabs, and throat washings. Similar probes for M. pneumoniae in the CSF or brain tissue have not been well studied clinically. Other rapid techniques for diagnosing M. pneumoniae in clinical samples include enzyme immunoassays and indirect immunofluorescence, but these are not widely available. The polymerase chain reaction has detected M. pneumoniae in the CSF, but its diagnostic utility remains uncertain. The diagnosis of Mycoplasma can also be supported by the exclusion of other pathogens that can cause a similar clinical picture and CSF findings. The differential diagnosis includes viruses such as measles, mumps, varicella zoster, herpes simplex, adenovirus, other respiratory viruses, and enteroviruses.

518

Immune and Infectious Disease

Other Infections and Mimicken

TREATMENT

It is unclear whether the use of conventional antibiotic therapy for M. pneumoniae provides any benefit for CNS disease. Neurologic complications have been reported in patients receiving adequate antimicrobial therapy. Erythromycin and tetracycline for 2 to 3 weeks are the drugs of choice for M. pneumoniae infections. There are not enough data to support a longer duration of therapy for extrapulmonary symptoms. Other effective antibiotics include the new macrolides and the fluoroquinolones. Although these new agents do not penetrate into the CSF very well, the correlation between achieving adequate antimicrobial CSF levels and clinical outcome is uncertain. Note that tetracyclines and fluoroquinolones cannot be used in children, adolescents, or pregnant women. Additional therapies directed at CNS disease have included corticosteroids, anti-inflammatory medications, antidiuretics, and plasma exchange. There have been no prospective randomized trials of these modalities. OTHER MYCOPLASMAS AND UREAPLASMAS

M. hominis and U. urealyticum have been identified as causes of meningitis in neonates. In one series, M. hominis and LJ. urealyticum caused 2.8% and 1.5% of neonatal meningitis, respectively. These infections may occur more commonly in newborn infants born to women in lower socioeconomic groups and those with little or no prenatal care. The neonatal meningitis

caused by these organisms is as likely to occur in term infants as in premature infants. Infants become exposed to these organisms in the birth canal during delivery, and up to 30% subsequently become colonized. There are rare case reports of adults with ventriculoperitoneal shunt and ventriculostomy infections caused by M. hominis. There are no reports of U.urealyticum causing CNS disease in adults.

SUGGESTED READINGS Cassell GH, Cole BC: Mycoplasmas as agents of human disease. N Engl J Med 304:80, 1981 Clyde WA Jr: Clinical overview of typical Mycoplasma pneumoniae infections. Clin Infect Dis 17(Suppl. 1):S32, 1993 Couch RB: Mycoplasma pneumoniae (primary atypical pneumonia). p. 1446. In Mandell GL, Douglas RG, Jr., Bennett JE (eds): Principles and Practices of Infectious Diseases. 3rd Ed. Churchill Livingstone, New York, 1990 Koshkiniemi M: CNS manifestations associated with Mycoplasma pneumoniae infections: summary of cases at the University of Helsinki and review. Clin Infect Dis 17(Suppl. 1):S52, 1993 Maida E, Kristoferitsch W CSF findings in Mycoplasma pneumoniae infections with neurological complications. Acta Neurol Scand 65:524, 1982 Ponka A CNS manifestations associated with serologically verified Mycoplasma pneumoniae infection. Scand J Infect Dis 12175, 1980

SECTION 1

DISEASES OF THE SPINAL CORD

82

Clinical Approach to Disease of the Spinal Cord Mark H. Libenson

The spinal cord is structurally the simplest portion of the central nervous system, yet disorders of the spinal cord have the potential to challenge the clinician with a wide variety of clinical presentations representing a wide range of mechanisms of disease. Pathologic processes encountered in spinal cord disease include some with a slow onset of symptoms, such as metabolic or neurodegenerative diseases of the spinal cord, and some that present as catastrophic neurologic emergencies necessitating rapid diagnosis and treatment, such as spinal cord compression or trauma. The well-understood arrangement of tracts and cell columns in the spinal cord often allows precise neuroanatomic localization of signs and symptoms, yet this same orderly anatomic organization is notorious for producing falsely localizing signs that can lead the unwitting clinician astray.

GROSS ANATOMY OF THE SPINAL CORD The spinal cord (medulla spinalis) is the caudal continuation of the lower brainstem (medulla oblongata), beginning at the foramen magnum and tapering over its 45-cm adult length to end in the filum terminale, a narrow connective tissue band that anchors the spinal cord to the coccyx. Over most of its course, the diameter of the spinal cord is 1 cm or less, except for expansions in the cervical and lumbar spinal cord that reflect the increased number of entering and exiting neurons relating to the limbs. In cross-section, the spinal cord generally is somewhat oval in shape, wider in its transverse diameter, especially in its uppermost portions and at the cervical and lumbar enlargements. Below the level of T12 the substance of the cord tapers rapidly, forming the conically shaped conus medullaris (Fig. 82-1). Viewed by the naked eye, this critical communication link between the body and the brain is strikingly frail. The unprotected spinal cord is a fragile structure and undoubtedly would be a more frequent site of injury were it not surrounded by an elaborate system of osseous, ligamentous, and fluid defenses that allow the great flexibility of the spinal column while protecting the spinal cord itself from outside injury. The spinal cord is encircled by a series of bony vertebral rings, stabilized by a complex ligamentous system, sheathed in a tough connective tissue covering (the dura), and surrounded by a fluid cushion (the cerebrospinal fluid). Unlike the situation in the cranium, where the dura is closely adherent to the cerebral hemispheres and plays an additional role as the inner periosteal lining of the cranial bones, the dural covering of the spinal cord is situated away from the spinal cord, forming a permanent subdural space (Fig. 82-2). Examined in cross-section, a central, distinctive butterflyshaped gray matter core is seen surrounded by white matter tracts. 520

The central gray contains neuronal cell bodies; the white matter consists mostly of the ascending and descending myelinated tracts of the spinal cord. A small, ependyma-lined central canal runs the length of the cord, and nearly all neurons that cross from one side of the spinal cord to the other do so in the commissure that lies anterior to this canal. Reflecting the organization seen in the central nervous system as a whole, there is a general tendency in the spinal cord for motor structures to be located anteriorly and sensory structures posteriorly. Thus, the posterior gray matter of the spinal cord receives the dorsal (sensory) roots, and the anterior gray of the spinal cord contains the anterior horn cells (motor neuron cell bodies), which give rise to the anterior (motor) roots. The dorsal and anterior roots join together outside the cord to form each segment’s spinal nerve, which pierces the dura and exits through its corresponding intervertebral foramen. The location of the white matter tracts is an important exception to the anterior-posterior organizational rule; that is, the descending motor (corticospinal) tracts are located posterolaterally, and the sensory white matter tracts are located both anteriorly and posteriorly (dorsal and ventral spinothalamic tracts and dorsal columns) (Fig. 82-3). Each spinal nerve is named for its adjacent vertebral body. This leads to two problems in nomenclature. Because there is an additional pair of spinal nerve roots as compared with the number of vertebral bodies, the first seven spinal nerves are named for the first seven cervical vertebrae, each nerve exiting through the intervertebral foramen above its correspondingly named vertebral body. However, the spinal nerve exiting below the level of C7 is called the C8 spinal nerve (the extra spinal root), although no eighth cervical vertebra exists. Because of this extra nerve root, all subsequent roots exit below the vertebral body for which they are named, beginning with T1 (Fig. 82-4). The 8 cervical roots, 12 thoracic roots, 5 lumbar roots, 5 sacral roots, and 1 coccygeal root total 31 spinal nerve root pairs. All of these contain both motor and sensory roots with the exception of C1, which lacks a sensory component (explaining the absence of a C1 dermatome). The second problem in spinal root nomenclature arises from the positions of the spinal nerves with respect to their vertebral bodies. In the third embryonic month, the spinal segments are closely aligned to their corresponding vertebral segments, but after this point in fetal development, the bony spinal column’s downward growth outpaces that of the spinal cord. This differential growth gives rise to the appearance that the lower portion of the spinal cord has ascended in the spinal canal relative to the vertebral column. Indeed, because the adult spinal cord ends as the conus medullaris at approximately the L1 level, the lumbar and sacral roots must plunge downward below the termination of the

Chapter 82

Dorsal root of.

& cs 7

Ventral root of spinal nerve C1

Posterior intermedate sulcus

Dorsal root T I

Clinical Approach to Disease of the Spinal Cord

52 1

the medulla, both of which descend and join together at the level of the foramen magnum to form the anterior spinal artery, which accepts branches from segmental vessels of varying sizes as it descends the anterior surface of the spinal cord. The largest such segmental (or radicular) artery is the anterior radicular artery of Adamkiewicz, which serves the lumbar enlargement of the spinal cord. The anterior spinal artery irrigates the anterior two thirds of the cord. One or two smaller posterior spinal arteries also arise from the vertebral arteries and course down the dorsal aspect of the spinal cord, serving a wedge-shaped area constituting the posterior third of the cord.

FUNCTIONAL NEUROANATOMY OF THE SPINAL CORD A large number of ascending and descending tracts have been identified and mapped in the spinal cord; the three most important of these in terms of neuroanatomic localization of spinal cord lesions are the corticospinal tracts, spinothalamic tracts, and the dorsal columns. Motor Systems

w Dorsal root T6

k

Dorsal root L1

L!

'

Filum terminate 1- Coccygeal nerve

FIG. 82-1. Posterior view of the spinal cord showing attached dorsal root filaments and spinal ganglia. (From Carpenter MB: Core Text of Neuroanatomy. 3rd Ed. Williams & Wilkins, Baltimore, 1985, with permission.)

spinal cord to find their respective intervertebral foramina, forming the distinctive cauda equina (horse tail). As a consequence, a pathologic process at the level of the L4 vertebral body would be potentially in close proximity to both the L4 nerve root and the lower spinal roots that have arisen from the conus medullaris at the approximate level of L1 but exit the spinal canal caudal to the L4 vertebral body. The vascular supply to the spinal cord consists of a single, larger anterior spinal artery and two smaller posterior spinal arteries. The anterior spinal artery is formed from the union of a contributing branch from each vertebral artery at the level of

The corticospinal tract arises from neurons whose cell bodies are located in the motor areas of cerebral cortex, including the giant cortical motor neurons called Betz cells. The axons of these upper motor neurons reach the anterior horn cells of the spinal cord by descending through the internal capsule, the peduncles of the midbrain, and the belly of the pons. They continue caudally, forming a distinctive paired structure on the anterior surface of the medulla, the pyramids, from which the term pyramidal tract is derived. Without synapsing, nearly all of these pyramidal tract s o n s cross at the level of the medulla and the uppermost cervical spinal cord to form the decussation of the corticospinal tracts. Having crossed, the axons abandon their anterior location and move posteriorly to the posterolateral funiculi of the spinal cord. Most of these neurons are destined to synapse on the anterior horn cells located in the anterior gray of the spinal cord, the cell bodies of the lower motor neurons. These descending corticospinal tract fibers are laminated in the spinal cord in a clinically important arrangement, with fibers destined for the lower limbs traveling more superficially in the cord and fibers destined for upper limbs traveling more deeply in the cord (Fig. 82-3). A clinically less important anterior corticospinal tract descends in the anteromedial white matter of the cord. Because they have already crossed in the medulla, damage to these corticospinal tract neurons (upper motor neurons) in the spinal cord results in ipsilateral clinical findings such as spastic weakness, increased deep tendon reflexes, and a Babinski sign (Table 82-1). When there is damage to the anterior horn cells (lower motor neurons), ipsilateral clinical findings occur at the level of the affected segments, including flaccid weakness, muscle wasting, decreased deep tendon reflexes, and fasciculations (in addition to a distinctive group of electrophysiologic findings in peripheral nerve and muscle seen during nerve conduction velocity testing and electromyography, such as decreased compound muscle action potential amplitude, polyphasic motor units, fibrillation potentials, positive sharp waves, and decreased F waves and H reflexes, described more fully in Chapter 21). Thus, unilateral spinal cord lesions causes ipsilateral motor findings on neurologic examination, of the upper motor neuron type when the corticospinal tract is involved and of the lower motor neuron

522

Spinal Cord and PeripheralNcuromuxular Disease

Diseases of the Spinal Cord

FIG. 82-2. Anterior view of the spinal cord and its coverings. The pia mater is seen closely adherent to the spinal cord compared with the overlying arachnoidal and dural layers. Dorsal and ventral spinal rootlets are seen coalescing to form the spinal nerves. The dorsal root ganglia are seen just distal to this junction. (From Carpenter MB: Core Text of Neuroanatomy. 3rd Ed. Williams & Wilkins, Baltimore, 1985, with permission.)

FIG. 82-3. Cross-section of the cervical spinal cord showing white and gray matter areas, including the lamination of the corticospinal and lateral spinothalamic tracts. AHC, anterior horn cells; AS, anterior spinothalamic tract; D, dorsal spinocerebellartract; K,faxiculus cuneatus; FG, fasciculus gracilis; LL, portion of corticospinal tract serving lower limbs; SC, substantia gelatinosa; UL, portion of corticospinal tract serving upper limbs; V, ventral spinocerebellar tract; S (sacral), L (lumbar), T (thoracic), and C (cervical) mark portions of spinothalamic tract that carry sensory information from these areas. (Adapted from Watson C: Basic Human Neuroanatomy, An Introductory Atlas. 2nd Ed. Little, Brown, Boston, 1977, with permission.)

Chapter 82

Clinical Approach to Disease of the Spinal Cord

523

type when anterior horn cells or their exiting motor roots are involved.

Sensory Systems

\ .....-

ca*'

FIG. 82-4. Spinal cord root levels in relation to the vertebral bodies. Note the close association of vertebral and nerve root levels in the cervical cord compared to the lumbar cord. (From Haymaker W, Woodhall B: Peripheral Nerve Injuries. 2nd Ed. WB Saunders, Philadelphia, 1953, with permission.)

There are two major ascending systems that transmit conscious sensory information in the spinal cord the spinothalamic tracts and the dorsal columns. The first-order neurons of both of these afferent systems begin as sensory structures situated in end organs (e.g., sensory receptors in skin and stretch receptors in muscle). The cell bodies of the first-order neurons of these sensory pathways are located in the dorsal root ganglia of the spinal nerves. These gangha are seen as distinctive prominences on the dorsal nerve roots just proximal to the point where the anterior and dorsal branches join in the intervertebral foramen to form the peripheral spinal nerve. The spinothalamic tracts transmit pain and temperature sensation, commonly tested at the bedside in the form of pinprick and cold sensation. As the axons of these neurons enter the spinal cord, most rise one or two levels (in the dorsolateral tract of Lissauer) before entering the dorsal gray of the spinal cord, where they synapse (in the substantia gelatinosa) with the second-order neuron of the spinothalamic system. This second neuron crosses immediately in the anterior commissure of the spinal cord and ascends in the anterolateral funiculus as the lateral spinothalamic tract. (A small number of spinothalamic fibers may remain uncrossed and ascend in the less clinically important anterior spinothalamic tract.) As a result, when the anterolaterally located spinothalamic tract is damaged in the spinal cord, the patient experiences sensory symptoms in the contralateral half of the body. This is contrary to the case of injuries to the motor system described earlier, where the symptoms are ipsilateral. Again, there is a clinically important lamination of this tract where, as in the corticospinal tract, sensory neurons arising from the lower body travel more superficially in the tract and neurons arising from higher levels travel more deeply in the tract. The dorsal columns transmit vibratory and proprioceptive information, commonly tested at the bedside by placing a vibrating tuning fork on bone and by testing the patient's ability to detect changes in joint position on passive motion. These neurons enter the spinal cord via the dorsal root alongside pain and temperature neurons, but instead of making an immediate synapse in the dorsal horn, as do the latter type of neurons, these axons enter the ipsilateral dorsal column immediately and do not synapse until they reach the gracile or cuneate nuclei of the medulla. Because this long, single neuron does not cross the midline until it passes through the foramen magnum, a lesion

rn TAM 82-1. Effects of Damage to the Major Functional Anatomic Units of the Spinal Cord CorticospinalTrack (Upper Motor Neuron)

Anterior Horn Calls (Lower Motor Neuron)

Spinohbmic Tracts

Dorsal Columns

Modalii

Motor

Motor

Pain and temperature

Symptoms

Spastic paralysis, hyperreflexia

flaccid paralysis, decreased reflexes

Loss of pain and tempera-

Ipsilateral, below level of lesion

Ipsilateral, radicular dishibution accordingto levels involved

Contralateral, below level of lesion

Joint position sense and vibration Loss of proprioception, vibration sense, paresthesias, Romberg sign Ipsilateral, below level of lesion

Distribution of symptoms in relation to sDinal cord lesion

ture, sensation, numb ness, anesthesia

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involving one side of the dorsal columns of the spinal cord causes ipsilateral loss of vibration and joint position sense. Because the sensory modality of light touch is transmitted through both the spinothalamictracts and the dorsal columns, light touch sensation is not completely lost unless both the spinothalamic and dorsal column systems are affected. SPINAL CORD LOCALIZATION Determining the location of a lesion in the spinal cord begins by asking the question, “Is the lesion in the spinal cord?” In general, neurologic localization begins with the attempt to explain all of the patient’s findings by a single lesion before invoking multiple lesions to explain a particular pattern of findings. Although the concept may seem self-evident, it is worth repeating that isolated spinal cord lesions do not disturb cortical or brainstem functions. Therefore, findings such as aphasias, disturbances of vision or eye movement, swallowing, or consciousness are not consistent with a simple spinal cord localization; the presence of such findings leads to the search for the lesion above the level of the foramen magnum. Apparent exceptions to this rule include the presence of Horner’s syndrome (the first-order neuron of the sympathetic innervation of the pupil, eye, and upper face descends from the hypothalamus and brainstem ipsilaterally in the spinal cord as low

as Tl). A second such apparent exception is pain and temperature abnormalities in the face (some trigeminal neurons subserving pain and temperature enter the pons and descend into the upper cervical cord as low as the C2 to C4 levels before synapsing in the nucleus of the spinal tract of V and ascending to the contralateral thalamus). Table 82-2 lists selected spinal cord syndromes by anatomic site. Spinal cord localization is especially suggested when a patient presents with one of the hallmark spinal cord syndromes. Although patients in clinical practice rarely present with textbook descriptions of these distinctive syndromes, recognition of partial expressions or fragments of these classic syndromes often is the first step in correct diagnosis. Complete Spinal Cord Transdon Syndrome

Complete spinal cord transection may be caused by trauma; compression from tumor, hematoma, or abscess; or transverse myelitis (viral, postviral, or demyelinative), among other causes. Transection of the spinal cord results in interruption of the long motor and sensory tracts with concomitant complete loss of voluntary motor and conscious sensory function below the level of the transection (Fig. 82-5). Damage to sensory and motor roots at the level of the transection results in complete abolition of reflexes

TAUE82-2. Selected Spinal Cord Syndromes by Anatomic Location Extradural

Osteoarthritis Disc herniation Epidural abscess Bony and meningeal metastases Epidural hematoma Cervical spondylosis Rheumatoid arthritis Ankylosing spondylitis Other degenerative spine diseases Paget‘s disease Craniocervicaljunction abnormalities Mucopolysaccharidosis Klippel-Feil Achondroplasia Platybasia, or basilar invagination PoWs disease Atlantoaxial dislocation Foramen magnum tumor lntradural

Neurofibroma (schwannoma) Meningioma Leptomeningeal carcinoma Sarcomas Vascular tumors

Viral myelitis Autoimmune (postinfectious) myelitis Vascular (ischemic or infarct) Arteriovenous malformation lntramedullaryabscess Paraneoplastic myelitis Tumors (ependymoma, astrocytoma, oligodendroglioma, lipoma, epidermoid, dermoid, teratoma, hemangioma, hemangioblastoma, metastatic carcinoma) Electrical injuries Spinal arachnoiditis Balb’s concentric sclerosis Select Tracts or Cell Columns

Amyotrophic lateral sclerosis Primary lateral sclerosis HIV-associatedvacuolar myelopathy Adrenomyeloneuropathy or adrenoleukodystrophy Spinocerebellar degenerations Vitamin B, deficiency (subacute combined degeneration) Familial spastic paraparesis Werdnig-Hoffmann disease Kugelberg-Welander disease Tabes dorsalis Poliomyelitisinfection HTLV-1-associated tropical spastic paraparesis Lathyrism

Central Cord Syndrome

Syringomyelia Hematomyelia (trauma) lntramedullary tumors Demyelinating disease Infarcts

Malfonnative

Spinal dysraphism Spinal bifida Meningocele Myelocele Myelomeningocele Diastematomyelia Diplomyelia Caudal regression syndrome Hydromyelia Arnold-Chiari malformation type II Tethered cord

Diffuse, Focal, or Multifocal Spinal cord trauma Hematomyelia Multiple sclerosis Radiation myelitis Transverse myelitis Devic disease (neuromyelitis optica) Abbreviations: HIV, human immunodeficiency virus; HTLV-I, human T-cell leukemia virus type 1.

Chapter 82

FIG. 82-5. Complete transection of the spinal cord. The area shaded dark gray in the diagram denotes the area of lost motor and sensory function below a complete lesion of the midthoracic spinal cord.

at the level of the lesion. Minutes after a complete cord transection, there follows a period of spinal cord hypoexcitability called spinal shock, which may last days to weeks. During this period, there is complete absence of reflex and autonomic activity below the level of the injury, with flaccid paralysis. In some cases, spinal cord reflexes above the level of the transection also may be depressed. When the period of spinal shock passes, hyperreflexia with spastic paralysis below the level of the injury supervenes. Transection of the spinal cord at high cervical levels results in tetraplegia. Transection at the level of C2 results in sensory loss over the whole body and the occipital area (indeed, all dermatomal regions except the trigeminal nerve’s sensory distribution). Lesions at the level of C4 and below may leave enough preserved phrenic nerve function (C3, C4, and C5) to allow adequate diaphragmatic function after the period of acute injury. Lesions from C6 to T1 involve diminishing subgroups of the muscles innervated by the brachial plexus and allow increasing function of the arms and hands. Horner’s syndrome (ptosis, miosis, anhidrosis, and absence of facial flushing) may be seen in cervical cord transection above the level of T1 because of disruption of descending sympathetic fibers. Full diaphragmatic innervation compensates for loss of innervation of the intercostal muscles and other auxiliary respiratory muscles. Spinal cord transection below the level of T1 allows complete use of the upper extremities, including the hands. With lesions above T6, the abdominal reflexes are lost. With lesions at T10, the upper abdominal reflexes are preserved; with those at T12, all abdominal reflexes are present. With transection levels from L1 to S2, there is decreasing involvement of the lower extremities. With spinal cord levels below S2, innervation of the lower extremity muscles is preserved, but bowel and bladder function is affected, as described later in this chapter. During the initial stage of spinal shock after cord transection at any level, reflex emptying of the bladder may be lost, resulting in

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525

FIG. 82-6. Complete hemisection of the right side of the spinal cord: Brown-Sbquard syndrome. Dark gray area: area of loss of motor function (paralysis) and dorsal column function (ioint position and vibration sense). Light gray area: area of loss of spinothalamic tract function (pain and temperature sensation). Black area: area of loss of root function with lower motor neuron signs.

FIG. 82-7. Central spinal cord syndrome. Dark gray area: area of sensory loss in the classic cape-like distribution as might be seen in a low cenrical-high thoracic lesion of the spinal cord. Light gray area: additional area of sensory loss that may be seen with a laterally enlarging lesion at the same level. Depending on the shape of the lesion and areas of the spinal cord involved, other motor and sensory functions may be affected as well (not shown).

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urinary retention and bladder distention. In lesions that occur above the sacral level leaving the spinal bladder center in the conus medullaris and the roots of the pudendal nerve (S2, S3, and S4) intact, automatic, reflex emptying of the bladder returns days to weeks after the injury. There may be urinary urgency and spasticity of the bladder sphincter. In sacral lesions that interrupt the bladder center, the bladder becomes autonomous with feeble, inefficient, and uncoordinated contractions of the detrusor muscle. Combinations of these spastic and atonic bladder syndromes may occur in partial cord lesions at the sacral level. Similarly, bowel function ceases immediately after complete cord transection at any level, with loss of rectal tone and the anal “wink” reflex. Spontaneous bowel peristalsis returns within a few days as a rule, as do the anal and bulbocavernosus reflexes when the cord lesion lies above the sacral level. Constipation and sexual dysfunction are common. Later, in the hyperreflexic stage, anal tone may actually increase significantly. In lesions of the lumbosacral cord, however, the anus remains patulous.

A

Syndrome of Spinal Cord Hemisection: The BrownShuard Syndrome Hemisection of the spinal cord results in the distinctive syndrome of ipsilateral paralysis and contralateral pain and temperature loss below the level of the lesion, known as the Brown-Sequard syndrome. Although often not as prominent clinically, ipsilateral vibration and proprioceptive loss also occurs (on the same side as the motor symptoms). In the complete syndrome, the ipsilateral anterior horn cells and dorsal roots are also affected at the level of the transection (Fig. 82-6). Thus, a complete hemisection of the right side of the spinal cord results in paralysis with increased reflexes (after the acute phase) and loss of joint position and vibration sense on the right side below the level of the lesion and loss of pain and temperature sense on the left side. If the lesion happens to occur at the level of the lumbar or cervical plexuses, lower motor neuron involvement at that level may be more easily observed with loss of segmental reflexes and, later, wasting and other signs of denervation in the muscles of the affected root

B

FIG. 82-8. (A and 6) T1-weighted MRI scans of the cervical spine showing a herniation of the C6-C7 intervertebral disc in a 35-year-old man. (A) Midsagittal plane; the spinal cord appears gray and is surrounded by cerebrospinal fluid, which appears black. The vertebral bodies appear as a column of rectangles anterior to the cord and show a bright signal because of increased fat content in the marrow. The C6-C7 disc can be seen protruding posteriorly (arrow). (B) The same scanning sequence, but the plane of the scan is now just to the left of the midline. A larger portion of the disc can be seen herniating posteriorly and appearing to impinge on the spinal cord.

Chapter 82

C

Clinical Approach to Disease of the Spinal Cord

517

D

FIG. 82-8. Continued (C and 0) T2-weighted scans of cervical spine of the same patient The cerebrospinal fluid now appears white in this sequence, surrounding the darker spinal cord. (C) Scan in midsagittal plane showing the same disc obliterating the subarachnoid space anterior to the spinal cord. There is no abnormal (bright) signal in the spinal cord to suggest damage to the spinal cord itself. (0) TZ-weighted with scan plane again just left of the midline. The substance of this left-sided cervical disc herniation is better seen in this scan, extending posteriorly and to the left, impinging on the area traversed by the left C6 nerve root.

level's distribution. Likewise, with a right-sided spinal cord hemisection, an isolated area of complete sensory loss to both dorsal column and spinothalamic tract modalities is seen on the right in the dermatomes at or just below the level of the hemisection. This results from interruption of all sensory neurons entering the cord on the right side at the affected level. Spinal cord hemisection may be caused by partial expressions of the causes of complete cord transections.

Syndrome of Extrinsic Splnal Cord Compression (Cord-Root Syndrome) Lesions that compress the spinal cord from a location outside the dura produce symptoms in the most superficial fibers of the long pathways first. Because of the specific lamination of the corticospinal and spinothalamic tracts, as described earlier (lowerextremity fibers most superficial and upper-extremity fibers deepest), cervical compressive lesions may cause sensory and motor symptoms to appear first in the lower extremities. Symptoms may then appear to ascend as the compression becomes

more severe and more deeply situated fibers are successively affected. This anatomic arrangement is notorious for producing falsely localizing signs. For example, a distinct level of sensory loss may be discernible at the level of the umbilicus (T10) in the case of a compressive tumor at the foramen magnum. The unwary clinician obtaining a magnetic resonance imaging scan of the thoracic cord might be falsely reassured by a normal result because the level of the spinal cord where the lesion is located is not imaged. Therefore, the level of a sensory deficit found on examination produced by extrinsic, compressive cord lesions only marks the lowest possible level of the lesion; the actual lesion may lie anywhere between the level of sensory loss and the foramen magnum. In addition to affecting the long tracts of the spinal cord, extrinsic compressive lesions often disrupt motor and sensory roots at the level of the lesion. Identification of a root level can be a very helpful sign; the upper limits of a sensory (or motor) level found on examination only mark the lowest possible location of the lesion in the spinal cord for the reasons described earlier. When, in addition, a focus of back pain is present or distinct lower

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hemisection per se, may resemble the Brown-SCquard syndrome in presentation. Except in the case of early lesions, there is often some bilaterality to signs and symptoms with lateral compressive lesions of the cord, especially when the contralateral cord becomes compressed against the opposite side of the spinal canal. In cases of lateral compression rather than hemisection, the half of the spinal cord ipsilateral to the compressive lesion usually is more symptomatic than the contralateral half.

Central (Intramedullary)Spinal Cord Syndrome The initial signs and symptoms caused by smaller intramedullary lesions of the spinal cord often are related to dysfunction of the anterior commissure of the spinal cord, which contains crossing spinothalamic tract neurons (Fig. 82-7). This can result in a cape-like distribution of anesthesia at the level of the lesion in the case of cervical lesions. Additional symptoms caused by the lesion depend on the additional cord regions the lesion involves in the transverse plane. Lesions that include the anterior gray matter of the spinal cord may destroy the anterior horn cells, causing weakness and wasting of muscles (lower motor neuron signs) at the involved levels. Further enlargement of the area of the lesion may result in involvement of the spinothalamic tracts. Because spinothalamic tract fibers serving the sacral areas travel most superficially in the spinal cord (as described earlier), expanding intramedullary lesions cause increasing areas of anesthesia, but with a tendency to sacral sparing, as these fibers are most distant from the center of the cord (Fig. 82-3). Thus, an expanding cervical central cord lesion may begin by causing an area of cape-like anesthesia involving the arms but with progressively descending sensory involvement to the point that only the saddle area is spared. Larger lesions may similarly affect the descending corticospinal tracts. The most common causes of such lesions are syringomyelia, intrinsic cord tumors, and hematomyelia.

Syndromes of the Cauda Equlna and Conus Medullaris Because the cauda equina is composed of the lumbosacral roots as they descend into the thecal sac below the termination of the spinal cord, pathologic processes in this area may cause a patchy distribution of symptoms, depending on which nerve roots are involved. Pain often is a prominent symptom. Lesions of the conus medullaris may involve a similar array of nerve roots, but because this region of the cord contains important reflex centers, disorders of bowel, bladder, and sexual function are often most prominent.

Other Spinal Cord Syndromes FIG. 82-9. (A) T1-weighted MR images of the spinal cord in a

15-year-old girl with transverse myelitis. The cervical spinal cord is abnormally enlarged (arrows). She presented with limb weakness, sensory changes in the legs, and blurred vision in the right eye associated with optic papillitis. The combination oftransverse myelitis and optic myelitis found in this girl is also called neuromyelitis optica or Devic disease. (s) T2-weighted images of the spinal cord in the same patient. There is a blush of abnormally increased T2 signal in the affected area (arrows). motor neuron signs are found at a specific level, the level of the lesion may be pinpointed. Likewise, localized pain or tenderness over a vertebral spinous process may help localize a process associated with a destructive bony lesion. Lateral compressive lesions, though not causing a spinal cord

Anterior horn cell syndromes occur, sometimes with associated upper motor neuron involvement. The most important disorder seen in adults associated with this pattern is amyotrophic lateral sclerosis, in which there is a progression of both lower (anterior horn cell) and upper (corticospinal tract) motor neuron signs. Spinal muscular atrophy type I (Werdnig-Hoffmann disease) is a pure anterior horn cell degeneration presenting in infancy, although more slowly progressive forms are recognized. Infection with the poliomyelitis virus, now rare, shows a predilection for the anterior horn cells and produces asymmetrical lower motor neuron involvement and a cerebrospinal fluid pleocytosis after a febrile illness. Cervical and lumbar degenerative spine disease may result in stenosis of the spinal canal at those levels. This syndrome of spinal cord stenosis may mimic amyotrophic lateral sclerosis by causing both upper motor neuron signs from spinal cord

Chapter 82

compression and lower motor neuron signs at multiple levels caused by loss in height of the intervertebral foramina at multiple levels. Occlusion of the anterior spinal artery produces a distinctive anterior spinal artery syndrome with loss of spinothalamic and corticospinal tract function. Dorsal column functions are generally preserved because this posterior, wedge-shaped area of the spinal cord is irrigated by one or two posterior spinal arteries. Therefore, the patient is paralyzed to a varying degree below the level of the stroke with complete loss of pain and temperature sensation but with preservation of vibration and joint position sense. Other

Clinical Approach to Disease of the Spinal Cord

929

patterns of infarction of the cord as a result of vascular occlusions may also occur. Certain patterns of spinal cord involvement, though not anatomically confluent, are characteristic of specific disease processes. Tabes dorsalis occurs as a late complication of syphilitic infection. There is marked degeneration of the posterior columns, which produces an ataxia based on sensory loss. Loss of the posterior roots in the lumbosacral area is responsible for abnormal bowel, bladder, and sexual function caused by loss of sensory inputs and probably also explains the lancinating pains characteristic of that disorder. Subacute combined degeneration is the term

A

FIG. 82-10. MRI scan of the spine in an 1 1-year-old girl with a low thoracic spinal cord astrocytoma. (A) T1 sagittal image of the spinal cord showing a tumor mass in the low thoracic area (arrowhead). (B) T I gadolinium-enhancedimages of the same area showing an area of intense enhancement within the tumor (arrowhead). Illustration continued on following page

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D

C

FIG. 82-10. Continued (C) Axial T2-weighted image of normal-appearing spinal cord at the level of T8 (above the lesion) in the same patient. The spinal cord is dark, surrounded by brightly colored spinal fluid. (0) Axial T2-weighted image of the spinal cord at the level of T10 showing abnormal enlargement of the cord, relative obliteration of the cerebrospinal fluid space, and abnormally increased signal in the substance of the cord.

used for the myelopathy associated with vitamin B,, deficiency (often caused by failure to absorb this vitamin from the gut caused by lack of intrinsic factor in patients with pernicious anemia). Corticospinal, spinothalamic, and dorsal column tracts of the cord are all affected, with the posterior column findings often most prominent.

DIAGNOSTIC TESTING IN SPINAL CORD DISEASE Careful history-taking and a methodical neurologic examination will often strongly suggest a specific diagnosis; electrophysiologic and radiologic testing may confirm the diagnostic impression. Spine radiographs give an idea of the caliber of the spinal canal, the heights of the intervertebral foramina, or the presence of bony spurs or other bony lesions. Plain radiographs of the spine may also show evidence of spine instability, fracture, or dislocation in cases of trauma. Flexion and extension views of the cervical spine may demonstrate the atlantoaxial subluxation that is common in patients with Down’s syndrome. Plain radiographs may also show degenerative disease of the spine suggestive of disc or spondylitic disease. The appearance of lytic vertebral lesions may lead to a diagnosis of metastatic disease. Certain spinal cord malformations may be suspected when certain findings, such as spina bifida occulta, butterfly vertebrae or hemivertebrae, or a bony spur traversing the cord (diastematomyelia) are present. Lumbar puncture allows analysis of the cerebrospinal fluid and measurement of its pressure. Spinal fluid culture and serology may help pinpoint infectious causes of spinal cord disease, such as spinal abscess. The isolated finding of very high protein levels in the spinal fluid suggests spinal block, usually from tumor. More modest increases in spinal fluid protein are observed in cases of myelopathy that are associated with polyradiculopathy. Cytologic studies of spinal fluid may help make a specific diagnosis of

malignancy. Cell counts in spinal fluid may point toward infection or other inflammatory processes. Measurement of spinal fluid immunoglobulin G (IgG), myelin basic protein, and oligoclonal bands may help establish the diagnosis of multiple sclerosis. After lumbar puncture, myelography may be performed by injecting contrast material through a spinal needle. The contrast medium outlines the subarachnoid space and allows visualization of the spinal cord, nerve roots, or intradural lesions, which appear as shadows or defects in the column of injected contrast. Extradural compressive lesions appear as an indentation on the thecal sac. Computed tomographic scan of the spinal cord after injection of contrast into the thecal space, a so-called computed tomographic myelogram, may be performed after such an injection. Use of both plain and computed tomographic myelography has, for the most part, been supplanted by magnetic resonance imaging of the spinal cord, which has revolutionized the diagnosis of spinal cord disease. Magnetic resonance imaging shows better detail, distinguishes better between normal and abnormal tissues, and has significantly improved the imaging of both extrinsic and intrinsic spinal cord disease (Figs. 82-8, 82-9, and 82-10). Somatosensory evoked potentials can be used to study spinal cord function. A sensory stimulus, usually in the form of a mild electric shock, is applied to a limb, and the resulting evoked potential is measured at multiple levels as it travels rostrally through the nervous system, including over the spinal cord and sensory cerebral cortex. Asymmetry in amplitude or latency or absence of the evoked potential may allow inferences regarding the location, and sometimes the cause, of a spinal cord lesion. In general, somatosensory evoked potential testing reflects conduction through the fastest-conducting (largest) sensory neurons in the spinal cord, the dorsal column neurons. Nerve conduction velocity and electromyographic testing often can give both direct and indirect information about spinal cord function.

Chapter 83

SUGGESTED READINGS Adam RD, Victor M: Diseases of the spinal cord. In Principles of Neurology. 7th Ed. McGraw-Hill, New York, 2001 Brazis PW, Masdeu JC, Biller J: Localization in Clinical Neurology. 3rd Ed. Little, Brown, Boston, 1996 Carpenter MB: Core Text of Neuroanatomy. 3rd Ed. Williams & Wilkins,

Baltimore, 1985 deGroot J, Chusid JG: Correlative Neuroanatomy. 21st Ed. Appleton & Lange, East Norwalk, CT, 1991

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53 1

Gray H: Gray’s Anatomy. 23rd Ed. WH Lewis (ed). Lea & Febiger, Philadelphia, 1936 Hughes J T Disorders of the spine and spinal cord. In Adams JH, Duchen LW (eds): Greenfield’s Neuropathology. 5th Ed. Oxford University Press, New York, 1992 Ludwig G Clinical symptomatologyof spinal cord lesions. pp. 178-216. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol. 2. Wdey, New York, 1969 Williams PL, Warwick R Functional Neuroanatomy of Man. WB Saunders, Philadelphia, 1975

Syringomyelia and Related Conditions Patrick A. Roth and Alan R. Cohen

Syringomyelia is a term used to describe a fluid-filled cavity in the spinal cord. It may be associated with several distinct conditions or may occur as an isolated entity. Syringomyelia has fascinated clinicians for years because the symptoms often are a striking recapitulation of those predicted from a centrifugal distortion of the normal cross-sectional anatomy of the spinal cord. The diverse causes of this entity have generated a great deal of interest in its pathogenesis. The advent of magnetic resonance imaging (MRI) has revolutionized our understanding of this disease by improving diagnostic capabilities, providing precise anatomic information both preoperatively and postoperatively, and improving our understanding of the pathogenesis (Fig. 83-1). The natural history of syringomyelia has never been adequately characterized. It appears to be variable, and it is thus difficult to predict the rate or extent of progression in any individual case. Most studies that have looked at the natural history of syringomyelia are retrospective and involve either many different treatments for a population of patients or several sequential treatments for an individual patient so that a predicted tempo or extent of progression cannot be reliably extracted to provide a sense of risk in any given case. These complex retrospective studies also limit our ability to evaluate critically and compare the various treatment modalities used. Because a substantial portion of patients who are symptomatic develop progressive problems, most surgeons initiate some form of treatment in cases of symptomatic syringomyelia.

syringohydromyelia or hydrosyringomyelia to group the two entities into one category and thus avoid the distinction. We use the traditional term syringomyelia to include both of these theoretic anatomic variants because the distinction often is difficult to display pathologically and there is no clinical relevance in

HISTORY The earliest report of syringomyelia is that of ktienne in 1564. He compared the cavitation of the spinal cord with the ventricles of the brain. The term syringomyelia was derived by Ollivier $Angers in 1824 from the Greek words syrinx, “to become hollow,” and my&, “marrow.” In 1863, Virchow suggested the alternative term hydromyelia because he believed that the central canal was the source of the abnormal fluid within the canal. In 1875, Simon proposed that the term syringomyelia be used to describe a fluid collection within the substance of the cord separate from the central canal and that the term hydromyelia be used to describe a dilation of the central canal. Several authors continue to distinguish syringomyelia from hydromyelia by using the two terms separately; others use the term

FIG. 83-1. Syrinx of the cervical cord with a septation.

Chapter 83

SUGGESTED READINGS Adam RD, Victor M: Diseases of the spinal cord. In Principles of Neurology. 7th Ed. McGraw-Hill, New York, 2001 Brazis PW, Masdeu JC, Biller J: Localization in Clinical Neurology. 3rd Ed. Little, Brown, Boston, 1996 Carpenter MB: Core Text of Neuroanatomy. 3rd Ed. Williams & Wilkins,

Baltimore, 1985 deGroot J, Chusid JG: Correlative Neuroanatomy. 21st Ed. Appleton & Lange, East Norwalk, CT, 1991

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Syringomyelia and Related Conditions

53 1

Gray H: Gray’s Anatomy. 23rd Ed. WH Lewis (ed). Lea & Febiger, Philadelphia, 1936 Hughes J T Disorders of the spine and spinal cord. In Adams JH, Duchen LW (eds): Greenfield’s Neuropathology. 5th Ed. Oxford University Press, New York, 1992 Ludwig G Clinical symptomatologyof spinal cord lesions. pp. 178-216. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol. 2. Wdey, New York, 1969 Williams PL, Warwick R Functional Neuroanatomy of Man. WB Saunders, Philadelphia, 1975

Syringomyelia and Related Conditions Patrick A. Roth and Alan R. Cohen

Syringomyelia is a term used to describe a fluid-filled cavity in the spinal cord. It may be associated with several distinct conditions or may occur as an isolated entity. Syringomyelia has fascinated clinicians for years because the symptoms often are a striking recapitulation of those predicted from a centrifugal distortion of the normal cross-sectional anatomy of the spinal cord. The diverse causes of this entity have generated a great deal of interest in its pathogenesis. The advent of magnetic resonance imaging (MRI) has revolutionized our understanding of this disease by improving diagnostic capabilities, providing precise anatomic information both preoperatively and postoperatively, and improving our understanding of the pathogenesis (Fig. 83-1). The natural history of syringomyelia has never been adequately characterized. It appears to be variable, and it is thus difficult to predict the rate or extent of progression in any individual case. Most studies that have looked at the natural history of syringomyelia are retrospective and involve either many different treatments for a population of patients or several sequential treatments for an individual patient so that a predicted tempo or extent of progression cannot be reliably extracted to provide a sense of risk in any given case. These complex retrospective studies also limit our ability to evaluate critically and compare the various treatment modalities used. Because a substantial portion of patients who are symptomatic develop progressive problems, most surgeons initiate some form of treatment in cases of symptomatic syringomyelia.

syringohydromyelia or hydrosyringomyelia to group the two entities into one category and thus avoid the distinction. We use the traditional term syringomyelia to include both of these theoretic anatomic variants because the distinction often is difficult to display pathologically and there is no clinical relevance in

HISTORY The earliest report of syringomyelia is that of ktienne in 1564. He compared the cavitation of the spinal cord with the ventricles of the brain. The term syringomyelia was derived by Ollivier $Angers in 1824 from the Greek words syrinx, “to become hollow,” and my&, “marrow.” In 1863, Virchow suggested the alternative term hydromyelia because he believed that the central canal was the source of the abnormal fluid within the canal. In 1875, Simon proposed that the term syringomyelia be used to describe a fluid collection within the substance of the cord separate from the central canal and that the term hydromyelia be used to describe a dilation of the central canal. Several authors continue to distinguish syringomyelia from hydromyelia by using the two terms separately; others use the term

FIG. 83-1. Syrinx of the cervical cord with a septation.

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Spinal Cord and Peripheral Neuromuscular Disease I Diseases of the Spinal Cord

A

FIG. 85-2. (A) TI-weighted axial MRI of the spinal cord showing a syrinx that is symmetric and central in location. (6) T2-weighted axial MRI of the spinal cord showing a more eccentric and asymmetric syrinx.

separating the two entities on the basis of pathogenesis, natural history, or appropriate treatment modalities (Fig. 83-2).

PATHOGENESIS The development of theories of the pathogenesis of syringomyelia is fascinating. Gardner proposed a hydrodynamic theory for the pathogenesis of a syrinx. According to his theory, the formation of

a syrinx was the result of a communication between the fourth ventricle and the central canal of the spinal cord coupled with a relative obstruction in the outlets of the fourth ventricle, resulting in a water-hammer effect with cerebrospinal fluid (CSF) being propelled into the central canal with each systolic pulsation of the brain. Williams, alternatively, suggested that a syrinx was formed as a result of craniospinal pressure dissociation. He postulated that a normal Valsalva maneuver results in flow of CSF from the

Chapter 85

intraspinal compartment into the intracranial compartment, followed by a return flow back into the intraspinal compartment after the Valsalva. With an obstruction at the foramen magnum, there would be a relative impedance to this bidirectional flow, and alternative conduits would be used, such as flow between the central canal of the spinal cord and the fourth ventricle. The theories of Gardner and Williams are based on the existence of a communication between the fourth ventricle and the central canal of the spinal canal. However, recent evidence based on both autopsy and MRI studies suggests that most syrinxes do not communicate with the fourth ventricle. This has lent some support to different theories of pathogenesis. Ball and Dayan in 1972 suggested that the syrinx was the result of flow across the spinal cord from the spinal subarachnoid space through Virchow-Robin spaces. Similarly, Aboulker in 1979 postulated that the syrinx was the result of flow across the spinal cord from the spinal subarachnoid space through the dorsal nerve root entry zone of the spinal cord. Milhorat et al. in 1993 suggested that the syrinx might result from a block of the normal cephalad-directed flow of CSF in the central canal, originating in the spinal cord parenchymal extracellular space. They pointed out that the central canal of the thoracic and lumbar segments of the spinal cord normally is obliterated in adults and that this might explain the predominance of cervical or cervicothoracic syrinxes in adults and the holocord syrinxes more commonly seen in children.

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Chiari I hindbrain malformation (Fig. 83-4) are difficulty using the hands and gait disturbances. These symptoms generally have their onset in adolescence or early adulthood. Patients typically complain of weakness or loss of agility in their hands. Occasionally, patients describe their hand symptoms as numbness. The gait abnormalities often are perceived initially as weakness, stiffness, or fatigue. These symptoms often are asymmetric early. Pain is the next most common presenting symptom. It is most often suboccipital in location. Typically, patients describe intensification of the pain with coughing or sneezing. This is also the case with the Chiari I malformation without syrinx, however. Occasionally, the pain has a radicular component in addition. Infrequently, the pain radiates into the arms or scapulae with a nonradicular, poorly localized, boring character, referred to as funicular pain. Bowel and bladder dysfunction are not prominent complaints early in the disease. In some patients, atrophy is apparent, particularly in the hands; others develop noticeable scoliotic spine deformities, causing them to seek medical attention. Some patients seek medical attention for repeated unrecognized burns of their hands. On examination, many of these patients demonstrate atrophy of the upper extremities. This typically involves the hands most prominently. Over time, contractures can occur in the hand,

EPIDEMIOLOGY Many of the modern classification schemes have divided syringomyelia into a communicating and noncommunicating form. The communication is that of the syrinx with the basal cisterns and ventricular system. The term communicating may also imply that the syrinx is an extension of a collection of CSF that is not being adequately absorbed. In other words, communicating syringomyelias may be subsumed under the category of hydrocephalus. In other nomenclatures, the term hydrornyelia is used synonymously with communicating syringomyelia. Noncommunicating syringomyelias are much more common than communicating syringomyelias and typically include all of the common conditions associated with syringomyelia such as the Chiari I and Chiari I1 hindbrain malformations (which account for about one half of all syrinxes identified by MRI), intramedullary tumors, trauma, arachnoiditis, and compression of the spinal cord or brainstem by either extradural or intradural masses (Fig. 83-3). When no cause for the syrinx is discovered, the term idiopathic syringomyelia often is applied. MRI has helped identify many concurrent conditions in cases of syringomyelia and has thus resulted in a marked reduction in the perceived prevalence of idiopathic syrinxes. Syringomyelia is so commonly associated with these other related conditions that it is impractical to consider it as an isolated entity when describing its clinical presentations.

CLINICAL PRESENTATION Syringomyella Assodated with a Hindbrain Malfonnatlon The symptoms and signs associated with a syrinx are logically remembered if one bears in mind the cross-sectional anatomy of the spinal cord. Often juxtaposed on the symptoms and signs caused by the syrinx are the symptoms and signs caused by the associated hindbrain malformation. The most common presenting symptoms of a syrinx with the

FIG. 83-3. Contrast-enhanced sagittal MRI of the cervicomedullary junction showing a hemangioblastoma with an associated cervical syrinx.

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Diseases of the Spinal Cord

FIG. 83-4. Sagittal T1-weighted MRI of the cervical spinal cord showing tonsillar herniation characteristic of the Chiari I malformation. There is also an associated syrinx that does not communicate with the

fourth ventricle.

causing a main en griffe (French for “griffin-claw h a n d ) appearance. This term has an interesting derivation; a griffin is a mythological monster that has the body and hind legs of a lion and the head, wings, and claws of an eagle. Scoliosis, when present, typically is centered on the cervicothoracic junction and can precede other neurologic symptoms by years. The classic neurologic sign encountered is a suspended, capelike, dissociated sensory loss involving the thorax and upper extremities. The presence of this sign on examination strongly localizes the lesion to within the parenchyma of the spinal cord. This finding is the result of disruption of the crossing spinothalamic tracts in the central portion of the cord. Sensation above and below the level of the syrinx can be normal if only the crossing fibers are affected. This forms the basis for the deficit being suspended. In addition, if the process involves only the spinothalamic tract, pain and temperature alone, and not fine touch or proprioception, are affected. This forms the basis for the deficit being dissociated. As the syrinx enlarges, it next affects the anterior horn cells, first the more central anterior horn cells that supply the axial musculature and then the more peripheral anterior horn cells that affect the appendicular musculature. This is the presumed basis of the scoliosis (axial muscle weakness) and segmental atrophy and

weakness of the distal arm, respectively. Further progression of the syrinx involves the intermediolateral cell column of the cord (when the syrinx extends into the thorax). This manifests as Horner’s syndrome. Finally, the corticospinal tract and posterior columns are affected, resulting in spasticity and difficulty with fine touch and joint position sense. Interestingly, the motor and sensory disturbances associated with a syrinx nearly always begin asymmetrically, although they end up affecting both sides. More chronic findings on examination include painless ulcerations of the fingers, edematous hands, and Charcot joints. The presentation of syringomyelia with the Chiari I1 malformation often is more subtle. These patients come to medical attention at birth. There is almost always an associated myelomeningocele, which causes a variable amount of extremity and bowel and bladder dysfunction, depending on the level of the myelodysplasia. Hydrocephalus is also a very common finding, so most of these patients need a ventricular shunt early in life. Most syrinxes found with the Chiari I1 malformation are asymptomatic. Sometimes, the syrinx extends the entire length of the spinal cord, and yet signs attributable to the syrinx are difficult to elicit. The syrinx may appear along with other signs of shunt malfunction. The syrinx has even been reported to appear before ventricular dilation in cases of shunt malfunction. Patients with the Chiari I1 malformation may present with a variety of symptoms and signs attributable to brainstem dysfunction during the neonatal period. These babies feed poorly, with choking, vomiting, and aspiration. They can become stridorous or apneic. Radiographic investigation may reveal hydrocephalus, a syrinx, a tight posterior fossa, or a combination thereof. It can be difficult to sort out which of the findings is contributing to the problem or whether the presentation is the result of an intrinsically disordered brainstem. The most common cause of a symptomatic Chiari I1 malformation is a shunt malfunction. This possibility should be entertained even if the initial imaging of the brain does not reveal enlarged ventricles because the ventricles occasionally do not change early in the course because of decreased compliance or displacement of CSF into a syrinx or into a bulging myelomeningocele repair site. In rare cases, the syrinx extends cephalad into the brainstem and is thus referred to as syringobulbia. This typically occurs in the tegmentum, eccentrically to one side or the other. Patients may experience changes in their voice and dysphagia. On examination, atrophy and ipsilateral deviation of the tongue and ipsilateral pain and temperature sensation loss of the face may be found. In addition, nystagmus or Horner’s syndrome may be present. Often, the symptoms and signs can be difficult to separate from the associated Chiari malformation and direct brainstem compression.

Syrinx Associated with Spinal Cord Tumor Intramedullary cord tumors account for 2% to 4% of all central nervous system tumors. Syrinxes have been found with all of the commonly occurring intramedullary spinal cord tumors and are thought to occur in 25% to 50% of these tumors. Syrinxes are more likely to occur in conjunction with cervical spinal cord tumors than with thoracic or lumbar spinal cord tumors. Astrocytomas, ependymomas, and hemangioblastomas account for more than 90% of these tumors. The CSF protein level often is increased in the syrinxes associated with spinal cord tumors. The syrinx can extend cephalad or caudad to the tumor or both.

Chapter 83

Because the symptoms attributable to both the intramedullary tumor and syrinx are caused by disruption of the spinal cord, the clinical relevance of the syrinx, as distinct from that of the tumor, often is hard to assess. Often, the sensory level corresponds to the location of the tumor and not the syrinx even if the syrinx extends multiple segments above or below the tumor. The most common presenting symptom in adults is pain. It is a complaint in up to 90% of all adults with intramedullary tumors. The pain is described as a poorly localized ache in the midline corresponding to level of the tumor. Often, the pain radiates into an extremity in a nonradicular pattern and is characterized as a poorly localized deep ache. Syrinxes that occur in conjunction with spinal cord tumors may also affect the motor and sensory modalities. Motor problems often begin asymmetrically and are usually most profound in the hands when the tumors are located in the cervical spine. Difficulties with gait can also develop later. Examination often reveals proximal weakness and, occasionally, atrophy. Distally, there may be diminished fast finger motion and agility. Sensory disturbances also tend to start asymmetrically and distally. These disturbances may spread proximally and then cross to the other side. The classic finding of a suspended, dissociated sensory loss is uncommon but, when present, is highly suggestive of an intramedullary process. Surgical removal of the tumor often also eliminates the associated syrinx. The presence of a syrinx confers a better prognosis for complete surgical resection of the spinal cord tumor.

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535

venous thrombosis involving a spinal cord vascular malformation. Occasionally, sudden deterioration is superimposed on a more chronic condition. Clinically, these malformations have a very variable presentation. The myelopathy is less likely to be a central cord-like syndrome, and paraparesis or quadriparesis is more likely to be an early finding. Tethered spinal cord syndrome can present with a slowly progressive myelopathy much like the syrinx. Often, symptomatic tethered cords present with an orthopaedic deformity. This more often involves the thoracolumbar or lumbar spine or lower extremities, as opposed to the deformities typical of the syrinx, which primarily affect the cervical or cervicothoracic spine or upper extremities. The orthopedic abnormalities associated with the tethered cord can be varus, valgus, or cavus changes of the

Post-traumatic Syringomyelia Post-traumatic syringomyelia is a syndrome characterized by progressive deficits corresponding to a portion of the spinal cord remote from a previous injury. It usually manifests several years after the spinal cord injury. The incidence of post-traumatic syringomyelia is thought to be between 0.3% and 3.2% (Fig. 83-5). The most common presenting symptom is pain. The pain can occur in the torso or an extremity and may be related to movement of the head, when cervical in location, or to straining. Later findings include paresthesias, weakness, and hyperhydrosis. These symptoms typically are related to superiorly located segments of the spinal cord. Interestingly, the symptoms can skip segments of the cord. The paresthesias and motor findings usually start, and remain, asymmetric. Occasionally, the pain is replaced with hypalgesia. DIFFERENTIAL DIAGNOSIS The differential diagnosis of syrinx includes a large spectrum of pathologic processes. One must consider the inflammatory myelopathies that affect the spinal cord. These may be infectious or idiopathic. Normally, the clinical course is more fulminant, evolving over a period of days. Likewise, the demyelinating diseases usually evolve over a time course too short to be mistaken for the more chronically evolving syrinxes. Spinal arteriovenous malformations can present with a more chronic myelopathy. These malformations are most commonly dural malformations and are the result of a fistula or fistulas supplied by a radicular artery or arteries. The pathophysiology is thought to be a myelopathy from venous hypertension as the result of the fistula. On imaging studies, large serpiginous arterialized veins are seen in the subarachnoid space. The eponym FoixAlaiouanine has been used to describe a vascular disorder characterized by a necrotizing myelitis believed to be secondary to

FIG. 83-5. Sagittal T1-weighted MRI of the cervicothoracic spinal cord showing a syrinx and an atrophic spinal cord. Previously, this patient had sustained a " gunshot wound of the cervical spinal cord.

536

Spinal Cord and Peripheral Neuromuscular Disease

rn Diseases of the Spinal Cord

foot; recurrent dislocations of the hip; or rotational abnormalities of an extremity or extremities. An isolated presentation of scoliosis is not uncommon. Patients occasionally present with progressive isolated gait abnormalities such as spastic or wide-based gaits. Sometimes patients develop a peculiar change in posture, consisting of flexion of the knees and increased lumbar lordosis. In addition to orthopedic deformities, patients with tethered cords may present with spinal cord or, less commonly, root dysfunction. Again, this typically affects the lower extremities and can involve pain, weakness, sensory changes, and bowel or bladder dysfunction. The tethered cord often is associated with a host of lesions, including myelomeningocele, myelocystocele, lipomyelomeningocele, spinal lipoma, meningocele, split cord malformation (diastematomyelia), and a thickened fdum terminale. The presence of any of these conditions along with a low-lying conus medullaris should alert the clinician to the possibility of the tethered cord syndrome. Of interest is the myelomeningocele that is often associated with a syrinx and is nearly always associated with a low-lying conus in children. When these children present with progressive myelopathy or orthopedic abnormalities, it is sometimes difficult to decide whether the predisposing condition is the syrinx, the tethered cord, or both. Finally, lesions extrinsic to the spinal cord can mimic intramedullary processes. This is epitomized by the central cord injury, which typically results from a hyperextension injury, usually at C p C 5 or C5-C6, and leaves the patient with weakness predominantly affecting the hands bilaterally and relative sparing of the legs. Sensory disturbances are variable but, when present, can occur as a suspended, dissociated sensory loss, as in syrinxes. The central cord syndrome can also occur in a much more chronic form, presumably from repeated minor trauma to the cord from an extrinsic lesion, usually arthritic spurs. On MRI, there is often a bright spot on T2-weighted images. Experimental compression of the upper cervical spine in monkeys can produce pathologic changes in the central parts of the spinal cord in the area of C8 and TI. This is thought to be the result of venous stasis and has been proposed as the cause of the central cord syndrome form extrinsic compression. Finally, extrinsic lesions that occur at the foramen magnum can present similarly to the extrinsic lesions of the midcervical spine. Patients with anterior cervicomedullary compression can present with a disproportionate amount of hand weakness. Sensory changes often are minimal unless the compression is dorsal at the cervicomedullary junction. This selective hand involvement is thought to occur because the decussation of the corticospinal tract destined for the hand occurs slightly more superior and ventral to the decussation of fibers destined for the lower extremities and can thus be selectively disturbed. This entity has been described as a cruciate palsy, referring to the compression at the crossing of fibers. DIAGNOSTIC EVALUATION In cases of suspected syringomyelia,the study of choice is an MRI scan. MRI is the most sensitive study and the most informative. In cases of known Chiari malformation (type I or 11) and suspected syrinx, a cervical MRI either confirms or rules out the diagnosis in almost all cases. If the presence of a syrinx is confirmed, it is also necessary to look at ventricular size. If a syrinx is found on MRI and there is no associated hindbrain malformation, history of trauma, or extramedullary

spinal canal mass, it is important to administer contrast medium to search for a spinal cord tumor. If localization suggests that the syrinx is more caudal than the cervical spine, the MRI should extend down to the level of the conus to look for the many causes of tethered cord or to look for a vascular malformation. For patients who cannot undergo MRI, the myelogram followed by a computed tomography (CT) scan is sensitive and informative. The initial CT scan displays the syrinx as a dilated spinal cord and may also show stigmata of the Chiari malformations or an extramedullarymass in the spinal canal. A delayed CT of 6 to 12 hours may show contrast in the syrinx itself. TREATMENT Neurosurgeons have developed many techniques to treat syringomyelia in the past several years. These include posterior fossa bony decompression for the associated Chiari malformation with or without duraplasty, subpial tonsillar resection, lysis of adhesions, myelotomy, and plugging of the obex. In addition, simple percutaneous aspiration of the syrinx, terminal ventriculostomy (sectioning of the terminal ventricle or proximal fdum terminale), syrinx-to-subarachnoid shunts, syrinx-to-peritoneum shunts, and subarachnoid-to-peritoneum shunts have been used. The treatment to a large extent depends on the radiographic features of the syrinx. If there is hydrocephalus and the syrinx appears to communicatewith the fourth ventricle or basal cisterns, the procedure of choice is a shunt. In cases of spinal cord tumors, the treatment is removal of the tumor. In the other cases of syrinx, the most effective treatment is more controversial. When a syrinx is associated with a Chiari I malformation, most neurosurgeons perform some type of posterior fossa decompression. In addition to the bone removal, there is a wide variation in technique, as mentioned earlier. No studies substantiate the superiority of any one method over another. We choose not to plug the obex because of its potential danger and because of recent evidence suggesting a lack of communication of the syrinx and the fourth ventricle in most cases. In cases in which there is a concomitant ventral compression of the brainstem (e.g., basilar invagination), it has been suggested that the anterior disease be corrected first to avoid settling of the cerebellum through the enlarged foramen magnum and subsequent exacerbation of the ventral compression. Most neurosurgeons reserve shunting of the syrinx to the subarachnoid space or other body cavities for cases of syrinx without hindbrain abnormalities or cases with progression of symptoms and radiographic persistence of syrinx despite posterior fossa decompression. Some neurosurgeons use shunting of the syrinx as a first line of treatment. Regardless of which method is used, around 20% of patients continue to deteriorate despite treatment. In addition, there is a subset of patients who do not progress, even without treatment. The inability to separate these two groups prospectively or retrospectively makes an analysis of the different treatments difficult. There is some suggestion that age greater than 40 years at presentation and a long duration of preoperative symptoms each confer a poor prognosis for successful treatment. CONCLUSION Syringomyelia is an important part of the differential diagnosis for subacute spinal cord dysfunction. It is a subject with a rich history and an evolving theory of pathogenesis. A lack of insight into the

Chapter 84

natural history of the disease has hampered our ability to evaluate different treatment modalities. The advent of MlU is likely to revolutionize our understanding of syringomyelia and clarify both its natural history and the most appropriate treatments.

SUGGESTED READINGS Abouker J: La syringomyelia et les liquides intra-rachidiens. Neurochirurgie Suppl 25:l-144, 1979

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537

Ball MY, Dayan AD: Pathogenesis of syringomyelia. Lancet 2:799-801, 1972 Gadner WJ: HYdrOdYnmiC mechanism of SyringomYelia. J New01 Neurosurg Psychiatry 28:247-259, 1965 Milhorat TH, Johnson WD, Miller JI et ak Surgical treatment of syringomyelia based on magnetic resonance imaging criteria. Neurosurgery 31:231-245, 1992 Milhorat TH, Miller 71, Johnson WD et ak Anatomical basis of syringomyelia occurring with hindbrain lesions. Neurosurgery 32:74& 754, 1993

Spondylosis and Disc Disease David S. Geckle and Mary Louise Hlavin

A careful clinical history and physical examination are critical for diagnosing, localizing, and treating degenerative spinal diseases, whether spondylosis or disc herniation. The combination of clinical symptoms and signs guides decision making regarding the need for diagnostic testing and appropriate therapy. Only a small fraction of patients with degenerative disease of the spine have a surgically significant disc herniation or spondylosis. History and physical examination remain the cornerstones to identifying these cases and optimizing diagnosis and treatment for patients with nonsurgical pathology. Neurologic diagnosis begins with a comprehensive history and a review of past medical problems. Chronic diseases (diabetes mellitus, arthritis, and collagen vascular diseases), prior spinal trauma or surgery, metabolic disturbances (acromegaly, hypoparathyroidism, and renal osteodystrophy), malignancy, intravenous drug abuse, and vascular disease are just a few of the factors that can predispose a patient to spinal disease. The presence or absence of such factors can aid in differentiating a benign disc or spondylotic disease from neuropathies, plexopathies, infection, metastasis, or other causes. LUMBAR DISEASE Lumbar spinal disease consists primarily of two entities: disc herniation and spinal stenosis. Herniations occur approximately equally among men and women; stenosis is more common among women than men. Approximately 95% of lumbar disc herniations occur at the LPL5 and L5-S1 levels where most of the flexion, extension, and lateral bending occur. Manual labor or prolonged periods of riding in motor vehicles predispose people to lumbar disc disease. Spinal stenosis, or narrowing of the lumbar spinal canal and foramina sufficient to result in compression of the neural structures, is caused by congenital or degenerative hyper-

trophy of vertebral facets and the ligamentum flavum. It may be focal or throughout the entire lumbar spine.

Clinlcal Features Low back pain is the most common manifestation of the herniated lumbar disc. Typically, the pain is a dull ache of gradual onset, which is worsened by exertion and relieved by rest. With acute herniations, it can often be a severe spasmodic pain of sudden onset exacerbated by any movement. Over time, the back pain usually progresses to sciatica, a progressive boring pain that radiates to the buttocks or down the posterolateral leg but may extend to the ankle or foot with lower disc herniations. This pain may be chronic or relapsing in nature and is often associated with sensory disturbances, typically paresthesias. The distribution of pain and sensory disturbances is useful in localizing the site of the lesion. Typical findings associated with lumbar root syndromes are summarized in Table 84-1. With far lateral disc herniations, the symptoms tend to be particularly severe. Lumbar stenosis generally presents with a slowly progressive course spanning several years. The patient typically complains of leg pain, often bilateral, that may be sharp and lancinating, dull and cramping, or burning in nature. It is usually triggered by walking, but standing or sitting for prolonged periods may exacerbate the condition. Generally, the pain is rapidly and dramatically relieved by lying down or sitting. Complaints of numbness, paresthesias, and leg heaviness or weakness during ambulation are common and may outweigh the pain component, although pain typically precedes their onset. Patients often report that they must walk in short stages, with frequent rest breaks. Although the symptoms of lumbar stenosis are caused by neural compromise, they are clinically similar to those of vascular insufficiency. Therefore, the term neurogenic cluudication often is

w TMLE 861. Common Lumbar Root Syndromes Root

Pain Location

Sensory Disturbance

Weakness

Reflex Change

L3

Anterior thigh, groin Anterior thigh Posterolateral thigh and calf, extending into great toe and dorsum foot Posterolateral thigh and calf, extending into lateral toes and heel

Anterior thigh Medial calf, medial foot Dorsum foot, great toe, lateral calf

lliopsoas (quadriceps) Quadriceps fibialis anterior, extensor hallicus longus Gastrocnemius, toe flexors

Patellar Patellar None

L4 L5

51

Lateral foot, posterior calf

Achilles

Chapter 84

natural history of the disease has hampered our ability to evaluate different treatment modalities. The advent of MlU is likely to revolutionize our understanding of syringomyelia and clarify both its natural history and the most appropriate treatments.

SUGGESTED READINGS Abouker J: La syringomyelia et les liquides intra-rachidiens. Neurochirurgie Suppl 25:l-144, 1979

84

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537

Ball MY, Dayan AD: Pathogenesis of syringomyelia. Lancet 2:799-801, 1972 Gadner WJ: HYdrOdYnmiC mechanism of SyringomYelia. J New01 Neurosurg Psychiatry 28:247-259, 1965 Milhorat TH, Johnson WD, Miller JI et ak Surgical treatment of syringomyelia based on magnetic resonance imaging criteria. Neurosurgery 31:231-245, 1992 Milhorat TH, Miller 71, Johnson WD et ak Anatomical basis of syringomyelia occurring with hindbrain lesions. Neurosurgery 32:74& 754, 1993

Spondylosis and Disc Disease David S. Geckle and Mary Louise Hlavin

A careful clinical history and physical examination are critical for diagnosing, localizing, and treating degenerative spinal diseases, whether spondylosis or disc herniation. The combination of clinical symptoms and signs guides decision making regarding the need for diagnostic testing and appropriate therapy. Only a small fraction of patients with degenerative disease of the spine have a surgically significant disc herniation or spondylosis. History and physical examination remain the cornerstones to identifying these cases and optimizing diagnosis and treatment for patients with nonsurgical pathology. Neurologic diagnosis begins with a comprehensive history and a review of past medical problems. Chronic diseases (diabetes mellitus, arthritis, and collagen vascular diseases), prior spinal trauma or surgery, metabolic disturbances (acromegaly, hypoparathyroidism, and renal osteodystrophy), malignancy, intravenous drug abuse, and vascular disease are just a few of the factors that can predispose a patient to spinal disease. The presence or absence of such factors can aid in differentiating a benign disc or spondylotic disease from neuropathies, plexopathies, infection, metastasis, or other causes. LUMBAR DISEASE Lumbar spinal disease consists primarily of two entities: disc herniation and spinal stenosis. Herniations occur approximately equally among men and women; stenosis is more common among women than men. Approximately 95% of lumbar disc herniations occur at the LPL5 and L5-S1 levels where most of the flexion, extension, and lateral bending occur. Manual labor or prolonged periods of riding in motor vehicles predispose people to lumbar disc disease. Spinal stenosis, or narrowing of the lumbar spinal canal and foramina sufficient to result in compression of the neural structures, is caused by congenital or degenerative hyper-

trophy of vertebral facets and the ligamentum flavum. It may be focal or throughout the entire lumbar spine.

Clinlcal Features Low back pain is the most common manifestation of the herniated lumbar disc. Typically, the pain is a dull ache of gradual onset, which is worsened by exertion and relieved by rest. With acute herniations, it can often be a severe spasmodic pain of sudden onset exacerbated by any movement. Over time, the back pain usually progresses to sciatica, a progressive boring pain that radiates to the buttocks or down the posterolateral leg but may extend to the ankle or foot with lower disc herniations. This pain may be chronic or relapsing in nature and is often associated with sensory disturbances, typically paresthesias. The distribution of pain and sensory disturbances is useful in localizing the site of the lesion. Typical findings associated with lumbar root syndromes are summarized in Table 84-1. With far lateral disc herniations, the symptoms tend to be particularly severe. Lumbar stenosis generally presents with a slowly progressive course spanning several years. The patient typically complains of leg pain, often bilateral, that may be sharp and lancinating, dull and cramping, or burning in nature. It is usually triggered by walking, but standing or sitting for prolonged periods may exacerbate the condition. Generally, the pain is rapidly and dramatically relieved by lying down or sitting. Complaints of numbness, paresthesias, and leg heaviness or weakness during ambulation are common and may outweigh the pain component, although pain typically precedes their onset. Patients often report that they must walk in short stages, with frequent rest breaks. Although the symptoms of lumbar stenosis are caused by neural compromise, they are clinically similar to those of vascular insufficiency. Therefore, the term neurogenic cluudication often is

w TMLE 861. Common Lumbar Root Syndromes Root

Pain Location

Sensory Disturbance

Weakness

Reflex Change

L3

Anterior thigh, groin Anterior thigh Posterolateral thigh and calf, extending into great toe and dorsum foot Posterolateral thigh and calf, extending into lateral toes and heel

Anterior thigh Medial calf, medial foot Dorsum foot, great toe, lateral calf

lliopsoas (quadriceps) Quadriceps fibialis anterior, extensor hallicus longus Gastrocnemius, toe flexors

Patellar Patellar None

L4 L5

51

Lateral foot, posterior calf

Achilles

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Spinal Cord and Peripheral Neuromuscular Disease

used. It is imperative to evaluate for the presence of true vascular claudication in these patients. One should always examine for the presence of diminished femoral or pedal pulses or trophic changes of vascular insufficiency. Because the two conditions may occur simultaneously, one must consider the diagnosis of lumbar stenosis when pain persists after successfulvascular reconstruction. Bladder dysfunction, though rarely the sole manifestation of a herniated disc, is typically but not always associated with conus or cauda equina compression. When associated with severe acute motor weakness, a massive central disc herniation is suggested. Sacral involvement leads to a cauda equina syndrome in 10% of patients with lumbar stenosis. It is important always to document a history of urinary retention or incontinence, impotence, and saddle sensory loss. Patients with a herniated lumbar disc tend to have slow, deliberate, limited movements. Often, they hold their lower back. Inspection of the spine in patients with disc herniation usually reveals a flattening of the normal lordotic curve and paravertebral muscle spasm. Approximately 50% of patients demonstrate a scoliosis to minimize traction on the affected nerve root, as seen in Figure 84-1. The seated patient tends to slide the hips forward to avoid the normal axial loading of the lower spine. The hip and knee of the symptomatic leg often are held in slight flexion to relieve tension on the affected root. Gait often is antalgic, with minimal weight bearing on the affected leg. With far lateral disc herniations, patients often are unable to walk and hold their leg in

A

Diseases of the Spinal Cord

extreme flexion, with pain on minimal movement. Patients with lumbar stenosis tend to assume a stooped posture because forward bending often relieves the pain. Lumbar extension, which may significantly narrow the neural foramina, often leads to acute bilateral sciatica in patients with lumbar stenosis. Percussion over the involved vertebrae often causes pain. Palpation along the sciatic nerve and into the sciatic notch, though generally causing pain, can rule out the presence of a peripheral nerve sheath tumor. With long-standing spinal disease, decreased muscle tone or bulk in the lower extremities may be seen. Circumferential measurements of thigh and calf can be used to verify this. Straight leg raising maneuvers usually do not exacerbate symptoms of lumbar stenosis but are useful in diagnosing disc disease. Lasegue’s sign, or the classic straight leg raising test, is positive in up to 95% of true disc herniation cases (Fig. 84-2). The bowstring sign, a straight leg raising until pain is elicited with subsequent flexion of the knee resulting in relief of pain, may be added for confirmation. A positive crossed straight leg raising test, or pain on raising the asymptomatic leg, is seen in approximately 30% of cases. This test produces pain as the involved root is dragged over a large or medially placed herniation (Fig. 84-3). Upper lumbar disc herniations produce pain with leg extension rather than flexion, providing the basis for the extensor sign or femoral nerve traction test. Tension on the upper nerve roots caused by this maneuver generally causes pain to the knee with L3 root impingement and below the knee with L4 root impingement.

B

FIG. 84-1. Scoliosis minimizes traction on the affected lumbar nerve root. (A) In laterally placed herniations, the patient leans away from the affected side. (B) In medially located herniations, the patient leans toward the symptomatic side. (From Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1:29, 1991, with permission.)

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539

stool. Because symptoms associated with lumbar stenosis may vary with exertion, it is important to perform motor testing both at rest and after activity. Deep tendon reflex changes are the most objective sign of disc disease. For good results, it is essential for the patient to be as relaxed as possible. Reinforcement maneuvers, such as isometric pulling of clasped hands, may be of use. Having the patient kneel on a chair is a useful trick in eliciting an ankle jerk. It is also important to recall that the deep tendon reflexes diminish with advancing age. Although diminution of the deep tendon reflexes is classically associated with disc herniation at a single level (Table 84-l), this pattern is not entirely reliable. For instance, a diminished patellar reflex is most often seen with a ruptured L3-L4 disc, but it can also be seen with a lesion at L2-L3. A decreased ankle jerk is most common with L5-S1 herniations; however, this finding may also be caused by compression of the S1 root by a large L&L5 disc. The neurologic examination often is normal in patients with spinal stenosis, although occasionally diminution of reflexes or distal sensory loss, suggesting multiple root compression, can be seen with advanced disease.

A

B

Spondylosis and Disc Disease

U FIG. 84-2. The classic straight leg raising test consists of two parts. (A) A straight leg raising followed by (B) a second lift with knee flexed. The

first should cause radiating pain (not merely tightness in the posterior thigh); the latter should not. (From Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1 :29, 1991, with permission.)

Patrick's sign, or the figure-four maneuver, may be useful in excluding hip disease, which can also result in pain referred to the low back (Fig. 84-4). Sensory examination is the most subjective part of the physical examination. Although generalizations about the patterns of sensory loss can be made, marked variations exist because of normal anatomic variation of dermatomal pattern, involvement of more than a single nerve root, or migration of a disc fragment. A far lateral disc herniation typically causes compression of the root one level higher than usually expected (Fig. 84-5). Table 84-1 reports the sensory changes most typically associated with lumbar root compression. Rectal sensory examination is critical because many patients are unaware of this deficit. Motor weakness, though the least frequently seen sign of disc herniation, provides another important adjuvant to lesion localization (Table 84-1). However, testing may be limited because exertion causes pain. Testing muscle groups that do not stretch irritated nerve roots can help to overcome this problem (Table 84-2). Given the inherent strength of the lower extremities, weakness on routine static testing may be difficult to perceive. Subtle weakness can be unmasked using active motor testing, that is, having the patient heel-and-toe walk, squat, or climb up onto a

FIG. 84-3. The crossed straight leg raising produces pain with a large medial disc but not one located laterally. (From Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1:29, 1991, with permission.)

Spinal Cord and Peripheral Neuromuscular Disease rn

540

Diseases of the Spinal Cord

\

../ FIG. 84-4. Patrick‘s sign is elicited by externally rotating the hip with both the hip and knee flexed. This should not cause pain in the patient with disc herniation but rather suggests hip pathology. (From Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1 :29, 1991, with permission.)

Diagnosis

FIG. 84-5. Far lateral disc herniations often compress the root above the disc space rather than that usually expected. (From Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1:29, 1991, with permission.)

I-

OUQS 41

84-2.

hout Root

Roots

Muscle CrOUD

u.LJ, L4 u,L5 u,L5

Thigh adductors Thigh abduction

L5, SI

Foot inversion Foot eversion

The value of plain spine radiographs in diagnosing lumbar disc disease remains controversial. Clearly, the plain spine film is the most effective method of evaluating alignment, an important consideration in preoperative planning for spondylotic disease. A narrowed disc space can indicate disc degeneration or protrusion; osteophyte formation suggests a more chronic process. Decrease of the anteroposterior and transverse diameters of the spinal canal, which is seen with severe developmental stenosis, often can be documented. In addition, plain films are invaluable in distinguishing disc disease from other conditions, which may present with similar symptoms, such as spondylolisthesis, spinal metastasis, fracture, infection, osteoarthritis, and vertebral hemangioma. Finally, radiographs can alert the surgeon to an occult spina bifida or spondylolysis preoperatively. Myelography provides an indirect means of evaluating disc herniation while simultaneously excluding other intradural pathology, such as tumors, arachnoiditis, and vascular malformations. It is important to visualize the thoracolumbar junction (TI0 to L1) to avoid missing a conus lesion or the occasional thoracic disc presenting with sciatica. In stenotic patients with a complete myelographicblock, flexion views may convert the block to partial, allowing visualization of the distal levels. When combined with postcontrast computed tomographic (CT) imaging, myelography provides the most accurate demonstration of bony anatomy. CT imaging is useful in evaluating the spine and surrounding structures. With the addition of intrathecal contrast, it can demarcate the thecal sac, cauda equina, and exiting nerve roots. CT is particularly helpful in assessing far lateral herniations and delineating bony anatomy. It is able to detect abnormalities of canal shape, lateral recess size, and neural foramina size, which are essential in evaluating spinal stenosis. Magnetic resonance imaging (MRI) allows simultaneous noninvasive imaging of the spine, intervertebral discs, thecal sac, conus, cauda equina, exiting nerve roots, and surrounding structures in multiple planes. It has emerged as the primary imaging technique in diagnosing spine disease. The addition of intravenous gadolinium has been shown to be accurate in distinguishing postoperative scarring from recurrent disc herniation.

Chapter 84

Although rarely indicated in straightforward cases of radiculopathy or stenosis, electromyography (EMG) may be a useful adjunct in complex cases. For maximal benefit, EMG should be performed 3 to 5 weeks after symptom onset to allow development of fibrillation potentials. Radiculopathy findings may disappear over time, so it is equally important not to wait too long. One must always correlate the EMG findings with the clinical setting. Do not allow positive EMG results to dictate surgical intervention when appropriate clinical symptoms and radiologic findings are not present. Treatment

Because more than 50% of patients with lumbar disc herniations respond to medical management, it is important to give nonsurgical therapy a trial in almost all patients. Clear indications for urgent surgical intervention include advanced neurologic deficit, cauda equina compression, sphincter dysfunction, neurologic deterioration with conservative management, and recurrent incapacitating episodes of pain. Persistent unacceptable disability from pain with nonoperative therapy is the most common indication for surgery. One must carefully weigh the psychosocial factors (litigation, secondary gain, depression, and so forth) involved in the patient’s disability before surgical intervention. Nonoperative therapy for disc herniation consists of bed rest with the use of selected analgesics, anti-inflammatory agents, and muscle relaxants to reduce symptoms caused by irritation and edema of the affected root. When symptoms have resolved, instruction in posture, back exercises, and moderation of daily activities (“low back school”) are important. Unless neurologic deterioration occurs, most physicians advocate at least 2 to 3 weeks of nonsurgical therapy. Occasionally, a brief course of oral steroids (such as a methylprednisolone dose pack) is useful in relieving symptoms of acute herniation. Although bed rest with lumbar flexion may provide temporary relief of painful radiculopathy, severe lumbar stenosis rarely responds to long-term nonsurgical management. In mild cases, flexion exercises and a lumbar corset or brace may result in relief by facilitating postural correction. Analgesics, anti-inflammatory agents, and muscle relaxants are useful in treating the radicular symptoms while awaiting surgical decompression. Definitive treatment for lumbar stenosis involves wide laminectomy with foraminotomies over the level of spinal compression. Discectomy is rarely indicated with adequate posterior decompression and may contribute to postoperative spinal instability. Inadequate decompression is a common cause of continued symptoms. Chronic cases of lumbar stenosis with advanced muscle atrophy or sphincter dysfunction are least likely to have full recovery. In patients with persistent postoperative mechanical low-back pain, spinal instability must be considered. In most cases, persistent nonradicular pain can be managed medically. In some, supplemental posterolateral spinal fusion may be needed. The decision to operate is based on the combination of clinical findings, the physician’s assessment, and the patient’s input, given all the options. The goal should be the most cost-effective and expeditious management to return each individual safely to full, productive activity.

CERVICAL DISEASE Benign cervical spine disease generally falls into one of two categories: radiculopathy or cervical myelopathic syndrome. How-

Spondyiosis and Disc Disease

541

ever, the pathogeneses of these differ somewhat and are essentially a result of two types of cervical disc anomalies: disc rupture (which results primarily but not exclusively in radiculopathy) and cervical arthrosis and spondylosis (which may result in radiculopathy, myelopathic syndrome, or both). The distinction between these two is essential because one is generally a self-limited condition and the other is progressive, and operative approaches to the two can differ significantly. Although there is no sex predilection to cervical disc disease, predominantly male patients are affected by spondylotic myelopathy. Cervical disc disease is less common than lumbar disease, accounting for only about one in seven spinal herniations. Like lumbar disc disease, most cervical herniations occur at one of two levels that bear the brunt of spinal motion and stress, either C5-C6 or C6-C7. Multiple simultaneous levels of involvement are rare in acute cervical disc herniation but are common with spondylitic disease. Approximately 5% of cervical disc herniations are recurrent. Spondylosis in the cervical spine typically is generated by bony marginal spurring stimulated by bulging discs and is usually located posteriorly or intraforaminally. In contrast, in the lumbar region, this lipping is almost exclusively anterolateral in location and rarely results in foraminal encroachment. Hypertrophy of the ligamentum flavum rarely causes symptoms in the cervical spine, although hypertrophy and ossification of the posterior longitudinal ligament (OPLL) is a well-defined problem. Patients with cervical spondylosis are twice as likely to have lumbar stenosis than the general population. Although generally not causative in and of itself, shallowness of the cervical canal predisposes patients to spondylotic myelopathy. Work-related stress, spasmodic torticollis, and congenital segmental defects such as Klippel-Fed undoubtedly play a role in generating cervical disease. The role of antecedent trauma is less clear. Clinical Features

Pain, paresthesias, and motor and sensory deficits are the hallmarks of cervical radiculopathy, although occasionally there may be a significant discrepancy between sensory and motor symptoms, resulting in either profound painless arm weakness with atrophy or severe incapacitating pain without other neurologic findings. The pain is typically proximal in distribution; the paresthesias are distal. Compression of the lower cervical roots produces very similar pain at the neck base, interscapular region, and shoulder and cannot be used to distinguish radiculopathies. However, cervical paraspinous or superior shoulder pain without radiation to the arm or scapular region should suggest C3-C4 disc herniation. A C6 radiculopathy sometimes causes chest pain, mimicking angina. Paresthesias generally are more accurate in localizing pathology, as summarized in Table 84-3. In addition to the more classic pins-and-needles paresthesia sensations, patients may complain of their hand or arm feeling “odd,” sometimes described as cool and other times just as “not their own.” Occasionally, a large centrally herniated disc results in acute quadriparesis with bowel or bladder dysfunction. Although the symptoms of bony spondylotic nerve root compression are similar to those of disc herniation, the course often is much more indolent. Although spastic paraparesis is the single most common presentation of cervical spondylotic myelopathy, it is distinctly unusual for symptoms to appear full blown or rapidly. Occasionally, however, symptoms can evolve rapidly after hyperextension. Early stages are typified by complaints of weakness and easy fatigability of the legs. The patient may note a

Spinal Cord and Peripheral Neuromuscular Disease

542

Diseases of the Spinal Cord

w TABU863. Common Cervical Root Syndromes Root

Pain location

Sensory Disturbance

Weakness

Reflex Change

C3,C4

Paraspinousmuscles, superior shoulder Neck, shoulder, anterior arm

Neck

Diaphragm, nuchal muscles, strap muscles Deltoid, supraspinatus, infraspinatus Biceps, brachioradialis (extensor carpi radialis, pronator teres) Triceps, latissimus doni, pectoralis major, supinator, pronator teres Intrinsic hand muscles, finger extensors Intrinsic hand muscles (Hornets syndrome)

None

c5

Shoulder Thumb, index finger, radial forearm

C7

Neck, shoulder, anterior upper arm, extending to antecubital fossa Neck, shoulder, dorsum of forearm

C8

Neck, shoulder, ulnodorsal forearm

T1

Neck shoulder, ulnar arm

Ring, little fingers, hypothenar eminence Ulnar forearm

C6

Middle finger

painless pseudoglove-like sensory loss, which prompts a futile investigation for carpal tunnel or peripheral neuropathy. Electriclike sensations with neck motion (Lhermitte’s phenomenon) are common, especially with neck extension. Neck or occipital pain and loss of temperature or pain sensation may be late symptoms. Patients with cervical radiculopathy typically hold their head rigid secondary to spasm. Extension of the head, like extension of the back in lumbar disease, often causes pain by compressing the exiting root against the facets. The Spurling maneuver, axial spine loading in conjunction with contralateral head rotation and extension, can be used to elicit pain much in the same manner as Lasegue’s sign. Flexion and extension may yield Lhermitte’s phenomenon in patients with myelopathy. As in the lumbar spine, motor and reflex changes are most specific for localizing pathology. These are summarized in Table 84-3. In the cervical region, in contrast to the lumbar region, roots are numbered by the vertebrae to which they are cephalad (e.g., the C6 root exits at the C5-C6 disc space level, just above the C6 pedicle and slightly superior to the disc space). Cervical roots exit laterally and ventrally and are held snugly against the disc while coursing toward the inferior pedicle while lumbar roots wrap more closely under the inferior pedicle. This is demonstrated in Figure 84-6. Subtle signs of C7 compression include weakness of the latissimus dorsi and pectoralis major. Latissimus function is evaluated by having the patient cough deeply while palpating these accessory muscles of respiration from behind. Unequal contractions indicate weakness. Pectoralis function is best tested using a pseudo-Froment’s sign or book test. Patients support a book between their palms with elbows extended, and the examiner then attempts to withdraw the book. Failure to maintain the humerus in adduction and involuntary elbow flexion indicates compensation for pectoralis weakness. Motor, sensory, and reflex changes are rare in early phases of spondylotic myelopathy. However, severe arthrosis results in obvious sensory losses, paraparesis, hyperreflexia, spasticity with scissoring of gait, and even upper extremity weakness. Long-term pathology may also be accompanied by anterior horn cell damage or exiting root injury (radiculopathy), resulting in a mixed picture of lower motor neuron findings (hyporeflexia, atrophy, and fasciculations) in the upper extremities combined with upper motor neuron findings in the lower extremities.

Biceps Biceps, brachioradialis Triceps None None

L3

A

I

L4

L5 FIG. 84-6. Comparison of (A) cervical and (B) lumbar root anatomy. The left half of each drawing depicts the bony anatomy; the right side demonstrates the intradural and foramina1 course of the nerve and their numbering. Note the closer application of the lumbar roots to the pedicle, which is found more laterally in the cervical region.

canal should equal the width of the body at its midportion and should be no more than 15% to 25% smaller than the body (Fig. 84-7). Absolute measurements of 14 mm or less indicate a narrow canal. Spurs and retrolisthesis may produce further impingement on canal size. However, it is important to remember that evidence of degenerative spine disease (disc space narrowing, osteophyte formation, and so forth) occurs in 25% to 50% of the population by age 50 and in 75% to 85% by age 65. These findings are most often incidental and asymptomatic. Oblique views may be used to assess neural foramina. Dynamic flexion and extension films are important to assess for anterolisthesis and retrolisthesis. MRI is rapidly supplanting CT myelography for assessing cervical spine disease. However, definition and evaluation of bony anatomy, including osteophyte encroachment on foramina and OPLL, can be inadequate with this imaging modality. CT scanning with intrathecal contrast may be needed for planning operative intervention, particularly with multilevel disease. It is important to remember that involvement at multiple levels can produce additive effects. Treatment

Diagnosis

Plain spine films can be important in evaluating cervical spine disease. Lateral views may demonstrate depth of canal, pedicle size, facets, and subluxation. As a general rule, the depth of the

As with lumbar radiculopathy, conservative therapy plays an important role in managing cervical radiculopathy. Cervical disc herniations usually are self-limited, and patients respond to nonoperative management, consisting of rest, local heat, modulation

Chapter 85

Vascular Disease of the Spinal Cord

543

In cases of severe pain or significant radicular weakness or sensory loss, urgent surgery is indicated. Acute cord compression from disc herniation, as manifested by rapidly progressive paresis, sensory level, or bowel or bladder involvement, also warrants emergency decompression. It is important to remember that long-standing compression with prolonged conservative treatment may lead to pain abatement with persistent weakness or numbness. Failure of return of strength or sensation is an indication for surgical intervention. In most cases cervical myelopathy is a progressive disease with little room for conservative management. Early diagnosis and surgery are key in preventing irreversible spinal cord injury, Cervical collars and nonsteroidal anti-inflammatory drugs may temporarily alleviate pain but do not address the underlying d'isease. Multiple surgical approaches exist for treating both cervical disc and spondylotic disease. These include anterior cervical discectomy with or without fusion, posterior laminectomy and foraminotomy, multiple anterior discectomies with fusion, anterior corpectomy with fusion, and multiple-level laminectomies. The ideal approach can be highly variable and individualized, both from patient to patient and from surgeon to surgeon.

FIG. 8 6 7 . Distance A represents canal width and should be no more than 15% to 25Vo smaller than 6,the vertebral body width.

or limitation of neck activity (through use of a cervical collar), traction, and pharmaceuticals, including anti-inflammatory agents, muscle relaxants, pain relievers, and occasionally steroids. It is imperative to ensure that there is no evidence of cord compromise before initiating traction to prevent cord injury. Head halter traction devices may be used, with initial weights starting at 5 lb and gradually increased as needed to no more than 5 lb per cervical level.

85

SELECTED READINGS Ehni B, Ehni G, Patterson RH Jr: Extradural spinal cord and nerve root compression from benign lesions of the cervical area. p. 2878. In Youmans JR (ed): Neurological Surgery. 3rd Ed. WB Saunders, Philadelphia, 1990 Garfin SR, Rydevik BL, Lipson SJet al: Spinal stenosis. p. 791. In Rothman RH, Simeone FA (eds):The Spine. 3rd Ed. WB Saunders, Philadelphia, 1992 Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1:29, 1991 Walton J, Gilliatt RW, Hutchunson M et al: Aids to the Examination of the Peripheral Nervous System. Bailliere Tindall, London, 1986

Vascular Disease of the St>inalCord Joseph H. Friedman

Vascular disorders of the spinal cord are rare, and most occur in the inpatient setting. Diagnosis may be difficult, and vascular causes of cord syndromes often are not considered. Spinal cord syndromes may be misdiagnosed as laboratory-negative multiple sclerosis or postencephalitic demyelination. Statistics on the incidence and prevalence of vascular cord syndromes are not very reliable as a result. Probably the most commonly recognized vascular disorder of the spinal cord is stroke associated with aortic surgery. However, stroke also occurs in other settings and, as in the brain, is either ischemic or hemorrhagic. Spinal cord vascular syndromes are more difficult to evaluate radiologically because of the small diameter and length of the cord, greater bone encasement, and the frequent problem of localization in which identical corticospinal signs can be caused by lesions anywhere in the thoracic cord. Table 85-1 lists vascular spinal cord syndromes. The spinal cord is supplied by the single midline anterior spinal

artery, which runs the length of the cord, and the two posterior spinal arteries (Fig. 85- 1). The posterior spinal arteries, unlike the anterior spinal artery, form a plexus, and often the artery becomes so small that it appears to be discontinuous. The vascular supply to the anterior and posterior spinal arteries varies with the level (Fig. 85-2). The cervical anterior and posterior spinal arteries are supplied by the vertebral arteries. At lower levels, there are variable numbers of segmental arteries that arise from the aorta and enter the cord via the nerve root sheaths. One vessel, the artery of Adamkiewicz, is larger than the others and supplies the lower thoracic and lumbar cord. This artery arises from the aorta and generally enters the spinal canal on the left side. The anterior spinal artery provides blood to about two thirds of the cord, including the anterior horns, the lateral spinothalamic tracts, and the corticospinal tracts, but not the posterior columns. The posterior spinal arteries supply the posterolateral portion of

Chapter 85

Vascular Disease of the Spinal Cord

543

In cases of severe pain or significant radicular weakness or sensory loss, urgent surgery is indicated. Acute cord compression from disc herniation, as manifested by rapidly progressive paresis, sensory level, or bowel or bladder involvement, also warrants emergency decompression. It is important to remember that long-standing compression with prolonged conservative treatment may lead to pain abatement with persistent weakness or numbness. Failure of return of strength or sensation is an indication for surgical intervention. In most cases cervical myelopathy is a progressive disease with little room for conservative management. Early diagnosis and surgery are key in preventing irreversible spinal cord injury, Cervical collars and nonsteroidal anti-inflammatory drugs may temporarily alleviate pain but do not address the underlying d'isease. Multiple surgical approaches exist for treating both cervical disc and spondylotic disease. These include anterior cervical discectomy with or without fusion, posterior laminectomy and foraminotomy, multiple anterior discectomies with fusion, anterior corpectomy with fusion, and multiple-level laminectomies. The ideal approach can be highly variable and individualized, both from patient to patient and from surgeon to surgeon.

FIG. 8 6 7 . Distance A represents canal width and should be no more than 15% to 25Vo smaller than 6,the vertebral body width.

or limitation of neck activity (through use of a cervical collar), traction, and pharmaceuticals, including anti-inflammatory agents, muscle relaxants, pain relievers, and occasionally steroids. It is imperative to ensure that there is no evidence of cord compromise before initiating traction to prevent cord injury. Head halter traction devices may be used, with initial weights starting at 5 lb and gradually increased as needed to no more than 5 lb per cervical level.

85

SELECTED READINGS Ehni B, Ehni G, Patterson RH Jr: Extradural spinal cord and nerve root compression from benign lesions of the cervical area. p. 2878. In Youmans JR (ed): Neurological Surgery. 3rd Ed. WB Saunders, Philadelphia, 1990 Garfin SR, Rydevik BL, Lipson SJet al: Spinal stenosis. p. 791. In Rothman RH, Simeone FA (eds):The Spine. 3rd Ed. WB Saunders, Philadelphia, 1992 Hlavin ML, Hardy RW Jr: Lumbar disc disease. Neurosurg Q 1:29, 1991 Walton J, Gilliatt RW, Hutchunson M et al: Aids to the Examination of the Peripheral Nervous System. Bailliere Tindall, London, 1986

Vascular Disease of the St>inalCord Joseph H. Friedman

Vascular disorders of the spinal cord are rare, and most occur in the inpatient setting. Diagnosis may be difficult, and vascular causes of cord syndromes often are not considered. Spinal cord syndromes may be misdiagnosed as laboratory-negative multiple sclerosis or postencephalitic demyelination. Statistics on the incidence and prevalence of vascular cord syndromes are not very reliable as a result. Probably the most commonly recognized vascular disorder of the spinal cord is stroke associated with aortic surgery. However, stroke also occurs in other settings and, as in the brain, is either ischemic or hemorrhagic. Spinal cord vascular syndromes are more difficult to evaluate radiologically because of the small diameter and length of the cord, greater bone encasement, and the frequent problem of localization in which identical corticospinal signs can be caused by lesions anywhere in the thoracic cord. Table 85-1 lists vascular spinal cord syndromes. The spinal cord is supplied by the single midline anterior spinal

artery, which runs the length of the cord, and the two posterior spinal arteries (Fig. 85- 1). The posterior spinal arteries, unlike the anterior spinal artery, form a plexus, and often the artery becomes so small that it appears to be discontinuous. The vascular supply to the anterior and posterior spinal arteries varies with the level (Fig. 85-2). The cervical anterior and posterior spinal arteries are supplied by the vertebral arteries. At lower levels, there are variable numbers of segmental arteries that arise from the aorta and enter the cord via the nerve root sheaths. One vessel, the artery of Adamkiewicz, is larger than the others and supplies the lower thoracic and lumbar cord. This artery arises from the aorta and generally enters the spinal canal on the left side. The anterior spinal artery provides blood to about two thirds of the cord, including the anterior horns, the lateral spinothalamic tracts, and the corticospinal tracts, but not the posterior columns. The posterior spinal arteries supply the posterolateral portion of

544

Diseases of the Spinal Cord

Spinal Cord and PeripheralNeuromuscular Disease

the cord, including the posterior columns on each side. The venous system draining the cord is composed of multiple small networks rather than particular large vessels with well-defined territories. The dura is supplied by dural branches of the intercostal or lumbar arteries that supply the cord. The pia is supplied by intramedullary spinal cord arteries. The subarachnoid space contains some vessels but fewer than the dura mater.

W

TABLE 85-1. Vascular Spinal Cord Syndromes

Acute Transient ischemic attack Infarct Subarachnoid hemorrhage Intramedullary hemorrhage Rapidly progressive Epidural hematoma Subdural hematoma Slowly progressive Arteriovenous malformation (dural or intradural)

B

STROKE A N D TRANSIENT ISCHEMIC ATTACK Clinical F e a t u r e s Ischemia of the spinal cord usually occurs in the distribution of the anterior spinal artery. Because the anterior portion is supplied by a single midline artery, in contrast to the paired posterolateral vessels and their plexus-type network that supply the dorsal portion, there is no collateral circulation in cases of hypoperfusion. Anterior cord ischemia typically causes the abrupt onset of radicular or diffuse back pain, flaccid weakness, sphincter dysfunction, and a sensory level for pain and temperature with preservation of the posterior column sensations of touch and position sense (Table 85-2). Obviously, the limbs involved and the sensory level depend on the level at which the ischemia occurs. Although the region of the cord most at risk because of poor collateral circulation is T5-T7, any region of the cord can become ischemic. Sulcal artery occlusion can produce a Brown-Skquard syndrome or other partial cord syndromes, whereas sustained hypotension or aortic dissection is more likely to produce a symmetric anterior cord syndrome.

J of, Post. Medullary Septum

L

t. Radicular A.

ha1 Branch

/ .Post. Ramus -Ant.

Ramus

V I F A n t . Radicular A. Ant. Medullary A. Ant. Spinal A.

Segmental A.

-Aorta

FIG. 85-1. Arterial supply to the spinal cord. (From Sliwa JA, MacLean IC: Ischemic myelopathy: a review of spinal vasculature and related clinical syndromes. Arch Phys Med Rehabil 73:365-372, 1992, with permission.)

Chapter 85 W Vascular Disease of the Spinal Cord

I

545

Etiology

t Basilar A. Ascending Cervical A. Deep Cervical A. ostocervical trunk hyrocervical trunk

Superior Intercostal A.

Ant. Medullary A.

Ilio-lumbar A. C o m m o n I l i a c A.

L a t e r a l S a c r a l A. with Sacral Segmental Arteries

FIG. 85-2. Origin of the segmental arteries. (From Sliwa JA, MacLean IC: Ischemic myelopathy: a review of spinal vasculature and related clinical syndromes. Arch Phys Med Rehabil 73:365-372, 1992, with permission.)

Posterior arterial and venous infarctions are very rare. Venous thrombosis can produce either bland or hemorrhagic infarction of the cord. Hemorrhagic infarcts tend to be sudden in onset, of rapid progression, and associated with back pain. Nonhemorrhagic infarcts are more insidious and indolent, developing over hours to days, without back pain. Embolic occlusion of veins is sudden in onset and often painful. Venous infarctions have a wider range of presentations than arterial occlusions because of the less well-defined vascular territories. Motor or sensory dysfunction or even central cord syndromes, such as dissociated sensory loss, can be seen, and the length of cord involved can be long. Posterior artery occlusions produce motor involvement in all cases, but of a variable degree. The sensory loss also is variable and may be limited to posterior column sensation. Bowel and bladder dysfunctions are common.

Aortic disease is the most likely cause of cord ischemia, but cardiac emboli, coagulopathies, and vasculitides are also potential causes. Syphilitic aortitis was the most common cause for cord stroke in the prepenicillin era, but atherosclerosis is thought to be the most common current cause. A rare cause of arterial emboli includes fibrocartilage. Atherosclerosis can cause spinal cord transient ischemic attacks (TIAs), infarcts, and slowly progressive syndromes. Aortic dissection may cause spinal cord ischemia and typically is associated with severe pain, probably from the vascular dissection itself independent of cord effects. Although cord infarcts may occur in a typical setting of atherosclerosis and peripheral vascular disease, it may occur in rare circumstances such as focal atherosclerosis after radiation treatment of a malignancy, aortic thrombosis, or a coagulopathy from an anticardiolipin antibody. A rare cause of cord stroke is sustained hypotension in a person who is maintained in an upright position, as may occur with a drug overdose in someone seated upright. Venous thrombosis may be idiopathic or associated with any thrombotic condition. Spinal cord TIAs may result from arterial narrowing, emboli, or transiently increased venous pressure. Steal phenomenon may also cause a TIA and occurs typically with an arteriovenous malformation (AVM) but has been observed with aortic coarctation. The differential diagnosis for transient cord dysfunction must include tumors, especially epidural metastases (Table 85-3). It is hypothesized that tumors cause transient neurologic dysfunction by a steal phenomenon, by arterial compression, or by increased venous pressure. Demyelinating diseases may also cause transient neurologic dysfunction and often are associated with pain, similar to that present with ischemia. If the episode is thought to be a TIA, then the proper evaluation depends on the clinical circumstances. Evaluation

The evaluation of a spinal cord stroke or TIA should include a two-dimensional echocardiogram and probably also a transesophaged echocardiogram (Table 85-4). Whether an aortic angiogram

TABLE85-2. Features of Spinal Cord Stroke Acute back and radicular pain Flaccid leg weakness (occasionally arm and leg) Loss of pain and temperature below lesion Preservation of touch and position senses Urinary retention

TAU -3.

DifferentialDiagnosis

Spinal cord transient ischemic attack Demyelinating disease Tumor Spinal stenosis or claudication Spinal cord stroke Tumor Epidural hematoma Subdural hematoma Syringomyelia Abscess, infection Demyelination Transverse myelitis Disc herniation Arteriovenous malformation

546

Spinal Cord and Peripheral Neuromuscular Disease

Diseases of the Spinal Cord

TABLE 85-4. Evaluation of Ischemic Spinal Cord Syndromes

(Transient Ischemic Attack and Stroke) Magnetic resonance imaging of cord with and without gadolinium Coagulation studies Rapid plasma reagin test to exclude syphilis Routine and transesophageal echocardiograms Consider helical computed tomography of aorta Angiogram Vasculitis evaluation

or a spinal angiogram should be performed is determined by the clinical circumstances. Evaluations for syphilis, a coagulopathy, or a vasculitis must be considered. Magnetic resonance imaging (MRI) of the spinal cord, including a contrast examination, should be considered mandatory to exclude a tumor masquerading as ischemia. There are two main problems in diagnosing spinal TIA and stroke. First, because they are so uncommon, they are not considered on the differential diagnosis. The second problem is in confirming the diagnosis once suspected. As with cerebral TIAs, the diagnosis is made on history, risk factors, and exclusion of alternative diagnoses. Unlike cerebral strokes, cord infarcts can rarely be visualized on computed tomography (CT) and only uncommonly with MRI. Spinal angiography is available only at centers with specialized neurosurgical services, is potentially harmful, may not reveal an occlusion if the embolus has dislodged or fragmented after causing infarction, and, finally, probably will not alter therapy, making it a questionable proposition. Thus, spinal cord infarct often is a diagnosis of exclusion. Spinal angiography probably has a morbidity rate of about 5% as a result of the dye load and the small, atherosclerotic vessels involved. It should be performed in cases of suspected spinal AVMs or other conditions in which a definitive diagnosis would alter management in a tangible fashion. Aortic dissection is a life-threatening diagnosis and, if considered possible, should be excluded with a CT angiogram (helical CT). Venous infarcts may occur in the setting of severe systemic disorders or with AVMs.

Treatment

Treatment for cord ischemia presumably is identical to that of cerebral ischemia, but no data exist. The risk of reembolization should be reduced by using anticoagulants for cardiac emboli and aspirin when atherosclerosis is the presumed mechanism. Treatment of any other identified condition (e.g., vasculitis, hypercoagulable state) should be implemented. There are no data to support or counter the use of heparin in an acute infarct or shortly after a TIA. The increased risk of hemorrhage into such a small structure as the spinal cord precludes its use except for treating a known thrombotic or cardiac embolic disorder. When the cause of stroke is an aortic dissection, this should be addressed as soon as possible. Obviously, these patients are the most at risk from surgery or cautious waiting. The prognosis for cord stroke is unclear. As with strokes in the cerebral circulation, the prognosis is highly variable and unpredictable in any particular patient. In one series of eight cases, the patients who survived were all able to walk out of the hospital. However, a different series reported significantly worse results, with most patients making little improvement and remaining unable to walk. Almost all patients in the second study suffered chronic limb pain for several months.

HEMORRHAGES AND VASCULAR MALFORMATIONS Epidural Hematomas

Spontaneous hematomas into the epidural space occur more often than those into the subdural space because of their differences in vascularity. They both cause severe localized pain at the site of the hemorrhage, followed shortly by radicular pain. A few hours to a few days later, focal spinal cord deficits develop, which include paraparesis, quadriparesis, a sensory level deficit, and bladder dysfunction. Syndromes such as the Brown-SCquard syndrome may also occur. Most patients with spontaneous hematomas have a bleeding diathesis caused by excessive anticoagulation, liver failure, or use of antiarthritic drugs, which interfere with platelet function. The ictus may be triggered by sudden major changes in intraabdominal or intrathoracic pressure but may also be precipitated by mundane activities such as straining to defecate or calisthenics. Epidural hematoma is also a feared complication of lumbar puncture in patients with coagulopathies. One recent study suggests that this is quite unlikely, however. lntradural Hematomas

Subdural hematomas may localize to any level of the cord but tend to be rostral and dorsal. In contrast, epidural hematomas are mostly anterior. The neurologic clinical features are similar for subdural and epidural hematomas, making a clinical distinction difficult before imaging. Progression of deficits is the rule until the bleeding abnormality is corrected and the clot evacuated. The differential diagnosis is that of a rapidly progressive, painful cord syndrome. This includes sudden disc herniation, epidural cord compression from cancer, spinal cord ischemia, arterial dissection, epidural abscess, intraparenchymal tumor, and cyst. If the patient is evaluated when the pain is the only symptom, then an epidural or subdural hematoma should be considered only if a bleeding abnormality is known. Because deficits progress over hours in the presence of a coagulopathy and outcome depends on the severity and duration of the deficits, this must be considered a neurosurgical emergency. An immediate MRI scan is the diagnostic test of choice while the coagulopathy is being reversed, followed by an emergency surgical decompression. Dural Arteriovenous Malformation

Spinal AVMs are anatomically divided into intradural and nonintradural. Intradural AVMs can present with subarachnoid hemorrhage (SAH) or with progressive neurologic deficits. Dural AVMs tend to occur in patients in their fifth and sixth decade, whereas intradural AVMs occur in patients 10 to 25 years old. Dural AVMs occur near the nerve root sheath and, unlike most other spinal cord vascular syndromes, tend to be slowly progressive and may not be painful. Dural AVMs are more common in older men than in women. The symptoms vary, depending on location. The legs are the most affected. Sensory levels, paraparesis, bladder dysfunction, and radicular pain are common. Diagnosis is difficult because of problems of imaging sensitivity. A careful dorsal myelogram is more sensitive than a spinal MRI scan, but even so an AVM may be missed. Spinal angiography is the most sensitive test.

Chapter 85

The differential diagnosis of a progressive cord syndrome in older patients must include demyelinating diseases and tropical and familial spastic paraparesis. When the signs are primarily motor, then motor neuron disease or a peripheral neuropathy is considered. Depending on the rapidity of progression, a cord tumor must be excluded. A ruptured spinal AVM causes severe spinal and radicular pain at the site of rupture followed by the usual signs of an S A H , meningismus and obtundation. If the history of pain is not obtained, a distinction from the usual cause of SAH, namely a ruptured berry aneurysm, cannot be made. Spinal AVMs make up only a small fraction of the total of S A H but should be considered when the cerebral angiogram is unrevealing, especially if a history is obtainable and points to a focal spinal onset. Because these malformations may rebleed, identification and treatment are important. There appears to be a predilection for SAH from spinal AVMs to affect women, particularly in pregnancy. Both subdural and dural AVMs may induce slowly progressive cord syndromes and must be considered in cases of otherwise unexplained cord disease. Weakness and sensory changes in the legs are the most common presenting features, rather than pain, as is true of other vascular disorders of the spinal cord. Pain may be present, either early in the course or on a chronic basis, but has no particular features to distinguish it from the more common low back pain radicular syndromes. Bladder and sexual dysfunction may also occur. Spontaneous thrombosis of spinal cord veins draining in intradural AVM, a rare phenomenon, is known as the FoixAlajouanine syndrome. It may lead to slow or rapid spinal cord dysfunction. This has recently been described with intracranial dural AVMs draining into spinal veins but is typically seen with spinal intradural AVMs. AVMs of the body may be associated with cord AVMs, as in the Klippel-Trenaunay-Weber syndrome. In this syndrome a cutaneous angioma may be accompanied by a spinal cord AVM. Symptoms tend to occur in older patients, although the malformations are thought to be congenital. Because diagnosis may be difficult, it is possible that presentations at younger ages are thought to be caused by laboratory-negative multiple sclerosis,

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an entity that becomes increasingly rare with age, or to other, as yet poorly defined nonvascular entities.

SUGGESTED READINGS Byrne TN, Benzel EC, Waxman S G Disease of the Spine and Spinal Cord. Oxford University Press, New York, 2000 Caplan LR, McKee A C Case records of the Massachusetts General Hospital: a 65-year-old woman with an abrupt paralysis of the legs and impairment of bladder and bowel function. N Engl J Med 324:322332, 1991 DeToffol B, Cotty P, Gaymard B, Velut S: Progressive necrosis of the conus medullaris: magnetic resonance imaging and surgical findings. Neurosurgery 26:147-149, 1990 Howard SC, Gajjar A, Ribeirio RC et al: Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia. JAMA 284~2222-2224, 2000 Katz JD, Ropper AH: Progressive necrotic myelopathy: clinical course 1-9 patients. Arch Neurol 57:355-361, 2000 Kim RC, Smith HR, Henbest ML, Choi BH: Nonhemorrhagic venous infarction of the spinal cord. Ann Neurol 15:379-385, 1984 Koenig E, Thron A, Scharder V, Dichgans J: Spinal arteriovenous malformations and fistulae: clinical neuroradiological and neurophysiological findings. J Neurol 236:26&266, 1989 Mattle H, Sieb JP, Rohner M, Mumenthaler M Nontraumatic spinal epidural and subdural hematomas. Neurology 37:1351-1356, 1987 Rosenblum B, Oldfield EH, Doppman JL, DiChira G Spinal arteriovenous malformations: a comparison of dural arteriovenous fistulas and intradural AVMs in 81 patients. J Neurosurg 67:795-802, 1987 Sandson TA, Friedman JH: Spinal cord infarction: report of 8 cases and review of the literature. Medicine 68:282-292, 1989 Satran R Spinal cord infarction. Curr Concepts Cerebrovasc Dis Stroke 22~13-17, 1987 Shephard RH: Spinal arteriovenous malformations and subarachnoid haemorrhage. Br J Neurosurg 65-12, 1992 Sliwa JA, MacLean I C Ischemic myelopathy: a review of spinal vasculature and related clinical syndromes. Arch Phys Med Rehabil 73:365-372, 1992 Wrobel CJ, Oldfield EH, DiChiro G et al: Myelopathy due to intracranial dural arteriovenous fistulas draining intrathecally into spinal medullary veins. Report of three cases. J Neurosurg 69:934-939, 1988

SECTION

2

MOTOR NEURON DISEASE

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Amyotrophic Lateral Sclerosis Jeremy M. Shefner

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor system. A complete understanding of the pathogenesis of ALS remains elusive; however, in the last decade there have been dramatic advances. Glutamate-mediated neurotoxicity has been implicated in the degenerative process, as has decreased capacity to handle oxidative stress. For approximately 10% of patients, the disease is inherited in an autosomal dominant fashion. A mutation in the gene for cytosolic Cu/Zn superoxide dismutase (SOD1) is now known to be responsible for the disease in a minority of patients with inherited disease. This mutation causes disease in a small number of patients with ALS, but its discovery has triggered investigations into a wide range of therapeutic possibilities. The recent development of a mouse model of ALS based on the human SOD mutation allows rapid screening of potential new treatments, increasing the likelihood of developing effective new treatments. For years, ALS has represented a special challenge for neurologists, who were confronted with intellectually intact, often young patients for whom only symptomatic care was available. Although treatment options are still limited, it is now clear that the disease course can be modified, both by drugs that delay the progression of disease and by active treatment of pulmonary and nutritional factors. The availability of disease-modifymg agents makes the need for early diagnosis and treatment critical. This chapter focuses on the diagnosis and care of patients with ALS. Hypotheses about the cause of the disease and detailed discussion of potential therapeutic agents are deferred.

DEFINITION ALS is defined as a disease involving progressive upper and lower motor neuron deterioration at multiple levels of the neuraxis. At presentation, patients may have signs and symptoms related to just upper motor neuron or lower motor neuron disease, but the diagnosis can be made with certainty only if both types of abnormalities are present. The World Federation of Neurology has established criteria for the diagnosis of ALS; on purely clinical grounds, a diagnosis of ALS requires the presence of both upper and lower motor neuron signs in the bulbar musculature and concurrent upper and lower motor neuron involvement in two of the three spinal regions (cervical, thoracic, and lumbosacral). Lower motor neuron signs include weakness, muscle wasting, and fasciculations; upper motor neuron signs include increased deep 548

tendon reflexes, spasticity, pseudobulbar features, extensor plantar responses, and other abnormal stretch reflexes. When patients fulfill these criteria, the physician is left with little in the way of differential diagnosis, even in the absence of confirmatory diagnostic tests. Most commonly, however, patients present with fragments of this syndrome, and the clinician must make appropriate use of neurophysiologic and radiologic tests to eliminate other possible diseases. Common initial presentations are discussed later in this chapter; in time, most patients who present with partial syndromes show spread of abnormalities, so the diagnosis becomes more obvious. However, some patients present with some features of ALS but not others and demonstrate progression that does not seem consistent with the diagnosis of classic disease. A small subgroup of patients presents with a purely spastic disorder, involving increased tone in bulbar and spinal musculature, slow and clumsy movements, but little muscle wasting or weakness. This syndrome has been named primary lateral sclerosis and was described in the 1800s shortly after the original descriptions of ALS. Almost from its initial description, there was argument about whether primary lateral sclerosis was a separate disease or an atypical presentation of ALS. It is generally believed that, in most cases, patients presenting initially with pure upper motor neuron signs eventually develop classic ALS. However, a minority of such patients appear to have disease limited to the descending cortical pathways. These patients have a more benign clinical course, with expected survival greater than 15 years. Another subgroup of patients presents with purely lower motor neuron signs; in these patients, reflexes usually are absent or reduced. Often, the presenting complaint is limited to weakness in one limb; with time, weakness spreads to involve multiple extremities. Some of these patients develop signs of upper motor neuron dysfunction and thus are classified as having classic ALS. Others remain with only lower motor neuron signs, showing increasing weakness and atrophy in multiple areas of the neuraxis. Formerly, these patients were said to have progressive muscular atrophy and were distinguished from patients with ALS on the basis of their lack of upper motor neuron signs and their slow progression. With increasing electrophysiologic sophistication, however, many of these patients are now known to have a motor neuropathy rather than an anterior horn cell disease; these patients are discussed in Chapter 89. A final group of patients are those presenting with signs limited to the bulbar musculature. Usually, by the time these patients are

Chapter 86

seen, both upper and lower motor neuron signs are seen together; most often, speech is spastic, and fasciculations of the tongue are obvious. Historically, this presentation was called progressive bulbar palsy and was distinguished from classic ALS. However, it is now generally believed that these patients will develop classic disease, and their clinical course is indistinguishable from that of other patients with ALS.

EPIDEMIOLOGY ALS is a rare disease. Its incidence of 1.5 in 100,000 population is fairly constant worldwide, except for some specific foci of higher incidence that probably represent toxic exposure. In the United States, approximately 5000 patients are diagnosed with ALS every year. Average lifespan after diagnosis is 3 to 5 years, so that there are approximately 20,000 patients living with ALS in the United States. Men are more likely to contract the disease than women, with recent studies suggesting a male-to-female ratio of about 1.5, except in familial disease, where the ratio is 1:1. In general, ALS is a disease of middle to late life. Although cases have been documented of onset in the teenage years, most studies show the average age of onset ranging from 55 to 60 years. The incidence appears to rise steadily until approximately age 65 and then declines slowly. The incidence does not vary according to race, environment, or occupation. Approximately 10Y0 of patients report a family history of ALS, most often in an autosomal dominant pattern. In 1993, a point mutation in the gene for SODl was discovered. Subsequently, many other point mutations in the same gene have been identified. Although there is some variability in patients with identical mutations, it is clear that specific mutations are associated with more rapid or more slowly progressive disease. Other than rate of progression, however, patients with familial ALS from an identified mutation are indistinguishable from those with sporadic disease. The mechanism by which mutations in SODl produce disease is still unclear. However, recent studies have shown that mice with a normal complement of murine SODl who are genetically modified to overexpress the human mutant gene develop a motor neuron disease resembling ALS. This clearly implies that protein coded by the mutant gene exerts a toxic effect because these mice do not have an SODl deficiency. As mentioned earlier, in some areas in the world the incidence of ALS is much higher than in the United States. On Guam, a small peninsula in Japan, and parts of New Guinea, incidence rates are up to 100 times higher than elsewhere in the world. Many studies have attempted to determine why these areas have such high rates of U S ; the most likely cause seems to be a toxin in the food supply.

CLINICAL FEATURES Although patients with classic ALS involving both the extremities and the bulbar musculature present with a very characteristic clinical picture, most patients with early disease have focal signs and symptoms. The most common initial symptom is that of arm weakness; about one half of all patients with ALS present in this fashion. A wrist drop is a characteristic early sign, often noted concurrently with intrinsic hand muscle wasting. For unclear reasons, flexor compartment forearm muscles usually are affected later in the disease. Because of this asymmetry of forearm involvement,the hand often assumes a clawed posture. The disease usually spreads regionally, going from the distal to the proximal

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arm; biceps and deltoid muscles usually are affected before the triceps. About one quarter of patients present with lower extremity symptoms, most commonly unilateral foot drop. As in the upper extremity, weakness tends to spread regionally, first to more proximal muscles in the same leg and then to the opposite leg before ascending to involve the arms. Most of the remaining patients present with symptoms of bulbar dysfunction or bulbar dysfunction in combination with other symptoms. Changes in the clarity of speech often are the first bulbar symptom, with difficulty swallowing also noted early. Patients notice that telephone communication is more difficult and often report that speech is more slurred late in the day. Swallowing liquids becomes difficult before solids; carbonated and alcoholic liquids are likely to be the least well tolerated, with thicker liquids tolerated better. Most of these signs and symptoms are related to lower motor neuron dysfunction; although upper motor neuron signs may be appreciated by the examining physician early in the course of ALS, they rarely are the cause of symptoms. Occasional patients present with initial complaints of limb stiffness and slowed movements, but such patients clearly are the exception. Even as the disease progresses and upper motor neuron signs become more apparent, lower motor neuron loss continues to be the most important factor affecting disability. Other less common presentations of ALS are isolated respiratory failure and diffuse fasciculations. Fasciculations are a common symptom in the general population and can precipitate a visit to a neurologist. In the absence of clear signs of motor neuron loss, however, fasciculations are almost never a harbinger of ALS. Physical examination of patients with isolated fasciculations usually is sufficient to provide reassurance. Electromyography (EMG) documents the presence of fasciculations but cannot distinguish between those that are benign and those that are associated with ALS. Muscle cramps are commonly reported by patients but almost always in association with significant upper motor neuron disease; they are not usually seen in otherwise normal limbs. A number of symptoms should make the physician doubt the diagnosis of ALS. Although end-gaze nystagmus and mild abnormalities of rapid eye movements can be seen, diplopia or vertigo are extremely uncommon. Vague sensory symptoms often are reported by patients, but objective sensory loss is rare and suggests alternative or concurrent disease processes. Often patients complain of a dysesthetic feeling; it is unclear whether this is a true sensory symptom or muscle soreness from overuse. Bowel or bladder incontinence is also said not to occur in ALS. However, constipation is a common complaint, perhaps related to loss of abdominal muscle tone. In addition, urinary urge incontinence often is reported, more often by women than by men. Urinary dysfunction is seen most often in two patient groups. Female patients who recall having temporary urgency incontinence after childbirth are likely to have recurrence of such symptoms. In addition, women (and occasionallymen) with a prominent upper motor neuron component to their disease may also report episodes of incontinence. In recent years, a number of carefully performed studies have yielded new information about how ALS progresses. Although patients report that periods of relative stability are interrupted by episodes of rapid deterioration, quantitative strength measurements have not confirmed these impressions. In several recent studies, patients were studied at regular intervals over a period of

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Spinal Cord and PeripheralNeuromuscular Disease W

years using a battery of tests, including quantitative measurements of individual muscle strength and pulmonary function tests of vital capacity and inspiratory and expiratory force. It was found that if measurements from local body areas were combined to produce separate scores for arms, legs, bulbar, and pulmonary performance, strength declined linearly in any given area. The rate of decline varied within the same patient for different body areas, so that, for example, pulmonary function could decrease more rapidly than lower extremity strength. However, if a certain body area declined in strength slowly initially, the decline tended to remain slow throughout the course of the disease. The observation that ALS progresses in a predictable manner within local body regions for individual patients has a number of important implications. First, it allows physicians to give patients some way to evaluate how fast they are progressing and, to some extent, what the future holds. Obviously, this information is more reassuring to slowly progressing patients, but most patients appreciate realistic appraisals of their disease course. In addition, the ability to predict with some accuracy the course of an individual patient is important in designing therapeutic trials, offering the potential to decrease the size of control groups by reducing random variability of the population. Another important recent observation is that the deficits in ALS tend to progress in a regional manner. Thus, patients presenting with distal leg weakness are likely to experience proximal spread of weakness or symptoms in the contralateral leg before cranial nerve or pulmonary symptoms are noted. Along with the observation that different body regions progress at different rates, the phenomenon of regional spread suggests that local conditions in the central nervous system affect the course of the disease.

LABORATORY EVALUATION AND DIFFERENTIAL DIAGNOSIS Fully established classic ALS necessitates little in the way of laboratory support. However, in patients who present with focal complaints, a wide differential diagnosis must be considered. Compressive spinal and root disorders must be ruled out in patients without bulbar signs; concurrent cervical myelopathy with multiple root entrapments can produce a syndrome of combined upper and lower motor neuron dysfunction that is very difficult to distinguish from ALS. Clinically, the presence of sensory symptoms should help lead to the correct diagnosis, but radiologic study is crucial. Currently, magnetic resonance imaging of the spine is the diagnostic modality of choice. Often, it is necessary to image the entire spine before concluding that a compressive syndrome is not present. For patients who present with prominent upper motor neuron signs in the bulbar musculature or the extremities, such entities as multiple strokes, mass lesions, and multiple sclerosis must be considered. Magnetic resonance imaging of the head in such patients is indicated and usually is a sufficient tool to rule out these diseases. Historically, lumbar puncture has been performed frequently on patients with a probable diagnosis of ALS. Extremely high cerebrospinal fluid protein levels occasionally led to an unsuspected diagnosis of spinal cord compression, and the possibility of infection was frequently discussed. With improved radiologic modalities, however, the utility of lumbar puncture in patients

Motor Neuron Disease

with classic signs has declined, and it is not necessary to perform this test routinely. Blood tests do not play a major role in the diagnosis of classic ALS. However, some patients may present with only lower motor neuron signs, early age of onset, or other atypical features such as superimposed extrapyramidal or cerebellar signs. Such patients must undergo specific laboratory tests based on their particular presentation. In patients who present primarily with lower motor neuron signs, the differential diagnosis includes motor neuropathy, plexopathy, toxic exposure, metabolic dysfunction, infection, and muscle disease. The syndrome of multifocal motor neuropathy with conduction block can mimic ALS with primarily lower motor neuron involvement; diagnosis is established through careful nerve conduction studies and clinical examination. In addition, antibodies to gangliosides often are present in peripheral blood; gangliosides are an essential component of nerve membranes. Thus, blood should be sent routinely for ganglioside antibodies in patients with suspected ALS and predominant lower motor neuron signs. Details of this syndrome are discussed in Chapter 89. A screen for heavy metal intoxication often is performed but rarely contributes to the diagnosis in patients with lower motor neuron signs. Both lead and mercury intoxication has been reported to be associated with ALS-like syndromes; however, the more usual presentation of toxicity is a predominantly motor neuropathy with some sensory abnormalities but no upper motor neuron signs. Aluminum toxicity has been invoked as a possible cause of ALS in areas where the incidence of ALS is high, but evidence that it causes a significant neuropathy or ALS-like syndrome in the United States is lacking. In general, unless there is a history of prior exposure, blood and urinary screens for heavy metals are not likely to be contributory. One rare inherited metabolic disease can be mistaken for ALS. Hexosaminidase deficiency usually is a severe multisystem disease of childhood; however, occasionally it can present as late as age 40 years with a progressive disease that can closely mimic ALS. Hexosaminidase deficiency is inherited as an autosomal recessive trait, two genotypes of which have been associated with motor neuron syndromes. However, both types also involve other brain systems, often causing extrapyramidal or cerebellar signs, psychiatric disorders, and seizures. In general, screening for hexosaminidase deficiency is not warranted in patients with classic ALS presenting after age 40; however, in younger patients or in patients with atypical features, a blood test is available. Infections rarely are a source of confusion in the diagnosis of motor neuron diseases. However, a few possibilities should be kept in mind. Lyme disease, caused by the infectious agent Borreliu burgdorferi, commonly causes a neuropathy or radiculopathy as a secondary effect. Usually, this neuropathy has both sensory and motor features, but occasionally motor dysfunction is noted in isolation. In patients with a predominantly lower motor neuron syndrome who live in endemic areas, Lyme titers should be obtained; however, because the incidence of incidental positive titers is high in such patients, determination of antibody type should also be performed, and a lumbar puncture to determine whether there is central nervous system antibody production may be necessary. Human T-cell lymphotrophic virus type I (HTLV-I) is a neurotropic virus associated with a progressive spastic disorder sometimes associated with a neuropathy, making it very difficult to distinguish from ALS. If patients are from areas in which HTLV-I is endemic and have any atypical features such as back pain,

Chapter 66 W Amyotrophic Lateral Sclerosis

bladder dysfunction, or absent bulbar signs, blood and cerebrospinal fluid tests for antibodies to HTLV-I are available.

ELECCROPHYSlOLOClCFEATURES Electromyography EMG has proved to be an important tool both in establishing the diagnosis of ALS and in elucidating its pathophysiology. The abnormalities seen in ALS are similar to those seen in other forms of neurogenic disease. Evidence of ongoing denervation is derived from the presence of abnormal spontaneous activity such as fibrillation potentials. As a consequence of denervation, surviving motor axons reinnervate muscle fibers, producing characteristic abnormalities in motor unit morphology, as recorded by conventional concentric EMG electrodes and by newer techniques such as single-fiber and macro-EMG. Although the abnormalities seen in ALS resemble those present in other diseases of the anterior horn cell and motor axon, the distribution of abnormal findings and the pace of disease progression often are useful in distinguishing ALS from other diseases. Fibrillation potentials and positive sharp waves reflect activity of individual muscle fibers that have lost their synaptic contact with motor neurons. The frequency with which fibrillations are observed in ALS varies according to the amount of weakness or atrophy of the muscle being studied, the duration of the disease, and the location in the body. In addition, fibrillation potentials are more likely to be seen in certain muscle groups than in others. In the limbs, fibrillations are present more often in distal than in proximal muscles, with facial and tongue muscles being less likely than limb muscles to show fibrillations. Interestingly, fibrillations are noted in thoracic paraspinal muscles in most patients. Diagnostically, this is a useful finding because spondylosis of the thoracic spine is uncommon compared with cervical and lumbar spondylosis, and abnormalities noted in the thoracic region are thus less likely to reflect root compression. One of the most characteristic abnormalities seen in patients with ALS is the presence of fasciculations. Clinically, they are seen in most patients; electrophysiologically, they are noted almost without exception, even in sites where involuntary movements are not appreciated. However, it should be noted that clinical and electrophysiologicfasciculations may be entirely benign and that there is no way to distinguish between benign fasciculations and those that represent motor neuron disease. The changes seen in motor unit morphology in patients with ALS are qualitatively similar to those that occur as a consequence of any form of neurogenic atrophy. As anterior horn cells are lost, viable motor axons establish synaptic contact with muscle fibers that have been denervated. The electrical correlate of this process is an increase in amplitude and duration of the motor unit action potential. On average, motor unit amplitude is increased by about a factor of 4 over normal, with units in severely involved muscles having amplitudes of approximately 10 times normal and amplitudes from units in only slightly affected muscles increased somewhat less. The increase in size of individual motor unit potentials reflects reinnervation by viable motor axons after the death of other anterior horn cells. Thus, the number of functioning motor units in a given muscle should decrease with disease progression. A number of methods for estimating the number of motor units have been developed for distal muscles and have more recently

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been extended to larger proximal muscles. In general, the number of motor units present in a given muscle is estimated by determining the maximum amplitude of the compound muscle action potential and then recording potentials from many single motor units. The total number of motor units is estimated by dividing the average amplitude of the single motor unit potentials into the amplitude of the compound motor action potential. Motor unit counting is a very useful way to measure disease progression objectively. By sequential performance of this test on individual patients over time, it has become clear that there is very substantial motor unit dropout before patients report loss of strength in a muscle and before the amplitude of the compound motor action potential has declined below normal. The most rapid dropout of motor units actually occurs very early in the disease, often before a muscle is symptomatically weak. In patients whose disease follows a chronic course, motor unit counts may remain stable for a long time period after dropping to approximately 10% to 20% of normal. Nerve Conduction Studies Although many patients with A L S report vague sensory symptoms, clinical sensory examination usually is normal. Therefore, it is not surprising that routine sensory nerve conduction studies are normal or nearly normal in most patients. However, just as very careful computerized tests of sensation have shown mild alterations in multimodal sensory function in patients with ALS, precise recordings of slower conducting sensory fibers have shown frequent mild abnormalities in the compound sensory action potential. This is consistent with autopsy studies, which have found up to 30% reductions in the number of dorsal root ganglion cells. In studies of motor function, conduction velocity in patients with ALS has been shown consistently to be normal or near normal until muscle atrophy becomes extreme. However, even when motor conduction velocity is normal, distal motor latency often is prolonged. Distal latencies that are prolonged out of proportion to proximal conduction velocity is a finding often associated with dying-back neuropathies in which the terminal axon is more affected than the cell body or proximal axon. Although ALS primarily causes a motor neuronopathy, recent morphologic studies suggest a component of dying-back axonopathy.

Dlagnostlc ElectrophysSologic CrHerSa ALS is primarily a clinical diagnosis. However, EMG and nerve conduction studies can be extremely important in establishing the diagnosis when insufficient clinical evidence is available. A number of criteria for electrophysiologic diagnosis have been suggested. As in many other diseases, the rigid application of criteria often is more a hindrance than a help; however, certain guidelines should be remembered. First, evidence of muscle denervation should be diffuse; that is, fibrillation potentials and large motor units should be present in multiple muscles of multiple extremities. Most published criteria require denervation to be present in three of four areas of the neuraxis, with the four areas being bulbar, cervical, thoracic, and lumbosacral. Second, there should be no evidence of motor conduction block. A formal discussion of conduction block is beyond the scope of this chapter, but conduction block implies that there is an area of axon through

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Motor Neuron Disease

which action potentials are not conducted, even though viable axon exists both proximal and distal to that area. Third, motor and sensory conduction velocity and compound sensory action potential amplitudes should be normal or nearly so from both arm and leg. If these conditions are fulfilled, the diagnosis of lower motor neuron disease can be considered confirmed. To make a diagnosis of ALS, however, clinical evidence of upper motor neuron disease must also be present.

TREATMENT Treatment of ALS has changed dramatically in the last decade. Although disease-modifymg treatment is still limited, care has evolved from a passive and supportive model to much more active intervention. Treatments include both accepted and experimental medications to alter disease course, as well as aggressive pulmonary support and nutritional supplementation. Movement toward an active treatment approach has been facilitated by publication in 1999 of a practice parameter for the care of patients with ALS that clearly spells out the levels of care that these patients need. Currently, only one drug has been clearly demonstrated to delay progression of ALS. Riluzole has been shown in two large, randomized, placebo-controlled trials to prolong survival in patients with ALS by approximately 10%. Its mechanism of action probably is reduction of glutamate-mediated toxicity, predominantly by inhibiting release, although a postsynaptic blockade also may occur. Other drugs that inhibit glutamate transmission are under investigation. Other possible avenues of treatment include reducing oxidative stress. Vitamin E has been shown to be effective in delaying disease onset in the mouse model of ALS discussed previously; for this reason, many patients take large doses of vitamin E. Recently, mitochondrial damage has been shown to be an early event in affected motor neurons; creatine, which has a protective effect on mitochondria, has also been beneficial in the ALS mouse. Clinical trials testing this agent are under way. Other therapeutic options currently being evaluated include cytochrome oxidase inhibitors and caspase inhibitors, both of which have shown promise in the ALS mouse. It is likely that an effective treatment will involve simultaneous treatment with a combination of agents, all acting on different aspects of the degenerative cascade. One avenue of treatment that has not proved useful is the administration of human growth factors. These agents have shown promise in multiple models of motor neuron disease (although not in the transgenic ALS mouse model). However, large therapeutic trials involving human ciliary neurotrophic factor, brain-derived neurotrophic factor, and insulin-derived growth factor have all been either negative or equivocal. Although only one agent has clearly demonstrated efficacy in altering the course of ALS, multiple other therapeutic options exist. Progressive pulmonary compromise is the cause of death in most patients with ALS and the source of significant disability. Noninvasive positive-pressure ventilation can improve patient comfort in many instances and may be life sustaining. However, availability of noninvasive ventilatory support does not obviate decisions regarding permanent assisted ventilation. Although a minority of patients with ALS ultimately choose tracheostomy and permanent ventilatory support, this option should be considered carefully. With appropriate family and financial resources, patients can remain at home while on a ventilator. Before such a course is

embarked upon, extensive education of both patient and caretaker is needed. Family members often do not fully comprehend the burden of such a course of action. However, with appropriate education, maintaining ventilated patients at home can provide an acceptable quality of life. In a recent study of 24 patients who elected home ventilation, 90% reported that they would make the same decision again; approximately 50% of the patients’ care givers said they would choose such an option for themselves should the need arise. Such care is very expensive; in the same study, the average cost of home ventilation for 1 year was about $150,000.

Aggressive nutritional support is also essential; not only does bulbar weakness have the potential to limit nutritional intake, but recent studies indicate that caloric needs of patients with ALS are actually greater. Initial treatment usually consists of dietary modification; ultimately, however, placement of a gastrostomy tube usually is necessary. The timing of this intervention is important; tube placement should occur before malnutrition has developed and before there is significant pulmonary compromise. The morbidity and mortality of gastrostomy tube placement are drastically increased in patients with impaired pulmonary status; the current standard of care dictates that tube placement be considered before a patient’s vital capacity falls below 50% of predicted. Ongoing evaluation of a patient’s ability to communicate is also a necessary part of the care of patients with ALS. Many patients develop dysarthria, leading to mutism at some point in their disease. Speech therapy has been of occasional benefit in such patients; in general, patients with primarily upper motor neuron bulbar symptoms do better with speech therapy than those with lower motor neuron weakness. A trial of speech therapy probably is warranted in all patients with worsening dysarthria. When vocal language can no longer be used, a number of options can be explored, ranging from computerized voice production devices for patients who have remaining upper extremity facility to systems that use eye movements. Early attention to this issue and detailed discussion with patients are crucial because it is much easier to make an appropriate decision about the best assistive device before communication is lost. Physical and occupational therapy and well-designed prosthetic devices can dramatically improve a patient’s functional status. Focal weakness can produce early gait problems, often caused by unilateral or bilateral foot drop. Ankle-foot orthoses can return many patients’ gait to almost normal. In patients with more significant lower extremity weakness, the involvement of a physical therapist with experience in neurologic disorders is essential. Although it may seem trivial, the right kind of cane or an appropriately modified walker can make a major difference in the life of a patient whose livelihood depends on the ability to ambulate. Similarly, disability from focal upper extremity weakness often can be treated with supports, braces, or modified instruments of daily living such as spoons or toothbrushes. A close association with a skilled occupational therapist gives patients assistance that neurologists by themselves cannot give. Spasticity is another symptom that can be treated with available agents. This is obviously more of a problem for patients with prominent upper motor neuron disease; although this is the case for the minority of ALS patients, for some it can be a significant problem. Baclofen is the most commonly used antispasticity drug for other neurologic disorders; however, its benefit is variable in patients with ALS. The major reason for this

Chapter 87

appears to be that dosages high enough to produce reductions in spastic tone also produce significant added weakness in this patient population. Tizanidine alone or in combination with baclofen may be more effective than baclofen alone in some patients. Benzodiazepines are occasionally useful but must be used very carefully in this group of patients already at risk for respiratory decompensation. Dantrolene, the other drug commonly used to treat spasticity, is almost always associated with unacceptable weakness in patients with ALS. An extremely important and overlooked component of the treatment of patients with ALS is attention to the patient’s emotional well-being. ALS is a devastating disease, producing progressive disability and dependence in the absence of intellectual deterioration. Depression in patients with ALS is nearly universal and is at least partially treatable. Patients and family members nearly always benefit from referral to local support groups and often from individual therapy. In addition, pharmacologic treatment often is useful. In the past, most commonly used antidepressant medications were associated with side effects such as fatigue and dry mouth that were particularly distressing to patients with ALS, but the recently developed selective serotonin reuptake inhibitors do not have these side effects and are much faster-acting than older antidepressants.

SUGGESTED READINGS Bed M F Mitochondrial dysfunction in neurodegenerative diseases.

W

Spinal Muscular Atrophy

SSJ

Cookson MR, Shaw PJ: Oxidative stress and motor neuron disease. Brain

Pathol 9:165-186, 1999 Ferrante RJ, Browne SE, Shinobu LA et al: Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 69:2064-2074, 1997 Miller RG, Rosenberg JA, Gelinas DF et al: Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 52:1311-1323, 1999 Moss AH, Casey P, Stocking CB et al: Home ventilation for amyotrophic lateral sclerosis patients: outcomes, costs, and patient, family, and physician attitudes. Neurology 43:438-443, 1993 Munsat T, Andres PL, Finison L et al: The natural history of motoneuron loss in amyotrophic lateral sclerosis. Neurology 3k409-413, 1988 Rosen DR, Siddique T,Patterson D et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:5942, 1993 Rothstein JD, Martin LJ, K u n d RW Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 3261464-1468, 1992

Shaw PJ, Eggett CJ: Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 247(Suppl 1):117-27, 2000

Shefner J M Motor unit number estimation in human neurological diseases and animal models. Clin Neurophysiol 112:955-964,2001 Tyler HR, Shefner JM: Amyotrophic lateral sclerosis. pp. 169-216. In Vinken P, Bruyn G, Klawans H (eds):Handbook of Clinical Neurology. Vol. 59. Elsevier, New York, 1991

Biochem Biophys Acta 1366:211-223, 1998

87

Spinal Muscular Atrophy Kathryn J. Swoboda, Kathryn N. North, and Linda A. Specht

Spinal muscular atrophy (SMA) is a lower motor neuron disorder characterized by degeneration of the anterior horn cells in the spinal cord and bulbar motor nuclei. The clinical hallmarks of the disorder are symmetric muscle weakness and atrophy of limb muscles with variable bulbar involvement and tremor and supporting electrophysiologic and pathologic evidence of motor denervation. The most common form of the disorder is linked to chromosome 5q13 and inherited in an autosomal recessive fashion. About 96% of patients with a classic presentation have a homozygous deletion of the telomeric copy of the survival motor neuron gene on chromosome 5q. In the Western world, acute SMA is the most common genetic cause of infantile death and is the second most common serious neuromuscular disorder after Duchenne muscular dystrophy. Patients most often present in infancy and early childhood, and the disease is categorized into subtypes based on severity of weakness. Life expectancy is markedly reduced and varies greatly between and within types. Other disorders called SMA in the literature but not linked to 5q are clinically and molecularly heterogeneous. These include an X-linked infantile form of SMA, SMA with severe early diaphrag-

matic involvement (SMA with respiratory distress, or SMARDl), and X-linked spinobulbar muscular atrophy, or Kennedy’s disease. These non-5q-linked SMAs are mentioned briefly.

CLINICAL FEATURES Degeneration of the anterior horn cells in the spinal cord and lower brainstem results in a lower motor neuron pattern of weakness and muscle wasting in the limbs and tongue. The pattern of weakness in the limbs is symmetrical, more proximal than distal, and more severe in the lower limbs. A “piano-playing” tremor of the outstretched hands is prominent in many patients. The muscles of the trunk are involved with intercostal weakness, and bulbar involvement results in atrophy and fasciculation in the tongue. Deep tendon reflexes are decreased or absent, and plantar reflexes, if present, are downgoing. Typically, the diaphragm is spared until late in the disease (in severe forms), and there is no involvement of cardiac or smooth muscle. Clinical exclusion criteria for SMA include the presence of sensory disturbance, intellectual impairment, or sphincter disturbance. A subset of severely affected infants are born with proximal joint contradures

Chapter 87

appears to be that dosages high enough to produce reductions in spastic tone also produce significant added weakness in this patient population. Tizanidine alone or in combination with baclofen may be more effective than baclofen alone in some patients. Benzodiazepines are occasionally useful but must be used very carefully in this group of patients already at risk for respiratory decompensation. Dantrolene, the other drug commonly used to treat spasticity, is almost always associated with unacceptable weakness in patients with ALS. An extremely important and overlooked component of the treatment of patients with ALS is attention to the patient’s emotional well-being. ALS is a devastating disease, producing progressive disability and dependence in the absence of intellectual deterioration. Depression in patients with ALS is nearly universal and is at least partially treatable. Patients and family members nearly always benefit from referral to local support groups and often from individual therapy. In addition, pharmacologic treatment often is useful. In the past, most commonly used antidepressant medications were associated with side effects such as fatigue and dry mouth that were particularly distressing to patients with ALS, but the recently developed selective serotonin reuptake inhibitors do not have these side effects and are much faster-acting than older antidepressants.

SUGGESTED READINGS Bed M F Mitochondrial dysfunction in neurodegenerative diseases.

W

Spinal Muscular Atrophy

SSJ

Cookson MR, Shaw PJ: Oxidative stress and motor neuron disease. Brain

Pathol 9:165-186, 1999 Ferrante RJ, Browne SE, Shinobu LA et al: Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 69:2064-2074, 1997 Miller RG, Rosenberg JA, Gelinas DF et al: Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 52:1311-1323, 1999 Moss AH, Casey P, Stocking CB et al: Home ventilation for amyotrophic lateral sclerosis patients: outcomes, costs, and patient, family, and physician attitudes. Neurology 43:438-443, 1993 Munsat T, Andres PL, Finison L et al: The natural history of motoneuron loss in amyotrophic lateral sclerosis. Neurology 3k409-413, 1988 Rosen DR, Siddique T,Patterson D et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:5942, 1993 Rothstein JD, Martin LJ, K u n d RW Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 3261464-1468, 1992

Shaw PJ, Eggett CJ: Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 247(Suppl 1):117-27, 2000

Shefner J M Motor unit number estimation in human neurological diseases and animal models. Clin Neurophysiol 112:955-964,2001 Tyler HR, Shefner JM: Amyotrophic lateral sclerosis. pp. 169-216. In Vinken P, Bruyn G, Klawans H (eds):Handbook of Clinical Neurology. Vol. 59. Elsevier, New York, 1991

Biochem Biophys Acta 1366:211-223, 1998

87

Spinal Muscular Atrophy Kathryn J. Swoboda, Kathryn N. North, and Linda A. Specht

Spinal muscular atrophy (SMA) is a lower motor neuron disorder characterized by degeneration of the anterior horn cells in the spinal cord and bulbar motor nuclei. The clinical hallmarks of the disorder are symmetric muscle weakness and atrophy of limb muscles with variable bulbar involvement and tremor and supporting electrophysiologic and pathologic evidence of motor denervation. The most common form of the disorder is linked to chromosome 5q13 and inherited in an autosomal recessive fashion. About 96% of patients with a classic presentation have a homozygous deletion of the telomeric copy of the survival motor neuron gene on chromosome 5q. In the Western world, acute SMA is the most common genetic cause of infantile death and is the second most common serious neuromuscular disorder after Duchenne muscular dystrophy. Patients most often present in infancy and early childhood, and the disease is categorized into subtypes based on severity of weakness. Life expectancy is markedly reduced and varies greatly between and within types. Other disorders called SMA in the literature but not linked to 5q are clinically and molecularly heterogeneous. These include an X-linked infantile form of SMA, SMA with severe early diaphrag-

matic involvement (SMA with respiratory distress, or SMARDl), and X-linked spinobulbar muscular atrophy, or Kennedy’s disease. These non-5q-linked SMAs are mentioned briefly.

CLINICAL FEATURES Degeneration of the anterior horn cells in the spinal cord and lower brainstem results in a lower motor neuron pattern of weakness and muscle wasting in the limbs and tongue. The pattern of weakness in the limbs is symmetrical, more proximal than distal, and more severe in the lower limbs. A “piano-playing” tremor of the outstretched hands is prominent in many patients. The muscles of the trunk are involved with intercostal weakness, and bulbar involvement results in atrophy and fasciculation in the tongue. Deep tendon reflexes are decreased or absent, and plantar reflexes, if present, are downgoing. Typically, the diaphragm is spared until late in the disease (in severe forms), and there is no involvement of cardiac or smooth muscle. Clinical exclusion criteria for SMA include the presence of sensory disturbance, intellectual impairment, or sphincter disturbance. A subset of severely affected infants are born with proximal joint contradures

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and ventilator dependency and have documented sensory nerve involvement. Extraocular muscle weakness, marked facial weakness, ptosis, cardiac involvement, and loss of hearing or vision are not associated with 5q SMA (Table 87-1).

CLASSIFICATION AND SUBTYPES Classic Spinal Muscular Atrophy

Childhood-onset SMA usually is classified into three groups on the basis of age of onset and clinical severity (Table 87-2). The acute infantile form (Werdnig-Hoffmann, or type I) presents before 6 months of age. Many infants are normal to examination during the first few months of life, although some are noted to be hypotonic at birth or to have exhibited decreased fetal movements. Children with this form of the disorder never attain the ability to sit. Progression to generalized paralysis of the limbs and trunk is rapid, and bulbar involvement, with fasciculations and wasting of the tongue, is a useful diagnostic sign. Although the infant remains visually alert, feeding difficulties, respiratory failure with aspiration, and recurrent respiratory infections usually lead to death by 2 years of age. An intermediate form of SMA (type 11, or chronic WerdnigHoffmann disease) has its onset between 6 and 18 months of age. These children may be assessed as normal during the first 6 months of life and attain the ability to sit. Subsequent motor development is arrested, and they are unable to stand unassisted. Bulbar dysfunction is less marked, and tongue fasciculation is less common than in type I, but the peripheral tremor may be more marked. As in type I, survival is linked to respiratory function, and death usually is secondary to respiratory infection or progressive restrictive pulmonary disease. Prolonged survival into the third or fourth decade and beyond, with or without the need for artificial ventilation, may occur in this group of patients. The mildest form of childhood-onset SMA (KugelbergWelander, or type 111) usually presents between 18 months and 17 years of age with proximal symmetrical muscle weakness, predominantly affecting the legs. These patients usually, but not always, retain the ability to walk, although joint contractures and scoliosis may become evident. Bulbar function usually is preserved, and these patients survive into adulthood. As in type 11, tremor is common and may be the presenting feature. This form of SMA is H TABU87-1.

Diagnostic Criteria of Spinal Muscular Atrophy

Inclusion Criteria Symmetrical muscle weakness, proximal greater than distal Trunk muscles involved, with poor head and trunk control in severe cases Intercostal weakness but sparing of the diaphragm Evidence of denervation, either clinical (fasciculations or tremor) or laboratory (EMG or muscle biopsy) Exclusion Criteria Clinical Central nervous system dysfunction Arthrogryposis Abnormalities of other organ systems Sensory loss Severe facial or extraocular muscle weakness Hypertonia or hyperreflexia

Laboratory High creatine kinase Aminoaciduria Organic aciduria Hexosaminidase A or B deficiency Monoclonal gammopathy Biopsy evidence of lipid or glycogen storage disease or mitochondrial abnormality Abnormally slow nerve conduction velocitv ~~

(Adapted from Munsat TL Workshop report. International SMA Collaboration. Neuromuscul Disord 1 3 1 , 1990, with permission.)

TABLE 87-2. Classification of Spinal Muscular Atrophy TVDe

Onset

0 (arthrogryposis)

Prenatal

I (acute) I1 (intermediate) 111 (mild) IV (adult)

Missed Milestones

Ane at Death 0-6 months

48 months

Never breathe independently Never sit Never stand

>18 months Adulthood

-

Adult Adult

Birth-6 months

Usually <2 years s2 years

(Adapted and modified from Munsat TL: Workshop report InternationalSMA Collaboration. Neuromuscul Disord 1:El, 1990, with permission.)

the most difficult to differentiate from the muscular dystrophies, and diagnosis may rely on evidence of denervation on electromyography (EMG) and muscle biopsy. Since genetic testing for survival motor neuron gene deletion has become readily available, an even broader spectrum of phenotypes have been defined for 5q-linked SMA, including a severe infantile form with congenital joint contractures and ventilator dependency from birth, sometimes called SMA type 0, and a milder adult-onset form called SMA type IV.

Other Forms Other forms of SMA are much more heterogeneous clinically and genetically. They do not conform to the original diagnostic criteria in Table 87-1 used to define linkage of classic SMA to chromosome 5q. Familial and sporadic forms have been identified that present with muscle weakness and evidence of denervation. Childhood forms include diffuse denervation in association with ophthalmoplegia, central nervous system malformation, olivopontocerebellar hypoplasia, pyramidal tract signs, or sensory involvement. A segmental or focal form results in localized weakness, particularly of the shoulder and hand, which may be associated with tremor. It is usually sporadic and briefly progressive, resulting in a fixed, localized deficit; progressive cases have been reported. Segmental atrophy of the spinal cord may be seen on magnetic resonance imaging. The most well-characterized form of non-5q SMA is Kennedy syndrome, or X-linked spinobulbar muscular atrophy (SMAXl). This X-linked recessive disorder typically has its onset in the third decade, with slow progression and involvement of the facial and bulbar muscles in addition to wasting of the proximal and, in some cases, distal musculature. There is usually asymmetry of clinical signs, with consistent and abundant fasciculations predominantly in the perioral muscles and intention tremor in the limbs. Striking gynecomastia is the first clinical sign in association with decreased fertility. Sensory abnormalities have been reported in some patients. The gene has been characterized at Xq12 and is an androgen receptor gene with an expansion of a tandem trinucleotide repeat (CAG) in the first exon. A more severe X-linked infantile form of SMA has been identified, designated X-linked infantile spinal muscular atrophy, with multiple congenital joint contractures and death in infancy. Linkage for this disorder has been established to Xpl1.3-qi 1.2. Another variant of infantile SMA is manifested by severe diaphragmatic involvement with early respiratory distress and eventration of the diaphragm. Another phenotypic clue in this disorder is the predominance of upper limb rather than lower limb weakness. The gene for this disorder was recently identified on

Chapter 87

chromosome 1lq13-21 and encodes immunoglobulin mubinding protein 2. This disorder is designated SMARD1, for SMA with respiratory distress type I. Other adult-onset forms of spinal muscular atrophy are also well described, including 12q-linked autosomal dominant distal spinal muscular atrophy and autosomal dominant adult-onset (Finkel-type) spinal muscular atrophy, characterized by proximal predominant weakness.

NATURAL HISTORY AND CONTROVERSIES Russman et al. studied 141 patients with SMA with diagnosis based on onset of weakness before 18 years, evidence of denervation on EMG or muscle biopsy, normal nerve conduction velocities, and no sensory deficits. All familial cases were recessive. Their results challenged the current classification system with regard to the prognostic implications of age of onset relative to function, rational rehabilitation, and life expectancy. Thirty-nine percent of their patients had type I disease (weakness noted before 6 months of age); 73% of patients had been able to sit independently, and 8% could walk independently at one time. One patient in this group was 3 1 years old. Some children attained new milestones after diagnosis. Forty-four percent had type I1 disease (onset between 7 and 24 months) with age range at evaluation from 1 to 38 years; 43% of this group had been able to walk at some time. Age of onset criteria have proved to be too arbitrary and too dependent on observer variability; ultimate prognosis correlates better with the best milestone achieved. In our experience, it is difficult to prognosticate for an infant with Sh4A who is not yet sitting unless he or she already has significant intercostal muscle weakness. Although most such infants never achieve the ability to sit, and they succumb to their illness by age 2 years, others eventually learn to sit during the latter half of their first year and go on to exhibit a stable course over many years or decades. The second important observation in Russman et al.’s study was that although strength in patients with SMA did not increase with age, their absolute strength did not decrease. However, cross-sectional data convincingly revealed loss of function with time, independent of age of onset. This observation is consistent with reports from families and clinical observation. It has been suggested that SMA may not be a degenerative disease resulting from the death of anterior horn cells. An alternative hypothesis is that a fetal defect of the anterior horn cell is responsible for SMA and that the defect is limited and develops later in patients with late-onset disease. However, more recently, the availability of genetic testing and identification of affected siblings early in their clinical course, longitudinal studies of motor unit number estimation in affected infants and children, and data from genetic animal models of the disorder support the premise that progressive lower motor neuron loss occurs variably in an acute or subacute process depending on the SMA subtype.

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In 1990, the genetic abnormality in the recessive forms of SMA was localized to chromosome 5qll.2-13.3, and the locus was subsequently narrowed to 5q13. All three types of childhood Sh4A are linked to the same locus in a number of studies. Analysis of 5q SMA families supports the view that with certain exceptions, there is little phenotypic intrafamilial variability, although occasional sibling pairs may have divergent courses and different survival characteristics, especially in the SMA I1 and 111 subtypes. If the index patient satisfies the inclusion criteria for SMA, more than 90% of all SMA families appear to be linked to chromosome 5q. The proportion of acute SMA families (type I) linked to 5q13 is higher and exceeds 98%. Prenatal molecular diagnosis for 5q-linked SMA is now routinely available via chorionic villous biopsy or amniocentesis. With polymorphic markers close to the SMA locus, more than 99% of 5q-linked families are informative. Appropriate allowances must be made in genetic counseling for sporadic cases caused by noninherited factors and for linkage heterogeneity or misdiagnosis. In 1995, the survival motor neuron gene (or SMN gene) was identified as the cause of 5q SMA, and mutation analysis was carried out in 229 patients with 5q SMA types I, 11, and 111. The chromosomal region including the survival motor neuron genes is complex, characterized by a 500-kb inverted duplicated region containing several nearly identical genes, present in zero to four copies per chromosome. The instability of this region leads to a higher probability of gene deletion and conversion events. Survival motor neuron 1 (SMN1) is the more telomeric of the genes and varies from its centromeric copy, SMNZ, by a critical base pair change in exon 7 that results in alternative splicing and an altered protein product. Variable size deletions can cause de novo mutations via unequal crossing over during paternal meiosis. This appears to be the most common mechanism in SMA type I. Alternatively, unequal crossing over can result in hybrid genes with their origin initiating in SMN2, effectively converting an SMNl to an SMN2 copy on that chromosome. Between 94% and 98% of Sh4A types I to I11 have homozygous deletions of the telomeric copy of the survival motor neuron gene SMN1. Compound heterozygosity for a deletion and point mutation account for about 2% to 4% of cases. The remaining 2% to 4% of cases are unlinked to 5q. The protein is widely expressed and plays a role in pre-messenger RNA processing and spliceosomal ribonuclear protein biogenesis and assembly. The precise mechanisms leading to the specificity of lower motor neuron involvement and cell death in SMA remain unknown. Recent evidence suggests that the number of SMNZ gene copies modifies disease severity. Overexpression of SMN2 genes in a knockout transgenic mouse model of SMA rescues the animals from nerve cell death. A gene that plays a role in motor neuron apoptosis maps close to but outside the critical SMA region (neuronal apoptosis inhibitory gene, or N A P ) . Parts of this gene are deleted in approximately 67% of type I SMA chromosomes, suggesting that this gene may also contribute to the SMA phenotype, although the role it plays, if any, remains uncertain.

~~

GENETICS AND DIAGNOSTIC TESTING SMA is inherited in an autosomal recessive pattern. There is no evidence of effect of birth order, parental age, social class, or seasonal influences. Carriers are normal clinically and on laboratory testing. SMA has an incidence of 1 in 6000 to 1 in 20,000 live births, with a carrier frequency of 1 in 50 to 80. In some Muslim countries, because of the high rate of consanguinity, the disease incidence is at least 40 times greater.

DIAGNOSIS Although the clinical phenotype in SMA often is fairly stereotyped in the more severe forms, it can be more difficult in the childhood and adult-onset cases. Diagnostic confirmation of SMA formerly relied primarily on electrophysiologic and muscle biopsy findings. In the appropriate clinical setting, most cases can now be quickly and easily diagnosed by DNA testing. Now, EMG testing and

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Motor Neuron Disease

muscle biopsy are reserved for cases in which the clinical phenotype is uncertain or DNA testing is negative. EMG typically shows evidence of denervation with fibrillationsand positive sharp waves. The finding most specific for the disease is the decreased recruitment of long-duration higher-amplitude units firing at increased frequency, consistent with a neurogenic process. Nerve conduction studies usually are normal, although conduction velocity in motor nerves may be decreased in the more severely affected children, and rare infants with congenital arthrogryposis have had documented sensory nerve involvement. Muscle biopsy demonstrates denervation atrophy with large patches of small atrophic fibers and residual fibers that are normal or increased in size (Fig. 87-1). Fiber-type grouping is evident on adenosine triphosphatase stains and is caused by collateral reinnervation. Mild elevations of creatine kinase (up to five times normal levels) and aldolase may be present in severe cases. It should be noted that creatine kinase levels may be transiently elevated in normal newborns, limiting the value of this test as a diagnostic finding in early infancy. Infants with SMA type I may manifest a secondary disorder of metabolism, with abnormal excretion of fatty acid oxidation metabolites in response to fasting or systemic illness. The presentation of acute infantile SMA must be differentiated from other causes of “the floppy infant,” which generally have different prognostic implications. In this setting, the presence of tongue fasciculations may be the most helpful clinical diagnostic feature supporting involvement of bulbar anterior horn cells. Atonic cerebral palsy usually is associated with upper motor neuron signs such as hyperreflexia and cognitive impairment. Primary muscle disorders such as the congenital myopathies, congenital muscular dystrophy, congenital myasthenia gravis, and infantile mitochondrial myopathies may be differentiated by family history, biochemistry, EMG, or muscle biopsy. Disorders of the peripheral nerves include hypomyelinating neuropathies and

polyneuritis; in such cases, nerve biopsy may also be needed. Other disorders of infancy to be considered include botulism, poliomyelitis, spinal cord transection or injury, or hypotonia associated with other genetic disorders such as Marfan’s or Prader-Wdi syndrome. There are other genetic syndromes in which involvement of the anterior horn cells may be a component and in which muscle biopsy may show a similar pathology to Werdnig-Hoffmann disease. Additional clinical features such as marked facial weakness, cognitive dysfunction,the presence of other exclusion criteria (Table 87-l), and nonlinkage to chromosome 5q should alert the clinician to consider alternative diagnoses. Later-onset SMA, especially forms without bulbar involvement, may present a more difficult diagnostic dilemma. Slowly progressive, symmetric proximal muscle weakness may be similar to that seen in the muscular dystrophies. EMG and muscle biopsy evidence of denervation provides the most important diagnostic clue as to the primary pathologic site. Clinical evidence of denervation may be the primary presenting feature of amyotrophic lateral sclerosis; however, this disorder is differentiated from the late-onset forms of SMA by the eventual development of upper motor neuron signs.

TREATMENT There is no specific therapy as yet for SMA, although the recent identification of compounds that can increase SMN protein in cell culture systems and genetic animal models of SMA is promising. Until then, management is limited to prevention and supportive care of associated respiratory, orthopedic, and nutritional issues. In the infantile-onset forms of the disorder, management should focus primarily on the symptomatic treatment of respiratory dysfunction and feeding difficulties. These patients are fragile and markedly hypotonic; orthopedic treatment is limited to daily range-of-motion exercises for the joints. Early implementation of

FIG. 87-1. Muscle biopsy from a patient with spinal muscular atrophy type I demonstrating denervation atrophy with residual hypertrophic fibers. (Magnification x300.)

Chapter 87

nasogastric feeds or insertion of a gastrostomy tube will minimize the risks of aspiration, ensure adequate nutrition, and facilitate the day-to-day care of the child. Noninvasive respiratory management techniques include use of continuous positive airway pressure during sleep or respiratory infections, use of an inexsufflator (cough-assist machine), supplemental oxygen, and chest physical therapy to help limit hospitalizations for pneumonia and prolong health and survival. Respiratory infections should be treated early with antibiotics. An individualized approach to severe respiratory infection or compromise should be developed with the child's family with regard to the use of artificial ventilation in the terminal stage of the illness. The aim of treatment for the later-onset or mild forms of SMA should be aimed at preserving mobility and minimizing respiratory complications, particularly restrictive pulmonary disease or pulmonary compromise caused by progressive scoliosis. Specific and early intervention can be helpful in maximizing the patient's health and potential. Physical therapy may be needed on a regular basis to minimize joint contractures and maintain mobility. The major orthopedic problems are scoliosis and hip dislocation; the age of onset and rate of progression appear to be directly related to the severity of muscle weakness. Scoliosis almost always begins in the first decade of life in types I1 and 111 SMA, and the curves invariably progress over time. In patients who are unable to walk, spinal bracing may improve sitting stability. The decision regarding operative intervention (spinal arthrodesis) is easier to make if frequent pulmonary function studies have been done to establish a profile for the individual patient. In our clinic, surgery is recommended for patients more than 10 years of age who have a flexible curve of 40 degrees or more and a forced vital capacity of more than 40%. Because worsening is invariable, the decision to intervene early should maximize the eventual result. Proximal muscle weakness also predisposes these patients to progressive subluxation and dislocation of the hip. In nonambulatory patients, it is important to prevent the hips from dislocating for reasons of comfort, good sitting balance, and maintenance of pelvic alignment; again, operative intervention may be needed. Patients who have type I11 SMA and are still able to walk present a difficult management problem even though they have the mildest form of the condition. These patients are also prone to subluxation of the hip because of proximal muscle weakness; however, surgical intervention with proximal femoral varus osteotomy results in additional weakening of the abductor muscles, and the physician should be cautious in recommending such a procedure in a patient who still walks. Although scoliosis is less marked, it does occur. Because these patients rely to a great extent on lumbar lordosis and a side-to-side waddle to walk, bracing or spinal arthrodesis may worsen their gait. It is therefore recommended that, in this small subset of patients, arthrodesis is postponed until the patient can no longer walk, Specific therapies for SMA may soon become a reality as we obtain a better understanding of the underlying pathogenesis and the mechanism of anterior horn cell degeneration. Before clinical

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trials in SMA can be implemented, we must address unanswered questions about the nature and timing of lower motor neuron loss in patients to most effectively intervene in the disease process; critical questions regarding the relationship between phenotype and genotype remain unanswered.

SUGGESTED READINGS Bertini E, Gadisseux JL, Palmieri G et al: Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. Am J Med Genet 33:328-335, 1989 Campbell L, Potter A, Ignatius J et ak Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am J Hum Genet 61(1):40-50, 1997 Evans GA, Drennan JC, Russman BS: Functional classification and orthopaedic management of spinal muscular atrophy. J Bone Joint Surg 63B516522, 1981 Greenberg F, Fenolio KR, Hejtmancik JF et al: X-linked infantile spinal muscular atrophy. Am J Dis Child 142:217-219, 1988 Grohmann K, Schuelke M, Diers A et al: Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nature Genet 2975-77, 2001 Iannacone ST, Browne RH, Samaha FJ et ak Prospective study of spinal muscular atrophy before age 6 years. Pediatr Neurol 9:187-193, 1993 Iannacone ST, Russman BS, Browne RH et ak Prospective analysis of strength in spinal muscular atrophy. DCNlSpinal Muscular Atrophy Group. J Child Neurol 15:97-101,2000 Kobayashi H, Baumbach L, Matise TC et al: A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xpl1.3-ql1.2. Hum Mol Genet 4 1213-12 16, 1995

Lefebvre S, Burgien L, Reboullet S et al: Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155-165,1995 Liu T, Specht LA: Progressivejuvenile segmental spinal muscular atrophy. Pediatr Neurol 9354-56, 1993 MacKenzie AE, Jacob P, Surh L, Besner A Genetic heterogeneity in spinal muscular atrophy: a linkage analysis based assessment. Neurology 44919-924, 1994

Mellins RB, Hays AP, Gold AP et ak Respiratory distress as the initial manifestation of Werdnig-Hoffmann disease. Pediatrics 53:33-40, 1974

Munsat TL: Workshop report. International SMA Collaboration. Neuromuscul Disord 131, 1990 Richieri-Costa A, Rogatko A, Levisky R et al: Autosomal dominant late adult spinal muscular atrophy, type Finkel. Am J Med Genet 9:119-128, 1981 Roy N, Mahadevan MS, McLean M et al: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80167-178, 1995 Russman BS, Iannacone ST, Buncher CR et al: Spinal muscular atrophy: new thought on the pathogenesis and classification schema. 7 Child Neurol 7:347-353, 1992 Shapiro F, Specht LA: The diagnosis and orthopaedic treatment of

childhood spinal muscular atrophy, peripheral neuropathy, Friedreich ataxia and arthrogryposis. J Bone Joint Surg 75A1699-1714, 1993 Wirth B: An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 15:22&237, 2000

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Postpolio Syndrome Dave Hollander

The development of the Salk and Sabin polio vaccines is one of the great triumphs of modern medicine. With the introduction of widespread vaccination programs, paralytic polio, the very name of which once conjured fear in both parents and physicians, has largely disappeared from modern industrialized countries. Most physicians currently in practice have never seen a case of acute polio. However, thousands of survivors of the great polio epidemics of the past remain. For them, the memory of their acute illness is very real and is evidenced by the residual amyotrophy and muscle weakness their limbs bear. The infirmities acquired by the victims of polio were initially believed to be static and nonprogressive. In the past few years, however, it has become evident that although the initial polio infection was monophasic in nature, the survivors of such infections may be prone to further progression of their symptoms decades after their original illness. This progression is called postpolio syndrome. The onset of postpolio syndrome typically occurs about 30 years after the original bout of polio. It is conservatively estimated to develop in 25% of polio survivors, but the true figure may be much higher. In the United States alone, there are estimated to be more than 500,000 polio survivors. Thus, the number of potential patients with postpolio syndrome is very significant. The core of postpolio syndrome consists of the triad of pain, fatigue, and progressive weakness. About one third of patients with postpolio syndrome display all these symptoms. Other less common features include the development of fasciculations and new muscle atrophy. Patients may have sleep apnea. The risk of developing these late sequelae is related to the severity of the initial illness (i.e., patients with severe polio are at greatest risk, and severely affected muscles are more likely to develop late weakness than clinically spared muscles). Nonetheless, even patients with mild polio may develop typical postpolio syndrome. The pain of postpolio syndrome usually is musculoskeletal in origin, arising from the muscles and joints. The muscle pains are exertion-induced, presumably related to the limited exercise capacity of previously denervated muscles. The joint pains are mechanical in nature, the result of the years of unbalanced forces and stresses placed on joints, tendons, and ligaments that have had to compensate for muscle and limb weakness. Such pains are particularly common in the large weight-bearing joints. Frank degenerative arthritis may develop in such joints and cause further pain. In addition, pain may also develop as a consequence of nerve or root entrapment. Degenerative disc disease of the spine or scoliosis may result in radiculopathies. The long-term use of braces and crutches may cause compressive neuropathies, such as ulnar neuropathy and carpal tunnel syndrome. Fatigue in postpolio syndrome may be mild and limited to individual, previously affected muscle groups or may be generalized. Such generalized fatigue may be severe and overwhelming, developing even after minimal exertion. Muscle weakness may develop in any muscle group, including those that had previously seemed spared. This reflects the fact that infection with the poliovirus usually involves motor neurons in a generalized rather than focal manner. Although certain regions of the neuraxis may be most severely affected, there is more

widespread, subclinical involvement. This new weakness typically progresses very slowly, but even so, there may be very significant functional consequences associated with it. Patients who had previously been ambulatory may now be forced to use assistive devices, and the ability to perform other activities of daily life may become impaired. Respiratory symptoms may develop in patients who had previous involvement of respiratory muscles. Muscle atrophy may develop in a minority of patients. The examination findings in patients with postpolio syndrome are largely similar to those seen in polio patients. Muscle atrophy, weakness, and areflexia typically are present, although in patients who had very mild polio, muscle bulk may appear intact. The weakness need not be limited to the amyotrophic limbs. Fasciculations may be present, and there may be atrophy of muscles that were originally unaffected. Bulbar findings are rare. Upper motor neuron findings are also extremely uncommon but may occur, presumably as a consequence of the meningoencephalitis associated with the original polio infection. Before these findings are ascribed to polio, however, other possible causes, such as cervical myelopathy or stroke, must be ruled out, especially if the upper motor neuron signs are prominent. Sensory changes are not a feature of postpolio syndrome but may occur secondarily, such as in cases of nerve entrapment. The diagnosis of postpolio syndrome is based on clinical grounds; laboratory tests help confirm the diagnosis but are not diagnostic in themselves. The most useful tests in this regard are electromyography (EMG) and muscle biopsy. Nerve conduction studies demonstrate reduced compound muscle action potentials in affected muscles but are otherwise normal. The needle component of the EMG may demonstrate widespread active and chronic denervative changes, even in muscles seemingly unaffected, reflecting the more widespread subclinical involvement at the time of the original infection. The active changes consist of fibrillation potentials and positive sharp waves. Fasciculations may also be present. The chronic changes are caused by denervation and subsequent reinnervation of muscle fibers. Motor unit potentials may be enlarged and prolonged, and there may be an increase in the number of polyphasic motor unit potentials. Recruitment is reduced. Single-fiber EMG studies demonstrate increased fiber density, jitter, and blocking. Muscle biopsies may show a mixture of myopathic and neurogenic changes. The myopathic changes consist of variation in fiber size, central nuclei, fiber splitting, and increases in connective tissue. The neurogenic changes consist of fiber type grouping, group atrophy (suggestive of chronic denervation), and small angulated fibers (suggestive of acute denervation). The diagnostic usefulness of these tests is limited by the fact that similar EMG and biopsy findings may be seen in patients with polio who do not suffer any of the late sequelae. Their main value lies in confirming the diagnosis of postpolio syndrome and helping to rule out other differential diagnostic considerations. This is particularly true in cases in which a clear history of polio is not available. Diagnostic criteria for postpolio syndrome have been suggested. These consist of a history of acute polio and subsequent recovery, a prolonged period of functional stability (longer than 10

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years), and then the development of new neuromuscular symptoms. When these criteria are all present, the diagnosis of postpolio syndrome is straightforward. However, care must be taken to not overdiagnose postpolio syndrome. The development of musculoskeletal pain alone does not necessarily constitute postpolio syndrome; such pains may develop in any patient with chronic disability from whatever cause. For this reason, there should also be evidence of new neuromuscular symptoms, such as weakness or fatigue. In some cases, the initial symptoms, particularly if limited to one limb, may resemble a radiculopathy or peripheral neuropathy. Imaging studies of the spine may be helpful in deciding whether a radiculopathy is present. EMG is less useful because it is often difficult to diagnose radiculopathies by EMG in the face of the widespread denervative changes that may already be present as a consequence of the initial polio infection. Entrapment neuropathies, on the other hand, may often be diagnosed by EMG studies. Further diagnostic pitfalls arise in patients in whom there is no known history of polio. Diagnoses such as chronic inflammatory demyelinating polyneuropathy and myasthenia gravis may be entertained in some of these patients. In such cases, the EMG studies are extremely important in ruling out these diagnoses. The picture of new-onset weakness, possibly associated with fasciculations and new atrophy and without sensory involvement, may be mistakenly diagnosed as early amyotrophic lateral sclerosis. Although the diagnosis of amyotrophic lateral sclerosis requires the presence of both upper and lower motor neuron findings, many cases initially present with just lower motor neuron findings and may resemble postpolio syndrome. (In the rare instances of postpolio syndrome associated with upper motor neuron findings, the similarity to amyotrophic lateral sclerosis is even greater.) EMG and muscle biopsy are not helpful in distinguishing between these two entities because similar changes may be seen in both conditions. In such cases, it is the slow rate of progression and lack of development of significant bulbar and respiratory symptoms, as well as the failure to develop upper motor neuron signs, that ultimately point to the diagnosis of postpolio syndrome. Occasionally, patients previously afflicted with polio subsequently develop amyotrophic lateral sclerosis. In these cases, the reverse features (i.e., rapid progression and development of bulbar and respiratory symptoms and upper motor neuron signs) lead to the correct diagnosis. The management of postpolio syndrome is largely symptom-

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atic. Pain often can be alleviated by the judicious use of orthotics and other assistive devices. Exercise is important in helping restore faulty postural alignment and may also help build up endurance, but fatiguing exercise may be detrimental in postpolio syndrome and should be avoided. Patients should be referred to a physical therapist for guidance in these matters. Anti-inflammatory medications may be used as needed. Fatigue is best managed by frequent resting periods. Pyridostigmine, an anticholinesterase agent, has not been shown to be of benefit. There is little that can be done at this time to prevent the progression of weakness in postpolio syndrome. Patients should be reassured that progression is slow and rarely life-threatening. The exception of this is in patients who have previously had significant respiratory involvement. Such patients may have minimal respiratory reserve and may decompensate years after their initial illness. They may need ventilatory support, especially at night. Even for the majority of patients who do not develop respiratory symptoms, however, deficits and loss of function will occur, often necessitating adjustments in lifestyle. This loss of function can be especially disheartening and difficult to accept for patients who have had to overcome disabilities in the past, often by pushing themselves to the very limits of their ability. They may now become profoundly depressed. Their depression and sense of frustration may be exacerbated by the fact that their symptoms, which by their very nature may be mild and vague, especially early on, often are not taken seriously by others. Some patients may undertake unreasonably strenuous rehabilitation programs that may aggravate their symptoms. Patient care in postpolio syndrome requires a thoughtful, supportive approach on the part of the treating physician.

SUGGESTED READINGS Dalakas MC: Why drugs fail in postpolio syndrome. Neurology 53:11661167, 1999 Dalakas MC, Bartfeld H, Kurland LT The postpolio syndrome: advances in the pathogenesis and treatment. Ann NY Acad Sci 753:1-412, 1995 Jubelt B, Cashman N R Neurologic manifestations of the post-polio syndrome. Crit Rev Neurobiol 3:199-220, 1987 Jubelt B, Drucker J: Poliomyelitis and the post-polio syndrome. pp. 38395. In Younger DS (ed): Motor Disorders. Lippincott Williams & Wilkins, Philadelphia, 1999 Munsat TL Post-Polio Syndrome. Butterworth-Heinemann,Boston, 1991

Atypical Motor Neuron Disease Barbara E. Shapiro

There are several disorders that primarily affect the motor system but may be distinguished from amyotrophic lateral sclerosis (ALS) on clinical, laboratory, electrophysiologic, or pathologic grounds. These disorders are referred to in this chapter as atypical motor neuron diseases (MNDs). ALS is a disorder characterized by selective destruction of upper motor neurons in the brain and lower motor neurons (anterior horn cells, cranial nerve nuclei) in the brainstem and spinal cord. Patients typically present with focal weakness and more widespread lower motor neuron signs (atrophy, fasciculations). Spasticity and pathologic reflexes (upper

motor neuron signs) may or may not be apparent on presentation but will eventually develop. In contrast, the atypical MNDs comprise a group of diseases that often lack upper motor neuron signs completely. Moreover, the site of lower motor neuron pathology in a large subset of these disorders, believed to be immune-mediated, is thought to be at the level of the motor nerve itself rather than the anterior horn cell. Furthermore, the motor nerve pathology may be demyelinating, axonal loss, or a combination of both. In addition, some atypical MNDs are known to affect the motor system in combination with cerebellar, extrapy-

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years), and then the development of new neuromuscular symptoms. When these criteria are all present, the diagnosis of postpolio syndrome is straightforward. However, care must be taken to not overdiagnose postpolio syndrome. The development of musculoskeletal pain alone does not necessarily constitute postpolio syndrome; such pains may develop in any patient with chronic disability from whatever cause. For this reason, there should also be evidence of new neuromuscular symptoms, such as weakness or fatigue. In some cases, the initial symptoms, particularly if limited to one limb, may resemble a radiculopathy or peripheral neuropathy. Imaging studies of the spine may be helpful in deciding whether a radiculopathy is present. EMG is less useful because it is often difficult to diagnose radiculopathies by EMG in the face of the widespread denervative changes that may already be present as a consequence of the initial polio infection. Entrapment neuropathies, on the other hand, may often be diagnosed by EMG studies. Further diagnostic pitfalls arise in patients in whom there is no known history of polio. Diagnoses such as chronic inflammatory demyelinating polyneuropathy and myasthenia gravis may be entertained in some of these patients. In such cases, the EMG studies are extremely important in ruling out these diagnoses. The picture of new-onset weakness, possibly associated with fasciculations and new atrophy and without sensory involvement, may be mistakenly diagnosed as early amyotrophic lateral sclerosis. Although the diagnosis of amyotrophic lateral sclerosis requires the presence of both upper and lower motor neuron findings, many cases initially present with just lower motor neuron findings and may resemble postpolio syndrome. (In the rare instances of postpolio syndrome associated with upper motor neuron findings, the similarity to amyotrophic lateral sclerosis is even greater.) EMG and muscle biopsy are not helpful in distinguishing between these two entities because similar changes may be seen in both conditions. In such cases, it is the slow rate of progression and lack of development of significant bulbar and respiratory symptoms, as well as the failure to develop upper motor neuron signs, that ultimately point to the diagnosis of postpolio syndrome. Occasionally, patients previously afflicted with polio subsequently develop amyotrophic lateral sclerosis. In these cases, the reverse features (i.e., rapid progression and development of bulbar and respiratory symptoms and upper motor neuron signs) lead to the correct diagnosis. The management of postpolio syndrome is largely symptom-

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atic. Pain often can be alleviated by the judicious use of orthotics and other assistive devices. Exercise is important in helping restore faulty postural alignment and may also help build up endurance, but fatiguing exercise may be detrimental in postpolio syndrome and should be avoided. Patients should be referred to a physical therapist for guidance in these matters. Anti-inflammatory medications may be used as needed. Fatigue is best managed by frequent resting periods. Pyridostigmine, an anticholinesterase agent, has not been shown to be of benefit. There is little that can be done at this time to prevent the progression of weakness in postpolio syndrome. Patients should be reassured that progression is slow and rarely life-threatening. The exception of this is in patients who have previously had significant respiratory involvement. Such patients may have minimal respiratory reserve and may decompensate years after their initial illness. They may need ventilatory support, especially at night. Even for the majority of patients who do not develop respiratory symptoms, however, deficits and loss of function will occur, often necessitating adjustments in lifestyle. This loss of function can be especially disheartening and difficult to accept for patients who have had to overcome disabilities in the past, often by pushing themselves to the very limits of their ability. They may now become profoundly depressed. Their depression and sense of frustration may be exacerbated by the fact that their symptoms, which by their very nature may be mild and vague, especially early on, often are not taken seriously by others. Some patients may undertake unreasonably strenuous rehabilitation programs that may aggravate their symptoms. Patient care in postpolio syndrome requires a thoughtful, supportive approach on the part of the treating physician.

SUGGESTED READINGS Dalakas MC: Why drugs fail in postpolio syndrome. Neurology 53:11661167, 1999 Dalakas MC, Bartfeld H, Kurland LT The postpolio syndrome: advances in the pathogenesis and treatment. Ann NY Acad Sci 753:1-412, 1995 Jubelt B, Cashman N R Neurologic manifestations of the post-polio syndrome. Crit Rev Neurobiol 3:199-220, 1987 Jubelt B, Drucker J: Poliomyelitis and the post-polio syndrome. pp. 38395. In Younger DS (ed): Motor Disorders. Lippincott Williams & Wilkins, Philadelphia, 1999 Munsat TL Post-Polio Syndrome. Butterworth-Heinemann,Boston, 1991

Atypical Motor Neuron Disease Barbara E. Shapiro

There are several disorders that primarily affect the motor system but may be distinguished from amyotrophic lateral sclerosis (ALS) on clinical, laboratory, electrophysiologic, or pathologic grounds. These disorders are referred to in this chapter as atypical motor neuron diseases (MNDs). ALS is a disorder characterized by selective destruction of upper motor neurons in the brain and lower motor neurons (anterior horn cells, cranial nerve nuclei) in the brainstem and spinal cord. Patients typically present with focal weakness and more widespread lower motor neuron signs (atrophy, fasciculations). Spasticity and pathologic reflexes (upper

motor neuron signs) may or may not be apparent on presentation but will eventually develop. In contrast, the atypical MNDs comprise a group of diseases that often lack upper motor neuron signs completely. Moreover, the site of lower motor neuron pathology in a large subset of these disorders, believed to be immune-mediated, is thought to be at the level of the motor nerve itself rather than the anterior horn cell. Furthermore, the motor nerve pathology may be demyelinating, axonal loss, or a combination of both. In addition, some atypical MNDs are known to affect the motor system in combination with cerebellar, extrapy-

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ramidal, cognitive, psychiatric, or mild sensory dysfunction. The motor system may also be affected in the setting of neoplasms, metabolic disorders, toxins, and drugs and as a result of electrical injuries, radiation, infections, spinal cord lesions, and old poliomyelitis. Although, strictly speaking, these do not constitute atypical MNDs, they are briefly discussed in this chapter. The atypical MNDs are important to identify for several reasons, including the possibility of uncovering a potentially treatable disorder, one that is inherited, or one that may not carry the same grave prognosis that ALS currently carries. This chapter focuses on the important clinical clues that suggest an atypical MND and then discusses some of the major disorders that should be considered in the differential diagnosis of uncommon presentations of MND. Important laboratory, electrophysiologic, and pathologic findings are discussed.

CLINICAL CLUES Most clinicians use pertinent clues on the neurologic examination and in the history to identify an atypical MND. Valuable clues include the following: Nonmyotomal pattern of weakness w Absence of significant muscle wasting in chronically weak limbs w Lack of concurrent upper and lower motor neuron signs in the same spinal segment Nonregional spread of weakness w Presence of sensory symptoms or signs Bladder or bowel dysfunction 8 Extraocular muscle weakness w Cerebellar, extrapyramidal, cognitive, or psychiatric dysfunction w Onset of illness before age 35 Duration of illness longer than 5 years w Lack of bulbar involvement after 1 year Positive family history w History of spontaneous remissions w History of malignancy, especially lymphoma

Nonmyotomal Pattern of Weakness Weakness in patients with ALS typically involves all muscles in a particular myotome, or spinal segment, because the site of lower motor neuron pathology is at the level of the anterior horn cell. Thus, both the biceps and deltoid tend to be weak at the same time because both are innervated by the same spinal segment, although by different motor nerves. In contradistinction, a disorder of the motor nerves themselves may produce a very different picture: The biceps may be weak, whereas the deltoid muscles are strong. Such a selective pattern of weakness, in the distribution of named nerves rather than myotomes, may be an extremely important clue pointing toward a disorder of motor nerves rather than anterior horn cells. This may easily be missed if muscle groups are not meticulously tested in isolation.

Absence of Significant Muscle Wasting in Chronically Weak Limbs Preserved muscle bulk in the face of chronic weakness may suggest that the weakness is a consequence of demyelination, in the form of a conduction block, through segments of motor nerves. Muscle wasting may not be seen if the axon remains intact. This again

places the pathology at the level of the motor nerve itself rather than the anterior horn cell. Electrophysiologic testing is of paramount importance to confirm the presence of a conduction block. Although the definition of conduction block remains controversial, most would agree that a drop in the area of the compound muscle action potential (CMAP) by more than 50% between proximal and distal stimulation sites constitutes a true conduction block.

Lack of Concurrent Upper and Lower Motor Neuron Signs in the Same Spinal Segment Although lower motor signs often predominate early in the course of ALS, one usually finds preserved or brisk reflexes in the same distribution as the muscles that are weak and wasted. Failure to find concurrent upper and lower motor neuron signs in the same spinal segments should prompt a search for another disorder. In cervical spondylosis, for example, brisk reflexes are noted at segments below the weakness and hyporeflexia, resulting from nerve root and spinal cord compression. Thus, the arms may be weak and wasted, whereas the legs are spastic. Such a pattern should alert one to the possibility of a spinal lesion.

Nonregional Spread of Weakness Weakness in ALS tends to spread in a regional fashion. For example, if the right arm is initially weak, it is more common for the right leg or the left arm to become involved next, but not the left leg. Although this is not an absolute rule, any deviation from such a pattern of weakness is a reasonable basis to investigate another cause of weakness.

Presence of Sensory Symptoms or Signs Although ALS does not involve sensory pathways, it is not uncommon for a patient to misinterpret a weak limb as numb, dead, or having altered sensation; however, a finding of true sensory loss on neurologic examination is a very important clue and should prompt the clinician to search for another explanation of the patient’s weakness.

Bladder or Bowel Dysfunction In practice, it is not uncommon for patients with ALS to report mild bladder incontinence or constipation. However, pronounced bladder or bowel dysfunction, especially early in the course of weakness, should prompt a search for another disorder.

Extraocular Muscle Weakness A finding of blurred or double vision or eye muscle weakness on examination should precipitate a search for another disorder.

Cerebellar, Extrapyramidal. Cognitive, or Psychiatric Dysfunction Progressive weakness accompanied by incoordination, ataxia, tremor, cerebellar dysarthria, dystonia, rigidity, depression, manic episodes, or dementia should raise one’s suspicion for a multiple system disorder. A detailed family history should be obtained because many of these disorders are genetic.

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Unusual fime Course of Illness

Onset of illness before age 35, duration of illness for more than 5 years, absence of bulbar involvement after 1 year, and history of spontaneous remissions are all unusual findings that should alert the clinician to the possibility of an atypical MND.

5 msec

CLINICAL SYNDROMES Atypical MNDs that can be differentiated from A L S and its variants are discussed in the following sections (Table 89-1). Presumed Immune-MediatedMotor Neuropathies

These disorders affect the motor nerves themselves and are characterized by progressive, asymmetric, predominantly lower motor neuron weakness. There is a presumed immunologic basis. Various names have been given to these disorders, including multifocal motor neuropathy with conduction block (MMN), multifocal motor conduction block neuropathy, and motor neuropathy with multifocal conduction blocks. In general, these patients are males with an age of onset less than 45 years and present with chronic asymmetrical weakness, often in distal upper extremity muscles, although proximal upper extremity weakness may predominate. Two key elements have been associated with these disorders and help in differentiating them from ALS: the finding of demyelination, generally in the form of conduction block outside typical entrapment sites, on electrophysiologic testing of motor nerves (Fig. 89-1); and the presence of high serum titers of antibodies directed against nerve gangliosides. Gangliosides are glycolipids that contain lipid and carbohydrate moieties and are found in great quantity on the exterior surface of the plasma membranes of nerve fibers. The major antiglycolipid W TMU 89-1. Atypical Motor Neuron Disorders

Immune-mediated motor neuropathies Non-immune-mediated lower motor neuron syndromes Benign focal amyotrophy Progressive muscular atrophy Progressive bulbar palsy Spinal muscular atrophy X-linked bulbospinal muscular atrophy Fazio-Londe disease Hereditary spastic paraplegia Multiple-system disorders with prominent motor signs Adult hexosaminidase A deficiency (late-onset Tay-Sachs disease) Spinocerebellar degenerations Autosomal dominant cerebellar ataxias Autosomal recessive cerebellar ataxias Adult polyglucosan body disease Other multiple-system disorders Shy-Drager syndrome Guamanian Parkinson amyotrophic lateral sclerosis Hallemorden-Spatzdisease Creutzfeldt-Jakob disease Huntington's disease Pick's disease Hyperparathyroidism Paraneoplastic disorders with motor system dysfunction Toxins and drugs Electrical injury associated with motor neuron disease Postradiation motor neuron disease Infectious and postinfectious syndromes Acute motor axonal neuropathy Retrovirus-associateddisorders Radiculopathy and myelopathy Postpoliomyelitis syndrome

7

r FIG. 89-1. Conduction block and temporal dispersion in a patient with immune-mediated multifocal motor neuropathy. Motor nerve conduction of the ulnar nerve recording at the abductor digiti minimi muscle. Stimulation sites from top to bottom: wrist, below groove, above groove, axilla, and brachial plexus. Note drop in the area of the compound muscle action from wrist to brachial plexus.

antibodies that have gained attention with respect to the motor neuropathies are those directed against GM- 1 gangliosides that share the Gal(p1-3)GalNAcepitope. These may take the form of monoclonal or polyclonal immunoglobulin (Ig) M or IgG antibodies, but the majority are polyclonal IgM. Elevated antiglycolipid antibodies are present in 20% to 90% of patients, depending on the method used. Using standard commercial enzyme-linked immunosorbent assay methods, the sensitivity of anti-GM1 antibody testing in MMN is 30% to 50%. A new Co-GM1 antibody measurement method described by Pestronk has a higher sensitivity, with high titers of serum IgM anti-GM1 antibodies found in 80% to 90% of patients with MMN but also in some patients with immune-mediated lower motor neuron syndromes without conduction blocks. Specificity and sensitivity are also increased by using the triad of high IgM binding to GM1 and NP9, a high-molecular-weight uncharacterized white matter antigen, but low reactivity to a nuclear protein, histone H3. This triad pattern of binding increases the specificity for detecting MMN or other immune-mediated lower motor neuron syndromes to nearly 90%, compared with using anti-GM1 alone. Many patients with immune-mediated motor neuropathies have been treated successfully with immunomodulating therapies. The patients most likely to respond to treatment present with chronic asymmetrical distal upper extremity weakness, with minimal sensory signs and evidence of conduction block through segments of motor but not sensory nerves on nerve conduction studies (NCSs). Such patients may have a remarkable response to

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intravenous human immunoglobulin (IVIg) treatment at a dosage of 400 mg/kg/day for 5 consecutive days, which is generally a safe first-line mode of treatment. Patients with an absolute deficiency of IgA must receive globulins that contain no IgA. Pretreatment with 50 mg oral diphenhydramine hydrochloride, two acetaminophen, and 100 mg IV hydrocortisone an hour before the infusion begins is recommended to prevent an allergic response. The treatment generally is repeated at this dosage for 2 to 5 days a month every month, depending on the treatment response. Quantitative motor testing is a useful way to follow the progression of the disease and treatment response. Some patients may need a full 5-day treatment course every month. Some degree of improvement occurs in up to 80% of patients with MMN treated with IVIg, with 50% to 60% of patients experiencing significant functional benefit. The dosage and frequency of IVIg infusion is based on the patient’s treatment response, and the period of maximal improvement after IVIg infusion should be monitored in each patient. The minimal dosage that produces optimal improvement is used for long-term maintenance therapy. Lack of improvement after two to three courses of IVIg infusion is considered a treatment failure. Despite improvement in strength, IVIg treatment usually does not reduce the titers of serum anti-GM1 antibodies. Patients who do not respond or do not receive a sustained effect can be given a trial of cyclophosphamide, which is the only immunosuppressive treatment reported to produce sustained long-term benefit in 50% to 80% of the patients with MMN. Cyclophosphamidecan be given either as an oral daily dosage of 2 mg/kg/day or monthly intravenous infusion. One recommended regimen is six monthly treatments of IV cyclophosphamide (1 g/m2), each dose preceded by two plasma exchanges. Adequate hydration, antiemetics, and medication to prevent hemorrhagic cystitis such as 2-mercaptoethanesulfonate are used concurrently. Blood counts must be carefully monitored sequentially after each dose, monitoring for leukopenia and pancytopenia. This regimen is effective in producing a sustained reduction in anti-GM1 antibody titers in 50% to 80% of patients, with functional benefit in most patients with reduced antibody titers. Remission usually persists for 1 to 3 years, and retreatment may be necessary. Cyclophosphamide treatment used concurrently with M g may play a role in minimizing the dosage of IVIg needed for sustained improvement and in preventing the long-term decrease in benefit. Oral cyclophosphamide has induced remission in a small uncontrolled study. The oral dosage is halved if the white blood cell count falls below 4000/mm3, and stopped if below 3000/mm3, until it comes back to 4000/mm3. If hematuria develops, the cyclophosphamide must be stopped immediately and should not be reintroduced. Treatment response may take 6 months to 1 year. The risks and benefits of cyclophosphamide must be explained carefully, including the need for weekly laboratory testing and the greater risk of developing a malignancy after a lifetime dosage of approximately 85 g. Corticosteroidtreatment usually is ineffective in treating MMN and may actually worsen the weakness. p-Interferon was effective in a few patients who did not respond to IVIg and cyclophosphamide, especially patients with shorter disease duration, less muscle strength impairment, and fewer sites with conduction blocks. Recently, Levine and Pestronk reported four patients with MMN and high anti-GM1 antibody titers who were treated successfully with a new monoclonal antibody directed against the B cell surface membrane marker CD20 (Rituximab), all of whom showed significantly improved motor function, as measured by quantita-

tive muscle strength testing, and a decrease in anti-GM1 antibody titers within 3 to 6 months. This treatment may play a future role in treating patients who experience relapse or deterioration of motor function after several years of IVIg or cyclophosphamide treatment. There are rare reports of patients with lower motor neuron syndromes and highly elevated anti-GM1 antibody titers but no conduction block through motor nerves, who have shown improved strength with monthly IV cyclophosphamide treatment in combination with plasma exchange. These patients present with chronic asymmetrical weakness in distal muscles greater than that in proximal muscles, usually in the upper extremities. Although there is no evidence of demyelination by NCSs, needle electromyography (EMG) examination reveals axonal loss in the form of active and chronic denervation and reinnervation. In some patients who respond to treatment, there is a concomitant fall in anti-GM1 antibody titers. Such patients are extremely important to recognize because of their potential response to treatment, yet there may be no way to distinguish them clinically or by EMG or NCS from patients with either a progressive muscular atrophy variant of ALS or benign focal amyotrophy (discussedlater in this chapter). Specific features that should alert the clinician to an immunemediated motor neuropathy include weakness in the distribution of named nerves rather than myotomes; notable absence of significant muscle wasting in chronically weak limbs; absence of upper motor signs, although there have been rare reported cases of patients with preserved or brisk reflexes in weak limbs; and minor sensory signs and symptoms. Thus, any patient presenting with a predominantly lower motor neuron syndrome should undergo careful, thorough electrophysiologic testing to look for features of demyelination: the presence of motor conduction block at nonentrapment sites, marked conduction velocity slowing, prolonged distal motor latencies, or prolonged late responses. Screening should be done for the presence of elevated titers of antiglycolipid antibodies and a monoclonal or polyclonal protein in serum and urine. However, it should be emphasized that the pathogenic role of antiglycolipid antibodies in immune-mediated lower motor neuron syndromes remains unclear for several reasons. As noted earlier, many patients who respond to treatment have progressive weakness and motor conduction block on electrophysiologictesting but do not have elevated antiglycolipid antibody titers. Although response to treatment often is accompanied by a drop in antibody titers, this is not a consistent finding. In addition, elevated antiglycolipid antibody titers are nonspecific, and mild to moderately elevated titers can be seen in classic ALS, polyneuropathies, and other neurologic and autoimmune disorders. Furthermore, there is variation between laboratories as to what is considered an elevated titer. Response to treatment in patients presenting with distal weakness without motor conduction block or elevated anti-GM1 antibodies, or in patients with predominantly proximal weakness without conduction block, with or without elevated anti-GM1 antibodies, has not yet been established.

Non-Immune-Mediated Lower Motor Neuron Syndromes Benign Focal Amyotrophy. A syndrome of slowly progressive weakness, benign focal amyotrophy (also called monomelic amyotrophy, Sobue’s disease) occurs predominantly in males in the second to fourth decades of life and most commonly affects distal hand muscles unilaterally. It has been reported most

Chapter 89 W

commonly in Japanese and Asian Indian populations but can occur in any ethnic group. Most cases are sporadic, although a familial form has been reported. Like ALS, the weakness tends to affect all muscles in the same spinal segment. However, weakness tends to stabilize after 1 or 2 years, and there is a conspicuous lack of upper motor neuron involvement. Electrophysiologic testing reveals chronic neurogenic changes on needle EMG in affected muscles, without evidence of conduction block. There is often mild involvement of the same spinal segments in the contralateral limb. Weakness occasionally presents in the lower extremities or proximal upper extremity muscles. The clues to this disorder are lack of upper motor neuron involvement, younger age of onset, predilection for distal hand muscles, and lack of progression over several years. However, it may be impossible to distinguish this disorder from classic A L S in its early presentation. Progressive Muscular Atrophy. Patients with a progressive muscular atrophy variant of ALS present with an asymmetrical pure lower motor neuron syndrome of weakness, wasting, and fasciculationsthat may progress for many years before death, with no upper motor neuron signs. Needle EMG examination reveals active and chronic denervation and reinnervation. Pathologic involvement of corticospinal tract involvement has been noted in some autopsied cases, confirming a diagnosis of ALS. Fazio-Londe Disease. Fazio-Londe disease is a rare disorder that generally presents in the first decade of life with progressive bulbofacial weakness that may eventuallyspread to the extremities. Unlike in typical MND, ocular muscles are also affected. Inheritance in the majority of cases is autosomal recessive, although some cases appear to be sporadic. Death commonly occurs as a result of respiratory failure within 2 years of onset. At autopsy, loss of anterior horn cells and brainstem motor nuclei is found, but the corticospinal tracts are unaffected.

Hereditary Spastic Paraplegia Hereditary spastic paraplegia is a heterogeneous group of genetic disorders characterized by progressive spasticity and in some patients weakness of the lower extremities. They are classified by their mode of inheritance (autosomal dominant, autosomal recessive, or X-linked) and by whether the spasticity is the sole manifestation of the disorder (uncomplicated or pure spastic paraplegia) or other neurologic abnormalities accompany the spasticity (complicated spastic paraplegia). Other features may include ataxia, dementia, mental retardation, optic neuropathy, retinopathy, peripheral neuropathy, amyotrophy, extrapyramidal dysfunction, deafness, and ichthyosis. The clinical presentation varies both within and between families. These disorders often can be distinguished from ALS by their associated neurologic and non-neurologic manifestations and family history. Treatment for hereditary spastic paraplegia is symptomatic and may include antispasticity agents such as baclofen, either oral or through an intrathecal pump, and tizanidine hydrochloride. Bladder spasticity also can be managed with appropriate medications. The course and prognosis are quite variable both within and between families.

Multiple-System Disorders with Prominent Motor Signs Adult Hexosaminidase A Deficiency. The adult form of hexosaminidase A deficiency (late-onset Tay-Sachs disease) is a rare inherited disorder in which long-standing, progressive lower motor neuron findings, including weakness, wasting, and fascicu-

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lations, invariably are present in varying degrees. Lower motor neuron signs usually predominate, and cerebellar findings of tremor, ataxia, and dysarthria, upper motor neuron findings of weakness and spasticity, and cognitive and psychiatric dysfunction (recurrent psychosis, depression) are common. Extrapyramidal findings are minimal. Onset of symptoms is most common in childhood, usually before the third decade, with survival often into adulthood. Because lower motor neuron findings predominate, such patients often are misdiagnosed with one of the spinal muscular atrophies, usually the Kugelberg-Welander type. The disorder is inherited in an autosomal recessive manner and is more prevalent in the Ashkenazi Jewish population than in other ethnic groups. Electrophysiologic testing usually yields normal NCSs. Needle EMG examination reveals large, prolonged polyphasic motor unit action potentials with abnormal spontaneous activity in the form of fibrillation potentials, positive sharp waves, fasciculations, and, in some patients, complex repetitive discharges. Hexosaminidase A is a lysosomal enzyme that participates in the metabolism of GM2 ganglioside. It is composed of an a and p subunit, located on chromosomes 15q and 5q, respectively, whereas hexosaminidase B is made up of two p subunits. An activator protein, GM2 activator, located on 5q, enhances the activity of both enzymes. Hexosaminidase deficiency results in lysosomal accumulation of GM2 ganglioside, resulting in degeneration of nerve cells. Unlike the infantile form (infantile Tay-Sachs disease), where hexosaminidaseA is absent and patients do not survive beyond infancy, these patients have a mutation in the subunit of the hexosaminidase A enzyme, resulting in a severe deficiency but not total absence of hexosaminidase A activity. Rare cases of patients with a p subunit mutation (combined hexosaminidase A and hexosaminidase B deficiency) have been reported. Clues that should alert the clinician to this disorder include the slow progression of a predominantly lower motor neuron syndrome with onset before the third decade, a positive family history, spasticity, and signs outside the motor system including dysarthria, ataxia, tremor, dystonia, dementia, and psychosis. There is often a wide variation in phenotype and severity of disease within the same family. The pattern of weakness may be unusual, with a remarkable sparing of some muscle groups, whereas others, such as triceps, are involved early. In one retrospective study of a large population of patients with a diagnosis of ALS, 50 patients with at least one atypical feature (duration of illness more than 7.5 years, age of onset of illness less than 35 years, or positive family history of ALS) were screened for abnormal levels of hexosaminidase A activity in peripheral blood leukocytes. No patient had hexosaminidase A deficiency, and less than 1% had white blood cell hexosaminidase A activity in the range of obligate heterozygotes. Although the disorder is rare, patients with an atypical motor neuron presentation, especially those with cerebellar, extrapyramidal, cognitive, or psychiatric dysfunction that cannot be explained on another basis, should be screened for hexosaminidase A and B deficiency. DNA testing can be done to determine the defective gene. Although there is no known medical treatment, stem cell therapy and substrate deprivation therapy in a mouse model of Tay-Sachs disease have shown some promise. Supportive therapy consists primarily of symptom management, including physical therapy for gait and balance training, speech therapy for dysarthria, and occupational therapy if clinically indicated. Furthermore, some medications used to treat psychosis and depression are known to be toxic to lysosomes and can worsen

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symptoms, including neuroleptics such as phenothiazines and tricyclic antidepressants, which are best avoided. Lithium carbonate, carbamazepine, benzodiazepines, and electroconvulsive therapy, alone or in combination, often are the treatment of choice, depending on the psychiatric presentation. Prenatal testing is available, and genetic counseling is important in families carrying the genetic defect. SpinocerebellarDegenerations. Several multiple-system disorders with progressive cerebellar ataxia as the salient feature have been described, often with accompanying lower motor neuron signs. Other accompanying features may include spasticity, ophthalmoplegia, optic atrophy, macular or retinal degeneration, dementia, peripheral neuropathy, or extrapyramidal signs, which easily distinguish them from typical ALS. These disorders are broadly classified as autosomal dominant or recessive cerebellar ataxias, and the genetic basis of many of these disorders is now known. Many of these disorders were at one time subsumed under the more general category of olivopontocerebellar atrophy. AUTOSOM DOMINANT CEREBELLAR ATAXW. The autosomal dominant cerebellar ataxias (ADCA I, 11, and 111) are a group of heterogeneous multiple-system disorders, with progressive ataxia as the predominant presenting symptom. Prominent motor system degeneration, including weakness, spasticity, wasting, and fasciculations, may develop. When motor system involvement is severe, the clinical picture may be confusing. However, other features, including large fiber sensory loss, optic atrophy, retinopathy, supranuclear ophthalmoplegia, extrapyramidal dysfunction, and dementia, should point the clinician toward a multiple-system disorder. Patients generally present in their third to fourth decades, although onset may be as early as the second decade or as late as the seventh. Many of the phenotypes are associated with CAG trinucleotide repeat expansions at various chromosomal locations, depending on the specific disorder. A more detailed discussion of these disorders can be found in Chapter 5. AUTOSOMAL RECESSIVE ATAXU Friedreich‘s ataxia is the most common form of autosomal recessive ataxia and commonly presents during adolescence with ataxia, dysarthria, nystagmus, upper motor neuron signs, diminished deep tendon reflexes, and large fiber sensory loss. Pes cams and hammer toes are common, as is cardiac dysfunction. The majority of patients with Friedreich’s ataxia have a GAA trinucleotide repeat expansion in intron 1 of the frataxin gene on chromosome 9q, although there is strong evidence for a second locus. A more detailed discussion of these disorders can be found in Chapter 5. ADULTPOLYCLUCOSAN BODYDISEASE.Adult polyglucosan body disease is an extremely rare neurologic disorder that presents in the fifth or sixth decade with progressive upper and lower motor neuron dysfunction, gait disturbance, urinary incontinence, dementia, and sensorimotor peripheral neuropathy. All components of the disorder may not be present initially, and the severity of clinical manifestations varies between patients. Some patients present with dementia, urinary incontinence, and gait disturbance, without upper or lower motor neuron signs, whereas others present with only upper and lower motor neuron signs resembling ALS, with only minimal central nervous system (CNS) manifestations. Cognitive impairment tends to occur in the advanced stages of the disease. There is no gender predisposition. Fewer than 30 cases are reported in the literature. Some cases appear to be sporadic and others familial, with a high proportion occurring in patients of Ashkenazi Jewish descent. The pattern of inheritance appears to be autosomal recessive in some case reports.

The pathologic hallmark of the disease is the presence of a large number of polyglucosan bodies, which structurally resemble Lafora bodies or corpora amylacea, in the CNS, predominantly within astrocytic processes in the subpial and subependymal regions, cerebellum, and myelinated axons in the peripheral nervous system. There is severe loss of anterior horn cells. Deposition of polyglucosan bodies is also seen in myocardium, liver, smooth muscles, and, to a lesser extent, skeletal muscles. Structurally, polyglucosan bodies are composed primarily of glucose polymers, with a small variable component of phosphate and sulfate groups and a minimal protein component, the nature of which is unknown. The presumed cause of adult polyglucosan body disease is genetic, especially in patients of Ashkenazi Jewish descent. A Tyr329Ser mutation in the glycogen branching enzyme gene, causing a deficiency of the glycogen branching enzyme, has been described in Ashkenazi Jewish patients with adult polyglucosan body disease, although a patient of non-Jewish descent with a novel missense mutation (Arg515His and Arg524Gln) in the glycogen branching enzyme gene was reported. Because a deficiency of the glycogen branching enzyme is found in only a subgroup of patients with adult polyglucosan body disease, primarily those of Ashkenazi Jewish descent, the disease may have more than one biochemical basis. The accumulation of polyglucosan bodies in the nervous system is the pathologic hallmark of the disease, although polyglucosan bodies are also seen in other diseases such as Lafora’s disease and type IV glycogenosis and as a nonspecific phenomenon in the aging nervous system (corpora amylacea). The mechanisms responsible for tissue damage include impairment of astrocytic processes secondary to massive accumulation of polyglucosan bodies, or the underlying metabolic defect may damage the neuron directly, with the accumulation of polyglucosan bodies occurring as a secondary effect. The clinical context that should prompt an evaluation for adult polyglucosan body disease is progressive upper and lower motor neuron dysfunction and gait instability that may resemble typical ALS, accompanied by dementia and urinary incontinence. Distal sensory loss may be found on clinical examination. Other diagnoses that may be considered initially include primary lateral sclerosis, late-onset multiple sclerosis, vitamin B,, deficiency, primary lateral sclerosis, the leukodystrophies, and spinocerebellar atrophy. Extensive white matter abnormalities are seen on brain magnetic resonance imaging (MRI), and electrophysiologic studies reveal mild to moderate slowing of motor nerve conduction velocity and low-amplitude or absent sensory nerve action potentials. A definitive diagnosis is based on pathologic findings of widespread deposition of polyglucosan bodies in the central and peripheral nervous systems. Sural nerve biopsy shows multiple intra-axonal polyglucosan bodies, which together with the appropriate clinical manifestations can confirm the diagnosis of adult polyglucosan body disease. Axillary skin biopsy shows polyglucosan bodies in the myoepithelial cells of apocrine glands and may be helpful in confirming the diagnosis of adult polyglucosan body disease. Reduction of glycogen branching enzyme activity in leukocytes is found mainly in Ashkenazi Jewish patients. There is no specific medical treatment for adult polyglucosan body disease other than supportive therapy. The disease usually progresses over a period of 1 to 20 years, eventually leading to death. Other Multiple-System Disorders. Several other-multiple system disorders may have prominent upper and lower motor neuron signs as part of their symptom complex. These disorders,

Chapter 89

including Shy-Drager syndrome, Guamanian Parkinson ALS, and Hdervorden-Spatz, Creutzfeldt-Jakob, Huntington's, and Pick's disease, each have unique clinical presentations.

Hyperparathyroidism Primary hyperparathyroidismhas been historically associated with a classic neuromuscular syndrome characterized by proximal weakness and fatigue, with occasional atrophy, tongue fasciculations, and hyperreflexia that may suggest a motor systems disease. Muscle cramps are not uncommon. However, the presence of mild sensory symptoms and abnormal mentation help distinguish it from typical ALS. A variety of clinical and EMG findings have been reported in the past, including those associated with disorders of muscle, neuromuscular junction, and nerve. However, more recent prospective investigations of patients with primary hyperparathyroidism have failed to substantiate the clinical or EMG findings previously reported. Discrepancies with earlier reports from the 1960s and 1970s that suggested a relationship between hyperparathyroidism and muscle and nerve disease may have resulted from more accurate and earlier testing for hyperparathyroidism currently available. In one case report, a patient with primary hyperparathyroidism secondary to hyperplasia presented with a 1-year history of weakness, dysarthria, dysphagia, and leg cramps. On examination, she was weak and wasted, with fasciculations, hyperreflexia, and spasticity. Some resolution of weakness and dysarthria occurred within a month of removal of the parathyroid tissue. When she died within a month from complications of bronchopneumonia, postmortem examination of the brain and spinal cord showed classic changes consistent with ALS. However, such case reports do not establish a causal relationship. One recent study reported five patients with ALS and primary hyperparathyroidism, among approximately 600 patients followed with ALS in a neuromuscular clinic over a period of 6 years. Patients with a diagnosis of ALS were screened with a serum calcium and parathyroid hormone level and asked whether they had ever been treated for hypercalcemia or hyperparathyroidism. All patients had muscle weakness, atrophy, and fasciculations. In four patients, the symptoms began in the lower extremities, and one patient presented with bulbar weakness. All five patients had upper motor neuron manifestations. In three patients the hyperparathyroidism was discovered during their evaluation for ALS, and in two patients the diagnosis of hyperparathyroidism preceded the diagnosis of ALS. EMG examination revealed widespread denervation in all patients. All of the patients died within 3 years of their parathyroid adenoma resection, secondary to progression of their MND. This study calls into question a causal relationship between MND and hyperparathyroidism because removal of the parathyroid adenoma did not alter the progression of the neurologic illness. Nevertheless, patients who present with true weakness and no other known cause should have calcium levels screened.

Paraneoplastk Disorders wRh Motor System Dysfundon Paraneoplastic disorders occur as a remote effect of cancer but are caused by neither direct tumor infiltration nor metastases. Reports of typical ALS and atypical MNDs have been described in association with several neoplasms, most commonly in association with malignant lymphoma. However, because the incidence of MND is so high in the general population, its finding in the setting

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of cancer may be purely coincidental. Epidemiologic studies do not support a higher co-occurrence of typical ALS and cancer. Although a small number of individual case reports have documented improvement or stabilization of patients with clinically typical ALS after treatment of their neoplasm, these cases are extremely rare and differ pathologically from classic ALS. Associations have been found with lung, renal, ovarian, uterine, and breast cancer, thymoma, lymphoma, and macroglobulinemia. The proposed mechanism of paraneoplastic MND is an immunemediated disease process. However, the specific antibody responsible for lower motor neuron syndromes has not been well identified, and the disorder appears to be related to multiple types of antibodies, depending on the clinical manifestations and the type of cancer. Malignant lymphoma has been associated with atypical as well as typical MND presentations. In atypical cases, patients present with a predominantly lower motor neuron syndrome of subacute progressive weakness, wasting, and fasciculationsin the absence of pain. The weakness often is asymmetric, with predominant involvement of the lower extremities. Minor sensory signs and symptoms may be present. Rarely, demyelination in the form of motor conduction block is noted on NCSs. The weakness may precede the lymphoma or vice versa. Cerebrospinal fluid (CSF) studies may reveal a slightly elevated protein or lymphocyte count, and a monoclonal protein may be found in the serum. The spectrum of weakness ranges from stabilization and complete recovery to progressive weakness resulting in death. Outcome does not appear to be systematically related to treatment of the lymphoma. Although the neurologic manifestations precede the diagnosis of cancer in many patients, it may be reasonable to search for a particular cancer in specific clinical settings. For example, Forsyth and Dalmau recommend that patients with pure upper motor neuron syndromes resembling primary lateral sclerosis undergo screening mammography to search for breast carcinoma. Patients with motor neuron involvement and encephalopathy should be screened for anti-Hu antibodies and small cell lung cancer. Patients with an atypical motor neuron syndrome and monoclonal protein on serum immunofktion or immunoelectrophoresis, elevated CSF protein, or other laboratory evidence suggestive of a lymphoproliferative disorder should undergo skeletal survey and bone marrow biopsy. Patients with acquired demyelination on NCSs and elevated lymphocytes in the CSF should be evaluated for such. Some recommend screening all patients with clinically typical ALS for lymphoma. Toxins and Drugs

Investigations into the possible role of environmental and industrial toxins and drugs in MNDs have taken the form of epidemiologic studies and case reports. Most investigators have focused on the possible role of heavy metals, including lead, manganese, and aluminum. Chronic exposure to lead may result in a predominantly lower motor neuron syndrome of weakness, wasting, depressed reflexes, and occasional fasciculations. The upper extremities, specifically wrist and finger extensors and intrinsic hand muscles, generally are most affected. Rare cases of weakness with hyperreflexia have been reported. Constitutional symptoms, including weight loss, abdominal pain, constipation, anorexia, and fatigue, as well as minor personality and mood changes, are not uncommon. Needle EMG studies may show

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evidence of active and chronic denervation. Although some epidemiologic studies have shown a higher incidence of lead exposure in patients with typical ALS, these studies do not necessarily prove causality. However, a careful history of occupational exposure is mandated in any patient with ALS because chronic lead exposure can result in a motor system disorder with upper and lower motor neuron signs and symptoms. In particular, atypical features with constitutional symptoms and CNS changes as described earlier should raise suspicion. Although chronic exposure to lead vapor is rare, it can be seen in the setting of battery workers and car radiator repairers. The diagnosis of lead toxicity rests on finding elevated levels in the urine; blood levels are too insensitive to long-term exposure. Other laboratory values of help include a mild microcytic anemia with basophilic stippling. Diagnosis is confirmed by using chelating agents and measuring an increase in urine lead levels. There have been rare reports of elevated aluminum levels in the CNS tissue of patients with Guamanian Parkinson ALS, which is thought to be diet-related. Rarely, a predominantly lower motor neuron syndrome of distal weakness and wasting is noted with prolonged exposure to dapsone for various dermatologic disorders. The site of pathology is thought to be distal motor axon, with denervation noted on needle EMG. The effect is believed to be dose-related. Weakness generally reverses with withdrawal of the drug. Nitrofurantoin very rarely causes a predominantly motor neuropathy with axonal features. ElectrScal Injury Associated with MND There are rare reports of children and adults who develop a syndrome of upper and lower motor neuron signs after electrical injuries from either lightning, high-voltage power lines, or shorted household circuits. Weakness begins at the original site of trauma, days to months after the shock, usually in the upper extremity. Later, the contralateral upper extremity and then the bulbar musculature and lower extremities become involved. There is a tendency for symptoms to spread in a regional fashion, as in classic ALS. Eventually weakness, atrophy, and fasciculations develop, with spasticity and hyperreflexia. Sensory loss may be noted in the original area of shock, although sensory potentials are normal on electrophysiologic testing. In the rare cases that have come to autopsy, the pathology was classic for ALS. Although a few studies of patients with classic ALS have shown a higher than expected incidence of prior electrical and other types of injury compared with controls, causality has not been established. The relationship between electrical injuries and motor neuron syndromes is poorly understood, and at this point there is no known recommended treatment.

Postradiation MND Very rarely, patients exposed to ionizing radiation to treat a neoplasm have been known to develop a pure lower motor neuron syndrome. These patients typically present with progressive weakness, wasting, and fasciculations in the lower extremities 3 months to several years after radiation to the pelvis or lumbar region. There is a notable absence of pain, sensory symptoms, or bladder or bowel dysfunction. Reflexes usually are depressed or absent in weak limbs. The lower extremity muscles are preferentially involved, although radiation may involve the entire neuraxis, with typically 3500 to 5600 rad. A delayed lower motor neuron bulbar palsy, consisting of dysarthria, dysphagia, and in some cases

neck weakness, has also been reported after radiation to the head and neck for various neoplasms. CSF usually is normal, although there may be a mild elevation of CSF protein to approximately 50 mg/dL. Needle EMG reveals fibrillation potentials and fasciculations with reduced recruitment of large, prolonged, polyphasic motor unit action potentials in weak muscles. Myokymic discharges may also be seen. In some cases, muscle biopsy has shown chronic neurogenic changes, including fiber type grouping and small angulated fibers. The weakness generally ceases after several months, although rare patients continue to progress over years. The site of pathology is thought to be at the anterior horn cell, although the mechanism of cell damage is poorly understood. Suggestions have included ischemic injury to vessels feeding the anterior horn cells, activation of a latent virus, and a direct toxic effect of the radiation on the anterior horn cells themselves. Although there is no specific treatment for postradiation MND other than supportive therapy, treatment with anticoagulation has been tried in a small number of patients with delayed radiationinduced cerebral radionecrosis and myelopathy with some recovery of function. However, treatment modalities used for cerebral radiation necrosis may not be as useful in radiation-induced MND because the presumed pathogenic mechanism may be different from that of radiation-induced myelopathy or cerebral radiation necrosis. The clinical course is slowly progressive and usually confined to the region of the spinal cord exposed to the original radiation. Most patients stabilize after several months, and usually survive for 15 to 20 years after the initial presentation, although the weakness can be severe and debilitating.

Infectiousand Postinfectious Syndromes A pure motor syndrome known as acute motor axonal neuropathy has been reported, characterized by symmetrical progression of weakness over days to weeks, usually in the setting of a preceding gastrointestinal illness, and associated with elevated antibody titers of Cmnpylobucter jejuni, anti-GM1, and anti-GDla. Reflexes in weak muscles usually are lost, but may be retained, or brisk. There are no accompanying sensory signs or complaints, and CSF shows an elevated protein with normal cell count. NCSs reveal lowamplitude compound muscle action potentials with normal distal motor latencies, F-wave latencies, conduction velocities, and sensory potentials. No conduction block is seen in motor nerve conduction studies. Needle EMG reveals fibrillation potentials with reduced recruitment of motor unit action potentials. The site of pathology is thought to be distal motor axon. Several cases have been described in China, especially during the summer, although more recent reports have been described in the United States. Presentation of these patients differs from that of patients with classic Guillain-Barrk syndrome in that there is an absence of sensory complaints or signs, and reflexes may be preserved or even brisk, especially during the recovery stages of the illness. Some patients recover quickly, although in others recovery may take weeks to months. Retrovirus-Associated MNDs. Human immunodeficiency virus (HIV) infection has been associated with a variety of nerve and muscle disorders. Infrequent cases of HIV-infected young adults with a classic presentation of ALS both clinically and by electrophysiologic testing have been reported. Even rarer cases of a pure upper motor neuron syndrome have been reported. Any young adult presenting with an ALS-type syndrome and HIV risk factors should be screened because early treatment of the HIV infection is important. Human T-cell lymphotropic virus-type 1

4

g

Consider

Lumbar Puncture for Elevated CSF Protein, WBC

I

Conduction Block Absent, Primarily Distal Weakness, Elevated Anti-Glycolipid Antibodies, and Denervation on EMG

Conduction Block, with or without Elevated AntiGlycolipid Antibodies

Primarily Motor Syndrome with:

Consider lmmunotherapy if:

I

HIV risk factors

History of Electrical Injury, Prior Irradiation, Polio

Exposure to ToxindDrugs, Especially Lead, Dapsone, Nitrofurantoin

Question for Neoplasm, Especially Lymphoma

HistoryMlork-up Should Always Include:

'

I I

Blood Studies for AntiGlycolipidAntibodies

I

I

If Pontocerebellar Atrophy, DNA Testing for Inherited Cerebellar Ataxia

1

Blood Hexosaminidase A,B Levels

MRI Scan of Brain for Pontocerebellar Atrophy

1

If Any of these Present:

Cognitive and/or Psychiatric Dysfunction

Cerebellar and/or Extrapyramidal Signs

Conduction Block Absent, but One of the Following Present:

I

Conduction Block Absent, but Weakness Primarily Distal with Denervation on EMG

L

FIG. 89-2. Algorithm for the diagnostic approach to patients with atypical motor neuron disease. IPEP, immunoprotein electrophoresis; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

If Monoclonal Protein Found, Consider Skeletal Survey, Bone Marrow Biopsy

Proceed with Appropriate

If Elevated WBC

Consider:

Blood Studies for SPEP, IPEP, UPEP

I

Blood Studies for AntiGlycolipidAntibodies

If Conduction Block Present, but Syndrome is Sensorimotor, Consider Other Demyelinating Neuropathy

I

*I

I

,

History of Weakness:

Spontaneous Remissions Age of Onset of Illness e 35 Years Duration of Illness > 5 Years Lack of Bulbar InvolvementAfter 1 Year

.

I

Conduction Block Present

I

EMG Studies to Look for Conduction Block in Motor Nerves

Non-Myotomal Weakness Weakness Without Muscle Wasting Lack of Upper Motor Neuron Signs in Weak Segments Non-Regional Spread of Weakness

Pattern of Weakness:

Are Any of the Following Present?

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(HTLV-1) has been associated with a progressive upper motor neuron syndrome consisting of spastic paraparesis, accompanied by bladder and sensory dysfunction, in a syndrome known as tropical spastic paraparesis, or HTLV- 1-associated myelopathy. The sensory findings and bladder dysfunction should alert the clinician to the presence of a disorder other than ALS. A motor neuron syndrome mimicking ALS is also observed in a series of patients with HTLV- 1 infection. The presence of spastic paraparesis or typical ALS symptoms associated with minor sensory findings or bladder dysfunction, especially in an area endemic for HTLV-1, should prompt a search for HTLV-1 antibodies.

Radiculopathy and Myelopathy One must always consider spinal lesions in patients presenting with progressive motor dysfunction. Cervical spondylosis, for example, may result in compromise of the cervical roots and spinal cord. In this situation, lower motor signs of weakness, atrophy, and fasciculations are seen at the level of the root compression, whereas upper motor neuron signs of hyperreflexia and spasticity are seen at levels below, from cord compression. This specific pattern of involvement-upper motor neuron signs at levels below lower motor neuron signs-should suggest the possibility of a spinal lesion. This condition should be suspected especially when there is a history of arthritis, neck pain, or neck spasm. An MRI scan of the cervical spine is useful in such a presentation. Other important clinical clues include sensory loss in the same root distribution as the weakness and vibratory and joint position loss in the lower extremities, presumably from posterior column dysfunction. There may be bladder or bowel dysfunction from cord compromise, which is unusual in MND. Needle EMG can be very helpful in documenting the extent of lower motor neuron involvement from cervical root compression, which should not be present at sites below the root compromise unless there is a coexisting process such as ALS. However, the coexistence of lumbosacral radiculopathy may also confuse the picture, with findings of denervation in leg muscles on needle EMG. There are also rare reported cases of fasciculations in the lower extremities in cases of cervical spondylosis with myelopathy, although clearly this should be considered an exception. Careful clinical and electrophysiologic examination are warranted to look for fasciculations and denervation and reinnervation in muscles outside the cervical and lumbosacral regions, such as bulbofacial and thoracic paraspinal muscles. These findings are very useful in clarifymg a potentially confusing clinical situation. Some patients with ALS and severe cervical spondylosismay derive temporary benefit from cervical decompression.

CONCLUSIONS Over the next several years, a greater understanding of the atypical MNDs, particularly the pathogenesis of the presumed immunemediated disorders, will undoubtedly emerge. Further clarification of these disorders will guide the workup and treatment. At present, any patient who presents with an atypical form of MND, either by clinical history or examination, should have a careful and

thorough workup to screen for the presence of a treatable or genetic disorder or one that has a more favorable course than typical ALS (Fig. 89-2). The evaluation should include at the very least thorough electrophysiologic testing to look for evidence of conduction block through segments of motor nerves, blood testing for elevated antiglycolipid antibody titers, serum and urine immunoprotein electrophoresis, and a careful family history. Patients with motor conduction block on electrophysiologic testing, with or without elevated antibody titers, or elevated antibody titers in the proper clinical context, may well benefit from immunosuppressivetherapy. The finding of a monoclonal protein in the blood or urine should lead to a skeletal survey and bone marrow biopsy. A positive family history with cerebellar, extrapyramidal, cognitive, or psychiatric dysfunction should alert one to the possibility of a multiple-system disorder. In such situations, evaluation should include at the very least an MRI scan of the brain to look for pontocerebellar atrophy, DNA testing to screen for an inherited cerebellar ataxia, and blood testing for abnormal levels of hexosaminidase A and B. All patients should be questioned for any history of toxin exposure, especially lead, a history of electrical injury, radiation, or polio, and constitutional symptoms that may suggest a neoplasm. Patients with spasticity and hyperreflexia at levels below lower motor neuron signs should undergo imaging of the appropriate spinal segments, preferably with an MRI scan, to look for evidence of combined root and cord compression that can be treated.

SUGGESTED READINGS Boonyapisit K, Shapiro B E Atypical motor neuron disorders. In Katirji B, Shapiro BE, Kaminski H et al; editors: Neurornuscular Disorders in Clinical Practice. Woburn, Mass., Butterworth-Heinemann,2002 Federico P, Zochodne DW, Hahn AF et ak Multifocal motor neuropathy improved by IVIg. Neurology 55:1256-1262,2000 Harding AE, Deufel T Advances in Neurology. Vol. 61. Inherited Ataxias. Raven Press, New York, 1993 Kornberg AJ, Pestronk A The clinical and diagnostic role of anti-GM1 antibody testing. Muscle Nerve 1 7 100-104, 1994 Navon R, Argov Z, Frisch A HexosaminidaseA deficiency in adults. Am J Med Genet 24179-196, 1986 Pestronk A Invited review: motor neuropathies, motor neuron disorders, and antiglycolipid antibodies. Muscle Nerve 14927-936, 1991 Pestronk A, Chaudhry V, Feldman E et ak Lower motor neuron syndromes defined by patterns of weakness, nerve conduction abnormalities,and high titers of antiglycolipid antibodies. Ann Neurol 27:3 16-326, 1990 Pestronk A, Choksi R Multifocal motor neuropathy. Serum IgM anti-GM1 ganglioside antibodies in most patients detected using covalent linkage of GM1 to ELISA plates. Neurology 49:1289-1292, 1997 Rosenfield M, Posner J: Paraneoplastic motor neuron disease. pp. 445-459. In Rowland LP (ed): Advances in Neurology. Vol. 56. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. Raven Press, New York, 1991 Sadiq S, Latov N Monoclonal gammopathy and motor neuron disease. Adv Neurol413420, 1991 Sadowsky CH, Sachs E Jr, Ochoa J: Postradiationmotor neuron syndrome. Arch Neurol33:786-787, 1976 Younger DS, Rowland LP, Latov N et ak Lymphoma, motor neuron diseases, and amyotrophiclateral sclerosis. Ann Neurol29:78-86, 1991

SECTION

3 DISEASES OF PERIPHERAL NERVE

90

Approach to and Classification of Peripheral Neuropathy Eric L. Logigian and David N. Herrmann

Nerve dysfunction has a limited repertoire of clinical expression (Table 90- 1) but hundreds of possible causes. Therefore, recognizing neuropathy usually is not difficult, whereas determining the cause often is. The best chance of making an etiologic diagnosis is through systematic classification of the neuropathy, as shown in Table 90-2. The questions appearing in Table 90-2 are answered with the help of several tools, the most important of which are the patient history, physical examination, and electrophysiologic studies, followed by various laboratory tests and examination of family members. The clinician can then determine whether knowledge of nerve histology is likely to be useful enough to justify performing a nerve biopsy. A simplified paradigm illustrating this approach to the evaluation of polyneuropathy is shown in Figure 90-1. Similarly, Tables 90-3,90-4,90-5, and 90-6 show how the various neuropathies can be classified based on clinical and electrophysiologic features.

FIBER TYPES

Signs and symptoms of a peripheral neuropathy reflect the fiber types (sensory, motor, and autonomic) that are affected. Dysfunction of each fiber type results in “negative” and “positive” symptoms and signs (Table 90-1). As the patient’s medical history unfolds, the nature of the symptoms tell us which fiber types are involved. Inquiry into what the patient can or cannot do often is useful. For example, motor fiber involvement of distal limb muscles may cause trouble with unscrewing jar lids from weakness of hand muscles or a tendency to trip when walking, caused by footdrop. Involvement of proximal limb muscles may cause trouble in reaching above the head to comb or dry the hair, getting out of a chair, or walking upstairs. Sensory loss often results in difficulty performing fine motor tasks (out of proportion to distal muscle weakness) such as buttoning, zipping, and knitting. In the lower extremities, sensory loss may lead to balance trouble, making it difficult to walk in the dark or put on stockings while standing on one foot. Pain is a common sensory manifestation of peripheral neuropathy. One should determine its quality using the patient’s own words: where it is centered, whether it radiates, and what exacerbates or improves it. The physical examination affords the opportunity to quantitate the negative deficits in the three fiber systems; positive motor or autonomic phenomena may also be observable. With respect to

motor fibers, disease of this fiber population is based on the presence of muscle atrophy and weakness. Particular attention should be paid to the tongue, spinati, deltoid and interossei muscles of the hand, the extensor digitorum brevis muscles of the feet, the calf, and tibialis anterior and quadriceps muscles. Quantitating muscle strength usually is performed with the confrontation method, but in powerful leg muscles such as the hip abductors and ankle plantar flexors, more subtle weakness may be elicited by standing on one foot (to elicit pelvic tilt) and by attempting to walk on tiptoes, respectively. With confrontation muscle testing, the 0- to 5-point MRC scale is most useful for severe muscle weakness, but not for more subtle weakness in the 4

TABU90-1. Signs and Symptoms of Peripheral Nerve Disease NeNeS

Involved

Negative

Positive

Motor

Weakness, wasting, clumsiness, areflexia, hypotonia, deformities (pes cavus, kyphoscoliosis) Sensory loss, ataxia, clumsiness, areflexia, hypotonia Postural hypotension, anhidrosis, impotence, bowel or bladder disturbance

Muscle twitches (fasciculations, myokymia), cramps

Sensory Autonomic

Tingling, pins and needles, burning Hyperhidrosis, gustatory sweating Foot ulceration, Charcot arthropathy

Trophic

TABU90-2. Causes of Neuropathy Area to Be Examined

Considerations

Anatomy

What fiber types (sensory, motor, autonomic) are involved? How is the neuropathy evolving in space? How is the neuropathy evolving in time? Are there dues to an inherited neuropathy? Is there evidence of an underlyingsystemic disease, malnutrition, or exposure to neurotoxins (e.g., medicines, solvents)? Is there predominant axon loss or dernyelination? Are there distinctive pathologic features? What is the functional severity?

Chronology Family history Associated conditions Physiology Pathology Severity

569

0

uul

r Consider HIV

/

t

Consider biopsy

Consider biopsy

Consider Consider systemic leprosy, vasculitis, perineuritis diabetes I

Subacute or chronic

1

Axonal

Subacute Acute or subacute

Consider ClDP

Consider HPPP

+

Chronic

4

Demyelinating

Multifocal or asymmetric

I

t

r Consider HMSN I, Ill, IV

t

Chronic

Consider ClDP

Consider HIV, MGUS, myeloma

Consider GBS

HIV

Consider

Subacute or chronic

.) Uniform slowing

.)

Acute

I

$. I

Consider biopsy

1

Consider axonal GBS

3

Consider biopsy

Idiopathic

Consider diabetes, malignancy, amyloidosis

Consider HMSN II

r

Subacute or chronic

Consider MFMN

Consider neuronopathy

Consider CIP, systemic vasculitis, toxins

Consider porphyria

F

Demyelinating

Pure motor

Axdnal

Axdnal

Acute or subacute

Generalized and symmetric

Demyelinating

t

$.

Pure autonomic

Consider neuronopathy

Pure sensory

Nonuniform slowing

Mixed

FIG. 90-1. A scheme for the diagnostic evaluation of polyneuropathy. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CIP, critical illness polyneuropathy; CBS, Cuillain-Barresyndrome; HIV, human immunodeficiency virus; HMSN, hereditary motor and sensory neuropathy (often used interchangeablywith Charcot-Marie-Tooth disease); HPPP, hereditary predispositionto pressure palsy; MFMN, multifocal motor neuropathy; MGUS, monoclonalgammopathy of undetermined significance. (Modified from Logigian EL: Peripheral neuropathy. pp. 325-331. In Feldmann E (ed): Current Diagnosis in Neurology. CV Mosby, Boston, 1994, with permission.)

Nerve biopsy?

Systemic disease, toxins, malnutrition?

Examination of family members?

Temporal evolution?

Physiology?

Spatial evolution?

Fiber types?

Chapter 90 rn Approach to and Classification of Peripheral Neuropathy

TMU 90-3.Differential Diagnosis of Neuropathy Based o n Clinical and Electrophysiologic Classification: Axonal and Symmetrical Sensorimotor, Axonal

Pndominantiy Motor Axonal

Acute AMSAN syndrome Vasculitis Alcohol, nutritional, toxic Subacute or chronic Vitamin B,2, B, deficiency Gastric surgery Celiac sprue, Whipple's disease Alcohol toxicity Arsenic, thallium toxicity N-Hexane toxicity Acrylamide, CS2 toxicity Organophosphate toxicity Ethylene oxide toxicity Colchicine, chloroquine toxicity Disulfiram toxicity Metronidazole toxicity Nitrofurantointoxicity Phenytoin toxicity HIV DSP Lyme disease HTLV-1 Paraneoplastic (solid organ tumors) MGUS associated (IgA/lgG) Multiple myeloma Amyloidosis Diabetes Hypothyroidism Acromegaly COPD CTD (SLE, Sjogren's, MOD) PNS vasculitis Sarcoidosis Benign, elderly

Acute AMAN syndrome Porphyria Dapsone toxicity Vincristine toxicity Critical illness polyneuropathy Acute alcohol-related neuropathy Subacute or chronic Subacute motor neuronopathy (paraneoplastic) CMTX, CMT2 (HMSN 2) Lead poisoning Vincristine Hypoglycemia (insulinoma) Sensory Only, Axonal

Acute Idiopathic sensory neuronopathy Paraneoplastic Acute pyridoxine toxicity Cis-platinum Paclitaxel Miller Fisher syndrome (may be demyelinating) HIV infection Subacute or chronic Paraneoplastic (anti-HU+ or anti-HU-) Paraprotein associated Sjogren's syndrome Mitochondria1cytopathy Thalidomide toxicity Dideoxycytidine toxicity Didanosine toxicity Pyridoxine toxicity Chronic inflammatory sensory neuropathy Primary biliary cirrhosis Vitamin E deficiency Friedreich's ataxia Hereditary sensory neuropathy (Wpe 1)

Abbreviations: AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy; CMT, Charcot-Marie-Tooth disease; COPD, chronic obstrucconnective tissue disease; tive pulmonary disease; CS2, carbon disulfide; 0, HIV DSP, human immunodeficiencyvirus distal symmetrical polyneuropathy; HMSN, hereditary motor and sensory neuropathy; HTLV-I, human T-cell lymphotrophic viNS type 1; MOD, mixed connective tissue disease; MGUS, monoclonal gammopathy of unknown significance; PNS peripheral nervous system; SLE systemic lupus erythematosus. Reprinted from Herrmann D and Logigian E: Approach to peripheral nerve disorders. In Katirj B, Kaminski H, Preston D et al. (eds): Neuromuscular Diseases in Clinical Practice. Butterworth-Heinemann, Wobum, MA, 2002, with permission.

to 5 range. This is because the MRC scale is nonlinear, and the range from 4 to 5 represents the upper 50% of the range of muscle force. For that reason, in patients with milder weakness, muscle strength is better estimated as a percentage of normal. In any case, limb muscles are tested along a proximal to distal axis from the shoulder and hip girdle muscles to those acting across the elbow and knee, to those acting at the wrist and ankle, and finally to the intrinsic hand and foot muscles. Most polyneuropathies selectively involve the longest nerve fibers and preferentially affect distal muscles, more in the legs than the arms. In the mildest cases, only the intrinsic foot muscles may be affected. In the severest, all muscles may be affected, including axial muscles innervated by short nerves such as the neck flexors and rectus abdominis. With respect to sensory fibers, the two most useful bedside tests

571

are sharp-dull discrimination (for small-fiber sensory function) and vibratory sense (for the large-fiber sensory system). The clinician establishes areas of reduced sensation in symptomatic areas (usually the toes and fingers) relative to more proximal asymptomatic areas, as well as areas where sensory stimuli are associated with positive or heightened phenomena (e.g., pain, H TMLE 90-4. Differential Diagnosis of Neuropathy Based o n

Clinical and Electrophysiologic Classification: Demyelinative (Clinically Symmetrical) Motor > Sensory Demyelinathg

(acquired)

Motor > Sensory Inherited (uniform

demyelination)

Acute AlDP SLE HIV-associatedAlDP Arsenic poisoning N-Hexane-associated neuropathy (initially) Diphtheria Gold toxicitv Subacute or chronic (acquired) ClDP (idiopathic or with associated condition) POEMS/Castleman syndrome MGUS-associated neuropathy (e.g., IgM) Hypothyroidism Amiodarone Perhexiline Chloroquine Cytosine arabinoside Tacrolimus GVHD, organ rejection

CMTlA,B (HMSN I) CMTX (may have nonuniform or intermediate electrophysiology) CMT3 (HMSN 111) CMT4 (HMSN IV) Metachromatic leukodystrophy Globoid leukodystrophy Cockayne's syndrome Tangiers disease (some cases)

-

Sensory and Motor Polyneuropathy with Indeterminate Electrophysi-

Ology Diabetes mellitus End-stage renal disease ClDP (some cases) CMTX

Abbreviobbns: AIDP, acute inflammatory demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinatingpolyneuropathy; CMT, Charcot-Marie-Toothdisease; GVHD graft versus host disease; HN, human immunodeficiencyvirus; HMSN hereditary motor and sensory neuropathy; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; SLE, systemic lupus erythematosus. Reprinted from Herrmann D, Logigian E: Approach to peripheral nerve disorders. In Katirj B, Kaminski H, Preston D et al. (eds): Neuromuxular Diseases in Clinical Practice. Buttenworth-Heinemann,Woburn, MA, 2002, with permission.

TAU 90-5. Differential Diagnosis of Neuropathy Based on Clinical and Electrophysiologic Classification: Clinically Asymmetrical Sensorimotor Axonal

Acute Vasculitis Endocarditis Perineuritis Subacute or chronic Vasculitis, isolated PNS Vasculitis, systemic Vasculitis with connective tissue disease -. .~~ Vasculitis, paraneoplastic (rare) Vasculitis with infection (HIV. . . hepatitis B and C) Cryoglobulinemia Diabetes mellitus Sarcoidosis Perineuritis Lyme disease ~

DemyelinatingMixed Motor and Sensoy

Acute AlDP (rarely asymmetrical) Subacute or chronic MADSAM Focal upper extremity demyelinating ClDP HPPP LeDrosv .

I

Demyelinating Motor Only

Subacute or chronic Multifocal motor neuropathy

Abbrevidorts: AIDP, acute inflammatory demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinatingpolyneuropathy; HIV, human immunodeficiencyvirus; HPPP, hereditary neuropathy with liability to pressure palsies; MADSAM, multifocal acquired demyelinating sensory and motor neuropathy; PNS, peripheral nervous system. Reprinted from Herrmann D, Logigian E: Approach to peripheral nerve disorders. In Katirj B, Kaminski H, Preston D et al. (eds): Neuromuscular Diseases in Clinical Practice. Buttetworth-Heinemann,Woburn, MA, 2002, with permission.

572

Spinal Cord and Peripheral Neuromuscular Disease rn Diseases of Peripheral Nerve

TAW 906. Predominantly Small-Fiber Neuropathies Acute

Chronic

Diabetes mellitus (e.g., insulin initiation) Acute pandysautonomia Acute idiopathic small-fiber sensory neuropathy

Primary amyloidosis Familial amyloidosis Fabry's disease Tangiers disease Hereditary sensory and autonomic neuropathies: (type 1 [some], 111, IV, v) Chronic idiopathic small-fiber sensory neuropathy

Reprinted from Herrmann D, Logigian E: Approach to peripheral nerve disorders. In Katirj 6, Kaminski H, Preston D et al. (eds): Neuromuscular Diseases in Clinical Practice. Buttewolth-Heinemann, Woburn. MA, 2002, with permission.

tingling). The more proximally the sensory disturbance extends, the more severe the neuropathy. In addition, because station, gait, and limb coordination depend on large-fiber sensory feedback, the Romberg sign and ataxia of gait and limb can be manifestations of sensory neuropathy and should be specifically elicited. Because pain often is a symptom of polyneuropathy, it should be remembered that many sensory neuropathies, particularly those with prominent or pure small-fiber involvement (Table 90-6), have spontaneous burning or pressure-induced pain as a major component and associated disability. The reflex examination, particularly the tendon jerks, is an easily performed and objective aspect of the physical examination. The presence of tendon areflexia in symptomatic limbs strongly supports the diagnosis of neuropathy affecting either the sensory afferents or motor efferents subserving the reflex arc. The presence of a plantar extensor response in a patient with symptoms consistent with polyneuropathy suggests that the correct diagnosis may be a central nervous system lesion, usually of the spinal cord. However, it should be remembered that there are certain diseases in which both the central and peripheral nervous systems are affected. The most important of these is vitamin B,, deficiency. The autonomic nervous system is difficult to assess even in the laboratory. At the bedside, one is generally limited to checking for orthostasis, anhydrotic skin in the extremities, and abnormal pupillary responses. Most polyneuropathies involve all three fiber types, particularly the sensory and motor populations. At onset, however, the only abnormalities may be positive sensory phenomena. Given time, significant motor and autonomic fiber involvement may occur. With more severe, longer-standing neuropathy, if only one fiber type appears to be involved, the clinician should consider one of the neuronopathies as a diagnosis. Sensory neuronopathy may be a paraneoplastic manifestation of small cell carcinoma with elevated anti-Hu antibody, an autoimmune manifestation of Sjogren's disease, or a toxic manifestation of pyridoxine abuse or may be idiopathic. For motor fibers, the diagnosis of motor neuron disease of some type should be considered. An alternative diagnosis in a patient with only lower motor neuron findings is multifocal motor neuropathy with conduction block, a disorder that should not be missed because, in contrast to the motor neuronopathies, it can be treated effectively.

SPATIAL EVOLUTION Determiningthe spatial distribution of the neuropathy is crucial in determining whether the disease is localized to one body part (e.g., limb, trunk, cranial-innervated structure), as in a radiculopathy,

mononeuropathy, or plexopathy, or whether it is a more generalized process. If the disease is generalized, the next question is whether its pattern of evolution is asymmetrical and multifocal or symmetrical and diffuse. By asking which body part was affected first, second, and so on, the clinician can learn whether the neuropathy evolved symmetrically or asymmetrically. For example, most acquired neuropathies present with a symmetrical sensory disturbance in the feet, which then ascends to the knees, followed by the fingertips, forearms, anterior chest wall, and top of head. Neuropathy that begins only in one leg, for example, or in both hands, sparing the feet, is more unusual and suggests an asymmetrical or multifocal process. The patient history is most important in making this distinction because cumulative multifocal deficits eventually may become confluent and appear on physical examination later in the course to be symmetrically, diffusely distributed when in fact they accrued asymmetrically. Still, the physical examination may show that some nerves are affected out of proportion to others by the presence of interlimb and intralimb asymmetries in nerve function. Asymmetrical or multifocal polyneuropathy suggests the syndrome of mononeuropathy multiplex. This syndrome has a differential diagnosis that includes many treatable forms of neuropathy (e.g., vasculitic neuropathy, leprosy, chronic inflammatory demyelinating polyradiculoneuropathy [CIDP],multifocal conduction block). Its recognition therefore is of key importance in evaluating patients with polyneuropathy. Finally, in generalized symmetrical polyneuropathy, there are some exceptions to the usual pattern of selective distal involvement. For example, in Guillain-BarrC syndrome, CIDP, or porphyric neuropathy, the girdle muscles may be as weak as or weaker than the distal limb muscles.

TEMPORAL EVOLUTION The temporal evolution of signs and symptoms is gathered in parallel with the spatial data. Only the history can provide precise temporal information about the disease, although the physical and electrophysiologicexaminationsmay provide some clues to disease chronicity. The two key points to ascertain are the time from onset to nadir, or from onset to the current state if the nadir has not been reached, and the pattern of the descent: smooth, stepwise, or relapsing-remitting. Acute sensorimotor neuropathy with a time to nadir of less than 6 weeks is caused by only a few conditions, the most common being Guillain-Barr6 syndrome; others to consider are porphyric neuropathy, rapidly progressive vasculitic neuropathies, various acute toxic neuropathies (e.g., ingestion of large amounts of thallium or arsenic), and critical illness polyneuropathy. Severe, subacute progressive, or stepwise sensorimotor polyneuropathy with a time to nadir of 2 to 12 months has a broader differential diagnosis. The main treatable neuropathies to exclude are CIDP and vasculitic polyneuropathy. The former sometimes has a relapsing-remitting course.

FAMILY HISTORY Patients with inherited polyneuropathy may remain asymptomatic for decades before seeking medical attention. Such patients typically have signs of neuropathy on examination but are unaware of their neuropathy (or those of family members) because of its slow progression. When such a patient finally seeks medical attention, clinicians may assume that the neuropathy is '

Chapter 90

acquired unless they pay attention to three clues. The first is that long-standing neuropathy may produce characteristic deformities of the foot (pes cavus) and of the spine (kyphoscoliosis). The second is that in comparison to most acquired neuropathies, typical hereditary sensorimotor neuropathy has little in the way of positive sensory phenomena. The third is that examination of family members, even when asymptomatic, may reveal polyneuropathy. Recently, genetic tests have become available for diagnosing the most common demyelinative hereditary neuropathies (hereditary motor and sensory neuropathy, type IA,hereditary predisposition to pressure palsy). The nonresearch indications for these tests still are not clear, but they are occasionally useful in evaluating patients with an atypical presentation for these disorders or for genetic counseling. SYSTEMIC DISEASE, MALNUTRITION, AND TOXINS In the review of systems, the clinician must exclude diabetes, connective tissue disease, underlying malignancy, infection, malnutrition, megavitaminosis, and exposure to drugs, alcohol, or toxins at the workplace. On physical examination, signs of malnutrition (cheilosis,tongue depapillation) should be sought in addition to skin rash, adenopathy, thyromegaly, joint swelling, breast masses, and stool guaiac. Various blood studies sometimes are helpful in documenting the presence of a systemic disease associated with neuropathy. In general, when the history and physical examination do not provide a clue to the presence of these diseases, the screening tests designed to detect their presence are negative. Certainly a fasting blood sugar should be obtained in any patient whose neuropathy is undiagnosed. However, given the vagaries of glucose tolerance testing, this test can be difficult to interpret. Electrolytes, particularly creatinine and blood urea nitrogen, should be obtained. A vitamin B,, level and complete blood count should be obtained, particularly in patients with a predominantly sensory neuropathy with or without corticospinal findings. Thyroid function tests usually are obtained, but they are rarely helpful. Similarly, detailed connective tissue screens in the absence of any symptoms or signs of connective tissue disease are rarely positive, and detailed testing to detect underlying neoplasia usually is fruitless. The exception is a patient with sensory neuronopathy and anti-Hu antibody in whom small cell carcinoma of the lung is likely. Otherwise, a simple chest radiograph, breast examination, and stool guaiac testing is usually enough. As many as 10% of patients with polyneuropathy have a monoclonal spike on serum electrophoresis. In many cases, the monoclonal protein appears to cause the neuropathy. It is therefore useful to obtain serum and urine protein and immunoelectrophoresis in a patient with otherwise idiopathic polyneuropathy. If a monoclonal paraprotein is found, then bone marrow biopsy and bone survey should be considered. The majority of such patients have no underlying hematologic disease and have what is now called monoclonal gammopathy of undetermined significance (MGUS) neuropathy. Approximately 50% of these patients have an immunoglobulin (Ig) G or IgA monoclonal protein; the remainder have IgM. In about one half of the patients with IgM, the IgM cross-reacts to myelin-associated glycoprotein (MAG); the other epitopes are not yet known. Patients with IgM monoclonal protein are more likely to have demyelinative physiology than are those with IgG or IgA, although there is a large overlap. There are occasional patients with an anti-MAG polyneuropathy who lack a monoclonal protein. Therefore, in a patient

Approach to and Classification of Peripheral Neuropathy

573

with predominantly sensory demyelinative polyneuropathy (characteristic of anti-MAG), it is reasonable to order this test even in the absence of an IgM or IgG spike. Although leprosy is the most common cause of neuropathy worldwide, in Western culture infectious causes of neuropathy are rare. The two to consider are human immunodeficiency virus (HIV) and Borrelia burgdorferi infections. Early in the course of HIV infection, Guillain-Barrk syndrome and CIDP can occur. Later, a painful sensory neuropathy may develop. In a patient with these kinds of neuropathies who is at risk for HIV, it is reasonable to obtain HIV titers. Lyme disease produces an acute painful radiculoneuropathy, often in association with facial palsy and meningitis in addition to a more chronic, milder sensory neuropathy. In patients with these syndromes who live in areas endemic for the organism, it is reasonable to obtain a serum Lyme titer. Otherwise, Lyme disease testing is more likely to yield false positives than true positives. An underused test is spinal fluid examination. In a patient with a chronic or subacute progressive polyneuropathy in whom other studies are not particularly helpful, the spinal fluid is useful in excluding cytoalbuminologic dissociation. This is seen most commonly in patients with diabetes or inflammatory demyelinating neuropathy. If cerebrospinal fluid protein is very high and the patient does not have diabetes, the diagnosis of CIDP should be considered even if electrodiagnostic and nerve biopsy studies are indeterminate. PHYSIOLOGY The electrophysiologic examination is very useful in several respects. It helps confirm the presence of polyneuropathy and differentiate it from other related disorders. It provides objective data concerning the severity, side-to-side symmetry, and chronicity of the neuropathy. Most importantly, physiologic studies are critical in localizing entrapment mononeuropathies or in determining whether polyneuropathy is primarily demyelinative or axonal. Furthermore, it can often differentiate acquired from hereditary demyelinating neuropathy by the presence of nonuniform slowing of nerve conduction. Because acquired demyelinating neuropathy is caused by a short list of treatable diseases (CIDP, some forms of MGUS neuropathy, multifocal conduction block, and osteosclerotic myeloma) and hereditary neuropathy by a short list of genetic diseases (e.g., hereditary motor and sensory neuropathies I, 111, and IV), electrophysiologicstudies to exclude predominant demyelination are central to the evaluation of polyneuropathy (Table 90-4). Still, it should be remembered that there are some problems with these tests. Unless special studies are performed, results may be negative in the rare pure autonomic or small-fiber sensory neuropathy (because routine electrophysiologic studies detect medium- and large-fiber abnormalities of the motor and sensory populations) and in mild sensory neuropathy with only paresthesia and no (or minimal) negative signs (because routine sensory studies document only negative phenomena).

NERVE BIOPSY Nerve biopsy is almost never performed simply to confirm nerve disease. The history, physical examination, and electrodiagnostic studies can almost always do that. Rather, nerve biopsy is reserved for diagnosis of a few rare diseases with a characteristic histologic signature, such as vasculitic neuropathy, followed by leprosy,

574

Spinal Cord and Peripheral Neuromuscular Disease W

Diseases of Peripheral NeNe

sarcoidosis, amyloidosis, and the leukodystrophies. It may also be used in progressive polyneuropathies in which the diagnosis remains uncertain despite complete workup. In such cases, the clinician would be looking for histologic evidence of inflammatory neuropathy or possibly demyelination in a patient who does not meet demyelinative criteria electrophysiologically.

DIAGNOSTIC CLASSIFICATION Answers to the questions posed earlier allow classification of the neuropathy into clinically useful categories. Tables 90-3, 90-4, 90-5, and 90-6 delineate such a classification according to fiber type involvement, spatial and temporal evolution, presence of systemic disease or neurotoxins, family history, physiology, and pathology.

SEVERITY Negative and positive symptoms of peripheral nerve disease result in functional problems that may range in severity from annoying paresthesia, mild gait ataxia, or minimal loss of hand dexterity without functional impairment to quadriplegia, deafferentation, or autonomic failure that leaves the patient bedbound and helpless. In determining disease severity, one should address both the primary symptoms and signs (Table 90-1) and the patient’s unique functional problems produced by the neuropathy on activities of daily living or on occupational tasks. Thus, the same polyneuropathy that is of minor severity for a sedentary executive could be debilitating for an athlete or a musician. Naturally, the pace of the workup and the aggressiveness of treatment depends on the functional severity of the neuropathy. PROBLEMS IN NEUROPATHY DIAGNOSIS Pseudoneuropathy Taken one by one, almost all physical findings that we commonly consider to be indicative of neuropathy are not. For example, distal muscle wasting and weakness is seen in the rare cases of distal myopathy or spinal muscular atrophy. Stocking sensory loss can be seen in patients with dorsal column lesions, as in spinal multiple sclerosis. Ankle areflexia can be seen in patients with spinal cord disease. The bedside diagnosis of polyneuropathy is most secure when a number of these signs occur together in the absence of signs suggesting disease elsewhere. Even then, it can be difficult to differentiate root from nerve disease clinically, as in a patient with spinal stenosis of the lumbosacral spine (e.g., polyradiculopathy) and a patient with progressive sensorimotor polyneuropathy. Both may have distal sensory loss, muscle weakness, and ankle areflexia. Clinically, the two may be differentiated by the presence of pseudoclaudication or radicular back pain in spinal stenosis and distal burning pain in neuropathy. The electrophysiologic clue is the presence of normal sensory potentials in spinal stenosis and low-amplitude potentials in polyneuropathy. Occasionally, cervical transverse myelitis and spinal shock together (e.g., flaccid areflexic paralysis) are confused with an acute polyneuropathy such as Guillain-Barrk syndrome. Clinically, the patient with spinal cord disease is distinguished by the presence of a sensory and motor level, a brisk cerebrospinal fluid pleocytosis, and the absence of peripheral demyelinative electrophysiology.

Pseudoradiculopathy Cervical radiculopathy caused by disc disease is common; brachial “plexopathy” (better called brachial neuritis) is not. Therefore, it is no surprise that the latter often is misdiagnosed as the former. This mistake has important implications because the diagnosis of radiculopathy typically prompts a magnetic resonance imaging study of the spine. It is rare for such studies to be totally normal, and inappropriate disc surgery is the unfortunate outcome. Clinically, the disorders are separable by the nature and location of the accompanying pain (usually centered in the neck with radiation to the arm and exacerbated by head movement in radiculopathy and centered in the shoulder without radiation or worsening with head movement in brachial neuritis) and the presence of characteristic neurologic deficits in the distribution of one or more cervical roots in radiculopathy and in one or more characteristic nerves (long thoracic, suprascapular, axillary, anterior interosseous) in brachial neuritis. In the lower extremity, a similar scenario may occur in patients with diabetic amyotrophy, herpes zoster, or lumbosacral neuritis who may be misdiagnosed as having lumbosacral radiculopathy caused by disc disease. Again, one of the major distinguishing features is the presence of radiating back pain and mechanical exacerbation of pain in lumbosacral radiculopathy; in the other conditions, the pain typically is more severe and not centered in the back or worsened by back range of motion.

Pseudostroke Acute mononeuropathies of the radial, proximal median, and peroneal nerves may initially be confused with plexus or root lesions or even stroke. Armed with an analytic approach and knowledge of anatomy, the clinician recognizes that all the deficits are in the territory of one nerve.

“Negative” Family History Hereditary neuropathy is very slowly progressive and is not characterized by many positive sensory phenomena. Therefore, it may not be noticed by the patient (or by affected family members) until late in life. Particularly with a “negative” family history and the absence of pes cavus deformity, examination of family members may be helpful in clinching the diagnosis of hereditary neuropathy in a patient with long-standing “idiopathic” neuropathy.

Indeterminate Physiology There are occasional patients with possible CIDP whose nerve conduction studies do not meet criteria for demyelinative physiology. Because this neuropathy often is progressive, severe, and treatable, a nerve biopsy to carefully search for demyelinative histology with teased fiber analysis and a spinal tap to exclude a high cerebrospinal fluid protein should be considered.

UnderlyingDiabetes The most common cause of neuropathy in Western culture is diabetes. The spectrum of diabetic neuropathy is broad. It can present as a mononeuropathy multiplex or as a symmetrical polyneuropathy involving single or multiple fiber types. Therefore, when a patient has neuropathy and diabetes, it is often assumed

Chapter 91

that the two are related. Most of the time, this is the case. However, there are occasional patients with very mild diabetes but very severe progressive neuropathy who may have some variant of CIDP. It is important to keep this in mind because these patients often respond to immunosuppressive drugs.

Atypical Amyotrophic Lateral Sclerosis In a similar vein, there are occasional patients with a distal sensory disturbance in the feet who have in addition severe, progressive muscle wasting and weakness. Initially, such patients may be assumed to have a severe, predominantly motor polyneuropathy. Over time the correct diagnosis of amyotrophic lateral sclerosis with a coincidental minor sensory neuropathy becomes obvious.

SUGGESTED READINGS Asbury AK, Gilliatt RW: Peripheral Nerve Disorders. Butterworth, London, 1984 Barohn RJ, Kissel JT, Warmolts JR, Mendell J R Chronic demyelinating polyradiculoneuropathy: clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 46878-884, 1989 Brown WF, Bolton CF: Clinical Electromyography.Butterworth, Boston, 1987

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Donofrio PD, Albers JW. AAEM Minimonograph #34: Polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 13:889-903, 1990 Dyck PJ, Lais AC, Ohta M et al: Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc 50621-637, 1975 Dyck PJ, Oviatt KF, Lambert EH: Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 10222-226, 1981 Dyck PJ, Thomas PK, Griffin JWet ak Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Herrmann D, Logigian E Approach to peripheral nerve disorders. In Katirj B, Kaminski H, Preston D et al (eds): Neuromuscular Diseases in Clinical Practice. Butterworth-Heinemann, Woburn, MA, 2002 Kelly JJ, Kyle RA, O’Brien P C Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31:1480-1483, 1981 Lewis RA,Sumner AJ: The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology 32:592596, 1982 Logigian EL Peripheral neuropathy. pp. 325-331. In Feldmann E (ed): Current Diagnosis in Neurology. Mosby, Boston, 1994 Logigian EL, Kelly JJ, Adelman LS: Nerve conduction and biopsy correlation in over 100 consecutive patients with suspected polyneuropathy. Muscle Nerve 17:101O-1020, 1995 Ropper AH, Wijdicks EFM, Truax BT Guillain-Bard Syndrome. FA Davis, Philadelphia, 1991 Schaumberg HR, Berger AR, Thomas PK Disorders of Peripheral Nerves. FA Davis, Philadelphia, 1991

Radiculopathies and Plexopathies Michael T. Hayes

One of the common problems encountered in the emergency room or in an outpatient setting is that of weakness, numbness, or pain in an extremity. The differentiation of sensory or motor dysfunction in a limb is daunting. As with most neurologic problems, careful clinical evaluation can result in an accurate anatomic localization of the lesion, which usually narrows the differential diagnosis significantly. Lesions involving the central nervous system and the individual named nerves are discussed elsewhere in this text; radiculopathies and plexopathies are discussed here.

RADICULOPATHIES Radiculopathies are the result of any process that affects the nerve at the level of the root. Disc disease, spondylosis, avulsion, metastasis, or any process that infiltrates the root may result in radicular symptoms. The clinical diagnosis of a lesion involving a specific root is based on a determination of the motor, sensory, and reflex abnormalities. Sensory abnormalities are well defined in peripheral nerve or plexus lesion but often are poorly defined or vague in a root lesion because of the overlap in abnormalities and variability of dermatomes. Motor and reflex changes are better localizing signs in radiculopathy (Table 9 1- 1).

Injury to the roots in the cervical region may occur for a number of reasons. Radiculopathy from disc herniation in the cervical region is less common than in the lumbosacral region. The C6 and C7 roots are the most frequently affected. In cervical spondylosis (in which bony overgrowth of a vertebra occurs after degeneration of a disc, forming a bar posteriorly), the C5 and C6 roots are most commonly involved. It is important to keep in mind that cervical spondylosis may also cause a myelopathy as the bar compresses the spinal cord. Although the radicular symptoms may be the patient’s major complaint, it is important to look for long tract signs such as spasticity and hyperreflexia below the level of the radiculopathy. Root avulsion is an important and debilitating cause of radiculopathy. It is the tearing of a root secondary to neck and shoulder injuries. The deficit that results is permanent. Two classic syndromes of avulsion are Erb‘s palsy (Duchenne-Erb syndrome) and Klumpke’s palsy. Erb’s palsy occurs with downward traction of the shoulder, forcing an extreme angle between the head and shoulder and causing tearing of the C5 and C6 roots. This has been most frequently described with forceps deliveries in which the head is forcibly pulled away from the undelivered shoulder. The clinical picture is that of a patient with minimal sensory changes but who is unable to abduct the shoulder or supinate the forearm and

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that the two are related. Most of the time, this is the case. However, there are occasional patients with very mild diabetes but very severe progressive neuropathy who may have some variant of CIDP. It is important to keep this in mind because these patients often respond to immunosuppressive drugs.

Atypical Amyotrophic Lateral Sclerosis In a similar vein, there are occasional patients with a distal sensory disturbance in the feet who have in addition severe, progressive muscle wasting and weakness. Initially, such patients may be assumed to have a severe, predominantly motor polyneuropathy. Over time the correct diagnosis of amyotrophic lateral sclerosis with a coincidental minor sensory neuropathy becomes obvious.

SUGGESTED READINGS Asbury AK, Gilliatt RW: Peripheral Nerve Disorders. Butterworth, London, 1984 Barohn RJ, Kissel JT, Warmolts JR, Mendell J R Chronic demyelinating polyradiculoneuropathy: clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 46878-884, 1989 Brown WF, Bolton CF: Clinical Electromyography.Butterworth, Boston, 1987

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Donofrio PD, Albers JW. AAEM Minimonograph #34: Polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 13:889-903, 1990 Dyck PJ, Lais AC, Ohta M et al: Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc 50621-637, 1975 Dyck PJ, Oviatt KF, Lambert EH: Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 10222-226, 1981 Dyck PJ, Thomas PK, Griffin JWet ak Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Herrmann D, Logigian E Approach to peripheral nerve disorders. In Katirj B, Kaminski H, Preston D et al (eds): Neuromuscular Diseases in Clinical Practice. Butterworth-Heinemann, Woburn, MA, 2002 Kelly JJ, Kyle RA, O’Brien P C Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31:1480-1483, 1981 Lewis RA,Sumner AJ: The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology 32:592596, 1982 Logigian EL Peripheral neuropathy. pp. 325-331. In Feldmann E (ed): Current Diagnosis in Neurology. Mosby, Boston, 1994 Logigian EL, Kelly JJ, Adelman LS: Nerve conduction and biopsy correlation in over 100 consecutive patients with suspected polyneuropathy. Muscle Nerve 17:101O-1020, 1995 Ropper AH, Wijdicks EFM, Truax BT Guillain-Bard Syndrome. FA Davis, Philadelphia, 1991 Schaumberg HR, Berger AR, Thomas PK Disorders of Peripheral Nerves. FA Davis, Philadelphia, 1991

Radiculopathies and Plexopathies Michael T. Hayes

One of the common problems encountered in the emergency room or in an outpatient setting is that of weakness, numbness, or pain in an extremity. The differentiation of sensory or motor dysfunction in a limb is daunting. As with most neurologic problems, careful clinical evaluation can result in an accurate anatomic localization of the lesion, which usually narrows the differential diagnosis significantly. Lesions involving the central nervous system and the individual named nerves are discussed elsewhere in this text; radiculopathies and plexopathies are discussed here.

RADICULOPATHIES Radiculopathies are the result of any process that affects the nerve at the level of the root. Disc disease, spondylosis, avulsion, metastasis, or any process that infiltrates the root may result in radicular symptoms. The clinical diagnosis of a lesion involving a specific root is based on a determination of the motor, sensory, and reflex abnormalities. Sensory abnormalities are well defined in peripheral nerve or plexus lesion but often are poorly defined or vague in a root lesion because of the overlap in abnormalities and variability of dermatomes. Motor and reflex changes are better localizing signs in radiculopathy (Table 9 1- 1).

Injury to the roots in the cervical region may occur for a number of reasons. Radiculopathy from disc herniation in the cervical region is less common than in the lumbosacral region. The C6 and C7 roots are the most frequently affected. In cervical spondylosis (in which bony overgrowth of a vertebra occurs after degeneration of a disc, forming a bar posteriorly), the C5 and C6 roots are most commonly involved. It is important to keep in mind that cervical spondylosis may also cause a myelopathy as the bar compresses the spinal cord. Although the radicular symptoms may be the patient’s major complaint, it is important to look for long tract signs such as spasticity and hyperreflexia below the level of the radiculopathy. Root avulsion is an important and debilitating cause of radiculopathy. It is the tearing of a root secondary to neck and shoulder injuries. The deficit that results is permanent. Two classic syndromes of avulsion are Erb‘s palsy (Duchenne-Erb syndrome) and Klumpke’s palsy. Erb’s palsy occurs with downward traction of the shoulder, forcing an extreme angle between the head and shoulder and causing tearing of the C5 and C6 roots. This has been most frequently described with forceps deliveries in which the head is forcibly pulled away from the undelivered shoulder. The clinical picture is that of a patient with minimal sensory changes but who is unable to abduct the shoulder or supinate the forearm and

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w TMU 91-1. Signs and Symptoms of Radiculopathy Root Lesion

Signs and Symptoms

c5

lnterscapular pain, proximal arm weakness (biceps, deltoid, infrascapular and suprascapular muscles), loss of biceps reflex. Pain radiating down the arm into thumb, proximal arm weakness, loss of biceps reflex. Pain radiating into third finger, triceps weakness (often triceps is innervated almost solely by C7). loss of triceps reflex. Pain radiating into fourth and fifth fingers, weakness of small muscles of the hand (median and ulnar innervated) if sensory loss extends from the fourth and fifth fingers up the ulnar aspect of the forearm (above the wrist as opposed to ulnar nerve lesions, in which sensory abnormalities do not extend above the wrist). Pain radiating down the inner aspect of the arm, weakness of hand muscles, Horner's syndrome. Weakness of knee extension and hip adduction, pain radiating from knee to medial malleolus, loss of knee reflex. If the root is entrapped, radicular pain sometimes mav be elicited bv reverse strainht len raising. Pain radiatin'g down poste;ior aspect of k g inib greaitoe, often significant weakness of ankle dorsiflexion (tibialis anterior often is innervated predominantly by L5), normal reflexes. Pain radiating down posterior aspect of leg and into latera1 aspect of foot, weakness of foot eversion, loss of ankle reflex.

C6

c7 C8

T1 L4

L5

s1

therefore, although the hand remains strong, the use of the limb is severely limited. Klumpke's palsy results from tearing of the C8 and T1 roots. The injury occurs with forceful upward traction on the arm. This type of injury may occur, for instance, with a fall in which the patient grabs for a ladder rung or some other support and wrenches the arm that is extended overhead. The patient suffers sensory loss in the fourth and fifth fingers and the ulnar aspect of the hand and forearm. All the intrinsic muscles of the hand are severely affected. The injury to the T1 root may be accompanied by Horner's syndrome (miosis, ptosis, and occasionally impaired facial sweating on the ipsilateral side to the injury) because sympathetic fibers that travel with the T1 root are also injured. Diagnosis of root avulsion is made after careful elicitation of the patient history and a thorough examination along with myelography, electromyography (EMG), and sensory evoked potentials. Myelography can be helpful in demonstrating avulsed roots, but it is not infallible. After an injury, a pseudomeningomyelocele can form. This gives the radiologic impression of an avulsed root, but the root is actually intact. Because it is a measure of actual nerve function, EMG is crucial in the diagnosis of complex cases in which plexopathy and radiculopathy are possible diagnoses. Radiculopathies can also be caused by infiltrating, ischemic, and inflammatory disorders. Infiltration of the meninges by metastatic cancer, especially lymphoma, may cause single or multiple radiculopathies. Sarcoidosis may result in radiculopathies and cranial neuropathies (especially cranial nerve seven and eight). Vasculitis, which often results in an asymmetrical pattern of peripheral nerve infarction, rarely affects nerve roots. Finally, inflammatory disorders from some infections (e.g., Lyme disease, herpes zoster) may result in clinical radiculopathies in the absence of abnormalities on imaging studies.

Lumbosacral Disc herniation is a more common problem in the lumbosacral region. The LPL5 and L5-S1 discs are the most frequently involved (causing symptoms referable to the L5 and S1 roots, respectively). The L3-L4 disc or L4 root is far less commonly involved. Table 9 1- 1 lists common signs and symptoms associated with each of these discs. In addition to the sensory, motor, and reflex changes noted earlier, patients should be questioned about what precipitates pain. Coughing, straining, and standing often worsen radicular pain caused by root entrapment. In L5 and S1 root entrapments, radicular symptoms (not merely low back pain) are worsened by straight leg raising. This is tested by having the patient lie supine and the examiner raising the patient's leg by the heel until symptoms are produced. In L4 entrapments, radicular symptoms may be produced with reverse straight leg raising. The patient is prone, and the examiner extends the hip to attempt to elicit symptoms. Exact anatomic localization of lumbosacral roots lesions is more difficult than cervical root lesions because the lumbosacral roots have such a long subarachnoid course as they form the cauda equina. Also, lesions of the cauda equina can be confused with lesions of the conus of the spinal cord. Cauda equina lesions usually involve more than one root. They may be caused by large, centrally herniated discs, severe spinal stenosis, or metastatic disease (commonly prostate cancer, leukemia, lymphoma, lung cancer, and some pinealomas). These lesions usually are exquisitely painful and involve sensation and reflexes above the sacral dermatomes early in the course. Sensory, motor, and reflex abnormalities are almost always asymmetrical. This asymmetry is very important to demonstrate clinically in making an early and accurate diagnosis. Lesions of the conus, which are most commonly caused by ependymomas, dermoid cysts, lipomas, arteriovenous malformations, and lymphomas and less commonly by other metastatic disease, begin with a constant, dull backache. The earliest sensory abnormalities are in the lowest sacral dermatomes and involve the genital and perianal areas because the lesion starts at the base of the conus and ascends. The patellar reflexes are spared until very late, and the neurologic abnormalities are very symmetrical, unlike cauda equina lesions. Workup of suspected cauda equina or conus injuries include radiologic assessment and neurophysiologic studies. Magnetic resonance imaging (MRI) is the most effective test to visualize the lumbosacral region. If MRI is not possible (e.g., if the patient has a pacemaker, is claustrophobic), then myelography followed by computed tomography is also effective. Plain radiographs are not sufficient to assess these lesions, even if they demonstrate an abnormality (such as a lytic lesion), because they do not demonstrate anatomy of the process compressing or infiltrating the roots or conus. Nerve conduction tests and EMG are extremely useful in demonstrating the extent and severity of the lesion in a way not possible with techniques that demonstrate anatomy but not neural function. Infectious entities such as cytomegalovirus (predominantly in patients infected with human immunodeficiency virus) may cause an exquisitely painful and debilitating polyradiculopathy. PLEXUS LESIONS

Lesions of the brachial and lumbosacral plexus may occur as a result of traumatic, inflammatory, neoplastic, or ischemic lesions.

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Sensory deficits may be much more pronounced, and weakness in single or multiple named nerve distributions is noted. The main entities in the differential diagnosis usually are root lesions or injuries to individual or multiple named nerves. Brachial

The brachial plexus is formed by the anterior rami of the C5-T1 roots, although the C4 and T2 rami may be involved in some patients. The C5 and C6 roots form the upper trunk, the C7 root becomes the middle trunk, and the C7 and C8 roots become the lower trunk. All three trunks split into anterior and posterior divisions. The posterior divisions of all three form the posterior cord, which gives rise to the axillary and radial nerves. The anterior division of the lower trunk becomes the medial cord and gives off the ulnar nerve and the C8 innervated median nerve muscles. The anterior divisions of the upper and middle trunks become the lateral cord, from which originate the musculocutaneous nerve and the remainder of the median nerve. The trunks pass through the supraclavicular fossa under the cervical and scalene muscles. The cords form just above the clavicle and first rib and pass, with the subclavian artery, through the thoracic outlet. A good guideline is that injuries occurring above the clavicle injure the trunks, those below the clavicle injure the cords, and those in the axilla injure the named nerves. Traumatic injuries to the brachial plexus occur with bullet or stab wounds or with blunt injury to the shoulder, as with firearm recoil or the football injury called “the stinger,” in which one player drives his helmet into the shoulder of another player. The latter two injuries produce clinical pictures not unlike an Erb’s palsy. Prolonged anesthesia with a patient’s arm held in a suboptimal position may result in plexus lesions. Pressure under the arm, as when patients use crutches, may also result in injury. Brachial plexus injuries may be seen as a complication of sternotomy, angiography done by the brachial artery approach, and, rarely, as a complication of an internal jugular catheterization. It is very important to differentiate plexus from root injury in traumatic injuries (which often involve both the neck and shoulder) because the former may be more amenable to surgical repair. Brachial neuritis, also called Parsonage-Turner syndrome or neuralgic amyotrophy, is believed to be an inflammatory lesion of the brachial plexus. It tends to occur in the third decade of life and affects males more than females by a 2:1 ratio. Although it may be idiopathic, it has been described as a sequela of a viral infection or vaccination. It may also be seen postoperatively. Initially, there is a deep boring pain in the shoulder, rapidly followed by weakness, generally in the proximal arm. Occasionally, the process is bilateral. This is an important point because few processes affect the brachial plexus bilaterally. Sometimes the abnormalities in the unaffected arm are subclinical and are appreciated only on electrophysiologic studies. The branches of the plexus that are affected most often are the axillary, radial, long thoracic, phrenic, suprascapular, and accessory nerves, although any part of the plexus may be affected. Occasionally, the lesion is very focal, as may be seen with isolated injury to the long thoracic nerve without any history of trauma. Rarely, the paraspinal muscles may be affected. This is not so much because this is not a true plexus lesion but rather because the lesion is inflammatory and occasionally may affect the posterior rami of the motor roots. A course of steroids has been advocated by some in the treatment of brachial neuritis; it is not unreasonable as long as the patient has no

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contraindications to steroids, but there is no good evidence that they are effective.Treatment is mainly supportive, putting the limb in a sling initially and then recommending a course of physical therapy as the patient improves. Usually the patient recovers over the course of 6 months to a year, occasionally with some residual effects. Rare cases of brachial neuritis are inherited. Patients may have repeated episodes, which are unusual for sporadic cases. Patients with the inherited form of brachial neuritis may display mild dysmorphic features, including hypotelorism. The brachial plexus may be affected by neoplasms. Pancoast syndrome or tumor occurs with local extension of a tumor growing in the apex of the lung to involve the first and second rib and the lower trunk (C8 and T1 and occasionally T2). The lesion is manifested by pain under the upper portion of the scapula and pain and numbness of the inner aspect of the arm and hand. There is weakness of C8 and T1 innervated muscles. Other lesions that often metastasize to the brachial plexus include lymphomas, melanomas, and breast cancers. Patients often are treated with radiation for neoplasms of the chest, neck, or plexus, and there may be secondary radiation damage to the brachial plexus. Radiation damage to the plexus may occur days to years after the course of radiation. Several clinical points help distinguish radiation injuries from recurrent cancer. Painless lesions of the upper plexus are more likely to be radiation-induced, whereas painful lower plexus lesions are more likely to be neoplastic. Myokymic discharges (a nonspecificmarker of neuron injury manifested by brief tetanic contractions of repetitively firing motor units) seen on EMG evaluation of the plexus are much more likely to be seen with radiation-induced lesions of the brachial plexus. MRI evaluation of the plexus may also help in the differentiation. One somewhat controversial form of brachial plexopathy is thoracic outlet syndrome. Thoracic outlet syndrome encompasses cases that have a demonstrable neurologic deficit (true or neurogenic thoracic outlet syndrome) and those with less well defined syndromes with normal examination results or results suggesting vascular rather than brachial plexus compromise. The neurogenic form occurs when the lower trunk and medial cord is compromised. This may occur with the presence of an anomalous fibrous band attached to a rudimentary rib off of the C7 transverse process or a more well-defined cervical rib. There are cases in which an anatomic abnormality is not evident on imaging studies. The value of EMG is disputed in thoracic outlet syndrome. One school of thought suggests that normal study results are common with true thoracic outlet syndrome. The EMG, when abnormal, is clear with abnormalities in the ulnar and medial antebrachial sensory potentials and denervation in the thenar and hypothenar muscle groups (C8 and T1 distribution muscles). Clinically, there should be sensory symptoms in the territory of the ulnar and medial cutaneous nerve of the forearm. Weakness should be demonstrable in the intrinsic muscles of the hand, and atrophy in those muscles may be seen. In fact, thoracic outlet syndrome is a rare entity compared with other nerve compression syndromes. Both intramedullary and extramedullary spinal cord syndromes may mimic the syndrome. Long tract signs suggesting a myelopathy and Horner’s syndrome should be specifically looked for. If the syndrome is still suspected, no definite abnormalities on neurologic examination are found, and there is no evidence of vascular insufficiency of the arm, a course of physical therapy emphasizing posture improvement (keeping shoulders from drooping) should be prescribed. We believe that surgery should not be contemplated in patients without definite evidence of nerve

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compression (atrophy and an appropriately abnormal EMG) or vascular compromise in which arteriography demonstrates a surgically correctable abnormality in the shoulder. The failure rate, rate of recurrence, and risk of serious neurologic complications are high. Hereditary neuropathy with liability to pressure palsies (HNPP, or tomaculous neuropathy) may present with a brachial plexus lesion in which patients suffer bouts of localized demyelination with pressure on a nerve. These patients may suffer mononeuropathies or brachial plexopathies. Usually the episodes are painless. Genetic testing is available. The underlying defect usually is a deletion of the peripheral myelin gene of chromosome 17; rarely, it is a point mutation. Treatment is supportive. Mononeuritis multiplex of any cause may mimic a brachial plexopathy early on but eventually involves single nerves in multiple limbs.

Lumbosacral It is important to keep in mind that the lumbosacral plexus is actually two plexi, the lumbar and the sacral. Injuries to the lumbar plexus can very often mimic symptoms of a femoral nerve lesion, with weakness of hip flexion and knee extension. Clinically and electrophysiologically, it is important to test the hip adductors, which get their innervation through the lumbar plexus also, but by way of the obturator rather than the femoral nerve. Lesions of the sacral plexus can be confused with lesions to its largest branch, the sciatic nerve. In addition to symptoms such as lower leg and hamstring weakness and sciatic distribution pain and paresthesias, there may be weakness of the gluteal muscles, the tensor fasciae latae, and the anal sphincter that can be demonstrated clinically or on EMG. Injuries to the lumbosacral plexus may occur as a result of traumatic, metastatic, inflammatory, ischemic, or hemorrhagic causes. Traumatic injuries to the lumbosacral plexus occur with crush injuries to the pelvis or with pelvic fractures. They may occur interoperatively with orthopedic surgeries to the hip (generally sacral plexus) or when retractors are used in abdominal procedures (lumbar plexus). Neoplasms that may invade the plexus include rectal, prostate, or cervical cancers or leukemias and lymphomas. Any mass, benign or malignant, in the pelvis may compress the plexus. Radiation injuries may also be a cause of lumbosacral plexopathies, as radiation to these tumors is fairly common. Unlike neoplastic invasion, radiation injuries tend to be painless. Because the radiation field usually is in the midline when treating these cancers, the symptoms often are bilateral. Even when the symptoms are not bilateral, findings on EMG may be bilateral,

helping to differentiate radiation injury from metastatic invasion, which tends, at least early in its course, to be unilateral. Myokymic discharges are seen on EMG in about 50% of radiation-induced lumbosacral plexopathies. Ischemic injuries to the lumbosacral plexus are seen with diabetes and in cases of mononeuritis multiplex. These tend to be apoplectic in nature and exquisitely painful initially. In diabetes, injuries to the femoral nerve or lumbar plexus result in the syndrome of diabetic amyotrophy, with intense burning pain in the thigh and weakness in the distribution of the femoral or the obturator nerves. Inflammatory lumbosacral plexopathies are less common than inflammatory brachial plexopathies, but they have been described, including a number of cases of painful lumbosacral plexopathies with high sedimentation rates that appeared to respond to steroids. A number of these cases were diabetic, however, and distinguishing them from ischemic plexopathies is difficult. In patients on anticoagulants or with hemophilia, bleeding into the iliopsoas muscle may cause a compressive femoral nerve or lumbar plexus lesion. APPROACH TO THE PATIENT The initial approach to a case depends on whether the symptoms and examination are more consistent with a radiculopathy or plexopathy. If a radiculopathy is suspected, then MRI is most helpful in determining the cause of root injury. Gadolinium is useful in cases in which there is suspicion of meningeal inflammation or infiltration as a cause of radiculopathy. EMG is a complementary study in that it helps characterize the severity of the root injury. Patients with clear radiculopathies, especially those demonstrated on EMG, who have no obvious lesion on radiologic studies may benefit from a lumbar puncture in assessing the patient for inflammatory, infectious, and neoplastic entities. In cases of suspected plexus lesions, EMG is most effective in determining the location and extent of a lesion. MRI may be helpful but is negative in cases of inflammatory, ischemic, traction-induced, or even some metastatic lesions. SUGGESTED READINGS Adams R, Victor M: Principles of Neurology. 5th Ed. McGraw-Hill, New York, 1993 Dawson D, Hallett M, Millender L Entrapment Neuropathies. 2nd Ed. Little, Brown, Boston, 1990 Kimura J: Electrodiagnosis in Diseases of Nerve and Muscle. 3rd Ed. FA Davis, Philadelphia, 1993 Oh S: Clinical Electromyography Nerve Conduction Studies. University Park Press, Baltimore, 1984

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InflammatoryDemyelinating Polyneuropathies

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Inflammatory Demyelinating Polyneuropathies James W Albers

The inflammatory demyelinating polyneuropathies are acquired disorders of peripheral nerves and nerve roots. The precise causes are unknown, but immunologic mechanisms play a major role. These disorders are among the most common forms of neuropathy, and up to 25% of idiopathic polyneuropathiesare estimated to have an autoimmune basis. Acute and chronic forms of inflammatory demyelinating polyneuropathy exist, differing primarily in their onset and relapse rate. Most are considered idiopathic, but the common association with a systemic disorder such as plasma cell dyscrasia is important in directing the clinical evaluation. The acute and chronic inflammatory demyelinating neuropathies share many clinical, electrodiagnostic, and therapeutic similarities, yet they represent different disorders.

ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY Clinical Features

Acute inflammatory demyelinating polyneuropathy (AIDP), also known as Guillain-Barre syndrome, acute inflammatory polyneuritis, or postinfectious polyneuritis, has an incidence of about 2 in 100,000. AIDP presents with progressive weakness, usually symmetrical, in the setting of areflexia, reduced distal sensation, frequent evidence of dysautonomia, and elevated cerebrospinal fluid (CSF) protein without pleocytosis. Although AIDP is a motor-predominant neuropathy, initial symptoms often are characterized by paresthesias. Diffuse back pain and muscle aching also are common in the course of illness but usually not as presenting symptoms. Most patients recall an antecedent illness, commonly a respiratory tract infection or gastroenteritis,within the four weeks before onset. Other illnesses and events associated with AIDP include hepatitis B, Epstein-Barr virus, cytomegalovirus, Lyme disease, toxoplasmosis, Campylobacrer enteritis, immunization, and surgery. Additional systemic illnesses, including human immunodeficiency virus (HIV) infection, Hodgkin’s disease, non-Hodglan’s lymphoma, and systemic lupus erythematosus, are associated with neuropathy. The neurologic presentations of each usually are not typical for AIDP, and they are better classified among the chronic forms of demyelinating polyneuropathy. Weakness in AIDP progresses rapidly and usually plateaus within three weeks of onset. Progression exceeding four weeks suggests an alternative diagnosis. Weakness typically begins distally, but it may begin proximally or in facial or bulbar muscles. An ascending paralysis, as described in the older literature, is uncommon. Prominent facial weakness occurs in about 50% of patients, but careful examination of orbicularis oculi muscles demonstrates weakness in almost all hospitalized patients with AIDP. Respiratory insufficiency necessitating mechanical ventilation occurs in 20% to 30% of patients, usually within 2 weeks of onset. Occasional patients with marginal respiratory function need intubation later during their hospitalization if decompensation occurs in response to aspiration or infection. Respiratory impairment is considered a major risk in AIDP. In addition, dysautonomia is associated with cardiac dysrhythmias and blood

pressure abnormalities, as well as bowel, bladder, and thermoregulation problems. Fisher’s syndrome is thought to be a variant of AIDP consisting of ophthalmoplegia, ataxia, and areflexia. The temporal profile and CSF studies in Fisher’s syndrome are indistinguishable from AIDP, and some patients have electrodiagnostic evidence of a demyelinating polyneuropathy, whereas others have findings suggestive of a brainstem encephalitis.

Elecbophysiologic Features The electrophysiologicevaluation in AIDP provides evidence of an acquired demyelinating polyneuropathy. Because most evaluations are performed early when the diagnosis is in question, the varieties

T m 92-1. Representative Electrodiagnostic Protocol for Evaluating Suspected Demyelinating Polyneuropathy Nerve Conduction Studies. 1. Test most involved site if mild or moderate, least involved site if severe. 2. Evaluate peroneal motor nerve (extensor digitorum brevis); stimulate ankle, below fibular head and knee. Measure F wave latency.b

3. If abnormal, evaluate tibia1 motor nerve (abductor hallucis); stimulate ankle and knee. Measure F wave latency. 4. If no responses, evaluate

5. 6.

7.

8.

a. Peroneal motor nerve (anterior tibialis); stimulate below fibular head and knee. b. Ulnar motor nerve (hypothenar); stimulate wrist and below elbow. Measure F wave latency. c Median motor nerve (thenar); stimulate wrist and elbow. Measure F wave latency. Evaluate sural nerve (ankle); stimulate calf. Evaluate median sensory nerve (index finger); stimulate wrist and elbow. If response is absent or focal entrapment is suspected, record from wrist and stimulate midpalm; evaluate ulnar sensory nerve (fifth digit); stirnulate wrist. If distal CMAP amplitude substantially larger (>IS%) than proximal CMAP amdkude. evaluate for abnormal temporal dispersion or partial condudi&n b l o c i a. Measure CMAP duration (distal and proximal) to identify abnormal dispersion. b. Evaluate CMAP amplitude and duration over short segments (few millimeters) to identify partial conduction block. c If capability exists, measure CMAP negative phase area (distal and proximal). Evaluate additional nerve if findings are equivocal. Definite abnormalities should result in a. Evaluation of contralateral extremity. b. Evaluation of specific suspected abnormality.

Needle Examination 1. Examine anterior tibialis, medial gastrocnemius, abductor hallucis, vas-

tus lateralis, biceps brachii, first dorsal interosseous (hand), and lumbar paraspinal muscles. 2. Any abnormality should be confirmed by examination of at least one contralateral muscle, lookina for symmetry. ’Muscles in parentheses indicate recording site for conduction studies. bAil F wave latency measurements are for distal stimulation sites. Record as absent if no response alter 15 stimulations. Abbrevioton: CMAP, compound muscle action potential. Modied from Aibers MI,Donofrio PD, McGonagle TK: Sequential electrodiagnostic abnormalities in acute inflammatory demyelinating polyradiculoneuropathy.Muscle Nerve 8:528-539, 1985, with permission.

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Spinal Cord and Peripheral Neuromuscular Disease W

-JL-

Diseases of Peripheral Nerve

-n-

A

Dlstal to proxlmal: Amplltude -5% Duratlon + l o % Area 0%

Ak!+5mv Elbow

Dlstal to proxlmal: Amplltude -62% Duratlon +55% Area -30%

FIG. 92-1. Motor nerve conduction studies from a normal subject (/eft) and from a patient with an acquired inflammatory demyelinating polyneuropathy (right), demonstrating abnormal temporal dispersion or partial conduction block.

of findings reported reflect, in part, temporal changes associated with cumulative demyelination and axonal degeneration. The evaluation is similar to that of any polyneuropathy. The goal is to document the presence of a peripheral localization and to identify the predominant pathophysiology. This entails evaluation of sensory and motor nerves in the upper and lower extremities, including proximal stimulation of motor nerves and F wave studies. A representative protocol is shown in Table 92-1. The hallmark of all acquired demyelinating neuropathies is evidence suggestive of multifocal demyelination. Conduction velocity slowing greater than can be explained by axonal loss is consistent with demyelination, but abnormal dispersion of motor responses and unequivocal conduction block are the cardinal features of acquired demyelination (Fig. 92-1). The earliest abnormalities include absent F and H waves and decreased motor unit recruitment. Only during subsequent examinations does evidence of segmental conduction block and conduction slowing become apparent. Some patients with normal conduction velocities have prolonged distal latencies, whereas other patients have normal distal latencies and shorter conduction velocities. These different presentations reflect the site of major abnormality, and most patients presenting with only prolonged distal latencies subsequently develop partial conduction block, abnormal temporal dispersion, and reduced conduction velocities. The electrodiagnostic features of acquired demyelination are imprecise and depend on identification of findings that cannot be explained by axonal degeneration alone (Table 92-2). During the first two weeks of illness, about 50% of patients with AIDP fulfill strict criteria for demyelination, compared with almost 85% by the third week of illness. During these first few weeks, an unusual pattern of abnormal median but normal sural sensory responses occurs in almost 50% of patients with AIDP. The extreme pattern of an absent median but present sural response in the appropriate clinical setting occurs almost exclusively in AIDP and is unusual in other types of generalized neuropathy. A small percentage of patients with otherwise typical AIDP never fulfill criteria for demyelination. Some of these patients are thought to have an axonal form of AIDP. The needle electromyography (EMG) examination has a limited role in evaluating patients with AIDP. The occasional demonstration of myokymic discharges during the first few weeks of illness may be helpful in establishing the diagnosis, and ultimate demonstration of profuse fibrillation potentials may be helpful in defining the magnitude and extent of denervation in establishing prognosis.

TME 92-2. Electrodiagnostic Criteria Suggestive of Chronic Acquired Demyelination Evaluation should satisfy at least three of the following in motor nerves (exceptions explained in footnotes): Conduction velocity less than 75% of the lower limit of normal (two or more nerves)a Distal latency exceeding 130% of upper limit of normal (two or more nerves)” Evidence of unequivocal temporal dispersion (increase in negative component duration exceeding 15% for proximal versus distal stimulation) or a proximal to distal amplitude ratio less than 0.7 (one or more nerves)boc F wave latency exceeding 125% of upper limit of normal (one or more nerves).”.” Txcluding isolated ulnar or peroneal nerve abnormalities at the elbow or knee, respectively. bExcludingisolated median nerve abnormality at the wrist ‘Excluding the presence of anomalous innervation (e.g., median to ulnar nerve crossover). Modified from Alben JW,Donofrio PD, McConagle TK: Sequential electrodiagnostic abnormalities in acute demyelinating polyradiculoneuropathy.Muscle Nerve 1985, 8:528-539, with permission.

Other Laboratory Features Other than CSF and electrophysiologic evaluations, laboratory studies have limited use in AIDP. Abnormal white blood count and liver function tests are common, but these are nonspecific findings thought to reflect an antecedent illness. Occasionally, elevated antibody titers to viral antigens help identify a specific antecedent event, but these findings have no therapeutic implications. The most important role of laboratory studies is in identifymg a systemic problem mimicking AIDP. For example, any patient with acute neuropathy and abnormal liver function studies, profound sensory loss, and unexplained leukopenia should be evaluated for arsenic intoxication (24-hour urine heavy metal screen and fingernail or hair arsenic analyses). Porphyric neuropathy also should be considered in patients with suspected AIDP, particularly if there is limited electrophysiologic evidence of demyelination, a history of recurrent episodes, or the triad of abdominal pain, psychosis, and polyneuropathy. CSF pleocytosis, although compatible with AIDP, should suggest an alternative diagnosis such as HIV-associated neuropathy. There is an association of otherwise typical AIDP with systemic lupus erythematosus. Serologic evaluation for collagen vascular disease or vasculitis therefore is indicated in the appropriate clinical setting. Some patients with the Fisher’s syndrome have an IgG antibody to GQlb ganglioside. Surd nerve biopsy may identify

Chapter 92 W

an underlying vasculitis or other systemic illness, but biopsy generally is not indicated. Treatment

Patients with AIDP almost never receive their primary treatment in the outpatient setting, but the most important initial treatment decision of whether to admit the patient occurs in the office or emergency department. The diagnosis often is difficult to establish at onset, and the initial symptoms can be nonspecific, with many potential causes. Most neurologists recall patients who were thought to have early AIDP but who resolved without progression. Whether these patients had a mild form of AIDP is unknown. Regardless, the decision to follow such patients in the outpatient setting is not straightforward. Patients with mild sensory symptoms but no signs often are observed as outpatients, as are patients who have minor signs and who appear stable and are not clearly progressing. Factors that influence the decision to admit the patient to the hospital include the duration, magnitude, distribution, and progression of symptoms or signs, as well as the presence of coexisting medical or related problems that interfere with the ability to provide reliable outpatient observation. Patients with suspected AIDP who have respiratory symptoms or a weak cough must be admitted. The medical management of AIDP is beyond the scope of this chapter. However, a few comments about treatment are important even in an outpatient-based context. The advent of respiratory intensive care units dramatically reduced mortality in AIDP to its current rate of approximately 2% to 5%. Therefore, all patients must be observed for respiratory deterioration, and pulmonary therapy is important in limiting atelectasis. Frequent monitoring of the volitional cough and the forced vital capacity (FVC) is important, and the decision of whether to intubate depends on the extent and rate of respiratory deterioration. Intubation is indicated if the FVC falls below 15 mL/kg, but a rapid decline of FVC should result in elective intubation independent of the absolute measurement, as should aspiration with poor tracheal toilet, pulmonary infection with shunting, or early signs of respiratory fatigue. Arterial blood gases are poor indicators of impending respiratory failure, and increasing restlessness, tachycardia, tachypnea, and sleepiness often precede blood gas changes. A low Po, and lower than normal Pco, may indicate early atelectasis with shunting. Hypercapnia generally precedes hypoxia but is a late finding of respiratory failure and a dangerous criterion for elective intubation. Most deaths among patients with AIDP involve medical complications of respiratory paralysis, but about 50% are sudden and presumably reflect cardiac dysrhythmias or hypotension. Although dysautonomia is not directly related to the extent of weakness, catastrophic cardiac dysrhythmia or blood pressure lability is unusual in patients with mild functional impairment. Minor cardiac dysrhythmias occur in about 20% of hospitalized patients, but arrhythmias sufficiently severe to affect blood pressure or necessitate medication occur in about 5% of patients. Most commonly, these are second- or third-degree atrioventricular blocks, for which a temporary pacemaker insertion is needed. Autonomic instability resulting in hypotension or new hypertension occurs in 10% to 15% of patients with AIDP. Hypotension is best managed by the rapid infusion of fluid,and sympathomimetics usually are not needed. Most agree that hypertension should not be treated unless severe and persistent. Corticosteroids are of unproven efficacy in AIDP, and their use

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is controversial. The few controlled studies that evaluated their use either were inconclusive or concluded that prednisone slowed recovery. The demonstrated importance of humeral factors in AIDP suggested that therapeutic plasma exchange (PE) might alter the course of illness. Several multicenter randomized studies, including the North American study of plasmapheresis and acute Guillain-Barre syndrome, confirmed the clinical, statistical, and economic efficacy of PE in established AIDP when initiated within the first few weeks after onset. In the North American study, patients who received PE underwent a series of three to five 40- to 50-mLlkg exchanges in 7 to 14 days. PE was not effective for all patients. However, overall the time by which 50% of patients reached independent ambulation was shortened by about 1 month for patients who received PE compared with remaining patients. For respirator-dependent patients who received PE, the median time of respiratory support was 11 days shorter and the time to unassisted ambulation was more than 2 months shorter than in the control group, without a significant increase in the nature or frequency of complications. Relapse occurred in only 4 (1.6%) of 245 patients in the North American study, 2 in each study arm. As PE became the accepted standard treatment, with the initial PE initiated soon after the diagnosis of AIDP was established, some centers observed an unexpectedly high relapse rate shortly after the course of PE was completed. Although unproven, this was thought to reflect premature discontinuation of treatment, before the acute monophasic illness had run its course. Therefore, interval PE sometimes is continued through the fourth or fifth week of illness to reduce the likelihood of limited relapse (Table 92-3). Although this period of treatment seems logical based on the known temporal progression of untreated AIDP, controlled clinical trials have not supported the need for additional PE treatment. A randomized trial comparing intravenous immunoglobulin ( M g ) with PE suggested that M g is at least as effective as PE in AIDP. Many neurologists believe that M g is an appropriate alternative first-choice treatment of AIDP. For some patients, such as those with poor venous access who need central lines for PE, M g offers a particular advantage. Regardless of the timing or form of treatment, it is establishedthat treatment with either PE or M g does not convert AIDP to a more chronic or relapsing form of neuropathy.

rn TABLE92-3.Suggested Therapeutic Plasma Exchange Schedule in AIDPa Interval from onset of neurologic symptoms <3 weeks: five exchanges of 1 plasma volume each over 7 to 14 daysb 3-4 weeks: no exchange if stable or improving with mild impairment; otherwise, five exchanges of 1 plasma volume, as above >4 weeks: no exchange unless progressing Interval from onset to completion of PE <4 weeks: consider additional intewal exchanges every 3 to 5 days through the end of week 5 to prevent limited relapse 9 weeks: no further exchanges unless Dronression of impairment 'For patienk in whom the diagnosis of AlDP is secure and there is at least moderate motor impairment (may be ambulatory). The schedule is an approximation, and the actual timing depends on availability of PE, stability and condition of patient coagulation factors, and other considerations. bSome protocols begin with daily exchanges for 2 days, switching to an every-otherday or every-3day schedule depending on coagulation factors (e.g., if preexdrange fibrinogen level < 100 mg/100 mL, consider postponing exchange or using plasma products as part of replacement solution). Abbreviations: AIDP, acquired inflammatory demyelinating polyneuropathy;PE, therapeutic plasma exchange.

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Treatment decisions are easiest when a severe impairment exists, and efficacy of PE and IVIg are established for patients who have lost the ability to walk. What about patients with very mild AIDP who do not appear to be progressing? Among ambulatory patients in whom the diagnosis of mild AIDP was secure, the French Cooperative Group concluded that two PEs were more effective than none. However, as the magnitude of severity increased, four PEs were more effective than two. The timing of treatment also is important. There is no indication for initial PE or M g treatment late in the course of AIDP, and few neurologists would initiate treatment after the fourth week of illness. Conversely, no treatment is without risk, and the diagnosis of AIDP must be secure before one embarks on a course of PE or IVIg treatments. Although it is important to initiate treatment expeditiously, there is no scientific evidence that a delay of a few days influences the course of illness. None of the immune-based treatments is equivalent to the use of antibiotics for an infection, and none has been shown to halt disease progression as soon as treatment is initiated. For example, a substantial number of patients treated with IVIg or PE before onset of respiratory impairment eventually need respiratory support despite treatment. Such progression should not be reason to abandon treatment because it does not indicate treatment failure. Prognosis

Most patients with AIDP ultimately recover, but neither PE nor M g is the ideal treatment, and prolonged hospitalizations and rehabilitation remain common, with 15% of patients having severe residual weakness. In general, clinical findings are poor predictors of outcomes in AIDP. Rapid evolution of weakness, advanced age, ventilator dependency, and a prolonged plateau before the onset of recovery suggest a poor prognosis. The best physiologic indicator of poor prognosis is an average motor evoked amplitude less than 20% of the lower limit of normal at plateau, although sequential recordings may be important in defining prognosis.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY Clinical Features Chronic inflammatory demyelinating polyneuropathy (CIDP) resembles AIDP but has a more prolonged course, usually with slow progression, often is relapsing, and generally is steroidresponsive. CIDP is not simply a prolonged form of AIDP. Diagnostic criteria for CIDP differ minimally from those used for AIDP, and the only reliable method for differentiating the two disorders early in their course is by an arbitrary judgment regarding the evolution of initial symptoms. Patients with CIDP usually have an interval between onset and peak impairment exceeding 4 weeks, averaging approximately 3 months. Whereas AIDP is a monophasic illness, CIDP includes monophasic, relapsing, and progressive forms. The term chronic relapsing polyneuropathy describes patients with clear relapses and remissions. Limited information exists about the natural course of patients with CIDP. Most patients receive some form of treatment, and relapses may occur in response to changes in medical therapy, masking the natural history. Regardless of whether relapses occur spontaneously or reflect changes in therapy, more than 40% of patients have a relapsing course. Less than 15% of patients demonstrate progression despite treatment.

Diffuse weakness, abnormal reflexes, elevated CSF protein, and electrophysiologic evidence of multifocal demyelination with or without superimposed axonal degeneration characterize CIDP. Sensory signs occur in more than 85% of patients with CIDP, probably more often than in AIDP. Identifiable antecedent events are uncommon, occurring in less than 30% of patients. Symmetrical motor or sensory symptoms are the initial manifestation in the majority of patients. Occasionally, gait ataxia is the presenting complaint. Facial weakness is common, particularly orbicularis oculi weakness, but is less prominent than in AIDP. Weakness usually begins in the distal lower extremities, and a proximal to distal gradient persists in most patients. About 50% of patients are nonambulatory during their most severe episode. Areflexia occurs in about 75% of patients with CIDP, and most patients have absent Achilles reflexes. Symptomatic dysautonomia is uncommon. Impairment typically is less than that experienced by patients with AIDP, but more than 75% of patients with CIDP develop at least moderate disability, preventing independent existence. Approximately 5% of patients with CIDP need respiratory support at some time during their illness. A major difference between AIDP and CIDP is the frequent association of a systemic illness in CIDP. The term CIDP is reserved for patients with idiopathic disease who do not have an associated illness. Nevertheless, at initial evaluation, it is impossible to distinguish patients with idiopathic CIDP from those with an associated systemic illness, and patients with idiopathic CIDP may develop a systemic illness after a negative initial examination. The most common associated disease is monoclonal gammopathy of undetermined significance (MGUS), but a variety of other associations exist, including those shown in Table 92-4. LewisSumner syndrome and multifocal motor neuropathy (MMN) are two disorders that resemble CIDP, and they should be considered in the differential diagnosis of CIDP because treatments differ. The Lewis-Sumner syndrome is characterized as an asymmetrical sensorimotor demyelinating polyneuropathy clinically resembling a mononeuritis multiplex. The acronym MADSAM (multifocal acquired demyelinating sensory and motor neuropathy) sometimes is used to describe this syndrome. MMN presents with slowly progressive, multifocal weakness and atrophy resembling lower motor neuron disease.

TABLE 92-4. Systemic Illnesses and Other Disorders Occasionally Identified in Patients Presenting with CIDP Monoclonal gammopathy of undetermined significance Amyloidosis Osteosclerotic myeloma Multiple myeloma POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome Waldenstrom's macroglobulinemia y-Heavy-chain disease Cryoglobulinemia Lymphoma Systemic lupus erythematosus Castleman's disease Human immunodeficiency virus infections Vasculitis (confluent mononeuritis multiplex)? Occult malignancy (paraneoplastic neuropathy)? Lewis-Sumner syndrome (multifocal demyelinatingsensory and motor neuropathy) Multifocal motor neuropathy

Chapter 92

ElectrophysiologicFeatures Electrophysiologic features in CIDP resemble those described late in the course of AIDP. For all practical purposes, patients with monophasic, relapsing, or progressive courses are electrodiagnostically indistinguishable. The electrodiagnostic criteria used as suggestive of acquired demyelination in CIDP differ little from those described for AIDP, being slightly more stringent to reflect changes related to chronic axonal stenosis or regeneration, both of which produce conduction slowing. Although strict criteria for demyelination are not always fulfilled, at least partial evidence of acquired demyelination is present in almost all patients with CIDP, and most clinicians consider this an important part of the diagnosis. Findings include slowing of motor conduction velocities, prolonged or absent F waves, abnormal temporal dispersion, and partial conduction block. Sensory conduction study results are abnormal, and the combination of absent or abnormal median sensory responses with normal sural responses occurs in approximately 30% of patients, a somewhat lower rate than in AIDP. Needle EMG abnormalities occur in most patients with CIDP, consistent with superimposed axonal degeneration and regeneration. Evidence of asymmetrical, multifocal conduction block, often profound, help identify MMN, easily distinguishing it from motor neuron disease. Other Laboratory Features Because subsets of patients with otherwise typical CIDP have an underlying systemic illness, and because some patients with idiopathic CIDP later develop a systemic illness, the laboratory evaluation of CIDP is particularly important. Depending on the presentation, the evaluation should include investigation for systemic lupus erythematosus and other collagen vascular diseases, vasculitis, diabetes, HIV infection, or malignancy. The presence of elevated serum titers of anti-GM, IgM is nonspecific but supports the diagnosis of multifocal motor neuropathy when the clinical and electrodiagnostic evaluations have suggested that diagnosis. Suggested laboratory studies are listed in Table 92-5, but additional evaluations may be indicated in special situations. All patients with presumed idiopathic CIDP should be evaluated for a plasma cell dyscrasia, beginning with a serum protein electrophoresis. Patients with mild CIDP and a normal serum protein electrophoresis who respond to treatment do not need immunologic reevaluation unless they relapse. If the evaluation remains normal after an initial relapse that responds to treatment, only relapses refractory to therapy warrant reevaluation. For patients with progressive CIDP, reevaluation should be performed about 6 months after the initial diagnosis and then approximately yearly. Reevaluation should include a serum immunoelectrophoresis (or immunofixation), urine immunoelectrophoresis, and radiologic skeletal survey. The skeletal survey is performed because of the occasional identification of a plasmacytoma in a patient without evidence of a monoclonal gammopathy. Surd nerve biopsy is of proven usefulness in identifymg acquired demyelination, but lack of specificity does not justify routine use. Biopsy is useful in identifymg vasculitis, amyloid deposits, cytoplasmic inclusions, neuroflamentous swollen axons, or evidence of other specific pathology. Because most patients with CIDP need immunosuppression, all patients at risk for possible tuberculosis should be evaluated for a response to purified protein derivative (PPD) and undergo a chest

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TABLE 92-5. Recommended Laboratory Investigations in CIDP All patients ANA Complete blood count ESR Glucose (random or fasting) Hepatitis antigen HIV antibody Liver function studies Serum protein electrophoresis Serum immunoelectrophoresis(or immunofixation) Urine immunoelectrophoresis Additional evaluations (depending on the seveiky of neuropathy, response to treatment, and clinical suspicion) Anti-MAC Anti-Cm, Angiotensin-converting enzyme Cryoglobulins ENA Lyme antibodies Thyroid function studies Urine Porphyrins and levulinic acid Heavy metals, including arsenic Imaging Chest and abdominal CT Radiologic skeletal survey Biopsy Sural nerve Bone marrow Before beginning immunosuppressive treatment Chest radiograph PPD Reevaluation in progressive CIDP Repeat immunologic evaluation in 6 months and then yearly serum immunoelectrophoresis(or immunofixation) Radiologic skeletal survey Sural nerve biopsy Abbreviations: ANA, antinudear antibody; CIDP. chronic inflammatory demyelinating polyneuropathy; Cr,computed tomography; E M extractable nudear antigen; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency~ N S ;MAG, myelinassociatedglycoprotein; PPD. purified protein derivative.

radiograph before initiation of treatment with prednisone or other cytotoxic agents, if a recent evaluation has not been performed.

Treatment The supportive treatment of patients with CIDP is identical to that described for AIDP, although respiratory distress necessitating intubation is less common and symptomatic dysautonomia is unusual. In contrast to AIDP, the majority of patients with CIDP receive most or all of their treatment in the outpatient setting. Treatment decisions regarding CIDP are more numerous than for AIDP because more types of treatment are available and the course often is protracted. However, there is less urgency in arriving at a treatment plan because disease progression is slower than in AIDP and it often takes a period of observation to determine whether the neuropathy is progressing or improving. Indeed, patients with equivocal or minor deficits at presentation may be observed without treatment, often for weeks or even months, to determine whether they are progressing or spontaneously improving. Patients who do not improve or continue to progress, or patients with more than minor motor deficits, should undergo treatment. Corticosteroids are of established efficacy in CIDP and have been the primary form of treatment for decades. The demonstrated efficacy of PE and M g the purported efficacy of a variety

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of immunosuppressants, including azathioprine, cyclophosphamide, melphalan, cyclosporin, mycophenolate mofetil, rituximab, and total lymphoid irradiation, have resulted in numerous treatment protocols. These protocols reflect individual physicians' preferences for specific treatments depending on disease duration, rate of progression, distribution, coexisting illness, and severity. Unfortunately, there are no generally accepted guidelines for selecting one protocol over another, and treatment decisions reflect the individual patient's situation. Most patients with CIDP (70 of 77) evaluated at the University of Michigan over a 12-year period received treatment during their initial episode. Therapies reflected the collective experience of the neuromuscular faculty and available treatments during the interval of review (1979 to 1991),and only minor differences probably occurred in the subsequent decade. Initial treatments included oral prednisone (32 patients), PE plus prednisone (24), PE alone ( l l ) ,PE plus azathioprine (2), and IVIg (1). Prednisone was given at 60 mg/day in adults for 1 to 3 months, followed by a gradual taper. PE schedules included five exchanges of 1 plasma volume

Diseases of Peripheral Nerve

each over 10 to 14 days. Azathioprine was given at 1 to 3 mg/kg/day when prednisone was contraindicated. Eleven patients received PE alone, and response to PE sometimes was taken as evidence supportive of the diagnosis. These and other protocols are summarized in Table 92-6. More recently, there has been a trend to use mycophenolate mofetil in place of azathioprine, based on the assumption that efficacy should be similar but with fewer initial side effects. There is no rationale at this time for switching patients already successfully treated with azathioprine to another agent. Treatment-related complications with prednisone and other forms of immunosuppression are not inconsequential, and review of all potential side effects and laboratory monitoring protocols is beyond the scope of this review. Patients receiving prednisone, the most commonly prescribed treatment for CIDP, need interval weight, blood pressure, serum glucose, and potassium measurements and should be placed on a high-protein, low-salt, low-fat diet. Supplemental calcium and vitamin D may reduce the risk of osteoporosis. Laboratory tests initially should be performed every

TABU 92-6. Alternative Protocols for Treating CIDP Treatment

Advantages

Disadvantages

Therapeutic Plasma Exchange. 5 exchanges over 7-1 4 days Weekly exchanges for 10 weeks 2 exchanges/week for 3 weeksb Alternate-day exchanges for 2 weeks'

Rapid response, usually in 7-14 days Few complications

Response short-lived (weeks to months) Central line if poor venous access Concurrent immunosuppression probably needed Expense

Rapid response, usually in days Proven efficacy Few complications

interval treatments needed Expense Limited availability Possible transmission of infectious disease Anaphylactic and hypersensitivity reactions

Established efficacy Response within weeks to months Fewer side effects once QOD schedule achieved Brief period of high-dose prednisone

High incidence of complications (weight gain, fluid retention, hypertension, hyperglycemia, insomnia and mood changes, cataracts, skin changes, osteoporosis, aseptic necrosis of hip, infection)

If tolerated and effective, maintenance schedule simple

Efficacy unproven, slow response (months) Drug fever, nausea and vomiting, bone marrow depression, hepatitis, possible risk of neoplasia, infertility, birth defects (contraindicated in childbearing years)

Possibly better tolerated initially than azathioprine, maintenance schedule simple

Similar to azathioprine

Avoid interval relapse after therapeutic plasma

Steroid complications as above

Avoid interval relapse after therapeutic plasma

Azathioprine or mycophenolate mofetil; complications as above

Avoid interval relapse after lVlg

Chronic immunosuppression complications as above

Intravenous Immunoglobulin 1 g/kg/day for 2 days (loading dose), followed by 1 g/kg/day at 2 and 4 weeks, and then monthly (several), depending on response 0.3-0.4 g/kg/day for 3 or 4 days; treat relapse with interval intravenous immunoglobulin infusionsd Prednisone 60 rng/day until response or 3 months; reduce alternate-day dosage by -1 5% of total 2-day dosage evely 2 weeks until 20 mg qod, then slow taper 120 mg/day for 1 week, reduce by 20 muweek for 5 weeks to 20 muday, then slow taper' Azathioprine Initiate at 1-2 mg/kg/day (50-100 mg); increase by 0.5-mg/kg increments as tolerated to 2.5 mg/kg; taper to maintenance dosage of 1-2 mg/kg/day, monitoring for mild leukopenia Mycophenolate Mofetil Initiate at 250 mg bid; increase to 500 mg bid and then to 1 g bid as tolerated, monitoring for leukopenia Concurrent therapeutic plasma exchange and prednisone concurrently Concurrent therapeutic plasma exchange and azathioprine or mycophenolate mofetil concurrently lVlg followed by alternative form of chronic immunosuppression

~

"All exchanges refer to 1 plasma volume each. bDyckPI, Daube J, O'Brien P, Pineda A: Plasma exchange in chronic inflammatoly demyelinatingpolyradiculoneuropathy. N Engl J Med 314:461-465,1986. 'Ropper AH, Weinberg D: Chronic immune demyelinating polyneuropathy (CIDP). Neurol Chron 1 :1-8,1992. dFaedJM, Day 6, Pollock M et al: High-doseintravenous human immunoglobulinin chronic inflammatory demyelinatingpolyneuropathy. Neurology 39:422-425, 1989. eExampleswitch and taper from qd to qod schedule; prednisone dosage for 2-week intervals: 60/60,60/45,60/30,60/15; 60/0,50/0,45/0,40/0,30/0,25/0,20/0. 'Data from Dyck PJ, O'Brien PC, Oviatt KF et al: Prednisone improves chronic inflammatorydemyelinating polyradiculopathy. N Engl J Med 314:461-465,1986.

Chapter 92 W

2 to 4 weeks. Those who are PPD-positive need concurrent antituberculosistherapy. Patients treated with azathioprine should undergo liver function studies and complete blood counts, repeated weekly for the first month and then at longer intervals if the medication is continued. Patients prescribed mycophenolate mofetil also need careful monitoring for possible leukopenia. For patients intolerant of these medications, cyclosporin (3 to 5 mg/kg/day) or cyclophosphamide (1 to 2 mg/kg/day or 1 g/square meter body surface area) is prescribed occasionally, with appropriate laboratory monitoring of renal and hematologic function. The objective of all the treatment protocols is to prevent relapse with the lowest possible maintenance immunosuppression.

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CONCLUSION Patients with inflammatory demyelinating polyneuropathies make up a substantial portion of patients with undiagnosed neuropathy presenting for evaluation. The acute and chronic forms of inflammatory demyelinating polyneuropathy have characteristic presentations, and the electrophysiologicfeatures are easily recognized. The importance of these neuropathies is disproportionate to their numbers because most are treatable, some are associated with unrecognized but treatable systemic disorders, and they provide clues to the pathogenesis of other obscure neuropathies.

Prognosis

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Most patients with CIDP have a good clinical outcome. Occasional patients with mild impairment improve spontaneously. For the more severely impaired patients, response to initial treatment occurs in about 80%, typically within 1 to 3 weeks after initiation of PE and somewhat longer after starting prednisone. Treatment with a second or third modality in poor responders increases the response rate to almost 90%. At 5 years after onset, more than 85% of patients have mild or no disability, with less than 10% of patients demonstrating a moderate to moderately severe impairment. Mortality related to CIDP or its treatment during the first 5 years after diagnosis is less than 5%. Unlike AIDP, relapse is common, with more than 45% of patients relapsing after initial response to treatment, usually within the first year, and averaging four relapses within the first 5 years. Most patients (approximately75%) need chronic treatment for their CIDP. The most common treatment is prednisone, usually a low-dose alternate-day schedule of 5 to 20 mg every other day. A small percentage of patients receive azathioprine (1 to 2 mg/kg/ day) or an equivalent maintenance immunosuppression therapy. Rare patients with a relapsing course demonstrate PE or IVIg dependence. Unfortunately, despite the good to excellent treatment response of CIDP, all neurologists who see large numbers of patients with CIDP recognize that some patients fail to respond to treatment. This includes patients who never respond to any treatments throughout their entire disease course, and patients who become refractory to treatment after an incomplete initial response. This failure to respond sometimes reflects the presence of an underlying systemic illness such as osteosclerotic myeloma or Castleman’s disease, but it also occurs in the absence of any identifiable associated disorder. Among such patients, the use of increasingly more potent treatment predictably results in an increasing number of iatrogenic problems. These problems include opportunistic infections with sepsis, superimposed critical illness myopathy or neuropathy, and compression fractures, to name a few. The prognosis among these patients is poor, and only rarely does some new combination of treatments result in sustained improvement.

Albers JW, Kelly Jr JJ: Acquired inflammatory demyelinating polyneuropathies; clinical and electrodiagnostic features. Muscle Nerve 12:435451, 1989 Asbury A K New concepts of Guillain-Barre syndrome. J Child Neurol 15:183-191, 2000 Barnett MH, Pollard JD, Davies L, McLeod JD: Cyclosporin A in resistant chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 21:454-460, 1998 Dyck PJ: Atypical varieties of chronic inflammatory demyelinating neuropathies. Lancet 355:1293-1294, 2000 Dyck PJ, Daube J, O’Brien P, Pineda A Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med 314:461-465, 1986 Dyck PJ, Lais AC, Ohta M et al: Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc 50:621437, 1975 Dyck PJ, OBrien PC, Oviatt KF et ak Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol 11:136-141, 1982 Gorson KC, Ropper AH, Adelman LS,Weinberg DH: Influence of diabetes mellitus on chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 23:3743, 2000 Guillain-Barre Syndrome Study Group: Plasmapheresis and acute Guillain-Barri syndrome. Neurology 35:1096-1 104, 1985 Hadden RD,Hughes RA: Treatment of immune-mediated inflammatory neuropathies. Curr Opin Neurol 12573-579, 1999 Lisak RF’, Brown MJ: Acquired demyelinating polyneuropathies. Semin Neurol 24048, 1987 Sater RA, Rostami A Treatment of Guillain-Barre syndrome with intravenous immunoglobulin. Neurology 5 1:S9-15, 1998 Simmons Z, Albers JW, Bromberg MB, Feldman E L Presentation and initial clinical course in patients with chronic inflammatory demyelinating polyradiculoneuropathy: comparison of patients without and with monoclonal gammopathy. Neurology 43:2202-2209, 1993 Chronic inflammatory demyelinating Simmons Z, Wald JJ, Albers polyradiculoneuropathyin children: I. Presentation, electrodiagnostic studies, and initial course, with comparison to adults. Muscle Nerve 2O:lOOS-1015, 1997 van der Meche FGA, Schmitz PIM, Dutch Guillain-Barrk Study Group: A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. N Engl J Med 326:1123-1129, 1992

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93 Diabetic Neuropathy Asa 1. Wilbourn and Bashar Katirji Diabetes mellitus (DM) probably is the most common serious metabolic disorder that afflicts humans. It is a major cause of morbidity and mortality in the United States, with an estimated prevalence of nearly 7%. An alarming statistic is that its prevalence in the United States increased 33% over a recent 8-year surveillance period (from 4.9% to 6.5% between 1990 and 1998). The increased prevalence correlated highly with obesity and was especially prominent in the pre-middle-aged population (ages 30 to 39 years). DM generally is considered under two main headings: insulindependent DM (IDDM) and non-insulin dependent DM (NIDDM) (Table 93-1). DM has four major complications: neuropathy, retinopathy, nephropathy, and vasculopathy. AU too often, more than one of these complications affect the same patient. Diabetic neuropathy is a generic term for any DM-related disorder of the peripheral nervous system (PNS), the autonomic nervous system ( A N S ) , and some of the cranial nerves (Table 93-2). The more common types of diabetic neuropathy are reviewed in this chapter, beginning with the generalized disorders, progressing to the regional disorders, and then concluding with the focal ones. Before individual types of diabetic neuropathy are discussed, however, two important facts must be emphasized. First, DM is such a widespread disorder, particularly in older adults, and its neurologic complications are so common that it should always be included in the differential diagnosis whenever patients present with any of a multitude of neurologic complaints. Vigilance in this regard can prevent not only the performance of unnecessary, expensive, diagnostic procedures (sometimes fruitlessly repeated at intervals) but also unneeded and potentially harmful treatments, including surgery. Conversely, it is equally important to avoid automatically attributing any neuromuscular abnormality that develops in a diabetic patient to DM because neurologic disease not related to DM occurs in the same incidence in both the diabetic and nondiabetic populations. Many patients have suffered

needlessly for prolonged periods of time with treatable PNS diseases (e.g., chronic inflammatory demyelinating polyneuropathy) because their symptoms were considered a neurologic manifestation of their DM and therefore not worthy of a comprehensive assessment. Second, diabetic neuropathy can develop or progress because of factors not directly related to DM. The reduction or elimination of these risk factors can be of substantial assistance in preventing or treating diabetic neuropathy. These factors include hypertension, hyperlipidemia, smoking, alcohol abuse, and peripheral vascular disease.

DISTAL SENSORIMOTOR POLYNEUROPATHY AND AUTONOMIC NEUROPATHY Of the various subgroups of diabetic neuropathy, generalized sensorimotor polyneuropathy of DM (GSMP-DM) is by far the most common. Because autonomic fiber involvement almost invariably is associated with the peripheral sensorimotor features, it is reasonable to consider involvement of both nerve fiber groups as a common entity. In general, the presence of GSMP-DM is related to the duration and severity of hyperglycemia. However, this form of diabetic neuropathy can occasionally be the presenting symptom of occult DM, and significant sensorimotor and autonomic abnormalities can be found in patients with only mild degrees of hyperglycemia. GSMP-DM increases in prevalence with advancing age and tends to correlate with diabetic retinopathy and nephropathy. Many patients with GSMP-DM are asymptomatic or have only minimal symptoms. When present, symptoms tend to be predominantly sensory in nature. Although some patients report loss of feeling, the majority complain of distal lower limb paresthesias and pain. The latter may be constant or episodic and may assume a wide variety of forms including burning, stabbing, or dull aching discomfort. Many patients report experiencing skin hypersensitivity, sometimes so severe that the mere touch of bedsheets produces

rn TABLE93-1. Classification of Primaly Diabetes Mellitus Characteristics

Insulin-Dependent Diabetes Mellitus

Non-Insulin-Dependent Diabetes Mellitus

Synonyms

Brittle DM, juvenile-onset DM, type 1 DM

Genetic defect Human leukocyte antigen and autoimmune associations Concordance rate for identical twins Possible cause

High Yes

Stable DM, adult- or mature-onset DM, type 2 DM High No

+50%

2 1 00%

Immune-mediated p-cell destruction

Dysfunctional p cell, with end-organ insulin resistance

Percentage of diabetes Femalemale ratio Age of onset (years) Body habitus Mode of onset Plasma insulin levels Major cause of death Types of diabetic neuropathy commonly associated

5%-10°h

90%-95%

1:1 Usually 4 5 Lean or normal Often abrupt Low or unmeasurable Diabetic coma; diabetic nephropathy All except polyradiculopathy; in young, only distal symmetrical polyneuropathy and autonomic neuroDathv r -

1.4-1.8:l Usually >30 Obese (>80%) Usually insidious Normal to high Cardiovascular disease All; often several coexisting

I

Modified from Wilbourn AJ: Diabetic neuropathies. In Brown WF, Bolton CF (eds). Clinical Electromyography.2nd Ed. Butterworth-Heinemann.Boston, 1993, p 479

Chapter 93

rn TABLE93-2.Diabetic Neuropathy (Partial Classification) Diabetic generalized sensorimotor polyneuropathy Diabetic autonomic neuropathy Diabetic polyradiculopathy Involving U-L4 roots: diabetic amyotrophy, diabetic lumbosacral radiculoplexus neuropathy, Bruns-Garland syndrome Involving T4-Tl2 roots: diabetic thoracic radiculopathy, diabetic thoracoabdominal neuropathy, truncal radiculoneuropathy Involving L5,51 roots Involving C5-C7 roots Diabetic limb mononeuropathies (carpal tunnel syndrome, ulnar neuropathy at the elbow) Diabetic mononeuropathy multiplex Diabetic cranial neuroDathies

extreme discomfort. Paresthesias (typically pins and needles or tingling sensations) may occur spontaneously or with contact. These sensory complaints often are accentuated at night and may interfere with sleep. Sensory symptoms typically develop and evolve slowly. Initially, they may be unilateral or bilateral but asymmetrical; however, ultimately, they become bilateral and symmetrical. Characteristically,they begin in the toes and feet and progress proximally; that is, they manifest a distal-to-proximal gradient in the lower limbs. Thus, the symptoms of GSMP-DM demonstrate a length-dependent pattern, with the longest axons involved, and initially at their most distal point. Consequently, patients with progressive lower limb sensory symptoms generally do not experience similar symptoms in their fingertips or hands until the lower limb symptoms are at or above the level of the knees. In severe progressive cases, sensory symptoms may develop over the anterior chest and abdomen. In most patients, the distressing painful component of GSMP-DM is self-limited and spontaneously improves after many months, but in some patients it progresses or at least persists indefinitely. Although the typical mode of evolution of GSMP-DM is slow and insidious, a more fulminant acute painful polyneuropathy, often associated with profound weight loss, also occurs. In the majority of patients with GSMP-DM, motor fiber involvement is minimal and typically is limited to weakness and atrophy of the intrinsic foot muscles. Uncommonly, foot weakness may be prominent, and with progressive proximal extension of the process, bilateral foot drop may result. A N S involvement often is subclinical in the early stages of the polyneuropathy, although it may be detected using sensitive methods to measure and quantitate autonomic function. In general, involvement of autonomic nerves also follows a lengthdependent pattern. In most patients, multiple organ systems are altered simultaneously. The sympathetic pupillodilator fibers may be affected early, causing miosis and sometimes difficulties with dark adaptation. Cardiovascular involvement typically begins with reduced vagal function and an asymptomatic increase in resting heart rate. When sympathetic cardiovascular dysfunction is more advanced, orthostatic hypotension may occur. Autonomic sudomotor fiber involvement often results in asymptomaticdistal lower extremity anhidrosis. Some patients note compensatory hyperhidrosis involving the face and upper torso. In advanced cases, generalized anhidrosis may occur. Autonomic involvement of the gastrointestinal system often results in constipation and, paradoxically, episodic nocturnal diarrhea. Gastric atony often causes postprandial nausea and bloating, along with early satiety. Involvement of genitourinary autonomic fibers may produce a neurogenic bladder, resulting in reduced sensation of bladder fullness and incomplete emptying; the latter may lead to recurrent

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urinary tract infections. Sexual dysfunction is commonly encountered with diabetic ANS involvement. In males, decreased erectile function, sometimes associated with retrograde ejaculation, is common; in women, reduced vaginal secretions and lubrication may occur. When ANS dysfunction is more advanced, the adrenal gland may be denervated, which may result in unawareness of hypoglycemia. This is caused by failure of the adrenal gland to release catecholamines in the setting of hypoglycemia and consequently the loss of sweating and tachycardia that typically alert the patient to hypoglycemia. The neurologic examination with GSMP-DM often reveals reduced superficial sensory perception to light touch, pinprick, and temperature sensation in a stocking distribution. Usually, joint position sense and vibratory sense are preserved. On occasion, even in patients with severe sensory symptoms, deep tendon reflexes may be intact, and no atrophy or muscular weakness can be detected. This pattern of clinical involvement suggests that GSMP-DM preferentially involves the smaller-diameter peripheral nerve fibers that subserve the superficial sensory modalities. This is sometimes called diabetic small fiber neuropathy. Much less commonly, patients may present with gait imbalance, caused by sensory ataxia, in the absence of small fiber symptoms, suggesting preferential large fiber involvement. Often, both large and small fibers appear to be equally involved, producing sensory deficits to all modalities, loss of deep tendon reflexes, and modest distal muscle weakness and atrophy. Typically, atrophy of the extensor digitorum brevis or minimal weakness of toe extension and flexion may be the only signs of mild motor fiber involvement. Infrequently, severe motor axon loss occurs, producing bilateral foot drop and significant lower limb weakness. In a few patients, acrodystrophic changes may occur, with accompanying foot ulcerations. Neuropathic arthropathy or Charcot joints are rare manifestations of GSMP-DM and when present almost always are confined to the bones of the foot. Because GSMP-DM produces a nonspecific type of generalized sensorimotor dysfunction, its differential diagnosis includes a wide range of sensorimotor polyneuropathies. Consequently, the mere occurrence of a sensorimotor polyneuropathy in a diabetic patient does not automatically indicate that the polyneuropathy is caused by the DM. In this respect, the diagnosis of GSMP-DM is one of exclusion. Some of the polyneuropathies included in the differential diagnosis of GSMP-DM are listed in Table 93-3. Many of these are easily differentiated from GSMP-DM by various clinical features or laboratory studies. Electrodiagnostic (EDX) studies are valuable in confirming the presence of GSMP-DM and characterizing its underlying pathophysiology of axon loss. With mild GSMP-DM, EDX abnormalities are found only in the lower extremities. These typically consist

rn TABLE93-3.Differential Diagnosis of Generalized Sensorimotor Polyneuropathyof DM Uremia Alcoholic or nutritional Connective tissue disorders Vasculitis Vitamin B,, deficiency Hypothyroidism Toxic (e.g., metals, drugs, solvents) Paraneoplastic Paraproteinemia Amyloidosis Hereditaw

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of unelicitable H responses, low-amplitude or unelicitable sensory (surd, superficial peroneal sensory) nerve conduction study (NCS) responses, unelicitable plantar NCS responses, mild slowing of conduction velocities on motor (peroneal, tibial) NCS, and fibrillation potentials in the intrinsic foot muscles, appearing either alone or in various combinations. With more advanced disease, the amplitudes of the motor NCS responses recorded from the intrinsic foot muscles decrease, and motor unit potential dropout is seen in those muscles on needle electrode examination. In the majority of patients assessed in the EDX laboratory, the PNS changes are severe enough that abnormalities are found in the upper limb, the initial ones usually being reduction of the sensory (median, ulnar, radial) NCS amplitudes. Such findings can be helpful for establishing the presence of a polyneuropathy because often the patients’ ages are such (i.e., older than 60 years) that both unelicitable lower limb sensory NCS responses and unelicitable H responses are of uncertain significance. Although these EDX features are characteristic of a primarily axon loss polyneuropathy, they are not diagnostic of GSMP-DM. Instead, they are nonspecific and are consistent with a wide variety of disorders. Nonetheless, the presence of principally axonal loss excludes acquired or familial demyelinating polyneuropathies. In a small percentage of patients with GSMP-DM, essentially limited to those who have predominantly small fiber symptomatology, the EDX examination is normal, or only minimal abnormalities are seen. This is because the entire study assesses only large myelinated nerve fibers. Examination of the cerebrospinal fluid (CSF) is rarely indicated in the evaluation of patients with suspected GSMP-DM. Typically, it is entirely normal, although a modest increase in CSF protein, rarely above 100 mg/dL, can be seen. Nerve biopsy is also rarely performed except to exclude a vasculitic neuropathy or amyloidosis. The biopsy findings in GSMP-DM are those of a nonspecific, primarily axon loss polyneuropathy. Depending on the clinical circumstances, a variety of laboratory tests often are obtained to exclude treatable causes of polyneuropathy that may be occurring in the setting of DM. Usually, these include a complete blood cell count, chemical profiles of the blood, vitamin B,,, folic acid, thyroid function studies, serum and urine for immunoelectrophoresis, sedimentation rate, and antinuclear factor. A wide variety of autonomic tests can be performed on diabetic patients with GSMP-DM to assess for associated A N S involvement. Noninvasive cardiovascular procedures, such as heart rate variability with deep breathing or Valsalva maneuver, are sensitive methods for detecting early cardiovagal impairment. Various sudomotor function tests, including sympathetic skin response, thermoregulatory sweat testing, and quantitative sudomotor axon reflex test may reveal abnormalities. Diabetic patients with symptomatic autonomic neuropathy need specific evaluation of the particular organ system involved. Hemodynamic tilt tests often are valuable when orthostatic hypotension is present. Gastrointestinal atony often is assessed with various radiographic techniques. Urinary bladder dysfunction can be investigated by quantitating the postvoiding residual urine, which typically increases in diabetic cystopathy; cystoscopy and urodynamic studies are needed to document and quantitate the degree of bladder dysfunction. Male sexual dysfunction, including erectile impotence, can be differentiated from psychogenic impotence with various tests, including penal tumescence studies during REM sleep. Traditionally, rigorous control of blood glucose has been the

foundation for treating GSMP-DM and autonomic neuropathy. The results of the Diabetes Control and Complications Trial and the United Kingdom prospective diabetes study have confirmed the long-held clinical belief that aggressive therapy with tight glycemic control can have a beneficial effect on the development and progression of GSMP-DM and autonomic neuropathy. Excellent control of blood glucose is associated with less polyneuropathy (as well as retinopathy and nephropathy) than is good control. Apart from blood glucose control, there are no approved agents at this time in the United States for treating GSMP-DM. Inhibitors of aldose reductase, the first enzyme of the polyol (sorbitol) pathway that converts glucose into sorbitol, are promising but have not yet shown any clear clinical or electrophysiologic benefit. Nerve growth factor, dietary supplementation (such as with myoinositol, thiamine, vitamin B,,, or pantothenic acid) have been proposed but without proven benefit. Orthostatic hypertension, a major symptom of autonomic diabetic neuropathy, may be treated with elastic stockings, increased salt intake, and elevating the head of the bed. Fludrocortisone and midodrine are effective but may cause unacceptable hypertension. Chronic gastroparesis may respond to multiple small meals and metoclopramide. The symptomatic management of GSMP-DM is directed primarily at the neuropathic pain, which is present in many patients. Improvement in glycemic control rarely decreases pain appreciably. Physical measures, such as warm socks at night and massage, may be comforting. Minor analgesics are seldom of significant benefit, and narcotics are inappropriate because of the chronic nature of the disorder. Many anticonvulsants are effective in treating painful GSMP-DM. Gabapentin is effective in GSMP-DM and is well tolerated. Carbamazepine is particularly effective when there is paroxysmal neuropathic pain. Divalproex sodium, topiramate, tiagabine, lamotrigine, and oxcarbazepine also are promising in reducing burning and lancinating neuropathic pain. Anticonvulsants typically are prescribed in conventional dosages until therapeutic levels are obtained. If the patient does not respond when therapeutic levels are reached, the drug should be discontinued. Tricyclic antidepressants are the treatment mainstay in GSMPDM, and many have shown to be effective. Their mechanism of antinociception is unknown but is independent of their beneficial effect on depression. The particular tricyclic drug used often is determined by the need for sedation to assist in sleep and the presence of symptomatic autonomic neuropathy that might be exacerbated by their potential anticholinergic side effects. Amitriptyline is the most widely used agent in treating GSMP-DM. Its sedating effect may provide additional benefits in pain-related insomnia. However, its anticholinergic side effects are common. Therefore, it should not be used in patients with cardiac conduction defects, ventricular arrhythmia, or unstable angina. It also may exacerbate underlying manifestations of diabetic autonomic neuropathy, such as worsening urinary or bladder dysfunction or constipation. Desipramine and nortriptyline are alternative tricyclic medications with low anticholinergic side effect profile; moreover, they are less sedating. In treating neuropathic pain, tricyclic agents may be effective at low dosages (e.g., 10 to 25 mg at bedtime). However, this dosage may be increased gradually up to 75 or 150 mg at bedtime if necessary. In contrast to the tricyclic antidepressants, the serotonin reuptake inhibitors, such as fluoxetine, sertraline, paroxetine, and citalopram do not appear to be effective in treating neuropathic pain associated with GSMP-DM,

Chapter 93

but may be useful if there is a concomitant depression. Phenothiazines, alone or in conjunction with tricyclics, have been reported to be helpful. However, it is difficult to justify the risk of tardive dyskinesia, considering the limited potential benefit of these drugs. Mexiletine, an oral lidocaine derivative, is well tolerated and sometimes beneficial in treating painful diabetic neuropathy. Mexiletine is useful when GSMP-DM is associated with autonomic neuropathy because it has no anticholinergic side effects. However, like all other cardiac antiarrhythmic agents, mexiletine sometimes exerts a proarrhythmic effect and could aggravate underlying cardiac arrhythmia and is contraindicated in second- and thirddegree heart blocks. Therefore, it should be used with caution in a patient with such arrhythmias. Common side effects include gastrointestinal disturbance, dizziness, and tremor. Mexiletine should be started slowly with low dosages of 150 mg per day for the first 3 days, then progressing to 300 mg per day for the next 3 days, and finally 10 mg/kg daily in divided doses thereafter. Clonazepam, L-dopa/carbidopa, and pramipexole are useful in treating restless legs associated with GSMP-DM. Clonidine and tizanidine are a,-adrenergic agonists and have been proposed as effective in treating painful diabetic neuropathy. Neither drug has been studied sufficiently to determine its precise role. Topical agents may provide high local concentration of medication with minimal systemic effects. Capsaicin, a component of certain hot pepper plant species, depletes substance P, a neurotransmitter for nociceptive afferent fibers and type C fibers. When applied three or four times per day over a 2- to 3-week period, capsaicin reduces pain levels by this mechanism. This depletion is likely to be secondary to its release from nerve terminals, a process that often initially produces a sensation of local burning, warmth, and pain. This side effect, which has tempered enthusiasm for the use of this drug, may be dampened by applying an anesthetic cream (such as lidocaine) before applying capsaicin ointment. DIABETIC POLYRADICULOPATHY GSMP-DM constitutes approximately 75% of all diabetic neuropathies. The other 25% consist of a variety of entities; the one often responsible for the most disabling symptoms is diabetic polyradiculopathy. Diabetic polyradiculopathy, similar to diabetic neuropathy, is an umbrella title; it includes several diabetic-induced clinical disorders that affect predominantly the proximal PNS limb and trunk fibers, often in an asymmetrical fashion. Included under this group designation are what some investigators formerly considered independent syndromes (e.g., diabetic amyotrophy and diabetic thoracic radiculopathy), certain neuropathic processes responsible at times for the lower extremity weaknesses associated with DM (e.g., diabetic foot drop) and some more diffuse disorders. Various subgroups of diabetic polyradiculopathy often appear in classifications of diabetic neuropathy under such terms as diabetic amyotrophy, asymmetrical or symmetrical proximal motor neuropathy, diabetic lumbosacral radiculoplexus neuropathy, and diabetic thoracoabdominal neuropathy. Although diabetic amyotrophy, the most common subgroup of diabetic polyradiculopathy, was well described by Garland and Taverner in 1953, it was not until 1981 that Bastron and Thomas proposed a unifying concept linking all the subgroups. They suggested that several of the non-GSMP-DM types of diabetic neuropathy have a common, underlying basis: injury, often

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sequential, of various lumbar, thoracic, and occasionally cervical roots, caused by DM. This hypothesis has not been universally accepted, primarily because there is controversy regarding the exact site of nerve fiber damage (e.g., roots, plexus, peripheral nerves) in diabetic amyotrophy. For example, Dyck contends that this debilitating PNS disorder is caused by microvasculitis simultaneously involving the roots (primarily L2-L4), the plexus (primarily lumbar), and the peripheral nerves (femoral and obturator, at least initially) in a multifocal manner, hence the cumbersome name diabetic lumbosacral radiculoplmus neuropathy (DLSRPN). Nonetheless, diabetic polyradiculopathy has great appeal because it permits what appears to be a number of independent neuropathic syndromes linked only by underlying DM to be viewed in a coherent manner, with regard to underlying pathophysiology, clinical features, and prognosis. Diabetic polyradiculopathy affects the motor and sensory root fibers, causing axon degeneration, presumably from ischemia. Characteristically, it severely involves one root or two or more contiguous roots. Although the process may remain focal, it often spreads to additional roots, either contiguous ones ipsilaterally or, particularly, the corresponding contralateral roots. This “territorial extension” occurs in nearly 70% of patients. The L2, L3, and L4 roots are the ones most likely to be affected, producing the clinical syndrome called diabetic amyotrophy or DLSRPN. The next most common subgroup is the syndrome of diabetic thoracic radiculopathy, also called diabetic thoracoabdominal neuropathy or diabetic truncal radiculoneuropathy, in which one or more thoracic roots, usually the lower ones (e.g., T6-T12), are affected. GSMP-DM often coexists with diabetic polyradiculopathy. The simultaneous occurrence of these two independent diabetic PNS disorders can create confusion about the nature of the underlying pathophysiology. It probably also has been responsible for pathologic changes caused by GSMP-DM being attributed erroneously to diabetic polyradiculopathy, particularly the subgroup that involves the L2-L4 roots (i.e., diabetic amyotrophy or DLSRPN). This is because much neuropathologic research focused on L2-L4 diabetic polyradiculopathy has been based on biopsies of distal cutaneous nerves (sural, less often superficial peroneal sensory), which not only derive from sensory roots other than L2-L4 (i.e., from the S1 and L5 roots, respectively) but also are very likely to show abnormalities secondary to their involvement by GSMP-DM. Diabetic polyradiculopathy involving the L2-L4 roots has a variable mode of onset and evolution. Typically, it occurs in patients over age 60 who have mild DM, often NIDDM. Most commonly, it begins unilaterally in the anterior aspect of the proximal lower extremity, with severe pain, followed by significant weakness and atrophy of the anterior thigh muscles. The pain typically subsides after several weeks, although it may last much longer. However, weakness persists and often is accompanied by an inexplicable weight loss, sometimes 10% of body weight or more. This constellation of symptoms often raises suspicion of an underlying malignancy. Neurologic examination often discloses atrophy of the anterior thigh muscles and a reduced or absent patellar tendon reflex. Muscle testing usually reveals weakness of hip flexors, knee extensors, and thigh adductors. The presence of abnormalities in the distribution of both the femoral and obturator nerves suggests on clinical grounds that the responsible lesion involves the lumbar plexus or L2-L4 roots. Many patients (approximately 70%) also have clinical evidence of GSMP-DM of varying severity.

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Diabetic polyradiculopathy affecting the L2-L4 roots may also present in a bilaterally symmetrical, painless fashion, with clinical features identical to those described earlier. Intermediate syndromes of bilateral but asymmetrical painless weakness, as well as other variations, also may occur. The differential diagnosis of diabetic polyradiculopathy subgroup includes a lumbar intraspinal lesion causing L2-L4 root compression, a lumbar plexopathy, and a femoral mononeuropathy. EDX studies usually are very helpful in documenting motor axon loss in the L2-L4 myotomes, including the thigh adductors, thereby excluding femoral mononeuropathy. The high or midlumbar paraspinal muscles typically show prominent active denervation, rendering a lumbar plexopathy less likely. It is usually necessary to perform imaging studies on the lumbar spine, either M N scanning or CT myelogram, to exclude a compressive lesion in the lumbar intraspinal canal. In certain patients, CSF examination to exclude inflammatory lesions or infiltration of the subarachnoid space with malignant cells is also advisable. In patients with the painless symmetrical syndrome, EDX studies are helpful in excluding myopathy, as are serum creatine kinase and aldolase assays. Diabetic polyradiculopathy may also involve the lower lumbar and sacral (L5-S2) roots, although this usually occurs in conjunction with higher lumbar (L2-L4) root involvement. One of the prominent clinical features of diabetic L5 radiculopathy is foot drop. Bilateral foot drop from bilateral diabetic L5 radiculopathy often is mistakenly attributed to severe GSMP-DM. Diabetic rather than compressive L5 radiculopathy should be suspected whenever a patient with DM develops substantial L5 myotomal weakness and pain that is not relieved by bed rest and is more severe at night. Diabetic thoracic radiculopathy results when diabetic polyradiculopathy affects thoracic roots, either in isolation or by territorial extension from ipsilateral L2-L4 involvement. Usually, one or more of the T6-Tl2 roots is involved unilaterally or, less often, bilaterally. The characteristic symptom is severe, persistent pain in the middle or lower thoracic region, radiating to the upper or middle abdomen. A dermatomal sensory loss often is demonstrable. The thoracic motor, as well as sensory fibers are sometimes affected, but generally this is subclinical and discovered only upon needle electrode examination of the thoracic paraspinal or abdominal muscles. The symptoms of diabetic thoracic radiculopathy often are attributed to an intra-abdominal disorder. Many asymptomatic gall stones have been removed in an attempt to treat the pain caused by diabetic thoracic radiculopathy. Even when it is appreciated that the lesion is at the root level, other causes of thoracic radiculopathies must be excluded. Neuroimaging studies, and sometimes other tests as well, are indicated. Rarely, diabetic polyradiculopathy may involve cervical roots. Typically, the midcervical roots, particularly C5-C7, are bilaterally affected. This usually occurs in combination with L2-L4 root involvement. All the subgroups of diabetic polyradiculopathy have a favorable ultimate prognosis. Approximately three quarters of patients show satisfactory functional recovery after 1 year. Therapy consists primarily of pain management and an aggressive physical therapy program for gait training to prevent falls and injuries and eventually to assist during recovery. There are anecdotal reports of the benefits of intravenous immunoglobulin in the subacute forms of diabetic polyradiculopathy. Although this treatment is based on the presence of an inflammatory process in some of these

neuropathies, there have been no controlled trials that support the use of IVIg in any diabetic neuropathies. PERIPHERAL MONONEUROPATHIES Whether compression or entrapment mononeuropathies have a higher incidence in diabetic patients who do not have GSMP-DM than in nondiabetics is debated. Nonetheless, it is indisputable that some mononeuropathies occur with a markedly increased frequency in diabetics with GSMP-DM. Median neuropathy at the wrist, or carpal tunnel syndrome (CTS), and ulnar neuropathy at the elbow, both often bilateral, are particularly common in patients with GSMP-DM. An important point is that patients with GSMP-DM whose lower limb symptoms are strictly distal to the knees are not likely to develop sensory complaints in their hands because of their polyneuropathy. Consequently, the majority of diabetic patients with known mild GSMP-DM who complain of hand pain and paresthesias usually have superimposed CTS or ulnar mononeuropathies (or occasionally both). Neurologic examination of the upper limbs often provides evidence of this, and EDX studies are very useful in confirming the presence of these superimposed lesions. Both CTS and ulnar neuropathy at the elbow should be managed aggressively to preserve nerve function in the hand. This entails carpal tunnel release or ulnar nerve operations in patients with severe, progressive symptoms. There is good evidence that these lesions respond as well to surgical treatment as similar lesions do in patients who do not have underlying GSMP-DM. A syndrome of mononeuritis multiplex occasionally is observed in patients with DM. Typically, patients note acute pain associated with a sensorimotor deficit in the distribution of the affected nerve. This mode of onset suggests an acute ischemic mechanism. Multiple nerves may be affected in a random, stuttering fashion. Differential diagnosis includes vasculitic neuropathy. As with the subacute diabetic polyradiculopathies, treatment with IVIg has been recommended, but its efficacy has not been proven. CRANIAL MONONEUROPATHIES Isolated cranial neuropathies affecting the third, sixth, and occasionally the fourth cranial nerves occur with increased frequency in diabetic patients. The most common cranial nerve syndrome is diabetic oculomotor (third nerve) neuropathy. This typically affects patients over age 50 years and is quite rare in children. Usually, it develops abruptly; in approximately half the patients, the oculomotor weakness is preceded by pain, often severe, located in the periorbital region. Occasionally, the pain precedes the weakness by several days. The clinical examination typically discloses oculomotor palsy with sparing of the pupillary fibers. This contrasts with compressive lesions of the oculomotor nerve, in which the pupillary fibers usually are the first to be affected. Pupillary sparing has been attributed to ischemia occurring centrally within the third nerve, resulting in the peripherally located parasympathetic pupilloconstrictor fibers being preserved. Nevertheless, the differential diagnosis of diabetic oculomotor palsy must include mass lesions causing third nerve compression, including aneurysms of the posterior communicating artery. Evaluation of a patient with diabetic oculomotor neuropathy usually includes brain imaging, and sometimes lumbar puncture and angiography are indicated. Much less often,

Chapter 94

an isolated palsy of the abducens nerve may result from DM. Isolated diabetic trochlear neuropathies are rare; more often they occur in conjunction with third or sixth nerve palsies. The differential diagnosis of these disorders, as for oculomotor palsy, includes space-occupying lesions and inflammatory disorders. Idiopathic facial neuropathy (Bell’s palsy) may occur with increased frequency in diabetic subjects, but the evidence for this is somewhat inconclusive. The principal symptoms resulting from these cranial neuropathies are pain and diplopia. The former is treated with analgesics, the latter with an eye patch. Typically, third nerve palsies resolve, at least partially, within a few months of onset. Diabetic cranial neuropathies occasionally recur; nonetheless, they are usually associated with a favorable prognosis and a good functional recovery.

SUGGESTED READINGS Bastron JA, Thomas J E Diabetic polyradiculopathy. Mayo Clin Proc 56:725, 1981

Beckonja M, Beydoun A, Edwards KR et ak Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAh4A 2801831-1836, 1998 Bird SJ, Brown MJ: Diabetic neuropathies. pp. 598-621. In Katirji B, Kaminski HJ, Preston DC et al (eds): Neuromuscular Disorders in Clinical Practice. Boston, Butterworth-Heinemann, 2002 Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-independent diabetes mellitus. N Engl J Med 329:977, 1993

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Dyck PJB, Norell JE, Dyck PJ: Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 53:2113-2 12 1, 1999

Garland H, Taverner D: Diabetic myelopathy. BMJ 1:1405, 1953 Greene DA, Pfeifer M A Diabetic neuropathy. p. 223. In Olefsky JM, Sherwin RS (eds):Diabetes Mellitus: Management and Complications. Churchill Livingstone, New York, 1985 Harati Y: Treatment of diabetic peripheral neuropathies. pp. 380-384. In Johnson RT, Griffm JW, McArthur JC (eds): Current Therapy in Neurologic Disease. 6th Ed. Mosby, St Louis, 2002 Kernel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52:1053-1061, 1995

Max MB, Lynch SA, Muir J et al: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250, 1992

Mendell J R Diabetic neuropathies. pp. 373-399. In Mendel JR, Kissel JT, Cornblath DR (eds): Diagnosis and Management of Peripheral Nerve Disorders. Oxford University Press, New York, 2001 Mokdad AH, Ford ES, Bowman BA et al: Diabetic trends in the U.S.: 1990-1998. Diabetes Care 23:1278-1283, 2000 Taylor BV, Dyck PJ: Classification of the diabetic neuropathies. pp. 407414. In Dyck PJ, Thomas PK (eds): Diabetic Neuropathy. WB Saunders, Philadelphia, 1999 UKPDS Group: UK Prospective Diabetes Study 33: intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 352:837-853, 1998 Wilbourn AJ: Diabetic neuropathies. p. 477. In Brown WF, Bolton CF (eds): Clinical Electromyography. 2nd Ed. Butterworth-Heinemann, Boston, 1993 Wilbourn AJ: Mononeuropathies. pp. 481-508. In Dyck PJ, Thomas PK (eds):Diabetic Neuropathy. 2nd Ed. WB Saunders, Philadelphia, 1999

Metabolic Neuropathy David H. Weinberg

Peripheral nerve diseases are common in both primary care and specialized neuromuscular medical practices. A seemingly endless list of diagnostic considerations confronts the thoughtful practitioner. The array of metabolic disorders that affect the peripheral nerves superficially appear the most formidable. This chapter presents a systematic approach to these diseases. First, it is essential to remember that generalized polyneuropathies associated with metabolic diseases are almost exclusively of the axonal type, with clear systemic manifestations of the underlying disease. Additionally, with the possible exception of an unusual case of vitamin B,, deficiency or diabetes mellitus, metabolic polyneuropathies are unlikely to be identified on a screening laboratory battery of tests for an axonal polyneuropathy in the absence of key systemic manifestations. Table 94-1 lists the conditions covered in this chapter with the critical associated medical symptoms or common laboratory abnormalities that should raise red flags and direct the focus of the medical workup to identify these metabolic disorders. Within the constraints of a such a broad chapter, whenever possible, the major topics are organized to reflect the symptoms or defining features of the associated metabolic disease to facilitate the pattern recognition necessary for diagnosis.

NUTRITIONAL AND GASTROlNTESllNAL DISORDERS The mechanism for the development of nutritional neuropathies in the United States and other industrialized countries occurs as a result of malabsorption, chronic alcoholism, dietary faddism, or drug toxicity (e.g., isoniazid). Usually dietary imbalance rather than starvation is a factor, and conditions that increase the metabolic demand for a vitamin often are present (e.g., pregnancy, surgery, infection, growth).

W m l n 6, (Thiamine) Deficiency In the United States, most thiamine deficiency cases occur in alcoholics. In chronic gastrointestinal diseases that can reduce thiamine (such as vomiting and malabsorption), Wernicke’s encephalopathy has occurred, but not commonly polyneuropathy. The predominant neurologic manifestation of thiamine deficiency in alcoholics is also Wernicke’s encephalopathy. There is still much debate about the cause of the peripheral neuropathy that is also seen. Some believe it is a direct toxic effect of alcohol, whereas others contend it is a manifestation of thiamine deficiency

Chapter 94

an isolated palsy of the abducens nerve may result from DM. Isolated diabetic trochlear neuropathies are rare; more often they occur in conjunction with third or sixth nerve palsies. The differential diagnosis of these disorders, as for oculomotor palsy, includes space-occupying lesions and inflammatory disorders. Idiopathic facial neuropathy (Bell’s palsy) may occur with increased frequency in diabetic subjects, but the evidence for this is somewhat inconclusive. The principal symptoms resulting from these cranial neuropathies are pain and diplopia. The former is treated with analgesics, the latter with an eye patch. Typically, third nerve palsies resolve, at least partially, within a few months of onset. Diabetic cranial neuropathies occasionally recur; nonetheless, they are usually associated with a favorable prognosis and a good functional recovery.

SUGGESTED READINGS Bastron JA, Thomas J E Diabetic polyradiculopathy. Mayo Clin Proc 56:725, 1981

Beckonja M, Beydoun A, Edwards KR et ak Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAh4A 2801831-1836, 1998 Bird SJ, Brown MJ: Diabetic neuropathies. pp. 598-621. In Katirji B, Kaminski HJ, Preston DC et al (eds): Neuromuscular Disorders in Clinical Practice. Boston, Butterworth-Heinemann, 2002 Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-independent diabetes mellitus. N Engl J Med 329:977, 1993

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Dyck PJB, Norell JE, Dyck PJ: Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 53:2113-2 12 1, 1999

Garland H, Taverner D: Diabetic myelopathy. BMJ 1:1405, 1953 Greene DA, Pfeifer M A Diabetic neuropathy. p. 223. In Olefsky JM, Sherwin RS (eds):Diabetes Mellitus: Management and Complications. Churchill Livingstone, New York, 1985 Harati Y: Treatment of diabetic peripheral neuropathies. pp. 380-384. In Johnson RT, Griffm JW, McArthur JC (eds): Current Therapy in Neurologic Disease. 6th Ed. Mosby, St Louis, 2002 Kernel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52:1053-1061, 1995

Max MB, Lynch SA, Muir J et al: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250, 1992

Mendell J R Diabetic neuropathies. pp. 373-399. In Mendel JR, Kissel JT, Cornblath DR (eds): Diagnosis and Management of Peripheral Nerve Disorders. Oxford University Press, New York, 2001 Mokdad AH, Ford ES, Bowman BA et al: Diabetic trends in the U.S.: 1990-1998. Diabetes Care 23:1278-1283, 2000 Taylor BV, Dyck PJ: Classification of the diabetic neuropathies. pp. 407414. In Dyck PJ, Thomas PK (eds): Diabetic Neuropathy. WB Saunders, Philadelphia, 1999 UKPDS Group: UK Prospective Diabetes Study 33: intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 352:837-853, 1998 Wilbourn AJ: Diabetic neuropathies. p. 477. In Brown WF, Bolton CF (eds): Clinical Electromyography. 2nd Ed. Butterworth-Heinemann, Boston, 1993 Wilbourn AJ: Mononeuropathies. pp. 481-508. In Dyck PJ, Thomas PK (eds):Diabetic Neuropathy. 2nd Ed. WB Saunders, Philadelphia, 1999

Metabolic Neuropathy David H. Weinberg

Peripheral nerve diseases are common in both primary care and specialized neuromuscular medical practices. A seemingly endless list of diagnostic considerations confronts the thoughtful practitioner. The array of metabolic disorders that affect the peripheral nerves superficially appear the most formidable. This chapter presents a systematic approach to these diseases. First, it is essential to remember that generalized polyneuropathies associated with metabolic diseases are almost exclusively of the axonal type, with clear systemic manifestations of the underlying disease. Additionally, with the possible exception of an unusual case of vitamin B,, deficiency or diabetes mellitus, metabolic polyneuropathies are unlikely to be identified on a screening laboratory battery of tests for an axonal polyneuropathy in the absence of key systemic manifestations. Table 94-1 lists the conditions covered in this chapter with the critical associated medical symptoms or common laboratory abnormalities that should raise red flags and direct the focus of the medical workup to identify these metabolic disorders. Within the constraints of a such a broad chapter, whenever possible, the major topics are organized to reflect the symptoms or defining features of the associated metabolic disease to facilitate the pattern recognition necessary for diagnosis.

NUTRITIONAL AND GASTROlNTESllNAL DISORDERS The mechanism for the development of nutritional neuropathies in the United States and other industrialized countries occurs as a result of malabsorption, chronic alcoholism, dietary faddism, or drug toxicity (e.g., isoniazid). Usually dietary imbalance rather than starvation is a factor, and conditions that increase the metabolic demand for a vitamin often are present (e.g., pregnancy, surgery, infection, growth).

W m l n 6, (Thiamine) Deficiency In the United States, most thiamine deficiency cases occur in alcoholics. In chronic gastrointestinal diseases that can reduce thiamine (such as vomiting and malabsorption), Wernicke’s encephalopathy has occurred, but not commonly polyneuropathy. The predominant neurologic manifestation of thiamine deficiency in alcoholics is also Wernicke’s encephalopathy. There is still much debate about the cause of the peripheral neuropathy that is also seen. Some believe it is a direct toxic effect of alcohol, whereas others contend it is a manifestation of thiamine deficiency

592

Spinal Cord and Peripheral Neuromuscular Disease

Diseases of Peripheral Nerve

T l w 94-1. Critical Features of Metabolic Diseases Associated with Neuropathies" Disease States

Medical Associations

Additional Neurologic Signs

PN Type

Frequency

Wernicke's encephalopathy

A

U

A

R

A

C

? ?

R R

Miscellaneous

Nutritional and Gastrointestinal Disorders and Neuropathy

Vitamin B, deficiency (beriberi) Vitamin B, deficiency

Vitamin B, deficiency

Alcoholism Drug-induced pernicious anemia or gastrointestinal disease (gastric or ileum)

Myelopathy, encephalopathy

Folate deficiency Vitamin B, deficiency

Malabsorption/diet Malabsorption/diet

Niacin deficiency (pellagra) Vitamin E deficiency

Malabsorption/diet Malabsorption

Hypophosphatemia

Hyperalimentation

Possible "burning feet" syndrome

R

Central nervous system prominent, myopathy and ophthalmoplegia Subacute, severe PN

Usually chronic; rare acute or subacute PN

Megaloblastic anemia; myeloneuropathy distinctive Sensory PN-unlikely PN-unlikely PN-unlikely Red blood cells: acanthowe5 PN small part of syndrome Can simulate Guillain-Barrk syndrome; < 1 mg/dL

A

R

A?

R

A

C

M

C R

Rare acute PN; CC < 5 mumin CTS and UN usually Median and UN usually

C

Chapter 93

Chronic Renal Failure and Neuropathy

Uremia

End-stage CRF

CTS

CRF Arteriovenous fistula

Mononeuropathy Mononeuropathy

DM Hypothyroidism Hyperthyroidism

Overt glucose intolerance Myxedema Overt Graves's disease

CTS or rare PN

Acromegaly

Overt acromegaly

Shunt ischemia

A

Endocrine and Neuropathy

A M A PN

U M R

MND-like syndrome: resolves with medication

?

R

Hypercalcemia

Subacute PN

A

R

Acute recurrent attacks; adolescent onset or frequent latent state; + FH

Rare Basedods paraplegia or CTS or rare PN

Common NMJ and muscle involvement Mild PN; late onset

DM

Hyperparathyroidism Psychiaty and Neuropathy

Porphyrias

Psychiatric Gastrointestinal: abdominal pain Variegate porphyria: cutaneous involvement

Metabolic Neuromuscular Disease in the Intensive Care Unit

A C Motor signs dominate Sepsis, encephalopathy, Subacute PN respiratory failure * U Pure motor Not PN NMJ blockers + steroids NMJ blockade Myopathy Renal k hepatic insuffiNot PN * U Pure motor ciency "Disorders not covered in this chapter are referenced for the appropriate chapter. Abbreviotons:A, axonal; C, common; CC, creatinine clearance; CRF, chronic renal failure; CTS. carpal tunnel syndrome; DM, diabetes mellitus; M, mixed; MND, motor neuron disease; NMJ, neuromuscularjunction; PN, polyneuropathy; R, rare; U, uncommon. Critical illness PN

(beriberi). In developing regions where the diet is based on machine-milled rice, beriberi is still a common disease. Clinical Features. The onset of the polyneuropathy tends to be chronic (or subacute) with dominant sensory complaints: paresthesias, numbness, and dysesthesias. Pain and cramps in the calves often are present, and the majority of patients have edema of the face and ankles. The examination reveals graded distal limb sensory abnormalities typical of axonal "dying back" polyneuropathies. Most have a modest degree of distal weakness and depressed ankle jerks. Some patients have enlarged hearts and others modest elevations in the serum creatine kinase levels. Both the signs and symptoms are potentially reversible after replacement. Treatment. Intravenous thiamine is recommended initially at dosages of 10 to 100 mg/day for 3 days, then 2.5 to 25 mg/day

orally until the circumstances promoting the deficiency are reversed. Vitamin B,, (Cobalamin) Deficiency

There is great variability in the clinical presentation of this deficiency state. The most common manifestations are hematologic (megaloblastic anemia), gastrointestinal (gastric or terminal ileum disease), and neurologic. Spinal cord involvement represents the classic neurologic syndrome; however, a sensorimotor polyneuropathy is becoming more frequently appreciated. It is rarely isolated from spinal cord disease, making the clinical appearance distinctive (myeloneuropathy). The earliest symptoms could represent both central and peripheral neuropathic components: paresthesias, distal loss of proprioception, and, to a lesser extent,

Chapter 94

impaired superficial sensation, depressed deep tendon reflexes, and occasionally mild distal weakness. Signs of a myeloneuropathy subsequently develop with Babinski signs and, at times, brisk knee jerks. Impaired cognitive function can also occur with confusion, irritability, depression, memory impairment, or an altered state of arousal. The diagnosis of cobalamin deficiency often is delayed, especially when the megaloblastic changes are absent or mild. Central nervous system signs and symptoms often are misinterpreted as multiple sclerosis or other central processes, and the peripheral nerve abnormalities are subtle. Folic acid supplementation can abolish the anemia and suppress the megaloblastic changes but not protect the central or peripheral nervous system from damage. Most B,,-deficient patients have pernicious anemia, the antibody-mediated destruction of intrinsic factor. Dietary inadequacies and local gastric or terminal ileum diseases preventing absorption are less likely causes. Laboratory Features. Most patients with B,, deficiency have megaloblastic anemia, but those without it do have megaloblastic bone marrow changes. Serum B,, level is the principal diagnostic test, but it is neither completely sensitive nor specific. If clinical suspicion is high with a normal or equivocal B,, value, additional testing should be done. Methylmalonic acid is a critical cobalaminrequiring precursor involved in DNA synthesis that is elevated in B,, deficiency. Both serum and urine levels are elevated in most patients. More recently, holo-trans-cobalamin 11, a necessary B,, transport protein, has been found to be deficient in the serum of these patients. The role of this latter test is still being defined. If B,, deficiency is diagnosed, a Schilling’s test is necessary to evaluate intrinsic factor function by determining the absorptive capacity of B12.Impaired B,, absorption caused by deficient intrinsic factor is characteristic of pernicious anemia. Intrinsic factor antibodies are fairly specific for pernicious anemia but not very sensitive: At least 40% of patients have negative test results. Antiparietal cell antibodies are more sensitive but less specific, limiting their usefulness. Treatment The conventional protocol is 1000 pg cyanocobalamin intramuscularly daily for the first week, followed by weekly injections for 1 month, then monthly injections for life. Oral cyanocobalamin is felt to be equally efficacious at 1 mg daily, but it has never gained general acceptance. Rapid improvement is noted almost immediately after treatment is begun, and a more gradual recovery follows over the next 4 to 6 months. Adequate folate intake is also necessary. Vitamin B, (Pyridoxine) Deflcleny In adults, pyridoxine deficiency polyneuropathy is seen exclusively in patients on specific medications (i.e., isoniazid, penicillamine, cycloserine, and hydralazine). This is expanded further in Chapter 99.

Metabolic Neuropathy

593

there is an associated polyneuropathy syndrome. If so, it is certainly mild and not a major element of the disease. Vltamln E Deficiency There is increasing evidence that profound vitamin E deficiency during childhood and adolescence may be responsible for a distinctive combination of central nervous system, peripheral nervous system, and muscle dysfunction. Again, the only recognized acquired human cause is malabsorption, and there can be a latency of many years before these rare neurologic problems slowly develop. Clinical Features. The earliest and most consistent neurologic findings are a loss of deep tendon reflexes, large-fiber sensory loss, and sensory ataxia. The appreciation of pain and temperature usually are spared. Muscle weakness and atrophy occur, often in a proximal myopathic distribution. Many patients have a progressive external ophthalmoplegia. The peripheral neuropathy usually is overshadowed by CNS and ocular and systemic (gastrointestinal) involvement. Laboratory Features. A defining abnormality on the red blood cell smear is the presence of acanthocytes. Muscle and nerve biopsies are consistent with a large-fiber axonal polyneuropathy. Autopsies have also demonstrated a loss of spinal cord sensory fibers in the posterior columns and spinocerebellar tracts. Although a myopathy seems minimal in human disease, it is a prominent feature in all animal models. Treatment Vitamin E replacement may prevent progression of the neuropathy. Oral dosages of up to 10,000 mglday are recommended, but parented intramuscular dosages of 50 to 100 mg are preferred.

Hypophosphatemia, an unusual electrolyte abnormality, occurs almost exclusively in patients on hyperalimentation. The symptoms begin with tingling paresthesias on the tongue, fingers, and toes, but it can acutely progress to severe generalized areflexic weakness with impaired sensation and cranial mononeuropathies simulating Guillain-Barrk syndrome. The serum phosphate level is always under 1 mg/dL. RENAL INSUFFICIENCY There are no clear peripheral nerve effects of acute renal failure; the neuromuscular problems result entirely from the muscle’s response to altered electrolyte concentrations. In contrast, patients with chronic renal failure (CRF) can suffer three potentially severe neuropathic consequences: uremic polyneuropathy, carpal tunnel syndrome and other compressive mononeuropathies, and ischemic mononeuropathies. Uremic Polyneuropathy

Other Water-Soluble Vitamin Defldency States A limited number of reports have proposed a predominantly sensory polyneuropathy associated with folate deficiency. Riboflavin (vitamin B2) is alleged to be responsible for “burning feet” syndrome seen in some malnutrition and malabsorption states. Pellagra is caused by niacin deficiency, but it is unclear whether

Clinical Features. The symmetric, predominantly sensory symptoms of a slowly progressive polyneuropathy develop in end-stage disease when the creatinine clearance is less than 5 mL/minute. The pattern of slowly ascending positive sensory phenomena followed by distal numbness and distal muscle atrophy and weakness is typical of the entire class of “dying back” axonal polyneuropathies. Other common but nonspecific symp-

594

Spinal Cord and Peripheral Neuromuscular Disease W

Diseases of Peripheral Nerve

toms include multifocal muscle cramping and the restless legs syndrome. The earliest signs of polyneuropathy include loss of vibration appreciation in the toes and depressed ankle reflexes. The early studies defining these features were done before hemodialysis, excluding an etiologic role for this procedure in the development of the polyneuropathy. Although laboratory autonomic testing often is abnormal, the clinical correlate usually is not functionally significant. A more rapidly progressive polyneuropathy with prominent motor features has been associated with CRF, with or without concomitant diabetes mellitus. Diabetes alone, critical illness polyneuropathy, or an inflammatory polyneuropathy would not explain all the published cases. It appears to be a rare event relative to the common slowly progressive axonal polyneuropathy described earlier. Laboratory Features. Electromyography (EMG) demonstrates an axonal polyneuropathy in most patients with CRF despite the fact that one half have no symptoms. Some authorities recommend routine monitoring of the nerve conduction studies with an adjustment of dialysis to prevent the polyneuropathy, but most contend that clinical observation and serum values of blood urea nitrogen and creatinine are adequate. The sympathetic skin response and the R-R interval variation testing are sued to evaluate sympathetic and parasympathetic autonomic function, respectively. Either or both of these tests can be abnormal in subpopulations of uremic patients. The sympathetic skin response correlates with the presence of a clinical dysautonomic syndrome of postural hypotension and impotence. Course. Adequate hemodialysis and peritoneal dialysis both halt the progression of uremic polyneuropathy, but improvement is rarely seen. However, renal transplantation results in a marked amelioration in the paresthesias within a few days or weeks. A more gradual resolution is seen in the fixed neurologic deficits over a period of weeks to months. As expected, the severity of the atrophy, weakness, and sensory loss predicts the pace and completeness of the recovery. The compressive mononeuropathies also improve. Renal rejection leads to a recurrence of the polyneuropathy; however, recovery is still expected if future transplantation is successful.

Carpal Tunnel Syndrome Carpal tunnel syndrome and other mononeuropathies (such as an ulnar mononeuropathy) are commonly seen in these patients. At least in carpal tunnel syndrome, amyloid deposition ( p2microglobulin) often is found in the wrist synovial and tendon tissues, leading to median nerve compression. Treatment is similar to that for the idiopathic mononeuropathy syndrome. The success of therapy depends on the degree of axonal damage at the time it is rendered.

Ischemic MononeuropathyAssociated with Artedovenous Fistulas The most common vascular access for chronic hemodialysis is through a Brescia-Cimino arteriovenous fistula in the forearm (between the radial artery and the cephalic vein). The shunting of blood through the forearm results in variable degrees of ischemia distal to the fistula, which is exacerbated during hemodialysis. Therefore, ischemic mononeuropathies occasionally can develop in either the median or ulnar nerves, although it appears to be uncommon compared with the compressive lesions referred to

earlier. The incidence and severity of this nerve damage appear to be higher for the less frequently used proximal arm fistulas. The development of symptoms or signs of a median, ulnar, or even a radial mononeuropathy in conjunction with the formation of one of these shunts justifies vascular ligation to prevent nerve damage.

ENDOCRINE NEUROPATHIES With the exception of diabetes mellitus, which is covered in Chapter 93, peripheral nerve problems are uncommon in association with endocrinopathies.

Thyroid Disease Hypothyroidism. The majority of patients complain of distal paresthesias, but it is usually limited to the hands and caused by a compressive median nerve mononeuropathy (carpal tunnel syndrome). The symptoms often improve with thyroid replacement therapy, obviating surgery. Infrequently, a mild clinical axonal polyneuropathy or an EMG demonstrating a subclinical polyneuropathy is present. Rare case reports of a more severe large-fiber polyneuropathy have been published with predominantly demyelinating features on EMG and nerve biopsy, Hyperthyroidism (Graves’s Disease). Hyperthyroidism is commonly associated with disorders of muscle and the neuromuscular junction, but peripheral nerve dysfunction usually is quite modest. In clinically evident Graves’s disease, the description of a flaccid paraplegia dates back to the nineteenth century (“Basedow’s paraplegia”). It must be exceedingly rare, as is a distal axonal polyneuropathy, which may improve following treatment.

Acromegaly Acromegaly is most commonly seen with a growth hormonesecreting tumor in the pituitary gland. The neurologic manifestations include both carpal tunnel syndrome, similar to that seen in hypothyroidism, and an axonal polyneuropathy. The early cases relating acromegaly and a polyneuropathy probably had concomitant diabetes mellitus (a common acromegaly concomitant illness). Symptoms usually occur late in the illness, are mild, and occur in the distribution of a typical axonal polyneuropathy.

Hyperparathyroidism Weakness and fatigability are common presenting complaints of patients with hyperparathyroidism. At times, the weakness can be severe and dominates the sensory complaints. There have been few systematic evaluations. The combination of generalized weakness, easy fatigability, atrophy, hyperreflexia, and limited, if any, sensory abnormalities suggests a motor neuron disease. It appears unlikely that the secondary hypercalcemia is responsible for the weakness. Removal of the etiologic parathyroid adenoma is uniformly associated with rapid improvement in strength and the other associated signs.

PSYCHIATRY AND NEUROPATHY: THE PORPHYRIAS The porphyrias are a group of seven hereditary disorders of heme biosynthesis, four of which can have an associated polyneuropathy (Table 94-2). Each form is associated with a specific enzymatic defect causing the accumulation of porphyrin precursors in its

Chapter 94

Metabolic Neuropathy

595

TABU94-2. Nosology of the Porphyrias Porphyria Types

Clinical Involvement

Diseases

Nomenclature (This Chapter)

Neuroporphyrias Neuroporphyrias Neuropsychiatric and gastrointestinal (autonomic) AIP, PP Neurocutaneousporphyrias Mixed neuropsychiatric, gastrointestinal and cutaneous HCP, VP Neuroporphyrias Cutaneous porphyrias Cutaneous PO, EP, CEP Not discussed Abbreviations: AIP, acute intermittent porphyria; CEP, congenital etythroporphyria; EP, erythropoietic porphyria; HCP, hereditary coproporphyria;PCT, porphyria cutanea tarda; PP, plurnboporphyria; VP, variegate porphyria.

Glycine + succinyl CoA

I

ALA synthetase

1

ALA dehydratase

1

PBG deaminase

A M

PP

PBG

AIP

TABLE94-3. Precipitating Factors Associated with Acute Porphyric Attacks

Barbiturates Chlordiazepoxide Chlorpropamide Ergotarnines Estrogens Criseofulvin

DN-

Other Factors

Methyldopa Phenytoin Rifampin Sulfonamides Tricyclic antidepressants

Alcohol Nutritional Hormonal Fever Fasting Sleep

Uro I

Uroporphyrinogen 111

1

Coproporphyrinogen 111

HCP

1

Copro-oxidase

Protoporphyrinogen IX

VP

1 I

Proto-oxidase

Protoporphyrin IX

Heme FIG. 94-1. Heme biosynthetic pathway with the neuroporphyrias listed on the left at the level of their respective enzymatic defects. AIP, acute intermittent porphyria; AIA, Gaminolevulinic acid; HCP, hereditary coproporphyria; PBG, porphobilinogen PP, plumboporphyria; VP, variegate porphyria.

own unique patterns (Fig. 94-1). All of the neuroporphyrias (except plumboporphyria) have autosomal dominant inheritance, but the penetrance is low. Thus, many asymptomatic relatives of an index patient have the genetic defect and the potential to both develop and transmit the disorder. The key points in the identification of these conditions are the association with psychiatric (and often gastrointestinal) symptoms uniformly preceding the development of the polyneuropathy and the episodic nature of many symptoms. Clinical Features. Acute intermittent porphyria, plumboporphyria, hereditary coproporphyria, and variegate porphyria all have similar neurologic manifestations, with hereditary coproporphyria and variegate porphyria also demonstrating photocutaneous lesions. Acute intermittent porphyria serves as the prototypic neuroporphyria by virtue of its frequency (yet all forms are rare). The onset of symptoms is unusual before adolescence. There is great variability in the phenotypic expression, with clinically latent disease at times being associated with vague mood disorders. Early attacks usually consist of colicky abdominal pain with constipation, vomiting, and fevers. Attacks typically last days to weeks and

recur intermittently. Psychiatric symptoms can accompany or precede the abdominal attacks, with many patients having long and complex psychiatric histories. The severity of the psychiatric episodes can vary widely, but they often include psychotic behavior, visual hallucinations, and frank delirium. Episodes often are associated with a defined group of established precipitating factors (Table 94-3), and symptoms can be lessened by sleep or an intake of sugar. Porphyria-associated polyneuropathy rarely presents without prior bouts of abdominal pain or a psychiatric history. Unlike the majority of axonal polyneuropathies, the onset with porphyria is acute or subacute. Pain in the extremities or back can be significant, but weakness usually predominates. The weakness can begin either distally or proximally, with both asymmetric and symmetric distributions. Severe cases can progress to a flaccid quadriparesis with respiratory failure. Muscle tenderness and cramps are common, as are autonomic dysfunction and weakness in cranial musculature (e.g., ophthalmoplegia, ptosis, anisocoria). Diagnostic clues to a porphyric polyneuropathy include an associated psychiatric or gastrointestinal illness, a positive family history, a relationship to specific precipitating factors (Table 94-3) and dark urine discoloration (porphobilinogen). Laboratory Features. Urine testing for heme biosynthetic intermediates is the best screening procedure for the neuroporphyrias. Figure 94-2 outlines the appropriate responses and interpretations, starting with the urine 8-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels. If ALA and PBG are normal during an acute episode, those symptoms are not from one of the neuroporphyrias. In acute intermittent porphyria, both ALA and PBG usually are elevated, even between attacks. Enzyme measurements are reserved for confirmation of the diagnosis or to identify asymptomatic family members whose urine ALA and PBG are normal. Neurophysiologic assessment of peripheral nerve function demonstrates predominantly axonopathy features, but changes of secondary demyelination may be present. This is distinct from Guillain-Barrk syndrome, which the subacute motor course may simulate. Course. Typically, there is progression of the polyneuropathy over about 6 weeks. Attacks often involve all extremities, cranial nerves, and respiratory muscles. Recovery begins within about 2

Spinal Cord and Peripheral Neuromuscular Disease w Diseases of Peripheral Nerve

5%

A M and PBG

During attack

Between attacks

I

I

t I Normal

Elevated

Elevated

Normal

I 1

I Not acute porphyria

Neuroporphyria

Possible neuroporphyria

Order stool porphyrins

Order stool porphyrins I

I

I

I I

Normal

Elevated protoporphyrin

Elevated coproporphyrin

1

1

AIP

VP

I Normal

I

1

HCP

Not acute porphyria

FIG. 94-2. Laboratory flow diagram for suspected neuroporphyria starting with urinary ALA and PBC. AIP, acute intermittent porphyria; AW, 6-aminolevulinic acid; HCP, hereditary coproporphyria; PBC, porphobilinogen; VP, variegate porphyria. (Modified from Tefferi A, Colgan JP, Solberg CA et al: Acute porphyrias: diagnosis and management. Mayo Clin Proc 69:289-291, 1994, with permission.)

months of peak weakness, and although slow, it is usually complete. Treatment. Avoiding provocative factors (Table 94-3) is the most important intervention. When an index patient is identified, it is crucial to search for carriers and asymptomatic patients so that education can prevent unnecessary exposures. Patients who develop severe polyneuropathy must be admitted to an intensive care unit (ICU) setting. Hematin and glucose prevent ALA synthetase induction and are felt by some to alleviate symptoms over several days. One recommended protocol is initiated with intravenous glucose at 10 to 20 g/hour. If there is no clinical change within 48 hours, hematin is added intravenously at 2 mg/kg/day. Potential systemic complications include hyponatremia, hypomagnesemia, azotemia, and autonomic instability.

METABOLIC NEUROMUSCULAR DISEASE IN THE CRITICALLY ILL PATIENT Seriously ill patients in the ICU present a difficult problem for the consulting neurologist. Over the years weakness has been attributed to the metabolic demands of systemic illness, disuse, the concomitant development of Guillain-Barr6 syndrome, or the unmasking of unrecognized illnesses such as myasthenia gravis or motor neuron disease. An enlarging and somewhat contradictory group of reports has recently been published describing weak patients in the ICU setting that do not fit these criteria. Although much progress has occurred in the field in recent years, this updated summary still must be viewed as a work in progress. When one is confronted with a weak patient in the ICU, the differential diagnosis is divided into four broad groups: critical illness polyneuropathy, neuromuscular junction blockade, critical illness myopathy, and a miscellaneous collection of uncommon disorders.

Critical Illness Polyneuropathy

Critical illness polyneuropathy (CIP) is a recently described disorder of surprising frequency in respirator-bound critically ill patients in the ICU. Many cases come to attention when unexplained ventilator dependency occurs in a patient during a complicated medical illness. Sepsis and multiple-organ system failure appear to be necessary concomitants for the development of critical illness polyneuropathy, and usually a significant (septic) encephalopathyprecedes the polyneuropathy. The encephalopathy complicates the diagnostic evaluation by limiting the sophistication of the neurologic examination during its evolution. Clinical Features. Critical illness neuropathy is an acute, axonal polyneuropathy that is dominated clinically by motor signs with weakness, depressed or absent reflexes, and respiratory insufficiency. Sensory loss can be mild or absent clinically, although sensory nerves usually are involved pathologically and on neurophysiologic testing. About one half of the cases can be demonstrated electrophysiologicallybefore the clinical syndrome is evident. laboratory Features. EMG and spinal fluid evaluations are important to separate this condition from Guillain-Bar& syndrome (in which demyelinating features on nerve conduction studies and an elevated spinal fluid protein are major differentiating points) and myopathy (in which the sensory potentials are normal). Low motor and sensory amplitudes usually are seen on nerve conduction studies, whereas the needle EMG examination characteristically contains fibrillation potentials and positive sharp waves in both the limb muscles and the diaphragms. These findings are consistent with an axonal degeneration disease mechanism. Neither demyelinating nor inflammatory features have been present on nerve biopsies. Prognosis. The prognosis is fairly good if the patient survives the primary illness. Most patients gradually recover over weeks to

Chapter 95

months, often with a normal EMG at 6 to 12 months. No specific treatment has been demonstrated to hasten recovery.

Neuromuscular Junction Blodcade After protracted exposure to certain nondepolarizing neuromuscular junction blocking agents (especially pancuronium and vecuronium), some patients have had prolonged and often severe weakness with depressed reflexes and normal sensation. Most of these patients have elevated levels of the drug, and in the case of vecuronium, elevated levels of the active metabolite (3desacetylvecuronium).Renal insufficiency with or without hepatic insufficiency appears to be the critical associated feature responsible for the prolonged neuromuscular blockade. The neuromuscular junction transmission defect is best demonstrated neurophysiologicallywith repetitive stimulation (decremental response), but many of the literature studies test mechanically with twitch tensions. The prognosis tends to be quite good, with recovery in hours to weeks. Treatment involves discontinuing the offending agent, providing medical support, and treating associated illnesses such as renal failure.

Crltlcal Illness Myopathy Another group of patients has recently been identified among critically ill, respirator-dependent patients in the ICU who also develop acute, severe weakness after prolonged exposure to specific nondepolarizing neuromuscular junction blocking agents (again, usually pancuronium and vecuronium) but with normal neuromuscular junction function. Many of these patients present with status asthmaticus and have also been given large dosages of corticosteroids. Although similar patients have been described after high-dose steroids or neuromuscular junction blockers alone, the numbers are small compared with those who have taken both. The combination of severe, flaccid, generalized weakness, respiratory failure, and depressed reflexes fits the phenotype of CIP and has been confused with this entity in the literature, but a myopathy has been convincingly demonstrated on both EMG and muscle biopsy. At least some patients reported with a pure motor form of CIP have this myopathic disorder. Furthermore, the nerve and muscle disorders often are present concurrently. Thick myofila-

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ment (myosin) loss has been stressed in numerous reports, but others have described panfascicular muscle fiber necrosis. In these latter cases, the creatine kinase is markedly elevated with the risk of rhabdomyolysis, but some patients have normal serum muscle enzyme levels, especially if tested later in the course of the illness. The weakness tends to improve over weeks to months if the patient survives the primary illness. No specific treatment is known. This disorder has been reported under a variety of names including critical illness myopathy, acute quadriplegic myopathy, thick filament myopathy, acute myopathy with selective loss of myosin filaments, acute corticosteroid myopathy, acute hydrocortisone myopathy, and acute necrotizing myopathy.

Miscellaneous Conditions A series of other diagnoses are considered in the ICU setting, but retrospective and prospective studies suggest that they must be quite uncommon. They include Guillain-Barrk syndrome, myasthenia gravis, botulism, motor neuron disease, porphyria, rhabdomyolysis (from causes other than critical illness myopathy), nutritional neuropathies, spinal cord syndromes, and antibiotic toxicity. ~~

~

SUGGESTED READINGS Aminoff MJ: Neurology and General Medicine. Churchill Livingstone, New York, 1989 Bolton CF The polyneuropathy of critical illness. J Intensive Care Med 9132-138, 1994 Bolton CF, Young GB: Neurological Complications of Renal Disease. Butterworths, Boston, 1990 Joynt RJ: Baker and Baker’s Clinical Neurology. JB Lippincott, Philadelphia, 1993 Lacomis D, Zochodne DW, Bird SJ: Critical illness myopathy. Muscle Nerve 23:1785-1788, 2000 Schaumburg HH, Berger AR, Thomas PK Disorders of Peripheral Nerves. FA Davis, Philadelphia, 1992 Swanson JW, Kelly JJ,McConahey WM: Neurological aspects of thyroid dysfunction. Mayo Clin Proc 56504-512, 1981 Zochodne DW, Bolton CF, Wells GA et al: Critical illness polyneuropathy. Brain 110:819-842, 1987

Infectious and Granulomatous NeuroDathies

Only a few peripheral neuropathies have infectious causes. These infectious disorders include those recognized for some time, such as leprosy and varicella zoster, as well as those more recently described, such as Lyme disease and human immunodeficiency virus (HIV) infection. Although sarcoidosis does not have a proven infectious cause, it can produce an inflammatory neuropathy with granuloma formation and therefore is included in this chapter.

LEPROSY

Leprosy is one of the most common causes of peripheral neuropathy in the world. Although the majority of cases occur in developing countries in the tropical latitudes, the United States also has a small endemic area, primarily in Texas and Louisiana. Although leprosy control programs have made great strides toward eliminating the disease (defined by the World Health Organization

Chapter 95

months, often with a normal EMG at 6 to 12 months. No specific treatment has been demonstrated to hasten recovery.

Neuromuscular Junction Blodcade After protracted exposure to certain nondepolarizing neuromuscular junction blocking agents (especially pancuronium and vecuronium), some patients have had prolonged and often severe weakness with depressed reflexes and normal sensation. Most of these patients have elevated levels of the drug, and in the case of vecuronium, elevated levels of the active metabolite (3desacetylvecuronium).Renal insufficiency with or without hepatic insufficiency appears to be the critical associated feature responsible for the prolonged neuromuscular blockade. The neuromuscular junction transmission defect is best demonstrated neurophysiologicallywith repetitive stimulation (decremental response), but many of the literature studies test mechanically with twitch tensions. The prognosis tends to be quite good, with recovery in hours to weeks. Treatment involves discontinuing the offending agent, providing medical support, and treating associated illnesses such as renal failure.

Crltlcal Illness Myopathy Another group of patients has recently been identified among critically ill, respirator-dependent patients in the ICU who also develop acute, severe weakness after prolonged exposure to specific nondepolarizing neuromuscular junction blocking agents (again, usually pancuronium and vecuronium) but with normal neuromuscular junction function. Many of these patients present with status asthmaticus and have also been given large dosages of corticosteroids. Although similar patients have been described after high-dose steroids or neuromuscular junction blockers alone, the numbers are small compared with those who have taken both. The combination of severe, flaccid, generalized weakness, respiratory failure, and depressed reflexes fits the phenotype of CIP and has been confused with this entity in the literature, but a myopathy has been convincingly demonstrated on both EMG and muscle biopsy. At least some patients reported with a pure motor form of CIP have this myopathic disorder. Furthermore, the nerve and muscle disorders often are present concurrently. Thick myofila-

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ment (myosin) loss has been stressed in numerous reports, but others have described panfascicular muscle fiber necrosis. In these latter cases, the creatine kinase is markedly elevated with the risk of rhabdomyolysis, but some patients have normal serum muscle enzyme levels, especially if tested later in the course of the illness. The weakness tends to improve over weeks to months if the patient survives the primary illness. No specific treatment is known. This disorder has been reported under a variety of names including critical illness myopathy, acute quadriplegic myopathy, thick filament myopathy, acute myopathy with selective loss of myosin filaments, acute corticosteroid myopathy, acute hydrocortisone myopathy, and acute necrotizing myopathy.

Miscellaneous Conditions A series of other diagnoses are considered in the ICU setting, but retrospective and prospective studies suggest that they must be quite uncommon. They include Guillain-Barrk syndrome, myasthenia gravis, botulism, motor neuron disease, porphyria, rhabdomyolysis (from causes other than critical illness myopathy), nutritional neuropathies, spinal cord syndromes, and antibiotic toxicity. ~~

~

SUGGESTED READINGS Aminoff MJ: Neurology and General Medicine. Churchill Livingstone, New York, 1989 Bolton CF The polyneuropathy of critical illness. J Intensive Care Med 9132-138, 1994 Bolton CF, Young GB: Neurological Complications of Renal Disease. Butterworths, Boston, 1990 Joynt RJ: Baker and Baker’s Clinical Neurology. JB Lippincott, Philadelphia, 1993 Lacomis D, Zochodne DW, Bird SJ: Critical illness myopathy. Muscle Nerve 23:1785-1788, 2000 Schaumburg HH, Berger AR, Thomas PK Disorders of Peripheral Nerves. FA Davis, Philadelphia, 1992 Swanson JW, Kelly JJ,McConahey WM: Neurological aspects of thyroid dysfunction. Mayo Clin Proc 56504-512, 1981 Zochodne DW, Bolton CF, Wells GA et al: Critical illness polyneuropathy. Brain 110:819-842, 1987

Infectious and Granulomatous NeuroDathies

Only a few peripheral neuropathies have infectious causes. These infectious disorders include those recognized for some time, such as leprosy and varicella zoster, as well as those more recently described, such as Lyme disease and human immunodeficiency virus (HIV) infection. Although sarcoidosis does not have a proven infectious cause, it can produce an inflammatory neuropathy with granuloma formation and therefore is included in this chapter.

LEPROSY

Leprosy is one of the most common causes of peripheral neuropathy in the world. Although the majority of cases occur in developing countries in the tropical latitudes, the United States also has a small endemic area, primarily in Texas and Louisiana. Although leprosy control programs have made great strides toward eliminating the disease (defined by the World Health Organization

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[WHO] as a prevalence of less than 1 per ~O,OOO),it remains a significant cause of morbidity and disability worldwide. In 1999, the number of patients registered in treatment programs in 82 reporting countries was about 730,000, down from 5.4 million in 1991, thanks largely to introduction of multidrug therapy in the 1980s. However, the annual incidence of new cases has remained consistently about 700,000. This may result in part from more vigorous case-finding endeavors and possibly from a cadre of asymptomatic carriers in endemic areas. Leprosy, also known as Hansen’s disease after Norwegian physician G. Armour Hansen, who discovered its cause in 1873, is the result of infection with the acid-fast bacillus Mycobacterium Zeprue. The infection is thought to spread primarily by nasal droplets. From the nasal mucosa, the bacilli are carried hematogenously to other areas of the body. Because the bacilli divide most actively between 27’ and 3OoC, superficial tissues that are slightly below core body temperature are preferentially infiltrated. These include the anterior one-third of the eye, the testes, the upper respiratory tract, the skin, and the peripheral nerves. Only about 5% of the world’s population is susceptible to infection. The incubation period is years. The first sign of infection may be a single, often self-healing, hypopigmented anesthetic skin lesion with indistinct borders (indeterminate leprosy). If the lesion does not heal, the disease may then progress to other forms. The form of the disease that occurs in an individual patient depends on the host’s T-cell-mediated immune response to M. leprue. Manifestations range on a spectrum from lepromatous (multibacillary) to tuberculoid (paucibacillary) leprosy. Borderline cases are an intermediate form with more widespread infection but a somewhat more active immune response. In tuberculoid leprosy, a strong immune response limits disease to five or fewer sharply demarcated, hypopigmented, slowly enlarging skin lesions, typically located on the extensor surfaces of the limbs, face, or buttocks. The central part of the lesions is anesthetic and dry because of involvement of small cutaneous nerves. Invasion of larger nerve trunks that course below the skin lesions leads to a mononeuropathy. Sensory nerves most often affected are the digital, sural, radial, and posterior auricular nerves. The ulnar, median, peroneal, and facial nerves are the most susceptible sensorimotor nerves. Biopsy of skin lesions demonstrates well-formed granulomas involving dermal nerve twigs. Bacilli cannot be found. If the host’s cell-mediated immune response is deficient, infection becomes widespread, resulting in lepromatous leprosy. Numerous erythematous macules, nodules, and plaques appear. Infiltration of forehead, nose, and earlobes causes the classic leonine facies, and loss of eyebrows and eyelashes (madarosis) occurs. A symmetrical sensory neuropathy develops over the coolest surface areas, where the bacilli are abundant. The dorsal surfaces of the extremities and the pinnae of the ears initially are involved. If left untreated, the process spreads so that only the scalp, crura, and axillae are spared. Invasion of superficial mixed nerves may produce palpable enlargement of the nerves and weakness. The ulnar nerve at the elbow usually is the first nerve thus affected, followed by the peroneal nerve. Eventually, a mononeuritis multiplex pattern becomes superimposed on the symmetrical sensory neuropathy. Involvement of the superficial branches of the facial nerve creates a distinctive “buccinator smile” with characteristic wrinkling extending from the corner of the mouth, which results from sparing of the deep buccinator muscle. Repetitive trauma, skin ulceration, and burns occur as the result of insensitivity to pain. Unlike neuropathies that affect deeper and

warmer tissues, the neuropathy of leprosy characteristically spares the muscle stretch reflexes. Autonomic modalities other than sweating are not involved. Nerve conduction studies may be normal if only small sensory nerves are involved; with more extensive disease, an axonal sensorimotor polyneuropathy or mononeuritis multiplex can be documented. Biopsy of skin lesions reveals inflammation invading the dermal nerves. Numerous bacilli are seen in the skin biopsy and in nasal smears and slit-skin smears from earlobes, elbows, and knees. The diagnosis is readily suggested by neuropathy occurring in association with typical skin lesions in a patient from an endemic area. However, a small but significant minority of patients present with mononeuropathy or mononeuritis multiplex, without evidence of skin lesions. In these patients, nerve biopsy usually is needed for definitive diagnosis. WHO treatment recommendations for paucibacillary leprosy are dapsone 100 mg daily and rifampicin 600 mg monthly, supervised, for 6 months. For patients with multibacillary leprosy, clofazimine 50 mg daily and 300 mg monthly is added. Formerly, a 24-month course of treatment was recommended, but recent field trials have indicated that 12 months of treatment may be sufficient for most multibacillary ‘cases, so WHO recommendations were amended. New regimens being tested are combinations of rifampin, ofloxacin, and minocycline. The course of leprosy may be complicated by immunemediated reactions, which may occur before, during, or after treatment. They may cause continued nerve damage in treated patients. In type 1 reactions, there is acceleration of host immune response. Indolent skin and nerve lesions may suddenly become inflamed and swollen, and there may be low-grade fever. Nerves become enlarged and tender. Rapid progression of neuropathy may occur but may be reversible with prompt treatment. Steroids often are needed, sometimes for weeks or months, to prevent permanent damage. Borderline patients are particularly susceptible to type 1 reactions. New patients presenting with nerve pain or new neuropathy symptoms in the previous 6 months may be treated with prednisone when multidrug therapy is initiated. Type 2 reactions, or erythema nodosum leprosum, occur most commonly in patients at the lepromatous end of the spectrum and are presumed to be caused by circulating antigen-antibody complexes. Manifestations include fever, tender skin nodules, arthritis, periostitis, orchitis, iridocyclitis, and nephritis. Treatment is primarily thalidomide in nonpregnant patients. Steroids are also used. In recent years, emphasis in leprosy treatment programs has shifted toward integrating patients into primary health services. The goal is to reduce the stigma associated with the disease and to give health care workers resources and training to deal with the rehabilitation and social issues associated with the disease. LYME DISEASE

Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted by Zxodes ticks. Lyme disease is the most common vector-borne infection in the United States. Between 1992 and 1998, more than 88,000 cases were reported to the Centers for Disease Control and Prevention (CDC). However, the disease is limited to the geographic regions where the vector is found. Endemic areas in the United States include the coastal Northeast, the upper Midwest, and the Pacific Coast. Although the disease is reported year-round, the majority of cases occur in June, July, and August, when ticks are most active. There are early and late clinical stages of Lyme disease. The

Chapter 95

early stage can be further subdivided into localized and disseminated disease. Early localized Lyme disease includes the development of erythema migrans. This red, macular rash usually expands from the center and develops a bull's-eye appearance. The rash typically is noted near the site of inoculation-on the groin, axilla, or thigh in adults, on the head or neck in children-and persists for 3 to 4 weeks. However, only 50% to 70% of patients infected by the organism after a tick bite develop erythema migrans. Flulike symptoms, including mild headache, chills, lymphadenopathy, or fever, may accompany the rash or occur alone. Neurologic abnormalities eventually occur in 5% to 15% of patients with untreated early Lyme disease. Diffuse or focal meningeal inflammation characterizes the early disseminated form of the disease and occurs within weeks after the initial infection. Ten to twenty percent of cases involving the central nervous system are not preceded by erythema migrans. Meningitis occurs in 80% of patients with neurologic involvement. Meningeal symptoms may be mild or may fluctuate and consist of severe headache, nuchal rigidity, and malaise. Increased cerebrospinal fluid (CSF) protein and lymphocytosis are common. Cranial neuropathies, most often unilateral or bilateral Bell's palsy (although essentially any cranial nerve can be affected), occur in 50% of patients with neurologic abnormalities. Recovery is spontaneous and usually complete. Cardiac abnormalities (heart block, carditis, cardiomyopathy)can occur in up to 8% of patients in this stage of the disease. Peripheral nerve involvement in the early disseminated stage usually takes the form of a radiculoneuritis. The initial manifestation is pain over a limb, the trunk, or the spine that begins subacutely and lasts for several days to months. The upper extremities are involved more often than the lower extremities. This eventually gives way to sensory and motor loss in the distribution of a nerve root, plexus, or peripheral nerve. The lesions may spread to involve multiple nerve distributions in a mononeuritis multiplex pattern. In addition, cases have been reported that appear similar to Guillain-Barrk syndrome. The chronic or late form of the disease occurs months to years after the onset of Lyme disease and is marked by the development of chronic arthritis. Diffusely aching muscles, psychiatric disturbances, and encephalomyelopathy may also occur at this stage. A peripheral neuropathy occurs in 30% to 50% of patients and is marked by painful paresthesias in a radicular distribution or a stocking-glove sensory loss. Electrophysiologic studies demonstrate an axonal sensorimotor neuropathy that may have a multifocal distribution. The pathologic mechanism probably is autoimmune. Nerve biopsy shows perivascular inflammation without spirochetes. Lyme disease should be suspected in patients with a disorder of the peripheral nervous system following erythema migrans or associated with aseptic meningitis. The diagnosis should also be considered in cases of mononeuritis multiplex and multiple cranial nerve palsies. If the only symptom is painful mononeuropathy, radiculopathy, or individual cranial nerve palsy, suspicion depends on whether the patient is fiom an endemic area. A history of a tick bite, outdoor work or activities, travel to an endemic area, or summer onset is also useful. However, Lyme disease often is overdiagnosed in patients with chronically aching muscles or subjective sensory problems, largely because of the misinterpretation of serologic tests. Because the spirochete is difficult to isolate fiom tissue, serologic testing has become the mainstay of diagnosis. Serum and spinal fluid testing for antibody to B. burgdorferi are commercially

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available and positive in 80% to 90% of patients with meningitis. False-positive serum titers occur in 5% of healthy subjects; therefore, in nonendemic areas, the positive predictive value of the test is extremely low. False positives have also been reported in syphilis and autoimmune diseases. Western blot analysis is useful as an adjunct to increase diagnostic specificity. Diagnosis depends on proving one of the following factors: previous physiciandocumented erythema migrans, specific CSF antibodies to B. burgdorferi, a rise in convalescent serum antibody titer, or seroconversion from a negative titer. False-negative results occur in the first 6 weeks of the infection before the patient has mounted a specific antibody response. Polymerase chain reaction (PCR) may increase sensitivity in early infection before seroconversion but cannot be used to prove active infection because the test does not distinguish between live and dead bacilli. CSF PCR is positive in less than half of patients with Lyme meningitis. In the chronic form of the disease, almost 100% of patients should have serum antibodies to B. burgdorferi. Prompt removal of the tick may prevent infection because infection is more likely with tick attachment longer than 72 hours. A human recombinant outer surface protein vaccine has been approved by the U.S. Food and Drug Administration. According to CDC guidelines, vaccination should be considered in people age 15 to 70 who have high risk of exposure to tick habitat in endemic areas. Pregnant women and people with treatment-resistant Lyme arthritis should not be vaccinated. Most patients with neurologic involvement from Lyme disease need parented antibiotics. The exceptions to this are patients with early Lyme disease with isolated Bell's palsy or a mild neuropathy and normal CSF. For these patients, oral antibiotic therapy can consist of either 100 mg doxycycline twice a day, 500 mg amoxicillinthree times a day, or cefuroxime 500 mg twice a day for 14 to 21 days. Doxycycline is contraindicated in pregnant women and children under age 9. For all other patients with neurologic manifestations or abnormal CSF, intravenous ceftriaxone 2 g/day, cefotaxime 2 g/day, or penicillin G 20 to 24 MU/day for four weeks is recommended. Patients with meningitis and radiculitis in the early stage of Lyme disease usually improve within days after beginning antibiotics. On the other hand, antibiotics probably do not affect the course of Bell's palsy caused by Lyme disease. Patients with late or chronic neurologic involvement may respond very slowly over a period of 3 to 6 months, or even longer, after therapy has been completed. Therefore, neurologic symptoms that persist after standard treatment should not be interpreted as an indication of inadequate antimicrobial therapy.

HIV-RELATED NEUROPATHY The true incidence and prevalence of neuropathy in HIV-positive patients are difficult to determine. Other comorbid conditions known to cause neuropathy, such as malnutrition, alcohol or illicit drug abuse, vitamin B,, deficiency, or diabetes, may make it difficult to determine the relationship of the viral infection to the neuropathy. Furthermore, central nervous system complications may predominate, obscuring the presence of neuropathy. Subdinical evidence of neuropathy, either by electrophysiologicstudies or on nerve pathology, is present in 50% to 90% of severely immunosuppressed patients. Patients with HIV who develop symptomatic neuropathy usually have CD4 counts of fewer than 200 cells/mm3 and other manifestations of severe immunosuppression. About 10% to 30% of patients with definite AIDS have

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symptoms of peripheral neuropathy. (Other neurologic aspects of HIV infection are covered in Chapter 76.) The types of peripheral neuropathies that can occur in HIV-infected patients are as follows: Distal symmetrical polyneuropathy Lumbosacral polyradiculopathy or cauda equina syndrome Mononeuritis multiplex Facial nerve palsy (Bell’s palsy) Inflammatory demyelinating polyradiculoneuropathy Herpes zoster radiculitis Autonomic neuropathy Diffuse infiltrative lymphomatosis syndrome Sensory ataxia or ganglioneuronitis As a general rule, distal symmetrical polyneuropathy and the lumbosacral polyradiculopathy or cauda equina syndrome occur late in the course of infection. Inflammatory demyelinating neuropathies occur earlier, and mononeuritis multiplex occurs at intermediate stages. Although there is no cure for AIDS, various therapeutic interventions are available for each type of neuropathy that may provide relief for the patient. When evaluating HIV-positive patients with neuropathy, it is important to realize that CSF abnormalities may be found in HIV-infected patients without neuropathy or other neurologic involvement. In a large population-based study of HIV-positive patients, 63% had at least one spinal fluid abnormality (elevated protein, cell count, immunoglobulin G [IgG] indedsynthesis, or oligoclonal bands). There was no correlation with stage of disease, CD4 counts, neurologic complications, or the presence of abnormalities on nerve conduction studies.

biopsies demonstrate a mixed axonal-demyelinating neuropathy with inflammatory cells in the endoneurium or around perineurial vessels. A patient with HIV may be taking medication that can also produce distal symmetrical polyneuropathy. Such medications include vincristine (for Kaposi’s sarcoma), dapsone (for Pneumocystis pneumonia), and isoniazid and ethambutol (for mycobacterial infections). However, the most common drug-induced neuropathy in these patients is caused by the nucleoside analogs dideoxycytidine (ddC), dideoxyinosine (ddI), and stavudine (d4T), which are used to treat HIV-infected patients. Peripheral neuropathy occurs in up to 50% of patients who receive ddC or ddI, and this is their primary limitation. A patient with an HIV-related distal sensory polyneuropathy may have worsening symptoms and signs when one of these neurotoxic drugs is added. Determining whether the neuropathy is HIV- or drug-related can be difficult, and often a trial-and-error approach of discontinuing the drugs and looking for improvement is necessary. However, even this approach is problematic because some patients who have a nucleoside neuropathy continue to worsen for up to 6 weeks after discontinuing the drugs, the so-called coasting period. If the symptoms resolve, some patients may tolerate reintroduction of the drug at one half the dosage. Patients with an underlying HIV-related neuropathy seem to be predisposed to developing nucleoside neuropathies. A review of the patient’s medications for any potentially neurotoxic drugs that might contribute to the neuropathy should be made, and if possible, such drugs should be stopped or the dosage decreased. Symptomatic treatments include tricyclic antidepressants, carbamazepine, phenytoin, gabapentin, lamotrigine, mexiletine, nonsteroidal anti-inflammatory agents (NSAIDs), capsaicin cream, and transcutaneous electrical nerve stimulation (TENS).

Distal SymmeMcal Polyneuropathy The most common of the HIV-related neuropathies is a distal symmetrical polyneuropathy. As previously noted, it occurs in the late stages of HIV infection. The cause of the neuropathy is unknown. Although the HIV virus has been cultured from the peripheral nerves of several patients with this neuropathy, other toxic, metabolic, or nutritional factors (e.g., vitamin B,, deficiency) may play a role, as noted earlier. Patients with distal symmetrical polyneuropathy first note numbness and paresthesias in the toes, later progressing to the knees. Occasionally, the fingers may become involved. Lancinating or burning pain occurs in many patients. On examination, there is a stocking-glove sensory loss to all modalities, although touch and vibration are more affected than proprioception. Muscle stretch reflexes often are lost only at the ankles. Some patients are hyperreflexic in the arms and at the knees, probably reflecting a coexistent HIV myelopathy. Of course, the sensory abnormalities can result from either process, and electrophysiologic studies are needed to confirm the presence of neuropathy in these cases. Eventually, patients with the distal symmetrical polyneuropathy can develop weakness in the feet and hands, typically sparing the proximal muscles. The primary pathologic process is sensorimotor axonal degeneration. Electrophysiologic findings consist of low-amplitude motor and sensory potentials on nerve conduction study. Conduction velocities are normal or only mildly reduced. Needle electromyography (EMG) often reveals fibrillation potentials in distal extremity muscles and neurogenic motor units. Nerve

Lumbosacral Polyradiculopathy or Cauda Equina Syndrome The HIV-related lumbosacral polyradiculopathy or cauda equina syndrome occurs almost exclusively in patients with AIDS. It is most often caused by cytomegalovirus (CMV) infection. Patients present with severe back pain radiating to the legs. Weakness and sensory loss begin asymmetrically in the lower extremities and progress rapidly over days to several weeks. Numbness may begin in one or both feet or in the saddle and sacral area. Patients become profoundly weak in the legs and often lose the ability to walk. A lumbar sensory level, lower extremity areflexia, and a neurogenic bladder usually develop. CSF findings include a striking polymorphonuclear pleocytosis, elevated protein (consistently more than 100 mg/dL), and a normal or low glucose. CSF cultures grow CMV in 50% of cases, but this may take 5 to 10 days. PCR for CMV in the spinal fluid may be helpful in confirming the diagnosis. Gadolinium-enhanced lumbosacral magnetic resonance imaging scans have demonstrated striking enhancement of the cauda equina roots. Patients often have evidence of retinitis, hepatitis, pneumonitis, or encephalitis. Electrophysiologic studies are not necessarily needed for accurate diagnosis and therapeutic intervention of these patients. If nerve conduction studies are done, the initial findings are a loss of peroneal and tibial motor amplitudes. As the weakness becomes profound, the responses often become unobtainable. After 2 weeks of weakness, the needle EMG show profuse fibrillation potentials

Chapter 95

in proximal and distal lower extremity muscles, and motor units have a reduced recruitment pattern. Intravenous ganciclovir therapy should be initiated immediately, even before CSF culture results are available. If the patient does not improve with ganciclovir or is already on ganciclovir for CMV infection elsewhere, foscarnet can be used as a second-line agent. Intravenous ganciclovir or foscarnet is continued for the remainder of the patient's life. Early institution of anti-CMV therapy in this disorder can improve strength and ameliorate sensory symptoms and pain in some patients. However, the long-term prognosis is poor, and most do not survive 3 months. The differential diagnosis for the lumbosacral polyradiculopathy syndrome in patients with AIDS consists of neurosyphilis, mycobacterium infections, and leptomeningeal lymphomatosis. These disorders are diagnosed by specific CSF studies for each disease (e.g., Venereal Disease Research Laboratory [VDRL] test, mycobacterial culture, cytology) and the absence of confirmatory evidence of CMV infection.

HIV-Related MononeurHis Multiplex Mononeuritis multiplex is an uncommon HIV-related neuropathy. Patients present with asymmetrical patches of sensory loss on the face, trunk, or extremities. Alternatively, symptoms can begin as foot drop, hand weakness, or a cranial motor neuropathy. Symptoms may resolve spontaneously, or they may progress to a more severe generalized neuropathy. In evaluating these patients, one must keep in mind their susceptibility to compression neuropathies caused by cachexia and weight loss. Patients with mononeuritis multiplex often can be placed into one of two groups: patients earlier in the course of HIV infection with preserved CD4 counts without evidence of CMV infection in other organs, and those late in the course of HIV infection with very low CD4 counts, who usually have evidence of CMV infection in other organs. Patients in the first group seem to have benign courses with spontaneous stabilization or improvement of the neuropathy. In the latter group, either the neurologic deficits may progress or the neuropathy may stabilize as the patient is treated for the extraneural CMV infection. This implies that at least some patients with mononeuritis multiplex have CMV as the cause of the neuropathy. However, the CSF in these patients does not show the dramatic abnormalities seen in the HIV-related cauda equina syndrome. Electrophysiologic studies confirm either isolated mononeuropathies or an asymmetrical sensorimotor axonal neuropathy. In general, electrophysiologic findings have not helped to distinguish this heterogeneous group of patients. Reports regarding the pathology have varied. Some investigators, especially in France, have found dramatic vasculitis of endoneurial and epineurial vessels. In the large collection of patients with mononeuritis multiplex seen at San Francisco General Hospital, this was not the finding. A component of axonal degeneration is found in most patients. CMV inclusion bodies have been reported in endothelial cells of peripheral nerves by some authors. The presence of vasculitis in some patients raises the possibility that the mononeuritis multiplex in some HIVinfected patients has an immune-mediated mechanism. There are reports of improvement with prednisone therapy in the patients with vasculitis. One patient was reported to have cryoglobulinemia and responded to plasmapheresis therapy. One approach to diagnosis and treatment is as follows. First, assess the stage of HIV infection and the CD4 count. If the patient

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is early in the course of the infection, with a CD4 count of more than 200 cells/mm3, the approach is more conservative because many of these patients may spontaneously improve. EMG and nerve conduction studies can determine the distribution and extent of the neuropathy. Serologic tests for syphilis and for the presence of cryoglobulins should be obtained. If the neuropathy is predominantly sensory and limited in distribution, as it often is in this stage, following the patient closely is reasonable. A more aggressive approach is justified in a patient with a CD4 count of fewer than 200 cells/mm3, who usually has a history of AIDSrelated complications. CSF studies are necessary to test for mycobacterial, cryptococci, syphilis, or CMV infection and for lymphomatous meningitis. The patient should be evaluated for evidence of CMV infection in other organs (eye, gut, lung); if infection is present, anti-CMV drugs should be started. If there is no evidence of neural or extraneural CMV infection, a sural or superficial peroneal nerve biopsy should be considered. This is probably the only clinical situation in which it is necessary to obtain a nerve biopsy in an HIV-infected patient. If CMV inclusions are observed, treat the patient with the appropriate antiviral agents; if vasculitis is present and there is no evidence of CMV, consider immunosuppressive treatment with prednisone. If cryoglobulinemia is present, consider plasmapheresis.

Fadal Nerve Palsy (Bell's Palsy) Bell's palsy occurs at the time of seroconversion, in the setting of AIDS or AIDS-related complex, or in the setting of Guillain-Barrk syndrome and chronic inflammatory demyelinating polyneuropathy. In most cases, the cause is unknown. Opportunistic infections and lymphomatous meningitis must be considered in the differential.

Inflammatory Demyelinatlng Polyradlculoneuropathy Both acute (Guillain-Barrksyndrome, with progression over 2 to 4 weeks) and chronic (chronic inflammatory demyelinating polyradiculoneuropathy [CIDP], with progression over 2 months or more) forms of inflammatory demyelinating polyneuropathy have been reported in HIV-infected patients. They tend to occur early in the course of HIV infection, perhaps at the time of seroconversion, but cases have also been reported in immunocompromised patients. The clinical and electrophysiologic presentations of these disorders are similar to those of the non-HIV-related demyelinating neuropathies (see Chapter 92). Proximal and distal limb weakness with areflexia and generally less prominent sensory loss are the classic presenting symptoms. The only distinguishing feature in HIV-infected patients is the presence of CSF pleocytosis (white blood cell count usually greater than 25/mm3). Nerve biopsies are not necessary but have revealed demyelination, remyelination, and inflammatory cells. Preferred treatment for either Guillain-Barrk syndrome or CIDP is intravenous y-globulin. Dosing is similar to that given to non-HIV-infected patients: a total of 2 g/kg in divided doses over 3 to 5 days. In CIDP, the initial induction dose is followed by single doses of 0.5 g/kg given every 2 to 4 weeks, depending on the clinical response. Corticosteroids and plasma exchange may also be effective but carry greater risks in these patients. Spontaneous improvement without treatment has been reported. Whether their recovery is worse than that of non-HIV-infected patients with similar neuropathies is unknown.

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Herpes Zoster Radlculltis Up to 10% of HIV-infected patients develop herpes zoster radiculitis (shingles). Immunocompromised HIV-infected patients who develop shingles may have sustained periods of new lesion formation and a failure of existing lesions to heal in the absence of antiviral therapy. All HIV-positive patients who develop herpes zoster limited to a dermatome are treated with oral acyclovir. However, in more widespread or disseminated outbreaks, intravenous acyclovir should be administered.

Autonomic Neuropathy HIV-infected patients can develop symptoms of presyncope, syncope, diminished sweating, diarrhea, impotence, and bladder dysfunction, presumably caused by an autonomic neuropathy. Most of these patients have AIDS, and they often have a coexistent distal symmetrical polyneuropathy.

Diffuse Infiltrative Lymphocytosis Syndrome Diffuse infiltrative lymphocytosis syndrome (DILS) is an uncommon cause of neuropathy in patients with HIV. It is an angiocentric immunoproliferative disorder characterized by diffuse CD8 lymphocyte infiltration of multiple organs, including lungs, esophagus, nerve, and muscle. The clinical features of the neuropathy overlap with the cauda equina syndrome and distal symmetrical polyneuropathy. Typically patients present with enlargement of the parotid and other salivary glands and sicca complex (dry eyes and dry mouth). Lymphocytic infiltration of other organs causes lymphadenopathy, uveitis, pneumonitis, gastritis, interstitial nephritis, dermatitis, hepatitis, and neuropathy. The neuropathy may be the initial manifestation of HIV infection. Patients typically complain of painful paresthesias in the feet, followed by an acute or subacute sensory motor loss in the distal lower extremities. About one-half may have early upper extremity involvement, and one third have asymmetrical findings. Although cranial neuropathies are uncommon, bilateral facial neuropathies have been reported. Laboratory features include CD8 lymphocytosis (typically greater than 1200/mm3), low to normal CD4 counts, mild CSF lymphocytosis, and modest CSF protein elevation. Nerve conduction studies reveal a predominantly axonal process, although occasional patients have demyelinating features. Nerve biopsy shows marked perivascular infiltrates of CD8 positive T-cells. Both epineurial and endoneurial vessels may be involved, but there is no transmural necrosis, as seen in true vasculitis. The feature that distinguishes DILS from angiocentric lymphoma-associated neuropathy is that the T-cell infiltrates are polyclonal, indicative of a non-neoplastic process. The neuropathy associated with DILS may respond well to treatment. In one series, 8 of 12 patients treated with zidovudine or corticosteroids showed complete resolution of neuropathy. Spontaneous improvement has also been reported.

Sensory Ataxia Caused by Canglioneuronitis Four cases of subacute sensory ataxia have been reported in HIV-infected patients. These patients had profound proprioceptive deficits and areflexia without weakness. Autopsy findings revealed inflammatory infiltrates in the sensory ganglia and

proximal roots. One case occurred at the time of HIV seroconversion, one case was in an asymptomatic HIV-positive patient, and two cases were in patients with AIDS. Because so few of these cases have been reported, the exact place of this condition in the spectrum of HIV-related neuropathies is uncertain.

HERPES SIMPLEX RADlCULlTlS Herpes simplex viruses (HSV) type 1 and type 2 are neurotropic DNA viruses, which may establish latent infection in dorsal root ganglia. Recurrent HSV mucocutaneous lesions may be accompanied or preceded by neuralgic symptoms at the site of the lesion or at a distant site within the area of the infected ganglion. Either type 1 or type 2 HSV may be associated with encephalitis, meningitis, myelitis, or radiculitis. Manifestations are determined largely by the site of inoculation. For a discussion of HSV encephalitis and meningitis, see Chapters 64 and 65. Radiculitis occurs more commonly in association with HSV type 2 infection than with HSV type 1 and usually involves lumbosacral nerve roots. Patients develop pain, paresthesias, and hypesthesia in a dermatomal distribution. Lower extremity weakness, hyporeflexia or areflexia, and sphincter disturbances are common. Urinary retention may be the presenting symptom. Genital or oral mucosal lesions may be absent. CSF analysis reveals a lymphocytic pleocytosis and elevated protein. Typically CSF glucose is normal, although low levels have been reported. HSV may be demonstrated by PCR or by culture. Treatment with ganciclovir or acyclovir may be beneficial.

HERPES ZOSTER RADlCULlTlS Herpes zoster radiculitis or cranial neuritis (shingles) results from a reactivation of varicella-zoster virus infection. After primary infection, the virus becomes latent in sensory ganglia. More than 90% of adults are seropositive for antibodies against varicellazoster virus. Other relevant aspects of varicella-zoster virus infection are covered in Chapter 66. There are generally no identifiable factors that precipitate reactivation of the virus, although advancing age and associated loss of cell-mediated immunity increase risk of its occurrence. By the ninth decade of life, the incidence reaches approximately 1% per year. In addition, immunosuppression secondary to cytotoxic drugs and malignancy increases the risk of developing shingles and disseminated zoster. The reactivation produces a vesicular rash in a dermatomal distribution. The thoracic dermatomes are involved in more than one half of cases, but the eruption can also occur in cranial nerve distributions and along cervical and lumbosacral dermatomes. The vesicular rash often is preceded by pain and paresthesias in the dermatome region by a week or more. Systemic signs such as fever, malaise, and headache can occur. In the majority of patients who are not immunocompromised, the vesicles dry up and resolve within 2 or 3 weeks, and there are no sequelae. In immunocompetent patients, oral valacyclovir 1000 mg three times/day for 7 days, famciclovir 500 mg three timedday for 7 days, acyclovir 800 mg five times/day for 7 to 10 days significantly reduces the time for cutaneous healing and resolution of acute pain. The incidence of postherpetic neuralgia (PHN) is not decreased in most studies, but antiviral treatment may shorten the duration of pain. Intravenous acyclovir is highly effective in preventing dissemination of the rash in immunocompromised

Chapter 95 H

patients. The role of corticosteroids is more controversial. There are no clear-cut indications for corticosteroids in treating shingles, and they should be avoided in immunocompromised patients. Vaccination with live attenuated virus has been shown to boost immune response against varicella zoster for 5 to 6 years in people over age 55 with a history of previous chickenpox infection. Whether vaccination of this population will decrease the incidence of shingles and PHN is yet to be determined. PHN generally is defined as the persistence of pain for longer than 4 to 12 weeks after the onset of the rash. Incidence of PHN ranges from 7% in patients less than 30 years of age to as much as 50% in patients over age 70. Immunocompromised patients and those with more severe acute manifestations of shingles are also at greater risk for PHN. The pain is most often continuous and burning, but lancinating pains are common. The pain may be so severe as to be disabling. Amitriptyline is an effective therapy for PHN. Other tricyclic antidepressants such as nortriptyline and desipramine are also effective and may be better tolerated. Gabapentin is well-tolerated and may replace tricyclics as first-line treatment. Carbamazepine is not effective for treating the constant burning neuralgia seen in these patients but may be useful for lancinating pains. If tricyclics are not effective, the short-term use of narcotics should be considered. Topical capsaicin cream applied three or four times a day for 2 to 4 weeks may be effective in some patients. Capsaicin should not be applied while the vesicular rash is still present. Topical lidocaine preparations, TENS units, and nerve blocks may be useful. Less common delayed complications of zoster infection include encephalitis, cranial arteritis, transverse myelitis, urinary retention, cranial nerve palsies, and focal weakness. Focal weakness in an extremity or in a cranial nerve distribution occurs in 5% to 10% of shingles cases and usually begins 2 to 4 weeks after the onset of the rash. The most common example of focal motor paresis is the onset of facial palsy after herpes zoster oticus (Ramsay Hunt syndrome). Weakness in cervical and lumbar root distributions also occurs. Thoracic muscle involvement is common but is seldom clinically apparent. These complications occur more often in patients with underlying malignancies. CSF in patients with focal motor weakness may show a pleocytosis with elevated protein, but this finding is also seen in 50% of patients who have uncomplicated shingles. Recovery from focal weakness is expected in 70% to 80% of patients and is usually complete.

SARCOIDOSIS Sarcoidosis is a generalized granulomatous process that typically affects the lungs, eyes, and parotid gland. Only in 5% of the cases is the nervous system involved clinically. In about 50% of these patients, the neurologic manifestation is facial nerve paralysis. Involvement of other cranial nerves, including the optic, glossopharyngeal, vagus, and acoustic, may occur alone or as part of a cranial mononeuritis multiplex. The incidence of peripheral neuropathy other than facial mononeuropathy in patients with neurosarcoidosis varies from 1% to 24%. The neuropathy may take one of several forms, including a sensorimotor axonal polyneuropathy, a mononeuropathy, or mononeuritis multiplex. A chronic, symmetrical, sensorimotor axonal polyneuropathy was the most common presentation in a small series published by Zuniga et al. These patients complain of paresthesias and numbness in the toes and fingers, often

Infectious and Cranulornatous Neuropathies

603

associated with burning, dysesthetic pain. On examination, there is a stocking-glove loss to all sensory modalities, distal areflexia, and in some cases distal weakness. Neurosarcoidosis may also present as mononeuritis multiplex with involvement of spinal roots or individual nerves. These patients often have cranial mononeuropathies as well. Patients may have unusual mononeuropathies, including patches of sensory loss on the trunk or phrenic nerve involvement, resulting in diaphragm paralysis and respiratory symptoms. Lumbar plexopathy and Guillain-Barre syndrome have been reported as well. In 50% of patients with neurosarcoidosis, neurologic symptoms are the presenting manifestation of sarcoidosis. Even patients without clinical evidence of neuropathy may show a reduction in sensory nerve action potential amplitudes in one or more nerves. The chest radiograph usually demonstrates hilar adenopathy or diffuse pulmonary infiltrates. Pulmonary function tests reveal decreased lung volumes and diffusion capacity. The serum angiotensin-converting enzyme often is elevated but lacks specificity and sensitivity. The CSF in patients with neuropathy may show a mononuclear pleocytosis, elevation of protein, or decreased glucose. Ocular examination may show granulomatous uveitis. Definitive diagnosis includes tissue biopsy, usually of an enlarged lymph node. Up to 40% of muscle biopsies demonstrate granulomas, even in patients lacking specific signs and symptoms. Sural nerve biopsies may show infiltration of the epineurium by inflammatory cells and granulomas with evidence of axon loss. Patients with mild distal sensory or sensorimotor neuropathies may not need immunosuppressive therapy. However, in patients with significant weakness, mononeuritis multiplex, or cranial nerve palsies, a trial of oral prednisone is recommended. The initial prednisone dosage typically is 60 mg/day and then is slowly tapered. Although isolated mononeuropathies often improve, very little is known about prognosis of distal symmetrical neuropathy in patients with sarcoidosis. SUGGESTED READINGS Barohn RJ, Gronseth GS, LeForce BR et al: Peripheral nervous system involvement in a large cohort of human immunodeficiency virusinfected individuals. Arch Neurol 50167-171, 1993 Jacobson RR, Krahenbuhl J L Leprosy. Lancet 353655-660, 1999 Johns CJ, Michele TM: The clinical management of sarcoidosis. Medicine 78:65-111, 1999 K o h a n B, Junck L, Elias SB et al: Polyradiculopathy in sarcoidosis. Muscle Nerve 22:608-613, 1999 Levin MJ, Barber D, Goldblatt E et al: Use of a live attenuated varicella vaccine to boost varicella-specific immune responses in seropositive people 55 years of age and older: duration of booster effect. J Infect Dis 178(S~ppl1):S109-S112, 1998 Recommendations for the use of Lyme disease vaccine. Recommendations of the Advisory Committee on Immunization Practices. MMWR 48(RR7):1-17, 21-25, 1999 Sabin TD, Swift TR, Jacobson RR: Leprosy. p. 1354. In Dyck PJ, Thomas PK, Griffin JW et al (eds): Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Sharma OP Neurosarcoidosis. Chest 112:220-228, 1997 Stern BJ, Krumholz A, Johns CJ: Neurosarcoidosis: Clinical presentations and management. Ann NY Acad Sci 465:722-730, 1986 Whitley RJ, Shukia S, Crooks RJ: The identification of risk factors associated with persistent pain following herpes zoster. J Infect Dis 178(S~ppl1):S71-S75, 1998 Zuniga G, Ropper AH, Frank J: Sarcoid peripheral neuropathy. Neurology 41: 1558-1561, 1991

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96

Spinal Cord and Peripheral Neuromuscular Disease

Diseases of Peripheral Nerve

Dysproteinemic Polyneuropathy John J. KelIF Jr.

One of the major advances in our understanding of polyneuropathies since the 1980s has been the realization that dysproteinemias or plasma cell dyscrasias and their accompanying monoclonal proteins (M-protein) or immunoglobulins often are associated with neuromuscular diseases. These syndromes may be distinctive and in several cases appear to be caused by the direct effects of the M-protein on peripheral nerves. For instance, M-proteins have been found to react with a variety of neuronal antigens found in myelin sheaths and axonal membranes. This chapter outlines our current knowledge in this rapidly advancing field and provides a clinical approach to these patients.

EPIDEMIOLOGY Based on prevalence surveys, it is estimated that up to 5% of all patients with polyneuropathy have a monoclonal gammopathy. The majority of these are likely to be polyneuropathies associated with monoclonal gammopathy of undetermined significance (MGUS) (Tables 96-1 and 96-2), with lower percentages of other syndromes. Based on these estimates, although inexact, these disorders undoubtedly are underdiagnosed.

HEMATOLOGIC EVALUATION A plasma cell dyscrasia or monoclonal gammopathy (Table 96-1) is defined as a proliferation of a single clone of plasma cells, either neoplastic or non-neoplastic, usually associated with the production of a monoclonal serum protein that can be measured in the serum, urine, or both. Monoclonal proteins, or more properly immunoglobulins (Igs), consist of a single heavy chain (IgM, IgG, IgD, or IgA) and a single light chain (K or 1).Polyclonal gammopathies comprise both light chains and generally more than one heavy chain. Occasionally, only the light chain or heavy chain may be secreted by the clone of plasma cells. Until recently, M-proteins were thought to have no biologic activity. It is now known that these proteins are secreted by expanded clones of immunoglobulin-secreting cells with activity directed at specific antigens. Many have idiotypically specific biologic activity, accounting for the remote effects of these monoclonal gammopathies. The M-protein is most commonly detected by screening patients with serum cellulose acetate electrophoresis. In cases in which a spike is seen on serum cellulose acetate electrophoresis and in all cases in which a monoclonal gammopathy is suspected,

such as idiopathic polyneuropathy or atypical motor neuron disease, immunoelectrophoresis or immunofixation should be performed, regardless of the results of serum cellulose acetate electrophoresis. These tests are more sensitive than serum cellulose acetate electrophoresis for the presence of a small M-protein and allow characterization of the single heavy and light chain, thus verifymg the monoclonal nature of the immunoglobulin. Of the two, immunofixation is more sensitive and detects M-proteins occasionally when immunoelectrophoresis is negative, but it is more expensive and technically more demanding. Urine should also be examined because monoclonal light chains (Bence-Jones proteinuria) occasionally may appear only in the urine, where their presence suggests either a malignant plasma cell dyscrasia or light-chain amyloidosis. After identification and characterization of a M-protein in serum or urine, further studies should be done to classify the plasma cell dyscrasia (Table 96-1). If a diagnosis of MGUS is made, M-protein levels should be monitored annually because a sudden increase could indicate malignant transformation of a formerly benign plasma cell dyscrasia, which can occur in up to 20% of cases.

POLYNEUROPATHY SYNDROMES MGUS-Associated MGUS-associated polyneuropathy syndromes comprise the largest number of polyneuropathies associated with plasma cell dyscrasias and are best approached by division into IgM-associated and non-IgM-associated types. The IgM group can be further divided into those with and without apparent antinerve activity. Table 96-3 presents the main neurologic features of these disorders. IgM Monoclonal Cammopathy with Antinerve Activity. By far the most common member of the group with antinerve activity is the neuropathy with antibody activity against myelin-associated glycoprotein (MAG), a glycoprotein with neural adhesion properties located on the sheath of peripheral nervous system (PNS) and central nervous system (CNS) myelin. This syndrome was first described by Latov and colleagues in 1980. Since then, multiple studies have shown that approximately 50% of all polyneuropathies associated with plasma cell dyscrasia are of IgM type, and of these, about 50% have anti-MAG activity. Other antinerve antibodies (Table 96-4) are much less common and are less clearly related to the polyneuropathy. Neuropathy associated with anti-MAG activity (anti-MAG

TABLE96-1. Classification of Common Plasma Cell Dyscrasias Disorder

Monoclonal gammopathy of undetermined significance Osteoxlerotic myeloma Multiple myeloma

Diamastic Criteria

Monoclonal protein in serum <3 g/dL and no malignancy or amyloid Solitary or multiple plasmacytomas with osteosclerotic features >lo%abnormal plasma cells in bone marrow or plasmacytoma and monoclonal protein in serum or urine or osteolytic lesions Waldenstrom's macroglobulinemia IgM monoclonal protein >3 g/dk >lo%lymphs or macroglobulinemia plasma cells in bone marrow Light-chain amyloid by histology Primary systemic amyloidosis Monoclonal heavy chain in serum or urine yHeavy-chain disease From Kelly JJ Jr, Kyle R& O'Brien PC et al: Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31:1480, 1981, with permission.

Chapter 96 W

neuropathy, Latov syndrome) is the most firmly established and best characterized of the antinerve antibody neuropathy syndromes. The detection of this disorder has increased steadily, probably because of better recognition of the syndrome by referring physicians and the wider availability of the anti-MAG antibody test. Based on our experience and that of others, a fairly consistent clinical picture has emerged. These patients present with the slow and insidious onset, after months to years, of progressive ascending numbness, usually without pain or autonomic involvement, and sensory gait ataxia. Intention tremor may be prominent in some. Weakness is usually much less pronounced; indeed, early on the clinical picture may resemble the sensory neuronopathy syndrome, with predominant discriminatory sensory loss and preserved power. The findings tend to be symmetrical and progress in a slow and steady proximal fashion, suggesting a length-dependent axonopathy. Most patients have thickening of the nerves in the upper arms, a finding generally absent in axonopathies. Neurodiagnostic laboratory studies, especially electromyography (EMG) (Table 96-5), are helpful in suggesting the diagnosis. Sensory nerve action potentials are absent or severely attenuated. Despite the fact that weakness generally is not pronounced in these patients, there is often marked slowing of motor conduction velocity and very prolonged distal latencies in the demyelinating range. Cerebrospinal fluid examination may disclose elevated protein (more than 100 mg/dL) in advanced cases. Although these studies can suggest the diagnosis in the proper clinical setting, the keys to diagnosis are the nerve biopsy and serologic studies. Nerve biopsies show combined axonal degeneration and demyelinating features, and most patients display immunostaining of the nerve by the M-protein, which is deposited on the surface of the myelin sheath. Ultrastructural studies show splitting and widening of the outer lamellae of myelin, possibly caused by the disadhesion activity of the anti-MAG antibodies, although the exact mechanism of antibody action is unknown. IgM and complement have been demonstrated in the region of myelin lamellar widening, although macrophages thus far have not been demonstrated to play a role in the myelin damage. Immunoblot and enzyme-linked immunosorbent assay studies disclose the anti-MAG antibodies in

TMLE 96-2. HematologicDiagnosis of 28 Patients with

Plasma Cell Dyscrasias and Polyneuropathy Diagnosis

Number

Monoclonal gammopathy of undetermined significance 16 Primary systemic amyloidosis 7 Multiple myeloma (includes osteosclerotic myeloma) 3 1 Waldenstrom’s macroglobulinemia y-Heavy-chain disease 1 From Kelly JJ Jr, Kyle RA. O’Brien PC et al: Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31:1480, 1981, with permission.

Dysproteinemic Polyneuropathy

6001

high titer in serum of these patients. These tests are commercially available from a number of sources. The IgM appears to react with a carbohydrate epitope that is shared by MAG and other glycoproteins and glycolipids in the PNS. Recognition of these patients is important because treatment that lowers anti-MAG levels with plasmapheresis or cytotoxic drugs promotes recovery. The pathophysiology of this neuropathy is not completely understood. When anti-MAG antibody-containing serum is injected directly into peripheral nerves, intense inflammation with complement-dependentdemyelination results. However, the morphologic picture is different from that observed in patients and more characteristic of the Guillain-Barre syndrome. A convincing animal model, induced by passive transfer of anti-MAG antibodyenriched serum, has been described. Treatment in these patients is difficult. They are often older adults and tolerate immunosuppressive drugs poorly. In addition, they respond poorly to steroids and need more powerful drugs such as cyclophosphamide. Plasmapheresis probably is effective but entails prolonged treatment. The role of intravenous immunoglobulin is unclear but, if effective, undoubtedly would also entail prolonged treatment, which is generally impractical. In my experience, a 6- to 9-month course of oral or intravenous pulse cyclophosphamide or fludarabine, designed to lower the M-protein level by at least one half, allows stabilization or clinical remission for several years in the majority of patients. I generally rely on oncologists to implement and manage this treatment. However, 1 to 2 years after therapy is stopped, the M-protein level gradually rises to pretreatment levels, and the deficit begins to reaccumulate. Thus far, I have not had to retreat anyone. MAG-nonreactive IgM neuropathies are much less common and less well characterized than anti-MAG neuropathy. IgM antibodies in these patients may react with a variety of antigens (see Table 96-4) but these reactions are, for the most part, less clearly related to disease activity. Some have axonal polyneuropathy by EMG. However, many have demyelinating features and are difficult to distinguish from anti-MAG polyneuropathy. In this group, immunofluorescent studies generally are negative, and myelin lamellar splitting is not observed. However, these patients may respond to treatment with steroids, plasmapheresis, or immunosuppressantsand cytotoxics. In other cases, these patients resemble in clinical course, laboratory study results, and response to treatment those with chronic inflammatory demyelinating polyradiculopathy (CIDP). IgG and lgA MCUS-Associated Polyneuropathies. The nature of IgG and IgA M-protein polyneuropathies is much less clear, and the neuropathies are much more heterogeneous. Many of these patients may have axonal polyneuropathies that are chronic and mild. Antinerve antibody activity of unclear significance is only occasionally demonstrated, and in general these patients respond poorly to therapy. In comparative studies, these patients were found to have less evidence of sensory loss than those with

rn TUKE 96-5. Main Neurologic Features of Dysproteinemia Polyneuropathy Syndromes Tommhv

TvDeofPN ~~~~~

MCUS-lgM MCUS-lgC, MCUS-lgA Amyloidosis OSM WM

Weakness ~

Distal Distal Distal Distal Distal

Sensow

Autonomic

~~~

+ ++ +/++ +++ ++

COUm ~~

+++ ++ +++ ++ ++

-

+++

-

-

Prog Prog Prog Prog Pron

CSF

MNCV

PlthOlOnv

++ + + +++ ++

Very slow Slow Mild slow Very slow Verv slow

SD SD, AD AD SD SD. AD

Abbreviobbns: AD,axonal degeneration; CSF, cerebrospinalfluid protein concentration;MCUS, monoclonal gammopathyof undetermined significance; MNCV, motor nerve conduction velocity; OSM, osteosderotic myeloma; PN, polyneuropathy;Pro& chronic progressive;SD,segmental demyelination;WM, Waldenstrsm’s macroglobulinemia. From Kelly JJ Jr, Kyle M,Latov N: PolyneuropathiesAssociated with Plasma Cell Dyscrasias. Martinus-Nijhoff, Boston, 1987, with permission.

606

Diseases of Peripheral Nerve

Spinal Cord and Peripheral Neuromuscular Disease

IgM gammopathies and less evidence of demyelination on electrophysiologic studies. Amyloidosis should be excluded, especially when there is a recent onset, rapid progression, and pain or autonomic symptoms. Less commonly, patients present with a CIDP-like picture, with demyelination on EMG and a good response to standard therapies used in CIDP. In these patients, osteosclerotic myeloma and the Crow-Fukase syndrome should be excluded by appropriate tests. PRIMARY SYSTEMIC AMYLOIDOSIS Primary systemic amyloidosis is perhaps the best characterized of the polyneuropathies associated with M-proteins and accounts for up to one-quarter of cases in some series of polyneuropathy associated with PCDs. This neuropathy characteristically occurs in older men and is very rare prior to the sixth decade of life. Most cases are unassociated with an underlying illness, but a few are associated with hematologic malignancies, such as myeloma and Waldenstrom’s macroglobulinemia. Primary systemic amyloidosis generally presents as a multiple system disease due to the deposition of fragments of the variable portion of a monoclonal light chain, most often kappa, in tissue. Patients present with a medical disease with associated (sometimes incidental) polyneuropathy (60%) or severe polyneuropathy with minimal organ involvement (40%). A similar illness can occur in a variety of inherited amyloid polyneuropathies, owing to an abnormal circulating prealbumin (transthyretin) protein due to a single amino acid substitution. Polyneuropathy does not occur in amyloidosis secondary to chronic inflammatory disease or familial CNS amyloidosis. Medical syndromes (Table 96-6) include the nephrotic syndrome caused by amyloid infiltration of the kidneys, cardiac

TABU 96-4. Antibody Activities of Monoclonal IgM in Peripheral Nerve Disorders Antibodv Activitv

Clinical Svndrome

Type of Pathology

MAG

Sensory > motor polyneuropathy Polyneuropathy Motor neuron disease

SD

Acidic glycolipids Cangliosides GM, and GD,b Chondroitin sulfate C Intermediate filaments Neurofilarnent Sulfatide

? SD, possible AD

Sensory polyneuropathy Polyneuropathy Polyneuropathy Sensorv polvneuropathv

AD SD AD AD

Abbreviations: AD, axonal degeneration; MAG, myelin-associatedglycoprotein;SD, segmental demyelination. Adapted from Steck AJ, Murray N, Dellagi K et al: Peripheral neuropathy associated with monoclonal IgM autoantibody. Ann Neurol45:711, 1988, with permission.

failure caused by amyloid cardiomyopathy, chronic diarrhea with wasting caused by amyloid infiltration of the gut wall, and autonomic neuropathy with prominent orthostatic hypotension. General laboratory studies reflect the medical syndromes, with proteinuria occurring in a high percentage, elevated erythrocyte sedimentation rate in about one half, and a mild increase in benign-appearing plasma cells in bone marrow in many. Up to 90% have an M-protein in serum or a monoclonal light chain in urine when thoroughly screened with serum and urine immunofixation. The patients lacking an M-protein, if the disease is not inherited, are called nonsecretory, although immunocytologic studies of their tissue disclose that the amyloid derives from single (monoclonal) light chains. Presumably, the serum concentration is too low in these patients to allow detection. The light chains are deposited in tissue, where they are digested by macrophages with the production of amyloid fibrils, which are then insoluble. The polyneuropathy has been well characterized. Sensory symptoms typically are most prominent and the earliest to appear. Almost all such patients present with numbness of the hands and legs, and complaints such as burning, aching, stabbing, and shooting pains are most common. In more than one half of patients, cutaneous sensations (light touch, pain, temperature) are more often and more severely affected than discriminative sensations (vibration and position sense). Occasional patients (about 20%) present with the typical symptoms of carpal tunnel syndrome before distal neuropathy symptoms appear, caused by amyloid infiltration of the flexor retinaculum of the wrist. Rare patients present with symptoms of autonomic dysfunction without symptoms of somatic sensory dysfunction. Symptoms and signs of weakness generally follow but usually are less prominent than the sensory findings. Exceptions are rare patients with amyloid infiltrative myopathy with proximal muscle weakness and patients with malignant plasma cell dyscrasias, such as myeloma, who may present with compressive radiculopathies that can mimic mononeuropathies or plexopathies. The findings tend to be symmetrical and predominant distally, with gradual proximal spread. Most patients soon complain of autonomic dysfunction with orthostatic lightheadedness and syncope, bowel and bladder disturbances, impotence, and sweating disturbances. Hypoactive pupils and orthostatic blood pressure drop with a fixed heart rate are the most easily detected autonomic signs at the bedside. Electrophysiologic studies (see Table 96-5) confirm the presence of a distal axonopathy that is maximal in the legs. Motor conduction velocities in the demyelinating range (less than 60% of the mean normal for that nerve) occur rarely, and then only in “unreliable” nerves, where the evoked compound muscle action potential is very low in amplitude. Sensory nerve action potentials usually are unobtainable. Often, there is evidence of disproportionate median nerve conduction slowing across the wrist because

TABLE 96-5. Major Electrodiagnostic Features of PN Associated with PCD Type of PN MGUS-lgM MGUS-lgC, MCUS-lgA OSM PSA

MM

Demyelinating

Axonal

+++ ++ +++ +

+ ++ + +++ ++

CTS

-

-

++ +

Pure Sensory

++ + + +

Other

+ + +++a

++b

aAutonomicinvolvement. bRoot involvementand polyradiculopathiessuperimposedon PN. Abbreviations: CTS, carpal tunnel syndrome superimposedon polyneuropathy;MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; OSM, osteosclerotic myeloma; PCD, plasma cell dyscrasia; PN, polyneuropathy;PSA, primary systemic amyloidosis. From Kelly JJ Jr: Peripheral neuropathiesassociated with monoclonal proteins: a clinical review. Muscle Nerve 8:138, 1985, with permission.

Chapter 96 H TABU 96-6.

Medical Syndromes in Amyloid Polyneuropathy Flequencv (%l

Syndrome

Orthostatic hypotension Nephrotic syndrome Cardiac failure Malabsorption

42 23 23 16

From Kelly JJ Jr, Kyle RA, OBrien PC et al: The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol 5:271, 1979, with permission.

W TABU96-7.

Results of Biopsy in Primary Amyloidosis with Neuropathy

Site

Rectum Kidney Liver Small intestine Bone marrow Sural nerve Other (skin. ninniva)

No. Patients 25 4 2 2 21 10 2

DysproteinemicPolyneuropathy

607

practical. There may be a role for frequent immunoabsorption treatment in the future. However, the nephropathy caused by light-chain deposition has been shown to at least partially reverse with a combination of melphalan and prednisone. Thus, these patients typically progress inexorably with increasing numbness and pain, autonomic failure, and weakness with added organ failure. Death usually occurs in 2 to 4 years from time of diagnosis and generally is caused by major organ failure, cardiac most commonly. Patients with pure neuropathies without significant organ failure survive longer.

MULTIPLE MYELOMA NEUROPATHY

Positive (%I

88 75 100 100 33 100 100

From Kelly JJ Jr, Kyle RA, O'Brien PC et al: The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol 5:271, 1979, with permission.

of carpal tunnel syndrome, which can suggest the diagnosis. Needle EMG shows the changes expected of a distal axonopathy, with abundant signs of distal denervation and reinnervation. Cerebrospinal fluid usually is acellular and with only mild, nonspecific elevations of protein levels, generally in the range of 50 to 70 mg/dL. Diagnosis depends on the discovery of amyloid in tissue. Sural nerve biopsy is very useful in detecting amyloid in most cases, although sometimes it must be sought through multiple sections. Amorphous deposits of amyloid on Congo red or cresyl violet stains typically appear in the perivascular regions of the epineurium or occasionally in the endoneurium. However, amyloid is classically defined by its appearance under polarized light when the Congo red-stained deposits emit an apple-green birefringence. Electron microscopy can also be used to identify the characteristic fibrils. In some hands, immunofluorescent staining for monoclonal light-chain fragments is useful, but it is technically difficult. Because amyloid can be absent in any single tissue, even in sural nerve biopsy specimens despite neuropathy, I generally suggest biopsy of more than one tissue. Other useful tissues to biopsy (Table 96-7) include rectum, fat pad, and other affected organs such as kidney. Teased fiber studies show predominantly axonal degeneration. However, the cause of nerve fiber damage is not always readily apparent in all cases. In some instances, marked axonal denervation can be evident with minimal amyloid infiltration. This has led to many theories of the pathogenesis of the neuropathy, including vascular and pressure changes by the amyloid deposits. However, direct toxic effects of the amyloid fibrils on nerve fibers and dorsal root ganglion cells seem more likely. Treatment is problematic. The amyloid fibrils are insoluble once deposited in tissue. Thus, improvement is unlikely even if amyloid deposition is halted. In addition, the neuropathy has resisted all attempts to halt its progression, even with aggressive treatment with combinations of anti-inflammatory medications such as steroids, alkylating agents such as melphalan and cyclophosphamide,and other chemotherapeuticdrugs designed to slow production of the light chains. Prolonged plasmapheresis designed to lower the light-chain concentration in serum is not

Multiple myeloma is a malignant plasma cell dyscrasia with high serum and urinary concentrations of M-proteins, infiltration of bone marrow by malignant plasma cells, and multiple bony lesions caused by plasma cell infiltration. Most neurologic complications are caused by secondary effects of the tumor (hypercalcemia, infections) or by malignant infiltration of nerve roots or secondary compression of spinal cord or nerve roots caused by vertebral fractures. Polyneuropathies are uncommon. They occur in only a few percent of patients with multiple myeloma and are diverse in nature, similar to the polyneuropathies associated with other malignancies. The exception is osteosclerotic myeloma, discussed separately later in this chapter. Neuropathies associated with typical lytic multiple myeloma include distal sensorimotor axonopathy, a CIDP-like picture, and a sensory neuropathy resembling the carcinomatous sensory neuropathy. In addition, these patients may also develop plasma cell dyscrasia polyneuropathy caused by deposition of light-chain fragments in tissue. In one series, 20% of neuropathies associated with multiple myeloma were caused by plasma cell dyscrasia. Superimposed root involvement may mistakenly suggest a picture of mononeuritis multiplex, which we have not seen in our patients with amyloidosis with the exception of carpal tunnel syndromes. The root and cord compressive syndromes should be managed by conventional means, but like nonmalignant primary systemic amyloidosis, the amyloid neuropathy does not respond to chemotherapy.

OSTEOSCLEROTIC MYELOMA POLYNEUROPATHY AND RELATED SYNDROMES Osteosclerotic myeloma is a rare and more benign variant of multiple myeloma. Less than 3% of untreated patients with myeloma have sclerotic bony lesions. In addition, whereas polyneuropathy is rare with typical multiple myeloma, it is common with osteosclerotic myeloma, occurring in 50% or more of reported cases. Also, patients with osteosclerotic myeloma usually are not systemically ill and usually present because of the neuropathy or other remote effects of the malignancy rather than as a direct effect of the malignancy, as usually occurs in multiple myeloma. Anemia, hypercalcemia, and renal insufficiency are uncommon in osteosclerotic myeloma, bone marrows are rarely infiltrated with malignant plasma cells, and the serum M-protein concentrations are low. Finally, the course of osteosclerotic myeloma is indolent, and these patients have prolonged survivals even without treatment. Thus, there is something singular about the syndrome of osteosclerotic myeloma and its paraneoplastic accompaniments. The syndrome can be difficult to diagnose even by experienced physicians. The polyneuropathy accompanying osteosclerotic myeloma is

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distinctive and homogeneous. Deficits are mainly motor and slowly progressive, without sudden changes in severity or tempo of progression. Patients present with the onset of weakness, mostly in distal limbs initially, with gradual proximal spread accompanied by reflex loss. Sensory loss typically is less striking and tends to disproportionatelyaffect the larger sensory fibers, with greater loss of discriminative sensation than cutaneous sensation. Pain and autonomic dysfunction, with the exception of impotence (actually caused by endocrine dysfunction), is very uncommon. Nerves often are palpably thickened. The deficit usually is very symmetrical and the tempo of progression very slow, often over months to years. In keeping with the nature of the underlying disorder, general laboratory studies usually are uninformative. The best clue to the diagnosis is the presence of a serum M-protein, which is present in about 75% to 80% of patients. However, the M-protein may be very small and obscured by the normal serum protein components in the electrophoresis, emphasizing the importance of immunoelectrophoresis or immunofixation in all patients with idiopathic polyneuropathy. The M-protein is characteristicallyIgG or IgA (never IgM), h light chain (rarely K), and rarely present in the urine, in contrast to multiple myeloma. Neurodiagnostic studies are helpful but nonspecific. Nerve biopsy studies disclose a reduced concentration of myelinated fibers with changes of mixed demyelination and axonal degeneration. There may be mild foci of mononuclear cells in the epineurium surrounding blood vessels. These changes are nonspecific and characteristic of a number of neuropathies, including CIDP and diabetic polyneuropathy. The EMG (Table 96-5) reveals a mixed axonal and demyelinating picture that again is nonspecific but helpful in categorizing the neuropathy into the group with clear-cut demyelinating features and thus making it more likely to be diagnosable. Cerebrospinal fluid typically reveals a normal cell count but a very high protein concentration, generally higher than 100 mg/dL and sometimes as high as several hundred milligrams per deciliter. Because all these findings are nonspecific, the diagnosis often hinges on the discovery of the characteristic bony lesions and subsequent bone biopsy. The osteosclerotic lesions may be solitary or multiple. They tend to affect the axial skeleton and very proximal long bones but spare the distal long bones and skull. They may be pure sclerotic or mixed sclerotic and lytic. Radioactive bone scans, although more sensitive than radiographs as a rule in detecting bony metastases, are not as sensitive as radiographs in detecting osteosclerotic myeloma lesions, probably because of the indolent nature of plasmacytomas. Therefore, all patients with unexplained polyneuropathies that fit the clinical profile as described earlier should be screened with a radiographic skeletal survey. On occasion, these lesions are misinterpreted by radiologists who are unfamiliar with their appearance and significance. Three of our patients were believed to have benign osteosclerotic lesions (fibrous dysplasia in a rib in two and a vertebral hemangioma in one) with negative radionuclide bone scans. We insisted on biopsy because of the clinical picture, and the presence of a serum M-protein and plasmacytomas was revealed, leading to effective treatment. ThFrefore, if there is any question of the significance of a bony lesion in a patient with a suggestive clinical picture, the radiographs should be reviewed by the neurologist with the radiologist, and the lesion should be biopsied if doubt remains. Open biopsy generally is preferable to needle biopsy, in our experience. The diagnosis of this disorder is of more than academic interest because these patients may be helped by tumoricidal treatment. Patients with solitary lesions do best. Radiotherapy in tumoricidal

dosages to the lesion results in elimination of the M-protein from the serum and gradual recovery of the neuropathy over the ensuing months in most patients. However, these patients should continue to be followed because they tend to relapse with the development of new lesions months to years later. This is usually heralded by the return of the neuropathy and other symptoms and the reappearance of the serum M-protein. Patients with multiple lesions are more difficult to treat. Radiotherapy generally is not an option. In some cases, aggressive chemotherapy can help these patients, but in general the outcome is not as favorable as for solitary lesions. Treatment usually includes large dosages of steroids and alkylating agents. Treatments that usually are effective in autoimmune inflammatory neuropathies, such as steroids alone or azathioprine, usually are ineffective in these patients. The cause of the polyneuropathy is not known, but most theories of pathogenesis have focused on some secretory product of the tumor, most likely the M-protein itself and specifically some component of the Alight chain. However, there is little evidence that the M-protein plays a direct role in the neuropathy or the systemic symptoms. Other secretory products of these tumors have recently been implicated, including cytokines and vascular endothelial growth factor. The pathogenesis of nerve damage in this disorder and whether it is an axonopathy or a primary demyelinating disorder remain unresolved at this time. This disorder is also of interest because many of these patients develop a multiple-system syndrome that goes by a variety of names, including POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), or Crow-Fukase syndrome. In addition to polyneuropathy, these patients have other features (Table 96-8) suggesting the presence of an underlying endocrinopathy or even malignancy. The reason for the endocrinopathy is unclear. Limited data suggest a disturbance of the hypothalamic-pituitary axis rather than primary end-organ failure, possibly caused by antibody activity against pituitary tissue. The organomegaly usually is nonspecific pathologically. Biopsy of affected lymph nodes generally discloses hyperplastic changes, sometimes resembling the pathologic findings in the syndrome of angiofollicular lymph node hyperplasia (Castleman’s disease), which is a benign localized or generalized hyperplastic lymph node syndrome of unknown cause. Of interest, patients with generalized angiofollicular lymph node hyperplasia without bony lesions may also have the manifestations of Crow-Fukase syndrome associated with serum M-proteins or polyclonal gammopathies. Thus, as discussed in the preceding paragraph, the main pathogenetic determinant of these syndromes probably is the presence of a serum product secreted by the tumor. The term POEMS syndrome for these cases is not entirely accurate and focuses attention on a small number of affected patients to the exclusion of others. For example, of the patients with osteosclerotic myeloma polyneuropathy, most have features other than neuropathy that are fragments of a multiple systemic disorder, but only a few would qualify for the POEMS diagnosis (Table 96-8). Thus, we prefer the term Crow-Fukase syndrome when referring to patients with polyneuropathy and multisystemic disorder, as suggested by Nakanishi et al.

MISCELLANEOUS SYNDROMES WaldensMm’s Macroglobulinemla It is sometimes difficult to separate Waldenstrom’s macroglobulinemia from I@-MGUS, and the latter may evolve into Waldenstrom’s macroglobulinemia over time. Thus, similar poly-

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TAW 96-8. Non-neurologicAbnormalities in 16 Patients with Osteosclerotic Myeloma and Polyneuropathy PAtlEhl

Abnormality

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Cynecomastia + Hepatomegaly + + + + Splenomegaly + + Hyperpigment + + + Edema + + + Lymphadenopathy + + Papilledema + + + Digit clubbing + + White nails Hypertrichosis + + Atrophic testes + Impotence + + + + Polycythemia + + + Leucocytosis + + + + + + Thrombocythemia 4Low plasma testosterone + + + High estrogen + + Low thyroxine + Hyperglycemia + From Kelly JJ Jr, Kyle RA, Miles JM et al: Osteoxlerotic myeloma and peripheral neuropathy. Neurology 33:202,1983, with permission.

neuropathy syndromes occur. The most common polyneuropathy probably is that associated with anti-MAG antibodies. This syndrome has the same features and clinical course as IgM-MGUS. Other patients may have either a CIDP-like picture, a distal ,aonal neuropathy, typical amyloid polyneuropathy, or even the sensory neuronopathy syndrome usually seen with small cell cancer of the lung.

Cryogiobuiinemia This disorder usually is divided into three types. In type 1, the M-protein itself is a cryoglobulin in the setting of a plasma cell disorder. In type 2, the cryoglobulin is a mixture of an M-protein of IgM type with rheumatoid factor activity against polyclonal immunoglobulins, usually occurring in the setting of a lymphoproliferative disorder. Type 3 occurs in the setting of a collagen vascular or other chronic inflammatory disease, and the cryoglobulin consists of polyclonal immunoglobulins. The polyneuropathy in all these syndromes is painful, symmetrical or asymmetrical, and sensorimotor and axonal in nature. Purpura occurs in distal limbs in a high percentage of patients, and the neuropathy generally is considered to be caused by a vasculopathy or vasculitis of skin and vasa nervorum. Lymphoma, Leukemia, and Cancer

These disorders can be associated with M-protein and polyneuropathy. In lymphoma with IgM M-protein, the IgM may have anti-MAG activity with the usual clinical and pathologic features. Other syndromes without clear antinerve activity in the M-protein fraction may respond to ablation of the malignancy. Still others have an unclear relation to the malignancy and show little response to tumoricidal treatment or to lowering of the M-protein concentration in serum. CONCLUSION

The field of plasma cell dyscrasiasand neuromuscular diseases has been a fruitful area for active research since the mid-1980s. It is

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very important to recognize patients with these diseases because treatment may lead to remission. Also, careful study of these patients may lead to a better understanding of the pathogenesis of polyneuropathies and possibly motor neuron disease. This may in turn lead to effective treatment for conditions for which there are now no effective treatments. Therefore, despite their infrequency, increased recognition of these disorders will continue to be a high priority for both peripheral nerve specialists and for general neurologists.

SUGGESTED READINGS Kelly JJ Jr: Peripheral neuropathies associatedwith monoclonal proteins: a clinical review. Muscle Nerve 8:138, 1985 Kelly JJ Jr, Adelman LS, Berkman E et ak Polyneuropathiesassociatedwith IgM monoclonal gammopathies. Arch Neurol45:1355, 1988 Kelly JJ Jr, Kyle RA, Latov N Polyneuropathies Associated with Plasma Cell Dyscrasias. Martinus-Nijhoff, Boston, 1987 Kelly JJ Jr, Kyle R4, Miles JM et ak Osteosclerotic myeloma and peripheral neuropathy. Neurology 33:202, 1983 Kelly JJ Jr, Kyle RA, Miles JM et al: The spectrum of peripheral neuropathy in myeloma. Neurology 31:24, 1981 Kelly JJ Jr, Kyle RA, OBrien PC et ak The natural history of peripheral neuropathy in primary systemic amyloidosis. Ann Neurol 5:271, 1979 Kelly JJ Jr, Kyle RA, OBrien PC et al: Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31:1480, 1981 Kyle RA: Plasma cell dyscrasias. p. 1-35. In Spitell JA Jr (ed): Clinical Medicine. Harper & Row, Philadelphia, 1981 Latov NR, Hays AF', Sherman WH: Peripheral neuropathy and anti-MAG antibodies. Crit Rev Neurobiol 3:301, 1988 Latov N, Sherman WH, Nemni R et ak Plasma cell dyscrasia and peripheral neuropathy with a monoclonal antibody to peripheral nerve myelin. N Engl J Med 303:618, 1980 Nakanishi T, Sobue I, Toyokura Y et ak The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 34:712, 1984 Steck AJ, Murray N, Dellagi K et al: Peripheral neuropathy associated with monoclonal IgM autoantibody. Ann Neurol 45:711, 1988 Suarez GA, Kelly JJ Jr: Polyneuropathy associated with monoclonal gammopathy of undetermined significance: further evidence that IgM-MGUS neuropathies are different than IgG-MGUS. Neurology 43:1377, 1993

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NeuroDathies in Connective Tissue Diseases Richard K. Olney

Peripheral neuropathies of several types develop in the clinical context of known diffuse connective tissue diseases. Also, certain presentations of peripheral neuropathy raise the distinct concern that the neuropathy may be the initial manifestation of a previously unsuspected connective tissue disease. To facilitate the recognition of these latter neuropathies, the first section of this chapter reviews each type of neuropathy and comments on the known or possibly unsuspected connective tissue diseases that may be associated. To facilitate recognition of neuropathy in a patient with a known connective tissue disease, the second section reviews certain diffuse connective tissue diseases and comments on their associated neuropathies. ~~~

PERIPHERAL NEUROPATHIES ASSOCIATED WITH CONNECTIVE TISSUE DISEASES The peripheral neuropathies that are associated most closely with diffuse connective tissue diseases are as follows: Vasculitic neuropathy Distal symmetrical axonal polyneuropathy Trigeminal sensory neuropathy Sensory neuronopathy Entrapment or compression neuropathy Among these neuropathies, the diagnosis and initiation of treatment is most important to accomplish in a timely manner for vasculitic neuropathy because it is the most rapidly evolving and potentially fatal, so its diagnosis is particularly emphasized. Vasculitic Neuropathy

Vasculitic neuropathy is defined by the pathogenetic mechanism that produces injury to the nerve fibers: Inflammatory occlusion of blood vessels produces ischemic infarction of one or more nerves. The probability of vasculitic neuropathy usually is suspected clinically when it presents as a mononeuropathy multiplex in a patient with a known connective tissue disease. However, the possibility of vasculitic neuropathy is also important to consider in many other patients. This neuropathy may be the initial manifestation of connective tissue disease, particularly polyarteritis nodosa. Furthermore, vasculitic neuropathy often presents as a generalized polyneuropathy with little or no asymmetry rather than as a mononeuropathy multiplex. Thus, the possibility of vasculitic neuropathy must be considered in many patients with neuropathy of undefined cause, especially in those patients in whom symptoms and signs have developed with asymmetry or without following a length-dependent distribution (this distribution is typical for distal symmetrical axonal polyneuropathy and is discussed further under that heading) or in whom functionally significant deficits have developed rapidly (that is, over weeks or months). In other words, the possibility of vasculitic neuropathy must be considered in many patients with neuropathy of undefined cause if there are clinical features that are atypical for the more common distal symmetrical axonal polyneuropathy.

When vasculitis produces acute ischemia of a nerve, the patient usually experiences an immediate deep aching pain in a poorly localized but proximal distribution in the affected limb. Several hours to several days after this proximal deep aching pain, the patient develops a burning pain in the cutaneous distribution of the affected nerve. In patients with less acutely evolving vasculitic neuropathy, the proximal deep aching pain may be overshadowed by a more prominent distal burning pain that develops over days or several weeks. On neurologic examination, most patients have weakness and abnormal sensation for pain and temperature, whereas a minority of patients have impairment of vibration and position sense. This sensory loss and weakness typically develop over several hours to several days in the distribution of the affected nerve in the acutely evolving cases or over days to weeks in a more confluent distal distribution in the more slowly evolving cases. In patients who present with the more obvious mononeuropathy multiplex, some nerves are more predisposed to involvement than others. The peroneal nerve is the most commonly affected by vasculitis, and the ulnar nerve is the most commonly involved in the upper limb. The nerve infarctions typically are located at “watershed” zones of poor perfusion, which are at the midthigh level for the peroneal division of the sciatic nerve and at the mid-upper arm level for the ulnar nerve. If affected, the tibial and median nerves usually are also infarcted at these same levels. After eliciting the patient history and conducting the physical examination, the first step in the diagnostic workup is electrodiagnostic evaluation. The electromyographic (EMG) and nerve conduction studies assess the severity and pathophysiologic basis of the clinical symptoms and signs. In vasculitic neuropathy, acute axon loss is the predominant pathophysiology identified. Thus, EMG studies reveal reduced recruitment of motor unit potentials that parallels the clinical weakness, and fibrillation potentials are seen in affected muscles 1 to 4 weeks after onset of weakness. Nerve conduction studies document decreased amplitude of sensory nerve and compound muscle action potentials, with normal or mildly reduced conduction velocities. In patients with clinically obvious multifocal nerve involvement, a further purpose of these studies is to distinguish multifocal nerve infarction from multifocal entrapment. Whereas focally decreased conduction velocity or partial conduction block is seen at common entrapment sites with multifocal entrapment, signs of multifocal axonal degeneration distal to the midthigh or mid-upper arm levels are seen in vasculitic mononeuropathy multiplex. In patients without clinically obvious multifocal nerve involvement, a further purpose of these studies is to seek signs of multifocal or non-lengthdependent axonal degeneration that are not obvious clinically. With sensory or motor nerve conduction studies, these signs include finding a more than twofold difference in the amplitude between the right- and left-sided responses of the same nerve (i.e., bilateral asymmetry), a low-amplitude response for one but not another nerve within a limb, or a low-amplitude response for an upper limb nerve if amplitude is normal for at least one lower limb nerve (i.e., non-length-dependence). With needle EMG studies, non-length-dependent axonal degeneration is identified by finding acute partial denervation (reduced recruitment of motor unit

Chapter 97

potentials with or without fibrillation potentials) in some but not other proximal muscles that seem normal clinically. The second step in the diagnostic evaluation is obtaining laboratory tests and possibly a nerve or muscle biopsy. The connectivetissue diseases associated with vasculitic neuropathy are as follows: Polyarteritis nodosa (usually not previously diagnosed) Rheumatoid arthritis (usually an established diagnosis) Others infrequently (either unsuspected or known) Systemic lupus erythematosus Systemic sclerosis Sjogren’s syndrome Churg-Strauss syndrome Wegener’s granulomatosis The two most common causes are polyarteritis nodosa and rheumatoid arthritis with vasculitis. However, the extent of laboratory testing depends very much on the clinical context. The least extensive workup is indicated in a patient with a mononeuropathy multiplex, electrodiagnostic evidence suggestive of vasculitic neuropathy, a previously known diagnosis of rheumatoid arthritis, and the laboratory signs of a highly elevated erythrocyte sedimentation rate and rheumatoid titer. In such a patient, treatment may be initiated with reasonable confidence in the diagnosis of vasculitis, without performing a biopsy or other tests. The most extensive testing is indicated in a patient without a previously known connective tissue disease or in a case with a more confluent neuropathy in whom the possibility of vasculitis is less certain. In these patients, laboratory tests often include complete blood count with differential and platelet count, erythrocyte sedimentation rate, antineutrophil cytoplasmic antibody, antinuclear antibody, rheumatoid titer, complement levels, hepatitis B and C serologies, chemistry tests of renal and liver function, and urinalysis. If the clinical suspicion of vasculitic neuropathy is sufficiently high, biopsy of nerve or muscle is requested at the same time the preceding tests are ordered. This request often is made the same day as the clinical and electrodiagnostic evaluation, with the biopsy performed within 1 to 3 days as an emergency procedure. If the possibility of vasculitic neuropathy becomes reasonable only after some or all of the laboratory tests return (for example, in a more slowly evolving neuropathy that is partially or fully confluent) then biopsy of nerve or muscle is arranged as an urgent procedure when the possibility becomes reasonable. Treatment of vasculitic neuropathy usually is initiated with glucocorticoids, either oral 1 mg/kg/day prednisone or intravenous 1 g/day methylprednisolone for 3 days followed by oral prednisone. If the vasculitis is limited to peripheral nerve and muscle (which is as common as polyarteritis nodosa and rheumatoid vasculitis), treatment may consist of prednisone for 4 to 12 months, or 2 mg/kg/day azathioprine may be added and continued for 1 to 2 years. If the vasculitis is systemic and necrotizing, 2 mg/kg/day oral cyclophosphamide often is added and continued for 1 or more years. Recovery from the sensory and motor deficits is likely in survivors, with meaningful improvement in 28% at 3 months, 60% at 6 months, and 86% at 1 year. Distal SymmcMcal Axonal Polyneuropathy

This type of neuropathy develops in most types of diffuse connective tissue disease, which include the following:

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Rheumatoid arthritis (a mild one in a majority with known rheumatoid arthritis if carefully sought) Systemic lupus erythematosus (in 6% to 21%with known systemic lupus erythematosus) Systemic sclerosis (in 10% to 15% with known systemic sclerosis) Sjogren’s syndrome (in 10% to 15% with known primary disease) Giant cell arteritis (in 7% with known giant cell arteritis) The presenting complaints usually are sensory symptoms in the toes or feet. Paresthesias and symptoms of sensory loss are characteristic. The paresthesias often are described as tingling, but other adjectives referring to nonpainful extra sensations are not unusual. Symptoms of sensory loss include diminished awareness of pain (e.g., awareness of cut on foot only when blood seen), temperature (e.g., toes cannot sense when water in bathtub is hot), touch (e.g., noticed while clipping toenails), or position (e.g., difficulty getting toes in socks or stockings). Loss of position sense also may be noticed as imbalance. Partial sensory loss is occasionally described as feeling as if walking on sand or marbles. Pain in the toes or feet is a common symptom, too, but less characteristic if not associated with paresthesias or sensory loss. Sharp stabbing and lancinating pain, as well as more constant burning pain, usually is caused by neuropathy. Dull aching and pressurelike pain are nonspecific. With distal symmetrical axonal polyneuropathy, sensory symptoms begin in the toes or feet symmetrically and gradually spread proximally over time in a length-dependent manner. At the time when distal lower limb symptoms have spread up to the midcalf level, similar symptoms usually begin in the fingertips symmetrically. Often, near this point in time, weakness at the ankles becomes an additional complaint. Symptoms that are caused by ankle weakness include slapping of the feet with walking, tripping over steps or thick carpet, or having to step higher consciously to avoid tripping. To distinguish distal symmetrical axonal polyneuropathy from vasculitic neuropathy, the length dependency and symmetry of symptoms and signs are important concepts. In distal axonal polyneuropathy, nerve fibers that are the same distance from the nerve cell bodies (or the same distance from the spinal cord) should be affected to a similar degree. Thus, both feet should be symptomatic near the same point in time (roughlywithin a month of each other), and fingers should not be affected until the lower legs are affected. If symptoms begin in one or both hands before involvement between the ankle and knee, this strongly suggests either vasculitic neuropathy or a superimposed compression neuropathy. The neurologic signs of distal symmetrical axonal polyneuropathy parallel those of the symptoms but may be quantitatively different (either more or less severe than the complaints). The initial signs usually are a decreased threshold for vibration perception in the toes and at the ankle and depressed or absent ankle tendon reflexes. A decreased threshold for pain perception (pinprick) and temperature (warm usually is more useful than cold, as feet themselves are often cool) is often observed as well. Wasting of intrinsic foot muscles and weakness of toe movements occasionally are seen early in the course of distal symmetrical axonal polyneuropathy but usually are delayed until the upper edge of the stocking decrease in sensation is up to the midcalf level. A decreased threshold for perception of pain, temperature, or vibration is seen in the fingers at about the same time the lower limb sensory level has spread up to the midcalf level.

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The first step in the diagnostic workup is electrodiagnostic evaluation to assess the severity and pathophysiologic basis for the clinical symptoms and signs. In distal symmetrical axonal polyneuropathy, signs of axon loss are seen most prominently in a distal and symmetrical distribution. Thus, EMG studies reveal reduced recruitment of motor unit potentials in distal more than proximal muscles and in intrinsic hand muscles no more severely than in muscles of anterior and posterior compartments of the lower leg. Reduced recruitment of motor unit potentials usually is accompanied by signs of chronic partial denervation with reinnervation (an increased incidence of long-duration, large-amplitude, or polyphasic motor unit action potentials) and, in more rapidly progressive cases, signs of acute denervation (reduced recruitment associated with fibrillation potentials). Nerve conduction studies document symmetrically decreased amplitude of sensory nerve and compound muscle action potentials, with normal or mildly reduced conduction velocities. If axon loss is not in a symmetrical and length-dependent distribution, then subsequent evaluation is refocused for a possible vasculitic neuropathy. The second step in the diagnostic evaluation is obtaining laboratory tests. In a patient with a known connective tissue disease, these usually include complete blood count with differential and platelet count, erythrocyte sedimentation rate, antibody titers that correlate with activity for that particular connective tissue disease, chemistry tests of renal and liver function, vitamin B,, level, thyroid function tests, serum protein electrophoresis, and urinalysis. The latter tests are obtained to evaluate the possibility of a cause for the polyneuropathythat is less directly related to the connective tissue disease. Distal symmetrical axonal polyneuropathy is rarely the first sign of an unsuspected connective tissue disease. The treatment of distal symmetrical axonal polyneuropathy often is symptomatic or rehabilitative. Symptomatic treatments usually are for pain and commonly include tricyclic antidepressants (usually amitriptyline, nortriptyline, or desipramine) or membrane-stabilizing drugs (usually gabapentin or carbamazepine). Rehabilitative treatments often include orthotic shoe inserts for activity-related pain or plastic ankle-foot orthoses for ankle weakness. Potentially curative treatment usually is limited to cases in which symptoms and signs turn out to be caused by a confluent vasculitic neuropathy.

Trigeminal Sensory Neumpathy Trigeminal sensory neuropathy is characterized by slowly progressive facial sensory symptoms, either unilaterally or bilaterally. The sensory symptoms often begin with a small unilateral patch of numbness that is around the mouth or on the cheek. This small patch typically expands gradually and unilaterally. The deficit typically is maximal over 6 to 24 months. Contralateral sensory symptoms do not develop in many patients but may develop in some, often after a delay of several years. Facial numbness often is associated with paresthesias or pain. The neurologic examination is abnormal for impaired perception of pain, temperature, or light touch in the symptomatic distribution. The corneal reflex is blunted or absent in many patients. The severity of sensory involvement can be documented objectively in a quantitative manner with blink reflex studies. An afferent delay (i.e., delayed ipsilateral R1 and bilateral R2) or an absent response is seen in about one half of patients. Trigeminal sensory neuropathy presents in two manners: Trigeminal neuropathy as initial or early manifestation of systemic sclerosis

Trigeminal neuropathy as a manifestation of a known connective tissue disease Sjogren’s syndrome Systemic lupus erythematosus Rheumatoid arthritis Dermatomyositis Undifferentiated connective tissue disease Based on the limited amount of pathologic data available, trigeminal sensory neuropathy appears to result from degeneration of peripheral myelinated axons caused by fibrosis or low-grade perivascular inflammation or vasculitis involving or distal to gasserian ganglion. Based on cases studied with magnetic resonance imaging, gadolinium enhancement of the cisternal preganglionic portion of the trigeminal nerve and of the gasserian ganglion that is often transient supports inflammation of or proximal to the ganglion. Even if this inflammation were caused by vasculitis, the development of systemic vasculitis is unusual. Furthermore, less than 10% of patients have even a subjective response to treatment with prednisone. Thus, trigeminal sensory neuropathy generally does not indicate the need to initiate prednisone or immunosuppressive therapy. However, trigeminal sensory neuropathy is important to recognize, because this often leads to the diagnosis and treatment of systemic sclerosis.

Sensory Neuronopathy Sensory neuronopathy is associated primarily with Sjogren’s syndrome. Most patients are middle-aged women who present with symptoms of sensory neuronopathy and are not known to have Sjogren’s syndrome. Although any limb may become symptomatic first, most patients present with symptoms in both legs and have gait ataxia. Other common chief complaints are clumsiness, incoordination, decreased awareness of limb position, or numbness. The onset often is insidious but may be acute or subacute. On neurologic examination, signs usually are most prominent in the lower limbs but can be most severe in one arm. Sensory impairment usually is greater for vibration and proprioception than for pain and temperature. Deep tendon reflexes usually are depressed or absent in affected limbs. Strength is normal but may seem mildly reduced because of the severity of incoordination. Romberg’s sign is positive if lower limbs are affected. Pseudoathetosis may be prominent if the upper limbs are involved. The first step in the diagnostic evaluation is electrodiagnostic testing. Sensory nerve action potentials typically are absent in affected limbs but, if recordable, have normal conduction velocities unless the amplitude is severely reduced. EMG and motor nerve conduction studies have normal results or mild abnormalities in such a limited distribution as to be of doubtful clinical significance. These results then confirm that the neuropathy is a sensory neuronopathy and that the differential diagnostic possibilities are limited to Sjogren’s syndrome, a paraneoplastic syndrome, a short list of toxic exposures, or unknown cause. If the patient has symptoms of dryness of the eyes or mouth, the second step in the diagnostic evaluation includes those directed at documenting Sjogren’s syndrome. Reduced lacrimation by Schirmer’s test, signs for keratoconjunctivitis sicca by the rose bengal test, evidence for Sjogren’s syndrome in minor salivary gland biopsy specimens, and elevated titers to antinuclear antibody or rheumatoid factor usually are present, whereas anti-Ro antibodies or arthritis is present in less than one third. Other testing may be performed to look for a primary or recurrent tumor

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and include anti-Hu (also known as antineuronal nuclear antibody, type 1) antibody. The pathogenesis of sensory neuronopathy in Sjogren’s syndrome is a dorsal root ganglionitis; dorsal root ganglia biopsy specimens have revealed lymphocytic infiltration with degeneration and loss of the neurons in the few patients who have undergone this procedure. Because of this pathogenetic mechanism, immunosuppressive treatment with cyclophosphamide or other drugs often is used, but the benefit of such therapy has not been established. About one half of patients stabilize and functionally improve during immunosuppression, but objective signs of improvement (as with larger sensory nerve action potentials) are not usually seen.

Entrapment or Compression Neuropathles An increased incidence of entrapment or compression neuropa-

thies is generally accepted in association with some connective tissue diseases. The association of the carpal tunnel syndrome and rheumatoid arthritis has been most thoroughly studied. During the course of rheumatoid arthritis, one quarter to one third of patients are likely to develop symptoms of carpal tunnel syndrome and have a positive Tine1 sign. One fifth to one quarter of patients with Sjogren’s syndrome or systemic sclerosis may also develop carpal tunnel syndrome. The predominant electrophysiologic abnormality in such cases is the prolongation of sensory or motor latency through the carpal tunnel. This electrodiagnosticfeature is useful in distinguishing entrapment or compression from vasculitic neuropathy. An increased incidence of ulnar neuropathy at the elbow and peroneal neuropathy at the fibular head has also been reported in rheumatoid arthritis. However, this seems to be based primarily on anecdotal reports rather than on prospective studies and therefore may represent a simple chance association rather than a predisposition.

Other Neuropathies Acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and brachial neuritis have been described in patients with known systemic lupus erythematosus and, rarely, in patients later found to have systemic lupus erythematosus. These associations may represent the chance occurrence of two diseases or may possibly reflect an abnormal immunologic mechanism that predisposes to both diseases. The nature of the association is speculative at this point.

CONNECTIVE TISSUE DISEASES ASSOCIATED WITH PERIPHERAL NEUROPATHIES The diffuse connective tissue diseases that are commonly associated with peripheral neuropathies are as follows: Rheumatoid arthritis Systemic lupus erythematosus Systemic sclerosis Sjogren’s syndrome Vasculitides Polyarteritis nodosa Allergic granulomatosis (Churg-Strauss syndrome) Giant cell arteritis Wegener’s granulomatosis

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Rheumatoid Arthritis Rheumatoid arthritis is the most common connective tissue disease. It affects 1% to 2% of adults worldwide and more than 10% of the population that is above age 65 years. A definite diagnosis of rheumatoid arthritis requires the documentation of at least four of seven criteria in the 1987 revision. The neuropathies associated with rheumatoid arthritis are as follows: Vasculitic neuropathy in less than 10% Distal symmetrical axonal polyneuropathy in majority Trigeminal sensory neuropathy Entrapment or compression neuropathies, especially carpal tunnel syndrome Systemic necrotizing vasculitis complicatesrheumatoid arthritis in 8% to 25% of cases by the time of death, usually after arthritis has been present for an average of 14 years. However, on rare occasions systemic necrotizing vasculitis is the major presenting feature of rheumatoid arthritis. Weight loss, rheumatoid nodules, and cutaneous lesions usually are seen with systemic necrotizing vasculitis. Clinically apparent vasculitic neuropathy develops in about one half of patients with systemic necrotizing vasculitis. Although the majority of patients with rheumatoid arthritis develop a mild sensory distal axonal symmetrical polyneuropathy, clinically significant vasculitic neuropathy develops in less than 10%. With rheumatoid vasculitis, the erythrocyte sedimentation rate usually is elevated, and the rheumatoid factor typically has a high titer. The development of vasculitis in patients with rheumatoid arthritis results in a poor prognosis. Even with steroid and immunosuppressivetherapy, the 6-month survival rate is 80% and the 5-year rate is 60%, similar to that for polyarteritis nodosa. Although clinically significant vasculitic neuropathy develops in less than lo%, a majority of patients with rheumatoid arthritis have evidence of a mild sensory distal symmetrical axonal polyneuropathy when detailed clinical and electrodiagnostic examinations are performed. If nerve biopsies are performed on these patients, variable amounts of intimal thickening and less frequent perivascular mononuclear infiltration often are seen in endoneurial and epineurial vessels. Similar changes are common in peripheral nerves taken at autopsy from patients who had rheumatoid arthritis without clinically evident neuropathy. Thus, a low-grade vasculitis is one possible explanation for the mild sensory distal symmetrical axonal polyneuropathy, although there is no convincing evidence that immunosuppressive treatment is beneficial for it. Exposure to toxic medications and other undefined factors may also be important in the pathogenesis of the mild sensory distal symmetrical axonal polyneuropathy.

Systemic Lupus Erythematosus Systemic lupus erythematosus is a common connective tissue disease in young women. Its general prevalence in adults is about 1 in 2000, but its prevalence is 1 in 250 in black women under 65 years and 1 in 1000 in white women of comparable age. Women are five times more likely to be affected than men. Systemic lupus erythematosus is diagnosed by the cumulative occurrence of at least 4 of 11 multiple-system or laboratory criteria. Although central nervous system involvement fulfills 1 of these 11 criteria, peripheral neuropathy does not. The neuropathies associated with systemic lupus erythematosus are as follows: Vasculitic neuropathy (rarely) Distal symmetrical axonal polyneuropathy in 6% to 25%

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Trigeminal sensory neuropathy Other neuropathies (rarely) Acute inflammatory demyelinating polyneuropathy Chronic inflammatory demyelinating polyneuropathy Brachial neuritis About 6% to 25% of patients develop polyneuropathy, typically a distal symmetrical axonal polyneuropathy with predominantly sensory symptoms and subacute or chronic evolution. Most are not caused by low-grade vasculitis; however, vasculitic neuropathy and demyelinating polyneuropathy are well described in occasional patients. When the neuropathy is produced by a systemic necrotizing vasculitis, improvement usually results from treatment with plasmapheresis, steroids, and immunosuppressive drags. Steroids or other immunotherapies are not clearly beneficial in cases with distal symmetrical axonal polyneuropathy. Systemic Sclerosis

Systemic sclerosis usually presents initially with Raynaud’s phenomenon. Some patients rapidly develop diffuse cutaneous signs with symmetrical, widespread thickening of the skin and have early visceral involvement. Others have limited cutaneous signs with symmetrical, distal limb and facial thickening and late visceral involvement. These latter patients usually have CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia). The association of systemic sclerosis with trigeminal sensory neuropathy has been recognized for a long time. Although systemic sclerosis was once though not to be associated with neuropathies in the limbs, recent observations suggest that 10%to 15% of patients may have a distal symmetrical axonal polyneuropathy.

Peripheral neuropathy is present in 10% to 15% of cases of primary Sjogren’s syndrome, usually a distal symmetrical one that begins with paresthesias in the feet. Although clinical symptoms and signs are limited to the sensory fibers initially, electrodiagnostic studies provide evidence of distal loss of sensory and motor axons in most patients. The erythrocyte sedimentation rate and the titer for rheumatoid factor are elevated in a majority of patients with neuropathy, and many have elevated titers for antinuclear antibody or Sjogren’s syndrome A (Ro) antibody. In patients with neuropathy, signs of cutaneous vasculitis are common, sensory loss may be asymmetrical, and biopsy of sural nerves often suggests vasculitis. Thus, a low-grade vasculitis may be the usual pathogenetic explanation for the mild distal, usually symmetrical axonal polyneuropathy in Sjogren’s syndrome. However, systemic necrotizing vasculitis is rare. Convincing evidence of a beneficial effect of steroid or immunosuppression is lacking for most patients with Sjogren’s syndrome and neuropathy unless vasculitis is present. Polyartedtis Nodosa

The neuropathies associated with systemic lupus erythematosus are as follows:

Polyarteritis nodosa is the most common type of systemic necrotizing vasculitis that produces vasculitic neuropathy, with involvement of small and medium-size arteries. It is usually seen in middle-aged or older adults, with male predominance. Peripheral neuropathy develops in about one half of patients. The neuropathy usually presents as a mononeuropathy multiplex or at least with asymmetry and is almost always caused by vasculitis. The vasculitic neuropathy is the major presenting symptom in more than one third of cases and clinically apparent at presentation in most of the remainder. In the one half who develop vasculitic neuropathy, it is usually present within the first year of polyarteritis. In patients with polyarteritis nodosa, symptoms and signs of systemic disease usually are present. Weight loss and fever are present in two thirds to three quarters of patients. Arthralgias and rash each occur in one half. Less common clinical features include hypertension and renal, cardiac, or gastrointestinal involvement. An elevated erythrocyte sedimentation rate occurs in all but 5%to 10%. Anemia, leukocytosis, or abnormal urinalysis is found in most patients. Hepatitis B surface antigen is positive in a significant minority and may be causally related to polyarteritis nodosa in those cases. The diagnosis entails the pathologic documentation of necrotizing vasculitis or the arteriographic demonstration of aneurysms at vessel bifurcations. Although arteriography of the renal, hepatic, or mesenteric vessels may support the diagnosis in many cases, similar abnormalities may be seen in Wegener’s granulomatosis, left atrial myxoma, and infective endocarditis. The highest sensitivity and specificity from invasive testing in patients who present with neuropathy are achieved with biopsy of an electrophysiologically abnormal cutaneous nerve or with a muscle biopsy. In 1990, the American College of Rheumatology proposed criteria for diagnosing and classifylng vasculitis caused by polyarteritis nodosa, whether presenting with or without neuropathy. In this study, an 82% sensitivity and a 87% specificity were achieved by satisfying 3 or more of the following 10 criteria:

Vasculitic neuropathy (rarely) Distal symmetrical axonal polyneuropathy in 10% to 15% Trigeminal sensory neuropathy Sensory neuronopathy

Weight loss (4 kg) Livedo reticularis Testicular pain or tenderness Myalgias

Sj6gren.s Syndrome Sjogren’s syndrome may develop as a primary connective tissue disease or may be secondary to another one, usually rheumatoid arthritis, systemic lupus erythematosus, or systemic sclerosis. Women are nine times more likely to affected than are men. Sjogren’s syndrome is characterized by dryness of the mouth (xerostomia) and the eyes (xerophthalmia). There are no universally agreed-upon criteria for its diagnosis. One recent proposal that is as well accepted as any requires four of the following six criteria for a definite diagnosis and three of six for a probable diagnosis: Specific symptoms of dry eyes Specific symptoms of dry mouth Evidence of keratoconjunctivitis with either a positive Schirmer’s test or a positive result on the rose bengal dye test Objective evidence of diminished salivary gland flow or salivary gland involvement An abnormal minor salivary gland biopsy The presence of autoantibodies (SS-A, SS-B, antinuclear antibody, or rheumatoid factor)

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Neuropathy Hypertension (diastolic > 90 mm Hg) Elevated blood urea nitrogen or creatinine Presence of hepatitis B surface antigen Characteristic arteriographic abnormality Pathologic evidence of necrotizing vasculitis Untreated patients with polyarteritis nodosa have a 6-month survival of 35% and a 5-year survival of 13%. Steroid therapy improves survival to 68% at 6 months and 50% at 5 years. The early use of cyclophosphamide allows up to a 94% 6-month survival. Either cyclophosphamide or other cytotoxic therapy permits up to an 80% 5-year survival. Although there is a trend for cyclophosphamide to improve survival, this difference has not proven to be statistically significant, so some authors do not recommend the routine addition of cyclophosphamide. Although adversely affected by visceral involvement, the prognosis does not seem to be influenced by the occurrence of vasculitic neuropathy. Allergic Granulomatosls (Churg-Strauss Syndrome)

The Churg-Straws syndrome, or allergic granulomatosis,has been considered a variant of polyarteritis nodosa by some. It may be diagnosed with 85% sensitivity and 99.7% specificity by the presence of four or more of the following six criteria: Asthma Peripheral eosinophilia Nonfixed pulmonary infiltrates Paranasal sinus abnormality Neuropathy A biopsy with a blood vessel that contains extravascular eosinophils. As with polyarteritis nodosa, vasculitic neuropathy is the only associated neuropathy. The prognosis and treatment of ChurgStrauss syndrome are essentially the same as those of polyarteritis nodosa. Giant Cell Meritis

Giant cell arteritis is perhaps the most common form of vasculitis, typically involving medium and large arteries that are branches of vessels originating from the aortic arch. Patients usually are older than 50 years, present with headache, and have an erythrocyte sedimentation rate elevated to 50 mm/hour or more. It is diagnosed most specifically by a temporal artery biopsy that

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documents a necrotizing arteritis with giant cells. In contrast to the approximate 50% prevalence of neuropathy in polyarteritis nodosa or Churg-Strauss syndrome, neuropathy has been found in only 14% of patients with giant cell arteritis, with about one half being diffuse peripheral neuropathies. Although the mechanism is uncertain, an immune-mediated cause for the neuropathy is implied by the majority of patients having improvement in neuropathic deficits with steroid therapy. Even though a small number of patients have developed an acute mononeuropathy or multiple mononeuropathies that suggest vasculitis, nerve ischemia seems related to thrombosis of nutrient or larger vessels because the vessels involved with giant cell arteritis are larger than the epineurial arterioles that are affected in vasculitic neuropathy. Wegenefs Granulomatosls

Wegener’s granulomatosis is diagnosed by identifymg granulomatous vasculitis of small vessels in the upper and lower respiratory tracts and a segmental necrotizing glomerulonephritis. Peripheral neuropathy develops in 11% to 16% of patients, with the majority being vasculitic mononeuropathy multiplex. In the minority of these patients with distal symmetrical polyneuropathy, coincidental renal failure is common and offers an alternative explanation.

SUGGESTED READINGS Arnett FC, Edworthy S, Block DA et al: The 1987 revised ARA criteria for rheumatoid arthritis (abstracted). Arthritis Rheum 31(3):315-324, 1988 JennetteJC, Fa& RE Small-vesselvasculitis. N Engl J Med 337(21):15121523, 1997 Klippel JH: Primer on the Rheumatic Diseases. 11th Ed. Arthritis Foundation, Atlanta, 1997 Lightfoot RW, Michel BA, Bloch DA et al: The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 33(8):108&1093, 1990 Masi AT, Hunder GG, Lie JTet al: The American College of Rheumatology 1990 criteria for the classificationof Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 33(8):1094-1100, 1990 Moore PM: Neurology of the vasculitides and connective tissue diseases. 7 Neurol Neurosurg Psychiatry 65(1):lO-22, 1998 Olney RK: Neuropathies associated with connective tissue disease. Semin Neurol 18(1):63-72, 1998 Tan EM, a h e n AS, Fries JF et al: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25(11):1271-1277, 1982 Vitali C, Bombardieri S, Moutsopoulos HM et al: Preliminary criteria for the classification of Sjogren’s syndrome. Arthritis Rheum 36(3):340347, 1993

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Spinal Cord and Peripheral Neuromuscular Disease H Diseases of PeripheralNerve

Toxic Peripheral Neuropathies Michael T. Pulley and Alan R. Berger

Peripheral neuropathies caused by toxin exposure are rare. The majority of cases are individual, sporadic intoxications, but outbreaks such as the Minamata Bay mercury disaster garner a disproportionate amount of attention. The sporadic occurrence of toxic peripheral neuropathies (TxPNs) makes diagnosis very difficult. Therefore, a high index of suspicion is needed to detect the unusual cases of suicidal or homicidal ingestion and rare small-scale occupational exposures. Establishing a relationship between occupational exposure to a toxin and a sporadic peripheral neuropathy often is challenging because of a vague exposure history. TxPNs often are identical clinically and electrophysiologically to those caused by metabolic abnormalities, nutritional deficiencies, or systemic illness. Testing for toxic substances is unhelpful either because the delay between exposure and examination allows the substance to be eliminated or because a reliable test of body burden is not available. Therefore, many naturally occurring peripheral neuropathies tend to be misdiagnosed as toxic in origin when an alternative cause is not obvious. The most common pathologic pattern of TxPNs is known as the central-peripheral distal axonopathy. Exposure to the toxin causes degeneration of the distal portions of peripheral sensory and motor axons as the initial damage. Continued exposure causes similar injury to the distal segments of corticospinal,spinocerebellar, and dorsal column axons. The damage to central tracts, which can result in spasticity, ataxia, and persistent sensory loss, may become apparent only after recovery of the peripheral sensory and motor axons. The lack of regeneration in central sensory and motor tracts results in persistent clinical deficits. CARDINAL TENETS OF NEUROTOXIC ILLNESS AFFECTING THE PERIPHERAL NERVOUS SYSTEM Recognition of TxPNs is based on understanding and applying basic tenets of neurotoxic disease rather than memorizing the characteristics of the many potential neurotoxins. The identification of a neurotoxic illness should satisfy, or at least not be inconsistent with, the following basic principles. Neurotoxins produce a consistent pattern of disease, dependent on the dosage and duration of exposure. People with neurotoxin exposure similar in duration and degree invariably manifest similar signs and symptoms as long as the toxin enters the circulation, and the agent, its metabolite, or its intermediate has similar access to the nervous system. If the exposure dosage or duration is different, the same toxin may produce strikingly different clinical syndromes, but a similar and consistent illness should result in patients with similar exposures. Individual susceptibility or idiosyncratic reactions do not occur if dosage and duration of exposure are similar. Therefore, a neuropathy is unlikely to be neurotoxic in nature if only one member of a group with similar exposure history develops a neuropathy. Similarly, neurotoxicity should be doubted when significantly different clinical manifestations occur in a group of people with identical chemical exposure. Symptoms of neurotoxic illness do not begin months to years after exposure but usually occur concurrent with or shortly after exposure. The two most common exceptions are the 2- to 6-week

delay after exposure to organophosphates and the occasional 2-month latency between cisplatin intoxication and neuropathic symptoms. Another cardinal feature of TxPNs is that the extent and severity of neuropathy usually are commensurate with the degree of toxin exposure. A single, brief, low-level exposure is unlikely to cause a devastating peripheral neuropathy. Although some lipid-stored agents (e.g., chlorinated hydrocarbons) may be detected in fat biopsies years after exposure, there is no evidence that this is associated with risk of future neurotoxicity. TxPNs usually stabilize and then gradually improve after removal of exposure to the neurotoxic agent. Some degree of recovery is the rule, except in the most severely affected patients. If there is no improvement or there is continued deterioration despite the cessation of exposure to a suspected neurotoxin, the neuropathy is unlikely to be neurotoxic in nature. In some cases, however, a toxic axonopathy may worsen transiently after cessation of exposure for several weeks (coasting) before recovery commences. The initial step in diagnosing a TxPN is a suspicion raised by a thorough occupational and environmental exposure history. Many patients do not suspect a relationship between their symptoms and chronic, low-level intoxication because most TxPNs are insidious in onset. The patient's personal hygiene, eating habits, and hobbies should be discussed. Does the patient wear protective devices at work and change clothes before coming home? Does the patient eat in the workplace and always wash hands before eating? Are others at work experiencing similar symptoms? Does transient removal from exposure, such as on weekends or holidays, improve symptoms? Does poor ventilation or inadequate drainage lead to an unacceptably high risk of toxin exposure? A visit to the workplace may be needed to answer these questions. Home visits may be needed to check hobby workshops, medicine cabinets, and food and water sources when domestic poisoning or substance abuse is suspected. Has there been recent pesticide application? Are there neighbors with similar illness? The neurologic examination is useful to demonstrate that deficits are in a pattern and of a severity consistent with neurotoxic illness. The clinical deficits resulting from a TxPN are symmetrical in distribution and distally predominate. Therefore, multifocal deficits suggest a diagnosis other than neurotoxic disease. Also, because TxPNs typically affect mixed nerve function, detecting purely small fiber sensory dysfunction makes neurotoxic disease unlikely. ORGANOPHOSPHATE

Background Organophosphorus (OP) compounds have numerous uses including insecticides, plastic modifiers, flame retardants, lubricants, petroleum additives, and antioxidants. Despite their widespread use, occupational group exposure is rare. The most common cause of OP intoxication is agricultural spraying. Although 150,000 to 300,000 cases of toxicity are reported annually, estimates are that only 2% of cases are reported to public health officials. Exposure to OP may result from working in the fields after spraying or from applying or preparing the pesticide. OP exposure may also result from intentional ingestion in suicide or homicide attempts.

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Dermal exposure is the most common route of OP intoxication, but absorption also occurs through the gastrointestinal (GI) and respiratory tracts. The mechanism of action of OP compounds is irreversible inhibition of the enzyme acetyl cholinesterase (AChE) by phosphorylation in nervous tissue and erythrocytes. AChE breaks down acetylcholinethat has been released from motor axons. Acetylcholine accumulation leads to excessive stimulation of nicotinic and muscarinic ACh receptors.

Three different clinical syndromes may occur with OP exposure. The primary determinants are the duration and extent of exposure, recent prior exposure, and the particular OP to which the person is exposed. Acute or Type I Syndrome. The type I OP syndrome begins less than 24 hours after exposure and therefore is known as the acute syndrome. The clinical manifestations result from activation of muscarinic cholinergic receptors. Thus, nausea and vomiting, diarrhea, salivation, sweating, micturition, and tachycardia or bradycardia are typical. Decreased alertness, cognitive impairment, fatigue, nervousness, and emotional lability are other potential symptoms of the type I syndrome. Convulsions and coma are seen in the most severe cases. Susceptibilityto the acute syndrome is increased by recent exposure to OP, which may have already diminished the amount of AChE. Because mental status abnormalities are common in the type I syndrome, differential diagnosis includes exposure to other toxins or recreational substance abuse. Intermediate or Type II Syndrome. The type I1 or intermediate OP syndrome appears 12 to 96 hours after exposure, whether or not the acute syndrome occurred. The intermediate syndrome may appear after apparent recovery from the acute syndrome. The symptoms result from overstimulation of nicotinic ACh receptors causing depolarizing neuromuscular blockade with resultant muscle weakness. Respiratory muscle weakness occurs first, followed by proximal muscle weakness, including that of the neck flexors. Although weakness of cranial nerve musculature may occur, including the extraocular muscles, distal extremity strength usually remains normal. Recovery begins 5 to 15 days after cessation of exposure and proceeds from the cranial muscles to the respiratory muscles and finally the proximal muscles and neck flexors. The differential diagnosis of the intermediate syndrome with prominent and often fulminant muscular weakness includes Guillain-Barrk syndrome, periodic paralysis, or a severe attack of myasthenia gravis. Organophosphate-Induced Delayed Polyneuropathy (OPIDP). A delayed central-peripheral axonopathy may develop

with exposure to some OPs. Ironically, the compounds that cause very mild cholinergic symptoms may cause more severe neuropathy. In contrast to most toxic neuropathies whose onsets coincide with toxin exposure, OPIDP usually begins 7 to 21 days after exposure. The OPIDP is independent of the presence of the type I or type I1 syndromes, is not related to AChE inhibition, and occurs more often with chronic, low-level exposure. Although the acute and intermediate syndromes occur more often, more long-term morbidity is associated with OPIDP. Initial manifestations include painful paresthesias in the feet and cramps in the calves. The most prominent manifestation is weakness. Distal lower extremities are affected early with foot drop, later progressing to involvement of the intrinsic hand muscles. Weakness is most severe within 2 weeks after onset. Sensory loss usually can be detected despite minimal

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sensory symptoms. Gait ataxia often is present and often is disproportionate to the degree of sensory loss. The ankle jerks are absent, but the status of the other reflexes depends on the degree of central nervous system (CNS) impairment and may be pathologically brisk. Cranial nerve involvement and autonomic dysfunction are rare.

Differential Diagnosis The differential diagnosis of OPIDP includes other toxins that cause central-peripheral distal axonopathy. There is an extensive differential diagnosis when OPIDP is mild and presents as a simple distal axonopathy.

Diagnostic Testing The laboratory workup usually is unhelpful in cases of OP toxicity. Recent exposure causes reduction of AChE levels in erythrocytes. Because AChE regeneration occurs at the rate of 1% per day, levels may have returned to normal if there is a significant delay between exposure and testing. Weakness usually is seen when AChE levels are reduced to less than 20% of normal. AChE levels are not helpful in patients suspected of having OPIDP, except to document recent exposure, because the degree of exposure does not correlate with severity or even the presence of neuropathy. Cerebrospinal fluid (CSF) protein may be mildly elevated in cases of OPIDP, but there are no inflammatory cells. Electrophysiologictesting after OP exposure may demonstrate spontaneous repetitive motor action potentials (SRMAPs) in response to single motor nerve stimulation. SRMAPs are additional motor responses following the usual compound motor action potential and are a sensitive indicator of OP exposure. However, presence of S W s does not reflect the degree of intoxication, correlate with the degree of weakness, or predict its occurrence. Repetitive nerve stimulation usually demonstrates a decremental response after weakness has started. Rapid stimulation rates may be necessary to demonstrate decrement when weakness is mild. When OP exposure is severe, SRMAPs may be absent, and decrement is evident even with slow rates of stimulation. OPIDP causes abnormalities of nerve conduction studies consistent with a sensorimotor axonal neuropathy. Despite only mild clinical sensory loss, sensory nerve action potentials are reduced in amplitude or absent. Paradoxically, motor nerve conduction studies are normal or reveal minimal slowing of conduction velocity despite prominent motor symptoms. Electromyography (EMG) reveals evidence of active and chronic denervation in distal limb muscles in OPIDP but is normal in the type I and type 11 syndromes.

Therapy Preventing OP toxicity involves educating those at risk, wearing protective clothing, practicing good hygiene, and monitoring exposure levels. Removing contaminated clothing and washing the skin may prevent further absorption in an exposed person. Administering atropine during the acute syndrome has no effect on subsequent development of the intermediate syndrome or OPIDP. Neuropathy may be detected by electrophysiologictesting in the early stages before it becomes irreversible. Treatment of OP intoxication depends on the symptoms that develop. In acute OP poisoning intubation may be needed even if respiratory failure does not occur. Airway protection may be

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necessary because of vomiting or copious secretions in a patient with impaired arousal. Gastric lavage and administration of cathartics are indicated if ingestion is suspected. Atropine is effective in the type I syndrome, but it has a short duration of action and must be given repeatedly. There is evidence of increased risk of ventricular arrhythmias in patients given atropine in the setting of respiratory failure. Therefore, the patient must be adequately ventilated before atropine is administered. Because atropine is specific for muscarinic receptors, it has no effect on depolarizing neuromuscular blockade caused by overstimulation of nicotinic receptors in the type I1 syndrome. Early administration of pralidoxime may help accelerate reactivation of AChE. As long as adequate supportive measures are taken, the prognosis of the acute and intermediate syndromes is good. CNS damage caused by respiratory failure may be permanent. Although severe cases of OPIDP may cause residual foot drop, claw hand deformity, or atrophy, mild cases have a good prognosis. As with all causes of central-peripheral distal axonopathy, the degree of damage to distal dorsal column and corticospinal axons in OPIDP is critical in determining the eventual outcome. CNS damage may become apparent only after recovery from the peripheral neuropathy.

HEXACARBONS Background The hexacarbons n-hexane and methyl n-butyl ketone (MnBK) are clear, colorless, volatile liquids at room temperature. Both are metabolized to the toxic compound 2,s-hexanedione. Hexacarbons gain entry to the body via inhalation, dermal contact, and, rarely, ingestion. These compounds are used as solvents and are components of glues and lacquers. Neuropathy caused by hexacarbon exposure has been reported in several outbreaks including cabinet-finishing plants in the United States and the sandalmaking and shoemaking industries of Japan. Recreational glue sniffing resulting in high-level, acute exposure has become a significant contributor to the problem of hexacarbon neuropathy. Classification

High-level acute exposure causes CNS depression and narcosis that resolves without sequelae. However, glue sniffing involves repeated high-level exposure and leads to peripheral nerve damage and a subacute neuropathy. This neuropathy is predominantly motor and often involves the cranial nerves. The acute neuropathy caused by high-level hexacarbon exposure may be associated with autonomic dysfunction including vasomotor instability, impotence, and hyperhidrosis or anhidrosis. Chronic low-level exposure to hexacarbons causes a lengthdependent central-peripheral distal axonopathy that develops gradually. Like OPIDP, the central-peripheral axonopathy caused by hexacarbons first damages distal peripheral axons, then distal corticospinal, spinocerebellar, and dorsal column axons. Symptoms progress in a length-dependent fashion with involvement of both large- and small-fiber sensory modalities. The ankle reflexes usually are absent, but the other tendon reflexes may be preserved. In severe cases, weakness is the predominant neurologic manifestation and involves distal arm and leg muscles. Advanced cases have abdominal pain, weight loss, malaise, and leg cramps. Hexacarbon neuropathy is well known for the coasting phenomenon.

Differential Diagnosh Acute hexacarbon neuropathy, especially that associated with glue sniffing, may be mistaken for Guillain-Barrk syndrome, given the subacute presentation with prominent weakness and autonomic dysfunction. The central-peripheral distal axonopathy seen with chronic hexacarbon exposure is also seen with neuropathies from organophosphate, acrylamide, and carbon disulfide intoxication. DiagnosticTesting

A very characteristic morphologic feature of the peripheral nerves of those with hexacarbon toxicity involves the formation of giant axonal swellings. Such axonal swellings are also seen with exposure to carbon disulfide and acrylamide and in the genetic neuropathy giant axonal neuropathy. The axonal swellings are caused by accumulation of neurofilaments, primarily in paranodal regions because of disruption of axonal transport and crosslinking. The result is a distal-central dying-back neuropathy. 2,5-Hexanedione, the toxic metabolite, can be measured in the urine, and its presence may indicate excess hexacarbon exposure before the appearance of significant toxicity. An unusual electrophysiologic finding in hexacarbon neuropathy is prominent slowing of distal motor conduction velocities. Screening nerve conduction studies, performed on asymptomatic workers employed in factories where cases of solvent polyneuropathy have been detected, may show slowed conduction velocities. CSF protein may be elevated if the nerve roots are involved, but the spinal fluid is acellular. Therapy

There are no treatments specific for hexacarbon neuropathy, so prevention is the key. Helpful measures include use of protective clothing and gloves to decrease dermal contact, use of ventilators in areas with high concentrations, and measurement of ambient air levels to evaluate the risk of exposure. Removal from exposure will prevent progression, but coasting, as described earlier, is common. Severe neuropathies often result in residual sensory loss, muscle atrophy, and distal weakness. Patients with mild hexacarbon neuropathy typically recover completely. Damage of the distal portions of central pathways can cause long-tract weakness, spasticity, ataxia, or dorsal column dysfunction. This may become apparent only after resolution of the peripheral neuropathy.

CARBON DlSULFlDE Background Carbon disulfide (CS,) is a clear liquid that vaporizes at room temperature and is readily absorbed by inhalation. It is used to produce viscose rayon fibers and cellophane films. It is also a major metabolite in the breakdown of the drug disulfiram (Antabuse), which is used as a deterrent for alcohol abuse. Although CS, absorption typically occurs by dermal contact or inhalation, absorption from the GI tract can occur. Classification

High-level CS, exposure that is acute or subacute leads to CNS dysfunction. This may include confusion, memory impairment, hallucinations, and emotional lability. Chronic low-level exposure causes a combination of neuropathy and neuropsychological abnormalities. Subclinical neuropathy, detected only by electro-

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physiologic testing, may be the only manifestation with low-level intoxication. With increased exposure, a progressive sensorimotor distal polyneuropathy emerges. Sensory impairment occurs first with distal paresthesias and numbness. Weakness is not usually a complaint but may be detected by careful examination. Prolonged exposure may lead to headache, dizziness, memory impairment, and depression. Exposed patients may also display CNS dysfunction such as spasticity or hemiparesis in addition to extrapyramidal signs of bradykinesia, cogwheel rigidity, and tremor. Dlfferentlal Diagnosis

CS, causes a neuropathy that is very similar to that caused by hexacarbons, organophosphates, and acrylamide. Exposure history is the key in differentiatingthe responsible agent. Laboratory tests may also be helpful. Diagnostic Testing

CS, exposure can be documented by measurement of urinary levels of the metabolite 2-triothiazolidine-Parboxylic acid. Abnormalities of motor and sensory nerve conduction studies seen in CS, neuropathy include prolonged latencies and conduction velocity slowing. EMG of distal leg muscles reflects the axonal degeneration and chronic motor unit reinnervation, even though weakness is not a prominent clinical feature. The CSF is acellular with a normal protein level. Carbon disulfide neuropathy is associated with the formation of giant axonal swellings, identical to those seen in acrylamide and hexacarbon neuropathies. These axonal swellings are caused by crosslinking and accumulation of cytoskeletal proteins, including neurofilaments.

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there may be progression to encephalopathy with seizures and truncal ataxia. This may be followed by a peripheral neuropathy. High-level acute exposure often leads to accompanying autonomic dysfunction with excessive sweating, vasomotor changes in fingers and toes, impairment of reflex heart rate, and blood pressure fluctuation. Chronic low-level exposure leads to neuropathy and dermatitis. Because acrylamide exposure is most often by dermal contact, a contact dermatitis typically is present before the clinical symptoms of neuropathy. CNS manifestations are rare in this setting. Chronic exposure is less likely to cause significant autonomic problems, but excessive sweating of the hands and feet is a common manifestation. Acrylamide exposure causes a central-peripheral distal axonopathy. Damage initially occurs in the distal portion of the longest peripheral axons, with subsequent damage to distal corticospinal, spinocerebellar, and dorsal column pathways. Initial findings include diffusely decreased reflexes and numbness in the distal lower extremities. Sensory loss involves large-fiber modalities of vibration and joint position sense rather than small-fiber function of pin and temperature sensation. Despite the dominance of sensory symptoms, physical examination may demonstrate weakness and cerebellar dysfunction. Differential Diagnosis

Other toxins described in this chapter also cause the centralperipheral distal axonopathy seen with acrylamide exposure. However, the symptom of excessive sweating in the hands and feet and accompanying contact dermatitis are unique to acrylamide. The giant axonal swellings seen in acrylamide toxicity are identical in morphology to those seen with hexacarbon or CS, exposure.

Therapy

Because therapeutic intervention is limited, prevention is essential. Respiratory exposure can be minimized by adequate ventilation, use of respirators, and regular air samplings. The compound pyridoxine is reactive with CS,, so it seems logical to treat with this compound to reduce toxicity. However, the available data do not indicate its effectiveness. The extent of recovery from CS, neuropathy is determined by the degree of peripheral nerve and CNS dysfunction present when exposure is terminated. Patients with mild cases usually recover filly, including most of the CNS abnormalities. In those with severe CS, neuropathy, more than one third have symptoms and signs of neuropathy 10 years later.

ACRYLAMIDE Background Acrylamide is a chemical component of agents used for grouting, and polyacrylamide is used as a flocculator in wastewater treatment plants. Acrylamide absorption takes place by inhalation, dermal contact, and rarely by ingestion. The monomer and its metabolite, glycinamide, are neurotoxic, whereas the polymer is innocuous. Classification

Acute acrylamide exposure that is low to moderate in intensity may cause anorexia, headache, malaise, and dizziness. The patient may not recognize his or her own behavioral changes, and the problem often is reported by observers. With high-level exposure

Diagnostic Testing

Acrylamide neuropathy is characterized electrophysiologically by reduced sensory potential amplitudes. Motor and sensory conduction velocities and motor potential amplitudes are normal. Electrophysiologic abnormalities have been documented in asymptomatic patients with acrylamide exposure. Sural nerve biopsy demonstrates reduced numbers of thickly myelinated large axons. Nerve biopsy may be helpful because acrylamide neuropathy is characterized by axonal swelling caused by disruption of axonal transport with resulting accumulation of neurofilaments in the paranodal region. However, these swellings are identical to those seen in carbon disulfide and hexacarbon neuropathies. Therapy

Prevention of acrylamide toxicity involves limiting exposure. This includes wearing protective clothing and gloves to limit dermal exposure, ensuring adequate ventilation, and using respirators in areas with high levels to prevent respiratory exposure. Gastric lavage may help reduce the level of intoxication if performed shortly after acute ingestion. Acrylamide neuropathy usually resolves completely in mild cases if further exposure is prevented. Residual loss of vibratory sensation may be apparent but asymptomatic. Residual spasticity, ataxia, profound sensory dysfunction, and memory problems may persist in more severe cases. These problems are more the result of damage to the distal portions of central sensory tracts than to peripheral nerve

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dysfunction. As with some other toxic neuropathies, worsening of symptoms after termination of exposure can occur (coasting).

VACOR Background Vacor, or N-3-pyridylmethyl-N-p-nitrophenyl urea (PNU), is a chemical used as a rodenticide. It is structurally related to nicotinamide. Exposure to vacor usually occurs by accidental or intentional ingestion. Classification

Vacor causes a severe acute distal axonopathy after even a single exposure. There is also significant autonomic involvement. Within the first hour after high-level ingestion, acute weakness of the limbs and impairment of postural reflexes are seen. The weakness progresses rapidly to become severe generalized weakness including the cranial nerve-innervated muscles. There is also urinary retention. Vacor also damages the p cells of the pancreas leading to acute diabetes mellitus and diabetic ketoacidosis. Studies of vacor-induced neuropathy in animals demonstrate abnormalities of fast axonal transport in distal nerves with degeneration of nerve terminals. The morphology of the neuromuscular junction also is abnormal. Impairment of fast axonal transport may explain the rapid onset of weakness. The few autopsy studies reported have demonstrated wallerian-like degeneration in the peripheral nerves, roots, and dorsal root ganglia.

Exposure to TCE usually is accidental, although cases of intentional inhalation have been reported. Absorption takes place by inhalation, and TCE is very lipid soluble. Classification

High-level acute TCE exposure is the most common scenario. The most prominent manifestation of toxicity is trigeminal nerve dysfunction. Sensory loss involves all three trigeminal divisions, and weakness of mastication may be present. Facial, optic, oculomotor, and glossopharyngeal neuropathies have also been reported. CNS dysfunction with altered mental status and ataxia are additional manifestations of acute exposure to TCE. Although there are reports of relationship to a distal sensorimotor peripheral neuropathy, this is poorly substantiated. Chronic TCE exposure has been linked to cognitive dysfunction and peripheral neuropathy. DiagnosticTesting

TCE toxicity results in abnormalities of trigeminal somatosensory evoked potentials. Patients exposed to TCE may demonstrate abnormal electrophysiology before the onset of symptoms. TCE also has been reported to cause slowing of conduction velocity in facial, trigeminal (blink), and extremity nerves. Cell loss in the cranial nerve nuclei, axonal degeneration, and myelin degeneration has been reported in autopsy studies. Therapy

Differential Diagnosis

The short latency between exposure and onset of symptoms makes the differential diagnosis limited. Rapidly progressive GuillainBarre may be considered because that also causes autonomic failure. However, the acute diabetes caused by vacor is unique. Diagnostic Testing

The electrodiagnostic findings in vacor neuropathy have not been described. Given the loss of sensory and motor axons, the likely finding is of reduced sensory and motor potential amplitudes with abnormal EMG findings consistent with an axonopathy. Therapy

Although the precise biologic mechanism of vacor neuropathy is unclear, it can be prevented experimentally by administering nicotinamide. Residual endocrine and autonomic dysfunction are common in those who survive the acute ingestion. Motor weakness usually improves over several months. TRICHLOROETHYLENL Background

Trichloroethylene (TCE) is a solvent used in the dry cleaning and rubber production industries. It is also used as a degreasing agent, as a cleaner for photographic equipment and lenses, and in the extraction of fats and oils from vegetables. TCE previously was used as an anesthetic agent. The toxicity appears to be caused by dichloroacetylene (DCA), a metabolite, rather than TCE itself.

As with most toxins, removing the person from the exposure

source is the first step. Energetic deep breathing promotes elimination of this volatile compound. Gastric lavage should be performed in cases of ingestion. Mental status changes typically resolve rapidly, but residual facial numbness is common. Longterm follow-up has demonstrated residual facial sensory loss as long as 18 years later. ALLYL CHLORIDE Background

Ally1 chloride is a reactive halogenated hydrocarbon. Industrial chemical manufacturing uses include epoxy resins and glycerin. Absorption of allyl chloride usually is by inhalation. Classification

High-level chronic exposure to allyl chloride results in a distal symmetrical neuropathy. The presenting symptoms include distal numbness and weakness that appear gradually. Examination also reveals reduced ankle reflexes. Abnormal accumulations of neurofilaments have been demonstrated in animal studies. Ally1 chloride toxicity is another cause of central-peripheral distal axonopathy. Dlfferential Diagnosis

Other toxic neuropathies cause a similar pattern of neuropathy and cytoskeletal abnormalities, including carbon disulfide and hexacarbons. Obtaining the proper exposure history is the key.

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Diagnostic Testing

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Abnormalities of nerve conduction studies include prolonged distal latencies, reduced conduction velocity, and reduced sensory and motor potential amplitudes. EMG demonstrates active and chronic denervation in distal muscles.

METHYL BROMIDE Background Methyl bromide is used in insecticides, fire extinguishers, and refrigerants. Absorption occurs by dermal contact or inhalation.

Therapy

Classification

Cessation of exposure usually results in good recovery.

Chronic, high-level exposure to methyl bromide causes multifocal neurologic dysfunction involving both the CNS and the peripheral nervous system. The pyramidal tracts, cerebellum, and mamillary bodies have been affected. High-level acute exposure may be fatal. Methyl bromide causes a distal sensorimotor polyneuropathy with onset after 3 to 7 months of exposure. Initial symptoms include paresthesias in the distal extremities followed by pain and ataxia. The optic nerves may be involved. Loss of color vision may be an early sign of toxic exposure to methyl bromide.

DIMETHYLAMlNOPROPRlONlTRlLE Background Dimethylaminoproprionitrile(DMAPN) was used as a catalyst in polymerization reactions in the production of polyurethane foams until it was discovered to be the causative agent in an outbreak of toxic axonopathy. No additional cases have been reported.

Differential Diagnosis Classification DMAPN causes a very unusual peripheral neuropathy. There are prominent urinary symptoms before the onset of sensory or motor complaints. The severity and onset of symptoms are determined by the degree of exposure. The initial symptoms include urinary hesitancy and abdominal pain. Reduced frequency of urination, decreased urinary stream, and incontinence follow. Eventually sexual dysfunction occurs with partial or complete impotence. Sensory symptoms develop in the feet at about the same time the sexual dysfunction begins. With continued exposure, sensory symptoms progress to the proximal legs and hands, and weakness develops in the distal legs. Sacral sensory loss to all modalities is common in DMAPN neuropathy. Although distal vibratory sensation is impaired, the deep tendon reflexes are surprisingly well preserved. Although the involvement of the small nerve fibers is suggested by the preservation of reflexes, autonomic features, and preferential loss of pain and temperature sensation, morphologic studies have not demonstrated this. Although bladder and sexual abnormalities are the rule, other autonomic functions are preserved. The cranial nerves are not affected.

Differential Diagnosis The differential diagnosis is primarily that of diabetic small fiber neuropathy or amyloid neuropathy.

Mercury is another toxin that has been reported to cause the combination of ataxia and other CNS dysfunction along with peripheral neuropathy.

Diagnostic Testing Electrophysiologic evaluation demonstrates a distal, motorpredominant axonopathy. Sural nerve biopsy reveals loss of large myelinated axons. Lumbar puncture reveals normal CSF.

Therapy The prognosis appears to be good in most cases. Recovery may be slow, taking 6 to 8 months in some cases.

ETHYLENE OXIDE Background Ethylene oxide (EtO) is a gas used to sterilize heat-sensitive medical equipment. EtO is also used in the production of antifreeze (ethylene glycol) and polyester fibers and polyethylene films. The primary route of exposure is via inhalation, although it can be absorbed by dermal contact or directly into the bloodstream if not allowed to evaporate completely from sterilized equipment.

Diagnostic Testing

Classificatlon

Urodynamic studies reveal bladder hypocontractility. Nerve conduction studies and EMG may be normal in mild cases of D W N neuropathy. Sensory potential amplitudes usually are reduced in the lower extremities. Motor conduction velocity may be abnormally slow in severe cases.

Acute exposure to EtO results in nausea, vomiting, headache, dizziness, and anorexia. There is also significant respiratory tract and mucous membrane irritation. EtO toxicity results in a distal sensorimotor axonopathy. The neuropathy may be seen after chronic low-level exposure or with subacute, high-level exposure. Symptoms include distal numbness and weakness, incoordination, and ataxia. Sensory loss is seen initially in the feet but begins to involve the hands with continued exposure. The weakness is also distal in onset. Deep tendon reflexes are diffusely reduced, and ankle jerks usually are absent. Chronic EtO exposure also causes CNS dysfunction. Manifestations include increased tone, dysarthria, and memory problems.

Therapy Removal from exposure is the only form of treatment. Young patients recover completely, but the prognosis is not as good in older patients. Residual bladder and sexual dysfunction are common in older adults.

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Diagnostic Testing

Electrophysiologic testing is consistent with a distal axonopathy. EMG reveals active and chronic denervation changes in distal muscles. Nerve conduction studies demonstrate low-amplitude sensory and motor potentials with normal conduction velocity or only mild slowing. Nerve conduction abnormalities may appear before the onset of symptoms in exposed patients. Sural nerve biopsy shows evidence of axon degeneration. Therapy

Removal from exposure is the only therapy. The prognosis usually is good for a gradual recovery from neuropathy once exposure is terminated. POLYCHLORINATED BIPHENYLS Background

Polychlorinated biphenyls (PCBs) have been used in electrical insulation and plasticizers. Although toxicity of PCBs has received a great deal of publicity, illnesses are more likely to be caused by impurities, not by “clean” PCBs. PCB use was banned in the 1970s, but contaminated products remain, and their disassembly may result in toxicity. PCB contamination of waterways and marine life is the most common source of exposure, but no cases of toxicity have been reported as a result of this type of exposure. Most cases of PCB toxicity reported recently have been in electrical workers removing PCB-contaminated transformers. However, an outbreak of neuropathy caused by PCB-contaminated cooking oil was reported in Taiwan. Because of their high lipid solubility, PCBs may remain in the tissues long after removal from exposure. Classification PCB exposure is associated with a distal, symmetrical sensorimotor peripheral neuropathy. Worsening of symptoms after termination of exposure has been described. It is believed that this is caused by deposition of PCBs in fat. Most patients who present with neuropathy have encephalopathy as well. Differential Diagnosis

The presentation of a subacute neuropathy with mental status changes is also seen with solvent (hexane, carbon disulfide) toxicity. Diagnostic Testing

LEAD Background

Neurologic dysfunction is a long-recognized consequence of lead exposure. Lead exposure was previously common because of widespread use of lead oxide in house paints, ceramic tableware, and toys. Tetraethyl lead was added to gasoline, and lead was used to solder metal food containers and drinking water pipes. Elimination of environmental sources of lead has dramatically decreased the incidence of lead toxicity. Exposure to lead also occurs in the industrial setting. Inorganic lead exposure has been reported in miners, solderers, cable makers, plumbers, automobile factory workers, pottery glazers, glass blowers, and workers in battery manufacturing, smelting, demolition, and automobile radiator repair. Lead exposure has also been reported to result from drinking “moonshine” whiskey, working in indoor gun firing ranges, and burning batteries for heat. Organic lead exposure results primarily from working with leaded gasoline products. Lead gains access to the tissues via ingestion, inhalation, or dermal contact.

Chronic, low-level lead exposure causes a peripheral neuropathy in adults and, rarely, in children. This neuropathy develops insidiously. Motor symptoms are prominent, and sensory signs are minimal or absent. The neuropathy causes weakness and atrophy of distal muscles, often initially involving the arms before the legs. Deep tendon reflexes are absent. Although focal deficits such as wrist and finger drop are common in early reports of lead neuropathy, it remains uncertain whether focal deficits were caused by unappreciated compression neuropathies superimposed on an underlying generalized neuropathy. Despite early concerns, it has not yet been conclusively shown that lead exposure results in amyotrophic lateral sclerosis or other progressive lower motor neuron degenerative syndromes. CNS dysfunction is a prominent component of lead toxicity. Children exposed to lead often present with an acute encephalopathy, developmental delay, loss of milestones, or long-term, mild cognitive impairment. Encephalopathy is occasionally seen in adults with acute high-level exposure and can progress to seizures, coma, or death. Ataxia, tremulousness, and choreiform movements may also indicate CNS involvement. Low-level chronic lead exposure may result in only mild cognitive or behavioral dysfunction. Lead toxicity leads to other organ system dysfunction that is usually present when the neuropathy becomes apparent. Typical effects include GI disturbance such as abdominal pain and constipation, a hypochromic microcytic anemia, and renal dysfunction. Nonspecific symptoms include weight loss and fatigue.

Electrophysiologic testing reveals slowing of conduction velocity in the sensory and motor nerves. PCB serum levels are available, but they do not correlate with the presence of neurologic symptoms and do not reflect the total body burden because PCBs are stored in fat.

The combination of a motor greater than sensory peripheral neuropathy, cognitive dysfunction, anemia, and GI symptoms suggests lead neuropathy but is also seen in porphyria.

Therapy

Dlagnostic Testing

Removal from exposure usually results in improvement. Persistent deficits are noted in most patients even several years later.

Lead levels are available in both urine and blood. Although blood lead levels are elevated after recent exposure, this is not a reflection

Differential Dlagnosis

Chapter 98

of the total body burden. Blood lead levels greater than 40 pg/lOO mL of whole blood are considered abnormal. Chelating agents increase the yield of urine lead measurement by drawing lead from the soft tissues and thereby facilitating its excretion. Twenty-fourhour urinary lead excretion of greater than 1 mg after chelation with calcium ethylenediaminetetraacetic acid (CaEDTA) is abnormal. The ratio of micrograms of lead excreted to milligrams of CaEDTA administered should not exceed 0.6. Peripheral blood smear shows a hypochromic, microcytic anemia. There may be basophilic stippling of erythrocytes. The electrophysiologic findings in lead neuropathy are somewhat controversial. Axonal and demyelinating abnormalities have been reported in nerve conduction studies. Sensory potential amplitudes are reduced, reflecting loss of sensory axons despite minimal or absent sensory symptoms and signs. Exposure to lead levels, previously felt to be safe, may lead to abnormal nerve conduction, and nerve conduction abnormalities may be present before the onset of symptoms. The degree of physiologic abnormalities correlates best with the degree of exposure. EMG reveals evidence of active denervation and chronic motor unit reinnervation, indicative of motor axon degeneration. Neuropsychological testing may reveal abnormalities of visuospatial functioning, memory, and attention.

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weeks of high-level exposure. The initial manifestations are painful paresthesias, burning, tingling, and aching in the toes and feet. Early in the course of the neuropathy, reflexes are reduced or absent. Weakness follows a length-dependent pattern of evolution and in severe cases may involve the respiratory muscles. Dermatologic abnormalities and bone marrow suppression often are present along with neuropathy in cases of high-level exposure. Worsening of the neuropathy may continue for several weeks after removal from exposure (coasting). Low-level, chronic arsenic exposure causes dermatologic abnormalities before symptoms of the neuropathy. Careful neurologic examination or electrodiagnostic testing may reveal abnormalities even in the early stages before symptoms develop. Skin changes include hyperkeratosis, mucous membrane irritation, Mee’s lines (white transverse lines in the nails), and skin hyperpigmentation. Low-level chronic arsenic exposure is also associated with vague generalized symptoms such as anorexia, malaise, generalized weakness, and vomiting. Continued exposure leads to symptomatic neuropathy. Complaints usually involve burning and numbness in the feet and eventually the hands. There may be a mild sensory ataxia caused by impaired joint position sense. Weakness, if present, involves only the distal muscles.

Differential Diagnosis Therapy Prevention of further exposure is the initial step in treating lead toxicity. Lead excretion is facilitated by the chelating agents calcium EDTA, dimercaprol (British anti-Lewisite, BAL), succimer, and penicillamine. Improvement usually begins 2 weeks after initiation of chelation therapy. Although succimer and penicillamine are adequate for milder cases, combination therapy with both EDTA and BAL is necessary for more severe intoxication that includes encephalopathy. Those presenting with encephalopathy and seizures have a significant risk of death. The prognosis of lead neuropathy is good except in the most severe cases. ARSENIC Background The use of arsenic as a poison for suicide or homicide is well known. Typically, an acute, high-level ingestion occurs. However, arsenic toxicity can also be caused by chronic low-grade exposure. Toxicity caused by arsenic exposure has been reported in the occupational setting including smelting of lead and copper ore, mining, and manufacture of integrated circuits or microchips. Other sources of arsenic exposure include tainted illicit drugs, contaminated well water, and burning of preserved wood or arsenic-contaminated fossil fuels. Arsenic is absorbed from the GI tract, via dermal contact, and by inhalation (particulate arsenic and arsine gas).

Classification Acute high-level exposure to arsenic is associated with severe GI distress including vomiting, diarrhea, and abdominal pain. Prominent autonomic dysfunction with hypotension, tachycardia, vasomotor collapse, and possible death are also seen with sudden high-level exposure. High-level exposure may also cause CNS dysfunction. This can either be short-term, such as an organic psychosis, somnolence, or stupor, or more permanent in the form of cognitive and behavioral problems. Neuropathy begins within

The rapid development of distal paresthesias, areflexia, and mild weakness may be mistaken for Guillain-Barrk syndrome. However, the absence of physiologic evidence of demyelination, the associated GI symptoms, and normal spinal fluid protein allow differentiation. The associated dermatologic abnormalities, particularly in the chronic form, may also be seen with thallium exposure. Acrylamide neuropathy also is associated with skin changes, and excessive sweating in the hands and feet usually occurs. Diagnostic Testing

After exposure to arsenic, urinary levels remain elevated for weeks. A level greater than 25 pg in a 24-hour specimen is considered abnormal unless there been recent ingestion of seafood. Chronic or past exposure to arsenic is detected by testing of nails and hair. Blood arsenic levels are not reliable even in acute, high-level exposure because it is cleared from the blood in 2 to 4 hours. Electrophysiologicfindings in arsenic neuropathy are typical of a distal axonopathy. Nerve conduction studies demonstrate reduced sensory and motor potential amplitudes and mild slowing of motor conduction velocities. Needle EMG reveals some abnormal spontaneous activity and reduced motor unit recruitment.

Therapy Urinary arsenic levels can be monitored in asymptomatic patients to allow early detection of excessive exposure. As with all other toxic neuropathies, prevention is the key. Treatment in the intensive care setting is indicated because of the significant mortality rate associated with acute, high-level arsenic toxicity. Aggressive fluid and electrolyte resuscitation may be necessary with the vasomotor collapse. Arsenic elimination is aided by chelation therapy with penicillamine and BAL. Treatment should be initiated as early as possible after exposure and continued for several months. Although chelating agents often are helpful,

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patients with severe cases may be left with significant residual dysfunction. Arsenic poisoning may also cause permanent CNS dysfunction.

THALLIUM Background The epidemiology of thallium toxicity has changed. In the past, high-level acute toxicity was most commonly caused by exposure to pesticides. Because these compounds have been eliminated from rat poisons and insecticides, occupational exposure is now more common. Although occasional reports of thallium poisoning from ingestion (either accidentally by children or intentionally by homicide or suicide) continue to surface, chronic low-level exposure is more common. Consumption of contaminated water or food may also lead to thallium toxicity. Thallium is absorbed through the GI tract, by inhalation, and through dermal contact.

DilagnostDc Testhg Sensitive methods are available that can detect microgram quantities of thallium. Levels can be measured in blood, urine, hair, and nails. The tissue that is most helpful depends on the timing of exposure relative to testing. Blood levels usually are helpful only acutely and do not reflect the total body burden. In cases where the baseline blood and urine thallium levels are normal, a challenge with potassium chloride causes an increase in urinary excretion. Hair and nails are the most sensitive indicators of chronic exposure or exposure that has since ceased. Nerve conduction studies reveal reduced sensory potential amplitudes caused by loss of large sensory fibers. There is usually mild conduction velocity slowing. Evidence of active denervation and chronic motor unit reinnervation is seen with EMG. Serial electrophysiologic testing can be used to monitor the severity of the peripheral neuropathy. The CSF protein is normal in cases of thallium neuropathy.

Therapy The presentation of thallium toxicity depends on the level and duration of exposure. Acute, high-level exposure leads to abdominal pain, diarrhea, and vomiting within hours. CNS manifestations include lethargy or coma. Thallium intoxication may also cause cardiac and respiratory failure. The neurologic or cardiopulmonary dysfunction may progress to death. Although alopecia is felt to be the classic sign of thallium intoxication, it is not specific for thallium and is not helpful in the acute setting. Alopecia is not invariably present and, when seen, appears 15 to 39 days after exposure. Thallium intoxication results in a distal, symmetrical polyneuropathy with symptoms developing in 2 to 5 days. Intense joint pains and burning paresthesias in the distal legs are the first complaints. Large and small sensory fibers are affected, and the neuropathy occasionallycan involve the hands or trunk. Although motor symptoms are unusual, careful examination often reveals mild, distal weakness. Subacute toxicity is seen with lower-level thallium exposure. Dermatologic manifestationsare prominent in this setting, including white striae of the nails (Mee’s lines), alopecia, and hyperkeratosis. The onset of neuropathy is delayed at least a week after exposure in subacute thallium toxicity. Pinprick sensation, light touch, and joint position sense are prominently affected. Gait difficulty early in the course is caused primarily by painful paresthesias in the feet. The tendon reflexes usually are preserved relative to the degree of sensory loss. Some distal weakness may be detected, but this is also mild. Autonomic nervous system dysfunction may lead to tachycardia or hypertension. Other reported neurologic manifestations with subacute thallium toxicity include cranial neuropathies, ataxia, and chorea. Chronic low-level thallium exposure is the least common scenario. This causes a neuropathy that is identical to that described earlier.

Differential Diagnosis Acute thallium neuropathy presenting with distal paresthesias and mild weakness may be confused with Guillain-Barr6 syndrome. However, weakness tends to be mild, and thallium intoxication causes prominent GI symptoms. Arsenic and thallium also cause GI symptoms, alopecia, and other dermatologic manifestations. They also result in painful neuropathy and autonomic dysfunction, making differentiation difficult.

Thallium toxicity can be prevented by avoiding exposure. Helpful measures include good personal hygiene, protective clothing, and enforcement of established workplace exposure levels. Thallium has an elimination half-life of 30 days. However, GI excretion may be enhanced by treatment with laxatives, Prussian blue, and activated charcoal. Administration of potassium chloride and forced diuresis promote renal excretion. Acute thallium intoxication often leads to permanent dysfunction. Residual CNS dysfunction can result from anoxic injury. There is usually a slow recovery from the acute neuropathy, but sensory deficits persist. Subacute thallium neuropathy has a more favorable prognosis for complete recovery. Full recovery from the neuropathy occurs within 6 months in most cases. Hair growth usually begins within 10 weeks of discontinuing exposure.

MERCURY Background Mercury intoxication became well known after large outbreaks. The Minamata Bay incident in Japan, caused by consumption of contaminated fish, is well documented. Another incident involved application of a fungicide containing organic mercury to grain in Iraq. Elemental mercury is a silver-colored liquid at room temperature. It is used in gauges such as barometers and thermometers. Inorganic mercurial salts and elemental mercury are present in dental amalgam, in the manufacture of chlorine, and in the natural gas industry. Organic mercurial compounds are used as industrial catalysts and as preservatives in latex paints. They are also found in disinfectants. Elemental mercury vapor is absorbed by inhalation. Organic mercury usually is absorbed through the GI tract. Mercury salts are absorbed through the skin and GI tract. Although studies have shown that those with mercury amalgam dental fillings inhale some mercury vapors, no clear relationship has been documented between dental fillings and any type of toxicity or disease process.

Although CNS dysfunction is the most prominent manifestation of mercury intoxication, there are some reports of peripheral

Chapter 98

nervous system effects. The form of mercury to which the patient is exposed determines the pattern of CNS dysfunction and the nature of systemic symptoms. Elemental mercury causes CNS toxicity without significant systemic illness because of its high lipid solubility. Micromercurialism is low-level elemental mercury toxicity. Symptoms are very nonspecific and include anorexia, tremor, fatigue, weight loss, and some GI dysfunction. Higher levels of elemental mercury exposure cause a severe tremor that may involve the head, face, and eyelids. Weakness and Babinski signs are also features of elemental mercury toxicity. Other symptoms include insomnia, hyperexcitability, and personality change. Exposure to mercury vapor leads to prominent neuropsychological dysfunction and irritation of the upper respiratory tract. Mercury salts also cause mental and psychiatric impairment. The expression “mad as a hatter” stems from the use of these salts in the felt of hatbands, causing behavioral and cognitive dysfunction. Mercury salts also cause renal failure and GI dysfunction. Organic mercurial toxicity is associated with sensory ataxia. This is caused by damage of sensory neurons in the dorsal root ganglion. Although the onset may be heralded by distal paresthesias, this is not caused by peripheral nerve damage. The paresthesias later progress to involve more proximal areas including the tongue. Organic mercurial compounds have varying effects depending on their structure. Complex organic mercury compounds are more likely to cause nephrotoxicity. Short-chain compounds such as methyl mercury cause tremor, hearing loss, constriction of visual fields, mental impairment, and dysarthria with prolonged exposure. A sensorimotor neuropathy has been described with exposure to all forms of mercury. The evidence for neuropathy caused by elemental mercury or mercuric salts is more substantial than that caused by organic mercurial exposure. Differential Diagnosis

Exposure to mercury vapor results in upper respiratory tract irritation and an acute neuropathy. The respiratory irritation may be mistaken for a viral infection and the ensuing acute neuropathy mistaken for Guillain-Barri syndrome. Diagnostic Testing

Laboratory studies that may be useful for investigating mercury intoxication include levels in the blood, urine, and tissues. Mercury blood levels are elevated in acute exposure. Long-term toxicity is assessed by mercury levels in hair samples or serial urine measurements after penicillamine administration. Neurophysiologic testing reveals an axonal neuropathy with predominant motor involvement. Peripheral neuropathy can be detected in those exposed to mercury while they are still asymptomatic.

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Therapy

Prevention of mercury toxicity involves educating those at risk. Other measures inciude monitoring airborne levels and using protective devices. Mercury intoxication is treated primarily by removal from exposure. Chelating agents such as BAL and penicillamine increase urinary excretion of mercury. However, it is unclear whether this speeds the recovery process. The prognosis for a complete recovery is good in most cases of mercury intoxication. However, there may be residual neurologic dysfunction as long as 30 years later.

SELECTED READINGS Abou-Donia MB, Ibrahim SM, Corcoran JJ et ak Neurotoxicity of glycidamide, an acrylamide metabolite. J Toxicol Environ Health 39447-464, 1993 Albers JW, Kallenbach LR, Fine LJ et al: Neurological abnormalities associated with remote occupational elemental mercury exposure. Ann Neurol 24651459, 1988 Chu CC, Huang CC, Chen RS, Shih TS: Polyneuropathy induced by carbon disulfide in viscose rayon workers. Occup Environ Med 52:404-407, 1995 DeBleecker J: The intermediate syndrome in organophosphatepoisoning: an overview of experimental and clinical observations. Clin Toxicol 33:683486, 1995 Feldman RG: Occupational and Environmental Toxicology. LippincottRaven, Philadelphia, 1999 Gross JA, Haas ML, Swift T F Ethylene oxide neurotoxicity: report of four cases and review of literature. Neurology 29:97&983, 1979 Herskowitz A, Ishii N, Schaumburg H: n-Hexane neuropathy: a syndrome occurring as a result of industrial exposure. N Engl J Med 285:82-85, 1971 Heyman A, Pfeiffer JB,Taylor H M Peripheral neuropathy caused by arsenical intoxication: a study of 41 cases with observation on the effects of BAL (2,3-dimercapto-propanol).N Engl J Med 254401-409, 1956 Letz R, Gerr F, Cragle D et al: Residual neurologic deficits 30 years after occupational exposure to elemental mercury. Neurotoxicology 21(4): 459474,2000 Nordentoft T, Anderson EB, Morgensen PH: Initial sensorimotor and delayed autonomic neuropathy in acute thallium poisoning. Neurotoxicology 19:421-426, 1998 Schaumburg HH, Spencer PS: Clinical and experimental studies of distal axonopathy: a frequent form of nerve and brain damage produced by environmental chemical hazards. Ann NY Acad Sci 329:14, 1979 Schaumburg HH, Spencer PS: Recognizing neurotoxic disease. Neurology 37:276-278, 1987 Seppalainen AM, Tola S, Herberg S, Kock B Subclinical neuropathy at “safe” levels of lead exposure. Arch Environ Health 30180-183, 1975 Wadia RS, Sadagtopan C, Amin RB, Sardesai HV Neurological manifestations of organophosphorus insecticide poisoning. J Neurol Neurosurg Psychiatry 328414347, 1974

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Spinal Cord and Peripheral Neuromuscular Disease rn Diseases of Peripheral Nerve

Drug-Induced Peripheral Neuropathies Janice E Wiesman and Robert G. Feldman

Peripheral neuropathy is a side effect of many medications, both prescription and over the counter (Table 99-1). When a patient presents with symptoms consistent with peripheral neuropathy, a detailed medication history is needed. Drug-induced neuropathy is more common in patients who are predisposed to neuropathy secondary to concomitant conditions such as diabetes mellitus, alcohol use, metabolic abnormalities (e.g., renal insufficiency), nutritional deficiencies, and chemical exposures. Typically, these neuropathies are axonal in nature and are dose dependent. Often, resolution is seen upon discontinuation of therapy. The mechanisms of drug-induced neuropathy include interference with microtubule formation and axonal flow, nutritional deficits, lipidosis, and impaired Schwann cell function (Table 99-2). This chapter provides a description of commonly encountered medications that are associated with peripheral neuropathy.

Peripheral neuropathy has been reported in up to 10% of patients undergoing long-term treatment. Central nervous system manifestations have also been reported. A reversible syndrome including ataxia, tremor, and occasional peripheral neuropathy was noted in 54% of patients in one study. Both peripheral and central nervous system symptoms typically resolve with discontinuation of the drug. Amiodarone’s toxic effect on nerves may be secondary to a drug-induced lipidosis. Amiodarone is an amphophilic drug that can bind to lipids and penetrate lysosomes in a manner similar to perhexiline and chloroquine. In contrast to the latter two, which produce a demyelinating neuropathy, the pathologic picture in amiodarone neuropathy is heterogeneous. Surd nerve biopsy has yielded a variable picture of the pathologic changes seen with amiodarone neuropathy. Primarily axonal, mixed axonal and

ALLOPURINOL Allopurinol is a xanthine oxidase inhibitor that reduces the production of uric acid. It is used to treat gout. Reports of neuropathy after long-term use are rare, and some authors question an association. Electrophysiologic evidence of both axonal and demyelinative components has been noted. Improvement occurs after withdrawal of the drug.

ALMlTRlNE Almitrine bismesylate is a selective pulmonary vasoconstrictor used to treat chronic obstructive pulmonary disease. A painful sensory neuropathy with numbness and paresthesia may develop months to years after the onset of treatment. It is often associated with weight loss, which itself may be a side effect of the drug. Recovery is typical after discontinuation but may be very slow. This has been attributed to the long half-life of the drug. Sural nerve biopsy shows axonal loss predominantly affecting large-diameter fibers; unmyelinated fibers are affected to a lesser degree. The cause of the neuropathy is thought to be toxic. High plasma concentrations have been reported in patients with neuropathy. The drug is metabolized by an oxidative reaction. In a group of patients with almitrine-induced polyneuropathy, all were found to be of the rapid metabolizer type. This is in contrast to patients with perhexiline-induced neuropathy, who are typically slow oxidizers. Hypoxia itself can cause a mild peripheral neuropathy, but almitrine neuropathy has been noted in patients without evidence of chronic hypoxia.

AMIODARONE Amiodarone is a class I11 antiarrhythmic agent that is associated with optic neuropathy (Table 99-3) and, less commonly, a sensorimotor or a predominantly motor peripheral neuropathy. Optic neuropathy is manifested by the insidious onset of slowly progressive bilateral, painless visual loss. This is in contrast to ischemic optic neuropathy, which tends to be acute, unilateral, and painful. Symptoms may be unilateral or bilateral and may include blurred vision, visual field abnormalities, and edema of the optic disk.

W TABLE 99-1.

Drug-Induced Neuropathies

Sensorv

Sensow-Motor

Motor

Alrnitrine Cytarabine Chloramphenicol Cisplatin Metronidazole Misonidazole Paclitaxel Pyridoxine Reverse transcriptase inhibitors Thalidornide

Arniodarone Aurothioglucose Colchicine Disulfiram Etharnbutol HMC-CoA reductase inhibitors Hydralazine lsoniazid Nitrofurantoin Perhexiline Phenytoin Surarnin Vinca alkaloids Zimeldine

Dapsone

W TABLE 99-2.

Pathology of Drug Induced Neuropathy

Axonal

Demyelinative

Mixed

Aurothioglucose Cisplatin Colchicine Cytarabine Dapsone Disulfirarn Etharnbutol HMC-CoA reductase inhibitors lsoniarid Metronidazole Nitrofurantoin Paclitaxel Perhexiline Reverse transcriptase inhibitors Vinca alkaloids

Zimeldine

Allopurinol Arniodarone Chloroquine Phenytoin Suramin

W TMLE 99-3.

Drugs Associated with Optic Neuropathy Arniodarone Chlorarnphenicol Disulfirarn Etharnbutol

Chapter 99

demyelinative and primarily demyelinativeneuropathies have been described. Lamellated lysosomal inclusion bodies are seen in Schwann cells, capillary endothelial cells, and muscle fibers. Similar lysosomal inclusions are also seen in perhexiline neuropathy, a demyelinative neuropathy. As predicted from the pathology, electromyography and nerve conduction studies have reported patients with axonal loss, patients with primarily demyelinative changes, and patients with a mixed neurophysiologic picture.

AUROTHIOCLUCOSE AND SODIUM AUROTHIOMALATE (GOLD) Aurothioglucose and sodium aurothiomalate are gold-containing compounds used to treat rheumatoid arthritis for more than 70 years. The mechanism of action is unknown. Dermatologic reactions are the most common side effect and are seen in approximately 15% of patients. Sensorimotor neuropathy is uncommon, with the incidence estimated at 0.5%. Symptoms may begin a few months after the start of treatment. Clinical manifestations include the typical paresthesias, numbness, and distal weakness but also include the unusual finding of myokymia. Neuropathy may present as an isolated symptom or in the company of immune-mediated signs such as rash and fever. Cerebrospinal fluid protein may be elevated. In an animal model, occurrence of neuropathy was found to be dose related. Recovery with cessation of therapy is the rule. Cranial neuropathies and encephalopathy have also been noted. Dimercaprol has been used to treat some complications of gold therapy but has not been useful in treating neuropathy. Sural nerve biopsy demonstrates either predominantly axonal degeneration involving all fiber types or predominantly segmental demyelination. It is not clear whether the demyelination is primary or secondary to axonal degeneration. Two mechanisms of action have been proposed: an autoimmune response or a direct toxic effect on the axon or cell body.

CHLORAMPHENICOL Chloramphenicolis an antibiotic used to treat a broad spectrum of bacterial infections including Salmonella typhi and ampicillinresistant Huernophilus influenzue. The risk of agranulocytosis and the availability of newer antibiotics have limited its use. Prolonged use of chloramphenicol has been associated with both optic neuropathy and a sensory neuropathy, with optic neuropathy being more common. Clinical manifestations of optic neuropathy may include loss of visual acuity, central scotoma, constriction of visual fields, and red-green dyschromatopsia. Funduscopic examination reveals peripapillary edema and hemorrhages around the optic nerve head. Neuropathy typically is seen after months of high-dose treatment. Chloramphenicol used in short courses is safer and less likely to induce neuropathy. Recovery typically is complete when the medication is discontinued, but residual deficits may be seen in some patients. Chloramphenicol inhibits mitochondrial protein synthesis. This toxic effect is attenuated by antioxidants, suggesting that the process is mediated, in part, by reactive oxygen species that may induce cell death. Interference with B vitamin-mediated processes has also been proposed as a possible mechanism of neurotoxicity. Impaired excretion of chloramphenicol caused by renal insufficiency may increase the risk for neurotoxic effects.

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CHLOROQUINE Chloroquine is used for both prophylaxis and treatment of malaria and in a variety of connective tissue and dermatologic diseases. It is an amphophilic substance, similar to amiodarone and perhexiline. Chloroquine is associated with the development of peripheral neuropathy. Clinical manifestations include loss of deep tendon reflexes; pain, paresthesias, and numbness typically are not present. Electrophysiologic abnormalities such as reduced motor unit number with increased motor unit size have been reported and attributed to axonal loss. Paradoxically, a report of sural nerve pathology described segmental demyelination and remyelination with lamellated, cytoplasmic inclusions in Schwann cells and perineurial and endoneurial cells. Axons were not affected. Generalized myopathy and cardiomyopathy are more familiar side effects of chloroquine. Myopathy presents with painless proximal muscle weakness. Electromyographic abnormalities are similar to those seen in polymyositis with small, easily recruited motor units and fibrillation potentials. Muscle pathology is significant for vacuolar degeneration of muscle fibers. The mechanism of neurotoxicity has not been fully elucidated, but inhibition of lysosomal enzyme activity probably is involved. The clinical manifestations resolve after the drug is discontinued.

CISPLATIN (PLATINUM) Cisplatin is a heavy metal complex containing platinum that is used to treat various solid tumors. It functions in a manner similar to alkylating agents, producing crosslinks in DNA. A predominantly large fiber, axonal, sensory neuropathy is common and may be severe with routine dosages. Neuropathy has been noted with standard dosing regimens and intra-arterial treatment. For systemic administration, an average total dosage of 500 mg/m’ has been reported as the threshold for development of neuropathy. Ototoxicity and neuropathy are dose-limiting side effects. Occasionally, neuropathy manifests after treatment is completed. Decreased vibration and joint position sense with lesser degrees of pain and temperature loss account for the typical clinical picture of difficulty with balance and sensory ataxia. Weakness occurs in severely affected patients. Even in patients with no symptoms, vibration threshold is elevated, and proprioception is diminished. Symptoms may improve after the drug is discontinued, but persistent abnormalities consistent with neuropathy are the rule. Electrophysiologic testing reveals decreased sensory amplitudes and mildly decreased conduction velocities consistent with axonal loss. Results of motor nerve conduction studies and electromyography may be normal. On nerve biopsy, degeneration of unmyelinated and myelinated fibers is seen along with secondary demyelination. Large fibers are preferentially affected. Damage to the posterior columns was seen at autopsy in a patient with severe neuropathy.

COLCHICINE Colchicine is an alkaloid agent obtained from the root of members of the genus Colchicum, a plant in the lily family. It is used to treat gout and primary biliary cirrhosis. Colchicinebinds to tubulin and blocks axonal transport in a way similar to that of the vinca alkaloids (Table 99-4).

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TABLE 99-4. Drugs That Interfere with Axonal Transport Colchicine Doxorubicin Paclitaxel Vinca alkaloids

Vacuolar myopathy is more common than the mild, axonal sensorimotor neuropathy that is seen occasionally. Symptoms typically start in the hands with numbness and paresthesias and are later noted in the feet. This pattern of symptom onset is typical of that seen with agents that interfere with axonal transport. Distal muscle atrophy and weakness follow. Creatinine phosphokinase usually is elevated; this may be on the basis of myopathy or motor axon loss. Onset of myoneuropathic symptoms is usually subacute, but acute onset has been reported in cardiac transplant recipients treated with colchicine for cyclosporin-induced gout. Decreased clearance in the presence of renal insufficiency may be associated with the development of neurotoxicity. Resolution of clinical and electromyographic abnormalities is seen with discontinuation of the drug. Nerve conduction studies show a mildly decreased velocity in both sensory and motor nerves. Electromyography reveals features of myopathy as well as fibrillation potentials and positive waves, pointing to motor axon loss. Muscle biopsy does not show inflammation; rather, sarcoplasmic vacuolar degeneration is seen. This vacuolation is similar to that seen with vinca alkaloids. Fiber type grouping, secondary to axonal loss, is also seen. Sural nerve biopsy is consistent with an axonal neuropathy affecting large myelinated fibers most severely.

WTARABINE (AM-C) Cytosine arabinoside is used to treat hematologic malignancies. The mechanism of action is thought to be related to inhibition of DNA polymerase. Its most common toxicities are myelosuppression and gastrointestinal distress. Occasionally, an axonal, sensory neuropathy is precipitated by use of intravenous cytarabine. The neuropathy may be mild or severe and may be accompanied by pain in the lower extremities and “moving toes,” probably a manifestation of the sensory neuropathy. Recovery is incomplete after discontinuation of the drug. Other neurologic complications include myelopathy when administered intrathecally, a necrotizing leukoencephalopathy when combined with brain irradiation and seizures, or an acute cerebellar syndrome when given intravenously. There is a single case report of a man who developed a brachial plexopathy on two occasions within hours of being given intravenous, high-dose cytarabine.

DAPSONE Dapsone is a sulfone antibacterial agent used to treat leprosy, Crohn’s disease, and certain dermatologic conditions (i.e., dermatitis herpetiformis, pyoderma gangrenosum, and cystic acne). Hemolytic anemia and neuropathy have been reported in patients as adverse effects of dapsone treatment. A predominantly motor neuropathy, though uncommon, is the major neurologic complication of therapy. Symptoms may develop from months to years after treatment begins, but the usual time of onset is within 5 years. Distal muscle atrophy and weakness in the upper and lower extremities are noted. Paresthesias without

objective sensory loss may be present. Deep tendon reflexes usually are preserved but may be hypoactive. This constellation of symptoms and signs is seen in patients without leprosy and so distinguishes a medication effect from the peripheral neuropathy that may be associated with leprosy. Recovery occurs when the therapy is discontinued, which also points to a drug effect. Electrophysiologic and biopsy studies demonstrate axonal loss. Motor nerve conduction studies show a reduced or absent compound muscle action potential with a normal or slightly reduced conduction velocity. Sensory studies are normal. Electromyography shows a loss of motor units with fibrillation potentials and positive waves. Motor nerve biopsy shows axonal loss. Dapsone, like isoniazid, is metabolized by acetylation. N-Acetyltransferase polymorphisms may be of clinical consequence, increasing the susceptibility of slow acetylators to peripheral neuropathy and other toxic effects induced by dapsone.

DlSULFlRAM Disulfiram is a dithiocarbamate compound that is used as an aversive method to discourage alcohol consumption. It blocks alcohol metabolism, resulting in acetaldehyde accumulation, which produces a number of unpleasant symptoms including headache, gastrointestinal distress, and diaphoresis. A sensorimotor neuropathy has been reported to occur weeks to months after initiation of therapy. Paresthesias, decreased sensation to all modalities, and weakness are noted initially in the feet and later the hands. Distal deep tendon reflexes are absent or diminished. The subacute onset of symptoms in patients who are well nourished and their resolution on withdrawal of the drug point to a medication effect as opposed to a sequela of chronic alcohol use. The development of neuropathy appears to be dose dependent; neuropathy is rare with dosages of less than 250 mg/day. Recovery after discontinuation of therapy is the rule; however, a case of severe, fulminant, irreversible neuropathy has been reported in a woman who ingested ethanol with a large dose of disulfiram. Optic neuropathy and encephalopathy that may or may not be accompanied by neuropathy have been described. Surd nerve action potentials are absent or low in amplitude, whereas motor conduction studies show mildly to moderately reduced conduction velocity with reduced compound muscle action potential amplitude. Electromyography reveals abnormal spontaneous activity. Electrophysiologic parameters return to normal after treatment is stopped. Nerve biopsy is consistent with axonal pathology, with evidence of regeneration of fibers in a biopsy taken during the recovery phase. Disulfiram is metabolized to carbon disulfide, which is a known neurotoxin. Disulfiram affects Schwann cells and disrupts axonal transport. Electron microscopy discloses axons distended by accumulation of neurofilaments, similar to the changes seen in experimental carbon disulfide exposure.

DOXORUBICIN Doxorubicin is an anthracycline antibiotic used as a chemotherapeutic agent. Its mechanism of action is interference with protein synthesis by intercalation into nuclear DNA. It passes easily into the dorsal root ganglia and interferes with protein synthesis by sensory neurons. This disrupts both fast and slow anterograde axonal transport. Interference with transport and neuronal loss in both motor and sensory systems has been produced in experimen-

Chapter 99 H Drug-Induced Peripheral Neuropathies

tal animals. There have been no reports of clinical neuropathy in humans using doxorubicin, possibly because of dose-limiting toxicities on the heart, kidney, and hematopoietic system.

ETHAMBUTOL Ethambutol hydrochloride is an antimycobacterial agent used to treat tuberculosis. Optic neuropathy, probably on the basis of a derangement of mitochondrial metabolism, is the most common neurologic side effect. Symptoms include reduced visual acuity, central scotoma, dilated retinal veins, and fundal hemorrhage. It occurs at standard dosages and is typically reversible with discontinuation of treatment, but permanent visual loss has been described, particularly in patients older than 60 years. There may also be a higher risk in patients with renal insufficiency. Fibers subserving macular vision are preferentially affected. Concurrent treatment with isoniazid increases the risk of optic neuropathy, suggesting that disruption of B vitamin-mediated processes may also be involved. A sensorimotor peripheral neuropathy, involving both small and large fibers, is much less common. This usually improves with discontinuation of the drug. Motor nerve biopsy studies in an experimental rat model demonstrated axonal loss and regeneration. Pathology was noted in both proximal and distal nerve segments.

ANTI-HIV MEDICATIONS Nucleoside analogue reverse transcriptase inhibitors including didanosine (ddI), lamivudine (3TC), stavudine (d4T), zalcitabine (ddC), and zidovudine (ZDV, formerly AZT) are used to treat human immunodeficiency virus (HIV) infection. All but ZDV have been implicated as the cause of a predominantly sensory, axonal, painful peripheral neuropathy. Neuropathy is more common with ddI and ddC than with 3TC and d4T. Neuropathy often is the dose-limiting side effect. Because peripheral neuropathy is a complication of HIV infection, it is often difficult, but important, to determine whether neuropathy is caused by medication or is a result of HIV infection. Incidence, severity, and progression of peripheral neuropathy upon exposure to these medications is a function of the following factors: stage of immunosuppression (CD4 count), dosage of medication, duration of treatment, and preexisting risk factors for neuropathy. Patients with low CD4 cell counts are at greater risk to develop neuropathy with these medications. Zidovudine is known to cause a mitochondrial myopathy, and this may complicate the diagnosis of neuropathy. Symptoms include painful distal paresthesias and numbness starting in the lower extremities and spreading proximally, eventually including the upper extremities. On examination, abnormalities of temperature, light touch, vibratory sensation, and joint position sense are found. Ankle reflexes are absent. Discontinuation of the medications or a decrease in dosage typically leads to partial resolution of symptoms, whereas a neuropathy associated with the infection will continue to progress. When ddI or ddC are withdrawn, patients may experience a worsening of symptoms lasting a few weeks before symptoms begin to resolve. This has been called coasting. The agents differ in their propensity to cause neuropathy. With ddC monotherapy, 25% to 65% percent of patients develop neuropathy. With ddI monotherapy, the number is 12% to 34%; with d4T,

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30% to 50%. Combining the drugs increases the incidence of neuropathy. Electrophysiologic testing demonstrates a sensory greater than motor, axonal neuropathy. In cell culture, neural cells exposed to ddI, ddC, and d4T demonstrated a dose-dependent inhibition of neurite regeneration. This was not seen with exposure to 3TC or ZDV. One mechanism of nerve damage is thought to be inhibition of mitochondrial DNA synthesis, but the existence of other mechanisms has also been proposed. In a rodent model, exposure to dd1 resulted in myelin splitting and intramyelin edema in sciatic nerve. There have been no reports of peripheral neuropathy caused by the use of protease inhibitors to treat HIV infection.

HMG-COA REDUCTASE INHIBITORS HMG-CoA reductase inhibitors are used to treat hypercholesterolemia and hyperlipidemia. This class of medication is typically associated with myopathy but there is a growing literature describing an association with neuropathy. This may occur in up to 10% of patients who are treated for more than 2 years. Symptoms improve with cessation of the drug and recur with re-exposure. Electrophysiological testing is consistent with an axonal, sensorimotor neuropathy. Surd nerve biopsy in one patient revealed axonal degeneration. The mechanism of damage is not known but may be related to a disturbance of axonal membrane function due to decreased cholesterol synthesis. Alternatively, these drugs may interfere with neuronal energy utilization through a known inhibition of ubiquinone, an enzyme in the mitochondrial respiratory chain.

HYDRAWINE Hydralazine is an antihypertensive agent that relaxes arteriolar smooth muscle. It is also used to treat congestive heart failure and preeclampsia. Rarely, it has been associated with a sensorimotor neuropathy. Manifestations include distal paresthesias and numbness along with mild distal weakness in some cases. As with isoniazid and phenelzine, the mechanism probably is related to vitamin B, depletion (Table 99-5). Hydralazine has been shown to inactivate pyridoxine and enhance its excretion. Administering pyridoxine during treatment may prevent neuropathy. The occurrence of neuropathy may be more likely in patients who are slow acetylators (Table 99-6). Complete recovery usually occurs after withdrawal of hydralazine.

TABLE 99-5. Drugs That Cause Vitamin B, Depletion Hydralazine lsoniazid PheneIzine

TABLE 99-6. Drugs with Greater Risk of Causing Neuropathy in Slow Acetylators Dapsone Hydralazine lsoniazid Perhexiline

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ISONIAZID Isoniazid is the hydrazide of isonicotinic acid. It is used to treat tuberculosis and HIV infection. Its therapeutic value results from its ability to block the synthesis of mycolic acids, which are components of the mycobacterial cell wall. A sensorimotor neuropathy may be seen soon after isoniazid therapy is initiated. Distal paresthesias and numbness are noted initially, followed by painful paresthesias and weakness if the drug is continued. The neuropathy resolves quickly if the medication is stopped at the first sign of symptoms. If the medication is continued and pain and weakness develop, recovery, though usually complete, occurs more slowly. Acute isoniazid overdose results in encephalopathy, seizures, and a subsequent peripheral neuropathy. Sural nerve biopsy demonstrates axonal degeneration of both myelinated and unmyelinated fibers. Motor nerve conduction studies show a prolongation of distal latency, reduced evoked response amplitude, and mildly decreased conduction velocity. Axonal degeneration occurs secondarily to a pyridoxinedeficient state created by the medication. Isoniazid inhibits the activity of pyridoxal phosphokinase. This results in decreased levels of pyridoxal phosphate, which normally serves as a coenzyme in decarboxylation and transamination of amino acids and metabolism of fatty acids. Isoniazid also combines with pyridoxine, resulting in increased excretion of the vitamin. Concurrent pyridoxine administration may prevent neuropathy. Isoniazid is metabolized by acetylation, and patients who are slow acetylators accumulate the drug and are at greater risk of neuropathy. Acetaldehyde, a metabolite of ethanol, has been shown to deplete vitamin B,; therefore, concurrent use of ethanol increases susceptibility to the neurotoxic effects of isoniazid. METRONIDAZOLE Metronidazole is used to treat anaerobic bacterial and protozoal infections as well as Crohn’s disease. It is a nitroimidazole compound, as is misonidazole. Common side effects include headache, gastrointestinal distress, and dry mouth. Neuropathy is unusual, usually occurring after prolonged exposure, and when it occurs it is sensory in nature. Both large- and small-fiber modalities are affected. Distal paresthesias and numbness begin in the feet and are later noted in the fingers. Distal tendon reflexes may be reduced or absent. Distal atrophy and weakness are not common. Symptoms improve upon discontinuation of the drug. In Crohn’s disease, neuropathy caused by metronidazole must be distinguished from the axonal neuropathy associated with the disease itself and from symptoms associated with vitamin B,, deficiency. Sensory nerve conduction studies show absent responses in the lower extremities and small-amplitude responses in the upper extremities. Motor nerve conduction studies typically are normal. Surd nerve biopsy studies support the electrophysiologic findings and reveal a primary axonopathy with loss of both myelinated and unmyelinated fibers. The mechanism of damage is not known. MISONIDAZOLE Misonidazole is a nitroimidazole compound that is used as a hypoxic cell radiosensitizer in treating malignant neoplasms. A painful sensory neuropathy often is the dose-limiting side effect. Electrophysiologic and histologic studies in humans are consistent with an axonal neuropathy with differential loss of large

fibers and secondary demyelination. In a small study looking at the protective effect of dexamethasone on the development of neuropathy, patients concurrently given dexamethasone had a lower incidence of neuropathy than those who received misonidazole alone. In neuron cell culture, misonidazole exposure resulted in changes in neurofilament proteins and loss of neurite projections. Electron microscopic study of biopsied nerve has shown axonal swelling with increase in neurofilaments. NITROFURANTOIN Nitrofurantoin is a wide-spectrum antibiotic used specifically for urinary tract infections. Sensorimotor neuropathy is uncommon. When it occurs, onset may be rapid, and the neuropathy may become severe and irreversible if the drug is not discontinued immediately. Patients typically complain of distal paresthesias and weakness beginning in the lower extremities and, if the medication is continued, progressing to the upper extremities. Examination may reveal diminished vibration sensation and reduced or absent deep tendon reflexes. Muscle atrophy may be seen in severe cases. Occasionally, a predominantly motor neuropathy occurs. Prognosis depends on the severity of the neuropathy. Of 92 patients on whom the results of follow-up examination were reported, 34 showed full clinical recovery, 45 showed improvement with residual sequelae, and 13 showed no improvement. Renal excretion is the primary route of elimination, so renal insufficiency may predispose to the development of neuropathy. In some patients it may be difficult to distinguish between the two causes. Because subacute neuropathy may exist in patients with uremia, use of nitrofurantoin should be avoided in the presence of renal failure. Older women using nitrofurantoin appear to be more susceptible than other groups to developing neuropathy. Despite these findings, a clear dose-response relationship has not been established. Electrophysiologic studies of patients with nitrofurantoininduced neuropathy revealed evidence of axonal loss and demyelination, including sensory nerve action potentials that are absent or reduced in amplitude, slowed motor nerve conduction velocities, and prolonged distal motor latencies. Electromyography may reveal fibrillation potentials and positive waves indicative of denervation of distal and proximal muscles as well as a decreased number of motor units in distal muscles. Mild abnormalities consistent with axonal loss have been demonstrated on electrophysiologic testing in asymptomatic patients using nitrofurantoin. Severe axonal degeneration has been reported with light and electron microscopic investigation. Autopsy examination of a severely affected patient showed degeneration of spinal roots and abnormalities of anterior horn and dorsal root ganglion cells. Nitrofurantoin may be directly toxic to neurons. It has been suggested that nitrofurantoin interferes with cellular energy metabolism. Although the mechanism of damage is not known, inhibition of acetyl-coenzyme A and disruption of pyruvate metabolism has been proposed. Toxic metabolites, such as semicarbazide, which has been shown to cause neuropathy in rats, have been proposed. PACLITAXEL Paclitaxel is a chemotherapeutic drug in the taxane family used to treat cancers of the breast and lung. It acts by binding to tubulin and interfering with mitosis.

Chapter 99 W

Paclitaxel causes a dose-dependent, predominantly sensory neuropathy that is not associated with axon length. Paresthesias typically begin in the hands and feet together. Loss of tendon reflexes, elevated vibratory threshold, and sensory ataxia follow. If treatment continues, small-fiber sensory modalities and motor function are impaired. Patients with diabetes, heavy alcohol use, and exposure to other chemotherapeutic agents that cause neuropathy are particularly susceptible to developing neuropathy with the use of paclitaxel. In some studies, 90% of patients receiving standard dosages noted symptoms. Symptoms can occur after a single standard dose. Sensory nerve conduction velocity and evoked response amplitudes are decreased. Motor nerve parameters may be normal. Histopathologically,axonal degeneration and secondary demyelination characterize the neuropathy. Large fibers are affected preferentially. In a rat model, degeneration of dorsal root ganglion cells was noted. The effect was thought to be that of a neuronopathy as opposed to a length-dependent axonal neuropathy. Paclitaxel binds to tubulin and interferes with microtubule dynamics by stabilizing tubules and preventing their depolymerization, thereby leading to mitotic arrest in dividing cells. Axonal degeneration in peripheral nerves is secondary to decreased axonal transport. This is similar to what is seen with colchicine and the vinca alkaloids. Studies of concurrent administration of glutamine or insulin-like growth factor for the prevention of neuropathy in patients treated with paclitaxel are under way.

PERHEXILINE Perhexiline maleate is an antianginal compound that, like amiodarone and chloroquine, is amphophilic and capable of penetration into lysosomes. The use of perhexiline for angina has been associated with the development of a sensorimotor neuropathy that typically occurs after a year of treatment in patients receiving a low dosage (200 mg/day) and earlier in those receiving a high dosage (400 mg/day). The neuropathy presents as distal pain and paresthesias progressing to weakness that affects both distal and proximal muscles. Autonomic symptoms and perioral dysesthesias have also been described. Patients with peripheral neuropathy also often have weight loss and liver dysfunction. Cerebrospinal fluid protein may be markedly elevated and associated with papilledema. Electrophysiologic testing reveals a striking reduction in nerve conduction velocity, consistent with demyelination. Although in most cases improvement occurs with treatment discontinuation, evidence of axonal loss portends a poor prognosis. Studies of human pathologic samples reveal lipid deposition in neurons of the dorsal root gangha and sympathetic ganglia. Nerve and muscle biopsy shows intracytoplasmic inclusions in Schwann cells, endothelial cells, and muscle fibers that are of lysosomal origin. Surd nerve biopsy demonstrates segmental demyelination with rare axonal degeneration. The effect on Schwann cells may result from inhibition of lysosomal enzyme activity. Perhexilinehas been used to produce an experimental model of peripheral neuropathy. Perhexiline is metabolized by enzymatic oxidation, and patients who develop neuropathy often have a reduced ability to oxidize the drug. Oxidation efficiency is genetically determined, and in an animal model, only rats with impaired oxidation developed peripheral neuropathy. This suggests that a genetic factor may predispose certain people to develop perhexiline-induced neuropathy.

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PHENEUINE Phenelzine sulfate is a derivative of hydralazine used to treat atypical depression and other psychiatric disorders. Its mechanism of action is inhibition of monoamine oxidase. There are rare reports of an associated, primarily sensory neuropathy. Electrophysiologic testing is consistent with axonal injury. Phenelzine reduces pyridoxine levels, similar to isoniazid and hydralazine, and that may be the mechanism of damage. However, this view has been challenged.

PHENYTOIN Phenytoin (diphenylhydantoin) is used to treat epilepsy and neuropathic pain. Peripheral neuropathy usually is mild and only discovered on clinical examination. Patients do not typically report symptoms. Diminished or absent deep tendon reflexes may be seen in the lower extremities. Deep tendon reflexes were absent in 18% of unselected patients who had been treated for more than 5 years. This rose to 50% in patients treated for 15 years. Mild sensory loss, particularly vibration sense, was noted in the lower extremities. Subtle symptoms of gait instability may be related to sensory ataxia caused by the neuropathy. There may be a relationship between duration of treatment, high plasma concentration of phenytoin, and low folate levels and the development of peripheral neuropathy. Rarely, an acute, severe neuropathy can develop that is reversible upon discontinuation of the medication. Nerve conduction studies demonstrate decreased evoked response amplitudes and mild slowing of conduction velocity, consistent with axonal injury. Sural nerve biopsy reveals loss of large, axons and secondary demyelination.

PROCARBAZINE Procarbazine is a hydrazine derivative used in Hodgkin’s disease, non-Hodgkin’s lymphoma, small cell carcinoma of the lung, and a variety of brain tumors. It inhibits DNA and RNA synthesis. Peripheral neuropathy has been noted in 10% to 20% of patients.

PYRIDOXINE Pyridoxine (vitamin B6)is an essential, water-soluble vitamin that is necessary for the function of a variety of enzymes. It is used to mitigate the increased excretion of pyridoxine by isoniazid, to treat pyridoxine-responsive epilepsy, and to treat mushroom poisoning by the false morel Gyrornitra esculenta. It is also used along with other medications that effectively decrease pyridoxine levels, such as cycloserine, hydralazine, and penicillamine. The recommended daily allowance is 2 mg; however, megadose treatment has been in vogue at various times to treat premenstrual symptoms, autism, and psychiatric illnesses and has been used by laypersons as a bodybuilding supplement. Over time, a daily dosage of 50 mg may cause a peripheral neuropathy. Dosages used to treat pyridoxine-dependent seizures have also been associated with neuropathy. A severe, primarily large-fiber, sensory neuropathy is characteristic, with sensory ataxia as the presenting symptom. Temperature and pain sensation are affected to a lesser extent than vibration and joint position sense. Weakness and paresthesia are not common. Symptoms typically subside when the drug is stopped but may persist for weeks before improvement is noted.

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Predictably, recovery is more rapid and complete after exposure to lower dosages. Electrophysiologic testing characteristically demonstrates absent sensory responses with preserved or mildly slowed motor conduction velocity. Axonal degeneration of both small- and large-diameter fibers is seen on sural nerve biopsy. Experimental studies have demonstrated degeneration of dorsal root and gasserian ganglion cells accompanied by centrifugal axonal atrophy and degeneration of peripheral and central sensory axons, implying a primary sensory neuronopathy. Ventral roots were unaffected. There is evidence that prolonged, low-dose exposure results primarily in a small-fiber neuropathy with sparing of ganglion cells, whereas shorter exposure to high dosages leads to a sensory neuronopathy and large-fiber neuropathy.

discontinuation of the drug. Some authors recommend baseline electrophysiologic evaluation with follow-up studies at 6-month intervals to detect the earliest onset of neuropathy. Sural nerve biopsy performed 2 to 6 years after thalidomide discontinuation showed selective loss of large-diameter fibers. This is at odds with the clinical symptoms and signs and the normal nerve conduction velocities that are typically seen. Nerve conduction studies show a decreased or absent sensory response and decreased motor evoked potential amplitude with little or no decrease in conduction velocity. Recovery of sensory nerve conduction parameters may not parallel clinical recovery. This may result from the loss of dorsal root ganglion cells. Cerebrospinal fluid protein may be elevated. VlNCA ALKALOIDS

SURAMIN Suramin has been used as an antitrypanosomal agent since 1920 and recently has shown promise in treating neoplasms. A severe, dose-dependent sensorimotor neuropathy has been described. The neuropathy is of two types: a chronic, axonal form and a subacute, inflammatory, demyelinating form. Bulbar and respiratory muscle weakness and autonomic symptoms and signs have been described. Electrophysiologic testing may reveal either an axonal or demyelinating neuropathy. The demyelinating form is responsive to discontinuation of the drug and plasmapheresis. Sural nerve biopsy demonstrates axonal degeneration and myelin abnormalities. Cerebrospinal fluid protein may be elevated. The mechanism of suramin’s chemotherapeutic activity is not known. However, studies in cell culture point to a disruption of glycolipid transport or metabolism. Dorsal root ganglion cells exposed to suramin accumulate ceramide, which leads to cell death. Multilaminar inclusion bodies composed of GM1 ganglioside are seen in Schwann cells investing the dorsal root cells.

THALlDOMlDE Thalidomide was initially used in Europe as a hypnotic but rapidly fell out of favor after reports of birth defects in infants born to mothers using the drug to alleviate morning sickness. There has been renewed interest in this immunomodulatory agent for use in severe rheumatoid arthritis, Crohn’s disease, graft versus host reactions after bone marrow transplantation, erythema nodosum leprosum, and many dermatologic diseases, including discoid lupus and treatment of aphthous ulcers in patients with human immunodeficiency virus infection. The mechanisms of action are not precisely known. Thalidomide-induced peripheral neuropathy is dose dependent. The incidence is between 25% and 50% of patients, approximately half of whom were symptomatic and half of whom showed an asymptomatic decrease in the sensory action potential amplitude of 50%. Neuropathic symptoms appear in a lengthdependent manner. However, weakness, which develops late in the course, tends to affect the proximal lower extremities. Paresthesias and numbness are noted in the feet and spread proximally. Small-fiber modalities are affected to a greater degree than the large-fiber modalities of vibration and joint position sense. Cramping in the lower extremities is common. Tendon reflexes may persist. Symptoms may begin after the drug is stopped. Resolution of symptoms, either fully or partially, occurs in only 50% of patients. Improvement may not begin for 3 years after

Vinca alkaloids are derived from the periwinkle plant (Vincu roseu). Vinblastine, vincristine, and vindesine are used to treat hematologic and lymphomatous malignancies. Vincristine is a more active agent than vinblastine and vindesine and has a higher incidence of peripheral neuropathy. This may result from the longer elimination half-life of vincristine. Vincristine, used at therapeutic dosages, will cause neuropathy in almost all patients. Indeed, neuropathy is the dose-limiting factor. The syndrome described here is routinely observed with the use of vincristine. The other vinca alkaloids may produce loss of reflexes and paresthesias but do not usually result in a severe neuropathy. Symptoms may begin as early as 2 months after initiation of treatment. Typically, loss of ankle jerks is the first clinical manifestation noted, and in approximately half of patients it progresses to total areflexia. Most patients initially notice paresthesias first in the fingers and then in the feet. Small-fiber modalities are affected more commonly than large fibers, and proprioception is uncommonly affected. Weakness is a more serious problem than sensory loss and may develop rapidly. Motor manifestations include cramping, weakness, and muscle atrophy. Weakness is most often noted in the distal muscles of the lower extremities and, peculiarly, in the extensors of the fingers and wrists, out of proportion to weakness seen in other distal upper extremity muscles. A neuropathy associated with severe distal lower extremity pain and weakness has been associated with the addition of hematopoietic colony-stimulating factors to vincristine in the treatment of lymphoma. Patients with hereditary sensory and motor neuropathy, type la, may be particularly susceptible to vincristine neuropathy. Neuropathic symptoms and weakness usually improve when the dosage is decreased or the drug is discontinued. Mild distal loss of small-fiber modalities may persist after paresthesias have resolved. Reflexes may return, but ankle jerks typically remain absent. Some patients are able to continue the drug at a lower dosage without reappearance of symptoms. Vinca alkaloids inhibit mitosis by binding with tubulin and interfering with the assembly of microtubules. Microtubules are also necessary for fast axonal transport, and this inhibitory effect on axonal transport is the likely mechanism of axonal damage. This mechanism would also explain the appearance of symptoms in the upper extremities before the lower extremities; those axons are shorter and would display the effects more quickly than the longer axons in the lower extremities. As may be expected, sural nerve biopsy demonstrates axonal degeneration with minor segmental demyelination. Regenerating fibers are seen several months after the drug is discontinued. After

Chapter 100

large intravenous doses, neurofilamentous accumulations are seen in dorsal root ganglia cells and throughout the central nervous system, including anterior horn cells. Similar changes are seen in anterior horn cells with intrathecal dosing. Nerve conduction studies show decreased sensory evoked response amplitudes and compound muscle potential amplitudes with normal or mildly decreased conduction velocity, as would be expected in an axonal neuropathy. Electromyography demonstrates fibrillation potentials and a reduced number of motor units in distal muscles, consistent with axonal loss. ZlMELDlNE Zimeldine is a 5-hydroxytryptamine reuptake inhibitor used to treat depression. It was withdrawn from the market because of a number of adverse reactions including an acute inflammatory

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demyelinating neuropathy similar to Guillain-Barresyndrome. An autoimmune mechanism has been implicated. SUGGESTED READINGS Argov Z, Mastaglia F L Drug-induced peripheral neuropathies. BMJ 1:663-666, 1979 Clark DW Genetically determinedvariability in acetylation and oxidation. Therapeutic implications. Drugs 29(4):342-375, 1985 Le Quesne PM: Neuropathy due to drugs. pp. 1571-1581. In Dyck P, Thomas PK (eds): Peripheral Neuropathy. WB Saunders, Philadelphia, 1993 Macdonald D R Neurologic complications of chemotherapy. Neurol Clin 9(4):955-967, 1991 Simpson DM, Tagliati M: Nucleoside analogueassociated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 9(2):153-161, 1995

100 Inherited Neuropathy Guillermo A. Suarez The inherited neuropathies are a group of heterogeneous disorders. Some are related to known metabolic derangements (e.g., Fabry’s disease), whereas others have no known cause (Table 100-1). A useful way to classify this latter group is based on the inheritance pattern, populations of neurons affected, natural history, and electrophysiologic and histopathologic findings. In the last few years, the tremendous advances in our understanding of the genetics of these disorders through gene mapping by linkage

analysis and gene isolation by molecular genetics have provided new ways to classify these disorders. An attempt to classify these conditions with a reference point is to consider which population (system) of neurons is predominantly affected. Selective degeneration of lower motor neurons is classified as hereditary motor neuropathy or, simply, spinal muscular atrophy. Degeneration of motor and sensory neurons indicates hereditary motor and sensory neuropathies (HMSNs).

W TMLE 100-1. Inherited Neuropathies

Disorder

Genetic Transmission

Clinical Features

Electrophysiologicfindings

Pathologic Findings

AD

Distal leg weakness and sensory loss

Slow NCV, reduced or absent SNAPs

Hypertrophic neuropathy

AD

Onset later in life

Near-normal NCV, absent SNAPs

Reduction in large MF, axonal atrophy

CMT neuropathies Type 1

IA: 17 (~11.2-12); PMP22 gene I B 1 (lq22-23); Po gene

Type 1 I

I/ A: 1p36 11 B: 3q /I C*: unknown /ID: unknown Type 111

*vocal cord paralysis AD, sporadic, AR?

Onset in infancy; delayed motor skills

Very slow NCV

Demyelination, axonal atrophy

Type x Chr. X (q12-qZl ); connexin 32 gene

X-linked

Distal leg weakness and sensory loss

Moderate slow NCV

Hypertrophic neuropathy

Type IV

AR

Slow NCV

Loss of fibers with demyeli-

(Dejerine-Sottas disease) mutations on PMP22 and Po genes

nation and onion bulbs

IVA: 8q13-21.1 IV B: 11q23 Hereditary neuropathy with liability to pressure palsies Deletion of 17~11.2-12; PMP22 nene

AD

Recurrent mononeuropathies, mild distal polyneuropathy

Multiple mononeuropathies, peripheral neuropathy

Demyelination, thickening of myelin sheath (tomaculous)

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MF, myelinated fibers; NCV, nerve conduction velocity; PMP, peripheralmyelin protein; SNAPs, sensory nerve action potentials.

Chapter 100

large intravenous doses, neurofilamentous accumulations are seen in dorsal root ganglia cells and throughout the central nervous system, including anterior horn cells. Similar changes are seen in anterior horn cells with intrathecal dosing. Nerve conduction studies show decreased sensory evoked response amplitudes and compound muscle potential amplitudes with normal or mildly decreased conduction velocity, as would be expected in an axonal neuropathy. Electromyography demonstrates fibrillation potentials and a reduced number of motor units in distal muscles, consistent with axonal loss. ZlMELDlNE Zimeldine is a 5-hydroxytryptamine reuptake inhibitor used to treat depression. It was withdrawn from the market because of a number of adverse reactions including an acute inflammatory

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633

demyelinating neuropathy similar to Guillain-Barresyndrome. An autoimmune mechanism has been implicated. SUGGESTED READINGS Argov Z, Mastaglia F L Drug-induced peripheral neuropathies. BMJ 1:663-666, 1979 Clark DW Genetically determinedvariability in acetylation and oxidation. Therapeutic implications. Drugs 29(4):342-375, 1985 Le Quesne PM: Neuropathy due to drugs. pp. 1571-1581. In Dyck P, Thomas PK (eds): Peripheral Neuropathy. WB Saunders, Philadelphia, 1993 Macdonald D R Neurologic complications of chemotherapy. Neurol Clin 9(4):955-967, 1991 Simpson DM, Tagliati M: Nucleoside analogueassociated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 9(2):153-161, 1995

100 Inherited Neuropathy Guillermo A. Suarez The inherited neuropathies are a group of heterogeneous disorders. Some are related to known metabolic derangements (e.g., Fabry’s disease), whereas others have no known cause (Table 100-1). A useful way to classify this latter group is based on the inheritance pattern, populations of neurons affected, natural history, and electrophysiologic and histopathologic findings. In the last few years, the tremendous advances in our understanding of the genetics of these disorders through gene mapping by linkage

analysis and gene isolation by molecular genetics have provided new ways to classify these disorders. An attempt to classify these conditions with a reference point is to consider which population (system) of neurons is predominantly affected. Selective degeneration of lower motor neurons is classified as hereditary motor neuropathy or, simply, spinal muscular atrophy. Degeneration of motor and sensory neurons indicates hereditary motor and sensory neuropathies (HMSNs).

W TMLE 100-1. Inherited Neuropathies

Disorder

Genetic Transmission

Clinical Features

Electrophysiologicfindings

Pathologic Findings

AD

Distal leg weakness and sensory loss

Slow NCV, reduced or absent SNAPs

Hypertrophic neuropathy

AD

Onset later in life

Near-normal NCV, absent SNAPs

Reduction in large MF, axonal atrophy

CMT neuropathies Type 1

IA: 17 (~11.2-12); PMP22 gene I B 1 (lq22-23); Po gene

Type 1 I

I/ A: 1p36 11 B: 3q /I C*: unknown /ID: unknown Type 111

*vocal cord paralysis AD, sporadic, AR?

Onset in infancy; delayed motor skills

Very slow NCV

Demyelination, axonal atrophy

Type x Chr. X (q12-qZl ); connexin 32 gene

X-linked

Distal leg weakness and sensory loss

Moderate slow NCV

Hypertrophic neuropathy

Type IV

AR

Slow NCV

Loss of fibers with demyeli-

(Dejerine-Sottas disease) mutations on PMP22 and Po genes

nation and onion bulbs

IVA: 8q13-21.1 IV B: 11q23 Hereditary neuropathy with liability to pressure palsies Deletion of 17~11.2-12; PMP22 nene

AD

Recurrent mononeuropathies, mild distal polyneuropathy

Multiple mononeuropathies, peripheral neuropathy

Demyelination, thickening of myelin sheath (tomaculous)

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MF, myelinated fibers; NCV, nerve conduction velocity; PMP, peripheralmyelin protein; SNAPs, sensory nerve action potentials.

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Degeneration of sensory and autonomic neurons is categorized as hereditary sensory and autonomic neuropathies (HSANs). Inherited neuropathies probably are the most common undiagnosed neuropathies. Dyck and colleagues reported that 42% of a series of 205 patients with undiagnosed neuropathies were found to have an inherited neuropathy when an appropriate kinship history was obtained (recording skeletal abnormalities such as high arches), and relatives were appropriately examined. It must be emphasized that a critical part of the examination is obtaining an appropriate family history by specifically asking whether the relatives have foot deformities, high arches, gait problems, muscle atrophy, trophic ulcers, or neuropathic symptoms.

HEREDITARY MOTOR AND SENSORY NEUROPATHY The classification of the inherited neuropathies and its nomenclature is constantly changing according to the new advances in the field. The group of HMSNs is also currently described as Charcot-Marie-Tooth (CMT) neuropathies. Originally, the term peroneal muscular atrophy or CMT disease was believed to be specific for one disorder. It is now known that this is not the case. Peroneal muscular atrophy occurs in several inherited neuromuscular disorders. Charcot and Marie emphasized the following features: pes cavus, progressive atrophy of distal leg muscles (legs resemble an inverted champagne bottle), tightness of Achilles tendons, hammertoes, and a steppage gait. Tooth emphasized that the disorder was inherited and concluded that it was caused by disease of the peripheral nerves. Landmark genetic, clinical, electrophysiologic, and pathologic studies of large kindreds by Dyck and Lambert allowed a separation in two main groups: the hypertrophic or demyelinating form, later called HMSN type I (CMT I), characterized by diffusely low motor nerve conduction velocities associated with nerve biopsy findings of axonal atrophy, demyelination, and onion bulb formations; and the neuronal form of CMT disease, subsequently named HMSN type I1 (CMT 11), characterized by normal or near-normal motor conduction velocity without hypertrophic neuropathy on nerve biopsy. The first group, hypertrophic type I, can be subdivided into patients with a classic phenotype as described by Charcot, Marie, and Tooth, and patients with recessively inherited or sporadic varieties, called HMSN type 111 (CMT III), or Dejerine-Sottas disease. This is usually a more severe demyelinating neuropathy, with onset in infancy or early childhood and with very low conduction velocities. The mode of inheritance generally is autosomal dominant in both CMT I and 11. However, in a minority of cases, the disorder is sporadic or affects siblings but not their parents. These cases have been attributed to possible autosomal recessive inheritance or most likely to a new mutation of a dominant gene, autosomal inheritance with nonpenetrance or reduced penetrance in the parents, or false paternity. X-linked inheritance has been established for the X-linked CMT neuropathy.

CMT I Genetic Transmission. The mode of inheritance of CMT I is heterogeneous and includes autosomal dominant transmission in the majority of families but also autosomal recessive and X-linked forms. There are several varieties:

CMT IA In most families with autosomal dominant inheritance, the CMT IA locus maps to a band (pl1.2-p12) on the

short arm of chromosome 17, which contains the peripheral myelin protein-22 (PMP22) gene. CMT IB: In a minority of patients, the CMT IB locus is on the long arm of chromosome l(lq22-q23), which harbors the myelin protein zero gene (P,). CMT IC: Families with autosomal dominant CMT and not linked to chromosome 1 or 17. CMT X Linkage analysis localized the locus to the proximal long arm of the X chromosome (Xq13.1). A gap junction protein, connexin 32, is the responsible gene that causes CMT X. CMT ID: A few families with autosomal dominant transmission have been linked to chromosome 10 (10q21) with mutations in the early growth response 2 gene (EGR2). Lupski and coworkers reported that a segment band of chromosome 17 (17pl 1.2-pl2) was duplicated in affected members of families with HMSN IA. The human peripheral myelin protein 22 gene (PMP22) is found in the region of the duplication. PMP22 encodes for the synthesis of a peripheral nervous system myeli protein. A few CMT IA kinships have found missense mutations of PMP22 in patients with CMT IA without the duplication. Most patients with genetically defined CMT IA have either a gene dose effect (duplication of 17pl 1.2-p12) or a mutation affecting the PMP22 gene on chromosome 17. Interestingly, the human PMP22 gene is deleted in patients with inherited tendency to pressure palsies, also known as hereditary neuropathy with liability to pressure palsies (HNPP) (discussed later in this chapter). Recently, two allelic mutations of the PMP22 gene have been found to produce a demyelinating neuropathy in mice. These observations strongly suggest that alterations in PMP22 expression, alone or in combination with yet unknown environmental factors, are responsible for this group of neuropathies. Clinical Features. Typically, only a small percentage of people with CMT I seek medical attention for neuromuscular symptoms; many actually have no symptoms. Patients have difficulty pinpointing the onset of neurologic problems, and presenting symptoms usually are difficulty in running, stumbling, slapping of the feet in walking, and muscle atrophy; they might not be aware of their problems until a relative or friend mentions that “their gait is funny.” Parents may report that children have weakness of ankles or running difficulty. Another common scenario is the incidental discovery of an indicator of neuropathy, such as an abnormal nerve conduction study (NCS): The electromyographer reports a more generalized nerve conduction abnormality, consistent with an inherited neuropathy, in patients who presented with low back pain, carpal tunnel syndrome, or other related disorders. The symptoms in HMSNs relate mainly to deficits, that is, weakness and atrophy of distal muscles. Sensory symptoms are those of a deficit-of-function “dead” feeling. Positive symptoms, such as prickling or “asleep numbness” and painful paresthesias, are not typical and should alert the physician to a possible acquired neuropathy. Autonomic symptoms usually are not reported by patients. Muscle cramps in the lower extremities, especially after exercise, are common. On clinical examination, the feet and legs are more affected than the hands. Inspection of the feet reveals pes cavus and hammertoes in approximately 70% of adult patients (Fig. 100-1). Kyphosis of the spine might be present in a small percentage of patients. Clinical enlargement of peripheral nerves or excessive

Chapter 100 W

FIG. 100-1. Typical pes caws and hammertoes of a patient with HMSN IA.

firmness is present in 25% of patients. The nerves between the axilla and the elbow should be assessed and palpated for enlarged nerves. Entrapment points, such as the ulnar nerve at the elbow, should be avoided because the nerve normally is thickened at that point. Muscle weakness and wasting affect muscles of the feet, peroneal, and anterior tibial muscles, usually in a symmetrical fashion. Later, in the upper limbs, a similar distal involvement occurs, first affecting intrinsic hand muscles. Deep tendon reflexes usually are diminished or absent in the lower and upper extremities, but there is significant variability in this sign. Classically, patients do not volunteer sensory symptoms, but sensory examination reveals distal impairment of sensation, usually affecting vibration and light touch in the feet and hands. Using quantitative sensory examination, an unequivocal abnormality of all sensory modalities is demonstrated. Occasionally, because of the sensory loss, high arches, atrophy of foot muscles, and calluses, ulcers develop over the metatarsal heads and over the tips of toes. In some patients, there is a prominent upper limb tremor with the typical features of an essential tremor, associated with the classic phenotype of CMT I. These cases have been labeled as Roussy-Levy syndrome, but there is no evidence that this is a distinct clinical or genetic disorder. There is significant variability in respect to severity of neuropathic deficits between individuals, even from the same kinship. There are asymptomatic cases, with slow nerve conduction values, and sometimes minimal changes on sural nerve biopsy. Laboratoy Features. The nerve conduction and electromyographic features are useful to separate CMT I from CMT 11. There is uniform slowing of motor conduction velocity in almost all nerves tested in patients with CMT I. There is good concordance of conduction velocity values within affected kindreds. Ulnar and median motor nerve conduction studies show the characteristic reduction in conduction velocity, but conduction studies in the

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635

lower extremities may not be very useful because of the more severe distal nerve fiber degeneration. Harding and Thomas proposed a criterion that a motor conduction velocity below 38 m/second be used as the cutoff value for CMT I. This is a useful criterion provided that the compound muscle action potential ( C W ) is at least 0.5 mV in the nerve where the conduction velocity is calculated, and the mean values of conduction velocity for the same nerve of all affected patients in the same kindred are used. If temporal dispersion of the CMAP or conduction block is found, an alternative diagnosis such as chronic inflammatory demyelinating polyneuropathy should be considered. Sensory nerves are also affected. Sensory nerve action potentials (SNAPS) are uniformly reduced or unrecordable using standard electrophysiologic techniques. Otherwise, routine laboratory studies, including cerebrospinal fluid (CSF) studies, provide normal results. DNA testing is commercially available and provides a good screening test for patients with suspected CMT neuropathies. Approximately 70% to 80% of patients with CMT IA test positive for the DNA duplication in chromosome 17~11.2-12. Pathologic Features. Pathologic studies (especially of sural nerves) show the typical features of a hypertrophic neuropathy, including onion bulb formation, made up of circumferentially directed Schwann cell processes, marked reduction in large myelinated fibers, increase in transverse fascicular area, and increased frequency of paranodal and segmental demyelination and remyelination. Extensive morphometric studies by Dyck and colleagues provide evidence of an axonal abnormality. There is clustering of demyelinating changes, increased frequency of demyelination and remyelination in distal segments, distal predominance of onion bulbs, and reduction in axon caliber relative to the number of myelin lamellae. These observations lend support to the hypothesis that axonal atrophy occurs first, and segmental demyelination may be secondary to it. This does not exclude a concomitant abnormality of Schwann cells. CMT IA and CMT IB

The inheritance pattern, clinical features, electrophysiologicfindings, course, and natural history of CMT IA and CMT IB overlap. Only molecular genetic techniques allow separation into these two groups. CMT IB is associated with mutations in the myelin protein zero gene (Po). CMT IA appears to be a less severe disorder than CMT IB. Treatment There is no specific treatment for CMT IA and IB. Clinical, genetic, and symptomatic counseling is important. Because of the high arches and foot deformities, proper foot care should be emphasized to avoid foot ulcers. Shoes should be comfortable,well made, and protective. The shoes and feet should inspected every day. Calluses must not be trimmed with a razor blade. If the patient develops a plantar ulcer, weight-bearing should be avoided until the ulcer has healed. Foot braces may be tried, but they are not necessary for every patient. If the brace does not improve gait, then it should not be worn. Foot surgery usually is reserved for patients who begin to develop valgus deformity of the ankle or severe degrees of pes cavus. The patient should understand that surgery is not going to cure the other manifestations of the disorder such as sensory loss and muscle weakness. Most affected patients are able to work full time, and there is no evidence that life expectancy is any different from that of the general population. Because of the distal weakness, training in an occupation that does not require fine motor skills may be recommended.

636

Spinal Cord and Peripheral Neuromuscular Disease rn Diseases of Peripheral Nerve

CMT II: Neuronal Form Genetic Transmission. CMT I1 is not as common as CMT I, and there is substantial genetic heterogeneity in this group. Linkage studies permit classification into four groups: CMT 2A, 2B, 2C, and 2D (Table 100-1). Clinical Features. The clinical features of patients with CMT I1 are similar to those with CMT I. However, there are some differences. Patients with CMT I1 usually are asymptomatic until later in life. Peripheral nerves usually are not clinically enlarged, and weakness of feet and leg muscles predominate; hands are less severely affected. Sensory loss is present in the distal extremities, and foot deformities (pes cavus) tend to be less marked. On the basis of the clinical phenotype, it is very difficult or impossible to separate CMT I1 from CMT I. laboratory Features. Motor nerve conduction velocities are near normal or normal in patients with CMT 11. The mean conduction velocity of ulnar nerves in the kindred studies was about 38 mlsecond. SNAPS are uniformly reduced or absent. Pathologic Findings. Sural nerve biopsies in patients with CMT I1 have shown reduction of large myelinated fibers, particularly distally, without significant demyelination on teased fibers. Small onion bulbs may be seen. CMT II with Diaphragm and Vocal Cord Weakness

A large kindred with autosomal dominant CMT I1 has been reported with a classic neuropathic phenotype, but in addition, 50% of the affected patients had vocal and diaphragm weakness. Death has been attributed to respiratory weakness, and intercurrent infections have been observed. Linkage studies have not localized this disorder to a known locus. CMT II:Autosomal Recessive

Ouvrier reported a more severe form of CMT I1 with onset in infancy or early childhood and recessive inheritance. The treatment of CMT I1 is similar to that of CMT I.

FIG. 100-3. Sural nerve biopsy of a patient with HMSN 111 (Dejerine-Sottas disease), transverse section embedded in epon and stained with methylene blue. Note prominent onion bulb formations and reduction in the number of myelinated fibers. (Courtesy of C. Ciannini, MD, Department of Pathology, Mayo Clinic, Rochester, MN.) CMT 111: Dejerine-Sottas Disease

CMT I11 is a rare hypertrophic neuropathy of infancy. Genetic studies have identified de novo mutations in the PMP22 gene and in the Pogene (an important structural protein of peripheral nerve myelin). The clinical features are those of a severe neuropathy with onset in early childhood. Motor development is delayed. Motor skills such as jumping and running are impaired. There is progressive muscular weakness affecting legs and arms. General areflexia, with prominent enlarged peripheral or cranial nerves, is typical (Fig. 100-2). There is definite sensory loss, and some patients have marked sensory ataxia. The course is progressive, with significant disability. Some patients are wheelchair-bound in early adulthood. Motor conduction velocity is markedly reduced, usually below 10 m/second. CSF protein levels often are elevated. Pathologic studies have shown enlargement of the transverse fascicular area, onion bulb formation (Fig. 100-3), segmental demyelination, reduction in the number of myelinated fibers, and axonal atrophy. Other cases reported as congenital hypomyelinated neuropathy probably represent a variant of CMT 111. The differential diagnosis includes acquired and inherited demyelinating neuropathies occurring in children. In patients labeled as having acquired neuropathy, the differential diagnosis must consider acute and chronic inflammatory demyelinating polyradiculoneuropathy; in those with inherited neuropathy, the differential diagnosis includes CMT I and 11, metachromatic leukodystrophy, Cockayne’s syndrome, HNPP, and other rare neuropathies. CMT IV

FIG. 100-2. Magnetic resonance imaging of the brain showing an enlarged and hypertrophied fifth cranial nerve in a patient with Dejerine-Sottas syndrome.

A rare form of CMT neuropathy with autosomal recessive transmission has been reported in families from Tunisia. One form has been mapped to chromosome 8 (8ql3-2 1) and designated CMT IVA. Another has been linked to chromosome 11 (1 lq23) and named CMT IVB. Other kinships have not linked to known loci, suggesting genetic heterogeneity. The phenotypic presentation is one of a severe demyelinating predominantly motor neuropathy with early onset in childhood. Patients have pes cavus and oiher ‘skeletal deformities and often need a wheelchair. The

Chapter I 0 0

EMG shows motor conduction values in the demyelinating range of 20 to 30 mhecond. The CSF protein content is normal, which helps to separate this neuropathy from the Dejerine-Sottas type or CMT 111.

X-Linked CMT Neuropathy (CMT X ) Genetic Transmission. Linkage studies localized CMT X to the long arm of chromosome Xq13. This region contains the connexin 32 gene, and mutations of this gene cause CMT X. Connexin 32 is an important gap junction protein localized around the nodes of Ranvier and Schmidt-Lanterman incisures. Clinical Features. The clinical features are similar to those of CMT I, with a neuropathy more severely affecting males and with onset in adolescence. Neuropathic deficits include distal muscle atrophy and weakness with foot drop and intrinsic hand muscle weakness with distal sensory loss. Deep tendon reflexes generally are hypoactive to absent. Pes cavus may be present in patients with this neuropathy. Laboratory Features. EMG studies have shown both axonal and demyelinating features with low-amplitude CMAPs and slowed conduction velocities. Sensory responses generally are of low amplitude or absent. Pathologic Findings. There is reduction of large myelinated fibers with evidence of demyelination and remyelination.

Refsum's Disease

The hypertrophic neuropathy associated with increased phytanic acid levels, or Refsums disease, is also called Refsum's neuropathy and used to be classified as HMSN type IV.The clinical features are distinctive and very different from the CMT profile and include retinitis pigmentosa, ataxia, skeletal malformations, and a predominantly sensory neuropathy. The main differential diagnosis is with the spinocerebellar degenerations, which often have an associated mild sensory neuropathy.

HMSN with Associated Features

There are families with the clinical phenotype of peroneal muscular atrophy, and they present with additional distinct features such as spastic paraparesis (HMSN V), optic atrophy (HMSN VI), retinitis pigmentosa (HMSN VII), deafness, and cardiomyopathy. In most family studies, the inheritance pattern was autosomal dominant.

1 Inherited Neuropathy

637

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES The main feature of HSAN is the prominent involvement of sensory and autonomic fibers. The primary pathologic foci of this disorder are mainly small-diameter pain and thermal sensory neurons (axons) and autonomic neurons. There is significant clinical and genetic heterogeneity. It would be desirable to classify these disorders by the altered cellular or genetic mechanism, but for most HSANs, this is not known. For practical purposes, a classification based on the inheritance pattern, clinical features, and system of neurons predominantly affected is used (Table 100-2). The loss of pain sensation and sensory loss predisposes to the development of foot complications, including plantar ulcers, secondary infections such as cellulitis, and osteomyelitis, which may lead to osteolysis, eventually resulting in acral mutilations.

HSAN I

HSAN I is a genetically heterogeneous disorder, dominantly inherited in most cases. Linkage studies have mapped the genetic loci to chromosome 9q22. Neuropathic symptoms may begin in the second or fourth decade of life and slowly progress over time. Spontaneous neuropathic pain typically is burning, aching, or lancinating in quality, affects mainly the feet and legs, and is aggravated by heavy walking or weight-bearing. Sometimes pain is related to local events such as calluses or plantar ulcers. Neurologic signs include sensory loss predominantly involving pain and temperature sensation, but all modalities may be affected. The decreased sensation typically affects feet and legs in a symmetrical fashion. Deep tendon reflexes are absent at the ankles but present in the upper extremities. In some kindreds, a variable degree of motor involvement with peroneal muscular weakness may be seen. High arches of the feet with frequent corns and calluses of the soles of the feet may have gone unnoticed for years. Foot complications such as the typical plantar ulcer in the metatarsal head region or sole of the foot is a late manifestation of HSAN I. Plantar ulcers are not caused only by sensory loss; other risk factors play a critical role. These include excessive use and abuse of feet, neglect of foot care, excess weight, and neglect of foot injury. Men, particularly those involved in heavy physical activity, tend to develop ulcers more often than women. If foot ulcers are not recognized and treated promptly, a sequence of events occurs, leading to local infection, osteomyelitis, and loss of a foot or leg. Electrophysiologic studies reveal absence of SNAPs. The neuropathologic features are those of a chronic neuropathic

TAW 100-2. Hereditary Sensory and Autonomic Neuropathies Disorder

Genetic Transmission

Electrophysiologk Findings

Pathologic Findings

Painful feet, decreased pain Abnormal small nerve fiber Reduction of small MF and UF and temperature sensation function SNAPs generally absent Reduction of MF and UF AR Onset in early childhood, planType II tar ulcers, mutilation of digits and toes Reduced SNAPs, abnormal Marked reduction of UF AR Prominent autonomic manifesType 111: Familial dysautonomia small nerve fiber function tations, absence of fungichromosome 9 (9q3 1-q33) form papillae, and defective lacrimation Type IV AR Congenital insensitivity to pain, Normal SNAPs Reduction of small MF anhidrosis Abbreviations: AD, autosornal dominant; AR, autosornal recessive; MF, rnyelinated fibers; SNAPs, sensory nerve action potentials; UF, unrnyelinatedfibers.

Type I

AD

Clinical Features

638

Spinal Cord and Peripheral Neuromuscular Disease W

Diseases of Peripheral Nerve

process affecting small myelinated and unmyelinated fibers with axonal atrophy, myelin remodeling, and axonal degeneration. The differential diagnosis includes other varieties of HSAN (discussed later in this chapter). Three features are helpful to separate these conditions. The first is age of onset: HSAN I begins in the second or even later decades of life, but the other varieties (HSAN I1 to V) probably are congenital, with onset at birth. The second is progression of deficits: In HSAN I there is slow progression over the course of years, which is seldom the case in the other varieties. The third is pattern of involvement: HSAN I tends to affect the lower extremities, whereas in the other varieties the lower and upper extremities and trunk are generally affected. Spinocerebellar degeneration (i.e., Friedreich's ataxia) is separated from HSAN I by the following main features: sensory loss that predominantly affects proprioception and vibratory sensation, cerebellar ataxia, and minimal autonomic and small-fiber dysfunction. Familial forms of amyloidosis are separated clinically by the presence of sexual and sphincter dysfunction.

HSAN IV

Swanson originally described two affected siblings with insensitivity to pain, mild mental retardation, defective temperature control, and anhidrosis. Subsequent case reports have been documented. Pathologic findings include loss of unmyelinated fibers and lesser reduction of small myelinated fibers. This disorder is recessively inherited. HSAN V

Low and colleagues reported a 6-year-old child with congenital loss of pain sensation with normal muscle strength, reflexes, and normal light touch and vibratory sensation. SNAPS were normal, but sural nerve biopsy revealed marked loss of small myelinated fibers. Additional cases have also been reported. Treatment and Management

HSAN II

HSAN I1 is a rare recessively inherited condition with onset early in life. Unlike in HSAN I, all sensory modalities are involved, affecting not only the lower extremities but also hands, face, and trunk. Children with this disorder are at risk for ulcers of the feet, hand, lips, and tongue, and mutilation of fingers and toes may occur. Repeated paronychia, plantar ulcers, and stress foot fractures usually are present. Neurologic examination reveals sensory loss that affects all modalities of sensation involving legs and hands. Reflexes are diminished or absent throughout. There is distal anhidrosis with sphincter dysfunction and impotence in men. SNAPS are absent. Pathologic studies of sural nerves have shown marked reduction to absence of myelinated fibers with a reduction in unmyelinated fibers as well. Donaghy reported the association of retinitis pigmentosa, spastic paraplegia, and neurotrophic keratitis with sensory neuropathy. HSAN 111: Familial Dysautonomia

Initially described by Riley (Riley-Day syndrome), HSAN 111 is a rare autosomal recessive sensory neuropathy with autonomic manifestations that affects mainly Ashkenazi Jews, with an estimated gene frequency in North American Jews of less than 1 in 100,000. The genetic locus has been established by linkage analysis and is located on chromosome 9q31433. Recent studies have identified the IKB kinase complex-associated protein (IKAP) gene in this region, and mutations of this gene cause HSAN 111. The clinical manifestations usually are present at birth and consist of deficient lacrimation, poor sucking, episodic hyperthermia, frequent respiratory infections, vomiting, and failure to thrive. Emotional stimulation usually provokes autonomic crises with hypertension, profuse sweating, and excessive mottling of the skin. Constant clinical features helpful in the diagnosis are the absence of fungiform papillae on the tongue, defective lacrimation (alacrima), and corneal insensitivity. Hyporeflexia, decreased pain sensation, and kyphoscoliosis become apparent later in life, Electrophysiologic studies reveal reduction in SNAPS with preserved motor conduction velocities. Sural nerve biopsies demonstrate a marked reduction in the number of unmyelinated fibers. Postmortem examinations have shown marked reduction in the number of neurons in autonomic and spinal ganglia.

Emphasis on prevention of foot ulcers is the most important aspect of treatment for HSAN. Instructions along the lines described earlier for CMT should be provided. Patients should be instructed not to abuse their feet. Children should avoid jumping from heights, and certain sports such as parachuting or kicking sports should be deemphasized. Careful foot care with daily inspection of feet and shoes is of utmost importance. Patients should wear shoes even inside the house. Foot care with daily soaks, followed by petroleum jelly lotion, is in order. Calluses should not be trimmed; rather, they should be rubbed off after soaking. If a plantar ulcer develops, weight-bearing must cease until it is healed. Prompt debridement with antibiotic coverage usually is needed. In most cases, acromutilations are seen in patients who abused their feet and neglected the injuries for a long time until it was too late to salvage the foot or leg. ~

HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES (HNPP)

HNPP is an autosomal dominant neuropathy with susceptibility to pressure palsies. Genetic studies using linkage analysis have localized the abnormality to band 17pl1.2-pl2 on chromosome 17. In contrast to CMT IA,this segment is deleted in HNPP. The human PMP22 gene, which is normally found in this region, is deleted in HNPP and duplicated in CMT IA. There are reports of a few families without linkage to chromosome 17, suggesting genetic heterogeneity. Usually, the clinical manifestations start in the second or third decade of the patient's life. Onset of symptoms follows trivial trauma, compression, or sleeping on a limb. The resulting palsy, usually painless, persists for days or weeks instead of resolving in minutes or hours. Typically, a mononeuropathy with sensory loss and weakness develops in the appropriate anatomic distribution. The most commonly affected nerve trunks are the peroneal nerve at the fibular head, the radial nerve in the spiral groove of the humerus, and the ulnar nerve at the elbow. The history of minor compression or trauma is not always present. On examination, a mononeuropathy with the corresponding sensory loss and weakness in the distribution of the affected nerve is the rule. An important point, not always described in the literature, is that many patients have signs, albeit minor, of a distal, more generalized neuropathy. There is mild distal symmetrical sensory

Chapter 100

loss, and ankle reflexes are depressed or absent. In some patients, the telltale signs of an inherited neuropathy (high arches, hammertoes) are present. Nerve conduction studies are helpful to detect conduction slowing or block at one or more entrapment sites. Prolonged distal latencies out of proportion to the slowing of conduction velocities have been reported as a useful distinctive electrophysiologic feature. A more diffuse motor and sensory polyneuropathy affecting both clinically affected and unaffected nerves also is a helpful clue to the diagnosis. Pathologic studies, mainly of surd nerve biopsies, have shown segmental demyelination and remyelination with distinctive focal thickening of the myelin sheath, called “sausages” or “tomaculous” (Fig. 100-4). Uncompacted axonal myelin and reduplicated segments of myelin have been demonstrated by electron microscopy studies (Fig. 100-5). These observations suggest that a primary abnormality of myelin formation underlies this disorder, which may predispose myelinated fibers to be more susceptible to environmental factors, such as local trauma or compression. It should be emphasized that establishing heredity is critical in taking the clinical history in a patient who presents with pressure palsy. Family history is revealed only after detailed and often specific questioning. The presence or recurrence of pressure palsies with associated mild signs of a generalized neuropathy is a helpful clue to distinguish HNPP from individual cases of pressure palsy. To separate HNPP affecting the brachial plexus from sporadic brachial plexus neuropathy, the following features are helpful. In HNPP, the onset usually is painless, in contrast to the severe pain found at onset in brachial plexus neuropathy. The relationship to trauma and the presence of a generalized neuropathy are helpful

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clues to the diagnosis of HNPP. Other multiple mononeuropathies associated with diabetes, leprosy, sarcoidosis, Lyme disease, or necrotizing vasculitis are considered in the differential diagnosis of HNPP but usually do not present major diagnostic problems. Molecular DNA analysis can demonstrate the PMP22 deletion in HNPP and secure the diagnosis. Screening for PMP22 mutations is performed only in selected cases. There is no specific treatment for this condition. The major point in management is education for the prevention of nerve injury by avoiding pressure damage. Individual pressure palsies are treated by appropriate splinting and physical therapy. Recovery may be prolonged, but the prognosis for return of function is good.

FAMILIAL AMYLOID POLYNEUROPATHY Inherited amyloidoses are autosomal-dominant disorders characterized by deposition of amyloid in peripheral nerves and other tissues. The clinical phenotypes of hereditary amyloidosis often have in common peripheral neuropathy with prominent autonomic manifestations, which differ in age of onset, genetic defect, clinical patterns of neuropathy, and other tissue involvement. The first familial amyloid polyneuropathy (FAP) described was the previously named Portuguese variety, reported by Andrade in 1952; it is the most common type, and the amyloid is derived from a point mutation on the transthyretin (TTR) molecule, formerly known as prealbumin. The first mutation reported was the methionine for valine substitution at position 30. Since then, 80 point mutations of the TTR gene have been identified. The former classification of the FAP into four types was replaced by new understanding of the basic molecular genetic variations. Mutations of three proteins-TTR, apolipoprotein Al, and gelsolinare the basis of the current classification. m-Related FAP

A

B

C

FIG. 100-4. Sural nelve biopsy of a patient with hereditary neuropathy with liability to pressure palsies (HNPP). (A) Transverse section embedded in epon and stained with methylene blue. Note several profiles showing focal thickening of the myelin sheath “sausages“ or “tomaculous.“ (6 and C) Teased fiber preparation showing distinctive focal thickening of the myelin sheath ”sausages.” (Courtesy of C. Ciannini, MD, Department of Pathology, Mayo Clinic, Rochester, MN.)

TTR-related FAP was originally described by Andrade in northern Portugal and was formerly known as FAP type I. It is dominantly inherited and is the most common FAP and has also been described in Brazil, Japan, Sweden, and elsewhere. Onset of symptoms usually occurs in the third or fourth decade but may occur later in life. Neuropathic symptoms are pain and paresthesias affecting the feet and legs first, often associated with marked sensory loss, mainly affecting pain and temperature sensation. Initially, a syndrome that mimics lumbosacral syringomyelia develops in the patient, and other sensory modalities are affected later. Autonomic symptoms are prominent and sometimes dominate the clinical picture, especially postural dizziness and hypotension, distal anhidrosis, impotence, urinary retention, and dysfunction of gastrointestinal motility with alternating episodes of diarrhea and constipation. Pupillary abnormalities with escalloped margins are also present. The sensory abnormalities with loss of pain and temperature may predispose to the occurrence of foot ulcers or inadvertent burns. Neuropathic joint degeneration is a late complication. Sensory loss progresses to involve the upper extremities, usually affecting all sensory modalities in later stages. Muscle weakness and areflexia appear as the disease advances. Infiltration of other organs, such as kidneys, heart, and eyes, is typical in this disorder. Amyloid deposits may be found in the flexor retinaculum overlying the median nerve at the wrist and producing symptoms of a median neuropathy at the wrist (carpal tunnel syndrome).

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Diseases of Peripheral Nerve

FIG. 100-5. Longitudinal section of large myelinated fiber from sural nerve of a patient with HNPP showing uncompacted inner lamellae of myelin characteristic of the disorder (bar = 1 pm). (From Yoshikawa H, Dyck PJ: Uncompacted inner myelin lamellae in inherited tendency to pressure palsy. J Neuropathol Exp Neurol 50:649, 1991, with permission.)

TMLE 100-3. Other Inherited Neuropathies Associated with Known Metabolic Defects Disorder

Genetic Transmission

Clinical Features

Metabolic Abnonnalitv

PathoIonic Findinns

MF loss, demyelination, and Infantile and adult forms; CNS Arylsulfatase A Schwann cell cytoplasm involvementwith mental retardation, blindness, metachromatic granules deafness, hypertonic tetraplegia; PNS involvement with weakness, areflexia, and slow NCV Onset at infancy; CNS white Segmental demyelination, inGalactosylceramidase AR Cloboid cell leukodystrophy clusion material within matter involvement with (Krabbe's disease) regression of motor skills, Schwann cell cytoplasm hypertonicity, seizures, and optic atrophy; PNS involvement with hyporeflexia and slow NCV Loss of MF and UF, Schwann Young males; spastic paraAbnormal P-oxidation of Adrenoleukodystrophy and X-linked adrenomyeloneuropathy paresis, peripheral neuropcell inclusions VLCFA athy, and signs of adrenal insufficiency X-linked Young males; painful smallSmall-fiber neuropathy; glycoa-Galactosidase Fabry's disease fiber neuropathy, anhidrolipid granules in vessels sis, skin angiokeratomas, kidney and vascular disease Three types: asymmetrical AR Tangier disease Clear vacuoles in Schwann Abnormal catabolism of highcell cytoplasm; demyelinadensity lipoproteins; very polyneuropathy with nortion, remyelination, and mal NCV; slowly progresslow plasma cholesterol ing symmetrical polyneuaxonal degeneration ropathy, mainly in the lower extremities; and polyneuropathy with a syringomyelia-like syndrome, orange tonsils Abetalipoproteinemia AR Large-fiber peripheral neuropAbsence of lipoproteins conReduction of MF athy, proprioceptiveloss, taining apolipoprotein B ataxia, pes cavus, atypical retinitis pigmentosa, acanthocvtosis Abnormalities in regulation of Porphyric neuropathy AD Porphyhc attacks painful criWallerian degeneration sis, progressive motor neuheme synthesis (AIP, VP, and HCP) rooathv, or enceohaiooathv Abbreveviotions: AD, autosomal dominant; AIP, acute intermittent porphyria; AR. autosomal recessive; CNS, central nervous system; HCP, hereditary coproporphyria; MF, myelinatedfibers; NCV, nerve conduction velocity; PNS, peripheral nervous system; UF, unrnyelinatedfibers; VLCFA, very long-chain fatty acids; VP, variegate porphyria.

Metachromatic leukodystrophy

AR

PLATE 100-1. Sural nerve biopsy of a patient with familial amyloidosis. Transverse section embedded in paraffin and stained with monoclonal antibodies to transthyretin (TTR). Note perivascular amyloid deposits showing a positive reaction with a monoclonal antibody to l l R .

Chapter 100

The disease runs a progressive course, and patients usually die of renal failure or cardiac complications 10 to 20 years after onset. Electrophysiologic studies in the early stages of the disease show an axonal predominantly distal sensory polyneuropathy with reduced or absent SNAPS and relative preservation of motor conduction velocity and CMAPs. Sural nerve biopsies reveal marked reduction in small myelinated and unmyelinated fibers, with widespread amyloid deposits throughout. Immunohistochemical studies of the amyloid deposits with monoclonal antibodies are helpful in providing evidence of hereditary amyloidosis. Inherited amyloidosis specifically reacts with antiserum against TTR (Plate 100-1). Amyloid deposits are also found in sensory and autonomic ganglia. The mechanism of nerve damage is unknown. Asymptomatic carriers of the mutant TTR gene can be detected by radioimmunoassay of serum. Because the liver mainly produces the abnormally mutated TTR, liver transplantation has been recommended to stop the production of the mutated TTR and modify the natural history of FAP. However, studies have shown limited benefits, mainly limiting the progression of neuropathic deficits in patients with mild neuropathy. Autonomic deficits have not improved, and patients with cardiac manifestations of amyloidosis tend to have a poor outcome after liver transplantation. Patient selection is important to minimize perioperative mortality, which is high in patients with advanced FAP. On balance, it appears that the potential benefits of liver transplantation should be carefully weighed against the risks, taking into account the duration and severity of FA!?. Apolipopmteh A1-Related FAP

The clinical manifestations of apolipoprotein A1 FAP are similar to those of TTR FAP except for early renal involvement and high incidence of duodenal ulcers. Autonomic involvement is not as florid as in TTR FAP. The amyloid of this form is not derived from TTR. The amyloid fibrils consist of a variant of apolipoprotein Al. Gelsolln FAP

Originally described in Finland and formerly know as FAF' IV (Meretoja), Gelsolin amyloidosis is characterized by ocular manifestations. Corneal opacity caused by amyloid infiltration, called lattice corneal dystrophy, is a cardinal clinical feature. A slowly progressive facial palsy with facial skin changes usually supervenes later. A mild generalized peripheral neuropathy without autonomic features may occur later.

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OTHER INHERITED NEUROPATHIES ASSOCIATED WITH KNOWN METABOLIC DEFECTS Other inherited neuropathies are summarized in Table 100-3.

SUGGESTED READINGS Adam D, Samuel D, Goulon-Goeau C et al: The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain 123:1495, 2000 Ben Othmane K, Middleton LT, Loprest LJ et ak Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome Ip and evidence of genetic heterogeneity. Genomics 17:370, 1993 Bergoffen J, Scherer SS, Wang S et ak Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262:2039, 1993 Dyck PJ: Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. p. 1065. In Dyck PJ, Thomas PK, Griffin JW et al (eds): Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Dyck PJ, Chance P, Lebo R, Carney JA Hereditary motor and sensory neuropathies. p. 1094. In Dyck PJ, Thomas PK, Griffin JWet a1 (eds): Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Dyck PJ, Litchy WJ, Minnerath S et ak Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol 35:608, 1994 Dyck PJ, Thomas PK, Griffin JW et al (eds): Peripheral Neuropathy. 3rd Ed. WB Saunders, Philadelphia, 1993 Fischbeck KH, ar Rushdi N, Pericak Vance M et ak X-linked neuropathy: gene localization with DNA probes. Ann Neurol20:527, 1986 Hayasaka K, Himoro M, Sawaishi Y et ak De novo mutation of the myelin Po gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type 111). Nat Genet 5:266, 1993 Keller MP, Chance PF: Inherited peripheral neuropathy. Semin Neurol 19:353, 1999 Lupski JR, de Oca Luna RM, Slaugenhaupt S et al: DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219, 1991 Mendell J R Charcot-Marie-Tooth neuropathies and related disorders. Semin Neurol 18:41, 1998 Pareyson D Charcot-Marie-Tooth disease and related neuropathies: molecular basis for distinction and diagnosis. Muscle Nerve 22: 1498, 1999 Roa BB, Dyck PJ, Marks HG et al: Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene. Nat Genet 5:269, 1993

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Diseases of Peripheral Nerve

10 1 Common Entrapment and Compression

Neuropathies of the Upper Extremity David M. Dawson

CARPAL TUNNEL SYNDROME Carpal tunnel syndrome is the result of compression of the median nerve within the carpal canal, a closed space bounded on the volar surface by the thick transverse carpal ligament. The normal cause of carpal tunnel syndrome is enlargement or hypertrophy of the nine flexor tendons that pass through this closed space. Both vascular effects on the median nerve and the effects of chronic recurring compression appear to play a role in the pathogenesis of the nerve disorder. Briefly stated, it appears that the demyelinative lesion of the nerve, which accounts for the focal nerve conduction slowing and probably for the neurologic symptoms, is a result of compression of the myelin sheaths, distortion of the nodes of Ranvier, and interruption of normal saltatory conduction. Some intermittent symptoms, such as nocturnal tingling, may be caused by interference with blood supply to the nerves because these symptoms are so easily reversible by change in wrist position. Carpal tunnel syndrome is important in two ways that are unique to this disorder. It was the first clinical physiologic correlation to be well described in the earliest days of clinical electromyographic testing in the 1960s, and it is the one entrapment neuropathy for which a major occupational role has been defined. For this latter reason, it is in the forefront of legal and compensation systems calculations, based on an industrywide effort to reduce the high incidence of this disorder in workers. In a review of medical records in Rochester, Minnesota, an incidence of 125 per 100,000 population was calculated in the late 1970s. In a recent survey in the Netherlands, 8% of the interviewees reported nighttime paresthesias of the hand, and of these about one third were found to have carpal tunnel syndrome, an incidence of 220 in 100,000. The prevalence of carpal tunnel syndrome in those who work with their hands is many times these baseline figures. The highest reported incidence thus far is 15%, in a group of meat cutters. The incidence of carpal tunnel syndrome is higher among electronic parts assemblers, musicians, dental hygienists, and of course those who use their hands in nonoccupational ways such as those who knit, do carpentry, or filet fish. In the nonoccupational group of patients with carpal tunnel syndrome, middle-aged women predominate, whereas of those who have an occupational basis for the condition, younger men are the peak population. Clinical Features

The clinical features of carpal tunnel syndrome are known to most practitioners. The most common and easily recognized clinical variant of the illness is slowly progressive nocturnal paresthesias, typically burning and unpleasant, located mostly in the hand. There may be some proximal radiation of the pain into the forearm and arm, rarely above the level of the shoulder. Many patients notice that some wrist positions exacerbate the symptoms, for example, when they drive with the wrist extended on the

steering wheel or when they hold a newspaper. In the earliest stages of the illness the symptoms are intermittent, and there are no neurologic findings on examination. As the condition progresses, symptoms become more persistent, and there may be decreased tactile sensation over the fingertips, typically over the index and middle fingers. Two-point discrimination over the fingertips is a reliable method of testing, as is light pinprick sensation over the dorsum of the fingers. Testing over the palmar surface of the fingers often is difficult, and it should be noted that the palm itself is spared because of the anatomy of the median nerve (i.e., the palmar cutaneous nerve arises proximal to the carpal tunnel). Other clinical variants of carpal tunnel syndrome are known. Some patients have pronounced autonomic disorder from the very beginning, such as sweating and dry skin or features that resemble Raynaud’s phenomenon. A few patients appear to have primary axonal damage from the beginning and present with dense sensory loss and atrophy of the thenar muscles. These patients may complain of weakness, which is most often caused by clumsiness and lack of discriminative ability of the sensory nerve fibers, but a few have weakness of thumb abduction and opposition. Not all patients with carpal tunnel syndrome present with slowly progressive illness; some present with acute loss of function, probably caused by vascular factors. The increased prevalence of carpal tunnel syndrome during pregnancy is well known, typically beginning in the sixth or seventh month and returning to baseline after delivery in more than 90% of women. A few women in whom this disorder develops during pregnancy do not recover sufficiently and have persistent problems. Occupational Considerations

Efforts have been made to define the exact occupational exposures that increase the incidence of carpal tunnel syndrome. These efforts have not been highly successful because there has been disagreement about the necessary features for the diagnosis, with some investigators using primarily neurophysiologic data, which have been unreliable in this setting for reasons that are discussed in this chapter. Highly repetitive wrist movement, vibrating tools, awkward wrist positions, and forceful movements of the hand seem to correlate with a high incidence of carpal tunnel syndrome. Workers whose occupation entails forceful repetitive movement of the hand have a higher incidence of carpal tunnel syndrome, at least ten times higher than that observed in workers who use the wrist without repetition and force. The matter remains under investigation. Some experts have not been able to find these correlations and believe that obesity, age, presence or absence of diabetes, and other nonergonomic factors are equally important. Nevertheless, major efforts are being made throughout the relevant industries to reduce the incidence of carpal tunnel

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syndrome and its major impact on the costs of productivity loss and medical care for affected workers. Electrophysiologic Features The electrophysiologic diagnosis of carpal tunnel syndrome depends on the demonstration of focal slowing of the median nerve at the wrist. This was first demonstrated by Simpson in 1956 and has been a mainstay of the investigation since that time. Distal motor studies across the wrist are easily performed but have a sensitivity of only about 50%. Prolongation of distal latency and conduction block between the palm and wrist are the two abnormalities commonly observed. When an inching technique is used across the palm, the exact area of neurophysiologic abnormality can be seen very clearly, and the sensitivity of the area is increased. The neurophysiologic disorder is localized within the palm, 2 to 4 cm distal to the wrist crease, which is at the distal edge of the volar carpal ligament. The most sensitive criterion for diagnosis of carpal tunnel syndrome is the demonstration of slowing of sensory or mixed nerve conduction at the wrist. Sometimes it is useful to test several digits to detect the abnormality. The use of an internal control, comparing a median conduction study with the analogous ulnar study, increases the electrophysiologicsensitivity to more than 90%. A comparison of the median mixed palmar latency with the ulnar mixed palmar latency across the wrist may prove useful. Likewise, a comparison of the median sensory latency of digit 4 to the ulnar sensory latency of digit 4 (digit 4 usually is dually innervated) is very sensitive in detecting subtle abnormalities of slowing. Comparison of the symptomatic and asymptomatic hands in the diagnosis of carpal tunnel syndrome often is not helpful because the asymptomatic hand is electrically affected in a high proportion of patients. Electromyographyis often used, primarily in the differential diagnosis. In patients with severe carpal tunnel syndrome and axonal loss, the abnormalities shown by electromyography should be seen in the opponens muscle and the abductor pollicis brevis. Approximately 95% of patients with clinically apparent carpal tunnel syndrome have definable neurophysiologic abnormalities. A few patients whose nerve conduction test appears to be normal respond to carpal tunnel release, which constitutes a false-negative result. Inevitably, there are also false positives, of which the most likely is the presence of abnormality in the asymptomatic hand, but there are also confounding false positives produced by other diseases, such as peripheral neuropathy, amyotrophic lateral sclerosis, and cervical spine disease. A well-planned individualized investigation usually can manage these difficulties.

DifferentialDiagnosis The most common differential diagnosis to be considered in a patient with apparent carpal tunnel syndrome is cervical radiculopathy-usually cervical root &which can often be recognized by the presence of neck pain, by pain that radiates to the arm in response to coughing or sneezing, and by a preponderance of pain proximally as opposed to distally (the opposite is true of carpal tunnel syndrome). When neurologic features are present, reflex loss, muscle atrophy, and sensory loss over the dorsum of the hand may be seen. Thoracic outlet syndrome (discussed later in this chapter) is most quickly recognized by showing that the symptoms occur with elevation and abduction of the arm or by showing that the

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neurologic deficit spans the territories of C8 and T1 nerve roots rather than the median nerve. Proximal median nerve dysfunction is most easily recognized by testing for the function of the flexor pollicis longus, which produces flexion of the distal joint of the thumb, or for flexion or pronation of the wrist. Transient ischemic attacks, affecting the contralateral cerebral hemisphere, usually do not produce anything the patient would describe as pain.

Treatment Conservative management of carpal tunnel syndrome involves splinting the wrist in a slightlyextended position, reducing activity that might have caused the syndrome to develop, and injecting a steroid underneath the volar carpal ligament. The steroid injection can be performed by any practitioner if the median nerve is avoided and the steroid is injected several centimeters proximal to the wrist creases so that it can diffuse among the flexor tendons to reduce swelling and inflammation. The objective of conservative management is to reduce the tissue pressure within the carpal canal, which rises with wrist extension or flexion or as a consequence of inflammation of the flexor tendons. Patients who have progressive symptoms and have not responded to simple conservative measures (Fig. 101-1) should be referred to a surgeon for volar carpal tunnel release. Repeated steroid injections are to be avoided because they can lead to complications. Late-stage carpal tunnel syndrome with advanced atrophy, sensory loss, and few symptoms is not improved by surgery. The rare patients who have acute development of symptoms should be seen as an emergency and operated on promptly because they can have irreversible loss of function. The responses to treatment generally are satisfactory. Patients who use their hands for heavy labor will not be able to return to work for 3 to 4 months after surgery. Those who have a sedentary job can go back to work with a bulky dressing on the wrist within a week. Many patients have some postoperative pain, produced by local pressure on the wrist or use of the wrist, and this may last for several months. The long-term effects of carpal tunnel syndrome surgery are good, but 10% of patients are worse after surgery. ULNAR NEUROPATHY AT THE ELBOW Ulnar neuropathy at the elbow is second only to carpal tunnel syndrome in incidence of entrapment neuropathy of the upper extremity. The patient usually presents with tingling into the little finger, accompanied by some degree of weakness of the hand. With advancing disease, the motor symptoms predominate, and in the end a patient with ulnar neuropathy may lose much hand function, including digital control and grip. This is in contrast to carpal tunnel syndrome, in which the sensory symptoms and pain tend to predominate throughout. The causes of ulnar neuropathy at the elbow are varied. An effort should be made when examining patients to ascertain the cause of the problem, but it must be recognized that even after careful neurophysiologic investigation and a surgical procedure, the exact cause of nerve compression can be difficult to corroborate. Probably the most common cause of ulnar compression at the elbow, particularly in the milder cases and in those associated with repetitive elbow flexion, is cubital tunnel syndrome (Fig. 101-2). In this abnormality the ulnar nerve is compressed by the edge of the aponeurosis of the flexor carpi

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A

B

FIG. 101-1. Carpal tunnel syndrome. (A) A hemostat has been placed under the transverse carpal ligament. The patient's fingers are to the left, and the wrist is to the right. (13) The ligament has been incised, exposing the median nerve directly beneath it. (From Dawson D, Hallet M, Millender L Entrapment Neuropathies. p. 44. Little, Brown, Boston, 1983, with permission.)

ulnaris, located about 2 cm distal to the tip of the elbow when the elbow is flexed. Sometimes a Tine1 sign can be elicited at that exact point, or an inching technique with nerve conduction testing can show that as the point of compression. In some patients, chronic trauma to the nerve, especially when the ulnar groove is shallow, can lead to symptoms. Recurrent subluxation of the nerve, which then rides up over the medial epicondyle, can be associated with ulnar nerve disorder, but it should be recognized that subluxation also occurs in patients who have no symptoms. In previous decades, prior fracture of the olecranon or other damage to the elbow joint would lead to slow progressive scarring of the nerve (tardy ulnar palsy). This condition is not often observed today. Clinical Features

Although sensory complaints are very common in patients with ulnar nerve disorder at the elbow, the sensory loss usually is slight

and is located over the little finger and adjacent parts of the palm. Sometimes the split down the ring finger, showing that the medial side is innervated by the ulnar nerve, is a helpful diagnostic point. The motor loss in ulnar nerve compression is important to verify correctly. Some patients, such as musicians, who need careful digital control, may be more aware of the motor disability than the examination can show. Use of the long-finger flexors and extensors, innervated by radial and median muscles, can compensate for many movements of the digits but not all. Finger abduction, especially abduction of the fifth and index fingers, is easily tested. Adduction is testable as well, especially adduction of the ring finger for which long-finger flexors and extensors cannot substitute. If there is marked weakness of lumbricals and interosseous muscles, power grip may be reduced; the patient may be aware of this, and it can be measured and demonstrated. An important muscle to test in the presence of an ulnar nerve lesion is the long flexor for the fifth finger. This is innervated in the

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H Common Entrapmentand Compression Neuropathiesof the Upper Extremity

forearm by the ulnar nerve and is the only reliably testable muscle in the forearm that is so innervated. The flexor digitorum profundus for digit 5 controls flexion of the terminal phalanx, which can be compared with other flexors in that hand or with the comparable muscle on the other side. Once that muscle has been shown to be abnormal, the site of the lesion is much better defined because ulnar nerve compression at the wrist is thereby excluded. Occupational Considerations

There is no clear-cut occupational exposure that leads to ulnar nerve disorder. Compression of the ulnar nerve can occur in the postoperative period. It is not rare to discover a patient with new weakness and sensory loss in the hand after a period of anesthesia. The mechanism for this is not well known, but sometimes pronounced prolonged flexion of the elbow, extension on an armboard, or compression by an external sharp edge of the table can be confirmed. Musicians seem particularly susceptible to ulnar nerve compression, and it has been observed particularly in violinists and flutists, both of whom practice many hours per day with one arm or both in a flexed position.

Differential Diagnosis The differential diagnosis of ulnar nerve compression at the elbow differs from that of carpal tunnel syndrome. However, the two conditions may be easily confused or confounded because at least one half of the patients interviewed cannot reliably report which digits are affected by paresthesias. Thoracic outlet syndrome (discussedlater in this chapter) may occur in a form in which there is pronounced disorder of the C8 and T1 nerve roots. Usually this is associated with a fibrous band or other structural abnormality of the brachial plexus. Such patients may resemble those with ulnar

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neuropathy but can be distinguished by the following facts: with C8-T1 root disorder, sensory loss is present over the medial side of the hand but extends upward over the territory of the medial antebrachial cutaneous nerve in the forearm. This does not occur with ulnar nerve palsies. Also, the muscle atrophy in neurogenic thoracic outlet syndrome includes all the muscles in the hand and may begin in the median territory, producing ulnar sensory loss and median weakness. Other problems with the brachial plexus must be considered on occasion, and metastatic carcinoma or stretch injuries of the plexus can resemble ulnar neuropathy as well. This is sometimes seen after cardiac surgery; in such patients the disorder appears to be related to the position of the arm during surgery, producing intrinsic muscle weakness and ulnar sensory loss, usually caused by brachial plexus stretch injury. Treatment

Treatment of ulnar neuropathies at the elbow is less satisfactory than that of carpal tunnel syndrome. Early mild cases may respond to a simple restriction of elbow flexion, using a bivalve cast or orthosis, which can be manufactured by an occupational therapist and worn during periods of rest or at night. Steroid injection therapy plays no role. Inflammatory medication may be helpful. With advancing motor or sensory loss or pain, a surgical approach is indicated. In some patients, especially those with mild early nerve compression, a simple release of the flexor carpi ulnaris aponeurosis, that is, a cubital tunnel release, may be sufficient. Beyond that point, surgeons can choose from several procedures. Some surgeons prefer an epicondylectomy, allowing the nerve to ride anteriorly into the bed of the removed epicondyle. Other surgeons prefer a transposition of the nerve in front of the epicondyle. The results of surgery are more commensurate with the degree of preoperative nerve disorder than they are with the

EPICONDYLE

APONEUROSIS

COLLATERAL LIGAMENT

FIG. 101-2. View of the medial side of the right arm, showing the course of the ulnar nerve past the medial epicondyle and entering the cubital tunnel under the edge of the aponeurosis of the flexor carpi ulnaris. (From Kincaid JC: The electrodiagnosis of ulnar neuropathy at the elbow. Muscle Nerve 1 1 :1005-1015, 1988, with permission.)

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Spinal Cord and Peripheral Neuromuxulsr Disease

Diseases of Peripheral Nerve

choice of procedure. Generally speaking, the pain is relieved, and some return of function can be anticipated in most cases. The surgical issues and the relationship of the apparent cause of the neuropathy to the choice of procedure are well described by Campbell.

in the brachial plexus by nerve conduction testing are now believed to be erroneous. Likewise, somatosensory testing, using an electrode over the spinal cord, does not appear to contribute to a diagnosis.

RADIAL NERVE ENTRAPMENT Elecbophysiologk Features The techniques for neurophysiologic investigation resemble those for carpal tunnel syndrome. Generally, the search is for an area of focal slowing near the elbow. It is common to find an abnormality of the ulnar nerve, either by a reduction of the ulnar sensory action potential from the fifth finger or by general slowing and dispersion of the motor action potential. Sometimes these occur without a discernible focal slowing or conduction block at the elbow unless there is careful attention to technique. The neurophysiologic differential diagnosis is extensive. Neurogenic thoracic outlet syndrome must be excluded, primarily by showing that there is no focal slowing of the ulnar nerve and that some median nerve innervated muscles are also affected. In addition, the medial antebrachial sensory potential often is useful to study, being reduced or absent in neurogenic thoracic outlet syndrome. Again, comparison with the opposite ulnar nerve may not be an effective technique because the other side can be affected as well. The presence of generalized peripheral neuropathy can be ascertained by showing a reduction in another sensory action potential, such as the radial or the sural nerves. THORACIC OUTLET SYNDROME The diagnosis of thoracic outlet syndrome appears to carry a very high rate of error and does not have the neurologic or electrophysiologic support that exists for other entrapment neuropathies. There are a few patients who have the so-called true neurogenic thoracic outlet syndrome, commonly caused by a fibrous band traversing the brachial plexus. These patients present with weakness, pain, and numbness in the hand according to a very specific neurologic pattern. These patients are very rare, and even recognized experts in the field have seen no more than a handful of cases. The second type of thoracic outlet syndrome is much more common, although the limits of the syndrome are very poorly defined. Patients present with numbness, tingling, and pain in the hand, without demonstrable neurologic deficit. The symptoms often depend on arm or shoulder position. In some centers in the United States the patients are operated on, typicallywith a removal of the first rib through a transaxillary approach. Many patients operated on in this way have persistent or increased symptoms postoperatively, and most neurologists usually do not recommend first rib removal in these circumstances. It may be that the syndrome is produced by shoulder or arm position and is related to muscular spasm. Often it responds to physiotherapy over a period of several months, attesting to the reversible positional nature of the deficit. Electrophysiologic investigation of patients with neurogenic thoracic outlet syndrome demonstrates reduced sensory action potentials in the little finger and medial forearm and denervation changes in many of the intrinsic muscles of the hand (both ulnar and median) and sometimes in the muscles of 'the forearm that contain a C8 component. Patients with functional or reversible thoracic outlet syndrome have normal studies. Earlier reports that slowing can be demonstrated across the thoracic outlet syndrome

The radial nerve can be affected by a compression or entrapment neuropathy in its proximal portions in the forearm. This produces a clinical picture consisting of partial weakness of extensors of the fingers. Because the nerve most commonly compressed is the posterior interosseous branch of the radial nerve, the extensor carpi radialis is not affected, and the patient retains the ability to dorsiflex the wrist, typically with some deviation of the wrist toward the radial side. The other muscles extending the thumb and the fingers may be sequentially or partially affected, often starting on the ulnar side of the hand. This may produce an unusual appearance that, once seen, can be subsequently recognized but is often confusing at first. Entrapment of the posterior interosseous nerve typically does not produce a sensory loss because the superficial radial nerve leaves the parent nerve before the point of the constriction. The radial tunnel syndrome is another version of radial entrapment at the elbow, in which there is pain at the site where this constriction occurs, typically 5 to 10 cm distal to the elbow joint itself. Tenderness there or radiating pain produced by compression during examination may suggest that the radial nerve is affected. This may occur with only minimal weakness of the hand. The electrophysiologicinvestigation of radial tunnel syndrome or radial nerve compression depends on attempting to show slowing to distal radial innervated muscles or electromyographic changes limited to radically innervated muscles. The manner is somewhat controversial, and there appear to be patients who have the syndrome with barely detectable electrophysiologic abnormalities.

MEDIAN NERVE COMPRESSION IN THE FOREARM A number of syndromes have been described in which the median nerve is affected near the elbow, typically within the mass of the pronator muscle. For this reason these syndromes often are collectively called pronator syndrome. A blow on the arm at that point, anomaly of the muscle or of an arterial supply at that point, possibly hypertrophy of the pronator muscle, and compression by the arch of the flexor sublimis muscle have all been described. Because the entire median nerve is affected at that point, one would theoretically expect sensory loss throughout the median nerve territory in the palm and fingers and weakness of finger flexion, wrist flexion, some thumb abduction, and so on. In fact, these findings are quite rare; the pronator syndrome is a rarely authenticated diagnosis, and even when it is found, the deficits in the median nerve seem to be very incomplete or partial. A branch of the median nerve just distal to the pronator muscle is the anterior interosseous nerve. This is a nerve without a cutaneous sensory supply, supplying motor fibers to the flexors of the thumb and index finger. This rarely is involved in compressive lesions within the pronator muscle, and a subcategory of pronator syndrome consists only of anterior interosseous nerve palsy. However, a more prevalent version of anterior interosseous nerve deficit is not compressive at all. It is a subcategory of idiopathic brachial neuritis, also known as Parsonage-Turner syndrome, For

Chapter 102

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some reason such patients very often have weakness of the deltoid, biceps, and serratus anterior and the muscles innervated by the anterior interosseous nerve. In summary, patients with a proximal median neuropathy in the region of the elbow should be viewed with skepticism. An anterior interosseous nerve palsy usually is caused by idiopathic brachial neuritis rather than by compression, and surgical exploration is not indicated. In the few patients in whom a pronator syndrome of some type exists, watchful waiting appears to be the best course in view of the vague nature of the syndrome in most instances and its unknown prognosis.

647

Dellon AL, Hament W, Gittelshon A: Nonoperative management of cubital tunnel syndrome: an 8-year prospective study. Neurology 43~1673-1677, 1993

Kaplan SJ, Glickel SZ, Eaton RG Predictive factors in the nonsurgical treatment of carpal tunnel syndrome. J Hand Surg [Br] 15:106-108, 1990

Katz JN,Larson MG, Sabra A et al: The carpal tunnel syndrome: diagnostic utility of the history and physical examination findings. Ann Intern Med 112:321-327, 1990 Miller R G Ulnar neuropathy at the elbow. Muscle Nerve 14:97-101, 1991 Nathan PA, Myers LD, Keniston RC et al: Simple decompression of the ulnar nerve: an alternative to anterior transposition. J Hand Surg [Br] 17~251-254, 1992

SUGGESTED READINGS Campbell WW: Ulnar neuropathy at the elbow. pp. 123-175. In Dawson DM, Hallett M, Wilbourn AJ: Entrapment Neuropathies. 3rd Ed. Lippincott-Raven, Philadelphia, 1999 Dawson DM, Hallett M, Wilbourn AJ: Entrapment Neuropathies. 3rd Ed. Lippincott-Raven, Philadelphia, 1999 Dellon AL: Review of treatment results for ulnar nerve compression at the elbow. J Hand Surg [Am] 14688-699, 1989

Rosenbaum RB, Ochoa J L Carpal Tunnel Syndrome and Other Disorders of the Median Nerve. 2nd Ed. Butterworth-Heinemann,Boston, 2002 Silverstein BA, Fine LJ, Armstrong TJ: Occupational factors and carpal tunnel syndrome. Am J Ind Med 11:343-358, 1987 Stock SR: Workplace ergonomic factors and the development of musculoskeletal disorders of the neck and upper limbs: a meta-analysis. Am J Ind Med 1987-107, 1991 Szabo RM, Chidgey L K Stress carpal tunnel pressures in patients with carpal tunnel syndrome and normal patients. J Hand Surg [Am] 14:624, 1989

102 Common Entrapment and Compressive

Neuropathies of the Lower Extremity Bashar Katirji Although not as prevalent as their counterparts in the upper extremity, focal peripheral neuropathies of the lower extremity can be a diagnostic challenge because they are commonly confused with lumbosacral radiculopathies or plexopathies. This is particularly true in older adults, in whom lumbosacral radiculopathies, caused by lumbar spine disease, are common, and incorrect diagnoses may lead to unnecessary spinal surgery.

PERONEAL NEUROPATHY AT THE FIBULAR HEAD Anatomy

In the upper thigh, while sharing a common sheath with the tibial nerve (also called medial popliteal nerve), the common peroneal nerve (also called lateral popliteal nerve) innervates the short head of biceps femoris, the only hamstring muscle it innervates (Fig. 102-1). After separating from the tibial nerve in the upper popliteal fossa, the common peroneal nerve gives off the lateral cutaneous nerve of the calf, which innervates the skin over the upper third of the lateral aspect of the leg. It then winds around the fibular neck, lying in close contact with it, and passes through a tendinous tunnel between the edge of the peroneus longus muscle and the fibula, sometimes called the fibular tunnel. Near that point, the common peroneal nerve divides into superficial and deep branches. The superficial peroneal nerve innervates the peroneus longus and brevis and the skin of the lower two thirds of the lateral aspect of the leg and the dorsum of the foot. The deep peroneal is primarily motor; it innervates the ankle and toe extensors (tibialis anterior, extensor hallucis, extensor digitorum

longus and brevis) and peroneus tertius in addition to the skin of the web space between the first and second toes. Etiology Peroneal neuropathy at the fibular head is the most common compressive neuropathy in the lower extremity, although its exact incidence and prevalence are unknown. In most cases, it results from prolonged compression of the peroneal nerve between an external object and the fibular head. The common predisposing factors for acute compression at the fibular head are as follows: Recent surgery (such as anesthesia for coronary bypass or craniotomy) Weight loss (including anorexia nervosa) Recent prolonged hospitalization (including bed rest, coma) Habitual leg-crossing (usually combined with weight loss) Diabetes Peripheral polyneuropathy Others (prolonged squatting “strawberry pickers,” braces, casts) Intraoperative compression is the most common cause of acute peroneal neuropathy at the fibular neck. The second most common cause is trauma, including blunt or open trauma, as well as surgical nerve injury. Fracture of the fibula, knee dislocation, knee surgery, and arthroscopy, lacerations, and vehicular car accidents may result in peroneal nerve injuries. Stretch injuries of the peroneal nerve may occur after severe inversion sprains of the

Chapter 102

Common Entrapmentand Compressive Neuropathiesof the Lower Extremity

some reason such patients very often have weakness of the deltoid, biceps, and serratus anterior and the muscles innervated by the anterior interosseous nerve. In summary, patients with a proximal median neuropathy in the region of the elbow should be viewed with skepticism. An anterior interosseous nerve palsy usually is caused by idiopathic brachial neuritis rather than by compression, and surgical exploration is not indicated. In the few patients in whom a pronator syndrome of some type exists, watchful waiting appears to be the best course in view of the vague nature of the syndrome in most instances and its unknown prognosis.

647

Dellon AL, Hament W, Gittelshon A: Nonoperative management of cubital tunnel syndrome: an 8-year prospective study. Neurology 43~1673-1677, 1993

Kaplan SJ, Glickel SZ, Eaton RG Predictive factors in the nonsurgical treatment of carpal tunnel syndrome. J Hand Surg [Br] 15:106-108, 1990

Katz JN,Larson MG, Sabra A et al: The carpal tunnel syndrome: diagnostic utility of the history and physical examination findings. Ann Intern Med 112:321-327, 1990 Miller R G Ulnar neuropathy at the elbow. Muscle Nerve 14:97-101, 1991 Nathan PA, Myers LD, Keniston RC et al: Simple decompression of the ulnar nerve: an alternative to anterior transposition. J Hand Surg [Br] 17~251-254, 1992

SUGGESTED READINGS Campbell WW: Ulnar neuropathy at the elbow. pp. 123-175. In Dawson DM, Hallett M, Wilbourn AJ: Entrapment Neuropathies. 3rd Ed. Lippincott-Raven, Philadelphia, 1999 Dawson DM, Hallett M, Wilbourn AJ: Entrapment Neuropathies. 3rd Ed. Lippincott-Raven, Philadelphia, 1999 Dellon AL: Review of treatment results for ulnar nerve compression at the elbow. J Hand Surg [Am] 14688-699, 1989

Rosenbaum RB, Ochoa J L Carpal Tunnel Syndrome and Other Disorders of the Median Nerve. 2nd Ed. Butterworth-Heinemann,Boston, 2002 Silverstein BA, Fine LJ, Armstrong TJ: Occupational factors and carpal tunnel syndrome. Am J Ind Med 11:343-358, 1987 Stock SR: Workplace ergonomic factors and the development of musculoskeletal disorders of the neck and upper limbs: a meta-analysis. Am J Ind Med 1987-107, 1991 Szabo RM, Chidgey L K Stress carpal tunnel pressures in patients with carpal tunnel syndrome and normal patients. J Hand Surg [Am] 14:624, 1989

102 Common Entrapment and Compressive

Neuropathies of the Lower Extremity Bashar Katirji Although not as prevalent as their counterparts in the upper extremity, focal peripheral neuropathies of the lower extremity can be a diagnostic challenge because they are commonly confused with lumbosacral radiculopathies or plexopathies. This is particularly true in older adults, in whom lumbosacral radiculopathies, caused by lumbar spine disease, are common, and incorrect diagnoses may lead to unnecessary spinal surgery.

PERONEAL NEUROPATHY AT THE FIBULAR HEAD Anatomy

In the upper thigh, while sharing a common sheath with the tibial nerve (also called medial popliteal nerve), the common peroneal nerve (also called lateral popliteal nerve) innervates the short head of biceps femoris, the only hamstring muscle it innervates (Fig. 102-1). After separating from the tibial nerve in the upper popliteal fossa, the common peroneal nerve gives off the lateral cutaneous nerve of the calf, which innervates the skin over the upper third of the lateral aspect of the leg. It then winds around the fibular neck, lying in close contact with it, and passes through a tendinous tunnel between the edge of the peroneus longus muscle and the fibula, sometimes called the fibular tunnel. Near that point, the common peroneal nerve divides into superficial and deep branches. The superficial peroneal nerve innervates the peroneus longus and brevis and the skin of the lower two thirds of the lateral aspect of the leg and the dorsum of the foot. The deep peroneal is primarily motor; it innervates the ankle and toe extensors (tibialis anterior, extensor hallucis, extensor digitorum

longus and brevis) and peroneus tertius in addition to the skin of the web space between the first and second toes. Etiology Peroneal neuropathy at the fibular head is the most common compressive neuropathy in the lower extremity, although its exact incidence and prevalence are unknown. In most cases, it results from prolonged compression of the peroneal nerve between an external object and the fibular head. The common predisposing factors for acute compression at the fibular head are as follows: Recent surgery (such as anesthesia for coronary bypass or craniotomy) Weight loss (including anorexia nervosa) Recent prolonged hospitalization (including bed rest, coma) Habitual leg-crossing (usually combined with weight loss) Diabetes Peripheral polyneuropathy Others (prolonged squatting “strawberry pickers,” braces, casts) Intraoperative compression is the most common cause of acute peroneal neuropathy at the fibular neck. The second most common cause is trauma, including blunt or open trauma, as well as surgical nerve injury. Fracture of the fibula, knee dislocation, knee surgery, and arthroscopy, lacerations, and vehicular car accidents may result in peroneal nerve injuries. Stretch injuries of the peroneal nerve may occur after severe inversion sprains of the

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Diseases of Peripheral Nerve

Cutaneous

distribution

A

F STINER

FIG. 102-1. Course and distribution of (A) the deep and (6) the superficial peroneal nerves. (From Haymaker W, Woodland

B: Peripheral Nerve Injuries. 2nd Ed. WB Saunders, Philadelphia, 1953, with permission.) ankle. Extrinsic masses (osteochondromas, ganglion cysts, lipomas, Baker cysts) or intrinsic nerve sheath tumors (schwannomas, neurofibromas, and neurogenic sarcomas) are more rare. True peroneal entrapment at the fibular tunnel usually is caused by an anomalous firm fibrous arch overlying the nerve but is extremely rare and occurs mainly in athletes, particularly runners. Clinical Features The onset of peroneal neuropathy is acute in intraoperative compression and trauma, although in patients with weight loss or in those hospitalized for a grave illness, the onset is more subacute and, at times, difficult to determine. When peroneal palsy is progressive, a mass lesion, nerve tumor, or, rarely, true entrapment should be suspected. In common peroneal neuropathies, the deep peroneal nerve often is more affected than the superficial nerve because of the topographic arrangement of the common peroneal nerve around the fibular neck. The exiting fascicles, forming the superficialbranch, are placed laterally, and the deep peroneal fibers are located medially in direct contact with the fibular bone. Selective deep peroneal neuropathy is less common, constituting about 5% of all peroneal lesions. Peroneal neuropathies in the thigh (i.e., sciatic nerve lesions affecting the common peroneal

nerve exclusively) are rare, accounting for less than 5% of all peroneal neuropathies. The disorder usually is unilateral but can be bilateral. Foot drop (i.e., severe weakness of ankle dorsiflexion) is the most common presentation of peroneal neuropathy. Foot drop can be complete or partial. The foot may drag behind, get trapped, or cause the patient to fall. Because of weak eversion and unopposed inversion, patients may sprain or fracture their ankles. Although numbness of the leg, usually involving the dorsum of the foot and lower lateral leg, is common, pain is rare. When present, it is deep and ill-defined, usually located around the knee. On examination, weakness is limited to ankle and toe dorsiflexion and to ankle eversion. Ankle inversion, toe flexion, and plantar flexion are normal. Pseudoweakness of ankle inversion is common when the foot drop is complete. To avoid pseudoweakness,the ankle should be dorsiflexed passively to 90 degrees before testing for ankle inversion. Hypesthesia to touch and pain is limited to the lower two thirds of the lateral leg and dorsum of the foot. Tinel's sign sometimes is elicited by percussing the peroneal nerve at the fibular neck. Knee and ankle reflexes and the hamstrings, glutei, and quadriceps muscles are normal. In deep peroneal neuropathy, the sensory manifestations are lacking (except occasionally in the first web space), and ankle eversion is normal.

Chapter 102 rn Common Entrapment and Compressive Neuropathies of the Lower Extremity

649

Common pemned n.--.--

B

FIG. 102-1. Continued Course and distribution of (A) the deep and (13) the superficial peroneal nerves. (From Haymaker W, Woodland B: Peripheral Nerve Injuries. 2nd Ed. WB Saunden, Philadelphia, 1953, with permission.)

Differential Diagnosis Foot drop may result from an upper or lower motor neuron lesion. The lower motor neuron lesions include common and deep peroneal neuropathy, sciatic neuropathy (especiallywhen affecting the common peroneal nerve predominantly or exclusively), lumbosacral plexopathy (particularly with lumbosacral trunk lesion), or L5 radiculopathy. Their clinical manifestations are shown in Table 102-1. Weakness of ankle inversion, toe or plantar flexion, or absent or depressed ankle jerk are key findings not consistent with peroneal nerve lesion. Radicular pain and positive straight leg test (Lasegue test) are common in L5 radiculopathy and may be present in plexopathy or sciatic neuropathy. In a large study of common peroneal neuropathy, physicians, including neurologists, clinically misdiagnosed 43% of patients as L5 radiculopathy or sciatic neuropathy. This was usually because of the difficulty in assessing ankle inversion and eversion in the presence of foot drop.

Electrodiagnosis Nerve conduction studies and needle electromyography (EMG) are essential for both diagnostic and prognostic purposes. Even when the clinical situation is clear, the electrodiagnostic studies help confirm the site of the lesion (fibular head, thigh, deep branch), estimate the extent of injury (based on the conduction

studies data) and its nature (demyelinating versus axonal versus mixed), and thereby predict the expected course of recovery (weeks or months). Nerve Conduction Studies. The peroneal motor and sensory conduction studies should be obtained bilaterally for comparison. In addition to the usual practice of recording the extensor digitorum brevis, it is essential to include the peroneal motor studies, recording the tibialis anterior, for two reasons. First, because the tibialis anterior is the principal ankle dorsiflexor, whether the disorder is demyelinating or axonal (and, thus, the prognosis) should be established using this most clinically relevant muscle. Second, the extensor digitorum brevis is not uncommonly atrophic (presumably caused by tight shoes), resulting in an erroneous conclusion that the lesion is axonal and severe. The findings on nerve conduction studies, shown in Figure 102-2, can be divided into six patterns: conduction block (complete and partial), axonal loss (complete and partial), mixed lesions (conduction block and axonal), and selective deep peroneal lesions. Focal slowing is present in a minority of patients, usually associated with conduction block. Low-amplitude or absent motor responses (consistent with pure axonal loss) are observed in 50% of cases, pure conduction block in 20%, and mixed lesions in 30%. Thus, significant axonal loss is present in at least 80% of the lesions, including cases associated with intraoperative compression. The superficial peroneal sensory amplitude is low to absent in axon loss common peroneal lesions. However, it is normal when

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W Tmu 102-1. The Differential Diagnosis of Common Causes of Foot Drop

Peroneal Neuropathy at the Fibular Head

15 Radiculopathy

Lumbar Plexopathy (Lumbosacral Trunk)

Sciatic Neuropathy (Mainly Peroneal)

Disc herniation, spinal stenosis Weak Weak Normal Normal (unless 51) Poorly demarcated, predominantly big toe Common, radicular

Pelvic surgery. hematoma, prolonged labor Weak Weak Normal Normal (unless S1) Well demarcated to L5 dermatome Common, can be radicular

Hip surgery, injection injury, coma Normal or mildly weak Normal or mildly weak Normal or mildly weak Normal or depressed Peroneal and lateral cutaneous of calf Can be severe

Low in amplitude or conduction block across fibular head Low or absent"

Usually normal but can be low in amplitude

Low in amplitude

Low in amplitude

Normal

Low or absent

Low or absent

Abnormal Normal Normal Normal

Abnormal Abnormal Normal or abnormal Usually normal

Abnormal Abnormal Normal or abnormal Usually normal

Abnormal Normal or abnormal Normal Abnormal

Absent

May be absent

Absent

Absent

Differential Diagnosis

Common causes Ankle inversion Toe flexion Plantar flexion Ankle jerk Sensory loss distribution

Compression (weight loss, perioperative), trauma Normal Normal Normal Normal Peroneal only

Pain

Rare, deep

Electrodiagnosis

Peroneal motor study to EDB or Tib ant Superficial peroneal sensory study Peroneal musclesb Tibia1 L5 muscles' Other L5 musclesd Biceps femoris (short head) Paraspinal muscles fibrillations

"Can be normal in purely demyelinating lesions or lesion of the deep peroneal nerve only. bBelowthe knee: tibialis anterior, extensor digitorum longus, extensor digitorum brevis. extensor hallucis, and peronei. Tibialis posterior and flexor digitorum longus. dCluteusrnedius and tensor fascia lata. Abbreviations: EDB, extensor digitorum brevis; Tib Ant, tibialis anterior.

the lesion is purely demyelinating or limited to the deep peroneal branch. It is also normal in radiculopathy but usually low or absent in lumbosacral plexopathy, sciatic neuropathy, or peripheral polyneuropathy. Therefore, to exclude these possibilities, the tibial motor and sural sensory studies and H reflex study should be performed. Needle EMC. At least one superficial and two deep peroneal innervated muscles should be sampled. In all cases, fibrillation potentials are seen in the affected muscles when studied at least 3 weeks after the onset of foot drop. Sampling nonperoneal muscles such as the tibialis posterior, flexor digitorum longus, or gluteus medius is essential. As shown in Table 102-1, these are normal in peroneal lesions, but abnormal in L5 radiculopathy and lumbosacral plexopathy. In axonal peroneal neuropathies, nonlocalizable by nerve conduction studies, sampling the short head of biceps femoris is necessary to rule out a high (proximal) common peroneal lesion (sciatic neuropathy affecting the peroneal predominantly or exclusively). In these lesions, the short head of the biceps femoris is abnormal. More commonly, when the tibial component of the sciatic nerve is involved, the other hamstrings, gastrocnemius, and abductor hallucis are also affected, but the glutei are spared.

Prognosis

It is difficult to prognosticate based on clinical evaluation only. In general, as with other peripheral nerve injuries, partial lesions fare better than complete lesions because local sprouting reinnervates muscle fibers effectively. The prognosis depends on the pathologic nature of the lesion, as shown in Table 102-2. In a large study of peroneal neuropathy, most patients had prominent axonal loss: Purely axonal lesions without demyelination were present in half of the patients and significant axonal loss in 80%. In contrast to

common belief, this applies equally to the perioperative peroneal neuropathies, including the subgroup following anesthesia for coronary bypass surgery.

In acute compressive lesions, patients should be observed to allow improvement by remyelination or reinnervation. Conduction block lesions recover spontaneously in 2 to 3 months as long as further compression is prevented. Proper padding of beds, prevention of leg crossing, and arrest or reversal of weight loss should be initiated promptly. A kneepad is helpful in ambulating patients. Ankle bracing is important when the foot drop is profound to help in ambulation and prevent ankle contractures and sprains. Surgical intervention is appropriate in certain situations: When the nerve is lacerated and visibly discontinuous. This repair could be primary (at the time of laceration suturing) or secondary (if local infection is feared). When clinical or EMG evidence of reinnervation cannot established in the tibialis anterior 4 to 6 months after. Here, the nerve lesion probably is severe, at least of the third degree. In slowly progressive peroneal neuropathies, a nerve tumor, ganglion, cyst, or, rarely, true entrapment is suspected and the nerve explored after appropriate electrodiagnostic localization. Imaging studies, particularly magnetic resonance imaging, are particularly helpful in these special situations. ~~

SCIATIC NEUROPATHY AT THE HIP OR THIGH Anatomy The sciatic nerve originates from the L4, L5, S1, and S2 roots and leaves the pelvis via the sciatic notch, usually underneath the

Chapter 102

W

Common Entrapmentand Compressive Neuropathiesof the Lower Extremity

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FIG. 102-2. Diagrams of the nerve conduction studies in peroneal mononeuropathies. (A) Normal; (6 and 6’) “pure” conduction block, partial and complete; (D and D’) ‘bure“axona/ loss, partid and complete; (C) mixed; (€1deep peroneal. RSP, recording site of the superficial peroneal sensoly response; RTA, peroneal motor response, recording tibialis anterior. Proximal latencies are not drawn to scale. (From Katirji MB, Wilbourn AJ: Common peroneal mononeuropathy: a clinical and electrophysiologic study of 116 lesions. Neurology 38:1726, 1988, with permission.)

rn T l w 102-1. Classification and Degrees of Peripheral Nerve Injury Sunderland

First Denree

Second Denree

Third Denne

Seddon Electrophysiology Pathology

Neurapraxia Conduction block Segmental demyelination

Axonotmesis Loss of axons Loss of axons with intact supporting structures

Neurotmesis Loss of axons Loss of axons with disrupted endoneurium

Excellent, recovery is usually complete in 2-3 months

Slow recovery, dependent on sprouting and reinnervation

Protractedand can fail because of misdirected axonal sprouts

Prognosis

Fourth Denree

Fifth Dearee

Neurotmesis

Neurotmesis Loss of axons Loss of axons with disruption of all supporting structures (discontinuous) Impossible without surgical repair

Loss of axons Loss of axons with

disrupted endoneurium and perineurium Unlikely without surgical repair

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Spinal Cord and PeripheralNeuromuscular Disease W

Diseases of Peripheral Nerve

piriformis muscle, with significant individual variability. It is composed of a lateral division, named the common peroneal nerve or the lateral popliteal nerve, and a medial division named the tibial nerve or the medial popliteal nerve. Though enclosed in a common sheath, these two nerves are separate from the outset and do not exchange fascicles. In the thigh, the tibial component of the sciatic nerve innervates most hamstring muscles (semitendinosus, semimembranosus, and long head of biceps femoris) and supplies a branch to the adductor magnus, and the common peroneal component innervates the short head of biceps femoris only. Etiology Sciatic nerve injury may occur after hip surgery or trauma, after intramuscular gluteal injections, or in the setting of unattended coma (such as with drug overdose) or coma associated with poor positioning (such as in the intensive care unit). Clinical Features

Sciatic neuropathy presents with foot drop, dysesthesia, and sensory loss. On neurologic examination, weakness of ankle dorsiflexion (tibialis anterior) dominates the picture. However, careful examination often detects weakness of hamstrings (knee flexion), gastrocnemius (plantar flexion), or tibialis posterior (ankle inversion). The ankle jerk usually is asymmetrically depressed or absent. Sensory loss and dysesthesia of the sole and dorsum of the foot and lateral leg are common.

D-ferential Diagnosis Partial sciatic nerve lesions, which usually present with foot drop, may be difficult to differentiate from peroneal neuropathy, lumbosacral radiculopathy, and lumbosacral plexopathy (Table 102-1). Careful history and neurologic and electrodiagnostic evaluations often are necessary for accurate diagnosis.

Electrodiagnosls The electrodiagnostic findings in sciatic neuropathy parallel the clinical manifestations. In severe lesions, there is evidence of common peroneal and tibial neuropathies with denervation of the hamstring muscles. In mild to moderate lesions of the sciatic nerve, it is not uncommon for the studies to suggest that the lesion is an axon loss common peroneal neuropathy because the peroneal nerve often is affected more severely than the tibial nerve (Table 102-1). Helpful nerve conduction clues for the presence of a sciatic nerve lesion include an asymmetrically low or absent sural sensory nerve action potential, H reflex, or tibial motor amplitude recording abductor hallucis. Therefore, it is highly recommended that the contralateral H reflex and sural sensory and tibial motor nerve conduction studies be done in all patients with foot drop, especially when a sciatic nerve lesion is considered in the differential diagnosis. Prognosis

The prognosis of sciatic nerve lesions generally is guarded. Many patients continue with residual neurologic findings. Other patients are left with chronic foot pain and disabling manifestations of reflex sympathetic dystrophy (allodynia with skin, nail, and bone dystrophic changes).

Most symptomatic sciatic nerve lesions necessitate pain management. Tricyclic antidepressants and anticonvulsants are the drugs of choice. This, coupled with physical therapy and ankle foot orthosis for foot drop, often assist patients in ambulation. Surgical intervention (neurolysis or grafting) is indicated in severe lesions from which spontaneous recovery is deemed impossible.

FEMORAL NEUROPATHY IN THE PELVIS OR AT THE INGUINAL LIGAMENT Anatomy The femoral nerve (also called the anterior crural nerve) is formed by the combination of the posterior divisions of the ventral rami of L2, L3, and LA spinal roots (the anterior divisions of the same roots form the obturator nerve) (Fig. 102-3). It immediately gives branches to the psoas muscle before it enters its substance. Then, covered by a tight iliac fascia, the femoral nerve passes between the psoas and iliacus muscles, where it innervates the latter. After passing underneath the rigid inguinal ligament, the femoral nerve branches widely into its terminal motor branches (to the quadriceps and sartorius) and sensory branches (to the anterior thigh), including the saphenous sensory nerve, which innervates the medial half of the leg.

EtEology

The femoral nerve can be compressed at the inguinal region or in the retroperitoneal pelvic space. The most common causes of femoral neuropathy are as follows: 1. Compression in pelvis by

a. Retractor blade during pelvic surgery: abdominal hysterectomy, radical prostatectomy, renal transplantation b. Iliacus or psoas retroperitoneal hematoma: anticoagulation (systemic or subcutaneous abdominal heparin), hemophilia, coagulopathy, ruptured abdominal aneurysm, femoral artery catheterization c. Pelvic mass: tumor, abscess, cyst, aortic or iliac aneurysm 2. Compression in the inguinal region by a. Inguinal ligament during lithotomy position: vaginal delivery, laparoscopy, vaginal hysterectomy, urologic procedures b. Inguinal hematoma: femoral artery catheterization, such as for coronary angiography and total hip replacement c. Inguinal lymphadenopathy 3. Stretch injury: hyperextension, dancing, yoga 4. Others: radiation, laceration, misplaced injection By far the most commonly reported causes are those related to pelvic surgery, such as abdominal hysterectomy or radical prostatectomy. During these surgical procedures, the femoral nerve is compressed between the retractor’s blade and the pelvic wall. Most cases occur after the use of self-retracting blades rather than handheld blades. Compression at the inguinal ligament during prolonged lithotomy positioning for various procedures, including vaginal delivery, prostatectomy, and laparoscopy, is not uncommon and probably is underestimated. Acute hemorrhage in the retroperitoneal space within the iliacus muscle and, less commonly, the psoas muscle results in a compartmental syndrome and secondary severe femoral nerve damage. Although diabetes has been reported to cause selective femoral neuropathy, most cases

Chapter 102 W

Common Entrapmentand Compressive Neuropathiesof the Lower Extremity

653

Vastus lateralis------

kstus intermedius-

cutaneous n of thigh

terminal branch

I

Cutanecus distribution from anterlor aspect

Cutaneousdistnbubm from medlal bspect

FIG. 102-3. Course and distribution of the femoral nerve. (From Haymaker W, Woodland B: Peripheral Nerve Injuries. 2nd Ed. WB Saunders, Philadelphia, 1953, with permission.)

are actually caused by more extensive disease affecting the lumbar plexus and roots (diabetic radiculoplexopathy or amyotrophy).

Clinical Features Most femoral neuropathies present acutely with lower extremity weakness. Patients report buckling of the knee and frequent falls, particularly when they attempt to partially flex the knee. When the hip flexors are weak, patients cannot climb steps because they cannot clear the foot of the weak leg from the tread of stairs. Sensory symptoms over the anterior thigh and medial leg are common. Groin or thigh pain is mild (except with retroperitoneal

hematomas). The neurologic examination reveals weakness of the quadriceps muscle (knee extension) with absent or depressed knee jerk. However, thigh adduction is normal. The iliopsoas muscle (hip flexion) usually is weak when the lesion is pelvic. It should be noted that the quadriceps assists in flexing the hip; therefore, mild hip flexion weakness can be falsely attributed to the iliopsoas weakness. Hypesthesia over the anterior thigh and medial calf is common. The presentation of patients with acute iliacus or psoas hematoma is unique. Usually, they experience acute severe pain in the groin, thigh, and sometimes lower abdomen. They often keep the hip flexed to minimize pain because hip extension (such as on

654

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Diseases of Peripheral Nerve

reversed straight leg test) is extremely painful. In most cases, the neurologic deficit is limited to the femoral nerve, but extensive hematomas may result in damage to the lumbar plexus and even the entire lumbosacral plexus.

Differential Diagnosis Femoral neuropathy should be differentiated from L2, L3, and L4 radiculopathy and from lumbar plexopathy (Table 102-3). Weakness of the thigh adductors, innervated by the obturator nerve, excludes a selective femoral lesion. Positive reversed straight leg test is common in lumbar radiculopathy but may occur with plexopathy and femoral nerve lesion caused by retroperitoneal hematoma. In plexopathy or L4 radiculopathy, weakness of ankle dorsiflexion (tibialis anterior) is common. In patients with femoral neuropathy and severe pain, particularly in the setting of anticoagulation or coagulopathy, a retroperitoneal hematoma should be suspected and a pelvic computed tomography scan obtained urgently.

Eledrodiagnosis The role of electrodiagnosis is confirmative in typical cases but is very helpful when true clinical weakness is not clear because of pain associated with recent abdominal surgery or delivery. In addition, the nerve conduction studies play an important role in predicting prognosis. Nerve Conduction Studies. The femoral motor and saphenous sensory studies should be performed bilaterally for comparison. The saphenous sensory studies are technically difficult in older adults or if there is leg edema. Because the femoral motor response, recording rectus femoris, can be evoked only at one site (the groin), the pathophysiologic process and prognosis depend the size (amplitude or area) of the response. In addition, because most femoral lesions are acute, care should be taken in accounting for the time for wallerian degeneration. The drop in sensory amplitudes lags behind that of motor amplitudes: The former reach their nadir in 8 to 11 days, the latter in 4 to 5 days. Thus, beyond the period necessary for wallerian degeneration (i.e., after 10 to 11 days), the femoral motor amplitude is low or absent and the saphenous sensory response is absent in axonal lesions, but both remain normal in purely demyelinating lesions. Needle EMG. The quadriceps and iliacus muscles should be sampled in all patients with suspected femoral neuropathy. Fibrillation potentials and impaired recruitment are seen in affected muscles. The motor unit potentials are normal unless sprouting has occurred; in that case, they become large (increased in duration, high in amplitude, and polyphasic). If the iliacus is abnormal, the lesion is pelvic, that is, not at the inguinal ligament. The thigh adductors and tibialis anterior are normal in femoral lesions (Table 102-3).

Prognosis In general, femoral neuropathy carries a good prognosis, even when the lesion is caused by axonal loss. Sprouting and reinnervation are optimal because the target muscle (quadriceps) is both proximal and near the site of injury. Among all causes of femoral neuropathies, lesions caused by iliacus compartmental hematoma have the worse prognosis. Demyelinating lesions, such as those after lithotomy positioning, recover completely in 3 to 4 months. The femoral motor amplitude or area, recording rectus femoris, is essential in prognosticating these lesions.

Management To prevent compression at the inguinal ligament, prolonged lithotomy positioning with extreme hip flexion and external rotation should be avoided. Also, avoiding using retractors during pelvic and gynecologic operations practically eliminates the intraoperative femoral nerve injuries. Most cases of femoral neuropathy are treated conservatively. The management of retroperitoneal hematoma (observation versus evacuation) is controversial. Ideally, hematoma evacuation should occur as soon as it is detected and before signs of severe femoral nerve injury occur. Obviously, stopping anticoagulation or correcting coagulopathy is necessary. Physical therapy is recommended in all patients. A knee brace is indicated in patients with severe weakness of the quadriceps to prevent falls.

TARSAL TUNNEL SYNDROME

Anatomy After innervating the gastrocnemius, soleus, tibialis posterior, flexor digitorum profundus, and flexor hallucis longus in the calf, the tibial nerve passes through the tarsal tunnel at the medial aspect of the ankle and innervates the skin and muscles of the sole of the foot (Fig. 102-4). The roof of the tarsal tunnel is composed of a thin fascia, the flexor retinaculum, which connects the medial malleolus to the calcaneus. There, the tibial nerve is accompanied by the tibial artery and the flexor digitorum longus and flexor hallucis longus tendons. At or slightly distal to the tunnel, the nerve divides into its three terminal branches: the calcaneal branch, a purely sensory nerve that innervates the skin of the sole of the heel; the medial plantar nerve, which innervates the abductor hallucis, flexor digitorum brevis, and flexor hallucis brevis in addition to the skin of the medial sole and, at least, the medial three toes; and the lateral plantar nerve, which innervates the abductor digiti quinti pedis, flexor digiti quinti pedis, adductor hallucis, and interossei in addition to the skin of the lateral sole and two lateral toes.

rn TABLE102-3. Differential Diagnosis of Femoral Neuropathy Thigh adducton Tibialis anterior (ankle dorsiflexion) Saphenous sensory nerve action potential ParasDinal fibrillations 'Abnormal in L4 radiculopathy only. bNormal in purely demyelinating lesions.

Femoral Neuropathy

Lumbar Plexopathy

lumbar Radiculopathy

Normal Normal Usually low or absentb Absent

Abnormal Abnormal Low or absent Absent

Abnormal Abnormal' Normal May be absent

Chapter 102 rn Common Entrapment and Compressive Neuropathies of the Lower Extremity

655

Etiology Tibia1 N e r v e

Flexor Retinaculum Branches Quadratus Plantae Muscle Lateral Plantar N e r v e

Medial Plantar Nerve Abductor HallucisMuscle FIG. 102-4. The tibial nerve at the ankle with its three terminal branches. (From Qck PJ, Thomas PK: Peripheral NeuroPathY. 3rd Ed.

WB Saunders, Philadelphia, 1993, with permission.)

Tarsal tunnel syndrome (TTS) is an uncommon disorder caused by compression of the tibial nerve or any of its three terminal branches under the flexor retinaculum. TTS is sometimes called medial tarsal tunnel syndrome to distinguish it from anterior tarsal tunnel syndrome, which is an entrapment of the terminal segment of the deep peroneal nerve under the extensor retinaculum in the dorsum of the foot. Many reported cases lack objective neurologic signs or electrophysiologic confirmation. Most well-documented cases are unilateral and idiopathic. Biomechanical causes, such as ill-fitting footwear or heel varus and valgus deformity may precipitate TTS, and runners, joggers, and dancers are at particularly high risk for developing this entrapment. TTS may also result from fibrosis caused by remote trauma to the ankle (sprain, fracture, or dislocation), tenosynovitis with or without rheumatoid arthritis, or mass lesion within the tunnel (varicose veins, ganglion, lipoma, schwannoma).

TAW 102-4. Other Entrapment and Compressive Neuropathies in the Lower Extremity NeNe

True Syndromes Lateral femoral cutaneous (meralgia paresthetica)

Ilioinguinal (inguinal neuralgia)

causes

Clinical Manifestations

Differential Diagnosis

Management

Entrapment at the inguinal ligament (idiopathic, pregnancy, obesity, diabetes, belt, beeper), pelvic mass, pelvic hematoma, or abdominal surgery Inguinal hernia repair, appendectomy, retroperitoneal mass or incision

Paresthesia and pain (deep and superficial) in lateral thigh; exam: well-demarcated sensory impairment of the lateral thigh; sensory conduction study technically difficult

L3 or L2 radiculopathy; femoral neuropathy

Burning pain in the lower abdomen, groin radiating to the scrotum and upper thigh, worse with walking; exam: sensory disturbance along inguinal ligament Painful paresthesias in upper thigh, scrotum, and medial groin; exam: sensory disturbance in scrotum and upper thigh, absence of cremasteric reflex Asymmetrical abdominal wall bulging and trivial sensory loss in suprapubic area Numbness in medial thigh with variable pain; exam: sensory loss in medial thigh; saphenous sensory conduction study useful

Cenitofemoral neuropathy (diagnostic nerve block might be needed), L1 or L2 radiculopathy, hip joint disease

Conservative because most resolve in months; local steroids sometimes helpful; decompression at the inguinal ligament rarely needed Analgesia and nerve blocks in postoperative cases; rarely, surgical exploration

Cenitofemoral

Appendectomy, inguinal hernia repair

lliohypogastric

Retroperitoneal mass or incision (nephrectomy)

Saphenous

Surgery for varicose veins or removal of saphenous vein for coronary artery graft. knee surgery, entrapment at Hunter's canal Hip surgery, pelvic fracture, obturator hernia, malignant pelvic neoplasm

Obturator

llioinguinal neuropathy (diagnostic nerve block might be needed), L1 or U radiculopathy, hip joint disease

Conservative

llioinguinal or genitofemoral neuropathy, L1 or L2 radiculopathy L4 radiculopathy, mild femoral neuropathy

Conservative

Leg weakness, pain, and paresthesias in thigh and inner leg; exam: weakness of thigh adductors

U and U radiculopathy,

Dependent on primary cause; surgical exploration rarely needed

Pain in the buttock and leg with ill-defined paresthesias; exquisite buttock tenderness near the sciatic notch; normal neurologic and electrodiagnostic examinations

Lumbosacral radiculopathy, particularly L5 and S1, hip joint disease, bursitis

Trivial; usually foot paresthesias and deep ankle pain; exam: atrophy of extensor digitorum brevis and hypesthesia in first web

Asymptomatic atrophy of extensor digitorum brevis, common or deep peroneal neuropathy at fibular head, L5 radiculopathv, arthritis

lumbar plexopathy, femoral neuropathy

Conservative; exploration of Hunter's canal rarely indicated

Disputed Syndromes

Piriformis syndrome

Anterior tarsal tunnel syndrome

Compression of the sciatic nerve at the pelvic outlet by the overlying piriformis muscle; history of trivial trauma to the buttock common; compressive bands or vessels common at surgery Compression of terminal segment of deep peroneal nerve by superficial fascia of ankle (tight shoes, fractures, sprains)

Conservative with physical therapy (prolonged stretching of piriformis muscle by flexion, adduction and internal rotation of the hip); surgical exploration rarely indicated Conservative with foot orthosis or local steroids

656

Spinal Cord and Peripheral Neuromuscular Disease

Diseases of Peripheral Nerve

Clinical Features

The most common symptom of TTS is burning pain and numbness of the foot and ankle, which may worsen after prolonged standing, walking, running, or jogging. Paresthesias in the sole without pain are less common, and subjective weakness and imbalance are extremely rare. The neurologic examination should document sensory impairment in the sole in the distribution of one or all of the terminal branches. The sensory loss spares the heel (innervated by the calcaneal branch) in 40% of patients. In 25% of patients with TTS, the sensory loss is only in the medial plantar nerve distribution, and in 10% it follows the lateral plantar nerve selectively. Tinel's sign, induced by percussion of the tibial nerve at the flexor retinaculum, is present in most patients. Muscle atrophy in one sole may be detected. Weakness is rare because the long toe flexors are intact. The ankle jerk and sensation of the dorsum of the foot are normal. Electrodiagnosis

Similar to the clinical presentation, the electrodiagnostic evaluation of the plantar nerves can be difficult for two reasons. First, sensory nerve action potentials, using surface stimulations and recordings, are technically difficult to elicit, especially in older adults with foot calluses or ankle edema. They are often absent in asymptomatic subjects. Second, needle examination of the muscles of the sole is painful and may show denervation changes in asymptomatic subjects, especially older adults. Nerve Conduction Studies. Both the motor and sensory studies should be attempted bilaterally for comparison. In addition to the routine tibial motor studies, recording abductor hallucis, the tibial motor study recording the abductor digiti quinti pedis should also be performed. The former evaluates the medial plantar nerve, and the latter evaluatesthe lateral plantar nerve. The amplitudes are low and latencies slow in less than half of the patients.

The orthodromic mixed plantar studies of the medial and lateral plantar nerves should be obtained by percutaneous (surface) stimulation of the medial and lateral plantar nerves on the sole of the foot while recording with surface electrodes over the tibial nerve posterior to the medial malleolus. These studies are the counterparts of the orthodromic median and ulnar palmar mixed studies performed to evaluate carpal tunnel syndrome. They are more sensitive than the motor studies but may be difficult to elicit in patients with foot calluses, ankle edema, or foot deformities, or even in normal adults over 45 years of age. Asymmetrical slowing or asymmetrically absent responses are diagnostic. Techniques for assessing solely the sensory fibers of the medial and lateral plantar nerves may be done but are technically difficult, must be averaged, and are not popular. Near-nerve needle recordings and stimulations have been advocated but are invasive and painful and may result in foot infection. Needle EMG. Sampling of the abductor hallucis and abductor digiti minimi pedis may show chronic neurogenic changes with or without fibrillations. Differential Diagnosis

The diagnosis of TTS is difficult because foot pain can be seen in a variety of orthopedic, rheumatologic, and neurologic conditions, including stress fracture, bursitis, arthritis, plantar fascitis, lumbosacral radiculopathy, peripheral polyneuropathy, and reflex sympathetic dystrophy. Accurate diagnosis is particularly difficult in patients with a prior history of trauma, and differentiating TTS from reflex sympathetic dystrophy can be challenging. Careful evaluation of the ankle and foot, including radiographs, bone scan, tomography, and EMG, often is necessary for correct diagnosis. Lesions of the medial or lateral plantar nerves at the tarsal tunnel may mimic selective lesions of these nerves within the sole of the foot, which may be caused also by trauma, bunion surgery, foot deformities (such as pes cavus), arthritis, or synovial cyst. A

llioinguinal Nerve T12

lliohypogastric Nerve Dorsal Nerve of Penis Perineal Nerves

Lateral Cutaneous Nerve of Thigh

Femoral & Genital Branches of Genito-femoral Nerve Obturator Nerve

Femoral Nerve

FIG. 102-5. Innervation of the skin of inguinal area and the upper thigh. (From Stewart JD: Focal Peripheral Neuropathies. 2nd Ed. Raven Press, New York, 1993, with permission.)

Chapter 102

Common Entrapment and Compressive Neuropathies of the Lower Extremity

careful history and a Tinel's sign distal to the tarsal tunnel are useful features. Electrodiagnostically, TTS should be differentiated from peripheral polyneuropathy and S l-S2 radiculopathies. The sural sensory or H reflex studies are abnormal in polyneuropathy, and the findings usually are symmetrical. In S1 radiculopathy, other muscles innervated by the S 1 root (such as the gastrocnemius) usually are affected, and the H reflex study usually is abnormal.

Prognosis Most patients improve without sequelae. Unfortunately, some patients, especially those associated with ankle trauma, may develop chronic pain and features of reflex sympathetic dystrophy.

Conservative treatment should be initiated in all patients first. Sources of pressure, such as ill-fitting shoes, should be identified and eliminated. Other conservative measures include minimizing ankle edema by elevation and special stockings, medial arch support o r bracing the foot with a light orthosis, antiinflammatory agents, or local injection with long-acting corticosteroids. Only a small proportion of patients need surgical decompression, and results vary. Good results can be achieved by selecting patients with documented entrapment in whom conservative treatment failed or patients with an identifiable mass. Less common compressive and entrapment neuropathies in the lower extremity are summarized in Table 102-4 and shown in Figure 102-5.

SUGGESTED READINGS Al Hakim M, Katirji MB Femoral mononeuropathy induced by the lithotomy position: a report of 5 cases and a review of the literature. Muscle Nerve 16891-895, 1993 Devi S, Lovelace RE, Duarte N: Proximal peroneal nerve conduction velocity: recording from anterior tibial and peroneus brevis muscle. Ann Neurol 2116-119, 1977

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Goldman JA, Feldberg D, Dicker D et al: Femoral neuropathy subsequent to abdominal hysterectomy. A comparative study. Eur J Obstet Gynecol Reprod Biol 20:385-392, 1985 Katirji B: Peroneal neuropathy. Neurol Clin 17:567-591, 1999 Katirji MB, Lanska DJ: Femoral mononeuropathy after radical prostatectomy. Urology 36539-540, 1990 Katirji MB, Wilbourn AJ: Common peroneal mononeuropathy: a clinical and electrophysiologicstudy of 116 lesions. Neurology 38:1723-1728, 1988 Katiji MB, Wilbourn AJ: High sciatic lesions mimicking peroneal neuropathy at the fibular head. Neurol Sci 121:172-175, 1994 Kent KC, Moscussi M, Gallagher SG et ak Neuropathy after cardiac catheterization: incidence, clinical patterns and long term outcome. J Vasc Surg 19:1008-1012, 1994 Kim DH, Kline DG: Management and results of peroneal nerve lesions. Neurosurgery 39:312-319, 1996 Kim DH, Kline D G Surgical outcome for intra- and extrapelvic femoral nerve lesions. J Neurosurg 83:783-790, 1995 Kuntzer T, van Melle G, Regli F: Clinical and prognostic features in unilateral femoral neuropathies. Muscle Nerve 20:205-211, 1997 Kvist-Poulsen H, Bore1 J Iatrogenic femoral neuropathy subsequent to abdominal hysterectomy: incidence and prevention. Obstet Gynecol 60516-520, 1982 Oh SJ, Meyer RD: Entrapment neuropathies of the tibial (posterior tibial) nerve. Neurol Clin 17:593-615,1999 Oh SJ, Sarala PK, Kuba T, Elmore R S Tarsal tunnel syndrome: electrophysiologicalstudy. Ann Neurol 5:327-530, 1979 Parziale JR, Hudgins TH, Fishman LM: The piriformis syndrome. Am J Orthop 25:819-823, 1996 Pickett JB: Localizing peroneal nerve lesions to the knee by motor conduction studies. Arch Neurol 41:192-195, 1984 Radin E L Tarsal tunnel syndrome. Clin Orthop 181:167-170, 1983 SourkesM, Stewart J D Common peroneal neuropathy: a study of selective motor and sensory involvement. Neurology 41:1029-1033, 1991 Sunderland S The relative susceptibilityto injury of the medial and lateral popliteal divisions of the sciatic nerve. Br J Surg 41:300-302, 1953 Vargo MM, Robinson LR, Nicholas JJ, Rulin MC: Postpartum femoral neuropathy: relic of an earlier era? Arch Phys Med Rehabil71:591-596, 1990 Young MR, Norris Femoral neuropathy during anticoagulant therapy. Neurology 26:1173-1175, 1976 Yuen EC, Olney RK, So YT: Sciatic neuropathy: clinical and prognostic features in 73 patients. Neurology 441669-1674, 1994 Yuen EC, So YT, Olney RK: The electrophysiologic features of sciatic neuropathy in 100 patients. Muscle Nerve 18:414-420, 1995

SECTION

4

DISEASES OF NEUROMUSCULAR TRANSMISSION

103 Myasthenia Gravis David C. Preston The neuromuscular junction (NMJ) forms an electrochemical link transmitting the nerve action potential to muscle. A variety of disorders are known to impair the NMJ at the presynaptic or postsynaptic membrane. Among these disorders, myasthenia gravis (MG) is the most common, with an incidence of 2 to 10 cases in 100,000 people per year. Over the last 30 years, the autoimmune pathophysiology of MG has been well elucidated with the recognition of antibodies directed against the nicotinic acetylcholine receptor. Because this disorder is treatable and potentially curable, prompt recognition, especially early in the clinical course, is important. Mortality and morbidity, once not unusual in patients with MG, have been dramatically reduced in the modem era with early diagnosis and the use of immunosuppression, plasma exchange, and thymectomy.

CLINICAL FEATURES Patients with MG present with muscle weakness and fatigue. Because the disorder is limited to the NMJ, there is no abnormality of mental state, sensory function, or autonomic function. Myasthenic weakness characteristically affects the extraocular muscles, bulbar muscles, proximal limb muscles, or a combination of these. Eye findings are the most common, with ptosis and extraocular muscle weakness occurring in more than 50% of patients at the time of presentation and developing in more than 90% at some time during their illness. Often, extraocular weakness may begin asymmetrically,with one eye involved and the other spared. A very small amount of extraocular weakness is subjectively noticed by the patient as visual blurring or frank double vision. Myasthenic weakness has been known to mimic third, fourth, and sixth cranial nerve palsies as well as, rarely, an intranuclear ophthalmoplegia. Unlike third nerve palsies, however, MG never affects pupillary function. Fixed extraocular weakness tends to occur later. After extraocular weakness, bulbar muscle weakness is most common, with difficulty in chewing, swallowing, and speaking. Some patients experience severe fatigability and weakness of mastication and are unable to keep the jaw closed after chewing. Myasthenic speech is nasal (from weakness of the soft palate) and slurred (from weakness of the tongue, lips, and face) but without any difficulty with fluency. When limb weakness develops in patients with MG, the proximal musculature usually is affected, often in a symmetrical pattern. Patients complain of difficulty arising from chairs or going up and down stairs, reaching with their arms, or holding their head up. Rare patients present with a limb-girdle form of myasthenia gravis alone, without weakness of eye movement or bulbar muscles. 658

The hallmark of MG is pathologic fatigability, that is, progressive muscle weakness with use. Patients typically improve after rest or upon arising in the morning, with worsening as the day passes. Generalized fatigue is a common complaint in many neurologic and non-neurologic disorders. In MG and other disorders of the NMJ, fatigue is limited to muscular fatigue alone and often progresses to frank muscle weakness. Patients with MG do not generally experience a sense of mental fatigue, tiredness, or sleepiness. The clinical examination in a patient suspected of having MG is directed at assessing muscular strength and demonstrating pathologic fatigability. When trying to assess subtle weakness, it is often more useful to observe the patient walking and performing functional tasks, such as arising from a chair or the floor, rather than relying on manual muscle strength testing. Pathologic fatigability may be demonstrated by having the patient look up for several minutes (looking for ptosis or extraocular weakness) and count aloud to 100 (looking for nasal or slurred speech) or by repetitively testing the proximal limb or neck muscles. The remainder of the neurologic examination is normal. Reflexes are generally preserved or are reduced in proportion to the amount of muscle weakness. MG may develop at any age, although it is more common in younger and middle-aged adults; women slightly outnumber men among younger patients, but more men are afflicted among middle-aged and older patients. In patients with MG, there is a well-recognized association of abnormalities of the thymus gland. Thymic hyperplasia is found in as many as 70% of all cases, and thymoma is found in 11%. Although the role of the thymus is not completely understood in MG, it is probably important in initiating and maintaining the autoimmune response. Another interesting group of patients with MG is the 15% who have the ocular form of the disease, whose symptoms remain limited to the extraocular and eyelid muscles. When patients first present with fluctuating extraocular weakness, it is not possible to predict from either clinical or laboratory testing whether the disease will subsequently generalize or remain in the benign restricted ocular form. If a patient has had restricted ocular myasthenia for 1 to 2 years, there is a high likelihood that the myasthenia will never generalize and will remain limited to the extraocular muscles. This has some implications for treatment because patients with ocular MG do not develop crises or other severe complications of generalized MG. Autoimmune MG may be seen in two other groups. Transient neonatal MG is recognized in 21% of neonates born to mothers with MG. Maternal immunoglobulin G (IgG) antibodies directed

Chapter 103

against the acetylcholine receptor are passed through the placenta, resulting in the same clinical syndrome. The illness usually is mild and self-limited, disappearing over the first few months of life as the maternal antibodies are degraded. Finally, MG may be seen as a complication of penicillamine treatment. The clinical syndrome is similar except that many patients slowly improve once the penicillamine has been withdrawn.

DIAGNOSIS The diagnosis of MG usually is straightforward and based primarily on the recognition of the clinical pattern of the disease, followed by the appropriate laboratory, electrophysiologic, and radiologic evaluations (Table 103-1). Tensilon lest

The Tensilon test is a simple and quick method to evaluate the possibility of neuromuscular junction disease. Tensilon (edrophonium hydrochloride), a short-acting acetylcholinesterase inhibitor, is given intravenously, which may quickly reverse myasthenic weakness. It is most useful when there is an obvious objective clinical parameter to follow (e.g., degree of ptosis or extraocular muscle weakness). The clinician cannot rely on subjective improvement by the patient. When performing a Tendon test, a double-blinded study is preferable. Two 1-mL syringes are drawn up: one with 10 mg of Tendon and the other with saline. The syringes are coded with the physician performing the test unaware of which one contains the Tendon. One syringe is selected. A test dose of 2 mg is given and flushed with normal saline. If no response is seen within 1 minute, the additional 8 mg is given, followed by a saline flush. A response is looked for over the next 3 minutes. The procedure is then repeated with the second syringe. Side effects of Tendon are those of cholinergic excess (e.g., salivation, bradycardia, tearing). Atropine should be readily available if needed to counteract these side effects. Although Tendon is generally considered a safe test, care must be exercised in all patients, especially older patients with cardiac disease, because, infrequently, bradycardia may lead to syncope, and in exceptional cases asystole has been documented. Acetylcholine Receptor Antibodies

Acetylcholine receptor antibodies are detected in more than 85% of patients with generalized MG. Antibodies are much less common in patients with restricted ocular MG, occurring in only 50% of cases. Acetylcholine receptor antibodies are highly specific for MG, with few false-positive results. In general, myasthenic patients with circulating antibodies have a high incidence of

ed Tendon test (preferably double blinded with cardiac monitoring) Acetylcholine receptor antibodies Anti-nuclear antibodies (ANA) Thyroid function tests Routine nerve conduction studies and EMC followed by repetitive nerve stimulation of both distal and proximal nerves Single-fiber EMC if repetitive nerve stimulation is negative or equivocal Chest imaninn KT or MRI)

Myasthenia Gravis

659

thymic abnormalities. Autoantibodies against other tissues including thyroid and gastric tissues often are present also. Autoimmune thyroid disease is particularly common and eventually develops in 5% to 12% of patients. RepetlUve Nerve Stimulation

Repetitive nerve stimulation (RNS) is an effective way to fatigue the NMJ and cause acetylcholine depletion. These studies are abnormal in more than 60% of myasthenic patients. A decremental response on RNS is the electrical correlate of clinical muscle fatigue and weakness in myasthenic patients. In normal subjects, slow RNS (2 to 3 Hz) results in little or no decrement, but in cases of MG, a decrement of the compound muscle action potential of 10% or more is characteristically seen. Both distal and proximal nerves can be tested. Although RNS of distal nerves (e.g., the ulnar nerve) is technically easier to perform, the diagnostic yield increases with stimulation of proximal nerves (i.e., spinal accessory, musculocutaneous, or facial nerves), which is not unexpected because the proximal muscles often are much more involved clinically than the distal ones. Every patient undergoing RNS also should undergo routine nerve conduction studies and electromyography (EMG). Although RNS is a sensitive test for MG, a variety of other disorders (e.g., any severe denervating disease, such as amyotrophic lateral sclerosis, the myotonic disorders, severe myopathies, and the Lambert-Eaton myasthenic syndrome) can also cause a decremental response that will be missed unless a complete study is performed. Single-Fiber EMG

Normally, when a motor axon is depolarized, the action potential travels distally and excites all the muscle fibers within that motor unit at roughly the same time. The variation in the time interval between the firing of adjacent muscle fibers from the same motor unit (jitter) can be measured with single-fiber EMG (SF-EMG). Jitter typically is prolonged in disorders of the NMJ even without overt clinical weakness. In addition, SF-EMG may demonstrate blocking of muscle fibers (i.e., the endplate potential of one muscle fiber of a motor unit falls below threshold, and subsequently its muscle fiber action potential is not generated). The clinical correlate of blocking is muscle weakness. In patients who have difficulty cooperating with the examination, stimulated SF-EMG can be done. In stimulated SF-EMG, an additional needle electrode is inserted in the muscle near the endplate to stimulate axonal twigs while the SF-EMG needle electrode records muscle fiber action potentials. Often the extensor digitorum communis muscle is selected for study. If possible, it is always useful to study a clinically involved muscle. Indeed, a normal single-fiber examination in a clinically weak muscle effectively rules out the diagnosis of MG. SF-EMG is the most sensitive test to demonstrate impaired neuromuscular junction transmission (abnormal in 95% to 99% of patients with generalized MG). However, it must be emphasized that SF-EMG, although quite sensitive, is not specific, and it is typically abnormal in neuropathic and myopathic disease. Although it might be tempting to consider having any patient with fatigue undergo SF-EMG, the test is best reserved for patients in whom the diagnosis of MG is strongly suspected and other tests have been negative or equivocal. SF-EMG often is a technically demanding examination for the patient and the electromyographer.

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Every patient with MG should undergo routine chest imaging with either computed tomography (CT) or magnetic resonance imaging (MRI) to look for evidence of thymic hyperplasia or thymoma. The presence of a thymoma is a clear indication for subsequent thymectomy. Early diagnosis of thymoma is important before invasion of the tumor beyond its capsule has occurred, with likely metastasis.

sion). In postsynaptic disorders such as MG, the number of quanta released by each stimulus is normal, but the effect of each quantum on its receptor is reduced. The net result is a lower endplate potential and a reduced safety factor of transmission at the NMJ. Thus, with slow repetitive stimulation in postsynaptic disorders, the endplate potential in some fibers may fall below threshold, with a resulting lack of a muscle fiber action potential. Clinically this manifests as signs and symptoms of weakness and fatigability, with a corresponding decrement during slow RNS.

ETIOLOGY

TREATMENT

The pathophysiology of MG is now well understood. MG is an autoimmune disease caused by sensitized T-helper cells and an IgG-directed attack on the nicotinic acetylcholine receptor of the NMJ. Thus, it is a disorder caused predominantly by antiacetylcholine receptor antibodies. A variety of experimental steps supports this hypothesis:

The treatment of patients with MG has improved substantially. Many options are available. Treatment consists of symptomatic agents (acetylcholinesterase inhibitors), immunosuppressives (steroids, azathioprine, cyclosporine), plasma exchange, intravenous immunoglobulin, and thymectomy.

Chest Imaging

Antibodies are present in the serum of most patients with MG. Antibodies can be passively transferred to animals, producing experimental myasthenia. Removal of antibodies allows recovery. Immunization of animals with an acetylcholine receptor produces antibodies and can provoke an autoimmune disease (experimental autoimmune MG), which closely resembles the naturally occurring disease. The mechanism of antibody damage to the receptor and motor endplate probably involves several steps. First, there is a complement-directed attack with destruction of the acetylcholine receptor and the junctional folds. Second, binding of the antibody to the receptor can cause stearic hindrance of acetylcholine binding at a neighboring site. Third, antibody binding can also result in increased removal of acetylcholine receptor from the membrane (modulation). Finally, rarely the antibody can bind to the acetylcholine receptor binding site itself and directly block acetylcholine binding. As mentioned earlier, there is a high incidence of thymic abnormalities in patients with MG. Fifty percent of patients with thymoma have MG. The role of the thymus in initiating and maintaining the autoimmune response in MG is unclear. However, it is notable that mammalian thymus expresses an acetylcholine receptor similar to that of embryonic muscle, and it is possible that this intrathymic acetylcholine receptor is the primary antigen-provoking antibody formation in the pathogenesis of MG. The abnormal and reduced numbers of acetylcholine receptors lead to impaired NMJ transmission. When a nerve action potential invades and depolarizes the presynaptic junction, voltagedependent calcium channels are activated, allowing an influx of calcium. The influx of calcium then results in release of acetylcholine from the presynaptic terminal. Acetylcholine is packed and released in discrete amounts known as quanta. Acetylcholine quanta then diffuse across the synaptic cleft and bind to acetylcholine receptors in the postsynaptic membrane, resulting in an endplate potential. Normally, the endplate potential is well above threshold and causes the generation of a muscle action potential. With slow repetitive stimulation (2 to 3 Hz), the number of quanta is greatly depleted during the first several seconds, and, subsequently, fewer are released. The corresponding endplate potential falls in amplitude but normally remains above threshold to ensure generation of a muscle action potential with each stimulation (i.e., the normal safety factor of NMJ transmis-

Acetylcholinesterase Inhibitors Symptomatic treatment consists primarily of giving acetylcholinesterase inhibitors such as pyridostigmine. These agents slow the degradation of acetylcholine in the synaptic cleft and effectively increase the amount of neurotransmitter available at the postsynaptic junction. Mestinon has a short half-life and must be dosed every 4 to 6 hours. The optimal dosage varies widely among patients. Patients typically are begun on half a tablet (30 mg) of pyridostigmine every 6 hours and slowly titrated to a higher dosage or more frequent dosing interval. There is no correct dosage. Some patients improve substantially on three to four tablets a day; others need far more. The major side effects are those of cholinergic excess, especially abdominal cramping and diarrhea, excessive perspiration, and salivation. Of course, excessive amounts can also cause weakness (cholinergic crisis). Most patients with MG respond well, at least initially, to these medications. Restricted ocular MG tends to be more refractory than generalized disease. For patients who have difficulty upon awakening in the morning, a slow-release form (Mestinon Timespan) is available as a 180-mg dose to be taken at bedtime.

Although acetylcholinesterase inhibitors are effective in most patients, the response generally is not completely satisfactory, and most patients have a better long-term response if the primary pathophysiology of the disease, the immune mechanism, is addressed. This consists of immunomodulating treatments such as steroids, other immunosuppressives, intravenous immunoglobulin, plasma exchange, and thymectomy. Steroids are the mainstay of therapy in MG. Improvement, including remission, usually can be obtained with oral steroids. The typical prednisone dosage is 1 mg/kg/day, taken as a single dose in the morning. Patients often are started on a low dosage (10 to 20 mg daily) while under close supervision or in the hospital because steroids, especially at high dosages, may cause transient worsening of myasthenia during the first 2 to 3 weeks. The dosage is slowly titrated up by 5 mg/day every 3 to 7 days until clinical benefit is obtained or a dosage of 1 mg/kg is reached. Improvement often begins in 1 or 2 months, with maximal improvement occurring at 6 to 12 months. After remission, patients can be switched to alternate-day steroids with the same total dosage and then slowly tapered. The chance of a successful taper is improved

Chapter 103

when the steroid dosage is tapered no faster than 5 mg/day/month. When the dosage reaches 40 to 50 mg every other day, tapering is best slowed to 2.5 mg/day/month. Often patients relapse several months after a successful taper and subsequent discontinuance. Many patients need a chronic low dose of steroids every other day to sustain a remission. The goal is to determine the lowest dosage of every-other-day therapy that will prevent a relapse. Unfortunately, when patients relapse, they often need a higher dosage of steroids, administered daily, to go back into remission, which must then be followed by another long, slow tapering process. Many patients, especially older adults, cannot tolerate the side effects of steroids (e.g., hypertension, weight gain, glucose intolerance, osteoporosis, cataracts, ulcers) and may need other types of immunosuppression. Azathioprine (AZA) has gained wide acceptance in myasthenia treatment and in many patients is the drug of choice. The concomitant use of AZA therapy commonly allows steroids to be tapered or discontinued. Clinical improvement is commonly delayed for 2 to 4 months but may not reach maximal benefit until after the first year or two. Patients typically are started on 50 mg daily as a single morning dose and slowly increased to 2 to 3 mglkglday over the next several weeks. Most patients tolerate M A without difficulty. However, adverse reactions may occur. The most common reactions are hematologic (anemia, leukopenia, thrombocytopenia), which necessitate close monitoring of blood counts during therapy (every 1 to 2 weeks initially). A typical hematologic endpoint is to let the white blood cell (WBC) count drop to 3500 to 4000/mm3 or the absolute lymphocyte count to drop to 5% to 10%. In addition, gastrointestinal disturbance, elevation of liver enzymes (two to 3 times normal), and susceptibility to serious infections may occur. Most of these complications can be dealt with by reducing the dosage (hematologic and liver enzyme abnormalities) or dividing the dosage with meals (gastrointestinal disturbance). Rarely, patients develop an acute, toxic hypersensitivity reaction to M A with fever, abdominal pain, and rash, which necessitates prompt and permanent discontinuance of the drug. Also of concern is the slightly increased risk of malignancy, especially lymphoma, which has been reported in nonmyasthenic patients treated with MA. Cyclosporin A (CSA), a drug that inhibits interleukin-2 and subsequently blocks cytotoxic lymphocytes and the proliferation of T-helper cells, is effective in preventing rejection in organ transplantation. This drug has also been found effective in several small studies of patients with MG. A typical induction dosage is 5 mg/kg, given as a divided dosage in the morning and evening. After remission, the dosage may be reduced gradually to a maintenance dosage of 2 to 3 mglkg. As with the other immunosuppressives, the goal is to determine the lowest dosage that prevents a clinical relapse. Trough CSA levels must be closely followed to maintain a level between 100 and 200 ng/mL. Blood pressure and renal function must be followed carefully. In regard to side effects, CSA is superior to other immunosuppressives in not suppressing the bone marrow. The major risks involve nephrotoxicity and hypertension. In addition, there are many potential drug interactions, most importantly the high likelihood of nephrotoxicity with the concurrent use of nonsteroidal antiinflammatory drugs. Prednisone, MA, and CSA are first-line therapies in MG treatment. The choice between the three is based primarily on the experience of the treating physician, with special emphasis on the side effect profile for the individual patient. Each of these agents has potential serious side effects. Obviously, they should never be used in any patient unless adequate compliance and follow-up are

Myasthenia Cravis

661

possible. The major errors in using these agents are in a dosage that is too low, a treatment duration that is too short, or nonaggressive treatment of side effects.

Plasma Exchange Removal of antibody allows clinical recovery in patients with MG. Often three to five large-volume plasma exchanges are needed to reduce the antibody level sufficiently. Plasma exchange is most appropriately performed when a patient has suddenly deteriorated and is in crisis or before major surgery such as thymectomy. It is in this situation, when rapid reversal of clinical weakness is necessary, that plasma exchange is most useful in minimizing further worsening or serious complications, such as intubation or pneumonia. However, as routine treatment for MG, plasma exchange is invasive and only temporary and is best reserved for the unusual patients who do not respond to other immunomodulating therapy.

IntravenousImmunoglobulin Intravenous immunoglobulin is used successfully in a variety of autoimmune diseases. Several reports have confirmed the efficacy of intravenous immunoglobulin in MG, including refractory patients for whom other traditional therapies have failed. Like plasma exchange, intravenous immunoglobulin is most useful when a patient with MG has suddenly deteriorated and rapid reversal of the weakness is important. It may also be useful in selected patients for whom plasma exchange is associated with side effects or difficulties with large volume intravenous access. As in other autoimmune conditions, patients initially are treated with dosages of 400 mg/kg/day for 5 days. Additional single doses are then given every 1 to 6 weeks, depending on the clinical response.

Thymectomy Most patients are successfully treated with the aforementioned approaches. The disease can be controlled in most patients, and it is now rare for patients to die of their illness. Myasthenia tends to be lifelong, and patients usually need prolonged therapy. Spontaneous remissions can occur, but relapses often occur again in the future. Immunosuppressives, especially prednisone, often are associated with potential long-term side effects. Although there has never been a prospective randomized trial, thymectomy is associated with a higher chance of complete remission or substantial improvement in MG patients. Patients with milder disease and relatively recent onset of symptoms (less than 3 years), without thymoma, are reported to respond best with thymectomy. Young patients with early myasthenia tend to do particularly well. Clinical improvement is commonly delayed 6 to 12 months after the operation and may continue for 5 years or more. In many centers, thymectomy often is not advised in patients older than 60 years because of other medical conditions that increase the risk of surgery (e.g., coronary artery disease) and the common observation that the thymus is atrophic in older adults. However, some studies have shown beneficial results in older adults. Therefore, each case must be individualized regarding the recommendation for surgery. The surgical technique (transcervical versus transsternal) has been debated by many clinicians. Most agree that, for thymectomy to be effective, the entire thymus gland must be removed, which usually necessitates a transsternal incision. In the modern era, the

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morbidity and mortality associated with thymectomy have been reduced dramatically, making routine use of this therapy much more attractive. Unless the myasthenia is in complete pharmacologic remission before surgery, patients should routinely undergo several days of plasma exchange before thymectomy to reduce the likely worsening as a consequence of the stress of surgery and to promote early postoperative extubation. In addition, patients who relapse years after thymectomy or who never obtained a complete remission from their initial thymectomy may benefit from repeat thymectomy, even if imaging studies do not demonstrate residual thymus tissue. In one study, five of six patients with chronic refractory myasthenia improved with repeat thymectomy. Because 20% of normal subjects have some ectopic thymus tissue in the anterior mediastinum, some surgeons have advocated an extended cervicomediastinal thymectomy, removing all thymic, fat, and lymphatic tissue from the anterior mediastinum, superior mediastinum, diaphragm, and neck. In one of the largest surgical series of 202 patients with MG from Johns Hopkins University, extended cervicomediastinal thymectomy was associated with an odds ratio for improvement more than two times higher than that of the standard transsternal thymectomy. The other indication for thymectomy, of course, is the presence of a thymoma. The myasthenia of patients with thymoma tends to be more severe than that of other myasthenic patients, and a combination of surgery and aggressive medical therapy often is needed.

Restricted Ocular Myasthenia Patients with restricted ocular myasthenia represent a therapeutic challenge, responding to immunosuppressive therapy and thymectomy as well as patients with generalized MG. However, controversy remains regarding how aggressively to treat these patients. Patients with ocular myasthenia may be treated very differently in major centers. Some investigators argue that ocular myasthenia is not a serious illness, and the risks of immunosuppression or surgery cannot be justified. In these centers, patients with restricted ocular myasthenia are treated with acetylcholinesterase inhibitors and local ophthalmologic therapy, such as eyelid crutches or eye patches. On the other hand, many clinicians argue that when a patient first presents with myasthenia involving only the extraocular muscles, it is not possible to know whether the disease will progress to generalized myasthenia (indeed, most will) and that nearly all treatments are most effective if begun early in the illness. Many patients with restricted ocular myasthenia consider themselves nearly disabled from diplopia alone. These issues must be discussed with each patient before a path of aggressive or nonaggressive therapy is chosen.

However, 28% experienced exacerbations in the postpartum period. Because MG has no effect on smooth muscle, it does not interfere with uterine contractibility and has no effect on labor and delivery. However, during labor and delivery, magnesium as a treatment for toxemia is contraindicated because it can provoke a crisis. In a similar manner, if cesarean section is needed, spinal anesthesia is preferable to general anesthesia; curare and other neuromuscular junction blocking agents should not be used. In the pregnant patient with MG, treatment can be used as in nonpregnant MG patients, including acetylcholinesterase inhibitors, steroids, plasma exchange, and intravenous immunoglobulin. Immunosuppressive agents, including azathioprine and cyclosporine, are used with caution and best avoided if possible. Azathioprine crosses the placenta, with evidence of teratogenicity in animals. Based on reports of azathioprine and cyclosporine used in pregnancy in other conditions, the risk in humans appears low; however, the risk of using these drugs must be balanced in the individual patient, weighing the risk of relapse of a potentially life-threatening condition if a drug is withdrawn during pregnancy. Myasthenic Crisis Rarely, the initial presentation of MG may be a myasthenic crisis. Of course, crisis may also occur in patients with known myasthenia. Recognition and treatment of myasthenic crisis is one of the most important neuromuscular emergencies. In the 1960s, the mortality rate of myasthenic crisis was 50%. Now, with modern intensive care units, early diagnosis, and effective therapy, mortality from crisis is a rare event. Patients with moderate to severe MG may develop increasing bulbar and respiratory weakness. Often, this is the result of a concurrent infection or the addition of a new medicine. Several drugs are well known to exacerbate MG (Table 103-2). In response to worsening weakness, patients take more and more anticholinesterase medicines. Excessive anticholinesterase treatment can itself lead to increased weakness (cholinergic crisis). If the condition is not recognized early, the patient may succumb to primary respiratory collapse or aspirate from increasing bulbar weakness. Patients in crisis, whether cholinergic or myasthenic, must be treated aggressively. Any myasthenic patient who reports sudden worsening of symptoms must be evaluated immediately. Although the literature stresses the difference between myasthenic crisis and cholinergic crisis, it is often impossible to tell them apart. Miosis, fasciculations, diarrhea, sweating, abdominal cramping, excessive TABU105-2. Drugs Reported to Exacerbate Myasthenia Cravis

Myasthenia Cravis in Pregnancy Because MG often affects women of childbearing age, special issues are encountered with pregnant women with MG. The effect of pregnancy on MG is highly variable and unpredictable. There is no correlation between the underlying severity of the disease and the risk of exacerbation with pregnancy. However, times of greatest risk are the first trimester and postpartum periods. In patients in remission, the risk of an exacerbation during pregnancy is 17%. In patients with symptomatic MG, 39% improved, 42% had no change, and 6% deteriorated during pregnancy.

Arninoglycosides Clindarnycin Colistin Erythromycin Lithium Phenytoin Polymyxin B Procainamide Propranolol and other p-blockers Quinidine Quinine Tetracycline Veraoarnil and other Ca++ channel blockers

Chapter 104 1 Lambert-Eaton Myasthenic Syndrome

Tmu 103-3. Treatment of Myasthenic Crisis 1. Admit to intensive care unit. 2. Stop all anticholinesterases. 3. Rule out and treat concurrent infection. 4. Identify and correct any electrolyte abnormality. 5. Follow respiratory status closely and intubate if vital capacity is falling and reaches 15 m u k g (or higher if patient is at risk for aspiration). 6. Plasma exchange (5-6 timesA weeks).

salivation, and bradycardia all suggest cholinergic overdose. Many clinicians use a Tendon test to try to distinguish between the two. However, it is often difficult to assess improvement in a patient who is in severe distress. The treatment of myasthenic crisis is straightforward (Table 103-3). The major risk to life is respiratory failure. Patients should be watched carefully and intubated early to avoid later pulmonary complications. Anticholinesterases should be stopped. They can be restarted in a few days and probably can be used at lower dosages. Plasma exchange in myasthenic crisis is very useful in lowering antibody titers and rapidly reversing weakness. If a patient has not previously been on steroids or other immunosuppressants and no electrolyte imbalance or infection is discovered to explain the decompensation, then these probably will be needed to prevent further crisis. It is then reasonable to begin prednisone in the hospital while the patient is intubated and receiving plasma exchange.

SUGGESTED READINGS Achiron A, Bar& YH, Miron S et al: Immunoglobulin treatment in refractory myasthenia gravis. Muscle Nerve 23:551-555, 2000

663

Batocchi AP, Majolini L, Evoli A et al: Course and treatment of myasthenia gravis during pregnancy. Neurology 52(3):447452, 1999 Brooke MH: A clinician's view of neuromuscular diseases. Williams & Wilkins, Baltimore, 1986 Bulkley GB, Bass KN, Stephenson GR et al: Extended cervicomediastinal thymectomy in the integrated management of myasthenia gravis. Ann Surg 226:324-334, 1997 Drachman DB: Myasthenia gravis. N Engl J Med 390:1791-1810, 1994 Drachman DB: Present and future treatment of myasthenia gravis. N Engl J Med 316:743-745, 1987 Engel AG: Myasthenia gravis and myasthenic syndromes. Ann Neurol 16:519-534, 1984 Gronseth GS, Barohn RJ: Practice parameter: thymectomy for autoimmune gravis (an evidence-based review). Neurology 55:7-15, 2000 Hankins JR, Mayer RF, Satterfield JR et al: Thymectomy for myasthenia gravis: 14-year experience. Ann Surg 201:618-625, 1985 Howard J F Intravenous immunoglobulin for the treatment of acquired myasthenia gravis. Neurology 51:S30-S36, 1998 Lanska DJ: Indications for thymectomy in myasthenia gravis. Neurology 40:1828-1829, 1990 Miano MA, Bosley TM, HeimamPatterson TD et al: Factors influencing outcome of prednisone dose reduction in myasthenia gravis. Neurology 41~919-921,1991 Miller RG, Filler KA, Kiprov D, Roan R Repeat thymectomy in chronic refractory myasthenia gravis. Neurology 41:923-924, 1991 Palace J, Newsom-Davis J: A randomized double-blind study of prednis-

olone alone or with azathioprine in myasthenia gravis. Neurology 5 0 1778-1783, 1998 Papatestas AE, Genkins G, Kornfeld P et al: Effects of thymectomy in myasthenia gravis. Ann Surg 20679-88, 1987 Tindall RSA, Rollins JA, Phillips JT et al: Preliminary I'esults of a

double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 316719-724, 1987

104 Lambert-Eaton Myasthenic Syndrome H. Royden Jones, Jr. The Lambert-Eaton myasthenic syndrome (LEMS) is the most common neurologic paraneoplastic syndrome. Although very rare, LEMS is the prototype presynaptic neuromuscular transmission disorder in adults. Most patients with LEMS are symptomatic less than a year; however, diagnostic recognition rarely is delayed as much as 8 to 25 years after initial symptoms. Clinical manifestations of LEMS usually precede pulmonary or radiographic definition of small cell lung cancer (SCLC) by a number of months to years. In most instances when a cancer is not already identified at the time of the LEMS presentation, the likelihood of developing a SCLC or other malignancy becomes significantly less after 4 years. In that instance one then presumes that LEMS has a primary immunologic basis similar to myasthenia gravis. Commonly, LEMS is associated with cigarette addiction, especially among those who eventually develop SCLC. The incidence of LEMS in patients with SCLC is about 2% to 3%. This paraneoplastic disorder has an autoimmune basis. A significant association occurs in the paraneoplastic as well as the primary autoimmune variant, with the presence of HLA-B8 in both forms of LEMS, perhaps more so in patients without an associated

malignancy. LEMS also rarely occurs with other malignancies. These include other primary lung tumors such as atypical carcinoids or large cell neuroendocrine lung tumors. Additionally, and very rarely, certain lymphoproliferative disorders, as well as breast, colon, stomach, gallbladder, pancreas, prostate, bladder, and kidney cancers are associated with LEMS. However, a number of patients with LEMS (25% to 50%) never develop an underlying malignancy. Therefore, LEMS often has a nonparaneoplastic, primary, autoimmune pathophysiologic mechanism. There is a prominent association, perhaps 25%, between LEMS and other autoimmune processes. These include thyroiditis, pernicious anemia, vitiligo, Addison's disease, Sjogren's syndrome, type I diabetes mellitus, scleroderma, psoriasis, rheumatoid arthriTis, and celiac disease. LEMS occurs infrequently, perhaps at no more thanj5% the frequency of myasthenia gravis (MG), its autoimmune p+tsynaptic mirror image. This disorder most commonly presents ''after age 40. On the unusual occasion when LEMS presents in younger adults or, exceedingly rarely, even in children, it is almost always the primary nonparaneoplastic, autoimmune form of LEMS that

Chapter 104 1 Lambert-Eaton Myasthenic Syndrome

Tmu 103-3. Treatment of Myasthenic Crisis 1. Admit to intensive care unit. 2. Stop all anticholinesterases. 3. Rule out and treat concurrent infection. 4. Identify and correct any electrolyte abnormality. 5. Follow respiratory status closely and intubate if vital capacity is falling and reaches 15 m u k g (or higher if patient is at risk for aspiration). 6. Plasma exchange (5-6 timesA weeks).

salivation, and bradycardia all suggest cholinergic overdose. Many clinicians use a Tendon test to try to distinguish between the two. However, it is often difficult to assess improvement in a patient who is in severe distress. The treatment of myasthenic crisis is straightforward (Table 103-3). The major risk to life is respiratory failure. Patients should be watched carefully and intubated early to avoid later pulmonary complications. Anticholinesterases should be stopped. They can be restarted in a few days and probably can be used at lower dosages. Plasma exchange in myasthenic crisis is very useful in lowering antibody titers and rapidly reversing weakness. If a patient has not previously been on steroids or other immunosuppressants and no electrolyte imbalance or infection is discovered to explain the decompensation, then these probably will be needed to prevent further crisis. It is then reasonable to begin prednisone in the hospital while the patient is intubated and receiving plasma exchange.

SUGGESTED READINGS Achiron A, Bar& YH, Miron S et al: Immunoglobulin treatment in refractory myasthenia gravis. Muscle Nerve 23:551-555, 2000

663

Batocchi AP, Majolini L, Evoli A et al: Course and treatment of myasthenia gravis during pregnancy. Neurology 52(3):447452, 1999 Brooke MH: A clinician's view of neuromuscular diseases. Williams & Wilkins, Baltimore, 1986 Bulkley GB, Bass KN, Stephenson GR et al: Extended cervicomediastinal thymectomy in the integrated management of myasthenia gravis. Ann Surg 226:324-334, 1997 Drachman DB: Myasthenia gravis. N Engl J Med 390:1791-1810, 1994 Drachman DB: Present and future treatment of myasthenia gravis. N Engl J Med 316:743-745, 1987 Engel AG: Myasthenia gravis and myasthenic syndromes. Ann Neurol 16:519-534, 1984 Gronseth GS, Barohn RJ: Practice parameter: thymectomy for autoimmune gravis (an evidence-based review). Neurology 55:7-15, 2000 Hankins JR, Mayer RF, Satterfield JR et al: Thymectomy for myasthenia gravis: 14-year experience. Ann Surg 201:618-625, 1985 Howard J F Intravenous immunoglobulin for the treatment of acquired myasthenia gravis. Neurology 51:S30-S36, 1998 Lanska DJ: Indications for thymectomy in myasthenia gravis. Neurology 40:1828-1829, 1990 Miano MA, Bosley TM, HeimamPatterson TD et al: Factors influencing outcome of prednisone dose reduction in myasthenia gravis. Neurology 41~919-921,1991 Miller RG, Filler KA, Kiprov D, Roan R Repeat thymectomy in chronic refractory myasthenia gravis. Neurology 41:923-924, 1991 Palace J, Newsom-Davis J: A randomized double-blind study of prednis-

olone alone or with azathioprine in myasthenia gravis. Neurology 5 0 1778-1783, 1998 Papatestas AE, Genkins G, Kornfeld P et al: Effects of thymectomy in myasthenia gravis. Ann Surg 20679-88, 1987 Tindall RSA, Rollins JA, Phillips JT et al: Preliminary I'esults of a

double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 316719-724, 1987

104 Lambert-Eaton Myasthenic Syndrome H. Royden Jones, Jr. The Lambert-Eaton myasthenic syndrome (LEMS) is the most common neurologic paraneoplastic syndrome. Although very rare, LEMS is the prototype presynaptic neuromuscular transmission disorder in adults. Most patients with LEMS are symptomatic less than a year; however, diagnostic recognition rarely is delayed as much as 8 to 25 years after initial symptoms. Clinical manifestations of LEMS usually precede pulmonary or radiographic definition of small cell lung cancer (SCLC) by a number of months to years. In most instances when a cancer is not already identified at the time of the LEMS presentation, the likelihood of developing a SCLC or other malignancy becomes significantly less after 4 years. In that instance one then presumes that LEMS has a primary immunologic basis similar to myasthenia gravis. Commonly, LEMS is associated with cigarette addiction, especially among those who eventually develop SCLC. The incidence of LEMS in patients with SCLC is about 2% to 3%. This paraneoplastic disorder has an autoimmune basis. A significant association occurs in the paraneoplastic as well as the primary autoimmune variant, with the presence of HLA-B8 in both forms of LEMS, perhaps more so in patients without an associated

malignancy. LEMS also rarely occurs with other malignancies. These include other primary lung tumors such as atypical carcinoids or large cell neuroendocrine lung tumors. Additionally, and very rarely, certain lymphoproliferative disorders, as well as breast, colon, stomach, gallbladder, pancreas, prostate, bladder, and kidney cancers are associated with LEMS. However, a number of patients with LEMS (25% to 50%) never develop an underlying malignancy. Therefore, LEMS often has a nonparaneoplastic, primary, autoimmune pathophysiologic mechanism. There is a prominent association, perhaps 25%, between LEMS and other autoimmune processes. These include thyroiditis, pernicious anemia, vitiligo, Addison's disease, Sjogren's syndrome, type I diabetes mellitus, scleroderma, psoriasis, rheumatoid arthriTis, and celiac disease. LEMS occurs infrequently, perhaps at no more thanj5% the frequency of myasthenia gravis (MG), its autoimmune p+tsynaptic mirror image. This disorder most commonly presents ''after age 40. On the unusual occasion when LEMS presents in younger adults or, exceedingly rarely, even in children, it is almost always the primary nonparaneoplastic, autoimmune form of LEMS that

664

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Diseases of Neuromuscular Transmission

is present. The youngest reported case initially had symptoms at age 1 year, but an appropriate diagnosis was not entertained until age 7. There is no particular sexual predominance, particularly with the almost equal percentage of women and men cigarette smokers. The neurophysiologic and immunologic characteristics of LEMS typify a presynaptic lesion of the neuromuscular junction. LEMS is indeed a mirror image of its much more common autoimmune cousin, the postsynaptic disorder MG. Repetitive motor nerve stimulation (RMNS) at 2 to 3 Hz may produce a decremental response in both LEMS and MG. The facilitation of the typical baseline low-amplitude compound muscle action potential (CMAP) to brief voluntary exercise is characteristic of LEMS and provides the basis for electromyographic diagnosis. Physiologic and immunologic investigations identified that the primary site of immunopathology involves the voltage-gated calcium channels (VGCC). An immunoglobulin G (IgG) antibody adheres to the peripheral cholinergic nerve terminals, blocking the calcium influx that normally occurs with nerve depolarization. This results in an inadequate release of acetylcholine quanta from motor and autonomic cholinergic nerve terminals. The VGCC present in the SCLC cells provides the presumed antigenic stimulus for antibody production in this paraneoplastic form of LEMS. The precise antigenic stimulus in the nonparaneoplastic varieties of LEMS remains to be identified. Presynaptic neurotransmitter release at the neuromuscular junction depends upon the presence of active P/Q type VGCCs through which calcium ions pass to facilitate the release of acetylcholine from the immediately available presynaptic quanta. This step is the essential process for acetylcholine to become available for postsynaptic binding at the neuromuscular junction. When autoantibodies adhere to the VGCC of the peripheral cholinergic nerve terminals, they block the calcium influx and eventually depolarization of the endplate. Muscular weakness is the primary clinical manifestation. The responsible IgG actually binds to the presynaptic neuromuscular junction. When an SCLC is present, one can find that this tumor expresses typical VGCC, providing the antigenic stimulus to produce VGCC antibodies. These antibodies have the ability to cross-react with various acetylcholine-releasing sites such as the neuromuscular junction, as well as various autonomic structures.

CLINICAL DIAGNOSIS A carefully derived history most often is the primary clinical clue leading to a LEMS diagnosis. Patients with LEMS characteristically present with a typical myopathic syndrome characterized by a predominantly proximal weakness. However, often the patient does not report other seemingly minor complaints, which are important clinical clues to the proper diagnosis. Such patients may believe that these seemingly minor concerns are not significant enough for her or him to mention to the physician. These characteristically include vague thigh numbness and stiffness or important symptoms and signs of dysautonomia, typically xerostomia and erectile dysfunction. On occasion, one may make a clinical diagnosis of LEMS very soon after meeting the patient. If the neurologist finds a patient who initially apologizes for sitting drinking a glass of water, primarily because of his or her very dry mouth, and who obviously has problems getting out of the chair to say “hello,” you may have all the clinical clues necessary to order the correct studies. This is especially true if the patient is a cigarette addict. This has

happened to me on a few occasions, especially with patients whose diagnosis had been “unclear” to prior examiners. The clinical presentation is similar whether LEMS is associated with the primary autoimmune form or the secondary paraneoplastic autoimmune type of disorder. However, the classic LEMS symptom constellation often is preempted by an interesting set of protean clinical manifestations. Twenty-three of 50 (46%) patients with LEMS seen at Queen Square (U.K.) and 18 of 23 (78%) seen at the Lahey Clinic had atypical symptoms including oculobulbar symptoms and signs that elsewhere led to a differential initial diagnosis. These were a chief complaint in 7 of 23 patients with LEMS. Diplopia occurred in 11, ptosis in 11, dysarthria in 10, and dysphagia in 8 patients. Therefore, early on, LEMS often mimics a number of more common neuromuscular disorders including MG, polymyositis, multiple sclerosis, occult malignancies, dysautonomias, or somatoform disorders, including hysteria. Occasionally, the clinical presentation of LEMS is preempted and therefore is confused by the earlier appearance of other SCLC-associated paraneoplastic disorders. These typically include a cerebellar ataxia or a primary sensory neuropathy. As with LEMS, each of these syndromes has a specific antibody identity; sometimes two and rarely all three clinical syndromes and their respective antibody markers are found in the same patient. LEMS muscle weakness classically mimics most myopathies with a proximal preponderance characterized by difficulties arising, walking, or climbing stairs. Although the proximal arm and neck muscles often are weak on examination, these are often not clinically significant to the patient and therefore are not initially reported to the physician. Fatigue is a prominent muscular symptom; it is often the initial LEMS manifestation. It is very important to note that in some patients, the initial neurologic examination is characterized by a seeming inconsistency or “give way” type of muscle weakness that may suggest that these patients do not have true weakness. In fact, 3 of the 22 patients with LEMS came to the Lahey Clinic with prior diagnoses of hysteria, malingering, or depression precisely because of a misinterpretation of their muscle testing results. These examination findings actually mirror the primary neuroimmunologic and corresponding neurophysiologic pathology. The facilitative component of their “give way” weakness represents the classic facilitative Ch&@ resnonse that typifies the electromyographic diagnostic LEMS facilitation findings with RMNS. When patients with suspected LEMS do not have detectable weakness, a subtle weakness may be better appreciated by watching the patient arise from a chair. On one occasion, clinically occult weakness in a patient of mine with a normal routine examination and a compelling history was precipitated by climbing stairs near my office. Bulbar symptoms often are thought to be less prominent than with MG. However, their presence far from excludes LEMS from diagnostic consideration. Eighteen of our 22 Lahey Clinic patients had some form of bulbar difficulty. This primarily included diplopia, ptosis, dysphagia, and dysarthria. A paradoxical lid elevation may occur with sustained upward gaze. This is secondary to LEMS facilitation, in contrast with MG, where this maneuver evokes increased ptosis. Muscle stiffness and tightness are also prominent LEMS symptoms in a few patients. Primary gait difficulty occasionally is the presenting symptom of LEMS. Unless this is a true gait ataxia secondary to concomitant paraneoplastic cerebellar degeneration or a primary sensory neuropathy, this pseudoataxia usually is secondary to subtle paraspinal and very proximal pelvic girdle weakness. In two of our patients, this clinical constellation previously led to an initial

Chapter 104

diagnosis of multiple sclerosis. Therefore, when one evaluates a patient with proximal limb weakness and a concomitant ataxia or neuropathy, this clinical setting is consistent with a LEMS diagnosis. Autonomic symptoms, including dryness of the mouth or erectile dysfunction in men, often give the astute clinician important clues that will lead to consideration of LEMS. However, the neurologist often needs to query the patient directly to gain this information. Other patients with LEMS sometimes report a feeling of vague numbness, especially prominent in the thighs. The combination of vague weakness, dry mouth, and paresthesias may mimic the common hyperventilation syndrome, a trap the unwary clinician must avoid. The muscle stretch reflexes typically are reported to be absent or depressed; however, these were normal in about 20% of our patients with LEMS. In the majority of the patients who have either sluggish muscle stretch reflexes or areflexia, we were able to demonstrate a characteristic postexercise facilitation. Similarly, this is also demonstrated with the muscle weakness. The second wind increase in strength is the clinical mirror image of the classic postexercise CMAP facilitation defined by electromyography (EMG). Occasionally sluggish pupillary light responses are found in patients with LEMS. This is another sign of autonomic dysfunction, also seen in botulism, another presynaptic neuromuscular transmission disorder. DIFFERENTIAL DIAGNOSIS Because the diagnosis of LEMS often is elusive during the initial stages of this disorder, especially with 18 of our 23 patients having a nonclassic clinical presentation, one must be always alert to this diagnostic possibility. The differential diagnosis includes a broad spectrum of neurologic disorders. Before our initial evaluation, the preceding diagnoses included MG in six patients, a myopathy in five, psychiatric issues in three, cerebellar degeneration or multiple sclerosis in two, a peripheral neuropathy in one, and orthostatic hypotension in another; one patient was presumed to have an occult malignancy, which proved to be true when the LEMS was diagnosed. The other four patients were diagnosed with LEMS subsequent to SCLC surgery. Two of these four developed postoperative respiratory depression, and in the remaining two patients typical LEMS symptoms developed a number of months to a year and a half after their surgery and during chemotherapy. One major clinical difference between MG and LEMS relates to the fact that in most instances MG has a preponderance of bulbar symptoms early in its course. The more generalized weakness, as well as the occasional respiratory compromise in MG, follows a period of predominant cranial nerve dysfunction. However, in our experience cranial nerve symptoms are quite common with LEMS. They are often mild, sometimes transient and usually are not the presenting symptom. Recently, however, we have had the opportunity to evaluate a patient with “antibody-negative myasthenia gravis” presenting with ptosis and diplopia. Much to our surprise, she indeed was antibody positive, but to only the VGCC antibody. Subsequently, she has developed increasing fatigue with some response to 3,4-diaminopyridine (3,4-DAP). Another difference between MG and LEMS is the prominence of autonomic symptoms found in LEMS. Uncommonly, LEMS and MG may occur in the same patient. This is confirmed by the concomitant presence of both VGCC and acetylcholine receptor antibodies in the same patient. Other rare presynaptic neuromuscular transmission disorders (e.g., botulism and magnesium intoxication)

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present acutely; in contrast, patients with LEMS rarely have a sudden clinical onset. Inflammatory myopathies, namely polymyositis (PM) and dermatomyositis (DM), typically have predominant proximal and neck weakness. This distribution is also common in LEMS. However, these patients with inflammatory myositis do not have subtle facilitation of strength immediately after the initial testing of each muscle. Usually the muscle stretch reflexes are preserved with both PM and DM. These patients also lack the typical autonomic and vague sensory symptoms classically seen with LEMS. Muscle tightness, stiffness, and pain are present in more than a third of our patients with LEMS. Therefore, metabolic myopathies such as McArdle’s disease rarely need to be considered, particularly in younger adults. In contrast, patients with LEMS do not have myoglobinuria. Both the inflammatory myopathies and some of the metabolic myopathies have elevated levels of serum creatine kinase (CK). This is also very uncommon with LEMS. If present, the CK elevation is very modest, in contrast to the usual marked elevation in DM and PM. Chronic inflammatory demyelinating polyneuropathy, with its insidious onset of proximal weakness and absent or reduced muscle stretch reflexes, also enters the LEMS differential diagnosis. No clinical evidence of facilitation of muscle strength or these reflexes is found in these patients. Distal paresthesias very occasionally may be the presenting symptom of LEMS. This is particular so when there is a conjoint autoimmune paraneoplastic sensory polyneuropathy. These patients have both positive VGCC antibodies associated with the anti-Hu antibodies that are the signature of a paraneoplastic sensory neuropathy. Multiple sclerosis also enters into the LEMS differentid diagnosis. Occasionally a patient with LEMS presenting with an ataxic gait initially is thought to have multiple sclerosis. At other times the clinician may note clues suggesting the presence of a paraneoplastic process, with one affecting primarily the cerebellum. Some patients with this clinical presentation have had repeatedly normal central nervous system imaging procedures. In some instances, it was not until proximal muscle weakness, per se became apparent, particularly affecting the paraspinal muscles and leading to an unstable gait, or concomitant signs of dysautonomia developed that a possible LEMS diagnosis was considered. The other possibility to consider in this setting, when differentiating the patient with multiple sclerosis or primary cerebellar degeneration, is a coexistent paraneoplastic autoimmune anticerebellar neuronal mechanism. LEMS also must be considered in any patient who is considered depressed, hysterical, or possibly malingering, especially those who present with vague weakness, paresthesias, or erectile dysfunction. At times, clinically defining the characteristic associated symptoms or observing for subtle signs of neurophysiologic facilitation with testing of proximal muscle strength or muscle stretch reflexes may provide important initial clues to a LEMS diagnosis. When these are present, the clinician can alert the electromyographer to test carefully for LEMS. DIAGNOSTIC STUDIES Tensilon Testing The clinical presentation of some patients with LEMS has many similarities to MG. Therefore, some patients with LEMS undergo Tensilon (edrophonium hydrochloride) testing. However, it is important to emphasize that a Tensilon test is actually a nonspecific evaluation of neuromuscular junction function. One

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study found that the Tendon test was “subjectivelyor objectively” positive in 14 of 21 patients with LEMS. Therefore, the response to this simple test cannot be used to differentiate MG from LEMS.

Electromyography Skillfully performed EMG still is the best clinically available, immediately useful study for diagnosing LEMS. Before performing the various RMNS studies, it is necessary to perform standard motor and sensory nerve conduction studies and needle EMG to exclude a number of other motor unit disorders. Typically, in LEMS, motor nerve stimulation demonstrates very markedly diminished CMAP amplitudes. These are often no more than 10% of normal size. One must be aware with early LEMS that the CMAPs may be normal, as noted in 2 of 50 patients in a major review of this subject by Newsom-Davis. In this instance, a repeat study 6 to 12 weeks later may demonstrate a drop in CMAP amplitude with a facilitation back to baseline after 10 seconds of voluntary exercise. Sensory nerve action potentials are normal except when there is a concomitant primary sensory neuropathy. In this instance, the sensory nerve action potentials are absent or of very low amplitude. The neurophysiologic diagnosis of LEMS depends primarily on the CMAP facilitation after a brief period of exercise. Usually at rest, most patients with LEMS demonstrating a significant neuromuscular transmission deficit with RMNS. This averaged a 27% decrement with 2 to 3 Hz stimulation. In contrast to MG, wherein documentation of a decrement may entail testing multiple

EXERCISE

3* Loter

nerves, particularly proximal or bulbar, the neuromuscular transmission disorders in patients with LEMS usually are present in all motor nerves tested. The crucial differentiation between a presynaptic and postsynaptic NMTD is the finding that brief voluntary exercise prompts a marked CMAP facilitation in patients with LEMS but not those with MG. High-frequency 20 to 50 Hz RMNS traditionally also results in a 100% or greater CMAP facilitation but this format is painful and sometimes prone to movement artifact. Therefore, testing for postexercise facilitation is preferred. To make an electromyographic diagnosis of LEMS, it is necessary to obtain postexercise facilitation greater than loo%, that is, at least twice the baseline. Usually patients with LEMS have 200% to 1000% CMAP facilitation (Fig. 104-1). It is very important for the electromyographer to have the patient exercise for only 10, absolutely no more than 15 seconds to achieve maximal postexercise facilitation to prevent its being masked by a longer period of exercise. A previous and improperly performed EMG contributed to the failure to detect a postexercise facilitation in three of our patients who were exercised too long (i.e., 30 to 60 seconds) at another EMG laboratory. The shorter period of exercise proved to be critical to our diagnosis of LEMS. Clinical examination and RMNS in 29 patients with SCLC and no symptoms of LEMS did not detect any subclinical cases. Conventional needle EMG in patients with LEMS demonstrates an increased number of low-amplitude, short-duration motor unit potentials, as seen with other myopathies. Their amplitude may enlarge with sustained contraction.

2 ’ Loter

10 ’ Later

“L 30

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M. G.

10 seconds

Br. Ca.

10 seconds

A

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T

FIG. 104-1. Effects of exercise on the compound muscle action potential (CMAP) of the hypothenar muscles evoked by maximal stimulation of the ulnar nerve at the wrist. The response of the rested muscle as recorded on the left is compared with responses at 3 seconds, 2 minutes, and 10 minutes after the end of a maximal voluntary contraction of this muscle for 10 to 15 seconds. Each record consists of superimposed CMAPs evoked at a rate of 3 Hz. Br. Ca, patient with LEMS and small cell lung cancer; M.C., patient with generalized myasthenia gravis; N, normal patient. The important finding in LEMS is the low-amplitude CMAP and the marked facilitation after brief voluntary exercise with an associated neuromuscular transmission defect. (From Rooke ED, Eaton LM, Lambert EH, Hodgson CH: Myasthenia and malignant intrathoracic tumor. Med Clin North Am 44:972, 1960 with permission.)

Chapter 104 H Lambert-Eaton Myasthenic Syndrome

Antibody Studies VGCC antibody testing is the final determinant of the accuracy of LEMS. This laboratory modality provides the definitive means to confirm the clinical and electromyographic impression of LEMS in both the paraneoplastic and the primary autoimmune forms of this disorder These P/Q type antibodies were present in 92% of 72 clinically definite LEMS patients studied by the Oxford group of Newsom, Davis, Vincent et al. They also demonstrated the presence of these P/Q VGCC antibodies in 3 of 90 SCLC patients (3.3%) who had no neurologic symptoms. Thus, a positive VGCC antibody test per se does not diagnose LEMS. One absolutely needs the typical clinical and electromyographic findings to support this diagnosis.

Chest Radiographs, Computed Tomography, and Magnetk Resonance Imaging Interestingly, just 5 of our 23 patients with LEMS had abnormal chest radiographs before their LEMS diagnosis: four with SCLC and the other with a lymphoma. When the electromyographic findings were typical for LEMS, a subsequent chest radiograph demonstrated perihilar masses in two others who then had a positive SCLC biopsy. By contrast, in the other patients, the post EMG chest radiograph was either normal or nondiagnostic. A computed tomography (CT) scan of the lung is indicated whenever a diagnosis of LEMS is made and the initial chest radiograph is normal. This is a more sensitive modality. It immediately led to an SCLC diagnosis in four of our seven newly diagnosed patients with LEMS. However, when the CT scan is negative, pulmonary cytologic studies, including sputum analysis and bronchial washings, are occasionally of value for the diagnosis of occult lung tumors in some LEMS cases. Repeat chest CT scan and magnetic resonance imaging (MRI) in patients with LEMS without documented SCLC, particularly middle-aged smokers, must be performed intermittently-possibly every 3 to 6 months-for at least 4 years after the initial LEMS diagnosis.

THERAPY Two primary forms of therapeutic modalities are available for patients with LEMS. One group is used to provide symptomatic neuromuscular transmission improvement. In the other instance, a set of options is available primarily to modify the autoimmune process. Historically, guanidine was the first symptomatic therapy used effectively for patients with LEMS. This drug enhances acetylcholine release from motor nerve terminals. Unfortunately, it is generally contraindicated because of its inherent renal and hematologic toxicity. Today it is used only in the rare instances when all other therapies have failed and the patient is very symptomatic. Another drug, 3,4-diaminopyridine (3,4-DAP), also promotes acetylcholine release from the presynaptic portion of the neuromuscular junction. It prolongs the VGCC open time. Currently it is available for LEMS treatment primarily in Europe. After a recent very positive major two-arm parallel treatment study at Duke, the U.S. Food and Drug Administration still declined to grant approval for routine 3,4-DAP use. However, they now permit its use with local institutional review board approval and concomitant submission of a protocol to the Food and Drug Administration for compassionate use. This medication provided significant clinical and neurophysiologic improvement in 25 of 26 patients

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with LEMS. It is as effective in patients with SCLC as in those with idiopathic autoimmune LEMS. In a 2000 study by Sanders et al., patients received 20 mg three times daily. When starting a patient de novo, the initial dosage usually is 5 mg three times daily (15 mg/day). Gradually one may work up to a maximum of 80 mg/day. Neurologists who use 3,4-DAP are urged to be cautious with large dosages because central nervous system irritability, usually manifested by seizures, is a major side effect. The anticholinesterase medication pyridostigmine also improves neuromuscular transmission. In contrast to MG, pyridostigmine is not always as effective for LEMS. However, anticholinesterases potentiate the effects of 3,4-DAP. When 3,4-DAP becomes more widely available, it has the potential if combined with pyridostigmine to be the first line of LEMS therapy. There is an important caveat in that pyridostigmine and 3,4-DAP provide only symptomatic therapy and do not address the autoimmune mechanisms responsible for both paraneoplastic and primary autoimmune LEMS. Of the various forms of chronic immunomodulation, prednisone is often the traditional drug of choice. However, in patients with SCLC or those at high risk for SCLC in whom a tumor has yet to be identified, initiation of immunosuppressive therapy theoretically may lessen the body’s immune response to the patient’s tumor. No data are available to confirm that hypothesis. I initiate an immunosuppressive medication only after a patient’s symptoms are disabling and she or he cannot effectivelybe returned to performing activities of daily living. In general, a dosage of 40 to 100 mg/day is given until improvement begins, which may take a few months. Next, one changes to an alternate-day dosage schedule, decreasing the low-day dosage by 10 to 20 mg every 10 to 15 days until a schedule of alternating 40 and 10 to 80 and 20 mg/day is achieved. Then the high-day dosage is gradually decreased to a maintenance level of alternating 10 and 0 to 30 and 15 mglday. Other clinicians suggest starting with the alternateday schedule of prednisone at a dosage of 1.0 to 1.5 mg/kg every other day. Azathioprine, starting with 50 mg daily and gradually increasing to 2.0 to 2.5 mg/kg daily, often combined with prednisone, may enhance the effectiveness of the treatment. However, azathioprine has a delayed onset of clinical effectiveness. Therefore it is not a good initial therapeutic modality. Intravenous immunoglobulin therapy for LEMS, with or without SCLC, may produce significant improvement with 1 g/kg on two consecutive days. Patients often note a return of strength beginning 2 to 3 days after infusion; the improvement may peak at 2 to 3 weeks and persist for a total of 4 to 6 weeks. Relapses may be controlled by repeat courses. This may become the primary LEMS immunotherapy, however a greater experience is needed to best assess MO’s therapeutic potential and relative risk benefit. Finally, plasmapheresis is another form of immunotherapy that is useful for patients with LEMS and significant weakness. This course of treatment may have a peak effect lasting just 2 weeks. When this temporary improvement is lost, another series of treatments may be needed within 6 weeks of the initial therapy. Its effectiveness often is less than when used for myasthenia gravis. Chemotherapy has been the primary treatment modality in seven of our patients with SCLC. In all seven instances, the tumor was not identified until after the LEMS diagnosis. One patient also had a pneumonectomy. The chemotherapy was very effective,with resolution of both clinical and neurophysiologic evidence of the LEMS and no sign of the lung tumor for 6 years. He then developed SCLC in the opposite lung and died a few months later.

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Another patient’s illness was stable for 1 year. One patient treated primarily with chemotherapy died within just a few months, and the other three patients with SCLC and LEMS who were similarly treated were lost to follow-up. Finally, a middle-aged man with LEMS was initially treated with prednisone. Chemotherapy was added when chest CT finally became positive 1 year after diagnosis. He died 6 months later. With the recent access to 3,4-DAP, we have treated two patients with a combination of this and chemotherapy. A larger study will be necessary to assess the value of this combined therapy.

Medications Contraindicated in Patients with LEMS Certain common medications may exacerbate LEMS symptoms. Cardiac drugs, including P-adrenergic and calcium channel blocking agents along with antiarrhythmic agents such as procainamide and quinidine also must be used cautiously in LEMS. The aminoglycoside antibiotics, quinine, and magnesium citrate cathartics may also potentiate the LEMS neuromuscular transmission defect by increasing weakness. Lithium, a cation, caused a significant exacerbation in one of our patients who was previously given a diagnosis of depression as a n explanation of her classic LEMS symptoms. Anesthesiologists need to be aware of a LEMS diagnosis because it is important that they select medications that will not prolong postoperative respiratory depression. O n rare occasions, this may be the initial manifestation of LEMS.

PROGNOSIS AND FOLLOW-UP In J. H. ONeill and colleagues’ seminal study, 18 of 23 patients with LEMS and SCLC died within 32 months of tumor diagnosis. They had a median survival of 8.5 months. There were 5 survivors; 3 had remission of LEMS with no detectable tumor from 2.9 to 4.2 years. In contrast, the prognosis in patients with primary autoimmune LEMS without SCLC was excellent in 21 patients, with a median follow-up of 6.9 years.

CONCLUSION The clinical manifestations of LEMS mimic a number of neurologic syndromes. These include MG, polymyositis, multiple sclerosis, and somatoform disorders. Evidence of muscle weakness may not always be present early on; one has to take care to not attribute reports of recent-onset fatigue or muscle tightness to psychological mechanisms such as depression or hysteria. Bulbar symptoms suggesting MG or brainstem stroke may also be present. Some patients with LEMS have a positive Tensilon test, but the acetylcholine receptor antibodies usually are negative. Other patients with LEMS have concurrent paraneoplastic syndromes, particularly cerebellar ataxia or a primary sensory polyneuropathy. A complete EMG, including a search for a neuromuscular transmission disorder and, most importantly, postexercise facilitation within 10 to 15 seconds of maximal voluntary exercise, is essential for the appropriate clinical diagnosis. The finding of positive VGCC in the clinical setting of LEMS confirms the diagnosis. The treatment of choice is 3,4-DAP, if available; however, at times prednisone, intravenous immunoglobulin, and rarely plasmapheresis may also be helpful. An SCLC is found in 50% of patients with LEMS; these patients generally have a poor prognosis, in contrast to those with the more benign idiopathic primary autoimmune form.

SUGGESTED READINGS Bird SJ: Clinical and electrophysiologic improvement in Lambert-Eaton syndrome with intravenous immunoglobulin therapy. Neurology 42:1422-1423, 1992 Blumenfeld AM, Recht LD, Chad DA et al: Coexistence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration: differential: effects of treatment. Neurology 41:1682-1685, 1991 Breen LA, Gutmann L, Brick JF, Riggs J R Paradoxical lid elevation with sustained upgaze: a sign of Lambert-Eaton syndrome. Muscle Nerve 14863-866, 1991 Brown JC, Johns RJ: Diagnostic difficulty encountered in the myasthenic syndrome sometimes associated with carcinoma. J Neurol Neurosurg Psychiatry 37: 1214-1224, 1974 Dalakas MC: Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 22( 11):1479-1497, 1999 Gutmann L, Phillips LH, Gutmann L Trends in the association of Lambert-Eaton myasthenic syndrome with carcinoma. Neurology 42~848-850,1992 Howard JF, Sanders DB, Massey J M The electrodiagnosis of myasthenia gravis and the Lambert-Eaton syndrome. Neurol Clin North Am 12~305-330, 1994 Kleopa KA,Teener JW, Scherer S S et al: Chronic multiple paraneoplastic syndromes. Muscle Nerve 23: 1767-1772, 2000 Lambert EH, Eaton LM, Rooke ED: Defect of neuromuscular conduction associated with malignant neoplasms. Am J Physiol 187:612413, 1956 Lang B, Waterman S , Pinto A et al: The role of auto-antibodies in Lambert-Eaton myasthenic syndrome. Ann NY Acad Sci May 13; 841:596-605, 1998 Lennon VA, Kryzer TJ, Griesmann GE et al: Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 332(22):1467-1474, 1995 Lundh H, Nilsson 0, Rosen I Current therapy of the Lambert-Eaton myasthenic syndrome. Prog Brain Res 84163-170, 1990 Lundh H, Nilsson 0, Rosen I, Johansson S: Practical aspects of 3,4-diaminopyridine treatment of Lambert-Eaton myasthenic syndrome. Acta Neurol Scand 88136-140, 1993 Maddison P, Lang B, Mills K, Newsom-Davis J Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer. J Neurol Neurosurg Psychiatry 70:212-217, 2001 McEvoy K: Diagnosis and treatment of Lambert-Eaton myasthenic syndrome. Neurol Clin North Am 12:387-399, 1994 Motomura M, Hamasaki S, Nakane S et al: Apheresis treatment in Lambert-Eaton myasthenic syndrome. Ther Apheresis 4:287-290,2000 Newsom-Davis J: Paraneoplastic neurological disorders. J R Coll Physicians Lond 33:225-227, 1999 Newsom-Davis J, Leys K, Vincent A et al: Immunological evidence for the co-existence of the Lambert-Eaton myasthenic syndrome and myasthenia gravis in two patients. J Neurol Neurosurg Psychiatry 54:452453, 1991 Oh SJ, Kim DS, Head TC, Claussen G C Low-dose guanidine and pyridostigmine: relatively safe and effective long-term symptomatic therapy in Lambert-Eaton myasthenic syndrome. Muscle Nerve 20(9):1146-1152, 1997 ONeil JH, Murray NMF, Newsom-Davis J: The Lambert Eaton myasthenic syndrome: a review of 50 cases. Brain 111:577-596, 1988 O’Suilleabhain P, Low PA, Lennon VA Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome serologic and clinical correlates. Neurology 50538-93, 1998 Rooke ED, Eaton LM, Lambert EH, Hodgson CH: Myasthenia and malignant intrathoracic tumor. Med Clin North Am 44977-988, 1960 Sanders DB, Howard J F High dose intravenous immunoglobulin treatment in Larnbert-Eaton myasthenic syndrome. The New York Academy of Sciences. Myasthenia Gravis and Related Disorders: Experimental and Clinical Aspects; PIII-44. Washington, DC, April 12-15, 1992

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Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 3,4-diaminopyridinein Lambert-Eaton myasthenic syndrome.Neurology 54603407,2000 Streib E Adverse effects of magnesium salt cathartics in a patient with the myasthenic syndrome (Lambert-Eaton syndrome).Ann Neurol2: 175176, 1977 Tim RW, Massey JM, Sanders D B Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response

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to therapy in 59 patients. Ann N Y Acad Sci 13(841):823-826, 1998 Ueno S, Hara Y: Lambert-Eaton myasthenic syndrome without calcium channel antibody: adverse effect of calcium antagonist diltiazem. J Neurol Neurosurg Psychiatry 55:409410, 1992 Voltz R, Carpentier AF, Rosenfeld MR et al: P/Q-type voltage-gated calcium channel antibodies in paraneoplastic disorders of the central nervous system. Muscle Nerve 22:119-122, 1999

105 Toxic and Metabolic Disorders of the

Neuromuscular Junction rn

Jackson Pickett There are many toxic and metabolic disorders of neuromuscular transmission. This chapter focuses on some of the more common disorders seen in the United States.

Proximal limb muscles Distal limb muscles Diaphragm

BOTULISM

Local toxin production in the gut may explain why constipation often is the first symptom. Cranial muscle weakness leads to difficulties with feeding and breathing. Breathing difficulties are

There are five types of botulism (Table 105-1); all are rare. AU forms of botulism have similar signs and symptoms but vary in the source of the toxin. The toxin acts by binding to autonomic and motor nerve terminals. After being taken up by nerve terminals, the toxin reduces the number of quanta of acetylcholine released by a nerve stimulus. Recovery from the toxin involves sprouting of nerve terminals, which form new synapses. This process can take months.

Infant Botulism Clinical Features. The most common form of botulism is infant botulism. More than 90% of affected infants are less than 6 months of age; the remaining 10% are under 1 year of age. The sexes are equally affected. The spectrum of infant botulism (Table 105-2) varies from sudden infant death syndrome to an otherwise healthy infant who has a change in stool character. Most of the reported cases have been severe enough to necessitate hospital admission. Epidemiologic studies have identified many factors in the development of infant botulism (Table 105-3). It is assumed that infants consume spores that germinate in the gut, forming organisms that produce toxin. In most cases the source of the spores is not found. The signs and symptoms of infant botulism severe enough to necessitate hospitalization are shown in Table 105-4. Initial symptoms include constipation, poor feeding, weak cry, and a loss of head control. These symptoms last from 5 hours to 1 week before admission. When fully developed, the disorder causes weakness of cranial and limb muscles and abnormalities of the autonomic, mainly parasympathetic, nervous system. Symptoms and signs usually peak in 1 to 2 weeks. Recovery starts after 3 to 5 weeks and often takes 1 to 4 months. The sequence of muscular involvement in infant botulism is as follows:

Autonomic nervous system Cranial muscles

W TABU 105-1. Median Number of Cases of Botulism

Reported in the United States Each Year

No. of Casesflear

TVpe

Infant botulism 71 Foodborne botulism 24 Adult infectious botulism 2 Wound botulism 3 Inadvertent caused by toxin treatment Not known Data from Shapiro RL Hatheway C, Swerdlow DL: Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 129:221, 1998.

W TABLE 105-2. Spectrum of Infant Botulism

Asymptomatic carriers of organism in stool Mild cases Constipation Feeding difficulties Mild weakness Failure to thrive Moderate to severe cases Hospitalized patients Sudden infant death syndrome

W TABLE 105-3. Possible Factors in the Development of Infant

Botulism Source of spores Geographic location: 50% of the US. cases found in California, Pennsylvania, and Utah Nature of soil Parents who work in soil Honey or corn syrup consumption Susceptibility of host Age: 1 week to 1 year Infants <2 months of age: rural living Infants >2 months of age: less than one bowel movement per day for 2 months, breastfeeding,and ingestion of corn syrup Switch from milk to solid foods

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Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 3,4-diaminopyridinein Lambert-Eaton myasthenic syndrome.Neurology 54603407,2000 Streib E Adverse effects of magnesium salt cathartics in a patient with the myasthenic syndrome (Lambert-Eaton syndrome).Ann Neurol2: 175176, 1977 Tim RW, Massey JM, Sanders D B Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response

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to therapy in 59 patients. Ann N Y Acad Sci 13(841):823-826, 1998 Ueno S, Hara Y: Lambert-Eaton myasthenic syndrome without calcium channel antibody: adverse effect of calcium antagonist diltiazem. J Neurol Neurosurg Psychiatry 55:409410, 1992 Voltz R, Carpentier AF, Rosenfeld MR et al: P/Q-type voltage-gated calcium channel antibodies in paraneoplastic disorders of the central nervous system. Muscle Nerve 22:119-122, 1999

105 Toxic and Metabolic Disorders of the

Neuromuscular Junction rn

Jackson Pickett There are many toxic and metabolic disorders of neuromuscular transmission. This chapter focuses on some of the more common disorders seen in the United States.

Proximal limb muscles Distal limb muscles Diaphragm

BOTULISM

Local toxin production in the gut may explain why constipation often is the first symptom. Cranial muscle weakness leads to difficulties with feeding and breathing. Breathing difficulties are

There are five types of botulism (Table 105-1); all are rare. AU forms of botulism have similar signs and symptoms but vary in the source of the toxin. The toxin acts by binding to autonomic and motor nerve terminals. After being taken up by nerve terminals, the toxin reduces the number of quanta of acetylcholine released by a nerve stimulus. Recovery from the toxin involves sprouting of nerve terminals, which form new synapses. This process can take months.

Infant Botulism Clinical Features. The most common form of botulism is infant botulism. More than 90% of affected infants are less than 6 months of age; the remaining 10% are under 1 year of age. The sexes are equally affected. The spectrum of infant botulism (Table 105-2) varies from sudden infant death syndrome to an otherwise healthy infant who has a change in stool character. Most of the reported cases have been severe enough to necessitate hospital admission. Epidemiologic studies have identified many factors in the development of infant botulism (Table 105-3). It is assumed that infants consume spores that germinate in the gut, forming organisms that produce toxin. In most cases the source of the spores is not found. The signs and symptoms of infant botulism severe enough to necessitate hospitalization are shown in Table 105-4. Initial symptoms include constipation, poor feeding, weak cry, and a loss of head control. These symptoms last from 5 hours to 1 week before admission. When fully developed, the disorder causes weakness of cranial and limb muscles and abnormalities of the autonomic, mainly parasympathetic, nervous system. Symptoms and signs usually peak in 1 to 2 weeks. Recovery starts after 3 to 5 weeks and often takes 1 to 4 months. The sequence of muscular involvement in infant botulism is as follows:

Autonomic nervous system Cranial muscles

W TABU 105-1. Median Number of Cases of Botulism

Reported in the United States Each Year

No. of Casesflear

TVpe

Infant botulism 71 Foodborne botulism 24 Adult infectious botulism 2 Wound botulism 3 Inadvertent caused by toxin treatment Not known Data from Shapiro RL Hatheway C, Swerdlow DL: Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 129:221, 1998.

W TABLE 105-2. Spectrum of Infant Botulism

Asymptomatic carriers of organism in stool Mild cases Constipation Feeding difficulties Mild weakness Failure to thrive Moderate to severe cases Hospitalized patients Sudden infant death syndrome

W TABLE 105-3. Possible Factors in the Development of Infant

Botulism Source of spores Geographic location: 50% of the US. cases found in California, Pennsylvania, and Utah Nature of soil Parents who work in soil Honey or corn syrup consumption Susceptibility of host Age: 1 week to 1 year Infants <2 months of age: rural living Infants >2 months of age: less than one bowel movement per day for 2 months, breastfeeding,and ingestion of corn syrup Switch from milk to solid foods

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TABU 105-4. Signs and Symptoms of Infant Botulism Site

Sign or Symptom

Autonomic nervous system

Constipation Sluggish pupils Flushed appearance Decreased tearing or salivation Bradycardia or tachycardia Hypotension or hypertension Urinary retention Poor feeding Reduced gag or suck reflex Facial weakness or ptosis Assisted ventilation Poor cry Weakness Reduced stretch reflexes Decreased activity

Cranial nerves

Somatic nerves

TABU 105-5. Differential Diagnosis of Infant Botulism infections Sepsis Meningitis Encephalitis Metabolic Abnormalities of cations and glucose Disorders of amino acid metabolism Hypothyroidism Metabolic encephalopathy Reye's syndrome Subacute necrotizingencephalomyelitis (Leigh's disease) Toxins Alcohols Anticholinergics Heavy metals Narcotics Organophosphates Neuromuscular Congenital myasthenia gravis Congenital myopathy Diphtheritic neuropathy Cuillain-Barre syndrome Infantile spinal muscular atrophy (Werdnig-Hoffman disease) Muscular dystrophy Poliomyelitis Tick paralysis

first caused by weakness of the bulbar muscles, leading to airway obstruction, and later by weakness of the respiratory muscles. Proximal limb and neck muscles often are weaker than distal muscles; the diaphragm is involved late in the course of the disease. A symmetrical descending paralysis is typical. Diagnosis. The combination of an infant who develops constipation, then feeding and respiratory difficulties, and later weakness of the neck and limbs, should suggest the diagnosis of infant botulism. Disorders to consider in the differential diagnosis are listed in Table 105-5. This differential can be reduced by screening for treatable infectious, metabolic, and toxic disorders; performing an electromyogram (EMG) and nerve conduction studies; searching for a tick; and sending blood and stool to be analyzed for botulinal toxin and organism. The usual results of the EMG and nerve conduction studies are shown in Table 105-6. The nerve conduction studies typically reveal small compound muscle action potentials (CMAPs). A decrement in the CMAP with slow repetitive nerve stimulation (i.e., 2 to 3 Hz) often occurs, implying a neuromuscular junction disorder. However, an increment in CMAP amplitude with rapid repetitive stimulation (i.e., 30 to 50 Hz) is characteristic and highly suggestive of a presynaptic

neuromuscular junction, such as botulism, where the number of quanta released by a nerve stimulus is markedly reduced. An increment lasting many minutes may be seen. Small and short motor unit potentials may be seen on needle EMG, localizing the disorder to the distal nerve terminals, neuromuscular junctions, or muscle fibers. In selected cases, single-fiber electromyography (SF-EMG) can be used to diagnose neuromuscular junction disorders, including botulism. SF-EMG measures the variability (i.e., jitter) in the onset of one muscle fiber action potential compared to another muscle fiber action potential of the same motor unit. In neuromuscular junction disorders, jitter increases. Conventional SF-EMG relies on cooperation of the patient in voluntarily maintaining contraction of the muscle being studied; such is not feasible when studying infants. In these cases, stimulated SF-EMG may be used to measure jitter. Stimulated SF-EMG also shows increased jitter. However, in presynaptic disorders, such as botulism, increased jitter improves as the frequency of stimulation increases, comparable to the increment in the CMAP seen with rapid repetitive stimulation. The diagnosis of infant botulism depends on the demonstration of the organism or toxin in the stool and the absence of toxin in any food. Toxin can be found in the serum in up to 12% of cases. In the United States, the type A toxin is most common in the West and type B in the East. Two types of toxin may be present in rare cases. The organism usually is Clostridium botulinum, but Clostridium butyricum (type E toxin) and Clostridium baratii (type F toxin) have been reported. To identify the toxin, mice are injected with serum or a stool extract, with and without antitoxin, and observed for death caused by paralysis. Both toxin and organism can be excreted in the stool for months, even as the infant recovers. Infants can improve before the toxin in the stool peaks. Treatment. The treatment of infant botulism in the hospital often involves intubation and mechanical ventilation, tube feedings, and Credk's maneuver to empty the bladder (Table 105-7). The hospital course varies from a few days to 6 months; about 5% of infants relapse. It is important to anticipate respiratory problems. A respiratory arrest occurs in about 30% of infants. All infants with difficulty coughing, gagging, or swallowing should be observed for apnea. Antitoxin has not been used because no toxin is detected in the serum in about 90% of cases, and serious allergic reactions have occurred when horse serum antitoxin has been given. The use of a human-derived antitoxin may soon clarify whether antitoxin is effective. For information on obtaining human botulinum immune globulin, contact the California Department of Health Services at 510-540-2646. If antibiotics are

rn TABLE105-6. Electrodiagnostic Studies in Infant Botulism studv

Result ~

Conduction studies Motor conduction velocities and latencies Normal Compound muscle action potential amplitude Low Sensory conduction studies Normal Rapid repetitive stimulation (>lo Hz) Increment 92% Decrement 47% Electromyography Positive sharp wave and fibrillation potentials 541 92% Small and short motor unit ootentials ._ . Data from Cornblath DR, Sladky JT,Surnner Al: Clinical electrophpiology of infantile botulism Muscle Nerve 6:448, 1983

Chapter 105 rn Toxic and Metabolic Disorders of the Neurornuscular Junction

TMU 105-7. Treatment of Infant Botulism Support respiratory system Monitor for apnea Prevent airway obstruction May need respirator for months Maintain nutrition May need tube feeding if unable to cough, gag, suck, or swallow Feed upright Urinary retention Crede's maneuver Treat urinary infections Of uncertain value Antibiotics Drugs to increase strength Human-derived antitoxin Laxatives and enemas

T m 105-8. Complications Seen in Infant Botulism Treatment All patients Apnea Autonomic instability C. difficile-associated diarrhea Pneumonia Sepsis Urinary tract infection lntubated patients Plugged endotracheal tube Postextubation stridor Recurrent atelectasis Subglottic stenosis Syndrome of inappropriate secretion of antidiuretic hormone Tracheal granuloma Tracheitis Tracheomalacia Unintended extubation

needed, drugs that inhibit neuromuscular transmission, such as aminoglycosides, should be avoided. With a mean hospital stay of 1 month and 80% of hospitalized infants on a respirator, treatment complications are expected (Table 105-8).Most involve the respiratory system or are caused by infections. Despite these problems in management and the presence of severe paralysis, only 2% to 3% of infants die, and the rest recover completely.

Foodborne Botulism Clinical Features. Foodborne botulism differs from infant botulism in that a source of toxin is present, and more than one half of the cases occur in outbreaks. Type A toxin is the most common (Table 105-9), and western states report more cases of botulism. The usual source of types A and B toxin is home-canned food, baked potatoes in aluminum foil, garlic in oil, sauteed onions kept under butter sauce, and cheese sauce; marine life is the typical source of type E toxin. Most patients with botulism are older than 10 years, and the median age is 30 to 40 years. The toxin does not cross the placenta, so the fetus of a mother with botulism is not at risk. The sexes are equally involved. The incubation period can vary from 2 hours to 8 days but usually is 12 to 36 hours. Typical initial signs and symptoms are blurred vision, diplopia, ptosis, dysarthria, dysphagia, and generalized weakness (Table 105-10).As with infant botulism, paralysis in foodborne botulism descends and usually is symmetrical, although 20% of the cases can be asymmetrical. Proximal muscles are weaker than distal, and

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arms are more involved than legs. Autonomic involvement includes blurred vision, orthostatic hypotension, urinary retention, constipation, dry mouth, and dilated, fixed pupils. In addition to weakness and autonomic dysfunction, there may be evidence of acute gastroenteritis with nausea, vomiting, abdominal pain, and diarrhea. The deficits peak in 4 to 5 days, and most improvement occurs in months, although 2 years later some patients still report dyspnea, fatigue, dry mouth, constipation, or impotence. Diagnosis. A symmetrical descending paralysis with a mixture of autonomic, especially parasympathetic, dysfunction should suggest the diagnosis of botulism. The diagnosis is supported by other cases with a common food source for the toxin. The diagnosis of botulism is confirmed by detecting the toxin in serum or stool, or the organism in the stool, or by demonstrating the toxin in the suspected food. Because the mouse assay is slow, electromyography may give more rapid support for the diagnosis. The changes in foodborne botulism are similar to those in infant botulism (Table 105-11). Milder cases may show a greater increment, and findings may vary with the limb studied. The differential diagnosis of foodborne botulism includes Guillain-Barrk syndrome Tick paralysis Shellfish poisoning Myasthenia gravis Lambert-Eaton syndrome Guillain-Barrk syndrome is an ascending, mainly motor polyneuropathy. It can be distinguished from botulism by the presence of sensory abnormalities, ascending weakness, and a high cerebro-

TABU105-9. Types of Distribution of Foodborne Botulism Toxin Tvpe

Percentage of Cases

A

50% 25% 25%

B C

GeographicSites

West of Mississippi East of Mississippi Alaska and Great Lakes

~~

Data from Shapiro RL, Hatheway C, Swerdlow DL: Botulism in the United States: a clinical and epidemiologic review. Ann intern Med 129:221, 1998.

TMU 105-10. Signs and Symptoms of Foodborne Botulism Symptoms Abdominal cramps or pain Blurred vision Constipation Diarrhea Diplopia Dizziness Dysphagia Dysphonia Nausea or vomiting Photophobia Sore throat Urinary retention or incontinence Weakness Signs Abnormal eye movement Ataxia Dilated and fixed pupils Dry mouth Nystagmus Postural hypotension Weakness

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Diseases of Neuromuscular Transmission

The differential diagnosis of wound botulism includes

rn TMLE 105-11. Electrodiagnostic Studies in Foodborne Botulism study

Result

Conduction studies Motor conduction velocities and latencies Normal Compound muscle action potential amplitude Low in 85% Sensory conduction studies Normal Repetitive stimulation 62% Increment with rapid stimulation Decrement with slow stimulation 8% Electromyography Small and short motor unit potentials increased jitter and blocking with single-fiber electromyography Data from Cherington M: Clinical spectrum of botulism: a review. Muscle Nerve 21 : 701,1998.

spinal fluid protein. A search for a tick is reasonable. Shellfish poisoning develops over minutes, and usually sensory symptoms and signs are present. Myasthenia gravis and Lambert-Eaton syndrome usually develop more slowly than botulism. Treatment. The key to successful treatment of a patient with severe botulism is respiratory support. Respiratory failure may develop insidiously. Patients with a vital capacity of less than 30% of predicted value usually need to be intubated. Antitoxin is often given, but its efficacy is uncertain, and allergic reactions to horse serum can occur in 10% of patients. A human-derived antiserum should produce fewer allergic reactions. If gastrointestinal function permits, toxin can be removed with ipecac, gastric lavage, or enemas. Guanidine and 4-aminopyridine can improve strength in some patients but do not reverse respiratory paralysis. With current management, only about 5% to 10% of patients die, although infectious complications are common. Wound Botulism Clinical Features. Wound botulism favors young men in-

volved in outdoor activities during the spring, summer, and fall. Usually the wound is obvious, with a compound fracture or crush injury. In recent years, wound botulism has increased and now is associated with drug injections, often resulting in skin abscesses, and intranasal cocaine administration, causing sinusitis. The symptoms and signs of wound botulism are similar to those of foodborne botulism, although the onset is slower with a median incubation period of a week. Patients with wound botulism lack the nausea, vomiting, and diarrhea often seen with foodborne botulism but may have fever and sensory abnormalities caused by the wound or its infection. About two thirds of patients with wound botulism need a respirator, and 10% to 15% die. Diagnosis. The combination of a wound and a descending paralysis should suggest the diagnosis of wound botulism. Circulating toxin in the serum is found in only about 46% of patients, and the organism can be grown from the wound in 50% to 60% of cases. About three fourths of the cases in which the toxin type is identified are caused by type A, with the remainder caused by type B. The most sensitive test for wound botulism is repetitive nerve stimulation. An increment with rapid repetitive stimulation usually is present and localizes the disorder to the presynaptic neuromuscular junction. In the future, enzyme-linked immunosorbent assays and polymerase chain reactions may aid in the diagnosis.

Tetanus Rabies Myonecrosis Acute cranial polyneuritis Tetanus differs from wound botulism by the presence of trismus and spasms of facial and somatic muscles. Rabies has a much longer incubation period, 30 to 70 days after an animal bite, extreme excitability, hydrophobia, and a cerebrospinal fluid pleocytosis. Myonecrosis spares the cranial nerves. Acute cranial polyneuritis has less autonomic involvement, can have abnormal conduction studies or an elevated cerebrospinal fluid protein level, and lacks an increment with repetitive stimulation. Treatment. Treatment focuses on supportive measures and local wound care. About two thirds of wounds appear to be clean, although cultures often reveal the organism. Antibiotics and antitoxin often are used, but their efficacy is unknown. Adult Infectious Botulism Clinical Features. Occasional cases of botulism in patients over the age of 1 year occur in which no wound or food is the source of the toxin. These cases probably have the same mechanism as infant botulism, in which the organism produces toxin in the gut. Production of the toxin in the gut, or autointoxication, is favored by gastrointestinal disease or surgery, gastric achlorhydria, or antibiotic treatment. Autointoxication should be suspected when the patient has consumed food that contains C. botulinum but not its toxin and a long incubation period is present.

DRUGS Drugs can impair neuromuscular transmission by unmasking or worsening an existing neuromuscular junction disorder, causing a neuromuscular junction disorder in a previously normal patient, or inducing the immune system to cause a syndrome resembling myasthenia gravis. The following drugs can induce an immunemediated syndrome resembling myasthenia gravis: Chloroquine D-Penicillamine Pyrithioxin Tiopronin Trimethadione The resemblance to myasthenia gravis with some of these drugs is close and includes a decrement with slow repetitive stimulation, increased jitter with single-fiber electromyography, and antibodies to the acetylcholine receptor. Most drugs aggravate, produce, or unmask a neuromuscular junction disorder by their direct effect (Table 105-12). An accurate history of drugs taken by the patient is needed for diagnosing drug-induced neuromuscular junction disorders. Renal or liver failure often accentuates the effects of drugs. The diagnosis can be confirmed by withdrawing the drug and observing the return of the patient to his or her previous state. Recovery from neuromuscular junction blocking agents can be prolonged and take several months.

Chapter 105 H Toxic and Metabolic Disorders of the Neuromuscular Junction

rn TABLE105-12. Drugs That Can Impair Neuromuscular Transmission by Their Direct Effect Antibiotics Aminoglycosides Amikacin Dihydrostreptomycin Centamicin Kanamycin Neomycin Netilmicin Streptomycin Tobramycin Fluoroquinolones Ciprofloxacin Monobasic amino acids Clindamycin Lincomycin Penicillin Ampicillin Polypeptides Colistimethate Colistin Polymyxin B and E Sulfonamides Tetracyclines Oxytetracycline Rolitetracycline Anticonvulsants Barbiturates Mephenytoin Phenytoin Trimethadione Botulinum toxin Cardiovascular drugs P-Blockers Nadolol Oxprenolol Pindolol Practolol Propranolol Bretvlium

Calcium channel blockers Verapamil Lidocaine Procainamide Quinidine Trimethaphan Hormones Adrenocorticotropic hormone Corticosteroids Estrogen Progesterone Thyroid hormone Neuromuscular blocking drugs Ophthalmic drugs Betaxolol Echothiophate Timolol Psychotropic drugs Lithium Monamine oxidase inhibitors Phenelzine Phenothiazines Chlorpromazine Promazine Rheumatologic drugs Penicillamine Chloroquine Miscellaneous drugs Aprotinin Azathioprine Diuretics D,L-Carnitine Emetine Methoxyflurane Sodium lactate infusion Trihexyphenidyl Radiographic contrast agents

HYPERMACNESEMIA Hypermagnesemia usually occurs in patients with renal failure who are given antacids or laxatives containing magnesium or treated for eclampsia with magnesium. The signs and symptoms of hypermagnesemia are as follows: Amnesia Ataxia Cardiac arrest Cutaneous flushing Dry mouth Hypotension Loss of stretch reflexes Nausea and vomiting Nystagmus Pupillary dilation Respiratory arrest Slurred speech Urinary retention Weakness These findings should suggest the diagnosis, and magnesium levels will confirm this impression. Electrodiagnostic studies reveal small

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CMAps, which increase in amplitude after brief exercise or rapid

repetitive stimulation. These abnormalities reflect a reduction in the release of acetylcholine at neuromuscular junctions. Hypermagnesemia treatment involves reduced magnesium intake, intravenous calcium, or hemodialysis, depending on the severity of the findings. Respiratory support may be needed.

ORGANOPHOSPHATE INTOXICATION Exposure to organophosphate compounds usually is accidental but can be caused by a suicide attempt or terrorist attack. They cause acute symptoms and signs (Table 105-13) by irreversibly inhibiting acetylcholinesterase. This leads to an accumulation of

TABLE 105-13. Acute Signs and Symptoms Seen with Organophosphate Compounds Muscarinic Abdominal pain Aching of eyes Airway obstruction Anorexia Blurred vision Bradycardia Bronchial contraction and secretion Conjunctival hyperemia Coughing Cyanosis Diarrhea Hypotension Involuntary defecation and micturition Lacrimation Laryngeal spasms Nasal hyperemia Nausea and vomiting Pulmonary edema Pupillary constriction Runny nose Salivation Sweating Urinary frequency Nicotinic (including autonomic ganglia) Areflexia Fasciculations Fatigability Hypertension Muscle cramps Ophthalmoparesis Pallor Respiratoryfailure Tachycardia Proximal > distal weakness Central nelvous system Anxiety Apathy Ataxia Cheyne-Stokes respiration Coma Confusion Decreased concentration and memory Depression Emotional lability Excessive dreaming Failure of central respiratory drive Insomnia Nightmares Restlessness Seizures Slurred speech Tension Tremor Withdrawal

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acetylcholine at peripheral muscarinic and nicotinic synapses and at central nervous system synapses. The acute cholinergic crisis consists of miosis, fasciculations of the eyelids, face, and calves, and excess secretion. Acute symptoms start in 5 minutes to 1 day and usually peak in 0.5 hour to 6 hours and last 1 to 5 days. Diagnosis is aided by a history of exposure, signs such as miosis and fasciculation, improvement with atropine and pralidoxime, and a reduction of cholinesterase activity in the serum or red blood cells. The cholinergic crisis can be followed by a myasthenialike state, which lasts for 2 to 7 days. Weeks after the exposure, a delayed neuropathy can develop. Laboratory tests may aid in the diagnosis. Serum and red blood cell cholinesterase activity is inhibited early and for prolonged periods after exposure. For this reason cholinesterase levels do not correlate with clinical severity. After a single stimulus to a motor nerve, the initial CMAP is followed by repetitive potentials. These repetitive potentials reflect an accumulation of acetylcholine at neuromuscular junctions, which depolarizes motor nerve terminals. Depolarized motor nerve terminals backfire and activate other muscle fibers via an axon reflex. Repetitive potentials not only are seen in organophosphate intoxication but also can occur in congenital myasthenic syndromes caused by a deficiency of acetylcholinesterase and prolonged open time of sodium channels and with other drugs that inhibit acetylcholinesterase reversibly. Repetitive potentials are the earliest and most common change seen with electrodiagnostic studies. Slow repetitive stimulation studies may reveal a decrement. The decrement is caused by a combination of collision of the orthodromic action potentials with the backfiring action potentials from earlier stimuli and desensitization of acetylcholine receptors caused by a buildup of acetylcholine. A decrement with repetitive stimulation predicts the need for respiratory support. The treatment of acute organophosphate intoxication involves supporting respiratory function, giving atropine and pralidoxime to reverse the inhibition of acetylcholinesterase, and terminating exposure. SNAKE BITES

A wide variety of snakes can inflict a bite that is potentially neurotoxic, including the following: Australian elapids Cobras Coral snakes Kraits Mambas North American rattlesnakes Old world vipers Sea snakes South American rattlesnakes Snake venom is a complex mixture, and it is unusual for neurotoxic features to dominate. In the United States, bites by the eastern coral snake and the Mojave rattlesnake can result in cranial and somatic muscular paralysis. Most snake bites involve young men bitten in summer. Typical neurotoxic symptoms and signs include paresthesias, ptosis, diplopia, weakness, and difficulty with breathing. Usually the diagnosis is obvious, although 15% of patients may lack fang marks, and neurotoxic symptoms can be delayed for up to a day. Treatment includes antivenom, support of

respiration, and treatment of other complications caused by the venom. SPIDER BITES

The black widow spider generates most neurotoxic spider bites. A typical case involves the female spider biting a child or young man on an extremity in the late summer or early fall. The bite may be painless or feel like a pinprick. Later, a cramping pain develops and muscle contractions ensue, often causing a rigid abdomen, trismus, and paroxysms of pain. The symptoms and signs seen after a black widow spider bite are shown in Table 105-14. Usually symptoms peak in a few hours, although in occasional cases symptoms peak in the second day. Most symptoms resolve in 1 to 2 days. Patients can feel weak or lethargic for up to 1 month. The diagnosis is based on knowing that the patient was bitten by a spider and identifying the type of spider. This is usually easy to do, although occasional patients may be bitten during sleep, and 20% of patients do not show evidence of a bite. The usual treatment consists of calcium gluconate, opioids, and benzodiazepines to relieve pain. An antivenom is available and effective but is derived from horse serum. Serious allergic reactions to the horse serum occur in about 3% of patients. For this reason, the antitoxin is most likely to be given to children, older adults, pregnant women, and patients with cardiovascular disease. SCORPION STINGS

Most scorpion stings are painful but otherwise spare the nervous system. In the United States, the chief neurotoxic scorpion is Centruroides exilicauda, which resides mainly in the Southwest, and its sting leaves no visible mark. Signs and symptoms of a Centrumides sting include the following: Local pain and paresthesia Pain and paresthesia remote to sting bite

TABLE 105-1 4. Signs and Symptoms of Black Widow Spider Bite Common Pain Muscle cramping and rigidity Abdominal rigidity Sweating Anorexia, nausea, and vomiting Hyperesthesia of skin Headache Restlessness Occasional Arrhythmias Bradycardia or tachycardia Bronchorrhea Cyanosis Delirium Fear of death Hypertension Increase or decrease in temperature Opisthotonos Piloeredion Priapism and ejaculation Psychosis Salivation Seizures Shock Trismus Urinarv retention

Chapter 105

Autonomic abnormalities Jerking or shaking of limbs or trunk Blurred vision Wandering eye movements Hypersalivation Trouble swallowing Tongue fasciculations Compromise of upper airway Slurred speech Patients with a severe sting should be hospitalized, sedated, given supportive care, and considered for antivenom therapy.

BEE AND WASP STINGS The main danger of bee and wasp stings is an allergic reaction to their venom. In rare cases, myasthenia gravis has developed after a wasp sting.

TICK PARALYSIS Tick paralysis is an uncommon disorder seen in the Pacific Northwest, Rocky Mountains, and southern United States. The tick season begins in March and ends in August, with a peak in May and June. The most common ticks in the United States are Derrnacentor andersoni and Dermacentor variabilis. Tick paralysis usually is caused by a gravid female tick that has fed for 4 to 7 days. About 80% of patients are children, and two thirds of the children are girls because they are more likely to have long hair, where the tick hides. About 20% of cases are in adults, and 80% of these are men. The disease starts with a day-long prodrome of irritability, lassitude, or generalized weakness. Over the next day or two a symmetrical flaccid paralysis develops in the legs and ascends to the arms and then the neck, pharyngeal, and respiratory muscles. Weakness can be proximal more than distal. Areflexia and paresthesia are common, but objective sensory loss is unusual. Early on and in mild cases, ataxia may be more prominent than weakness. From 10% to 12% of patients, almost always children, die. Most laboratory tests are normal. Nerve conduction studies reveal involvement of motor and sensory nerves, with mild slowing of conduction velocity, a reduced amplitude of the evoked response, and prolonged distal latencies. The diagnosis of tick paralysis is suggested when a young girl develops an ascending areflexic paralysis in the spring or summer. These abnormalities resemble Guillain-Barrk syndrome. The correct diagnosis hinges on finding and removing a tick, found on the head or neck in 60% to 70% of the cases. The tick should be removed by steady traction. Once the tick is completely removed, improvement usually is rapid, but paralysis can progress for up to 2 days after tick removal.

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PLANTS CONTAINING NICOTINE A number of plants contain pyridine and piperidine alkaloids,

including nicotine, that can cause the following signs and symptoms: Nicotinic Weakness Fasciculations Paralysis Tachycardia Coma Seizures Hypertension Muscarinic Salivation Lacrimation Urination Gastrointestinal cramping Vomiting Miosis Bronchospasm Bradycardia Diaphoresis

Severe plant poisonings are unusual and are treated with activated charcoal if the ingestion is recent, atropine to block muscarinic symptoms, anticonvulsants for seizures, and ventilatory support if needed. Patients must be monitored for rhabdomyolysis and renal failure.

SUGGESTED READINGS Barrons RW Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy 17:1220, 1997 Bond G R Snake, spider, and scorpion envenomations in North America. Pediatr Rev 20:147, 1999 Cherington M Clinical spectrum of botulism. Muscle Nerve 21:701, 1998 Cornblath DR, Sladky JT, Sumner AJ: Clinical electrophysiology of infantile botulism. Muscle Nerve 6448, 1983 Felz MW, Smith CD, Swift TR A six-year-old girl with tick paralysis. N Engl J Med 34290,2000 Furbee B, Wermuth M: Life-threatening plant poisonings. Crit Care Clin 13:849, 1997 Maselli RA, Bakshi N Botulism. Muscle Nerve 23:1137, 2000 Midura, T F Update: infant botulism. Clin Microbiol Rev 9:1, 1996 Shapiro RL, Hatheway C , Swerdlow DL Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 129:221, 1998. Walker FG, Bilden EF, Gibly RL: Envenomations. Crit Care Clin 15:353, 1999

SECTION

5

DISEASES OF MUSCLE

106 Amroach to Patients with Muscle Disorders Anthony A. Amato Evaluating patients with neuromuscular disorders can be challenging. As in other neurologic diseases, the key to arriving at the correct diagnosis is carefully localizing the lesion. Weakness can be the result of central lesions (brain or spinal cord processes, e.g., brainstem infarct, central pontine myelinolysis, transverse myelopathy), anterior horn cell disease (e.g., amyotrophic lateral sclerosis [ALS], poliomyelitis), peripheral neuropathy (e.g., Guillain-BarrC syndrome [GBS]), neuromuscular junction defects (botulism, Lambert-Eaton myasthenic syndrome, myasthenia gravis), or myopathic disorders. The most important aspect of assessing patients with neuromuscular disorders is taking a thorough history of the patient’s symptoms, disease progression, and past medical and family history and performing a detailed neurologic examination. Based on the findings on the history and physical examination, the clinician should order specific laboratory tests, electrophysiologic tests, and muscle or nerve biopsies rather than using a shotgun approach to diagnosis. It is usually not difficult to distinguish generalized weakness secondary to cerebral or brainstem insults from other causes of muscle weakness because in these central disorders weakness is accompanied by impaired consciousness. However, myelopathies can be more troublesome. Compressive lesions of the spinal cord and nerve roots can result in a combination of upper and lower motor neuron abnormalities that can mimic ALS and vice versa. Acute transverse myelitis may result in rapid quadriparesis, in which the deep tendon reflexes are initially absent from a “shocked cord.” Such cases may be confused initially with GBS. Although transverse myelitis and GBS usually are associated with sensory loss, a true sensory level is not evident in GBS but should be evident in myelopathies. Motor and sensory symptoms and signs are helpful in distinguishing peripheral neuropathies from anterior horn cell disorders, myopathies, and neuromuscular junction disorders. However, some types of peripheral neuropathy are predominantly or purely motor and therefore can be difficult to distinguish from these other disease processes. Most neuropathies are associated with distal greater than proximal weakness. However, significant proximal weakness can be seen in certain peripheral neuropathies (e.g., GBS, chronic inflammatory demyelinating polyradiculoneuropathy). Furthermore, although usually associated with proximal weakness, certain myopathies and rarely even neuromuscular junction disorders can manifest with primarily distal weakness. ALS is the result of degeneration of upper and lower motor neurons. The degeneration of lower motor neurons leads to 676

muscle weakness, atrophy, and fasciculations that typically begin focally. Upper motor neuron involvement manifests as spasticity and pathologically brisk deep tendon reflexes. Although most patients over time develop both upper and lower motor neuron deficits, some patients continue to have pure lower motor neuron abnormalities, and others have only upper motor neuron signs. Some of the hereditary spinal muscular atrophies present with generalized symmetrical proximal greater than distal weakness and can be difficult to distinguish from myopathic disorders. The key in distinguishing neuromuscular junction defects from myopathies is the fluctuation in symptoms and signs in the former. Patients with myasthenia gravis usually fatigue with repetitive activity, whereas patients with Lambert-Eaton syndrome can actually improve with continued physical exertion. Neuromuscular junction disorders have a predilection to affect the extraocular muscles, which are less commonly affected in myopathies. The following discussion on approaching patients with neuromuscular complaints emphasizes myopathic and neuromuscular junction disorders. The workup of patients with peripheral nerve disorders is discussed in Chapter 90.

MEDICAL HISTORY While obtaining the medical history, the clinician should attempt to define onset and course of the illness and the distribution of symptoms. Disorders presenting in infancy (Table 106-1) are different from those that manifest later in childhood or early adult life (Table 106-2)or in late adulthood (Table 106-3).Importantly, the rate of progressiou must be assessed as some disorders progress acutely over days or weeks (Table 106-4),whereas others evolve more slowly over months (Table 106-5).Furthermore, the course of the disease may be monophasic, relapsing, or chronic and progressive. The patients’ presenting symptoms depend on the muscle groups that are predominantly affected. Proximal leg weakness usually manifests initially as progressive difficulty climbing stairs and arising from a chair, commode, or the floor. Affected patients often use their arms to help pull themselves up the stairs with a hand rail or push themselves up from a sitting position. Patients with weakness of the anterior compartment of the distal leg develop foot drop, and they complain of frequent tripping or stubbing of the toes. When the distal legs are affected, patients have difficulty standing on their toes. Shoulder girdle weakness affects the patient’s ability to lift his or her arms overhead (e.g., as in brushing one’s hair or lifting

Chapter 106 W Tmu 106-1. Differential Diagnosis of the

Floppy Infant

Central nervous system disorders (most common cause) Anterior horn cell Spinal muscular atrophy type 1 and 2 Peripheral neuropathy Congenital hypomyelinatingor arnyelinating neuropathy Charcot-Marie-Tooth (CMT) 111 (Dejerine-Sottas) CMT I and CMT II (rare) Giant axonal neuropathy Neuromuscular junction Infantile botulism Infantile myasthenia gravis Congenital myasthenia Myopathy Congenital myopathies (all of them can present in infancy) Muscular dystrophies Congenital muscular dystrophies Dystrophinopathy or sarcoglycanopathy (rare) Congenital myotonic dystrophy Metabolic myopathies Glycogen storage defects Acid maltase deficiency Debrancher deficiency Branching enzyme deficiency Myophosphorylase deficiency (rare) Disorders of lipid metabolism Carnitine deficiency Fatty acid-Acyl-CoA dehydrogenase deficiencies Mitochondrial myopathies Benign and fatal infantile myopathy Leigh’s syndrome Endocrine myopathies (e.g., hypothyroidism)

objects). Patients with hand weakness complain of difficulty in grasping or gripping objects. They describe problems opening jar tops and turning doorknobs. Patients with neck weakness may have difficulty lifting their head off a pillow. Furthermore, sudden braking or accelerating in a car can cause the head to jerk back and forth. Involvement of cranial muscles may result in ptosis, diplopia, dysarthria, or difficulty chewing and swallowing. The examiner should inquire about extreme fluctuations in strength during the day or associated with physical activities. Fluctuations in strength are more typical of neuromuscular junction disorders. Ask patients whether they have noticed any muscle atrophy or enlargement of their muscles. Specific neuromuscular conditions are associated with fasciculations, myalgias, cramps, stiffness or myotonia, periodic paralysis, and myoglobinuria. The clinician should ask about sensory symptoms. Patients may complain of feeling “numb,” but this word has different meanings for different people. The examiner should specifically ask the patient about the presence or absence of sensory loss, tingling, prickly, electrical, stabbing, burning, and dull aching pain. Fatigue is a very nonspecific symptom, and the majority of patients referred to my neuromuscular clinic for evaluation of fapgue do not have a primary neuromuscular disorder. Although many patients complain of “feeling weak all over,” their neuromuscular examination typically is normal or limited by give-way. Clearly, patients with neuromuscular disorders experience fatigue. However, patients with neuromuscular disorders usually have objective muscle weakness on examination. Evaluation of muscle pain is another common reason for referral to neuromuscular clinics. Most neuromuscular disorders, including myopathies, are not associated with severe muscle pain or tenderness. Some patients with muscular dystrophy or inflammatory myopathy describe mild to moderate, nontender, deep,

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aching discomfort in the muscles that is seldom severe enough to warrant analgesics (Table 106-6). However, severe myalgias and tenderness can accompany fasciitis, myositis related to infections, and rhabdomyolysis or myoglobinuria caused by various metabolic myopathies, electrolyte disturbances, and toxins. Patients with psychosomatic iUness often complain of severe generalized muscle pain and tenderness unrelieved by analgesic medications. They usually also describe generalized weakness or fatigue. Despite these severe symptoms, there is no objective evidence of a neuromuscular disease on clinical examination, laboratory testing, electrophysiologic studies, or muscle biopsy. The medical history of patients is important because certain illnesses are associated with specific neuromuscular disorders. For example, inflammatory myopathies may be seen in patients with connective tissue disease, concurrent autoimmune disorders may be present in patients with myasthenia gravis (MG), LambertEaton myasthenic syndrome (LEMS) is associated with small cell lung cancer and other autoimmune disorders, and neuropathies are common in patients with systemic diseases (e.g., diabetes mellitus, human immunodeficiency virus infection, cancer). The

W TABLE 1

Weakness Presenting in Childhood or Early Adulthood

Anterior horn cell Spinal muscular atrophy type 3 Poliomyelitis Amyotrophic lateral sclerosis (rare) Peripheral neuropathy Acute or chronic inflammatorydemyelinating polyneuropathy Hereditary neuropathies Neuromuscular junction Botulism Myasthenia gravis Congenital myasthenia Lambert-Eaton syndrome Myopathy Congenital myopathies Central core Multicore Centronuclear Nernaline Myofibrillar Muscular dystrophies Dystrophinopathy (Duchenne or Becker) Limb girdle muscular dystrophies Congenital muscular dystrophy (partial merosin deficiency) Myotonic dystrophy Other dystrophies (e.g., FSHD, EDMD) Metabolic myopathies Glycogen storage defects Acid maltase deficiency Debrancher and branching enzyme deficiency Disorders of lipid metabolism Carnitine deficiency Fatty acid-Acyl-CoA dehydrogenase deficiencies Mitochondrial myopathies Periodic paralysis Electrolyte imbalance Hyperkalemia Hypokalemia Hypophosphatemia Hypercalcemia Endocrine myopathies Toxic myopathies Inflammatory rnyopathies Dermatomyositis Polymyositis (after age 20 years) Infectious rnyositis Abbreviations: EDMD, Emety Dreifuss muscular dymophy; FSHD, facioxapulohumerai muscular dystrophy.

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TABU106-3. Weakness Presenting in Middle t o Late Adulthood Anterior horn cell Spinal muscular atrophy type 3 Kennedvs disease poliomyelitis Amyotrophic lateral sclerosis Peripheral neuropathy Hereditary neuropathies Acute or chronic inflammatory demyelinating polyneuropathy Drug-induced or toxic neuropathies Diabetic neuropathy Amyloid Vasculiis Neuromuscular junction Botulism Myasthenia gravis Lambert-Eaton syndrome Myopathy Congenital myopathies Myofibrillar myopathy (other types are uncommon) Muscular dystrophies Dystrophinopathy (Becker) Limb girdle muscular dystrophies Oculopharyngeal dystrophy Bent spine or dropped head syndrome Metabolic myopathies Glycogen storage defects Acid maltase deficiency Debrancher deficiency Disorders of lipid metabolism (rare) Mitochondria1myopathies Periodic paralysis Familial hypo-KPP manifest within the first three decades Familial hyper-KPP usually manifests in the first decade Electrolyte imbalance Hyperkalemia Hypokalemia Hypophosphatemia Hypercakemia Endocrine myopathies Toxic myopathies Myopathy associated with systemic disease (e.g., cancer), poor nutrition, disuse Amyloid myopathy Inflammatory myopathies Inclusion body myositis (most common inflammatory myopathy after age 50 years) Dermatomyositis Polymyositis (after age 20 years) Infectious myositis Abbreviations: hyper-KPP, hyperkalemic periodic paralysis; hypo-KPP, hypokalemic periodic paralysis.

review of systems should assess symptoms associated with specific disorders (e.g., arthralgias to assess for underlying connective tissue disease). It is essential to obtain an accurate family history. When a hereditary disorder is suspected, try to examine other affected family members. Some patients may claim a family history of a particular disorder, but when affected family members are examined a different disease may be diagnosed. For example, I have seen patients who stated that muscular dystrophy runs in their family. However, on examination of these affected family members, their disease turned out to be spinal muscular atrophy. In addition, some family members who are asymptomatic may be found to have subtle signs of disease on a thorough examination, leading to the correct diagnosis of a hereditary neuromuscular disorder. The clinician must inquire about current and recent medications, alcohol, tobacco, drug abuse, and previous exposures to environmental toxins to rule out a toxic neuropathy or myopathy.

The severity of the neuromuscular disorder depends on the type of toxin and the dosage and duration of the exposure.

PHYSICAL EXAMINATION After the medical history, a complete neurologic examination should be performed. Most importantly, ascertaining the pattern of involvement will help narrow the differential diagnosis. Most rn TABU 106-4. Neuromuscular Disorders Presenting with Acute or Subacute Proximal Weakness Anterior horn cell Poliomyelitis Peripheral neuropathy Guillain-Barre syndrome Porphyria Diphtheria Tick paralysis Toxic neuropathies Diabetic amyotrophy Vasculitis Carcinomatous infiltration (e.g., leukemia, lymphoma) Paraneoplastic neuropathy Neuromuscular junction Botulism Lambert-Eaton syndrome Myasthenia gravis Myopathy Periodic paralysis Electrolyte imbalance Endocrinopathies Inflammatory myopathies Dermatomyositis Polymyositis Infectious myositis (Note: Inclusion body myositis does not present acutely) Toxic myopathies Metabolic myopathies Glycogen and lipid disorders in association with myoglobinuria

W

TABU106-5. Differential Diagnosis of Chronic Progressive Proximal Weakness

Anterior horn cell Amyotrophic lateral sclerosis Spinal muscular atrophy type 3 Kennedy's disease Peripheral neuropathy Chronic inflammatory demyelinating polyneuropathy Multifocal motor neuropathy Toxic neuropathies Neuropathy associated with systemic disorders Connective tissue disease (e.g., vasculitis) Diabetes mellitus Amyloidosis Paraneoplastic Carcinomatous infiltration (e.g., leukemia, lymphoma) Neuromuscular junction Lambert-Eaton syndrome Myasthenia gravis Myopathy Muscular dystrophies Congenital myopathies Periodic paralysis Electrolyte imbalance Endocrinopathies Inflammatory myopathies Dermatomyositis Polymyositis Infectious myositis Toxic myopathies Metabolic myopathies (some glycogen and lipid storage disorders, mitochondrial myopathies)

Chapter 106

TABLE106-6. Disorders Associated with Muscle Pain Mild forms of muscular dystrophy (e.g., Becker muscular dystrophy, limb girdle muscular dystrophy) Metabolic Myopathies Glycogen storage diseases (e.g., phosphorylase, phosphofructokinase deficiencies) Myoadenylate deaminase deficiency Mitochondrial cytopathies Hypothyroid myopathy Toxic myopathies (e.g., cholesterol-loweringagents, cyclosporine, chloroquine) Inflammatory myopathy Idiopathic (dermatomyositis, polymyositis, overlap myositis) Infectious myositis (including human immunodeficiency virus infection) Fasciitis Eosinophilic myalgia syndrome Polymyalgia rheumatica Fibromyalgia

TABU 106-7. Disorders with Proximal Weakness Anterior horn cell Poliomyelitis Amyotrophic lateral sclerosis Spinal muscular atrophy Kennedqs disease Peripheral neuropathy Cuillain-Barre syndrome Chronic inflammatory demyelinatingpolyneuropathy Porphyria Diphtheria Tick paralysis Diabetic amyotrophy Polyradiculopathy secondary to carcinomatous infiltration (e.g., leukemia, lymphoma), infection (Lyme disease, human immunodeficiency virus, cytomegalovirus), sarcoidosis Neuromuscular junction Botulism Lambed-Eaton syndrome Myasthenia gravis Congenital myasthenia Myopathy Limb girdle muscular dystrophies Congenital myopathies Periodic paralysis Electrolyte imbalance Endocrinopathies Inflammatory myopathies Dermatomyositis polymyositis Inclusion body myositis infectious myositis Toxic myopathies Metabolic myopathies (various glycogen and lipid storage disorders and mitochondria1myopathies)

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muscle wasting, and frontal balding. A characteristic rash typically is present in patients with dermatomyositis. Therefore, specific neuromuscular disorders can be diagnosed or at least strongly suspected just by observing the patient while taking his or her medical history. For a proper and thorough examination, the patient must undress except for undergarments and a gown. Watch the patient arise from the seat and walk. Watch the patient stand and walk from the side as well as from the front and back. On side viewing, the clinician can detect excessive lumbar lordosis, hyperextension of the knee (genu recurvaturn), and ankle contractures in patients

TABLE 106-8. Differential Diagnosis of Distal Weakness Cervical disease Multilevel radiculopathy (C7, CB, T1) Lower trunk brachial plexopathy Syringomyelia Tumor of the cord Lumbosacral disease Tumor of the conus medullaris Polyradiculopathy (L4, L5, S1, S2) Lumbosacral plexopathy Motor neuron disorders Distal spinal muscular atrophy Amyotrophic lateral sclerosis Neuromuscular junction Myasthenia gravis (rare) Congenital myasthenia gravis (e.g., slow ion channel defect) Peripheral neuropathies Charcot-Marie-Tooth disease and related hereditary neuropathies Multifocal demyelinating motor or sensorimotor neuropathies Vasculitis Toxic or metabolic neuropathies Intrinsic muscle disorders Distal myopathies or dystrophies Facioscapulohumeral muscular dystrophy Scapuloperoneal syndromes Emery-Dreifuss muscular dystrophy Oculopharyngodistal muscular dystrophy Myotonic dystrophy Acid maltase deficiency Debrancher enzyme deficiency Phosphorylase b kinase deficiency Myofibrillar myopathy Central core disease Centronuclear myopathy Nemaline myopathy Inclusion body myositis Focal myositis

w TAW 106-9. Neuromuscular Causes of F'tosis or Ophthalmoplegia

myopathies preferentially affect the proximal more than distal muscles, and the converse is true in most types of peripheral neuropathy. However, proximal weakness can be seen in disorders other than myopathies (Table 106-7). Furthermore, distal muscles can be weaker than the proximal muscles in certain myopathies and other neuromuscular disorders besides peripheral neuropathies (Table 106-8). A few neuromuscular disorders have a predilection for involving the extraocular muscles (Table 106-9). The physical examination begins while the clinician is obtaining the history of the present illness. Extraocular, facial, jaw, pharyngeal, tongue, and neck weakness may be apparent by just observing the patient during history taking. Ptosis, ophthalmoparesis, or dysarthria may be evident while one is talking to the patient, leading to consideration of myasthenia gravis. Patients with myotonic dystrophy often have facial weakness, temporalis

Peripheral neuropathy Guillain-Barre syndrome Miller-Fisher syndrome Neuromuscular junction Botulism Lambert-Eaton myasthenic syndrome Myasthenia gravis Congenital myasthenia Myopathy Mitochondrial myopathies Kearns-Sayre syndrome Progressive external ophthalmoplegia Oculopharyngeal and oculopharyngodistal muscular dystrophy Myotonic dystrophy (ptosis only) Congenital myopathy Myotubular Nemaline (ptosis only) Hyperthyroidism or Graves's disease (ophthalmoplegia without ptosis)

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with proximal muscle weakness. An excessive lordosis and a wide-based, waddling gait often accompany hip girdle weakness. Patients with quadriceps weakness hyperextend the knee (known as genu recurvatum or back-kneeing) to provide stability to the knee while standing and walking. Exaggerated lumbar lordosis and genu recurvatum may also lead to toe walking. A steppage gait is evident in patients with foot drop caused by weakness of the anterior compartment of the distal lower extremity. Instead of striking the ground first with the heel of the foot, the patient lands flat-footed or strikes the ground with the toes first. To avoid tripping, the patient lifts the knee higher than normal so that the foot clears the ground during the swing phase of ambulation. Also, watch the patient walk on his or her heels and toes to help assess distal lower extremity strength. Weakness of the shoulder girdle may result in winging of the scapula, drooping of the shoulders, and inward rotation of the arms. In addition, the clavicles may become displaced horizontally, and there can be diagonal or horizontal displacement of the anterior axillary lines. One may also observe that internal rotation of the arms leads to the palm of the hands facing to the back (dorsum of hand facing forward) rather than the palms facing the body. Inspect the muscles of the face, trunk, and extremities for atrophy, hypertrophy, or fasciculations. Palpate the muscles for tenderness and check the tone. In addition, muscles can be percussed in the upper and lower extremity as well as the face, including the tongue, to look for myotonia. Action myotonia is assessed for by having the patient make a grip for a brief period and then try to relax. Patients with myotonia have delayed relaxation. Myotonia generally improves with repetition, whereas paramyotonia worsens with repetitive activity. Paramyotonia occurs in patients with paramyotonia congenita and is best demonstrated by having patients repeatedly open and close their eyes; eventually patients have difficulty completely opening their eyes. Percussion of muscles can elicit other abnormalities. In so-called rippling-muscle disease, a wave of muscle contractions emanating from the site of percussion is seen. Patients with hypothyroidism may have mounding of the percussed muscle (myoedema). I use the Medical Research Council (MRC) scale for uniformity in grading manual muscle strength. The MRC scale is as follows: grade 0, no visible contraction; grade 1, trace contraction; grade 2, full movement across the joint with gravity eliminated; grade 3, full movement across the joint against gravity; grade 4, full movement against gravity plus some resistance; grade 5, normal strength. A modification of this scale usually is used by adding plus (e.g., 4+) or minus signs (e.g., 3-) next to the numbers for a finer distinction or degrees of muscle weakness between the larger grades. I routinely grade the strength of the orbicularis oculi, jaw, and tongue; neck flexion and extension; shoulder abduction, flexion, and extension; elbow flexion and extension; wrist flexion and extension; finger and thumb flexion, extension, and abduction; hip flexion, extension, and abduction; knee flexion and extension; ankle dorsiflexion; plantar flexion, inversion, and evasion; and toe flexion and extension. Because the MRC scores reflect movement against gravity, these muscle groups must be tested against gravity. Therefore, neck flexion should be assessed with the patient supine; neck extension, hip extension, and knee flexion with the patient prone; and hip abduction with the patient on his or her side. It is essential to place the patient in these various positions to accurately assess muscle strength. Muscle function is also evaluated by observing the patient arise

from the floor or a chair or climb steps. Have the patient hop on one foot at a time to detect subtle weakness. Recording the time necessary to accomplish specific tasks (e.g., climbing ten steps or walking 30 feet) is helpful, especially in monitoring the patient. In patients with myasthenia gravis, measure the distance of the interpalpebral fissures and record the time it takes for ptosis to appear after sustained upgaze. Muscle tone is graded as normal, decreased, or increased. Corticospinal tract lesions lead to increased tone or spasticity. Myopathies, neuromuscular junction disorders, and neuropathies are associated with normal or decreased tone. Deep tendon or muscle stretch reflexes are graded as 0, absent; 1+, decreased (requiring reinforcement maneuvers to obtain); 2+, normal; 3+, brisk (spread to other muscle groups); 4+, pathologically brisk (clonus). Hyperreflexia is seen in patients with upper motor neuron lesions, and hyporeflexia is decreased in patients with lower motor neuron disease and peripheral neuropathy. Reflexes are normal in patients with myasthenia gravis but are usually diminished in patients with Lambert-Eaton syndrome. Deep tendon reflexes may be normal or diminished in myopathies. Plantar responses usually are assessed by stroking the sole of the foot and looking for pathologic dorsiflexion or extension of the big toe (a positive Babinski sign). The pathologic extension of the big toe can also be demonstrated by stroking the lateral aspect of the foot (Chaddock’s sign), after rubbing the anterior aspect of the shin (Oppenheimer’s sign), or after a prick of the extensor aspect of the toe (Bing’s sign). Plantar responses are extensor in patients with corticospinal tract involvement. However, in patients with significant weakness of the toes, a plantar response may be unobtainable and therefore not interpretable. Test sensory perception to various modalities (temperature, pain, touch, vibration, and proprioception). Temperature and pain are conveyed by small-diameter nerve fibers, whereas deep touch, vibration, and proprioception are conveyed mainly by large-diameter sensory nerves. Some neuropathies predominantly affect small-diameter nerve fibers, whereas other neuropathies have a predilection for larger fibers. The sensory examination is normal in patients with pure motor neuron disease, myopathy, or MG unless the patient has a concurrent neuropathy. Patients with LEMS may experience mild sensory symptoms. Muscle weakness in infants usually is characterized by an overall decrease in muscle tone (floppy infant). It is important to examine the parents of floppy infants for clues to the infant’s neuromuscular disorder (e.g., myasthenia gravis, myotonic dystrophy). Infants are more difficult to examine than older children and adults. The examiner should observe the infant lying supine for any spontaneous muscle movement. Infants can be positioned prone to see whether they are capable of extending their head. An inability to do so suggests weakness of the neck extensor muscles. Assess neck flexion strength by pulling the child from the supine to sitting position while looking for head lag. The infant should be held prone in the examiner’s hands to see whether the head and extremities droop (so-called ragdoll appearance). The vigor of crying heard during the examination helps assess bulbar strength in the infant. The site of the lesion (upper motor neuron, anterior horn cell, peripheral nerve, neuromuscular junction, or muscle) usually is apparent after a detailed medical history and physical examination are obtained. In the patient in whom the site is still unclear, further testing is needed. Electromyograms (EMGs) and nerve conduction studies (NCSs) are useful in localizing the lesion to the anterior horn cell, peripheral nerve, neuromuscular junction, or muscle.

Chapter 106

Features on EMG or NCS may also help identify the specific disorder (e.g., MG, LEMS, Charcot-Marie-Tooth disease type 1). Finally, rather than a shotgun approach to ordering additional laboratory tests, specific tests are requested depending on the localization of the disease process. It is essential to diagnose neuromuscular disorders early and correctly, particularly for treatable diseases (e.g., inflammatory neuropathies and myopathies, MG, LEMS). Even in chronic disorders in which progression cannot be halted (e.g., muscular dystrophy, ALS), diagnosis is important because therapies (e.g., physical, occupational, and speech therapy) are available to improve quality of life. Furthermore, correct diagnosis is essential for genetic counseling. The remainder of this chapter outlines the specific tests that are ordered when evaluating a patient suspected of having a neuromuscular junction disorder or myopathy.

ELECTRODIACNOSTICEXAMINATION In general, I routinely perform at least two motor and sensory NCSs in an arm and a leg when evaluating patients for a neuromuscular disorder. In addition, it is important to do an EMG of proximal and distal muscles as well as thoracic paraspinal muscles. If a neuromuscular junction process is considered, I perform repetitive nerve conduction studies and, if this is not informative, single-fiber EMG. Nerve Conduction Studies

Motor and sensory NCSs are invaluable in assessing patients with neuromuscular disorders, particularly in looking for evidence of a peripheral neuropathy. Sensory NCSs are normal in motor neuron disease, myopathies, and neuromuscular junction diseases. Motor NCSs demonstrate normal amplitudes, distal latencies, and conduction velocities in myasthenia gravis. In LEMS, the amplitudes of the compound muscle action potentials (CMAPs) usually

L.

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are low. After the muscle is exercised for 10 to 15 seconds, the CMAP amplitude typically is 200% higher than the baseline value in patients with LEMS. Motor NCSs usually are normal in patients with myopathies. However, in very weak muscles, particularly in patients with distal myopathies, the CMAP amplitudes can be diminished. Repetitive Nerve Stimulation

Repetitive stimulation studies are used to diagnose neuromuscular junction disorders (i.e., botulism, LEMS, congenital myasthenia, and MG). The technique is easier to perform on distal muscles (e.g., abductor digiti minimi) because these muscles can be stabilized and stimulation is generally less painful. However, the sensitivity of the test is less in the distal muscles in patients with myasthenia gravis. More proximal muscles (e.g., trapezius, quadriceps, and face) are more likely to demonstrate decrement, but repetitive stimulation at these sites is technically more difficult secondary to diminished ability to stabilize the muscle groups, and the procedure usually is more painful at these sites. As noted earlier, patients with myasthenia gravis have normal baseline CMAP amplitudes. However, on slow rates (2 to 3 Hz) of repetitive stimulation, a decrementing response (more than 10%) may be observed (Fig. 106-1). Ten seconds of exercise may correct this decrement (postexercise facilitation). If decrement is not seen at rest, it is important to exercise the muscle for 1 minute and then perform repetitive stimulation once a minute for 5 minutes to look for the decrement (postexercise exhaustion). In botulism and LEMS, the baseline motor amplitudes are low. Decrements may be seen after low rates of repetitive stimulation. An incrementing response may be seen after fast rates of repetitive stimulation (20 to 50 Hz; Fig. 106-2). This is a very painful procedure and is rarely necessary because 10 seconds of exercise usually can reproduce a significant increase in amplitude from baseline as noted earlier.

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FIG. 106-1. Myasthenia gravis. Repetitive nerve stimulation at 3 Hz of the median nerve recording from the abductor pollicis brevis demonstrates a significant decrement (more than 1go/,) supportive of a neuromuscular junction defect.

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Spinal Cord and Peripheral Neuromuscular Disease

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FIG. 106-2. Lambert-Eaton myasthenic syndrome. Repetitive nerve stimulation of the ulnar nerve recording from the adductor digiti minimi at 30 Hz reveals a low-amplitude (1.54 mv) wave followed by an incrementing response to more than 300% of the baseline amplitude.

Needle Electromyography The routine needle EMG is performed with particular attention paid to motor unit action potential (MUAP) duration, morphology, amplitude, and recruitment. It is also important to assess for the presence of abnormal insertional and spontaneous activity. A thorough examination of multiple muscles is necessary, especially in mild or moderately severe disease states. By assessing these various components, the electromyographer usually can determine whether the lesion is neuropathic or myopathic. Special techniques such as quantitative EMG may be needed in difficult or borderline cases. Single-fiber EMG is useful in diagnosing patients with myasthenia gravis in whom repetitive stimulation, a Tendon test, and autoantibody testing are uninformative. Single-fiber EMG measures the “jitter” between two single muscle fibers belonging to the same motor unit. Jitter is increased in myasthenia gravis. However, increased jitter is not specific for myasthenia gravis because it can be seen in any pathologic process involving remodeling of the neuromuscular junction (e.g., reinnervation in motor neuron disease, neuropathies, necrotizing myopathies).

LABORATORY EVALUATION Myasthenia CravSs Approximately 40% of patients with myasthenia gravis have thymic hyperplasia, and 10% have a thymoma. Therefore, a chest computed tomography (CT) scan should be obtained in all patients with myasthenia gravis. The presence of a thymoma is an absolute indication for thymectomy. It is controversial whether or not to thymectomize patients with nonthymomatous generalized myasthenia gravis. Most experts in the field would not thymectomize purely ocular myasthenia unless there was evidence of a thymoma. Acetylcholine receptor antibodies are detectable in 70% to 80% of patients with ocular myasthenia gravis and up to 90% of

patients with more severe generalized myasthenia. Antistriatal muscle antibodies are present in approximately 30% of adults with myasthenia gravis, roughly 80% of whom have thymomas. However, one can have a thymoma without antistriatal antibodies. Therefore, the lack of these antibodies does not obviate a chest CT scan. I also order antinuclear antibodies and a thyroid function test because of the increased frequency of other autoimmune diseases and hyperthyroidism in patients with myasthenia gravis. Lambert-Eaton Myasthenic Syndrome LEMS can occur as paraneoplastic complication (approximately two thirds of cases) or as a primary autoimmune disorder without an underlying cancer. Small cell cancer of the lung is responsible for 90% of the malignancies associated with paraneoplastic LEMS. The majority of patients with cancer are more than 40 years old, and symptoms of LEMS usually precede detection of the malignancy by several months or years. I order chest CT scans, mammograms, and pelvic CT scans on patients with LEMS. I also recommend a gastrointestinal evaluation if the patient has signs or symptoms of gastrointestinal involvement. Antibodies directed against the voltage-gated muscle calcium channel (Lambert-Eaton syndrome) are present in 90% of patients with paraneoplastic and primary autoimmune LEMS. There is a higher frequency of other autoantibodies and autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease) in the primary form of LEMS.

Botulism is caused by the exotoxin of Clostridium botulinum. Infantile botulism is contracted by ingestion of bacterial spores (e.g., usually from contaminated honey), which subsequently colonize the gut and release the toxin. Wound botulism can occur after colonization of deep wounds, as occurs in compound

Chapter 106

fractures, or subcutaneous injection sites in drug addicts. Botulism can also arise from food poisoning resulting from the direct ingestion of the toxin from improperly canned and cooked foods. The toxin can be assayed in the serum and stool in suspected cases. Polymerase chain reaction (PCR) can also be used to identify the organism in biological specimens and food. Myopathies The single most useful blood test in a patient evaluated for weakness is a serum creatine kinase (CK) level. The upper limit of normal in the ambulatory population for serum CK depends on the person’s sex and race and is typically higher than most established laboratory normative data. For instance, the upper limit of normal for serum in black men is just over 500 IU/L; in black women, white men, and Hispanics the CK can be more than 300 IU/L; and in white women the upper limit of normal is more than 200 IU/L. Importantly, mild elevations in serum CK can be seen in neurogenic process such as motor neuron disease or other rapidly denervating process in which large amounts of muscle are damaged. However, the serum CK is rarely elevated above 1000 IU/L in these conditions. In addition, it is important to note that not all patients with myopathies have elevated serum CK levels. Furthermore, the serum CK levels do not necessarily correlate with the severity of the underlying myopathy. Other enzymes that are routinely screened for on routine laboratory tests (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT], lactate dehydrogenase [ LDH], and aldolase) may also be elevated in myopathies and in liver disease. To distinguish elevation of these enzymes caused by liver disease from a myopathic process, a serum CK that is specific for muscle disease and gamma-glutamyltransferase (GGT) that is specific for liver disease should be obtained. In this regard, treatment of inflammatory myopathies with certain immunosuppressive agents (i.e., azathioprine and methotrexate) is hepatotoxic. Therefore, while following the liver functions tests of such patients on treatment, it is essential to check to GGT and CK levels, not just the AST, ALT, or LDH, because these later enzymes may become elevated from an exacerbation of the underlying myositis rather than from liver damage. I also order routine electrolytes in patients suspected of having a myopathy. Hyperkalemia and hypokalemia can be caused by a number of conditions and can result in generalized weakness. Likewise, hypercalcemiaand hypocalcemia may lead to generalized weakness. Thyroid function tests are obtained because both hyperthyroidism and hypothyroidism are associated with myopathies. In patients suspected of having an inflammatory myopathy, an erythrocyte sedimentation rate and antinuclear antibody test are ordered to assess for an underlying connective tissue disease. A serum protein electrophoresis or immunofixation looking for a monoclonal gammopathy should be ordered to help diagnose primary amyloidosis. With the explosion in our understanding of molecular genetics, there is an ever-expanding list of hereditary myopathies that can be diagnosed by way of DNA testing. In male patients with a limb girdle pattern of weakness, I start out by ordering DNA testing for dystrophin mutations on whole blood. Approximately two thirds of dystrophinopathies have mutations detectable by routine PCR and Southern blot analysis of whole blood DNA. Therefore, a negative mutation analysis for dystrophin does not rule out a dystrophinopathy. If this test is negative, I proceed with a muscle biopsy. The tissue can be immunostained for deficiencies in

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dystrophin, sarcoglycan, merosin, dysferlin, and caveolin-3, and a Western blot can be performed to look for calpain deficiencies. The diagnoses of myotonic dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal dystrophy, and EmeryDreifuss muscular dystrophy usually are clinically obvious but can be confirmed by DNA testing of whole blood. DNA testing is also available for the most common mutations associated with hyperkalemic and hypokalemic periodic paralysis. Certain mitochondrial myopathies can also be confirmed by way of mutational analysis of mitochondrial DNA (mtDNA) in leukocytes (e.g., myoclonic epilepsy with ragged red fiber myopathy; mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; and neuropathy, ataxia, retinitis pigmentosa syndrome), but in others, DNA analysis of muscle tissue is needed (many of the mtDNA depletion and deletion syndromes). PHARMACOLOGICTESTING The edrophonium (i.e., Tendon) test is useful in diagnosing myasthenia gravis. Edrophonium is an anticholinesterase and results in a transient increase in acetylcholine in the neuromuscular junction and theoretically improves strength. Anticholinergic side effects of edrophonium include bradycardia, nausea, vomiting, increased tearing, and lacrimation. Clinicians should monitor the pulse and blood pressure of patients and be prepared to administer atropine to counteract the anticholinergic effects of edrophonium. To perform the edrophonium test, I place a butterfly needle in an antecubital vein, keeping the catheter open with saline. A 2-mg (0.2-mL) test dose of edrophonium is administered because some patients are extremely sensitive to even low dosages. If there is no improvement after 30 seconds, the remaining 8 mg is administered in small increments (2 mg every 15 seconds). If the patient has an objective improvement or severe side effect, the rest of the injection may be halted. It is most important to assess an objective sign of weakness, not the patient’s subjective response. It is important to evaluate objective measures of improvement. In this regard, the degree of ptosis or improvement in extraocular motility is the most useful sign to follow. The edrophonium test should not be considered positive if the patient states that he or she feels stronger if there is no objective improvement. Unfortunately, the test is not always positive in patients with myasthenia gravis. Furthermore, a modest response to edrophonium may be seen in other disorders such as LEMS, combined or overlap MG and LEMS, U S , congenital myasthenic syndromes, botulism, and GBS. MUSCLE BIOPSIES Many patients with a myopathy should undergo a muscle biopsy for accurate diagnosis. The clinical examination, laboratory workup, and electrophysiologic studies may indicate that the patient has a myopathy but not the specific type of muscle disorder. However, muscle biopsies are not indicated to evaluate patients complaining of muscle pain, weakness, or fatigue without objective signs of a myopathy (e.g., elevated serum CK levels, abnormal EMG, objective weakness on manual muscle testing). Muscle biopsies may be performed through an open (minor surgical procedure) or closed (needle or punch) procedure. Some authorities prefer open muscle biopsy because several large samples can be obtained and processed for routine and electron microscopy, metabolic analysis, and protein analysis (Western blot). Others recommend needle muscle biopsies in which the

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individual sample sizes are small but many more areas of potentially affected muscle tissue can be assessed via smaller incisions. I prefer open biopsy, especially in multifocal processes, such as in inflammatory myopathies and in myopathic disorders for which electron microscopy is needed to confirm a diagnosis. The muscle selected for biopsy should be mildly weak, preferably MRC grade 4.If the muscle is too weak (e.g., MRC grade 3 or less), the tissue typically has end-stage damage, and it is often impossible to distinguish certain myopathic disorders from severe neurogenic atrophy. In patients with little weakness on examination, electromyography can be helpful in selecting the muscle to biopsy. However, it is important to biopsy the contralateral muscle to avoid artifact from needle electromyography. The easiest muscle to biopsy is the biceps brachii, if it is affected. Alternative muscles are the deltoid or quadriceps. The gastrocnemius muscle should be avoided because there can be neurogenic changes related to an asymptomatic radiculopathy, which may make diagnosis of a myopathy difficult. The muscle specimen is routinely analyzed by light and electron microscopy. In addition, biochemical assays for various enzyme deficiencies (e.g., glycogen and lipid storage diseases), Western blot for specific protein abnormalities (e.g., dystrophin), and DNA analysis for genetic mutations (e.g., mitochondria1 myopathies) can be performed on the biopsy specimen. Amyloid deposition can be detected with Congo red or crystal violet staining. Various immune staining techniques are used to diagnose specific muscular dystrophies (e.g., dystrophin staining for Duchenne and Becker muscular dystrophy, merosin staining for congenital muscular dystrophy, sarcoglycan stains for limb girdle muscular dystrophies, emerin stain for Emery-Dreifuss muscular dystrophy). Immune staining is also useful in the early diagnosis and in understanding the pathogenesis of the different inflammatory myopathies and vasculitis (e.g., stains for complement, membrane attack complex, immunoglobulins, human leukocyte antigens, and cell markers). Electron microscopy is used for detailed evaluation of the ultrastructural components of muscle fibers.

SUGGESTED READINGS Amato AA, Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin 15:615-648, 1997

Barohn RJ: Approach to peripheral neuropathy and neuronopathy. Semin Neurol 18:7-18, 1998 Barohn RJ, Amato AA, Griggs RC Overview of distal myopathies: from the clinical to the molecular. Neuromuscul Disord 8:309-316, 1998

Brooke MH: Clinical evaluation of patients with neuromuscular disease. pp. 1-31. In Schapira AHV, Griggs RC (eds): Muscle Diseases. Butterworth-Heinemann, Boston, 1999 Cherington M: Clinical spectrum of botulism. Muscle Nerve 21:701-710, 1998

Cohn RD, Campbell K P Molecular basis of muscular dystrophies. Muscle Nerve 23:1456-1471, 2000 Drachman DB Myasthenia gravis. N Engl J Med 330:1797-1810, 1994 Dumitru D: Electrodiagnostic Medicine. Hanley & Belfus, Philadelphia, 1995

Griggs RC, Mendell JR, Miller RG: Evaluation and Treatment of Myopathies. FA Davis, Philadelphia, 1995 Gronseth GS, Barohn RJ: Practice parameter: thymectomy of autoimmune myasthenia gravis (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 507-15, 2000 Howard J F Adverse drug effects on neuromuscular transmission. Semin Neurol 10:89-102, 1990 Lennon VA Serologic profile of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology 48(Suppl 5): S23-S27, 1997

Maselli RA: Pathophysiology of myasthenia gravis and Lambert-Eaton syndrome. Neurol Clin 12:285-303, 1994 McEvoy KM: Diagnosis and treatment of Lambert-Eaton myasthenic syndrome. Neurol Clin 12:387-399, 1994 Mitchell P, Bebbington M Myasthenia gravis in pregnancy. Obstet Gynecol 80:178-181, 1992 Morel E, Eymard B, Vernet-der Garabedian B et al: Neonatal myasthenia gravis: a new clinical and immunologic appraisal on 30 cases. Neurology 38138-142, 1988 Nations SP, Wolfe GI, Amato AA et al: Distal myasthenia gravis. Neurology 52:632-634, 1999

Pascuzzi RM, Kim YI: Lambert-Eaton syndrome. Semin Neurol 1035-41, 1990

Plauche W C Myasthenia gravis in mothers and their newborns. Clin Obstet Gynecol 3482-99, 1991 Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 3,4-diaminopyridinein Lambert-Eaton myasthenic syndrome. Neurology 54603-607, 2000

Tim RW, Massey JM, Sanders DB: Lambert-Eaton syndrome: electrodiagnostic findings and response to treatment. Neurology 54:2 176-2178, 2000

107 Muscular Dystrophies Basil T. Darras

Muscular dystrophies are genetically determined primary diseases of muscle, characterized pathologically by muscle fiber degeneration. The main symptom and sign of muscular dystrophies is weakness, which is usually progressive. Pathologic, clinical, and genetic criteria have been used as the basis for their classification. Table 107-1 lists the principal forms of muscular dystrophy and their mode of inheritance.

DUCHENNE AND BECKER MUSCULAR DYSTROPHIES (DYSTROPHINOPATHIES) Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are progressive myopathies, inherited as X-linked recessive traits. DMD is the most severe form of muscular dystrophy, with an incidence of about 1 in 3300 live male

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individual sample sizes are small but many more areas of potentially affected muscle tissue can be assessed via smaller incisions. I prefer open biopsy, especially in multifocal processes, such as in inflammatory myopathies and in myopathic disorders for which electron microscopy is needed to confirm a diagnosis. The muscle selected for biopsy should be mildly weak, preferably MRC grade 4.If the muscle is too weak (e.g., MRC grade 3 or less), the tissue typically has end-stage damage, and it is often impossible to distinguish certain myopathic disorders from severe neurogenic atrophy. In patients with little weakness on examination, electromyography can be helpful in selecting the muscle to biopsy. However, it is important to biopsy the contralateral muscle to avoid artifact from needle electromyography. The easiest muscle to biopsy is the biceps brachii, if it is affected. Alternative muscles are the deltoid or quadriceps. The gastrocnemius muscle should be avoided because there can be neurogenic changes related to an asymptomatic radiculopathy, which may make diagnosis of a myopathy difficult. The muscle specimen is routinely analyzed by light and electron microscopy. In addition, biochemical assays for various enzyme deficiencies (e.g., glycogen and lipid storage diseases), Western blot for specific protein abnormalities (e.g., dystrophin), and DNA analysis for genetic mutations (e.g., mitochondria1 myopathies) can be performed on the biopsy specimen. Amyloid deposition can be detected with Congo red or crystal violet staining. Various immune staining techniques are used to diagnose specific muscular dystrophies (e.g., dystrophin staining for Duchenne and Becker muscular dystrophy, merosin staining for congenital muscular dystrophy, sarcoglycan stains for limb girdle muscular dystrophies, emerin stain for Emery-Dreifuss muscular dystrophy). Immune staining is also useful in the early diagnosis and in understanding the pathogenesis of the different inflammatory myopathies and vasculitis (e.g., stains for complement, membrane attack complex, immunoglobulins, human leukocyte antigens, and cell markers). Electron microscopy is used for detailed evaluation of the ultrastructural components of muscle fibers.

SUGGESTED READINGS Amato AA, Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin 15:615-648, 1997

Barohn RJ: Approach to peripheral neuropathy and neuronopathy. Semin Neurol 18:7-18, 1998 Barohn RJ, Amato AA, Griggs RC Overview of distal myopathies: from the clinical to the molecular. Neuromuscul Disord 8:309-316, 1998

Brooke MH: Clinical evaluation of patients with neuromuscular disease. pp. 1-31. In Schapira AHV, Griggs RC (eds): Muscle Diseases. Butterworth-Heinemann, Boston, 1999 Cherington M: Clinical spectrum of botulism. Muscle Nerve 21:701-710, 1998

Cohn RD, Campbell K P Molecular basis of muscular dystrophies. Muscle Nerve 23:1456-1471, 2000 Drachman DB Myasthenia gravis. N Engl J Med 330:1797-1810, 1994 Dumitru D: Electrodiagnostic Medicine. Hanley & Belfus, Philadelphia, 1995

Griggs RC, Mendell JR, Miller RG: Evaluation and Treatment of Myopathies. FA Davis, Philadelphia, 1995 Gronseth GS, Barohn RJ: Practice parameter: thymectomy of autoimmune myasthenia gravis (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 507-15, 2000 Howard J F Adverse drug effects on neuromuscular transmission. Semin Neurol 10:89-102, 1990 Lennon VA Serologic profile of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology 48(Suppl 5): S23-S27, 1997

Maselli RA: Pathophysiology of myasthenia gravis and Lambert-Eaton syndrome. Neurol Clin 12:285-303, 1994 McEvoy KM: Diagnosis and treatment of Lambert-Eaton myasthenic syndrome. Neurol Clin 12:387-399, 1994 Mitchell P, Bebbington M Myasthenia gravis in pregnancy. Obstet Gynecol 80:178-181, 1992 Morel E, Eymard B, Vernet-der Garabedian B et al: Neonatal myasthenia gravis: a new clinical and immunologic appraisal on 30 cases. Neurology 38138-142, 1988 Nations SP, Wolfe GI, Amato AA et al: Distal myasthenia gravis. Neurology 52:632-634, 1999

Pascuzzi RM, Kim YI: Lambert-Eaton syndrome. Semin Neurol 1035-41, 1990

Plauche W C Myasthenia gravis in mothers and their newborns. Clin Obstet Gynecol 3482-99, 1991 Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 3,4-diaminopyridinein Lambert-Eaton myasthenic syndrome. Neurology 54603-607, 2000

Tim RW, Massey JM, Sanders DB: Lambert-Eaton syndrome: electrodiagnostic findings and response to treatment. Neurology 54:2 176-2178, 2000

107 Muscular Dystrophies Basil T. Darras

Muscular dystrophies are genetically determined primary diseases of muscle, characterized pathologically by muscle fiber degeneration. The main symptom and sign of muscular dystrophies is weakness, which is usually progressive. Pathologic, clinical, and genetic criteria have been used as the basis for their classification. Table 107-1 lists the principal forms of muscular dystrophy and their mode of inheritance.

DUCHENNE AND BECKER MUSCULAR DYSTROPHIES (DYSTROPHINOPATHIES) Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are progressive myopathies, inherited as X-linked recessive traits. DMD is the most severe form of muscular dystrophy, with an incidence of about 1 in 3300 live male

Chapter 107

TISU 107-1. Muscular Dystrophies Form of Dvstrophv

Inheritance

Duchenne Becker Emery-Dreifuss Limb-girdle 2A, 2B. 2C, 2D,. . . Congenital Distal Facioscapulohumeral Limb-girdle lA, lB, l C , lD,. . . Emery-Dreifuss Oculopharyngeal Myotonic Proximal myotonic myopathy Distal

X-linked recessive Autosomal recessive Autosomal dominant

births and a prevalence rate in the total population of about 3 per 100,000. BMD has a similar presentation but a milder clinical course. The incidence of BMD is about 1 in 30,000 male births. In addition, there is an intermediate group of patients with either mild DMD or severe BMD, who are also known as outliers. It is now well known that all three types of muscular dystrophy are allelic, resulting from dystrophin deficiency caused by mutations of a single gene, called the dystrophin gene. Other dystrophinopathies, occurring at a lower incidence, include the following:

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running, jumping, going up steps, and similar activities; an unusual waddling gait, lumbar lordosis, and calf enlargement usually are observed. Muscular weakness selectively affects proximal limb muscles before distal and the lower extremities before the upper. Early on, the patient may complain of leg pains. Jumping and running are almost impossible in most cases, and, in arising from the floor, affected boys use hand support to push themselves to an upright position (Gower’s sign). Neck flexor weakness occurs at all stages of the disease and distinguishes boys with DMD from patients with milder presentations; at least early on, patients with BMD and an intermediate phenotype, or outliers, appear to have preserved neck flexor strength. Cardiac muscle is also affected. Most children with DMD often have varying degrees of nonprogressive impairment of cognitive function, although an occasional child may have average or above-average intelligence. Physical examination shows pseudohypertrophy of the calf muscles (Fig. 107-1) and, in some instances, quadriceps and other muscles, lumbar lordosis, waddling gait, shortening of the Achilles tendons (Fig. 107-2), and hyporeflexia or areflexia. The shortening of the Achilles tendons and equinovarus deformity are related to imbalance between plantar flexors, invertors, and the tibialis anterior muscles; the former muscles remain very strong until late in the course of the disease, while the latter ones weaken gradually. Cranial nerve innervated muscles and sphincters remain essen-

X-linked dilated cardiomyopathy (XLDCM) Isolated quadriceps myopathy Muscle cramps with myoglobinuria Asymptomatic elevation of muscle enzymes Manifesting DMD or BMD carrier females

Clinical Aspects Great heterogeneity in the clinical features and course of the various dystrophinopathies has been observed, creating a spectrum ranging from very mild to very severe presentations. The severe end of the spectrum includes DMD, BMD, and the outliers or intermediate phenotype when skeletal muscle is primarily affected and XLDCM when the heart is the organ primarily affected. Isolated quadriceps myopathy, muscle cramps with myoglobinuria, and asymptomatic elevation of muscle enzymes represent the mild end of the dystrophinopathy spectrum in males. DMD or BMD carrier females can be asymptomatic or can manifest mild to severe symptoms. The main distinction between DMD and BMD is made by the age of wheelchair dependency, which is less than 13 years in DMD and beyond 16 years in BMD. Patients who become wheelchairbound between 13 years and 16 years are classified as outliers or as exhibiting an intermediate phenotype. The mild end of the BMD spectrum has been extended by several investigators to include patients with an increase in serum concentration of creatine kinase (CK) and abnormal dystrophin on muscle biopsy, but with subclinical skeletal muscle involvement. The distinction between BMD and XLDCM is hard to make in these atypical patients when they develop severe cardiomyopathy. Duchenne Muscular Dystrophy. In children with DMD, although there is histologic and laboratory evidence of myopathy from birth, the onset of weakness usually occurs between 2 and 3 years of age; in some cases, it may be delayed and become apparent after the age of 3 years. The child usually has difficulty with

FIG. 107-1. Pseudohypertrophy of the calf muscles in a patient with Duchenne muscular dystrophy. (Courtesy of Theodore Munsat, MD, New England Medical Center, Boston.)

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FIG. 107-2. A family of five brothers, all with Duchenne muscular dystrophy. Note the calf pseudohypertrophy, scapular winging, and the associated lumbar lordosis, which, combined with the forward pelvic tilt and heel cord tightening, lead to toe-walking or even standing, as seen in the oldest boy. (Courtesy of Danilo A Duenas, MD, Miami Children's Hospital, Miami.)

tially unaffected. Neck flexors are weaker than extensors, biceps and triceps usually are weaker than deltoids, wrist flexors are less involved that extensors, and the quadriceps are involved more than hamstrings. Between 3 and 6 years of age there may be some evidence of improvement, which is gradually followed by relentless deterioration, leading to wheelchair confinement by the age of approximately 13 years. Wheelchair-bound children tend to develop contractures and scoliosis with deterioration of pulmonary function. As a result of evolving cardiomyopathy, 90% of patients with DMD exhibit abnormalities in their electrocardiogram (ECG) (increased R/S amplitude ratio in lead V1, deep Q waves in left [V5, V6] precordial leads). Intra-atrial and atrioventricular and ventricular conduction disturbances also occur. The incidence of cardiomyopathy increases gradually in teenage years, with about one third of patients being affected by age 14 years, one half by age 18 years, and all patients after age 18 years. Echocardiography showed diminished contractility of the myocardium. The majority of patients with DMD remain free of cardiovascular symptoms until late in the disease course, probably because of their inability to exercise, which may mask cardiac symptoms. In the late stages of the disease, congestive heart failure and arrhythmias may develop, especially during intercurrent infections. Intestinal hypomotility, also known as intestinal pseudo-obstruction, is an important and sometimes life-threatening complication in patients with DMD. It seems to be related to smooth muscle degeneration. Most die in their late teens or twenties from respiratory insufficiency or cardiac failure secondary to progressive cardiomyopathy. In some cases, the immediate cause of death is not apparent. Assisted ventilation can prolong a patient's life

expectancy, but the patient will depend on others for activities of daily living. Becker Muscular Dystrophy. In Becker dystrophy the age of onset of symptoms usually is later, between 5 and 15 years or sometimes even in the third or fourth decade or later, and the degree of clinical involvement is milder; cardiac disease and mental retardation are not as common or as severe as in the Duchenne variety. Also, contractures are not as likely to develop in BMD. In addition, in Becker and intermediate types of muscular dystrophy there is relative preservation of neck flexor muscle strength. Patients with BMD typically remain ambulatory beyond the age of 16 years and into adult life; they usually survive beyond 30 years. Mean age at death is in the mid-40s. Nevertheless, the BMD spectrum includes men with onset of symptoms after the age of 40 years who remain ambulatory even into their 60s. The degree of clinical involvement is milder, but the pattern of muscle wasting is similar to the one noted in DMD. Pelvic girdle and thigh muscles are involved first, and calf muscle pseudohypertrophy occurs early in most but not all patients. Tibialis anterior and peroneal muscle groups are less affected. Shoulder girdle weakness develops later after the onset of proximal lower extremity weakness. In a series of 67 patients, lower extremity weakness was noted first at the mean age of 11 years and upper extremity weakness at the mean age of 31 years. Calf muscles, forearm, and hand intrinsics remain strong until the late stage of the disease. Calf pain during or after exercise was reported as a presenting symptom in 25% and as a complaint at some point during the course of the disease in 91% of all patients. Only 2 of the 67 patients presented with myoglobinuria. Thus, muscle pain is very common in patients with BMD, but myoglobinuria occurs

Chapter 107

infrequently. In patients with BMD, facial muscles usually are preserved. Creatine kinase (CK) values usually are highly elevated in Becker dystrophy and therefore cannot be used to differentiate between the two types of dystrophy. Furthermore, the distinction between Becker dystrophy and limb-girdle muscular dystrophy (LGMD) often is hard to make in cases with a negative family history of BMD. However, the calf muscle pseudohypertrophy usually is not as striking in LGMD as it is in DMD and BMD. Manifesting DMD and BMD Carrier Females. Carriers usually are free of symptoms but may have mildly elevated serum CK and usually mild calf hypertrophy. In approximately 8% of the cases, however, they can present with mild myopathy of the limb-girdle type or even DMD or BMD. Cardiac involvement usually is subclinical; however, a recent cross-sectional study demonstrated that 8% of definite DMD carriers had dilated cardiomyopathy, compared with none in BMD carriers. Only 38% of the studied population of carriers had a completely normal heart investigation. The remaining had subclinical ECG or echocardiography abnormalities. Some carriers can even manifest severe cardiac symptoms.

Genetics Dystrophin Gene. The DMD/BMD gene, now known as dystrophin gene, was isolated recently; it is the largest gene yet

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identified in humans, spanning approximately 2.3 Mb at Xp21. The protein product dystrophin has a total molecular weight of 427 kDa and is recognized on Western blots of human skeletal muscle proteins using antidystrophin antibodies. With the use of immunocytochemistry, dystrophin has been localized to the cytoplasmic face of the plasma membrane of muscle fibers. It has also been shown that dystrophin is part of a large, tightly associated glycoprotein complex containing many other proteins (Fig. 107-3). It is believed that in normal cells, the dystrophin stabilizes the glycoprotein complex and protects it from degradation; in the absence of dystrophin, the complex becomes unstable. There is almost always secondary reduction in the amount of proteins of the glycoprotein complex in the muscle tissue of patients with DMD. The loss of associated membrane proteins as a result of dystrophin deficiency may initiate the degenerative changes seen in muscular dystrophy. Dystrophin Gene Mutations. Of the DMD/BMD mutations identified so far, most are deletions, detected with the dystrophin cDNA in approximately 65% of patients with DMD and 85% of patients with BMD. Partial gene duplications have also been reported in a small percentage of patients (about 5%). In the remaining 30% to 35% of patients without detectable deletions or duplications, the molecular lesions represent point mutations or splicing errors. Furthermore, some patients with Duchenne- or Becker-like phenotypes but without a clear-cut X-linked pattern of inheritance have been shown to harbor defects in other genes,

FIG. 107-3. The dystrophin-associated protein complex. Arrows indicate the protein components mutated in various muscular dystrophies. The laminin 1x2-chain gene is mutated in a subtype of congenital muscular dystrophy without structural brain anomalies and the sarcoglycan proteins in patients with sarcoglycanopathies (autosomal recessive LGMDs). BMD, Becker muscular dystrophy; CMD, congenital muscular dystrophy; DMD, Duchenne muscular dystrophy; LGMD, limb-girdle muscular dystrophy. (Courtesy of Dr. Bonnemann and Dr. Kunkel, Children's Hospital, Boston.)

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some of which encode the dystrophin-associated glycoproteins (e.g., sarcoglycans). Published studies have failed to reveal any apparent correlation between the size of dystrophin gene deletions and the severity and progression of the DMD/BMD phenotype. The molecular basis of DMD and BMD seems to be related to the disruption or preservation of the amino acid reading frame by the deletion mutations. The latter either disrupt or preserve the reading frame in most cases of Duchenne or Becker muscular dystrophy, respectively. Dystrophin. Dystrophin can be detected easily on immunoblots of 100 pg of total muscle protein derived from a small portion of a muscle biopsy by using antidystrophin antibodies. The quantity and quality of dystrophin can be evaluated either visually or by using densitometry. If the 427-kDa dystrophin protein is normal in size and amount, the diagnosis of DMD or BMD can almost be excluded. More than 99% of DMD patients display complete or almost complete absence of dystrophin in skeletal muscle biopsy specimens. Most patients with BMD (about 85%) have dystrophin of abnormal molecular weight, either smaller (80%) or larger (5%), in gene deletion or gene duplication cases, respectively, which often is low in quantity. However, about 15% of patients with BMD have normal-sized protein of low quantity. The test is very specific because patients with neuromuscular diseases other than DMD or BMD have normal dystrophin. Dystrophin immunoblotting can be used to predict the severity of the evolving muscular dystrophy phenotype. It seems that what determines the severity of the disease is the quantity of the dystrophin molecule rather than its size. Patients with DMD have less than 5% of the normal quantity of dystrophin. Patients with dystrophin levels between 5% and 10% of normal, regardless of protein size, seem to develop an intermediate phenotype (mild DMD or severe BMD). Patients with mild to moderate Becker phenotype usually have levels above 20% (Table 107-2). Diagnosis

Until a few years ago, the diagnosis of DMD or BMD was based on myopathic symptoms and signs, highly elevated serum CK values, myopathic changes on electromyography (EMG) and muscle biopsy, and sometimes a positive family history. The cloning of the gene defective in DMD and BMD and the characterization of its protein product, dystrophin, have provided molecular diagnostic tools for accurate diagnosis of this disorder. Serum Muscle Enzymes. Before the age of 5 years, the serum CK levels usually are 10 to 200 times the upper limit of normal, or even higher. Thus, CK values of 10,000 to 50,000 IU/L are not unusual in DMD and BMD. In a child with DMD, during the first 3 years of life, the serum CK concentration is always more than 10

rn TABU 107-2. Quantity and Size of Dystrophin in Dystrophinopathies Clinical Phenotype

Duchenne

Dystrophin Protein Sizea

Normal or abnormal size Intermediate or seNormal or abnormal vere Becker size Mild or moderate Normal size Becker Abnormal size 'Size and quantity measured by Western blot analysis.

Dystrophin Quantity.

0%-5% 5%-20%

20%-50% 20%- 100%

times the upper limit of normal; if it is less than that, the diagnosis should be questioned. CK levels in DMD are elevated even during the first year of life, when the child is asymptomatic, and they peak between the ages of 2 and 3 years. However, the CK concentration tends to decline gradually with advancing age, at a rate of about 20% per year; the decline is related to the progressive elimination of dystrophic muscle fibers, which are the source of the elevated serum CK levels. Serum CK concentration can be markedly elevated in Becker dystrophy, as in DMD, and therefore cannot be used as a way to differentiate between the two types of dystrophy. At age 20, in a series of 52 patients with BMD, the mean serum CK concentration was elevated 35-fold; however, the highest elevation is observed in the first 10 years of life and, as in DMD, it declines with advancing age and disease progression. Electromyography. EMG shows myopathic changes, usually short-duration, low-amplitude polyphasic rapidly recruited potentials, particularly in proximal muscles. Needle examination may also show increased insertional activity with fibrillation potentials. Early on, the nerve conduction studies, including repetitive nerve stimulation, are normal. With disease progression, the compound muscle action potentials decrease in amplitude, the insertional activity diminishes, motor unit potentials become very small with decreased recruitment, and the fibrillation potentials disappear. At the end, the muscle becomes electrically silent. However, it should be noted that patients with classic DMD or BMD do not need electrodiagnostic studies for diagnostic purposes, but in sporadic cases of BMD or symptomatic carrier females with modest creatine phosphokinase (CPK) elevation (less than 1000 IU/L) and proximal muscle weakness, EMG may have to be considered to exclude a neuropathic process (e.g., spinal muscular atrophy [SMAI 1. Muscle Biopsy. The muscle biopsy demonstrates degeneration, regeneration, isolated opaque hypertrophic fibers, and significant replacement of muscle by fat and connective tissue. The degenerating necrotic fibers are recognized on trichrome staining by their green-blue color (instead of the normal deep blue staining) and their glassy or homogenous cytoplasm. Increased variability in muscle fiber size is also observed, with larger than normal fibers in younger patients followed, with progression of the disease, by the appearance of numerous muscle fibers of a smaller-than-normal size. Regenerating fibers are clusters of small fibers with basophilic cytoplasm and vesicular nuclei. Hypercontracted fibers are called opaque or large dark fibers. Their origin is unclear, but they could be produced at the time of the muscle biopsy and be an artifact of tissue removal, perhaps enhanced by the fragility of the plasma membrane. Central nuclei are present in 2% to 4% of the fibers. Type 1 fiber predominance is seen in most patients. Inflammatory cell infiltrates are seen in the perimysium, endomysium, and perivascular spaces and consist mostly of mononuclear cells, especially macrophages. Another striking characteristic is the development of endomysial and perimysial fibrosis with disease progression; in the late stage of the disease only a few muscle fibers remain, separated by large zones of connective tissue and fat. The differences in the microscopic appearance of muscle in DMD and BMD correlate well with the severity of the disease, with fewer necrotic, hypercontracted, and regenerating fibers seen in milder phenotypes. Dystrophin Immunostaining. In muscle biopsies derived from patients with DMD, there is no detectable staining with antidystrophin antibodies, but in patients with BMD, either normal or partial staining of the sarcolemma is observed. In patients with other neuromuscular diseases, there is homogene-

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C

F

I

M

N

FIG. 107-4. lmmunostaining of frozen sections of skeletal muscle biopsies. (D-N) Antidystrophin antibodies using indirect immunofluorescence. (A-C) Hematoxylin and eosin-stained sections corresponding to 0,E, and F, respectively. There is complete absence of immunofluorescence at the sarcolemma in a muscle section from a patient with Duchenne muscular dystrophy (DMD) (C, 0,compared with the homogeneous staining of the plasma membrane in normal muscle (4, 0) and in muscle biopsies from patients with Emery-Dreifuss muscular dystrophy (G), Fukuyama type of congenital muscular dystrophy (H), limb-girdle muscular dystrophy (0,facioscapulohumeral muscular dystrophy (I), myotonic dystrophy (K), and Kugelberg-Welander type of spinal muscular atrophy (L). In a frozen section of muscle from a patient with Becker muscular dystrophy (B), partial staining of the sarcolemma is observed (€). Note the mosaic pattern of immunostaining in muscle biopsies from a symptomatic (M) and an asymptomatic (N) DMD carrier. (Modified from Arahata K et al: Nature 333:861, 1988; Arahata K et al: N Engl J Med 320:138, 1989; Darras BT: J Pediatr 1 17:1, 1990; M courtesy of E. Bonilla, MD, Columbia University, New York)

ous staining of the plasma membrane (Fig. 107-4).The test appears useful in identifymg sporadic cases of symptomatic females with high CK or clinical weakness, or asymptomatic female DMD carriers in families without a male proband or in families with no detectable deletion or duplication and uninformative linkage analysis results. Symptomatic and asymptomatic DMD carriers with elevated CK values may exhibit a characteristic mosaic pattern of dystrophin immunostaining (Fig. 107-4). However, a negative (normal) result does not exclude carrier status because of the possibility of nonrandom X chromosome inactivation, and also the possible selective loss of dystrophinnegative fibers. The dystrophin immunostaining and X chromosome inactivation tests are not commercially available at this point, but they can be performed in selected clinical or research laboratories.

Algorithm for the Diagnosis of DMD and BMD The precise diagnostic approach in a male child or adult with markedly elevated CK values and evidence of myopathy on physical examination is shown in Figure 107-5. Sporadic Cases. In sporadic cases (i.e., family history negative for DMD and BMD), the clinical presentation can be clear, highly suggestive of DMD or BMD, or not, depending on the clinical features and the age of the child. In both cases, the first step in molecular diagnosis is DNA testing for a dystrophin gene mutation, by multiplex polymerase chair reaction (PCR) or Southern blot assay (Fig. 107-5).If a deletion or duplication is found by PCR or Southern blot assay, its reading frame status allows prediction of the phenotype (DMD or BMD) in most instances. Because of the rare occurrence of exceptions to the

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Male child or adult Highly elevated CK levels or clinical myopathy

Clinical expression clear and negative family history (sporadic case)

Clinical expression not clear and negative family history

Positive family history based on clinical diagnosis only (familial case)

I

DNA deletion test using multiplex PCR assay and/or Southern blot assay

I

I

DNA deletion test using multiplex PCR assay and/or Southern blot assay

I I

No deletiin detected

Deletion or duplication

In-frame

Out-of-frame

Muscle biopsy (optional) Deficient

Western blot assay immunostains

I‘ Family testing via linkagehaplotype

deletion analysis Decreased amount andor altered size

Western blot assay for dystrophin for prognostic confirmation (optional)

muscular

dystrophy

FIG. 107-5. Algorithm for the laboratory diagnosis of sporadic and familial cases of DMD and BMD and for family testing (carrier detection and prenatal or presymptomatic diagnosis). (Modified from Darras BT: Duchenne/Becker muscular dystrophy. Scientific American Medicine, Vol. 3 [Neurology] pp. 1-9, Scientific American, 1993.)

“in-frame/out-of-frame” rule, the clinician has the option of a muscle biopsy, which can be performed to assess the quantity and size of dystrophin and thereby more precisely predict the severity of the disease. Familial Cases. In cases with a positive family history of typical DMD or BMD (i.e., familial cases), molecular diagnosis may not be necessary if the clinical diagnosis has been confirmed in another affected family member by analysis of the dystrophin protein or DNA. In such familial cases, the clinical course in the older affected relative adequately, although not always, predicts the severity of the evolving muscular dystrophy phenotype in other family members. However, it should be remembered that extragenic factors may modify the clinical progression of DMD and BMD, even among members of the same family with the same mutation. If the diagnosis is DMD or BMD has been made clinically in other family members but has not been confirmed previously by analysis of dystrophin or DNA, the PCR-based DNA deletion test should be attempted first because it is less invasive than a muscle biopsy. If a mutation is found, muscle biopsy becomes unnecessary because, as explained earlier, except for rare exceptions the clinical

course is most likely to be the same as in other affected family members (Fig. 107-5). Females with Dystrophinopathy. Female patients can have an early-onset, progressive muscular dystrophy and therefore be symptomatic if they have 45X, 46XY, or Turner mosaic karyotypes; apparently balanced X/autosome translocations with breakpoints in Xp21, within the dystrophin gene, and preferential inactivation of the normal X and a normal karyotype but nonrandom X chromosome inactivation leading to diminished expression of the normal dystrophin allele. Therefore, chromosomal analysis is indicated in all symptomatic females, especially the ones with highly elevated serum CK .levels, following the exclusion of other neuromuscular diseases (e.g., polymyositis, SMA) by EMG or muscle biopsy. Further study with a dystrophin assay or a DNA deletion test may be diagnostic in a symptomatic female, especially in cases with 45X, 46XY, or Turner mosaic karyotypes. Treatment

Therapeutic interventions in DMD and BMD are aimed at maintaining function, preventing contractures, and providing

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psychological support. Passive stretching exercises to prevent contractures of the iliotibial band, the Achilles tendons, and flexors of the hip are the mainstays of physical therapy. Lightweight plastic ankle-foot orthoses (AFOs) should be applied if the foot remains in plantar flexion during sleep. Standing or walking can be maintained by using long-leg braces. Surgery can be performed to release contractures of the hip flexors, iliotibial bands, and Achilles tendons. Standing and ambulation seem to prevent scoliosis. After age 12, pulmonary function studies, ECG, and chest radiographs should be performed yearly to monitor the pulmonary and cardiac functions. Overnight mouth intermittent positive pressure can be used to treat symptomatic nocturnal hypoventilation, and respiratory assistance may be used during periods of respiratory infection. Clinical studies provide evidence that prednisone improves the strength and function of patients with DMD. This improvement begins within 10 days, with a single dose of 0.75 mg/kg/day of prednisone for maximal improvement, and reaches a plateau after 3 months. Observed side effects include weight gain, hypertension, behavioral changes, growth retardation, and cataracts. Prednisone may be recommended for selected ambulatory patients over age 5 and continued if the side effects are not severe. Immunosuppression with azathioprine does not have a beneficial effect. Cyclosporin has been reported to improve clinical function in children with DMD who received the medication for 8 weeks. However, because of the rare reports of cyclosporininduced myopathy in patients receiving the medication for other reasons, the use of cyclosporin in DMD remains controversial. Oxandrolone, an anabolic (androgenic) steroid, has been shown in a pilot study to be beneficial in DMD, but a randomized, prospective trial did not show a significant benefit; although there was a difference in strength on some measures, the efficacy was not of a magnitude to justify its use. Aminoglycoside treatment of cultured cells can suppress stop codons in vitro and also in the ma'x mouse. Myoblast transfer has been attempted recently in humans, but the results, so far, have not been encouraging. Stem cell transplantation, aminoglycoside therapy, and other experimental gene therapies are under evaluation. EMERY-DREIFUSS MUSCULAR DYSTROPHY

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive (chromosome Xq28), autosomal dominant, or autosomal recessive condition (chromosome 1q21) with onset in late childhood or adult life. Mutations in the emerin (Xq28) and lamin A/C genes (lq21) are responsible for the EDMD form of muscular dystrophy. The muscle weakness and wasting in EDMD have a humeroperoneal distribution, often starting in the arms, with weakness of both the biceps and triceps and relative preservation of the deltoid muscles. Later on, distal leg weakness with atrophy of the peroneal muscles is noted. In some cases mild facial weakness may be observed as well. The myopathy tends to be slowly progressive. Contractures at the elbows are noted early, often associated with toe-walking as the first manifestations of the disease. Contractures of the posterior aspect of the neck, lower spine, and Achilles tendons also occur. Cardiac involvement is common and consists of a cardiomyopathy, with atrioventricular (AV) block and often atrial paralysis. The ECG may show varying degrees of AV block, small T waves, and atrial arrhythmias. The cardiomyopathy may lead to sudden death in approximately 50% of the affected patients, usually early in adult life.

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Laboratory studies show modest elevation of CK, which is rarely above a few hundred units per liter. Although the EMG usually displays myopathic features, it may also reveal evidence of denervation. The muscle biopsy usually shows mild myopathic changes with internal nuclei, variation in fiber size, focal connective tissue proliferation, and occasional necrotic fibers. In the X-linked variety of EDMD, DNA testing for emerin gene mutations is now available. Recently, DNA testing for the lamin A/C gene mutations has become commercially available also. Therefore, at this point, the value of muscle biopsy in EDMD is limited if the mutation analysis is positive for an emerin or lamin A/C mutation; however, a muscle biopsy can provide further evidence for the diagnosis of X-linked EDMD by demonstrating via immunohistochemistry absence of nuclear immunostaining for emerin. Furthermore, a muscle biopsy may confirm the myopathic nature of the process in atypical, sporadic cases or in rare cases without detectable mutations. The differential diagnosis includes the rigid spine syndrome, which, in addition to the elbow and ankle contractures, usually is associated with very limited flexion of the spine and mild and slowly progressive myopathy. However, cardiomyopathy has not been observed. Because the cardiac involvement in EDMD is potentially fatal, the cardiac status of the patient should be investigated even if he or she is asymptomatic. Installation of a cardiac pacemaker may be life-saving in patients with evidence of AV block. Holter monitoring should be considered in patients with normal electrocardiograms.

MYOTONIC DYSTROPHY Clinical Aspects

Myotonic dystrophy (DM) is the most common form of muscular dystrophy among Caucasians, with a prevalence estimated at 3 to 5 per 100,000 population and an incidence of 1 in 8000. DM is a multisystem disorder, transmitted by autosomal dominant inheritance, with variable penetrance. In the classic form, DM has its onset in adolescence or adulthood, but a neonatal form also occurs. The main clinical features of DM are myotonia (delayed muscle relaxation after contraction), weakness, and wasting affecting facial muscles and distal limb muscles, frontal balding (in males), cataracts, cardiomyopathy with conduction defects, multiple endocrinopathies, and low intelligence or dementia. The face is long, with wasting of the masseter and temporal muscles; there is also variable ptosis and facial diplegia (Fig. 107-6). The neck is thin because of wasting of the sternocleidomastoids. There may be associated dysarthria, swallowing difficulties, and mild external ophthalmoplegia. Myotonia can be an early symptom, demonstrated by percussion of muscles, usually of the thenar eminence, and by the difficulty of releasing the grasp. Later in the course of the disease, the progressive muscle weakness and wasting become the predominant features, leading to severe distal weakness in the hands and feet. Endocrinopathies include hyperinsulinism, rarely diabetes, adrenal atrophy, infertility in women, testicular atrophy, and growth hormone secretion disturbances. Smooth and cardiac muscle involvement usually are expressed by disturbed gastrointestinal mobility and cardiac conduction defects. The congenital form of the disease occurs in children born to mothers with myotonic dystrophy and presents with profound hypotonia at birth, associated with facial diplegia, feeding and respiratory difficulties, and skeletal deformities, such as clubfeet.

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FIG. 107-6. Congenital myotonic dystrophy. Note the facial diplegia, ptosis, temporal and masseter muscle wasting, and characteristic appearance of the mouth (like an inverted V). (Courtesy of N. Paul Rosman, MD, New England Medical Center, Boston.)

Later, during childhood, delayed developmental progression is noted. A genetically distinct form of DM with remarkable clinical similarity to classic DM but no chromosome 19 CTG repeat expansion has been mapped to chromosome 3q (DM2). Until recently, the diagnosis of myotonic dystrophy was based on clinical features, family history, EMG, and muscle biopsy findings. EMG demonstrates myopathic potentials and myotonia. Muscle histology may reveal internal nuclei, type I fiber atrophy, and ring fibers. However, the diagnosis could not be confirmed easily in many cases, especially mildly affected ones. The recent identification of the myotonic dystrophy mutation has provided molecular diagnostic tests for almost 100% accurate diagnosis of this disorder in both symptomatic and asymptomatic patients. Genetic Diagnosis

The DM locus was mapped by linkage analysis to chromosome 19q13.3; this genetic localization finally led to the recent identification of the genetic defect in DM, which is thought to be an amplified trinucleotide CTG repeat, located in the 3’ untranslated region of a gene, which putatively encodes a serine-threonine protein kinase (myotonin-protein kinase [DMK]). Although this CTG repeat is polymorphic, it is stable in normal subjects. In contrast, the CTG repeat in DM chromosomes is unstable and can become significantly enlarged. In normal subjects, the two alleles contain 5 to 50 copies of the CTG repeat. However, normal subjects with 38 to 49 copies of the repeat are classified in a borderline category because of the small possibility of expansion of the CTG repeat in their offspring or family members. Mildly affected patients or asymptomatic premutation carriers have 50 to 99 CTG repeats, whereas severely affected subjects have 100 to 2000 or more copies (full mutation) (Table 107-3). To date, a large

number of affected patients have been assessed by both Southern blot and PCR, and an increase in CTG copy number has been documented in more than 99% of subjects. Amplification of the CTG repeat has been proposed to be the molecular mechanism for genetic anticipation, which is the increasing severity of the disease phenotype in successive generations; in DM families, the CTG copy number increases during successive generations. A positive correlation has been observed between increased number of CTG repeats and earlier age of disease onset. Conversely, in a few families, reduction in size of the trinucleotide repeat mutation has been observed during transmission, with a decrease in disease severity. However, it is not possible to predict the age of onset of the disease in a particular patient on the basis of the CTG copy number. For a given number of repeats (greater than loo), a wide range in disease severity may be observed. Nonetheless, infants with severe congenital DM, as well as their mothers, are shown to have on average a greater amplification of the CTG repeat. The greater the CTG repeat expansion in the mother, the higher the probability of a DM offspring being affected with the congenital form of the illness. Unfortunately, these new developments do not explain the exclusive maternal inheritance in cases of congenital DM. Genomic imprinting and the presence of a maternal intrauterine factor have been proposed as two possible mechanisms. The amplification is detectable by Southern blotting, in most cases using DNA extracted from peripheral blood leucocytes. However, this type of analysis may fail to detect expansions where the CTG copy number is less than 150; in some of these patients, who usually are mildly affected, analysis by PCR is important. Conversely, some very large expansions may fail to amplify by PCR. Therefore, both techniques must be used in the molecular diagnosis of DM. Treatment

DM treatment is symptomatic. As patients develop distal weakness, braces for foot drop usually are helpful. The myotonia often responds to medications that stabilize membranes, such as phenytoin, gabapentin, carbamazepine, quinidine, procainamide, mexiletine, and acetazolamide. Theoretically, however, procainamide and quinine prolong the conduction intervals, which are already abnormally prolonged in many patients with DM. Mexiletine is a far better option than phenytoin, carbamazepine, gabapentin, quinine, and procainamide, and it is usually effective in a dosage ranging from 75 to 200 mg two to three times daily. Its main side effects are gastrointestinal, which improve when the drug is taken with food. Tocainide is as effective as mexiletine, but it may suppress the bone marrow. However, because these patients are troubled primarily by the weakness and less by the myotonia, they may benefit more from mechanical devices such as ankle supports than from membrane stabilizers. PROXIMAL MYOTONIC MYOPATHY

In the last 10 years, a subgroup of families with myotonia, weakness, and cataracts but with other features atypical for DM were identified because they had no abnormal expansion of the CTG repeat in the DM gene on chromosome 19. The description of these families and their lack of linkage to the classic DM locus led to the recognition of proximal myotonic myopathy (PROMM) as a clinically and genetically distinct condition. The core features of PROMM are autosomal dominant

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TABLE107-3. CTC Repeat Expansion in Myotonic Dystrophy Category

Normal

Borderline Normal

Permutation Carriers

Full Mutation

Number of repeats Clinical DhenoWDe

5-37 Normal

38-49 Normal

50-99 Mildlv svmDtomatic or no svmDtoms

More than 100 Svmptornatic

inheritance in at least two generations, absence of CTG repeat expansion on chromosome 19, predominantly proximal weakness, cataracts identified by slit lamp examination, and electromyographic myotonia. Additional supportive features include myalgias and painful muscle cramps, fluctuating weakness and stiffness, calf pseudohypertrophy, diabetes mellitus or insulin resistance, hypothyroidism, cataracts, cardiac conduction defects, deafness, and gastrointestinal symptoms. Hypersomnia and significant cognitive delay or brain atrophy on magnetic resonance imaging are not features of PROMM. Also, a congenital form of PROMM does not occur; most patients have onset of symptoms in their 30s or 40s. Furthermore, the occurrence of genetic anticipation has not been documented. The diagnosis is primarily clinical and supported by the absence of CTG expansion or genetic linkage to the DM gene on chromosome 19. CK levels usually are elevated 2- to 10-fold, but normal levels may be seen in a number of patients. In addition to classic DM, the differential diagnosis includes other myotonic disorders, inflammatory myopathies, neuromuscular transmission defects, and mitochondrial disease. Because of the less severe involvement of cardiac and respiratory muscle function, the prognosis usually is better in patients with PROMM. No specific therapy exists for PROMM, but careful monitoring of cardiac status is indicated. LIMB-GIRDLE MUSCULAR DYSTROPHIES LGMD was first described by Erb in 1884. The term limb-girdle dystrophy embraces a number of conditions with heterogenous causes; a European Neuromuscular Center (ENMC) meeting in 1995 defined LGMD as a muscular dystrophy with predominantly proximal distribution of weakness that, early in the course of the disease, spares distal muscles as well as facial and extraocular muscles. Most cases are inherited in an autosomal recessive fashion and, as is to be expected, are sporadic. However, families with an autosomal dominant pattern of inheritance have been described as well. The age of onset of LGMD varies from early childhood to adulthood, but typically the onset is not congenital. In some cases, weakness may be noted early, leading to significant disability during childhood; in other cases the weakness may not be apparent until early in adult life. With the exception of a few cases with rapid progression, the course usually is slowly progressive. The weakness affect the shoulder girdle (scapulohumeral type) or the pelvic girdle (pelvifemoral type). Most childhood-onset cases have a pelvifemoral distribution of weakness. In many adult patients, the disease involves both shoulder and pelvic girdles with gradually increasing proximal limb weakness leading to restriction of mobility and eventually to wheelchair confinement. Neck flexor and extensor muscles may be involved concomitantly. Facial weakness usually is mild and, in some cases, totally absent. Even in mild cases, there is preferential weakness and atrophy of the biceps muscle. Low back pain may be a prominent symptom in patients with LGMD. Intellect usually is normal, and cardiac or other systemic involvement is not as common as in dystrophinopathies.

TABU1074. Limb-Girdle Muscular Dystrophies Type

Gene Location

Protein

LCMD-1A LCMD-1 B LCMD-1 C LCMD-1D LCMD-1E LCMD-2A LCMD-2B LCMD-2C LCMD-2D LCMD-2E LCMD-2F LCMD-2C LCMD-2H LCMD-21

5q22-q31 lqll-q21 3p25 6q23 7q 15ql5-q21 2p13 13q12 17q12-q21 4q12 5q33-q34 17qll-ql2 9q31-q34.1 19q13.3

Myotilin Lamin A/C Caveolin-3 ? ? Calpain-3 Dysferlin YSarcoglycan a-Sarcoglycan p-Sarcoglycan GSarcoglycan Telethonin

? ?

Inheritance

AD AD AD AD AD AR AR AR AR AR AR AR AR AR

Abbreviations:AD, autosomal dominant; AR, autosomal recessive; LGMD, limb-girdle

muscular dystrophy.

The discovery of the genetically distinct subtypes of LGMD has led to nomenclature designating autosomal dominant LGMD as LGMD- lA, lB, lC, and so forth and autosomal recessive LGMD as LGMD-2A, 2B, 2C, and so forth. The current status of this classification is shown in Table 107-4. Mutations within the same gene may result in different phenotypes, sometimes not consistent with the strict definition of LGMD; for example, LGMD-2B and Miyoshi distal myopathy are caused by dysferlin gene mutations, whereas mutations in the gene encoding lamin A/C may result in the phenotypes of autosomal dominant Emery-Dreifuss muscular dystrophy, LGMD-lB, or cardiomyopathy with conduction system disease. Sarcoglycanopathies are early-onset autosomal recessive LGMDs caused by mutations in a-,p-, y-, and 6-sarcoglycans, which are members of the dystrophin-associated glycoprotein complex (Fig. 107-3). The pattern of weakness in sarcoglycanopathies is reminiscent of DMD and BMD, including the calf hypertrophy, but cognitive function is preserved. In calpain deficiency (calpainopathy) the pattern is more atrophic, with significant involvement of the periscapular muscles, biceps, gluteus maximus, adductors, and hamstrings. The early weakness and atrophy of the gastrocnemius with inability to walk on the toes and high CK are very supportive of dysferlinopathy, and an early foot drop may indicate a telethoninopathy. Cardiac involvement is common in LGMD-1B (laminopathy) and LGMD-1D and unusual in LGMD- 1A (myotilinopathy), LGMD- 1C (caveolinopathy), and LGMD-1E. Cardiomyopathy may occur in a subset of patients with sarcoglycanopathy. CK is usually modestly elevated but can be very high in sarcoglycanopathies, dysferlinopathy, and caveolinopathy. EMG shows myopathic changes with small polyphasic potentials; a muscle biopsy reveals dystrophic changes with degeneration and regeneration of muscle fibers, fiber splitting, internal nuclei, fibrosis, moth-eaten, and whorled fibers. Most autosomal recessive LGMDs have earlier onset, rapid progression, and high CK values. If the CK is more than 1000 IUlL in a patient with a myopathic LGMD-like phenotype, thereby making other nonmyopathic motor unit disorders (e.g., SMA) less

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likely, one should proceed to a dystrophin DNA test; given that this test is positive in 65% to 80% but not all DMD and BMD cases, a dystrophinopathy is not excluded by a negative result. The next appropriate diagnostic procedure is a muscle biopsy; immunohistochemistry with antibodies against a - , p-, y-, and 6-sarcoglycans, dystrophin, dystroglycans, and merosin may offer a means for a specific biopsy diagnosis (e.g., a-sarcoglycanopathy) but not always. If the biopsy suggests a myopathic process but DNA testing and immunohistochemistry for all of the above-mentioned proteins is normal, myotilin, calpain-3 (LGMD-2A), dysferlin (LGMD-2B), and telethonin (LGMD-2G) testing may need to be pursued in selected research laboratories. The patients with autosomal dominant LGMD usually have a later age at onset and a more ingravescent clinical progression. The CK values in these patients may not be as grossly elevated. However, in LGMD- 1C, related to caveolin mutations, CK values are elevated 4- to 25-fold, and the clinical onset of this form of LGMD may begin in childhood; if clinically suspected, DNA testing for caveolin mutations is currently available only in research laboratories. Some sporadic dominant cases, and even autosomal recessive ones with modest CK elevation, may be clinically indistinguishable from SMA type 111, the KugelbergWelander form of SMA. Because SMA type I11 may also have a modest CK elevation (less than 1000 IU/L), in this setting an EMG is particularly useful for differentiating a neurogenic from a myopathic process and thus deciding to proceed with DNA testing for possible SMA or a muscle biopsy for a potential myopathy. Treatment is supportive and is aimed at preventing contractures because substantial disability may result from them. Therefore, a passive stretching physical therapy program must be instituted early. Later in the course of the disease, cardiorespiratory monitoring is indicated.

Diseases of Muscle

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

Facioscapulohumeral (FSH) dystrophy was first described by Duchenne (1872) and, subsequently, by Landouzy and Dejerine (1884). The classic form of FSH dystrophy is inherited in an autosomal dominant fashion and has been mapped to chromosome 4q35. Although FSH dystrophy usually is slowly progressive, it can be extremely variable in its severity and even the age of onset. The infantile variety of FSH dystrophy has a very early onset (usually within the first few years of life) and is rapidly progressive, with wheelchair confinement by the age of 9 or 10 years in most cases. There is profound facial weakness, inability to close the eyes in sleep, and inability to smile and to show any evidence of facial expression. The weakness rapidly involves the shoulder and hip girdles with lumbar lordosis, pronounced forward pelvic tilt, and hyperextension of the knees and the head upon walking. Marked weakness of the wrist extensors may result in a wrist drop. The infantile variety of FSH dystrophy often is sporadic. In the classic form of FSH dystrophy, the onset usually is in the second or third decade and the progression is slow, with almost normal lifespan. The facial muscles are involved initially with inability to close the eyes tightly, smile, or whistle; a pouting appearance of the lips, smooth face, and mild dimpling in the areas lateral to the angles of the mouth are characteristic (Fig. 107-7A and B ) . However, the facial weakness can be mild early on and may remain mild for many years. The muscles of the shoulders and upper arms are also involved with marked atrophy of the biceps and triceps, but relative preservation of the deltoid muscles (Fig. 107-7C). There is significant scapular winging (Fig. 107-8) and characteristic appearance of the shoulders with bulging of the trapezii muscles (Fig. 107-7A), riding of the scapulae upward and over the lateral parts of the thorax, and forward jutting of the medial ends of the clavicles when the arms are

CD

ICB

FIG. 107-7. Facioscapulohumeral muscular dystrophy. (A) Horizontal and widened appearance of the mouth, with vertical dimpling on either side of the mouth; the rest of the face is unlined. (B) Pouting appearance of the lips, when viewed from the side. (C) Atrophy of the arm caused by wasting of the biceps and triceps. The deltoid and muscles of the forearm are preserved ("Popeye" arm). (0)Hypertrophy of the extensor digitorum brevis muscle, in spite of marked foot drop, seen as bulging on the lateral aspect of the foot. (Adapted from Book M: A Clinician's View of Neuromuscular Disease. Williams & Wilkins, Baltimore, 1986, with permission.)

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weakness may show some improvement by surgical fixation of the scapulae. Because loss of scapular fixation may recur after surgery, it would be advisable to recommend surgery on one side and, if successful, to consider fixation of the other side later. Wrist and ankle supports may be useful also. Despite the pronounced inflammatory response in muscle biopsies, therapy with corticosteroids is not advocated.

OCULOPHARYNGEAL MUSCULAR DYSTROPHY

FIG. 107-8. Facioscapulohumeral muscular dystrophy. Profound scapular winging with rising of the scapulae upward and laterally. (Courtesy of N. Paul Rosman, MD, New England Medical Center, Boston.)

abducted. Distal muscles of the upper extremities usually are spared, but a foot drop may occur (scapuloperoneal variety). Inspection of the extensor digitorum brevis (EDB) muscle is helpful in diagnosing FSH because it is usually hypertrophic in FSH (Fig. 107-70); atrophy of the EDB muscle is common in peripheral motor neuropathies. In a number of cases, the disease progresses rapidly in middle age, leading to significant disability. Exudative telangiectasia of the retina with an associated sensorineural hearing loss (Coats’s syndrome) has been described to occur in some cases of FSH dystrophy. The EMG displays myopathic features; the muscle biopsy shows variability in fiber size, with a lot of large hypertrophic fibers, a few angulated atrophic fibers, and often a significant inflammatory response. Histologic differentiation from polymyositis is based on the fact that hypertrophy of the muscle fibers is not seen in the latter. CK is only mildly elevated and is rarely elevated in patients presymptomatically. A commercial DNA test is now available for FSH muscular dystrophy; most patients with classic FSH for whom detailed molecular studies have been done carry a chromosomal rearrangement within the subtelomere of chromosome 4q (4635). A tandem array of 3.3-kb repeated DNA elements (D4Z4) is deleted in patients with FSH. In the general population, the number of repeat units varies from 10 to more than 100; in patients with FSH, an allele of 1 to 10 residual units is observed because of the deletion of an integral number of these units. This new diagnostic test is positive in 95% to 98% of typical FSH cases. Nonetheless, the exact gene defect is not known yet, so the sensitivity of the genetic test for atypical cases remains uncertain. In typical cases, we see no value in performing a muscle biopsy. Treatment of FSH is primarily supportive. The eyes must be checked for evidence of telangiectasia, which is usually treatable with photocoagulation of the abnormal vessels. Because the deltoid muscles usually are preserved, patients with significant

Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy characterized by ocular and pharyngeal muscle involvement. It presents with ptosis, dysarthria, and dysphagia, but it can also be associated with proximal and distal extremity weakness. The onset usually is in middle age, with usually asymmetrical involvement of the levator palpebrae muscles first and progressive extraocular weakness. It is a slowly progressive myopathy, and although ptosis can occlude vision, severe dysphagia can sometimes lead to weight loss and death if not treated. OPMD is distinguished from FSH muscular dystrophy by the fact that the extraocular weakness in OPMD is far more severe; it is also distinguished by the distribution of weakness. OPMD can also be confused with myotonic dystrophy, but myotonia is absent in OPMD; ocular muscle involvement is rarely severe in early myotonic dystrophy. The differentiation from a mitochondrial myopathy might pose a problem. However, the associated features of retinitis pigmentosa, ataxia, elevated cerebrospinal fluid protein, cardiac conduction defects, and developmental delay often seen in mitochondrial myopathies help in the differentiation. Muscle biopsy shows variation of fiber size and rimmed vacuoles. CK levels may be elevated. In a small number of patients, cricopharyngeal myotomy has been attempted with improvement of the dysphagia. OPMD is an autosomal dominant myopathy with complete penetrance and a high incidence in the Canadian province of Quebec, where it is estimated at 1 in 8000 people. The frequency of OPMD in France is lower, at 1 in 200,000 people. It appears that a single founder chromosome is responsible for OPMD in the French Canadian population. OPMD has been linked to chromosome 14ql1, and a GCG repeat expansion has been shown in the PABP2 gene (poly-A binding protein 2). Ninety-eight percent of control French Canadian chromosomes had 6 GCG repeats, and 2% had 7 repeats. In OPMD, the expanded alleles range from 8 to 13 repeats. The OPMD repeat is short, with small and stable expansions. The PABP2 protein has been localized to the nucleus, where it seems to be involved in mRNA polyadenylation.

DISTAL MUSCULAR DYSTROPHY Distal myopathies are a heterogeneous group of myopathies characterized by weakness starting distally but gradually progressing to proximal muscles as well. Almost all forms of distal myopathy can present as early as the second decade, but the onset is usually between 40 and 60 years. Their current clinical and genetic classification is shown in Table 107-5.

CONGENITAL MUSCULAR DYSTROPHY This term has been applied to infants who are hypotonic and weak at birth and in whom muscle biopsies show changes consistent with muscular dystrophy. Arthrogryposis is commonly seen in the newborn period. The Fukuyama type of congenital muscular

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TABLE107-5. Distal Muscular Dystrophies Tvpe

Inheritance

Initial Weakness

CK

Biopsy

Locus/Cene

Miyoshi: early adult onset type II (LGMD 28')

Autosomal recessive or sporadic

Legs: posterior compartment

Increased 10-1 50x normal

2p13 dysferlin

Nonaka: early adult onset pe I familial IBM ) Laing: early adult onset type 111

Autosomal recessive or sporadic

Legs: anterior compartment

Autosomal dominant Autosomal dominant

Moderate myopathic changes, no vacuoles Myopathic; vacuoles in some cases Vacuolar myopathy

14q

Welander: late adult tVpe I Markesbery-Griggs/ Udd: late adult onset type II

Legs: anterior compartment Neck flexors Hands: fingers and wrist extensors Legs: anterior compartment

Slightly to moderately elevated, usually <5x normal Slightly elevated, <3x normal

Myopathic, usually without vacuoles; gastrocnemius often end stage Vacuolar myopathy

Y (

Autosomal dominant

Normal or slightly elevated Normal or slightly elevated

9pl-ql

2pl3 2q

"Limb girdle muscular dystrophy type 28 co-localizeswith Miyoshi distal myopathy. bAutosomal recessive familial inclusion body myopathy (IBM), also known as quadriceps-sparingmyopathy, has been genetically linked with Nonaka distal myopathy. Modified from Orrell RW, Griggs RC: Facioscapulohurneral dystrophy, scapuloperoneal syndromes, and distal myopathies. In Jones HR Jr, De Vivo D, Darras BT (eds): Neuromuscular Disorders of Infancy and Childhood. Butterworth Heinemann, Boston, in press.

dystrophy (CMD) is more common in Japan, and it is characterized by hypotonia, generalized weakness, severe developmental delay, seizures, and microcephaly. The gene for the Fukuyama type CMD was recently localized to chromosome 9q31-33. A combination of CMD and demyelination of the cerebral hemispheres (leukodystrophy) has been described in Caucasian children. When CMD is associated with ocular dysplasia, hydrocephalus, and cerebral malformations, the term cerebro-ocular dysplasia is applied. Ocular abnormalities include cataracts, optic nerve hypoplasia, corneal clouding, and retinal dysplasia o r detachment. Thus, CMD is not a single entity, but embraces a number of conditions in which evidence of muscular dystrophy is evident at birth. Serum CPK may be normal o r elevated, and muscle biopsy is characteristically abnormal with extensive fibrosis, degeneration, and regeneration of muscle fibers and proliferation of fatty and connective tissue. In some cases, the clinical course is static, but in most patients it progresses very slowly. In a few cases, however, actual improvement has been seen. No definitive treatment is available for this disorder. To date, a laminin-a2 (merosin, in the chromosome 6q22 form of CMD) and fukutin (in Fukuyama CMD) genetic defect has been delineated in a subset of these patients. Laminin-a2 (merosin) is a component of the dystrophin-associated protein complex (Fig. 107-3). Commercial DNA testing for merosin o r fukutin mutations is not available at the moment. At EMG, the motor unit potentials are of short duration and low amplitude, and no abnormalities usually are seen o n insertion. As with the various congenital myopathies, the diagnosis is made by muscle biopsy, which shows widespread dystrophic changes; as expected, in merosin-negative cases muscle immunostaining with antimerosin antibodies usually is negative for merosin.

SUGGESTED READINGS Duchenne and Becker Muscular Dystrophies (Dystrophinopathies) Arahata K, Ishiura S et ak Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide. Nature 333(6176):861-863, 1988 Barton-Davis ER, Cordier L et al: Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest 104(4):375-381, 1999

Bushby KM, Gardner-Medwin D: The clinical, genetic and dystrophin

characteristics of Becker muscular dystrophy. I. Natural history. J Neurol 240(2):98-104, 1993 Darras BT Molecular genetics of Duchenne and Becker muscular dystrophy. J Pediatr 117:l-15, 1990 Darras BT, Jones HR Jr: Diagnosis of neuromuscular disorders in the era of DNA analysis. Pediatr Neurol 23(4):289-300. 2000 Darras BT, Koenig M et al: Direct method for prenatal diagnosis and carrier detection in Duchenne/Becker muscular dystrophy using the entire dystrophin cDNA. Am J Med Genet 29(3):713-726, 1988 Fenichel GM, Griggs RC et al: A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy. Neurology 56: 1075-1079, 2001

Griggs R, Moxley R et al: Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months). Neurology 433520-527, 1993 Hoffman EP, Fischbeck KH et al: Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy. N Engl J Med 318(21):1363-1368, 1988 Hoffman EP, Kunkel LM et al: Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 39(8):1011-1017, 1989 Hoogerwaard EM, van der Wouw PA et al: Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 9(5):347-35 1, 1999

Mendell J, Moxley R et al: Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med 3201592-1597, 1989

Monaco AP, Bertelson CJ et al: An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2( 1):90-95, 1988 Sharma KR, Mynhier MA et al: Cyclosporine increases muscular force generation in Duchenne muscular dystrophy. Neurology 43:527-532, 1993

Emery-Dreifuss Muscular Dystrophy Bione S, Maestrini E et al: Identification of a novel X-linked gene responsible for Emery-Dreihss muscular dystrophy. Nat Genet 8(4): 323-327, 1994

Bonne G, Di Barletta MR et ak Mutations in the gene encoding lamin N C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 21:285-288, 1999 Di Barletta MR, Ricci E et al: Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifussmuscular dystrophy. Am J Hum Genet 66(4):1407-1412, 2000 Hopkins LC, Jackson JA et al: Emery-Dreifuss humeralperoneal muscular dystrophy, an X-linked myopathy with unusual contractures and bradycardia. Ann Neurol 10:230-237, 1981

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Rowland LP, Fetell M et al: Emery-Dreifuss muscular dystrophy. Ann Neurol 5:111-117, 1979

Myotonic Dystrophy Aslanidis C, Jansen G et al: Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 355(6360):548-551, 1992 Brook JD, McCurrach ME et ak Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3’ end of a transcript encoding a protein kinase family member. Cell 68(4):799-808, 1992 Brunner HG, Nillesen W et ak Presymptomatic diagnosis of myotonic dystrophy. J Med Genet 29:780-784, 1992 Griggs RC, Davis RJ et ak Cardiac conduction in myotonic dystrophy. Am J Med 59:3742, 1975 Harley HG, Rundle SA et al: Unstable DNA sequence in myotonic dystrophy. Lancet 339:1125-1128, 1992 Harper PS: Myotonic Dystrophy. WB Saunders, London, 1989 Moxley RT 111: Channelopathies. Curr Treat Options Neurol2:31-47,2000 Suthers GK, Huson SM et al: Instability versus predictability: The molecular diagnosis of myotonic dystrophy. J Med Genet 29761-765, 1992

Proximal Myotonic Myopathy Moxley RT 111, Udd B, Ricker K: 54th ENMC International Workshop. PROMM (proximal myotonic myopathy) and other proximal myotonic syndromes. Neuromuscul Disord 8:508-518, 1998 Ricker K, Koch MC, Lehmann-Horn F et ak Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44:1448-1452, 1994 Ricker K, Koch MC, Lehmann-Horn F et ak Proximal myotonic myopathy. Clinical features of a multisystem disorder similar to myotonic dystrophy. Arch Neurol 52:25-31, 1995 Thornton CA, Griggs RC, Moxley RT 111: Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol 35:269-272, 1994

Limb-Girdle Muscular Dystrophies Bittner RE, Anderson LV et al: Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B [letter]. Nat Genet 23(2):141-142, 1999 Brooke MH: Limb-girdle dystrophy. pp. 178-181. In Brooke MH (ed): A Clinician’s View of Neuromuscular Diseases. Williams & Willcins, Baltimore, 1986 Bushby KM: Diagnostic criteria for the limb-girdle muscular dystrophies: report of the ENMC Consortium on Limb-Girdle Dystrophies. Neuromuscul Disord 5( 1):71-74, 1995 Bushby KM, Beckmann JS: The limb girdle muscular dystrophies: proposal for a new nomenclature. Neuromuscul Disord 4337-343, 1995 Lim LE, Campbell K P The sarcoglycan complex in limb-girdle muscular dystrophy. Curr Opin Neurol 11(5):443-452, 1998 Matsuda C, Aoki M et al: Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy. Neurology 53(5):11191122, 1999 McNally EM, de Sa Moreira E et ak Caveolin-3 in muscular dystrophy. Hum Mol Genet 7(5):871-877, 1998 Minetti C, Sotgia F et ak Mutations in the caveolin-3 gene cause autosomal

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dominant limb-girdle muscular dystrophy. Nat Genet 18(4):365-368, 1998 Moreira ES, Wiltshire TJ et al: Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 24(2): 163-166, 2000 Richard I, Brow 0 et ak Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81( 1):27-40, 1995 Richard I, Roudaut C et ak Calpainopathy: a survey of mutations and polymorphisms. Am J Hum Genet 64(6):1524-1540, 1999

FacioscapulohumeralMuscular Dystrophy Carroll JE, Brooke M H Infantile facioscapulohumeral dystrophy. In Serratrice G, Rowr H (eds): Peroneal Atrophies and Related Disorders. Masson, New York, 1979 Hewitt JE, Lyle R et al: Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet 3(8):1287-1295, 1994 Ketenjiam AU Scapulocostal stabilization for scapular winging in facioscapulohumeral dystrophy. J Bone Joint Surg 60A476-480, 1978 Kohler J, Rohrig D et ak Evaluation of the facioscapulohumeral muscular dystrophy (FSHD1) phenotype in correlation to the concurrence of 4q35 and 10q26 fragments. Clin Genet 55(2):88-94, 1999 Munsat TL, Piper D et ak Inflammatory myopathy with facioscapulohumeral distribution. Neurology 22:335-347, 1972 Ricci E, Galluzzi G et ak Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol 45(6):751-757, 1999 Tawil R, Figlewicz DA et al: Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium. Ann Neurol43(3):279-282, 1998 Taylor DA, Carroll JE et ak Facioscapulohumeral dystrophy associated with hearing loss and Coats syndrome. Ann Neurol 12:395-398, 1982

Oculopharyngeal Muscular Dystrophy Brais B, Bouchard J, Xie Y et al: Short GCG expansions in the PABP2 gene cause oculo-pharyngeal muscular dystrophy. Nat Genet 18:164-167, 1998 Victor M, Hayes R, Adams RD: Oculopharyngeal muscular dystrophy: familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 267:1267-1272, 1962

Congenital Muscular Dystrophy Helbling-Leclerc A, Zhang X et al: Mutations in the laminin alpha Z-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 11:216-218, 1995 Kamoshita S, Konishi Y et ak Congenital muscular dystrophy as a disease of the nervous system. Arch Neurol 33:513-516, 1976 Kobayashi K, Nakahori Y et ak An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394(6691): 388-392, 1998 Toda T, Segawa M et ak Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. Nat Genet 5(3):283-286, 1993 Tome FM, Evangelista T et al: Congenital muscular dystrophy with merosin deficiency. C R Acad Sci 111 317:251-357, 1994

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108 Inflammatory Myopathy lsabelita R. Bella and David A. Chad The term inflammatory rnyopathy refers to a spectrum of disorders that have in common the presence of lymphocytic infiltration of muscle tissue. Included in the clinical spectrum are infectious myopathies, sarcoid myopathy, and some dystrophic and toxic myopathies that have an inflammatory component. In this chapter we focus our attention on a group of uncommon, immunologically mediated inflammatory myopathies that include three distinct conditions: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. Despite their rarity, they demand our attention for several reasons. First, for many patients the myopathy (PM or DM) is eminently treatable, but a positive response to immunotherapy depends on early diagnosis and prompt initiation of therapy. Inclusion body myositis appears resistant to treatment, but accurate diagnosis is crucial so that long-term therapy with potent immunosuppressive drugs is avoided. Second, because an inflammatory myopathy (notably PM or DM) may be the first manifestation of a systemic disorder such as malignancy or connective tissue disease, accurate diagnosis of the myopathy allows the physician to recognize these complicating disorders when they are at an early and more manageable stage of their course. Third, because many different myopathic (and some nonmyopathic) disorders resemble the inflammatory myopathies, early and accurate recognition that weakness is caused by PM, DM, or inclusion body myositis allows the physician to avoid costly tests and procedures.

with a predilection for the older patient (usual age of onset more than 50 years). The clinical features of PM and DM are summarized in Table 108- 1. PM and DM are characterized by the subacute development of proximal muscle and neck flexor weakness, with progression of symptoms over weeks to months. In some patients, muscle aches and tenderness may occur early in the course of the illness. Sensation is normal and tendon reflexes are preserved unless the muscle is severely weak and atrophic. Dysphagia, from involvement of the striated muscle of the upper esophagus and pharynx, is present in 30% to 50% of patients. In contrast to PM and DM, inclusion body myositis progresses over many years and, in addition to proximal and neck flexor muscles, affects distal muscles early in its course. Asymmetrical involvement of finger flexors, wrist flexors, knee extensors, and ankle dorsiflexors often occurs. The quadriceps muscle may be selectively involved, leading to severe weakness and atrophy; patients commonly complain of frequent and unexpected falls. The average duration of symptoms from onset to diagnosis is 3 to 5 years. Inclusion body myositis often is misdiagnosed, most often as PM resistant to treatment, but neurogenic features may prompt the diagnosis of amyotrophic lateral sclerosis. In all the inflammatory myopathies, facial and extraocular muscles are rarely affected; indeed, involvement of cranial muscles should raise the possibility of another diagnosis.

CLINICAL FEATURES

Other Organ Involvement

The inflammatory myopathies are uncommon, with only 5 to 10 new cases per million per year in the United States. Peak incidence of PM and DM occurs in patients between the ages of 45 and 64. However, DM has a bimodal age distribution with a smaller peak in the juvenile age group (5 to 14 years). Women outnumber men by 2 to 1; moreover, African American women have a greater risk of developing these diseases than do white women, with the former group showing a higher mortality. In contrast, inclusion body myositis occurs more often in men (ma1e:femaleratio of 2 1 )

Skin Manifestations of Derrnatomyoritis. DM is distinguished by its characteristic rash, which usually accompanies, but may precede by weeks to months, the onset of weakness. The rash and muscle enzyme elevations may be the only manifestation of DM early in its course. The typical cutaneous manifestations of DM are the heliotrope rash and Gottron sign. The heliotrope rash is a lilac discoloration of the periorbital skin, especially the upper eyelids, and usually is associated with periorbital edema. The Gottron sign (also known as Gottron’s papules or plaques) is

rn TABLE108-1. Clinical Features of Inflammatory Myopathies Clinical Characteristic

Polvmvositis or Dermatomvositis

Inclusion Bodv Mvositis

lime course Distribution of weakness

Weeks to months Proximal muscles, neck flexors Dysphagia in 30%

Rash

In DM: heliotrope, V sign, shawl sign, Cottron’s sign (all may be subtle) Primarily in DM Interstitial lung disease and cardiac conduction defects most common Malignancy (especially in DM) Connective tissue disease (especially scleroderma) Straightforward for DM; complex for PM, with broad differential diagnosis Usually good

Months to years Proximal muscles, neck flexors Dysphagia in up to 60% Distal weakness occurs early Asymmetrical Predilection for volar forearm and quadriceps None

Childhood form Other organ involvement Associated diseases Diagnostic process Response to immunosuppressive treatment

Very rare Not typical No increase in risk of malignancy Connective tissue diseases do occur Often difficult with delay in diagnosis; simulates amyotrophic lateral sclerosis Poor

Chapter 108

erythematous, violaceous raised papules and plaques occurring over bony prominences, especially the knuckles and proximal and distal interphalangeal joints, but can also be seen on the elbows, knees, and ankles. Another cutaneous manifestation is a flat, erythematous, sometimes photosensitive rash seen in the malar, perioral, forehead, anterior neck, anterior chest (V sign), and back and shoulder (shawl sign) areas. Periungual telangiectasias, cuticular overgrowth, and nailfold infarcts may also be seen, and the fingers may’ be cracked and rough, with dirty-looking horizontal lines. Another distinguishing feature is the presence of subcutaneous calcificationlocated on the hands or arms; it is more often seen in juveniles (up to 40%). Breaks in the skin created by extruded calcification may lead to secondary infection. A less well recognized eruption seen in DM is an erythematous, scaling, and atrophic rash known as poikiloderma, particularly over extensor surfaces and upper back. Pulmonary and Cardiac Involvement There are several causes of lung involvement in PM and DM. Weakness of pharyngeal muscles and an ineffective cough caused by respiratory muscle weakness may cause aspiration pneumonia. In advanced cases, marked respiratory muscle weakness may lead rarely to respiratory insufficiency. Treatment with immunosuppressive agents may lead to pyogenic and atypical lung infections or methotrexate lung toxicity. In 10% of patients with PM and DM, interstitial lung disease occurs; dyspnea and a nonproductive cough are the most common symptoms. In these patients, auscultation of the chest may reveal bilateral basilar rales, and chest roentgenogram typically reveals nodular, linear, or reticulonodular infiltrates. Pulmonary function testing shows the classic restrictive pattern of reduced total lung capacity without air flow obstruction. Pathologically, there is inflammation and subsequent fibrosis of the alveolar walls, with subsequent impairment in gas exchange. An important serum marker in these patients is the anti-Jo-1 antibody; interstitial lung disease is present in 50% of patients with the anti-Jo- 1 antibody. Cardiac abnormalities in PM and DM consist primarily of electrocardiographic (ECG) abnormalities, occurring in up to 40% of patients. The most common abnormality is nonspecific ST-T wave changes. Other conduction abnormalities include heart block, bundle branch block, and arrhythmias (tachyarrhythmias and sick sinus syndrome). Symptomatic cardiac involvement such as congestive heart failure, myocarditis, pulmonary hypertension, or valvular disease is uncommon. Indeed, a recent study found the incidence of symptomatic cardiac involvement to be 6% while there was more than 50% prevalence of electrical changes, highlighting the disparity between clinical and ECG abnormalities. However, symptomatic cardiac involvement may be the most important clinical factor associated with poor prognosis. One study found 32% mortality in patients with cardiac involvement and 8% in those without. Fibrosis of the conduction system may be responsible for the ECG conduction defects. The muscle-brain fraction of creatine kinase is not useful in predicting the presence or absence of cardiac involvement. Pathologically, the myocardium of patients with PM or DM who had congestive heart failure resembles that of skeletal muscle, with the presence of interstitial inflammatory cell in!% trates, necrosis, variation in myocyte size, degeneration of myocytes, and fibrosis. One autopsy series found an active myocarditis in 25% of patients, all of whom had clinical evidence of congestive heart failure and ongoing skeletal muscle involvement. In two thirds of patients with cardiac involvement, an

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antibody reacts to tissue ribonucleoproteins, suggesting a pathogenic role for humeral immunity in cardiac damage.

Association with Malignancy It is likely that there is an greater frequency of malignancy in patients with inflammatory myopathy, but the risk has been difficultto define precisely. A recent population-based study found a definite increased risk of cancer in patients with DM; patients with PM had a higher risk of cancer than the general population, but it is questionable whether the risk is real. A recent review of the literature suggests that approximately 25% of patients with DM already have a malignancy or will be afflicted later, whereas the incidence of malignancy in PM probably occurs at a lower rate and may not be different from that of the general population. Although malignancy appears to be more common in older patients, young adults may have cancer-associated myositis. Many types of malignancies have been reported to occur with PM and DM, including carcinoma of the breast, stomach, lung, pancreas, skin, colon, and prostate. There is a suggestion that gynecologic malignancies, particularly ovarian cancer, may be more common than other tumors. Overall, however, it appears that the types of malignancies correspond to the types typically found in a particular age group. Muscle weakness may occur 1 month to 6 years before discovery of the tumor or 4 months to 5 years after the discovery of malignancy; however, most malignancies are identified within 2 years of the presentation of myositis. Several case reports suggest that the symptoms of myositis parallel the course of malignancy, with improvement following treatment of the tumor and recurrence of symptoms with development of metastasis. Several clinical and laboratory features are negatively associated with malignancy, including the presence of an accompanying connective tissue disease, the presence of pulmonary fibrosis, and the finding of a myositis-specific antibody. In most patients with PM or DM we recommend a directed search for a malignancy. We perform a complete history and physical examination (with rectal, pelvic, and breast examinations), and our laboratory testing includes stool analysis for occult blood, urinalysis, complete blood count and differential, electrolytes, chest radiograph, mammography, pelvic ultrasound, prostate-specific antigen (in older men), and follow-up of any abnormalities found. Inclusion body myositis does not appear to have an association with malignancy; only 8 cases of malignancy have been reported in more than 100 patients described in the literature.

Association with Connective Tissue Disease PM and DM may occur as isolated entities, but up to 24% are associated with a connective tissue disorder (the so-called overlap group), usually systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, systemic sclerosis, and mixed connective tissue disease. Patients with the overlap syndrome are more likely to present with arthralgia and arthritis; their muscle disease often is milder than in isolated PM or DM. PM and DM may also be associated with systemic autoimmune disorders such as ulcerative colitis, primary biliary cirrhosis, and chronic graft versus host disease. Ranitidine and Lupron therapy has also been reported as a causative factor. Inclusion body myositis may also be associated with collagen-vascular disorders such as Sjogren’s syndrome and systemic lupus erythematosus.

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Association with Autoantibodies Several autoantibodies to nuclear and cytoplasmic antigens involved in protein synthesis, found in 35% to 40% of patients with PM and DM, are called myositis-specific autoantibodies (MSAs) because they occur most commonly or exclusively in these disorders. These MSAs may arise many months before the development of myositis symptoms, and they correlate with disease activity, disappearing as the myositis enters remission. It is rare for a patient to have more than one MSA, so each one defines a specific subgroup of patients. The absence of an MSA cannot exclude the diagnosis of PM or DM, but their presence has a strong predictive value in defining subgroups of patients with similar clinical manifestations, disease severity, and response to therapy (Table 108-2). Approximately a dozen MSAs have been described. The clinically most important MSAs are the antisynthetases, found in 25% to 30% of patients with PM and DM; the anti-SRP (signal recognition particle) autoantibody, detected in 4% to 5% of cases of PM; and the anti-Mi-2 (nuclear helicase) autoantibody, found in 5% to 10% of patients with DM. A fourth autoantibody, the anti-PM-Scl autoantibody, is more appropriately called myositisassociated autoantibody (rather than specific) because it is most closely associated with connective tissues disease and is found in the overlap syndrome: PM associated with scleroderma. Fifty percent of autoantibody-positive patients have this clinical combination, others have an undifferentiated connective tissue disease, and some have scleroderma without myositis. Anti-U1RNP has a strong association with myositis in the context of mixed connective tissue disease (features of scleroderma, systemic lupus erythematosus, rheumatoid arthritis) but is also not specific. Similarly, anti-Ro/SSA autoantibody is more closely associated with connective tissue disease than myositis per se. Among the five antisynthetases that have been defined, anti-aminoacyl tRNA synthetase (anti-Jo-1) MSA is the most prevalent, occurring in 20% of patients with PM and DM. The anti-Jo-1 autoantibody is directed at histidyl-tRNA synthetase (the enzyme responsible for catalyzing the formation of histidyltRNA from histidyl and its cognate tRNA). Patients with anti-Jo-1 often have a constellation of clinical features that has been called the antisynthetase syndrome. These features include onset of myositis in the spring, association with nonerosive symmetrical small joint arthritis, low-grade fevers, Raynaud’s syndrome, mechanic’s hands, and most importantly, interstitial lung disease (found in 50% to 75% of patients who are anti-Jo-1 positive). These patients often relapse with tapering of corticosteroids. Their

c Autoantibodies Autoantibody

Clinical Features

Antisynthetase (anti-Jo-1)

20% of patients with DM and PM Acute onset in spring Association with interstitial lung disease and nonerosive arthritis Frequent relapse during prednisone taper 50/0 of PM Onset in autumn Acute weakness with myalgias Frequent myocarditis Resistance to prednisone Poor prognosis (25%. 5-year survival) 5%-10% Of DM Acute onset with florid rash Good response to immunosuppressive therapy

Anti-SRP

Anti-Mi-2

5-year survival rate is 70%, with most dying of pulmonary complications. A small number of patients with anti-Jo-1 autoantibody have no evidence of myositis but have other features of the syndrome. Patients with the anti-SW autoantibody present with the acute onset of severe PM, with myalgias in the autumn. Their disease is characterized by frequent cardiac involvement (myocarditis), resistance to immunotherapy, and poor prognosis. Almost all patients with anti-Mi-2 autoantibody (directed at a nuclear antigen) have DM and present with weakness and a florid rash (50% have the shawl sign and nearly 100% the V sign). Response to therapy is good, and the prognosis is favorable.

LABORATORY FEATURES The key laboratory features of the inflammatory myopathies are summarized in Table 108-3. Creatine kinase levels are elevated 5 to 50 times above normal in patients with PM and DM, whereas in those with inclusion body myositis, these levels usually are not elevated more than 10-fold (usually 3- to 5-fold); however, 4% to 5% of patients with active myositis can have normal levels. The erythrocyte sedimentation rate usually is normal but may be elevated in the presence of connective tissue disease or malignancy. Antinuclear antibodies are present in 15% to 47% of patients, usually those with associated connective tissue disorders. Although other enzymes including lactate dehydrogenase, the transaminases, and aldolase are also elevated in active myositis, the creatine kinase (CK) is most reliable, correlating best with clinical course and other markers of disease activity. Needle electromyography (EMG) in the acute stage of active myositis reveals myopathic-appearing motor action unit potentials (brief, small amplitude, polyphasic), which are recruited early, along with increased insertional activity, fibrillation potential activity, positive sharp waves, and complex repetitive discharges (this abnormal insertional spontaneous activity, ordinarily considered the hallmark of acute neurogenic disease, may be produced by segmental necrosis of muscle fibers causing separation of a distal fiber segment from the part carrying the endplate). An important observation is that fibrillation potentials in myositis are most common in paraspinal muscles (and in some cases are limited to the paraspinal muscles); therefore, the study of these muscles should be part of every workup for myositis. However, completely normal needle EMG is unusual and should prompt reconsideration of the diagnosis. In the chronic stages of myositis some of the motor unit action potentials are found to be high in amplitude, long in duration, and polyphasic with satellite potentials. These neurogenic changes may result from reinnervation by secondary collateral sprouting to the previously denervated muscle fiber segments. Indeed, after 2 or more years of myositis, it is common to encounter both long- and short-duration motor unit action potentials in the same muscle. Because of the chronic nature of inclusion body myositis, needle EMG often discloses these mixed myopathic and neurogenic features. The distribution of EMG findings in PM and DM follows a proximal to distal gradient, correlating to the pattern of weakness detected on clinical examination. In inclusion body myositis, however, the EMG abnormalities often are strikingly asymmetrical, multifocal, and distally predominant. Nerve conduction studies in PM and DM usually are normal except in severe or long-standing disease when there may be low motor amplitudes. In inclusion body myositis, several studies have

Chapter 108

Inflammatory Myopathy

701

TMLE 108-3. Laboratory Diagnosis of Inflammatory Myopathy Laboratoy Feature

Polymyositis or Dermatornyositis

Inclusion Bodv Myositis

Creatine kinase Erythrocyte sedimentation rate Myositis specific antibodies

Elevated (5- to 50-fold) Usually normala Anti-Jo-1 (20%) Anti-SRP (5% in PM) in DM) Anti-Mi-2 (5%-10% fibrillation potential activity Early recruitment Brief, low-amplitude, polyphasic motor unit action potentials

Elevated (3- to 5-fold. rarely >lO-fold) Usually normal” None

Electromyography

Muscle biopsy

Inflammation Necrosis and regeneration Perifascicular atrophy (in DM) ‘May be elevated in setting of connective tissue disease or malignancy. bMayalso be seen in chronic PM and DM. Abbreviations: DM, dermatomyositis;PM, polymyositis.

found a higher incidence of a mild axon loss peripheral neuropathy. EMG is an excellent gauge of disease activity. In the active phase of the myositis, there is widespread and abundant fibrillation potential activity, positive sharp waves, and increased insertional activity. With successful treatment, fibrillations and positive waves become smaller in amplitude (in contrast to the 100- to 200-pV fibrillations seen in the acute phase) and are less abundant. EMG may also be helpful in differentiating a superimposed corticosteroid myopathy or recrudescence of myositis. Evidence of membrane irritability would be evident in the former and absent in the latter.

PATHOLOGY Muscle biopsy examination is an important diagnostic tool in evaluating a patient suspected of having an inflammatory myopathy. Not only does it help exclude other potential causes for the patient’s symptoms, but it is important to differentiate between the various types because prognosis, treatment, and association with malignancy differ for each type. Pathologically, all the inflammatory myopathies are characterized by mononuclear inflammatory cell infiltrates, myofiber necrosis, and regeneration. (Because inflammatory infiltrates in muscle may be randomly scattered, a single biopsy may miss the inflammatory cells despite multiple sections. Therefore, rarely, patients with inflammatory myopathies are found to have normal muscle biopsies.) Differences in histologic appearance exist between the various forms, which help differentiate one from another. In PM, inflammatory infiltrates made up of lymphocytes (mainly CD8+), monocytes, and possibly plasma cells are found within fascicles in the endomysial connective tissue. Also commonly seen in PM and inclusion body myositis is the invasion of nonnecrotic myofibers by mononuclear inflammatory cells. DM is characterized histologically by the presence of atrophic fibers localized to the periphery of their fascicles, a feature designated as perifascicular atrophy and found in approximately 90% of juvenile patients and 50% of adult patients (Fig. 108-1). Occasionally the entire fascicle may be composed of atrophic myofibers, a pattern probably caused by microvascular ischemia. Unlike PM, the inflammatory cells are found in a perivascular distribution and in the perimysial connective tissue rather than the endomysium. Microvascular changes are prominent in this disor-

Fibrillation potential activity Early recruitment Brief, low-amplitude, polyphasic motor units High-amplitude long-duration motor unit action potentialsb Inflammation Necrosis and regeneration Rimmed vacuoles

der. There is a marked decrease in the number of capillaries per unit area within areas of perifascicular atrophy. Capillary necrosis, thrombosis, and endothelial hyperplasia may be seen. A highly characteristic electron microscopic finding is the presence of undulating tubular arrays in the endothelial cells of intramuscular capillaries. Direct immunofluorescence microscopy may show immunoglobulin (IgG, IgM) and complement (usually C3) deposits in the vasculature, and in many instances C 5 K 9 membrane attack complex deposition has been found in endomysial capillaries (Fig. 108-2). In inclusion body myositis (Fig. 108-3), the inflammatory infiltrate is located in the endomysium, simiiar to PM but differentiated from it by the presence of rimmed vacuoles (basophilic material lines the vacuoles and by electron microscopy is shown to consist of membranous whorls) and small groups of angulated fibers. Although these small fibers are reminiscent of neurogenic atrophy, the atrophy affects both fiber types, and fiber type grouping suggestive of reinnervation is rare. Additionally, there is a marked variation in fiber size (hypertrophic as well as atrophic fibers) and an increase in endomysial fibrosis highlighting the chronic nature of this myopathy. Pathognomonic inclusion body myositis is the presence of 15- to 18-nm nuclear and cytoplasmic filamentous inclusions that appear tubular and are found near the periphery of vacuoles and membranous whorls. Recently, rimmed vacuoles were found to be immunoreactive to ubiquitin, P-amyloid, prion protein, phosphorylated tau, ubiquitin, and apolipoprotein E. Mitochondrial alterations (ragged red fibers, increase in number of mitochondria, paracrystalline inclusions on electron microscopy) in addition to mitochondrial deletions have also been found in patients with inclusion body myositis.

PATHOGENESIS Although the exact mechanism of fiber damage is not completely known, there is increasing evidence of an immune pathogenesis. In DM, the intramuscular microvasculature is believed to be the primary target of humeral processes mediated by complement membrane attack complex. The earliest lesion that precedes inflammation or structural changes in muscle fibers is deposition of the C5b-9 membrane attack complex in intramuscular capillaries. Complement deposition leads to necrosis and thrombosis of capillaries, small arteries, and venules found predominantly in the periphery of the fascicle, resulting in ischemia, myofiber destruction, and perifascicular atrophy. Consistent with the notion that

Spinal Cord and PeripheralNeuromurcular Disease rn Diseases of Muscle

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B

A

FIG 108-1. Derrnatornyositis. Perifascicular atrophy is typical of derrnatornyositis and at times involves the entire fascicle (frozen section; ATPase; pH 9.6; x l 0 ) . (A) Perivascular inflammation (frozen section: hernatoxylin-eosin; x25). (6) Degenerating muscle fiber showing vacuoles and cytoid bodies (frozen section; hernatoxylin-eosin; x l 5 0 ) .

A

B

FIG 108-2. Derrnatomyositis. (A) Electron micrograph showing undulating tubular arrays in a capillary endothelial cell; *, red blood cell ( ~ 8 , 0 0 0 )( .6) Membranolytic attack complex (MAC) deposition in capillaries (frozen section; MAC antibody; xl50).

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FIG 108-3. Inclusion body myositis. Endomysial inflammatory infiltrate (lymphocytes, macrophages) surrounds nonnecrotic fiber. Chronic myopathic changes are also seen: variation in fiber size, split fiber, internalized nuclei, small groups of atrophic fibers (frozen section; hematoxylin-eosin; x50). (Inset) Rimmed vacuole in a small angulated fiber (frozen section; Gomori trichrome; XI 50).

DM is mediated largely by humeral immunity is that the inflammatory infiltrate is composed mainly of B cells and helper T cells. In PM and inclusion body myositis a cell-mediated immune mechanism is highly suspected because the majority of inflammatory cells are made up of T cells and macrophages. These cytotoxic T cells are thought to recognize antigenic targets associated with major histocompatibility complex 1 antigen in muscle fibers as they surround and destroy healthy, nonnecrotic fibers. A viral pathogenesis has also been implicated in inclusion body myositis as the filamentous inclusions resemble myxovirus nucleocapsids. Immune and degenerative mechanisms appear to be involved in the pathogenesis of inclusion body myositis, but the relative importance of each is not clear. Support for immune-mediated mechanisms comes from the observation that there is a severalfold more frequent occurrence of invasion of nonnecrotic fibers by T cells than Congo red-positive fibers. On the other hand, prednisone treatment decreases inflammation while increasing the number of vacuolated and amyloid-positive fibers, suggesting that immune mechanisms are secondary and that the disease is primarily degenerative. DIAGNOSIS Many different conditions may simulate the inflammatory myopathies. Table 108-4 lists the more common disorders and their key differentiating features. The presence of characteristic weakness and rash, CK elevation, abnormal EMG, and distinctive histopathology establishes the diagnosis of definite DM. The diagnosis of inclusion body myositis is fairly straightforward based on the clinical characteristics of long

W TMLE 108-4. Conditions That May Simulate the

Inflammatory Myopathies Disorder

Key DifferentiatingFeatures

Corticosteroid myopathy

EMG: no fibrillation potentials Normal creatine kinase Muscular dystrophy Muscle biopsy: dystrophin-deficient myofibers, dystrophin-associated (Becker, limb-girdle) glycoprotein-deficient Positive family history Psychomotor slowing, myoedema Hypothyroid myopathy High thyroid-stimulatinghormone Positive history Toxic myopathf Vacuolar myopathy, scant inflammation EMC: myotonia Acid maltase deficiency Vacuolar myopathy Biochemical confirmation on muscle HIV serum positivity HIV myopathy HIV positivity in muscle macrophages Ptosis and opthalmoparesis Myasthenia gravis Weakness, fatigability Positive Tensilon test Lambert-Eaton syndrome Autonomic component EMC: postexercise facilitation Diabetic polyradiculopathy EMG: polyneuropathy Abnormal serum glucose and hemoglobin A,, Muscle atrophy with fasciculations Amyotrophic lateral sclerosisb Hyperreflexia Neurogenic atrophy EMG: conduction block Multifocal motor neuropathy Normal (or slightly elevated) creatine kinase Clinical and electrical myotonia Myotonic dystrophy' Extramuscular manifestations 'Especially cholesterol-loweringagents chloroquine and colchicine. bMay simulate inclusion body myositis. 'Distal weakness reminiscent of inclusion body rnyositis. Abbreviations: EMG, eledrornyography; HIV, human immunodeficiency virus.

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course, distal involvement and asymmetries, the modest CK elevation, combined myopathic and neurogenic EMG, and unique histologic appearance. The main differential diagnostic consideration for inclusion body myositis usually is amyotrophic lateral sclerosis because both may present with asymmetrical, distal weakness and neurogenic motor unit potential changes on EMG. Inclusion body myositis may also be initially diagnosed as PM, usually because the muscle biopsy specimen fails to disclose the clues of rimmed vacuoles and myopathic grouping, and electron microscopy either is not done or does not reveal the characteristic cytoplasmic inclusions. The lack of response to immunotherapy leads to reconsideration of the diagnosis in these cases and may prompt a second muscle biopsy, which may allow the diagnosis to be established. The diagnosis of PM is most challenging of all. Without the characteristic cutaneous manifestations, a unique distribution of weakness, a defining EMG signature, or a specific pathologic appearance, PM may simulate dystrophies, metabolic myopathies, endocrine myopathies, toxic myopathies, and infectious myopathies. In the last few years, the presence of a myositis-specific autoantibody in patients undergoing a workup

for suspected inflammatory myopathy has assisted in establishing the diagnosis of PM. An algorithm outlining the evaluation of a patient with suspected inflammatory myopathy is proposed in Figure 108-4.

TREATMENT The natural history of PM and DM without therapy has never been formally studied. It is possible that in some patients these diseases would improve or resolve spontaneously. However, it has been our practice to institute immunotherapy (corticosteroids) in patients who are impaired in their daily activities. Patients with minimal weakness may be closely followed without specific treatment. Because of the presumed autoimmune pathogenesis of these disorders, the mainstay of pharmacologic therapy is immunosuppression. Treatment with corticosteroids has been based on empirical evidence and not on adequately controlled trials. Nonetheless, we join most investigators in the view that cortico-

Clinical features Proximal muscle weakness (also distal muscle weakness in IBM) + I - Myalgias Rash (in DM) Subacute onset (chronic in IBM) +I- Dysphagia

’ Laboratory studies Creatine kinase TSH ESR, ANA Glucose Myositis-specificautoantibodies Depending on clinical suspicion

TESWANA J Evaluate for associated connective tissue disease SS-A and SS-B antibodies Rheumatoidfactor Liver function tests Rheumatology consultation

Electromyography Include needle exam of paraspinal muscles High- and low-frequency repetitive stimulation in selected cases

1Myopathywith denewating potentials

a Muscle biopsy

If muscle biopsy shows PM or DM

6 Search for malignancy

Thorough general examination CBC, electrolytes Stool for occult blood Chest roentgenogram Mammography, pelvic ultrasound Prostate-specificantigen 9 Search for other organ involvement Chest roentgenogram Electrocardiogram Echocardiogram Pulmonary function tests

FIG. 108-4. Evaluation of suspected inflammatory myopathy.

Chapter 108 H

rn TMLE 108-5. Management of Inflammatory Myopathies Specific Therapy

Guidelines for Use

Corticosteroids (prednisone) 1 mg/kg qd for 3-4 weeks If sustained improvement for several weeks, taper slowly to 1 mg/kg qod over 10 weeks Once on qod schedule, taper by 5-1 0 mg every 3 to 4 weeks Azathioprine” If no response to prednisone after 6 to 8 weeks, begin with 50 mg PO qdb Increase by 50 mg/week to total daily dosage of 2-3 mg/kg

Supplement vitamin D and calcium Low-salt diet, antacids Follow weight, glucose, lytes Exercise program Monitor complete blood count, white blood cells, platelets, and transaminases weekly until maintenance dosage is reached Goal is absolute lymphocyte count of 1000 and mean corpuscular volume greater than 100 Follow laboratory studies every 2 months

W e prefer azathioprine; others choose methotrexate or cyclophosphamide. %is is a test dosage; 10% develop a severe flulike reaction, and the drug must be stopped.

steroid therapy is beneficial in PM and DM; inclusion body myositis differs in that it responds poorly to any type of therapy and probably accounts for PM cases previously believed to be treatment-resistant. We recommend treating patients with PM or DM whose weakness interferes with activitiesof daily living. In Table 108-5 we summarize our management strategies. We institute prednisone at 1 mg/kg per day taken as a single morning dose. Improvement usually occurs 2 to 8 weeks after initiation of therapy. It is difficult to know when to start reducing the prednisone dosage, but we generally maintain a high daily dosage for 3 to 4 weeks (unless an unacceptable side effect develops). Once a clear sustained improvement in muscle strength has occurred and the serum CK level has fallen, one can begin to gradually taper the prednisone dosage over a period of 10 weeks to 1 mg/kg every other day. If improvement has continued during the period of conversion, one can then continue to taper by 5 to 10 mg every 3 to 4 weeks until the lowest possible dosage that controls the disease is reached. A patient destined to have a good response generally shows substantial return of function in the first 4 to 6 months of treatment. In patients on long-term corticosteroid therapy, corticosteroidrelated myopathy is a consideration when an increase in weakness occurs without a major change in the CK levels, especially if the urinary creatine level is elevated. If a trial of reduced corticosteroid therapy leads to improvement in strength, the diagnosis of corticosteroid-related myopathy is confirmed. An EMG may also help to distinguish corticosteroid-related myopathy from an exacerbation of inflammatory myopathy; in the latter we expect abundant fibrillation potential activity in weak muscles, whereas in the former these potentials are generally absent. Some patients do not improve even after 3 months of corticosteroid therapy. At that point, addition of cytotoxic immunosuppressive agents such as azathioprine, cytoxan, and methotrexate probably is indicated, but although it is successful in some, in many patients improvement may be only partial and slow in coming. In refractory cases of PM, intravenous gammaglobulin was demonstrated to have a beneficial effect in uncontrolled studies. For DM, a placebo-controlled study showed dramatic improvement in muscle strength and skin rash. Repeated muscle

Inflammatory Myopathy

705

biopsies showed improvement in the muscle fiber diameters with resolution of the immunopathology. Although inclusion body myositis has been recognized for some time as a disorder refractory to immunosuppressant treatment, some investigators have reported improvement with corticosteroids. It has been our practice to carefully weigh the risks and benefits of corticosteroids and recommend a 3-month treatment trial with prednisone if the patient is otherwise healthy and is at an early stage of the disease. In our experience, a positive response to therapy is unusual. Recently, a double-blind, placebocontrotled crossover study of intravenous gammaglobulin in patients with inclusion body myositis failed to show a statistically significant improvement in overall muscle strength. However, there was a trend toward improvement in swallowing and lower limb strength, suggesting that a role may yet be found for intravenous gammaglobulin in inclusion body myositis, perhaps as a stabilizing modality. On a positive note, a recent study has shown that the inflammatory myopathy with COX-negative muscle fibers, which resembles inclusion body myositis clinically with regard to slow progression and resistance to corticosteroids, showed improved muscle strength in response to methotrexate therapy. Prognosis and Outcome

Although features such as the severity of the weakness at onset of the disease, degree of CK elevation, and extent of abnormality of the muscle biopsy do not necessarily correlate with outcome, a number of unfavorable prognostic factors have been identified. First, patients with PM and DM associated with malignancy have a significantly higher mortality rate than those without a neoplasm. Second, patients with myositis-specific autoantibodies, specifically antisynthetase autoantibodies, and anti-SRP autoantibody have a poorer prognosis and are less likely to respond to corticosteroids. Patients with anti-Jo- 1 autoantibody are at higher risk for interstitial lung disease, which may be a cause of increased morbidity and mortality. Third, patients with a delay in diagnosis greater than 18 months have a poor chance of complete response to prednisone. Fourth, in the last decade it has become clear that inclusion body myositis responds poorly, if at all, to treatment with corticosteroids and immunosuppressive agents. For patients with PM or DM who lack unfavorable prognostic factors, however, the outlook for a favorable response to treatment is good. Two thirds of the corticosteroid-treatedpatients with PM and DM improve to the point of no functional disability after 3 years of therapy. For the 20% to 30% of patients whose disease remains active despite optimum dosage and duration of corticosteroid treatment, one or more of the immunosuppressive agents mentioned in this chapter often prove helpful, and in the last few years intravenous gammaglobulin has emerged as an additional effective modality. Although discontinuation of all medication ultimately may be possible for some patients, many will need a low dosage of corticosteroids to remain asymptomatic or at least stable at a partially improved state. Indeed, PM or DM or either associated with a connective tissue disease (overlap group) may be reactivated (relapse) after a period of stability, leading to deterioration in strength, reappearance of the rash of DM, increase in CK, or some combination of features. Relapses (2 to 6 per patient) were noted in 60% of patients over periods of up to 13 years. Although they could occur at anytime during the course of the illness, they were most common during the stable stage of drug maintenance.

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CONCLUSION

SUGGESTED READINGS

The inflammatory myopathies include three distinct entities: PM, DM, and inclusion body myositis. Diagnosis of DM usually is fairly straightforward because there are very few other conditions that present with weakness and a rash. In addition, the muscle histopathology of perifascicular atrophy and capillary damage is characteristic. The diagnosis of PM is more challenging because the differential diagnosis of proximal muscle weakness is extensive. However, when weakness is joined by elevation in the level of serum CK, myopathic EMG with fibrillation potentials, and inflammatory cells surrounding nonnecrotic muscle fibers in a biopsy specimen, the diagnosis becomes more secure. When the clinician suspects PM o r DM, a careful assessment of cardiac and pulmonary function should be undertaken because of the propensity of these diseases to affect the heart and lung. In addition, searches for associated collagen vascular disorders and malignancy (especially in DM) are warranted. The diagnostic process is most difficult in inclusion body myositis because it evolves so slowly with features that may suggest a chronic neurogenic disorder. The serum CK level may be only minimally elevated, and EMG may show a complex pattern of mixed myopathic and neuropathic changes. However, the muscle histopathology of rimmed vacuoles and filamentous inclusions is fairly specific and establishes the diagnosis. The inflammatory myopathies are felt to be immune-mediated disorders, with humeral immunity playing an important role against the microvasculature in DM, whereas lymphocytes are directed against the myofibers in PM and inclusion body myositis. Although still predominantly used as a research tool, the recently discovered myositis-specific autoantibodies will help identify patients with associated pulmonary and connective tissue disorders and possibly help predict their clinical course. The treatment of PM and DM with prednisone usually is gratifymg, especially if it has been instituted early in the courses of these diseases. Unfortunately, inclusion body myositis often is refractory to any of the traditional immunotherapies, but it is critically important to recognize this condition, thereby avoiding prolonged use of potentially toxic therapies.

Callen J P Dermatomyositis and malignancy. Clin Dermatol 11:61, 1993 Carpenter S, Karpati G: The major inflammatorymyopathies of unknown cause. Pathol Annu 16205, 1981 Dalakas M C Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis. Neurology 51(Suppl 5):537-545, 1998 Dalakas M C Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 325:1487-1498, 1991 Dalakas MC, Sonies B, Dambrosia J et ak Treatment of inclusion-body myositis with IVIG: a double-blind, placebo-controlled study. Neurology 48~712-716, 1997 Devere R, Bradley WG: Polymyositis: its presentation, morbidity and mortality. Brain 98:637, 1975 Gonzalez-LopezL, Gomez-Nara JI, Sanchez L et al: Cardiac manifestations in dermatopolymyositis. Clin Exp Rheumatol 14373-379, 1996 Haupt HM, Hutchins GM The heart and cardiac conduction system in polymyositis-dermatomyositis:a cliiicopathologic study of 16 autopsied patients. Am J Cardiol 50:998, 1982 Hochberg MC, Feldman D, Stevens MB Adult onset polymyositisl dermatomyositis: an analysis of clinical and laboratory features and survival in 76 patients with a review of the literature. Semin Arthritis Rheum 15168-178, 1986 Lacomis D, Oddis CV: Myositis-specific and -associated autoantibodies: a review from the clinical perspective. J Clin Neuromuscul Dis 2( 1):3440, 2000

Levine TD, Pestronk A Inflammatory myopathy with cytochrome oxidase negative muscle fibers: methotrexate treatment. Muscle Nerve 21: 1724-1728, 1998

Mastaglia FL, Ojeda VJ: Inflammatory myopathies. Ann Neurol 12215, 317, 1985

Phillips BA, Zilko P, Garlepp MJ, Mastaglia F L Frequency of relapses in patients with polymyositis and dermatomyositis. Muscle Nerve 21: 1668-1672, 1998

Rowland LP, Clark C, Olarte M: Therapy for dermatomyositis and polymyositis. p. 451. In Griggs RC, Moxley RT (eds): Advances in Neurology. Vol. 17. Raven Press, New York, 1977 SigurgeirssonB, Lindelof B, Edhag 0 et ak Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 326363, 1992 Stonecipher MR, Callen JP, Jorizzo I L The red face: dermatomyositis. Clii Dermatol 11:261, 1993 Targoff IN: Immune manifestations of inflammatory muscle disease. Rheum Dis Clin North Am 20:857-880. 1994

Chapter 109 rn Endocrine, Nutritional, and Drug-Induced Myopathies

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109 Endocrine, Nutritional, and Drug-Induced

Myopathies This chapter describes the skeletal muscle disorders associated with hyperfunction and hypofunction of the adrenal, thyroid, parathyroid, and pituitary glands. Iatrogenic steroid myopathy and its differentiation from inflammatory myopathy are discussed. Muscle weakness associated with osteomalacia, alcohol abuse, and medication side effects are also discussed. The muscle disorders associated with endocrine disorders are summarized in Table 109-1 and the toxic myopathies in Table 109-2.

ADRENAL DYSFUNCTIONAND IATROGENIC STEROID MYOPATHY Glucocorticoidand Adrenocorticotropic Hormone Between 50% and 80% of patients with Cushing’s disease and up to 21% of patients treated with glucocorticoids for more than 6 months develop weakness and myalgias insidiously. Proximal leg

weakness and myalgias are most common, and cranial nerveinnervated muscles and sphincters usually are spared. Serum levels of muscle-associated enzymes (lactate dehydrogenase, serum glutamic oxaloacetic transaminase, creatine kinase [ CK], and aldolase) usually are normal. Patients with Cushing‘s disease and iatrogenic steroid myopathy share similar clinical and biochemical profiles. Patients with glucocorticoid-induced myopathy usually manifest at least one of the following signs of glucocorticoid excess: moon facies, buffalo hump, fragile skin, or osteoporosis. Electromyographic (EMG) findings are variable. Typically, insertional activity is normal, and the motor unit potentials are either normal or of low amplitude and short duration. Muscle biopsy may show selective atrophy of type 2 muscle fibers. Glucocorticoids alter muscle carbohydrate and protein metabolism and may interfere with intracellular calcium homeostasis. Although the exact interaction of steroid-induced metabolic and physiologic changes in producing steroid myopathy is not precisely

rn TAW 10B-1. Summary of Endocrine Myopathiies Metabolic Disorder

Pattern of Weakness

Serum Level of Muscle Enzymes

Glucocorticoid excess

Proximal

Normal

Adrenal insufficiency

Generalized and cramping

Normal

Hyperthyroidism

Usually normal; may be elevated in thyroid storm

80% have short-duration motor

Thyrotoxic periodic paralysis Endocrine ophthalmopathy

Proximal weakness out of proportion to atrophy; bulbar involvement flaccid generalized weakness Limited to extraocular muscles

Normal

Impaired muscle fiber excitability

Hypothyroidism

Proximal weakness

Elevated

Growth hormone excess

Proximal weakness with minimal atrophy

Slightly elevated

Hypopituitarism

Usually normal

Hyperparathyroidism

Severe weakness and fatigability Proximal and atrophic bulbar and sphincter muscles are spared

Normal

Decreased motor unit potential sizes; increased frequency of polyphasic potentials with activity

Osteomalacia

Proximal weakness, wasting, myalgia

Usually normal

Short duration, low-amplitude polyphasic motor unit potentials

Hypoparathyroidism

Tetanic mild weakness

Mildly elevated

Electromyographic

Other

Normal or motor unit potentials are of low amplitude and short duration Normal

Buffalo hump, fragile skin, osteoporosis

unit potentials

Usually normal or mildly elevated Usually normal, but lowamplitude polyphasic motor unit potentials, increased insertional activity, and positive waves may be seen 50% of patients have myopathic changes; hypertrophic neuropathy and nerve entrapment of median nerve may also be present

Exercise or excessive K+ intake may result in flaccid quadriparesis May be associated with myasthenia gravis Usually associated with hypokalemia May be unilateral or bilateral; patient may be hyperthyroid, euthyroid, or hypothyroid Myoedema

Nerve entrapments are common

Primary hyperparathyroidism has increased [Ca] and alkaline phosphatase, reduced [PO,’-], and brisk reflexes

Decreased [Ca] and [Mgl; distal numbness

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TAFILE109-2. Summary of Toxic Myopathies Toxic Causes

Pattern of Weakness

Serum Level of Muscle Enzvmes

Other Considerations

Prescribed Medicationsand Vi mi n s

Lovastatin, clofibrate, bezafibrate, etofibrate, biclofibrate, and gemfibrozil

Weakness, cramps, tenderness, painful proximal myopathy

Elevated

Labetalol

Generalized

Elevated

€-Amino caproic acid

Elevated

Emetine

Axial and proximal muscles Progressive proximal muscle wasting Proximal and axial

Colchicine Vincristine

Proximal Proximal

Elevated Usually not elevated

D-Penicillamine Procainamide

Proximal myopathy Proximal

Elevated Elevated

Cyclosporine

Generalized

Usually mild elevation

Hypervitaminosis E

Proximal and painless

Elevated

Vitamin E deficiency

Mild elevation

Etretinate

Generalized, including extraocular Proximal

isotretinoin

Proximal

Chloroquine

Elevated Elevated

Myotonia may develop with clofibrate and related agents; lovastatin and clofibrate rnyopathies most likely to occur with renal failure or hypothyroidism; ”statin” agents in combination with CYP3A inhibitors may induce rhabdomyolysis Other P-adrenergic agents can exacerbate myasthenia gravis (blockers) or myotonia p2agonists or blockers) Therapy duration more than 4 weeks; disseminated proximal muscle fiber necrosis on biopsy Myopathy after patients take at least 500 muday for at least 1 year Reversible and related to dosage and duration of therapy Associated with sensory neuropathy Neuropathy is a more common side effect of this agent Resembles polymyositis; may involve myocardium interstitial myositis as part of drug-induced lupus syndrome Myopathy may be severe when used with lovastatin or colchicine Usually occurs when the patient overuses an overthe-counter preparation Usually associated with lipid malabsorption

Usually mild elevation or normal Usually mild elevation or normal

Myalgias present; may need to distinguish from psoriatic arthritis Arthralgias may also be present

May be focal or generalized May be focal or generalized Generalized

Elevated

Myoglobinuria may develop from myoischemia

Elevated

Muscle necrosis usually develops as a consequence of pressure necrosis Muscle injury may be a consequence of overactivity

Generalized or focal; pain is prominent Generalized flaccid weakness Proximal

Elevated

Nonprescription Drugs

Cocaine Heroin Phencyclidine

Elevated

Ethanol

Acute necrotizing myopathy Acute hypokalemia myopathy Chronic myopathy

May be normal or slightly elevated Elevated

known, it appears that the net result of glucocorticoids is to induce muscle protein catabolism. Steroid myopathy is treated by decreasing the steroid dosage to the lowest possible level, adapting an alternate-day dosing schedule, and converting to a nonfluorinated steroid. Exercise may be useful in preventing and treating muscle weakness and wasting in patients receiving glucocorticoids. Recovery may take many weeks. Acute illness myopathy, which is clinically manifest by a flaccid quadriplegia developing in critically ill patients, may occur in association with administration of high-dose systemic glucocorticoids (as for status asthmaticus or after organ transplant). Factors that may contribute to the rapid development of myopathy are immobility, use of nondepolarizing neuromuscular blocking agents, and concurrent sepsis. As in steroid myopathy, there is significant muscle protein catabolism, but here it is potentiated by sepsis (which also induces muscle catabolism) and by muscle inactivity that is initially caused by neuromuscular blockade and subsequently by muscle membrane inexcitability.

Myoglobinuria may result in renal failure in severe cases May be painful when associated with hypomagnesemia Mav represent a combination of ethanol-induced damage and poor nutrition

Elevated levels of adrenocorticotropic hormone may be myopathic. Some patients treated for Cushing’s disease with bilateral adrenalectomy develop hyperpigmentation and either clinical, EMG, or biopsy evidence of myopathy despite adequate glucocorticoid replacement. Their myopathy differs pathologically and clinically from steroid myopathy. Proximal weakness and wasting may develop up to 1 year after adrenalectomy. The exact mechanism of adrenocorticotropic hormone-induced myopathy is not known at this time.

GlucocorticoidVersus Inflammatory Myopathy Steroid myopathy may be difficult to distinguish from inflammatory myopathy; however, some clinical clues may help. Weakness that occurs within 4 weeks of the onset of steroid treatment probably is caused by a flare in the inflammatory process and is best treated by continuing or increasing the glucocorticoid dosage. Elevated muscle enzymes suggest a flare of the inflammatory myopathy, but normal enzyme levels may be observed with an

Chapter 109 W

inflammatory myopathy. Weakness without any other signs of steroid use probably is caused by inflammation. Muscle biopsy distinguishes inflammatory myopathy from steroid myopathy only if active inflammation is found.

Adrenal Insufficiency Adrenal insufficiency may cause severe generalized weakness, muscle cramping, and fatigue in approximately 25% to 50% of patients. Addison’s disease may also produce respiratory muscle weakness and precipitate myasthenia gravis. The weakness and fatigue usually correct rapidly with glucocorticoid replacement. The serum levels of muscle-associated enzymes usually are normal, as are the EMG findings. Muscle biopsy is unremarkable except for diminished glycogen content. Patients with primary adrenal insufficiency may develop flaccid quadriparesis associated with hyperkalemia. The disorder is triggered by potassium intake or exercise and resolves with lowering the serum potassium by glucose administration or glucocorticoid replacement. Contributing factors to muscle weakness and fatigability in adrenal insufficiency are circulatory insufficiency (exerciseinduced hypotension), fluid and electrolyte imbalance (hyponatremia, hyperkalemia, and hypovolemia), impaired carbohydrate metabolism, and starvation. The treatment for Addisonian myopathy is glucocorticoid and mineralocorticoid replacement.

THYROID DISEASE Hyperthyroidism Hyperthyroidism can cause weakness that usually begins several months after the onset of thyrotoxicosis. Proximal weakness is common and is often out of proportion to muscle atrophy. Arms may be affected more than legs, which results in scapular winging and shoulder girdle wasting. Distal weakness can occur but usually develops later and is less severe than proximal weakness. Severe atrophy can occur in some patients. A prospective study found that weakness evolved rapidly early in the course of the disease, it resolved completely within the first months of treatment, and improvement correlated better with serum free thyroxine levels than with serum CK. Thyrotoxic patients commonly complain of fatigue, exercise intolerance, myalgias, and breathlessness. Respiratory insufficiency necessitating ventilatory support may occur. Bulbar muscles and the esophagus may be involved. Sphincters usually are spared. Serum levels of CK, serum glutamic oxaloacetic transaminase, lactate dehydrogenase, and myoglobin usually are normal or low. However, in thyroid storm, serum CK may be extremely high in association with rhabdomyolysis. Weakness and atrophy are proportional to the duration of illness. Thyrotoxicosis causes biochemical and electrophysiologic derangements in muscle that result in reduced efficiency of contraction, which is consistent with the clinical observation that weakness usually is more severe than atrophy. The sudden onset of generalized weakness with bulbar palsy in thyrotoxic patients may be acute myasthenia gravis, and a Tensilon test and anti-acetylcholine receptor antibody titers are warranted. There is a significantly greater incidence of thyroid disorders in patients with myasthenia gravis than expected by chance: 5.7% of myasthenic patients are hyperthyroid, 5.3% are hypothyroid, and 2.1% have nontoxic goiter. In addition, 8% to 17% of euthyroid myasthenic patients have circulating antithyroid antibodies. The

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incidence of thyroid disease in the general population is only approximately 1.5%. Conversely, approximately 0.35% of patients with hyperthyroidism have myasthenia gravis, which is 30 times higher than the prevalence of myasthenia gravis in the general population. Thyrotoxicosis usually precedes or develops simultaneously with myasthenia gravis. Rarely, signs of thyrotoxicosis appear after myasthenia gravis is diagnosed. Both hyperthyroidism and hypothyroidism worsen the course of myasthenia gravis. Thyrotoxic myopathy is treated by returning the patient to the euthyroid state. P-Adrenergic blocking agents may improve muscle strength, especially of respiratory muscles. Glucocorticoids block the peripheral conversion of thyroxine to triiodothyronine and may be useful in the acute treatment of thyrotoxicosis.

Thyrotoxic Periodic Paralysis Thyrotoxic periodic paralysis, a complication of thyrotoxicosis, is clinically manifested as weakness lasting minutes to days that is either generalized (proximal more than distal) or involves groups of muscles that were recently exercised or cooled. Bulbar and respiratory muscles are involved later or are spared. Occasionally, respiratory function may be compromised during severe attacks. Sphincters usually are spared. Serum potassium usually is decreased during the attack. However, normokalemia has been reported. Serum phosphate may also be reduced. Most cases of thyrotoxic periodic paralysis are sporadic, whereas the majority of cases of hypokalemic periodic paralysis are familial. The age of onset is older than 20 in more than 90% of patients of thyrotoxic periodic paralysis, whereas 60% of patients with familial hypokalemic periodic paralysis have their first attack before 16 years of age. The male:female ratio is approximately 6:l in thyrotoxic periodic paralysis and 3:l in familial hypokalemic periodic paralysis. Most of the reported cases of thyrotoxic periodic paralysis have occurred in Oriental patients and Native Americans, whereas familial hyperkalemic periodic paralysis is uncommon in Orientals. The mainstay of treatment of thyrotoxic periodic paralysis is to return the patient to a euthyroid state. Propranolol alone successfully prevented paralytic attacks in some cases. Mild exercise may abort an impending attack. The treatment for acute paralytic attacks is potassium replacement, respiratory support, and airway protection.

Endocrine Ophthalmopathy Thyroid ophthalmopathy (TO) may be considered under the rubric of endocrine myopathy in that the extraocular muscles are the major target of an autoimmune attack (although this attack is believed to be directed against their supporting connective tissue rather than the muscle fibers themselves), and the cardinal features of thyroid orbitopathy largely reflect resultant enlargement of the extraocular muscles. These features include lid retraction and lid lag, chemosis and conjunctival injection, proptosis, restrictive ophthalmoplegia, compressive optic neuropathy, and exposure keratopathy. Orbital inflammation with edema, in conjunction with accumulation of glycosaminoglycans and orbital fat, accounts for much of this picture; uncommonly, the enlarged extraocular muscles compress the optic nerve at the apex, resulting in insidious visual loss. The restrictive ophthalmoplegia of TO, which is often asymmetrical, results from chronic inflammation leading to fibrosis of the extraocular muscles, with a tethering effect such that duction cannot be forced manually by the examiner. There is

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a predilection for the medial and inferior recti, thus limiting movements away from their fields of action (i.e., abduction and elevation). Most patients with TO have other features of thyroid dysfunction; it is estimated that about 90% have Graves’s disease, 5% have Hashimoto’s thyroiditis, and 5% do not have readily explainable thyroid disease. Up to 45% of patients with Graves’s disease have some (often mild) features of TO, but fewer than 10% exhibit severe orbitopathy. TO is essentially a clinical diagnosis made when some or all of the clinical features just noted are found in a patient with abnormal thyroid function studies. Women, smokers, and patients who have received radio-iodine treatment or lithium therapy are at higher risk for developing TO than the general population. In the absence of laboratory evidence of thyroid dysfunction, one must consider other causes of orbitopathy and specifically of restrictive ophthalmoplegia, including tumors, infiltrative processes, and trauma to the orbit. Computed tomography or magnetic resonance imaging scans through the orbit may or may not show extraocular muscle enlargement. Elevating the head of the patient’s bed may alleviate orbital congestion because fluid tends to accumulate overnight. Corneal protection may be achieved with artificial tears and ocular lubricants, although some patients may need lid surgery. Surgery has also been used to correct strabismus, but patching of one eye is an easier and more conservative means of addressing diplopia. High-dose oral glucocorticoid therapy generally is the first treatment modality tried in compressive optic neuropathy. Decompressive surgery and (for patients considered to be poor surgical candidates or intolerant of long-term steroids) orbital radiation are the other options. Surgical orbital decompression is indicated if visual loss is not responsive (within a period of several days, generally) to glucocorticoids; however, surgery does not address the underlying inflammatory process, and the procedure often worsens restrictive ophthalmoparesis. Hypothyroidism

Hypothyroid myopathy manifests with insidious proximal weakness and muscle stiffness, slowed tendon reflexes (classically a prolonged relaxation time of the ankle jerk), and less commonly cramps and muscle enlargement; the triad of muscle stiffness, cramps, and muscle enlargement in the context of hypothyroidism is Hoffman’s syndrome. Myoedema is the mounding of muscle after light percussion and is present in about a third of patients but is also found in malnutrition states. Rarely, respiratory muscle weakness or rhabdomyolysis is seen. Patients with hypothyroid myopathy commonly have coexisting peripheral or entrapment neuropathies; a recent prospective study found evidence of sensorimotor axonal neuropathy in about 40% of patients evaluated and carpal tunnel syndrome in about 30%. Serum CK is elevated in most hypothyroid patients regardless of whether myopathy is clinically present; this elevation may be up to 10 times normal levels. Serum CK does not correlate with severity of weakness. Electromyography may show myopathic motor units but is often normal. Muscle biopsy may show type 2 fiber atrophy but is nonspecific for the diagnosis. Impaired carbohydrate metabolism may limit force generation in hypothyroidism. Repair and replacement of myofibrillar proteins may be limited by reduced protein turnover. Slow contraction and relaxation appear to reflect diminished myosin ATPase activity and impaired calcium uptake by the sarcoplasmic reticulum. Diminished cardiac output and reduced P-adrenergic sensi-

tivity may contribute to exercise intolerance. As in hyperthyroidism, multiple biochemical and physiologic derangements reduce muscle efficiency in hypothyroidism. Treatment consists of returning the patient to the euthyroid state with hormone replacement. Patients generally make a good, if gradual, recovery, although it has recently been suggested that the weakness of hypothyroidism is more resistant to treatment than that of hyperthyroidism. Rare cases of hypothyroid myopathy refractory to thyroid replacement have been found to represent proximal myotonic myopathy. Hypothyroidism may unmask proximal myotonic myopathy in genetically susceptible patients. Pituitary Dysfunction Growth Hormone Excess. Acromegalic patients may develop an insidious onset of proximal weakness with minimal muscle wasting. Serum levels of CK or aldolase may be slightly elevated. Approximately 50% of acromegalic patients have myopathic EMG changes. Diffuse hypertrophic neuropathy or nerve entrapment, usually of the median nerve, develops in about half of acromegalic patients. Thus, it is possible to find myopathic changes in the deltoid and neuropathic changes in the opponens pollicis. The neuropathy and myopathy develop independently and follow separate courses. Despite increased fiber diameter, acromegalics have decreased force-generating capacity. Decreased sarcolemrnal excitability and reduced myofibrillar adenosine triphosphatase activity may contribute to the weakness. Impaired carbohydrate metabolism and possibly restricted muscle blood flow may also partially explain the fatigability. The exact cause of growth hormone excess myopathy is not clear. The myopathy usually resolves after growth hormone levels return to normal. Surgical removal is the currently preferred treatment for growth hormone-secreting pituitary tumors. Focused a-radiation is an alternative treatment, particularly for large tumors. Bromocriptine may be useful as an adjunct to surgical therapy or radiotherapy. Pituitary Insufficiency. Pituitary failure in adults (Simmonds’s disease) causes severe weakness and fatigability with disproportionate preservation of muscle mass. Thyroid and adrenal cortex hormone loss are primarily responsible for the myopathy, with less of a contribution from growth hormone loss. The causes of adult panhypopituitarism include thrombosis of the pituitary circulation, pituitary or hypothalamic tumors, head injury, granulomatous destruction, and meningitis. In adults, the major deficits stem from loss of thyroid and adrenal corticoid hormones, and treatment therefore is appropriate replacement. However, children need growth hormone for normal muscle development.

PRIMARY AND SECONDARY HYPERPARATHYROIDISM AND METABOLIC BONE DISEASE Primary Hyperparathyroidism Primary hyperparathyroidism commonly results in symmetrical proximal weakness and atrophy. Patients often complain of weakness and fatigability, and severely affected patients may have a waddling gait or be unable to walk. The bulbar muscles and sphincters usually are spared. Tendon reflexes may be brisk. Significant laboratory findings include elevated urinary creatine excretion and normal levels of CK and aldolase. Serum alkaline phosphatase and calcium concentrations are elevated, and the

Chapter 109

serum phosphate is low. The severity of the weakness does not correlate with serum calcium or phosphate concentrations. In addition to myopathy, a peripheral neuropathy occurs in some patients with hyperparathyroidism. Parathyroidectomy appears to alleviate symptoms and improve strength.

Secondary Hyperparathyroidism A resistance to the metabolic actions of parathyroid hormone results in secondary hyperparathyroidism. This may lead to a myopathy that is indistinguishable from primary hyperparathyroidism. Chronic renal insufficiency is also a common cause of secondary hyperparathyroidism and myopathy. Parathyroid hormone excess, uremic toxins, vitamin D deficiency, aluminum toxicity, and carnitine deficiency have all been implicated in the pathogenesis of this myopathy. Osteomalacia secondary to malnutrition, malabsorption of vitamin D, or abnormal vitamin D metabolism may present as proximal muscle weakness, atrophy, and myalgias. The clinical presentation is also similar to that of primary hyperparathyroidism. Despite their diverse causes, the muscle disorders associated with primary or secondary hyperparathyroidism and osteomalacia appear to result from elevation in parathyroid hormone (primary and secondary hyperparathyroidism) or impaired action of vitamin D (secondary hyperparathyroidism and osteomalacia). Treatment of these disorders is directed at removing the primary cause. Consequently, patients with primary hyperparathyroidism improve with removal of the adenoma, and the myopathy of osteomalacia improves with vitamin D replacement. Patients with chronic renal failure may benefit from partial removal of hyperfunctioning parathyroid glands and treatment with 1,25(OH),D, or 1-OH-D3,which can be converted in the lung to 1,25(OH),D,. Renal transplantation may improve weakness.

Hypoparathyroidism and Pseudohypoparathyroidism Hypoparathyroidism is most commonly caused by inadvertent surgical excision of the parathyroid glands or damage to their vascular supply. Idiopathic hypoparathyroidism can exist as an isolated entity, in association with thymic agenesis (DiGeorge’s syndrome), or as part of a familial condition associated with deficiency of adrenal, thyroid, and gonadal function. Pseudohypoparathyroidism is a defective cellular response to parathyroid hormone associated with a normal or elevated level of parathyroid hormone. It is characterized by signs of hypoparathyroidism in association with distinctive skeletal anomalies and often intellectual impairment. In both pseudohypoparathyroidism and true hypoparathyroidism, patients are hypocalcemic and hypomagnesemic, and the most commonly associated muscle disorder is tetany. Hypomagnesemia or hypocalcemia results in hyperexcitability of nerve fibers. This is manifested as perioral and distal paresthesias, carpopedal spasm, and diffuse muscle cramping. In severe cases, laryngeal muscle spasm can occur. The treatment of choice is intravenous infusion of calcium at 15 to 20 mg/kg body weight over 4 to 6 hours. In severe cases accompanied by seizures, 1 to 2 ampules of calcium gluconate can be administered by slow intravenous push with simultaneous monitoring of heart rate and blood pressure. If hypomagnesemia is present, 1 g magnesium sulfate can be given by slow intravenous push. The magnesium dosage must be reduced in the presence of renal insufficiency.

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Chronic treatment of hypocalcemia includes dietary supplementation of vitamin D and 2 to 5 @day of elemental calcium. Magnesium supplementation is needed to treat hypomagnesemia. Myopathy rarely complicates hypoparathyroidism. Weakness and creatine phosphokinase elevation may be mild, and muscle biopsy may be normal or show atrophic fibers. In addition to correcting hypocalcemia, hypomagnesemia, and hyperphosphatemia, calcium supplementation and vitamin D treatment help correct the myopathy. A similar syndrome has been described in patients with pseudohypoparathyroidism who had elevated serum CK and lactate dehydrogenase activity without weakness. The serum levels of muscle-associated enzymes are normalized with calcium and vitamin D treatment. The relationship between these syndromes and hypoparathyroidismor pseudohypoparathyroidismis unclear. Some patients with mitochondrial myopathy have associated hypoparathyroidism. TOXIC MYOPATHIES

PrescriptSonMedications Myalgia, or muscle cramping, has been reported with a large number of medications, including captopril, cimetidine, clofibrate, clofibride, colchicine, cytotoxic agents (particularly in a setting of cachexia), danazol, diuretics (particularly in association with hypokalemia), D-penicillamine, enalapril, ethylchorvynol, gold, lansoprazole, isoetharine, labetalol, lithium, L-tryptophan, mercaptopropionylglycine, metolazone, nifedipine (and other similar calcium channel blockers), pindolol, procainamide (with or without a drug-induced lupus syndrome), rifampicin, salbutamol, suxamethonium, azidothymidine (AZT), and zimeldine. Painless proximal myopathy is seen with chloroquine and occasionally with amiodarone (which more commonly causes peripheral neuropathy). Rhabdomyolysis is associated with a number of illicit drugs but also with commonly prescribed agents, including clozapine. A focal fibrous myopathy with “woodenhard” muscles is described with repeated intramuscular injections of pentazocine. Some more common medication-induced myopathic conditions are considered in greater detail here. Hypocholesterolernic Drugs. Lovastatin, a 3-hydroxy-3methylglutaryl-coenzyme A reductase inhibitor, rarely causes a myopathy when used alone. One large study of patients monitored for 4 years on combination therapy of simvastatin or pravastatin with gemfibrozil or ciprofibrate did not identify a single patient with myopathy or rhabdomyolysis. However, when statin agents are used with gemfibrozil or cyclosporine, myopathy is more likely to develop. Patients with severe hepatobiliary dysfunction or renal insufficiency may be at a higher risk of developing a myopathy when using lovastatin alone. Rhabdomyolysis is appreciated when such “statin” drugs are used with CYP3A4 inhibitors (ketoconazole, itraconazole, macrolide antibiotics, nefazodone, ritonavir, grapefruit juice). Clofibrate and related agents (bezafibrate, etofibrate, biclofibrate, lovastatin, and gemfibrozil) may induce a myopathy characterized by the acute onset of cramps, weakness, and tenderness, with an elevation of serum transaminases and CK. Myotonia may develop in some patients in response to hypocholesterolemic agents, especially clofibrate. Accumulation of the active metabolite of clofibrate, chlorophenoxyisobutyric acid, may occur in renal failure, nephrotic syndrome, and hypothyroidism and may cause the myopathy. Some patients may also have an associated peripheral neuropathy. Decreasing the dosage or halting the drug will be followed by gradual recovery.

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Medications That Act on the Autonomic Nervous System.

Labetalol, a selective a- and nonselective 0-adrenergic receptor blocker, may produce a severe generalized myopathy with markedly elevated CK that improves with discontinuation of the medication. p-Adrenergic blockers may interfere with neuromuscular transmission and exacerbate myasthenia gravis. Some p,-selective blockers or agonists can exacerbate myotonia. Other Prescription Medications. E-Aminocaproic acid inhibits fibrinolysis and has been used in different bleeding disorders. A myopathy affecting axial musculature whose symptoms begin 4 or more weeks after initiation of treatment is an uncommon complication. The cause may be altered muscle membrane function or ischemia to the muscles. Chloroquine is an antimalarial agent that may cause a myopathy after treatment with at least 500 mg/day for at least 1 year. Progressive painless proximal muscle wasting and weakness are characteristic. An associated neuropathy and cardiomyopathy may occur. The myopathy is slowly reversible after discontinuation of the medication. Clozapine, an atypical neuroleptic, is described to cause rhabdomyolysis in the absence of traditional risk factors for the condition. It is speculated that defects in calcium-dependent potassium channels may predispose certain patients to this complication. Emetine has been used as an amebicide, as an emetic in acute poisoning, and in alcoholic aversion therapy. Proximal limb and trunk muscles are primarily affected, but a generalized myopathy may also ensue. The degree of muscle damage depends on the dosage of emetine and the duration of exposure. Emetine myopathy is reversible. Colchicine may induce a proximal myopathy, especially in patients with renal insufficiency. Distal sensory involvement secondary to axonal neuropathy is common. Plasma colchicine and CK usually are elevated. Discontinuation of colchicine improves strength and the sensory neuropathy. Although vincristine commonly causes an axonal peripheral neuropathy, some patients develop a proximal myopathy. These side effects are dose-related and usually disappear 6 weeks after finishing treatment. However, some patients continue to have symptoms for a prolonged time. D-Penicillamine can cause an inflammatory myopathy that is indistinguishable from polymyositis. Immunoregulatory mechanisms may be altered by this medication, and anti-Jo-1 antibodies, previously considered specific for idiopathic myositis, may be found in the penicillamine-induced myositis. Myocardial involvement may be fatal. Halting the drug results in recovery. Various other agents, including nonsteroidal anti-inflammatory drugs and HMG-CoA reductase inhibitors (“statins”) may rarely cause dermatomyositis. Procainamide may cause interstitial myositis as part of a lupus-like vasculitic reaction. Drug-induced lupus with associated myalgias has also been reported with minocycline. Zidovudine (AZT) causes a progressive, painful mitochondrial myopathy. CK is normal or only moderately elevated. Human immunodeficiency virus myositis can resemble polymyositis with inflammatory infiltrates. AZT myopathy may be caused by impaired mitochondrial function. Ragged red fibers can be found in AZT myopathy, but inflammatory infiltrates usually are not present. A clear clinical and pathologic distinction between AZT myopathy and human immunodeficiency virus myositis may not be possible to make. Recent investigations suggest that AZT may not cause myopathy; however, it may nonetheless be prudent to

consider a trial off the medication, when the patient’s condition permits. Cyclosporine by itself may result in a mild myopathy; however, cyclosporine in combination with lovastatin or colchicine may produce a more severe myopathy with rhabdomyolysis. Animal studies demonstrated cyclosporine-induced mitochondrial dysfunction, which may underlie the myopathy. Vitamins and Related Agents. Hypervitaminosis E may result in proximal muscle weakness and elevated serum CK. Etretinate is a vitamin A derivative that is used to treat psoriasis. Skeletal muscle damage is an uncommon side effect and is manifested as proximal muscle weakness and tenderness. Isotretinoin is used to treat severe acne. Mild and transient arthralgias and myalgias occasionally can be seen. Niacin has also been implicated as a cause of myopathy. Miscellaneous Agents. Organophosphate exposure usually results in a neuropathy; however, a myopathy may also result secondary to increased neurotransmitter in the neuromuscular junction. Hypokalemic myopathy may be a consequence of numerous causes. Weakness, hypotonia, and depressed deep tendon reflexes from hypokalemia may result from treatment with laxative overdose, thiazide diuretics, mineralocorticoids, and toluene abuse. Weakness in the proximal muscles can develop quickly and can progress to flaccid paralysis of the limbs. Serum CK usually is elevated. Potassium replacement usually results in complete recovery. Illicit Drugs

Cocaine abuse may be associated with myoglobinuria, either as a direct toxic effect or secondary to associated ischemia. Overdose of other sympathomimetic drugs, such as amphetamines, may result in acute rhabdomyolysis and resultant myoglobinuric renal failure. This has been described in many instances with the popular drug of abuse MDMA (3,4-methylenediaminometh-amphetamine,or “Ecstasy”). Phencyclidine ingestion may also cause myoglobinuria and acute renal failure. Excessive isometric motor activity may be the cause of phencyclidine myopathy because the drug does not appear to have a direct toxic effect on muscle. Another hallucinogen of abuse (the incidence of which may be increasing), ketamine, may produce agitation and rhabdomyolysis. Depression of consciousness associated with heroin ingestion may result in pressure-induced muscle injury. Chronic intramuscular heroin injection may cause a focal myopathy characterized by fibrotic and inflammatory changes. The myopathy may reverse within 6 months on a regimen of corticosteroids, D-penicillamine, and physical therapy. Ethanol-AssociatedMyopathies

Ethanol is myotoxic. Acute, hypokalemic, and possibly chronic myopathies occur among alcoholics. Acute necrotizing myopathy commonly occurs with a background of chronic alcohol abuse. Excessive ingestion of alcohol results in noninflammatory muscle necrosis characterized as an acute onset of severe muscle pain, cramps, weakness, swelling, and tenderness. This myopathy may be generalized or focal. When occurring in the calves, this myopathy can resemble venous thrombophlebitis. Recovery depends on the extent of muscle destruction and may take several months. Severe cases may result in acute renal failure.

Chapter 110 rn Metabolic Myopathies

Acute hypokalemic myopathy is a complication of chronic alcoholism. The acute onset of painless weakness in the proximal limb muscles or limb girdle muscles without muscle cramps, tenderness, or swelling is characteristic. Serum CK and aldolase are elevated, and serum potassium is low. The potassium loss may occur through vomiting and diarrhea. Hypokalemia can also develop from alcohol-induced hypomagnesemia. When the patient is hypokalemic and hypomagnesemic, the myopathy often is painful. Strength improves with potassium and magnesium replacement. Protracted high-dose alcohol consumption may cause a progressive deterioration of skeletal muscle function, and a chronic myopathy is estimated to affect up to one third of chronic alcohol abusers. However, alcoholics are also at risk for peripheral neuropathies, which may confound assessment of “myopathic” weakness. Typically, the myopathy manifests as mild proximal weakness and muscle wasting, often with elevated serum muscle enzymes. Biopsy may reveal type 2 fiber atrophy. Cardiomyopathy and hepatic cirrhosis may be more common in patients with chronic alcoholic myopathy than in alcoholics without clinical myopathy. Abstinence appears to result in at least partial recovery of strength, and a recent study found that chronic alcoholics who continued to consume moderate dosages (up to 60 g ethanol daily) exhibited some recovery of strength as well. Thus, the degree of functional recovery from chronic alcoholic myopathy seems to be inversely proportional to alcohol consumption.

Nutritional Myopathies The impact of vitamin D deficiency, or osteomalacia, on skeletal muscle is discussed earlier in this chapter. Vitamin E deficiency may result in generalized muscle weakness, including ocular muscles.

Acute Myonecrosis IncludingBites and Stings Severe myonecrosis can occur as a consequence of general anesthesia, status epilepsy, or prolonged unconsciousness, and in the latter case it is probably caused by pressure necrosis. In addition, a large number of agents have been implicated in causing acute myonecrosis with myoglobinuria. This condition is associated with extreme elevation in serum levels of muscle-associated enzymes and myoglobinuria. Extreme muscle swelling may produce compartment syndromes, leading to nerve entrapments and limb ischemia. In addition, venoms that are associated with

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diffuse rhabdomyolysis are the tiger snake, taipan, mulga, and seasnake. The venom of the Arkansas and Honduran tarantulas causes irreversible injury to the muscle fiber plasma membranes, leading to diffuse myonecrosis.

ACKNOWLEDGMENTS This work was supported by the Office of Research and Development, Medical Research Service of the Department of Veterans Affairs (Drs. Kaminski and Ruff). Dr. Kaminski is also supported by a National Institutes of Health Grant.

SUGGESTED READINGS Delbridge L, Marshman D, Reeve T et al: Neuromuscular symptoms in elderly patients with hyperparathyroidism: improvement with parathyroid surgery. Med J Aust 14974, 1988 Dourmishev AL, Dourmishev LA: Dermatomyositis and drugs. Adv Exp Med Biol 455:187, 1999 Duyff RF, Van den Bosch J, Laman DM et ak Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 68750,2000 Fernandez-Sola J, Nicolas JM, Sacanella E et ak Low-dose ethanol consumption allows strength recovery in chronic alcoholic myopathy. QJM 93:35, 2000 Horak HA, Pourmand R Endocrine myopathies. Neurol Clin 18:203,2000 Kaminski HJ, Ruff RL: Endocrine myopathies (hyper- and hypofunction of adrenal, thyroid, pituitary glands and iatrogenic glucocorticoid myopathy). p. 1726. In Engel AG, Franzini-Armstrong C (eds): Myology. 2nd Ed. McGraw-Hill, New York, 1994 Kiss1 Jr, Mendell J R The endocrine myopathies. p. 527. In Rowland LP, DiMauro S (eds): Myopathies. Vol. 62. Handbook of Clinical Neurology. Elsevier, New York, 1992 Mastaglia FL: Toxic myopathies. p. 595. In Rowland LP, DiMauro S (eds): Myopathies. Vol. 62. Handbook of Clinical Neurology. Elsevier, New York, 1992 Ruff RL: Why do ICU patients become paralyzed? Ann Neurol 43:154, 1998 Sansone V, Griggs RC, Moxley RT: Hypothyroidism unmasking proximal myotonic myopathy. Neuromuscul Disord 1 0 165, 2000 Weber M, Diener HC, Voit T, Neuen-Jacob E: Focal myopathy induced by chronic heroin injection is reversible. Muscle Nerve 23:274, 2000 Weiner AL, Vieira L, McKay CA et al: Ketamine abusers presenting to the emergency department: a case series. J Emerg Med 18:447, 2000 Zaidat 00, Ruff RL, Kaminski HJ: Endocrine and toxic myopathies. p. 363. In Schapira A, Griggs R (eds): Muscle Diseases. Butterworth Heinemann, London, 1999

110 Metabolic MvoPathies Ami K. Mankodi and Robert C. Griggs Metabolic myopathies are a group of inherited diseases associated with biochemical defects of skeletal muscle energy metabolism (adenosine triphosphate synthesis). The major energy sources for muscle contraction are glycogen, glucose, and fatty acids depending on the type, intensity, and duration of exercise. For example, at rest muscle uses predominantly fatty acids, whereas during intense aerobic exercise, carbohydrate oxidation provides energy to

muscle. In low-intensity exercise, glycogen is the initial fuel; a few hours into exercise fatty acids are the main substrates to produce energy. In disorders of glycogenolysis or glycolysis, exercising muscle is more vulnerable at the initiation of exercise or during bouts of intense exercise, whereas in defects of fatty acid oxidation symptoms occur after prolonged mild to moderately intense exercise.

Chapter 110 rn Metabolic Myopathies

Acute hypokalemic myopathy is a complication of chronic alcoholism. The acute onset of painless weakness in the proximal limb muscles or limb girdle muscles without muscle cramps, tenderness, or swelling is characteristic. Serum CK and aldolase are elevated, and serum potassium is low. The potassium loss may occur through vomiting and diarrhea. Hypokalemia can also develop from alcohol-induced hypomagnesemia. When the patient is hypokalemic and hypomagnesemic, the myopathy often is painful. Strength improves with potassium and magnesium replacement. Protracted high-dose alcohol consumption may cause a progressive deterioration of skeletal muscle function, and a chronic myopathy is estimated to affect up to one third of chronic alcohol abusers. However, alcoholics are also at risk for peripheral neuropathies, which may confound assessment of “myopathic” weakness. Typically, the myopathy manifests as mild proximal weakness and muscle wasting, often with elevated serum muscle enzymes. Biopsy may reveal type 2 fiber atrophy. Cardiomyopathy and hepatic cirrhosis may be more common in patients with chronic alcoholic myopathy than in alcoholics without clinical myopathy. Abstinence appears to result in at least partial recovery of strength, and a recent study found that chronic alcoholics who continued to consume moderate dosages (up to 60 g ethanol daily) exhibited some recovery of strength as well. Thus, the degree of functional recovery from chronic alcoholic myopathy seems to be inversely proportional to alcohol consumption.

Nutritional Myopathies The impact of vitamin D deficiency, or osteomalacia, on skeletal muscle is discussed earlier in this chapter. Vitamin E deficiency may result in generalized muscle weakness, including ocular muscles.

Acute Myonecrosis IncludingBites and Stings Severe myonecrosis can occur as a consequence of general anesthesia, status epilepsy, or prolonged unconsciousness, and in the latter case it is probably caused by pressure necrosis. In addition, a large number of agents have been implicated in causing acute myonecrosis with myoglobinuria. This condition is associated with extreme elevation in serum levels of muscle-associated enzymes and myoglobinuria. Extreme muscle swelling may produce compartment syndromes, leading to nerve entrapments and limb ischemia. In addition, venoms that are associated with

713

diffuse rhabdomyolysis are the tiger snake, taipan, mulga, and seasnake. The venom of the Arkansas and Honduran tarantulas causes irreversible injury to the muscle fiber plasma membranes, leading to diffuse myonecrosis.

ACKNOWLEDGMENTS This work was supported by the Office of Research and Development, Medical Research Service of the Department of Veterans Affairs (Drs. Kaminski and Ruff). Dr. Kaminski is also supported by a National Institutes of Health Grant.

SUGGESTED READINGS Delbridge L, Marshman D, Reeve T et al: Neuromuscular symptoms in elderly patients with hyperparathyroidism: improvement with parathyroid surgery. Med J Aust 14974, 1988 Dourmishev AL, Dourmishev LA: Dermatomyositis and drugs. Adv Exp Med Biol 455:187, 1999 Duyff RF, Van den Bosch J, Laman DM et ak Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 68750,2000 Fernandez-Sola J, Nicolas JM, Sacanella E et ak Low-dose ethanol consumption allows strength recovery in chronic alcoholic myopathy. QJM 93:35, 2000 Horak HA, Pourmand R Endocrine myopathies. Neurol Clin 18:203,2000 Kaminski HJ, Ruff RL: Endocrine myopathies (hyper- and hypofunction of adrenal, thyroid, pituitary glands and iatrogenic glucocorticoid myopathy). p. 1726. In Engel AG, Franzini-Armstrong C (eds): Myology. 2nd Ed. McGraw-Hill, New York, 1994 Kiss1 Jr, Mendell J R The endocrine myopathies. p. 527. In Rowland LP, DiMauro S (eds): Myopathies. Vol. 62. Handbook of Clinical Neurology. Elsevier, New York, 1992 Mastaglia FL: Toxic myopathies. p. 595. In Rowland LP, DiMauro S (eds): Myopathies. Vol. 62. Handbook of Clinical Neurology. Elsevier, New York, 1992 Ruff RL: Why do ICU patients become paralyzed? Ann Neurol 43:154, 1998 Sansone V, Griggs RC, Moxley RT: Hypothyroidism unmasking proximal myotonic myopathy. Neuromuscul Disord 1 0 165, 2000 Weber M, Diener HC, Voit T, Neuen-Jacob E: Focal myopathy induced by chronic heroin injection is reversible. Muscle Nerve 23:274, 2000 Weiner AL, Vieira L, McKay CA et al: Ketamine abusers presenting to the emergency department: a case series. J Emerg Med 18:447, 2000 Zaidat 00, Ruff RL, Kaminski HJ: Endocrine and toxic myopathies. p. 363. In Schapira A, Griggs R (eds): Muscle Diseases. Butterworth Heinemann, London, 1999

110 Metabolic MvoPathies Ami K. Mankodi and Robert C. Griggs Metabolic myopathies are a group of inherited diseases associated with biochemical defects of skeletal muscle energy metabolism (adenosine triphosphate synthesis). The major energy sources for muscle contraction are glycogen, glucose, and fatty acids depending on the type, intensity, and duration of exercise. For example, at rest muscle uses predominantly fatty acids, whereas during intense aerobic exercise, carbohydrate oxidation provides energy to

muscle. In low-intensity exercise, glycogen is the initial fuel; a few hours into exercise fatty acids are the main substrates to produce energy. In disorders of glycogenolysis or glycolysis, exercising muscle is more vulnerable at the initiation of exercise or during bouts of intense exercise, whereas in defects of fatty acid oxidation symptoms occur after prolonged mild to moderately intense exercise.

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There are two major clinical presentations: Myopathies with exercise intolerance (Table 110- 1) Myopathies with fixed progressive muscle weakness (Table 110-2)

METABOLIC MYOPATHIES WITH EXERCISE INTOLERANCE These diseases are characterized by acute recurrent reversible muscle dysfunction resulting in exercise-induced muscle pain, cramps, and stiffness accompanied by muscle destruction. Severe episodes of muscle destruction may be associated with muscle weakness, swelling, and tenderness reflecting the extent of muscle injury (rhabdomyolysis). Creatine kinase (CK) levels are elevated, and urine often is cola-colored because of myoglobinuria during these episodes. The metabolic causes of recurrent episodes of myoglobinuria include defects in carbohydrate metabolism, fatty acid metabolism, oxidative phosphorylation (respiratory chain), and myoadenylate deaminase deficiency. However, in as many as 50% of patients, a biochemical defect is not detected. A small proportion of these patients are found to have an X-linked myopathy with abnormal dystrophin. Disorders of Carbohydrate Metabolism Muscle Clycogenosis. The old term glycogen storage disorders is no longer used because the crisis in muscle energy metabolism generated by a block in glycogenolysis or glycolysis is more important than the accumulation of glycogen in muscle in causing the myopathy. We review these diseases in terms of the metabolic flow in the glycogenolytic and glycolytic pathways (Fig. 110-1). Phosphorylase b Kinase Deficiency (Glycogenosis Type VIM). Phosphorylase b kinase deficiency has four distinct phenotypes based on the tissue involved muscle, heart, liver, or muscle and liver. Liver disease is the most common presentation. Pure muscle disease is characterized by mild exercise intolerance, cramps, and infrequent myoglobinuria (resembling a mild form of myophosphorylase deficiency). The inheritance usually is X-linked and rarely autosomal recessive. The lactate response to the forearm exercise test (described later in this chapter) is normal, in contrast to McArdle’s disease. Muscle biopsy and serum CK levels do not

TABLE110-1. Myopathies with Exercise Intolerance Disorders of carbohydrate metabolism Muscle glycogenosis Phosphorylaseb kinase deficiency Myophosphorylase deficiency (McArdle‘s disease) Phosphofructokinase deficiency Phosphoglyceratekinase deficiency Phosphoglyceratemutase deficiency Lactate dehydrogenase deficiency Disorders of lipid metabolism Carnitine palmitoyl transferase II deficiency Very-long-chain acyl-CoA deficiency Trifunctional protein deficiency Short-chain 3-hydroxyacyl-CoAdeficiency Long-chain acyl-CoA deficiency Respiratory chain defects Coenzyme Qlo deficiency Comdex 1,111, or IV defects Myoadenylate deaminase deficiency

T m u 110-2. Myopathies with Fixed Muscle Weakness Disorders of carbohydrate metabolism Muscle glycogenosis Acid maltase deficiency Debrancher enzyme deficiency Brancher enzyme deficiency Phosphorylase b kinase deficiency (rare) Myophosphorylase deficiency (rare) Phosphofrudokinase deficiency (rare) Disorders of lipid metabolism Primary carnitine deficiency Mitochondria1mvopathies

help in diagnosis. Management is similar to that of McArdle’s disease. Myophosphorylase Deficiency (Clycogenesis Type V; McArdle‘s Disease). McArdle’s disease is the most common of

the glycogenoses associated with exercise intolerance and recurrent myoglobinuria. It is usually inherited as an autosomal recessive trait. Males are more often affected than females. The disease is limited to skeletal muscle. Muscle fatigue, exercise intolerance, and myalgia often begin during childhood, but severe exercise-induced painful contractures, often called “cramps” by the patients, do not occur until adolescence or early adulthood. Myoglobinuria occurs in about 50% of the patients. The onset of pain is associated with brief intense isometric exercise (e.g., lifting heavy weights) or less intense but sustained dynamic exercise (e.g., walking uphill). Rest may rapidly relieve the aching unless exercise is intense and prolonged, when pain may persist for several days. Slowing down at the first sign of fatigue may enable the patient to sustain exercise at a slower pace for a longer period, the so-called second wind phenomenon. Examination in between the episodes usually is normal, but during a bout of rhabdomyolysis, muscle swelling, tenderness, and weakness may be present. After repeated episodes of myoglobinuria, fixed proximal limb weakness may develop in older patients. LABORATORY FINDINGS. Serum CK levels at rest are elevated in a majority of patients and rise many-fold after exercise. Myoglobin may be detected in the urine during severe episodes of muscle pain. The forearm exercise test shows little or no rise in venous blood lactate levels. Muscle biopsy shows an absence of myophosphorylase activity by a histochemical reaction. Periodic acid-Schiff (PAS)-positive, glycogen-filled subsarcolemmal blebs usually are present. Necrotic and regenerating fibers can be seen after an episode of rhabdomyolysis. Biochemical analysis of a muscle specimen confirms the deficiency of myophosphorylase and usually shows excess glycogen. E X H A UFOREARM ~ EXERCS IE TEST. This test is used to narrow the differential diagnosis in a patient presenting with exercise intolerance. A catheter is introduced in a retrograde manner in an antecubital vein and connected to a three-way stopcock. Blood samples are drawn through the side port, and the patency of the catheter is maintained with a slow infusion of normal saline. The forearm muscles are exercised by squeezing a hand dynamometer to 50% of maximum grip strength until exhaustion (usually about 10 minutes). Ischemia produced by inflating a sphygmomanometer cuff above arterial pressure sometimes is used but is unnecessary and can cause severe muscle necrosis. Blood samples obtained at baseline, immediately after exercise, and 1,3,5, and 10 minutes after exercise are analyzed for ammonia and lactate levels. In a normal person, venous lactate level increases by three to five

Chapter 110

times after exercise, and ammonia level doubles. Little or no rise in lactate levels indicates a block in the glycolytic pathway. Failure of ammonia to rise is associated with myoadenylate deaminase deficiency. Failure of both lactate and ammonia levels to rise often indicates suboptimal exercise. TREATMENT.There is no specific treatment. High-carbohydrate meals and strenuous exercise should be avoided. Patients should stop exercise when their muscles begin to ache. The management of episodes of rhabdomyolysis includes bed rest and vigorous hydration. If myoglobinuria is present, sodium bicarbonate and fluids should be administered intravenously to alkalinize the urine to prevent acute tubular necrosis. Furosemide (40 to 80 mg IV)is also indicated in severe myoglobinuria.

Metabolic Myopathies

coexistent hemolytic anemia, and a few may have gouty arthritis caused by hyperuricemia (myogenic). The inheritance is an autosomal recessive trait (chromosome 1). Males are more commonly affected. LABORATORY FINDINGS. Abnormal tests include an elevated CK levels and increase in reticulocyte count. Serum bilirubin and uric acid levels may be elevated. Venous lactate levels do not rise after the forearm exercise test. Muscle biopsy may show subsarcolemmal and intermyofibrillar accumulation of PAS-positive material consisting of mostly normal glycogen. In some patients, abnormal polysaccharide may also accumulate in skeletal muscle. A biochemical assay confirms the enzyme deficiency. Management is similar to that of McArdle’s disease.

Phosphofnrctokinase Deficiency (Clycogenosis Type WI; Tarui Disease). The clinical presentation is similar to that of

Phosphoglycerate Kinase Deficiency (Clycogenosis Type IX).

There are three distinct phenotypes: hemolytic anemia, central nervous system dysfunction (seizures, mental retardation, behav-

McArdle’s disease. A few patients may have jaundice caused by

v Glucose

Lysosornal degradation Acid rnaltase Glycogen

Branching enzyme UDPG

PLD

Glucose-1-P

4 Glucose-6-P I

1

Fructose6-P

1

I

I

Phosphofructokinase

I

Glyceraldfhyde 3-P

1 Phosphoglyceratekinase

Phosphoglycerate rnutase

I

Phosphoenol pyruvate

I Lactate I

715

I Lactate dehydrogenase

FIG. 110-1. Metabolic flow in glycogenolysis and glycolysis. PLD, phosphorylase limit dextran; UDPG, uridine diphosphate glucose.

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ioral abnormalities, stroke) or exercise intolerance with recurrent myoglobinuria. The inheritance is X-linked. The clinical presentation of the muscle disease and management are similar to those of McArdle’s disease. Other Defects of Clycolysis Associated with Exercise Intolerance. Phosphoglycerate mutase deficiency (glycogenosis type X), lactate dehydrogenase deficiency (type XI), and aldolase A deficiency (type XI) are rare diseases with autosomal recessive inheritance. The phenotype and management are similar to those of McArdle’s disease.

Disorders of Fatty Acid Metabolism Camitine Palmitoyl Transferase II (CPTII) Deficiency. This is the most common cause of myoglobinuria among inherited diseases. It is inherited as an autosomal recessive trait. The CPTII is encoded by a gene located on chromosome lp32. CPT enzymes (I and 11) are involved in shuttling fatty acids across the inner mitochondrial membrane. Thus, CPT deficiency results in poor use of fatty acids, which are the main substrates for energy during sustained low-intensity exercise. CPTI is not present in skeletal muscle and therefore is not relevant to myopathy. Patients with CPTII deficiency typically complain of muscle ache and tenderness on low-intensity, prolonged exercise. Fasting exacerbates symptoms and may even precipitate an episode of myoglobinuria in combination with exercise. Muscles are weak, tender, and swollen during severe episodes. Additional precipitating factors are a lack of sleep, emotional stress, and cold exposure. A rapidly lethal infantile phenotype characterized by hypoketotic hypoglycemia, generalized steatosis, multiple malformations, and an infantile hepatomuscular form presenting as hypoketotic hypoglycemia, lethargy, seizures, hepatomegaly, cardiomegaly, and cardiac arrhythmias are rare presentations. LABORATORY FINDINGS.Serum CK usually is normal but may rise after exercise. Forearm exercise testing shows a normal rise in venous lactate and ammonia levels. The muscle histology usually is normal but may show a slight increase in the number or size of lipid droplets. The enzyme deficiency is demonstrated by a biochemical assay on the muscle biopsy specimen. A high-carbohydrate diet may benefit some patients. Avoidance of prolonged fasting and exercise is the key to the current management of CPTII deficiency. Myoglobinuria is managed as in McArdle’s disease. Defects in poxidation (Mitochondrial Myopathies). A syndrome of recurrent myoglobinuria and hypoglycemic encephalopathy, usually beginning in childhood or adolescence, has been associated with deficiency of long-chain acyl-CoA dehydrogenase (LCAD) and short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). Muscle weakness and cardiomyopathy may be present. Recently two other important potential causes of recurrent myoglobinuria have been identified very-long-chain acylcoenzyme A deficiency (VLCAD) and trifunctional protein (TP) deficiency. Both prepare long-chain fatty acids for P-oxidation in mitochondria matrix. A rapidly lethal infantile form associated with the latter two enzyme deficiencies is characterized by hypoglycemia with Reye’s syndrome-like episodes, cardiomyopathy, and sudden infant death syndromes. Medium-chain acyl-CoA deficiency is a much more common disease of P-oxidation, but it rarely causes myopathy. Multiple acyl-CoA deficiency (MADD; glutaric aciduria type 11) has neonatal and adult forms. The neonatal form is characterized by Reye’s syndrome-like episodes and congenital anomalies and usually is lethal. The adult form is

similar to CPTII deficiency. Biochemical muscle analysis permits the diagnosis in most patients. Dietary treatment and administration of L-carnitine (50 to 100 mg/kg/day in divided doses) or riboflavin (100 mg/day) may be beneficial.

Defects in Oxidative Phosphorylation (Mitochondria1 Myopathies) Defects of complex I (nicotinamide adenine dinucleotide ubiquinone oxidoreductase), complex I11 (ubiquinol-cytochrome c oxidoreductase), and complex IV (cytochrome c oxidase) have each been associated with myopathy characterized by exercise intolerance and premature fatigue. Fixed weakness affecting the proximal limb muscles and, in some patients, the respiratory muscles may develop later in the course of the disease. Symptoms may appear in childhood. Myoglobinuria occurs in some patients. Lactic acidosis is present at rest and is exaggerated by exercise. Muscle biopsy reveals ragged red fibers. Biochemical analysis of muscle biopsy tissue confirms the specific enzyme defect, but in some patients a molecular diagnosis may be needed. Coenzyme Ql0 (CoQ,, Ubiquinone) Deficiency. CoQ,, is the final acceptor of electrons derived from P-oxidation. The clinical presentation is characterized by the triad of exercise intolerance and recurrent myoglobinuria, central nervous system dysfunction (seizures and mental retardation), and ragged red fibers with markedly increased lipid droplets on muscle biopsy. Biochemical analysis of the muscle biopsy tissue confirms the diagnosis.

Myoadenylate Deaminase Deficiency Myoadenylate deaminase deficiency has an incidence of 2.5% in the healthy adult population. Exertional myalgia is the predominant symptom. Rare patients may complain of recurrent myoglobinuria. The inheritance is autosomal recessive. In most instances, it is not clear whether the enzyme deficiency is the cause of the symptom or the association is merely coincidental. The physical examination usually is normal. Venous ammonia does not rise, whereas the rise in lactate is normal during the forearm exercise test. The enzyme deficiency is demonstrated by specific histochemical stain, and the diagnosis is confirmed by a biochemical assay showing less than 5% residual enzyme activity. There is no specific treatment. Oral ribose before and during exercise (maximum 1 g/kg body weight) and xylitol 15 to 20 g/day have been shown to be beneficial in a single patient each. In most patients the symptoms are benign and nonprogressive, and lifestyle modification with avoidance of strenuous activity usually is sufficient.

MYOPATHIES WITH FIXED PROGRESSIVE MUSCLE WEAKNESS This group of diseases includes mitochondrial diseases and defects of carbohydrate and lipid metabolism (Table 110-2).

Disorders of Carbohydrate Metabolism Muscle Clycogenosis. In contrast to myopathies with exercise intolerance, glycogen accumulation in the muscle is more severe. In addition, only one enzyme defect in skeletal muscle is specific, compared with all but one in the previous group. The role of substrate deficiency and energy production seems to be of less importance in causing muscle weakness. Neurogenic involvement in acid maltase deficiency, disruption of myofibrillar contractile

Chapter 110 rn Metabolic Myopathies

apparatus by accumulation of glycogen, and involvement of another organ (e.g., heart or liver) may contribute to muscle weakness. Acid Maltase Deficiency (Clycogenosis Type 11). Acid maltase (a-glucosidase) is a lysosomal enzyme involved in glycogenolysis. Deficiency of this enzyme is inherited as an autosomal recessive trait (chromosome 17q21-23). It accounts for approximately 15% of patients with glycogenosis. The glycogen accumulates in lysosomal vacuoles and in the cytoplasm. The use of non-membrane bound glycogen and glucose is not affected, so patients do not complain of exercise intolerance. There are three recognized clinical presentations. The severe infantile form (Pompe’s disease) presents within first 3 months of life with hypotonia, generalized weakness, macroglossia, hepatomegaly, and cardiomegaly. Feeding difficulties and respiratory muscle weakness are prominent. The disease is rapidly progressive, and most patients die by 2 years. The juvenile form presents in the first decade of life with delayed motor milestones and proximal limb and respiratory muscle weakness. The disease is slowly progressive. In some patients, calf hypertrophy may be present, leading to misdiagnosis of dystrophinopathy. Death by respiratory failure usually occurs in the second or third decade of life. The adult-onset form presents in third or fourth decade with slowly progressive proximal weakness predominantly affecting pelvic girdle muscles, mimicking limb-girdle muscular dystrophy or polymyositis. Rare features are abnormal muscle stretch reflexes (hypoactive or absent), scapuloperoneal weakness, face or tongue weakness, asymmetrical muscle weakness, and macroglossia (about 8% to 10% of patients). Muscle atrophy commensurate with weakness has been noted in about one fifth of patients. As in the other two forms, respiratory muscles are particularly affected. Indeed, about one third of patients complain of restless sleep, early morning headaches, or excessive daytime sleepiness, indicating impending respiratory failure. Liver and heart are not primarily affected but may be affected as a consequence of chronic respiratory failure. LABORATORY FINDINGS. In all three forms, serum CK levels are elevated, being highest in the infantile form (up to 10 times normal levels). Electromyography (EMG) shows frequent spontaneous activity, including myotonic discharges, fibrillation potentials, and complex repetitive discharges. These are particularly prominent in the paraspinal muscles of adult patients. Myopathic potentials (short-duration, small-amplitude motor unit action potentials) are recorded in proximal limb muscles. Electrocardiogram may show left axis deviation, short PR interval, large QRS complexes, inverted T waves, ST segment depression, and persistent sinus tachycardia in the infantile and juvenile forms, indicating hypertrophic cardiomyopathy. Pulmonary function tests show a restrictive defect with decrease in forced vital capacity, maximal inspiratory and expiratory pressures, and early diaphragm muscle fatigue. Muscle histology reveals a vacuolar myopathy, most marked in the infantile form. The vacuoles stain positively with PAS (glycogen) and acid phosphatase (indicating lysosomes, Fig. 110-2). The glycogen may be found free in sarcoplasm as well. Glycogen accumulation in anterior horn cells, Schwann cells, and bulbar neurons has been demonstrated. The diagnosis can be confirmed by biochemical analysis of enzyme deficiency in the muscle, fibroblast, lymphocytes, leukocytes, and urine. TREATMENT.There is no effective treatment. Dietary modifications including low-carbohydrate and ketogenic diets are not of

717

FIG. 110-2. Transverse section of a vastus muscle shows vacuolar myopathy in acid maltase deficiency. Note that the vacuoles stain with acid phosphatase (lysosome) and also with PAS (glycogen; not shown). Bar: 200 pm.

any benefit. In uncontrolled studies a high-protein diet was found to be of some help in improving muscle weakness and respiratory function. Recently with recombinant DNA techniques using adenoviral or retroviral vectors, the enzyme activity was restored in myotubes, myoblasts, and fibroblasts in in vitro experiments. Intravenous recombinant human enzyme normalized glycogen content in heart, muscle, and liver in enzyme-deficient quails. With the development of a mouse knockout model, our chances of understanding the pathophysiology and finding a specific treatment will improve. Until gene therapy is available for patients, vigilant watch on cardiac and respiratory function will remain the mainstay in management. Forced vital capacity should be measured in all patients periodically. When impending respiratory failure is suspected, nocturnal oximetry and capnography should be done to assess the need for ventilatory assistance during sleep. Nasal positive pressure ventilation may be used in some patients, but others will need tracheostomy. Adult patients with respiratory failure may live for many years if appropriately supported. Debrancher Enzyme Deficiency (Clycogenosis Type 111; Cori-Forbes Disease). This is a benign disease presenting in

childhood with growth retardation, fasting hypoglycemia, and hepatomegaly. These symptoms resolve around puberty, and later in life patients may present with slowly progressive, distal more than proximal weakness. Patients may complain of muscle fatigability, but myoglobinuria does not occur. In 50% of patients, muscle atrophy may be so severe that a diagnosis of peripheral neuropathy or motor neuron disease is suspected. Cardiomyopathy and hepatomegaly occur and may be useful in the diagnosis. It is inherited as autosomal recessive trait (chromosome lp21) and accounts for about 25% of patients with glycogenosis. LABORATORY FINDINGS. Serum CK levels are elevated (2 to 20 times normal). An electrocardiogram may show arrhythmia, conduction defects, and evidence of hypertrophic nonobstructive cardiomyopathy. EMG is similar to that described in acid maltase deficiency. Nerve conduction velocities may be slowed. Venous lactate production in forearm exercise test may be reduced. The muscle biopsy shows PAS-positive vacuoles. Biochemical analysis in the muscle confirms the diagnosis.

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TREATMENT.There is no effective treatment for muscle weakness. Fasting hypoglycemia can be prevented by frequent lowcarbohydrate and high-protein meals. Supportive therapy is indicated in patients presenting with congestive cardiac failure. Liver transplantation has not improved muscle weakness or cardiac failure.

Brancher Enzyme Deficiency (Clycogenosis Type 1% Andersen's Disease). This disorder is inherited as an autosomal recessive trait (chromosome 3). The enzyme is necessary to create

branched glycogen molecules, so its deficiency results in abnormal polysaccharide accumulation in the skeletal muscle, liver, heart, and central nervous system. There are several different forms of presentation. The classic and predominant form presents in infants with progressive liver cell failure, hepatosplenomegaly, growth retardation, sometimes muscle weakness, and cardiomegaly. The patients usually die of liver failure by 5 years of age. In adults the enzyme deficiency may cause predominant progressive muscle weakness and atrophy (proximal or distal). The brancher enzyme deficiency has also been reported in some patients with adult polyglucosan body disease, characterized by progressive upper and lower motor neuron loss, neurogenic bladder, dementia, and cerebellar ataxia. LABORATORY FINDINGS. Serum CK levels are normal or only slightly elevated. Dilated cardiomyopathy and conduction defects can occur. An electromyogram is myopathic, with an increase in spontaneous activity, as described in acid maltase deficiency. Peripheral nerve conduction may be slowed. In adult polyglucosan body disease, nerve conduction studies may show sensorimotor axonal neuropathy. Muscle histology shows accumulation of finely granular and filamentous polysaccharide (polyglucosan bodies). This accumulated material is PAS-positive, like glycogen, but diastase resistant. TREATMENT.Liver transplantation has helped improve cardiac, liver, and neuromuscular function in some children. No other effective therapy is reported. Other Diseases. Deficiency of myophosphorylase, phosphorylase b kinase, and phosphofructokinase has rarely been associated with late-onset progressive limb muscle weakness. In addition, deficiency of myophosphorylase or phosphofructokinase has been associated with rapidly progressive lethal weakness in infants. Disorders of Lipid Metabolism Carnitine Deficiency Syndrome. Carnitine plays an essential role in transporting long-chain fatty acids across mitochondria1 membranes. Thus, deficiency of carnitine impedes the transport of fatty acids and thereby reduces adenosine triphosphate synthesis. The primary carnitine deficiency is inherited as an autosomal recessive trait. There are two clinical forms. In the systemic form, carnitine levels are low in plasma, heart, liver, and skeletal muscle. The disease presents during early childhood with proximal muscle weakness, hypoglycemic hypoketotic encephalopathy resembling Reye's syndrome, hepatomegaly, and cardiomyopathy. In the pure myopathic form, the major manifestation is slowly

progressive axial and proximal limb weakness beginning in childhood or occasionally in adulthood. Facial and respiratory muscle weakness or cardiomyopathy can occur. Muscle cramps and exercise intolerance are less common. The plasma levels of carnitine are normal. LABORATORY FINDINGS. Serum CK levels are normal or elevated up to 15 times normal. The electromyogram is myopathic. Conduction defects and cardiomegaly can occur. Muscle biopsy shows vacuolar myopathy with abundant large lipid droplets stained by oil-red-0 stain for neutral lipids. The diagnosis is confirmed by biochemical assay of muscle for carnitine levels. Secondary causes of carnitine deficiency must be excluded: renal failure, cirrhosis, valproate therapy, organic aciduria, and defects in respiratory chain enzymes. TREATMENT.Carnitine replacement remains the mainstay in treatment. L-Carnitine is administered orally 50 to 100 mglday in divided doses. Systemic carnitine levels return to normal. However, muscle levels remain low. Still, patients improve remarkably in muscle strength and cardiac function. In fact, the symptoms may revert to normal state on prolonged carnitine replacement. Severe episodes of hypoglycemic hypoketotic encephalopathy are treated with parented infusion of glucose and L-carnitine.

SUMMARY Muscle aches, cramps, and fatigue are the most common presenting symptoms encountered in neuromuscular clinics. Such patients complain of pain and fatigue on minimal activity or at rest. It is important to recognize symptoms of postexertional myalgia, fatigue, and weakness or episodes of myoglobinuria. In addition, elevated CK levels and abnormal EMG findings may support the need for further investigations such as forearm exercise test, muscle biopsy, and biochemical analysis. Although no specific treatment is available for most of these diseases, advances in recombinant DNA technologies and development of animal models may improve the prognosis in future.

SUGGESTED READINGS DiMauro S , Haller HG Metabolic myopathies: substrate use defects. pp. 225-250. In Schapira AHV, Griggs RC (eds): Blue Books of Practical Neurology: Muscle Diseases. Butterworth-Heinemann, Woburn, h4A, 1999 Griggs RC, Mendell JR, Miller R Metabolic myopathies. pp. 247-293. In Evaluation and Treatment of Myopathies. FA Davis, Philadelphia, 1994 Griggs RC, Mendell JR, Miller R Mitochondrial myopathies. pp. 294-317. In Evaluation and Treatment of Myopathies. FA Davis, Philadelphia, 1994

Moxley RT, Chinnery P, Turnbull D: The metabolic myopathies. In Karpati G, Hilton-Jones D, Griggs RC (eds): Disorders of Voluntary Muscle. 7th Ed. Cambridge University Press, Cambridge, UK, 2000 Rahman S , Schapira AHV Mitochondrial myopathies: clinical features, molecular genetics, investigation, and management. pp. 177-224. In Schapira AHV, Griggs RC (eds): Blue Books of Practical Neurology: Muscle Diseases. Butterworth-Heinemann, Woburn, MA, 1999

Congenital Myopathies

Chapter 111

719

11 1 Congenital Myopathies James A. Russell The nosology of the inherited disorders of muscle remains inadequate and in flux. To date, molecular biological tools have provided as many questions as answers. Genotypic and phenotypic correlations remain incomplete. No current system allows the adequate reconciliation of clinical, histologic, and genetic data into a lucid classification of the disorders that have been historically and currently classified as the congenital myopathies. Before the advent of muscle histochemistry and electron microscopy, the congenital myopathies were referred to as benign congenital hypotonias. Central core disease was described in 1956 by Shy and Magee and remains the phenotypic prototype for the category as a whole. For the past 45 years, the congenital myopathies have been considered to be one of the major categories of inherited muscle disease, the others being the muscular dystrophies, the lipid and glycogen storage disorders, the mitochondrial myopathies, and the periodic paralyses. The congenital myopathies have been defined primarily by histologic criteria. The classic or typical (although not exclusive) phenotype is of a neonate or infant with hypotonia and proximally predominant or generalized weakness, a slowly progressive or nonprogressive course, and associated skeletal abnormalities. In this setting, the muscle biopsy is diagnostic if one of the typical histologic patterns is demonstrable in the absence of inflammation, necrosis, and regeneration. The application of molecular genetic tools has changed our understanding of these conditions and, as a result, their nosology and classification (Table 111-1). Some of these disorders are of

H TMLE 11 1-1.

suspect validity in view of their rarity. The European Neuromuscular Centre considers central core disease, nemaline myopathy, and centronuclear or myotubular myopathy to be the classic congenital myopathies. Cylindrical spiral myopathy, fingerprint body myopathy, tubular aggregate myopathy, vacuolar myopathy associated with cardiomyopathy and mental retardation, and hyaline body or myofibrillar lysis myopathy are considered probable entities. Cap disease, reducing fiber myopathy, and actin filament myopathy are designated as possible disorders. Lamellar body myopathy, zebra body myopathy, and broad A band myopathy are considered to be rare and of dubious validity. The following observations provide some insight into the clinical and genetic heterogeneity of these disorders and the ways in which they may overlap with muscle diseases not typically classified as congenital. The clinical features in an individual patient may be adequate to prompt suspicion of a congenital myopathy but are rarely specific enough to allow accurate prediction of a specific congenital myopathy type. The natural history of any specific congenital myopathy, as historically defined is quite variable, ranging from infantile mortality to a benign course and normal life expectancy. The histologic features of the congenital myopathies are variable within individuals and kindreds. They are neither completely specific nor sensitive for the group as a whole. Clinically affected relatives may have muscle biopsies that

Classification of Congenital Myopathies

Name

Mutation

Gene

Protein

Central core Central core Central core Nernaline rod Nernaline rod Nemaline rod Nernaline rod Myotubular Centronuclear Centronuclear CFTD Multi-minicore Cylindrical spiral myopathy Fingerprint Myofibrillar rnyopathy (desmin)

AD

19q3 1 14

Ryanodine Myosin ? Tropomyosin (TPM3) Nebulin (NEM2) a-Actin (ACTAl) ? Myotubularin tyrosine phosphatase (MTMX) ? ? ? ? ? ? Desmin

Myofibrillar myopathy

AD, sporadic, AR, X-linked

Tubular aggregates

AD ? ? X-linked Sporadic, AD, AR

Vacuolar myopathy, cardiomyopathy, mental retardation Hyaline rnyopathy (myofibrillar lysis rnyopathy) lamellar body Broad A band Zebra body rnyopathy Trilaminar fiber Sarcotubular

? ? AD AR, sporadic AD, AR, sporadic AR X-linked AD AR Sporadic AR (rare AD)

? Recessive AD, sporadic

? ? ? ?

? lq21-q23 2q21.2-q22 1q42.1

? XQ28

? ? ? ? ? ? 2q24-31 12q 1Oq22.3 12q 1Oq22.3 ?

? ? ? ? ? ? ?

Abbrewidons: AD, autosomal dominant; A h autosomal recessive; CFTD, congenital fiber type disproportion.

? ?

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are different from the proband. In certain circumstances, muscle biopsy findings appear to change over time in the same patient. Muscle histochemistry in a given patient may manifest more than one of the features supposedly characteristic of a singular entity in the same patient and family (e.g., rods and cores). The same histologic features observed in congenital myopathies (e.g., rods, fingerprint bodies, congenital fiber type disproportion) may be seen in other inherited, experimental, or acquired pathologic conditions. There is genotypic variability. A specific congenital myopathy as historically defined may result from mutations of different genes on different chromosomes.

the core suggests that accumulation of the abnormal protein may be contributory to muscle injury. In myofibrillar myopathy, mutations of the desmin gene and desmin accumulation often occur, but it is unknown whether these events are causally related to the impaired development or injury to muscle. Despite this knowledge of the gene product in any of these disorders, our understanding is limited as to how the absence of protein or presence of abnormal protein translates into the observed abnormalities in myofiber Structure or muscle weakness.

This chapter focuses on the more common of those disorders currently classified as congenital myopathies. Emphasis is placed on classification, genetics, pathophysiology, clinical features (both of the category as a whole and individual disorders), differential diagnostic considerations, the role of laboratory testing, and management. The congenital muscular dystrophies and the mitochondria1 myopathies are considered in Chapters 107 and 110, respectively.

Although certain clinical features are more common in individual congenital myopathies, there is sufficient overlap to preclude a definite diagnosis of a specific congenital myopathy on clinical grounds alone. Clinicians have found it helpful to group them into severe, typical, and mild phenotypes, in a manner analogous to the spinal muscular atrophies. The severe phenotype usually is recognized before (reduced fetal movements), at, or soon after delivery. It is usually the result of one form of X-linked myotubular myopathy, one recessive form of nemaline myopathy, or congenital fiber type disproportion. The affected child is severely hypotonic, with cardiopulmonary and feeding difficulties. The child may or may not survive the neonatal period. If he or she does, ventilator dependency is common and independent ambulation rare. The typical phenotype usually is recognized in infancy or childhood. The child is usually thin, hypotonic, and weak in a proximal or generalized pattern, with delayed motor milestones. Facial and pharyngeal weakness are common, and neck and masticatory weakness, foot drop (notably in some forms of dominantly inherited nemaline myopathy), and scapular winging may occur. Ptosis and ophthalmoparesis are most commonly associated with centronuclear myopathy but may rarely be features of other congenital myopathies as well. Deep tendon reflexes are diminished or absent. The natural history seems to be one of limited progression or nonprogression, although periods of apparent worsening may occur with growth spurts, immobility, or intercurrent illness. Cardiopulmonary problems are less prevalent in this group than in more severely affected neonates but may occur. Nocturnal hypoventilation may occur, even in ambulatory patients. This occurs most commonly in nemaline myopathy and requires close surveillance. The mild phenotype may not be recognized until adulthood. An affected person may come to medical attention for orthopedic rather than neuromuscular reasons. Alternatively, the problem may go unrecognized until a more severely affected child is born. This occurs most commonly with central core disease. A wide variety of dysmorphic skeletal features are associated with the congenital myopathies and often provide a diagnostic clue. They include dolichocephaly, temporomandibular ankylosis, high-arched palate, micrognathia, kyphoscoliosis, congenital dislocation of hips, pes cavus or planus, rigid spine, equinovarus or equinovalgus, pseudohypertrophy of calves, joint contractures, torticollis, pectus excavatum, increased lumbar lordosis, ectomorphic body habitus, short stature, and hip dysplasia. Mental retardation in the absence of hypoxemia and other end organ involvement is rare in the common forms.

CLASSIFICATION AND GENETICS Congenital myopathies and their currently known chromosomal abnormalities are listed in Table 111-1. The congenital myopathies may be inherited in a dominant, recessive, or X-linked pattern. Seemingly sporadic cases occur as well. They may result from unrecognized recessive inheritance, false paternity, dominant inheritance with subclinical expression in a parent, spontaneous mutation in the proband, or an acquired pathophysiology with biopsy features mimicking a congenital my0p athy.

PATHOGENESIS Our understanding of the pathogenesis of the congenital myopathies is limited. In myotubular myopathy, there appears to be persistence and overexpression of the fetal cytoskeletal proteins vimentin and desmin, proteins that normally diminish or disappear by term. It has been hypothesized that the persistence of these proteins prevents the normal migration of myofiber nuclei and maintains them in a central position, implying that myotubular myopathy is a consequence of maturation arrest. This hypothesis is countered by the observation that vimentin and desmin intermediate filaments are found in normal concentrations in centronuclear myopathy, a disorder in which muscle nuclei occupy the same central location in the myofiber. Additionally, this hypothesis is further refuted by the observation that histochemical differentiation between type I and type I1 myofibers is readily demonstrable in both myotubular and centronuclear myopathies but cannot be demonstrated in myotubular stage of normal muscle ontogenesis. More recently, myotubularin, the defective protein in myotubular myopathy, has been demonstrated to have tyrosine phosphatase activity and is thought to play a role in normal signal transduction during late myogenesis. In central core disease, mutations in the ryanodine receptor gene and enhanced ryanodine receptor immunostaining within

CLINICAL FEATURES

Chapter 111

INDIVIDUAL CONGENITAL MYOPATHIES: CLASSIC FORMS Few if any clinical features allow certain, specific distinction between individual congenital myopathies and other neuromuscular disorders. Certain clinical features appear to be more common in some congenital myopathies than others. These features are outlined in Table 11 1-2.

Central Core Disease Central core disease is the prototype of the congenital myopathies, first described by Shy in 1956. Its inheritance pattern is dominant. Typical cases begin in infancy or childhood, manifesting hypotonia, proximal weakness, and associated skeletal abnormalities. Muscle cramping, exercise intolerance, and preservation of deep tendon reflexes are more common in central core disease than in the other congenital myopathies. Independent ambulation and a normal life expectancy is the rule rather than the exception. The histopathologic hallmark is the existence of single circular or ovoid area of impaired reduced nicotinamide adenine dinucleotide staining. These cores run the entire length in each of the TAW 111-2. Clinical Features That May Help to Identify Individual Congenital Myopathies Clinical Feature Severe phenotype with neonatal onset Mild phenotype with late life recognition Cardiomyopathy Ventilatory muscle involvement Disproportionate axial muscle involvement, rigid spine Calf hypertrophy Cramps, myalgias, rigidity, and exercise intolerance Foot drop or scapular winging Ptosis and ophthalmoparesis Bifacial weakness Skeletal abnormalities Temporomandibularankylosis Malignant hyperthermia Seizures Mental retardation

Disorders in Which This Feature Occursa Nemaline (AR), myotubular, C m , central core, multiminicore, reducing body, myofibrillar Central core, centronudear, nemallne rod (AD), myoflbrillar, reducing body, multi-minicore, cylindrical spirals Myotubular, nemaline (AR), central core, multi-minicore MUM-mlnlcore, myotubular, nemaline (AR). C m . centronuclear MUM-minicore, CFID Myofibrillar Central core, cylindrical spirals, myofibrillar, tubular aggregate, trilaminar Nemaline, myoflbrillar, centronuclear, sarcotubular Centronudear, myotubular, multi-minicore, nemaline, reducing body, myofibrillar, CFTD Nemallne, myofibrillar, CFTD Central core, centronudear, multi-minicore, CFID, myofibrillar Nemaline rod, centronuclear Central core, multl-minlcore Centronuclear, fingerprint Fingerprint, myofibrillar, vacuolar with cardiomyopathy, mental retardation Myofibrillar

Peripheral neuropathy 'Bold indicates common occurrence. AbbreriatJons: AD, autosomal dominant;AR, autosomal recessive; CFTD, congenital fiber type disproportion. Modified from Coebel HH,Lenard HG: Congenital myopathies. p. 33 1. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 18. Elsevier, Amsterdam, 1992, with permission.

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numerously affected type 1 myofibers. Ultrastructurally, the material in the cores appears as aggregated or disorganized myofibrlllar components that immunostain for desmin and the ryanodine receptor protein in some cases. The disorder has been linked to mutations of the ryanodine receptor gene on chromosome 19q13.1 in most cases. Other nonlinked families with central cores have been detected as well. There is a hypertrophic cardiomyopathy phenotype linked to the myosin gene on chromosome 14. Mutations of the ryanodine receptor gene may predispose to malignant hyperthermia susceptibility, particularly if near the amino terminus of the protein.

NemalEne Rod Myopathy Nemaline rod myopathy, first described in 1963, has a more variable genotype and phenotype. It may result from a dominant or recessive pattern of inheritance. Severe cases result from a recessive inheritance pattern. Reduced fetal movements and polyhydramnios may occur. Affected patients are severely hypotonic, with bifacial weakness, depressed deep tendon reflexes, and an impaired ability to swallow and breath. A thin face and dental malocclusions are common. Arthrogryposis, cardiomyopathy, and ophthalmoparesis are uncommon. The mortality rate is high. The more typically affected patient has a mild disorder with thin limbs, hypotonia, proximal weakness, and skeletal dysmorphisms. As with the majority of congenital myopathies, milder cases first recognized in adulthood occur. There are at least four different nemaline genotypes, three of which are currently defined (Table 111-1). An autosomal dominant form results from a mutation on the tropomyosin 3 gene on chromosome lq21. This produces a typical phenotype if heterozygotic or a severe phenotype if homozygotic. Recessive or sporadic cases are more common. The most common seems to be linked to the nebulin gene on chromosome 2q21.2422. The third defined genotype is linked to a mutations in the a-actin gene on chromosome lq42. There are other families that are currently unlinked. The nemaline rods appear to arise from the Z disk and are composed of the proteins a-actinin and actin. They are cytoplasmic except in the severe neonatal form, where they may be intranuclear. The histopathology is described in Table 1 1 1-3.

Centronuclear or Myotubular Myopathy The nosology of this entity has been historically confusing. Myotubular myopathy was first described in a Dutch kindred in 1969, and the term was coined as a result of the similar appearance between abnormal myofibers in biopsy specimens and fetal myotubes. When this hypothesis was challenged, centronuclear myopathy became the preferred term. Currently, myotubular myopathy is used to describe the severe X-linked form of the disease and centronuclear myopathy the more benign, dominantly inherited form that assumes the typical phenotype. As with the severe infantile form of nemaline myopathy, affected males with the X-linked form of myotubular myopathy often are born prematurely, with polyhydramnios. Their length and head size often are larger than normal and their weight less. Flaccidity, apnea, areflexia, ptosis, ophthalmoparesis, and an inability to swatlow are the norm. Ophthalmoparesis may be delayed. Contractures of the hips and knees and cryptorchidism

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TABLE111-3. Histopathology of the Congenital Myopathies Myopathy

Description of Abnormalities

Important Stains (Best Stain in Bold)

CFTD

Type 1 fiber predominance, type 1 fiber atrophy or hypotrophy, common to many of the congenital myopathies. CFTD, central cores: circumscribed, centrally located areas extending the length of the myofiber with a disrupted myofibrillar network and absent mitochondria; may occupy 20%-100% of fibers in a given biopsy. CFTD, nemaline rods: thin, rodlike structures (red on MCT) that appear to arise from the 2 disk based on their contiguity, a similar lattice structure, and their makeup (a-actinin). CFTD, central nuclei: a single large central nucleus with surrounding halo seen in 50% or more of fibers.

ATPase

Central core Nemaline rod Myotubular or centronuclear Multi-minicore Cylindrical spirals Fingerprint Myofibrillar

Tubular aggregates Vacuolar myopathy, cardiomyopathy, mental retardation Hyaline myopathy (myofibrillar lysis myopathy) Cap disease Reducing body

Actin filament myopathy Zebra body Trilaminar

CFTD, similar to central core except cores are multiple, not centrally located, do not extend the length of the sarcomere, and are unstructured with disruption of the surrounding myofibrillar network. Subsarcolemmal or intermyofibrillar clusters staining bluish with H&E, red with MGT, (+) with NSE and MA, faint with NADH and (-) with ATPase and SDH. Concentrically wrapped lamellae on EM. CFTD, atrophic fibers with myofibrillar disorganization at the periphery. Subsarcolemmal, non-membrane bound convoluted lamellae with fingerprint configuration. Amorphous granular or hyaline material staining bluish on MCT staining which may be subsarcolemmal or diffuse in distribution, vacuoles and cytoplasmic and spheroid body formation. lmmunostaining reveals the accumulation of desmin and other intermediate filaments. Intensely staining (MCT red, H&E blue, NADH, MA), peripherally located, irregularly outlined aggregates (-) stain for SDH. Numerous vacuoles, cytoplasmic bodies. CFTD with subsarcolemmal zones in type 1 fibers staining (-) for NADH, PAS, and intensely for ATPase, devoid of myofibrils and organelles. Large subsarcolemmal crescent (+) stain for NADH and MCT, (-) stain for ATPase and SDH, myofibrils perpendicular to long axis. Round or polymorphic subsarcolemmal masses that stain purple on MCT, pink on H&E, and brown with MNT and positively for desmin, cytoplasmic bodies staining red with MCT, rimmed vacuoles, 16- to 17-nm tubulofilamentous inclusions with EM. Excess of thin filaments, stain (-) for ATPase. Inner zone staining red, intermediate staining green, and outer staining purple. Inner zone devoid of contractile elements. Microvacuolization of type 2 fibers.

NADH, SDH, PAS, phosphorylase, ATPase (areas of absent staining) MCT

H&E, MCT, (central nuclei visualized), ATPase (central hole unstained) Same as central core H&E, MCT, NSE, MA, NADH, ATPase, SDH, EM NADH, EM MCT, desrnin

MCT, H&E, NADH, SDH, MA, EM MCT

ATPase pH 4.2, NADH, PAS, EM NADH, MCT, ATPase, EM

MNT, H&E, EM, MCT, desmin

lmmunostain for actin, Aware, EM EM MCT, NADH, ATPase, EM

Sarcotubular EM Abbreviations: ATPase, adenosine triphosphatase; CFTD, congenital fiber type disproportion; EM, electron microscopy; H&E, hematoxylin and eosin; MA, myoadenylate deaminase; MCT, modified Comori trichrome; MNT, menadione-nitrobluetetrazolium; NADH. reduced nicotinamideadenine dinucleotide; NSE, nonspecific esterase; PAS, periodic acidSchiff; SDH, succinate dehydrogenase.

may occur. Mortality in the neonatal period is common. Muscle biopsy findings are described in Table 1 1 1-3. The disorder arises from a mutation of the myotubularin gene at X28. Centronuclear myopathy is dominantly inherited. Its phenotype follows the characteristics of the typical forms of nemaline and central core disease described earlier. Congenital Fiber Size Disproportion This disorder was first described by Brooke and Engel in 1969. Its existence remains controversial because it may occur alone, in association with histologic features of other congenital myopathies, or in association with a number of other inherited metabolic disorders. Congenital fiber type disproportion is a histologic entity, defined by a biopsy picture of type 1 fiber predominance and type 1 fiber atrophy or hypotrophy in the absence of other abnormalities. The histological pattern is common in other congenital myopathies. The phenotype of congenital fiber type disproportion includes both a severe infantile and typical syndrome and does not differ significantly from the other severe infantile and typical pheno-

types. Little is understood of the genetics and pathophysiology of this entity. Multi-Minicore Disease Once again, there is great genotypic and phenotypic heterogeneity in this disorder. It was first described by Engel and Gomez in 1966. Recessive and sporadic cases predominate, although dominant inheritance exists. The most common phenotype is a childhood onset, with weakness often worse in axial muscles. Scoliosis and ventilatory muscle involvement occur. Ophthalmoparesis has a 25% prevalence. Most children gain the ability to ambulate independently but are never able to run. Severe, neonatal onset as well as adult-onset cases occur. The cores may be difficult to detect by light microscopy, and semithin longitudinal sections imbedded in plastic may be needed for detection. Unlike central cores, minicores occur in both fiber types and are unstructured, meaning that the surrounding sarcomeres are out of register and disorganized. Multicores have been seen in the biopsies of patients with the ryanodine receptor mutation for central core disease and in biopsies of patients with

Chapter 11 1

rods and central nuclei. This once again calls into question the specificity of any given histopathologic feature.

Myofibrillar Myopathy Myofibrillar myopathy is the currently preferred term for another diverse disorder or group of disorders characterized by abnormal inclusions of degraded and compacted myofibrillar material that arises from the Z disks. This entity has been historically referred to by a wide variety of names, including cytoplasmic body myopathy, spheroid body myopathy, and, most recently, desmin-related or desmin storage myopathy. Predictably, myofibrillar myopathy will eventually be found to represent two or more disorders. In many cases, myofibrillar myopathy seems to arise from mutations in one or more intermediate filaments, proteins that have their largest role in the alignment of actin fibers at the Z disk level in utero. Desmin is the most noteworthy but by no means the only example of an intermediate filament that is abnormal in structure and quantity in these disorders. Desmin accumulation within myofibers is a consistent but nonspecific characteristic. Myofibrillar myopathy is loosely classified here as a congenital myopathy. It is often dominantly inherited or sporadic, but both recessive and X-linked inheritance occur. The typical age of onset is 20 to 40 years, but cases recognized in infancy and late adulthood have been described. Patients may experience mild or severe handicaps. Distal muscles, particularly foot dorsiflexors, often are the most severely affected. The weakness may progress to a generalized pattern and may even affect the facial, bulbar, neck, and ventilatory muscles. A large portion of patients have a cardiomyopathy that may be the presenting feature and may be hypertrophic, congestive, or restrictive. Conduction defects and even sudden death may occur. Clinical, electromyographic, or histologic evidence of a neuropathic component is not rare. The histopathologic features are described in Table 111-3. A significant number (but not all) of affected patients have mutations of the desmin gene on chromosome 2q25. Other mutations have been described (Table 111-1).

OTHER CONGENITAL MYOPATHIES The other congenital myopathies are far less common and are listed in Tables 111-1, 111-2, and 111-3.

DIFFERENTIAL DIAGNOSIS Differential diagnostic considerations vary, depending on the age of onset and the clinical features of the patient. This discussion is limited to the typical presentation, that of the floppy infant. Most floppy infants have central nervous system pathology as the apparent cause of their hypotonia. The neuromuscular causes for the floppy infant syndrome include other myopathies, anterior horn cell diseases, rare congenital neuropathies, and neuromuscular transmission disorders. Other myopathies that may present clinically as congenital hypotonia include congenital muscular dystrophy, myotonic muscular dystrophy, glycogen and lipid storage disorders, and the mitochondrial disorders. Clinical features may be helpful but are rarely distinctive. Contractures are common, for example, in congenital muscular dystrophy. Examination of the mother and DNA analysis provide the usual means of diagnosis in neonatal

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myotonic dystrophy. An abnormal electromyogram (EMG) and elevated creatine kinase are more likely to occur in the noncongenital myopathies presenting in infancy, with the exception of centronuclear or myotubular myopathy, in which an abnormal EMG is common. Muscle biopsy often is needed for definitive diagnosis. Infantile spinal muscular atrophy (Werdnig-Hoffinan disease) is the most common neuromuscular cause of hypotonia in most institutions. Electromyography and nerve conduction studies almost always identify this disorder as neurogenic in a laboratory with adequate pediatric experience. DNA mutational analysis is the preferred diagnostic modality. The same holds true for congenital hypomyelinating neuropathy and Dejerine-Sottas disease, in which abnormal sensory potentials on nerve conduction studies accompany widespread evidence of denervation on the EMG. The congenital myasthenic syndromes are uncommon. Edrophonium testing, repetitive stimulation techniques, or the observation of stimulus-linked repetitive compound muscle action potential on motor conduction studies aid in diagnosing these disorders. Polio, Guillain-Barrk syndrome, infantile botulism, and the inflammatory myopathies are rare causes of the floppy infant syndrome that are unlikely to be confused with the congenital myopathies because of their more typical acute or subacute clinical course.

DIAGNOSIS At present, diagnosis is based on clinical suspicion and histopathologic confirmation. On occasion, repeat biopsy may be needed. Mutational DNA analysis may allow diagnosis in individual cases in the future.

Creatine Klnase Creatine kinase is a minimally useful tool in evaluating a suspected congenital myopathy. It may be mildly elevated or it may be normal. A creatine kinase value greater than two times normal should suggest an alternative diagnosis.

Elecbodiagnostic Evaluation With the exception of occasionally low-amplitude compound muscle action potentials, nerve conduction study results are normal. Early recruitment of motor unit potentials and motor units of short duration and low amplitude (the so-called myopathic pattern) has been described as a common finding in the congenital myopathies. In the experience of the electromyography laboratory at Children’s Hospital of Boston, many biopsy-proven congenital myopathies are associated with normal electromyographic studies. Distinction between pathologically small motor unit potentials and normal small motor unit potentials of infancy is understandable. This problem may predispose to both falsepositive and false-negative study results. Fibrillation potentials are common in centronuclear myopathy and have been reported in nemaline myopathy, congenital fiber type disproportion, cytoplasmic body myopathy, and reducing body myopathy. Myotonia and complex repetitive discharges have been reported in centronuclear myopathy and cytoplasmic body myopathy.

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Muscle Biopsy

Muscle histopathology remains the cornerstone of diagnosis (Figs. 11 1-1 through 11 1-5). Unfortunately, no single pattern of abnormality defines a specific congenital myopathy. Congenital fiber type disproportion (i.e., type 1 fiber predominance and type 1 fiber atrophy) is common to almost all congenital myopathies but may not be apparent in a given patient or in a particular biopsied location. Many of the histologic characteristics that have historically defined a particular congenital myopathy type may occur together at a single biopsy site (e.g., the concurrence of central

cores and nemaline rods). Histologic abnormalities are not uniformly distributed, and sampling error and changes in the histologic finding may occur over time. It is the predominant histopathologic finding when coupled with the appropriate clinical presentation that forms our current basis of diagnosis. The biopsy specimen usually is obtained from the quadriceps on the side not invaded by the EMG needle. An alternative site might be chosen if the quadriceps seemed clinically spared or if the muscle seemed so severely afflicted that an end-stage biopsy might be expected. In myopathies in which electromyographic examina-

FIG. 111-1. Central core disease. A muscle biopsy from a 7-year-old boy with lifelong developmental delay associated with heel cord shortening. A cross-section stained with reduced nicotinamide adenine dinucleotide demonstratesthat the majority of myofibers lack oxidative activity in a corelike configuration, usually in a central location. (Courtesy of Thomas Smith, MD, University of Massachusetts Medical Center, Worcester, MA.)

FIG. 111-1. Nemaline rod disease. A muscle biopsy from a 63-year-old man with a few years of recognized proximal weakness, temporomandibular joint ankylosis, and heel cord tightness. A modified Cemori trichrome-stained cross-section demonstrates darkly stained rodlike structures scattered throughout the majority of myofibers.

Chapter 11 1

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FIG. 111-3. Nemahne rod disease. A longitudinally oriented electron micrograph from a muscle biopsy of a child with nemaline myopathy demonstrating the longitudinal orientation of the rods and their relationship to the Z disks.

FIG. 1 11-4. Centronuclear myopathywith fiber type disproportion. A muscle biopsy from a 12-year-oldgirl with ptosis, distal weakness greater than proximal weakness, and tight heel cords. An adenosine triphosphatase-stained cross-section (pH 4.3) demonstrates type 1 fiber atrophy and predominance as well as numerous fibers with absent central staining representing the locations of unstained nuclei. (Courtesy of Douglas Anthony, MD, and Natasha Lec, MD, Boston Children's Hospital, Boston.)

tions are more helpful, an EMG may help in suggesting a high-yield site to biopsy. A description of the histologic abnormalities in the congenital myopathies and the stains and techniques that accentuate them are listed in Table 111-3. It should be emphasized that with the exception of centrally located nuclei, frozen sections and histochemical stains are needed for diagnosis. Paraffin sections by themselves are inadequate for diagnosis in the majority of these disorders. Ultrastructural analysis may be required in the less common forms of congenital myopathy.

Other

There has been recent interest in using magnetic resonance imaging in diagnosing muscle disease. Its primary use has been to supplant the role of electromyography in documenting myopathy and to direct the site of muscle biopsy. Although its usefulness in individual cases of certain types of myopathy has been well established, it is not clear that its specificity and sensitivity are adequate to be used routinely in diagnosing the congenital myopathies.

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FIG. 111-5. Centronuclear myopathy. A longitudinally oriented electron micrograph from the muscle biopsy of a 2-day-old infant with hypotonia, facial weakness, micrognathia, and contractures of the elbows and knees. A centrally placed nucleus surrounded by an area of myofibrillar disruption is demonstrated. The peripherally located myofibrillar architecture is largely preserved.

There are currently no commercially available testing sites for DNA analysis in the congenital myopathies.

MANAGEMENT There are no specific treatments for the congenital myopathies. The management goals are for the most part similar to those for other chronic neuromuscular conditions: Maintain optimal, independent neuromuscular function for as long as possible, with particular attention to ambulation Reduce the risk of falls and injury Maintain patient comfort Prevent or correct joint contractures, particularly spine deformities and kyphoscoliotic cardiopulmonary disease Maintain appropriate nutrition (adequate calories in those with feeding difficulties, caloric restrictions in those with a propensity to obesity) Provide genetic counseling Manage high-risk pregnancies Prevent or promptly treat aspiration and other forms of pneumonia Recognize and treat associated cardiomyopathy, symptomatic cardiac conduction defects necessitating pacemaker implantation, and pulmonary hypertension Avoid malignant hyperthermia and provide treatment if it occurs Address the psychosocial issues affecting patients and their families Reassure patient and parents, when appropriate, that in the majority of childhood-onset or later cases, neither significant progression or mortality is anticipated

The development of a uniform management protocol for patients with congenital myopathy is impeded by the clinical heterogeneity and variable natural history and by the absence of controlled data pertaining to the management of these disorders. A brief review of the therapeutic options follows. It is beyond the scope of this chapter to provide detailed management guidelines for the numerous orthopedic complications. Surgical intervention should be performed by an orthopedist skilled in corrective neuromuscular procedures. The goals of the surgery and the likelihood of success should be understood by all involved parties. Prolonged immobilization after any surgery is to be avoided. Few controlled studies address management of the congenital myopathies. Recommendations presented here are in large part extrapolated from the more systematically studied Duchenne’s muscular dystrophy. Contractures may be present at birth (i.e., arthrogryposis multiplex congenita) or may be acquired, concomitant with the development of weakness in the muscle groups affecting the joints in question. The treatment goals are to restore or maintain function in a joint still capable of independent movement, to maintain comfort, or on occasion to allow improved hygienic care. Restoration of passive mobility to a joint whose surrounding muscles are incapable of effective movement serves little purpose. Contractures that may occur in the upper extremities include adduction of the shoulder, flexion and pronation of the elbow, flexion and ulnar deviation of the wrists, and flexion of the metacarpophalangeal and proximal interphalangeal joints. The foundation of prevention and treatment is daily passive range-ofmotion exercises. If passive range of motion becomes limited, nocturnal orthoses, particularly for the wrist and fingers, should be considered. Tendon releases and transfers are uncommonly performed. Prevention of lower extremity and spinal contractures is best accomplished by keeping the patient ambulatory. Canes, crutches,

Chapter 11 1

and walkers may be useful if adequate upper extremity strength permits their use. Long leg braces (i.e., knee-ankle-foot orthoses with knee locks) are not readily embraced by patients, in part because of their weight and in part because of the severity of falls that may occur with their use. When used, they are almost always in conjunction with a walker. Common contractures include flexion and abduction of the hip, flexion of the knee, and equinovarusposturing of the ankle. Daily passive range-of-motion exercises and orthoses usually are the first line of treatment. A variety of tendon lengthening, release, and transfer procedures have been used for all of the aforementioned contractures. Shapiro prefers an individualized approach, avoiding for the most part both prophylactic and palliative surgical intervention. Lengthening of the hamstring and Achilles tendons and posterior tibial tendon transfers are the most common procedures and should be undertaken primarily in patients who have incentive to continue walking. Although surgical procedures have been performed after a child has lost ambulatory capability, it is unlikely that they will lead to restored walking if the child has been in a wheelchair for 6 months or more. Most, if not all, surgical procedures after this 6-month window should be undertaken for comfort considerations only. The management of kyphoscoliosis involves wheelchair adaptations, spinal orthoses, and surgical intervention. Unfortunately, none of these procedures has slowed the progression of restrictive lung disease in patients with Duchenne’s muscular dystrophy. Wheelchair seating systems using narrow frames, firm seats and backs, dual seat belts, and lateral chest wall supports are chosen primarily for comfort. Spinal arthrodesis enhanced by metallic instrumentation has been used to stabilize spinal curves in patients with congenital myopathy. In Duchenne’s dystrophy, in which the natural history is better understood and progression is inevitable, intervention may take place when the curve is as small as 10%. In the congenital myopathies, in which significant kyphoscoliosis is rare, it is prudent to document progression before surgical intervention, ideally acting before the curve exceeds 40%. Scapular fixation techniques are of little use in patients with congenital myopathy and significant scapular winging. Unlike facioscapulohumeral dystrophy, concomitant weakness of the deltoids and other shoulder girdle muscles precludes any functional benefit in the majority of patients with congenital myopathy. Congenital dislocation of the hip may be treated successfully with closed reduction and spica casting in infancy but may necessitate femoral osteotomy in those older than 18 months. Patients with any degree of cardiopulmonary compromise should be immunized against influenza and pneumococcus. Baseline forced vital capacity, negative inspiratory force measurements (age permitting), and electrocardiograms should be obtained. An echocardiogram should be obtained if there is any

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clinical suspicion of cardiac involvement or if the type of congenital myopathy places the patient at increased risk of cardiomyopathy.

ACKNOWLEDGMENTS I would like to thank Dr. Thomas Smith of the University of Massachusetts Medical Center, Department of Pathology, for his permission to use the pathologic material in Fig. 111-1; Drs. Douglas Anthony and Natasha Lec of Boston’s Children’s Hospital, Department of Pathology, for their permission to use Fig. 111-4; and Drs. Douglas Anthony and Fred Shapiro of Boston Children’s Hospital, Department of Orthopedics, and Roy Jones of the Lahey Clinic for their helpful review of the manuscript.

SUGGESTED READINGS Bodensteiner JB: Invited review: congenital myopathies. Muscle Nerve 12131-144, 1994 Dalakas MC, Park KY, Semino-Mora C et ak Desmin myopathy: a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 342770-780, 2000 Engel A G Myofibrillar myopathy. Ann Neurol46681483, 1999 Fardeau M: Congenital morphologically specific myopathies and malignant hyperthermia. In Course 2FC005. In Neuromuscular Panorama: The Past, Present and Prologue to the Future. Annual Meeting of the American Academy of Neurology, San Diego, 2000 Fardeau M, Tome FS: Congenital myopathies. pp. 1487-1532. In Engel AG, Franzini-Armstrong C (eds): Myology. 2nd Ed. McGraw-Hill, New York Ferreiro A, Estournet B, Chateau D et al: Multi-minicore diseasesearching for boundaries: phenotype analysis of 38 cases. Ann Neurol 48:745, 2000 Goebel HH, Anderson J R Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies):56th European Neuromuscular Centre (ENMC) sponsored International Workshop. Neuromuscul Disord 950-57, 1999 Goebel HH, Lenard H G Congenital myopathies. pp. 331-368. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 18. Elsevier, Amsterdam, 1992 Iannaccone S T Progress in the understanding of the congenital myopathies. In Course 3PC007. In Update on Myopathies. Annual Meeting of the American Academy of Neurology, San Diego, 2000 Jones HR Jr: EMG evaluation of the floppy infant: differential diagnosis and technical aspects. Muscle Nerve 13:338, 1990 Kaplan JC, Fontaine B: Neuromuscular gene locations. Neuromuscul Disord 105-IX, 2000 Scacheri PC, Hoffman EP, Fratkin JD et ak A novel ryanodine receptor gene mutation causing both cores and rods in a congenital myopathy. Neurology 55:1689-1696, 2000 Shapiro F, Specht L The diagnosis and orthopaedic treatment of inherited muscular diseases of childhood. J Bone Joint Surg 75-A439, 1993

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112 Myotonia and Periodic Paralysis Barbara E, Shapiro and Robert H. Brown, Jr. In recent years, several lines of investigation have delineated the molecular basis for an expanding family of disorders of ion channels or receptors, including seven inherited muscle diseases: hypokalemic periodic paralysis, hyperkalemic periodic paralysis, Andersen’s syndrome, paramyotonia congenita, myotonia congenita, potassium-aggravated myotonia, and myotonic dystrophy. To a remarkable degree, it is now possible to integrate the clinical features of these diseases with an understanding of the mutant channel proteins at the molecular level. This chapter provides an overview of these diseases, with an emphasis on their clinical management and laboratory diagnostic testing. CLINICAL DISORDERS M yotonia Myotonia is a disorder of skeletal muscle characterized by excessive electrical irritability of the muscle membrane. Clinically, it causes muscle stiffness that typically worsens in the cold. On electromyography (EMG), myotonic muscle demonstrates abnormally long bursts of muscle fiber action potentials that wax and wane in amplitude and frequency after discrete stimuli such as percussion. It is useful to distinguish between dystrophic and nondystrophic myotonic disorders (Table 112-1). The major disorder in the former category is myotonic dystrophy; nondystrophic myotonias include hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita, myotonia congenita, and potassium-aggravated myotonia (Table 112-2). Hypokalemic periodic paralysis (HypoPP) and Andersen’s syndrome are not associated with myotonia.

Hypokalemic and Hyperkalemic Periodic Paralysis As the name implies, the central clinical problem in the periodic paralyses is episodic weakness. This may be profound, causing almost total limb paralysis. Fortunately, it usually spares diaphragm TABLE112-1. Classification of Periodic Paralyses and Myotonias Disease

Gene

Chromosome

Nondystrophic

Hyperkalemic periodic paralysis Paramyotonia congenita Potassium-aggravated myotonia Hypokalemic periodic paralysis Andersen‘s syndrome Myotonia congenita Autosomal dominant Ohomsen’s) Autosomal recessive (Becker‘s generalized) Schwartz-Jampel

Na+ channel K+ channel Na+ channel Na+ channel

17 11 17 17

Ca++channel Na+ channel K+ channel

1 17 17

CI- channel

7

CI- channel

7

?

1

Myotonin (protein kinase) ?

9

Dystrophic

Myotonic dystrophy type I Mvotonic dwtrophv tvPe 2

3 -

matic and cardiac function and mentation. During HypoPP, serum potassium levels usually are low, and the converse is true during HyperPP. Other clinical features distinguish these disorders. HypoPP is rarely associated with myotonia, whereas this is common in the hyperkalemic form. HypoPP typically begins in adolescence and affects males more severely than females. In fact, some females with HypoPP may never experience attacks of weakness. It is provoked by ingesting carbohydrates and may be aborted with ingestion of potassium. HyperPP usually begins in early childhood and shows no influence of gender on severity. It is triggered by fasting or potassium ingestion and may be aborted with ingestion of sweets. Several clinical attributes are common to both entities. In both disorders, attacks may be frequent, may last up to several hours, and may be triggered by cold or rest after exertion. During paralysis, skeletal muscle is depolarized and electrically silent in both diseases. Particularly in HyperPP, exercise may ameliorate symptoms of an impending attack of weakness; conversely, long periods of inactivity may provoke attacks. Some patients with hyperkalemic or hypokalemic periodic paralysis may develop slowly progressive, irreversible proximal muscle weakness.

Andersen’s Syndrome Andersen’s syndrome is characterized by the triad of periodic paralysis, characteristic physical features, and prolonged QT interval with ventricular arrhythmias. Patients present in childhood or adolescence with all or some of these features. The periodic paralysis may be accompanied by hypokalemia, normokalemia, or hyperkalemia. Attacks of weakness may occur spontaneously or be triggered by rest after exercise or alcohol. Generalized limb and neck flexor weakness may be present between attacks. Myotonia is not present. Some patients report intermittent muscle pain without attacks of weakness. Patients often can work through the muscle pain by continuing with mild exercise. Prolonged QT interval is present in about 80% of patients and may be the only finding in some patients from a family with otherwise typical Andersen’s syndrome. Patients may present in childhood with cardiac arrest, with no history of periodic paralysis, although they may experience periodic paralysis in later years. Characteristic physical features include short stature, high arched palate, hypertelorism, low-set ears, broad nose, micrognathia, clinodactyly of the fingers, short index fingers, and syndactyly of the toes. Scoliosis may be present.

Paramyotonia Congenita Patients with paramyotonia congenita present in infancy with muscle stiffness that affects primarily bulbofacial, neck, and hand muscles. Most patients also develop episodes of paralysis, usually in response to sustained exposure to cold. The electromyogram of such patients is pathognomonic, showing diffuse myotonic discharges in proximal and distal muscles at rest, increased electrical irritability (fibrillation potentials) and myotonic discharges with mild cooling, and electrical silence during paralysis as the muscle is cooled below 20°C. In general, serum potassium

AD Na channel

Acetazolamide, dichlorphenamide Mexiletine AD Na channel

Na channel, K channel

AD

Ca channel, Na

channel

AD

Acetazolamide, dichlorphenamide Mexiletine

Warming

Yes No Cold

Infancy

No

PotassiumAggravated Myotonia

Acetazolamide, dichlorphenamide Mexiletine

Warming, exercise

Minutes to days Minutes to days Yes No Cold, fasting, rest after exercise

Infancy

Rarely

Paramyotonia Congenita

Acetazolamide, dichlorphenamide Mexiletine

Carbohydrates, exercise

Minutes to days Minutes to days Yes No Cold, fasting, rest after exercise

Infancy

Puberty

Hours to days Hours to days No No Cold, rest after exercise, carbohydrates Potassium, exercise

Yes

Hyperkalemic

Yes

AD, autosomal dominant; AR, autosomal recessive.

Reduce myotonia Genetic Inheritance pattern Gene

Therapy Prevent paralysis

Ameliorators

Attack duration lnterictal interval Myotonia Systemic features Triggers

Clinical Recurrent weakness Onset

Hypokalemic

PERIODIC PARALYSES

TABLE112-2. Features of the Periodic Paralyses and Nondystrophic Myotonias

CI channel

AR

Mexiletine

Warming, exercise

Yes No Cold

Childhood

No

Generalized Myotonia

CI channel

AD

Mexiletine

Warming, exercise

Yes No Cold

Childhood

No

Myotonia Congenita

Myotonin kinase

AD

Mexiletine

Yes Yes Cold

Childhood

No

Myotonic Dystrophy

K channel

AD

Acetazolamide, dichlorphenamide

Exercise

Childhood to puberty Hours to days Hours to days No Yes Rest after exercise, alcohol

Yes

Andersen's Syndrome

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Spinal cord and Peripheral Neuromuscular Disease H Diseases of Muscle

levels are normal in these patients during attacks, although challenge with potassium infusions may reduce the amplitudes of compound muscle action potentials in some patients, similar to that seen in HyperPP. In paramyotonia congenita, repeated muscle contractions may worsen the myotonia; this paradoxical myotonic (hence paramyotonia) response is opposite that usually seen with myotonia. The distal limbs and facial muscles tend to be particularly affected by cold exposure in these patients. Therefore, there may be difficulty opening the eyes or rapidly releasing grip. Myotonia Congenita

Patients with myotonia congenita do not develop episodes of paralysis, with rare exception, but are continuously stiff. In effect, myotonia congenita muscle often is in a state of isometric contraction. As a result, the muscles of these patients acquire a robust, hypertrophied appearance, especially in the proximal arms, thighs, calves, and facial muscles, giving rise to the characteristic “Herculean” appearance. Despite this, normal function is significantly impaired by the excessive stiffness. Patients describe worsening of symptoms in the cold and lessening of symptoms with continued exercise. One form of this disease begins in early childhood and is dominantly inherited; this was first described by Julius Thomsen, who was also affected. Another form, recessive generalized myotonia, is more common and was described by Becker. This begins in later childhood and is inherited as an autosomal recessive trait. Potassium-Aggravated Myotonia

At least two features distinguish potassium-aggravated myotonia from myotonia congenita. In potassium-aggravated myotonia but not myotonia congenita, myotonia is exacerbated by measures that increase serum potassium; in addition, myotonia in potassiumaggravated myotonia is less cold sensitive. Patients do not experience episodes of paralysis. Three forms of potassiumaggravated myotonia have been distinguished on the basis of the degree of variability of the myotonia and response to treatment. In myotonia fluctuans, patients present in adolescence with myotonia, but not weakness, that is provoked by delayed rest after exercise and by potassium ingestion. Patients with this disorder may go very long periods (months) without symptomatic myotonia. By contrast, patients with myotonia permanens present in childhood with severe, unremitting generalized myotonia, at times sufficient to impair breathing. In acetazolamide-responsive myotonia, also known as atypical myotonia congenita, patients experience intermittent painful myotonia beginning in childhood that has a predilection for axial and proximal limb musculature. Severe disabling spasms and acute lumbar scoliosis may occur on some days, and on other days patients are asymptomatic. Symptoms are markedly reduced with acetazolamide. Myotonic Dystrophy

By contrast with the nondystrophic myotonic disorders, myotonic dystrophy is not confined solely to skeletal muscle. Rather, myotonic dystrophy is a multiple-system disorder that may involve skeletal muscle, the brain, the cardiac conducting system, and the endocrine system (insulin-resistant diabetes and testicular atrophy are common). These patients have a characteristic facial appearance with thinning of the temporalis and masseter muscles, frontal balding, ptosis, and a tendency toward slackness of muscle tone

around the mouth. In one form of this disease, myotonic dystrophy type 1, patients can develop extreme distal limb weakness and wasting. In myotonic dystrophy type 2, the progressive weakness involves distal as well as proximal muscles. As the name implies, these patients usually have some degree of myotonia, although it is less severe than in the nondystrophic myotonias. In fact, patients with myotonic dystrophy may not volunteer complaints of muscle stiffness but on questioning may describe such manifestations of stiffness as difficulty releasing the hand from a doorknob on a cold day. Newborn infants with myotonic dystrophy type 1 may be strikingly hypotonic and floppy. Often the diagnosis of mild myotonic dystrophy in a mother is established only after she gives birth to a floppy newborn. MUSCLE BIOPSY

Microscopic analysis of skeletal muscle in the periodic paralyses, paramyotonia congenita, and myotonia congenita is normal early in the illness. In patients with a long history of protracted paralytic episodes, there may be vacuoles within the muscles. After several decades, some patients develop irreversible proximal muscle weakness with vacuolar changes on muscle biopsy, including female patients with HypoPP who may never have experienced paralytic episodes. These subtle features contrast with the more myopathic findings in myotonic dystrophy muscles, which may show fiber size variation, fibrosis, central nuclei, ring fibers, and chains of nuclei. Electron microscopic evaluation sometimes shows duplication of T tubules as an early manifestation of the vacuolar change. PATHOPHYSIOLOGIC STUDIES

In normal nerve and muscle at rest, the intracellular compartment is hyperpolarized by about 90 mV with respect to the extracellular milieu. The resting conductances (g) for potassium and chloride are large compared with that for sodium, and therefore the resting potential (V,) is determined largely by the Nernst potentials for potassium and chloride. An action potential occurs when the membrane is depolarized beyond the threshold for all-or-nothing excitation. In this circumstance, the conductance for sodium increases rapidly such that V, approaches the equilibrium potential for sodium (ENa). Repolarization occurs for two reasons. The abrupt activation or rise in, g is self-terminating because the depolarized sodium (Naf) channel rapidly closes or inactivates. Slightly thereafter, an outward, repolarizing potassium (K+) current is activated. Thus,, ,g falls and g, rises. Both factors drive V, back toward E, and Eel. In muscle, an additional factor affects the rate at which V, relaxes back to the normal resting potential. Much of the outflow of K+ ions across the membrane is into the muscle cell transverse tubules (T tubules), whose interiors are topographically outside the muscle cell. Because the T tubules are extremely narrow, a small, outwardly flowing K+ current can lead to significant increases in the effective extracellular K+ inside the T tubule. As indicated by the Nernst potential, this increases E, across the T tubule membrane and slows restoration of V,, closer to the threshold for all-or-nothing firing. Fortunately, even with repetitive firing of the muscle cell, gCl is sufficiently large that it can “clamp” V,, counteracting the change in E,. As noted later in this chapter, this clamping of V, by the chloride channel is critical for normal, stable excitability of the muscle fiber. Numerous investigations indicate that in the nondystrophic

Chapter 112

myotonias, myotonia and paralysis are closely related, reflecting different degrees of the same abnormality: conductance changes that slightly depolarize V,, rendering V, closer to the firing threshold. In theory, this could arise from an increase in g,, or a decrease in either g, or gel. With mild depolarization of V, (failure of full restoration of V, after excitation), the muscle cell initially becomes more readily excitable (more myotonic). As the degree of pathologic depolarization increases, the muscle becomes inexcitable and thus unable to contract to generate force. This phase corresponds to the paralytic phase of periodic paralysis.

Hyperkalemic Periodic Paralysis, Paramyotonia Congenita, and Potassium-Aggravated Myotonia In 1963, experimental data from patients with periodic paralysis led Creutzfeld and colleagues to speculate that HyperPP arises from excessive membrane depolarization because of a defect in Na+ conductance. This possibility has subsequently been examined by several investigators, prominently including LehmannHorn, Rudel, and Ricker. In muscle from patients with HyperPP, they documented that increasing extracellular K+ increases total inward current and simultaneously depolarizes the membrane potential in excess of the depolarization predicted by the Nernst equation. Both the increment in background current and the depolarization induced by elevated bath K+ were reversed by the addition of a Na+ channel-blocking agent, tetrodotoxin. Cannon et al. extended these observationsin patch clamp studies of muscle grown in culture from biopsies of a patient with HyperPP. In this system, a fraction of the Na+ channels showed imperfect inactivation; the fraction increased with increasing extracellular K+ concentrations. These and many other studies implicate a defect in Na+ conductance in the pathogenesis of HyperPP associated with mutations of the muscle sodium channel gene. Recently, Abbott et al. described two families with a clinical syndrome of HyperPP without myotonia who had a mutation in a potassium channel subunit. The mechanism of paralysis in HyperPP associated with a potassium channel mutation is not as well understood but may be secondary to destabilization of the resting potential. Paramyotonia congenita and potassium-aggravated myotonia are caused by mutations in the same muscle Na+ channel gene associated with HyperPP. A key difference in the Na' channel mutations that produce HyperPP or paramyotonia and the mutations that produce potassium-aggravated myotonia is the duration of the membrane depolarization produced by the mutation. In HyperPP and paramyotonia congenita, the Na+ channel point mutations enable altered Na+ channels to either remain open or repeatedly open, resulting in prolonged membrane depolarization. However, the mutations associated with potassium-aggravated myotonia do not produce prolonged membrane depolarization. These brief depolarizations cause myotonia without weakness, in contrast to the persistent depolarization that results in initial hyperexcitability followed by depolarization-induced membrane inexcitability and paralysis. Interruption of Na+ channel slow inactivation facilitates the production of a persistent depolarizing Na+ current, and slow inactivation is disrupted by several of the point mutations associated with HyperPP. Disruption of both inactivation processes allows the mutant channels to remain open or to repeatedly open for prolonged times. Slow inactivation is not disturbed by the mutations that produce potassium-aggravated myotonia. It is not known how reduced temperature induces paralysis in paramyotonia.

Myotonia and Periodic Paralysis

731

Hypokalemic Periodic Paralysis Two forms of HypoPP have been identified, the more common one associated with mutations of the muscle Ca" channel gene and a rarer form associated with mutations of the muscle Na+ channel gene. The ionic pathophysiology of HypoPP has not been as precisely delineated as that of HyperPP or myotonia congenita. Lehmann-Horn and associates established in the 1980s that affected muscle becomes depolarized and demonstrates an augmented net inward current on exposure to medium with low K+. Weakness in both forms of HypoPP is produced by prolonged membrane depolarization leading to loss of membrane excitability. The mechanism of membrane depolarization in HypoPP associated with mutations of the muscle Ca" channel gene is better understood. The Ca" channel mutations in HypoPP alter membrane excitabilityindirectly by changing the properties of two other channels: inward rectifier K+ channels (which contribute to setting the resting potential) and Na+ channels. Reduced K+ conductance facilitates membrane depolarization. A decreased density of Na+ channels reduces membrane excitability and facilitates depolarization-induced loss of membrane excitability. Reduced density of functional Na+ channels is a feature of HypoPP associated with Ca" channel mutations and Na" channel mutations. The low density of Na+ channels in both forms of HypoPP prevents membrane hyperexcitabilityfrom developing with membrane depolarization. Consequently, myotonia is not present in HypoPP.

Andersen's Syndrome Andersen's syndrome is associated with mutations of the Kir2.1 subunits of the muscle K+ channel. Four K i d . 1 subunits form an inward rectifier K+ channel in skeletal and cardiac muscle, which helps to set the resting potential of cardiac and skeletal muscle cells. In Andersen's syndrome, mutant subunits form nonfunctional inward rectifier K+ channels. It is postulated that the mechanism of paralysis in Andersen's syndrome therefore may be destabilization of the resting potential.

Myotonia Congenita It is observed experimentally that reduction of gcI in normal skeletal muscle produces a tendency toward easily triggered, sustained, repetitive membrane firing. In the 1960s, reports documented that membrane chloride conductance is lower in muscle of patients with Thomsen's disease. Two animal models lend credence to the role of an abnormal chloride conductance in myotonia. Bryant documented that congenital goat myotonia arises because of a reduction in skeletal muscle chloride permeability. In an elegant analysis, Adrian and Bryant demonstrated that sustained, repetitive myotonic firing of this goat muscle requires both a reduced chloride conductance and the accumulation of K+ ions in an intact T tubule system. In 1991, Steinmeyer and colleagues cloned a mammalian, voltage-dependent chloride channel "ClC-1" and demonstrated that this is disrupted in a myotonic mutant mouse (adrladr mouse).

Myotonic Dystrophy The defect in patients with myotonic dystrophy type 1 is an expansion of a cytosine, thymine, guanine (CTG) nucleotide repeat in the 3', noncoding region of a protein kinase gene.

732

Spinal Cord and Peripheral Neuromuscular Disease

Diseases of Muscle

However, the pathophysiologic mechanisms by which this untranslated CTG expansion causes progressive weakness and multiple-system defects remains unclear. Several mechanisms have been proposed to date. The CTG expansion in DNA may affect adjacent genes in the region of the myotonin protein kinase (DMPK) gene, resulting in a regional gene effect; the transcribed CTG repeat expansion in RNA may result in a toxic gain of function; or the CTG expansion may result in a partial deficiency (haploinsufficiency) of the DMPK gene. It is possible that all of these mechanisms come into play, with the combined effect leading to the variable and multisystemic nature of the disease. The mechanisms underlying disease expression in myotonic dystrophy type 2 are unknown.

GENETIC AND MUTATION ANALYSIS HyperkalemicPeriodic Paralysis, Paramyotonla Congenh, and Potassium-Aggravated Myotonia The dominantly inherited disorders of HyperPP, paramyotonia congenita, and potassium-aggravated myotonia arise from mutations in the a subunit of the skeletal muscle Na+ channel on chromosome 17q23; indeed, more than 20 different mutations have been identified in the gene for this subunit in affected patients. These mutations produce minor amino acid changes that typically affect residues that are highly conserved across multiple species. Some fall into well-defined functional domains of the channel. The rarer, K” channel variant of HyperPP is associated with mutations in the KCNE3 gene, which encodes the MinKrelated peptide 2 (MiRP2) on chromosome 11. MiRP2 coassembles with a voltage-gated K+ channel subunit, Kv3.4, to form a channel complex that contributes to regulation of the resting potential. Hypokalemic Periodic Paralysis

In 1994, genetic linkage was established between HypoPP, a dominantly inherited disease, and a locus in human chromosome 1 encoding the a subunit of a voltage-sensitive muscle Ca” channel, the so-called dihydropyridine receptor. Two different mutations have been identified in most families with these diseases. A third, less common mutation has been recognized. In 1994 Plassart et al. also reported a large French family with HypoPP that did not link to the muscle Ca” channel gene; this condition was clinically indistinguishable from that of other patients with HypoPP. Subsequently, mutations were identified in the a subunit of the muscle Na+ channel gene, and the term HypoPP type 2 was used to denote this condition. Andersen‘s Syndrome

Andersen’s syndrome is inherited in an autosomal dominant fashion with incomplete penetrance. In 2001, Plaster et al. described several families with Andersen’s syndrome with mutations in the K+ channel Kir2. 1 subunit of the inward rectifying K’ channel gene KCNJ2, on chromosome 17q23. However, genetic heterogeneity is likely because no mutations in Kir2.1 were found in three families studied by Plaster et al. Some families may have mutations in the regulatory regions or regulatory proteins of Kir2.1, and mutations in unrelated genes may also account for some patients with Andersen’s syndrome.

Myotonia Congenita

Both genetic linkage and mutation analyses have established the fact that mutations in the CIC-1 gene on chromosome 7q underlie the two types of myotonia congenita: Becker’s autosomal recessive generalized myotonia and dominantly inherited myotonia congenita (Thomsen’s disease). Myotonic Dystrophy

The myotonic dystrophies are also dominantly inherited. In 1992, Brook and associates described a new protein kinase named myotonin, encoded by the myotonic dystrophy gene. The defect in patients with myotonic dystrophy type 1 is an expansion of a CTG repeat in the 3’, untranslated region of this gene. This defect is genetically unstable, tending to expand even between single generations from a slightly enlarged “premutation” to much larger forms; in general, there is a strong correlation between the length of the CTG repeat and the severity of the myotonic dystrophy. The functional significance of these mutations is not well defined. Myotonic dystrophy type 2 is linked to a 3cM region on chromosome 3q21. At least one other locus that has not yet been mapped is suggested by genetic exclusion data.

DIFFERENTIAL DIAGNOSIS AND EVALUATION An algorithm for evaluating these patients is outlined in Figure 112-1. Perhaps the most useful initial question is whether the problem is recurrent weakness, myotonia, or both. Recurrent weakness with low and high potassium levels rapidly defines distinct entities: hypokalemic and hyperkalemic paralysis. Recurrent weakness with normal potassium can be seen either as a variant of HyperPP, in which case the serum potassium may rise within the normal range during attacks, or as paramyotonia congenita, in which case cold generally provokes the attacks of weakness. Recurrent weakness in the setting of characteristic facial features (low-set ears, hypertelorism, broad nose, micrognathia) and other typical physical features (short stature, high arched palate, clinodactyly of the fingers, short index finger, syndactyly of the toes) should suggest the diagnosis of Andersen’s syndrome. Myotonia may be seen in HyperPP and paramyotonia congenita, but not HypoPP or Andersen’s syndrome. Myotonia without periodic weakness, if aggravated by potassium, usually reflects a defect in the sodium channel, as in potassium-aggravated myotonia. Myotonia without periodic weakness, which is neither potassium sensitive nor part of a multiple-system disease, typically arises from defects in the muscle chloride channel, as in myotonia congenita. The presence of multiple-system defects argues strongly in favor of the diagnosis of myotonic dystrophy. There are few other disorders in this differential evaluation. In Schwartz-Jampel syndrome, children with a distinctive facial and physical appearance, including short stature, short neck, and multiple facial anomalies (micrognathia, low-set ears, pursed lips, upwardslanting eyes, blepharophimosis, exotropia, and microcornea), are myotonic but do not have recurrent paralysis. Patients with recurrent weakness with disturbed serum potassium levels but no clear family history of periodic paralysis merit a thorough evaluation for alternate causes of hypokalemia or hyperkalemia. Particularly striking is the conjoining of HypoPP with thyrotoxicosis, an entity more prevalent in Japan than in the United States. If there is diagnostic ambiguity, provocative testing may be

Chapter 112

1

In Attack

In Attack

I") + [

Multi-system Defects

J

L

Aggravated

No

1 Low

Normal

733

Myobnia without Weakness

Periodic Weakness

1

Myotonia and Periodic Paralysis

High

I

No

Yes

Yes

4

(GAL) v

AR

1 1

)

AD

I

FIG. 112-1. Evaluation of the patient with periodic paralysis and myotonia.

helpful. Thus, one may provoke hypokalemic weakness by administering oral glucose (5 g/kg, to a total of 100 g); if the diagnosis is strongly suspected and the oral glucose challenge is ambiguous, one may infuse intravenous glucose ( 3 g/kg over 1 hour), possibly with added insulin. During this procedure, the serum potassium should be monitored three or four times per hour, with close ECG monitoring as well. Provocative testing for HyperPP can be performed using oral potassium loading (1 mEq/ kg), with frequent potassium monitoring and ECG surveillance for at least 3 hours after loading. Cooling a limb while monitoring EMG may assist in establishing the diagnosis of paramyotonia congenita. In these patients, cooling to 3OoC induces fibrillation potentials; additional cooling below 2OoC may produce electrical silence concurrently with clinical paralysis of the cooled muscles. It may be useful to monitor the amplitude of the compound muscle action potential during this process; the amplitude may drop dramatically with cooling in patients with paramyotonia congenita. The mainstay of laboratory investigations of these patients is screening of blood DNA for mutations in genes now established to be defective in each disorder (Tables 112-1 and 112-2). These studies use only a small blood sample and can be performed rapidly. The selectivity of the specific mutations for each disorder is close to 100%; the rate of false negatives probably is less than 10%. For these reasons, an accurate DNA diagnosis is costeffective, obviating muscle biopsy in most cases.

TREATMENT Myotonia associated with these disorders may be difficult to treat. In our experience, the most consistently helpful drug is mexiletine,

a sodium channel-blocking lidocaine derivative. Benefit may also be seen with other membrane-active compounds such as phenytoin. Attacks of weakness may be reduced in frequency with the carbonic anhydrase inhibitor acetazolamide; a related, more potent inhibitor, dichlorphenamide, was also found to be effective. In HypoPP, there appears to be little benefit from chronic (daily) potassium administration. On the other hand, some patients with HyperPP report benefit from chronic use of a potassium-wasting diuretic. Acute attacks of weakness in periodic paralysis usually respond to management of the serum potassium abnormality. In HypoPP, it almost always suffices to administer potassium orally. If intravenous fluids are administered to patients with HypoPP, high-sodium solutions may exacerbate weakness. For this reason, some authors suggest using mannitol solutions for intravenous infusion. The arrhythmias in patients with Andersen's syndrome generally are unresponsive to the commonly used anti-arrhythmic agents, including tocainide, procainamide, flecainide, quinidine, sotalol, and amiodarone. These agents may actually worsen the weakness or prolong the QT interval. Imipramine has been used in a few patients to treat the arrhythmias without exacerbating the weakness. Patients with Andersen's syndrome should undergo a thorough cardiac evaluation. SUGGESTED READINGS Abbott GW, Butler MH, Bendahhou et al: MiRPw forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104217-231, 2001 Brook JD, McCurrach ME, Harley HG et al: Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3N end of a transcript encoding a protein kinase family member. Cell 69:385395, 1992

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Bryant S H Myotonia in the goat. Ann N Y Acad Sci 317314-325, 1979 Cannon SC, Brown RH Jr, Corey D P A sodium channel defect in hyperkalemic periodic paralysis: potassium-induced failure of inactivation. Neuron 6619-626, 1991 Catterall W Structure and function of voltage-sensitive ion channels. Science 242:50-61, 1988 Creutzfeld OD, Abbott BC, Fowler WM et ak Muscle membrane potentials in episodica adynamia. ElectroencephalogrClin Neurophysiol 15:508515, 1963

Engel AG: Evolution and content of vacuoles in primary hypokalemic periodic paralysis. Mayo Clin Proc 45:774-851, 1970 Fontaine B, Khurana T, Hoffman E et ak Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 250:100CL1002, 1990

Hoffman EP, Lehmann-Horn F, Rudel R Overexcited or inactive: ion channels in muscle disease. Cell 80:681-686, 1995 Jurkat-Rott K, Lehmann-Horn F, Elbaz A et ak A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 3:1415-1419, 1994

Lehmann-Horn F, Grzeschik KH, Jentsch TJ: Tight linkage of recessive and dominant forms of human myotonia to skeletal muscle chloride channel gene. Science 257:797-800, 1992 Lipicky RJ, Bryant SH, Salmon JH: Cable parameters, sodium, potassium and chloride and water content and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita. J Clin Invest 50:2091-2103, 1971 Plassart E, Elbaz A, Santos JVet ak Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP). Hum Genet 94551-556, 1994

Plaster NM, Tawil R, Tristani-Firouzi M et ak Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511-519,2001 Ptacek L, Tawil R, Griggs RC et ak Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863-868, 1994 Ranum LPW, Rasmussen P, Benzow K et ak Genetic mapping of a second myotonic dystrophy locus. Nat Genet 19:19&198, 1998 Ricker K, Koch MC, Lehmann-Horn F et al: Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44:1448-1452, 1994 Roses AD: Myotonic dystrophy. pp. 633-646. In Rosenberg RN, Prusiner SB, DiMauro S et a1 (eds): The Molecular and Genetic Basis of Neurologic Disease. Butterworth-Heinemann, Boston, 1993 Rudel R, Lehmann-Horn F Membrane changes in cells from myotonia patients. Physiol Rev 65:310-356, 1985 Rudel R, Ricker K, Lehmann-Horn F Genotype-phenotypecorrelations in human skeletal muscle sodium channel diseases. Arch Neurol50: 12411248, 1993

Shapiro BE, Ruff RL: Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis and related syndromes. In Katirji B, Kaminski H, Preston DC et al (eds): Neuromuscular Disorders in Clinical Practice. ButterworthHeinemann, Boston, 2002 Steinmeyer K, Ortland C, Jentsch TJ: Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Nature 354:301-304, 1991

113 Abnormal Muscle Activity Ludwig Gutmann MYOKYMIA Myokymia is a clinical phenomenon characterized by undulating, vermicular, rippling, and wavelike movements spreading across the muscle surface. It is closely related to neuromyotonia. Both disorders may be related to K+ channel abnormalities. Myokymia may occur in a focal o r generalized fashion. Depending on the nature of the underlying problem, the facial muscles may be more commonly involved than those of the extremities. Myokymia occurs focally as a manifestation in a number of disorders, the most common of which are GuillainBarre syndrome, multiple sclerosis, radiation plexopathy, and brain stem tumors. Myokymia occurs in a generalized fashion in timber rattlesnake (Crotulus horridus horridus) envenomation and episodic ataxia type 1. The disorders that most commonly produce myokymia and their underlying myokymic discharges affect the axon membrane microenvironment through such mechanisms as demyelination, radiation changes, direct toxic effects, ischemia, hypoxia, hypocalcemia, edema, and alterations in Kf channels by autoantibodies o r genetic abnormalities. Axon compression is a n uncommon cause of myokymia. One may see occasional isolated myokymic discharges involving a single motor unit in compressive neuropathies (e.g., carpal tunnel syndrome) and radiculopathies, but these are not sufficiently widespread to be noted clinical myokymia. The clinically observable myokymia is associated with charac-

teristic electromyographic (EMG) activity called myokymic discharges. The myokymic discharges typically are short bursts of motor unit potentials. The motor unit potentials within the burst fire at a rate of 5 to 150 Hz and appear as doublets, triplets, or multiplets (Fig. 113-1). Each myokymic burst usually fires recurrently at 2 to 10 Hz in a rhythmic o r semirhythmic fashion. Occasionally, bursts may fire much less frequently, such as once every 20 to 30 seconds. Myokymic bursts with more spikes generally fire at a slower frequency. The actual rate of firing of myokymic bursts varies from one neighboring unit to the next, resulting in a complex firing arrangement within the muscle. The discharges may originate in the intramedullary portion of the motor axon, as in multiple sclerosis and pontine gliomas. They may arise peripherally in the motor axons, as in Guillain-Barrk syndrome and radiation plexopathy. Disorders in which myokymia has been reported include the following (asterisk indicates those in which it is regularly seen): Guillain-Barre* Multiple sclerosis* Radiation plexopathf Intramedullary o r extramedullary pontine tumors o r masses* Timber rattlesnake envenomation* Chronic inflammatory demyelinating polyneuropathy Neoplastic o r inflammatory meningoradiculitis

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Diseases of Muscle

Bryant S H Myotonia in the goat. Ann N Y Acad Sci 317314-325, 1979 Cannon SC, Brown RH Jr, Corey D P A sodium channel defect in hyperkalemic periodic paralysis: potassium-induced failure of inactivation. Neuron 6619-626, 1991 Catterall W Structure and function of voltage-sensitive ion channels. Science 242:50-61, 1988 Creutzfeld OD, Abbott BC, Fowler WM et ak Muscle membrane potentials in episodica adynamia. ElectroencephalogrClin Neurophysiol 15:508515, 1963

Engel AG: Evolution and content of vacuoles in primary hypokalemic periodic paralysis. Mayo Clin Proc 45:774-851, 1970 Fontaine B, Khurana T, Hoffman E et ak Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 250:100CL1002, 1990

Hoffman EP, Lehmann-Horn F, Rudel R Overexcited or inactive: ion channels in muscle disease. Cell 80:681-686, 1995 Jurkat-Rott K, Lehmann-Horn F, Elbaz A et ak A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 3:1415-1419, 1994

Lehmann-Horn F, Grzeschik KH, Jentsch TJ: Tight linkage of recessive and dominant forms of human myotonia to skeletal muscle chloride channel gene. Science 257:797-800, 1992 Lipicky RJ, Bryant SH, Salmon JH: Cable parameters, sodium, potassium and chloride and water content and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita. J Clin Invest 50:2091-2103, 1971 Plassart E, Elbaz A, Santos JVet ak Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP). Hum Genet 94551-556, 1994

Plaster NM, Tawil R, Tristani-Firouzi M et ak Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511-519,2001 Ptacek L, Tawil R, Griggs RC et ak Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863-868, 1994 Ranum LPW, Rasmussen P, Benzow K et ak Genetic mapping of a second myotonic dystrophy locus. Nat Genet 19:19&198, 1998 Ricker K, Koch MC, Lehmann-Horn F et al: Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44:1448-1452, 1994 Roses AD: Myotonic dystrophy. pp. 633-646. In Rosenberg RN, Prusiner SB, DiMauro S et a1 (eds): The Molecular and Genetic Basis of Neurologic Disease. Butterworth-Heinemann, Boston, 1993 Rudel R, Lehmann-Horn F Membrane changes in cells from myotonia patients. Physiol Rev 65:310-356, 1985 Rudel R, Ricker K, Lehmann-Horn F Genotype-phenotypecorrelations in human skeletal muscle sodium channel diseases. Arch Neurol50: 12411248, 1993

Shapiro BE, Ruff RL: Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis and related syndromes. In Katirji B, Kaminski H, Preston DC et al (eds): Neuromuscular Disorders in Clinical Practice. ButterworthHeinemann, Boston, 2002 Steinmeyer K, Ortland C, Jentsch TJ: Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Nature 354:301-304, 1991

113 Abnormal Muscle Activity Ludwig Gutmann MYOKYMIA Myokymia is a clinical phenomenon characterized by undulating, vermicular, rippling, and wavelike movements spreading across the muscle surface. It is closely related to neuromyotonia. Both disorders may be related to K+ channel abnormalities. Myokymia may occur in a focal o r generalized fashion. Depending on the nature of the underlying problem, the facial muscles may be more commonly involved than those of the extremities. Myokymia occurs focally as a manifestation in a number of disorders, the most common of which are GuillainBarre syndrome, multiple sclerosis, radiation plexopathy, and brain stem tumors. Myokymia occurs in a generalized fashion in timber rattlesnake (Crotulus horridus horridus) envenomation and episodic ataxia type 1. The disorders that most commonly produce myokymia and their underlying myokymic discharges affect the axon membrane microenvironment through such mechanisms as demyelination, radiation changes, direct toxic effects, ischemia, hypoxia, hypocalcemia, edema, and alterations in Kf channels by autoantibodies o r genetic abnormalities. Axon compression is a n uncommon cause of myokymia. One may see occasional isolated myokymic discharges involving a single motor unit in compressive neuropathies (e.g., carpal tunnel syndrome) and radiculopathies, but these are not sufficiently widespread to be noted clinical myokymia. The clinically observable myokymia is associated with charac-

teristic electromyographic (EMG) activity called myokymic discharges. The myokymic discharges typically are short bursts of motor unit potentials. The motor unit potentials within the burst fire at a rate of 5 to 150 Hz and appear as doublets, triplets, or multiplets (Fig. 113-1). Each myokymic burst usually fires recurrently at 2 to 10 Hz in a rhythmic o r semirhythmic fashion. Occasionally, bursts may fire much less frequently, such as once every 20 to 30 seconds. Myokymic bursts with more spikes generally fire at a slower frequency. The actual rate of firing of myokymic bursts varies from one neighboring unit to the next, resulting in a complex firing arrangement within the muscle. The discharges may originate in the intramedullary portion of the motor axon, as in multiple sclerosis and pontine gliomas. They may arise peripherally in the motor axons, as in Guillain-Barrk syndrome and radiation plexopathy. Disorders in which myokymia has been reported include the following (asterisk indicates those in which it is regularly seen): Guillain-Barre* Multiple sclerosis* Radiation plexopathf Intramedullary o r extramedullary pontine tumors o r masses* Timber rattlesnake envenomation* Chronic inflammatory demyelinating polyneuropathy Neoplastic o r inflammatory meningoradiculitis

Chapter 113

Abnormal Muscle Activity

735

the radiation occurred. It is often associated with other neurogenic changes. Myokymia is unlikely to be caused by tumor infiltration or traumatic plexopathy. Therefore, its presence suggests radiation as a cause. Timber rattlesnake envenomation is invariably associated with bilateral facial myokymia and myokymia of the extremities. The facial myokymia occurs as a result of a hematogenous spread of the toxin and disappears within several hours of the patient receiving antivenin therapy. The myokymia in the bitten extremity persists several days before clearing. Episodic ataxia with myokymia type 1 is a rare autosomal dominant disorder. Its importance lies in the fact that it is caused by a point mutation of the K+ channel gene, KCNAl on chromosome 12P.

NEUROMYOTONIA

200 m s FIG. 113-1. Myokymic discharge appearing as a recurrent multiple

once in each sweep. Other smaller myokymic discharges occur in the background.

Anoxic or ischemic rhombencephalopathy Syringobulbia Basilar invagination Gold therapy Cardiopulmonary rest Episodic ataxia with myokymia type 1* Subarachnoid hemorrhage Facial myokymia, at times subtle, with its associated myokymic discharges, occurs in 15% of patients with Guillain-Barre syndrome. Myokymia in the extremities also occurs but is much less common. In Guillain-Barre syndrome, the facial myokymia often is bilateral and associated with mild facial weakness. It appears within the first 3 weeks of the illness and is present up to 1 month before clearing. The limb myokymia in this disorder is also transient. Its occurrence in the extremities in chronic inflammatory demyelinating polyneuropathy is seen occasionally. In multiple sclerosis, myokymia also involves facial muscles much more often than those of the extremities. In the face, it is usually unilateral, transient, and present for only a few weeks. Recurrent episodes occasionally occur and may be on the same or opposite sides. It may be associated with mild facial weakness, and at times the myokymia is sufficiently prominent to result in a persistent contraction of the involved side of the face. Facial myokymia in the presence of a posterior fossa tumor or mass is seen most often with a pontine glioma. It has been reported with other masses, including cerebellar astrocytomas, metastatic tumors, and acoustic neuromas. The myokymia is unilateral and may persist for many months to years. A persistent contraction of the involved side of the face has been reported in a number of cases. Brachial and lumbosacral plexopathy caused by radiation often are associated with myokymia. Myokymia usually is present in only one or a few muscles of the involved extremity but occurs in 60% to 70% of cases. The myokymia may be present decades after

Neuromyotonia is a syndrome of continuous generalized or focal muscle contraction caused by many underlying myokymic discharges and, to a lesser degree, neuromyotonic discharges. Neuromyotonic discharges are prolonged bursts of motor unit potentials, firing at a frequency of 150 to 300 Hz for up to a few seconds, usually beginning and ending abruptly (Fig. 113-2). The potential amplitude may wane but can easily be distinguished from myotonic discharges of muscle fiber origin. Unlike myokymic discharges,the bursts do not recur repetitively in a rhythmic fashion and may be initiated by needle movement, voluntary effort, or nerve percussion. In 1961, Isaacs described a syndrome, now named after him, characterized by continuous muscle fiber activity with stifmess, cramps, and increased sweating. The myokymic and neuromyotonic discharges continue during complete proximal nerve blocks and are abolished by curare blockade. Neuromyotonia often is associated with underlying fibrillation potentials and fasciculations and, in addition to the aforementioned characteristics, continues during sleep and general anesthesia. Carbamazepine and phenytoin may alleviate the symptoms. In a recent review, Newsom-Davis and Mills reported five cases that had associated autoimmune manifestations, including oligoclonal bands in cerebrospinal fluid and improvement after plasma exchange. Additional cases in the literature have been associated with thymoma, myasthenia gravis, elevated acetylcholine receptor antibody titers, and penicillamine therapy. Morvan’s syndrome is another neuromyotonic syndrome that has an additional encephalopathy with insomnia, confusion, and hallucinations. Both are associated with antibodies to K+ channels. Focal neuromyotonia may occur in the face, neck, or extremities. It represents an exaggeration of focal myokymia. The difference is that it is more severe and has a persistent or exercise-induced contraction. COMPLEX REPETITIVE DISCHARGES Complex repetitive discharges are a dramatic but nonspecific EMG abnormality seen in a variety of myopathic and neurogenic processes. These include muscular dystrophies, polymyositis, motor neuron disease, radiculopathies, chronic polyneuropathies, and myxedema. Their presence implies chronicity of the disorder but otherwise provides little diagnostic or other useful information. The appearance of complex repetitive discharges on the EMG screen is invariably sudden and dramatic. Their complex and

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Spinal Cord and Peripheral Neuromuscular Disease rn Diseases of Muscle

I"

b

1.0 mV 100 ms

FIG. 113-2. Single neuromyotonic discharge.

somewhat bizarre appearance resulted in the previously used term bizarre high-frequency discharges. Complex repetitive discharges represent the synchronous firing of a group of muscle fibers. The complexes recur at rates of 5 to 100 Hz. The complex waveform of each individual discharge remains uniform, the shape may change suddenly within a train of discharges, and the train of discharges begins and ends abruptly (Fig. 113-3). The appearance and sound of complex repetitive discharges are distinctly different from those of myokymia, neuromyotonia, myotonia, and cramps; the sound is that of a machine gun firing. Altered muscle membrane properties are in large part the pathophysiologic basis for complex repetitive discharges. It has been proposed that each individual complex within a complex repetitive discharge is composed of a series of individual muscle action potentials linked together by ephaptic transmission between involved muscle fibers. In some cases, nerve blocks and curare failed to abolish the complex repetitive discharges, and in other cases they persist despite curare. Their precipitation by a nerve action potential has been described by Besser and Gutmann.

_I

1 mV

20 ms

FIG. 113-3. Complex repetitive discharge.

CRAMPS Cramps are involuntary, usually painful contractions of a group of muscle fibers that last seconds to minutes. They may occur in otherwise normal individuals in any muscle but most commonly occur in the calves, often at night. They may be precipitated by contraction of the involved muscle and alleviated by stretching the muscle. Pathologic states that predispose to cramps include hyponatremia (as in athletes undertaking strenuous activities in hot weather) and a variety of neurogenic disorders including the motor neuron diseases, radiculopathies, and polyneuropathies. A cramp-fasciculation syndrome has been described in association with myalgias, stiffness, and exercise intolerance. This may be present for years on either a sporadic or hereditary basis and unassociated with any other neurogenic changes. Cramps involve the spontaneous and synchronous firing of multiple motor units. The motor unit discharges are irregular and occur at high frequencies, usually ranging from 40 to 60 Hz. The physiologic origin of cramps has not been clearly defined. It has

been postulated that there may be both central and peripheral mechanisms. They have been precipitated by repetitive nerve stimulation distal to nerve blocks in some patients predisposed to cramps but not in others. Quinine and carbamazepine have been reported to help alleviate cramps. The effect of diazepam and baclofen (yaminobutyric, acid and y-aminobutyric, acid agonists, respectively) in patients with motor neuron disease has led to the suggestion that some cramps may result from impaired function of suppressive interneurons mediated by y-aminobutyric acid as the neurotransmitter.

HEMIFACIAL SPASM Hemifacial spasm is characterized by clonic contractions of unilateral facial muscles, usually beginning about the eye and then spreading to other muscles of the involved side of the face. This is

Chapter 1 13

based on the synchronous intermittent firing of multiple motor units, with the generator being located proximally in the facial nerve. Despite the often dramatic appearance of the hemifacial spasm, it is unlikely to be associated with any serious underlying disorder in the posterior fossa. It is thought that most cases are caused by an aberrant blood vessel compressing the facial nerve shortly after it exits the pons. The intermittent clonic activity involving the orbicularis oculi may interfere with vision, and the cosmetic aspect of the problem may be distressing. Neuroimaging of the posterior fossa is unlikely to be helpful. Carbamazepine and phenytoin are occasionally helpful in decreasing or abolishing the hemifacial spasm. Botulinum toxin injections are useful in decreasing the clonic contractions, especially in the orbicularis oculi. Posterior fossa exploration to remove the aberrant blood vessel, compressing the nerve, or altering its location is the most definitive therapy, but such surgery has a number of potential postoperative complications. MYOTONIA Myotonia is the delayed relaxation of a muscle after voluntary contraction or percussion. The delayed relaxation is accompanied by myotonic discharges. The latter are repetitive discharges at 20 to 80 Hz of single muscle fibers having the appearance of a positive wave or fibrillation potential. The waxing and waning quality of the discharges creates the “dive bomber” sound. The discharges originate in the muscle membrane because neither nerve block nor neuromuscular junction block with curare alters the myotonia. In most myotonic syndromes, the myotonia improves as the muscle warms up with repeated use. In paramyotonia, it worsens with repeated muscle contractions. The myotonic disorders include myotonic dystrophy, the sodium channel disorders (hyperkalemic periodic paralysis, paramyotonia congenita, and

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737

potassium-sensitive myotonia congenita), and myotonia congenita.

SUGGESTED READINGS Besser R, Gutmann L Muscle action potential precipitated complex repetitive discharge. Muscle Nerve 11:1190-1191, 1988 Denny-Brown D, Foley JM: Myokymia and the benign fasciculation of muscular cramps. Trans Assoc Am Physicians 61:88-96, 1948 Gutmann L AAEM minimonograph #37: Facial and limb myokymia. Muscle Nerve 1443-49, 1991 Isaacs H: Continuous muscle fibre activity in an Indian male with additional evidence of terminal motor fibre abnormality. J Neurol Neurosurg Psychiatry 30:126-133, 1967 Newsom-Davis J, Mills KR Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Brain 116453469, 1993 Nix WA, Buffer NJ, Roontga S et al: Persistent unilateral tibialis anterior muscle hypertrophy with complex repetitive discharges and myalgia: report of two unique cases and response to botulinum toxin. Neurology 42:602-606, 1992 Obi T, Mizoguchi K, Matsuoka H et al: Muscle cramp as the result of impaired GABA function: an electrophysiologicaland pharmacological observation. Muscle Nerve 6:1228-1231, 1993 Ptacek LJ, Johnson KJ, Griggs RC: Genetic and physiology of the myotonic muscle disorders. N Engl J Med 32k482-489, 1993 Rasminsky M: Ephapfic transmission between single nerve fibers in the spinal nerve roots of dystrophic mice. J Physiol (Lond) 305:151-169, 1980 Tahmoush AJ, Alonso RJ, Tahmoush GP, Heiman-Patterson TD: Crampfasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder. Neurology 141021-1024, 1991 Trontelj J, Stalberg E Bizarre repetitive discharges recorded with single fiber EMG. J Neurol Neurosurg Psychiatry 4 6 3 10-316, 1983 Vincent A Understanding neuromyotonia. Muscle Nerve 23:655-657, 2000

SECTION

1

PARKINSON’S DISEASE AND PARKINSONIAN SYNDROMES

1 14 Parkinson’s Disease: Recognition, Diagnosis,

and Measurement Lewis R. Sudarsky Parkinson’s disease is among the most common movement disorders. Its prevalence is roughly 120 in 100,000 in the United States and in other parts of the industrialized world where it has been surveyed. Onset of Parkinson’s disease is unusual before age 40. Thereafter, the incidence increases sharply with age, ultimately affecting 1.5% of the population over 65, and 2.5% over 85. The illness was first described as a “shaking palsy” by James Parkinson in the early nineteenth century. There has been an explosion of knowledge since the early 1960s, with improvements in therapeutics that have fundamentally altered the natural history of the disease. Neuropathologic examination in Parkinson’s disease reveals a loss of pigmented neurons from the pars compacta of the substantia nigra. These cells contain neuromelanin and make the neurotransmitter dopamine. Microscopic examination reveals pigmented neurons undergoing neurodegeneration; some contain a characteristic eosinophilic inclusion (Lewy body). Lewy bodies contain accumulations of a-synuclein protein and ubiquitin. The dopaminergic projections from the substantia nigra influence motor processing in the basal ganglia: Dopaminergic neurons facilitate execution of movement and help suppress unwanted movement. Loss of 50% to 60% of these cells from the substantia nigra results in critical dopamine deficiency in the striatum. Excess inhibitory output of the basal ganglia complex produces the bradykinesia and rigidity of Parkinson’s disease. The cause of Parkinson’s disease is not known; there have been few epidemiologic clues to define the cause. Four studies have looked at Parkinson’s disease in twins to examine the role of heredity. The most recent and complete is a study by Tanner et al, drawn from a registry of U.S. veterans. 71 monozygotic and 90 dizygotic twin pairs were identified; the concordance was 13%, above background level but not particularly high. When the inquiry was restricted to patients with onset after age 50, concordance was equal in monozygotic and dizygotic twins, suggesting that heredity does not play a large role in these cases. Under age 40, a positive family history is more common. Lucking et a1 found a substantial number of young-onset Parkinson’s patients with parkin gene mutations, even in the absence of an affected relative. A mutation on chromosome 4q in the gene for a-synuclein has been associated with autosomal dominant Parkinson’s disease with young onset in several large families, although this mutation appears to be rare in North America. For patients with sporadic Parkinson’s disease there may be a variety of genetic and environmental risk factors, and a large sibling pairs study is under way to further examine these issues. 740

RECOGNITION OF PARKINSON’S DISEASE Parkinson’s disease is appreciated on clinical grounds; no laboratory tests are used routinely to establish the diagnosis. The cardinal clinical features are bradykinesia, rigidity, and tremor. Shuffling gait and flexed posture are also characteristic and are sometimes listed together as a fourth principal sign. Bradykinesia-slowness of movement-is the most disabling aspect of Parkinson’s disease. Patients describe it as stiffness, weakness, or a pervasive slowness that affects every aspect of movement. Dressing, eating, and other activities of daily living take extra time. There is also paucity of movement (akinesia) and difficulty initiating movement. Patients experience some loss of dexterity for buttoning, handwriting, and fine finger movement. Many describe difficulty getting up from a chair or getting out of the car, movements that require truncal mobility and complex postural adjustments. This same difficulty is likely to be reflected in the patient’s tennis serve, golf swing, or bowling score. It is difficult for patients with Parkinson’s disease to perform two complex motor acts at the same time, so many such activities acquire a slow, deliberate character. Arrests of ongoing movement sometimes occur (freezing). Rigidity is uniform through the range of movement and can be palpated in the neck as well as about the wrist. Rigidity is often associated with cogwheeling, a ratchety quality appreciated during passive movement. The tremor of Parkinson’s disease is a resting tremor, greatest in repose and less active during movement. It is a presenting feature of the illness for up to 70% of patients. Resting tremor is prominent when the patient is seated but often subsides when full relaxation is achieved, as in sleep. The tremor has a frequency of 3 to 5 Hz. It is typically a pronation-supination tremor of the forearm, with wrist and finger flexion (pill-rolling). Tremor may also involve the lower limbs or jaw, although it does not typically produce a whole head or vocal tremor. Some patients with Parkinson’s disease have an action tremor as well as a resting tremor, whereas others have no discernible tremor. (Isolated occurrence of an action tremor should not be confused with Parkinson’s disease.) Although there is variability in the presentation, a degree of bradykinesia usually is needed for a definite diagnosis. The most typical case begins asymmetrically in the limbs with a resting tremor. A flexed posture and marche a petits pas both evoke the impression of Parkinson’s disease, but these are nonspecific signs. Flexion bias in postural and limb muscles can be seen with other basal ganglia disorders. A shuffling gait occurs in a variety of conditions, reflecting injury to frontal and subcortical systems.

Chapter 1 14 H Parkinson‘s Disease: Recognition, Diagnosis, and Measurement

Beyond these core features, Parkinson’s disease is a diagnosis of impressions. Associated features contribute to the clinical picture. There is a paucity of facial expression: sometimes a blank stare, occasionally a look of consternation. Reduced blinking gives way to blepharospasm as the eyes are approached. There is inability to inhibit blinking with tap on the glabellar prominence. A curious transformation of handwriting is regularly described, with involution into a tiny scrawl (micrographia). In stance, the patient is bent forward at the neck and back, resulting in a simian posture. The arms do not swing naturally in gait, and there is a tendency to turn en bloc, “as if the joints were soldered” (Charcot’s description). Dysarthria in Parkinson’s disease is distinctive: speech is hypophonic and rapid, without normal prosody (emotional expression). There is sometimes stammering or palilalia (perseverative repetition of syllables). Patients often are unaware of problems with their speech intelligibility and need to make a specific effort to slow down. Drooling is a bothersome feature for some patients, with reduced swallowing and accumulation of saliva. Seborrhea is also characteristic of Parkinson’s disease, with increased oil production from the sebaceous glands of the skin. Sensory symptoms are not typical but are described. Many patients experience migratory discomfort associated with muscle stiffness. Loss of olfactory acuity is consistently present and may be an early indicator. Occasionally a bit of edema is observed in an affected limb, a finding that has been attributed to venous stasis from akinesia. Dementia occurs in 10% to 20% of patients with Parkinson’s disease but is not typically a presenting feature. (Mental change in Parkinson’s disease is discussed in Chapter 118.) There is no lab test or biological marker to use as an adjunct in diagnosis. Magnetic resonance imaging often is obtained in patients with atypical features to rule out a systemic degeneration or ischemic change in the basal ganglia as a cause of symptomatic Parkinsonism. DIFFERENTIAL DIAGNOSIS

Unfortunately, features that permit recognition and diagnosis of Parkinson’s disease are not entirely specific. From 15% to 25% of patients followed in a Parkinson’s clinic turn out to have a related disorder rather than idiopathic Parkinson’s disease. In the London Brain Bank project, patients were examined during life by senior neurologists applying rigorous diagnostic standards. Despite extra effort and attention to the problem of diagnosis, more than 20% of cases did not meet pathologic criteria for Parkinson’s disease at postmortem examination. Table 114- 1 lists the various causes of parkinsonian syndromes. Some patients presenting with a symmetrical akinetichgid disorder have a related neurodegenerative disorder with involvement of the striatum. Progressive supranuclear palsy, multiplesystem atrophy, and corticobasal degeneration can all present with parkinsonism. With time, other manifestations (abnormal eye movements, cerebellar or corticospinal tract signs) emerge that help characterize the disorder. These less restricted degenerative disorders are known collectively as atypical parkinsonism or parkinsonism-plus syndrome. A parkinsonian syndrome may also be the result of encephalitis, trauma, or toxic or metabolic injury to the nervous system. Postencephalitic parkinsonism of the kind discussed in the book Awakenings is now rare. Drug-induced parkinsonism is important to recognize because it is common and fully reversible. The syndrome results from the motor effect of medications that

741

TABLE 114-1. Parkinsonism-Plus Syndromes Progressive supranuclear palsy Multiple system atrophy Shy-Drager syndrome Striatonigral degeneration Olivopontocerebellaratrophy Parkinson’s-amyotrophic lateral sclerosis-dementia of Guam Diffuse Lewy body disease Corticobasal degeneration Alzheimer‘s/Parkinson’s overlap syndrome Huntington’s disease: rigid variant Frontotemporal dementia with Parkinsonism Primary pallidal atrophy Causes of Seconday Parkinsonism Toxic MPTP (methyl-4-phenyl-tetrahydropyridine) Manganese Carbon monoxide Drug-induced Neuroleptic drugs Metoclopramide, prochlorperazine Reserpine Vascular disease (“arteriosclerotic parkinsonism”) Basal ganglia lacunae Binswangets disease Hydrocephalus Trauma Tumor Chronic hepatocerebral degeneration Wilson’s disease Infectious Postencephalitic parkinsonism Creutzfeldt-Jakob disease Acquired immunodeficiencydisease

depress dopaminergic function, most typically neuroleptic, antipsychotic drugs. These drugs are highly tissue bound, and symptoms often persist weeks after the offending medication has been discontinued. Some patients with vascular disease develop Parkinson syndrome after lacunar infarction of the basal ganglia. The phenomenon of “atherosclerotic parkinsonism” has been controversial because basal ganglia lacunae often are asymptomatic, but widespread ischemic injury to the striatal complex ultimately produces bradykinesia and rigidity. The extrapyramidal syndrome is not pure: Mental change and corticospinal and corticobulbar tract findings often are associated. Most such patients have hypertension, and findings of small vessel disease can be appreciated on imaging studies. In the London Brain Bank study, asymmetry at onset and presence of a typical resting tremor were findings more likely to be associated with a diagnosis of Parkinson’s disease at autopsy. There is always a degree of uncertainty when confronted with a symmetrical akinetichigid disorder. In cases characterized by axial rigidity, postural instability, and a shuffling gait, the diagnostic uncertainty is particularly high. These features have been observed to cluster with older age at onset and the presence of dementia in clinical studies. Some such patients have evidence of hydrocephalus or periventricular white matter disease on magnetic resonance imaging. Postural instability typically is a late feature of Parkinson’s disease, whereas it occurs early with progressive supranuclear palsy and related disorders. A dramatic initial response to levodopa or carbidopa may be helpful in separating Parkinson’s disease from the related disorders in Table 114-1. Many of these parkinsonian syndromes respond partially to levodopa, but a dramatic initial response and the

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Movement Disorders H Parkinson‘s Disease and Parkinsonian Syndromes

emergence over time of levodopa dose dependence suggest the diagnosis of idiopathic Parkinson’s disease.

MEASUREMENT OF PARKINSONISM It would be helpful if we could assess the degree of nigrostriatal cell loss to provide a measure of disease severity. Because many patients with Parkinson’s disease are depressed, subjective complaints do not always parallel the evolution of the illness over time. The degree of parkinsonism is not always well reflected in the standard neurologic examination and case recording. Disease duration and total duration of levodopa therapy are helpful landmarks of the patient’s status. The onset of motor response fluctuations and dyskinesias is correlated with greater loss of nigrostriatal dopamine. It is necessary to have objective measures for clinical trials (drug trials and surgical intervention studies). Measurement of Parkinson’s-related motor disability typically is used as a basis for comparison and clinical follow-up. In their landmark article on the natural history of Parkinson’s disease in the prelevodopa era, Hoehn and Yahr recognized five stages of the illness (Table 114-2). The Hoehn and Yahr global staging system is widely accepted and easy to apply. It characterizes the major landmarks of disease progression but does not distinguish small degrees of change. Loss (or gain) of one stage implies a large change in clinical status. The unified Parkinson’s disease rating scale (UPDRS) is more detailed and is the most widely used instrument in clinical research. It includes sections on mental status, activities of daily living, motor performance, and side effects of therapy. In the motor section of the scale, 14 items are scored from 0 to 4 for severity (Table 114-3). For example, resting tremor is scored based on its amplitude and consistent presence. There is a substantial literature on the validity and reliability of the unified scale, and a videotape has been produced to standardize its application. After 5 to 8 years of levodopa therapy, a majority of patients develop fluctuations in response. Motor fluctuations complicate the assessment because the motor score is but a snapshot from a moving picture of the patient’s day. For these patients, separate scores can be recorded in the “on” and “off state. (For research purposes, “off scores generally are recorded after an overnight washout.) It is useful to record the total daily “off” time, usually obtained from the patient’s history. Some patients are able to keep a daily log of on, off, and onldyskinesia for each waking hour, which is a great help in adjusting their medication. The percentage of waking hours in the “on” and “off state is a useful index of treatment efficacy. The other major dimension of Parkinson’s-related disability is the gradual loss of independence in daily activities. Schwab and England constructed an activities of daily living scale to measure disability in this context. The scale ranges from 100% (fully independent in activities of daily living) to 0% (bedridden, H TMLE 114-2. Parkinson’s Disease Rating: Hoehn and Yahr Staging Stage 1 :The disease manifestations are unilateral. Stage 2: Symptoms and signs are bilateral, with good preservation of balance. Stage 2.5: There is mild bilateral disease, early imbalance with recovery. Stage 3: Disease is mild to moderate disease, with some postural instability, physical independence. Stage 4: Disability is severe, but the patient is still able to walk unaided. Stage 5: The patient is not able to stand and walk without assistance.

TME 114-3. Fourteen Motor Elements of the Unified Parkinson‘s Disease Rating Scale(UPDRS)’ Speechb Facial expression Tremor at restb Action tremor Rigiditf Finger tapsb Hand movement Pronation-supination of the hands Leg agility Getting out of a chairb Posture Gaitb Postural stabilitf Body bradykinesiab These 14 standard elements are scored on the motor section of the UPDRS. bSomeitems are redundant;the scale can be collapsed to these eight items without loss of validity, accordingto Van Hilten et al (1 994).

needing to be fed). Scoring of activities of daily living is based on the patient’s subjective reporting. The Schwab and England scale focuses on more advanced disability, whereas patients with Parkinson’s disease now maintain independence much longer. The UPDRS looks at particular tasks problematic in moderate to advanced Parkinson’s disease, such as cutting food, handling utensils, dressing, and washing. It also scores walking, falling, and freezing, again based on the patient’s report. All these rating scales suffer an important limitation: Interobserver variability limits the precision of the measurement. The scales are also insensitive to mild degrees of impairment and cannot define the point at which Parkinson’s disease is first expressed. For research purposes, these semiquantitative clinical assessments sometimes are supplemented with direct measures of motor performance. Bradykinesia (slowness of movement) and akinesia (paucity of movement) are the major causes of disability in Parkinson’s disease. Timed tests of movement are most commonly used to quantify bradykinesia. Pronation-supination of the wrist, alternately tapping the palm and dorsum of the hand against the knee, can be timed for 10 or 20 cycles. Likewise, two targets can be placed 12 inches apart and the patient instructed to alternate finger taps between the two targets. Neurophysiology In the neurophysiology lab, initiation and execution of a movement can be recorded with great precision. Reaction time is the interval between presentation of a “go” signal and the first agonist electromyographic burst. Movement time is the interval between initial muscle activity and completion of the movement. Both reaction time and movement time are prolonged in Parkinson’s disease. Tremor amplitude and frequency can be documented in the laboratory by surface electromyography or accelerometric recording. The disturbance in postural control and locomotion in Parkinson’s disease likewise can be measured quantitatively. Most informative is a timed “get up and go” test. The patient is seated in a flat, hard chair without arms. He or she is instructed to stand up, walk a fixed distance, turn around, return, and sit down. The entire complex performance can be timed. Start hesitation, freezing, turn hesitation, and difficulty getting out of a chair are all reflected in the measurement. Platform tests of balance are insensitive to postural instability in Parkinson’s disease until the problem is at an advanced stage.

Chapter 115 H Initial Therapy of Parkinson‘s Disease

The dopamine cells in the midbrain are too few to appreciate on standard imaging tests such as computed tomography or magnetic resonance imaging. They are best seen with the aid of a metabolic probe. Positron emission tomographic studies using “Ffluorodopa demonstrate reduced uptake in the striatum in Parkinson’s disease, particularly marked in the putamen. Quantitative analysis may reveal deficiencies in DOPA uptake in a very early or even preclinical Parkinson’s. These studies are the accepted standard for evaluating dopaminergic cell activity in transplantation neurosurgery. A number of ligands have been developed for the postsynaptic dopamine receptor and the dopamine transporter protein in the (presynaptic) nerve terminal. Dopamine transporter markers such as P-CIT provide a good quantitative measure of the degree of nigrostriatal nerve terminal loss. Single photon emission computed tomography with these agents is more widely available than positron emission tomography and has been used as an outcome measure in clinical trials. ~

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Hughes AJ, Daniel SE, Kilford L, Lees AJ:Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathologicalstudy of 100 cases. Neurol Neurosurg Psychiatry 33:181-184, 1992 Lang AE,Lozano AM: Parkinson’s disease. N Engl J Med 33931044-1053, 1130-1143, 1998 Lucking CB, Durr A, Bonifati V et ak Association between early-onset Parkinson’s disease and mutations in the pnrkin gene. N Engl J Med 342:1560--1567,2000 Marsden CD: Parkinson’s disease. J Neurol Neurosurg Psychiatry 57:672681, 1994 Parkinson Study Group: Dopamine transporter brain imaging to asses the effects of pramipexole vs. levodopa on Parkinson disease progression. JAMA 287~1653-1661,2002 Tanner CM, Ottman R, Goldman SM et al: Parkinson disease in twins: an etiologic study. JAMA 281:341-346, 1999 van Hilten JJ, van der Zwan AD, Zwinderman AH, Roos RA: Rating impairment and disability in Parkinson’s disease: evaluation of the Unified Parkinson’s Disease Rating Scale. Mov Disord 9( 1):8&88 Vingerhoets FJG, Schulzer M, Calne DB, Snow BJ: Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 41:58-64, 1997 Watts RL, Mandir AS Quantitative methods of evaluating Parkinson’s disease. In Olanow CW, Lieberman AN (eds): The Scientific Basis for the Treatment of Parkinson’s Disease. Parthenon, Park Ridge, NJ, 1992

Hoehn M, Yahr M Parkinsonism: onset, progression and mortality. Neurology 1R427-442, 1967

115 Initial Therapy of Parkinson’s Disease Cathy Chuang and Cheryl Waters The pharmacologic treatment of Parkinson’s disease (PD) can be divided into two categories: neuroprotective and symptomatic. While the disease is still mild, one initial potential goal is to slow down or stop progression of the disease. Such an approach uses purported neuroprotective agents, which may interfere with further degeneration of neurons in the substantia nigra. Although several agents are considered to be possibly neuroprotective based on theoretical and experimental evidence, at present we have no therapy that definitely has been proven to slow or stop progression of PD. Therefore, initial management of PD focuses mainly on symptomatic treatment, which can only diminish or control the symptoms but has no effect on disease progression. A third possible approach to PD is restorative therapies, such as growth factors and fetal or stem cell transplantation. These will not be discussed because they are unavailable and are being studied in both basic research and clinical trials. When approaching the initial treatment of PD, it is important to determine whether a patient needs symptomatic therapy. The primary question to ask is whether the symptoms are impairing the patient’s overall level of functioning. A rest tremor, which may not be physically disabling, can still interfere with both social and work interactions and therefore may warrant symptomatic treatment. Maintaining a high level of functioning and independence should be the main goal of symptomatic treatment. However, if

symptoms are very mild and nondisabling, potential neuroprotective agents would be a more appropriate strategy.

THEORETICAL BASIS OF NEUROPROTECCION The cause of Parkinson’s disease remains unknown. However, one of the main rationales for neuroprotective therapies has been based on the hypothesis that oxidative stress plays a major role in the degeneration of nigral neurons. The oxidative stress hypothesis derives primarily from the observation that dopamine metabolism results in the generation of free radicals and reactive oxygen species such as hydrogen peroxide. This occurs by two mechanisms: Auto-oxidation of dopamine leads to formation of neuromelanin, which can then generate the free radical species quinone and semiquinone and other reactive oxygen species; and enzymatic oxidation by monoamine oxidase (MAO) leads to the formation of hydrogen peroxide (H202),which can react with iron and form the highly reactive and cytotoxic hydroxyl radicals (OH) by the Fenton reaction (see the following equation). H202 usually is inactivated by catalase or reduced glutathione (GSH). The role of oxidative stress in the pathogenesis of PD is supported by biochemical measurements in postmortem studies that demonstrate increased levels of iron in the substantia nigra pars compacta (SNc), reduction of GSH in the SNc correlating with disease

Chapter 115 H Initial Therapy of Parkinson‘s Disease

The dopamine cells in the midbrain are too few to appreciate on standard imaging tests such as computed tomography or magnetic resonance imaging. They are best seen with the aid of a metabolic probe. Positron emission tomographic studies using “Ffluorodopa demonstrate reduced uptake in the striatum in Parkinson’s disease, particularly marked in the putamen. Quantitative analysis may reveal deficiencies in DOPA uptake in a very early or even preclinical Parkinson’s. These studies are the accepted standard for evaluating dopaminergic cell activity in transplantation neurosurgery. A number of ligands have been developed for the postsynaptic dopamine receptor and the dopamine transporter protein in the (presynaptic) nerve terminal. Dopamine transporter markers such as P-CIT provide a good quantitative measure of the degree of nigrostriatal nerve terminal loss. Single photon emission computed tomography with these agents is more widely available than positron emission tomography and has been used as an outcome measure in clinical trials. ~

SUGGESTED READINGS

743

Hughes AJ, Daniel SE, Kilford L, Lees AJ:Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathologicalstudy of 100 cases. Neurol Neurosurg Psychiatry 33:181-184, 1992 Lang AE,Lozano AM: Parkinson’s disease. N Engl J Med 33931044-1053, 1130-1143, 1998 Lucking CB, Durr A, Bonifati V et ak Association between early-onset Parkinson’s disease and mutations in the pnrkin gene. N Engl J Med 342:1560--1567,2000 Marsden CD: Parkinson’s disease. J Neurol Neurosurg Psychiatry 57:672681, 1994 Parkinson Study Group: Dopamine transporter brain imaging to asses the effects of pramipexole vs. levodopa on Parkinson disease progression. JAMA 287~1653-1661,2002 Tanner CM, Ottman R, Goldman SM et al: Parkinson disease in twins: an etiologic study. JAMA 281:341-346, 1999 van Hilten JJ, van der Zwan AD, Zwinderman AH, Roos RA: Rating impairment and disability in Parkinson’s disease: evaluation of the Unified Parkinson’s Disease Rating Scale. Mov Disord 9( 1):8&88 Vingerhoets FJG, Schulzer M, Calne DB, Snow BJ: Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 41:58-64, 1997 Watts RL, Mandir AS Quantitative methods of evaluating Parkinson’s disease. In Olanow CW, Lieberman AN (eds): The Scientific Basis for the Treatment of Parkinson’s Disease. Parthenon, Park Ridge, NJ, 1992

Hoehn M, Yahr M Parkinsonism: onset, progression and mortality. Neurology 1R427-442, 1967

115 Initial Therapy of Parkinson’s Disease Cathy Chuang and Cheryl Waters The pharmacologic treatment of Parkinson’s disease (PD) can be divided into two categories: neuroprotective and symptomatic. While the disease is still mild, one initial potential goal is to slow down or stop progression of the disease. Such an approach uses purported neuroprotective agents, which may interfere with further degeneration of neurons in the substantia nigra. Although several agents are considered to be possibly neuroprotective based on theoretical and experimental evidence, at present we have no therapy that definitely has been proven to slow or stop progression of PD. Therefore, initial management of PD focuses mainly on symptomatic treatment, which can only diminish or control the symptoms but has no effect on disease progression. A third possible approach to PD is restorative therapies, such as growth factors and fetal or stem cell transplantation. These will not be discussed because they are unavailable and are being studied in both basic research and clinical trials. When approaching the initial treatment of PD, it is important to determine whether a patient needs symptomatic therapy. The primary question to ask is whether the symptoms are impairing the patient’s overall level of functioning. A rest tremor, which may not be physically disabling, can still interfere with both social and work interactions and therefore may warrant symptomatic treatment. Maintaining a high level of functioning and independence should be the main goal of symptomatic treatment. However, if

symptoms are very mild and nondisabling, potential neuroprotective agents would be a more appropriate strategy.

THEORETICAL BASIS OF NEUROPROTECCION The cause of Parkinson’s disease remains unknown. However, one of the main rationales for neuroprotective therapies has been based on the hypothesis that oxidative stress plays a major role in the degeneration of nigral neurons. The oxidative stress hypothesis derives primarily from the observation that dopamine metabolism results in the generation of free radicals and reactive oxygen species such as hydrogen peroxide. This occurs by two mechanisms: Auto-oxidation of dopamine leads to formation of neuromelanin, which can then generate the free radical species quinone and semiquinone and other reactive oxygen species; and enzymatic oxidation by monoamine oxidase (MAO) leads to the formation of hydrogen peroxide (H202),which can react with iron and form the highly reactive and cytotoxic hydroxyl radicals (OH) by the Fenton reaction (see the following equation). H202 usually is inactivated by catalase or reduced glutathione (GSH). The role of oxidative stress in the pathogenesis of PD is supported by biochemical measurements in postmortem studies that demonstrate increased levels of iron in the substantia nigra pars compacta (SNc), reduction of GSH in the SNc correlating with disease

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severity, and evidence of oxidative damage to lipids, proteins, and DNA as shown by increased levels of lipid hydroperoxides, reactive carbonyls, and 8-hydroxy-2’deoxyguanosine. Dopamine + 0, + H,O H,O, + Fe2+

=,homovanillic acid + H 2 0 2 > OH-

+ OH + Fe3+

The discovery of the neurotoxin MPTP ( 1-methyl-4-phenyl1,2,3,6-tetrahydropyidine) has also shed light on the pathogenesis of PD in addition to providing a useful animal model for research studies. MPTP selectively destroys the substantia nigra, producing parkinsonism in humans and animals. This toxin is converted to MPP+ (1-methyl-4-phenylpyridiniumion) by MAO-B and exerts its effect via this active metabolite. MPP+ is taken up by mitochondria and inhibits both complex I and a-ketoglutarate dehydrogenase. Complex I inhibition results in increased free radical generation from the respiratory chain and therefore can contribute further to oxidative damage. In addition, MPP+ may also generate free radicals directly. The role of a complex I defect in the pathogenesis of PD is further supported by the observation in postmortem studies of a 30% to 40% decrease in complex I activity and immunostaining in the SNc of patients with PD. In addition, reduced complex I activity has been reported in platelets and muscle of patients with PD. Mitochondria1 dysfunction induced by MPP+ has also been shown to play a role in apoptosis, the proposed major cause of cell death in PD. PROPOSED NEUROPROTECTIVE AGENTS Monoamine Oxidase Inhibitors Because of the role of MA0 in both the oxidation of dopamine to hydrogen peroxide and the conversion of MPTP to MPP+, neuroprotective strategies have focused much attention on inhibitors of this enzyme. The main agent studied has been the selective h4AO-B inhibitor selegiline. It has a half-life of 2 hours but its metabolites, L-amphetamine and L-methamphetamine, have halflives of 17.7 and 29.5 hours, respectively. Inhibition of MAO-B by drugs such as selegiline prevents the formation of MPP+ and the development of experimental parkinsonism in animal models. In vivo studies have shown that selegiline can protect against free radical formation induced by dopamine turnover, MPP+, and a variety of other toxins. In addition, selegiline has been found to have potential neuroprotectiveproperties that are separate from its MAO-B inhibitory effect. Selegiline administration has been shown to increase levels of a variety of protective antioxidant molecules including superoxide dismutase, catalase, GSH, and glutathione peroxidase. Selegiline has been also shown to augment the release of trophic factors and antiapoptotic molecules such as bcl-2. Initial evidence reported by Knoll in rodents and a retrospective study by Birkmayer in patients with PD suggested that selegiline therapy may result in longer survival and less disability. This prompted several prospective, double-blind, placebocontrolled studies. The largest study, DATATOP, investigated both selegiline and a-tocopherol (vitamin E) in 800 untreated patients with PD. In this study, a symptomatic benefit confounded the results of a potential neuroprotective effect. However, subgroup analysis suggested that a symptomatic benefit was not enough to explain the delayed progression, and there may have also been a neuroprotective component that delayed the need for levodopa in the selegiline-treated group. After the initial 2-year double-blind DATATOP trial was

completed, open-label extension studies offered selegiline treatment to all patients regardless of whether they had reached the endpoint of needing levodopa therapy. These extension phases did not support a neuroprotective effect of selegiline treatment. In 1993, a second randomization was undertaken in the DATATOP patients who had needed levodopa. Independentlyof their original assignment, subjects were randomized to continue selegiline or to switch to placebo. Preliminary analyses suggest that selegiline increases the risk of dyskinesias but decreases the risk of motor fluctuations and freezing. There has been some controversy over the possibility of increased mortality in patients treated with selegiline. The Parkinson’s Disease Research Group of the United Kingdom (PDRG-UK) reported the results of an open-label prospective trial of 520 patients with PD treated with either levodopa and selegiline or levodopa alone. After an average of 5.6 years of treatment, those treated with selegiline and levodopa had 60% higher mortality than those treated with levodopa alone. However, a similar increase in mortality has not been seen in other studies. A meta-analysis evaluated mortality in five prospective, long-term, double-blind, randomized, controlled studies of patients with early PD treated with selegiline and levodopa, and no difference in mortality was detected. The higher mortality in the PDRG-UK study is hard to explain but may have been related to greater disease severity, the high dropout rate (50% did not complete the study on their original treatment assignment), or poor study design, which used an intention-to-treat analysis (which placed responsibility for death on the original treatment group despite later changes in treatment) rather than an on-treatment analysis. More recently, three other double-blind, placebo-controlled studies have demonstrated that treatment with selegiline delayed the need for either levodopa or other dopaminergic agents, slowed the onset of motor fluctuations, and decreased the need for an increase in levodopa dosage. Therefore, selegiline treatment can be useful as monotherapy to spare levodopa use or in combination therapy with levodopa to reduce the needed levodopa dosage and potentially slow disease progression. In both instances, the recommended dosage is 5 mg twice a day, with the last dose given at noon because later dosing can cause insomnia. Dosages higher than 10 mg/day can cause a hypertensive crisis when foods rich in tyramine are ingested. Side effects of nausea, dizziness, and confusion are uncommon when selegiline is used as monotherapy, but cognitive dysfunction and psychosis are more liely to occur when used with levodopa and in older adults.

Antioxidant Therapy Based on the oxidative stress hypothesis, there has been interest in the use of antioxidants for neuroprotection in PD. Proposed antioxidants include vitamin E, vitamin C, GSH, N-acetylcysteine (a precursor of GSH), coenzyme Q-10, reduced NADH, and selenium (a cofactor of glutathione peroxidase). In DATATOP, subjects were treated with 2000 IU of vitamin E daily. No significant benefit was demonstrated in this treatment arm. The question of brain bioavailability of oral vitamin E was assessed by measuring CSF levels. This demonstrated a 74% higher level of vitamin E in subjects than in controls. At present, there is insufficient evidence that antioxidants provide any neuroprotective effect for patients with PD. More extensive clinical trials are necessary to support their general use in early PD treatment.

Chapter 115

SYMPTOMATIC TREATMENT Several medications are available that have been shown to alleviate the symptoms of PD. The extensive list includes levodopa, dopamine agonists (bromocriptine, pergolide, cabergoline, pramipexole, and ropinirole), selegiline, amantadine, catechol-0methyltransferase (COMT) inhibitors used with levodopa, and anticholinergic agents. It is widely accepted that levodopa, the immediate metabolic precursor of dopamine, is the most effective medication for treating parkinsonian signs and symptoms. Given alone, more than 95% of levodopa is converted to dopamine in the periphery by dopa decarboxylase, with minimal active drug crossing the blood-brain barrier. But when it is given as Sinemet (levodopa plus carbidopa, a peripheral dopa decarboxylase inhibitor), the central nervous system effect of levodopa is potentiated and peripheral side effects of nausea and vomiting decrease. However, over time (5 years on average), the majority of patients treated with levodopa develop response fluctuations that present as wearing-off of the effect after shorter periods of time, delayed ons, dosage failures, and sudden, unpredictable offs. In addition, many patients develop levodopa-induced dyskinesias, which can often be disabling and sometimes painful. Because of these troublesome motor fluctuationswith levodopa therapy, adjunctive therapy with dopamine agonists has been used in attempt to smooth out motor responses. In addition to the concern about motor fluctuations and dyskinesias, it is unknown whether levodopa is neurotoxic, contributing to the progression of nigral cell degeneration. This hypothesis of levodopa toxicity is based on observations that the metabolism of levodopa and dopamine produces free radicals, which could cause nigral cell death. Because of these concerns, the early treatment of PD has been subject to fierce debate and controversy, with some advocating early levodopa treatment and others in support of delaying levodopa treatment in hopes of avoiding these motor complications and potential toxicity of levodopa. Many who support use of levodopa early in the disease course argue that the motor complications are not secondary to levodopa treatment but are simply a manifestation of disease severity. The reason for this disagreement lies in the incomplete evidence of the potential role of levodopa in hastening disease progression in PD. There is both in vitro and in vivo evidence of potential neuronal death produced by levodopa, but there are also studies that show that high dosages of levodopa are safe in normal animals and humans. It has been suggested that levodopa may be toxic only to the already degenerated nigral neurons in PD or in chemically lesioned animals. However, a recent study in 6-hydroxydopamine(OHDA) lesioned rats showed no evidence of neuronal death as a consequence of levodopa therapy. Because of this concern about levodopa toxicity, some clinicians advocate using dopamine agonists as monotherapy for initial treatment of PD to delay the need for levodopa and thereby potentially delay the onset of motor complications. In addition, it has also been proposed that dopamine agonists may be potentially neuroprotective and therefore should be considered early in the treatment of PD.

Dopamine Agonlsts Dopamine agonists are pharmacologic agents that mimic the action of dopamine by directly stimulating dopamine receptors in

Initial Therapy of Parkinson's Disease

14s

the striatum. They are considered to be the most effective symptomatic treatment after levodopa. There are five types of dopamine receptors (D1-D5), and dopamine agonists bind nonselectively to these receptors to varying degrees. Dopamine agonists can be divided into the ergot and nonergot agonists. Ergot Agonists: Bromocriptine, Pergolide, Cabergoline. The first dopamine agonists used to treat PD were the ergot derivatives bromocriptine and pergolide. Bromocriptine has been generally recommended for use as adjunctive treatment with levodopa to control motor fluctuations and therefore is used mainly in more advanced disease. Most studies found that the bromocriptine dosage must be built up to 30 mg/day or more. Several trials have investigated the use of bromocriptine monotherapy in the initial treatment of PD. Early studies generally showed decreased incidence of motor complications but found the benefit of bromocriptine monotherapy to be short-lived (usually less than 1 year), often necessitating the early addition of levodopa. The PDRG-UK compared bromocriptine monotherapy with levodopa therapy in early Parkinson's disease. This study confirmed that bromocriptine was less effective than levodopa, but the incidence of dyskinesias and on-off fluctuations was significantly lower in the bromocriptine-treated group. Montastruc and others performed a 5-year open-label, controlled study comparing bromocriptine to which levodopa was later added with levodopa alone in untreated patients with PD. Their results showed that adding levodopa after 3 years of bromocriptine monotherapy delayed the occurrence of motor fluctuations and dyskinesias compared with levodopa alone, without any significant difference in UPDRS motor scores. Several studies have looked at the use of bromocriptine in combination with levodopa as a strategy to delay the onset of motor complications. These have shown conflicting results, with some showing equal efficacy of combination therapy with lower incidence of motor complications and others showing no improvement in motor fluctuationswith Combination therapy and better efficacy with levodopa alone. Whether used alone or in combination, the initial dosage is half of a 2.5-mg tablet twice daily with meals, increasing by 2.5 mg/day every few days. The most common side effects are nausea, sedation, postural hypotension, hallucinations, and confusion. Dopamine agonist monotherapy and combination therapy with levodopa has also been evaluated with other agonists. In a 3-month double-blind, placebo-controlled study, pergolide, a D1/D2 agonist, was found to be safe and effective as monotherapy in the early treatment of PD. In a long-term study of pergolide in combination with levodopa, 48% (151 of 314) of patients treated with both pergolide and levodopa had continued benefit after 3 years, and 40% maintained improvement after 4 years. Twentynine percent of de novo patients (18 of 62) had continued benefit on pergolide monotherapy for up to 3 years. The incidence of both wearing off and dyskinesias was highest in the patients initially treated with levodopa and lowest in the patients treated with pergolide alone. A double-blind randomized study has compared initial treatment with pergolide versus levodopa in early PD (PELMOPET). One-year interim analysis was significant for a delay in motor complications in pergolide-treated patients, but this difference did not persist after 3 years. In addition, there was a trend toward better efficacy in the levodopa-treated group. Adverse effects were more common in the pergolide group. Fluorodopa positron emission tomography scans did not show any significant difference in PD progression between groups. The initial dosage is 0.05 mglday for the first 2 to 3 days, followed by

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an increase by 0.10 or 0.15 mg/day every third day over the next 12 days. The dosage can then be increased by 0.25 mg/day every third day, aiming for a therapeutic dosage of 0.75 mg to 3 mg/day in divided doses three times per day. Some patients experience initial worsening before benefit, and first-dose hypotension can also occur. Most common side effects include dyskinesias, dizziness, hallucinations, nausea, somnolence, insomnia, constipation, diarrhea, and dyspepsia. Cabergoline, a long-acting dopamine agonist (not approved for PD treatment in the United States), was studied in a 3- to 5-year double-blind, randomized trial comparing initial therapy of PD with cabergoline alone or in combination with levodopa versus levodopa alone. The development of motor complications was significantlyless in the cabergoline-treated group than in subjects only receiving levodopa. Thirty-five percent of patients remained on cabergoline monotherapy after 3 years. There was a trend toward more improvement in UPDRS motor scores in the levodopa-treated group. However, there was no significant difference in UPDRS activities of daily living (ADL) scores between the two treatment groups, and in patients who did not need open-label levodopa therapy, the extent of improvement in motor disability was also similar between groups. Nonergot Dopamine Agonists: Pramipexole and Ropinirole. Pramipexole is a D2/D3 dopamine agonist that has been studied extensively as monotherapy in early PD and found to be very effective. In a 6-month double-blind, randomized study by Shannon et al of 335 patients with early PD, pramipexole significantly reduced the severity of parkinsonian symptoms compared with placebo. Mean daily dosage was 3.8 mg/day, and adverse events included nausea, constipation, and insomnia. In a 10-week study conducted by the Parkinson Study Group, 264 patients were randomized to five different dosages of pramipexole and were found to have significantly better UPDRS scores than those given placebo. These two short-term double-blind studies were continued in two long-term open-label trials, which found pramipexole to be effective and well tolerated in early PD for 3 years or more. The likelihood of remaining on pramipexole without requirement of levodopa after 4 years was 38% to 41%. Pramipexole monotherapy was also compared with levodopa therapy in a 2-year multicenter, double-blind, randomized controlled study of 301 patients with early PD (CALM-PD study). Open-label levodopa was permitted after the 10-week escalation phase. Fifty-three percent of patients in the pramipexole group needed supplemental levodopa, and 35% of levodopa-treated patients needed supplemental levodopa. Pramipexole treatment resulted in significantlylower occurrence of motor complications (28%) compared with treatment with levodopa alone (51%). However, there was a greater improvement in total UPDRS scores in the levodopa-treatedgroup. The majority of motor fluctuations occurred after the use of supplemental levodopa. Adverse events were more common in the pramipexole-treated group, specifically with somnolence, hallucinations, and peripheral edema. The P-CIT striatal single photon emission computed tomography uptake demonstrated a 35% reduction in dopamine transporter loss over 4 years in the pramipexole group. The recommended starting dosage is 0.125 mg three times daily and should be increased weekly by 0.125 or 0.25 mglday, aiming for a therapeutic dosage of 1.5 to 4.5 mg/day. There is some suggestion that the total daily dosage of 1.5 mg is sufficient for a therapeutic response. Ropinirole, a D2/D3 dopamine agonist, has been evaluated in several studies as monotherapy in early PD. Sethi and others studied ropinirole monotherapy in 147 patients with early PD in a

double-blind, placebo-controlled trial. The primary outcome measure was the number of patients who completed the study without the need to start levodopa. Significantly fewer ropiniroletreated patients needed levodopa compared with controls. However, 37% of ropinirole-treated patients withdrew because of adverse effects, compared with 16% of placebo-treated patients. The most common adverse effects were somnolence, dizziness, and arthralgias. A 3-year double-blind, randomized controlled trial compared ropinirole monotherapy with bromocriptine in 355 patients with early PD. Ropinirole was found to be more effective than bromocriptine as determined by UPDRS ADL and motor scores and as evidenced by fewer patients (33.9%) in the ropinirole-treated group needing levodopa than in the bromocriptine-treated group (41.9%). A 5-year double-blind, randomized controlled trial compared ropinirole with levodopa treatment in early PD, with the primary endpoint evaluating the occurrence of dyskinesias. Sixty-six percent of ropinirole-treated patients needed. levodopa supplementation, compared with 36% of patients randomized to levodopa therapy. The incidence of dyskinesias was significantlylower in the ropinirole-treated group, regardless of levodopa supplementation. In addition, disabling dyskinesias occurred in only 8% of the ropinirole group, compared with 23% in the levodopa group. The occurrence of wearing off was also lower in the ropinirole group (23%) than in the levodopa group (34%). However, the difference in UPDRS motor scores from baseline was significantlybetter, and the occurrenceof freezing was lower in the levodopa group. The incidence of somnolence and hallucinations was higher in the ropiniroletreated group. Studies using "F-DOPA positron emission tomography demonstrated better preservation of imaging markers in the ropinirole group. Recommended starting dosage is 0.25 mg three times daily, and the dosage should be increased weekly, aiming for a therapeutic dosage of 12 to 16 mg per day. Side effects are similar to those of other dopamine agonists and include nausea, dizziness, postural hypotension, dyskinesias, edema, somnolence, confusion, and hallucinations. Therefore, dopamine agonists can be effective as monotherapy in the initial treatment of PD, but most patients need levodopa supplementation after a variable time period, ranging from months to years. This variability is likely to be related to the heterogeneity of patients with PD, with some having a more benign course and others a more progressive course. Dopamine agonists in combination with levodopa appear to result in a lower incidence of motor complications than levodopa alone. This effect may occur simply because they allow a lower dosage of levodopa to be used. When deciding which dopamine agonist to use for symptomatic therapy, there are two main factors to consider: efficacy and side effect profile (Table 115-1).With the exception of bromocriptine, controlled studies have not compared one agonist with the other. One study has shown that bromocriptine is less effective than ropinirole. However, the remaining agonists (pergolide, pramipexole, and ropinirole) are generally believed to be equal in efficacy. Although the nonergot agonists are less likely to cause ergot-related side effects such as St. Anthony's fire and pulmonary or retroperitoneal fibrosis, all the agonists are generally equivalent in their side effect profile. The most common side effects are nausea, dyskinesias, leg edema, hallucinations, confusion, and somnolence. However, recently a previously unreported form of somnolence was reported in which patients suddenly fell asleep without any warning of drowsiness. These sleep attacks resulted in motor vehicle accidents involving patients treated with pramipex-

Chapter 115 H Initial Therapy of Parkinson's Disease

rn TABU115-1. Side Effects with Dopamine Agonists Common Side Effects

Uncommon Side Effects

Brornocriptine

Nausea

Pergolide Ca bergoline

Hallucinations Somnolence

Red, inflamed skin (St. Anthony's fire) Erythromelalgia Pleural thickening and effusions Retroperitonealfibrosis

Ergot Agonists

Confusion Dyskinesias Leg edema Constipation Postural hypotension Nonergot Agonists Prarnipexole Same as above Ropinirole

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glaucoma, constipation, memory impairment, confusion, hallucinations, and urinary retention. The risk of side effects is greater in older adults. The starting dosage of trihexyphenidyl is 1 mg at mealtimes, and is increased by 2 mg/day for 3 to 5 days to 6 mglday three times a day. Benztropine is begun with 0.5 to 1 mg at bedtime, and the dosage can be increased gradually to 4 to 6 mglday as needed, divided two or four times a day. Procyclidine is initiated with 2 mg three times a day, after meals, and increased to 5 mg three or four times a day.

Levodopa Sleep attacks

ole and ropinirole who fell asleep at the wheel. Since that initial report, these sleep attacks have also been reported with levodopa and other dopamine agonists, but only pramipexole and ropinirole have a package insert warning about this potential risk of falling asleep without perceived warning. Therefore, when prescribing either one of these agonists, it is important to advise people about this potential risk, especially if they drive. Despite the general equivalence of the three major dopamine agonists, if one is not effective or poorly tolerated, it is worth trying another agonist. When switching from one agonist to another, one can switch directly to another agonist using the estimated dosage equivalents without needing to taper off one or gradually increasing the other. The dosage equivalent of pergolide and pramipexole is estimated to be 1:1, and 1 mg of pergolide or pramipexole is equivalent to 3 or 4 mg of ropinirole.

Amantadine Amantadine is an antiviral agent found to have an antiparkinsonian effect with several proposed mechanisms of action. These include the release of dopamine from central neurons, delay of dopamine uptake by neural cells, blockade of N-methyl D-aspartate (NMDA) receptors, and anticholinergic effects. As monotherapy or in combination with other antiparkinsonian medications, it is given at a dosage of 100 mg two or three times a day. Side effects include hallucinations, confusion, leg edema, and livedo reticularis. In mild symptoms of early PD, amantadine reportedly results in 20% to 40% global improvement in two thirds of patients when given as monotherapy. It seems to have minimal effect on tremor, and there is no evidence of tolerance development. Amantadine has also been found to be beneficial at decreasing levodopa-induced dyskinesias, so it can also be useful as combination therapy with levodopa.

Anticholinergics: Trihexyphenidyl, Benztmpine, and Procyclidine Anticholinergic agents are generally effective for treating tremor and have little effect on rigidity and bradykinesia. However, the response of tremor is variable, and more severe tremors usually are not responsive. Therefore, anticholinergics are effective mainly in treating mild tremors of early PD. The use of these drugs often is limited by side effects, which include dry mouth, narrow-angle

Although the use of levodopa in early PD remains a controversial issue, there is general agreement about the early use of levodopa in treating older adults (over 65 years), who are at higher risk of having cognitive side effects of confusion or hallucinations from dopamine agonists, amantadine, or anticholinergics. In addition, the motor complications of levodopa are less likely to occur in older adults. There are two main formulations of levodopa: immediate-release Sinemet (carbidopdlevodopa) and controlledrelease Sinemet (Sinemet CR). Immediate-release Sinemet has a faster onset but shorter duration of action. Sinemet CR has a delayed onset but a longer duration of action. It has been hypothesized that Sinemet CR, which provides a more steady plasma levodopa concentration, would decrease the incidence of motor fluctuations. A 5-year randomized multicenter study comparing treatment with immediate-release and controlledrelease Sinemet in 618 early levodopa-naive patients with PD did not reveal a significant difference in the occurrence of motor fluctuations or dyskinesias. However, the patients who completed the study (61%) may have had a more benign form of PD because they had a lower prevalence of motor fluctuations and dyskinesias than expected and were still on low dosages of levodopa after 5 years. This lower disease severity may have been a confounding factor because the occurrence of motor fluctuations may be an expression of disease severity. In this study, Sinemet CR provided a significant improvement in ADL measures compared with standard Sinemet. This may have been secondary to the slightly higher dosages of Sinemet CR (bioavailable dosage of 510 mg/day versus 426 mg/day) but also suggests that one may be able to use higher dosages of Sinemet CR without producing a higher incidence of motor fluctuations or dyskinesias. The improvement in ADL scores with Sinemet CR may have also been secondary to a lower severity of off periods and dyskinesias, which was not specifically measured in this study. Other clinical trials have demonstrated improvement in PD after conversion from standard Sinemet to CR, but some patients needed supplementation with standard Sinemet to maintain an optimal response. Therefore, it is not clear which form of levodopa is more effective in early PD treatment, and they may be more effective in combination. Immediate-release Sinemet may be more useful when the patient needs a faster onset of action, such as the first dose of the day, and Sinemet CR may be more useful when a longer duration of action is needed, such as at bedtime. The available dosages of Sinemet are 25/100, 10/100, and 25/250 mg. The starting dosage of Sinemet is 25/100 (25 refers to the carbidopa dosage and 100 refers to the levodopa dosage), one half tablet daily or twice daily with meals, increasing by one half tablet every 4 to 7 days. When replacing regular Sinemet with Sinemet CR, one must take into account that the bioavailability of Sinemet CR is only approximately 80% of that of standard Sinemet, so it may be necessary to increase the dosage by 25%. The

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TABLE115-2. Management of Levodopa Side Effects Side Effect

Management

Nausea

Take Sinemet with food Carbidopa Domperidone Quetiapine Clozapine (weekly CBCs needed) Increase salt intake in diet Increase fluid intake Compression stockings fludrocortisone Midodrine Lower levodopa dosage Add amantadine

Psychosis Orthostatic hypotension

Dyskinesias

available strengths of Sinemet CR are 50/200 (scored) and 25/100 (nonscored). All preparations are now available in generic form for lower cost. Sinemet CR should not be chewed, or its controlled-release properties will be lost. The most common side effects are nausea, vomiting, lightheadedness, orthostatic hypotension, psychosis including visual hallucinations or paranoid ideation, and dyskinesias. Extra carbidopa 25 mg three times a day or domperidone 10 mg two or three times a day (available in Canada and Europe) can be used to alleviate nausea. Atypical antipsychotics such as quetiapine or clozapine can be used to treat psychosis without worsening parkinsonism. Additional salt, fludrocortisone, or midodrine (an a-adrenergic agent) can be used for orthostatic hypotension. The recommended dosage of fludrocortisone is 0.1 mg/day, gradually increasing to 0.4 mg/day as needed. The starting dosage of midodrine is 2.5 mg twice daily at breakfast and lunch and increasing by 2.5 mg daily, up to a maximum dosage of 10 mg three times a day (Table 115-2).

NONPHARMACOLOGICTREATMENT Besides medical therapy, other essential interventions can significantly improve the symptoms of PD and should be undertaken early in the disease course. Of utmost importance in maintaining a high level of functioning is regular exercise and physical therapy. Patients should be encouraged to continue participating in exercises they enjoy such as walking, swimming, bicycling, hiking, golfing, and tennis. Other activities such as ballroom or square dancing can also help to maintain physical capabilities. Physical therapy that focuses on stretching exercises is very beneficial in diminishing muscle stiffness and rigidity, and gait training can be helpful for balance problems. For patients with speech difficulties, speech therapy can improve hypophonia. Occupational therapy focuses on improving ADLs, specific adaptations for continuation of employment, and exercises that can enhance fine motor coordination. Adaptations of the home environment may also be necessary, such as grab bars in the bathroom, specialized utensils, and easy-hold cups. Dietary considerations are also important. Constipation is a common problem in PD. Therefore, interventions such as increased dietary fiber and good hydration may facilitate regular bowel habits. For those with symptomatic orthostatic hypotension, compression stockings and increased salt intake can be helpful. Swallowing problems should be addressed by a speech therapy evaluation, swallowingstudy, and, if necessary, a change in the consistency of solids or liquids to avoid aspiration.

Seborrheic dermatitis has been associated with PD and can be managed by neutral or bland acne soap, ketoconazole shampoo, or shampoos, lotions, or creams containing selenium or pyrithione zinc. Psychotherapy may be beneficial for patients who have depression, anxiety, or difficulty coping with their illness. Counseling for family members and caregivers may be useful.

CONCLUSION There are many options to consider in the initial management of PD. When symptoms are still very mild and not very disabling, selegiline can be considered for its mild symptomatic benefit and potentially neuroprotective effect. Amantadine and anticholinergics can also be considered in patients whose symptoms are mild or in those with tremor. When more effective dopaminergic agents are needed to alleviate symptoms, one needs to decide whether to treat early with levodopa or to use a levodopa-sparing strategy and treat with dopamine agonist monotherapy. Because levodopa is generally more effective, if symptoms are very disabling, levodopa is likely to be a better choice. However, for younger patients who are at greater risk of developing complications from levodopa therapy, dopamine agonists are the treatment of choice. Levodopa therapy should be recommended as initial treatment in older adults to avoid the higher incidence of cognitive side effects from agonists. Pergolide and the newer nonergot agonists, pramipexole and ropinirole, show little difference in efficacy and tolerability. Nonpharmacologic therapies such as exercise, physical, occupational, and speech therapy, and a high-fiber diet may be offered early in the disease to maintain an optimum level of functioning and well-being.

SUGGESTED READINGS Barone P, Bravi D, Bermegjo-Pareja F et al: Pergolide monotherapy in the treatment of early PD: a randomized, controlled study. Neurology 53:573-579, 1999 Fahn S: Is levodopa toxic? Neurology 47(Suppl 3):S184-195, 1996 Koller WC, Hutton JT, Tolosa E et ak Immediate-release and controlledrelease carbidopa/levodopa in PD: a 5-year randomized multicenter study. Neurology 53:1012-1019, 1999 Korczyn AD, Brunt ER, Larsen JP et ak A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson’s disease. Neurology 533364370, 1999 The Parkinson Study Group: Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 328:176-183,1993 The Parkinson Study Group: Pramipexole vs. levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 284(15): 1931-1938, 2000 Prasad KN, Cole WC, Kumar B: Multiple antioxidants in the prevention and treatment of Parkinson’s disease. J Am Coll Nutr 18(5):413-423, 1999 Rascol 0,Brooks DJ, Korczyn AD et ak A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 3421484-1491, 2000 Shoulson I and the Parkinson Study Group: DATATOP a decade of neuroprotective inquiry. Ann Neurol44(Suppl 1):S16&166, 1998 Waters CH:Therapeutics of Parkinson’s disease. pp. 79-91. In LeWitt P, Oertel W (eds): Parkinson’s Disease: The Treatment Options. Martin Dunitz Ltd, London, 1999 Weiner WJ: The initial treatment of Parkinson’s disease should begin with levodopa. Mov Disord 14(5):71&724, 1999

Chapter 116 rn Improving Responses to Levodopa

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1 16 Improving Responses to Levodopa Peter Le Wilt MD

Parkinson’s disease (PD) is unique among neurodegenerative disorders in the near-complete relief of signs and disabilities that can be achieved with dopaminergic therapy. This difference has been shown most dramatically by use of the natural amino acid precursor of dopamine, levodopa (L-dihydroxyphenylalanine,or L-DOPA).Restoring striatal dopaminergic neurotransmission by levodopa (LD) administration is efficacious even when the dropout of substantia nigra neurons is extensive. Benefits of LD can be observed in almost all parkinsonian signs and symptoms. In the first few years of therapy (sometimes called the honeymoon period), LD dosages in the range of 200 to 600 mg/day generally offer highly satisfactory control of parkinsonism without the need for adjunctive medications. The aspects of PD that tend to be most disabling, such as slowness of movement and decreased dexterity, have the greatest likelihood for improvement with LD. Other clinical features such as resting tremor sometimes cannot be controlled to the same extent. However, LD’s overall effectiveness in idiopathic PD usually is dramatic and rapid in onset. Its benefit generally exceeds those of other available medications, including dopaminergic agonists possessing even greater potency at activating striatal dopaminergic receptors. For these reasons, LD has served as the standard against which all other antiparkinsonian therapy is judged. A trial of LD often is used to confirm the diagnosis of PD, even though other neurodegenerative disorders with parkinsonism sometimes show improvementswith this drug. When LD was first developed more than three decades ago, treatment with this drug seemed to provide a cure. The marked improvements usually achieved at the start of therapy for most patients with PD tend to continue indefinitely. The limits to maintaining the same degree of benefit from LD therapy include the progression of the underlying disorder, which can lead to impaired posture and balance unresponsive to LD. Several types of adverse reactions can be prominent at the start of LD therapy. These side effects, including sedation, nausea, and postural hypotension, can limit how rapidly the drug can be introduced, although tolerance generally develops over several weeks. Antinausea medication with trimethobenzamide can be helpful and does not exacerbate parkinsonism as other medications of this class do. The most effective antinausea medication, domperidone, is not available in the United States. Postural hypotension often responds to one or more strategies for counteracting the drop of blood pressure upon standing. These include increasing intake of salt or fluid (or both), indomethacin, dihydroergotamine, fludrocortisone, or midodrine. Often the need for such treatments diminishes with time after tolerance to LD has developed. The main shortcoming of chronic LD therapy for many patients is a gradual decline in the previously consistent benefit derived from this drug. Gaps in sustained control of parkinsonian signs, characterized by the reemergence of parkinsonian features at regular intervals between doses, occur for at least half of all patients after 2 or more years of therapy. Another side effect commonly developing during chronic LD use is involuntary movement (dyskinesia and sometimes dystonia). The potential for

these problems was unsuspected when LD first became available. One of the few voices raising concern was that of Professor Oleh Hornykiewicz, who commented as far back as 1970 that “while LD was the most natural substance for treating the striatal dopamine deficiency syndrome, it was far from perfect as a drug.” Sometimes these imperfections in clinical control can be evident even within a few months after the start of LD. The dual problems of wearing-off during each LD dosing cycle and LD-induced involuntary movements can develop in the same person. These problems can develop even in patients for whom the drug, at its best, continues to provide full relief of PD years after its initiation. Because motor fluctuations and dyskinesias are such common occurrences by 3 years after the start of LD, it is unclear why they do not occur for all patients. It is not known why some LD-treated patients with PD continue to have consistent, uncomplicated responses to this drug. Pulsatile stimulation of dopaminergic receptors has been suspected to be a causative factor in motor fluctuations and dyskinesias. However, there are several alternative explanations, and the mechanisms for these problems are still the subject of active research. In any case, once these idiosyncratic response patterns have developed, they tend to be irreversible. Even with attempts to minimize LD intake, dyskinesias can persist as regular peak effect responses. Although wearing-off responses often are associated with the same degree of improvement from each dose of LD over a shortened period of benefit, some patients lose the extent of antiparkinsonian improvement they once may have achieved with this drug. After several years of LD therapy, adverse effects in the psychic realm such as hallucination, paranoid and delusional thoughts, and other psychotic ideation can emerge, especially in the older patient with coexistent cognitive decline. With all the problems associated with chronic LD therapy, some researchers have been concerned that this drug might impart direct toxicity. In vivo studies have not supported this speculation. Although some long-term trials indicate that fewer adverse outcomes may be associated with the initial use of dopaminergic agonists, there is no evidence of a detrimental side to LD therapy with respect to the underlying disorder. Pharmacologic research has explored many options for dealing with the limitations of LD therapy. With respect to motor fluctuations and dyskinesias, there are several ways to extend the action of LD and to tailor its responses to more desirable outcomes. This chapter discusses several issues of practical importance for managing their common complications of chronic PD therapy. The topics listed in Table 116-1 are discussed in detail in this chapter.

MAXIMAL USE OF ALTERNATIVES TO LEVODOPA Although LD is the gold standard of antiparkinsonian therapy, other drugs also can relieve mild disabilities such as tremor, decreased arm swing, and various manifestations of slowed movement. Amantadine and anticholinergics have a place in PD therapeutics as alternatives or supplements to LD therapy. One option for some mildly affected patients is to delay starting LD.

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TABLE 116-1. Checklist for Monitoring Levodopa Therapy Have alternatives to levodopa (LD) been used? Are the timing and quantities of LD dosing optimal for achieving maximal benefit? Are patients likely to benefit from strategies to extend effects from each LD dose? Have there been adverse effects that call for a change in the regimen? Have new patterns of drug response developed, warranting the addition of dopaminergic agonists? Is the patient a candidate for neurosurgical interventions offering improvements beyond medication benefits? Does declining benefit from LD suggest a neurologic diagnosis different from Parkinson’s disease? Has the medication regimen been assessed for cost-effectiveness? Are supportive services for patients and their families being used to their maximum?

Whether long-term exposure to LD therapy might accelerate disease progression has been controversial for many years. While this view is not supported by clinical studies or experimental animal models of parkinsonism, chronic LD use is a risk factor for the development of dyskinesias. Although it is inappropriate to delay offering LD to a patient with significant disability, many clinicians delay the start of LD for minimally symptomatic patients. Amantadine and anticholinergics add to the number of medications taken and carry their own possible side effects, but these drugs can be effective and may reduce long-term LD exposure. For parkinsonian features of slowed movements, decreased dexterity, and similar problems, treatment with dopaminergic agonists may be appropriate. These drugs include bromocriptine, pergolide, pramipexole, and ropinirole. Dopaminergic agonists duplicate many of the benefits provided by LD therapy. Although they are more expensive, entail longer buildup schedules, and can have more side effects, these drugs may offer better long-term outcomes than LD. Several studies have been conducted comparing monotherapy regimens of dopaminergic agonists with LD. In each instance, the maximal benefits for symptom relief were somewhat less with the dopaminergic agonists. However, there was a lower incidence of dyskinesias and motor fluctuations, suggesting that these alternatives to LD might lower risks for problems commonly developing after sustained LD use. These studies have also shown that LD combined with a dopaminergic agonist from the start or shortly afterward may also confer a better outcome than LD alone. Recent findings from long-term studies of ropinirole and pramipexole as initial therapy suggested that these drugs also might possess neuroprotective actions. As compared with the use of carbidopa or LD, treatment with either of these dopaminergic agonists was associated with less loss of striatal dopaminergic innervation. Although these intriguing findings are not proof of a clinically significant neuroprotective action, the results of both the pramipexole and ropinirole studies provide an argument for using these (or possibly other dopaminergic agonists) instead of LD therapy. Several laboratory studies provide clues of how these drugs might delay the progression of PD. For patients presenting the earliest stages of PD, a common sign (and a feature that can be indicative of worsening parkinsonism) is just a resting tremor. The impact of tremor on comfort, self-image, or even livelihood should not be underestimated, even though this feature usually is not a source of much disability. Often, the use of anticholinergic drugs or amantadine can provide more relief of tremor than LD or other dopaminergic drugs. Unfortunately, in some instances tremor does not respond to conventional antiparkinsonian medications. There are a few addi-

tional pharmacologic options. One is clozapine, an atypical neuroleptic that has a unique (and as yet uncharacterized) mode of action at reducing parkinsonian tremor. Only small dosages (e.g., 12.5 to 25 mg/day) of clozapine are needed. Clozapine use necessitates regular monitoring of the white blood cell count but can be quite safe in the small dosages generally effective against tremor. Botulinum toxin selective denervation of affected forearm muscles has been tried but generally is ineffective against tremor. Another pharmacologic approach is medication effective for treating essential tremor, P-adrenergic-blocking drugs and primidone. Though primarily effective for postural or action tremors, these drugs occasionally help control resting tremors in patients with PD. Neurosurgical interventions to treat tremor from parkinsonism and other causes can be highly effective and are established therapies. Like thalamotomy, high-frequency electric pulsing (deep brain stimulation, DBS) of the thalamus and the subthalamic nucleus from implanted electrodes can provide tremor control even in patients with unresponsiveness to all antiparkinsonian medications. The clinical results from DBS are better in general than from electrolytic lesioning techniques. Both lesioning and DBS procedures achieve permanent results. These surgical procedures are now carried out at many highly experienced centers throughout the United States. In addition to tremor, DBS of the subthalamic nucleus can provide dramatic improvements of gait disorders, start hesitation, rigidity, and other parkinsonian features.

OPTIMIZING TIMING AND AMOUNTS OF LD THERAPY LD therapy entails periodic monitoring and dosage adjustment. The features of parkinsonism can change over time, as can the patterns of drug response. For many patients, the most obvious change is development of a regular onset and decline in the antiparkinsonian effects from each dose of LD. This variability in clinical effect closely follows the timing of rise and fall in plasma LD concentrations. Analysis of the relationships between the drug’s pharmacokinetics and clinical actions suggests that the central nervous system response to the drug is subject to a short delay (approximately 5 to 15 minutes) as compared with peripheral LD pharmacokinetics. The loss of a long-duration benefit from each dose of LD seems to imply that, initially, the striatum is able to store and slowly release dopamine for long periods of time. Eventually, this storage capacity is lost. When a patient develops wearing-off responses, there are new challenges and several options for achieving consistent response to LD. Although a specific mechanism for these phenomena has not been elucidated, neuroimaging of the brain with respect to LD uptake has been informative. Patients with PD and typical wearing-off fluctuation patterns have been studied by administration of ‘%uorodopa in trace amounts for positron emission tomography studies. After intravenous injection of this labeled LD analogue, the rise in striatal activity of the parent tracer (or its metabolites) in subjects with PD was briefer for patients with LD wearing-off responses than for controls. Similar results came fiom experiments in rodents investigating the timing of LD metabolism in a lesioned nigrostriatal system. These studies have provided in vivo correlates of clinical observations showing shortened dopaminergic stimulation derived from each oral dose of LD. Based on these observations, strategies to increase constancy of LD delivery to the brain have been devised. Because LD pharmacokinetics and clinical response are closely correlated, modification of the dosing schedule is a logical start for improving outcomes. Verification of a wearing-off response pattern is a first step. Although a home diary of “on” and “off

Chapter 116

timing with respect to LD doses may be useful, most patients are aware if they experience a rise and fall of antiparkinsonian effect following each dose of medication. With immediate-release preparations of LD (combined with carbidopa), the rise and fall of plasma LD concentrations typically follows an elimination half-life cycle of 2.5 to 3.5 hours. Pharmacokinetic-pharmacodynamic studies have shown that LD’s half-life correlates well to its duration of antiparkinsonian effect. The factors imparting the greatest source of variability in plasma LD concentrations are associated with its absorption. LD enters the bloodstream via a facilitated large neutral amino acid uptake mechanism located in the duodenum and jejunum. LD uptake is subject to competition by other dietary amino acids and other gastrointestinal (GI) factors such as transit time and duodenal pH. Only a small fraction of ingested LD reaches the brain. Typically, patients treated with LD need 300 to 800 mg/day for optimal effect. Generally it is taken as 100 to 150 mg LD per dose and at intervals of 3 to 6 hours. The patient experiencing wearing-off responses may be helped by a change to interdose intervals of 2 to 3 hours. The amount of LD per dose can be reduced as shorter interdose intervals are adopted. A decrease to less than %hour intervals does not provide any greater consistency of LD benefits. Usually, the failure of significant improvement from dosing with LD as close together as 2 hours indicates another type of motor fluctuation that might warrant management by means other than extension of LD effect. For patients with a great deal of sensitivity to each dose of LD, it may be necessary to divide carbidopa and LD pills into small fragments to minimize the amount absorbed at any one time. Even though the small tablet (100 mg) is scored only for breaking in half, most patients can create 25-mg dosing increments for titration to optimal effect. Preparing the oral dose of carbidopa and LD in a liquid suspension offers another way to ingest precisely measured fractions of this drug. Neither LD nor carbidopa dissolves in water, and so the suspension must be agitated (by swirling) to permit accurate measurement of LD content by liquid volumes. Careful use of LD in liquid suspension can permit dosing with precise amounts of the drug, especially with quantities between the limited dosage increments possible with whole or half tablets. Patients can prepare a suspension by

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adding one 25/100 carbidopalLD tablet for each 50 mL of water to achieve a 2-mg/mL LD concentration. By adding 100 mg ascorbic acid (vitamin C) to each 500 mL of the suspension, patients can prevent LD oxidation (which is evident from a blackening of the solution with a flocculent precipitate). The timing of LD intake can be a critical determinant of optimal drug effect. Like their physicians, patients should become familiar with the pharmacokinetic profile of immediate-release LD (Fig. 116-1). Also illustrated is the delayed rise and fall of LD derived from the sustained-release preparation (Sinemet CR and generic versions). The bioavailability of LD from the sustainedrelease preparations is approximately 70% that of the immediaterelease formulations. Although measurement of plasma LD concentration is not practical for management decisions in the usual clinical setting, the timing of absorption and wearing-off can be inferred from these usual pharmacokinetic patterns. In actuality, the profiles of plasma LD concentration can differ markedly from dose to dose. This variability can be the consequence of factors such as GI transit time and the timing of meals. Most patients find that taking the drug without food gives the best chance of absorbing each dose of LD. Therefore, ingesting this medication at least one half hour before meals or an hour afterward is advisable. If patients develop nausea or other types of GI distress from LD taken without food, these problems generally can be alleviated with a few crackers or a slice of bread. LD absorption can also be subject to interference by protein intake in meals. As described earlier, the entrance of LD into the bloodstream is controlled by an active process of large neutral amino acid uptake. Some reports have given the impression that competition for LD uptake by dietary protein-derived amino acids is a common cause of motor fluctuations. However, most clinical experience indicates that irregularity in LD absorption is only rarely related to the protein content in the diet. It is possible to test for sensitivity to protein by experimenting with meals containing either high- or low-protein content. A patient can evaluate how well parkinsonism is controlled by LD during days when a high-protein lunch was consumed, in comparison to outcomes on days during which lunch contained little or no protein. If the high protein intake interferes with the antiparkinsonian effect, a patient can make dietary alterations to improve the quality of LD 1200

900 C

.-0 4-

mL *

FIG. 116-1. Typical plasma concentrations of levodopa over time following oral dosing with: (a) two tablets of immediate-release carbidopa/levodopa 25/100 mg (solid line); (b) one tablet of sustained-release carbidopa/levodopa 50/200 mg (Sinemet CR 50/200; dotted line); and (c) the effect of a 200 mg tablet of the catechol-0-methyltransferase inhibitor entacapone (Comtan) on two tablets of immediate-release carbidopa/levodopa 25/100 mg (broken line).

C

g~

sp m

600

8

3

0

-I

300

L

I

ing

2

6

4

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8

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responses. In this rare situation, a patient can plan for a uniform protein intake for each meal and redistribute daily protein intake predominantly to a meal at the end of the day. There are other reasons for delayed or incomplete LD absorption. Gastric retention of ingested LD can be a limiting factor of absorption and subsequent delivery to the central nervous system. Variations in the stomach‘s release of the drug can add an hour or more to the usual delay of 15 to 30 minutes between pill ingestion and the onset of clinical effect. Delayed uptake has been described to occur after lunch (the “siesta stomach syndrome) or in other situations when ingested LD fails to act. STRATEGIES TO EXTEND EFFECTS OF EACH LD DOSE Sustained-Release LD Preparations When variation in clinical benefits develops with the use of immediate-releaseLD, one option is a switch to a sustained-release preparation. These formulations were designed to provide extra duration of antiparkinsonian effect and a more gradual decline in plasma LD concentration. Two sustained-release products were developed in the 1980s after much experimentation with alternative preparations. Madopar CR (formerly Madopar HBS) is a capsule transformed into a gelatinous diffusion body that floats on the fluid contents of the stomach. Madopar CR, which contains 100 mg LD and 25 mg benserazide, is not available in the United States. Another LD preparation designed for delayed release of its contents has been marketed in the United States and elsewhere as Sinemet CR. This product is also available as a generic equivalent. Sinemet CR is a scored tablet with a mixture of 50 mg carbidopa and 200 mg LD embedded in a polymeric matrix. It is also prepared in a tablet containing 25 mg carbidopa and 100 mg LD. Both Madopar CR and Sinemet CR have delays of hour or more after ingestion to reach peak LD concentration. The extension of LD effect is, on average, up to 2 hours longer than that of immediate-release LD preparations. Sinemet CR and Madopar CR have shown effectiveness at decreasing end-of-dose and other types of motor fluctuations in some patients. Comparisons between the two products suggest that their pharmacokinetic profiles are similar. However, many clinicians comparing the utility of Sinemet CR with Madopar CR have found Sinemet CR to achieve a much more reliable extension of LD’s effect. Less of the LD content is absorbed from both the Sinemet CR and the Madopar CR preparations (only about 70%, on average), as compared with immediate-release forms. Patients switching from an immediate-release to a sustainedrelease LD formulation can achieve an increase in duration and improved consistency of effect. Sometimes, the switch to the sustained-releaseproduct leads to a simplified medication schedule or improved medication compliance in a setting such as a nursing home. Unfortunately, there is ample evidence that sustained-release preparations do not always result in more consistent LD plasma concentrations. Many patients have experienced more variability in clinical effect from Sinemet CR than from immediate-release LD taken regularly at intervals of 2 to 3 hours. For patients experiencing LD response fluctuations, sustainedrelease carbidopa and LD can be combined with immediaterelease forms to optimize intake of this drug at each dosing interval. For the first dose of the day, the immediate-release preparation can be used. Many patients receiving sustained-release LD need booster doses of immediate-release LD (25/100 mg) to

achieve small increments of increased LD effect. Breaking in half the carbidopa and LD CR 50/200 tablet does not eliminate its sustained-release properties, although the exposed pill surface somewhat hastens LD absorption. A patient in need of more rapid medication effects might chew a fraction of the tablet to offset its delayed release properties. The main application for sustained-release preparations is to lessen the abruptness of wearing-off responses. Although this is sometimes successful, the peak effect of LD may be too much for some patients because the sustained-release formulation contains either 100 or 200 mg of LD per dose. This can be associated with a higher occurrence of dyskinesias. The more gradual rise in plasma LD concentration may also be associated with a less abrupt onset of peak effect dyskinesia or dystonia (which typically occurs 30 to 60 minutes after a dose of LD). The greater period of drug effect with sustained-release LD can be useful for patients with frequent awakening during the night because of dystonic cramping, tremor, or difficulty in attaining a comfortable sleeping position. Although sustained-release LDS more gradual rise and fall in drug concentration might seem to be beneficial for all patterns of motor fluctuation, some patients are not helped. This has been recognized with the diphasic (dyskinesia-improvementdyskinesia pattern) of LD response. Trials of Sinemet CR have shown exacerbation in the duration of dyskinesias experienced by such patients. Patients with increased occurrence of dyskinesias or other LD-related side effects may need to reduce the amount of controlled-release preparation in their afternoon doses because of plasma accumulation of LD. Catechol-0-MethyltransferaseInhibition

Other approaches to extend the duration of LDS effect have been sought in peripherally acting inhibitors of catechol-0methyltransferase (COMT). Two drugs have been developed for this purpose: tolcapone and entacapone. COMT activity is present throughout the body, including red blood cells, liver, kidney, and gut. A large fraction of orally ingested LD is converted by COMT to 3-O-methyldopa, an inactive metabolite that cannot revert to the synthesis of dopamine. Bloodstream concentrations of 3-0methyldopa generally exceed those of LD with conventional antiparkinsonian therapy. Inhibition of COMT with tolcapone or entacapone results in decreased LD clearance, resulting in more sustained plasma concentrations. The prolongation of LD’s elimination half-life does not generally result in an increase of peak LD concentrations in the first hour after its intake (Fig. 116-1). Both COMT inhibitors are excluded from the brain in conventional dosages, so they do not retard the degradation of dopamine by this enzyme in the brain. The peripheral clearance of LD can be reduced by approximately one third with the use of tolcapone or entacapone. This can result in a much more gradual decline in plasma LD concentrations, resulting in longer duration of effect and less abrupt wearing-off of LD actions in patients experiencing this type of fluctuation. Its benefits are in part caused by an increase of the fraction of an LD dose entering the brain, an effect that can be duplicated in part by increased LD dosing. Possibly the most important clinical value for COMT inhibition is an overall reduction in variability of plasma LD concentrations, resulting in more consistency of LD effect in a disorder for which clinical control by medications can become increasingly unpredictable. Both tolcapone and entacapone are highly selective inhibitors of COMT whose sole action in PD is by enhancement of LD effect.

Chapter 116

Tolcapone is recommended for use at either 100 or 200 mgldose at 6-hour intervals, based on a longer duration of action than entacapone. Entacapone, available only in a 200-mg tablet, is recommended for administration with each dose of LD (either immediate or sustained release). However, the duration of entacapone effect as a COMT inhibitor permits it to be administered as far apart as 4-hour intervals for maximal effect. Tolcapone has been associated with a few instances of fatal liver damage, leading to its withdrawal from marketing in Europe and elsewhere. The mechanism (or even proof) of a direct connection between the drug and this idiosyncratic outcome has not been established, however. Although most people treated with this COMT inhibitor did not show any evidence of hepatotoxicity, tolcapone’s availability in the United States is limited to patients for whom other comparable therapy fails. Because entacapone acts in identical fashion to tolcapone, there is currently little use of tolcapone (although the latter probably is more potent as a peripherally acting COMT inhibitor and has a longer duration of effect). COMT inhibition can be regarded as an all-or-none event that can be of value in patients whose parkinsonian control has become highly dependent on moment-to-moment concentrations of plasma LD. Increases of daily “on” time by approximately 1 hour have been reported in patients with typical wearing-off responses. Tolcapone and entacapone do not tend to improve other types of motor fluctuations such as start hesitation or unpredictable “off states. For the patient willing to take LD at intervals as close as 2 hours, COMT inhibition generally does not offer any additional advantage. However, given the variability of plasma LD concentrations often experienced with the use of sustained-release LD preparations, COMT inhibitors can offer an improvement (and the more expensive sustained-release LD preparation can be eliminated). The start of COMT inhibitors can be without a titrated introduction. However, the immediate effect can be an increase of LD delivery to the brain, so patients experiencing dyskinesias or other peak effect LD actions should reduce their LD intake. A trial as short as 1 week can establish whether a new regimen of COMT inhibition is of value. The clinical effects of these drugs are gone within 1 day of their discontinuation because both tolcapone and entacapone are reversible inhibitors of the enzyme. Apart from an increase of dopaminergic side effects such as dyskinesias, the main adverse reactions of tolcapone and entacapone are the rare occurrences of GI bloating and diarrhea, both of which can develop after several weeks of therapy and cease once the drugs are stopped. Current regulations for the use of tolcapone include biweekly testing for elevations in liver-derived enzymes and a detailed informed consent process emphasizing the rare possibility of potentially fatal hepatotoxicity.

Monoamine Oxldase-B Inhibition Another approach for lessening wearing-off responses involves inhibition of central nervous system monoamine oxidase (MAO). This enzyme is the initiating step in the major pathway of dopamine catabolism. MA0 has been differentiated into two forms on the basis of substrate specificity. In PD therapeutics, drugs with a broad-spectrum inhibition of MA0 (which are used to treat’depression) pose a problem because MAO-A inhibition would permit hypertensive reactions to result from dietary tyramine. Selective MAO-B inhibition potentiates the antiparkinsonian effects of dopamine without risk of adverse reactions from tyramine. A selective and irreversible inhibitor of MAO-B,

Improving Responses to Levodopa

753

selegiline (also known as deprenyl), has been used to augment LD’s effects. Selegiline can be used safely at dosages of 10 mglday in chronic therapy for PD. By blocking the breakdown of dopamine derived from each dose of LD, selegiline augments the duration of its clinical action. In postmortem studies, conventional selegiline treatment produced more than 90% inhibition of striatal MAO-B. A lo-mglday dosage of selegiline has been widely adopted in using the drug for adjunctive therapy, although it is likely that chronic treatment with a much lower dosage would also achieve full MAO-B inhibition. Studies using regimens of up to 40 mglday revealed no additional antiparkinsonian actions over results achieved from 10 mglday. Another important consideration in using selegiline is that after discontinuation of the drug, its effects as an MAO-B inhibitor linger for several weeks. Selegiline does not alter the absorption or peripheral metabolism of LD. Additional properties of selegiline besides MAO-B inhibition are unlikely to contribute to its pharmacologic profile in augmenting dopamine’s action. The metabolites of selegiline may cause some of the adverse effects some patients experience from this drug. A conventional daily dosage of selegiline is converted to small quantities of L-amphetamine and L-methamphetamine. It is unliiely that these metabolites have any effect on parkinsonism. Administered with LD, selegilineaugments both the magnitude and the duration of LD’s effects. This can occur even with sustained-release LD preparations. Extensive clinical experience with selegiline supports the use of selegiline as a means for potentiating LD’s clinical effects. Most studies have shown the increased duration of effect to be no more than 30 to 45 minutes per dose of immediate-release LD. For some patients, selegiline therapy can lessen the problem of wearing-off decline in LD’s action. However, not all patients experiencing wearing-off will respond. Other types of motor fluctuations such as start hesitancy or sudden “off’ states ‘do not improve with selegiline, nor is selegiliie useful in treating patients with involuntary movements because it can exacerbate this problem. Dysphoric reaction, vivid dreams, hallucinations, and sleep disturbance are other possible dose-related side effects. Adjunctive therapy with selegiline can be beneficial for patients who are undermedicated with LD. Sometimes, the same types of improvement with selegiline could also be achieved by an increased dosage or closer spacing of the LD intake. For patients already receiving LD at a maximally tolerated dosage, addition of selegiline calls for a reduction in LD intake by 20% or more to avoid peak dose side effects. Based on its action as an irreversible inhibitor of MAO-B, it seems that the actions of selegiline should be lasting, although some studies have shown that even when there is benefit, it can decline after several months. As an MAO-B inhibitor, selegiline should be regarded as having an all-or-none effect on LDS actions. A brief trial can demonstrate its value for enhancing LDS benefits. No dietary restrictions are needed with the use of selegiline at a daily dosage of 5 to 10 mglday. When daily intake exceeds 30 mglday, however, the drug loses its selectivity for MAO-B and could produce hypertensive reactions if the patient ingests tyramine. A few serious adverse drug interactions have been described to result from coadministration with selegiline. With meperidine (also known as pethidine outside the United States), a toxic adverse reaction resembling opiate overdosage has been described. Other compounds with opiate properties might also produce similar adverse reactions with selegiline. An idiosyncratic adverse reaction between antidepressant medications (particularlythe selective serotonin reuptake

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blockers) and selegiline has been reported, resembling the idiosyncratic reaction described with meperidine. Enteral LD Infusion

Although the pharmacokinetic profiles of sustained-release LD preparations can improve the constancy of LD's effect, irregularities in gastric emptying can still govern the absorption of the drug. Domperidone does not always increase gastric emptying for the purpose of enhancing LD's uptake. Even if the stomach regularly delivers the drug to the upper GI tract, some irregularity in its uptake is inevitable because of the influences of meals, GI motility, and other factors. For some patients, the therapeutic window for LD can be so narrow that the only means for adequate control is through an invariant plasma blood concentration. Intravenous LD infusions, adjusted to an optimal drug delivery rate for symptomatic relief, have shown that antiparkinsonian control can be improved by constant plasma LD concentrations. Similarly, methods for direct enteral infusion of LD suspensions have been shown to improve on the dose-by-dose variability associated with the drug taken in tablet form. A permanent route of enteral access can be installed with minimal discomfort, sometimes on an outpatient surgical basis. This method of per-gastric duodenal or jejunal infusion makes use of a small-bore feeding tube inserted through the abdominal wall and connected to a portable pump. This procedure has few complications apart from the infusion tubes curving back into the stomach or knotting. An alternative means of enteral infusion is insertion of an infusion tube by jejunostomy. Although fewer tube reinsertion procedures may be needed with jejunostomy, it entails an abdominal operation, in contrast to the outpatient radiologic procedure for placing a per-gastric feeding tube. For patients unable to improve their clinical state by adjusting their oral intake of LD or adjunctive medications, continuous enteral infusion can offer great benefits. This physical means for bypassing the pylorus also provides an opportunity for a rate-controlled delivery of the drug to its primary absorptive sites in the duodenum and jejunum. Patients using enteral infusion are not constrained to the dosing regimens limited to the quantities of LD in available formulations. The infusion permits precise adjustment to either the optimal rate of delivery or the bolus dose needed for desired effects. The portable pumps currently available permit the LD delivery needed to achieve either stable or readily altered plasma concentrations of LD. The infusion rate can be adjusted in extremely small increments of drug delivery as titration proceeds in search of optimal effect. With continuous enteral LD infusion, the clinical effect from each rate change becomes evident within 5 minutes. Constant infusion avoids the occurrence of peak concentrations and the consequent surge of dopaminergic effect that are associated with use of conventional LD preparations. Consequently, dyskinesias can be diminished or eliminated. Although the constant infusions can result in increased daily needs for LD in some instances, the net effect can be a marked improvement in the control of motor fluctuations. PArCLRNS OF DRUG RESPONSE WARRANTING CHANGE IN TREATMENT REGIMEN

With chronic therapy of parkinsonism, changes in clinical control of symptoms over time may herald new targets for treatment. Involuntary movements, dystonic postures, painful spasms, and sudden freezing may develop as inevitable consequences despite

regular doses of LD. Attempts to alter LD intake may be unsuccessful at modulating these problems, which often respond to dopaminergic agonists (Table 116-2). Therapy with bromocriptine, pergolide, ropinirole, or pramipexole can bring about more on time and fewer freezing episodes.Although these drugs differ in their structures, dopamine receptor subtype stimulation profiles, and pharmacokinetics,their net antiparkinsonian effect is similar. Not all patients improve from or can tolerate dopaminergic agonists. If introduced gradually over up to 2 months, these drugs produce tolerance to their acute side effects such as nausea, vomiting, and hypotension. Dose-limiting side effects can include sedation, vivid dreams, and hallucinations. Sometimes one agonist is much more effective or better tolerated than another, and so a switch between these drugs often is warranted in patients achieving suboptimal control. In addition to helping with unpredictable and sudden off states, the dopaminergic agonists present another solution for managing the wearing-off in LD effect. Because of their longer plasma half-lives, the addition of a dopaminergic agonist can help to lessen the tendency for an abrupt loss of clinical effect in LD-treated patients. Another situation in which dopaminergic agonists can improve antiparkinsonian control is for peak effect dyskinesias. Patients whose disabling involuntary movements emerge at the height of LD's antiparkinsonian actions sometimes can be helped by a decrease in the LD dosage and the addition of a dopaminergic agonist. Other problems related to advanced PD could also be responsive to dopaminergic agonists. The tendency to fall as a result of retropulsion usually is not helped, but gait hesitancy, causing imbalance, can be improved by adding a dopaminergic agonist to an LD regimen. Dopaminergic agonists can be useful for early morning dystonia, a problem in which the feet are subject to painful spasms related to the gradual loss of dopaminergic effect over the course of the night. The extended duration of effect from dopaminergic agonists, like that of sustained-release LD, can avert this problem when these medications are taken at bedtime. Apart from this indication, antiparkinsonian medications are not generally advisable for use during

W

TABLE 116-2. Situations Warranting the Use of Dopaminergic Agonists

When there is inadequate benefit in control of parkinsonism from a daytime levodopa (LD) regimen greater than 800 muday With the occurrence of start hesitation or unpredictable "off" states such as freezing episodes As substitute for LD when intolerable dyskinesias occur With the occurrence of early morning dystonia (typically unilateral dystonic foot cramping) With peak effect and end-of-dose dystonic reactions associated with LD therapy (or preceding its start) As an alternative treatment for patients with the diphasic (dyskinesiaimprovement-dyskinesia)pattern of LD response For enhancing the consistency of antiparkinsonian control in a patient experiencing dose-by-dose fluctuations in L D s effects, even if other extension strategies have failed For controlling parkinsonian features minimally responsive to LD treatment (such as resting tremor or imbalance) or when little overall benefit from LD has occurred Rarely, when LD therapy is not well tolerated (because of nausea, hallucinations, sleep disturbance, or dyskinesias and despite the increased potency of the dopaminergic agonists) As initial monotherapy (or in combination with LD) to avoid long-term adverse outcomes of LD therapy (motor fluctuations, dyskinesias) and, possibly, for a neuroprotective action against Parkinson's disease progression

Chapter 116 rn ImprovingResponsesto Levodopa

sleeping hours because they can cause vivid dreams and sometimes enhance nocturnal myoclonus. In the past decade, there has been little formal investigation of drug holidays, the notion that abrupt discontinuation of LD and other antiparkinsonian medications might lessen LD-induced adverse effects. Although there has been limited support for the concept in terms of outcomes for several weeks after a drug holiday, the abrupt stopping of antiparkinsonian medications can be uncomfortable and dangerous. Drug withdrawal has been associated with a neuroleptic malignant syndromelike response, aspiration pneumonia, and deep vein thrombosis from marked rigidity and immobility. It is possible that the claimed benefits of drug holidays in the past were actually the consequence of reduced intake of LD, especially if the daily dosage was excessive previously. ADVERSE EFFECTS THAT CALL FOR A CHANGE IN THE TREATMENT REGIMEN The following problems may be indications for changes in medications.

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clozapine and quetiapine can be highly effective for improving these problems without exacerbating parkinsonism. Olanzapine and risperidone are also effective but can increase parkinsonian features.

Forgetfulnessand Other Cognitive Decline Sometimes an accompaniment of too much dopaminergic therapy, decreased memory function and confusion can also develop in patients receiving anticholinergic medication. Even if this problem is not recognized initially, forgetfulness always calls for reducing and stopping anticholinergic agents, and this should be carried out from time to time to assess both benefits and possible contributions to impaired cognitive abilities. Surprisingly, anticholinergic therapy also is very well tolerated by some older adults. A trial of cholinesterase inhibitors, including donepezil, rivastigmine, or galantamine (Reminyl) for several weeks can be used to assess the potential for one of these drugs to improve cognitive impairments without exacerbating parkinsonism.

Postural Hypotension Peak Effect Dyskinesias or Dystonla Dyskinesias can be quite benign, sometimes unnoticed by patients. If they are troublesome, several measures can be taken. The total LD intake or the amount per dose may need to be decreased. Sometimes dyskinesias and dystonia are more prominent in the afternoon and evening because of cumulative effects of LD taken earlier in the day. If so, dosage reduction later in the day is appropriate. An increase in the intensity of peak effect involuntary movements can result from previous addition of selegiline or a dopaminergic agonist. If so, these adjunctive medications can be decreased or eliminated if they provide no additional benefit. Dyskinesias sometimes can be blocked with amantadine (100 to 300 mg/day). Other pharmacologic approaches include the use of neuroleptic medications in small dosages, such as 2.5 to 5 mg molindone, a selective D, dopamine receptor blocker. Other drugs that can be used in small dosages for this purpose include risperidone and pimozide. With small neuroleptic dosages, it may be possible to lessen involuntary movements without much interference with LD’s antiparkinsonian actions. Another approach to lessen LD-induced dyskinesias has been the use of clozapine. A recent study found that this atypical neuroleptic substantially reduced the amount of time patients spent in a dyskinetic state. Whereas other neuroleptics would antagonize the control of bradykinesia, clozapine does not. Quetiapine also has shown usefulness at lessening adverse effects of LD therapy, such as dyskinesias, but without exacerbating parkinsonism.

Vivid Dreams, Hallucinations, and Psychotic Thinking All forms of dopaminergic therapy, anticholinergics, and amantadine can cause these problems, sometimes in a dose-related manner. A reduction in the amounts of these drugs taken at the end of day can improve quality of sleep by lessening the extent of disruptive dreams or myoclonic jerks. Occasional benign hallucinations or illusions that are not believed (i.e., they are not associated with delusional thinking) may be easily tolerated by some patients. Although these problems can presage the eventual development of more psychotic overtones, some patients may regard benign hallucinations as an acceptable tradeoff for the benefits of the medications. Unlike other neuroleptic drugs,

Often asymptomatic,postural hypotension is seen in patients with PD who are receiving dopaminergic therapy. The extent of postural blood pressure drop can be alarming even if the patient is experiencing no lightheadedness. It may be that, with chronic orthostatic change in blood pressure, the recordings made in the arm cease to represent core blood pressure to the brain. Symptomatic hypotension may be a cause for reduction in the regimen of antiparkinsonian drugs. However, a trial of alternative medications can be undertaken to counter the blood pressure drop. These include salt and water loading, fludrocortisone, midodrine, and indomethacin. Slight elevation of the head of the bed can lessen the diuresis of salt retained during the day. In addition, the more chronic stimulation of the renin-angiotensin system may help to counter any tendency for orthostatic hypotension. RESPONSES TO MEDICATIONS SUGGESTING AN ALTERNATIVE DIAGNOSIS When an LD regimen of 750 mg/day (with carbidopa) has been unable to improve parkinsonism, the problem might be an incorrect diagnosis. Several other neurodegenerative disorders (including progressive supranuclear palsy and the variant forms of multiple system atrophy, including Shy-Drager syndrome and olivopontocerebellar degeneration) have prominent parkinsonism but minimal or no effect from a trial of LD. Because these disorders may be difficult to distinguish from typical PD (especially in their early stages), the failure of response to LD may be the first clue for an alternative diagnosis. Rarely, cases of acquired parkinsonism (such as brainstem or striatal lesions, certain toxic exposures, or increased intracranial pressure) show a response to LD. It is also important to recognize that even in typical PD, features such as resting tremor, micrographia, or imbalance may fail to respond to LD or other medications. COST-EFFECTIVENESS PD medications are expensive burdens for patients and health care systems. Drugs should be reevaluated from time to time to determine whether they are a good value. As mentioned earlier,

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there are several alternative ways to alleviate certain problems in PD therapeutics. For example, although controlled-release LD preparations can offer convenience and more sustained antiparkinsonian effects, their higher cost may lead patients to choose conventional and less expensive immediate-release carbidopa and LD, to be taken more frequently. Dopaminergic ergots can help prevent the wearing-off of LD’s effect (as can selegiline or COMT inhibitors), but sustained-release LD preparations or frequent doses of LD may be more cost-effective for solving this particular problem. Some patients may want to undergo a trial of reducing medication intake to weigh the benefits and costs of therapy. In this way, patients can derive a sense of how much change in disability is achieved from each increment in medication. The question of whether chronic regimens of medications are continuing to help is particularly appropriate for reassessing amantadine. This drug can lose effectiveness over time. Although some patients have continued benefit from 300 mg/day, others achieve the same results with 100 or 200 mg/day. A trial of reducing the dosage of amantadine (over the course of 2 weeks).canbe used to reassess its current value. The same questions can be asked of other adjunctive medications. COMT inhibitors, dopaminergic agonists, and sustainedrelease LD preparations may be helpful against the wearing-off of effect. Sometimes, combination regimen medications have evolved that duplicate each other at targeting the wearing-off problem. Trials of reducing medication intake might reveal the minimum of these drugs needed for adequate symptomatic control. Because patients sometimes do not know whether starting a new medication has actually led to any benefit, a trial reduction might help to clarify this issue. Generic equivalents for Sinemet (carbidopa and LD) and bromocriptine have recently become available in addition to amantadine and LD. These preparations offer substantial savings to patients and are not known to differ in clinical actions from the brand name products.

services. Some patients feel that particular exercise programs have had a major impact on their well-being. Although the best form of exercise varies on the basis of age, level of physical conditioning, and gait or balance disturbance, most patients can benefit from a variety of exercise programs. Patients often need reassurance that the temporary exacerbation of tremor after exercise does not exacerbate the underlying disorder. Depression in patients with PD can be disguised by motor aspects of the disorder (which can also create the image of the disorder by psychomotor retardation and a depressed facial expression). The speech difficulties common in PD can lead to social withdrawal. Encouragement of outlets for communication in support groups, in family discussions, or with mental health professionals is important. Several forms of speech therapy are available, including a program called the Lee Silverman Voice Training Technique. Many patients with PD, like others with physical disability in the golden years of retirement, are extremely frustrated and frightened by the impact of the disorder on their lives. To the extent that unrealistic perceptions of PD govern their thoughts, reassurance of the current status of this disorder is often important. Practitioners should acquaint themselves with studies in which the natural history of PD has been explored because benign outcomes of this disease are well known, and the rate of disability in others can be realistically described. Many patients with PD are alarmed about the possible impact of the disorder on their mind. Although some patients do develop dementia or other types of impairment, many patients have retained full mental capacities even after 10 or more years with the disorder. Patients may need frank assessments of their condition from time to time, not just optimistic reassurance from their physician. Finally, patients can draw a great deal of optimism from the active realm of research into the causes and treatments of PD. For some patients, involvement in clinical trials has helped them to cope with this disorder. Several therapies for extending or augmenting LD effect are currently under development.

SUPPORTIVE SERVICES FOR PATIENTS AND FAMILIES A wide range of information sources and services are available for patients and their families. Several national and statewide PD support organizations provide newsletters, fact sheets, advisory services, and support group meetings. A number of well-written and accurate books describe the experience of living with parkinsonism. Some communities have geriatric services that can be used to great advantageby patients with parkinsonism and their families. Rehabilitation approaches to parkinsonism include gait training, equipping the home for impaired ambulation and balance, and increasing endurance in the face of disabling bradykinesia and other aspects of impaired motor control. Learning tricks to overcome freezing and using walkers or canes to enhance independent ambulation are all reasonable goals for rehabilitation

SUGGESTED READINGS Agid Y, Ahlskog E, Albanese A et ak Levodopa in the treatment of Parkinson’s disease: a consensus meeting. Mov Disord 1491 1-913, 1999 Factor SA, Weiner WJ (eds): Parkinson’s disease: diagnosis and clinical management. Demos, New York, 2002 Goetz CG, Koller WC, Poewe W et ak Management of Parkinson’sdisease: an evidence-based review. Mov Disord 17(Suppl 4):S1-166, 2002 LeWitt PA, Oertel WH (eds): Parkinson’sDisease:The Treatment Options. Martin Dunitz Publishers, London, 1999 Nutt JG, Holford NHG The response to levodopa in Parkinson’s disease: imposing pharmacological law and order. Ann Neurol 39:561-573, 1996 Riley DE, Lang AE: The spectrum of levodopa-related fluctuations in Parkinson’s disease. Neurology 43:1459-1464, 1993

Chapter 117

Surgical Treatment of Parkinson’s Disease

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1 17 Surgical Treatment of Parkinson’s Disease Drew S. Kern and Rajeev Kumar Surgical treatment for Parkinson’s disease (PD) became popular in the 1950s with the realization that thalamic lesions greatly relieved tremor. However, with the introduction of levodopa in the late 1960s the number of surgeries performed greatly diminished. In the past decade, there has been a reemergence of surgical treatment for PD for several reasons. First, patients have become disabled despite maximal drug therapy from levodopa-induced motor complications including dyskinesias. Second, there is an increased understanding of basal ganglia circuitry and the pathophysiology of PD. This is partially the result of studies using rodent and 1 -methyl+phenyl- 1,2,3,6-tetrahydropyridine (MPTP) nonhuman primate models of PD. Finally, significant advancements in neuroimaging (especially magnetic resonance imaging) and intraoperative electrophysiologic recordings have increased surgical targeting accuracy. The classic model of basal ganglia organization (Fig. 117-1) involves a direct and indirect pathway modulating input received from the cerebral cortex. Dopamine released in the striatum via projections from the substantia nigra pars compacta (SNc) binds to D, and D, receptors. D, receptors are excitatory and stimulate striatal neurons of the direct pathway; conversely, D, receptors are inhibitory, and D, stimulation inhibits striatal neurons of the indirect pathway. Striatal neurons of both pathways use the neurotransmitter y-aminobutyric acid (GABA) but differ in neuropeptide cotransmitters. Stimulation of the direct pathway results in inhibition of the globus pallidus pars interna (GPi) and the substantia nigra pars reticulata (SNr). Stimulation of the indirect pathway reduces inhibitory output from the striatum to the globus pallidus pars externa (GPe), which then inhibits the subthalamic nucleus (STN). The STN contains the only glutamatergic excitatory outputs in the basal ganglia and projects primarily to the GPi and SNr but also sends widespread

FIG. 117-1. Simplified schematic diagram detailing the major afferent and efferent projections of the basal ganglia in healthy normal subjects and in Parkinson’s disease. Thickness of arrows represents relative degree of excitation or inhibition. Black arrows, inhibitory projections; gray arrows, excitatory projections. CPe, globus pallidus pars extema; CPi, globus pallidus pars interna; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.

projections to the GPe, pedunculopontine nucleus, striatum, and SNc. The main inhibitory outputs of the basal ganglia are the GPi and SNr, which send inhibitory projections to the brainstem, and the ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus. Therefore, in normal movement there is activation of the direct pathway and inhibition of the indirect pathway, resulting in VL and VA facilitation of appropriate movement selection via projections to motor cortical association areas including the supplementary motor area. PD is characterized primarily by loss of dopaminergic neurons in the SNc. Therefore, according to the model, the direct pathway is underactive and the indirect pathway is overactive, and there is reduced thalamic facilitation of normal movement. Therefore, surgical treatments that decrease basal ganglia inhibition of the thalamus may alleviate parkinsonism. As a result, neurosurgeons have targeted the hyperactive GPi and STN. The ventralis intermedius (Vim) nucleus of the thalamus receives predominantly cerebellar afferents and is thought to be an important part of the multiple oscillating loops responsible for the generation of tremor. Surgical intervention at this site may interrupt its rhythmic firing and improve tremor. This model of basal ganglia circuitry has several anatomic and functional inadequacies. Studies using retrograde tracers have identified extensive branching of striatal axons to multiple projection sites, unlike the model that suggests few specific projection sites. Furthermore, there are many inputs from regions other than the basal ganglia received by the STN that have not been addressed. These structures can profoundly influence function and include the cerebral cortex, the centromedian nucleus and parafascicular nucleus of the thalamus, and the pedunculopontine nucleus. Supporting evidence for this observation comes from rat models that report only a 20% increase in STN

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neuronal firing after GPe lesioning. The model also predicts that lesions of the GPi should amplify levodopa-induced dyskinesias, but in clinical practice they are relieved. Although understanding of basal ganglia function has improved in the past decade, there are clear gaps in our knowledge that are being critically investigated.

PATIENT SELECTION Selecting appropriate patients for surgery typically involves a team consisting of a movement disorder neurologist, a functional neurosurgeon, and a neuropsychologist. The role of the neurologist is to ensure that the diagnosis is correct and that all nonsurgical treatments have been used. Confirmation of PD as the diagnosis, as opposed to an atypical parkinsonian syndrome (such as multiple-system atrophy or progressive supranuclear palsy), is extremely important. The neurosurgeon evaluates the patient’s general health with respect to the risks of surgery and frankly discusses with the patient the potential complications of surgery including intracerebral hemorrhage, which could result in serious neurologic disability or death. The neuropsychologist performs an in-depth cognitive examination to determine whether there are any signs of dementia and interviews the patient and caregiver to determine whether there are behavioral abnormalities such as anxiety, depression, or other psychiatric symptoms. There are no well-established criteria for surgery that predict both efficacy and adverse effects; however, some basic guidelines adopted by many surgical teams exist. In general, appropriate candidates for surgery lack significant cognitive impairment or unstable medical problems and have substantial disability in performance of activities of daily living (ADL) caused by marked motor fluctuations and levodopa-induced dyskinesias despite optimal medical therapy. Patients who are cognitively impaired or have excessive anxiety are poor candidates for surgery because of their inability to provide useful intraoperative feedback, difficulty with postoperative management (specifically in programming deep brain stimulation), and increased risk of worsening their preexisting cognitive deficits. Other contraindications include severe uncontrolled hypertension, cancer, or cardiac, renal, hepatic, or pulmonary diseases. Patients must have emotional support available from family or other caregivers. Postoperatively, there may be a difficult adjustment period associated with the new role of the patient being less dependent on others because of marked improvement of parkinsonian disability. Caregivers must

W TABLE117-1.

also help patients attend multiple deep brain stimulation (DBS) programming visits (often after overnight drug withdrawal). Table 117-1 lists the major criteria and predictors to be considered when selecting patients for surgery. The degree of improvement obtained with a supramaximal dosage of levodopa after overnight withdrawal of antiparkinson medication is highly predictive of the response to STN DBS and probably also to pallidal interventions. With the exception of tremor, signs that are not improved with levodopa fail to improve with surgery and include cognitive and psychiatric problems, on-period freezing, and levodopa-refractory dysarthria, dysphagia, and postural instability. Furthermore, the levodopa test reinforces for the patient and family realistic expectations of the results of surgery. Determining the appropriate timing of surgery can be difficult because surgery for PD is elective and is undertaken to improve patient’s quality of life. The patient and the physician should frankly compare the potential for significant improvement and potential adverse effects of more aggressive drug therapy compared with surgery. Many factors must be considered in this decision, including the patient’s personal, professional, and social situation. Regardless, surgery should not be unnecessarily delayed until the patient loses his or her job or there is a significant decrease in independence and loss of quality of life.

ABLATION AND DEEP BRAIN STIMULATION The two most widely used surgical techniques are ablation and DBS. Both procedures produce similar results despite fundamental methodologic differences. There are three major surgical sites for intervention: the Vim nucleus of the thalamus, the GPi, and the STN. The initial surgical method for both ablation and DBS is similar and involves neuroimaging (computed tomography or magnetic resonance imaging) with a stereotactic headframe in place and then physiologic confirmation of the target site using intraoperative stimulation or recording techniques. Thereafter, either a radiofrequency lesion (ablation) or a permanently implantable electrode (for DBS) is placed at the target site. Systematic complications of stereotactic surgery include a 1% to 2% probability of symptomatic hemorrhage per side operated, resulting in permanent neurologic deficit or death. The equipment for DBS includes a quadripolar electrode implanted into the brain and held stationary by fixation to the skull. The electrode lead is connected to a cable that runs under

Selection Criteria for Surgery in Parkinson‘s Disease

Inclusion Criteria

Exclusion Criteria

Significant impairment of ADLs and quality of life caused by motor fluctuations and levodopainduced dyskinesias despite maximal drug therapy Physically healthy with potentially a long life expectancy after surgical treatment Physical and mental stamina to provide feedback during a lengthy operation Understand risks of surgery Preoperativeand postoperative emotional S U D D O ~ ~

Significant cognitive impairment Uncontrolled cardiac, renal, hepatic, or pulmonary disease, cancer, or hypertension Significant psychiatric illness including anxiety, mood disorders, and severe depression Marked cerebral atrophy or extensive white matter T2 signal changes

Predictive Factors for Good Outcome Shorter duration of disease Younger patients Very high degree of improvement of parkinsonism with levodopa

Predictive Factors for Poor Outcome Unrealistic expectations, such as a belief of being cured Presence of levodopa-refractory features of parkinsonism (with the exception of tremor)

Chapter 117

FIG. 117-2. DBS hardware as implanted in a patient.

the scalp and skin of the neck and connects to a pulse generator placed subclavicularly (Fig. 1 17-2). Stimulation settings are adjusted by means of a transducer placed on the skin overlying the pulse generator. The following stimulation parameters are adjustable: frequency (100 to 185 Hz is most effective), pulse width (typically 60 to 120 pV), voltage (usually 1.0 to 3.6 V), and stimulating contacts (monopolar or bipolar stimulation). The clinical effects of DBS result from a combination of the microlesion caused by electrode implantation alone (minor effect that often gradually disappears as perielectrode edema resolves postoperatively) and stimulation (major effect). The mechanism of DBS is unknown, but similarity to the clinical effects of ablation suggests that DBS may be inhibitory. It has been suggested that DBS may activate local inhibitory interneurons. Another possibility is that of neuronal jamming, whereby activation of fibers transfers nonphysiologic and incomprehensible messages to downstream target nuclei, which are then disregarded. DBS has many advantages over ablation. Electrode implantation causes fewer permanent neurologic complications because less brain tissue is destroyed than in ablation because radiofrequency lesions may be inadvertently expanded or misplaced to involve important structures adjacent to the intended target. In addition, autopsy studies suggest that long-term continuous

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stimulation does not cause significant anatomic damage to adjacent brain tissue. The effects of DBS are reversible, with symptoms returning to preoperative levels when stimulation is stopped. The hardware can also be removed at any time if indicated. In contrast, the effects of ablation are irreversible and not adjustable without additional surgery, which may occasionally be needed to expand an inadequate lesion. With DBS, stimulation parameters can be fmely adjusted to maximize beneficial results and minimize adverse effects caused by current spread to adjacent structures. Finally, the electrodes can be surgically repositioned if they are initially suboptimally situated. Ablation also has advantages over DBS. Ablation and electrode implantation are performed with the patient awake; however, DBS entails additional surgery performed under general anesthesia to implant the pulse generator and connector wire. Furthermore, the pulse generator must be surgically replaced every 3 to 7 years because of battery drainage. Several visits typically are necessary after electrode implantation to adjust the stimulation parameters, especially for patients undergoing GPi or STN DBS, whereas minimal follow-up is needed after ablation. With DBS, approximately 25% of patients experience hardware complications within 2 to 3 years postoperatively. The most notable complications involve mechanical hardware breakage and skin erosion over the hardware (which may be associated with cutaneous infection). These problems usually involve the peripheral components and necessitate replacement of damaged or infected hardware and sometimes treatment with antibiotics. In patients with severe postural instability and frequent falls, ablative surgery may be a better choice because falls may damage or displace DBS hardware. DBS is also a very expensive procedure, with the hardware alone costing approximately $20,000. Therefore, in many areas of the world, lesioning procedures are the only affordable surgical option. THALAMlC SURGERY

Lesions of the Vim (thalamotomy) and thalamic DBS are effective in markedly reducing or eliminating severe tremor and may diminish rigidity and levodopa-induced dyskinesias contralateral to the surgical side, but they do not improve other features of PD such as bradykinesia and gait disorders (Table 117-2). Reports of improvement in bradykinesia probably are artifactual and reflect reduction of tremor that interferes with evaluation of bradykinesia. Unilateral ablation and DBS predominantly improve contralateral tremor. Tremor is also slightly reduced ipsilaterally with thalamic DBS. Therefore, patients with severe bilateral tremor

TMLE 117-1. Effects of Unilateral and Bilateral Ablation and DBS of Vim Nucleus, CPi, and STN in Patients with Parkinson's Disease BILATERAL

UNILATERAL

Vim Motor UPDRS off Motor UPDRS on ADL UPDRS off ADL UPDRS on Dyskinesiason Medication dosage

10%-30% -10% No change No change No change No change

GPi

-30% No change -30% -30%

-75% No change

Vim

STN

25%-50% 0%-39% -30% -30% No change

-

No change No change

GPi

30%-50% -25% 30%-40% 3 w 0 % 80%-100%

No change

sm -50% -25% 30%-50% 20%-30% 60%-1ooorb 50%-100%

Percentages representaverage reduction in standardized rating scale scores, symptoms, and drug dosage comparedwith baseline measurementsfor combined unilateral or bilateral surgery (ablation or DBS). Dashes indicate no reported data. All percentagesrepresent average reductionsat 6-12 months postoperatively."ow'represents assessments scored after overnight drug withdrawal, and "on" indicatesscores with drug treatment Abbreviobbns: ADL activitiesof daily living; DBS, deep brain stimulation; CPi, globus pallidus pars interna; STN, subthalamic nucleus; Vim, ventralis intermedius.

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benefit most from bilateral procedures. Bilateral thalamotomy is associated with a high incidence of severe dysarthria and adverse cognitive effects, whereas these complications are avoided with bilateral thalamic DBS or unilateral thalamic DBS performed contralateral to a previous thalamotomy. Mild paresthesias usually affecting the contralateralhand or face occur in most patients with unilateral or bilateral thalamic DBS. Mild dysarthria and dysequilibrium are more common with bilateral than with unilateral thalamic DBS and occur in 10% to 30% of patients. All of these side effects usually are easily managed by stimulation adjustments and are outweighed by marked bilateral tremor reduction. Thalamic DBS more effectively reduces rest than action tremor and distal limb greater than proximal limb or axial tremor. Certain skills that may be impaired by tremor in PD such as handwriting are improved, but ADL scores are not substantially improved because the greatest sources of disability in PD are bradykinesia and gait disorders. Head and voice tremor is also markedly relieved after bilateral thalamic DBS but is improved much less with only unilateral thalamic DBS. Long-term data indicate sustained reduction of tremor beyond 1 year, although stimulation intensity often may need to be increased with disease progression. Left thalamic DBS may slightly reduce lexical verbal fluency, but otherwise thalamic DBS has not been reported to significantly impair cognition. Schuurman et al (2000) recently reported a randomized, controlled trial comparing unilateral thalamotomy and unilateral thalamic DBS in patients with PD, essential tremor, and multiple sclerosis. Efficacy in controlling contralateral limb tremor was similar as measured 6 months postoperatively;however, thalamotomy was associated with a higher rate of complications, which reduced the overall functional improvement in patients treated with this therapy. In the thalamotomy group, 11 of 23 patients experienced complications, compared with only 2 of 21 patients who received thalamic DBS. Dysarthria was common with both thalamotomy and thalamic DBS, whereas cognitive deterioration, hypesthesia, gait or balance disturbances, and arm ataxia were unique to thalamotomy. Adverse effects in the DBS group were minimized by the adjustability of stimulation. Historical reports suggest that approximately 60% to 80% of patients who receive unilateral thalamotomy experience transient side effects lasting up to 1 week, including facial or arm paresis, arm ataxia, confusion, dysarthria, gait disturbances, or memory impairment. Furthermore, 20% to 45% of thalamotomy patients have persistent adverse effects lasting at least 6 months after surgery. We have observed that many patients who initially underwent thalamotomy or thalamic DBS for treatment of tremor have subsequentlyneeded GPi or STN surgery to treat other symptoms, such as bradykinesia, gait disorder, and levodopa-induced dyskinesias, which have become more pronounced with progression of PD. Furthermore, STN DBS seems to reduce tremor as effectively as thalamic surgery. Therefore, thalamic procedures can no longer be recommended as a treatment for patients with PD, and we advocate GPi or STN surgery as the initial surgical procedure in patients with severe medication-refractory tremordominant PD. PALLIDAL AND SUBTHALAMIC SURGERY STN and GPi surgery improve all cardinal features of PD, including tremor, bradykinesia, rigidity, and levodopa-induced dyskinesias; however, there are significant differences with respect to clinical and adverse effects.

The preferred site for GPi lesioning (pallidotomy) is the posterior and ventral portion of the GPi (sensorimotor portion), which contains cells that fire in relation to movement. Gross et al (1999) have reported a relationship between ablation site in this region and improvement of various features of parkinsonism: Centrally located lesions maximally improve bradykinesia, postural instability, and gait; anteromedial lesions improve rigidity and contralateral levodopa-induced dyskinesias most; and posterolateral lesions have the greatest effect on tremor. Furthermore, anteromedial lesions may impair cognition and memory, whereas posterolateral lesions lead to improvement on neuropsychological measures. Therefore, most investigatorsbelieve that it is important to completely lesion the sensorimotor portion of the GPi (posterior, ventral, and lateral) while avoiding nonmotor associative regions (anteromedially)and other adjacent structures that if lesioned result in cognitive and motor complications. Unilateral pallidotomy improves off-drug parkinsonian motor signs approximately 30% (50% contralaterally) and largely abolishes contralateral levodopa-induced dyskinesias. Although contralateral improvements may be sustained up to 5 years, ipsilateral and axial improvement in parkinsonism is lost by 1 year postoperatively, and improvement in ipsilateral dyskinesias is lost between 1 and 2 years after surgery. As a result, off-drug ADL scores are improved by 30% for up to 2 years. Unfortunately, patients tend to return to levels of dependence comparable to baseline between 2 and 5 years postoperatively. Unilateral pallidotomy reduces motor fluctuations and time spent in the off state for up to 2 years. On-period motor scores are not significantly improved, and antiparkinson medication usually cannot be reduced after unilateral pallidotomy. Nevertheless, on-period ADL scores are improved, probably by reduction of levodopa-induced dyskinesias (Table 117-2). Adverse effects related to unilateral pallidotomy that generally subside within the first 2 weeks postoperatively include dysarthria, impaired balance, and confusion. Transient contralateral facial weakness and bulbar dysfunction are also common and may persist in 2% to 3% of patients. Visual field deficits, specifically homonymous superior, central, and inferior quadrantanopias contralateral lesions that are extended into the optic tract, are present in small percentage of patients. Right hemisphere lesions are associated with impairment in visual learning, including difficulty drawing complex shapes; however, these adverse effects generally resolve by 6 months postoperatively. In comparison, left pallidotomy may mildly impair verbal learning (specifically verbal memory, working memory, initial encoding, and delayed free recall) with measurable deficits persistent beyond 12 months postoperatively. In rare instances, behavioral changes that range from loss of social interaction to impulsivity and poor judgment can also persist after surgery. Bilateral pallidotomy compared with unilateral pallidotomy results in 10% to 25% greater improvement of off-period parkinsonism and almost complete elimination of all levodopainduced dyskinesias. Although bilateral pallidotomy may be performed without complications, several case reports suggest that bilateral pallidotomy often may be accompanied by dysarthria and dysphagia, possibly because of inadvertent lesioning of the corticobulbar tracts. Furthermore, severe global cognitive decline and a disabling dysexecutive and obsessive-compulsive disorderlike psychiatric syndrome have been reported, possibly caused by the lesions encroaching on nonmotor anteromedial portions of the pallidum. Therefore, bilateral pallidotomy cannot be routinely

Chapter 11 7

recommended as a treatment for PD. Useful alternatives include unilateral pallidotomy with contralateral GPi DBS or bilateral STN or GPi DBS because DBS yields similar results with fewer persistent complications. Only a few small case series have been reported detailing the effects of STN lesioning (subthalamotomy). Historically, STN lesioning was thought to be associated with a high risk of hemiballism. However, recent studies indicate that this complication rarely occurs in PD because it is likely that the parkinsonian state protects against the development of hemiballism. Compared with unilateral pallidotomy, unilateral subthalamotomy results in greater reduction of motor UPDRS scores in both on and off states. In addition, the need for antiparkinson medication is reduced. These improvements are sustained for at least 2 years. Bilateral subthalamotomy may result in greater improvement than unilateral subthalamotomy. Preliminary data indicate a 57% improvement in motor UPDRS scores and 50% to 100% reduction of drug therapy. Although transient dyskinesias are common, no permanent dyskinesias has been reported. There are few data on the adverse effects of this procedure, but left-sided lesions may be more apt to impair verbal memory than right-sided lesions. The reported overall clinical effects of unilateral GPi and STN DBS are extremely similar to those reported with lesioning of the anatomic sites (Table 117-2). Unilateral S T N DBS should be undertaken with some caution because the need to reduce antiparkinson medication may lead to a lopsided effect, with the ipsilateral side of the body being undertreated. Nevertheless, in very asymmetrical tremor-dominant patients, we have been able to successfully apply this intervention without complications. Bilateral GPi and STN DBS demonstrate similar overall motor effects. Off-period motor and ADL UPDRS scores and levodopainduced dyskinesias are markedly improved, there may be slight improvement in on-period UPDRS motor scores, on-period ADL scores are modestly improved, and motor fluctuations are dramatically reduced. Most reports suggest that the benefits of bilateral STN DBS are maintained for at least 2 years. There are few data on the long-term effects of bilateral GPi DBS; however, some case series suggest a significant deterioration after 1 or 2 years. Some patients have subsequently undergone bilateral STN DBS with marked and sustained improvements 6 months postoperatively (Table 117-2). Although both STN and GPi DBS reduce dyskinesias, the mechanism of improvement differs. STN stimulation has a pronounced antiparkinsonian effect and may induce dyskinesias or reduce the threshold for levodopa-induced dyskinesias. As a result, antiparkinson medication must be reduced to reduce dyskinesia. On average, patients are able to reduce drug therapy by 50%, and 10% to 20% of patients are able to stop all drug therapy for at least 1 year with elimination of all motor fluctuations. Stimulation of the globus pallidus has location-specific effects. Stimulation of the ventral GPi suppresses levodopa-induced dyskinesias and improves rigidity but blocks the beneficial effects of levodopa on bradykinesia and gait. Stimulation of the dorsal globus pallidus (probably GPe) improves bradykinesia and rigidity but may induce dyskinesias. Therefore, stimulation in the middle of the pallidum is the optimal location because this allows one to obtain improvement in parkinsonism and direct dyskinesia suppression. However, as with pallidotomy, antiparkinson drug therapy usually is not altered. Although there has been no large randomized study comparing GPI with STN DBS, some data suggest that STN DBS may be superior. As mentioned earlier, STN DBS allows marked reduction

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or discontinuation of antiparkinson medication, which is largely unchanged with GPi DBS. Furthermore, STN stimulation uses less battery power because of lower stimulation parameters probably because the STN is a smaller target than the pallidum. This results in fewer surgeries to replace the battery and, as a result, less cost. The STN may be an easier surgical target because it is more clearly identified by magnetic resonance imaging. Despite these advantages, STN DBS necessitates more frequent follow-up visits with complex postoperative management of medication and other problems, including stimulation-induced dyskinesias, mood changes, stimulation-induced dysarthria, and sialorrhea. The majority of adverse effects of bilateral GPi and STN DBS are transient, occurring as the optimal stimulation parameters are adjusted. Stimulation-induced adverse effects with GPi DBS include paresthesias and tonic motor contraction caused by internal capsule stimulation and nausea and phosphenes with stimulation of the optic tract. Bilateral GPi DBS has been reported to be cognitively well tolerated, although lexical fluency may be reduced. STN stimulation induces dyskinesias in most patients with optimally placed electrodes and pretarsal blepharospasm (often necessitating treatment with botulinum toxin injection) in 10% to 20% of patients. Involuntary laughter, mania, and hypersexuality have been rarely reported, possibly caused by stimulation of nonmotor limbic portion of the STN. In addition, severe acute depression may be induced with inadvertent stimulation of the SNr, inferior to the STN. Levodopa has significant psychotropic effects in many patents with PD, and its withdrawal may occasionally result in abulia, anhedonia, or depression or unmask restless legs syndrome. In younger cognitively intact patients, STN DBS is extremely well tolerated, slightly impairs lexical fluency, and may actually improve working memory. However, in older patients (especially those with borderline cognitive function), a variety of cognitive processes reliant on intact frontostriatal circuitry may be significantlyimpaired in the worst cases, lending to a mental state comparable to progressive supranuclear palsy. HUMAN FETAL TRANSPLANTATION There have been several clinical studies involving human fetal transplantation in the past decade. Transplanted fetal mesencephalic tissue can produce large amounts of dopamine, establish connections and integrate into the denervated host striatum, and improve parkinsonism. Of historical interest only is autogenous adrenal medullary cell transplantation; however, poor benefit and high morbidity and mortality led to the abandonment of this treatment in the 1980s. Results of the various open label unilateral and bilateral transplantation studies are difficult to interpret because of methodologic differences between studies including amount of fetal tissue implanted (1 to 4 fetuses per side), age of fetus (5 to 17 weeks postconception), use (or nonuse) of immunosuppressive drug therapy, and graft site (putamen, caudate, or both). With unilateral transplantation, contralateral motor symptoms in the off state improve by 10% to 50%, and time spent in the on state without dyskinesias increases by 0% to 65%; however, ipsilateral symptoms are not reduced. Bilateral transplantation can safely be performed and reduces total UPDRS scores (motor and ADL) 18% to 50%, and the need for drug therapy may be reduced. Long-term evaluations of transplantation indicate sustained survival of grafted neurons assessed by PET scans and autopsies. Furthermore, improvement of off-period parkinsonism may be sustained

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for 10 years after bilateral or unilateral transplantation. The greatest risks of transplantation are intracerebral hemorrhage and infection caused by immunosuppression therapy. Additional complications that have been reported include depression, panic disorders, transient confusion, and hallucinations. Freed et al (2001) recently reported a double-blind sham surgery study of bilateral putaminal implantation. At l-year postoperatively there was no significant difference in UPDRS scores between those receiving real and sham surgery. However, motor and ADL UPDRS scores improved in patients younger than 60 years old receiving transplantation, although tremor and freezing of gait was not improved. Between 1 and 2 years postoperatively, further improvements in off-period parkinsonism in this patient cohort have been noted in patients of all ages. As in STN DBS, these improvements have correlated with the degree of preoperative levodopa responsiveness; however, the reliability and magnitude of the improvement have not been as great as those seen with STN DBS. Freed et al (2001) also reported off-state or “runaway” dyskinesias in several of their bilaterally transplanted patients with the best improvement of parkinsonism. Another group using different transplantation methods has also recently reported this worrisome complication, although this group found no correlation between the improvement in parkinsonism and the development of off-phase dyskinesias. Off-period dyskinesias originally were attributed to excessive growth of grafted dopaminergic neurons; however, a recent study indicates that fluorodopa uptake does not correlate with off-period dyskinesias. The mechanism of off-period dyskinesias is unknown and warrants further study. In several patients dyskinesias have been troublesome enough to necessitate specific antidyskinetic drug therapy or pallidal surgery. Typically, transplantation of 3 to 4 fetuses per putamen (or 6 to 8 donors per patient) are necessary to obtain adequate symptomatic relief despite recent developments in drug technology (such as lazaroid tirilazad) that increase the survival rate of transplanted dopaminergic neurons. The ethical issues surrounding this treatment, the large amount of fetal tissue needed to treat one patient with PD, and the difficulty in obtaining donor tissue make it unlikely that this treatment will ever become widespread. Nevertheless, this experience has paved the way for transplantation of dopaminergic neurons obtained from other, more readily available sources. DWELOPMENT OF NOVEL SURGICAL APPROACHES A number of novel surgical interventions are being investigated as treatments for PD. Retinal pigment epithelial cells produce DOPA as an intermediate during eumelanin production. One eye may provide enough dopaminergic cells for transplantation to treat hundreds of patients, and this source is readily obtainable from cadavers. A pilot study of 6 patients who underwent unilateral transplantation demonstrates 30% to 48% improvement in off-period parkinsonism 12 months postoperatively. Stem cells are pluripotent cells that may be obtained from blastocyst-stage embryos and even from adults (with bone marrow stromal cells being the most promising candidate). Once obtained, these cells may be replicated in culture and then driven to differentiate into a

dopaminergic phenotype by application of different growth factors. Large numbers of cells may then be obtained for transplantation. Recent work has demonstrated survival, integration into the host, and reversal of a rodent model of parkinsonism after transplantation. The use of neurotrophic factors has also been explored in PD. Glial cell line-derived neurotrophic factor (GDNF) promotes the sprouting of dopaminergic terminals, increases dopamine production from existing neurons, and prevents nigrostriatal tract degeneration. Although intracerebroventricular injection of GDNF in rodent and nonhuman primate models of PD demonstrates sprouting of neurons and improvement in motor symptoms, a phase 1 and 2 human clinical trial resulted in a high incidence of adverse effects and no clinical improvement. However, a small open label pilot study of direct intrastriatal GDNF infusion has reported remarkable benefits without the adverse effects seen in the intracerebroventricular injection study. Multiple vector systems derived from viruses or liposomes can deliver genes that express trophic factors, such as GDNF. Direct injection of a lentiviral vector to deliver GDNF in a nonhuman primate model of PD has been demonstrated to result in long-term GDNF gene expression and marked improvement of parkinsonism. If successful in human PD and if a system whereby GDNF production could be regulated is developed, this therapy may be superior to most other surgical interventions currently under study. In the past decade, there have been rapid advances in our understanding of the pathogenesis of PD. It is likely that current surgical treatments of PD will be replaced in the next decade by new restorative therapies. Furthermore, as the roles of the various genetic and environmental contributions to PD pathogenesis are identified, it is likely that curative or preventive therapy using genetic engineering techniques will be developed. SUGGESTED READINGS Alvarez L, Macias R, Guridi J et al: Dorsal subthalamotomy for Parkinson’s disease. Mov Disord 16:72-78, 2001 Deep-Brain Stimulation for Parkinson’s Disease Study Group: Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 345:956963,2001 Fine J, Duff J, Chen R et al: Long-term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. N Engl J Med 342:1708-1714, 2000 Freed CR, Greene PE, Breeze RE et al: Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 334710-719,2001 Gross RE, Lombardi WJ, Lang AE et ak Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson’s disease. Brain 122:405-416, 1999 Kordower JH, Emborg ME, Bloch J et ak Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290767-773, 2000 Kumar R, Lozano AM, Kim YJ et ak Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 51:850-855, 1998 Parent A, Cicchetti F: The current model of basal ganglia organization under scrutiny. Mov Disord 13:199-202, 1998 Schuurman PR, Bosch DA, Bossuyt PMM et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 342:461-468, 2000

Chapter 118

Mental Changes in Parkinson’s Disease

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118 Mental Changes in Parkinson’s Disease Joseph H. Friedman

A number of behavioral abnormalities occur in Parkinson’s disease (PD) that contribute significantly to morbidity and greatly complicate its management. Although it is clear that these conditions are more common in patients with PD, it is not clear whether they are intrinsic to the pathologic process itself or are a response to living with an incurable, progressive, disabling condition. Dementia is more common in patients with PD than in age-matched controls. It usually occurs after several years of the illness and correlates with disease severity; ultimately it affects about 30% of patients. Other common mental changes include the following:

Depression occurs in about 50% of patients with PD and is medication responsive. Fatigue is a major problem in 30% of patients with PD, correlating better with depression than disease severity and often predating diagnosis. Sleep disorders are very common, manifested mainly as difficultystaying asleep and falling back to sleep once awake, leading to daytime somnolence and sleep fragmentation. Vivid dreams and yelling in sleep are very common. REM behavior disorder is a rare disorder in the general population but not uncommon in PD in both treated and untreated patients and may predate onset of the motor signs of PD. Visual hallucinosis occurs in 20% to 30% of drug-treated patients. Psychosis occurs in 5% to 10% of drug-treated patients.

DEMENTIA Patients with PD are subject to the same dementing illnesses as other people. Dementia of the Alzheimer’s type, vascular dementia, and other conditions presumably develop at the same rate as in an age-matched population without PD. Although there is speculation that Alzheimer’s disease and PD may have a clinical and pathologic relationship, presumably they are somewhat different phenomenologically. Patients with PD develop a dementia that is thought to be part of their primary PD pathology. Mild dementia can be difficult to recognize in PD because of the confounding effects of motor dysfunction and medication. The DSM-IV criteria defining dementia are difficult to apply strictly to PD. There is no specific “Parkinson’s dementia.” Pathologically, there is a large overlap among PD with dementia, Alzheimer’s disease, and diffuse Lewy body disease. Similarly, there is a large overlap among the clinical aspects of all of the dementias. Although one can statistically discriminate discrete populations having a “subcortical” dementia, characterized by deficits in memory, ordering, verbal fluency, problem solving, and visual perception tasks, from those with a “cortical” or Alzheimer’s-type dementia, with memory problems, aphasia, agnosia, or apraxia,

individual cases often are more difficult to categorize because patients often have both cortical and subcortical problems. It is possible that the subcortical type of dementia in PD is more slowly progressive than dementia of the Alzheimer’s type, but this is unknown. Cholinesterase inhibitors enhance memory in patients with dementia of Alzheimer’s type but have not been adequately tested in the dementias of PD. Theoretically, the cholinergic drugs may worsen the cholinergic-dopaminergic imbalance in PD, leading to worsening motoric dysfunction, and should therefore be used cautiously in patients with PD. Worsened motor function should reverse upon drug discontinuation, however, so this is not a risky undertaking.

DEPRESSION The incidence of depression is also higher in PD than in the general population. Whether this is intrinsic to the disease or reactive is debated. Most studies have demonstrated a higher rate of depression in PD than in age-matched controls, but one often-cited study found no difference in prevalence between patients with PD and a cohort matched for disability with rheumatoid arthritis. Some data suggest that the quality of depression in PD is somewhat different from that in idiopathic depression, with fewer suicide attempts and fewer feelings of guilt and failure but with more irritability and pessimism about the future. Regardless of the epidemiology or theoretical aspects of depression, each patient must be approached individually. Recognizing depression may be difficult. Because interpreting the affect of most patients with PD is problematic, it takes experience or long-term knowledge of the patient to use facial expression,speech changes, and interactive style as a guide. Occasional patients complain that others think that they are depressed or angry when they are not, because of the masked facial expression. Loss of motivation, feelings of sadness, loss of appetite, loss of libido, and anhedonia are the symptoms most important to evaluate. Fatigue, sleep disturbances, declining social interactions, and weight loss, which suggest depression in patients without PD, are so common in nondepressed patients with PD that although they are more common in depressed patients with PD, they are not good guides to the diagnosis of depression. Depression also must be distinguished from apathy, which is often present with dementia and probably is untreatable. Apathy may be seen in PD without dementia but is not common. A person with advanced PD may be unable to do much for enjoyment and may be resigned rather than apathetic or depressed. Complicating the diagnosis of depression is the possibility that the patient will deny feeling depressed even when depression is present. Information from family members can be very helpful in making the diagnosis. Treating depression in PD is made difficult by the frailty of the patients and the common problem of drug intolerance, especially

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in patients already taking several psychoactive medications. There have been at least five double-blinded placebo-controlled trials of different antidepressantsin PD, all finding the drugs to be effective in ameliorating depression and some noting concomitant improvement in parkinsonism. There are no studies comparing one antidepressant to another. It appears that antidepressants are as effective in treating depression in PD as in the population without PD. Therefore, the choice of drug should depend on the individual patient and the physician’s degree of comfort with the various medications. Coexisting problems that may help guide an antidepressant drug choice include drooling, prostatism, urinary urgency, insomnia, daytime somnolence, confusion, dementia, cardiac rhythm abnormalities, and orthostatic hypotension. Tricyclics are useful for a patient who may benefit from an anticholinergic agent, especially if insomnia is present. A patient who drools and has tremor or a spastic bladder may experience improvement in affect from the antidepressant actions of a tricyclic such as amitriptyline or imipramine and physical improvement from the anticholinergic side effects. A patient with insomnia and anxiety may respond better to a sedating drug such as trazodone, nefazodone, or mirtazapine. The new serotonin reuptake blockers are thought to be activating and may help patients with excessive somnolence and inertia during the day. They also have few side effects and are well tolerated in general. They should be given in the morning, unlike the other antidepressants, which are usually given at night to avoid inducing or exacerbating insomnia. The serotonin reuptake inhibitors can cause restlessness or akathisia and on rare occasion may induce or worsen parkinsonism. Therefore, some PD experts do not use these drugs as first line antidepressants. Members of the Parkinson Study Group were evenly split on this question. The selective serotonin reuptake inhibitor antidepressants may interact with selegiline, the monoamine oxidase-B (MAO-B) inhibitor, to cause a “serotonin syndrome.” This is undoubtedly rare. There is some confusion regarding selegiline and depression, with some believing it has antidepressant properties. This occurs only at dosages high enough to make the drug a nonselective MAO-A and MAO-B inhibitor and therefore a drug with the same potential for hypertensive crises as phenelzine and tranylcypromine. Electroconvulsive therapy is another option for treating depression in PD and probably is underused. Electroconvulsive therapy is generally recommended for patients who are either refractory to antidepressant medications or who cannot tolerate them. Electroconvulsive therapy has a beneficial effect on the motor aspect of PD independent of its effect on mood. The motoric benefit usually lasts days to weeks but can last longer. About 75% of electroconvulsive therapy-treated patients with PD improve motorically, and a higher percentage improve psychiatrically. After electroconvulsive therapy for depression, oral antidepressants are still needed, but at lower dosages to maintain a patient in remission than to achieve remission. There is scant data on maintenance electroconvulsivetherapy in PD. ANXIETY, OBSESSIVE-COMPULSIVE TRAITS, AND FATIGUE Anxiety and obsessive-compulsive personality traits may be more common in PD. These conditions do not correlate with disease severity. Data are sparse. Shulman et al. have described the syndrome of “inner tremor,” when patients feel tremulous but are

not. This feeling correlated with anxiety and was unrelated to visible tremor or PD severity. Anxiety may respond to the selective serotonin reuptake inhibitor antidepressants and to the usual anxiolytics. Fatigue is another common problem that does not correlate with disease severity. It is a complicated symptom that includes sleepinessas well as physical, emotional, and mental fatigue. About 50% of patients with PD at all levels of disease severity describe it as one of their three worst symptoms. DRUG-RELATED MENTAL EFFECTS The mental side effects of the antiparkinsonian drugs are legion. Sleepiness, mania, hypersexuality, confusion, personality changes, visual hallucinosis, vivid dreams, psychosis, and even depression itself have been reported as drug effects. These problems occur in a large percentage of patients. Older patients, especially demented ones, are more likely than others to experience mental side effects. The anticholinergic drugs, such as trihexyphenidyl and benztropine, are so likely to cause mental side effects, particularly memory loss, confusion, and hallucinations, that they should be used extremely cautiously in older adults and almost never in demented patients. Sleep Disorders

Levodopa and the dopamine agonists often cause various sleep abnormalities. The most common are vivid dreams and sedation. Patients report dreams so realistic that only their content reveals to the patient that the phenomena experienced were dreams and not reality. In the case of the confused patient, the dream often is mistaken for reality. In patients who are slightly demented, the vivid dream sometimes is interpreted as real when the content is believable (for example, that a car accident had occurred during the night on the street in front of the house). More confusing to the patient is waking up in the middle of a dream, thinking it is real, and waking the spouse. It is important to distinguish dream phenomena from confusion because the former usually can be treated simply with an explanation and reassurance, whereas the latter requires a reduction in PD medications. Patients with PD often yell, laugh, curse, or scream in their sleep. This is almost always a problem for the spouse or the rest of the household and not for the patient because it causes awakening only uncommonly. Equally problematic are the almost as common jerking, hitting, and kicking that occur during sleep, again without awakening the patient. A less common phenomenon is FEM behavior disorder, in which patients sometimes are not hypotonic during E M sleep and act out their dreams, leading to falls and family complaints about nocturnal confusion. This occurs when the dream involves the patient defending himself or his spouse from attack. Often the patient is actually hitting the spouse. This syndrome may predate the onset of the motor signs of PD. Therefore, it is important to take a complete history about altered behavior because episodic behavioral alterations may turn out to be benign drug effects on sleep rather than the beginning of a dementing or psychotic process. Nightmares are infrequent and may be drug induced. They are more common in people with a premorbid history of them. Unfortunately, levodopa may exacerbate nightmares by making them more vivid and better remembered in addition to causing the sufferer to cry and yell during sleep.

Chapter 118

Visual HalludnosSs

Visual hallucinosis occurs in about 20% to 30% of drug-treated patients followed over the long term. It is the experience of seeing real-appearing images in the presence of a clear sensorium. At first, the images are perceived as real, but after the first few attempts to touch them cause them to disappear, the patient learns to distinguish the hallucination from reality and usually is not much bothered by it. Hallucinations tend to be people, often children or small adults. They are strangers in most cases but may be relatives, friends, or deceased acquaintances and are silent even when ostensibly conversing, closing doors, or performing other tasks that should make noise. The visions are free of emotional content, very different from the situation in primary psychoses, such as schizophrenia, in which the hallucinations (almost always voices) say demeaning or nasty things or behave in ways to excite or engage the person. In levodopa-induced hallucinosis, the visions may appear at any time of day but are more common in the evening and tend not to upset the patient. Light does not abort their appearance, nor does darkness increase them. They often occur when the person is alone or engaged in a routine social activity, such as watching television with a spouse, and appear only rarely when the patient is involved in absorbing activities such as entertaining guests, playing with grandchildren, or visiting a doctor’s office. The hallucinated people most commonly watch the patients, showing no emotion themselves. A visual hallucination must be distinguished from a visual illusion, which is a misperception, with something seen as other than what it is. These usually occur in shadowy or dark areas and tend to take on a menacing aura. Patients also experience a feeling of another person being near them and report looking up or turning around to see who it is. Visual illusions are not seen clearly, whereas visual hallucinations are seen as clearly as or even more clearly than real objects. Occasionally, objects rather than people are hallucinated, but friendly animals such as dogs, horses, and cats may be perceived as well as insects. The hallucinations may persist for seconds, minutes, or hours but tend to last minutes and to recur. They usually disappear when “touched and usually ignore attempts to engage them in conversation (they do not usually move their lips, attempt sign language, or write on paper pads). The same person or group usually visits the patient repeatedly. When the patient is demented or psychotic, the hallucinations are perceived as real and may cause serious behavioral disturbances, especially if they are threatening. Auditory, tactile, or olfactory hallucinations are much less common but may occur in psychosis typically in people already suffering visual hallucinations. Treatment usually entails a reduction in drug dosage, but for some patients the loss of motor function that ensues is more difficultto tolerate than the hallucinosis, and some patients choose not to reduce their dosage. Psychosis Psychosis, a major mental disturbance in which reality is significantly misperceived, causing a marked decline in psychosocial functioning, occurs in 5% to 10% of patients treated over the long term. It is more common in older adults and demented patients but occurs in previously mentally intact patients with PD with no prior psychiatric history. On formal neurologic examination, they score perfectly on the mini-mental status examination unless there is an attention deficit.

Mental Changes in Parkinson‘s Disease

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The psychosis induced by levodopa and the dopaminergic drugs tends to be stereotypic. Visual hallucinations occur along with paranoid delusions. Most common is the delusion that the spouse is having a sexual affair. In the case of single patients, a common delusion is that their savings are being looted by the children or the caretaker is plotting to place them in a nursing home. Unfortunately, the appearance of psychosis makes management at home more difficult and is the single most important predictor of nursing home placement in patients with PD. Some patients believe they are about to die, that they are dead already, that loved ones have just died, and so forth. In fact, psychosis appears to be associated with an increased mortality. Phenomena that are rare in primary psychoses, such as Capgras’s syndrome, the syndrome of reduplication in which the caretaker or some other significant person or even object has been replaced by a replica that looks and behaves like the original, may occur. Unlike schizophrenia, dopaminergic psychosis has only “positive” phenomena. There is no loosening of associations, anhedonia, poverty of thought, loss of ego boundaries, or blunting of affect. A delirious or encephalopathic state may also occur, in which attention span is diminished and disorientation occurs. Usually psychosis develops insidiously, although it may appear suddenly after a new medication is begun or an old one increased. However, psychosis onset in a patient on a stable medication schedule is common, and the early features often are overlooked if not asked about at routine evaluations. For example, it is common for psychosis to be present for months before being brought to the physician’s attention. Until recently, management of psychosis was almost impossible. One could reduce medication, attempt a drug holiday, or start a neuroleptic antipsychotic when a dosage reduction was not sufficient. Since the commercial release of clozapine, the situation has changed dramatically. Management of psychosis is now fairly straightforward in most cases. It is important to keep in mind that neurologically impaired patients often suffer adverse mental and motor effects when affected by an intercurrent nonneurologic process. Therefore, it is important to exclude medical problems such as infection, renal failure, thyroid dysfunction, or a new, nonneurologic medication as the underlying problem. However, this is usually not the case, and structural lesions are not worth looking for without a clear indication, such as a new focal sign or head trauma. Electroencephalography is nearly useless in this situation. Once the physician is satisfied that the problem is a druginduced psychosis, then any drugs that can be eliminated should be. Anticholinergic drugs have the highest mental adverse effect profile of the anti-PD medications and should be stopped at the onset of psychosis. Other anti-PD medications should then be tapered and discontinued, if possible, without jeopardizing motor function. The general approach is to reduce and then discontinue a single drug rather than reducing several drugs, with the aim of reducing polypharmacy as much as possible. There appears to be better tolerance for a single drug at a high dosage than for multiple drugs at low to moderate dosages, although no data exist to support this widely held tenet. If a recent medication change precipitated the psychosis, then it should be reversed; otherwise, the order of drug discontinuation should be as follows: anticholinergics, selegiline, amantadine, dopamine agonist, catechol-0-methyltransferase (COMT) inhibitor, and then levodopa. Once the lower limit of motor function has been reached, quetiapine or clozapine should

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be started if psychosis has not improved. These are atypical antipsychotics, which cause no parkinsonian side effects. Numerous studies now attest to their efficacy and tolerability when used properly, although only clozapine has two double-blind placebo controlled trials to support its use. Only if the patient cannot be treated at home is hospitalization justified. Clozapine should be initiated at 6.25 mg/day and quetiapine at 12.5 mg/day given at bedtime. The usual effective daily dosage is in the 6.25- to 50-mg range for clozapine and 25 to 100 mg/day for quetiapine. This is in contrast to the dosages used in schizophrenia, which are 300 to 900 mg daily. In general, the dosage is increased depending on response and adverse effects. Unlike schizophrenics, psychotic patients with PD may respond within 1 or 2 days. It seems that once the dosage is sufficient to allow the patient to sleep through the night, the psychosis remits. Therefore, it is suggested that the dosage be increased until the patient sleeps through the night. If this does not improve the psychosis, the dosage must be increased. Most patients do best if the dosage is given only at bedtime to reduce the daytime sedative side effects and to help keep the patient and caregiver sleeping through the night. It should be noted that not all atypical antipsychotic drugs are equal when it comes to PD. Risperidone worsens motor function in most patients. Olanzapine worsens motor function in about 40% to 50% of patients. Newer agents are under development. How long patients need to remain on the antipsychotic is unknown. Most patients, once on an atypical antipsychotic, can have their anti-PD medications increased without problem. If psychosis recurs when anti-PD drugs are increased, then the antipsychotic dosage is increased.

SUGGESTED READINGS Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 149:443-454, 1992 Faber R, Trimble MR Electroconvulsive therapy in Parkinson’s disease and other movement disorders. Mov Disord 6:293-303, 1991 Fenelon G, Mahieux F, Huon R, Ziegler M Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 123:733745, 2000

French Clozapine Study Group: Clozapine in drug-induced psychosis in Parkinson’s disease. Lancet 91692041-2042, 1999 Friedman JH, Factor S A Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 15(2):201211, 2000

Friedman JH, Friedman H: Fatigue in Parkinson’s disease. Neurology 43:20 16-20 18, 1993

Hughes AJ, Daniel SE, Blankson S, Lees AJ: The clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol50:140-148, 1993 Parkinson Study Group: Low dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 340:757763, 1999

Per1 DP, Olanow CW, Calne D: Alzheimer’s disease and Parkinson’s disease: distinct entities or extremes of a spectrum of neurodegeneration? Ann Neurol44(Suppl 1):S19-S31, 1998 Poewe W, Luginger E Depression in Parkinson’s disease: impediments to recognition and treatment options. Neurology 52(Suppl 3):52-56, 1999

Richard IH, Kurlan R A survey of antidepressant drug use in Parkinson’s disease. Neurology 99:1168-1170, 1997 Starkstein SE, Mayberg HS, Prezioi TJ, Robinson RG A prospective longitudinal study of depression, cognitive decline, and physical impairments in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 55:377-382, 1992 Stein MB, Heuser U, Juncos JL, Uhde Tw: Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry 147:217-220, 1990

1 19 Multiple-System Atrophy: Striatonigral

Degeneration and Shy-Drager Syndrome Paula Ravin The term multiple-system atrophy (MSA) generally refers to a broad class of parkinsonian syndromes with features not normally seen in idiopathic Parkinson’s disease. It has been noted in numerous neuropathologic studies that MSA is found in 8% to 10% of patients diagnosed with idiopathic Parkinson’s disease and, in some, is clinically indistinguishable. However, the postmortem examination of such patients reveals variable degrees of neurodegenerative changes in cerebellar, striatal, nigral, and subcortical structures such as the thalamus, nucleus accumbens, septal nuclei, hypothalamus, locus ceruleus, and a variety of parasympathetic nuclei (dorsal vagal nucleus, Edinger-Westphal nucleus, Onuf nucleus of the sacral cord, and so on), hence the term multiplesystem, although atrophy is not the only anatomic change. A

number of reports give evidence of focal gliosis, neuronal loss, glial cytoplasmic inclusions, depletion of specific neurotransmitters (y-aminobutyric acid, dopamine, norepinephrine, glutamate), and functional changes in metabolism of glucose or dopamine binding characteristics on positron emission tomography. Oppenheimer and Graham coined the term multiple-system atrophy in a paper in 1969 broadly categorizing patients into three subclasses: Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophies, the latter of which is further subdivided into familial and sporadic forms. The syndrome of Steele-Richardson-Olszewski or progressive supranuclear palsy is not included because it represents a distinctive clinical picture of supranuclear downgaze palsy, axial dystonia, cognitive impair-

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be started if psychosis has not improved. These are atypical antipsychotics, which cause no parkinsonian side effects. Numerous studies now attest to their efficacy and tolerability when used properly, although only clozapine has two double-blind placebo controlled trials to support its use. Only if the patient cannot be treated at home is hospitalization justified. Clozapine should be initiated at 6.25 mg/day and quetiapine at 12.5 mg/day given at bedtime. The usual effective daily dosage is in the 6.25- to 50-mg range for clozapine and 25 to 100 mg/day for quetiapine. This is in contrast to the dosages used in schizophrenia, which are 300 to 900 mg daily. In general, the dosage is increased depending on response and adverse effects. Unlike schizophrenics, psychotic patients with PD may respond within 1 or 2 days. It seems that once the dosage is sufficient to allow the patient to sleep through the night, the psychosis remits. Therefore, it is suggested that the dosage be increased until the patient sleeps through the night. If this does not improve the psychosis, the dosage must be increased. Most patients do best if the dosage is given only at bedtime to reduce the daytime sedative side effects and to help keep the patient and caregiver sleeping through the night. It should be noted that not all atypical antipsychotic drugs are equal when it comes to PD. Risperidone worsens motor function in most patients. Olanzapine worsens motor function in about 40% to 50% of patients. Newer agents are under development. How long patients need to remain on the antipsychotic is unknown. Most patients, once on an atypical antipsychotic, can have their anti-PD medications increased without problem. If psychosis recurs when anti-PD drugs are increased, then the antipsychotic dosage is increased.

SUGGESTED READINGS Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 149:443-454, 1992 Faber R, Trimble MR Electroconvulsive therapy in Parkinson’s disease and other movement disorders. Mov Disord 6:293-303, 1991 Fenelon G, Mahieux F, Huon R, Ziegler M Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 123:733745, 2000

French Clozapine Study Group: Clozapine in drug-induced psychosis in Parkinson’s disease. Lancet 91692041-2042, 1999 Friedman JH, Factor S A Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 15(2):201211, 2000

Friedman JH, Friedman H: Fatigue in Parkinson’s disease. Neurology 43:20 16-20 18, 1993

Hughes AJ, Daniel SE, Blankson S, Lees AJ: The clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol50:140-148, 1993 Parkinson Study Group: Low dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 340:757763, 1999

Per1 DP, Olanow CW, Calne D: Alzheimer’s disease and Parkinson’s disease: distinct entities or extremes of a spectrum of neurodegeneration? Ann Neurol44(Suppl 1):S19-S31, 1998 Poewe W, Luginger E Depression in Parkinson’s disease: impediments to recognition and treatment options. Neurology 52(Suppl 3):52-56, 1999

Richard IH, Kurlan R A survey of antidepressant drug use in Parkinson’s disease. Neurology 99:1168-1170, 1997 Starkstein SE, Mayberg HS, Prezioi TJ, Robinson RG A prospective longitudinal study of depression, cognitive decline, and physical impairments in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 55:377-382, 1992 Stein MB, Heuser U, Juncos JL, Uhde Tw: Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry 147:217-220, 1990

1 19 Multiple-System Atrophy: Striatonigral

Degeneration and Shy-Drager Syndrome Paula Ravin The term multiple-system atrophy (MSA) generally refers to a broad class of parkinsonian syndromes with features not normally seen in idiopathic Parkinson’s disease. It has been noted in numerous neuropathologic studies that MSA is found in 8% to 10% of patients diagnosed with idiopathic Parkinson’s disease and, in some, is clinically indistinguishable. However, the postmortem examination of such patients reveals variable degrees of neurodegenerative changes in cerebellar, striatal, nigral, and subcortical structures such as the thalamus, nucleus accumbens, septal nuclei, hypothalamus, locus ceruleus, and a variety of parasympathetic nuclei (dorsal vagal nucleus, Edinger-Westphal nucleus, Onuf nucleus of the sacral cord, and so on), hence the term multiplesystem, although atrophy is not the only anatomic change. A

number of reports give evidence of focal gliosis, neuronal loss, glial cytoplasmic inclusions, depletion of specific neurotransmitters (y-aminobutyric acid, dopamine, norepinephrine, glutamate), and functional changes in metabolism of glucose or dopamine binding characteristics on positron emission tomography. Oppenheimer and Graham coined the term multiple-system atrophy in a paper in 1969 broadly categorizing patients into three subclasses: Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophies, the latter of which is further subdivided into familial and sporadic forms. The syndrome of Steele-Richardson-Olszewski or progressive supranuclear palsy is not included because it represents a distinctive clinical picture of supranuclear downgaze palsy, axial dystonia, cognitive impair-

Chapter 119 w

Multiple-System Atrophy: Striatonigral Degenerationand Shy-Drager Syndrome

ment, and mild parkinsonism and has discrete pathologic changes associated with the diagnosis. CLINICAL DIAGNOSIS

Correct identification of MSA presents a challenge even to experts in movement disorders. The relevance of distinguishing these disorders early on pertains to prognosis, predicted responses to medication, possibility of a genetic association that can be identified (and may soon be tested with marker gene), and referring patients to research centers with special interest in MSA. The typical signs and symptoms of Parkinson’s disease are not always found in MSA early on or may be insignificant clinically compared with other features. Classic resting tremor, for example, is found in 30% of idiopathic Parkinson’s disease initially but only about 5% or so of MSA cases, with sustension or intention tremor seen in another 40% of idiopathic Parkinson’s disease initially and 1OYo of MSA cases. Rigidity with akinesia or bradykinesia is common to both disorders, but postural instability often is seen early in MSA, whereas it is usually found in more advanced or late-onset idiopathic Parkinson’s disease and does not evolve as rapidly. Recent articles attempting to distinguish idiopathic Parkinson’s disease and MSA retrospectively on clinical grounds have suggested certain other distinguishing features or red flags to look for in making an initial differential diagnosis and refining it over the first 2 to 3 years of observation. To start with, the mean age at onset of MSA (all subtypes) is 53, with progression of disability to death in an average of 7 to 10 years, as opposed to idiopathic Parkinson’s disease, with a mean age at onset of 60 and progression over 10 to 20 years. The malelfemale ratio of MSA appears to be 1.8:l.O in familial olivopontocerebellar atrophy, 2.0:1.0 in Shy-Drager syndrome, and unclear in striatonigral degeneration, in which cumulative data suggest a slight male predominance, as in idiopathic Parkinson’s disease ( 1.2:1.O). In a review of the literature on MSA through 1994, Quinn and Wenning noted that 80% of cases were “parkinsonian type,” and 20% were “cerebellartype.” The presence of truncal or limb ataxia, dysarthria, scanning speech, a positive Romberg test, and lateral nystagmus with square wave jerks along with rigidity and bradykinesia points to the olivopontocerebellar atrophies. Autonomic dysfunction usually is seen before dopaminergic therapy in all patients with MSA. It is most prominent in Shy-Drager syndrome, where incapacitating orthostatic hypotension results in patients being wheelchair-bound in 5 to 7 years. More subtle signs such as persistent impotence in males, heat intolerance, sudden fluctuations in blood pressure with “hot flashes,” and loss of sweating in the palms, axilla, and groin can precede the parkinsonian features of MSA by up to 10 years. The majority of patients with striatonigral MSA have asymmetrical rigidity and dystonia, with pyramidal signs emerging before dopaminergic therapy. Early motor fluctuations (occurring before 5 years) with levodopa therapy are seen particularly in striatonigral patients with older onset than the early-onset Parkinson’s disease patients with motor fluctuations. The initial improvement in parkinsonian features from moderate levodopa therapy (300 to 500 mg daily) is not as robust in MSA as in Parkinson’s disease either. Patients with Shy-Drager syndrome may experience improvement in bradykinesia and rigidity with levodopa but cannot tolerate dosage increases over several years because of exacerbation of symptomatic orthostatic hypotension. Loss of responsivity to levodopa after 5 to 7 years is common in

767

MSA. In some cases of olivopontocerebellar atrophy (OPCA) a poor response to dopamine agonists also indicates widespread loss of dopamine receptor sites. Neurogenic bladder features are found in both MSA and Parkinson’s disease, but urinary retention, bladder dyssynergia, and frank bladder or bowel incontinence are seen much earlier in MSA. Another sign of autonomic failure that seems to be unique to MSA is the “cold hands sign” reported by Klein et al. They documented a baseline skin temperature significantly lower in patients with MSA than in those with Parkinson’s disease or controls before and after cooling. The appearance of dusky or violaceous hands with blanching and delayed circulatory return, especially on the side of earliest symptoms, may be a red flag in MSA. At a consensus conference on MSA in 1998, a consortium of movement disorder specialists worldwide defined three diagnostic categories of MSA based on the clinical domains of autonomic dysfunction,parkinsonism, cerebellar dysfunction, and corticospinal tract dysfunction. “PossibleMSA” is represented by one clinical domain and two features from other domains, “probable MSA” is autonomic dysfunction plus poorly levodopa-responsive parkinsonism or cerebellar dysfunction, and “definite MSA” is pathologically confirmed by the presence of high-density ghal cytoplasmic inclusions and degeneration of the nigrostriatal or olivopontocerebellar tracts. Exclusion criteria include symptomatic onset before age 30, positive family history, hallucinations unrelated to medication, focal cortical signs (alien limb, aphasia, parietal lobe dysfunction), and other systemic illness reproducing these signs. The presence of DSM-defined dementia, supranuclear palsy, or slowing of vertical saccades would also be outside the realm of MSA. The consortium recommended using only two subcategories for MSA-parkinsonian type (MSA-p) and cerebellar type (MSA-c)-to emphasize the consistent neuropathology linking the syndromes of Shy-Drager, striatonigral degeneration, and olivopontocerebellar degeneration because clinical parameters alone are not reliably discriminative.Table 119-1 summarizes the variety of symptoms and signs that may be useful in making an early clinical diagnosis of MSA most accurately. Cognitive dysfunction can occur in MSA but often is evidenced only by subtle tests of frontal lobe function in MSA-p. Cognitive change is occasionally observed in MSA-c, as it is with some of the dominant hereditary ataxias. Changes in mood and affect with irritability, lability, and depression are commonly noted in SCA-2, for example. These patients have deficits in executive function on neuropsychological testing with progression of their illness (see Chapter 124 on progressive ataxia). DIAGNOSTIC TESTS A variety of structural, functional, and physiologic tests have been proposed to increase the sensitivity and specificity of MSA diagnosis. Reports of urodynamic and detrusor or anorectal sphincter electromyography being diagnostic are controversial because of technical difficulties in performing and interpreting such studies. Magnetic resonance imaging of the brain has been refined to highlight the signal intensity differences in the striatum and cerebello-brainstem structures in MSA and Parkinson’s disease, including phosphorus magnetic resonance spectroscopy, gradient echo sequencing, and magnetic resonance imaging volumetric measurements. A high correlation between image details and clinical diagnoses has been claimed but not confirmed by pathologic diagnoses to date. P-CIT single photon emission

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TABLE119-1. Signs and Symptoms of MSA MSA PD

SND

SD

OPCA

PSP

Age of onset

60f7

53f7

52f6

70f6

Duration of disease

10-20

7-10

5-10

28 f 4 (FOPCA) 49 f 6 (SOPCA) 10-25 (FOPCA)

Rigidity Bradykinesia Orthostasis Neurogenic bladder Response to levodopa Dyskinesia, dystonia Tremor Rapid progression Cognitive dysfunction

*

+ +

+ +

* ++I-

U

+ (young onset) * + ("subcortical")

+ * + +

U

+ +

+ ("subcortical")

6-15 (SOPCA) f f f f f f

+

-H

f

f

++t (FOPCA)

+ (SOPCA)

6-10

+ ++ + -

U

+++

Abbreviations: FOPCA,familial olivopontocerebellaratrophy; MSA, multiplesystem atrophy; OPC& olivopontocerebellaratrophy; PD, Parkinson's disease; PSP, progressivesupranuclear palsy; SD, Shy-Drager syndrome; SND, striatonigral degeneration; SOPCA, sporadic olivopontocerebellaratrophy; -, absent; +, mild; +,moderate; +I+, marked.

computed tomography, Altropane single photon emission computed tomography, and fluorodopa positron emission tomography brain scans also recognize qualitative and quantitative differences between Parkinson's disease and MSA but with substantial overlap of the clinical spectrum. NEUROPATHOLOGIC FEATURES As noted earlier in this chapter, the definitive diagnosis of MSA is most accurately determined by the postmortem pathology. Histologically, the putamen shows marked loss of nerve cells, with associated gliosis in the posterior and lateral portions. The anteromedial putamen and head of the caudate may evidence lesser changes in some cases, as seen in Huntington's disease. Melanin pigment or siderin granules are left behind from the degenerated putamen neurons and may also accumulate in the globus pallidus and substantia nigra-pars reticulata (not the pars compacta). Varying degrees of neuron loss are found in pontine nuclei, the inferior olives, Purkinje cells of the cerebellar hemispheres, and the intermediolateral columns of the thoracic and lumbar spinal segments or Onuf nucleus in the sacral cord. Lewy bodies have long been considered the sine qua non for the diagnosis of idiopathic Parkinson's disease. They are identified as intracytoplasmic eosinophilic inclusions 5 to 25 pm in diameter, with a dense core and smudgy halo antigenically similar to neurofilament. In MSA, they may be slightly higher common than in normal aging controls but not to the extent seen in idiopathic Parkinson's disease. The distribution of Lewy bodies in both MSA and idiopathic Parkinson's disease is generally the same, whereas the degree of gliosis, nigral cell degeneration, and pigmented deposits (melanin, lipofuscin, or siderin) is much greater in all the brainstem nuclei involved in MSA. Glial cytoplasmic inclusions in MSA contain alpha synuclein, a synaptic protein that is also found in Lewy bodies. The familial olivopontocerebellar atrophies tend to have an even more widespread neuron loss and reactive changes (gliosis and demyelination, axonal thinning, or gross atrophy) involving all the same areas affected by sporadic olivopontocerebellar atrophy. In addition, there is often a neuronal wipeout in the dentate nuclei, locus ceruleus, corticospinal tracts, Clarke columns and spinocerebellar tracts, posterior column, and anterior gray

horns. These extensive lesions explain the diversity and severity of clinical signs found in most cases of familial olivopontocerebellar atrophy, whereas spontaneous olivopontocerebellar atrophies are fairly stereotypic in appearance. The observation of extremely dense deposits of lipofuscin in all areas of neuron loss seen in a patient with familial olivopontocerebellar atrophy and glutamate dehydrogenase deficiency has been a confounding factor in characterizing the neuropathologic features of olivopontocerebellar atrophies uniformly. It seems that there are a variety of look-alikes in this subdivision of MSAs that may differ in their primary metabolic defects but lead ultimately to a characteristic pattern of cellular loss. THERAPEUTIC STRATEGIES

The therapy for MSA depends on which systems degeneration presents the most troublesome symptoms because parkinsonian features usually are not the predominant ones. Also, as noted earlier, response to dopaminergic drugs is poorly sustained and may include worsening of orthostatic hypotension. Dyskinesias often occur with levodopa therapy after an average of 2.5 years of replacement with low to moderate dosages and can be seen simultaneously with axial rigidity, resting tremor, bradykinesia, and bulbar dysfunction (dysphagia and dysarthria). A slight response to levodopa may be evident only in up to 40% of patients with MSA, and clinical deterioration occurs after withdrawal of dopaminergics (e.g., for a drug holiday) with failure of an enhanced response to levodopa after reintroduction a few weeks later. Vague feelings of unsteadiness and overt falls early in the course of disease are common to all forms of MSA and may be aggravated by treatment with neuroleptic drugs given for presumed vestibulopathy, bringing out the parkinsonian aspects of these disorders instead. If postural changes in systolic pressure of more than 20 mm Hg are found without dopaminergic therapy, further assessment of the autonomic nervous system can help define appropriate choices of drug therapy. Testing of the baroreceptor arc includes measuring Valsalva ratio, performing the cold pressor test, and observing changes in blood pressure and electrocardiogram rhythm with hypoventilation and slow, steady breathing. These are simple physiologic tests of the integration of both the

Chapter 1 19

Multiple-SystemAtrophy: Striatonigral Degenerationand Shy-Drager Syndrome

afferent and efferent limbs of the arc and vagal tone. More sophisticated testing of catecholamine responses and pharmacologic rechallenge tests are best performed in a dedicated laboratory setting where the exact conditions of the tests and their responses can be measured and interpreted accurately. Mild orthostatic hypotension can be remedied with a combination of support hose or Jobst stockings (if tolerated) and volume expansion by adding salt to the diet. Often low-dose fludrocortisone (0.1 mg/day to 0.2 mg three times daily) is helpful if not contraindicated by a history of congestive heart failure. Indomethacin at 25 to 50 mg three times daily or ibuprofen at 400 to 800 mg three times daily can indirectly result in higher mean arterial pressures. Midodrine, a selective a-agonist, can be used safely in patients with coronary disease, but adequate volume expansion is needed to increase sympathetic tone and upright blood pressure. Supine hypertension, irritability, scalp tingling, and short duration of effect (less than 4 hours) are the main drawbacks of this drug. Patients should be advised to avoid standing abruptly after prolonged sitting and to try to stay well hydrated and avoid overexposure to hot and humid environments. They should minimize vasovagal responses by avoiding large meals, excessive alcohol, and straining at bowel movements. Sleepingin an elevated position (head of bed up 30 degrees) in reverse Trendelenburgcan ameliorate early morning hypotension by increasing the renin secretion overnight. Cardiac pacing and implantable devices for noradrenergic replacement therapy (an autonomic pacing system) are still under investigation and show promise for the more refractory condition of primary autonomic failure without central nervous system involvement. When dopaminergic therapy is no longer tolerated for the extrapyramidal symptoms, amantadine or anticholinergicsmay be beneficial in controlling tremor, rigidity, and bradykinesia at dosages comparable to those used in idiopathic Parkinson’s disease. A coincidental benefit is mild urinary retention as a side effect of these drugs in the face of urgency and incontinence seen in mild to moderate MSA. However, acute or severe urinary retention may ensue if the patient with MSA also has detrusor dyssynergia. The neurogenic bladder problems of MSA can include incomplete voiding, leading to recurrent infections caused by urinary stasis, or involuntary urethral sphincter relaxation with incontinence of small or large volumes. On rare occasions this is accompanied by the same phenomenon in the anal sphincter, causing double incontinence in advanced MSA. Treatment includes standard precautions such as urinary acidification and episodic to chronic antibiotic treatment plus a postvoid Cred6 maneuver and toileting schedules. Judicial limitations of fluid intake at night and protective garments or condom catheters can improve urinary hygiene as well. Chronic constipation may parallel the course of the bladder disturbance and is addressed with bulk agents, stool softeners, increased daytime fluid intake, and laxatives or enemas when all else fails. Osmotic laxatives such as lactulose syrup or polyethylene glycol for patients with diabetes can be used judiciously to promote bowel motility when recurrent impaction or painful cramps occur with other agents. The gait disorder of MSA typically is multifactorial and should be evaluated by experienced physical,and occupational therapists. Loss of postural reflexes is the most dangerous component and is not remediable with medication. Teaching safety awareness and use of assistive devices for ambulation are key to maintaining patient independence. Other factors such as extrapyramidal tone,

769

postural hypotension, and limb ataxia may be diminished by adding amantadine (50 to 100 mg three times a day) to anticholinergic therapy at least for the first 1 or 2 years after diagnosis, but often not beyond that. Finally, speech and swallowing disturbances in MSA are refractory to pharmacologic therapy but must be evaluated to reduce the risk of aspiration and fatal choking. Vocal pacing, respiratory exercises, and language boards can help patients communicate effectively when speech quality is grossly impaired. Standard aspiration precautions combined with an H, blocker or proton pump inhibitor may also delay serious problems with pneumonia or reactive airway disease. CONCLUSIONS

Multiple system atrophy is an apt term for a class of diseases that have in common parkinsonism and the following atypical features: Extrapyramidal signs like those of idiopathic Parkinson’s disease but less responsive to dopaminergic therapy initially or within 2.5 years of using moderate dosages of levodopa Additional symptoms and signs of pathology in the cerebellum, pyramidal tract, autonomic nervous system, and numerous brainstem nuclei Frequent development of spontaneous or dopa-induced dystonia and dyskinesia, also within a few years of presentation Earlier mean age of onset and more rapid progression to disability than idiopathic Parkinson’s disease Characteristic pathologic changes on postmortem examination, with neuron loss and gliosis but without prominent Lewy bodies Current research in MSA relates to early diagnostic discrimination between idiopathic Parkinson’s disease and the striatonigral degeneration variant by performing positron emission tomography or single photon emission computed tomography scanning with selective markers, identifjmg a common metabolic derangement that may cause systemic breakdown, and gathering enough epidemiologic data to identify a possible genetic precursor or environmental exposure contributing to these diseases. Whereas MSA is far less common than idiopathic Parkinson’s disease, its atypical features often lead families and physicians to pursue further studies. The opportunity for better understanding of all parkinsonian disorders therefore lies in identifying patients with MSA, offering them specialized care, and ultimately encouraging their participation in research studies. SUGGESTED READINGS Gilman S, Low P, Quinn N et al: Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 163394-98, 1999 Hughes AJ,Colosimo C, Kleedorfer B et al: The dopaminergicresponse in multiple system atrophy. J Neurol Neurosurg Psychiatry 55:100@1013, 1992 Klein C, Brown R, Wenning G et al: The “cold hands sign” in multiple system atrophy. Mov Disord 12(4):514-518, 1997 Penny J B Multiple system atrophy and non-familial olivopontocerebellar atrophy are the same disease. Ann Neurol 37:553-554, 1995 Polinsky RJ: Multiple system atrophy: clinical aspects, pathophysiology and treatment. pp. 487498. In Jankovic J (ed): Neurologic Clinics. Vol. 2. WB Saunders, Philadelphia, 1984 Quinn N, Wenning G Multiple system atrophy. In Battistin et a l (eds): Advances in Neurology. Vol. 69. Lippincott-Raven, Philadelphia, 1996

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Movement Disorders W

Parkinson’s Disease and Parkinson-like Syndromes

120 Progressive Supranuclear Palsy Douglas G. Cole and Nutan Sharma

Steele, Richardson, and Olzewski described progressive supranuclear palsy in 1964, and the disorder has since become a well-established clinicopathologic entity. Its dominant clinical feature is parkinsonism. Although rare, it may be the most common clinicopathologically defined atypical parkinsonian disorder. CLINICAL FEATURES Patients generally present in their fifties and sixties, less often in their forties, seventies, or eighties. The presentation may include imbalance, loss of manual dexterity, visual disturbances, dysarthria, dysphagia, altered intellectual function, personality changes, or insomnia. All features are not invariably present in every patient, but most evolve eventually during the course of the illness. Postural instability and visual disturbances are characteristic and often early symptoms of progressive supranuclear palsy. Some patients begin to fall suddenly and without apparent explanation (paroxysmal disequilibrium). Most develop a tendency to fall backward, but they may fall in any direction. Some describe difficulty walking on an incline or on uneven surfaces, maintaining balance when lifting a heavy object, or arising from a chair or getting out of a car. Visual difficulties reflect primarily impaired voluntary control of eye movements. Patients may describe difficulty navigating when walking down stairs or problems reading a book or trying to find food on a plate. They often complain of blurred vision and occasionally of diplopia. They may describe difficulty in opening or closing their eyes. Some say that they simply cannot see. Establishing the presence of early imbalance or visuomotor impairment in the history of a patient with parkinsonism strongly favors the diagnosis of progressive supranuclear palsy; sustained absence of either of these symptoms makes its diagnosis unlikely. Speech and swallowing commonly deteriorate. Choking develops insidiously but then becomes a major source of morbidity. Most patients develop cognitive impairment (i.e., a modest loss of cognitive function compared with their baseline). Fewer are thought to develop dementia (i.e., a more profound and widespread decline of memory and other cognitive functions that alone is sufficient to compromise social and vocational abilities). Depression and personality changes are common. As in many parkinsonian disorders, sleep disturbances also are common. Examination of patients with progressive supranuclear palsy reveals symmetrical, axially predominant parkinsonism, abnormal eye movements, gait instability, and pseudobulbar palsy. Axially predominant parkinsonism is characterized by rigidity and hypokinesia that is most prominent in the muscles of the neck and trunk. On casual observation, the examiner may note that the patient moves his or her head abnormally slowly or en bloc with the trunk. Passive motion of the neck, especially to flexion and extension, reveals rigidity. The magnitude of this rigidity may vary, but neck tone is rarely normal, even in the early stages of progressive supranuclear palsy. When severe, it can be associated with retrocollis and dystonic extension of the entire trunk.

1

Patients with progressive supranuclear palsy lose facial expressiveness. Some patients develop rigidity of the limbs, but others have normal limb tone despite severe axial rigidity. Loss of manual dexterity is common. Fine movements of the fingers and hands become slow and uncoordinated. This loss of precise motor control may occasionally be exacerbated by apraxia, but prominent apraxia is uncommon. Abnormal eye movements are a critical feature of progressive supranuclear palsy. The most typical abnormality is impaired voluntary gaze. The examiner may suspect a defect in eye movements when calling the patient’s name in the waiting room: Instead of turning the eyes briskly toward the sound of his or her name, the patient slowly turns the head or even the whole body. On more formal examination, one can observe that when the patient holds his or her head still and tries to follow a moving object with the eyes or to move the eyes in a particular direction without a visual target, the eye movements are incomplete, absent, slow, or fractionated. When the patient fixes the eyes on a stationary object while allowing the examiner to move his or her head, however, the eyes display a full range of motion (intact oculocephalic reflex or “doll’s head response”).The ability to converge the eyes is lost. Typically, gaze remains conjugate. Usually, the voluntary eye movement most prominently affected in progressive supranuclear palsy is downgaze. Although impaired voluntary downgaze strongly suggests the diagnosis of progressive supranuclear palsy in the correct context, it is not pathognomic for the disease. For example, impaired downgaze and parkinsonism can be seen in central nervous system Whipple’s disease, which, though exceedingly rare, is eminently treatable. Furthermore, some patients with progressive supranuclear palsy display more involvement of horizontal or upgaze than downgaze. In this regard, one should note that decreased range of voluntary upgaze is common in older adults. This eye movement finding alone is rarely sufficient for suspecting that a patient has progressive supranuclear palsy. The severity of eye movement abnormalities in progressive supranuclear palsy is variable. When dramatic, supranuclear gaze palsy is easy to appreciate. When subtle, it may be detectable only through close observation. For example, some patients may have only slowing of the fast phase of opticokinetic nystagmus. The presence of square wave jerks and inability to suppress the vestibulo-ocular reflex can bolster suspicion of progressive supranuclear palsy. Other patterns of eye movement abnormalities occasionally develop in patients with this disease. Several patients have been described with an internuclear ophthalmoplegia. Other patients lose all eye movements, including reflex eye movements. Rare patients retain normal eye movements throughout the course of the disease. Exceptional cases notwithstanding, the importance of a careful visuomotor examination in any patient with parkinsonism cannot be overemphasized. The combination of prominent impairment of

Chapter 120

voluntary eye movements and parkinsonism suggests progressive supranuclear palsy until proven otherwise. In this disease, visual function can also be compromised by abnormal opening and closing of the eyes. Many patients with the disease have retracted upper eyelids, which gives them a characteristic staring expression. Decreased blink frequency, common in many parkinsonian disorders, makes patients susceptible to corneal injury. Alternatively, some patients with progressive supranuclear palsy fmd that they are unable to open their eyes voluntarily. This so-called apraxia of eyelid opening, when severe, can produce functional blindness. However, visual acuity is not primarily affected in progressive supranuclear palsy. Patients with the disease typically have difficulty arising from a chair, and when they try to sit down, they often begin to topple backward uncontrollably. When standing, they may hold the trunk erect. They stand and walk with a normal base, bilateral symmetrical diminution of armswing, and en bloc turning. Their steps may be shuffling or festinating. The ability to walk in tandem or hop or stand on either foot is lost. Some patients display retropulsion when pulled from behind. Others fall spontaneously. Eventually, patients become unable to walk. Dysarthria and dysphagia in progressive supranuclear palsy reflect pseudobulbar palsy. Speech is slurred and quiet. Some patients develop difficulty initiating speech or irregular, halting speech or festinating speech. They may eventually become anarthric. Drooling is prominent. The gag reflex may be hyperactive or hypoactive. Aspiration is common. Primitive reflexes and frontal release signs, such as the glabellar response, root response, snout reflex, grasping, and palmomental response, are common. Utilization behavior, echolalia, palilalia, or perseveration can be dramatic. Emotional incontinence can evolve. Evidence of intellectual deterioration with the disease includes generalized cognitive slowing, inattentiveness, and memory loss. In some patients, the magnitude of intellectual decline equals that of the loss of voluntary motor control, and true dementia ensues. In others, however, intellectual decline remains mild for years, despite disabling loss of motor function. Because motor dysfunction can progressively compromise a patient’s ability to communicate, establishing the intellectual status of a patient with progressive supranuclear palsy often entails careful and patient questioning. However, one should not assume that a patient with the disease is demented on the basis of physical debility. Rest tremor is rare in progressive supranuclear palsy. Absence of such a tremor on history or examination is an important clue to the diagnosis. Strength, primary sensation, and cerebellar function are preserved. Occasional patients develop mild hyperreflexia or an extensor plantar response, but pyramidal tract dysfunction is not a prominent feature of the illness.

Progressive Supranuclear Palsy

77 1

fies Parkinson’s disease. The symmetrical distribution of parkinsonism in progressive supranuclear palsy contrasts with the asymmetrical parkinsonism usually found in Parkinson’s disease. Retrocollis, erect posture, and dystonic extension of the trunk are uncommon in patients with Parkinson’s disease; mild anteroflexion of the neck and hunched posture are more typical. Rest tremor is almost always present at some point during the course of illness in patients with Parkinson’s disease. Finally, patients with Parkinson’s disease usually experience sustained and dramatic benefits from levodopa. This is not the case for patients with progressive supranuclear palsy. Other atypical parkinsonian disorders that respond poorly to levodopa may resemble progressive supranuclear palsy. Corticobasal ganghonic degeneration produces asymmetrical parkinsonism associated with severe apraxia and parietal sensory deficits. Multiple-system atrophies, such as striatonigral degeneration, Shy-Drager syndrome, and the olivopontocerebellar atrophies, produce varied patterns of deficits reflecting involvement of the corticospinal system, the cerebellar system, the autonomic nervous system, and the peripheral nerves. Some of these disorders are hereditary. Normal pressure hydrocephalus is a poorly understood syndrome in which patients can develop gait ataxia followed by urinary incontinence and dementia. This syndrome should rarely, if ever, be confused with progressive supranuclear palsy. However, it is important to keep this diagnosis in mind for any patient who presents with impaired gait because occasional patients with early stages of normal pressure hydrocephalus improve after drainage of cerebrospinal fluid. Clues to the diagnosis of normal pressure hydrocephalus include the temporal evolution of symptoms (which is critical), the presence of hydrocephalus on imaging, normal cerebrospinal fluid pressure, and the absence of any atypical features. Multiple cerebral infarctions can produce pseudobulbar palsy, but we have not seen infarctions alone mimic the entire syndrome of progressive supranuclear palsy. A history of stepwise decline is a clue to the presence of vascular disease. Spongiform encephalopathies sometimes enter into the differential diagnosis but tend to produce evidence of cortical dysfunction, such as myoclonus, and tend to progress rapidly. The clinical pictures of Alzheimer’s disease and Pick’s disease may overlap with that of progressive supranuclear palsy. Usually, the relative prominence of dementia compared with motor involvement indicates the correct diagnosis, but sometimes the scenario can confound even the most experienced observer. Wilson’s disease and central nervous system Whipple’s disease are rare but important to consider because they are treatable. Uncommon hereditary disorders, such as adult-onset Niemann-Pick disease and Joseph‘s disease, can mimic progressive supranuclear palsy on rare occasions.

DIFFERENTIAL DIAGNOSIS The major diagnostic considerations in a patient who may have progressive supranuclear palsy are other parkinsonian neurodegenerative disorders, most importantly Parkinson’s disease. It has been estimated that about 5% of patients diagnosed with Parkinson’s disease actually have progressive supranuclear palsy. Several clues are especially helpful in differentiating the two disorders. In contrast to progressive supranuclear palsy, imbalance and impaired vision are rare in the initial stages of Parkinson’s disease. The eye movement defects so typical of the former are not seen in the latter. Whereas axial parkinsonism is the rule in progressive supranuclear palsy, appendicular predominance typi-

DIAGNOSIS The diagnosis of progressive supranuclear palsy rests on recognition of the characteristic syndrome. In a typical case, a single imaging study of the brain, ideally a magnetic resonance scan, is appropriate to screen for coexistent disorders such as cerebral infarctions. This study may reveal prominent atrophy of the midbrain, with enlargement of the third ventricle, but these are not reliable findings. Patients who may have disorders with a biochemical signature, such as Wilson’s disease, should be evaluated accordingly.

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Movement Disorders rn Parkinson’sDisease and Parkinson-like Syndromes

In some patients, a firm diagnosis cannot be made at the time of presentation. Rarely, characteristic abnormalities on positron emission tomography (PET) or single photon emission computed tomography (SPECT) can support a suspected diagnosis of progressive supranuclear palsy. Generally, however, the most important step is to follow patients over time. Usually, the diagnosis of progressive supranuclear palsy becomes apparent. BIOLOGIC BASIS Progressive supranuclear palsy is a tau-opathy. Tau proteins are phosphorylated, microtubule-associated proteins that are abundant in the central nervous system. Human tau proteins are encoded by a single gene consisting of 16 exons on chromosome 17q21. The tau isoforms found in the brain are generated by alternative mRNA splicing of 11 of these exons. In the adult human brain there are six tau isoforms that differ in the presence of either three or four microtubule-binding domains. In the brain with progressive supranuclear palsy, there is selective enrichment of tau isoforms that contain four microtubule-binding domains. Although the pathogenesis of progressive supranuclear palsy is unknown, there is increasing evidence of a genetic influence. One polymorphism in the tau gene, a dinucleotide repeat in the intron between exons 9 and 10, is associated with progressive supranuclear palsy at a greater-than-chance frequency. However, the role that a particular tau polymorphism may play in the pathogenesis of progressive supranuclear palsy remains to be elucidated. The brains of patients with progressive supranuclear palsy demonstrate tau pathology. Specifically, tau-immunopositive tufted astrocytes within the putamen and tau-immunopositive oligodendroglia within the white matter are seen. There is also an abundance of straight neurofibrillary tangles and neurophil threads consisting of hyperphosphorylated tau protein. In addition, there are neuronal loss, gliosis, and globose neurofibrillary tangles. Neuronal loss and gliosis are severe in the substantia nigra, subthalamic nucleus, globus pallidus (especially the internal portion), and superior colliculus. In some cases, neuronal loss is so severe in these areas that little remains but a skein of glia. Neuronal loss is slightly less prominent in the pretectum, locus ceruleus, periaqueductal gray matter, and substantia innominata. The brains of many patients show additional involvement of the motor nuclei in the brainstem (particularly the ocular motor nuclei), striatum, thalamus, dentate nucleus of the cerebellum, and basal forebrain. The distribution of globose neurofibrillary tangles largely parallels that of neuronal loss, but no efforts have been made to establish a quantitative correlation between the two findings. Subtle pathologic changes may be found in the cortex, especially in the frontal regions. The dopamine system is markedly abnormal. PET and postmortem studies have shown that dopamine in the striatum is profoundly depleted. Dopamine is preserved in the cortex, however, indicating sparing of the mesocortical dopamine projections. PET and postmortem autoradiographic studies indicate that pharmacologically defined D2 dopamine receptors are decreased in the striatum, but striatal D1 dopamine receptors are preserved. This situation contrasts with that found in Parkinson’s disease, in which striatal dopamine loss is associated with normal or elevated numbers of striatal D2 receptors. Consistent abnormalities have not been found in acetylcholine, serotonin, or norepinephrine levels. However, these neurotransmitters have been studied in only a few patients.

PET and SPECT have demonstrated decreased metabolic activity of the cortex, especially the frontal cortex, as well as the basal ganglia, thalamus, and pons. The observed metabolic abnormalities of the frontal cortex contrast with the relative lack of pathology seen by light microscopic analysis. Degeneration of the striatonigral axis probably contributes to parkinsonism in progressive supranuclear palsy but may not fully explain motor impairment. Changes in ‘8F-6-fluorodopa uptake measured with PET, an index of the integrity of nigrostriatal dopaminergic nerve terminals, do not correlate with the Hoehn and Yahr scale score, an index of parkinsonian disability. Loss of voluntary eye movements indicates compromise of the supranuclear brain structures, such as the superior colliculi and the frontal lobes, which regulate eye movements. Preservation of reflex eye movements indicates sparing of the neuromuscular apparatus directly responsible for eye movements (i.e., the ocular motor nuclei and their associated nerves and muscle). Internuclear ophthalmoplegia suggests involvement of the medial longitudinal fasciculus. Loss of reflex eye movements indicates that pathology has extended to the ocular motor nuclei themselves. Pseudobulbar palsy arises from bilateral degeneration of extrapyramidal structures. Recent evidence indicates that oxidative damage and mitochondrial dysfunction may play a role in the pathogenesis of progressive supranuclear palsy. Elevated levels of two markers of lipid peroxidation, malondialdehyde and 4-hydroxynonenal, have been found in the midbrain, subthalamic nucleus, and superior frontal cortex of brains from patients with progressive supranuclear palsy. Mitochondria from patients with progressive supranuclear palsy have been shown to have specific defects in complex I activity. One possible mechanism for the development of progressive supranuclear palsy is that subclinical defects in mitochondrial metabolism may produce pathologic consequences with the accumulation of age-dependent oxidative damage.

TREATMENT Efforts to treat progressive supranuclear palsy have sought to exploit the strategy of neurotransmitter replacement that has been successful in treating Parkinson’s disease. Some patients derive modest benefit from levodopa, but this benefit is rarely as dramatic as for patients with Parkinson’s disease, and it wanes rapidly. Nevertheless, when it is used judiciously, there is little risk to a trial of levodopa. The patient’s unsatisfactory response to levodopa over time often provides an important clue to the diagnosis of progressive supranuclear palsy. Three factors are likely to account for the failure of dopamine replacement in progressive supranuclear palsy: Loss of striatal D2 dopamine receptors may compromise the benefits of dopamine, the output of the basal ganglia is funneled through the internal globus pallidus (because the internal globus pallidus degenerates in progressive supranuclear palsy, any benefits of restoring striatal activity probably would be limited because striatal signals could not be transmitted to the rest of the brain), and widespread degeneration of subcortical structures besides the basal ganglia decreases the likelihood that simply normalizing basal ganglia function would restore normal brain function. Other approaches to treatment have included the use of direct dopamine receptor agonists, cholinergic agents, serotonin agonists or antagonists, and tricyclic antidepressants. These trials have been disappointing. The a’-adrenergic antagonist idazoxan was shown in a double-blind, placebo-controlled crossover study to amelio-

Chapter 121

rate imbalance and manual dexterity in a small number of patients, but the magnitude of improvement was small. The use of idazoxan is also hampered by side effects and limited availability. Treatment is otherwise palliative. Insomnia responds well to low dosages of trazodone. Focal areas of dystonia or painful rigidity can be treated with injections of botulinum toxin. Precautions to prevent falls and aspiration are important.

COURSE The syndrome of progressive supranuclear palsy worsens inexorably. Typical life expectancy from time of onset is about 5 years, although the range varies from 1 year to more than 2 decades. Patients are at risk for bone fractures and brain trauma from falls, sepsis, wound infections, and aspiration pneumonia. They eventually become unable to walk, speak, or swallow and often develop a fixed posture of dystonia in extension. Death is caused by intercurrent illness or inanition. It is important to provide patients and families with accurate information regarding the course and complications of progressive supranuclear palsy to help them make realistic plans for treating the secondary complications of the disorder when they occur.

UNRESOLVED ISSUES Careful observation since the 1960s has firmly established progressive supranuclear palsy as a clinicopathologic entity. Nevertheless, many issues regarding the disease are unresolved. For example, the nature and true extent of dementia in those with the disease must still be determined. The status of the cholinergic, noradrenergic, serotonergic, and amino acid neurotransmitter systems must be clarified. Understanding the potential involvement of neurotransmitter systems must incorporate new information provided by molecular biologic identification of multiple, previously unrecognized receptor subtypes. The significance of both tau-immunopositive neurofibrillary tangles and tauimmunopositive aggregates within astrocytes and oligodendroglia must be determined. In addition, the role of different tau polymorphisms in increasing the risk of developing progressive supranuclear palsy warrants further study. Beyond these phenomenologic issues are several more perplexing enigmas. Current understanding of the pathophysiology of basal ganglia disorders suggests that loss of dopamine results in parkinsonism by allowing overactivity of the inhibitory input from

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the internal globus pallidus to the thalamus. Experimental and human studies suggest that destruction of the subthalamic nucleus or internal globus pallidus can restore normal thalamic activity and thereby ameliorate parkinsonism. Parkinsonism in progressive supranuclear palsy, a disorder in which there is concurrent degeneration of the substantia nigra, subthalamic nucleus, and internal globus pallidus, is not consistent with this scheme. This apparent paradox remains to be reconciled. However, it suggests that pallidotomy, which may be useful to treat intractable Parkinson’s disease, will not help patients with progressive supranuclear palsy. Furthermore, the pathophysiology of dementia in progressive supranuclear palsy, when it occurs, is obscure. Some suggest that degeneration of subcortical structures alone can cause dementia by deafferentating the cortex. Others believe that dementia occurs only when the brain is subject to a second, independent process, such as Alzheimer’s-type degeneration or infarction. A thud possibility is that the subtle cortical pathology in progressive supranuclear palsy observed by some indicates functionally significant pathology sufficient to impair cognition. Most importantly, the cause of neuronal degeneration in the disease is unknown. In short, the recognition and characterization of progressive supranuclear palsy have raised more questions than they have answered. Efforts to treat, and ultimately reverse, the effects of the disease will require answers to these questions. No experimental model of the disease exists. For the time being, at least, new insights into the disease will come from clinically based investigation. Patients should be informed about available research studies and encouraged to participate in them when appropriate.

SUGGESTED READINGS Agid Y, Javoy-Agid F, Ruberg M et al: Progressive supranuclear palsy: anatornoclinicaland biochemical considerations. pp. 191-206. In Yahr MD, Bergmann KJ (eds): Advances in Neurology. Vol. 45. Raven, New

York, 1986 Albers DS, Augood SJ: New insights into progressive supranuclear palsy. Trends Neurosci 24:347-352, 2001 Hughes AJ, Daniel SE, Kilford L, Lees AJ: Accuracy of cliiical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55181-184, 1992 Steele J C Progressive supranuclear palsy. Brain 95:693-705, 1972 Steele JC, Richardson JC, Olszewski J: Progressivesupranuclearpalsy. Arch Neurol 10:333-358, 1964

121 Diffuse L e w Bodv Disease 4

4

Daniel Z. Press Diffuse Lewy body disease (DLBD) is a recently defined but common neurodegenerative disorder that lies on the interface of movement disorders and dementia. The hallmarks of DLBD are cognitive decline, parkinsonism, visual hallucinations, and a fluctuating course. The clinical and pathologic features of DLBD place it between idiopathic Parkinson’s disease (PD) and Alzheimer’s disease (AD), overlapping both. Patients with DLBD can

present with typical PD; the diagnosis of DLBD becomes clear with the development of memory problems and visual hallucinations. Patients with DLBD can present primarily with cognitive symptoms suggesting AD, only early parkinsonism and visual hallucinations distinguish DLBD from AD. The prevalence of DLBD has not been clearly determined. Estimates range from 10% to 25% of all dementias, making it the second most common cause

Chapter 121

rate imbalance and manual dexterity in a small number of patients, but the magnitude of improvement was small. The use of idazoxan is also hampered by side effects and limited availability. Treatment is otherwise palliative. Insomnia responds well to low dosages of trazodone. Focal areas of dystonia or painful rigidity can be treated with injections of botulinum toxin. Precautions to prevent falls and aspiration are important.

COURSE The syndrome of progressive supranuclear palsy worsens inexorably. Typical life expectancy from time of onset is about 5 years, although the range varies from 1 year to more than 2 decades. Patients are at risk for bone fractures and brain trauma from falls, sepsis, wound infections, and aspiration pneumonia. They eventually become unable to walk, speak, or swallow and often develop a fixed posture of dystonia in extension. Death is caused by intercurrent illness or inanition. It is important to provide patients and families with accurate information regarding the course and complications of progressive supranuclear palsy to help them make realistic plans for treating the secondary complications of the disorder when they occur.

UNRESOLVED ISSUES Careful observation since the 1960s has firmly established progressive supranuclear palsy as a clinicopathologic entity. Nevertheless, many issues regarding the disease are unresolved. For example, the nature and true extent of dementia in those with the disease must still be determined. The status of the cholinergic, noradrenergic, serotonergic, and amino acid neurotransmitter systems must be clarified. Understanding the potential involvement of neurotransmitter systems must incorporate new information provided by molecular biologic identification of multiple, previously unrecognized receptor subtypes. The significance of both tau-immunopositive neurofibrillary tangles and tauimmunopositive aggregates within astrocytes and oligodendroglia must be determined. In addition, the role of different tau polymorphisms in increasing the risk of developing progressive supranuclear palsy warrants further study. Beyond these phenomenologic issues are several more perplexing enigmas. Current understanding of the pathophysiology of basal ganglia disorders suggests that loss of dopamine results in parkinsonism by allowing overactivity of the inhibitory input from

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the internal globus pallidus to the thalamus. Experimental and human studies suggest that destruction of the subthalamic nucleus or internal globus pallidus can restore normal thalamic activity and thereby ameliorate parkinsonism. Parkinsonism in progressive supranuclear palsy, a disorder in which there is concurrent degeneration of the substantia nigra, subthalamic nucleus, and internal globus pallidus, is not consistent with this scheme. This apparent paradox remains to be reconciled. However, it suggests that pallidotomy, which may be useful to treat intractable Parkinson’s disease, will not help patients with progressive supranuclear palsy. Furthermore, the pathophysiology of dementia in progressive supranuclear palsy, when it occurs, is obscure. Some suggest that degeneration of subcortical structures alone can cause dementia by deafferentating the cortex. Others believe that dementia occurs only when the brain is subject to a second, independent process, such as Alzheimer’s-type degeneration or infarction. A thud possibility is that the subtle cortical pathology in progressive supranuclear palsy observed by some indicates functionally significant pathology sufficient to impair cognition. Most importantly, the cause of neuronal degeneration in the disease is unknown. In short, the recognition and characterization of progressive supranuclear palsy have raised more questions than they have answered. Efforts to treat, and ultimately reverse, the effects of the disease will require answers to these questions. No experimental model of the disease exists. For the time being, at least, new insights into the disease will come from clinically based investigation. Patients should be informed about available research studies and encouraged to participate in them when appropriate.

SUGGESTED READINGS Agid Y, Javoy-Agid F, Ruberg M et al: Progressive supranuclear palsy: anatornoclinicaland biochemical considerations. pp. 191-206. In Yahr MD, Bergmann KJ (eds): Advances in Neurology. Vol. 45. Raven, New

York, 1986 Albers DS, Augood SJ: New insights into progressive supranuclear palsy. Trends Neurosci 24:347-352, 2001 Hughes AJ, Daniel SE, Kilford L, Lees AJ: Accuracy of cliiical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55181-184, 1992 Steele J C Progressive supranuclear palsy. Brain 95:693-705, 1972 Steele JC, Richardson JC, Olszewski J: Progressivesupranuclearpalsy. Arch Neurol 10:333-358, 1964

121 Diffuse L e w Bodv Disease 4

4

Daniel Z. Press Diffuse Lewy body disease (DLBD) is a recently defined but common neurodegenerative disorder that lies on the interface of movement disorders and dementia. The hallmarks of DLBD are cognitive decline, parkinsonism, visual hallucinations, and a fluctuating course. The clinical and pathologic features of DLBD place it between idiopathic Parkinson’s disease (PD) and Alzheimer’s disease (AD), overlapping both. Patients with DLBD can

present with typical PD; the diagnosis of DLBD becomes clear with the development of memory problems and visual hallucinations. Patients with DLBD can present primarily with cognitive symptoms suggesting AD, only early parkinsonism and visual hallucinations distinguish DLBD from AD. The prevalence of DLBD has not been clearly determined. Estimates range from 10% to 25% of all dementias, making it the second most common cause

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rn TME 121-1. Consensus Criteria for the Clinical Diagnosis of Probable and Possible DLBD The central feature of DLBD is progressive cognitive decline affecting normal social or occupational function. Prominent or persistent memory impairment may not be present at onset but generally develops with progression. Prominent deficits generally include attention, visuospatial function, and frontal-subcortical skills (working memory, executive function, slowed processing). Two of the following core features are necessary for a diagnosis of probable DLBD, and one is necessary for possible DLBD: Fluctuating cognition with marked variations in attention and alertness Recurrentvisual hallucinations Spontaneous motor features of parkinsonism Features supportive of the diagnosis are Repeated falls Syncope Transient loss of consciousness Neuroleptic sensitivity Systematized delusions Hallucinations in other modalities A diagnosis of DLB is less likely in the presence of Stroke, with evidence of focal neurologic signs or ischemic lesion on imaging Evidence on examination of a different illness or brain disorder sufficient to account for the clinical picture Adapted from McKeith IG, Calasko D, Kosaka K et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB internationalworkshop. Neurology 47:1113-1124, 1996.

of dementia in older adults, following only Alzheimer’s disease. Diagnostic criteria for DLBD with good specificity have been established (Table 121-l),but the sensitivity of the criteria are not as good. Thus, DLBD often is misdiagnosed as AD. Despite these difficulties, many patients present in a characteristic manner, and in these cases the clinician can be fairly confident in the diagnosis and consider specific treatments.

To complicate nosologic and pathologic matters further, the majority of cases of DLBD have some degree of concomitant Alzheimer’s changes. Amyloid plaques are more common than neurofibrillary tangles. The extent of AD changes is variable, and a subgroup of cases exist without any plaques or tangles, confirming that “pure” DLBD is sufficient to cause dementia. Various names have been proposed to express the frequent overlap of AD and DLBD, including “Lewy body variant AD” and the less specific “dementia with Lewy bodies”, which encompasses any dementing illness associated with Lewy bodies. One way of sorting these mixed disorders is to view DLBD as existing along two spectra, one being the degree of Alzheimer’s changes and the other the degree of cortical and subcortical Lewy bodies (Fig. 121-1). Although these distinctions are useful in theory, distinguishing between the groups antemortem is not yet possible. DIAGNOSIS The criteria for diagnosis are solely clinical. Progressive cognitive decline is necessary, but additional features must be present: fluctuations in cognition and alertness, recurrent formed visual hallucinations, or motor features of parkinsonism (Table 121-1). DLBD is also strongly associated with REM sleep behavior disorder (RBD), and RBD supports the diagnosis of DLBD. There are no serologic markers for the disorder. The ApoE4 genotype is more common in both DLBD and AD but is not sufficiently common to be clinically useful for diagnosis. The clinical criteria are as follows.

Progressive Cognitive Decline The cognitive profile of DLBD is similar to that of AD. Both diseases impair memory, naming, visuospatial function, and

PATHOPHYSIOLOGY The role of Lewy bodies in the pathophysiology of both DLBD and PD remains a mystery. Lewy bodies are intracytoplasmic, spherical eosinophilic neuronal inclusions that are the neuropathologic signature of idiopathic PD. They contain a number of proteins, including ubiquitin and a-synuclein. Lewy bodies typically are found in subcortical nuclei such as the substantia nigra, where they are easily visualized with routine stains. In contrast, cortical Lewy bodies are difficult to visualize on routine studies. Specialized stains for their constituent proteins have aided greatly in their identification and in the development of pathologic criteria for diagnosing DLBD. In DLBD, Lewy bodies are particularly common in limbic regions such as the cingulate, entorhinal cortex and amygdala. In the nonlimbic cortex, the temporal lobe usually is more affected than the frontal and parietal lobes. With careful pathologic review, nearly all cases with cortical Lewy bodies have some Lewy bodies in subcortical regions and vice versa. Lewy body disorders vary along two dimensions: parkinsonism and dementia. In PD subcortical Lewy bodies predominate, and the clinical feature is a movement disorder. In DLBD cortical Lewy bodies predominate, and the clinical presentation is of dementia. The severity of the dementia in DLBD correlates with the number of cortical Lewy bodies seen pathologically. Some patients with PD clinically and without dementia also have large numbers of cortical Lewy bodies postmortem. Although the general correlation of cortical Lewy bodies with dementia is strong, cortical Lewy bodies are not pathognomonic of dementia.

Subcortical

Cortical

Lewy Body Distribution FIG. 121-1. A schematic overview categorizing the overlap between lewy body disorders and Alzheimer‘s disease based on the severity of the Alzheimer‘s pathology and the distribution of the Lewy bodies. Dementia with Lewy bodies is the inclusive term. PD = Parkinson’s disease; AD = Alzheimer‘s disease; DLB = Dementia with Lewy bodies; and DLBD = Lewy Body Disease.

Chapter 121 W

T a m 121-2. Differential Diagnosis of Parkinsonism and Dementia

Diffuse Lewy body disease Alzheimefs disease Frontotemporaldementia Normal pressure hydrocephalus Vascular dementia Progressive supranuclear palsy Corticobasalganglionicdegeneration Multiple system atrophy Dementia pugilistica Wilson’s disease

executive or frontal lobe function. There are some potentially useful clinical distinctions between the disorders. Patients with DLBD often have unusually severe visuospatial deficits and disproportionate cognitive slowing on timed tasks. Their memory usually fails at the retrieval stage (they may recognize items that they could not recall) as compared to the failure of storage in AD (the information is lost completely). The rate of progression of dementia in DLBD generally is slightly faster than AD, but there is a great deal of overlap.

Parkinsonism Estimates of the rate of parkinsonian signs in DLBD range from 45% to loo%, probably because of differences in ascertainment and definition. When parkinsonian signs are present in DLBD, they closely mirror those of idiopathic Parkinson’s disease. Rigidity and bradykinesia are present in approximately 90% of both groups. Rest tremor is less common in DLBD but still present in 55%, as compared to 85% of patients with PD. The parkinsonian symptoms of DLBD usually are mild. They are levodopa responsive but generally do not warrant treatment. Parkinsonism can be seen in other neurodegenerative disorders including AD, frontotemporal dementia, and vascular dementia (Table 121-2). The presence of tremor and the treatment responsiveness favor the diagnosis of DLBD from the other non-PD parkinsonian syndromes.

Visual Hallucfnatlons Approximately 80% of patients with DLBD have visual hallucinations. Visual hallucinations are very rare in AD in the absence of ocular causes, and their presence is highly suggestive of DLBD. The hallucinations often are of people or animals and resemble those seen as a side effect of excessive dopaminergic stimulation in patients with PD. Some degree of insight into their nature generally is present, but this recedes over the course of the disease. The hallucinations are not typically threatening and may upset the caregiver more than the patient. Hallucinations occasionally are associated with paranoid delusions or delusional beliefs that loved ones have been replaced (Capgras’s syndrome).

Fluctuations in Cognition and Alertness Unlike with AD, patients with DLBD often show marked variations in cognitive performance and level of alertness that can be discerned by caregivers. Fluctuations can occur rapidly, over a minutes to hours, or very gradually over weeks to months. The depth of the fluctuations can range from episodes of simple daytime sleepiness or mild impairments in concentration to

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episodes of wakeful unresponsiveness, or “going blank.” The short-term fluctuations in cognition and in level of arousal recently have been shown to correlate closely with rapid changes (over seconds) in the electroencephalogram background frequency. These fluctuations probably are caused by damage to brainstem alerting and arousal systems.

Sleep Disorders In REM sleep behavior disorder (RBD), the normal atonia of REM sleep does not occur, allowing movements, often vigorous, during REM periods, as if acting out dreams. The best clinical assessment for RBD is to ask a patient’s bed partner if there are abnormal, even violent movements during sleep. RBD is a frequent precursor of PD, with one study finding that 38% of patients develop a parkinsonian disorder. RBD often is associated with dementia, and 90% of patients with both diagnoses meet clinical criteria for DLBD. In the few cases that have come to autopsy, the diagnosisof DLBD has been confirmed pathologically.

Neuroimadng Routine neuroimaging with magnetic resonance imaging or computed tomography is not clinically definitive in separating DLBD from AD or PD, but it is essential to diagnose vascular dementia and normal pressure hydrocephalus, both of which have parkinsonian features and dementia. Distinguishing DLBD from AD is more of a challenge. An absence of medial temporal lobe atrophy on structural magnetic resonance imaging suggests DLBD rather than AD, but if medial temporal lobe atrophy is present, either diagnosis is possible. Functional studies of nigrostriatal dopamine function with ‘8F-fluorodopapositron emission tomography scanning may separate DLBD from AD, but this technique has not been validated and is generally not clinically available.

TREATMENT There is no treatment to slow the progression of the neurodegeneration in DLBD. A large subset of patients with DLBD have concomitant Alzheimer’s changes, predominantly amyloid plaques. One study has shown that large dosages of vitamin E (a-tocopherol), 1000 IU twice daily, may slow the progression of AD and are very well tolerated. Although vitamin E has not been specifically tested in DLBD, it is a reasonable agent to prescribe. In the future, agents that either specifically prevent a-synuclein deposition in Lewy bodies or prevent amyloid deposition in plaques would be worthwhile agents to investigate. Symptomatic treatment options are available, but the side effects often worsen some feature of the disease. The parkinsonism in DLBD responds to dopaminergic agents. Levodopa is less likely than dopamine agonists to worsen hallucinations. Anticholinergics should be avoided because of the likelihood of markedly worsening the cognitive symptoms. Levodopa should be used only when motor symptoms are functionally limiting, and it should then be used at the lowest effective dosage (generally 150 to 300 mg levodopa divided into three daily doses). If hallucinations worsen during treatment, there are two options: lower or discontinue the medicine or introduce a low dosage of an atypical neuroleptic. Visual hallucinations occur in DLBD even without the provocation of levodopa. Whether provoked or spontaneous, visual hallucinations often can be managed without medication. They

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often occur in patients with impaired vision, so efforts to maximize visual acuity, such as keeping rooms well lit and treating any primary visual problems, are helpful. If the hallucinations are not disturbing to the patient, then educating the family in how to adapt to them may be sufficient. If the hallucinations are disturbing or debilitating to the patient or the family, then a trial of an atypical neuroleptic is warranted. Very low dosages of clozapine (6.25 to 37.5 mg) have been demonstrated to treat hallucinations in PD without exacerbating the parkinsonism. Concerns over agranulocytosis,excessive sedation, and lowering of seizure threshold makes this agent less practical clinically. Low dosages of quetiapine or olanzapine may be more practical, although neither has been well investigated. Risperidone often is considered to be an atypical neuroleptic but clearly worsens parkinsonism in patients with dementia and should be avoided. Typical neuroleptics can induce profound, even fatal worsening of the parkinsonism and should be avoided in any patient in whom DLBD is a diagnostic consideration. Another useful treatment is cholinesterase inhibitors. The cholinergic deficit in DLBD often is even more severe than that of AD. Open-label trials and one multicenter, double-blind, placebocontrolled study confirm that cholinesterase inhibitors can both improve the cognitive symptoms and ameliorate many of the psychiatric symptoms without worsening the parkinsonism. The three agents currently available are donepezil, rivastigmine, and galantamine. They appear to be equally effective. Side effects of both result primarily from their cholinomimetic properties (nausea, vomiting, headaches, and excessively vivid dreams). Because confusion, hallucinations, sleep disturbance, and delusions may appear early and repeatedly in the course of DLBD, home care of patients with DLBD often is very difficult for caregivers. The symptoms of DLBD often lead to nursing home placement, regardless of the underlying diagnosis. Efforts to support families through the course of the disease are crucial. The assistance of well-trained social workers should be sought early in the course of the disease. Preparation will allow a much smoother transfer if nursing home care becomes necessary.

PROGNOSIS

diagnosis is predicated on specific features including parkinsonism, dementia, visual hallucinations, and fluctuating levels of attention. Symptomatic treatment is available, but side effects generally limit the benefit. Cholinesterase inhibitors are an exception and can improve both the dementia and the psychiatric symptoms. DLBD probably represents more than just the manifestations of the pathologic overlap of two common disorders, PD and AD. Clarification will include a better understanding of the pathophysiology of cortical Lewy bodies and the ability to clinically discern the degree of AD changes and Lewy body changes in patients antemortem.

ACKNOWLEDGMENT This work was supported by NIH grant NS10980. Special thanks to Michael P. Alexander, MD, for editorial review.

SELECTED READINGS Barber R, Gholkar A, Scheltens P et ak Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology 52:1153-1158, 1999 Boeve BF, Silber MH, Ferman TJ et ak REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 51:363-370, 1998 Hu XS, Okamura N, Arai H et al: "F-Fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia with Lewy bodies. Neurology 55:1575-1577, 2000 Lennox G: Dementia with Lewy bodies. pp. 67-79. In Growdon J, Rossor M (eds): The Dementias. Vol. 19. Butterworth-Heinemann, Boston, 1998

Louis ED, Klatka LA, Liu Y, Fahn S: Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse Lewy body disease and 34 pathologically confirmed cases of Parkinson's disease. Neurology 48:37&380, 1997 Luis CA, Barker WW, Gajaraj K et ak Sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsy-verified sample. Int J Geriatr Psychiatry 14:526-533, 1999 McKeith IG, Galasko D, Kosaka K et ak Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB international workshop. Neurology 47~1113-1124, 1996

The rate of progression of DLBD is somewhat quicker than that of PD or AD. The mean survival from diagnosis for DLBD generally is between 6 and 9 years, as compared to 8 to 11 years for PD and AD.

McKeith IG, Grace JB, Walker Z et al: Rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial. Int J Geriatr Psychiatry 15:387-392, 2000 McKeith IG, Perry EK, Perry RH: Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Neurol-

SUMMARY

Salmon DP, Galasko D, Hansen LA et al: Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn 31:14&165,

O ~ Y53:902-905,

Many of the manifestations of DLBD reflect the underlying pathology of both cortical Lewy bodies and frequent Alzheimer's changes. A number of fundamental questions about the pathophysiology and the nosology remain. The accurate clinical

1999

1996

Walker MP, Ayre GA, Cummings JL et ak Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. Neurology 541616-1625, 2000

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122 Corticobasal Degeneration Lewis R. Sudarsky

HISTORY This disease was first described by Rebeiz, Kolodny, and Richardson in 1968. The original report featured clinical and neuropathologic findings in three patients; all three presented with an asymmetrical akinetic-rigid syndrome, involuntary movements, and signs of cortical dysfunction. Because of the distinctive,poorly staining ballooned neurons seen at postmortem, the entity was called corticodentatonigral degeneration with neuronal achromasia. This descriptive term has evolved into corticobasal degeneration (CBD), now an accepted designation for the syndrome and pathology detailed in this chapter. Corticobasal degeneration is most often seen in a Parkinson’s practice or movement disorder clinic; it is substantially less common than progressive supranuclear palsy (PSP) or multiplesystem atrophy. Typical patients present with a movement disorder and are observed to have cortical signs. There is usually no family history of this or any related neurodegenerative disease. We now appreciate that classic CBD is part of a broader clinical spectrum. Patients who present in this fashion with a motor control disorder have neuropathologic features in common with patients who present with frontal dementia (see Chapter 138) or restricted cognitive impairment (e.g., primary progressive aphasia). CBD may be more difficult to recognize when cognitive change is the salient presenting feature.

PATHOLOGY AND RELATlONSHlP TO PICK‘S DISEASE Postmortem examination of the brain reveals cortical atrophy with ventricular enlargement. Most of the atrophy is frontoparietal, particularly affecting the perirolandic cortex. There is also a degree of gross atrophy and evidence of neuronal degeneration in the basal ganglia and thalamus. Involvement of the forebrain is characteristically asymmetrical. In the brainstem, there is loss of pigmented cells from the substantia nigra. Microscopic examination of the cortex and basal ganglia reveals neuronal loss and gliosis. There are ballooned neurons, which stain poorly with standard neuropathologic techniques. These are similar to the ballooned neurons observed in Pick’s disease, although there are no Pick bodies in CBD. Other findings include globose neurofibrillary tangles, neuronal inclusions, and astrocytic plaques that immunostain densely for tau protein. A four-repeat isoform of tau protein is deposited in the brain in CBD, as is the case in PSP. These cytoskeletal markers suggest a relationship between CBD, PSP, Pick‘s disease, and other neurodegenerative diseases characterized by tau protein pathology and aggregation (tauopathies).

CLINICAL PRESENTATION CBD typically presents in the sixth, seventh, or eighth decade of life. Onset is gradual and insidious, as with any neurodegenerative disease. A majority of patients (64% in series of Rinne et al.) begin with sensorimotor disability in one arm or hand. Some present with imbalance and difficulty walking. The disorder is distinctly

asymmetrical, and asymmetry can often be appreciated on imaging studies. Enough of the typical features are present within a year to allow recognition and diagnosis. Patients exhibit a combination of motor features and cortical signs (Table 122-1). The most typical cases begin as an asymmetrical, bradykinetic or rigid disorder, a hemi-Parkinsonian syndrome without rest tremor. The disability in the involved hand often is out of proportion to the amount of bradykinesia. Response to levodopa usually is partial and not sustained. Over time patients identify the affected limb as awkward and useless and preferentiallyuse the other side. With progression, the patient may exhibit a dystonic hand; alien limb phenomena develop in 50% of patients over the first 2 years. Hand dystonia may be severe, with clawing of one or two fingers into the palm, producing skin maceration. In the series of Rinne et al., 28% of patients presented with a gait disorder: stiffness and disequilibrium, shuffling, and sometimes an awkward dystonic gait. These patients progressed to exhibit imbalance and postural instability, sometimes unexplained backwards falls. Those whose illness began in the lower limbs often had falls within a year. Other motor features characterize CBD in the first 3 years, including myoclonus, dysarthria, and an oculomotor disorder. Myoclonus may be observed in the more involved limb as a component of the rigidity and dystonia or bilaterally in the upper limbs, with action producing a “jerky action tremor.” This myoclonus often is stimulus sensitive. Dysarthria often is present within a year of onset, sometimes earlier if patients exhibit pronounced oral or buccal apraxia. The oculomotor features are not specific; slow saccades often are observed. Head thrusts or eye blinks may be needed to initiate gaze to the side. Some patients develop apraxia of lid opening. In addition to motor features, patients with CBD exhibit signs of cortical dysfunction. These also are most typically asymmetrical and focal, rather than global, although 7 of 36 patients (19%) in the series of Rinne et al. had some generalized cognitive impairment. Cortical sensory loss often is an early feature, and some patients have sensory complaints at presentation. Examination may reveal tactile extinction, astereognosis, or agraphesthesia in the presenting limb. Many patients with otherwise typical

rn TAME122-1. Early Clinical Features of Corticobasal Degeneration Insidious onset, age 50-80 (mean age 60) Motor features &ymmetrical, akinetic-rigid disorder Imbalance or postural instability Upper limb dystonia Myoclonus, “jerky action tremor oculomotor disorder: slow saccades, head thrusts to initiate gaze Cortical signs ldeomotor apraxia Cortical sensory loss Alien limb Dhenomena

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Parkinson’s disease have sensory complaints, but sensory loss sets this illness apart, Apraxia in CBD is also evident principally in the most affected limb and must be distinguished from clumsy execution caused by primary motor deficit. Ideomotor apraxia (using the terminology of Heilman) usually is observed and is correlated with regional involvement of cerebral cortex (the parietal lobe and supplemental motor area). Alien limb movements develop in 50% of patients over the first 2 years, and these movements make CBD distinctive among neurodegenerative disorders. The limb, usually the more severely affected arm and hand, will wander in a semipurposeful fashion. It will often grope for and grasp objects, sometimes manipulating objects involuntarily. It may actively interfere with the use of the other arm. Patients describe their limb as “having a mind of its own” but generally do regard it as part of their own body, in contrast to the alien limb of patients with ischemic neurologic deficits involving the parietal lobe. Imaging studies (computed tomography, magnetic resonance imaging) usually reveal asymmetrical cerebral volume loss, most dramatic in the perirolandic cortex. Single photon emission computed tomography and positron emission tomography studies show reduced metabolism in frontal and parietal regions, thalamus, and basal ganglia. Markers of dopaminergic function such as 18F-DOPAuptake and ‘231-P-CITdemonstrate a loss of nigrostriatal dopamine neurons in patients with CBD. Physiologic studies also show abnormalities in patients with more advanced disease. Electroencephalogram shows asymmetrical slowing, and action myoclonus may be recorded using surface electromyography. DIFFERENTIAL DIAGNOSIS

At the initial presentation, CBD can easily be mistaken for Parkinson’s disease, which is substantially more common. The diagnosis should be considered in a patient with unilateral Parkinsonism unresponsive to levodopa, especially if there are elements of apraxia in the affected limb. Once all the findings have unfolded, CBD is a distinctive syndrome and is usually recognized easily by clinicians who have encountered it previously. In a clinicopathologic study from the National Institutes of Health, the sensitivity was low (35%) but the specificity near perfect when cases were reviewed based on findings at the first visit. In a group of patients with neurodegenerative disorders, the best predictive correlation with the diagnosis of CBD was for patients with limb dystonia, apraxia, myoclonus, and asymmetry. The clinical picture begins to blur after 3 or 4 years, and the appearance of late-stage patients is less distinctive. A variety of neurodegenerative diseases can cause abnormalities of cortical function and Parkinsonism. A differential diagnosis composed from this list includes PSP, frontotemporal dementia with Parkinsonism, multiple-system atrophy, diffuse Lewy body disease, Parkinson’s with dementia, and Alzheimer’s with extrapyramidal features. Making a pathologic diagnosis based on clinical features at this stage is not always easy. Again, marked asymmetry, early apraxia, and sensory loss favor a diagnosis of CBD. NATURAL HISTORY AND TREATMENT

The course of neurodegeneration in CBD is progressive, and the illness is substantially more aggressive than Parkinson’s disease. As a rule, there are bilateral signs with a degree of generalized rigidity in 3 to 5 years. Loss of ambulation usually occurs within this time frame, earlier if the illness begins in the lower limbs. In the

study of Wennig et al., mean duration of illness to death was 7.9 years. In the series of Rinne et al., follow-up examination at 5 years found that the disability had spread to an arm and leg in 80% and four limbs in 73%. The presenting limb invariably was dystonic and fixed. Dysarthria and dysphagia are a substantial problem as the illness progresses. Ninety percent of patients exhibit oculomotor problems, including difficulty with gaze initiation, at 5 years. Therapeutic options are not very satisfactory. Most of the treatment is symptomatic and supportive because there is no disease-modifymg therapy. There is dwindling response to dopaminergic medications after the first year. Clonazepam is used to control myoclonus with some benefit. Baclofen sometimes is used to treat rigidity. Physical therapy is used to maintain mobility, and assistive devices can help with ambulation unless postural instability is advanced or apraxia makes use of a walker problematic. When dysphagia progresses and begins to produce aspiration, patients must decide whether to pursue a feeding gastrostomy. OVERLAP WITH PSP AND OTHER NEURODEGENERATIVE DISEASES

At a more advanced stage, with generalized rigidity, postural instability, and elements of supranuclear gaze palsy, the syndrome of CBD overlaps with PSP. Some patients who appear to have CBD at presentation develop a more symmetrical, akinetic-rigid disorder with severe oculomotor difficulty. A number of these overlap patients have the pathology of PSP at postmortem. (Patients with CBD typically exhibit more apraxia than patients with PSP, which may be a useful distinguishing feature.) In a recent study at the Mayo Clinic, 13 patients identified during life with CBD were retrospectively reviewed after postmortem examination. Pathology was that of CBD in seven but was that of another neurodegenerative disease in six. This experience suggests that the clinical syndrome of CBD, however distinctive, may not be a homogenous morbid entity. We need a better understanding of the neurobiology of the disease and identification of biological markers to help with diagnosis within this family of neurodegenerative disorders. It is hoped that new insights about the neurobiology of the tauopathies will lead to a novel therapeutic strategy for this and related diseases. SUGGESTED READINGS

Bergeron C, Pollanen S , Weyer L et al: Unusual clinical presentations of cortico-basal ganglionic degeneration. Ann Neurol 40:893-900, 1996 Boeve BF, Maraganore DM, Parisi JE et ak Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53:795-800, 1999

Gibb WRG, Luthert PJ, Marsden CD: Corticobasal degeneration. Brain 112~1171-1192, 1989

Litvan I, Agid Y, Goetz C et ak Accuracy of the clinical diagnosis of corticobasal degeneration: a clinico-pathologic study. Neurology 48: 119-125, 1997

Rebeiz JJ, Kolodny EH, Richardson E P Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18:20-33, 1968 Riley DE, Lang AE, Lewis A et ak Cortical-basal ganglionic degeneration. Neurology 401203-1212, 1990 Rinne 70, Lee MS, Thompson PD, Marsden CD: Corticobasal degeneration: a clinical study of 36 cases. Brain 117: 1183-1 196, 1994 Wennig GK, Litvan I, Jankovic J et al: Natural history and suMval of 14 patients with corticobasal degeneration confirmed at autopsy. J Neurol

Neurosurg Psychiatry 64184-189,

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Chapter 123

Secondaly Parkinsonism

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123 Secondary Parkinsonism Jeffrey D. Macklis

In addition to idiopathic Parkinson’s disease, a wide variety of more common and more rare disorders can present with similar symptoms of parkinsonism, mimicking the clinical presentation of Parkinson’s disease to varying degrees. Depending on the age of the patient, relevant concurrent illness, clinical circumstances, time course, and specifics of the neurologic examination, investigating these possibilities may include only clinical awareness or in-depth laboratory and neuroimaging evaluation. This chapter briefly reviews some of the more relevant causes of secondary parkinsonism, roughly in the order of decreasing prevalence in most practice settings. The complex of parkinsonian symptoms, including cogwheel rigidity, bradykinesia, rest tremor, and postural instability, can result in part from dysfunction at a variety of levels in the nigrostriatal system, most commonly resulting in functional dopamine deficiency. Therefore, disruption of this system by drugs or infarction in the striatum, imbalance of dopaminergic versus cholinergic striatal innervation, or toxic or viral injury to nigral neurons themselves can cause symptoms that alone can be difficult to differentiate from the idiopathic nigral neuron degeneration of Parkinson’s disease. In general, neurodiagnostic studies are most helpful in ruling out various secondary parkinsonian syndromes and other distinct diseases. In the current climate of health care cost containment, it is not warranted and not feasible to investigate all possibilities in all patients; this chapter may provide a framework in which to choose how extensive a diagnostic evaluation to pursue and in which direction to proceed.

DRUG-INDUCED PARKINSONISM Almost as common as idiopathic Parkinson’s disease is parkinsonism resulting from prescribed medication. Historically, this has resulted most commonly from the antipsychotic and antiemetic phenothiazines (chlorpromazine and related compounds), butyrophenones (haloperidol and related compounds), and metoclopramide. More recently, the introduction of the newer classes of atypical antipsychotics such as clozapine, respiridol, and olanzapine have reduced the incidence of such syndromes somewhat because these agents are thought much less likely to induce secondary parkinsonism. However, though seemingly much less common with these agents, secondary parkinsonian syndromes still arise as a result of these drugs. Extremely rarely, and typically only at very high dosages, secondary parkinsonism can result from the antihypertensives reserpine and methyldopa. Although case reports of parkinsonism from piperazine derivative calcium channel blockers and the antiarrhythmic amiodarone exist, the significance is uncertain, and these agents are rare in most clinical settings. The standard neuroleptic compounds exert their action at least partially via dopaminergic blockade within the striatum, and reserpine and methyldopa act via dopamine depletion. Druginduced parkinsonism can occur at all ages and usually is readily treated by dosage adjustment or withdrawal. Diagnosis is by careful elicitation of medication history and by diagnostic or therapeutic dosage reduction. It may not be possible

to eliminate all parkinsonian features while maintaining successful antipsychotic treatment, but diagnosis sometimes can help with choices among alternative antipsychotic or sedative medications. Although the atypical antipsychotic medications have a much lower incidence of parkinsonian side effects, clozapine necessitates complex monitoring for the risk of neutropenia, so respiridol and olanzapine have become preferred agents in this class. Although the occurrence of parkinsonian side effects in a population is not clearly dose dependent, on an individual basis the effects of all of these compounds are dose dependent and fully reversible. Resolution of symptoms takes days to weeks after discontinuation and should leave no residual symptoms or signs (although rarely months to years must pass until full resolution). Of course, idiopathic Parkinson’s disease may exist as an underlying illness and may be worsened by pharmacotherapy with these agents, in which case small dosages may cause pronounced symptoms.

VASCULAR PARKINSONISM Vascular infarction or compromise in the striatum or subcortical white matter can mimic some aspects of idiopathic Parkinson’s disease. Most often, this takes the form of small vessel disease, resulting in multiple lacunar infarctions. Because the average age of onset for Parkinson’s disease (approximately60) falls within the range common for stroke, the clinical circumstances,presentation, and constellation of clinical signs are central to correct diagnosis. In addition, it is not uncommon for small vessel disease and multiple appropriately placed lacunae to coexist with idiopathic Parkinson’s disease. Although the diagnosis of the primary cause of parkinsonism in these mixed cases can be imperfect and highly dependent on the relative progression of pyramidal and extrapyramidal signs over time, diagnosis can be aided by observing the response to dopaminergic medication. However, more commonly, the clinical onset and signs are more easily differentiated between idiopathic Parkinson’s disease and parkinsonism resulting from multiple infarctions. This diagnosis initially was used to suggest a cause for Parkinson’s disease in the late nineteenth century. It continued through periods of favor and disfavor over the next century and now is used more generically to describe secondary parkinsonism resulting from vascular disease. Although controversial in the past, this broader use provides a framework in which to view an important and common part of the differential diagnosis of secondary parkinsonism. Attention to diagnosing vascular disease and managing underlying risk factors can be important in avoiding complications of occult hypertension and cardiovascular disease in addition to avoiding largely ineffective dopaminergic therapy with potentially important cardiovascular side effects. Vascular parkinsonism most commonly occurs in patients with multiple risk factors for small vessel disease, especially hypertension and prior history of stroke. Lacunar infarctions in the striatum and subcortical white matter (or less often the brainstem or cerebellum) can occur in relative clinical silence in a diffuse

780

Movement Disorders

Parkinson’s Disease and Parkinsonian Syndromes

bilateral distribution or with a clearly ictal onset. Therefore, the presentation typically is either subacute and symmetrical (unlike the typically asymmetrical presentation for idiopathic Parkinson’s disease) or acute and unilateral. Stepwise progression can occur, but such a clear history is uncommon given the often subtle initial symptoms of these small infarctions. Rest parkinsonian tremor, festination, and seborrhea are uncommon, whereas associated pyramidal signs and superimposed gegenhalten rigidity often are present. Dementia, pseudobulbar palsy, and cerebellar signs can also be present, depending on the distribution of vascular infarction. Diagnosis can be aided by neuroimaging, especially by magnetic resonance imaging to look for an appropriate distribution of lacunar infarctions or small vessel disease. The most common imaging findings are multiple infarcts in the caudate, putamen, or globus pallidus. Response to levodopa often is not as successful as in Parkinson’s disease because the lack of dopamine processing by nigral neurons typically is not the limiting disorder. Often, as with other subtle stroke symptoms and signs, gradual resolution can occur in the absence of specific therapy. Alternatively, vascular parkinsonism can progress along with findings of more diffuse cerebrovascular disease. Sinemet or direct dopaminergic agonists can be somewhat effective at alleviatingsymptoms in some cases. However, reducing the risk factors for stroke, especially hypertension, and initiating antiplatelet therapy are the most effective interventions to slow progression. Cognitive changes resulting from diffuse Binswanger’s encephalopathy can exacerbate cognitive changes from dopaminergic medication and complicate treatment.

STRUCTURAL PARKINSONISM Although usually easy to differentiate from idiopathic Parkinson’s disease, a variety of structural lesions can cause a subset of parkinsonian features, including gait abnormalities and bradykinesia. Usually, other historical or clinical features are present to aid in differential diagnosis. Basal ganglionic or midbrain mass lesions, normal-pressure or obstructive hydrocephalus, and chronic subdural hematoma can all lead to such variable presentations. Gait abnormalities usually are the presenting symptom, and atypical tremor and rigidity are common. Parkinsonian rest tremor is rarely present, pyramidal signs are the rule, and symptoms suggestive of individual diagnoses often are present and helpful. For example, headache or seizure with a mass or subdural hematoma, cognitive dysfunction and incontinence with normal-pressurehydrocephalus, and subacute progression all raise suspicion for one of these disorders. Neuroimaging often can rule out or confirm one of these clinically suspected disorders. The disorder is thought to involve either direct striatal compression and compromise, periventricular white matter compromise, or direct midbrain injury with nigral dysfunction, depending on the location of the mass lesion or the type and extent of the hydrocephalus. This is one of the few situations in which imaging is indicated in parkinsonian syndromes; in combination with vascular parkinsonism, these disorders present with atypical signs for parkinsonism and often lateralized pyramidal tract findings, pointing the way for neuroimaging. Response to dopaminergic therapy is variable, with some thought that good response indicates midbrain compromise from the mass or hydrocephalus, and poor response reflects primary striatal compromise. In cases of normal pressure hydrocephalus, mass, or subdural hematoma, appropriate further neurodiagnos-

tics and possible surgical intervention are warranted. In many cases, dopaminergic therapy can be used symptomatically before or after primary therapy.

TOXIC PARKINSONISM Although l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP) emerged in the 1980s and 1990s as the most important recent and most scientifically illuminating toxic cause of secondary parkinsonism, a variety of industrial and agricultural toxins, often occupation related, can cause parkinsonism. Many of these toxins are mitochondrial poisons that interfere with electron transport. Others cause diffuse neurotoxicity with a marked effect on the basal ganglia. Careful elicitation of occupational and chemical exposure history is crucial to diagnosis because laboratory confirmation is possible only in a few situations. Although modern industrial standards and safeguards have drastically reduced the toxin levels in modern U.S. work settings, older workers, immigrants from developing countries, and patients with subtle syndromes may still need diagnosis of these toxin exposures. The best-known industrial toxin that can cause parkinsonism is manganese, which can be found in mine ore or, potentially, in vapors from unventilated welding. Such industrially related parkinsonism was much more common in the nineteenth and early twentieth century (“manganese madness”) and now is quite uncommon in this country. Manganese absorption occurs via the respiratory and gastrointestinal tracts and reaches high brain levels. Initial dementia and behavioral changes are the cardinal features, including agitation, psychosis, and aggression, following a time course from months to many years, depending on the exposure level. These changes classically make the transition over time to a more subdued affect and parkinsonian features. Patients can present with dystonia in addition to quite typical but symmetrical parkinsonian findings, with the exception of rare rest tremor. Diagnosis is by careful elicitation of the patient history; confirmation by serum or cerebrospinal fluid levels is available but rarely needed. Eliminating the manganese exposure can reduce or stabilize symptoms and signs over a period of months. A more modern toxin that produces a pathologic and clinical syndrome nearly identical to idiopathic Parkinson’s disease is the synthetic narcotic contaminant MPTP, which caused a localized epidemic of toxic parkinsonism among intravenous drug abusers using the synthetic heroin analog l-methyl-4-phenyl-4propionoxypiperidine (MPPP) near San Jose, California, in the early 1980s. Monoamine oxidase-B (MAO-B) converts MPTP to 1-methyl-4-phenyl-pyridiniumion (MPP), a mitochondrial electron transport poison responsible for the specific degeneration of dopaminergic substantia nigra neurons in this disorder. This neurotoxicology was one of the early indications for using selegiline as an MAO-B inhibitor in Parkinson’s disease. Although a few industrial exposure cases have been suggested, they are not seen in most practices. The clinical presentation, apart from the typically much younger age at onset of these patients, can mimic Parkinson’s disease remarkably, although rest tremor can be absent or less striking than other clinical signs. Diagnosis is by patient history, although circumstantial support via toxic screen may be helpful. In experimental settings, positron emission tomography has demonstrated striatal dopamine reduction strikingly similar to that in Parkinson’s disease. Response to standard dopaminergic therapy has been beneficial, although the severity of many cases and the frequency of “freezing” as a limiting symptom have made treatment less satisfactory in many patients. In limited experimen-

Chapter 123

tal trials of fetal nigral neuron transplantation, good therapeutic response has been obtained, thought to be especially long-lasting in MPTP cases because this is a static insult without ongoing degenerative disease. A number of organic solvents, most notably carbon disulfide (used in rayon and cellophane production) and, less often, methanol, have been associated with secondary parkinsonism. Exposure to carbon disulfide and other industrial solvents is largely via the respiratory tract, although cutaneous absorption is also possible. Methanol exposure usually is via illicit ingestion. The clinical presentation, progression, and complex of symptoms and signs are very similar to those for manganese intoxication noted earlier. Although they were largely a problem of the nineteenth and early twentieth centuries in the United States, lax industrial safeguards in less developed countries make these organic toxins relevant in some patient populations. Neuropathologically,necrosis in both the substantia nigra and globus pallidus could account for the parkinsonian findings appearing in combination with diffuse encephalopathy and peripheral neuropathy with carbon disuliide, and methanol results in putamen degeneration. Carbon monoxide intoxication can also result in parkinsonian features, along with the diffuse encephalopathic, ataxic, and often dystonic findings that result from injury to the globus pallidus, hippocampus, cerebellar Purkinje cells, and deep cortical regions. Rarely would such a presentation be confused with idiopathic Parkinson’s disease. Similarly, a variety of organic toxins including cytosine arabinoside (AraC), pyridines, amines, nitrides, sulfatides, and excitatory amino acid analogues have been reported to cause parkinsonian features in rare cases. Some agricultural pesticides and herbicides, including paraquat, diquat, and other mitochondrial poisons, have been associated with toxic parkinsonism. Response of most of these toxic syndromes to standard dopaminergic therapy is variable but typically unsatisfactory. Recently, experimental evidence has been found of direct association of a parkinsonian syndrome in rodents with one mitochondrial toxin, rotenone. Such animal models allow both insights into the pathophysiology of nigral neuron degeneration and directed trials of preventive antioxidant therapies. Although it is unclear whether such toxin-induced parkinsonism has broad implications for understanding the causes and subtleties of the more common idiopathic Parkinson’s disease, reproducible animal models of functional loss resulting from nigral neuron death are very useful in pharmacologic prophylaxis and both pharmacologic and surgical therapeutics. In addition, these findings of nigral neuron degeneration in rodents further support the importance of similar environmental, occupational, and industrial exposure in these small but important categories of human parkinsonian disease.

POST-TRAUMATIC PARKINSONISM Both significant, isolated head trauma and more chronically acquired pugilistic parkinsonism from career-long boxing can result in partially parkinsonian syndromes. The disorder in the acute cases is thought to involve a combination of rotation shearing axonal injury and the hemorrhagic petechial microvascular disease associated with such rotation forces. Because the midbrain can be the site of maximal rotation in these cases, even injuries resulting in only subtle changes elsewhere can result in clinical parkinsonism. Alternatively, the parkinsonian symptoms and signs can be a small part of a complex of multifocal central nervous system injury that becomes clearly delineated only after

Secondary Parkinsonism

78 1

partial recovery from the acute post-traumatic hospital course. In boxers with a history of repetitive head blows associated with less dramatic rotation injuries, the same mechanism is thought to underlie the clinical syndrome. Although mild concussive injuries are common in all boxers, professionals without head protection and with more numerous episodes of loss of consciousness are thought to accumulate the most clinically marked parkinsonism. In the former isolated injury cases, a history of serious head trauma with concussion or coma is the rule, and parkinsonism typically is accompanied by cognitive changes, pyramidal or cerebellar signs, and often localizing midbrain signs on examination. Unlike in many other secondary parkinsonian syndromes, rest tremor is common. Pugilistic parkinsonism is centrally related to occupation as a boxer or history of repeated low-level head injury. Dementia and parkinsonism, including rest tremor, are the central features, although ataxia and superimposed pyramidal signs from the same disorder or from unrelated prior subdural hematoma are not uncommon. Neuroimaging typically shows diffuse cerebral atrophy and can reveal diffuse, bilateral basal ganglia calcifications from microhemorrhage, subtle midbrain white matter changes on magnetic resonance imaging, or no additional definitive findings. Imaging is also indicated to rule out chronic subdural hematoma as an atypical cause of secondary parkinsonism. Other neurodiagnostic studies, including electroencephalographyand neuropsychological testing, are indicated depending on the clinical setting, but other studies are rarely helpful. Response to standard dopaminergic therapy can be beneficial, although patients usually do not improve much because of the broader underlying disorder. Because of the spectrum of neurologic symptoms in addition to parkinsonism, treatment is symptomatic and individualized. Often, not much can be done therapeutically beyond providing appropriate social support and community services.

ENCEPHALITIC PARKINSONISM Although encephalic parkinsonism was quite prevalent after the epidemic of Economo’s encephalitis (or encephalitis lethargica) from approximately 1915 to approximately 1935, few survivors remain, and no more recent equivalent encephalitic epidemic has been associated with such parkinsonian features. Other viral encephalitides and syphilitic encephalitis have been associated with secondary parkinsonism in a much more limited number of cases. The parkinsonian symptoms and signs could develop over a wide period after the acute illness, from almost immediately to more than 10 years later. The parkinsonian findings usually lacked typical rest tremor. Dystonia, tics, and diffuse cognitive changes were common as well, along with other neurologic findings that varied between patient populations studied. Pathologically, dopaminergic nigral neurons were strikingly reduced in number, without Lewy body formation, along with more diffuse neuronal injury and gliosis responsible for other elements of the syndrome. Although patients initially responded well to levodopa therapy when it was introduced in the 1960s, they were found to be extremely sensitive to toxic side effects with small dosages and especially prone to dyskinetic and cognitive complications. ~~

METABOLIC DISEASES WITH PARKINSONIAN FEATURES A few well-recognized metabolic disorders can include parkinso-

nian features among their broader and more defining clinical

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Movement Disorders

Non-Parkinsonian Movement Disorder

symptoms and signs. Although it is beyond the scope of this chapter to describe each of these disease states in detail, it is useful to keep these disorders in mind in the broadest differentiation of atypical parkinsonism in correctly aged and appropriate patients. Because the parkinsonism associated with these disorders is not isolated even at the onset, confusion with idiopathic Parkinson’s disease is unlikely in most cases. Specific elements of the family or personal histories can direct appropriate use of diagnostic testing in individual circumstances. Wilson’s disease, a copper metabolism disorder with autosomal recessive inheritance and reduced ceruloplasmin levels resulting in hepatic and central nervous system copper deposition, can present with prominent basal ganglionic or cerebellar symptoms and signs. Parkinsonism is rarely found in isolation; dystonia, dysarthria, and nonrest tremor are common initial symptoms. Onset typically occurs in the teens and twenties, but patients in early school age through their fifties have been described. Because onset can occur much earlier than that of most idiopathic Parkinson’s disease, this diagnosis should be considered in especially young patients with parkinsonian findings. Diagnosis is by family history, slit lamp examination for Kayser-Fleischer rings, and assay of abnormal copper metabolism with decreased serum ceruloplasmin in 95% of cases, and increased urinary copper excretion. Hepatic biopsy for increased copper deposition is definitive in combination with other findings. Treatment is centrally via limitation of copper intake and absorption and via chelation therapy. Dopaminergic symptomatic therapy could confound observation of the clinical response to therapy and is rarely useful. Other rare disorders can present with parkinsonian features among more diffuse neurologic findings. Acquired hepatocerebral degeneration can display a clinical picture similar to that of Wilson’s disease, with mixed extrapyramidal findings, infrequent rest tremor, and prominent cognitive changes. Prominent degeneration in the globus pallidus, caudate, and putamen typically is seen. Both hypoparathyroidism and pseudohypoparathyroidism can result in bilateral basal ganglia calcification and symmetrical parkinsonian features, including rest tremor, rigidity, and gait disturbance, along with dystonia and chorea. Parkinsonism is not found in isolation, with paresthesias, tetanic contractures, and seizures being the most common accompanying features. Hallervorden-Spatz disease, an autosomal recessive illness with iron deposition and degeneration of the globus pallidus, substantia nigra, and red nucleus, typically presents in childhood or

adolescence and progresses over 1 or 2 decades. Parkinsonian features are mixed with prominent pyramidal and cognitive changes. Symptomatic dopaminergic therapy has been attempted with variable, limited results. Both pancreatic encephalopathy and central pontine myelinolysis can result in basal ganglionic lesions and have been described with parkinsonian features during the course of the illness. Attention to such rare associations may allow early diagnosis in some of these atypical parkinsonian disorders.

CONCLUSION Although idiopathic Parkinson’s disease often is straightforwardto diagnose in its classic age range of onset, clinical features, progression, and response to dopaminergic therapy, a broader differential diagnosis should be considered when atypical features are present or when parkinsonism occurs in younger patients. A range of secondary parkinsonian syndromes exist, some of which are fully or partially reversible with appropriate diagnosis and management. Because of the protean nature of many parkinsonian syndromes, the history often is more helpful in specific diagnosis than the neurologic examination; specialized neurodiagnostic studies can be used to support or confirm a suspected diagnosis, but a broad laboratory screen is rarely indicated. Although most of the secondary parkinsonian syndromes are rare, they represent an important class of disorders of the nigrostriatal system that have illuminated the basis of Parkinson’s disease and its potential therapies.

SUGGESTED READINGS Adams JH, Duchen LW. Greenfield‘s Neuropathology. 5th Ed. Oxford University Press, New York, 1992 Adams RD, Victor M: Principles of Neurology. 5th Ed. McGraw-Hill, New York, 1993 Betarbet R, Sherer TB, MacKenzie G et d.Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3(12):1301-1306, 2000

Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 25;219(4587):979-980, 1983

Rowland LD Merritt’s Textbook of Neurology. 8th Ed. Lea & Febiger,

Philadelphia, 1989 Stern MB, Koller W C Parkinsonian Syndromes.Marcel Dekker, New York, 1993

SECTION

2 NON-PARKINSONIAN MOVEMENT DISORDERS

124 Spinocerebellar Ataxias H

Christopher M. Gomez

The spinocerebellar ataxias (SCAs) are a complex group of disorders, characterized by progressive gait Unsteadiness, hand incoordination, and dysarthria caused by degeneration of the cerebellum or its spinal pathways. The disorders that make up this heterogeneous syndrome progress slowly over years to decades and thus are distinguished from viral, postviral, paraneoplastic, and immune disorders that more typically cause acute, subacute, or relapsing-remitting ataxia. Because of the heterogeneity of this syndrome and the difficulties with case ascertainment, the prevalence of this heterogeneous group of disorders is difficult to estimate. Most specialists agree that one half to two thirds of patients visiting ataxia clinics have a demonstrable hereditary form of the disease. Epidemiologic studies in Europe, Japan, and northern Africa have estimated the prevalence of all forms of ataxia to be 4.5 to 15 in 100,000, and of hereditary ataxia in several studies to be 4.8 to 6.4 per 100,000. Since the late 1800s and until the modern genetic revolution, neurologists used purely clinical observations, such as differences in age of onset, rate of progression, hereditary pattern, and associated clinical features to attempt to understand and classify the different SCA subtypes. These classifications culminated with that of A. E. Harding and continue to serve as a framework on which to begin diagnostic workups and expand clinical definitions in the modern genetic era. In the past 10 years there has been an explosion in progress in understanding the genetics of hereditary ataxia. The mutational basis for at least 9 forms of recessively inherited ataxia and at least 13 forms of dominantly inherited SCA has been established. The existence of an additional 6 forms of dominantly inherited SCA has been suggested by genetic linkage studies. Numerous insights from these genetic discoveries have greatly aided in interpreting clinical data and initiating investigation into the pathogenesis of ataxia. Despite remarkable advances in the genetics of ataxia, there are few definitive treatments for patients with progressive ataxia. This is particularly the case for approximately one third of patients with ataxia who have an apparently nonhereditary condition that has been called sporadic SCA. For this heterogeneous group of patients treatment is limited to symptomatic approaches and diagnosis and management of complications.

RECESSMLY INHERITED AND X-LINKED ATAXlAS About one half of patients with a hereditary ataxia have a recessively inherited condition (Table 124-1). The two most common and important of forms of recessively inherited ataxia are ataxia telangiectasia (AT) and Friedreich’s ataxia (FRDA). How-

ever, recent advances in the genetics of hereditary ataxia have enabled the recognition of several rarer forms of recessively inherited and X-linked ataxia, which may have similar ages of onset or clinical presentation to those of AT and FRDA (Table 124-1). Because some, such as hereditary ataxia with vitamin E deficiency, may have definitive treatments, their distinction is important. Ataxia Telangiectasia

AT is the most common form of infantile-onset cerebellar ataxia, with a prevalence estimated at 1 to 2.5 per 100,000. In the classic form of AT, progressive gait unsteadiness begins in the second year of life, soon after the patient begins to walk. Slurring of speech and hand incoordination follow soon afterward. There may be a history of mild mental delay. Peculiar head thrusting movements with voluntary gaze sometimes are seen, arising from a characteristic gaze apraxia. Rarely, milder forms may have age of onset of cerebellar symptoms as late as 9 years of age or may present with the gaze apraxia and resting tremor along with the systemic signs. AT is a systemic condition in which the underlying cellular abnormality is related to defective DNA repair. Patients with AT have immunologic incompetence, higher risk of malignancy, and progeric features. Patients often have a history of recurrent sinopulmonary and cutaneous infections, such as impetigo, before the onset of neurologic abnormalities. Chronic sinusitis and bronchiectasis often are present. Patients with AT also have a higher frequency of lymphoreticular malignancy and germ cell tumors in childhood and adenocarcinoma and other solid tumors as adults. First-degree relatives, obligate carriers of the recessively inherited mutation, also have a higher incidence of adenocarcinoma. There is often a delay in development of secondary sex characteristics and a delayed or irregular menstrual cycle, indicating the presence of hypogonadism. Small ocular and cutaneous telangiectasias, initially most evident on the conjunctiva and pinnae, may not be present during the first few years after onset of ataxia but spread to skin creases, oral mucosa, knees, and elbows. Premature graying of hair, senile keratoses, and atrophic skin, present in older children, indicate an accelerated aging process. Patients often are of short stature because of growth retardation. The mental status examination may suggest slowed cognitive function. Cranial nerve examination reveals a marked impairment of voluntary gaze. Patients have extremely slow or absent saccadic eye movements. When asked to look to one side they thrust their head toward the target, and the eyes follow with a slow eye movement, more resembling a pursuit 783

Abetalipoproteinemia

(IOSCA)

Infantile-onset spinocerebellar ataxia

Late-onset Friedreich’s ataxia (LOFA)

Friedreich’s ataxia with retained reflexes (FARR)

Friedreich’s ataxia

progression, no dysarthria, hyperreflexia, mild or no cerebellar ataxia B. Episodes of vertigo A. Ophthalmoplegia, deafness, sensory axonal neuropathy, athetosis, epilepsy areflexia, athetosis, optic atrophy A. Late milestones, nyctalopia, blindness, retinitis pigmentosa, nystagmus, proprioceptive loss, areflexia B. Babinski, generalized weakness

A. Late onset, slow

sition sense, saccadic intrusions, Babinski B. Optic atrophy, deafness A. Hyperreflexia, Babinski, reduced vibratory sense B. Spasticity, atrophy

A. Areflexia, absent po-

1-20

1-2

25-68

13-45

2-25

1-9

A Ocular apraxia, cho-

Ataxia telangiectasia

reoathetosis, nystagmus B. Areflexia, peripheral neuropathy, mental retardation

Age

Neurologic Findings.

Disorder

TABLE124-1. Recessive Ataxia

Microsomal triglyceride transfer protein (MTP) gene/ 4q22-24; ApoB gene/2p24

1Oq23-q24

Frataxin-l/X25/FRDAl

Frataxin-1/X25/FRDA1

Frataxin-1/X25/FRDA1

ATM phosphoinositol 3-kinase

Protein/Cene/Locus

Truncating mutations, deletions, missense mutations, Q1450X. R2495X

CAA < 500

CAA 408 ? 252, C130V

missense and truncations, M 1 I, I154F. W173C, L106X,A> C lnt3

CAA 719 f 184, most

>70 distinct missense, deletion, nonsense, frame shift, splicingtruncation mutations

Mutations and Alleles

Mutations in ATM; increased X-ray sensitivity, a-fetoprotein levels; chromosoma1 breakage (translocations); reduced imrnunoglobulin levels Genetic screen for GAA repeats in FRDA gene > 120; sequence analysis for point mutations No malignancy, telangiectasias, normal immunity

Steatorrhea, scoliosis, occasional liver cirrhosis

Reduced apolipoprotein B, acanthocytes, reduced vitamins A, E, absent MTP in intestinal biopsy

Genetic linkage to IOSCA locus Hypergonadotropic hypogonadism in females

No cardiomyopathy

Genetic screen for CAA repeats in FRDA gene > 120; sequence analysis for point mutations Genetic screen for CAA repeats in FRDA gene > 120; sequence analysis for point mutations

FARR LOFA

Diagnosis Variants

Scoliosis, pes cavus, milder cardiomyopathy

Immunodeficiency, recurrent infections, neoplasia (leukemia, lymphoma, germ cell tumors, breast), telangiectasias, short stature Cardiomyopathy, scoliosis, pes cavus, diabetes

Non-CNS

2

s

%

2

sB

21

?

5.

5

P

?

0

A. Seizures, delayed milestones, mental retardation, muscle weakness, pyramidal signs B. Lactic acidosis

CoQlO deficiency

HEXA gene 15q23-q24 HEXB 5q13

3-1 7

Scoliosis, camptodactyly, achalasia, gastrointestinal dysmotility Skeletal muscle, recurrent myoglobinuria, ragged red fibers

?

Birth-1 6 yr

None

None

Cardiomyopathy, dermal xanthomas, tendon xanthomas

1q31-32/AXPCl

Truncation mutations

Start codon, deletions, insertion, missense, truncationframeshift mutations 86 HEXA and 23 HEX6 and mutations, e.g., HEXB R505Q C269S 1207V A505Q (a G-to-A transition) within intron 12

2-1 4

3-20

a-Tocopherol transfer protein (ITPA)/ 8ql3.1-13.3

3-62

'Neurologic findings in addition to cerebellar dysarthria, hand and gait incoordination. A, usual; 6, common.

Posterior column and retinitis pigmentosa

Autosomal recessive spastic ataxia of CharlevoixSaguenay

A. Motor neuron disease, pyramidal tract 6. Dementia, myoclonus, optic atrophy, supranuclear gaze paresis, psychosis, dystonia A. Nystagmus, spasticity, axonal peripheral neuropathy, Babinski, ankle areflexia, deep sensory 6. Lower limb amyotroqhy. A. Retinitis pigmentosa, proprioceptive loss, intact pain, areflexia, dysarthria

flexia, Babinski 6. Dystonia, retinopathy

A. Leg weakness, are-

Hexosaminidase A and B deficiency

Ataxia with isolated vitamin E deficiency (AVED) Tay-Sachs; Sandhoff's

Ataxia with pigmentary retinopathy, with normal vitamins A, E, Frataxin-1, phytanic acid Reduced CoQlO in skeletal muscle

Reduced vitamin E with normal vitamins A, D, K; normal fat absorption and lipid profile Reduced hexosaminidase activity using natural, sulfated substrate, membrane-bound lamellar cytoplasmic inclusions in rectal ganglia Juvenile onset, spastic ataxia with nystagmus, normal cardias, neg. fratest

786

Movement Disorders

Non-Parkinsonian Movement Disorders

than a saccade. Some patients have nystagmus. There is severe trunk and gait unsteadiness. Upper limbs are uncoordinated, with inaccurate grasp of objects and intention tremor, Speech is slowed and dysarthric. Facies appear impassive. There may be choreoathetoid movements of the limbs and titubation of the head. Deep tendon reflexes are depressed or absent. Plantar responses, initially flexor, may become extensor with time. Sensation is initially normal, but vibratory sense may be lost with disease progression. Romberg sign is notably absent. With progressive ataxia, patients usually are wheelchair-bound in childhood. The neuropathy is progressive, and reduced muscle power and neurogenic atrophy develop in the late stages of the disease. Survival beyond the third decade is rare. Death may result from continued neurologic deterioration, aspiration and pneumonia, malignancy, or, rarely, infections. Infections are common in AT because of severe immunologic incompetence. There are deficiencies in cell-mediated and humoral immunity in these patients. Lymphoid organs are poorly developed, and there is serum deficiency in immunoglobulins, particularly immunoglobulin A. Serum a-fetoprotein, normally a tumor marker, often is elevated. Magnetic resonance imaging (MRI) demonstrates marked atrophy of the cerebellum, particularly the vermis, with an enlarged fourth ventricle and cisterna magna. The brainstem is spared. There are occasional white matter T2 signal intensities. Cerebrospinal fluid examination may show a slight increase in protein. The electroencephalogram shows nonspecific abnormalities. Nerve conduction studies show small or absent sensory nerve action potentials and slight slowing of motor nerve conduction velocity. Electromyography reveals evidence of denervation late in the disease. Pathologic studies have demonstrated more uniform findings than in the clinical presentation. There is striking loss of Purkinje cells and variable loss of granule cells in the cerebellar cortex. Inferior olivary neurons and dentate neurons are also depleted. In distinction from FRDA, the spinal cord is largely intact, but there is some loss of myelin in the dorsal columns and loss of neurons in the sensory and autonomic ganglia and motor neurons. Sural nerve biopsies may show loss of large myelinated fibers and lipid deposits. There is no specific treatment for AT. Prevention and treatment of infections and early diagnosis and treatment of malignancies have the most significant impact on long-term survival. Because of the marked radiosensitivity of nonmalignant tissues in AT, tumors should not be treated with radiotherapy. From the neurologic standpoint patients are managed with supportive and preventive measures. Dysphagia and aspiration should be minimized. Physical therapy and rest combine to allow patients to cope with increasing disability. Although AT is an autosomal recessive condition, and carriers have no neurologic phenotype, they do have a higher incidence of malignancies. The gene responsible for AT was identified in 1993 by classic positional cloning methods. The AT gene spans 150 kb, consists of 66 exons, and encodes a 350-kDa protein, ATM (ataxia telangiectasia mutated). The ATM protein is localized mainly in the nucleus and has homology to a phosphatidylinositol3-kinase. AT variants of several types have been recognized. Some of them have a later onset and milder and slower progression of neurologic abnormalities. Some patients have a significantly longer lifespan. Some have no obvious neurologic abnormalities and only the immunologic, cutaneous, and malignancy abnormalities.

The basic cellular defect that underlies the neurologic, neoplastic, and immunologic abnormalities of AT appears to be related to defective DNA repair. Chromosomal translocations, especially with chromosomes 7 and 14, can be identified in peripheral blood lymphocytes and increase with age and during culture in vitro. Cells in culture have increased sensitivity to ultraviolet, gamma, and X irradiation. At least 70 different AT gene mutations have been found in patients with AT. The majority of these are frame-shift or nonsense mutations and are predicted to cause a truncated protein. Missense, splicing, and in-frame deletion mutations are less common. Except in cases of consanguinity, most patients are actually compound heterozygotes rather than true homozygotes. Patients from certain ethnic groups (e.g. Amish, Mennonite, Costa Rican, Polish, British, Italian, Turkish, Iranian, Israeli) have a high prevalence of specific ATM mutations, which may sometimes aid in choice of which mutations to look for to make a molecular diagnosis. Mutations predicting early protein truncation lead to more severe AT phenotype. The pathogenic mechanism by which the deficiency of ATM leads to the many facets of the disease is yet to be elucidated on clinical grounds. Infantile onset ataxia with typical cutaneous signs, ocular motor apraxia, and retained dorsal column sensation can establish the diagnosis. Reduced serum immunoglobulins and raised a-fetoprotein or increased numbers of chromosomal rearrangements or accumulation during culture strongly suggest the diagnosis. There is no commercially available screen for detecting ATM mutations. The differential diagnosis includes other sporadic, recessively, or dominantly inherited forms of progressive ataxia with onset in this age range. The distinct syndrome of congenital nonprogressive ataxia may be initially suspected until progression is noted. In the absence of signs of AT or chromosomal rearrangements, as may occur early in the disease, the other conditions usually can be excluded on clinical grounds and with laboratory studies (Table 124-1). Friedreich’s Ataxia

FRDA, which represents about one half of all cases of hereditary ataxia, has a prevalence of 2 to 4 per 100,000 and is the most common form of hereditary ataxia. The classic form has an age of onset between 2 and 25 years, and about 25% have an atypical presentation with milder phenotype and onset after 25 years. As with AT, genetic advances have partially explained the phenotypic variability and have allowed recognition of striking clinical variants. Typically, gait unsteadiness begins in childhood, often simultaneous with spinal scoliosis. Gait ataxia progresses steadily, but worsening of both ataxia and scoliosis may seem greater during rapid growth in puberty. Dysarthria and hand incoordination usually develop in the next few years. Gait unsteadiness is particularly poor in darkness because of prominent involvement of posterior columns. Optic nerve atrophy occurs in approximately 25% and sensorineural hearing loss in 10% of patients with FRDA. Loss of sensory nerve action potentials, measured in nerve conduction studies, occurs early in the disease. Progression of the ataxia in the classic form is fairly uniform, and patients are wheelchair bound 12 years after onset. Death may occur from the mid-thirties to the sixth and seventh decades, particularly with the milder variants. Death often is related to cardiomyopathy, diabetes, or aspiration pneumonia.

Chapter 124

Several significant nonneurologic complications occur in FRDA. Spinal scoliosis or kyphoscoliosis is present in more than 90% of patients and may appear before the onset of imbalance. Intervention with bracing or surgical placement of stabilizing rods may be necessary to avoid deformities that reduce mobility and pulmonary function. Ten to twenty percent of patients with FRDA develop diabetes mellitus, an average of 15 years after onset of ataxic symptoms. Cardiac disease is a prominent feature of FRDA, present in nearly all patients with the typical form. The principal change is a progressive hypertrophic cardiomyopathy. Some patients experience exertional dyspnea, although because the neurologic impairment in FRDA reduces activity, the reduced cardiac output rarely leads to exercise intolerance. Palpitations are also common. The electrocardiogram typically shows T wave inversions or evidence of left ventricular hypertrophy. Some patients develop arrhythmias, particularly supraventricular and atrial fibrillation with advanced disease. The principal change in the heart is fibrosis and thickening of the myocardium, which may lead to either concentric hypertrophy or asymmetrical septal hypertrophy with outflow obstruction. In advanced stages there may be a dilated cardiomyopathy. Histologically, there is interstitial fibrosis, with infiltration of inflammatory cells and deposition of fatty deposits and iron deposits. On examination, typically, kyphoscoliosis is present. With wheelchair-bound patients, lower extremities often have pes cavus deformity and cyanotic venous stasis changes. Mental status is intact. Pallor of the optic disks occasionally is present. Eye movements demonstrate a characteristic pattern consisting of frequent spontaneous or pursuit-evoked large-amplitude saccadic intrusions (square wave jerks). Visual pursuit is saccadic, and there may be dysmetric saccades but rarely nystagmus. Depending on the stage, spinocerebellar dysfunction and incoordination of voluntary movements, including dysarthria, hand incoordination, and gait unsteadiness may be mild to severe. Motor examination often shows reduced tone in the upper extremities. There may be mild muscle atrophy, particularly of the lower extremities. Lower extremities may be quite spastic, particularly in the retained reflexes variant (described later in this chapter). Choreoathetoid movements may be present. Deep tendon reflexes may be detectable early in the disease, at some joints, but soon disappear. Plantar responses usually are extensor. Position sensation is absent in the lower extremities, but pain and temperature sensation are intact. Pathologically, FRDA is characterized by severe atrophy of the spinal cord, greatest in severity in the cervical cord. There is demyelination of the dorsal columns and pyramidal tracts and cell loss in Clark‘s columns, dorsal root ganglia, and anterior horns. In the dorsal roots and peripheral nerves there is loss of the large myelinated fibers that process from the periphery in a dying-back process. There is also patchy cell loss and gliosis in the cerebellum and medulla. The elucidation of the genetic basis for FRDA has allowed recognition of several clinical variants of FRDA that would be excluded from the diagnosis of FRDA on clinical grounds. Patients with the syndrome of juvenile-onset SCA with retained deep tendon reflexes, once recognized only as a distinct clinical entity, have been recognized within FRDA families. Patients with this syndrome, which has been called Friedreich’s ataxia with retained reflexes, have a lower incidence of decreased position sense loss, pes cavus, and less severe cardiomyopathy than areflexic “typical” patients with FRDA. Other patients have spastic paraparesis or

H

SpinocerebeiiarAtaxias

787

generalized chorea, some may have severe optic neuropathy, and some may have no evidence of dysarthria. Some patients (15%) experience onset of ataxic symptoms significantly beyond 25 years and as late as 60 years. This condition has been called late-onset Friedreich‘s ataxia. They have a lower occurrence of skeletal deformities and cardiomyopathy as well as a longer mean interval to wheelchair confinement. The recognition of these patients is important for management and for potential treatment with rational therapies. There is no definitive treatment for FRDA, and management chiefly involves supportive care and avoidance of complications. As in all patients with ataxia, physical therapy and rest allow patients to cope with increasing disability. Dysphagia and aspiration should be minimized. Spasticity may be managed with baclofen. Progressive scoliosis unresponsive to bracing should be treated with surgical stabilization of the spine by placement of Harrington rods. Cardiac disease and diabetes should be managed symptomatically. Recent studies have suggested that administration of the cofactor coenzyme Q l O (CoQlO) may significantly improve cardiomyopathy, possibly through its action as a free radical scavenger. The gene and mutational basis for FRDA were elucidated in 1996. The gene affected, X25, consists of seven alternatively spliced exons, the principal product of which encodes a 210-amino acid protein, frataxin. Frataxin, which is highly conserved in evolution, localizes to the inner mitochondrial membrane. The principal mutation of X25 consists of an expansion of an unstable repeat of the trinucleotide GAA, normally present in the first intron, resulting in reduced levels of frataxin mRNA. The GAA trinucleotide repeat present in the normal X25 gene exhibits length polymorphism, with normal alleles ranging from 7 to 38 repeats. An interruption of a (GAGGAA)n sequence is present in most normal alleles over 27 repeats. Disease is associated with 66 to more than 1700 repeats, and 98% of all FRDA alleles contain more than 600 repeats. Certain alleles, both premutation alleles and disease-associated alleles, are unstable during meiosis, prone to either contraction or expansion. Premutation alleles are those that have lost the (GAGGA4)n interruption and are prone to expansion to become either larger premutation alleles or disease-associated alleles. Missense or nonsense mutations in the X25 coding region represent rarer alleles. These are normally found through nucleotide sequence analysis of the X25 gene in patients with ataxia bearing a single pathologic GAA repeat, who are thus compound heterozygotes (4%). There is a statistically significant correlation between the size of the shorter of the two GAA repeats and clinical features in FRDA, including age of onset, presence of leg muscle weakness or wasting, duration until wheelchair use, and prevalence of cardiomyopathy, pes cavus, and scoliosis. For example, the GAA repeat size accounts for 50% to 75% of the variance in age of onset. Nevertheless, phenotypic variability between siblings with identical repeat number or even between monozygotic twins with FRDA demonstrates that factors such as somatic heterogeneity of the GAA expansion or environmental factors modify disease phenotype. The diagnosis of FRDA is based on clinical grounds and on genetic testing for the GAA repeat expansion in the X25 gene. The differential diagnosis includes all childhood-onset SCAs but particularly those with overlapping signs such as autosomal recessive spastic ataxia of Charlevoix-Saguenay, posterior column ataxia with retinitis pigmentosa, abetalipoproteinemia, ataxia with vitamin E deficiency, and infantile-onset SCA. These conditions present with combinations of ataxia, proprioceptive loss, spastic-

788

Movement Disorders

Non-Parkinsonian Movement Disorders

ity, and diminished reflexes between ages 1 and 20 as with FRDA, and, except for infantile-onset SCA, can be confirmed by a blood or genetic test. An ataxic variant of Charcot-Marie-Tooth neuropathy type 1 has a similar presentation. Recent dramatic advances in the genetics of FRDA have provided important insights into the pathogenesis of FRDA. Frataxin appears to play a role in iron transport in mitochondria. Single-cell yeast genetically deficient of their frataxin homologue develop damaged mitochondria that accumulate excess iron. In a similar fashion, iron deposits can be detected in cardiac muscle from patients with FRDA. Accumulated cellular iron leads to overproduction of oxygen free radicals, which are believed to be responsible for significant subcellular toxicity caused by oxidative damage. Patients with FRDA have elevated serum and urinary levels of oxidatively damaged DNA and lipids. There is recent promising evidence that a synthetic analogue of CoQlO can reduce the levels of these oxidized metabolites and improve cardiac function. Ataxia with Isolated Vitamin E Deficiency Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare form of autosomal recessive progressive ataxia with features similar to those of FRDA. Although it arises most commonly before 20 years of age, the age at onset ranges from 3 to 62 years. Patients develop progressive gait unsteadiness and dysarthria that progresses to wheelchair confinement at a more variable (3 to 37 years) pace than that of FRDA. Examination usually reveals dysarthria, hand incoordination, gait unsteadiness, areflexia, and vibratory and proprioceptive sense loss. More than one half of patients have extensor plantar responses. Diffuse muscle weakness most prominent distally may be present in 42% of patients. Retinopathy (9%) and dystonia or bradykinesia (13%) are found in minority of patients. Cardiomyopathy is also found in about 19% of patients. Skin may show xanthelasmata or tendon xanthomas. Electrophysiologic studies reveal mildly delayed nerve conduction, decreased amplitudes of sensory action potentials, and sensory delay in the posterior columns. Pathologically peripheral nerve examination demonstrates a dying-back process. There is severe dying-back degeneration of the posterior columns, massive accumulation of lipofuscin in neurons including dorsal root ganglion cells, and mild loss of Purkinje cells. The diagnosis of AVED is made by determination of serum vitamin E (a-tocopherol) levels, which are severely reduced or absent. In distinction from Bassen-Kornzweig disease and other causes of fat malabsorption, other fat-soluble vitamins are not reduced, and patients have no steatorrhea and have normal levels of abetalipoprotein. The condition is caused by defective a-MTP, which was established by conventional linkage analysis, followed by demonstration of mutations in the MTP gene. The a-MTP is a cytosolic liver protein that is presumed to function in the intracellular transport of a-tocopherol. At least 13 different mutations have been found in this gene, approximately half of which are missense and the remainder protein truncating. Twenty to fifty percent of patients are compound heterozygotes, which may help explain the clinical variability. Reduced levels of a-tocopherol may lead to impaired scavenging of oxygen free radicals, leading to oxidative damage of cellular proteins, lipids, and nucleic acids. Treatment consists of supplementation with oral vitamin E at a dosage of 800 mg twice daily, along with supportive care.

Maternally Transmitted Ataxias Mitochondrial disorders resulting from a variety of mutations of the mitochondrial genome give rise to a complex array of neurologic disorders (Table 124-2). This complexity results from the varied types of genes affected in the mitochondrial genome and the occurrence of both mutant and wild type mitochondria in the same cell, a state called heteroplasmy. Progressive ataxia may be a prominent feature in patients bearing either of two well-recognized mutations of the mitochondrial genome. The mutation T8993G causes a missense mutation, L156R, in the MTATP6 gene, resulting in an amino acid change from a highly conserved leucine to arginine in mitochondrial H(+)-ATPase. This point mutation can lead to two different neurologic pictures. In the case of extreme heteroplasmy, infants with cognitive impairment infantile spasms suffer from necrotizing encephalomyopathy, which has been called maternally inherited Leigh‘s disease (MILS). When a greater proportion of the normal mitochondria are present, patients develop a condition called neurogenic muscle weakness, ataxia, and retinitis pigmentosa with subacute, optic atrophy (NARP). Each family member may have a neurologic picture between the two extremes of MILS and NARP, depending on the proportion of mutant mitochondria, having a variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy, in a pedigree pattern consistent with maternal transmission. Similarly, the mutation T8993C leads to a L156P mutation and a similar neurologic spectrum. Similarly, patients with the mitochondrial DNA mutations A8344G or A8344C, affecting the tRNA lysine, may have infantileonset spastic quadriparesis, myoclonic epilepsy with ragged red fibers and stroke, chronic progressive external ophthalmoplegia, or ataxia with deafness, myopathy, and neuropathy along with axial lipomas (Ekbom’s syndrome). The diagnosis of mitochondrial disorders is difficult to establish. Because of heteroplasmy, the number of mutant mitochondrial genomes may be low, making the mutation difficult to detect. DNA analysis of mitochondrial DNA from muscle may be of higher yield. There is no definitive treatment for mitochondrial disorders. Treatment options may differ depending on the effect of the mutation. Treatment considerations include CoQ10, vitamins A, E, B,, and B,, C, thiamine, and riboflavin.

AUTOSOMAL DOMINANT SCA The autosomal dominant SCAs are a genetically heterogeneous group of neurodegenerative disorders characterized by progressive motor incoordination, often in association with other progressive neurologic deficits. Patients with these conditions typically have an affected parent or can trace the condition in family members in earlier generations. Most affected patients have a similar onset of slowly progressive gait ataxia, dysarthria, and hand incoordination, rarely preceded for several years by symptoms of diplopia or vertigo. Patients may first notice trouble walking down stairs, on uneven terrain, or in the dark, running, or performing other activities requiring greater balance. These subtle changes may be accompanied by occasional slurring of speech. Eventually imbalance and dysarthria are more obvious, and problems with upper limb incoordination and dysphagia develop. Symptoms may be more easily recognized when there are other affected family members.

A. Motor delay, ataxia, and dysarthria in males B. Spasticity

A. Neurogenic muscle weakness, ataxia, and retinitis pigmentosa, optic atrophy B. Migraines

Photomyoclonic epilepsy, deafness

X-linked ataxia with sideroblastic anemia

Neurogenic muscle weakness, ataxia, and retinitis pigmentosa with subacute, optic atrophy (NARP)

Myoclonus epilepsy and ragged red fibers (MERRF)/ Ekbom’s

Infancy-42

2-52

Infancy

Age

tRNA-Lys gene, tRNALeu gene, mitochondrial DNA

Mitochondrial ATPase 6 gene

Mitochondrial iron transporter gene (ABC7)

Protein/Cene/Locus

*Neurologic findings in addition to cerebellar dysacthria, hand and gait incoordination. A, usual; B, frequent

Neurologic Findings.

Disorder

rn TAW 124-2. X-Linked and Maternally Transmitted Ataxia

A83446 mitochondrial tRNA-Lys, A32436 mitochondrial tRNALeu

T 89936, in mitochondrial ATPase 6 gene L156R; T8993C, L156P

1400M missense

Mutations and Alleles

Short stature, cardiomyopathy, ragged red fibers, axial lipornas, diabetes mellitus, hypertension, skeletal deformities

Mild asymptomatic anemia or microcytic anemia

Non-CNS

Maternally inherited Leigh’s, extreme heteroplasmy, necrotizingencephalomyopathy, cognitive impairment, infantile spasms Progressive external ophthalmoplegia, migraine; dementia, lactic acidosis, spastic quadriparesis; arrested mental and motor development

Variants

Increased CSF lactate, sequence analysis of mitochondrial DNA

CBC (Pappenheimer bodies), FEP, bone marrow biopsy (ring sideroblasts) Increased CSF lactate, hypocitrullinemia, sequence analysis of mitochondrial DNA

Diagnosis

e bJ

d

3

i

790

Movement Disorders rn Non-Parkinsonian Movement Disorders

In the past 8 years, the existence of at least 13 genetically and clinically distinct types of autosomal dominant SCA has been confirmed. These rapid developments resulted primarily from improved technology for genetic research, the advances of the human genome project, and the fact that several SCAs are caused by a similar, novel mutational mechanism, the unstable polynucleotide repeat. The characterization of this mutational mechanism has provided important insights into disease pathogenesis and has helped explain certain aspects of clinical presentation. Table 124-3 summarizes the clinical and genetic aspects of the autosomal dominant SCAs. In an effort to improve the classification of these diseases, a nomenclature has been established by the Human Genome Organization. Each form of autosomal dominant spinocerebellar degeneration that is assigned to a unique chromosomal locus by genetic linkage studies is designated by the symbol SCA, followed by a number. SCA1, the first disorder of this type, was isolated in 1994, and the locus for SCA16 was identified in 2001. In five of these the chromosomal locus is known, but the gene has not yet been isolated. In the remaining eight, the responsible mutation is an expansion of an unstable repeated nucleotide sequence in one of several unrelated genes. These genes happen to contain, within their sequence, trinucleotide or pentanucleotide repeats that are polymorphic over a small size range and repeat number. Five of the responsible genes encode a tract of glutamine residues that is expanded in the diseaseassociated alleles, and in the other three, the expanded repeat occurs in a noncoding region. In some cases, particularly with large repeat sizes, the entire neurologic picture appears to vary even within the same family, for example from a purely ataxic syndrome to one of dystonia and rigidity in SCA3. Progressive cerebellar dysfunction leads to great overlap in the clinical and pathologic features of the SCAs. In the earliest stages of disease and in the mildest forms, when extracerebellar signs are not prominent, the SCAs are all similar. As the disease progresses, certain neurologic features may appear that are unique or prevalent in some SCA types. This is often best demonstrated upon examination of other family members in different stages of the disease. SCAlSCA4 and SCA7 generally are more severe conditions, with more extensive involvement of brainstem and motor pathways, often giving rise to shorter lifespan than other forms of autosomal dominant ataxia that have been called pure cerebellar ataxia. The latter conditions, including SCA5, SCA6, SCA8, SCA10, SCA11, SCA13, SCA16, particularly when some associated features such as seizures in SCAlO are not noted, have strong clinical overlap. The worldwide distribution of the genetically diagnosable SCAs is not uniform. Some SCA types extremely common in one world region have not been detected in others. This variability may result from the prevalence within certain ethnic populations or other genetic isolates of premutations (large normal alleles) that more readily give rise to pathologic alleles. Autosomal Dominant Ataxias Caused by Trinucleotide Repeats and Clutamine Tracts

Five of the eight autosomal dominant ataxias whose genes have been identified are caused by an expansion of the trinucleotide repeat CAG within five distinct genes. These repeats encode expanded tracts of glutamine in five distinct and unrelated proteins. This newly discovered mutational mechanism also underlies three additional neurodegenerative disorders-Huntington disease, dentato-rubro-pallido-luysianatrophy, and X-linked

spinobulbar muscular atrophy-indicating its importance in neurologic disease. The genes responsible for these disorders normally contain a repeated sequence that encodes a tract of glutamine residues. The CAG trinucleotide repeat appears to be particularly prone to changes in the repeat number, leading, even in normal genes, to heritable, in-frame expansions and contractions of the polyglutamine tract. For these proteins, variability in the size of the polyglutamine tract over a small range appears to have no clinically significant consequences. However, there is a threshold, different for each disorder, beyond which expansion of the polyglutamine tract leads to neurologic disease. The expanded polyglutamine tract adversely affects protein folding or protein-protein interactions, rendering the mutant protein toxic to some neuronal types. Purkinje cells appear to be particularly vulnerable in this process. In most cases, the toxicity of the mutant protein appears to be unrelated to the original function of the wild type protein but is instead attributed to a newly acquired property that is harmful to nerve cells. The genetic change has been called a toxic gain of function. The cellular basis for this toxicity has not been clarified but appears in many cases to require transport of the mutant protein to the nucleus. The pathologic CAG repeat alleles are prone to expansion (or contraction) during gametogenesis, particularly in the case of SCA1, SCA2, SCA3, and SCA7. A clear inverse correlation exists between age of onset and the length of the CAG repeat allele in SCA1-SCA3, SCA6, and SCA7, implying that longer polyglutamine tracts, encoded by larger CAG repeats, generate more toxic proteins. When children inherit a larger CAG repeat allele from one of their parents than is borne by the affected parent, they usually develop symptoms at an earlier age than did their parent, a phenomenon known as anticipation. The degree of anticipation differs for each SCA type and appears to depend on the stability of the repeat. Anticipation is uncommon in SCA6 and more often seen in SCA1, SCA3, and SCA7. Anticipation in a family may be so dramatic that a child may be diagnosed with what is believed to be a sporadic neurodegenerative disease years before his or her parent or grandparent who has the gene expansion becomes symptomatic. Spinocerebellar Ataxia Type 1

Among patients with SCA, the proportion with SCAl ranges from 3% in Japan (0% in Korea and Portugal) to 40% in Russia and South Africa and is found in about 6% of US.patients with SCA. SCAl typically emerges in the third or fourth decade, but severe forms of childhood- or juvenile-onset SCAl have been documented that are known to be caused by the more severely expanded alleles. The initial symptom is gait unsteadiness, but increasing dysarthria and dysphagia soon follow. The rate of progression in adult-onset SCAl may vary widely, with confinement to wheelchair between 3 and 17 years after onset and death 10 to 30 years after onset. Death often is related to respiratory failure caused by bulbar involvement. Patients with juvenile-onset disease (whose symptoms appear before age 13) have still more severe disease, having more widespread central nervous system involvement and being fatal before age 16. On examination patients typically have hypermetric saccades, nystagmus, brisk deep tendon reflexes, and Babinski signs along with cerebellar signs early stages of disease. Ophthalmoparesis in the form of slowing saccadic velocity, restricted horizontal versions, or upgaze palsy may develop, and nystagmus disappears

Axial myoclonus Pure ataxia, prominent nystagmus, head tremor Episodes of ataxia, +/- vertigo, nausea, migraine headache, confusion; SCA6-like progressive ataxia Dementia, psychosis, myoclonus, postural abnormalities, seizures

Prominent nystagmus, hyperreflexia Action tremor, paucity of movements, hyperreflexia, Babinski's Moderate MR

16-65

Any age

12-42 20-66

1-45

8-55

15-43

10-49

Prion/prp/ 2Opter-pl2

a l A subunit of P/Q type voltage-gated calcium channel/ CACNAlA/19pl3

SCA13/ 19pl3.3-13.4 SCA14/19ql3.4-ter SCA16/8q22.1-24.1

Protein phosphatase 2A(PPP2R2B/ 5q3 1-5q33

SCAl1/15q14-21.3

E46L/SCA10/22ql3

SCA8/13q21

15-66

1-50

a l A subunit of P/Q type voltage-gated calcium channel/ CACNAlA/19pl3 Ataxin-7/SCA7/ 3p21.1-pl2

129V. 129M

Several sequence polyrnorphisms

Episodic weakness

Subacute dementia; fatal insomnia

P102L, P1 OSL, A117V,Y145X, V1 SOV, E200K, M232R

NA NA

NA

Hypotonia, cerebral atrophy, PDA, CHF

Infantile spasms, microcephaly, hypotonia, pigmentary retinopathy, PDA, anemia Severe rigidity

Variants

Splice site, missense mutations

NA NA

NA

NA NA NA

CAC 66-93

NA

AllCT 800-4500

CTA/CTC 101-345

CAG 41-306

CAG 19-33

NA

NA

CAC 56-86

CAC 34-750

CAG 35-83

Mutations and Alleles

CAC 6-29

NA

AllCT 10-29

CTA/CTC 19-80. >350

CAG 7-16

CAG 4-1 8

NA

SCA5/11 q

10-68

19-7 1

NA

CAC 12-43

16q24-ter

Ataxin-3/SCA3/ 14q21

CAC 15-31

26-72

5-65

Normal Alleles

CAC 6-39

Neurologic findings in addition to cerebellar dysarthria, hand and gait incoordination. CHF, congestive heart failure; GI-2, episodic ataxia type 2; FHM, familial herniplegic migraine; NA, not available; PDA, patent dudus arteriosus.

UD/GSS Prion ataxia

EA-UFHM

SCAI 6

SCA14

SCAI 3

SCAI 2

SCAl1

SCAlO

SCAB

sCA7

SCA6

SCA5

sCA4

S W

Diplopia, facial myokymia, dystonia, rigidity, sensory neuropathy Sensory neuropathy, areflexia or pure Slow progression, pure ataxia, minima1 nystagmus, early dysarthria Slow progression, prominent nystagmus, episodic vertigo Macular retinopathy, early color loss and blindness, spasticity, slow saccades Usually pure ataxia, some bizarre eye movements, some cognitive impairment Seizures

Ataxin-Z/SCAZ/ 12q23-24.1

SCA2

16-3 1

Protein/Cene/Locus

Ataxin-l/SCAl/6~23

15-63

Lingual, limb, amyotrophy, early hyper LOSS of saccades, dementia, patchy areflexia

Anticipation

Age

Neurologic Findings.

Disorder

SCAl

TABU 124-5. Dominant Ataxia

No commercial genetic test; linkage to CACNAlA/ 19~13;detection of CACNAlA mutation EEC, CSF 14-1-3-3 protein, brain biOPSY

NA NA

NA

CAG repeats >65 in SCAI 2 gene

AllCT repeats >800 in SCAI 0 gene

CTA/CCC repeats at the SCA8 locus 101-345

CAC repeats >40 in SCA7 gene

the CACNAlA gene

CAC repeats >19 in

SCA3 gene

CAC repeats >55 in

SCAI gene CAC repeats >33 in SCA2 gene

CAC repeats >38 in

Diagnosis

792

Movement Disorders

Non-Parkinsonian Movement Disorders

as the disease progresses. Numerous neurologic signs may be present with advancing disease. There may be mild cognitive impairment, signs of optic nerve atrophy, fasciculations or frank atrophy in the tongue or perioral muscles, diminished voluntary cough, chorea or dystonia, hypotonia, fasciculations or atrophy of the limb muscle, decreased or absent deep tendon reflexes, and loss of proprioception or vibration sense. Computed tomography (CT) and MRI brain scans in SCAl reveal cerebellar and pontine atrophy. In neuropathologic studies there is neuronal cell loss of Purkinje cells, dentate nucleus, the inferior olive, and mild cell loss in cranial nerve nuclei 111, IV, IX, X, and XII. The axons of degenerating Purkinje cells have eosinophilic spheres or “torpedoes.” There is demyelination of several white matter tracts, including the restiform body and brachium conjunctivum, the dorsal and ventral spinocerebellar tracts, and, to a lesser degree, the posterior columns. The differential diagnosis includes all autosomal dominant SCAs. Patients with cerebellar ataxia with prominent fasciculations and atrophy of the tongue should be suspected of having SCA1. SCAl is caused by an expansion in CAG repeat in the SCAl gene on 6p23 that leads to an elongated tract of glutamine residues within the protein ataxin-1. Ataxin-1 is a nuclear protein of unknown function. The altered folding of ataxin-1 caused by the expanded polyQ tract is detrimental to several types of neurons, especially in the cerebellar Purkinje cells and brainstem motor neurons. In transgenic mice expressing this gene, toxicity entails transport of the protein to the nucleus, where it is sequestered into ubiquitinated aggregates that may be a cellular pathway for turnover of abnormal proteins. Similar intranuclear ubiquitinated aggregates are seen in brains in SCA3, SCA7, Huntington’s disease, and DRPLA. The diagnosis of SCAl is established by the demonstration of expansion in one CAG repeat allele in the SCAl locus greater than 38 repeats in a patient with ataxia.

There is marked loss of inferior olivary neurons in the brainstem and marked loss in the substantia nigral neurons. In the spinal cord, marked demyelination in the posterior columns and to a lesser degree in the spinocerebellar tracts is seen. Motor neurons and neurons in Clarke’s column are reduced in size and number, and there is thinning of myelin in anterior and posterior roots. In some cases the cerebral cortex is thinned, and the white matter is atrophic and gliotic, particularly in the frontal and temporal lobes. The differential diagnosis includes all other autosomal dominant cerebellar ataxias. The saccadic abnormalities in SCA2 resemble those of AT, normally an infantile onset, recessively inherited ataxia. They are also seen in SCA7, a condition associated with visual impairment. The combination of extremely slow or absent saccades with segmental or complete areflexia but normal color vision in one or more family members with autosomal dominant ataxia strongly suggests the diagnosis of SCA2. SCA2 is caused by an expansion in CAG repeat in the SCA2 gene on 12q23-24.1 that leads to an elongated tract of glutamine residues within a novel protein, ataxin-2. Like that of the affected proteins in SCA1, SCA3, and SCA7, the function of ataxin-2 is also unknown, but unlike the other known ataxia-associated proteins in SCAl, SCA3, and SCA7, ataxin-2 is predominantly a cytoplasmic protein. Transgenic mice overexpressing mutant ataxia-2 become ataxic, but there is no Purkinje cell loss. Unlike ataxin-1, toxicity of ataxin-2 does not entail transport into the nucleus. The diagnosis of SCM is established by the demonstration of an expansion in one CAG repeat allele in the SCA2 locus greater than or equal to 34 repeats in a patient with ataxia.

SpinocerebellarAtaxia Type 2

SCA3, or Machado-Joseph disease, is the most common recognized form of SCA in most populations. The proportion of patients with SCA3 ranges from 7% in India (0% in South Africa and Italy) to 74% in Portugal, and it is found in about 21% of U.S. patients with SCA. The age of onset of SCA3 usually is the second to the fourth decade. There are also reports of rare childhoodonset variants with severe disease, as well as variants with rigidity. Initial symptoms usually are unsteadiness or stiffness of gait, clumsiness, and slurred speech, but a significant proportion of patients develop diplopia before any gait difficulty. Typically the disease is slowly progressive, leading to the need for assistive devices including a wheelchair 10 to 15 years after onset. Death results from pulmonary complications and cachexia 6 to 29 years after onset. Neurologic examination depends on the stage of the disease. There are variants of SCA3, caused in part by larger expanded alleles. Patients with the more cerebellar form of the disease may show ataxic gait and limb movements, gaze-evoked nystagmus, saccadic visual pursuits, and dysarthria. In more advanced disease other neurologic findings appear, including restricted upgaze, disconjugate eye movements, often a staring appearance to the eyes, or total ophthalmoplegia, temporal and facial atrophy, characteristic action-induced perioral twitches, lingual atrophy and fasciculations, dysphagia, and reduced cough, loss of distal sensation, and hyperreflexia combined with distal areflexia. Some family members may manifest a substantially different neurologic picture, with prominent parkinsonism or dystonia combined with rigidity or peripheral neuropathy.

The proportion of patients with SCA2 ranges from 4% in Portugal (0% in Russia) to 47% in Italy and is 15% for U.S. patients with SCA. The mean age of onset of SCA2 is in the fourth decade but progression is more rapid when onset occurs before age 20. A form of infantile-onset SCA2 has been recognized, associated with extreme expansions of SCAZ alleles, in which children have infantile spasms, severe hypotonia, pigmentary retinopathy, dysphagia, and failure to thrive and usually die before 2 years of age. In adult-onset SCA2 confinement to wheelchair may occur 10 to 20 years after onset, and death may occur 10 to 30 years after onset. Death may be caused by respiratory or autonomic failure. SCAZ is characterized by slowly progressive ataxia, sometimes with leg stiffness or painful leg muscle cramps at night. Mild dementia has been reported, which appears to be predominantly an impairment of executive functions. Examination may reveal very mild dysarthria; slowed, hypometric, or absent saccades; supranuclear ophthalmoplegia; fasciculations in the face and tongue; dystonia and chorea; and segmental or total loss of reflexes. As with SCA1, MFU brain scans reveal cerebellar and pontine atrophy. In neuropathologic studies of the cerebellum, findings are similar to those of SCA1. Purkinje cells are severely reduced in number. In the remaining Purkinje cells, dendritic branching is reduced, and torpedo-like formations are present in axons. Granule cells also are reduced in number, whereas Golgi and basket cell neurons and deep cerebellar neurons are well preserved.

Spinocerebellar Ataxia Type 3, or Machado-Joseph Disease

Chapter 124 rn Spinocerebeliar Ataxias

Brain imaging reveals pontocerebellar atrophy in most cases, but the cerebellar cortex sometimes is remarkably preserved in cases of the dystonic form of the disease. Nerve conduction studies often reveal reduced amplitude of sensory and motor nerve action potentials and evidence of denervation. Neuropathologic studies demonstrate that cerebellar Purkinje cells and inferior olivary neurons are more spared than the other dominantly inherited ataxias. Typically there is prominent loss of pontine neurons, neurons of the substantia nigra, anterior horn cells, and Clarke’s column in the spinal cord, as well as neurons in many cranial motor nuclei. The vestibular nucleus often is prominently involved. The differential diagnosis includes all other autosomal dominant cerebellar ataxias. The presence of cerebellar ataxia in one family member and dystonic-rigid condition in another firstdegree relative strongly suggests a diagnosis of SCA3. As with SCA1, the CAG repeat expansion in SCA3 occurs in a novel gene on 14q21 that leads to an elongated tract of glutamine residues within a novel, nucleocytoplasmic protein, ataxin-3. Mutant ataxin-3 proteins form intranuclear ubiquitinated aggregates in neurons in SCA3 brain. The diagnosis of SCA3 is established by the demonstration of an expansion in one CAG repeat allele in the SCA3 locus greater than 55 repeats in a patient with ataxia. SpinocerebellarAtaxia Type 6 and I t s Allellc Disorders

The proportion of patients with SCA6 ranges from 2% in Italy (0% in China, Portugal, and Brazil) to 31% in Japan, and it is found in about 15% of U.S. patients with SCA. The age of onset ranges from 19 to 71 years, with a mean age of onset in the fifth decade. Age of onset may vary between siblings with the same mutation by as much as 12 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance in about 90% of cases. The remainder of patients present with dysarthria. Symptoms progress slowly, and eventually all patients have gait ataxia, upper limb incoordination, intention tremor, and dysarthria. Patients with SCA6 occasionally manifest episodic ataxia or episodic vertigo. Diplopia occurs in about 50% of patients. Others experience visual disturbances related to difficulty fixating on moving objects. Dysphagia and choking are common. Lifespan is not shortened. Neurologic examination in SCA6 reveals frequent gaze-evoked horizontal and vertical nystagmus. All patients develop dysarthria, hand incoordination, and gait ataxia. Hyperreflexia and extensor plantar responses occur in up to half of patients. Patients with SCA6 do not have sensory complaints, restless legs, stiffness, migraine, primary visual disturbances, or muscle atrophy. MRI brain scans in SCA6 show essentially pure cerebellar atrophy. Nerve conduction studies are not revealing. Neuropathologic studies show striking loss of cerebellar Purkinje cells with preservation of other neuronal regions. The differential diagnosis includes all other autosomal dominant cerebellar ataxias. Of the other SCAs, SCA6 most closely resembles SCA5, SCA8, and SCAll and the Japanese kindreds linked to the SCA4 locus, although nystagmus may be prominent in only some of these conditions. The presence of slowly progressive ataxia with prominent gaze-evoked horizontal and vertical nystagmus and a straightforward autosomal dominant inheritance pattern strongly suggests SCA6. Episodic ataxia type 2 (EA-2) is a dominantly inherited condition characterized by bouts of ataxia, dysarthria, vertigo, and

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nausea, sometimes accompanied by migraine-like headache, confusion, and muscle weakness, lasting minutes to hours. Emotional stress, fatigue, exercise, and certain foods often precipitate spells. In addition to the ataxia there may be severe nystagmus during attacks. Between bouts of ataxia there may be gaze-evoked nystagmus and a milder degree of ataxia that increases over the years, coming to resemble that of SCA6. The condition is inherited in a autosomal dominant pattern. MRI often shows cerebellar atrophy, as in SCA6. This condition is to be distinguished from episodic ataxia type 1 (caused by mutations in a potassium channel), in which bouts of ataxia last seconds to minutes and completely resolve. The bouts of ataxia, particularly in EA-2, are prevented by administration of acetazolamide (500 to 1000 mg/day) or valproate (500 to 1500 mg/day), although it is not known whether the progression of the ataxia is slowed. Familial hemiplegic migraine (FHM) is a dominantly inherited condition of intermittent migraines in which at least some of the family members have transient hemiparesis or hemibody numbness as aura of migraine accompaniment. These patients may sometimes note some unsteadiness during attacks and with time may also have interictal ataxia and cerebellar atrophy on MRI. Standard migraine therapies, especially valproate, are successful in managing the migraines, but it is likely that progressive ataxia continues. SCA6 is caused by an expansion in a CAG repeat in the gene CACNAlA on 19~13.1,previously recognized to encode the a l A subunit, the main pore-forming subunit for the P/Q type voltage-gated calcium channel. The CAG repeat is in the extreme 3’ region, encoding a polyglutamine tract in the C terminus. These channels are highly expressed in cerebellar Purkinje cells. There is some evidence that this change in structure of the C terminus alters the function of the P/Q type channels, causing them to open more readily and remain open longer and favoring overload of Purkinje cells with calcium. The diagnosis of SCA6 is established by the demonstration of an expansion in one CAG repeat allele in the SCA6 locus greater than 19 repeats in a patient with ataxia. EA-2 and FHM are allelic disorders of the SCA6 that are associated with several CACNAlA point mutations, predicting truncation or amino acid substitution of the ala subunit. The diagnoses of FHM and EA-2 are difficult to establish because genetic testing is not available for the various mutations. Spinocerebellar Ataxla Type 7

SCA7 is a rare form of SCA in all populations. The proportion of patients with SCA7 ranges from 0.5% in Germany and Russia (0% in Portugal, Korea, India, and China) to 16% in some regions in Spain, and it is found in about 4.5% of U.S. patients with SCA. The age of onset of the symptoms ranges widely, from infancy to the fifth or sixth decade. As with SCA1, SCA2, and SCA3, the very early-onset forms are much more severe and rapidly progressive. SCA7 is characterized by abnormalities in color vision and central visual acuity, because of a macular pigmentary degeneration, and in adults visual symptoms often precede the cerebellar symptoms or are detectable upon development of imbalance. Typical cerebellar signs of gait unsteadiness, incoordination, and dysarthria develop soon afterward and progress to a bedridden state. Rate of progression depends on age of onset. In the infantile-onset form there is rapidly progressive cerebellar and brainstem degeneration, and visual loss may be difficult to ascertain before death. Otherwise, retinal degeneration is progressive and leads to blindness. When visual symptoms appear at or before adolescence,

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blindness can occur within a few years. Ataxia progresses to wheelchair confinement in 5 to 10 years. On examination, initial visual findings may be subtle and detectable only using tests of color vision. Funduscopy may show subtle granular changes in the macula. With more advanced disease, central visual acuity may diminish to the 20/200 range, color discrimination is lost, and there are more prominent pigmentary macular changes. With onset of near total blindness the pigmentary retinopathy is advanced but still has a macular pattern. Saccades are markedly slowed or entirely absent. In blind patients this is evident using the patient’s hand as a psychic target or by electronystagmography. Hyperreflexia and spasticity are evident early in the disease, as are extensor plantar responses. Patients have an ataxic gait and dysarthric speech with some component of spasticity. MRI imaging in SCA7 has shown cerebellar atrophy without brainstem involvement. Electroretinograms initially show a decrease in the photopic (cone) response, followed by a decrease in the scotopic (rod) response. The retinal degenerative component distinguishes this hereditary ataxia from other forms of SCA. In cases of extreme expansion of the SCA2 gene, pigmentary retinal degeneration can also develop. Recessive ataxias such as posterior column and retinitis pigmentosa, abetalipoproteinemia and AVED, mitochondrial encephalopathies such as NARF’, and Leber’s hereditary optic neuropathy can present with ataxia and, in some cases, with a concomitant visual degeneration. Aside from the retinal involvement, there is clinical and pathologic overlap between SCA7 and other SCAs. Although the loss of saccades is similar to that of SCA2, the hyperreflexia and spasticity in the same patient may distinguish this condition from SCA2, where reflexes are diminished. Infantile- and childhood-onset SCA7 may be confused with lipid storage diseases, such as ceroid lipofuscinoses, except the hereditary pattern is autosomal dominant. These conditions can be distinguished by DNA or other laboratory tests. Like SCAl and SCA3, SCA7 is caused by a CAG repeat expansion a novel gene on 3p21.1 and leads to an elongated tract of glutamine residues within a novel protein, ataxin-7. Mutant ataxin-7 proteins also form intranuclear ubiquitinated aggregates in neurons in SCA7 brain. The diagnosis of SCA7 is established by the demonstration of an expansion in one CAG repeat allele in the SCA7 locus greater than 36 repeats in a patient with ataxia. Autosomal Dominant Ataxias Caused by Noncoding Nucleotide Repeats

Three types of autosomal dominant SCA are caused by trinucleotide or pentanucleotide repeat expansions in noncoding regions of genes. As in the polyglutamine disorders, the repeated sequences are polymorphic in the normal genes; that is, they have a range of normal allele sizes. Disease results when these repeats become expanded to a pathologic size range. The molecular and cellular basis for the dominant pathologic effect of changes in gene structure that do not alter protein sequence and for the progressive cerebellar degeneration and ataxia is unknown. Spinocerebellar Ataxia Type 8

SCA8 originally was described in association with a single large kindred of individuals with adult-onset SCA having a dominant inheritance pattern with incomplete penetrance. In the original study there was clear distinction between normal and pathologic

alleles in a single family. However, there were numerous intermediate alleles of uncertain significance in multiple small families and in sporadic cases. Subsequent studies have reinforced the concept that such alleles should not be considered pathogenic and that the diagnosis of SCA should be confined to a narrower range of pathologic alleles (Table 124-3). Patients with pathologic alleles have a characteristic presentation. Symptoms first appear between ages 18 and 65, with a mean of 39 years. Initial symptoms consist of gait ataxia, dysarthria, and dysphagia. Findings on examination include spastic and ataxic dysarthria, gaze-evoked nystagmus, limb and gait ataxia, limb spasticity, and diminished vibratory sensation. Progression generally is fairly slow, but severely affected family members become confined to wheelchair by the fourth or fifth decade. MRI and CT brain scans show cerebellar atrophy. There are no pathologic studies to date. SCA8 is associated with an expansion of a polymorphic CTA/CTG repeat in the 3’ untranslated region of a gene located at 13q21. The gene, called kelch-related protein because of homology to the Drosophila protein, kelch, consists of either three or four exons. The length of the repeat present in the general population is 16 to 37 repeats in 99% of alleles. The repeat length that is likely to result in disease ranges from 107 to 127 CTG repeats. The diagnosis of SCA8 is suggested by the demonstration of expansion in one CTG repeat allele in the SCA8 locus greater than 106 repeats and less than approximately 300 repeats in a patient with ataxia. Spinocerebellar Ataxia Type 10

SCAlO is a form of autosomal dominant cerebellar ataxia that was recently described in several kindreds of Mexican origin. The age of onset ranges from 10 to 49 years. Initial symptoms of the disease are gait unsteadiness, clumsiness, and dysarthria. In a significant number of patients generalized motor seizures develop within a few years after onset of the ataxia. Some patients have low IQ. Findings on examination include nystagmus, dysarthria, gait and limb ataxia, and nystagmus, with normal reflexes and motor function. Seizures respond to anticonvulsants. MRI brain scans demonstrate cerebellar atrophy. There have been no pathologic studies to date. SCAlO is caused by expansion of a pentanucleotide (ATTCT) repeat in intron 9 of a novel gene on chromosome 22q13 of unknown function. Normal ATTCT repeats range from 10 to 22 ATTCT units. The expansions of the ATTCT repeat, which have not been accurately sized, are massive, up to 22.5 kb longer than the normal alleles. The SCAlO gene consists of 12 exons that span 173 kb of genomic DNA. The open reading frame encodes a 475-amino acid protein that is 82% identical to the mouse ortholog. The diagnosis of SCAlO is established by the demonstration of expansion in one ATTCT repeat allele in the SCAlO locus greater than 800 repeats in a patient with ataxia. Patients with intermediate expansions of 30 to 799 repeats would also be candidates for a possible diagnosis of SCA10, and a more detailed examination of the kindred would be appropriate. Spinocerebellar Ataxia Type 12

SCA12 has been described in two families, one American and one East Indian. If the common presenting symptom of action tremor is referenced, the age of onset is broad, ranging from 8 to 55 years, with a mean of 34 years. The initial symptom is tremor in nearly all cases. The clinical features are variable, especially the degree of cerebellar dysfunction. Findings on examination include occa-

Chapter 124

sional cognitive impairment, gaze-evoked nystagmus, action, postural, or kinetic tremor of the head or arms, bradykinetic limb movement, paucity of spontaneous movement, rare focal dystonia, mild to moderate gait and limb ataxia, and mild dysarthria, hyperreflexia, and Babinski signs. CT scanning and MRI show cerebellar and cerebral atrophy. The electroencephalogram and electromyogram with nerve conduction studies are normal. SCA12 is caused by expansions of a CAG repeat tract that lies 133 nucleotides upstream of the reported transcription start site of the PPP2FUB gene at 5q31333. This gene encodes a brain-specific regulatory subunit of the protein phosphatase PP2A. Normal CAG repeat alleles have 7 to 28 repeats. Pathologic alleles have 55 to 78 CAG repeats. The diagnosis of SCAl2 is established by the demonstration of expansion in one CAG repeat allele in the SCA12 locus greater than 55 repeats in a patient with ataxia. Intermediate expansions of 29 to 54 repeats are also candidates for disease alleles, but more detailed examination of the kindred is needed.

Autosomal Dominant Ataxias with a Defined Genetic Locus Genetic linkage studies have confirmed the existence of at least five other forms of autosomal dominant ataxia and have localized the responsible genes to intervals of 3 and 10 cM. Newly diagnosed patients with dominant SCA and negative gene tests may represent new kindreds with these less well-characterized ataxias. The differential diagnosis includes all other autosomal dominant cerebellar ataxias. The genes for each of these dominant ataxias are tightly linked to small chromosomal regions between defined microsatellitemarkers (Table 124-3). Until the genes are identified, the diagnosis of these disorders can only be suspected by demonstration of genetic linkage using these markers. The designations for SCA9 and SCA15 have been reserved. Clinical features for these subtypes have not yet been reported.

Spinocerebellar Ataxia v p e4 SCA4 was originally described in a single large Utah family whose disease was mapped genetically to a locus of 16q22.1. The age at onset of disease ranges from 19 to 59 years (mean 39 years), but it usually appears in the fourth or fifth decade. Patients initially develop gait unsteadiness, followed by difficulty with fine motor tasks and often dysarthria. The condition is slowly progressive over decades, typically leading to wheelchair dependence. Patients often admit to sensory loss or paresthesias. However, there is wide variability in the severity of disease among family members, and some patients develop foot deformities and severe bulbar symptoms. Examination shows prominent distal sensory loss for multiple modalities, at times encompassing the entire limbs, and partial or complete areflexia. Loss of ankle jerks is an early finding. Sensory nerve amplitudes are diminished or absent. Recently, six Japanese families with autosomal dominant cerebellar ataxia were identified whose disease was genetically linked to the same chromosomal region, 16q22.1. In these the age of onset ranged from 45 to 72 years (mean 55.9 years), with gait ataxia and dysarthria as initial symptoms. Findings on examination were gait and limb ataxia and horizontal gaze nystagmus. Sensation was normal in all subjects except for one 85-year-old patient. Tendon reflexes were mostly normal, except that some subjects (16.6%) had slightly decreased ankle jerks. In further contrast to the Utah patients, sensory and motor nerve conduction

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studies were normal in these patients. MRI of the brain in both groups shows cerebellar atrophy without obvious brainstem involvement. The gene for SCA4 has been genetically mapped to 16q22.1. Isolation of the SCA4 gene will be necessary to confirm that these two conditions are allelic disorders.

Spinocerebellar Ataxia Types 5,11, and 16 SCA5 was originally described in an American family of AngloSaxon origin descending from the grandparents of President Abraham Lincoln. The genetic locus was assigned to chromosome 11. Subsequently, a second SCA family of French origin was identified with a similar clinical presentation in which the responsible gene is located in the same region. Initial symptoms consist of slowly progressive gait unsteadiness and dysarthria. The age of onset was 10 to 68 years, usually in the third decade. The ataxia is very slowly progressive, and some patients remain ambulatory for more than 10 years. Examination shows evidence of a pancerebellar syndrome with intact or increased reflexes, normal plantar reflexes, and normal sensory examination. Facial myokymia is a prominent feature among the French kindred. Nystagmus is less prominent than in SCA6 or SCA8. MRI shows a marked global cerebellar atrophy with sparing of the brainstem. The gene for SCA5 has been genetically mapped to 1l p l l - q l l . SCAl1, which has been described in one British family, has a similar age of onset (15 to 43 years, mean 25 years) and clinical picture to those of SCA5, consisting of a slowly progressive cerebellar syndrome without clinical evidence of involvement of other brainstem pyramidal or extrapyramidal regions. Nearly all patients are ambulatory, with a mean disease duration of 24 years. SCAll does not appear to shorten lifespan. All people in the kindred continue to be ambulatory, with a mean disease duration of 23.9 f 13.4 years. Examination demonstrates dysarthria, limb and gait incoordination, nystagmus, and mild hyperreflexia with normal plantar reflexes. Brain imaging shows isolated cerebellar atrophy. The gene for SCAll has been genetically mapped to a 7.6-cM interval 15qlPq21.3. SCA16 has been described in one Japanese kindred. Patients in this family develop slowly progressive gait unsteadiness and dysarthria beginning between ages 20 and 66. Examination reveals cerebellar signs including truncal and limb ataxia, scanning dysarthria, and horizontal gaze-evoked nystagmus and impaired visual pursuit. MRI scans show pure cerebellar atrophy. The gene for SCA16 has been genetically mapped to a 37.6-cM interval 8q22.1424.1.

Spinocerebellar Ataxia Types 13 and 14 SCA13 and SCA14 were described in two kindreds whose disease maps genetically to two adjacent loci on chromosome 19. SCA13 was described in a single four-generation French kindred with autosomal dominant cerebellar ataxia. The disease in this family has onset in childhood, often in the first year of life. Initial symptoms are clumsiness and dysarthria, along with evidence of cognitive slowing. Examination demonstrates cerebellar signs, nystagmus, and pyramidal signs in some. Neuropsychiatric testing reveals moderate mental retardation (IQ, 62 to 76), and mild developmental delay in motor acquisition. MR brain imaging shows moderate cerebellar and pontine atrophy. The gene for SCA13 has been genetically mapped to an 8-cM interval chromosome 19q13.3.

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SCA14, described in a single four-generation Japanese kindred, has a distinct clinical picture from that of SCA13. The age of onset ranges from 3 to 42 years. Initial symptoms are gait ataxia in many cases. However, in several patients with an earlier onset initial signs include an irregular tremulousness of the neck and axial musculature, described as intermittent axial myoclonus, followed soon afterward by mild ataxia. Disease progression usually is slow. Other findings on examination included gaze-evoked nystagmus, saccadic visual pursuits, upper and lower limb ataxia, dysarthria, and reduced Achilles reflexes. Neuroimaging studies reveal cerebellar atrophy. The gene for SCA14 has been genetically mapped to a 10.2-cM interval 19q13.4-qter, surprisingly near the region defined for SCA13.

SPORADIC ATAXIA About half of patients with SCA do not appear to suffer from a form of familial SCA (Table 124-4). Nevertheless, some of these patients may actually have an unsuspected form of hereditary ataxia. Five to eight percent of patients with sporadic ataxia are found to have GAA expansions in the frataxin-1 gene and have a variant of FRDA. An additional 2% to 11% of patients with

TMU 124-4. Approach for Patients with Ataxia and No Known Family History Routine studies Metabolic panel (diabetes, liver disease, renal disease) CBC differential (pernicious anemia, sideroblastic anemia) TFT (hypothyroidism) VDRL (syphilis) Lyme serology (Lyme disease) Erythrocyte sedimentation rate Vitamin E, vitamin B,, vitamin B,2, nicotinamide Brain and spine MRI (cerebellar atrophy, demyelinating disease, posterior fossa mass) Alcohol history Immune ataxias Serum antibodies to voltage-gated calcium channels, glutamic acid decarboxylase, glutamate receptors, and the Purkinje cell autoantibodies anti-Yo, anti-Ri, anti-Ti, and anti-Hu Serum antigliadin antibodies Cryptic hereditary ataxias Dominant SCAl-SCA3, SCAC-SCAB, SCAlO gene tests for dominant ataxias (commercially available) SCAI 2, SCAI 5 (research) Mutations in PRP gene P102L, P1OSL, A1 17V, Y 145X, V1 SOV, E200K, M232R (Gerstmann-Straussler disease) Recessive Frataxin-1 (GAA)n repeat gene test, FRDA genetic screen for frataxin mutations Quantitative immunoglobulins, a-fetoprotein, chromosome breakage study, X-ray sensitivity, ATM mutations (research); blood studies to exclude ataxia telangiectasia Vitamin E level, lipoprotein electrophoresis (AVED/ abetalipoproteinemia) Hexosaminidase A assay with sulfated substrate (atypical hexosaminidase A deficiency) Muscle biopsy for CoQlO (muscle CoQlO deficiency) Sacsin mutations (research) (ARSACS) Very long chain fatty acids (Refsum’s disease) X-linked CBC, differential for sideroblasts @-linked sideroblastic anemia with ataxia) Very long chain fatty acids (adrenomyeloneuropathy) Mitochondria1 Fasting and 2-hour postprandial plasma glucose, pyruvate, and lactate CSF lactate Mitochondria DNA mutations 18993, A8244 Prion-associated ataxias CSF 14-1-3-3 orotein (sooradic or hereditaw orion-associated ataxia9

apparently sporadic ataxia have a form of SCA for which a genetic test is available, such as SCA1. In the case of recessive conditions, for which a single occurrence of the disease is not unusual, the diagnosis of FRDA may not be suspected on clinical grounds because of some atypical features. These patients are important to identify, particularly because of the unique complications for which they are at risk and because they are candidates for emerging therapies for FRDA. In the case of autosomal dominant conditions, the diagnosis may not be suspected because the affected parent is unknown, dies before disease onset, has a milder condition or later age of onset than the patient, or bears only a premutation, or for other reasons the disease has reduced penetrance. These patients are important to recognize for similar reasons as well as for potential issues of family genetic counseling. Finally, other cases may represent mitochondrial disorders that are difficult to diagnose. Therefore, in the absence of a family history, genetic screening for the available genetic ataxias is appropriate if no other cause is demonstrable because up to 20% may be hereditary. If patients with unsuspected hereditary ataxia are discounted, about one third of patients with progressive ataxia have a truly sporadic form of the disease. These patients do not have a clinically recognizable, recessively inherited form, such as AT or FRDA, and have no family history of ataxia or neurologic disease that could have been an undiagnosed case of ataxia. Genetic testing is negative for the current genetically characterized forms, such as SCA1-SCA3, SCA6-SCA8, and FRDA. These conditions, called sporadic SCA, are the most challenging group of ataxias from a diagnostic, prognostic, and management standpoint. On one hand, the emphasis on genetic testing has caused frustration among these patients and physicians because of a lack of a definitive genetic diagnosis. Although the genetic advances have yet to impact the treatment of ataxia, patients with the diagnosis of sporadic ataxia will not have the benefit of genetic counseling or of an accumulating experience on the natural history and prognosis of the disease. On the other hand, the insights gained from genetic studies of SCA, particularly of SCA8, have shown that variable penetrance can obscure the presence of a hereditary condition. Thus, there remains the lingering concern that a given patient with sporadic ataxia may have an unrecognized hereditary ataxia. Patients with sporadic ataxia usually have one of two clinical presentations. Onset of sporadic ataxia typically occurs in the sixth decade but may occur over a wide age range. Approximately two thirds of these patients develop a condition characterized by cerebellar ataxia alone (i.e., with little or no involvement of other regions of the nervous system). These patients have a more slowly progressive form, may remain ambulatory for well beyond 5 years, and do not have a shortened lifespan. Neurologic examination, which may resemble that of patients with SCA6, reveals essentially cerebellar signs of dysarthria, truncal ataxia, and hand incoordination, often with nystagmus and brisk deep tendon reflexes. Occasionally vibratory sense is reduced and ankle reflexes are absent. The remaining approximately one third of patients with sporadic ataxia develop a form of multiple-system atrophy, characterized by ataxia associated with a combination of dementia, ophthalmoplegia, bulbar findings, tremor, bradykinesia or rigidity, autonomic dysfunction, or other neurologic abnormalities. These patients often have a more aggressive course leading to confinement to wheelchair by 5 years and in which frequent aspiration, reduced respiratory drive, or urinary retention leads to premature death by respiratory failure or sepsis. Neurologic examination, which resembles that of patients with SCAl, SCA2,

Chapter 124

or SCA3, may reveal slowed saccades and restricted ocular versions or nystagmus, spastic dysarthria, dysphonia, bradykinesia, resting or postural tremor, rigidity, spasticity, extensor plantar responses, and, rarely, amyotrophy. Brain imaging in sporadic ataxia shows cerebellar atrophy in nearly all cases at the time of presentation. Those with the ataxic form of multiple-system atrophy may simultaneously have generalized cerebral atrophy or may develop prominent atrophy of the pons, particularly the basis pontis with time. Conditions that may present as a form of sporadic SCA include Creutzfeldt-Jakob disease (CJD),subacute cerebellar degeneration, hypothyroidism, vitamin deficiency, chronic ethanol abuse, or a mitochondrial disorder. Sporadic ataxia has been associated with several different autoantibodies, although this finding is more typical of subacute cerebellar degeneration. Nevertheless, the majority of patients with sporadic ataxia have a truly idiopathic condition. After excluding a role for medical causes of ataxia in a given patient, such as diabetic polyneuropathy, hypothyroidism, or vitamin deficiency, consideration should be given to rare, but potentially identifiable conditions. Included among these are ataxia associated with antibodies and ataxic variants of prion disease.

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the disorder is transmissible through certain treatments such as corneal transplants. Although ataxia often is a prominent feature of CJD, such patients usually have multiple other neurologic findings (pyramidal or extrapyramidal signs, myoclonus, akinetic mutism) and typical electroencephalographic changes (periodic sharp waves) that allow recognition of this condition. T2- or diffusion-weighted MR images in these cases may demonstrate multiple scattered cortical and deep gray matter hyperintensities. There may be generalized cortical atrophy but usually no cerebellar atrophy. There is also an ataxic variant of the disease more common among iatrogenic CJD and the autosomal dominant forms (Gerstman-Straussler-Schenkerdisease). In the ataxic variant other neurologic findings are present, but ataxia is the most prominent feature. Cerebellar atrophy has been documented in some of these patients. The electroencephalogram may not show the typical changes. The finding of an increase in the neuronal proteins, 14-3-3 protein and neuron-specific enolase, in cerebrospinal fluid supports the diagnosis but is a nonspecific finding. Hereditary CJD is associated with certain alleles of the prion protein gene (PrP), particularly with variations at codons 102,117, 129 (methionine or valine), and 178. The various forms of CJD progress more rapidly than the SCAs and are uniformly fatal. No treatments exist €or these conditions.

Antibody-AssociatedAtaxias

Ataxia associated with autoantibodies is more commonly manifested in the syndrome of subacute cerebellar degeneration associated with malignancy (see Chapter 178). However, in the early stages the presentations of these conditions may be similar. Autoantibodies to several antigens found in cerebellar Purkinje cells have been found in sera of patients with ataxia. Antibodies to voltage-gated calcium channels, glutamic acid decarboxylase (GAD), and glutamate receptors, as well as the Purkinje cell autoantibodies called anti-Yo, anti-Ri, and anti-Ti are associated with ataxia, usually in association with malignancies such as small lung carcinoma, adenocarcinoma of the breast or ovary, or Hodgkin’s disease. Rarely, these antibodies, particularly in the case of anti-GAD, may be found in sera of patients with progressive ataxia. The presentation of ataxia in association with these antibodies in an otherwise healthy patient should prompt an extensive workup for occult malignancy. Except in the case of anti-GAD antibodies and anti-VGCC antibodies, there is no evidence demonstrating that autoantibodies have a role in the pathogenesis of ataxia. Some of these antibodies may be markers of another autoimmune process or merely an indicator of cerebellar damage. Plasmapheresis has not had any convincing benefit in these conditions. Antibodies to gliadin (the protein in gluten), as found in celiac sprue, have been detected in sera of patients with ataxia. Patients with ataxia may have a history of gastrointestinal symptoms or may have simply an abnormal jejunal biopsy. The ataxia is said to be unrelated to vitamin malabsorption. These patients are important to recognize because there is some evidence that ataxia may improve with dietary restriction of gluten. No distinguishing clinical features are found in the antibody-associated ataxias. Prion-AssociatedAtaxia

CJD and its variants are spongiform encephalopathies caused by accumulation of proteinaceous particles called prions, typically manifesting as rapidly progressive dementia (see Chapter 79). There are both autosomal dominant and sporadic variants, and

MANAGEMENT OF PROGRESSIVE ATAXIA There are no definitive therapies that delay or halt the progression of the disease. The focus in care for these patients is on optimizing their ability to compensate for and cope with a chronic progressive neurologic condition and on managing symptoms and complications. This is accomplished through the proper referrals for physical and occupational therapy and by encouraging exercise and psychological counseling. Canes and walkers help prevent patients from falling. Early use of a cane may avoid psychological stigma and may prevent confusion with alcohol intoxication. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs often is helpful. Prophylactic eye care, including use of sunglasses and limitation of ultraviolet exposure, should be encouraged to limit extraneous damage to the retina in the case of SCA7. Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria. Weighted eating utensils and dressing hooks help maintain a sense of independence. Weight control is important because obesity can exacerbate difficulties with ambulation and mobility. When dysphagia becomes troublesome, video esophagrams can identify maneuvers and the consistencies of food least likely to trigger aspiration. Tremor-controlling drugs do not work well for cerebellar tremors, but these patients may also develop postural or resting tremors that are amenable to conventional symptomatic therapy. Drugs used in Parkinson’s disease, such as amantadine and levodopa, may be of benefit when extrapyramidal signs such as bradykinesia and rigidity are present. Spasticity responds to baclofen. Drooling may be managed by anticholinergic medications aided by a suction apparatus. Seizures, for example in SCA10, respond to anticonvulsants. Axial myoclonus, as occurs in SCA13, responds to diazepam or valproate. Vertigo and oscillopsia may respond to vestibular suppressant medications, such as antihistamines or Lioresal. Vitamin supplements are recommended, particularly if caloric intake is reduced. Because of toxic effects may be additive, patients should avoid alcohol.

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SUGGESTED READINGS Allikmets R, Raskind WH, Hutchinson A et al: Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 8(5):743-749, 1999

Delatycki MB, Williamson R, Forrest SM: Friedreich ataxia: an overview. J Med Genet 37( 1):l-8, 2000 De Vivo D C The expanding clinical spectrum of mitochondrial diseases. Brain Dev lS(1):l-22, 1993 Federico A, Palmeri S, Malandrini A et al: The clinical aspects of adult hexosaminidase deficiencies. Dev Neurosci 13(4-5):280-287, 1991

Geneclinics: Hereditary Ataxia Overview http://www.geneclinics.org/profiles/ataxias/details.htm~ Gomez CM: Inherited ataxia. In Johnson RT (ed): Current Therapy and Neurologic Disease. WB Saunders, Philadelphia, 2001 Handbook of ataxia disorders. In Klockgether T (ed): Neurological Disease and Therapy. Vol. 50. Marcel Dekker, New York, 2000 Harding AE: The hereditary ataxias and related disorders. In Clinical Neurology and Neurosurgery Monographs. Vol. 6. Churchill Livingstone, New York, 1984 Higgins JJ,Morton DH, Loveless JM: Posterior column ataxia with retinitis pigmentosa (AXPC1) maps to chromosome lq3 1 4 3 2 . Neurology 52( 1):146-150, 1999

Klockgether T, Wullner U,Spauschus A, Evert B: The molecular biology of the autosomal-dominant cerebellar ataxias. Mov Disord 15(4):604612, 2000

Musumeci 0, Naini A, Slonim AE et al: Familial cerebellar ataxia with muscle coenzyme QlO deficiency. Neurology 56(7):849-855, 2001 Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim/ Ouahchi K, Arita M, Kayden H et ak Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9(2):141-145, 1995 Poser S, Zerr I, Schroeter A et al: Clinical and differential diagnosis of Creutzfeldt-Jakobdisease. Arch Virol Suppl 16:153-159, 2000 Puccio H, Koenig M: Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum Mol Genet 9(6):887-892, 2000 Richter A, Morgan K, Bouchard JP et al: Clinical and molecular genetic studies on autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Adv Neurol61:97-103, 1993 Sharp D, Blinderman L, Combs KA et al: Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365:65-69, 1993 Spacey SD, Gatti RA, Bebb G The molecular basis and clinical management of ataxia telangiectasia. Can J Neurol Sci 27(3):184-191, 2000

Tan E, Ashizawa T Genetic testing in spinocerebellar ataxias: defining a clinical role. Arch Neurol 58(2):191-195, 2001

125 Tremors Frisso Potts Tremor is an involuntary, rhythmic oscillation of a body part produced by synchronized contraction of antagonist muscles. These oscillations tend to have a consistent frequency and can be made to appear and disappear by postural adjustments of the body part. These characteristics, discussed later in this chapter, allow us to differentiate tremors from other kinds of movement disorders.

DIAGNOSIS The easiest way to classify tremors clinically is as follows: Tremor at rest: Parkinson’s disease Tremor during voluntary activity (action tremors): Physiologic tremor Enhanced physiologic tremor Essential or familial tremor Neuropathic tremor Writing tremor Orthostatic tremor Cerebellar tremor Tremors at rest are most obvious when the affected body part is in repose and are abolished or much diminished during voluntary movement. The opposite is true of action tremors. The clinical examination of the tremulous patient usually starts with visual inspection while the patient sits on a straight-backed, armless chair, forearms resting supinated at the thighs and hands

allowed to rest between the slightly abducted knees. This position will bring out most tremors at rest. In some cases, it may be necessary to ask the patient to perform complex silent calculations or cause other types of mild mental stress (e.g., asking the patient who the fifth vice-president of the United States was) to distract the patient and bring out the tremor. This is especially true if the patient has become adept at hiding the tremor. As a general rule, the less attention the patient pays to a resting tremor, the more likely it is to occur. Asking the patient to hold his o r her arms outstretched with fingers spread will activate most action tremors. In some cases, it may be necessary to ask the patient to perform a precise maneuver such as holding a pencil point close to but not touching a small target. Other provocative maneuvers are discussed further later in this chapter. Clinical observation may be further refined by electrophysiologic studies, such as electromyography, that record the frequency and amplitude of the tremor and the pattern of underlying muscle activity. These tremor tests are painless and easily performed, and they increase diagnostic accuracy, especially in cases of mixed tremor types or tremors that fail to respond to treatment. Figure 125-1 demonstrates the patterns seen in some commonly encountered tremors.

TREMOR AT REST Rest tremor is seen exclusively in Parkinson’s disease and in drugor toxin-induced parkinsonism. Most often, the tremor involves the muscles of the forearm, giving the characteristic pill-rolling appearance. The tremor may also be seen in other parts of the

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SUGGESTED READINGS Allikmets R, Raskind WH, Hutchinson A et al: Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 8(5):743-749, 1999

Delatycki MB, Williamson R, Forrest SM: Friedreich ataxia: an overview. J Med Genet 37( 1):l-8, 2000 De Vivo D C The expanding clinical spectrum of mitochondrial diseases. Brain Dev lS(1):l-22, 1993 Federico A, Palmeri S, Malandrini A et al: The clinical aspects of adult hexosaminidase deficiencies. Dev Neurosci 13(4-5):280-287, 1991

Geneclinics: Hereditary Ataxia Overview http://www.geneclinics.org/profiles/ataxias/details.htm~ Gomez CM: Inherited ataxia. In Johnson RT (ed): Current Therapy and Neurologic Disease. WB Saunders, Philadelphia, 2001 Handbook of ataxia disorders. In Klockgether T (ed): Neurological Disease and Therapy. Vol. 50. Marcel Dekker, New York, 2000 Harding AE: The hereditary ataxias and related disorders. In Clinical Neurology and Neurosurgery Monographs. Vol. 6. Churchill Livingstone, New York, 1984 Higgins JJ,Morton DH, Loveless JM: Posterior column ataxia with retinitis pigmentosa (AXPC1) maps to chromosome lq3 1 4 3 2 . Neurology 52( 1):146-150, 1999

Klockgether T, Wullner U,Spauschus A, Evert B: The molecular biology of the autosomal-dominant cerebellar ataxias. Mov Disord 15(4):604612, 2000

Musumeci 0, Naini A, Slonim AE et al: Familial cerebellar ataxia with muscle coenzyme QlO deficiency. Neurology 56(7):849-855, 2001 Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim/ Ouahchi K, Arita M, Kayden H et ak Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9(2):141-145, 1995 Poser S, Zerr I, Schroeter A et al: Clinical and differential diagnosis of Creutzfeldt-Jakobdisease. Arch Virol Suppl 16:153-159, 2000 Puccio H, Koenig M: Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum Mol Genet 9(6):887-892, 2000 Richter A, Morgan K, Bouchard JP et al: Clinical and molecular genetic studies on autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Adv Neurol61:97-103, 1993 Sharp D, Blinderman L, Combs KA et al: Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365:65-69, 1993 Spacey SD, Gatti RA, Bebb G The molecular basis and clinical management of ataxia telangiectasia. Can J Neurol Sci 27(3):184-191, 2000

Tan E, Ashizawa T Genetic testing in spinocerebellar ataxias: defining a clinical role. Arch Neurol 58(2):191-195, 2001

125 Tremors Frisso Potts Tremor is an involuntary, rhythmic oscillation of a body part produced by synchronized contraction of antagonist muscles. These oscillations tend to have a consistent frequency and can be made to appear and disappear by postural adjustments of the body part. These characteristics, discussed later in this chapter, allow us to differentiate tremors from other kinds of movement disorders.

DIAGNOSIS The easiest way to classify tremors clinically is as follows: Tremor at rest: Parkinson’s disease Tremor during voluntary activity (action tremors): Physiologic tremor Enhanced physiologic tremor Essential or familial tremor Neuropathic tremor Writing tremor Orthostatic tremor Cerebellar tremor Tremors at rest are most obvious when the affected body part is in repose and are abolished or much diminished during voluntary movement. The opposite is true of action tremors. The clinical examination of the tremulous patient usually starts with visual inspection while the patient sits on a straight-backed, armless chair, forearms resting supinated at the thighs and hands

allowed to rest between the slightly abducted knees. This position will bring out most tremors at rest. In some cases, it may be necessary to ask the patient to perform complex silent calculations or cause other types of mild mental stress (e.g., asking the patient who the fifth vice-president of the United States was) to distract the patient and bring out the tremor. This is especially true if the patient has become adept at hiding the tremor. As a general rule, the less attention the patient pays to a resting tremor, the more likely it is to occur. Asking the patient to hold his o r her arms outstretched with fingers spread will activate most action tremors. In some cases, it may be necessary to ask the patient to perform a precise maneuver such as holding a pencil point close to but not touching a small target. Other provocative maneuvers are discussed further later in this chapter. Clinical observation may be further refined by electrophysiologic studies, such as electromyography, that record the frequency and amplitude of the tremor and the pattern of underlying muscle activity. These tremor tests are painless and easily performed, and they increase diagnostic accuracy, especially in cases of mixed tremor types or tremors that fail to respond to treatment. Figure 125-1 demonstrates the patterns seen in some commonly encountered tremors.

TREMOR AT REST Rest tremor is seen exclusively in Parkinson’s disease and in drugor toxin-induced parkinsonism. Most often, the tremor involves the muscles of the forearm, giving the characteristic pill-rolling appearance. The tremor may also be seen in other parts of the

Chapter 125

FIG. 125-1. Tremor recordings in (A) physiologic tremor, (6) Parkinson’s disease, and (C) essential tremor. Surface electromyographic tracings are from wrist extensors (WE) and from wrist flexors (WF). The accelerometric tracing from the index finger is at the bottom of each tracing. Note diminution of tremor as subject goes from rest to reaching for an object (6).Time base is 1 second.

Tremors

799

-

wJ--

WE WF

body, although it is unusual for this to happen without some involvement of the upper extremities. Voluntary movement abolishes or markedly decreases the amplitude of the tremor. Thus, it rarely affects the patient’s writing or interferes severely with activities of daily living. However, there are patients in whom the severity of the tremor makes it more than a cosmetic nuisance. As many as 20% of patients with resting tremor of Parkinson’s disease may have a superimposed action tremor, A tremor recording in Parkinson’s disease demonstrates alternating electromyographic (EMG) bursts in antagonist muscles at a frequency of 3 to 7 Hz (Fig. 125-1).The tremor appears to be generated by rhythmic activity of the lower motor neuron caused by descending rhythmic discharges from the hemispheres and uninfluenced by segmental stretch reflexes because dorsal rhizotomy does not affect the tremor. The recording has the appearance of voluntary flexion-extension, pronation-supination movements of the hand; with little effort, a normal subject may generate a tremor recording indistinguishable from that of an affected individual. The supranuclear origin of the tremor is also supported by the presence of rhythmic neuronal bursts in the contralateral sensorimotor cortex and ventrolateral thalamus in monkeys with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP)-induced parkinsonism. Similar activity has been recorded from the thalamus of patients with Parkinson’s disease. These bursts are not affected by deafferentation and can be eliminated by lesions of the appropriate thalamic nuclei with consequent resolution of the tremor. The tremor usually improves with dopaminergic treatment for Parkinson’s disease. Occasionally, the decrease in rigidity brought about by these drugs uncovers or enhances the resting tremor. For these cases, and for those who fail to respond to dopaminergic treatment, concomitant therapy with anticholinergic agents should be tried. A daily dosage of 1 to 6 mglday of benztropine mesylate or 2 to 12 mg trihexyphenidyl hydrochloride may be useful. The medication should be given in three or four divided doses, and the least amount needed for beneficial effect used. When pharmacotherapy fails, severe cases of tremor at rest may be approached surgically. Stereotactic thalamotomy of the ventral intermediate nucleus and chronic electrical stimulation of this site without thalamotomy have shown encouraging results. Lately, stereotactic pallidotomy and cerebellar stimulation have gained increased acceptance.

ACTION TREMORS

Not every investigator agrees with the use of the term action tremor. There are those who prefer the term postural tremor, whereas others prefer to divide these tremors into kinetic (those occurring during movement) and static (those occurring while the limb is held in a fixed position). Further categorization introduces the term tusk-specific tremor, referring to tremors that occur only during a specific movement or task. I have chosen not to burden the reader with multiple subdivisions and I discuss each action tremor under this fairly broad term. Tremors, in general, are very sensitive to changes in metabolic or emotional states. Anxiety tends to increase the amplitude of tremors, especially of action tremors, and it may be the precipitating cause in some cases. Many medications, including the following, are known to produce or enhance action tremor: Corticosteroids Methylxanthines Lithium Heavy metals Thyroid hormone Glutamates Catecholamines Neuroleptics Tricyclics Nicotine Bromides Valproic acid Physiologic Tremor

Physiologic tremor is the most ubiquitous of the tremors discussed earlier. AU people have it to a greater or lesser extent. It can be easily demonstrated by having a subject hold out an arm with fingers outstretched. The tremor usually is so slight that it cannot be seen on the fingers, but if a piece of paper is laid across the hand, the oscillations are amplified and become obvious. The genesis of this tremor probably is the combination of such disparate elements as individual motor unit recruitment rates and the intrinsic elastic properties of joints and other bony and

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connective tissue components. Mechanical perturbations caused by circulatory pulse waves may also contribute to the tremor. No treatment is required. Enhanced Physiologic Tremor

Enhanced physiologic tremor is easily seen in the outstretched fingers; it is of much larger amplitude than physiologic tremor and it can be disabling. Although it does not affect gross movements such as tracking an object, it affects writing and other precise tasks. This tremor may be seen and heard because it may affect the speech apparatus. Tremor recording shows a regular rhythm at about 10 Hz, and the surface EMG activity shows alternating bursts in antagonist muscles. The tremor is associated with muscle fatigue and may be induced in normal subjects by the administration of epinephrine or its congeners. Expectedly, it is the tremor of fear and anxiety, notably of stage fright. This tremor may also be a result of metabolic derangements. It is the tremor of hyperthyroidism, Cushing’s disease, and withdrawal from alcohol and minor sedatives. Therefore, it is important to look for underlying conditions causing a hyperadrenergic state. This is especially true if the tremor is continuous rather than intermittent, as would be the case in anxiety. The drugs listed earlier in this chapter may produce or enhance this tremor. The catecholamines’ effect is mediated by peripheral P-adrenergic receptors. That the locus of action of these drugs is outside the central nervous system has been demonstrated by intra-arterial infusion experiments. Conversely, blockade of these drugs with propranolol diminishes or abolishes the tremor. It appears that these receptors are instrumental in producing synchronous a-motor neuron discharges by enhancing the stretch reflex arc. What is not known is the exact location of the receptors and how they go about modulating neural activity. Removing underlying causes (environmental or metabolic) is the best management. When this is not possible, single doses of 20 to 40 mg propranolol provide relief for several hours. This is especially useful in the prophylactic treatment of performing artists. If there is concern over the potential bronchoconstrictive or hypoglycemic effect of propranolol’s P,-blockade, pure PIblockers (metoprolol) may be used. These are not as effective, and higher dosages may be needed. Essential Tremor

Also known as familial, rubral, or static tremor, essential tremor is most often seen affecting the upper extremities while a patient carries out precise tasks. It may involve other body parts, however, and gives the voice a quavering sound when it affects pharyngeal and laryngeal muscles. It is most common in older age groups and is responsible for most cases of so-called senile tremor. Although 60% of patients with essential tremor have a family history, sporadic cases abound. Transmission appears to be autosomal dominant, but the gene locus has not been found. An important diagnostic point is that this tremor rarely, if ever, affects a body part without affecting the upper extremities first. The literature is replete with cases of isolated essential tremor involving neck muscles, a single digit, or a foot. In most of these cases, closer examination would find a focal dystonia presenting as tremor. In general, patients with essential tremor have no other neurologic symptoms or signs. However, this tremor often coexists with acquired dystonias, such as writer’s cramp and torticollis. As many as 20% of patients with Parkinson’s disease have a

superimposed essential tremor. This does not necessarily mean that patients who develop essential tremor are at a higher risk than the general population for developing Parkinson’s disease. The frequency of the tremor ranges from 5 to 10 Hz, faster in younger patients and decreasing with age, even in the same person. Surface EMG recordings demonstrate synchronous bursts in antagonist muscles (Fig. 125-1). In cases of dystonia presenting as tremor (the nodding head of torticollis is a classic example) or in cases of dystonia and tremor coexisting, the EMG pattern would nicely tease out the complex interaction between the participating muscles. This tremor probably is suprasegmental in origin because manipulation of segmental reflex arcs has little effect on its amplitude or rhythm. Positron emission tomography studies using radioactive water or carbon- 15-labeled carbon dioxide suggest that abnormal activation of the cerebellum and red nucleus may play a role in its genesis. At present, its pathophysiology is unknown. A remarkable feature of this tremor is its response to alcoholic beverages. Within minutes of ingesting 0.5 to 1 ounce of ethanol, patients experience a decrease in tremor amplitude that may last for several hours. As the effect dissipates, a transient worsening may occur. Well-controlled studies have confirmed this effect and have shown that its action is within the central nervous system because intra-arterial injection of ethanol has no effect on the tremor. P-Blockers also have a beneficial effect on the tremor, but unlike ethanol, a single intravenous or oral dose has no effect; they may not be effective unless administered for several days. As a general rule, nonselective P-blockers are more effective than selective P,- or P,-blockers. Lipophilic P-blockers are more effective than nonlipophilic ones because of their greater penetration of the blood-brain barrier. Some patients may respond to as little as 30 mg/day propranolol in divided doses; others may need ten times that much. The same warnings about P-blockers discussed earlier for enhanced physiologic tremor apply here. Because of P-blockers’ side effects, primidone is fast becoming the drug of choice. Again, the dosage must be individually adjusted. As little as 5 mg/day is useful for some, whereas others need nearly toxic dosages. For optimal response with either drug, start at a very low dosage with weekly increments to tolerance. Some patients respond to P-blockers and some to primidone. Combination therapy is rarely useful. Gabapentin has been beneficial for some patients. Dosages as low as 600 mg per day may be effective, but usually higher dosages are needed. Its low incidence of side effects makes it an attractive alternative. Those who do not respond to these drugs may benefit from methazolamide in dosages of 100 to 300 mg/day or nicardipine in dosages of 30 to 60 mg/day. Judicious use of botulinum toxin injection (as described later in this chapter) may be the treatment of choice for patients whose tremor does not respond to these agents. When pharmacotherapy fails, a patient may find relief from surgical ablation of the ventralis lateralis or ventral intermediate thalamic nucleus. Chronic stereotactic stimulation of the ventral intermediate nucleus or chronic cerebellar stimulation may also be useful in those who do not respond to drug therapy. Neuropathic Tremor

Neuropathic tremor is seen in a variety of acquired neuropathies. It is important to differentiate it from the essential tremor associated with hereditary sensorimotor neuropathy type I. The acquired neuropathies most likely to produce a tremor are chronic

Chapter 125 H Tremors

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relapsing demyelinating polyneuropathy and immunoglobulin M (1gM)-associated paraproteinemic neuropathy. Causality is suggested by the fact that in a single patient, changes in the amplitude of the tremor vary directly with changes in the severity of the neuropathy. The tremor is generally irregular at a rate of 6 to 8 Hz. The EMG from antagonist muscles demonstrates bursts of varying amplitude and duration without a consistent pattern. The presence of the tremor is not related to the degree of weakness or sensory loss. Slowing in motor conduction velocity often is seen in neuropathic tremor, but the degree of slowing is not related to severity. The pathophysiology of these tremors is unclear, and there probably are multiple mechanisms involved in their genesis. One of these may be desynchronization of afferent volleys from muscle spindles and Golgi tendon organs. The demyelinative features of the neuropathy probably play an important role because in primarily axonal neuropathies (e.g., associated with alcohol, diabetes), tremor is absent or barely noticeable, whereas the tremor may appear during recovery from Guillain-Barre syndrome. Some patients may respond to propranolol or Mysoline, but therapy is best directed at the neuropathy.

minutes after assuming the standing posture and is abolished by walking. It involves mainly the lower extremity and trunk muscles, although some weight-bearing tasks in the upper extremities may produce tremor in susceptible people. Most patients suffering from this tremor have no other neurologic complaint, but there are reports of an association with essential tremor and painful cramp syndromes. One case associated with aqueductal stenosis and another with chronic relapsing demyelinating polyneuropathy have been reported. The upright posture itself is not responsible for the tremor; rather, it appears that the isometric muscle activity needed for weight-bearing is the trigger. Surface EMG recording shows synchronous bursts in antagonist muscles occurring at rates as high as 30 Hz in some patients and as low as 7 Hz in others. Some authors have proposed that the tremor is caused by impaired feedback from muscle spindles. However, its physiologic and pharmacologic underpinnings remain unknown. Primidone in the dosages cited earlier or clonazepam in daily dosages of 4 to 6 mg may improve some patients.

Writing Tremor

Also known as cerebellar outflow tremor, cerebellar tremor is seen in late cortical atrophy of the cerebellum and in lesions of the cerebellar outflow tract, such as occur in multiple sclerosis. It is different from the appendicular dysmetria and ataxia associated with hemispheric cerebellar lesions. The tremor is manifested as regular oscillations of the trunk or limbs while maintaining a posture. The axial and proximal limb muscles demonstrate an alternating pattern of EMG bursts at about 3 Hz. The tremor also affects goal-directed movement because as a limb approaches a target, the more distal muscles start to show the alternating bursts, and the tremor increases in amplitude. Patients show less tremor if they keep their eyes open and observe the limb during the task, a phenomenon called visual stabilization. The mechanism for the tremor is unknown; it appears to be unrelated to abnormalities of stretch reflex or proprioceptive input. Pharmacotherapy has yielded disappointing results. There has been some success using high dosages (600 to 1200 mg/day) of isoniazid hydrochloride. However, at these levels, liver toxicity is common. Carbamazepine has also been helpful for some patients. As in many other devastating tremors, stereotactic ablation of the ventral intermediate thalamic nucleus may be useful.

Any action tremor may affect penmanship, but some patients demonstrate a tremor predominantly during writing. The tremor is most often unilateral and shows no familial tendency. It may occur as an isolated symptom or accompany other tremors or focal dystonias. It has been dubbed primary writing tremor, but it seems that it is the pronated, slightly extended position of the wrist rather than the act of writing itself that produces the tremor. This tremor may also be triggered by eliciting stretch reflexes from muscles responsible for forearm pronation. Tremor recordings vary from patient to patient. In some patients, bursts of EMG activity at a rate of 4 to 6 Hz can be recorded from antagonist muscles. The pattern may be synchronous or alternating, and the bursts in a single recording may vary in amplitude and duration. In some cases, a single muscle shows tonic activity and its antagonist a pattern of bursts. All this suggests that this tremor has more in common with acquired dystonias, or the so-called occupational cramps, than with the tremors mentioned earlier. As is generally true of dystonias, its pathophysiology is unknown. Systemic therapy for this tremor relies mainly on the use of anticholinergic drugs in dosages described earlier under “Tremor at Rest.” Atropine and scopolamine in the usual cardiac dosages have been tried but have not produced encouraging results. P-Blockers, alcohol, levodopa, and neuroleptics are not useful. Biofeedback and other forms of therapeutic self-hypnosis have been used with varying success. These treatments are quickly giving way to intramuscular botulinum toxin injection. Upon identifymg the muscles most active in the tremor, minute amounts of the toxin are injected to produce selective weakness or paralysis of the offending muscles. The number of injections necessary depends as much on the severity of the tremor as on the skill of the administering physician. Orthostatic Tremor

Although the true incidence of orthostatic tremor is not known, it is much less common than other types of action tremor. It is seen primarily in older patients and occurs during the act of standing. The tremor appears after a latent period of several seconds or

Cerebellar Tremor

SUGGESTED READINGS Cardoso FEC, Jankovic J: Hereditary motor-sensory neuropathy and movement disorders. Muscle Nerve 16:904-910, 1993 Deep-Brain Stimulation for Parkinson’s Disease Study Group: Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 345:956-963,2001 Elble RJ, Moody C, Higgins C: Primary writing tremor: a form of focal dystonia? Mov Disord 5:118-126, 1990 Fitzgerald PM, Jankovic J: Orthostatic tremor: an association with essential tremor. Mov Disord 6:60-64, 1991 Goetz CG, Horn SS: Treatment of tremor and dystonia. Neurol Clin 19:129-144, 2001 Hark GM, Lindberg M, Bergenheim AT Impact of thalamic deep brain stimulation on disability and health-related quality of life in patients with essential tremor. J Neurol Neurosurg Psychiatry 72:47-52, 2001 Louis E D Essential tremor. N Engl J Med 345:887-891, 2001 Matsumoto J, Morrow D, Kaufman K et ak Surgical therapy for tremor in multiple sclerosis: an evaluation of outcome measures. Neurology 57:1876-1882, 2001

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Munchau A, Schrag A, Chuang C et ak Arm tremor in cervical dystonia differs from essential tremor and can be classified by onset age and spread of symptoms. Brain 124:1765-1776, 2001 Walker FO, McCormick GM, Hunt VP: Isometric features of orthostatic tremor. Muscle Nerve 13:918-922, 1990

Wills AJ, Jenkins LH, Thompson PD et al: Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomography study. Ann Neurol 36636442, 1994 Zesiewicz TA, Hauser RA: Phenomenology and treatment of tremor disorders. Neurol Clin 19:651-680, 2001

126 Huntington’s Disease Walter 1. Koroshetz Huntington’sdisease is an autosomal dominant neurodegenerative disease that leads to marked atrophy of basal ganglia structures, the caudate, and putamen, as well as less marked atrophy of other brain nuclei. It is thought to be the most common inherited adult neurodegenerative disease, affecting 1 in 15,000 in the United States. The average age of onset is approximately 38 years old; much younger-onset cases and onset in older adults also occurs less commonly. The hallmark of the illness is an involuntary movement disorder, chorea. Some patients have little or no chorea and instead appear slow and rigid (i.e., with parkinsonian characteristics). The illness leads to death, with an average duration of symptoms of about 20 years. The gene that causes the disease has been identified. The Huntington mutation is an expanded trinucleotide (CAG), repeat that causes an excessively long polyglutamine stretch located in a novel protein called huntingh’n. How the mutation leads to the onset of a disorder of motor, emotional, and cognitive control in people who have matured normally until middle age is still a mystery. The gene discovery has made genetic diagnosis common, both in neurologically normal patients (presymptomatic testing) and in neurologically or psychiatrically impaired patients (diagnostic testing). Transgenic animal models of the disease provide researchers with powerful new tools to search for effective treatments. It is hoped that research will soon uncover the cause of the slow neuronal loss, which is stimulated by the mutation and underlies the tragic illness. CLINICAL MANlFESTATlONS

Huntington’s disease is characterized by progressive impairment of a patient’s cognitive, emotional, and motor control, which is accompanied by neuronal death in the central nervous system, primarily in the caudate and putamen of the basal ganglia. Primary sensory pathways do not appear to be affected. Cerebellar function is affected only in an atypical Huntington’s disease variant, with signs usually beginning in childhood. The psychological effects of the disease are magnified by the fact that it is autosomal dominantly inherited and that affected patients usually have witnessed the entire course of the disease in their parent by the time they begin to show signs. Older siblings may also be severely disabled or have already died. Because it is an autosomal dominant disorder, a thorough family history is essential to make the clinical diagnosis. Care is needed to avoid errors of incorrectly attributing any neurologic or psychiatric symptom to Huntington’s disease in the presence of a family history. A negative family history that is taken as absolute, without investigation, can also lead to errors in not diagnosing Huntington’s disease in an affected patient.

The disease progresses slowly and often in a pattern consisting of three phases. Early on, affected patients have difficulty maintaining their premorbid level of function at work, school, or home. Emotional disorders may be prominent, there is disability caused by poor motor control, and chorea is usually present. In this stage, patients can maintain their own activities of daily living. Toward the end of stage 1 the person loses the ability to remain employed or drive an automobile and becomes reliant on family or society for some level of support. In stage 2, dysarthria affects communication, and dysphagia may occur. Disordered motor control may lead to falls, chorea may be prominent, and mentation is dulled. Such patients must be supervised to avoid self-injury, prevent poor financial decisions, and even maintain adequate nutrition, housing, and cleanliness. In stage 3, dystonia and rigidity may set in, choreoathetosis may be continuous, and the person eventually becomes bedridden and unable to speak or swallow. The course of the disease progresses fairly linearly down the Boston Independence and Physical Disability Scales (Table 126-1). The Total Functional Capacity Score, which is presented in Table 126-2, is more sensitive to progression of the disease in stages 1 and 2. Presenting Signs and Symptoms

Patients with Huntington’s disease present with a variety of clinical syndromes. Most commonly, a person at risk for this disease begins to fall behind in performance at work or home in the fourth or fifth decade of life. Slowness in executing tasks, inflexibility, forgetfulness, poor judgment, and increased irritability may impair their usual level of ability. The patient may present with a history of recent change in the degree of difficulty of his or her job or recent job loss. Family members often report that a change in personality has occurred in the 3 to 5 years before clinical symptoms. Increased numbers of motor vehicle accidents may occur. Increased irritability is common; occasionally florid psychiatric disorders predominate for years before the motor signs of Huntington’s disease appear. Symptoms of a motor disorder in early-stage Huntington’s disease are not specific but are very suspicious if definite slow worsening occurs in a person with a known affected parent. The spouse may report that the affected person began to have sudden jerking movements during sleep over the past few years. These must be distinguished from the sleep-onset myoclonus that occurs in a normal person but is often incorrectly assumed to be a sign of Huntington’s disease in at-risk people. Clumsiness of fine finger movements is detected by some people (i.e., typists, musicians, and carpenters). A deterioration in baseline handwriting skills is common. Unexplained falls, dropping of objects, and a change in

802

Movement Disorders rn Non-Parkinsonian Movement Disorders

Munchau A, Schrag A, Chuang C et ak Arm tremor in cervical dystonia differs from essential tremor and can be classified by onset age and spread of symptoms. Brain 124:1765-1776, 2001 Walker FO, McCormick GM, Hunt VP: Isometric features of orthostatic tremor. Muscle Nerve 13:918-922, 1990

Wills AJ, Jenkins LH, Thompson PD et al: Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomography study. Ann Neurol 36636442, 1994 Zesiewicz TA, Hauser RA: Phenomenology and treatment of tremor disorders. Neurol Clin 19:651-680, 2001

126 Huntington’s Disease Walter 1. Koroshetz Huntington’sdisease is an autosomal dominant neurodegenerative disease that leads to marked atrophy of basal ganglia structures, the caudate, and putamen, as well as less marked atrophy of other brain nuclei. It is thought to be the most common inherited adult neurodegenerative disease, affecting 1 in 15,000 in the United States. The average age of onset is approximately 38 years old; much younger-onset cases and onset in older adults also occurs less commonly. The hallmark of the illness is an involuntary movement disorder, chorea. Some patients have little or no chorea and instead appear slow and rigid (i.e., with parkinsonian characteristics). The illness leads to death, with an average duration of symptoms of about 20 years. The gene that causes the disease has been identified. The Huntington mutation is an expanded trinucleotide (CAG), repeat that causes an excessively long polyglutamine stretch located in a novel protein called huntingh’n. How the mutation leads to the onset of a disorder of motor, emotional, and cognitive control in people who have matured normally until middle age is still a mystery. The gene discovery has made genetic diagnosis common, both in neurologically normal patients (presymptomatic testing) and in neurologically or psychiatrically impaired patients (diagnostic testing). Transgenic animal models of the disease provide researchers with powerful new tools to search for effective treatments. It is hoped that research will soon uncover the cause of the slow neuronal loss, which is stimulated by the mutation and underlies the tragic illness. CLINICAL MANlFESTATlONS

Huntington’s disease is characterized by progressive impairment of a patient’s cognitive, emotional, and motor control, which is accompanied by neuronal death in the central nervous system, primarily in the caudate and putamen of the basal ganglia. Primary sensory pathways do not appear to be affected. Cerebellar function is affected only in an atypical Huntington’s disease variant, with signs usually beginning in childhood. The psychological effects of the disease are magnified by the fact that it is autosomal dominantly inherited and that affected patients usually have witnessed the entire course of the disease in their parent by the time they begin to show signs. Older siblings may also be severely disabled or have already died. Because it is an autosomal dominant disorder, a thorough family history is essential to make the clinical diagnosis. Care is needed to avoid errors of incorrectly attributing any neurologic or psychiatric symptom to Huntington’s disease in the presence of a family history. A negative family history that is taken as absolute, without investigation, can also lead to errors in not diagnosing Huntington’s disease in an affected patient.

The disease progresses slowly and often in a pattern consisting of three phases. Early on, affected patients have difficulty maintaining their premorbid level of function at work, school, or home. Emotional disorders may be prominent, there is disability caused by poor motor control, and chorea is usually present. In this stage, patients can maintain their own activities of daily living. Toward the end of stage 1 the person loses the ability to remain employed or drive an automobile and becomes reliant on family or society for some level of support. In stage 2, dysarthria affects communication, and dysphagia may occur. Disordered motor control may lead to falls, chorea may be prominent, and mentation is dulled. Such patients must be supervised to avoid self-injury, prevent poor financial decisions, and even maintain adequate nutrition, housing, and cleanliness. In stage 3, dystonia and rigidity may set in, choreoathetosis may be continuous, and the person eventually becomes bedridden and unable to speak or swallow. The course of the disease progresses fairly linearly down the Boston Independence and Physical Disability Scales (Table 126-1). The Total Functional Capacity Score, which is presented in Table 126-2, is more sensitive to progression of the disease in stages 1 and 2. Presenting Signs and Symptoms

Patients with Huntington’s disease present with a variety of clinical syndromes. Most commonly, a person at risk for this disease begins to fall behind in performance at work or home in the fourth or fifth decade of life. Slowness in executing tasks, inflexibility, forgetfulness, poor judgment, and increased irritability may impair their usual level of ability. The patient may present with a history of recent change in the degree of difficulty of his or her job or recent job loss. Family members often report that a change in personality has occurred in the 3 to 5 years before clinical symptoms. Increased numbers of motor vehicle accidents may occur. Increased irritability is common; occasionally florid psychiatric disorders predominate for years before the motor signs of Huntington’s disease appear. Symptoms of a motor disorder in early-stage Huntington’s disease are not specific but are very suspicious if definite slow worsening occurs in a person with a known affected parent. The spouse may report that the affected person began to have sudden jerking movements during sleep over the past few years. These must be distinguished from the sleep-onset myoclonus that occurs in a normal person but is often incorrectly assumed to be a sign of Huntington’s disease in at-risk people. Clumsiness of fine finger movements is detected by some people (i.e., typists, musicians, and carpenters). A deterioration in baseline handwriting skills is common. Unexplained falls, dropping of objects, and a change in

Chapter 126 w

TMLE126-1. Boston Independence and Physical Disability Scales Boston Independence Scale

Boston Physical Disabilii Scale

100: No special care needed 090: No physical care needed if

100: Normal, no disease evident 090: Onset: minimal signs, slight

difficult tasks are involved

facial or extremity movement disorder 080: Normal daily activity with effort, gait disturbance, stumbling, slurred speech

080: Predisease level of employ-

ment changes or ends; cannot perform household chores to predisease level; may need help with finances 070: Self-care maintained for bathing, limited household duties (cooking and use of knives), driving terminates; unable to manage finances 060: Needs minor assistance for dressing, toileting, bathing; food must be cut for patient 050: 24-hour supenision appro-

priate; assistance needed for bathing, eating, toileting 040: Chronic care f a c i l i needed;

limited self-feeding, liquefied diet 030:Patient provides minimal assistance in own feeding, bathing, toileting 020: No speech, must be fed 010: Tube fed, total bed care

070: Limited activity, occasional

falls, oven chorea, less speech with dysarthria, occasional dysphagia 060: Can be left alone for short

period of time, several falls, can walk up to 1 block outside of home 050: Needs assistance in walking, limited ambulation at home, difficulty communicatingand swallowing 040:Limited a b i l i t o walk assisted; single-word utterances 030:Confined to wheelchair, unintelligible speech, frequent choking 020: Completely bedridden, anarthria 010: Fuced posture necessitating total care, gastrostomy, cathe terization

the usual pattern of walking or speaking are other common symptoms that may herald the onset of clinical Huntington’s disease. Because the mutation is inherited and patients are clearly normal during childhood and throughout early adulthood and only slowly develop the clinical syndrome in early to middle adulthood, there can be no true “onset” of illness. Huntington’s disease is inexorably progressive, although patients accumulate disability at various rates. Diagnosis usually is made when chorea without other cause becomes evident. However, studies of at-risk people and newly diagnosed patients reveal that even before chorea occurs, certain “soft signs” may appear. The speed of saccadic eye movements is slowed, and there may be an abnormal delay before the production of a saccadic eye movement to a command. Repetitive fine finger movements, repetitive tongue movements, or repetitive lingual pronunciations may be slow and clumsy. Patients may have difficulty learning a sequence of motor acts (Luria three-step test). Restless movements may occur that resemble normal repositioning movements but at increased frequency. Stereotyped “habit” movements may be more apparent, or small-amplitude flicks of the fingers may be seen while the patient holds hands outstretched or walks. Neuropsychological evaluation may reveal deficits in memory or in the ability to respond to changing instructions (changing sets). Clinical depression is common in the years just preceding or encompassing the time of clinical diagnosis. The suicide rate in this time period is markedly increased.

Huntington’s Disease

803

Chorea The combination of fluid or jerky, writhing, torsional movements in all extremities resembles a form of primitive dance, and the word chorea is from the Greek word meaning “to dance.” In the early stages of the illness, the movements often are quick flicks of the fingers or muscles about the mouth or ankles. One common variant in which the fingers are quickly extended resembles the motion of flicking the ashes off a cigarette. The movements in the face may resemble winking or quick, wry smiling movements. As indicated earlier, there is often an increased frequency and constancy of movements that are seen commonly in normal people and associated with restlessness. A small proportion of affected people never demonstrate chorea. In most affected patients, chorea is unsightly but not truly disabling. It can affect function in that patients may spill liquids, hit extremities against sharp or hot objects, or drop objects during a choreic movement. However, in some chorea becomes so pronounced (largeamplitude continuous writhing movements) that it interferes with all normal motor activity. Chorea is inhibited by neuroleptic agents and enhanced by dopamine agonists. Treatment with high or even moderate dosages of neuroleptic drugs is problematic because it may worsen the voluntary movement disorder in a dose-dependent fashion. As the disease progresses, the involuntary movements change in form. In some patients, the movements increase in amplitude and frequency so that the person is in constant motion while awake. The person may walk with grotesque contortions of both axial and appendicular musculature. As the illness progresses, some patients demonstrate a slowing of writhing movements to choreoathetosis. In the late stages of the illness, the predominant disorder is dystonia, a fixed, abnormal, usually twisted posture. Progression to rigidity and dystonia can be iatrogenically produced by treating chorea overaggressively with neuroleptic drugs.

Disordered Motor Control Major disability comes from the disordered voluntary motor disorder in Huntington’s disease. This aspect of the disease

TABLE 126-2. Total Functional Capacity Scale (Shoulson inventory) Occupation 0 =unable 1 =marginal work only 2 = reduced capacity for usual job 3 =normal Finances 0 = unable 1 =major assistance 2 =slight assistance 3 =normal Domestic chores 0 = unable 1 =impaired 2 = normal Activities of daily living 0 =total care 1 =gross tasks only 2 =minimal impairment 3 = normal Care level 0 =full-time skilled nursing 1 =home or chronic care 2 = home

004

Movement Disorders W

Non-Parkinsonian Movement Disorders

progresses until there is almost no ability to make goal-directed purposeful movements to the extent that swallowing, speaking, and even sitting are no longer possible. Huntington’s disease contains much of the bradykinesia found in Parkinson’s disease without the same rigidity or tremor but instead with overlying chorea. This is not surprising because both diseases cause a dysfunctional striatum. In the motor control sphere, the old teaching that Parkinson’s and Huntington’s diseases cause opposite nervous system effects is incorrect. In the early stages, the voluntary motor disorder is characterized by slowness and incoordination. There is usually trouble in making rhythmic movements or fast, repetitive, fine movements with the tongue or fingers. When patients are asked to tap the index finger to the thumb or tap the tongue to the top lip repetitively, the movements are made more slowly than normal, and there are occasional deviations from the desired pattern. Patients have a peculiar inability to regularly time fast tapping movements with the hand. A test that demands changing the motor program is very difficult. To test these patients, they are asked to tap out a sequence of three motor acts (tap thigh alternately with a fist, then the side of the hand, and then the palm of the hand, then repeat the sequence). A similar disability is seen when the patient is asked to tap the front and back surface of the dominant hand on the palm of the nondominant hand alternately (dysdiadochokinesia). A change in the pattern of speech occurs, and some family members consider this to be the first sign of the disease. An alteration in pronunciation and in the normal phrasing and timing of speech is likely to be what is noticed early. On examination, repetitive lingual sounds are pronounced poorly (i.e., “la, la, la, la, la”), whereas repetitive buccal sounds are performed better (i.e., “me, me, me, me, me”). Swallowing movements are also affected by the motor control disorder in Huntington’s disease. Swallowing difficulty often begins with trouble swallowing dry foods such as crackers, cookies, or dry cereals. Patients are unable to strip such food pieces from the pharynx and may inhale them instead. Next, thin liquids such as water and soda are trouble; this can sometimes be remedied by the use of a straw to deliver the fluid straight to the back of the mouth because the tongue coordination necessary to do so may not be present. Thicker liquids are easier to propel into the hypopharynx, and a custard consistency usually is the easiest to swallow, even in the later stages of the illness. Gait and posture are severely affected by the disease as it progresses. Gait may become wide based, but more characteristically the steps are irregular in both timing and placement of the feet. Because of the combination of gait disorder and slurred speech, patients are not uncommonly misdiagnosed as inebriated by law enforcement officials. Postural instability occurs over time, and affected patients cannot balance on one foot or walk tandem in a straight line. In the early or middle stage of the disease, they may exhibit retropulsion when given a light shove backward. Falling becomes a serious issue in the middle and later stages of the illness. A number of patients with Huntington’s disease sustain subdural hematomas or orthopedic injuries during falls. As the disease progresses into the later stages, all lose the ability to walk and even to maintain balance for the standing or upright sitting position. There is an apraxia, which affects functional movement in patients with Huntington’s disease. Occasionally a patient is misperceived as lazy or depressed because he or she is seen as not performing even the most simple tasks about the house. On examination, the patient may be unable to mimic the most basic hand postures, and it is clear that he or she cannot learn or

produce the movement necessary for activities of daily living. Because of slowness, incoordination, apraxia, and chorea, patients in the middle stage of Huntington’s disease lose the ability to write, use keys, button clothing, tie shoelaces, wash dishes, feed themselves without spilling food, and so forth. In the later stages, affected patients are totally dependent on others for feeding, clothing, and bathing because of the total lack of voluntary control of movement. Death caused by Huntington’s disease usually is triggered by aspiration pneumonia caused by pharyngeal dysfunction. Speech patterns change early in the illness, with slurring and poor modulation of volume and tone. As the illness progresses, dysarthria becomes more severe, and, in the later stages, speech becomes unintelligible. Patients with end-stage Huntington’s disease can do little more than moan or produce incoordinated vowel sounds. Swallowing dysfunction also occurs throughout the course of the illness. Choking spells usually do not occur until the later stages, although some patients have had occasional coughing or choking with swallowing in the early stages. As the disease progresses, the texture of food must be altered to allow effective swallowing. More time must be allotted to meals. Because swallowing usually is slower than other movements, it is important to come up with strategies to ensure that the mouth is emptied before more food is taken in. Thickening liquids and softening and moistening solid foods (pureed) usually is necessary as the disease progresses. Patients in later stages of Huntington’s disease need to be fed patiently by others. Pharyngeal dysfunction eventually becomes so severe that nutritional needs cannot be met orally in the late stage of the illness. Aspiration of oral contents occurs as a final event, leading to pneumonia. Reflexes usually are hyperactive; there may be clonus at the ankle. Tone is increased in the late stages of the illness coincident with dystonia, and tone is increased in the bradykinetic and rigid juvenile cases. In early-stage Huntington’s disease, the tone in an extremity can be normal until the examiner attempts to produce passive movement or the patient produces active movement in another extremity. The tone generally is greatly increased by these stimuli. Despite severe dementia, frontal lobe signs usually are not seen (grasp, suck, and rooting reflex). Vertical eye movements can be limited in end-stage disease. With middle- to late-stage disease, horizontal eye movements are linked to unsuppressible head turn or blinks. No deficits in pupillary reflexes, heating, visual acuity, visual fields, or primary sensation are apparent in Huntington’s disease. Muscular wasting is seen, but the cause is not clear. Cerebellar signs such as dysmetria and nystagmus are not usually seen. Autonomic abnormalities are not usually noted until later in this disease. Patients in its end stage become incontinent, usually associated with dementia. Some patients with Huntington’s disease have experienced unusual episodic sweating. In the late stages, we have seen occasional patients with recurrent high fevers, elevated creatine phosphokinase levels, and diaphoresis. A source of infection should be looked for in such cases but may not always be uncovered.

Psychiatric Disorders Depression is extremely common in patients with Huntington’s disease, and it may become apparent before the neurologic signs enable the clinical diagnosis. The suicide risk is increased in at-risk and affected patients. Depressed mood usually responds to antidepressants, but the response often is a partial one. Depression

Chapter 126

may occur in the context of a mixed psychiatric disorder, or there may be cycling of mania and depression. An unusual feature of some patients with Huntington’s disease is an overwhelming apathetic disorder, usually with a less pronounced dysthymic disorder. Patients often are poor at generating spontaneous, constructive activity. It is not uncommon for patients with Huntington’s disease to become extremely sedentary and spend most of the day in the house, either in bed or watching television. Some seem drawn to stay in bed and strongly oppose attempts to mobilize. With structure and guidance, a much more productive level of activity can be sustained longer into the illness. Distinguishing apathy from depression is difficult and often reduces to behavior resistant or responsive to antidepressants. A disorder of emotional control is common in patients with Huntington’s disease. This is often manifested by an increased level of irritability, with or without an underlying anxiety disorder. Angry outbursts in the home can be extremely disruptive and are one of the main causes for institutionalization of patients with Huntington’s disease. These outbursts often occur suddenly and without warning. They are usually short-lived (minutes), but their repercussions for other family members may be longer lasting, especially if they are associated with physical violence. The patient with Huntington’s disease may be contrite when confronted with the history but unable to alter the pattern of behavior. The trigger for emotional outbursts is not uncommonly a demand for assistance that is not met immediately or a request by the patient with Huntington’s disease that is not considered reasonable by a caregiver or family member. Occasionally, emotional dyscontrol is a manifestation of delusional thought or severe depression. We have seen some patients in whom episodes of emotional dyscontrol coincide with intense feelings of hunger occurring before a scheduled meal. Cigarette smoking also appears to be exceedingly common in people with Huntington’s disease, and the urge to smoke often is magnified to the extreme. Episodes of anger often occur in the context of some obstruction to smoking. In some very severe cases, hitting out or an angry outburst appears almost reflexive and triggered by most interactions. More commonly it is related to obstruction of the affected patient’s obsessive, perseverative behavior. One must inquire into the safety of children or older adults living in the home with a patient who suffers from emotional dyscontrol. A true psychotic disorder with hallucinations can occur, but it is rare as part of Huntington’s disease. Paranoia, delusional thought, bizarre behavior, and anxiety disorders occur more commonly in combination with disordered emotional control. Obsessive-compulsive behavior is very common in patients with Huntington’s disease. Patients may become fixated on a specific activity, such as smoking, watching television, visiting a specific place, warding off a specific person, continuing to drive, exercising, or returning to a broken home. Inflexibility and the inability to put off gratification combined with this perseverative thought can create major management trouble in the home or institution. Fear of being alone or removed from the family, fear of bathing, fear of leaving the house, fear of heights, and fear of choking are not uncommon and may complicate patient care.

Cognithre Disorders In Huntington’s disease, there is early memory impairment. This progresses over time and is accompanied by impaired attention, distractibility, and inflexibility. Previous mental tasks may take much longer and may be accompanied by more frequent errors.

Huntington‘s Disease

801

Reasoning ability, simple arithmetic processes, temporal ordering, and abstract thought all become severely impaired. Patients do most poorly on tests that entail a change in strategy. They have trouble with tasks that entail visual spatial integration of input, which may contribute to their driving disability. They have difficulty in generating and executing plans necessary to accomplish even simple goals at work or in the home. The dementia of Huntington’s disease is a subcortical dementia. Unlike Alzheimer’s disease, the memory disorder does not progress to amnesia. It appears that new memories can be made and old memories recalled, but this occurs less often as the disease progresses. There is eventually a poverty of thought; only a small proportion of events can be recalled. Perseveration and impersistence are prominent as the disease progresses. Patients with Huntington’s disease have severe impairment of motor skill learning. We have found a special inability for such patients to learn sequence information. In end-stage disease, either very limited and primitive communication or no apparent communication with the patient is possible. There is not a true aphasia, although speech production can diminish to the point that only a rare vocalization occurs. This can progress to mutism and lack of ability to follow even the simplest command. The condition most resembles severe abulia because early on coaxing is needed to obtain responses, and responses can occur in a specific context.

Sleep Disorders Patients may complain of inability to sleep or daytime drowsiness. Sleep studies often demonstrate abnormal sleep architecture, with frequent awakenings associated with motor jerks. Some patients improve with the use of clonazepam at bedtime. Amitriptyline at bedtime may also be helpful. Nutritionaland Metabolic Disorders

Many physicians caring for patients with Huntington’s disease suspect that there is a hypermetabolic disorder. Weight loss is common and can be extreme and rapid. Institutionalized patients who are sedentary except for their chorea and dystonia can need a huge caloric intake (3000 to 4000 cal/day) to maintain their body weight. It is our impression that patients do worse clinically as their weight decreases and sometimes improve as they gain weight. In our study of factors associated with slow progression of illness, with the exception of age at onset, weight at the time of diagnosis was the most statistically significantly associated variable. No particular food group is known to be of special benefit. Highcalorie nutritional supplements often are necessary to maintain body weight. Clinical Variants

In most cases, symptoms and signs of Huntington’s disease occur as outlined earlier, with soft signs and chorea first becoming manifest around age 40. The disease progresses over 20 years. The Boston Independence and Physical Disability Scales (Table 126-1) provide a means to chart the progression of the disease in an almost linear fashion from onset to end-stage disease. However, some patients deviate significantlyfrom the more common clinical course. Juvenile cases of Huntington’s disease occur uncommonly, and they are usually inherited from an affected father or from a mother who was also affected as a juvenile. The genetic cause of this

806

Movement Disorders

w Non-Parkinsonian Movement Disorders

paternal sex effect is discussed later in this chapter. Juvenile disease often presents as an akinetic or rigid syndrome without chorea. The saccadic eye movement velocity usually is very slow. Myoclonic tremor is common. Seizures may occur. Patients with juvenile Huntington’s disease often present with failing grades and a deterioration in their coordination. Their disease tends to progress more rapidly, and our data suggest that the rate of progression is closely associated with onset age. People without signs of Huntington’s disease until their seventh or eighth decade usually have a very slow progression of disability. They often present with chorea without dementia and often are misdiagnosed as suffering from senile chorea. Unfortunately, the transmission of the HD gene is associated with “anticipation” when transmitted through the father. The children of a father with late-onset Huntington’s disease can develop signs of the illness much earlier than their parents; this difference usually is associated with inheritance of a larger CAG repeat length in the child. This results from the instability of the mutation in spermatogenesis, where tremendous variation of CAG repeat length occurs (Duayao et al. 1993). In some patients, severe, disabling psychiatric disorders may cause disability years to decades before physical signs of the disease become evident.

nucleus. There is a fine structure to the caudate and putamen neural architecture, which also exhibits region-specific changes as the disease progresses. The pathologic features of Huntington’s disease have been mimicked to some degree by animal model studies using toxins. Intrastriatal injection of chemicals that activate the N-methyl+aspartate type of glutamate receptor in the brain cause degeneration of spiny neurons in animals and selective sparing of the diaphorase-staining aspiny neurons. More interestingly, chemicals that block mitochondrial function also lead to the pattern of neuronal death seen in the brain of a patient with Huntington’s disease. In addition, selective striatal damage is seen when these chemicals are administered systemically. There is also a described clinical syndrome in humans who have accidentally ingested one such mitochondrial inhibitor, 3-nitropropionic acid, which is characterized by striatal damage and dystonia. These observations have led to speculation that a mismatch between the energy demand caused by glutamate neurotransmission and the energy supply, as determined by mitochondrial function, leads to neuronal death, preferentially in the striatum and especially in spiny neurons. In further support of this theory, it has been found that the brain lactic acid levels are increased by excessive glutamate neurotransmission and by mitochondrial failure. Most importantly, brain lactate levels have been found to be elevated in patients with Huntington’s disease.

NEUROIMAGING FEATURES There is progressive atrophy of the caudate and putamen in patients with Huntington’s disease. Pathologic and morphometric imaging studies have shown that the degree of caudate atrophy is proportional to the affected person’s CAG repeat length divided by age (Penney and Rosas). The caudate nucleus normally protrudes into the ventricle so that atrophy is easily observed as an increase in the width of the lateral ventricle. There is loss of the usual convexity of the lateral wall of the ventricle, caused by caudate atrophy, leading to the so-called boxcar ventricular shape on computed tomography. Generalized brain atrophy is commonly seen along with caudate atrophy in the later stages of the illness. In patients with late onset, the caudate atrophy often is considered proportional to the cortical atrophy, and the diagnosis is not apparent by imaging alone. In juvenile Huntington’s disease, there may be an increased T2-weighted signal in the caudate on magnetic resonance imaging.

PATHOLOGIC FEATURES AND CLUES TO PATHOGENESIS The brain weight in end-stage Huntington’s disease is greatly reduced, but the cerebellar weight often is normal. The caudate in end-stage disease is severely atrophic and may consist only of a tissue paper-thin layer of glial cells with occasional neurons intermixed. The progression of the clinical signs of the disease appears to correlate with the pathologic grading of the degree of caudate atrophy. Interestingly, from a neurobiologic viewpoint, the neuronal death that occurs in Huntington’s disease is cell-type specific. In the atrophic caudate, interneurons that stain for nicotinamide adenine dinucleotide phosphate diaphorase and somatostatin are preferentially spared. The spiny neurons, which receive glutamatergic afferents from cortex and dopaminergic afferents from nigra and send GABAergic efferents to the pallidum are preferentially affected. There is also a gradient of cell death that occurs. The wave of cell death as the disease progresses seems to march from dorsal to ventral and medial to lateral in the caudate

MOLECULAR GENETICS The gene mutation that causes Huntington’s disease was identified in 1993. With the use of polymorphic DNA markers and linkage analysis in multiple large pedigrees, the gene was localized to the short arm of chromosome 4 in 1983. It was the first case of location of a disease gene based on DNA analysis of affected families, so-called reverse genetics. The HD mutation is an expansion of a trinucleotide repeat (CAG),, which codes for a polyglutamine stretch of amino acids in a novel protein. In unaffected people, the HD gene can contain up to 33 (CAG) repeats; the average number of repeats in this gene in the normal population is approximately 22. In people with Huntington’s disease, there are more than 38 (CAG) repeats in the HD gene that was inherited from an affected parent. People with Huntington’s disease usually also have a normal HD gene allele with fewer than 33 (CAG) repeats. The discovery of the gene mutation led to the explanation of a number of puzzling issues in the genetics of Huntington’s disease. Patients with juvenile Huntington’s disease were found to have inherited exceedingly long (CAG), repeats. Whereas most patients with Huntington’s disease have an allele with 40 to 55 (CAG) repeats, patients with the juvenile form have more than 60 and as many as 80 (CAG) repeats in their HD gene. As discussed earlier, patients with juvenile Huntington’s disease usually inherited the disease from an affected father. It was found that the length of the expanded (CAG), repeat could further expand in father-to-child transmissions. Indeed, the (CAG), length was fairly constant in all tissues except in the sperm, where it was found to be unstable. Sperm from affected men contained a wide variety of (CAG), repeat numbers. It is thought that fertilization by a sperm with a very high (CAG), repeat length in the HD gene gives rise to an offspring with juvenile Huntington’s disease. With the exception of the juvenile cases [(CAG), greater than 601, the actual (CAG), repeat length in patients with Huntington’s disease has little or no predictive value.

Chapter 126

Are there new HD mutations? We and others have followed individuals and families in whom a person with a clinical syndrome identical to Huntington’s disease was found in the absence of a family history of affected parents. We wondered whether these cases represented new mutations or manifestations of another disease. After the discovery of the HD mutation, we found that the suspected people did have the HD gene. More interestingly,family members who were elderly and not affected by Huntington’s disease had (CAG), repeats in the intermediate range (33 to 38), more than those found in the general population but less than those found in people with the disease. The appearance of “de novo” cases was explained by expansion of an HD allele in the intermediate (CAG), zone into the HD gene range (more than 38) during transmission from father to child. NEUROBIOLOGY OF THE HUNTINGTON’S DISEASE PROTEIN It is expected that a great deal will be learned about the pathogenesis of Huntington’s disease from studies of the H D mutation. It is hoped that the development of transgenic mouse strains containing the HD mutation will provide a faithful model of the disease to develop strategies aimed at preventing the progression of neuronal death. Homozygous knockout of the H D gene is fatal in a transgenic mouse model. Transgenic mouse models with expanded CAG in the huntinghn gene develop progressive neurologic and neuropathologic changes that vary with the specifics of the model. Indeed, even a fly model has been developed in which expanded CAG repeats in the huntingtin gene are associated with degeneration of the light-gathering apparatus, the rhabdomere. A uniform feature of the mouse models has been the finding of cellular and nuclear inclusions composed of the mutant huntingtin protein. This finding in the mouse led investigators to search for and find identical inclusions in humans with HD. Similar inclusions have been found in other CAG repeat disorders. Their role in neurodegeneration (i.e., whether they represent a cause or effect) is not known. A variety of molecular abnormalities have been isolated in the mouse models, including activation of caspase enzymes involved in programmed cell death, activation of the proteolytic enzyme calpain, and decreased production of the neurotrophin brainderived neurotrophic factor (BDNF). A major discovery has been the finding of altered gene transcription caused by mutant huntingh’n’s expanded polyglutamine repeat. This alteration seems to preferentially affect the genes regulated by a specific transcription factor, the SP-1 transcription factor. The expanded polyglutamine repeat in the huntingtin protein leads to a gain of some destructive function. This probably occurs because the abnormally long polyglutamine stretch in huntinghn binds to and alters the function of a normal protein or proteins. If a central molecular disorder can be identified, then agents may be designed to ameliorate the action of the mutant hunh’ngtin. Highthroughput screens, which check hundreds of thousands of compounds for their ability to alter one specific action or another of the mutant huntingth, are already up and running. Promising compounds will be identified that can then be tested in mouse models of Huntington’s disease for their ability to ameliorate neurologic deterioration and death. A number of assumptions still underlie any one strategy’s ability to bring a successful agent to patients, but the general method seems promising with persistent effort.

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The HD gene messenger RNA and protein are not confined to nervous tissue but have been found in all tissues. HD gene message and protein are also found in all brain regions, in brain tissue from people affected with the illness, and in brain tissue from normal subjects. There does not seem to be a differential localization of the messenger RNA or the protein to the striatum. This suggests that it may be possible to follow the molecular pathology of the mutant huntingtin protein in a nonneural tissue such as skin or white blood cells. GENETIC TESTING Presymptomatic testing for Huntington’s disease became available with the use of linkage analysis in appropriate families in 1983. The discovery of the gene mutation has simplified the genetic diagnosis, and it is now available in a variety of clinical laboratories. Because of the absence of a treatment that could prevent or slow down progression of the illness, there is no health benefit to early diagnosis. Many people want to know their gene status to plan their careers, families, and finances. However, because of the tragic nature of the illness and the occurrence in loved ones, many people live in constant fear of inheriting the illness. The emotional stress of living at risk can motivate people to seek presymptomatic testing. A favorable outcome can be a great relief, but there is generally a 50% chance that the result will be unfavorable. The stress of living with the knowledge that one has the HD gene can be much more severe than that of living with a 50% risk. During genetic counseling, many patients (30% to 50%) realize that the stress of living at risk is preferable to the stress of learning about an unfavorable gene status and drop out of testing. For this reason, it is recommended that presymptomatic testing be performed with careful counseling and with some delay between the request for testing and the actual DNA analysis. This allows the person at risk to weigh carefully the potential personal effects of knowing that they will surely inherit the disease that had previously disabled their parent, siblings, or other relatives. Because of the high prevalence of depression in the years preceding diagnosis, it is also considered wise to screen patients coming for genetic testing for depressive disorder and especially suicidality because the stress of an unfavorable test result in the context of a uncontrolled depressive disorder may be tragic. TREATMENT No treatment is known to slow the progression of the neuronal degeneration in Huntington’s disease. Medical treatment is tailored to specific issues that arise and affect the patient’s functional level. A number of experimental therapies have been tried in affected individuals. CARE-HD Study

In a National Institute of Neurologic Disease and Stroke (N1NDS)funded, randomized, double-blind study the Huntington’s Disease Study Group (HDSG) evaluated the ability of two agents, remacemide and coenzyme QlO (CoQlO), to slow progression of Huntington’s disease. Remacemide was chosen because it was an investigational N-methyl D-aspartate receptor blocker available in an oral form. CoQlO was chosen because it is a chemical active in mitochondrial electron transport and a free radical scavenger. CoQlO in dosages of 360 mg/day was shown to partially reverse the elevated brain lactate observed in patients with Huntington’s

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disease by magnetic resonance spectroscopy. Since the Coenzyme Qlo and Remacemide in Huntington’s Disease (CARE-HD) study design and execution, both CoQ 10 and remacemide were found to extend survival in transgenic HD mice. The CAFE-HD study was carried out using a 2 x 2 factorial design with one quarter of the mild to moderately affected patients in the placebo group, one quarter in the CoQlO alone group, one quarter in the remacemide alone group, and one quarter receiving both agents. Three functional scales were used to evaluate the study population of 325 affected patients over a 30-month period along with a variety of neuropsychological and motor tests. Remacemide had a minimal affect on reducing chorea scales, but loss of function occurred at the identical rate in those taking remacemide and those not on remacemide. In those treated with 600 mglday of CoQ10, deterioration also began at the identical rate as seen in those not on CoQ10. However, after 6 to 12 months there was a trend toward slowing of progression of disease in the CoQlO treated group on all three of the functional scales. This decrease of 15% to 20% in decline over 30 months did not reach statistical significance on the primary endpoint of the study, the total functional capacity scale (TFC; P = .15). Slowing of progression was statistically significant on the functional assessment scale ( P = .05), and the P value was .06 on the independence scale. No significant side effects of coQl0 were noted. Some have interpreted this as a negative study for both remacemide and coQ10. Others have been more convinced that the coQ10-treated group progressed identically with the noncoQl0 group over the first two or three evaluation periods, and then the groups began to diverge in their rate or decline, as might be expected with a neuroprotective agent (Fig. 126-1). The consistency of the differences seen on all three functional scales makes noise from the measurement devices an unlikely explanation of the difference. However, it remains possible that noise in the randomization could account for the difference, with more slow progressors assigned to the coQlO group by chance. Officially the HDSG interpreted this as the first study to show a trend toward benefit of a particular treatment in Huntington’s disease. There has been very little enthusiasm to pursue this 15% to 20% slowing of decline caused by coQl0 with another study. Instead the consensus has been to test another treatment coming from the transgenic animal studies that might show a greater benefit. The availability of transgenic mouse and even fly models of Huntington’s disease offers the opportunity for investigators to test a large number of compounds for their ability to delay neurologic deterioration or death. Treatment with unsaturated fatty acids, minocycline to inhibit caspase, creatine supplementation to improve cellular energy stores, n-butyric acid to inhibit histone deacetylase, and cystearnine inhibition of transglutaminase are other strategies in small clinical trials or under consideration.

Depression Depressive symptoms are common in patients with Huntington’s disease. They may be tied to despair arising from situational issues such as declining function in the workplace, inadequate supports in the home, financial difficulties, and social isolation. Psychological counseling and guidance in managing the disability that comes with this disease can cause remarkable change. Maintenance of structured activities for the affected patient, either at home, through local Huntington’s disease societies, in long-term care institutions, or in day care programs often is very helpful in helping the affected person to maintain a sense of self-worth.

CHANGE IN TOTAL FUNCTIONAL CAPACITY SCALE IN CARE-HD

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Antidepressant medications can be of great help in those with a serious mood disorder. Tricyclic antidepressants (amitriptyline, imipramine, and nortriptyline) and serotonergic agents (fluoxetine or sertraline) have been used most commonly. Initially, low dosages are prescribed and changes in dosage made at 3-week intervals until depression responds or toxicity develops. Amitriptyline before bedtime is also useful in some patients for their sleep disorder. Unlike patients with Alzheimer’s or Parkinson’s disease, patients with Huntington’s disease do not have increased sensitivity to the anticholinergic side effects of the tricyclics. Fluoxetine can suppress appetite, so weight should be carefully monitored. The tricyclics may also be useful because they tend to stimulate appetite. Occasional patients respond poorly to all attempts to treat their severe depression. In many cases, a partial improvement occurs, but some chronic dysthymic disorder persists for decades. In occasional patients with severe incapacitating depression, monoamine oxidase inhibitors or electroshock therapy has been successful. Depressed patients with Huntington’s disease may also suffer from emotional dyscontrol disorders. Suicide is not rare, and patients should be questioned about suicidal intent. In patients with a history of suicidal thought or with impulsive behavior, care should be taken to limit the amount of antidepressant and other

Chapter 126

medications prescribed at one time. When appropriate, a family member or caretaker should administer the medications.

Chorea does decrease in frequency, speed, and amplitude with dopamine blocking agents but often at the price of increased incoordination, dystonia, and bradykinesia. In many cases, chorea is overmedicated with neuroleptic drugs, to the patient’s disadvantage. It is therefore important to determine whether treatment is leading to a functional improvement, as opposed to a cosmetic improvement, in chorea at the cost of decreasing motor function. In general, haloperidol dosages greater than 5 mg/day are met with worsening motor function, although exceptions are common. In some patients, benzodiazepines such as clonazepam are helpful. Emdonal Dyscontrol Management of the emotional outbursts is perhaps the most difficult and important task for the caregiver. Sudden verbal or physical abuse of self or others is the most common reason for institutionalization of patients with Huntington’s disease. Patients should first be evaluated for those events in the environments that trigger the outbursts. Common-sense but creative changes such as adjustments in the time of feeding if outbursts are triggered by hunger, a relaxation strategy when anxiety occurs, and setting schedules and safe havens for smoking, can be very helpful. In some, there is an underlying depression or mania, and treatment with antidepressants, carbamazepine, valproate, or lithium is helpful. In some, there is a chronic sleep disorder, and irritability is related to sleep deprivation and improves with more restful sleep. Clonazepam, carbamazepine, and valproate may be helpful in limiting the level of irritability that underlies the emotional dyscontrol. Some patients are inappropriately fixated on specific concerns or demands. These are often the most difficult to manage; a trial of antidepressants that are useful in treating obsessive-compulsive disorder (fluoxetine or clomipramine) can be of some help. In some instances, a delusional thought disorder underlies the outbursts, and this may not always be apparent because of the patient’s communicative disability. Neuroleptic agents such as haloperidol and thioridazine (more sedating) are effective in some instances, but their psychiatric benefits are balanced by their tendency to cause increased bradykinesia and rigidity. The motor control side effects of the neuroleptic medications tend to increase as the disease progresses. Quetiapine and clozapine are the most useful agents because they are potent antipsychotic agents with minimal extrapyramidal side effects. Quetiapine can be especially helpful in managing the emotional dyscontrol of Huntington’s d’isease. In difficult-to-control patients, often a combination of medications is used. In addition to antidepressants and atypical neuroleptics, valproate or carbamazepine should be tried in an attempt to level mood; high-dose propranolol and lithium can be effective in some severe dyscontrol disorders. Motor Control Disorder

No medical treatment is known to have a major effect on this very disabling aspect of the disease. Emphasis should be placed maintaining safe ambulation and swallowing as long as possible. Physical therapy and conditioning exercises can improve a patient’s safety and function. Some patients are thrown off balance

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by their chorea, and a very small dosage of haloperidol may decrease the rate of falling. However, haloperidol worsens the postural stability, so it also increases the rate of falling in some. In some rare patients with a parkinsonian variant of Huntington’s disease, a small dosage of a dopamine agonist is helpful. Alterations in diet are necessary to prevent aspiration, with a soft, thick, moist substance being the most easily swallowed.

CONCLUSION With discovery of the gene mutation and development of transgenic animal models of the disease, there is new hope that scientific and clinical research will offer promising therapies based on new knowledge about the pathogenesis and effects of the gene mutation in Huntington’s disease. At present, the families and patients afflicted by Huntington’s disease often live a life that is very different from that of the average American. There is a great need for understanding and knowledgeable physicians, social workers, genetic counselors, physical therapists, and other care providers to help affected patients maintain their self-worth and dignity throughout neurodegeneration. SUGGESTED READINGS

Bittenbender JB, Quadvasel F A Rigid and akinetic forms of Huntington’s chorea. Arch Neurol 7:275, 1962 Duayao M, Ambrose C, Myers R et al: Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4387-392, 1993 Dunah AW, Jeong H, Griffin A et al: Spl and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296(5576): 2238-2243, 2002 Ferrante RJ, Andreassen OA, Dedeoglu A et ak Therapeutic effects of coenzyme QlO and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 22(5):1592-1599, 2002 Gervais FG, Singaraja R, Xanthoudakis S et al: Recruitment and activation of caspase-8 by the huntinghn-interacting protein Hip-1 and a novel partner Hippi. Nat Cell Biol 4(2):95-105, 2002 Gusella JF, Wexler NS, Conneally PM et ak A polymorphic DNA marker genetically linked to HD. Nature 306234, 1983 Haydon MR Huntington’s Chorea. Springer-Verlag, New York, 1981 Hersch S, JonesR, Koroshetz W, Quaid K The neurogenetics genie: testing for the Huntington’s disease mutation. Neurology 44:69-73, 1994 Huntington G On chorea. Med Surg Rep 26317-321, 1872 Huntington’s Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971-983, 1993 Huntington’s Study Group: A randomized, placebo-controlled trial of Coenzyme Qloand Remacemide in Huntington’s Disease (CARE-HD). Neurology 57:397404, 2001 Myers RH, MacDonald M, Koroshetz W et ak De novo expansion of a (CAG), repeat in sporadic Huntington’s disease. Nat Genet 5:168-173, 1993

Myers RH, Vonsattel JP, Stevens TJ et ak Clinical and neuropathologic assessment of severity in HD. Neurology 38:341-347, 1988 Nasir J, Floresco S , OKusky JR et ak Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioural and morphological changes in heterozygotes. Cell 81:811, 1995 Rosas H, Koroshetz WJ: Huntington’s disease. In Choi DW, Marcoux F (eds): Handbook of Experimental Pharmacology: CNS Protection. Springer Verlag, Heidelberg, 2002 Rosenblatt A, Ranen NG, Nance MA, Paulsen JS: A Physician’s Guide to the Management of Huntington’s Disease. 2nd Ed. Huntington’s Disease Society of America, New York, 1999 Young AB, Shoulson I, Penney JB et al: Huntington’s disease in Venezuela: neurological features and functional decline. Neurology 36244-249, 1986

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127 Tardive Dyskinesia and Other Drug-Related

Movement Disorders Edison Miyawaki

TD is a clinically diverse syndrome in which choreatic, athetoid, dystonic, or other abnormal involuntary movements manifest late in the course of neuroleptic treatment. Research definitions cite a minimum of 3 months’ exposure to a neuroleptic, persistence of involuntary movements 1 month after stopping the offending drug, and exclusion of other identifiable causes. In clinical practice, however, dyskinesias may appear after a shorter time on the medications and may persist even after very brief exposure. Reports from the preneuroleptic era (e.g., Kraeplin in 1919 or Leonhard in the 1930s) described various strange, adventitious movements in psychotic patients. These presumably sporadic dyskinesias, as well as cases of senile chorea in people without psychiatric illness, have raised questions about the direct causeand-effect relationship between neuroleptics and tardive syndromes. Over time, however, it has become clear that TD is a distinct, if heterogeneous, clinical syndrome.

in and out of the mouth. Not all facial movements during neuroleptic treatment represent TD: Perioral tremor (rabbit syndrome) is understood as a sign of drug-induced parkinsonism, and orofacial dyskinesias may be seen in older, edentulous patients without history of neuroleptic use. Involuntary movements of the proximal limbs and trunk in TD are also common and may be of such large amplitude and high velocity as to suggest ballismus. Some cases reach bizarre proportions, as in “copulatory” pelvic thrusting. Distal movements also occur, including “air guitar” fingers, foot tapping, and extension of the great toe. Choreoathetosis is the term applied to many of these manifestations, but there is an additional, monotonously repetitive quality in TD that is characteristic. Terms such as tardive stereotypy and rhythmic chorea have been applied as a consequence. As with other movement disorders, the involuntary movements in TD worsen with emotional stress, diminish with sedation, and disappear with sleep. Dystonia may accompany stereotypic or choreoathetoid movements in TD. In some cases, the sustained abnormal postures of the limbs, head, neck, or trunk may be the dominating feature, and some have thought that tardive dystonia is a separate syndrome with predilection for younger age groups. Mean age of onset is 40 according to the literature, but all ages are at risk. Older patients may be predisposed to focal dystonias, particularly of the head and neck. Torticollis, retrocollis, oromandibular dystonia, and truncal dystonia are characteristic. Striking lateroflexion and backward twisting of the trunk on the waist (called Pisa syndrome) has been observed both acutely and in tardive fashion. The dystonias often are the most debilitating aspects in TD: Morbidity results from problems in gait, dystonia-induced rib fractures, eating-induced dystonias, opisthotonic posture (severe arching of the back and retrocollis), and other disabilities. Additional tardive syndromes have been described. Akathisia, a restlessness partially relieved by volitional activity, is a well-known acute effect of neuroleptics, but it has also been observed as a late effect. Recurrent oculogyric crises can occur after discontinuation of long-term neuroleptic treatment. Various reports of respiratory dyskinesia underscore the idea that any muscle group under voluntary control can be affected in TD: Periodic tachypnea, other irregular respirations, grunting, and dysphagia have all been described. Rarely, tremor can be a tardive phenomenon. Although typically seen in drug-induced parkinsonism, tremor can worsen upon withdrawal of the offending drug and may respond to dopamine-depleting agents. Tardive myoclonus has also been reported.

Phenomenology

Natural History and Epidemiology

The most common signs involve orofacial and lingual movements. Onset is insidious, and early features are restless tongue movements, patterned facial movements resembling tics, and increased eyeblink frequency (blepharospasm). Later signs include “vacuous” chewing movements, lip smacking, and tongue movements

TD is a variable disease, but a wealth of data suggest that its natural history can be affected by prudent neuroleptic management. TD can remit when neuroleptics are discontinued promptly upon diagnosis, or TD can attenuate with reductions in neuroleptic dosage, often a more feasible alternative in the clinical setting.

A number of major drug-related movement disorders are associated with the use of the so-called typical antipsychotics. The major mechanism of action of these traditional neuroleptics (drugs that produce effects on the nervous system) is dopamine receptor antagonism. Through the 1990s, however, atypical antipsychotics were prescribed increasingly in neurology and psychiatry. These newer neuroleptics have two aspects that make them atypical: They are mixed dopamine and serotonin receptor antagonists, and they result in fewer acute and late extrapyramidal effects. The 1990s also saw the ascendency of serotonin reuptake inhibitors for treating depression and other disorders, and reports have surfaced about various movement disorders associated with their use. The atypical antipsychotics and serotonergic antidepressants are changing the landscape of the major drug-related movement disorders. New cases of tardive dyskinesia and other traditional, neuroleptic-induced syndromes may have become less common, but they have not disappeared, and other interests have emerged. Also in the 1990s, a large body of work addressed basal ganglia pathways whose dysregulation may be responsible for a variety of drug-associated phenomena. Attention has focused particularly on levodopa-induced dyskinesia in Parkinson’s disease, but the implications are wide ranging. This chapter addresses classic drug-induced syndromes and incorporates a number of nonneuroleptic toxicities into that discussion; it ends an overview of basal ganglia pathophysiology as it relates to drug effects.

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In long-term studies, the likelihood of clinical improvement in TD correlates with duration of time off drug or, alternatively, the length of follow-up. Studies examining outcome after more than 5 years show the greatest numbers with clinical improvement. Despite these optimistic views, some cases of TD persist indefinitely and can worsen over time. In the 1980s, it was generally agreed that prevalence of TD was on the order of 20% among psychiatric patients. Gardos and Cole estimated that the risk of developing TD for a schizophrenic patient treated with neuroleptics for 1 continuous year was approximately 5%. Kane et al. have quoted a cumulative incidence of 20% after 4 years of treatment (roughly 5% per year, in agreement with Gardos and Cole). More recently, attention has shifted to questions about the likelihood of developing TD during treatment with one of four FDA-approved atypical antipsychotics: clozapine, risperidone, olanzapine, and quetiapine. Kane followed 28 patients who had received clozapine for at least 1 year. Two patients, both of whom had previously taken typical neuroleptics, appeared to develop mild TD on clozapine. A prospective study of 122 risperidone- and haloperidol-treated older adults (61 in each group) concluded that the risk of TD was significantly less on risperidone; life table analysis was used based on a %month period of observation. In a large, double-blind, prospective study comparing 1 year of olanzapine treatment with haloperidol treatment, TD risk in the olanzapine group was one tenth that of the haloperidol group, and it was estimated that the annual risk of TD during olanzapine treatment was less than 1%. A case report of TD during quetiapine treatment has been published, but systematic data are not available at this time. In sum, TD can still occur during treatment with atypical antipsychotics,but the likelihood appears significantlyless than has been reported for typical antipsychotics.

Risk Factors The literature regarding predispositions to TD has addressed patient and drug treatment variables. Reports have been various and often contradictory. Authorities seem to concur that age (greater than 60 years), female gender, diagnosis of an affective disorder, and a history of prior neuroleptic-induced movement disorder are major patient-related risk factors. Older patients are more likely to develop severe and persisting forms of TD. Prevalence data find higher rates among women than men (27% versus 21%). Older women exhibit the highest rates for both TD and spontaneous dyskinesia. Among the affective disorders, recurrent depression in particular seems to confer high risk, perhaps because of the intermittent nature of mixed antidepressant and antipsychotic treatments. Patients who experience prior adverse neuroleptic reactions are at greater risk for TD, but experts are mixed about the type of reaction-acute dystonic reactions or drug-induced parkinsonism-that confers the greatest risk. Among treatment-related variables, a number of potential factors have been examined, including drug type, dosage, and concomitant medications. Perhaps the only point of consensus is that no specific type of typical neuroleptic (phenothiazine,thiothixene, or butyrophenone) is more likely than the other to cause TD. Higher dosage and longer duration of treatment have long been thought to increase risk, but evidence to confirm either suspicion has been curiously wanting. Another widely held notion is that concomitant use of anticholinergics during neuroleptic treatment increases the likelihood of TD. Although anticholinergics can worsen existing dyskinesia, their use in psychiatric patients before

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the development of TD may not be a significant risk factor. Anticholinergics are useful in treating acute and tardive dystonias, and the varying anticholinergic properties of typical neuroleptics do not appear to increase or decrease the likelihood of TD. Dmerential Diagnosis

TD must be distinguished from other neuroleptic-induced movement disorders and from other drug-associated dyskinesias. Parkinsonism, dystonia, or akathisia can coexist with TD in one quarter to one third of cases. Dyskinesias similar to those seen in TD have been reported in association with a number of commonly used drugs (Table 127-1); movements generally remit with discontinuation of the non-neuroleptic drug in question. In general, TD distinguishes itself from other drug-induced syndromes because signs may persist after discontinuation of the neuroleptic. Sporadic dyskinesias described in schizophrenia may also persist, but they are often less rhythmic and more variable and complex. Adventitious orofacial movements associated with de-

w TMLE 127-1. Drugs Associated with Hyperkinetic Movements (Other Than Typical Neuroleptics) Drugs not commonly recognized as dopamine antagonists Prochlorperazine Metoclopramide Amoxapine (7-hydroxy metabolite) a-Methyl-p-tyrosine Drugs associated with dyskinesia in idiopathic Parkinson’s disease Levodopa or carbidopa Dopamine agonists (bromocriptine, pergolide, pramipexole, ropinerole, amantidine) Drugs associated with chorea, stereotypy, or dyskinesia during acute use or withdrawal Alcohol Amphetamines (and other stimulants) Anticholinergics (including atropine) Anticonvulsants (carbamazepine, ethosuximide, methsuximide, phenytoin, topiramate, valproate) Antihistamines Baclofen Benzodiazepines(triazolam in particular) Buspirone Caffeine Calcium channel blockers (cinnarizine, flunarizine, verapamil) Chloroquine-basedantimalarials Clebopride Cyclosporine Diazoxide Digoxin Fentanvl Flecainide H,-specific blockers: cimetidine, ranitidine lsoniazid Methadone Methyldopa Mianserin Pentamidine Reserpine Steroids (anabolic and oral contraceptives) Theophylline Other drugs, other movements Cefiazidime, other P-lactam antibiotics (asterixis) Morphine and meperidine (myoclonus) Monoamine oxidase inhibitors (tremor, myoclonus) Lithium (tremor, myoclonus) Drugs and treatments that may aggravate an existing tardive state Tricyclic antidepressants Lithium Cannabis Electroconvulsivetherapy

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mentia and edentulism also mimic TD. Neuroleptic withdrawal may itself result in dyskinesias that can take days, weeks, or months to resolve. TD and these so-called withdrawal dyskinesias may have a common pathophysiologic mechanism. TD shares clinical features with many basal ganglia diseases. Meige’s syndrome is an idiopathic focal dystonia characterized by blepharospasm and oromandibular dystonia that typically begins in middle age and may not be distinguishable from orofacial TD. Idiopathic torsion dystonia, young-onset parkinsonism, and doparesponsive dystonia, all diseases with a predilection for the young, may mimic tardive dystonia. Facial tics and grimacing characterize Tourette’s syndrome, although childhood onset and the characteristic fluctuating course in Tourette’s help differentiate it from TD. Many idiopathic disorders are progressive and are not associated with prior neuroleptic exposure, in contrast to the static or slowly resolving course of TD. Other differential diagnostic considerations include medical disorders associated with choreoathetosis: hyperthyroidism, hypoparathyroidism, hyperglycemia, Syndenham’s chorea, chorea associated with lupus, the antiphospholipid antibody syndrome, chorea gravidarum, Henoch-Schonlein purpura, and neuroacanthocytosis. Rare cases of brain tumors or other space-occupying lesions have manifested as dyskinesias. Stereotyped mannerisms are common in mental retardation, autism, pervasive developmental disorders, viral encephalitis, and various storage and metabolic diseases (e.g., ceroid lipofuscinosis, phenylketonuria). A peculiar stereotypy (hand- and self-clasping) characterizes Rett’s syndrome, an autistic disorder of girls recently linked to mutations of a methyl-CpG binding protein gene (MECP2) located on the X chromosome. Other basal ganglia disorders have prominent neuropsychiatric features and movements that may be confused with TD. As a general rule, the presence of neurologic signs other than dyskinesia or dystonia (e.g., pyramidal signs, ataxia, prominent dementia) suggests an alternative diagnosis. Huntington’s disease, an autosomal-dominant dementia linked to chromosome 4, can present with either early dyskinesia or subtle personality change, but it is relentlessly progressive. Unlike in Huntington’s disease, pure chorea is an unusual sign in TD. Wilson’s disease is an autosomal recessive disorder linked to chromosome 13; consanguinity is common in the family history. Onset of symptoms can occur in childhood, adolescence, or early adulthood. Two major forms have been described: Rigidity is the hallmark of a dystonic form, whereas tremor, dysarthria, clumsiness, and gait instability characterize a pseudosclerotic form. Both are progressive, and both involve evidence of abnormal copper deposition (in Descement’s membrane at the corneal limbus, in liver, and in the lentiform nucleus). Hemochromatosis and alcoholic cirrhosis with portosystemic shunting have been associated with a non-Wilsonian hepatolenticular degeneration with similar motoric features. Hallervorden-Spatz disease is an autosoma1 recessive disorder with onset in childhood. Progressive spasticity, dystonia, choreoathetosis, and dementia accompany pathologic deposition of iron in the globus pallidus and brainstem. Treatment

Prevention is the answer to any iatrogenic problem, so the indications for neuroleptics should be clear, the need for ongoing treatment should be reassessed regularly, and minimum effective dosages should be used. Beyond dosage reduction or neuroleptic

discontinuation as a general, first-line strategy, different TD syndromes warrant different treatment approaches. Options in Tardive Dystonia. Anticholinergics (e.g., trihexyphenidyl) have been used traditionally as a first-line agent, but high dosages often are needed, and side effects often are limiting. Benzodiazepines (e.g., clonazepam) are also useful alone or in combination with anticholinergics. Again, high dosages may be necessary, with attendant concerns about dependency and sedation. Baclofen may be of some benefit. Tetrabenazine, a dopaminedepleting agent, is not commonly available in the United States, but it has been used quite successfilly in movement disorder clinics. Tetrabenazine is a modest dopamine receptor antagonist and therefore runs the theoretical risk of perpetuating TD as it treats it. Reserpine is a commonly available alternative to tetrabenazine. Orthostatic hypotension and depression are major side effects for both drugs. The notion that anticholinergics can exacerbate coexisting choreoathetosis is open to question, but if a dystonia improves on an anticholinergic, it should be slowly withdrawn and reintroduced only if dystonias reappear. In general, it is wise to limit polypharmacy whenever possible. Particularly in the case of the TDs, however, response can be lackluster; multiple agents at one time or serial empirical trials often are necessary. Three options exist in recalcitrant cases. Some have advocated use of atypical antipsychotics early in TD treatment. To date, the greatest experience has been with clozapine, but the risk of agranulocytosis and blood-monitoring considerations have led most clinicians to reserve its use until other trials have failed. Botulinum toxin, a widely accepted treatment for focal and segmental dystonias, is an effective treatment in tardive dystonia, but not all dystonias are amenable because of the size or numbers of muscles involved. Surgeries, particularly lesions of the thalamus or globus pallidus, have been explored in case reports. Options in Choreoathetoid TD. Because TD appears to be less common with the atypical antipsychotics, many patients on typical antipsychotics have been switched to one of the four approved atypicals with the idea that TD might also be managed to some degree. When such a strategy is adopted, use of clozapine should be reserved for the last, for reasons cited earlier. Increasingly, the atypicals are being used as first-line agents to treat psychotic conditions, but the risk of TD still exists. Therefore, other treatment options still must be entertained. Oxidative stress has been an interest in TD as elsewhere in neurology: Vitamin E, at dosages of 1600 IU/day, is advocated, but its efficacy is unclear. Agents that augment y-aminobutyric acid (GABA) neurotransmission are popular, including not only the benzodiazepines (particularly clonazepam and diazepam) but also valproic acid, and, uncommonly, y-vinyl GABA. Baclofen, a third GABA-ergic agent, has been used at high dosages, but it sedates and has itself been associated with chorea in a case report. As in tardive dystonia, tetrabenazine and reserpine have been used in difficult cases. High dosages may be needed, and benefits often are delayed for weeks to months. Use of electroconvulsive therapy in TD is controversial: In some reports, it has worsened rather than improved adventitious movements. The benefits of pallidal or thalamic surgeries are theoretically viable but untested. Options in Tardive Akathisia. In acute akathisia, anticholinergics have little effect, except in cases in which there is coexisting parkinsonism. In tardive akathisia, anticholinergics are not useful. P-Blockers may be an option, but in general tetrabenazine and reserpine seem most effective. There has been little reported on tardive akathisia with use of the atypical antipsychotics.

Chapter 127

ACUTE DYSTONIC REACTIONS As in TD, clinical phenomenology in the acute dystonic reactions is diverse. Oculogyric crises, blepharospasm, trismus, oromandibular dystonia, abnormal tongue positions (e.g., the bon-bon sign, when the tongue fixes to the inside of the cheek), myoclonic contractions of the face, neck, and extremities, and glossopharyngeal contractions (which may present with stridor) may all manifest in combination or in isolation. Spasmodic torticollis or retrocollis is common, and, in children, dramatic truncal presentations (opisthotonus, tortipelvis) may occur. Acute dystonic reactions occur early in the course of treatment with typical neuroleptics, usually within the first 5 days, but serotonin-specific drugs (including the selective agonists buspirone and sumatriptan) may also precipitate such reactions. Acute dystonic reactions occur in perhaps 2% of patients who receive typical neuroleptics, but African American and Asian American men may be at greater risk. High-potency neuroleptics such as haloperidol and fluphenazine are more likely to result in acute dystonia than lower-potency agents such as chlorpromazine and thioridazine. Patients treated with depot injections may present with multiple episodes, often within 72 hours of administration. Neuroleptic use in any medical or psychiatric context may result in acute dystonic reactions. Anticholinergics (e.g., parenteral diphenhydramine or benzotropine) abort the acute dystonias; benzodiazepines are a second-line option. Prophylactic use of anticholinergics may be indicated in psychiatric settings because of the formidable compliance problems that can result from an acute reaction.

AKATHlSlA Akathisia (from Greek, “not sitting”) is a disorder in which various excessive movements (forced marching, rocking in place, even moaning) are associated with an inwardly felt discomfort, variously described as a pulling or drawing feeling in the legs or a profound anxiety. Movements can be voluntarily suppressed, but only for a time. Haskovec (1901) first described the phenomenon in hysteria; later authors observed it in Parkinson’s disease, encephalitis lethargica, and postencephalitic parkinsonism. Many now believe that akathisia is a form of drug-induced parkinsonism. Akathisia shares features with restless legs syndrome, but in the latter, symptoms tend to manifest only‘when recumbent and typically in the evening, and other features are absent, including myoclonus, periodic movements of sleep, and dystonic postures in the legs and feet. Pseudoakathisia is motor restlessness without associated subjective distress. Acute akathisia should be suspected in any patient with subjective and objective restlessness after first neuroleptic exposure, change to a higher-potency agent, or an increase in dosage of a standing neuroleptic. Worsening “psychotic” agitation in the context of escalating neuroleptic dosage may be a clue to neuroleptic-induced akathisia. “Cyclic” akathisia has been described in patients who receive regular depot neuroleptic injections. Akathisia has also been associated with the serotoninselective reuptake inhibitors, particularly fluoxetine and paroxetine. Pharmacologic treatments have had inconsistent results. Traditionally, anticholinergics have been a mainstay, but their efficacy in akathisia is less convincing than in neuroleptic-induced dystonia or in drug-induced parkinsonism. When akathisia is accompanied by parkinsonism, anticholinergics are a reasonable first-line agent.

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Lipophilic P-adrenergic drugs (e.g., propranolol) may be the most effective treatment, and benzodiazepines can relieve subjective distress.

DRUG-INDUCED PARKINSONISM (DIP) Any or all of the cardinal signs of idiopathic Parkinson’s disease-resting tremor, bradykinesia, rigidity, and postural instability-may be produced by neuroleptics and by a variety of other drugs, as reviewed in Table 127-2. Unlike in TD, differences in neuroleptic type influence the likelihood of developing DIP Higher-potency agents (e.g., haloperidol, fluphenazine, and thiothixene) present greater risk than lower-potency agents (e.g., chlorpromazine). Although the atypical neuroleptics are associated with less DIP, risperidone in particular may result in DIP in dose-dependent fashion, with greater risk at more than 6 mg per day; older adults may be vulnerable at significantly lower dosages. Ninety percent of cases develop within the first 72 days of treatment, according to an old but often-cited survey. Many manifest DIP in the first 3 weeks. Prevalence figures vary widely, from 10% to more than 65%, perhaps reflecting the underdiagnosis of DIP in some settings, such as among institutionalized older adults. However, there is agreement that older patients on high-potency agents are at particular risk. Bradykinesia or akinesia may be the only manifestation; rigidity and reduced armswing are early and frequent findings. Mutism, drooling, and dysphagia may be prominent. Tremor is less common in DIP than in idiopathic Parkinson’s disease, but when present it is often asymmetrical and may be of resting, postural, or action varieties. Perioral tremor should be considered a focal manifestation of DIP. DIP has been reported during neuroleptic withdrawal, and persisting parkinsonism has been described for as long as 18 months in small numbers of patients. In an older adult population, 25% of patients with DIP developed signs of idiopathic Parkinson’s disease within 41 months of drug discontinuation. These observations have prompted speculation that DIP can manifest in those who are vulnerable to the development of idiopathic Parkinson’s disease and other related disorders. Individual sensitivity to neuroleptics has been invoked to explain the absence of a clear dosage-response relationship in DIP. Two clinicopathologic cases have been reported in which DIP resolved after neuroleptic discontinuation, but nigral degeneration, Lewy

R ’IrA.rr 12T-Z Drugs Assodated with Parkinsonism Typical antipsychotics Drugs not commonly recognized as dopamine antagonists (see Table 127-1) Risperidone, especially a t more than 6 mg per day Lithium Valproic acid Selective serotonin reuptake inhibitors (SSRls): fluoxetine, paroxetine, fluvoxamine SSRls in combination with Cimetidine Selegiline Other monoamine oxidase inhibitors Chronic cocaine Alcohol withdrawal Cisapride Lovastatin Amiodarone Diltiazem Other calcium channel blockers, flunarazine, and cinnarizine (these agents chemicallv resemble the neuroleotic trifluoDerazine)

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bodies, and neurochemical evidence for loss of striatal dopamine were documented at autopsy. DIP should be managed with reduction in neuroleptic dosage, change to a lower-potency agent, or discontinuation of an offending drug. When such interventions are ineffective, the anticholinergics trihexyphenidyl and benztropine often are used. Amantidine may also be effective. Clinicians have traditionally understood a reciprocity between dopamine and acetylcholine in the basal ganglia, as supported by the use of anticholinergics in DIP and in idiopathic Parkinson’s disease, or in light of cases in which parkinsonism has emerged during treatment with cholinesterase inhibitors such as physostigmine or tacrine. However, it appears that dopamine receptor blockade differs qualitativelyfrom depletion states, and anticholinergics may be preferentially beneficial only in DIP. Levodopa reverses parkinsonism in animals and humans exposed to reserpine, a dopamine-depleting drug, but dosages of levodopa to as high as 1 gram have not been effective in treating DIP. Some 28 reports have been published regarding motoric effects of the selective serotonin reuptake inhibitors (SSRIs), specifically fluoxetine, paroxetine, and fluvoxamine. DIP, akathisia, and dystonic reactions have been described. Signs develop within days or weeks of treatment. Concomitant neuroleptic use in some cases led to an early theory that drug interactions or SSRI-mediated effects on drug metabolism were responsible, but alternative mechanisms have been studied to account for an isolated SSRI effect, including serotonergic modulation of dopamine neurotransmission. Rigidity, tremor in some cases, and shuffling gait all reverse with discontinuation of the SSRI.

NEUROLEPTlC MALIGNANT SYNDROME (NMS) NMS is an uncommon complication of neuroleptic therapy, thought to occur in less than 1% of patients. Both the typical and atypical neuroleptics have been implicated. Hyperthermia (more than 37OC) and muscle rigidity are cardinal features, which appear after first drug exposure or after an increase in dosage. Associated phenomena include a confusional state, autonomic instability (tachycardia, blood pressure fluctuations, sweating, tachypnea), elevations in creatine phosphokinase, leukocytosis, and metabolic acidosis. Various combinations of these signs may occur. Acute withdrawal of levodopa or dopamine agonists in Parkinson’s disease may induce an NMS-like condition. Lithium may act synergistically with neuroleptics to induce NMS in some cases. Infection, dehydration, and use of high-potency neuroleptics are other predisposing factors. All ages are at risk; men and women are affected equally. Mortality, estimated at 10% to 25%, typically results from pulmonary embolism associated with deep vein thrombosis, renal failure, cardiovascular collapse, or pneumonia. Differential diagnosis includes meningoencephalitis, systemic infection, heat stroke, traumatic or other rhabdomyolysis, anticholinergic or lithium toxicity, strychnine poisoning, tetanus, generalized dystonia (various causes), and the serotonin syndrome. Two additional entities, lethal catatonia and malignant hyperthermia, merit separate comment. Lethal catatonia is a condition that was first described before the use of neuroleptics. It is associated with psychotic agitation and, in its most severe forms, akinesia, rigidity, fixed abnormal postures, and mutism. Profoundly catatonic patients may manifest fever and dysautonomia. Some have argued that lethal catatonia is clinically equivalent to NMS except for the neuroleptic exposure (analogy may be drawn to hyperkinetic movement disorders similar to TD seen in

unmedicated psychotic patients). Malignant hyperthermia (MH) is a hereditary disorder in which patients exposed to inhaled anesthetics or succinylcholine develop a severe akinetic rigidity that does not respond to pancuronium or associated muscle relaxants. MH may occur in the absence of a family history, especially in patients with known preexisting muscular dystrophies or myopathy. In patients at risk for MH, biopsied muscle fibers exhibit exaggerated contractility upon exposure to halothane and caffeine. Similar muscle changes can occur in NMS, but they have been inconsistently observed, and the mechanism for such abnormalities may differ in NMS (e.g., neuroleptics may affect calcium levels at sarcoplasmic reticulum). Anesthetics do not predispose to NMS, and patients with MH are not at greater risk for NMS. Muscle relaxants such as pancuronium have been used safely in very severe forms of NMS. Dopaminergic blockade, perhaps at the level of hypothalamus, has been the most popularly espoused mechanism for NMS. Henderson and Wooten postulated the hypothalamic effect in 1981, based on a case in which a parkinsonian patient with a history of a psychotic disorder and chronic haloperidol therapy developed NMS upon withdrawal of dopamine agonists. Traditional neuroleptics may affect temperature regulation to some degree in all patients. The reasons why certain patients progress to NMS are obscure, but in an interesting prospective study of 26 episodes in 25 patients over 9 years, reduced serum iron levels (less than 10 kmol/L) were consistently observed at the time of diagnosis, often with normalization after the NMS resolved. Reduced serum iron may change central dopamine receptor sensitivity and thereby predispose to NMS, but other factors probably play a role. Treatment in NMS is largely supportive. Neuroleptic, anticholinergic, and lithium salts should be discontinued. Fluid status must be monitored closely. Concurrent infection must be excluded or treated aggressively. Low-dose heparin lessens the risk of deep venous thrombosis. Bromocriptine, dantrolene sodium, and levodopa may each have a role in refractory cases, but their efficacy is unclear. Their routine use is not universally accepted. In some patients, reinstituting neuroleptic treatment after a bout of NMS is necessary. Even when the same neuroleptic or one of similar potency is reintroduced, risk of recurrence is estimated at 50%. Why the risks are not higher is unclear. Neuroleptic rechallenge should be delayed for at least 2 weeks after a bout of NMS to minimize risk, and use of lower-potency agents is preferable.

SEROTONIN SYNDROME Perhaps the earliest case of what has come to be known as the serotonin syndrome dates to 1955, when a recurrent, then fatal encephalopathyoccurred in a patient who received repeated doses of meperidine while being treated with iproniazid, a monoamine oxidase inhibitor. In addition to being a narcotic, meperidine also inhibits serotonin reuptake. In the 1990s, treatment with SSRIs, particularly in combination with the monoamine oxidase inhibitors, resulted in diverse clinical toxicities. The term serotonin syndrome was popularized at that time, and its common manifestations include encephalopathy, dysautonomia, fever, rigidity, myoclonus, and hyperreflexia. Unlike in NMS, elevations in creatine phosphokinase and leukocyte count are uncommon but can occur. Exposure to drugs that enhance serotonergicaction is a sine qua non, but that list is long (Table 127-3) and includes drugs with multiple neurotransmitter actions (e.g., tertiary amine

Chapter 127 W

Tardve Dyskinesia and Other Drug-Related Movement Disorders

TABU 127-3. Some Drugs That Enhance Serotonergic Neurotransmission

Amitriptyline Buspirone Clomipramine Cocaine Dextromethorphan Fenfluramine Fluoxetine Fluvoxamine lmipramine lsocarboxazid Levodopa Lithium Lysergic acid diethylamide Methylenedioxymethamphetamine Meperidine Paroxetine Phenelzine Selegiline Sertraline Tranylcypromine Trazodone Venlafaxine

tricyclic antidepressants) and drugs not commonly known to have major serotonergic effects. Lithium is an example of the latter, although its toxicities are familiar to the clinician: Lithium produces tremor at therapeutic dosages, and at toxic levels it causes encephalopathy with rigidity and myoclonus. The spectrum of signs seen in lithium toxicity could also be the spectrum of the serotonin syndrome. In both cases, toxicity can be benign or severe but not necessarily dose dependent in the case of the serotonin syndrome. The mental status ranges from subtle encephalopathy to frank coma. Generalized seizures occur in a minority of cases. Motor dysfunction is a major aspect of the disorder, particularly myoclonus, hyperreflexia, rigidity (which may be limited to the legs), and ataxia. Reflex and tone abnormalities are generally bilateral; bilateral extensor toes manifest in a minority of patients. An internal ophthalmoplegia is not uncommon: Dilated, unreactive pupils may be seen in an estimated 25% of cases. Other autonomic features are similar to those seen in NMS, including prominent diaphoresis, fever, pulse and blood pressure fluctuations, and tachypnea. Although some authors cite a relationship between the serotonin syndrome and the carcinoid syndrome, others have found that skin flushing, nausea, diarrhea, and abdominal pain are rare. The syndrome carries a good prognosis if the offending drug is discontinued or if overdose is treated aggressively. In severe cases, seizures, coma, hyperthermia, disseminated intravascular coagulation, and metabolic acidosis may occur. Cyproheptadine, a serotonin antagonist with affinity for 5-HT,, and 5HT, receptors, has been used as antidote in some case reports, but treatment is largely supportive.

PATHOPHYSIOLOGY IN THE DRUG-INDUCED MOVEMENT DISORDERS Dopamine plays a complex modulatory role on pathways that influence movement in general. In a prevailing model, paucity of movement and excessive, involuntary movement result from imbalance between so-called direct and indirect connections between the striatum, particularly the caudate and putamen, and the motor thalamus. The relationship between the two pathways

815

has been characterized as a push-pull relationship in which the direct pathway facilitates normal movement, and the indirect pathway inhibits unwanted movement. Both are influenced by dopamine projections arising from midbrain structures, including the substantia nigra pars compacta and the ventral tegmental area. Dopamine’s actions at the striatum differ on the basis of distinct receptor types expressed on striatal neurons. Normally, dopamine excites neurons of the direct pathway that express D1-type receptors, whereas dopamine inhibits neurons of the indirect pathway that express D2-type receptors. Some have questioned the neatness of the D1 direct-D2 indirect division because many striatal neurons coexpress both types, but dopamine clearly has receptor-dependent effects on pathways that operate in parallel in both normal and disease states. Postsynaptic dopamine receptor supersensitivity has been implicated in the pathogenesis of TD, but the hypothesis is problematic in at least two important respects: It does not fully explain the time course of TD, and it does not explain why TD happens only in a minority of cases. Acute dopamine blockade reliably results in receptor supersensitivity in a short time frame (perhaps days), not the longer time frame over which some, but not all, patients develop motor complications. Upon discontinuation of dopamine receptor blockade, supersensitivity reliably disappears (perhaps over months), yet some dyskinesias may persist for longer periods of time. Thus, major reservations exist about a supersensitivity hypothesis, especially if one assumes that receptor changes must be directly responsible for the development of a toxicity. But a perturbation of a diffusely projecting neurotransmitter system such as dopamine may have more complicated effects in which supersensitivity still plays a role. All neuroleptics that block D2 receptors are associated with an increased risk for both DIP and TD. To account for the time course of motor complications and for the lack of universality of those complications, however, other potentially adaptive receptormediated effects must be involved. These alternative effects may involve other classic neurotransmitter systems (serotonergic, GABAergic, and cholinergic) or cotransmitter expression (e.g., substance P and dynorphin associated with direct pathway projections or enkephalin and neurotensin associated with indirect pathway projections). A new perspective on dopamine’s modulatory effects is emerging in which a specific drug perturbation can have ramified effects, which in turn suggest ongoing plastic or adaptive change in response to that exposure. In idiopathic Parkinson’s disease, dopamine denervation results in imbalanced activities of direct and indirect pathways, but a variety of non-dopamine changes have also been reported. One notable, recent set of observationsin Parkinson’s disease points to enhanced glutamatergic activity of projection neurons arising from cerebral cortex and terminating on medium spiny striatal neurons, associated with presynaptic D2 receptor supersensitivity. Enhanced excitatory neurotransmission has also been implicated in the pathogenesis of TD. In the setting of chronic levodopa treatment associated with dyskinesia in Parkinson’s disease, changes in gene expression, as measured by the induction of so-called immediate-early genes, are observed in specific patterns throughout the striatum. These studies have been conducted primarily in animal models, but they are instructive in a larger sense. The patterns of induction may relate to specific kinds of treatment (e.g., drugs with mixed D1 and D2 effects versus D1- or D2-specific effects), but, more importantly, induction of these genes may alter aspects of neuronal function over long periods of time, with variable effects on the balance of

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pathways in the basal ganglia. The effects of immediate-early gene expression may include system changes (e.g., persisting druginduced changes in the patterns of neuronal discharge in basal ganglia structures). This ongoing area of work represents an extension of synaptic models of drug effects that have dominated thinking in psychopharmacology over the past quarter century.

SUGGESTED READINGS Baldassano CF, Truman CJ, Nierenberg A et a1 Akathisia: a review and case report following paroxetine treatment. Compr Psychiatry 37(2):122124, 1996

Beasley CM, Dellva MA, Tamura RN et ak Randomized double-blind comparison of the incidence of tardive dyskinesia in patients with

schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 174(1):23-30, 1999 Caley C F Extrapyramidal reactions and the selective serotonin-reuptake inhibitors. Ann Pharmacother 31(12):1481-1489, 1997 Casey DE: Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia. Psychiatr Clin North Am 16(3):589-610, 1993 Diederich NJ, Goetz CG: Drug-induced movement disorders. Neurol Clin North Am 16(1):125-139, 1998 Friedman JH: Drug-induced parkinsonism. pp. 41-83. In Lang AE, Weiner WJ (eds): Drug-Induced Movement Disorders. Futura, Mount Kisco, NY, 1992

Gardos G, Cole J O Overview: public health issues in tardive dyskinesia. Am J Psychiatry 137(7):776-781, 1980 Graybiel AM, Canales J J, Capper-Loup C Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis. Trends Neurosci 23(Suppl):S71-77, 2000 Hasan S, Buckley P Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry 155(8):1113-1116, 1998 Henderson VW, Wooten G F Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockage? Neurology 31(2):132137, 1981 Jeste DV, Lacro JP, Bailey A et ak Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr SOC47(6):716-719, 1999 Kane JM: Tardive dyskinesia: epidemiological and clinical presentation. pp. 1485-1495. In Bloom FE, Kupfer J (eds): Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, 1995 Kane JM, Woerner MG, Pollack S et ak Does clozapine cause tardive dyskinesia? J Clin Psychiatry 54(9):327-330, 1993 Leo RJ: Movement disorders associated with serotonin reuptake inhibitors. J Clin Psychiatry 57(10):449-454, 1996 Miyawaki E, Meah Y, Koller W C Serotonin, dopamine, and motor effects in Parkinson’s disease. Clin Neuropharmacol 20(4):300-3 10, 1997 Simpson GM: The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry 61(Suppl4):3944, 2000 Sternbach H: The serotonin syndrome. Am J Psychiatry 148(6):705-713, 1991

128 Primary and Secondary Generalized Dystonias Joseph Jankovic Dystonia is a neurologic syndrome dominated by involuntary, sustained (tonic), or spasmodic (rapid or clonic), patterned, and repetitive muscle contractions, often causing twisting and other abnormal movements or postures. The most common forms of dystonia include blepharospasm, an involuntary closure of eyelids caused by forceful contractions of the orbicularis oculi; oromandibular dystonia, manifested by jaw closure (trismus, bruxism) or jaw opening; cervical dystonia, manifested by torticollis, retrocollis, anterocollis, and other twisting movements of the neck; and writer’s cramp. Because of its variable presentation and fluctuating intensity, dystonia is still often wrongly attributed to psychological causes. Traditional descriptions of dystonia emphasize that the muscle contractions are sustained; therefore, rapid movements often are not recognized as dystonic. These rapid movements resemble myoclonus, which is a jerklike movement produced by brief muscular contractions (positive myoclonus) or inhibitions (negative myoclonus). Some patients have both dystonia and myoclonus (dystonia-myoclonus syndrome). The latter disorder often improves with alcohol intake. One of the most characteristic features of dystonia, which helps differentiate it from the other hyperkinetic movement disorders, is that dystonic movements, whether slow or rapid, are repetitive and patterned (involving the same group of muscles). This is in contrast to chorea, which consists of brief movements that flow randomly from one body part to another. Tics are abrupt movements (or sounds) that are usually more intermittent and coordinated than dystonia or myoclonus, more easily suppressible, and often preceded by

premonitory symptoms such as an urge or a tension that is temporarily relieved by the execution of the tic. Some tics are more sustained and are called dystonic tics. Although dystonic movements usually are continual, the timing and intensity of the movements can be influenced by various factors, including emotion, fatigue, relaxation, motor activity, sensory tricks, and sleep. Rarely, dystonia can fluctuate so much that it might be absent in the morning and become pronounced and disabling in the afternoons and evenings. This diurnal dystonia usually occurs in children and young adults, may be associated with parkinsonian features in the patients and their relatives, and usually improves dramatically with levodopa. Not all patients with dopa-responsive dystonia have diurnal variations, and many patients with dopa-responsive dystonia are initially misdiagnosed as having cerebral palsy. Another type of noncontinual dystonia is the paroxysmal dystonias. These are characterized by an abrupt onset or an exacerbation of dystonic movements lasting seconds to hours. They may be induced by a sudden movement (kinesigenic dystonia) or may occur spontaneously (nonkinesigenic dystonia). Paroxysmal dystonia may be sporadic or inherited, but head trauma, certain metabolic disorders, and other causes can produce paroxysmal dystonia. An example of secondary paroxysmal dystonia is the oculogyric crisis, characterized by sudden, intermittent conjugate eye deviations, sometimes seen in patients with postencephalitic parkinsonism, Tourette’s syndrome, and druginduced dystonia.

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pathways in the basal ganglia. The effects of immediate-early gene expression may include system changes (e.g., persisting druginduced changes in the patterns of neuronal discharge in basal ganglia structures). This ongoing area of work represents an extension of synaptic models of drug effects that have dominated thinking in psychopharmacology over the past quarter century.

SUGGESTED READINGS Baldassano CF, Truman CJ, Nierenberg A et a1 Akathisia: a review and case report following paroxetine treatment. Compr Psychiatry 37(2):122124, 1996

Beasley CM, Dellva MA, Tamura RN et ak Randomized double-blind comparison of the incidence of tardive dyskinesia in patients with

schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 174(1):23-30, 1999 Caley C F Extrapyramidal reactions and the selective serotonin-reuptake inhibitors. Ann Pharmacother 31(12):1481-1489, 1997 Casey DE: Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia. Psychiatr Clin North Am 16(3):589-610, 1993 Diederich NJ, Goetz CG: Drug-induced movement disorders. Neurol Clin North Am 16(1):125-139, 1998 Friedman JH: Drug-induced parkinsonism. pp. 41-83. In Lang AE, Weiner WJ (eds): Drug-Induced Movement Disorders. Futura, Mount Kisco, NY, 1992

Gardos G, Cole J O Overview: public health issues in tardive dyskinesia. Am J Psychiatry 137(7):776-781, 1980 Graybiel AM, Canales J J, Capper-Loup C Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis. Trends Neurosci 23(Suppl):S71-77, 2000 Hasan S, Buckley P Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry 155(8):1113-1116, 1998 Henderson VW, Wooten G F Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockage? Neurology 31(2):132137, 1981 Jeste DV, Lacro JP, Bailey A et ak Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr SOC47(6):716-719, 1999 Kane JM: Tardive dyskinesia: epidemiological and clinical presentation. pp. 1485-1495. In Bloom FE, Kupfer J (eds): Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, 1995 Kane JM, Woerner MG, Pollack S et ak Does clozapine cause tardive dyskinesia? J Clin Psychiatry 54(9):327-330, 1993 Leo RJ: Movement disorders associated with serotonin reuptake inhibitors. J Clin Psychiatry 57(10):449-454, 1996 Miyawaki E, Meah Y, Koller W C Serotonin, dopamine, and motor effects in Parkinson’s disease. Clin Neuropharmacol 20(4):300-3 10, 1997 Simpson GM: The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry 61(Suppl4):3944, 2000 Sternbach H: The serotonin syndrome. Am J Psychiatry 148(6):705-713, 1991

128 Primary and Secondary Generalized Dystonias Joseph Jankovic Dystonia is a neurologic syndrome dominated by involuntary, sustained (tonic), or spasmodic (rapid or clonic), patterned, and repetitive muscle contractions, often causing twisting and other abnormal movements or postures. The most common forms of dystonia include blepharospasm, an involuntary closure of eyelids caused by forceful contractions of the orbicularis oculi; oromandibular dystonia, manifested by jaw closure (trismus, bruxism) or jaw opening; cervical dystonia, manifested by torticollis, retrocollis, anterocollis, and other twisting movements of the neck; and writer’s cramp. Because of its variable presentation and fluctuating intensity, dystonia is still often wrongly attributed to psychological causes. Traditional descriptions of dystonia emphasize that the muscle contractions are sustained; therefore, rapid movements often are not recognized as dystonic. These rapid movements resemble myoclonus, which is a jerklike movement produced by brief muscular contractions (positive myoclonus) or inhibitions (negative myoclonus). Some patients have both dystonia and myoclonus (dystonia-myoclonus syndrome). The latter disorder often improves with alcohol intake. One of the most characteristic features of dystonia, which helps differentiate it from the other hyperkinetic movement disorders, is that dystonic movements, whether slow or rapid, are repetitive and patterned (involving the same group of muscles). This is in contrast to chorea, which consists of brief movements that flow randomly from one body part to another. Tics are abrupt movements (or sounds) that are usually more intermittent and coordinated than dystonia or myoclonus, more easily suppressible, and often preceded by

premonitory symptoms such as an urge or a tension that is temporarily relieved by the execution of the tic. Some tics are more sustained and are called dystonic tics. Although dystonic movements usually are continual, the timing and intensity of the movements can be influenced by various factors, including emotion, fatigue, relaxation, motor activity, sensory tricks, and sleep. Rarely, dystonia can fluctuate so much that it might be absent in the morning and become pronounced and disabling in the afternoons and evenings. This diurnal dystonia usually occurs in children and young adults, may be associated with parkinsonian features in the patients and their relatives, and usually improves dramatically with levodopa. Not all patients with dopa-responsive dystonia have diurnal variations, and many patients with dopa-responsive dystonia are initially misdiagnosed as having cerebral palsy. Another type of noncontinual dystonia is the paroxysmal dystonias. These are characterized by an abrupt onset or an exacerbation of dystonic movements lasting seconds to hours. They may be induced by a sudden movement (kinesigenic dystonia) or may occur spontaneously (nonkinesigenic dystonia). Paroxysmal dystonia may be sporadic or inherited, but head trauma, certain metabolic disorders, and other causes can produce paroxysmal dystonia. An example of secondary paroxysmal dystonia is the oculogyric crisis, characterized by sudden, intermittent conjugate eye deviations, sometimes seen in patients with postencephalitic parkinsonism, Tourette’s syndrome, and druginduced dystonia.

Chapter 128

The severity of dystonia varies from a barely noticeable and often unrecognized symptom to disabling muscle contractions rendering the patient unable to ambulate or fully participate in activities of daily living. In several of my patients, the dystonic muscle contractions were so severe they produced muscle breakdown and myoglobinuria. Primary (idiopathic) dystonia often starts as a task-specific dystonia (e.g., writer’s cramp). With increasing severity, however, the dystonic movements may occur in other, less specific activities and at rest and may eventually overflow to adjacent or other muscles. If left untreated, dystonia may evolve into fixed postures and contractures. Secondary dystonia usually is present at rest, even at onset. Dystonia often is associated with either dystonic or essential tremor. Dystonic tremor is actually a rhythmic dystonia, most evident when the patient voluntarily attempts to move in the direction opposite to the force of dystonia. Thus, a patient with torticollis to the right, when attempting to maintain primary head position, may develop lateral irregular tremor that disappears when the patient allows the head to turn to the right (in the direction of the torticollis). In contrast, patients with coexistent essential tremor continue to have the oscillatory movement regardless of the direction of the force of the dystonia. Although the two types of tremor usually can be identified clinically, the differentiation may be aided by the use of electromyography. It is not yet clear whether the postural tremor associated with dystonia, such as the hand flexion-extension tremor seen in 25% of patients with cervical dystonia, is a form of essential tremor or whether it is an expression of some dystonia-related physiologic abnormality. A pathogenic relationshipbetween dystonia and essential tremor is suggested by the frequent occurrence of essential postural tremor in family members of patients with dystonia. In some patients, head and trunk tremor (2- to 5-Hz frequency) may precede the onset of dystonia and may be the initial manifestation or forme fiuste of dystonia (dystonic tremor). Certain task-specific tremors (e.g., primary writing tremor) may actually represent forms of focal dystonia. Some patients with primary writing tremor voluntarily contract their forearm muscles in an attempt to control the hand tremor. This compensatory muscle contraction is sometimes wrongly attributed to dystonia. Besides essential tremor and myoclonus, dystonia occasionally is also associated with other movement disorders, including parkinsonism. The epidemiology of dystonia has not been studied by appropriate methods, but it has been estimated that there are at least 100,000 people with dystonia in the United States. If dystonic writer’s cramp were included, the true prevalence would be much greater because most patients with dystonic writer’s cramp do not seek medical attention.

CLASSIFICATION There are many ways to classify dystonia, but it is convenient to categorize dystonia according to its age at onset, cause, and anatomic distribution.

Age at Onset Age at onset is one of the most predictable determinants of future course and prognosis. Dystonia may start at any age and may be categorized as either infantile (less than 2 years), childhood (2 to 12 years), juvenile (13 to 20 years), or adult onset (older than 20 years). Childhood-onset dystonia, particularly common among Ashkenazi Jews, often is characterized by caudal-rostral progres-

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sion, with legs being more involved early in the course. Whereas childhood-onset dystonia usually becomes generalized, adultonset dystonia usually remains focal or segmental. A typical presentation of childhood-onset dystonia is inversion of one foot while running or a writer’s cramp; the best examples of adultonset dystonia are blepharospasm and torticollis. Causes Dystonia either occurs alone, without any other neurologic deficits (called primary torsion dystonia), or may be a symptom of an underlying disorder (so-called secondary dystonia). Primary torsion dystonia can be either sporadic (idiopathic) or inherited, and it is not associated with any cognitive, pyramidal, cerebellar, or sensory abnormalities. The most important advance in our knowledge about genetic dystonia has been the identification of a 3-base-pair (GAG) deletion in the q32-34 region of chromosome 9 of families with autosomal dominant primary dystonia (DYT1 dystonia). In about one third of those carrying this mutation in the DYTl or TORRlA gene, dystonia is expressed clinically (30% to 40% penetrance). The onset usually is in childhood, typically presenting with distal, action dystonia that gradually progresses to a generalized disorder. DNA testing for the DYTl dystonia has demonstrated that many cases thought to be sporadic are actually inherited. This is particularly true among dystonic patients of Ashkenazi Jewish origin, in whom DYTl dystonia accounts for 90% of all cases of dystonia. The TORlA gene encodes torsinA. Although the function of torsinA is still not fully understood and its role in the pathogenesis of primary dystonia is still unknown, the protein is known to be a member of the AAA+ superfamily of chaperone proteins predominantly expressed in dopaminergic neurons. Other gene loci or mutations causing dystonia include a locus on 7q2 1-23 responsible for myoclonic dystonia, mutations in the GTP-cyclohydrolase 1 (GCH1) gene on chromosome 14q causing dopa-responsive dystonia, and a gene marker on chromosome 19q13 responsible for the rapid-onset dystonia-parkinsonism syndrome. Not all dystonias are of genetic origin; some are sporadic and others are secondary to some specific causes (Table 128-1). Of the secondary dystonias, Wilson’s disease is particularly important to recognize because early treatment of this autosomal recessive disease, caused by mutations in the gene on long arm of chromosome 13 encoding copper transporting P-type ATPase, can result in a complete or nearly complete abolishment of neurologic and liver problems. Almost any metabolic or structural lesion of the brain, particularly if it involves the putamen, other basal ganglia, and rostral brainstem structures, can produce dystonia. Besides Wilson’s disease, another important cause of secondary dystonia is drug-induced dystonia. The dopamine receptorblocking drugs (neuroleptics,such as the major tranquilizers, and gastrointestinal drugs, such as metoclopramide) can cause not only an acute transient dystonic reaction but also a persistent dystonic disorder (tardive dystonia). Besides central causes, which presumably account for most dystonias, peripherally induced dystonia caused by an injury to a nerve or a nerve root, often associated with reflex sympathetic dystrophy, is being increasingly recognized as an important cause of focal and segmental dystonia. About 40% of all patients with dystonia have been previously misdiagnosed as having a psychogenic illness. In actuality, however, less than 5% of all dystonias seen in a movement disorder clinic are of psychogenic origin, and the frequency is even lower in

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TABU 118-1. Etiologic Classification of Dystonia 1. Primary dystonia A. Sporadic

B. lnheriied (all autosomal dominant) Classic (Oppenheim's) dystonia (DMl, 9q34) Childhood- and adult-onset cranial-cervical-limb dvstonia (DM6.8p21-22) Adult-onset cervical and other focal dystonia (OW, 18p) 11. Dystonia-plus syndromes A Sporadic Parkinson's disease Progressive supranuclear palsy Multiple system atrophy Corticobasal degeneration B. lnheriied 1. Autosomal dominant Dopa-responsive dystonia (DRD) (OMS, CTP cyclohydrolase I 14q22.1) Dystonia-myoclonus (1 1q23) Dystonia-ataxia (SCA 3 and SCA 6) 2. Autosomal recessive Dopa-responsive dystonia caused by tyrosine hydroxylase deficiency (1 1p l 1.5) Biopterin-deficientdiseases Aromatic amino acid decarboxylase deficiency (dopamine agonistresponsive dystonia) 111. Heredodegenerative diseases (typically not pure dystonia) A X-linked recessive Lubag (X-linked dystonia-parkinsonism, DM3, Xql2-Xq2 1) Pelizaeus-Merzbacher disease Lesch-Nyhan syndrome Dystonia-deafness(Xq22) Deafness, dystonia, retardation, blindness B. Autosomal dominant Rapid-onset dystonia-parkinsonism (RDP) Juvenile Parkinsonism-Dystonia Huntington's disease (IT1 5,4p 16.3) Spinocerebellar degenerations (SCA3, SCAC) Dentato-rubral-pallidoluysian atrophy (DRPLA) Hereditary spastic paraplegia with dystonia Thalamo-olivary degeneration with Wernicke's encephalopathy C. Autosomal recessive Wilson's disease (Cu-ATPase, 1 3q14.3) Neurodegenerationwith brain iron accumulation type 1 (NBIA 1) (Hallervorden-Soak disease. 20012.3-01 3) Hkoprebetalipopioteinernia,acanihocyt&is, ietinitis pigmentosa, and oallidal degeneration (HARP svndrome) Ataxia telangiectaga Associated with metabolic disorders 1. Amino acid disorders Clutaric acidemia Methylmalonic acidemia Homocystinuria Hartnup's disease Tyrosinosis 2. Lipid disorders Metachromatic leukodystrophy Ceroid lipofuscinosis Niemann-Pick type C (dystonic lipidosis, "sea blue" histiocytosis) Cangliosidoses, CM 1, CM2 variants Hexosaminidase A and B deficiency 3. Other metabolic disorders Biopterin-deficient diseases Triosephosphate isomerase deficiency Aromatic amino acid decarboxylase deficiency (dopamine agonistresponsive dystonia) Biotin-responsive basal ganglia disease D. Mitochondria1 Leigh's disease Leber's disease ~

~

~

~

~

E. Unknown inheritance Neuroacanthocytosis ReWs syndrome lntraneuronal inclusion disease Infantile bilateral striatal necrosis Familial basal ganglia calcifications Hereditary spastic paraplegia with dystonia Deletion of 18q With a known, specific cause Perinatal cerebral injury and kernicterus: athetoid cerebral palsy, delayed-onset dystonia Infection: Viral encephalitis, encephalitis lethargica, Reye's syndrome, subacute sclerosing panencephaliiis, Jakob-Creutzfeldt disease, HIV infection Other: tuberculosis, syphilis, acute infectious torticollis Drugs: levodopa and dopamine agonists, dopamine receptorblocking drugs, fenfluramine, anticonvulsants, flecainide, ergots, certain calcium channel blockers Toxins: MN, CO, CS2, cyanide, methanol, disulfiram, 3-nitroproprionic acid, wasp sting Metabolic: hypoparathyroidism Paraneoplastic brainstem encephalitis Vitamin E deficiency Primary antiphospholipid syndrome (PAPS) Cerebral vascular or ischemic injury Sjogren's syndrome Multiple sclerosis Central pontine myelinolysis Brainstem lesions Spinal cord lesions Syringomyelia Brain tumor Arteriovenous malformation Head trauma and brain surgery (thalamotomy) Lumbar stenosis Peripheral trauma (with causalgia) Electrical iniurv IV. Other hyperkinetk jndromes associated with dystonia A. Tic disorders with dystonic tics B. Paroxysmal dyskinkias Paroxysmal kinesigenic dyskinesia (PKD) (1 6pll.2-q12.1) Paroxvsmal nonkinesinenic dvskinesia (PNKD) (2a33-35) ParoGmal exertion-iiduced'dyskinesia (PEDj (1 6pl2-ql2) Paroxysmal hypnogenic dyskinesia (PHD) (20q13.2-13.3) V. Psychogenic VI. Pseudodystonia Atlanto-axial subluxation Syringomyelia Arnold-Chiari malformation Trochlear nerve palsy Vestibular torticollis Posterior fossa mass Soft tissue neck mass Congenital postural torticollis Congenital Klippel-Feil syndrome Isaac's syndrome Sandiffer's syndrome Satoyoshi's syndrome Stiff person syndrome Ventral hernia

Chapter 128

general neurologic practice. The differentiation between psychogenic and neurologic dystonia is one of the most formidable challenges facing the clinical neurologist. Because primary dystonia is not associated with any laboratory abnormalities, the diagnosis of psychogenic dystonia must be based on positive criteria; it is not sufficient to merely exclude other causes. Certain clues usually provide evidence of a psychogenic cause. These include false weakness, false sensory symptoms, multiple somatizations, self-inflicted injuries, bizarre movements or pseudoseizures, obvious psychiatric illness, and other features that are incongruous with typical dystonia. Relief of dystonia with psychotherapy, powerful suggestion, placebo, or physiotherapy excludes a neurologic cause because complete and permanent remissions are rare in organic forms of dystonia. Improvement under hypnosis or with amobarbital is not particularly helpful because both can ameliorate even neurologic dystonia. On the other hand, acute exacerbation and relief of the dystonia by a powerful suggestion coupled with intravenous or oral placebo provides important support for the diagnosis of psychogenic dystonia.

Dystonia is classified according to its anatomic distribution as focal, segmental, multifocal, generalized, and unilateral (hemidystonia). Cranial Dystonia. Craniocervical structures are most often affected in adult-onset dystonia. Blepharospasm, an involuntary bilateral eye closure produced by spasmodic contractions of the entire (pretarsal, preseptal, and periorbital) orbicularis oculi muscles, often is accompanied by dystonic movements of the eyebrows and of the paranasal, facial, masticatory, labial, lingual, oral, pharyngeal, laryngeal, and cervical muscles. Blepharospasm often is exacerbated by exposure to bright light, wind, and air pollution, as well as by activity and stress. In most patients with blepharospasm, the onset often is heralded by increased frequency of blinking associated with a sandlike feeling of irritation in the eyes. Blepharospasm usually starts with clonic contractions of the eyelids, gradually progressing to more sustained and forceful eye closure. Eventually, patients have difficulty reading, watching television, driving, and performing other daily activities that depend on normal vision. If left untreated, up to 15% become functionally blind. Various maneuvers such as wearing dark glasses, pulling on an upper eyelid, pinching the neck, talking, humming, or singing can transiently relieve the involuntary eye closure in some patients. Afflicted women outnumber men 3 to 1 and, in most, symptoms commence by 50 years of age. Oromandibular Dystonia. Oromandibular dystonia consists of involuntary spasms of jaw, mouth, and tongue muscles producing jaw closure and trismus (jaw clenching) and bruxism (tooth grinding), often causing secondary dental wear and temporomandibular joint syndrome. In addition, involuntary tongue movements, jaw opening, or jaw deviation may cause difficultieswith chewing, speaking, and swallowing. Oromandibular dystonia should be differentiated from hemifacial or hemimasticatory spasm, tardive dyskinesia, tetany, tetanus, and mechanical disorder of the temporomandibular joint. Focal cranial and oromandibular dystonias are also discussed in Chapter 129. Cervical Dystonia. Cervical dystonia is the most common form of focal dystonia encountered in movement disorder clinics. Although torticollis, lateral rotation of the head, is the most common abnormal posture, the majority of patients have a

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819

combination of torticollis, laterocollis, retrocollis, and anterocollis. In addition to cervical involvement, at least one third of all patients with cervical dystonia have scoliosis, suggestingadditional involvement of the thoracic muscles. Local pain accompanies cervical dystonia in more than one third of all patients. The pain can be caused by intense muscular spasms or by associated cervical spondylotic radiculomyelopathy. Cervical dystonia often is exacerbated during periods of stress or fatigue and usually is relieved by relaxation and various sensory maneuvers. Up to 20% of patients achieve spontaneous remission, but the dystonia usually recurs after several months. In most patients, cervical dystonia is a lifelong disorder, and in about 20% of patients, it progresses to a segmental or generalized dystonia. As in other forms of dystonia, the abnormal muscle contractions that produce head deviation can be temporarily controlled by a variety of sensory tricks, such as touching the chin, face, or back of the head. Although this observation suggests that cervical dystonia can be influenced by altering the proprioceptive input, the exact mechanism of the counterpressure, sensory trick, or geste antagoniste phenomenon is not known. Focal cervical dystonia is discussed in more detail in Chapter 129. Laryngeal Dystonia (Spasmodic Dysphonia). The career of a teacher, a trial attorney, or a professional singer can be prematurely ended with the development of spasmodic dysphonia. Despite growing evidence in support of neurologic origin, the symptoms are still too often attributed to psychogenic causes. Dystonia of the larynx may cause excessive and uncontrolled closing of the vocal folds (adductor spasmodic dysphonia), producing effortfid and strained voice interrupted by frequent breaks in phonation. The abductor form of spasmodic dysphonia is much less common, and it consists of prolonged vocal fold openings, producing breathy and whispering voice and phonatory pauses extending into vowels. The adductor spasmodic dysphonia is caused by hyperadductions of the thyroarytenoid vocalis complex, and the abductor form of spasmodic dysphonia is caused by contractions of the posterior cricoarytenoid muscle. Whereas nearly all cases of adductor spasmodic dysphonia are thought to represent a form of focal dystonia (see also Chapter 129), many cases of abductor dysphonia are thought to be of psychogenic origin. Many patients with spasmodic dysphonia also have voice tremor, and in some cases isolated voice tremor precedes the onset of spasmodic dysphonia by several years. Limb Dystonia. Idiopathic limb dystonia usually starts as an action dystonia. In contrast, secondary dystonia, caused either by central (brain) or peripheral (nerve or root) injury or lesion, often is present at rest, even at the onset. The task-specific focal dystonias seen in many occupational cramps (e.g., graphospasm or writer’s cramp) are the most common example of idiopathic arm dystonia. The task- or position-specific dystonias often occur with writing, typing, and feeding, during certain sport-related activities, and while playing musical instruments. Like other forms of dystonia, hand and arm dystonias often are associated with either dystonic or essential tremor. For example, some patients with writer’s cramp may display involuntary supination of the hand away from the desk, and when the patient volitionally pronates the hand in the act of writing, a twisting, jerking movement may appear. Such dystonic tremor occurs only during a specific action, and the tremor may not be evident when arms are outstretched in front of the body or when placed in any other position. However, about one third of patients with focal, task-specific dystonia experience a coexistent postural, essential tremor manifested by a flexion-extension oscillation of the hand

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Movement Disorderr 1 Non-Parkinsonian Movement Disorders

during posture holding. When dystonia affects the foot in an adult, the possibility of Parkinson’s disease or a parkinsonian syndrome as the cause of the foot dystonia should be considered. Besides the striatal foot, some patients with Parkinson’s disease have a striatal hand deformity, often confused with rheumatoid arthritis. In children, the foot can twist into an equinovarus posture when the patient is running or walking, or the leg might kick during walking. The foot and leg dystonia may evolve into a fixed dystonic posture, commonly causing plantar flexion, extension at the knee, and flexion-adduction at the hip. Trunk Dystonia. Trunk dystonia can result in scoliosis, lordosis, kyphosis, tortipelvis, and opisthotonic posturing. At onset, abnormal movements of the trunk may be seen during walking or running, but in the advanced stages of the disease, the trunk deformities become fixed and present even when the patient is sitting or lying. Many patients with trunk dystonia have a bizarre gait resembling the gaits of various animals, hence the terms dromedary-, monkey-, and ducklike gait. Various sensory tricks, such as placing the hands in the pockets, behind the neck or back, or on the hip, might enable the patient to walk almost normally. Also, running, walking backward, or dancing might improve the truncal dystonia and dystonic gait. Hemidystonia. In contrast to other types of dystonias, which are usually idiopathic, about 85% of patients with hemidystonia have computed tomography or magnetic resonance imaging evidence of contralateral basal ganglia lesion or a history of hemiparesis. Besides ischemic or hemorrhagic strokes, other causes of hemidystonia include perinatal or other head trauma, thalamotomy, encephalitis, neurodegenerative disorders, arteriovenous malformation, and porencephalic cyst. Whereas a long delay of several years between injury and onset is typical for dystonia related to perinatal injury, the latency between the acute lesion and subsequent onset of dystonia often is less than 6 months in adult patients. ANATOMY, BIOCHEMISTRY, AND PATHOPHYSIOLOGY Although in most patients with dystonia no specific abnormality can be identified by neuroimaging or autopsy studies, there is convincing evidence supporting a central origin (basal ganglia, brainstem, or both) for this movement disorder. Some brains of patients with atypical dystonia have been found to have a mosaic pattern of striatal gliosis. Studies of patients with secondary dystonia have identified lesions involving the basal ganglia, particularly the putamen, and the rostral brainstem. The involvement of basal ganglia in dystonia is also supported by the finding of reduced glucose metabolism, as demonstrated by position emission tomography scans, in the basal ganglia, the frontal projection field of the mediodorsal thalamic nucleus, and the frontal cortex of patients with idiopathic torsion dystonia. No consistent abnormalities have been demonstrated in the few brains of patients with dystonia examined at autopsy. Neurophysiologic studies in patients with dystonia show prolonged firing of electromyelographic activity with cocontraction of antagonist muscles, repetitive and slow spasms of 1 to 2 seconds each and separated by equal periods of relative electromyelographic silence (previously called myorhythmia), postural 6- to 10-Hz frequency tremor, reduced reciprocal inhibition, and abnormal H reflex and blink reflex recovery cycle. These findings have been interpreted as indicating enhanced excitatory drive to the rostral brainstem or reduced spinal and brainstem inhibition.

TREATMENT Despite the paucity of knowledge about the cause and pathogenesis of most dystonic disorders, the symptomatic treatment of dystonia has markedly improved, largely as a result of the introduction of botulinum toxin. This therapeutic intervention is discussed in Chapter 129. Before contemplating symptomatic therapy, potentially curable causes of dystonia, such as certain drug-induced dystonias or Wilson’s disease, should be considered. Physical therapy, including well-fitted braces, may be helpful to some dystonic patients but are usually unsatisfactory when used alone. Although there is little scientific rationale for the drugs used to treat dystonia, about one third of patients benefit from some pharmacologic therapy (Table 128-2). The selection of a particular choice of therapy is guided largely by personal clinical experience and empiric trials. The first treatment of choice usually is determined by its low potential for adverse effects and by the anatomic distribution of dystonia. Although less than 10% of all children with dystonia have dopa-responsive dystonia, all patients with childhood-onset dystonia should be first treated with levodopa and carbidopa (Sinemet). Anticholinergic medications such as trihexyphenidyl have been found to be most effective for generalized dystonia. This therapy generally is well tolerated when the dosage is increased slowly. It is generally recommended to start with a 2-mg preparation, one half tablet at bedtime, and advancing up to 12 mg/day over the next 4 weeks. Some patients

H TABLE 128-2. Treatment of Dystonia

Focal Dyrtonias

Blepharospasm Botulinum toxin injections Clonazepam, lorazepam Trihexyphenidyl Orbicularis oculi myectomy Oromandibular dystonia Botulinum toxin injections Trihexyphenidyl Baclofen Spasmodic dysphonia Botulinum toxin injections Voice and supportive therapy Cervical Botulinum toxin injections Trihexyphenidyl Diazepam, lorazepam, clonazepam Tetrabenazine Cyclobenzaprine Carbamazepine Baclofen (oral) Peripheral surgical denervation Task-specific dystonias (e.g., writer‘s cramp) Benztropine, trihexyphenidyl Botulinum toxin injections Occupational therapy Segmental and Generalized Dystonias

Levodopa (in children and young adults) Trihexyphenidyl, benztropine Diazepam, lorazepam, clonazepam Baclofen (oral, intrathecal) Carbamazepine Tetrabenazine (with lithium) Triple therapy: tetrabenazine, fluphenazine, trihexyphenidyl lntrathecal baclofen infusion (axial dystonia) Peripheral denenration Thalamotomy and globus pallidus deep brain stimulation

Chapter 129

need 60 to 100 mg/day but may experience dosage-related drowsiness, confusion, memory difficulty, and hallucinations. Pyridostigmine, a peripherally acting anticholinesterase, and eye drops of pilocarpine (a muscarinic agonist) often ameliorate at least some of the peripheral side effects such as dry mouth, urinary retention, and blurred vision. Many patients need a combination of several medications and treatments. Benzodiazepines (clonazepam or lorazepam) may provide additional benefit for patients whose response to anticholinergic drugs is unsatisfactory. Baclofen may be helpful for oromandibular dystonia but is only minimally effective for generalized dystonia. In selected cases of severe axial and generalized dystonia, however, continuous intrathecal infusions of baclofen may be useful. Dopamine receptor-blocking drugs or neuroleptics (e.g., fluphenazine) have been used to treat dystonia, often in conjunction with anticholinergics. However, the use of dopamine receptor-blocking drugs to treat dystonia should be discouraged because of the potential for development of tardive dyskinesia. This risk may be minimized by coadministering reserpine or tetrabenazine. Tetrabenazine, a presynaptic dopamine-depleting drug, has been useful in some patients with dystonia, but its availability in the United States is limited. Attacks of kinesigenic paroxysmal dystonia may be controlled with anticonvulsants (e.g., carbamazepine, phenytoin), but the nonkinesigenic forms of paroxysmal dystonia are less responsive to pharmacologic therapy, although clonazepam and acetazolamide may be beneficial. Surgical approaches, such as local denervation, muscle excision, and stereotactic procedures such as thalamotomy or globus pallidus deep brain stimulation, play an increasingly important role, particularly in treating generalized dystonia.

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Bressman SB, Sabatti C, Raymond D et al: The DYTl phenotype and guidelines for diagnostic testing. Neurology 54:1746-1 752, 2000 Duffey P, Butler AG, Hawthorne MR, Barnes H: The epidemiology of primary dystonia in the north of England. pp. 121-125. In Fahn S, Marsden CD, DeLong DR (eds): Dystonia 3, Adv Neurol, Vol. 78, pp. 12 1-126. Lippincott-Raven, Philadelphia, 1998 Fahn S, Bressman S, Marsden CD: Classification of dystonia. Adv Neurol 78~1-10, 1998

Hallett M: Physiology of dystonia. Adv Neurol 78:ll-18, 1998 Hewett 1, Gonzalez-Agosti C, Slater D et al. Mutant torsin A, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells. Hum Mol Genet 9:1404-1414, 2000 Jankovic J: Can peripheral trauma induce dystonia and other movement disorders? Yes! Mov Disord 16:7-12, 2001 Jankovic J: Dystonia: medical therapy and botulinum toxin in dystonia. pp. 169-184. In Fahn S , Marsden CD, DeLong DR (eds): Dystonia 3, Adv Neurol, Vol. 78, pp. 169-184. Lippincott-Raven, Philadelphia, 1998

Jankovic J: Re-emergence of surgery for dystonia. Editorial commentary. J Neurol Neurosurg Psychiatry 65:434, 1998 Jankovic J, Brin M: Botulinum toxin: historical perspective and potential new indications. Muscle Nerve 2O(Suppl 6):S129-S145, 1997 Nemeth A The genetics of primary dystonias and related disorders. Brain 125:695-721, 2002

Nygaard TG, Raymond D, Chen C et al: Localization of a gene for myoclonus-dystonia to chromosome 7q2 1-23. Ann Neurol 46794798, 1999

Swoboda KJ, Soong BW, McKenna C et al: Paroxysmal kinesigenic dyskinesia and infantile convulsions. Clinical and linkage studies. Neurology 553224230, 2000 Vitek JL, Chockkan V, Zhang J-Y et al: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballism. Ann Neurol46:22-35, 1999

SUGGESTED READINGS Adityanjee, Yeken AA, Jampala VC, Mathews T: The current status of tardive dystonia. Biol Psychiatry 45:715-730, 1999

Warner TT, Jarman P The molecular genetics of dystonias. J Neurol Neurosurg Psychiatry 64:427429, 1998

129 Focal Dvstonia: Treatment with Botulinum Toxin Daniel Tarsy By contrast with generalized dystonia, which usually begins in childhood (see Chapter 128), adult-onset idiopathic dystonia usually remains localized to one body part without progression or spread to neighboring body regions. Whereas childhood-onset dystonia usually begins in the lower extremities, most adult dystonias begin in muscles of the face, neck, or upper extremities, where they remain focal. Occasionally, dystonia may spread to adjacent body parts to become segmental. Focal dystonias are listed in Table 129-1 with their more common names. Adult-onset focal dystonias are considered to be focal manifestations of idiopathic torsion dystonia. The involuntary movements and abnormal postures of focal dystonia also occur in generalized dystonia, and focal dystonias in adults sometimes spread to adjacent body regions to produce segmental dystonia. Examples of

segmental dystonia include the association of blepharospasm with oromandibular dystonia (Meige’s syndrome) and spasmodic torticollis with dystonic writer’s cramp. Adult-onset focal dystonia is far more common than childhood generalized dystonia. The reported prevalence of idiopathic adult-onset dystonia is 295 in 1,000,000, compared with 34 in 1,000,000 for generalized dystonia, but is undoubtedly underestimated in current studies. Recent prevalence estimates have indicated at least 250,000 cases of idiopathic dystonia in the United States. Because in many cases focal dystonia is incorrectly attributed to psychological causes, underdiagnosis is common, and long delays in diagnosis and appropriate treatment result. Dystonia is a syndrome of sustained muscle contractions that cause repetitive torsional movements and abnormal postures.

Chapter 129

need 60 to 100 mg/day but may experience dosage-related drowsiness, confusion, memory difficulty, and hallucinations. Pyridostigmine, a peripherally acting anticholinesterase, and eye drops of pilocarpine (a muscarinic agonist) often ameliorate at least some of the peripheral side effects such as dry mouth, urinary retention, and blurred vision. Many patients need a combination of several medications and treatments. Benzodiazepines (clonazepam or lorazepam) may provide additional benefit for patients whose response to anticholinergic drugs is unsatisfactory. Baclofen may be helpful for oromandibular dystonia but is only minimally effective for generalized dystonia. In selected cases of severe axial and generalized dystonia, however, continuous intrathecal infusions of baclofen may be useful. Dopamine receptor-blocking drugs or neuroleptics (e.g., fluphenazine) have been used to treat dystonia, often in conjunction with anticholinergics. However, the use of dopamine receptor-blocking drugs to treat dystonia should be discouraged because of the potential for development of tardive dyskinesia. This risk may be minimized by coadministering reserpine or tetrabenazine. Tetrabenazine, a presynaptic dopamine-depleting drug, has been useful in some patients with dystonia, but its availability in the United States is limited. Attacks of kinesigenic paroxysmal dystonia may be controlled with anticonvulsants (e.g., carbamazepine, phenytoin), but the nonkinesigenic forms of paroxysmal dystonia are less responsive to pharmacologic therapy, although clonazepam and acetazolamide may be beneficial. Surgical approaches, such as local denervation, muscle excision, and stereotactic procedures such as thalamotomy or globus pallidus deep brain stimulation, play an increasingly important role, particularly in treating generalized dystonia.

Focal Dystonia: Treatment with Botulinurn Toxin

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Bandman 0, Valente EM, Holmans P et ak Dopa-responsive dystonia: a clinical and molecular genetic study. Ann Neurol 44:649456, 1998

Bressman SB, Sabatti C, Raymond D et al: The DYTl phenotype and guidelines for diagnostic testing. Neurology 54:1746-1 752, 2000 Duffey P, Butler AG, Hawthorne MR, Barnes H: The epidemiology of primary dystonia in the north of England. pp. 121-125. In Fahn S, Marsden CD, DeLong DR (eds): Dystonia 3, Adv Neurol, Vol. 78, pp. 12 1-126. Lippincott-Raven, Philadelphia, 1998 Fahn S, Bressman S, Marsden CD: Classification of dystonia. Adv Neurol 78~1-10, 1998

Hallett M: Physiology of dystonia. Adv Neurol 78:ll-18, 1998 Hewett 1, Gonzalez-Agosti C, Slater D et al. Mutant torsin A, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells. Hum Mol Genet 9:1404-1414, 2000 Jankovic J: Can peripheral trauma induce dystonia and other movement disorders? Yes! Mov Disord 16:7-12, 2001 Jankovic J: Dystonia: medical therapy and botulinum toxin in dystonia. pp. 169-184. In Fahn S , Marsden CD, DeLong DR (eds): Dystonia 3, Adv Neurol, Vol. 78, pp. 169-184. Lippincott-Raven, Philadelphia, 1998

Jankovic J: Re-emergence of surgery for dystonia. Editorial commentary. J Neurol Neurosurg Psychiatry 65:434, 1998 Jankovic J, Brin M: Botulinum toxin: historical perspective and potential new indications. Muscle Nerve 2O(Suppl 6):S129-S145, 1997 Nemeth A The genetics of primary dystonias and related disorders. Brain 125:695-721, 2002

Nygaard TG, Raymond D, Chen C et al: Localization of a gene for myoclonus-dystonia to chromosome 7q2 1-23. Ann Neurol 46794798, 1999

Swoboda KJ, Soong BW, McKenna C et al: Paroxysmal kinesigenic dyskinesia and infantile convulsions. Clinical and linkage studies. Neurology 553224230, 2000 Vitek JL, Chockkan V, Zhang J-Y et al: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballism. Ann Neurol46:22-35, 1999

SUGGESTED READINGS Adityanjee, Yeken AA, Jampala VC, Mathews T: The current status of tardive dystonia. Biol Psychiatry 45:715-730, 1999

Warner TT, Jarman P The molecular genetics of dystonias. J Neurol Neurosurg Psychiatry 64:427429, 1998

129 Focal Dvstonia: Treatment with Botulinum Toxin Daniel Tarsy By contrast with generalized dystonia, which usually begins in childhood (see Chapter 128), adult-onset idiopathic dystonia usually remains localized to one body part without progression or spread to neighboring body regions. Whereas childhood-onset dystonia usually begins in the lower extremities, most adult dystonias begin in muscles of the face, neck, or upper extremities, where they remain focal. Occasionally, dystonia may spread to adjacent body parts to become segmental. Focal dystonias are listed in Table 129-1 with their more common names. Adult-onset focal dystonias are considered to be focal manifestations of idiopathic torsion dystonia. The involuntary movements and abnormal postures of focal dystonia also occur in generalized dystonia, and focal dystonias in adults sometimes spread to adjacent body regions to produce segmental dystonia. Examples of

segmental dystonia include the association of blepharospasm with oromandibular dystonia (Meige’s syndrome) and spasmodic torticollis with dystonic writer’s cramp. Adult-onset focal dystonia is far more common than childhood generalized dystonia. The reported prevalence of idiopathic adult-onset dystonia is 295 in 1,000,000, compared with 34 in 1,000,000 for generalized dystonia, but is undoubtedly underestimated in current studies. Recent prevalence estimates have indicated at least 250,000 cases of idiopathic dystonia in the United States. Because in many cases focal dystonia is incorrectly attributed to psychological causes, underdiagnosis is common, and long delays in diagnosis and appropriate treatment result. Dystonia is a syndrome of sustained muscle contractions that cause repetitive torsional movements and abnormal postures.

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Movement Disorders W

Non-ParkinsonianMovement Disorders

rn TABLE129-1. Focal Dystonias

CRANIAL DYSTONIA

Dvstonia

Common Names

Cranial dystonia

Blepharospasm Oromandibular dystonia Jaw opening Jaw closing Spasmodic dysphonia Adductor dysphonia Abductor dysphonia Pharyngeal dystonia Lingual dystonia Spasmodic torticollis Writer‘s cramp Occupational cramps Inversion foot dystonia

Cervical dystonia Arm dystonia Leg dystonia

Dystonic movements may either be slow and sustained (tonic) or rapid (clonic), are typically repetitive, and are patterned, by contrast with choreic movements, which are more random and unpredictable, and myoclonus, which is rapid, rhythmic, and unassociated with alterations in posture. In some cases, rapid dystonic movements are difficult to distinguish from myoclonic jerks; therefore, the term myoclonic dystonia has been introduced. Some of these result from voluntary attempts to resist an abnormal posture, such as the patient with torticollis whose head pulls slowly to the right and jerks intermittently to the left. Essential tremor may coexist with focal dystonia to produce an associated tremor of the head and upper extremities. Dystonic movements in primary dystonia are characteristicallymade worse during voluntary movements. Action dystonia refers to involuntary movements that occur only during voluntary use of a group of muscles and are absent at rest. Some are task specific, such as writer’s and other occupational cramp disorders; vocal cord, jaw, or tongue spasms activated by speech; pharyngeal contractions during swallowing; and foot dystonia while walking. As the dystonia progresses, it appears more spontaneously and may be precipitated by movements in other body parts. In severe cases, the dystonia may progress to a permanent fixed posture with or without contractures. Dystonia usually increases with fatigue or stress and improves or is abolished with relaxation and sleep. Some patients acquire sensory tricks or compensatory postures that partially suppress the dystonic movements and postures but complicate the appearance of the movement disorder. Botulinum toxin has radically changed the management of adult-onset focal dystonia; its use in cranial and cervical dystonia is the subject of this chapter. In many cases, botulinum toxin has become the treatment of choice. Botulinum toxin works by inhibiting calcium-dependent acetylcholine release at the neuromuscular junction and has been especially effective in treating oculomotor disorders, blepharospasm, spasmodic dysphonia, and spasmodic torticollis. Botulinum toxin is the treatment of choice in blepharospasm and produces benefit in 70% to 80% of patients. Oromandibular dystonia of the jaw-closing and jaw-opening types benefits from botulinum toxin, but injection requires special attention to anatomic details and, in the case of pterygoid and digastric injections for jaw-opening dystonia, carries the risk of dysphagia. Botulinum toxin is used in spasmodic torticollis after preliminary trials with medication but is increasingly being used as a first-line treatment in this situation as well. Botulinum toxin is also the treatment of choice for spasmodic dysphonia, a condition in which medications and speech therapy are ineffective.

Cranial dystonia is a combination of dystonic movements of the eyelids, face, and jaw that is also known as Meige’s syndrome. Onset usually is between ages 40 and 60 and is more common in women than men. Blepharospasm is the most common manifestation of cranial dystonia and produces involuntary forced closure of the eyelids and increased eyeblink frequency. Differential diagnosis includes secondary forms of blepharospasm caused by neuroleptic drugs, Parkinson’s disease, progressive supranuclear palsy, Wilson’s disease, and lesions of the brainstem. Local irritative disorders of the eyes and eyelids would be expected to cause transient rather than chronic blepharospasm. Blepharospasm is bilateral but sometimes asymmetrical in distribution. Unilateral blepharospasm usually is caused by hemifacial spasm, which is not a dystonia but an irritative disorder of the facial nerve that causes myoclonic facial muscle contractions limited to one side of the face. The contractions of the orbicularis oculi in blepharospasm may be brief, causing repetitive blinking, or persistent, causing prolonged, forced closure of the eyes. Some patients manifest apraxia of eyelid opening, resulting in difficulty opening the eyes in the absence of orbicularis oculi spasm. Driving, bright lights, watching television, and reading are common aggravating factors. During examination, patients often display more prominent blepharospasm while relating their history than while quietly listening or being examined. Sensory tricks used to suppress blepharospasm are limited but may include jaw or neck movements, coughing, chewing gum, or placing a finger or hand near or on the upper lids. Eyebrow lifting and ticlike movements of the lower face and mouth may occur, representing attempts to control the blepharospasm; these movements do not necessarily warrant a diagnosis of Meige’s syndrome. Pharmacologic treatment usually is unsatisfactory but has included anticholinergic drugs, benzodiazepines, baclofen, and tetrabenazine. Surgical interventions such as myectomy and selective facial nerve section have been used with limited success and often produce cosmetically unacceptable facial muscle weakness. Botulinum toxin is the treatment of choice in patients unresponsive to medication and results in significant improvement in a majority of patients in terms of both eyeblink frequency and intensity of blepharospasm. Botulinum toxin is injected in dosages of 2.5 U subcutaneousiyinto the medial and lateral upper eyelid and lateral lower eyelid and intramuscularly into the lateral canthus. The pretarsal portion of the upper lids should be injected in patients with eyelid opening “apraxia.” Diffusion into the middle portion of the upper eyelid must be avoided to prevent levator palpebra weakness. Therapeutic effect usually is evident within several days and lasts approximately 3 months. Unwanted effects include ptosis, ecchymosis, diplopia, ectropion, blurred vision, and dry eyes. Excessive weakness may prevent normal eye closure during sleep and should be managed with appropriate ophthalmic lubrication. Oromandibular dystonia is the second most common manifestation of cranial dystonia. It may occur alone but is often associated with other cranial dystonias such as blepharospasm, lingual or pharyngeal dystonia, or spasmodic dysphonia. Differential diagnosis includes tardive dystonia, edentulous jaw movements, and bruxism. Jaw muscles may be involved asymmetrically or even unilaterally and produce involuntary jaw opening, jaw closing, or jaw deviation. Associated movements of the lower face are common and may include contractions of the platysma, pursing movements of the lips, tongue protrusion, and spasmodic

Chapter 129 H Focal Dystonia: Treatment with Botulinum Toxin

contractions of the mouth and pharynx. Blepharospasm, oromandibular dystonia, and spasmodic movements of the face and neck typically occur synchronously in repetitive and sometimes rhythmic fashion. In early stages, they may be triggered by speaking or chewing; later, they are precipitated by other facial movements; eventually, they become continuous. Oromandibular dystonia produces major disability, including pain, speech impairment, difficulty eating, and trauma to oral and dental structures. Pharmacologic therapy usually is ineffective but, similar to blepharospasm, has included anticholinergic drugs, benzodiazepines, baclofen, and tetrabenazine given alone or in combination. Botulinum toxin has been used with some success in oromandibular dystonia, but administration requires more detailed anatomic knowledge and is more prone to complication caused by spread of toxin than treatment of blepharospasm. Combined management by an otolaryngologist and speech pathologist is strongly recommended. Jaw-closing oromandibular dystonia is technically easier to treat and less often associated with dysphagia. Injections are made into masseter and medial pterygoids and, if necessary, temporalis muscles. Jaw-opening dystonia requires injection into lateral pterygoids and anterior digastrics. Pterygoid injections must be done under electromyographic guidance and usually can be done extraorally by someone experienced in the anatomy of this region. Other muscles usually can be located by palpation but are also best injected under electromyographic guidance. Dosages of botulinum toxin vary widely, and treatment should begin with small dosages titrated according to response over several treatment sessions. Typical dosages for masseter are 25 to 75 U; temporalis, 15 to 75 U; pterygoids, 5 to 50 U; and anterior digastrics, 2.5 to 30 U. Two to three injections are administered per muscle in small volumes per injection to reduce potential for regional spread. Dysphagia is the most common adverse effect and is more common after injection of jaw-opening than jaw-closing muscles. Nasal dysarthria, weakness of chewing, and local pain are other occasional adverse effects. SPASMODIC DYSPHONIA Spasmodic dysphonia, also called laryngeal dystonia, is an action dystonia in which there is involuntary adduction or abduction of the vocal cords activated by speech, resulting in abnormal voice production. Adductor dysphonia accounts for approximately 90% of cases of laryngeal dystonia and consists of involuntary approximation of the vocal cords caused by contraction or tensing of the thyroarytenoid (vocalis) muscles during speech. This results in a characteristic voice disorder in which patients speak in an effortful, strained, and staccato pattern with frequent short breaks in vocalization. In abductor dysphonia, involuntary separation of the vocal cords caused by contraction of the posterior cricoarytenoid muscles produces a characteristic breathy or whispered voice pattern with loss of volume. Some patients with adductor dysphonia compensate for adduction by whispering, whereas in a few patients, adductor and abductor dysphonia coexist, with one predominating over the other in most cases. Spasmodic dysphonia often is misdiagnosed as psychogenic in origin, but there is no evidence to support this view, and patients with spasmodic dysphonia usually can be distinguished from patients with truly psychogenic voice disorders by appropriate otolaryngologicexamination and voice evaluation techniques. Differential diagnosis includes voice tremor as a manifestation of essential tremor, extrapyramidal disorders affecting voice production, structural abnormalities of the vocal cords, and

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chronic inflammatory vocal cord conditions. Pharmacologic treatment is entirely unhelpful in this disorder and, by contrast with other focal dystonias, is not worth undertaking before the use of botulinum toxin. Vocal therapy techniques may be worthwhile in some cases, especially when there seems to be a nondystonic contribution to the voice disorder. Recurrent laryngeal nerve section can produce relief of symptoms, but adverse effects are common, and follow-up studies have shown a high relapse rate. Surgical techniques designed to relax or tighten the vocal cords are currently under investigation but are too new to assess. Before using botulinum toxin, patients should undergo neurologic, otolaryngologic, and voice evaluation. Fiberoptic laryngoscopy to exclude anatomic abnormalities and to confirm hyperadduction or hyperabduction is desirable. Voice recording and videostrobolaryngoscopy sometimes are indicated to exclude other voice disorders that may be difficult to differentiate from spasmodic dysphonia. Early treatment of spasmodic dysphonia with botulinum toxin used injections of 15 to 30 U into a single vocal cord. However, currently bilateral injections usually are given in a dosage range of 1.5 to 7.5 U per cord. After administration of appropriate local anesthesia, the cricothyroid membrane is penetrated with a 27-gauge electromyographicinjection needle, with the patient in a supine position. The needle is directed 30 degrees laterally and superiorly into the vocal cord. The vocal cord is identified electromyographically by increased spontaneous activity or activation with phonation, and botulinum toxin is injected into one or two sites on each side. In some centers, botulinum toxin has been injected by an indirect laryngoscopic approach, which has the advantage of not requiring electromyographicguidance. An initial dosage of 2.5 to 5.0 U bilaterally is recommended, with the understanding that there is a wide variability in response. Some patients experience insufficient therapeutic effect and need an additional injection, whereas others may experience excessive effect, manifested by a period of breathy or aphonic speech lasting for as long as several weeks. When benefit occurs, it usually appears within several days. The most common adverse effect is breathy speech or aphonia, which dictates future dosage adjustments. Dysphagia is uncommon and usually is limited to subjective difficulty drinking liquids without aspiration. Once the appropriate dosage is determined for individual patients, it should be expected that nearly all patients will experience significant improvement in speech. Duration of benefit is highly variable and ranges between 6 weeks and 6 months, with an average duration of 3 to 4 months. Abductor dysphonia is treated by posterior cricoarytenoid (PCA) or cricothyroid injection. Injection of PCA is more difficult than with thyro-arytenoid injection and requires positioning of the electromyographicallyguided needle posterior to the lamina of the thyroid cartilage. Only one posterior cricoarytenoid muscle is injected at a time because of the risk of bilateral abductor paralysis. Overall success with this method is less than for adductor dysphonia and sometimes requires careful bilateral injections, cricothyroid muscle injection, or thyroplastic procedures.

CERVICAL DYSTONIA Cervical dystonia, also known as spasmodic torticollis, is the most common focal dystonia that comes to medical attention. Secondary forms may result from a variety of orthopedic, neurologic, and infectious disturbances of the craniocervical junction, but most of these occur in children or young adults, are related to

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Movement Disorders W

Non-Parkinsonian Movement Disorders

obvious underlying causes, and do not produce the characteristic features of idiopathic cervical dystonia as it presents in adults. Like other focal dystonias, cervical dystonia was once believed to be psychogenic in origin, but psychological studies and general clinical experience do not support this view. Onset usually is between ages 30 and 50, and women are affected slightly more often than men. Symptoms usually begin with mild neck stiffness or subtle postural deviations of the head. A small number of patients report neck pain at onset, although with the exception of post-traumatic cases, onset usually is unrelated to immediate antecedent trauma. As the disorder progresses, pain and discomfort become prominent in 75% of patients and usually are localized to the posterior paracervical region and shoulder. Pain is much more prominent than in other focal dystonias and probably is of musculoskeletal or radicular origin. Pain typically is located in the posterior cervical region ipsilateral to the direction of head rotation or head tilt and almost never occurs in the affected sternomastoid muscle. Symptoms of cervical spondylosis and radiculopathy may complicate the clinical picture after several years of persistent cervical dystonia. Several abnormal head postures occur, consisting of various combinations of rotation (torticollis), lateral tilt (laterocollis), hyperextension of the head (retrocollis), and forward flexion (antecollis). Torticollis and laterocollis are the most common postures, whereas pure retrocollis and antecollis are less common in idiopathic cervical dystonia. Retrocollis is particularly common as a manifestation of tardive dystonia caused by neuroleptic drugs. Most patients display a combination of these postures, with the most common head position consisting of rotation of the head to one side with upward deviation of the chin and lateral tilt of the head to the opposite side. Symptoms often increase with fatigue and tend to be worse late in the day. Patients use a variety of sensory tricks, which are usually more effective early rather than later in the course. These begin with a light touch on the chin, but in more severe cases, a hand on the back or side of the neck or head is needed for relief. Head support while lying down usually reduces torticollis, but some patients experience an exacerbation of symptoms when in a reclining position. Some patients gain relief with use of a high-backed chair or recliner and drive with the assistance of a head rest. Fixed deformities, such as sternomastoid hypertrophy and elevation or anterior displacement of one shoulder, may appear with time. Most patients exhibit tonic deviation of the head, but in some cases clonic jerks are prominent. In many cases, these are caused by the patient’s effort to suppress the abnormal posture. Head tremor is common and is caused by dystonic tremor or associated essential tremor. The clinical course usually is one of slow progression over the first several months to years. followed by a static course. Spontaneous but usually temporary remissions have been reported in 5% to 10% of patients and usually occur within 5 years of onset. Most patients with cervical dystonia do not benefit from oral medications. Ordinary muscle relaxants typically are ineffective and have usually been tried before neurologic referral. The drugs of choice for treating cervical dystonia are anticholinergic drugs such as trihexyphenidyl, with which there has been the greatest experience. As many as 20% of patients respond to low or moderate dosages of 4 to 10 mg. Although the percentage of responders is low, the response may be good enough to obviate botulinum toxin treatment. Unfortunately, adverse effects are common even at low dosages and include nausea, dry mouth, drowsiness, visual disturbance, forgetfulness, urinary retention, and glaucoma. Some patients manifest mild choreiform dyskine-

sias that clear after discontinuation of treatment. Sensitivityto side effects in adults usually precludes high-dose anticholinergic treatment. Benzodiazepines such as diazepam, lorazepam, or clonazepam often are helpful for symptomatic pain management but carry the risk of dependency and susceptibility to withdrawal symptoms after chronic use. Baclofen and carbamazepine are of little or no benefit, whereas dopamine receptor antagonists such as haloperidol are contraindicated for chronic use because of risk of tardive dyskinesia. Nonpharmacologic therapies used to treat cervical dystonia have included hypnosis, biofeedback, relaxation techniques, psychotherapy, acupuncture, and braces, but in the majority of cases these are unhelpful. Physical therapy plays a limited role in treating cervical dystonia but is useful as an adjunct to maximize range of motion and for pain management in patients who have partially benefited from other treatments. Currently, patients with cervical dystonia are diagnosed earlier and seek treatment sooner than patients treated in the early years of botulinum toxin therapy. It is important to understand the ways in which cervical dystonia is disturbing because all symptoms or signs are not equally benefited. Involuntary movements and pain are the two major manifestations. Involuntary movements are disturbing because of the jerking head movements, the cosmetic effect produced by postural deformities, difficulties in carrying out routine activities of daily living such as working, driving, reading, and watching television, subjective gait disturbance, fatigue related to constant efforts to suppress the involuntary movements, and head tremor. Chronic pain, social withdrawal, and reactive depression are common consequences. It is worthwhile to review these areas of disability in detail both before and after treatment so that expectations before treatment and gains after treatment can be more readily identified. It is important to understand the anatomy of neck muscles and the way in which abnormal postures relate to contractions of specific cervical muscles (Table 129-2). The need for electromyography to assist botulinum toxin injection of cervical muscles is controversial and depends largely on the skills of the treating physician. Observed abnormal head postures usually can be correlated with a predictable pattern of muscle involvement. Careful observation and analysis of the patient’s posture, involun-

H TABLE 129-2.

Action of Commonly Injected Cervical Muscles

Muscle

Action ~~

~

Sternomastoid

Contralateral rotation lpsilateral tilt Anterior flexion

Trapezius

Shoulder elevation lpsilateral tilt Neck extension

Splenius capitis

lpsilateral rotation lpsilateral tilt Neck extension

Levator scapulae

Shoulder elevation lpsilateral tilt

Scalenus group

lpsilateral tilt Head flexion

Deep postvertebrals (semispinalis, longissimus capitis)

lpsilateral tilt Head extension

Chapter 129 W

tary movements, and voluntary movements, together with palpation of often hypertrophied muscles, usually allows appropriate selection of muscles for injection. Rotational torticollis is produced by the combined effect of sternomastoid contraction rotating the head contralaterally and contraction of ipsilateral posterior cervical muscles-splenius capitis, longissimus capitis, and oblique capitis inferior-rotating the head ipsilaterally. Although some authors include trapezius as a head rotator, it primarily tilts the head ipsilaterally, is extremely thin in the paracervical region, and in most cases does not require injection. Splenius capitis is a much thicker muscle and, in patients with cervical dystonia, often is hypertrophied and easily palpable in the posterior cervical triangle behind and below the mastoid, where it emerges from under the trapezius. In most cases, injection of ipsilateral splenius and contralateral sternomastoid is sufficient, and electromyographyis unnecessary. Because the semispinalis is a posterior cervical muscle that sometimes rotates the head contralaterally, it may be worth injecting this muscle with electromyographic guidance on the side contralateral to head rotation in cases resistant to routine patterns of injection. The oblique capitis inferior is a small and much deeper muscle that cannot be identified without electromyography and may also require injection in some cases. Laterocollis is produced by contraction of the ipsilateral sternomastoid (clavicular more than sternal head), levator scapulae, scalenus muscles, splenius, and trapezius. In this case, electromyographyis useful in estimating the degree to which each muscle contributes to head tilt. In most cases, weakening of ipsilateral sternomastoid, levator scapulae, and splenius is sufficient. Injections into the scalenus group usually are avoided because they are deep, more likely to be associated with dysphagia, and lie in close anatomic relationship to the brachial plexus and lung. Retrocollis probably is the easiest form of cervical dystonia to treat and requires injections into splenius capitis, trapezius, and sometimes deeper posterior cervical muscles such as semispinalis. Side effects are rare and limited to occasional excessive neck extensor weakness. Antecollis often is resistant to treatment with botulinum toxin. Although sternomastoid muscles, scalenes, and platysma contribute to anterior head flexion and are easily injected, the more important prevertebral head flexors, longus colli and longus capitis are more powerful muscles that require special expertise and fluoroscopic and electromyographic monitoring for injection. If electromyography indicates a significant contribution by sternomastoid and scalenes, bilateral injection of these muscles may be considered but is associated with a higher incidence of dysphagia. Typical initial injections into the sternomastoid are 50 to 70 U; splenius capitis, 80 to 100 U; trapezius, 60 to 80 U; levator scapulae, 30 to 50 U; scalenus muscles, 20 to 40 U; and deeper posterior cervical muscles, 80 to 100 U. Women, patients with smaller neck muscles, or patients with previous surgical denervation, and patients given bilateral injections should receive lower dosages to reduce the incidence of dysphagia and excessive neck muscle weakness. Botulinum toxin has been demonstrated to be safe and effective in a number of open and controlled trials. Although subjective improvement sometimes seems to exceed objective measures of benefit, published studies have uniformly shown significant improvement for both abnormal head posture and pain in 60% to 80% of patients. Initial response to treatment should be documented carefully to justify follow-up treatments. The degree of

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torticollis observed in the examining room may not adequately represent the amount of improvement. Although in many cases improvement in head posture is apparent, family members sometimes are better observers than the patient, who is often less aware of head position. Pain relief, increased range of motion, reduced dystonic tremor, reduction in the need to voluntarily suppress abnormal postures, and resultant improvements in mood are useful indicators of treatment response. The cause of primary resistance is uncertain, but 20% to 25% of patients do not respond to treatment. Patients treated early may respond more favorably than patients with chronic cervical dystonia, possibly because of muscle contractures and fixed postures. A change in the pattern of muscle activity whereby uninjected, deeper posterior cervical muscles develop increased spasm may account for other treatment failures. The use of botulinum toxin in cervical dystonia is remarkably safe. Immediate side effects are limited to occasional small subcutaneous hematomas and rare pneumothorax. When possible, patients should discontinue aspirin for several days before injections. Patients anticoagulated with warfarin with prothrombin times in therapeutic range can be safely injected. Occasional brief pain may occur if the needle encounters the greater occipital nerve in the suboccipital region or the brachial plexus during scalene injection. Later-appearing adverse effects include dysphagia, neck weakness, and new patterns of cervical pain. Dysphagia is uncommon if dosages in sternomastoid muscles are kept below 60 U. Higher injections closer to the mastoid and into the posterior aspect of this muscle also minimize this side effect. When it occurs, dysphagia appears 5 to 6 days after injection and lasts for 2 to 4 weeks. Dysphagia is primarily for solid foods and is easily managed with soft solids or thick liquids and modification of swallowing techniques such as turning the head toward the weak side. Aspiration is possible but is rare in botulinum-induced dysphagia. A modified barium swallow with fluoroscopy may demonstrate unilateral pharyngeal weakness but is not necessary for routine management in most cases. Excessive weakness in neck muscles is uncommon, but patients may experience difficulty elevating the head from a bent position or turning in bed because of excessive posterior cervical muscle weakness. Occasionally, patients experience increased pain at the injection sites or a new distribution of cervical or shoulder pain within the first several weeks of injection. This usually occurs in patients with pretreatment cervical pain and may be caused by new patterns of muscle use and ligamentous stretch. Generalized fatigue, myalgia, and weakness are uncommon and in controlled studies have not exceeded similar effects after placebo. Although single-fiber electromyographic studies may show evidence of neuromuscular blockade in muscles distant from the injection site and minor abnormalities of autonomic cardiovascular reflexes have been demonstrated, clinical manifestations of these laboratory observations have not been apparent. BOTULINUM TOXIN Clostridium botulinum produces seven antigenically distinctive toxins that are all potent paralytic agents. These are designated as A, B, C, D, E, F, and G. These toxins are polypeptides with a molecular mass of 150,000 Da. When the single-chain toxin is cleaved, it yields a dichain molecule in which a heavy chain of about 100,000 Da is linked by a disulfide bond to a light chain of approximately 50,000 Da. In this form, botulinum toxin is capable of producing neuromuscular junction blockade. Botulinum toxin

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produces weakness by blocking acetylcholine release. The steps involved in this process include binding to the preterminal membrane, internalizing the toxin, and blocking neurotransmitter release. The heavy chain of the toxin is responsible for binding to the presynaptic nerve terminal, whereas the light chain is responsible for blocking acetylcholine release. Botulinum toxin A has been shown to exert its effect by cleaving the synaptic protein SNAP-25, which is a constituent of the synaptic vesicle membrane. As a result of this cleavage, the presynaptic vesicle loses its ability to fuse with the nerve terminal membrane to initiate exocytosis. In animal studies, botulinum toxin has been shown to reach the central nervous system, where it binds to brain synaptosomes. However, the toxin’s clinical effect in botulism or local muscle paralysis after injection is not believed to be caused by central nervous system mechanisms. After injection into a muscle, the toxin diffuses several centimeters from the injection site. Because the radius of spread appears to be determined by the dosage and volume injected, injections of smaller dosages and volumes may reduce spread to adjacent muscles, thereby reducing incidence of unwanted weakness in adjacent muscles. Clinical studies comparing efficacy of multiple and single injections have produced inconsistent results, and it is currently recommended that two to four injections be given into each treated muscle. Long-term effects of intramuscular botulinum toxin have been studied widely in animals but only occasionally in humans. In experimental animals, botulinum toxin causes denervation atrophy, whereas in human studies of orbicularis oculi muscles, atrophy and fibrosis persist up to 4 months after exposure to botulinum toxin. Botulinum toxin produces sprouting of motor axon terminals in both animal and human studies. Some of these sprouts end blindly, whereas others appear to terminate on muscle motor endplates. It is unlikely that axonal sprouting is responsible for recovery of muscular strength after botulinum toxin injection, most histologic studies show incomplete sprouting unlikely to represent functionally effective reinnervation. The dosage of botulinum toxin capable of producing significant systemic toxicity in humans is not known. In monkeys, the median lethal dosage for botulinum toxin A is estimated at 40 U/kg. This would amount to approximately 3000 units in a 75-kg man. The lethal oral dosage is also not known with certainty but has been estimated to be in the vicinity of lo4 to lo6 times the parenteral dosage. In recent years, the appearance of secondary resistance has emerged as an increasing problem in botulinum toxin clinics. It is presumed that many if not all of these cases are caused by the appearance of blocking antibodies to botulinum toxin A. Interestingly, experience with botulism food poisoning has failed to show antibodies to botulinum toxin in surviving patients. Unfortunately, there is no assay for botulinum toxin entirely dependable antibodies. An in vivo mouse neutralization assay is available, and enzyme-linked immunosorbent assay has also been used to detect botulinum antibodies but has not been correlated with the presence of secondary resistance. In several studies, the frequency of detectable botulinum antibodies has been in the range of 3% to 5%, with evidence that increased dosage and reduced interval between injections are related to the presence of antibodies. Botulinum toxin B is now available for treatment of patients who have developed antibodies to Botulinum toxin A. Botulinum toxin should be administered by a physician well acquainted with the diagnosis and treatment of disorders characterized by excessive and inappropriate muscle spasm. It is

important to carefully review the anatomy relevant for the body part being injected. Although not necessary in every case, electromyography often is helpful in using botulinum toxin for cranial and cervical dystonias. Since its introduction into clinical practice, significant adverse effects have been extremely rare. Despite its extreme potency, it is a remarkably safe drug increasingly used to treat spasmodic muscles in a wide variety of body locations. Although there is no information regarding potential adverse effects in pregnancy, it is recommended that botulinum toxin not be used in pregnant or lactating women. Primary muscle disorders such as myasthenia gravis, LambertEaton syndrome, motor neuron disease, and primary myopathies are relative contraindications to the use of botulinum toxin. However, because the amount of toxin that reaches the systemic circulation after local intramuscular injection is minute, this may not necessarily constitute an absolute contraindication in a dystonia for which no other treatment is available.

SUGGESTED READINGS American Academy of Neurology Therapeutics and Technology Assess-

ment Subcommittee: Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 40:1332, 1990 Blasia J, Chapman ER, Link E et al: Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365:160, 1993 Blitzer A Botulinum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol98:93, 1989 Blitzer A, Brin M F Laryngeal dystonia: a series with botulinum toxin therapy. Ann Otol Rhinol Laryngol 100:85, 1991 Blitzer A, Brin MF, Stuart C et al: Abductor laryngeal dystonia: a series treated with botulinum toxin. Laryngoscope 102:163, 1992 Comella CL, Buchman AS, Tanner CM et al: Botulinum toxin injection for spasmodic torticollis: increased magnitude of benefit with electromyographic assistance. Neurology 42:878, 1992 Conference Report: Clinical use of botulinum toxin. NIH Consensus Development Conference Statement. Arch Neurol 48:1294, 1991 Dutton JJ,Buckley E G Botulinum toxin in the management of blepharospasm. Arch Neurol43:380, 1986 Gifianda P, Vita G, Nicolosi C et al: Botulinum toxin therapy: distant effects on neuromuscular transmission and autonomic nervous system. J Neurol Neurosurg Psychiatry 55:844, 1992 Greene P, Kang U, Fahn S et al: Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 401213, 1990

JankovicJ, Brin M F Therapeutic uses of botulinum toxin. N Engl J Med 3241186, 1991 Jankovic J, Schwartz KS: Longitudinal experience with botulinum toxin injections for treatment of blepharospasm and cervical dystonia. Neurology 43:834, 1993 Ludlow CL The treatment of speech and voice disorders with botulinum toxin. JAMA 264:2671, 1990 Marsden CD: The focal dystonias. Clin Neuropharmacol9(Suppl2):S49, 1986 Marsden CD: The problem of adult-onset idiopathic torsion dystonia and other isolated dyskinesias in adult life. Adv Neurol 14259, 1976 Schantz EJ, Johnson EA Properties and use of botulinum toxin and other microbial neurotoxins in medicines. Microbiol Rev 56:80, 1992 Sloop RR, Cose BA, Escutin RO: Human response to botulinum toxin injection: type B compared with type A. Neurology 49:189-194, 1997 Zuber M, Sebald M, Bathien N et al: Botulinum antibodies in dystonic patients treated with type A botulinum toxin: frequency and significance. Neurology 43:1715, 1993

Chapter 130

Task-Specific Focal Dystonia

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130 Task-Specific Focal Dystonia Michael E. Charness

Dystonia is a movement disorder characterized by involuntary, sustained contraction of muscles, resulting in tremor, repetitive movements, or abnormal postures. Focal dystonia affects a single body region, such as the face (Meige’s syndrome), neck (torticollis), or upper extremity (writer’s cramp or musician’s cramp). Task-specific focal dystonia (TSFD) or occupational cramp is a disorder of involuntary movements elicited by the performance of skilled, stereotyped, repetitive movements. Simple cramp is the occurrence of TSFD only during a specific skilled task. Dystonic cramp is the occurrence of TSFD during a variety of related tasks, such as typing, writing, and playing the piano. In some patients, there is progression from simple cramp to dystonic cramp.

EPIDEMIOLOGY Writer’s cramp occurs in approximately 300 patients per million, as determined by analysis of a Mayo Clinic database. A European study estimated a prevalence for writer’s cramp of 14 per million. The true prevalence of musician’s cramp is unknown; however, TSFD is diagnosed in approximately 10% to 15% of patients presenting to performing arts clinics. Several series have confirmed that TSFD is more common among men than among women.

CLINICAL FEATURES The onset of TSFD usually is insidious. Patients with writer’s cramp often describe a clear deterioration in their handwriting without recollection of the precise onset. Similarly, many musicians with TSFD recollect a moment when their playing became particularly troublesome but also recall having some difficulty playing months to years earlier. In musicians, the onset of TSFD precedes the diagnosis by an average of 5 years. TSFD tends to worsen and then stabilize without involving other body segments. About 5% of patients develop TSFD of the contralateral limb. Only rarely is there spontaneous remission, and in many instances TSFD significantly limits or ends the careers of professional musicians. Writer’s cramp is typically painless. Attempts to write produce tightness in the upper extremity, slowness of movements, and a marked degradation of penmanship. In most patients, writing produces involuntary contraction of the flexors of the thumb, index finger, and wrist. Grip may be so forceful that the pencil breaks. Dystonic muscle contraction sometimes leads to tremor. Straining to write for prolonged periods of time sometimes causes muscle tightness and pain in the hand, forearm, arm, neck, and shoulders. In some patients, there is involuntary extension of the index finger or the thumb, causing the pencil to drop. Involuntary movements usually are evident within the first few seconds of writing. In this respect, TSFD differs clearly from the muscle pain, tightness, and occasional cramping that occur commonly after prolonged writing. Patients commonly alter their customary style for gripping the pencil, sometimes with significant improvement. Whereas cursive writing on a horizontal surface may be extraor-

dinarily difficult, cursive writing on a vertical surface, such as a blackboard, may be nearly normal. Many patients with writer’s cramp can type normally. Conversely, many patients with typinginduced cramp can write normally. For high-level musicians, the motor aspects of performance are automatic, and their major focus is on musical interpretation. Often, the first symptom of TSFD in musicians is the uncustomary effort needed to play their instruments. This heightened effort may create the perception that performance has declined, even before the problem is apparent to professional colleagues, critics, or an audience. Over time, patients also note involuntary muscle contraction, tightness in their upper extremities, and a greater deterioration in performance, which then becomes apparent to others. Dystonic movements may occur selectively during certain sequences of finger movement, such as ascending scales but not during descending scales. In other instances, extended hand positions provoke dystonia, causing difficulty playing chords or octaves but not scale passages.

DIAGNOSIS TSFD is diagnosed clinically, based on the history and physical examination. The history is often so characteristic that the diagnosis becomes clear, even before the patient is examined. Brain imaging studies are normal in most patients with TSFD. For patients with TSFD and an otherwise normal physical examination, brain imaging can be omitted. There are no clinically useful electrodiagnostic, biochemical, or genetic tests for confirming the diagnosis. TSFD sometimes occurs early in the setting of Parkinson’s disease or in Wilson’s disease. In patients with writer’s cramp, the involuntary movements are not always evident because the fingers and thumb are fixed around the writing instrument. One often appreciates increased tension in the hand and forearm that commences with writing. More striking is the slow, laborious production of illegible handwriting, sometimes associated with tremor. In mild cases, it is helpful to compare handwriting samples from before and after the onset of symptoms. In musicians, TSFD can be heard as well as seen. There may be a marked degradation of performance, leaving a concert artist sounding like a beginner. In milder cases, the level of performance must be evaluated in relation to the patient’s previous level of accomplishment, based on an occupational history or old recordings. Because the hands are not wrapped around a writing instrument, involuntary movements often are more apparent than in writer’s cramp. Many different patterns of abnormal movement can be appreciated, including flexion of the little and ring fingers, extension of the digits, or flexion of the index finger and thumb (Fig. 130-1). Often there is associated flexion or extension of nearby digits, which patients recognize as compensatory. In selecting muscles for injection with botulinum toxin, it is important to distinguish the primary abnormal movements from the compensatory movements.

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FIG. 150-1. Different patterns of dystonia in three pianists. Top left: flexion of the right little and ring fingers at the PIP joints. Bottom left: extension of the right index finger at the MCP and PIP joints. Bottom right: flexion of the right index finger at the PIP joint and thumb at the IP joint. (From Charness ME, Ross MH, Shefner JM: Ulnar neuropathy and dystonic flexion of the fourth and fifth digits: clinical correlation in musicians. Muscle Nerve 19:431-437, 1996, with permission.)

Wind players may develop a TSFD affecting the embouchure, manifesting as lip tremor, tongue protrusion, jaw closure, and elevation or depression of a corner of the mouth. Air leaks may be visible between the lips on one side of the mouthpiece, and there is marked degradation in the quality and articulation of notes. Some patients with task-specific jaw closure develop difficultywith speech or eating. It is essential to observe the affected task in TSFD because physical examination is otherwise normal in most patients. When a piano is not available, tapping on a tabletop can sometimes reproduce dystonic movements. There may be tightness and tenderness of muscles in the shoulder girdle and neck, the result of sustained playing or writing with excessive muscle contraction. There are sometimes signs of nerve entrapment, which may antedate the dystonia or may develop as a result of the sustained abnormal postures and increased muscle tone. In a minority of patients, dystonic movements or tremor are apparent in the outstretched hands. Some patients have a task-specific disorder characterized by tremor rather than sustained muscle contraction. In patients with primary writing tremor, there is little or no tremor of the outstretched hands, but writing produces a high-amplitude 5- to 7-Hz tremor. A similar disorder is observed in musicians, who exhibit tremor while playing their instrument but manifest little tremor otherwise.

PATHOPHYSIOLOGY The hallmark of TSFD is prolonged bursting of co-contraction in agonist and antagonist muscles during the performance of a skilled task. Electromyographic recordings also reveal reduced activation of selective muscles and loss of fine control. Some physiologic abnormalities are apparent in the absence of movement. There is reduced reciprocal inhibition of the H reflex, decreased spinal inhibition, increased cortical excitation, and reduced intracortical inhibition. Frank distortions in the cortical representations of the digits have been identified by brain mapping in patients with TSFD. The distance between the cortical sensory representations of digit pairs is smaller in musicians with TSFD than in nondystonic musicians or in normal controls. There is also fusion of the cortical sensory representation of the digits and inversion of the position of the thumb and little finger representations. These findings are consistent with observations in monkeys that alterations of sensory input can lead to a reorganization of the sensory cortex. Indeed, patients with TSFD show a defect in the discrimination of temporally and spatially related sensory input to the hand. The organization of the motor cortex is also altered in patients with TSFD. TSFD arises primarily in musicians with high levels of skill and develops rarely during the acquisition of the skill. Therefore, TSFD may emerge through a perversion of the plastic neural responses

Chapter 130

that are associated with the learning and rehearsal of highly skilled movements. The rapid, repetitive hand movements involved in executing skilled movement may independently contribute to the development of TSFD by producing peripheral nerve or soft tissue injury, activating sensory pathways that influence motor programs, or changing the local balance of cortical inhibition and excitation. Physiologic studies of patients with TSFD provide evidence for alterations in the planning of movement, the anatomic organization of sensorimotor function, and the integration of sensory information that guides motor processes. Some of these abnormalities are bilateral, even in the presence of unilateral symptoms, and therefore may precede the development of TSFD. Learning an advanced skill is common to all musicians; therefore, additional factors must account for the development of TSFD in a minority. TSFD occurs with increased frequency among first-degree relatives of patients with Oppenheim’s dystonia (DYTl). One reported family had multiple affected members with writer’s cramp and mutations in the DYTl gene. A study of 18 consecutive musicians with TSFD did not reveal any with mutations in the DYTl gene. A majority of musicians develop TSFD in the setting of nerve entrapment, soft tissue injury, learning of a second musical instrument, stress, or alterations in musical technique. These conditions may independently alter sensorimotor representation within the nervous system. Many musicians with dystonic flexion of the little and ring fingers have an ipsilateral ulnar neuropathy. In some, the severity of the dystonia and the ulnar neuropathy fluctuate in parallel. Interestingly, patients with ulnar neuropathy and no TSFD show the same pattern of co-contraction in agonist and antagonist muscles as patients with TSFD. Although patients with isolated ulnar neuropathy have reduced reciprocal inhibition of the H reflex and decreased spinal inhibition, they do not exhibit the increased cortical excitation observed in patients with TSFD. What triggers the transition from ulnar neuropathy to TSFD is unknown. ~~

TREATMENT Treating TSFD is difficult, and success is inversely proportional to the need for neuromuscular perfection. Only a few world-class musicians with TSFD have regained top concert form. A larger number of musicians with TSFD have improved sufficiently to enlarge their repertoire and increase their range of playing and teaching opportunities. Treatment of embouchure dystonia in wind players has been particularly frustrating, with few successes. Small improvements in TSFD result in larger functional gains for writers than for musicians; therefore, treatment of writer’s cramp often is more successful than treatment of musician’s cramp. The ubiquity of computers and the decreased need for writing in many jobs has also decreased the burden of writer’s cramp and the need for treatment. Voice-activated input software provides an occupational alternative for patients with typist’s cramp. Rest alone is rarely helpful in TSFD. Musicians have returned to playing after as long as 5 years of rest without any improvement in their TSFD. One drummer did recover completely after 25 years of rest, but this is hardly a viable option for most patients. Approximately 10% of patients benefit from anticholinergic medications; however, these are poorly tolerated and rarely used for long periods of time. A small proportion of my patients have found gabapentin to be mildly helpful. Hypnotherapy, biofeed-

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back, and occupational therapy are modestly successful in some patients. Changes in hand position, ergonomics, and instrument redesign can be beneficial. Fat pens and writing devices are clearly helpful for some patients with writer’s cramp. The use of gloves, splints, or elastic bands fastened around a finger sometimes produces improvement, perhaps by altering sensory feedback, but benefits rarely endure. Instrument redesign has enabled some musicians to continue performing. One musician redesigned his flute to largely eliminate a focal dystonia that was triggered by placing the left index finger on the instrument. Plastic “figure-8” rings can limit involuntary flexion of individual digits and are useful adjuncts in selected patients. Several highly motivated musicians have experienced substantial improvement in TSFD after motor retraining. These retraining programs involve the complete avoidance of dystonic playing and the slow rehearsal of nondystonic playing, often with the assistance of visual imagery. Improvement occurs over months to a few years, during which time patients are unable to engage in professional performance. Many patients with writer’s cramp learn to write with the nondominant hand. Between 10% and 25% of these patients develop dystonia in the nondominant writing hand. Constraint-induced movement therapy involves applying splints that limit movement to one digit at a time. Patients are encouraged to practice their instruments while splinted in an attempt to reverse the fusion of sensorimotor maps and regain independence of finger movement. Enthusiasm for this approach has not survived early reports of success. Limb immobilization and sensory discrimination training have also been used to correct the abnormal sensory maps of patients with TSFD. Several uncontrolled trials in small series of patients have yielded promising results, but these findings need to be replicated. Injection of subparalyzing dosages of lidocaine can improve TSFD for several days, perhaps by reducing the Ia afferent input from muscle spindles, which contributes to TSFD. This approach is not practical for most patients. Slow repetitive transcranial magnetic stimulation of the motor cortex transiently improves writer’s cramp, but a practical clinical application has not yet been described. Some patients with ulnar neuropathy and dystonic flexion of the little and ring fingers have experienced improvement in their dystonia after treatment of their ulnar neuropathy. Surgical correction of an ulnar neuropathy is a reasonable consideration when TSFD and ipsilateral ulnar neuropathy do not respond to conservative measures. The selective weakening of dystonic muscles with botulinum toxin produces transient improvement in a majority of patients with TSFD. However, when followed for several years, a majority of patients discontinue treatment because of insufficient response, expense, or poor access to a qualified provider. The goal of treatment is to produce sufficient weakness to prevent dystonic contraction without also compromising the task. Patients with dystonic contraction of a small number of easily identified muscles are better candidates for injection than those with complex patterns of dystonia. There is clearly less latitude for excessive weakness in musicians than in writers because musical performance is readily degraded by mild weakness. Even the targeted level of weakness may compromise musical performance. Botulinum toxin injection does not address several physiologic abnormalities in TSFD, including the failure of certain muscles to contract and the spread of contraction to multiple adjacent muscles. Nonetheless, in carefully selected patients, the improve-

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ment from botulinum toxin injection can sometimes be striking, even if not complete. For upper extremity dystonia, botulinum toxin is injected through a hollow electromyographic needle after anatomic and physiologic localization of the target muscle. Weakness develops over a few days to a week. It is helpful to assess patients 2 weeks after the first injection to evaluate the therapeutic response and the pattern and magnitude of weakness. An injection may be unsuccessful because it produces too much or too little weakness in the targeted muscles. Spread of toxin to adjacent, nontargeted muscles occurs in a majority of cases and may also compromise the therapeutic response. Botulinum toxin reduces the release of acetylcholine at the neuromuscular junction, leading to chemodenervation of the target muscle. The resulting weakness, whether beneficial or excessive, is always reversible within 1 to 6 months; therefore, injections must be repeated several times annually. Injection of botulinum toxin also causes a functional reorganization of the motor cortex, suggesting an additional mechanism of action. In a minority of patients with TSFD, repeated injection of botulinum toxin leads to the development of neutralizing antibodies, with progressive blunting of the therapeutic response.

By1 NN, McKenzie A Treatment effectiveness for patients with a history of repetitive hand use and focal hand dystonia: a planned, prospective follow-up study. J Hand Ther 13:289-301,2000 Candia V, Elbert T, Altenmuller E et ak Constraint-induced movement therapy for focal hand dystonia in musicians. Lancet 353:42, 1999 Charness ME, Ross MH, Shefner JM: Ulnar neuropathy and dystonic flexion of the fourth and fifth digits: clinical correlation in musicians. Muscle Nerve 19:431437, 1996 Elbert T, Candia V, Altenmuller E et ak Alteration of digital representations in somatosensory cortex in focal hand dystonia. Neuroreport 9~3571-3575, 1998 Friedman JR, Klein C, Leung J et ak The GAG deletion of the DYTl gene is infrequent in musicians with focal dystonia. Neurology 55:14171418, 2000 Frucht SJ, Fahn S, Greene PE et al The natural history of embouchure dystonia. Mov Disord 16:899-906,2001 Marsden CD, Sheehy MP Writer’s cramp. Trends Neurosci 13:14&153, 1990 Newmark J, Hochberg FH: Isolated painless manual incoordination in 57 musicians. J Neurol Neurosurg Psychiatry 50:291-295, 1987 Priori A, Pesenti A, Cappellari A et ak Limb immobilization for the treatment of focal occupational dystonia. Neurology 57:405-409, 2001 Ross MH, Charness ME, Sudarsky L, Logigian E L Treatment of occupational cramp with botulinum toxin: diffusion of toxin to adjacent noninjected muscles. Muscle Nerve 20593-598, 1997

SUGGESTED READINGS Bain PG, Findley LJ, Britton TC et ak Primary writing tremor. Brain 118:1461-1472, 1995

13 1 Tics and Tourette’s Syndrome Frederick 1. Marshall and Roger Kurlan

In 1885, Georges Gilles de la Tourette began cataloging and organizing movement disorders at the suggestion of his mentor, Jean Charcot. Having earlier translated Beard’s article on the peculiar “Jumping Frenchmen of Maine,” the 28-year-old Tourette struck out to find evidence of their progenitors on the wards of the Salpetriere in Paris. Instead, he came on a small group of patients who suffered from multiple motor and vocal tics. Of the nine patients described in his original article, five suffered from scatologic outbursts, a symptom that provoked them to selfimposed social isolation and prompted generations of physicians, including Charcot himself, to presume a psychiatric cause for the disorder. The syndrome of Gilles de la Tourette, now properly called Tourette’s syndrome, has captured the imagination of clinicians ever since. It was not until the 1960s, however, that Tourette’s syndrome emerged from its status as a rare curiosity. With the introduction of haloperidol treatment and the demonstration that chronic motor and vocal tics could be suppressed medically, the disorder became the concern of neurologists as well as psychiatrists. More than any other advance, the success of neuroleptic treatment placed Tourette’s disorder firmly in the center of an emerging understanding of the links between brain and behavior.

DEFINITION, PHENOMENOLOGY, AND NATURAL HISTORY

Despite compelling evidence of its hereditary nature and of the genetic link with a spectrum of other neurobehavioral disorders such as obsessive-compulsive disorder and attention deficit hyperactivity disorder (ADHD), there remains no disease-specific biologic marker for Tourette’s disorder. Therefore, the diagnosis of Tourette’s disorder rests on recognition of its characteristic signs and symptoms. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria include the presence of both multiple motor tics and one or more vocal tics at some time during the illness (not necessarily concurrently); duration longer than 1 year, during which time there is no tic-free interval longer than 3 months; onset before age 18; marked distress or significant impairment in social, occupational, or other important areas of functioning; and absence of possible confounding agents or conditions (e.g., stimulants, Huntington’s disease, postviral encephalitis). The remaining primary tic disorders include chronic tic disorder and transient tic disorder. The former differs from Tourette’s syndrome in that either motor or vocal tics (but not

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ment from botulinum toxin injection can sometimes be striking, even if not complete. For upper extremity dystonia, botulinum toxin is injected through a hollow electromyographic needle after anatomic and physiologic localization of the target muscle. Weakness develops over a few days to a week. It is helpful to assess patients 2 weeks after the first injection to evaluate the therapeutic response and the pattern and magnitude of weakness. An injection may be unsuccessful because it produces too much or too little weakness in the targeted muscles. Spread of toxin to adjacent, nontargeted muscles occurs in a majority of cases and may also compromise the therapeutic response. Botulinum toxin reduces the release of acetylcholine at the neuromuscular junction, leading to chemodenervation of the target muscle. The resulting weakness, whether beneficial or excessive, is always reversible within 1 to 6 months; therefore, injections must be repeated several times annually. Injection of botulinum toxin also causes a functional reorganization of the motor cortex, suggesting an additional mechanism of action. In a minority of patients with TSFD, repeated injection of botulinum toxin leads to the development of neutralizing antibodies, with progressive blunting of the therapeutic response.

By1 NN, McKenzie A Treatment effectiveness for patients with a history of repetitive hand use and focal hand dystonia: a planned, prospective follow-up study. J Hand Ther 13:289-301,2000 Candia V, Elbert T, Altenmuller E et ak Constraint-induced movement therapy for focal hand dystonia in musicians. Lancet 353:42, 1999 Charness ME, Ross MH, Shefner JM: Ulnar neuropathy and dystonic flexion of the fourth and fifth digits: clinical correlation in musicians. Muscle Nerve 19:431437, 1996 Elbert T, Candia V, Altenmuller E et ak Alteration of digital representations in somatosensory cortex in focal hand dystonia. Neuroreport 9~3571-3575, 1998 Friedman JR, Klein C, Leung J et ak The GAG deletion of the DYTl gene is infrequent in musicians with focal dystonia. Neurology 55:14171418, 2000 Frucht SJ, Fahn S, Greene PE et al The natural history of embouchure dystonia. Mov Disord 16:899-906,2001 Marsden CD, Sheehy MP Writer’s cramp. Trends Neurosci 13:14&153, 1990 Newmark J, Hochberg FH: Isolated painless manual incoordination in 57 musicians. J Neurol Neurosurg Psychiatry 50:291-295, 1987 Priori A, Pesenti A, Cappellari A et ak Limb immobilization for the treatment of focal occupational dystonia. Neurology 57:405-409, 2001 Ross MH, Charness ME, Sudarsky L, Logigian E L Treatment of occupational cramp with botulinum toxin: diffusion of toxin to adjacent noninjected muscles. Muscle Nerve 20593-598, 1997

SUGGESTED READINGS Bain PG, Findley LJ, Britton TC et ak Primary writing tremor. Brain 118:1461-1472, 1995

13 1 Tics and Tourette’s Syndrome Frederick 1. Marshall and Roger Kurlan

In 1885, Georges Gilles de la Tourette began cataloging and organizing movement disorders at the suggestion of his mentor, Jean Charcot. Having earlier translated Beard’s article on the peculiar “Jumping Frenchmen of Maine,” the 28-year-old Tourette struck out to find evidence of their progenitors on the wards of the Salpetriere in Paris. Instead, he came on a small group of patients who suffered from multiple motor and vocal tics. Of the nine patients described in his original article, five suffered from scatologic outbursts, a symptom that provoked them to selfimposed social isolation and prompted generations of physicians, including Charcot himself, to presume a psychiatric cause for the disorder. The syndrome of Gilles de la Tourette, now properly called Tourette’s syndrome, has captured the imagination of clinicians ever since. It was not until the 1960s, however, that Tourette’s syndrome emerged from its status as a rare curiosity. With the introduction of haloperidol treatment and the demonstration that chronic motor and vocal tics could be suppressed medically, the disorder became the concern of neurologists as well as psychiatrists. More than any other advance, the success of neuroleptic treatment placed Tourette’s disorder firmly in the center of an emerging understanding of the links between brain and behavior.

DEFINITION, PHENOMENOLOGY, AND NATURAL HISTORY

Despite compelling evidence of its hereditary nature and of the genetic link with a spectrum of other neurobehavioral disorders such as obsessive-compulsive disorder and attention deficit hyperactivity disorder (ADHD), there remains no disease-specific biologic marker for Tourette’s disorder. Therefore, the diagnosis of Tourette’s disorder rests on recognition of its characteristic signs and symptoms. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria include the presence of both multiple motor tics and one or more vocal tics at some time during the illness (not necessarily concurrently); duration longer than 1 year, during which time there is no tic-free interval longer than 3 months; onset before age 18; marked distress or significant impairment in social, occupational, or other important areas of functioning; and absence of possible confounding agents or conditions (e.g., stimulants, Huntington’s disease, postviral encephalitis). The remaining primary tic disorders include chronic tic disorder and transient tic disorder. The former differs from Tourette’s syndrome in that either motor or vocal tics (but not

Chapter 131 H Tics and Tourette‘s Syndrome

both) must be present for more than 1 year. Transient tic disorder differs from both chronic tic disorder and Tourette’s syndrome in that symptoms must be of less than 1 year’s duration. It is now widely suspected that these disorders exist on a continuum of severity; the underlying genetic defect in Tourette’s syndrome expresses itself in milder form as chronic or transient tic disorder. There are also a number of secondary causes of tics. Tics may occur in hereditary neurologic disorders such as Huntington’s disease, the neurocutaneous syndromes, dystonia musculorum deformans, and neuroacanthocytosis. Perinatal encephalopathy, stroke, head trauma, carbon monoxide poisoning, and central nervous system infections (e.g., encephalitis lethargica, Sydenham’s chorea) have all been reported as causes of tics. Drugs that have been implicated include anticonvulsants (carbamazepine, phenobarbital, and phenytoin), cocaine, psychostimulants, and levodopa. The antipsychotics themselves may cause tardive tics. Among the hyperkinetic movement disorders, tics may be differentiated on several grounds. In addition to being abrupt in onset and duration, they are characterized by a tendency to spontaneously fluctuate, to be multifocal and migratory, and to be at least temporarily suppressible. Often, the patient may describe premonitory symptoms of a sensory nature, such as a “tickle” or “urge:’ which are then relieved by the movement itself. Tics tend to increase during times of stress. To the extent that they are suppressed for any length of time, however, tics generally reemerge in force once the patient relaxes. The physical and emotional burden of suppressing tics often is overwhelming, and patients describe a feeling of exhaustion attendant on efforts to keep their tics from emerging. Most patients say their tics tend to become less severe during intense concentration on or distraction by some other activity. Tics may be subdivided into simple and complex types and motor and vocal forms. Simple motor tics are defined as abrupt contractions of a single muscle group, such as eye blinking, head jerking, or wrist flicking. By contrast, complex motor tics involve the coordinated contractions of a series of muscle groups. The resultant movements may take on an almost purposeful appearance, as exemplified by touching or stroking behaviors, dancelike movements, or copropraxia (obscene gestures). Vocal tics may be thought of as a particular variety of motor tic involving contractions of the laryngeal, pharyngeal, respiratory, or oronasal musculature. Simple vocal tics are inarticulate noises that do not convey meaning. Examples include snorting, grunting, barking, and clicking. Complex vocal tics generally are words or fragments of words. Despite the emphasis placed upon coprolalia (obscene speech) as a symptom of Tourette’s syndrome, less than 20% of patients ever suffer from this symptom. Although it is perhaps the most socially stigmatizing manifestation of Tourette’s syndrome, most patients may be reassured that the symptom, if it occurs, tends to be transitory. Many patients with Tourette’s syndrome demonstrate a tendency to repeat their own words (palilalia) or the last words that they hear (echolalia). Similarly, they may mimic or copy the gestures and movements of others (echopraxia). These behaviors may be manifestations of the underlying tic disorder or may blend into the realm of obsessive-compulsive disorder. One important means of differentiating complex tics from compulsions is to question the patient about the meaning, if any, he or she ascribes to the behavior. Whereas tics are not associated with any preformed ritualistic set of notions about their significance, compulsions invariably are. For example, compulsive acts often are performed according to specific rules, such as repeating acts a

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certain number of times or in a particular order. Complex motor tics, on the other hand, do not have such ritualistic qualities. Tourette’s syndrome and the related primary tic disorders generally have their onset in the childhood years. As many as 20% of school-aged children develop some sort of transitory tic. These are often ignored by the family and other care providers or are attributed to the passing mannerisms of a “childish” nature. Estimates of the lifetime risk of full-blown Tourette’s syndrome vary widely, but a likely assessment would be 30 to 100 cases per 100,000 people. There is a 3:l ratio of males to females with the syndrome. It occurs in all races and socioeconomic classes. The clinical picture is uniform across cultural groups, save for a decreased incidence of coprolalia among Japanese. The most likely location for the initial tic to present is the face and eyes, with decreasing incidence of tics occurring in a rostral-caudal fashion throughout the remainder of the body. Approximately 12% to 37% of people with Tourette’s syndrome present with simple vocal tics (eg., throat clearing) as the initial symptom, with far fewer presenting with complex vocal tics. A number of studies have established the long-term prognosis of the disorder. When tics alone are considered, the general consensus is that approximately one third of patients will enjoy complete remission by late adolescence or early adulthood. Another one third will have a significant decrease in both the amount and severity of their tics. The final one third of patients will remain symptomatic throughout early adulthood and middle age. Little is known about Tourette’s syndrome in older adults. The most famous of Tourette’s original patients, the Marquise de Dampierre, is said to have lived out her life in seclusion, dying at age 86. However, collective experience indicates that tics and obsessive-compulsive disorder tend to diminish with advanced age.

RELATED DISORDERS The genetic association between Tourette’s syndrome and obsessive-compulsive disorder is now widely accepted. Approximately 50% of patients with Tourette’s syndrome suffer from symptoms of obsessive-compulsive disorder. Typical compulsions relate to ritualistic cleaning and grooming behaviors (e.g., hand washing, showering, teeth brushing), ordering and arranging objects, checking and rechecking objects in the environment (e.g., locks, switches, electrical outlets, stoves), counting, hoarding, and repeating certain actions (e.g., walking though a doorway, touching a piece of furniture). Common obsessions include fear of contamination, fear of thinking evil or sinful thoughts contrary to one’s religion, fear of losing potentially vital objects or loved ones, recurring thoughts of doing harm to self or others, and recurring sexual thoughts and images that are ego-dystonic. Evidence for the hypothesis that obsessive-compulsive disorder is an alternative expression of the genetic trait for Tourette’s syndrome comes from family studies demonstrating an increased incidence of obsessive-compulsive disorder among first-degree relatives of Tourette’s syndrome probands. Segregation analyses of Tourette’s syndrome families implicate a major gene inheritance pattern with variable expression of Tourette’s, obsessivecompulsive, and chronic tic disorders. There appears to be a gender-specific penetrance of these traits, with males showing almost complete penetrance when considering Tourette’s and chronic tic disorders alone. Females, on the other hand, show a lower penetrance for Tourette’s and chronic tic disorders alone,

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increasing to about 70% when obsessive-compulsive disorder is added. Between 20% and 60% of children with Tourette’s syndrome have symptoms compatible with a diagnosis of ADHD, including decreased attention span, poor impulse control, difficulty concentrating, and hyperactivity. Indeed, the symptoms of ADHD often predate the onset of tics, prompting treatment with stimulant medications that may trigger or worsen the underlying tic disorder. The association between ADHD and Tourette’s syndrome is generally less well documented than that between obsessivecompulsive disorder and Tourette’s syndrome. Some family studies demonstrate that ADHD segregates separately from Tourette’s syndrome; in any event, an etiologic relationship is difficult to establish with certainty. In addition to ADHD and obsessive-compulsive disorder, patients with Tourette’s syndrome often suffer from other comorbid behavioral difficulties, including depression, anxiety, and conduct disorder. Personality characteristics such as irritability, argumentativeness, and impulsivity all may occur, either as a part of the disorder itself or as a reaction to it.

TREATMENT Tourette’s syndrome is multifaceted, necessitating an individualized assessment and treatment plan for each patient. In general, one or another aspect of the disorder emerges as most troublesome. One patient may find that the tics are disabling, whereas another may be incapacitated by obsessive fears. Once identified, the patient’s primary problem may be specifically targeted. It is important to bear in mind that most patients with Tourette’s syndrome have only mild to moderate symptoms. Such patients typically are well adapted to their social, educational, and family environments and may ideally avoid medication altogether. If interventions are to be made, they are often most useful in the context of a restructured environment. This is particularly true in the case of school, where patients may benefit from such simple measures as supportive counseling, self-paced learning, one-onone tutorials, and small group teaching. We regard the home as a place of refuge where it is not necessary for the patient to expend energy in the taxing effort to suppress tics. Family and individual supportive counseling may be of benefit here as well. Treatment with medications should be reserved for patients with disabling symptoms, as defined with regard to maladaptations in home, work, or school environments. A large variety of agents are available for the treatment of tics, obsessive-compulsive symptoms, attention deficit, hyperactivity, and other related behavioral disorders (Table 131- 1). Agents must be selected on the basis of target symptoms and potential side effects. Dosages should be titrated slowly, seeking the least amount of drug that is both effective and tolerable. Haloperidol was introduced as a highly effective tic-suppressing agent in the late 1960s. Before its introduction, clinicians tended to view Tourette’s syndrome as a psychological disorder. The remarkable response rate (75% to 80%) forced a new understanding of the syndrome in terms of a derangement in brain dopaminergic systems. With the more recent clarification of the link between obsessive-compulsive disorder and Tourette’s syndrome, this formulation has expanded to include serotonergic models as well. The major action of the neuroleptics in tic suppression is thought to rest on their blockade of dopamine D2 receptors. The antipsychoticagent clozapine, with its predominant

TABU 151-1. PharmacologicTreatments of Tourette’s Syndrome Problem

Anent

Tics

Clonidine, guanfacine Atypical antipsychotics Neuroleptics Tetrabenazine, reserpine Other drugs Botulinum toxin injections (for dystonic tics) Selective serotonin reuptake inhibitors Clonidine, guanfacine, rnethylphenidate

Obsessive-compulsive symptoms Attention deficit hyperactivity disorder

action at the D4 receptor, has not been effective in patients with Tourette’s syndrome previously responsive to haloperidol. Although haloperidol is an effective medication for Tourette’s syndrome, it is important to avoid the reflexive use of this agent. We favor starting at a very low dosage, 0.25 mg nightly, and working up slowly by 0.25 to 0.5 mg every 4 to 7 days until symptoms are relieved or side effects appear. Most patients respond at dosages of 5 mg/day or less. We prefer not to exceed 15 mg/day. In an effort to avoid the worst effectsof sedation, we aim for a single bedtime dosing schedule. Motor side effects of haloperidol include acute dystonic reactions, drug-induced parkinsonism, akathisia, and tardive dyskinesia. In addition, patients may develop disabling drowsiness, depression, increased appetite with attendant weight gain, and school and social phobias. Pimozide is the only neuroleptic currently marketed specifically to treat Tourette’s syndrome. It has been shown to be as effective as haloperidol for suppressing tics. The motor side effect profile is similar to that of the other neuroleptics, including haloperidol, fluphenazine, and trifluoperazine. Like the latter agents, however, pimozide may be less sedating than haloperidol. Any of these neuroleptics can be used satisfactorily to suppress tics. The most serious potential side effect of pimozide is prolongation of the Q-T interval. There are rare reports of sudden death at dosages greater than 60 mg/day (which is much higher than the dosages typically used to treat tics). An electrocardiogram should be obtained before starting this medication, and it should be monitored during the period of dosage adjustment. Patients may begin treatment at 1.0 mg (one half tablet) nightly. Medication should be slowly titrated to achieve the minimum effective dosage. Maximum recommended dosage for pimozide is 0.2 mg/kg/day, generally not greater than 10 mg/day. A newer class of antipsychotic drugs has become available that have more variable actions at dopamine receptor subtypes and generallyappear to have a lower risk of extrapyramidal side effects. Because of their more favorable side effect profile, these atypical antipsychotics often are used before the classic neuroleptic antipsychotics for tic control. The following atypical agents appear to be effective tic suppressants: risperidone (0.25 to 10 mg/day), olanzapine (2.5 to 15 mg/day), and ziprasidone (20 to 160 mg/day). The Q-T interval on the electrocardiogram should be monitored during treatment with ziprasidone. A number of nonantipsychotic tic-suppressing agents have gained adherents among clinicians treating patients with Tourette’s syndrome. In general, these agents are less reliably effective than the neuroleptics, but their side effect profiles are favorable, so they are often used as first-line agents.

Chapter 131

The centrally acting antiadrenergic agent clonidine has been used extensively for tic suppression, and a recent double-blind study has confirmed its efficacy. The comorbid occurrence of behavioral difficulties often prompts consideration of clonidine therapy because this agent is also effective for treating ADHD. Side effects include drowsiness, orthostatic symptoms, headache, and irritability. Acute withdrawal may lead to rebound hypertension, agitation, and tachycardia. Effects of treatment may take up to 3 months to manifest. Clonidine is started in dosages of 0.05 mg (one half a tablet)/day and gradually increased until thrice-daily dosing is achieved. Dosages generally do not exceed 0.5 mg/day total. A transdermal delivery system, Catapres-TTS (Boehringer Ingelheim, Ridgefield, CT), allows dosing once a week and is useful in children who find it difficult to swallow pills. The patches come in sizes of 3.5, 7.0, and 10.5 cm2 (corresponding to 0.1, 0.2, and 0.3 mg/day). Another drug with pharmacologic effects similar to clonidine is guanfacine, and it has the advantages of single daily (bedtime) dosing and causing less sedation. The dosage range is 0.5 to 4 mg/day. Other agents that have been reported to have a role in tic management include clonazepam, reserpine, tetrabenazine, and the calcium channel blockers. Case reports of carbamazepine, lithium, corticosteroids, estrogens, and clomiphene have been conflicting. Trials of the opiate antagonist naloxone have not confirmed earlier reports of success with this agent. Local intramuscular injections of botulinum toxin can be used to treat patients with painful dystonic (consisting of muscle tightening or twisting) tics. Treatment of obsessions and compulsions associated with Tourette’s syndrome has rested primarily on the use of serotonin reuptake inhibitors. A variety of such drugs are available, including clomipramine, fluoxetine, sertraline, fluvoxamine, paroxetine, and citalopram. Treatment of ADHD has been dominated by the use of stimulants. The most common medication prescribed is methylphenidate, which has been shown superior to dextroamphetamine and pemoline in comparative studies. Side effects include agitation, insomnia, headaches, anorexia, weight loss, and lowered seizure threshold. Although psychological dependence can occur with long-term use of high-dose methylphenidate, it has not been reported in children treated for ADHD. This agent is contraindicated in patients with glaucoma. The typical dosage range for methylphenidate is 0.1 to 0.3 mg/kg two or three times a day. New long-acting forms of methylphenidate are available (Concerta, Metadate CD) that allow single morning dosing. A recent double-blind, placebo-controlled study does not support earlier concerns that methylphenidate worsens tics. In fact, in this study tics actually lessen over time after the introduction of methylphenidate. Whether other forms of stimulants can worsen tics has not been assessed.

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Attractive alternatives to stimulant medications are clonidine and guanfacine, which appear to be effective against both tics and ADHD. We often use these drugs as first-line agents for youngsters with Tourette’s syndrome whose school performance is impaired by hyperactivity and attention problems. As noted earlier, patients with Tourette’s syndrome often suffer from poor interpersonal relationships on the basis of behavior disturbances. These may range from simple character traits such as defensiveness and argumentativeness to full-blown personality disorders. The underlying link between these problems and Tourette’s syndrome is difficult to establish with certainty. Whether they are specific to Tourette’s syndrome or merely a result of the emotional, social, and personal difficulties associated with living with the disease is not well understood. In any case, these behavior disturbances have proven extremely difficult to treat with medications. Rather, a coordinated approach, involving supportive counseling, family therapy, and school and community interventions, appears most useful. As always, it remains important to maintain a low threshold of suspicion for depression, which can be difficult to assess in children.

SUMMARY Tourette’s syndrome represents one end of the spectrum of primary tic disorders. Recognition of the clinical heterogeneity of the syndrome has been a major advance in recent years and has enabled a more rational approach to therapy based on targeting dominant symptoms. With knowledge that Tourette’s syndrome is inherited has come hope that the underlying genetic defect will soon be unraveled.

SUGGESTED READINGS Bruun RD, Budman CL The natural history of Tourette’s syndrome. Adv Neurol 58:1, 1992 Cohen DJ, JankovicJ, Goetz CG (eds): Tourette syndrome. Adv Neurol 85,2001 JankovicJ: Diagnosis and classificationof tics and Tourette syndrome.Adv Neurol 58:7, 1992 Kurlan R (ed): Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders. Marcel Dekker, New York, 1993 Kurlan R Tourette’ssyndrome: current concepts. Neurology 39:1625, 1989 Leckman JF, Cohen DJ (eds): Tourette’s Syndrome. Tics, Obsessions, Compulsions. Wiley, New York, 1999 Shapiro AK, Shapiro ES, Young JG,Feinberg TE (eds): Gilles de la Tourette Syndrome. 2nd Ed. Raven Press, New York, 1988 Tourette Syndrome ClassificationStudy Group: Definitions and classification of tic disorders. Arch Neurol 50:1013, 1993 The Tourette’s Syndrome Study Group: Treatment of ADHD in children with tics. Neurology 58:527, 2002

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132 Mvoclonus 4

fiona Molloy and Mark Hallett Myoclonus is not a diagnostic term but rather a descriptive one. It refers to a neurologic symptom or sign and is nonspecific with regard to neuroanatomic source, pathogenesis, or underlying cause. Myoclonic movements are involuntary and manifest as brief, unexpected shocklike jerks of an area of the body. Myoclonus can arise from any level of the central nervous system (CNS) including the cortex, basal ganglia, brainstem, and spinal cord. Myoclonic movements may consist of a simple jolt of a muscle group or may be sufficiently forceful to make a whole limb move vigorously. Myoclonus may occur in isolation, in the absence of other neurologic or systemic manifestations, and as a normal phenomenon such as in the hiccup. Although myoclonic movements usually are not associated with a loss of consciousness, myoclonus may occur in conjunction with epilepsy and in such situations can be considered a fragment of a seizure. Both a quick, forceful muscular contraction (“positive” myoclonus) or, less commonly, a sudden lapse of muscular tone (“negative”myoclonus or asterixis) may be experienced, or both may be present. Negative myoclonus may be one sign of CNS electrophysiologic instability accompanying toxic metabolic encephalopathy; myoclonus also often occurs after cardiorespiratoryarrest (postanoxic myoclonus). The diagnosis of myoclonus has important clinical, prognostic, and therapeutic implications. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Differential diagnosis and treatment of myoclonus often pose a challenge to the neurologist. When myoclonus is suspected, a comprehensivehistory and physical examination should be carried out. Clinical history should carefullydetermine onset,t’imecourse, drug or toxin exposure, history of seizures, past or current medical problems, mental status changes, and family history. The neurologic examination should include movement distribution, temporal profile, and activation characteristics. Distribution can be focal, multifocal, segmental, or generalized. The temporal profile may be continuous or intermittent, rhythmic or irregular. If intermittent, myoclonus can occur sporadically or in trains. The activation of myoclonus may be at rest (spontaneous), induced by various stimuli (reflex myoclonus), induced by voluntary movement (action myoclonus), or the result of a combination of these factors. All activation characteristics should be noted as absent or present. The frequency and regularity of the myoclonic movements can vary from once a month, as in early morning myoclonic seizures, to continuous jerking over months, as in epilepsia partialis continua. Suspected myoclonic movements may be enhanced by certain maneuvers. For example, action myoclonus is enhanced by moving the body part, facial myoclonus by closing the eyes or showing the teeth, and upper extremity myoclonus by either postural movement or most prominently by kinetic movements such as finger-nose-finger maneuver. Somatosensory stimuli such as stretching the fingers or tapping on any part of the affected limb may elicit reflex myoclonus.

Myoclonus can mimic many other abnormal movements such as tics, chorea, tremor, dystonia, or disorders of the peripheral nervous system such as fasciculations. Although tics may be as brief in duration as myoclonic movements, there are several distinguishing features; for example, tics usually are stereotyped movements resulting from the need to move. These movements may be partially suppressed by the patient and are thought to be triggered by “psychic tension” that dissipates after the movement has been made. The involuntary movements of chorea may produce muscle jerking, but the characteristic slower movements and irregular flow from one part of the body to another often help differentiate chorea from myoclonus. Tremor is the most common differential for rhythmic myoclonus; however, tremor’s characteristic sinusoidal rhythmicity helps distinguish it from a myoclonic movement. Disorders arising in the peripheral nervous system that can be confused with myoclonus include fasciculations, myokymia, and hemifacial spasm; however, electrophysiologicstudies can be particularly helpful with the diagnosis in such situations because they show characteristic findings with needle electromyography. Myoclonus may exist concurrently with other involuntary movement disorders in the same patients. For instance, some families with essential tremor and myoclonus have been described, myoclonus and dystonia are combined in inherited myoclonic dystonia, and both action and reflex myoclonic jerks may be present in patients with Huntington’s chorea.

CLASSIFICATION Numerous systems have been used to classify myoclonus. Three of the most succinct and commonly used approaches rely on classifying the condition according to clinical characteristics, etiologic factors, and physiologic mechanisms. Clinical Characteristics

Myoclonic movements may be classified according to a wide range of clinical characteristics, including location, rhythm, relationship to movement, and precipitating or eliciting stimuli. The whole body, or most of it, may be affected in a single jerk (generalized myoclonus). Many different parts of the body may be affected, not necessarily at the same time (multifocalmyoclonus), or myoclonus may be confined to one particular region of the body (focal or segmental myoclonus). Myoclonic jerks may occur repetitively (as in palatal myoclonus) or irregularly and unpredictably (as in propriospinal myoclonus). Myoclonus may be evident at rest, on maintaining a posture, or on movement (action myoclonus). Jerks may be triggered by external stimuli (reflexmyoclonus), which can be visual, auditory, or somatesthetic (touch, pinprick, muscle stretch). Asterixis is the most common form of negative myoclonus and can be demonstrated by asking the patient to extend the arms and wrists in a sustained posture. When asterixis is present, wrist extension is suddenly inhibited and the hands flap. Negative myoclonus can also involve muscle groups in the lower extremi-

Chapter 132

ties, giving rise to the classic bouncy gait that can lead to frequent falls. Electrophysiologically, asterixis consists of silent electromyographic (EMG) discharges, usually lasting 50 to 200 msec, resulting in a brief loss of antigravitational activity and postural control. Negative myoclonus can have a physiology similar to cortical myoclonus with electrophysiologic correlates and may be induced by sensory stimulation. Asterixis is particularly significant because the phenomenon often is associated with a toxic or metabolic encephalopathy. Negative myoclonus tends to be treatment resistant. EUologic Factors

For the therapeutic purposes, it is important to establish the cause of myoclonus to determine a reversible or partly treatable cause. Myoclonus can be associated with many neurologic disorders and is seen with structural or metabolic lesions of the spinal cord, brainstem, and cerebellum and occasionally in normal individuals. Physiologic Classifkation

An underlying cause is not always evident. Therefore, in many clinical situations, physiologic classification of myoclonus can be more advantageous. This approach guides symptomatic treatment by determining the site and mechanism of origin of the symptoms, precipitating factors, and pathways of spread. Different myoclonic disorders, with markedly varying causes, genetic susceptibilities, and prognostic implications may fall into the same physiologic group, sharing homogeneous electrophysiologic properties that usually point to common physiologic abnormalities. The physiologic classification of myoclonus divides the condition broadly into two main groups: epileptic (cortical origin) and nonepileptic (subcortical origin, including structures such as basal ganglia, brainstem, and spinal cord) types. Epileptic myoclonic movements originate in the sensorimotor cortex and are propagated via the corticospinal tract. Epileptic myoclonus may manifest as isolated muscle jerks or repetitive focal myoclonic jerks, as in epilepsia partialis continua, or may be one of multiple seizure types within an epileptic syndrome. Photic cortical myoclonus originates in a hyperexcitable motor cortex and is driven by a normal-appearing occipital response. Seizures may well occur together with epileptic myoclonus, and the disorder often is idiopathic. Most myoclonic jerks of cortical origin are accentuated by action and sensory stimulation. Physiologic characteristicsof epileptic myoclonus include EMG burst length of 10 to 50 msec, agonists and antagonists usually firing synchronously, and an electroencephalogram (EEG) correlate. Based on neurophysiologiccharacteristics, epileptic myoclonus is further classified into three subtypes: cortical reflex myoclonus, reticular reflex myoclonus, and primary generalized epileptic myoclonus. Like other types of myoclonus, cortical reflex myoclonus is not disease specific. Cortical reflex myodonus manifests as brief muscle jerks, representing a fragment of focal or partial epilepsy, and can be provoked by sensory stimulation. Myoclonusrelated activity may not be recognized on conventional EEG. Jerk-lockedEEG or back-averaging (averaging the EEGs backward in time with respect to the myoclonus) is a helpful electrophysiologic technique to localize myoclonus of cortical origin. The EEG shows a focal positive-negative event over the sensorimotor cortex contralateral to the jerk, preceding both spontaneous and reflexinduced myoclonic jerks. Giant somatosensory evoked potentials (SEPs) are common in cortical myoclonus. Stimuli generating

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giant SEPs often provoke a subsequent EMG burst of myoclonic activity (the C-reflex) at a latency compatible with conduction through fast corticomotoneuron pathways from the motor cortex to muscle. After a cortical potential, activation propagates in a rostrocaudal direction so that contraction of facial muscles (masseter [fifthcranial nerve] before the orbicularis oculi [seventh cranial nerve]) is followed by contraction of the muscles in the neck, arms, trunks, and legs in descending order. Reticular reflex myoclonus arises in the reticular formation and represents a type of generalized epileptiform activity. The jerky movements usually are generalized, favoring proximal more than distal and flexor more than extensor muscle groups. Voluntary action and sensory stimulation tend to increase the jerking. Electrophysiologic characteristics of this disorder are as follows: EMG bursts occur, lasting 10 to 30 msec and triggered by sensory stimulation or by action; the EEG correlates, when present, are not time-locked to the muscle activation; and the EMG activity begins in the neck muscles and travels up the brainstem and down the spinal cord. Postanoxic myoclonus has been extensively studied neurophysiologically and can feature both cortical and reticular reflex myoclonus. Clinically, there are both multifocal and generalized jerks, and physiologic studies should reveal features of both disorders. Primary generalized epileptic myoclonus is a fragment of primary generalized epilepsy. There are two well-described clinical presentations: focal jerks often involving only the fingers, called minipolymyoclonus; and generalized synchronous whole-body jerks not unlike those seen with reticular reflex myoclonus. The EEG correlate is a slow, bilateral, frontocentrally predominant negativity similar to the wave of a primary generalized paroxysm.

SPECIAL ENTITIES Epileptic Myoclonus Epileptic myoclonus refers to epilepsies characterized exclusively or predominantly by brief myoclonic, atonic, or tonic seizures. Epileptic myoclonus can be positive or negative in type. Disorders classified within this group include infantile spasms, LennoxGastaut syndrome, cryptogenic myoclonic epilepsy, myoclonus associated with petit mal, and juvenile myoclonic epilepsy of adolescence. Of these conditions, juvenile myoclonic epilepsy is the most common epileptic syndrome presenting with myoclonus, usually in adolescence. The main symptom is myoclonic jerks, usually without loss of consciousness, predominantly in the morning after awakening from sleep. Generalized tonic-clonic seizures also tend to occur in the morning. Linkage studies suggest that a gene on chromosome 6 is involved in juvenile myoclonic epilepsy, at least in some families. Progressive Myoclonus Epilepsy

Progressive myoclonus epilepsy (PME) is a group of neurodegenerative diseases characterized by progressive encephalopathy, myoclonus (spontaneous, action, and stimulus sensitive),generalized tonic-clonic and other seizures, dementia, and ataxia. The differential diagnosis of PME includes several rare childhoodonset metabolic conditions, including sialidosis (cherry red spot myoclonus syndrome), mitochondrial encephalopathy (such as myoclonic epilepsy and ragged red fibers), Lafora body disease, Unverricht-Lundborg disease, and neuronal ceroid lipofuscinosis (Batten’s disease). Myoclonic movements associated with PME are most pronounced on movement.

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Progressive myoclonic ataxia (Ramsay-Hunt syndrome) sometimes is distinguished from PME by mild or absent seizures and minimal or nonexistent dementia; myoclonus and ataxia are the major problems. The myoclonus associated with this disorder often is stimulus sensitive.

diarrhea, fever, and sweating. This syndrome has been reported after treatment with tryptophan, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants, alone or in combination. Basal Ganglia Disease

The myoclonus observed in Creutzfeldt-Jakob disease, a clinical hallmark of the encephalopathy, can occur at rest or be exacerbated by action or a stimulus. EEG reveals a characteristic pattern of periodic sharp wave complexes in the majority of patients. Myoclonus is also seen in patients with the AIDS dementia complex. Patients with Alzheimer’s disease may exhibit myoclonus, which typically occurs late in the illness and can present as stimulus-induced multifocal distal jerking. Myoclonus is also a feature of some childhood retardation syndromes, including Rett syndrome and Angelman syndrome. In both disorders, the myoclonus is cortical in origin. Metabolic Encephalopathies Including Endocrine Disorders

Disorders such as hepatic failure, renal failure, hyponatremia, hypoglycemia, and nonketotic hyperglycemia can give rise to myoclonus. Treatment should be directed to the underlying condition. For example, myoclonus in patients with chronic renal failure on hemodialysis can be caused by aluminum toxicity and can be treated successfully with chelation therapy with desferrosamine mesylate. A progressive neurologic disorder including ataxia and myoclonus has been reported with coeliac disease. The neurologic syndrome is dominated by action and stimulus sensitive myoclonus of cortical origin, often associated with ataxia and infrequent seizures. The condition may progress despite strict adherence to diet, and no treatment is known. The opsoclonus-myoclonus syndrome (dancing eyes-dancing feet syndrome) can have a variety of symptomatic causes, of which idiopathic and paraneoplastic are the most common. There are clinical and etiologic differences between adult and pediatric presentations. About half of the pediatric cases have an underlying neuroblastoma. In adults, opsoclonus and myoclonus may occur in brainstem encephalitis, whether inflammatory or paraneoplastic. Whipple’s disease may also be associated with a similar clinical picture. An autoimmune origin seems likely because there is a distinctive pattern of serum immunoglobulin M (IgM) and IgG binding to neural tissues and antigens. Symptoms respond to steroids or adrenocorticotropic hormone. Multifocal action myoclonus is the most common form of myoclonus associated with this syndrome. Toxic Encephalopathies Including Drug Side Effects A wide variety of drugs and toxins may provoke multifocal and

generalized myoclonus, as may organ failure. Among drugs, antidepressants (particularly the selective serotonin reuptake inhibitors), anesthetics, anticonvulsants (particularly at toxic levels), withdrawal of benzodiazepines and propranolol, lithium, monoamine oxidase inhibitors, and levodopa can all cause myoclonus. Among toxins, bismuth, heavy metals, glue, and gasoline sniffing can cause myoclonus. Myoclonus is prominent in the serotonin syndrome together with confusion, agitation,

Myoclonus is a rare clinical feature of Parkinson’s disease. Myoclonic movements are more common in multiple-system atrophy in which the involuntary movements are cortical in origin with enlarged SEPs, and the distribution is asymmetrical or focal. Myoclonic jerks, both action and stimulus sensitive, are prominent, characteristic features of corticobasal degeneration. The myoclonus is of cortical origin and stimulus sensitive with a short latency that may be helpful in differential diagnosis. Myoclonus may also be a feature of Huntington’s disease, Wilson’s disease, and, less commonly, Hallervorden-Spatz disease. Hereditary dentatorubral-pallidoluysianatrophy is transmitted as an autosoma1 dominant trait and manifests with myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, and dementia. The myoclonus associated with this disorder often is stimulus sensitive. Postanoxic Myoclonus

Postanoxic myoclonus, originally described by Lance and Adams in 1963, occurs in patients after cerebral anoxic insult. The acute posthypoxic period may be dominated by generalized myoclonus. Generalized myoclonic status epilepticus in the first few days after the insult carries a very grave prognosis, and these patients often die. If patients recover, the characteristics of the myoclonus are altered, and generalized jerks are replaced with spontaneous, action-induced and stimulus-sensitive myoclonus restricted to the limbs. In addition to action myoclonus, Lance and Adams described cerebellar ataxia, postural lapses, gait disturbance, and generalized seizures. Long-term follow-up studies have shown that myoclonus, neurologic abnormalities, and disability improve over time. Gait disturbance (bouncy gait) caused by postural lapses in the trunk and lower extremities is the most disabling feature and most resistant to treatment. Electrophysiologic studies have shown cortical reflex myoclonus in most cases, but exaggerated startle response or reticular reflex myoclonus may also occur. The site of the responsible lesion in the brain is not clear, but there does appear to be a disorder of serotonin metabolism, a speculation supported by both the therapeutic response to 5-hydroxytryptophan and by the normalization of decreased cerebrospinal fluid levels of 5-hydroxyindoleacetic acid following successful therapy. Focal CNS Damage

The cause of focal cortical myoclonus can be almost any type of focal cortical lesion; tumors, angiomas, and encephalitis should be suspected. Curiously, particularly in patients with epilepsia partialis continua, the cortex can appear normal histologically. Surgical excision of the excitable tissue has cured the myoclonus in several patients, and this approach should be considered. Nonepileptic Myoclonus

Nonepileptic myoclonus implies that the neuronal discharge originates subcortically in structures between the cortex and spinal cord. Electrophysiologic studies help to differentiate between

Chapter 132 W

epileptic myoclonus and nonepileptic myoclonus. In nonepileptic myoclonus, EMG bursts are longer (40 to 300 msec), and the antagonist muscle activity is synchronous or asynchronous. Because of its subcorticalnature, there is no EEG correlate, and the SEPs, even during active jerking, do not show large-amplitude responses. Some myoclonic jerks represent a normal physiologic phenomenon, such as sleep jerks (hypnic jerks) and hiccup. Essential myoclonus manifests as a nonprogressive multifocal myoclonus. With a few possible exceptions, other neurologic deficits are absent. The condition may be inherited as an autosomal dominant trait, presenting in the first or second decade with a benign course, although most cases are sporadic. The distribution of muscles affected may be focal, segmental, generalized, or multifocal. Myoclonic movements associated with this condition often are induced or aggravated by action but may also occur spontaneously. In some patients, the physiologic abnormality is that of action-induced ballistic EMG bursts with inappropriate overflow into other muscles. In some families described with essential myoclonus, there are manifestations of dystonia; some individuals have both, others have either myoclonus or dystonia. The myoclonus in such families may respond to alcohol and is therefore called alcohol-sensitive myoclonic dystonia. In other families, both essential myoclonus and essential tremor are found together and independently. Exaggerated startle syndrome (hyperekplexia) is characterized by an abnormal exaggerated motor response or jump in response to an unexpected sensory stimulus (auditory, somatesthetic, or visual). The startle can vary from a blink with contortion of the face to an actual jump resulting in a fall to the ground. There is no associated loss of consciousness. An exaggerated startle syndrome may be caused by local brainstem pathology (anoxia, inflammatory lesions including sarcoidosis and multiple sclerosis, and hemorrhage) and also can occur as an inherited condition (hereditary hyperekplexia) transmitted as an autosomal dominant trait. Hyperekplexia must be distinguished from startle-evoked epileptic seizures, a condition associated with congenital focal cerebral lesions. In response to startle, there is a tonic spasm of the contralateral side followed by a complex partial seizure. Nocturnal myoclonus encompasses a variety of myoclonic conditions that can occur during drowsiness or sleep. Physiologic forms include the hypnic jerk, and pathologic forms include isolated periodic movements in sleep, restless legs syndrome with periodic movements in sleep, and excessive fragmentary myoclonus in NREM sleep. Periodic movements in sleep are commonly present in the sleep disorder laboratory, and the diagnosis is facilitated by the characteristic EMG pattern. The EMG bursts are of the tonic type, lasting 500 to 2000 msec, occurring every 10 to 30 seconds, and are most prominent in the tibialis anterior muscles. These movements tend to occur in NREM sleep but can also appear in drowsiness when the patient is conscious of the movement. Segmental myoclonus may arise in the spinal cord or brainstem. Simple spinal segmental myoclonus usually is a secondary phenomenon; the underlying cause should be determined and treated appropriately. Lesions of the spinal cord that may lead to muscle jerks include infection, degenerative disease, tumor, cervical myelopathy, and demyelinating disease. Such movements may also follow spinal anesthesia or the introduction of contrast media into the cerebrospinal fluid. Movements consist of focal, repetitive rhythmic jerks confined to one or more adjacent spinal segments. Spinal myoclonus usually is unaffected by sleep. Another type of spinal myoclonus is propriospinal myoclonus,

Myoclonus

837

which also arises in the spinal cord and involves many spinal segments linked by long propriospinal pathways. The cause is not always clear, although a focal spinal cord lesion occasionally is found. Clinically the disorder is characterized by nonrhythmic repetitive axial jerks, which usually start in the abdominal muscles and spread up and down the trunk. The jerks can be spontaneous or stimulus induced. Diagnosis is confirmed using EMG studies, which classically show the myoclonus originating in the midthoracic region and spreading slowly (about 5 mhecond) in both a rostra1 and caudal direction. Palatal myoclonus, also commonly called palatal tremor, manifests as rhythmic palatal movements. Palatal myoclonus comprises two separate disorders: essential palatal tremor, where an ear click is a prominent feature, and symptomatic palatal tremor, which is associated with cerebellar disturbances. The ear click described in essential palatal tremor is caused by rhythmic contractions of the tensor veli palatini (innervated by trigeminal nerve). The pathophysiology of essential palatal tremor is unknown, and investigations including magnetic resonance imaging of the brain typically are normal. In symptomatic palatal tremor, a focal brainstem lesion may be identified (usually vascular, traumatic, encephalitic, neoplastic, or demyelinating). The underlying pathology interrupts the pathway between the red nucleus, inferior olive, and dentate nucleus. The resulting denervation of the contralateral inferior olive leads to its hypertrophy, which can be visualized on magnetic resonance imaging. In this case, the palatal movement is caused by contractions of the levator veli palatini (innervated by the nucleus ambiguus). Myoclonus may also be psychogenic in origin. Certain features that help establish the psychogenic nature include clinical symptoms and signs inconsistent with “organic” myoclonus, evidence of underlying psychopathology (particularly marked anxiety), and the presence of an incongruous sensory deficit or inconsistent weakness. Physiologic investigation may reveal the presence of a Bereitschaftspotential before EMG bursts on jerk-locked backaveraging of the EEG, which is associated with a voluntary movement. More than 50% of patients have been reported to improve after gaining insight into the psychogenic mechanisms of their movement disorder. TREATMENT

Myoclonus can be a disabling condition, and treatment is largely empirical because few well-controlled double-blind studies of antimyoclonic agents have been performed, and clinical ratings of the effectiveness of treatment have been mostly descriptive. Once the likely cause and neuroanatomic origin of a patient’s myoclonus are established, therapy should be initiated. Resolution of an underlying encephalopathy or withdrawal of an offending drug or toxin may result in partial or total resolution of the myoclonus. In cases where a reversible cause cannot be identified, pharmacologic intervention is the treatment of choice. Many of the drugs used to treat cortical myoclonus have anticonvulsant properties (Table 132-1) and usually act by enhancing y-aminobutyric acid inhibitory activity. Clinical response may be more robust when two or three drugs are combined. One practical approach to treating cortical myoclonus is to initiate therapy with sodium valproate and, if there is no response, to add clonazepam. If symptom relief is not adequate, piracetam may then be added. Although piracetam has antimyoclonic activity (particularly useful in cortical myoclonus) and is well tolerated at dosages up to 24 @day,its mechanism of action is

838

Movement Disorders rn Non-Parkinsonian Movement Disorders

TABU132-1. Approach to the Drug Treatment of Myoclonus Treatment

Dosage Range (mg/day)

Cortical Myoclonus Clonazepam Valproate Piracetam Primidone Acetazolamide Lisuride (photic myoclonus) L-5-Hydroxytryptophan

0.5-20 1200-2000 1200-1 6,000 500-750 up to 200 1-2 up to 3000*

Reticular Myoclonus Clonazepam Valproate

0.5-20 750-2000

Segmental Spinal Myoclonus Clonazepam Trihexyphenidyl Tetrabenazine

0.5-20 u p to 35 50-200

Essential Myoclonus Benztropine Sumatriptan Phenytoin

4-9 Up to 6 mg (subcutaneously) 250-325

Nocturnal Myoclonus Clonazepam LevodoDa Pergolide

0.5-20 UD to 300 0.'125-0.25

*In combination with a peripheral aromatic amino acid decarboxylase inhibitor (such as carbidopa 100 to 300 muday). Not available in the United States; its usefulness is limited by poor tolerabilii.

unclear. Piracetam is one of the most widely used antimyoclonic agents in Europe. However, this drug is not available in the United States. Primidone and acetazolamide may also be effective as adjunctive therapies in severely affected cases. Not all antiepileptic medications are antimyoclonic, and some, such as phenytoin or carbamazepine, may even exacerbate myoclonus, as described in PME resulting from Unverricht-Lundborg disease. Efficacy of newer anticonvulsants such as vigabatrin, gabapentin, and lamotrigine remains to be established. However, both vigabatrin and gabapentin may paradoxically worsen some types of myoclonus. The extent of symptomatic control achieved in patients with epileptic myoclonus usually is striking at the beginning of treatment, but long-term responses can vary. Both the antioxidant N-acetylcysteine and alcohol have been reported to display potent antimyoclonic activity in Unverricht-Lundborg disease. Negative myoclonus often is resistant to drug therapy, and, as a result, disabling postural lapses in antigravity leg muscles usually are prominent, resulting in the typical bouncy unsteady stance and gait, often with falls. Reticular, spinal, and other segmental myoclonus usually responds best to clonazepam. Adjunctive treatment may include baclofen, serotonin reuptake inhibitors, and 5-hydroxytryptophan (a serotonin precursor) either alone or with a peripheral decarboxylase inhibitor. The risk of a potentially lethal eosinophiliamyalgia syndrome greatly limits the use of 5-hydroxytryptophan. Essential myoclonus sometimes improves with alcohol, a P-blocker such as propranolol, or an anticholinergic agent such as trihexyphenidyl. Dopamine depleters such as tetrabenazine may also have an adjuvant role. Treatment with alcohol should be

avoided because of the potential for abuse, and patients may experience a rebound of symptoms upon cessation of drinking. The ear click in essential palatal myoclonus is the symptom necessitating therapy. Several drugs such as clonazepam, tryptophan, carbamazepine, trihexyphenidyl, flunarizine, and sumatriptan may be useful. Botulinum toxin injections to the tensor velum palatini may successfully treat the ear click, although excess weakness of the soft palate may result. This technique should be used only by skilled physicians who have undergone specialist training in this procedure. The goal of treatment for restless leg syndrome is to reduce the symptoms and improve the quality of sleep. Clonazepam and temazepam have been shown to be effective in treating periodic movements of sleep. Opiates, direct dopamine agonists, and levodopa have also been shown to be worthwhile. An evening dose of a dopamine agonist such as pergolide is first-line treatment in patients with nocturnal myoclonus and restless legs syndrome. Clonazepam and valproic acid should be the first line of therapy in patients with posthypoxic myoclonus. If symptoms do not improve with these agents, 5-hydroxytryptophan may tried, although its side effect profile limits its practical use. Piracetam is particularly helpful for patients with documented cortical myoclonus. Adrenocorticotropic hormone is indicated for treating infantile myoclonic epilepsies, and corticosteroids and immunoglobulins are indicated for treating opsoclonus-myoclonus.

SUGGESTED READINGS Berkovic SF, Andermann F, Carpenter S,Wolfe LD: Progressive myoclonic epilepsies: specific causes and diagnosis. N Engl J Med 315:29&305, 1986 Brown P, Thompson PD, Rothwell JC et ak Axial myoclonus of propriospinal origin. Brain 114197-214, 1991 Deuschl G, Tor0 C, Valls-Sol6 J et al: Symptomatic and essential palatal tremor. 1. Clinical, physiological, and MRI analysis. Brain 117:775788, 1994 Earley CJ, Yaffee JB, Allen Rp: Randomized, double-blind, placebocontrolled trial of pergolide in restless legs syndrome. Neurology 51:1599-1602, 1998 Hallett M: Myoclonus and myoclonic syndromes. pp. 2717-2723. In Engel J Jr, Pedley TA (eds): Epilepsy: A Comprehensive Textbook. Vol. 3. Philadelphia, Lippincott-Raven, 1997 Koskiniemi M, Van Vleymen B, Hakamies L et ak Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry 64344-348, 1998 Lance JW, Adams RD: The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 8 6 1 11-136, 1963 Obeso JA, Artieda J, Rothwell JC et al: The treatment of severe action myoclonus. Brain 112:765-777, 1989 Obeso JA, Rothwell JC, Marsden C D The spectrum of cortical myoclonus: from focal reflex jerks to spontaneous motor epilepsy. Brain 108:193224, 1985 Shibasaki H: Electrophysiological studies of myoclonus. Muscle Nerve 23~321-335, 2000 Werhahn KJ, Brown P, Thompson PD, Marsden CD: The clinical features and prognosis of chronic posthypoxic myoclonus. Mov Disord 12:216-220, 1997

839

Chapter 133 H Movement Disorders in Sleep and Restless Legs Syndrome (Ekbom’s Syndrome)

133 Movement Disorders in Sleep and Restless Legs Syndrome (Ekbom’s Syndrome) H

Bruce Ehrenberg

Thomas Willis, in 1685, was the first to describe patients troubled by restless leg movements, and he noted that they often had insomnia. Ekbom published a series of articles about restless legs syndrome (RLS) in the 1940s. Symonds described abnormal twitches during sleep-“nocturnal myoc1onus”-which he distinguished from “common nocturnal jerks.” The latter are now called sleep onset myoclonus, hypnic jerks, or sleep starts and are considered normal, as are the twitches of various skeletal muscles without synchrony, periodicity, or symmetry usually seen during rapid eye movement (REM) sleep. Symonds’s patients with nocturnal myoclonus all had insomnia, and at least one patient had periodic arousals at 1-minute intervals, consistent with the modern definition of periodic limb movements disorder of sleep (PLMD; this term has replaced nocturnal myodonus). The current definition allows for the fact that patients present with hypersomnia, although cause-effect ties are unproven. Lugaresi et al. were first to polygraphically record periodic leg movements in sleep from patients with PLMD. They recorded similar nocturnal phenomena from patients with RLS, thus indicating that these two disorders may be physiologically linked. His group also studied the sleep manifestations of various other forms of pathologic myoclonus and found that spinal myoclonus and facial spasms often persist during sleep, cortically mediated epileptic myoclonus (rhythmic jerks of epilepsia partialis continua, repeated partial motor seizures of Jacksonian epilepsy, and spasm of subacute sclerosing leucoencephalitis) gradually decreases with onset of sleep, and movements of extrapyramidal origin (choreoathetosis,hemiballismus) or subcortical and brainstem origin (palatal myoclonus, opsoclonus) reliably disappear in sleep. Nevertheless, nocturnally these disorders must be carefully differentiated from PLMD, as should the myoclonic manifestations of Alzheimer’s and Creutzfeldt-Jakob disease. Likewise, the fasciculationsof amyotrophic lateral sclerosis and other diseases of the anterior horn cell or lower motor neuron, which are mediated at the spinal cord level and do not disappear in sleep. The REM behavior disorder is a nocturnal syndrome with movements ranging from fragmentary myoclonus to gross body movements during REM sleep, often involving widespread motion of limbs in an acting-out fashion, as though the patient were physically involved in a dream; this may be seen in an idiopathic form or with degenerative disorders such as olivopontocerebellar degeneration or more often as an early premonitory indication of idiopathic Parkinson’s disease and may be related to a loss of the generalized motor inhibition normally found in human REM sleep. The tremor of Parkinson’s disease diminishes or stops during sleep. However, periodic leg movements of sleep (PLMS) are common in Parkinson’s patients, and this was originally thought to be a direct effect of levodopa treatment. However, the PLMs are active through the night, and considering the short half-life of the levodopa used in the early studies, it is likely that most of the observed movements occurred after the dopaminergic effects had worn off. Indeed, levodopa is now a useful treatment for the leg

TABU133-1. Movement Disorders and Sleep TvDe of Movement

Tremor (essential or Parkinson’s) Choreoathetosis(including Huntington’s) Hemiballismus Spinal myoclonus Palatal myoclonus and epileptic myoclonus Opsoclonus Epilepsia partialis continua Other sleep-related epilepsy Spasms of subacute sclerosing panencephalitis Torsion dystonias Paroxysmal nocturnal dystonia Rapid eye movement behavior disorder Periodic limb movements disorder Restless legs syndrome Sleepwalking (somnambulism) Sleep bruxism (teeth-grinding) Fragmentary non-REM myoclonus Benign neonatal sleep myoclonus Sleep starts Rhythmic movement disorder [head-bannind

NREM

REM

Awake

-

+ +

f

-

+ + + + +

* f

f

+

Rare ?

f

f

-

+

-

+

f

+

+ -

Rare Rare f + (normal) Rare Rare

movements of RLS and PLMD. Similarly, dopaminergic blockers such as chlorpromazine or haloperidol are known to cause worsening of RLS (and probably of PLMD as well). The question as to whether there is an increased prevalence of PLMD or RLS in Parkinson’s disease is unresolved, in part because there is a high baseline prevalence of these disorders in the relevant age group. Sleep bruxism (nocturnal teeth-grinding) and fragmentary myoclonus of non-REM (NREM) sleep are two other movement disorders found in sleep that share some common features with RLS and PLMD and may be distant cousins physiologically. Table 133- 1 summarizes the relationship of several movement disorders to the major phases of waking and sleep. DEFINITIONS AND METHODS Clinical Features Periodic Limb Movements Disorder of Sleep. PLMD is defined by clinical hypersomnolence plus the characteristic repetitive episodes of stereotyped limb movements (PLMS refers to the same type of movements in a patient who may or may not be hypersomnolent). Although the arms can be involved, most patients have only leg movements, usually consisting of big toe extension, sometimes combined with partial flexions of the ankle, knee, and hip (it has been noted that there may also be fanning of the smaller toes, thus mimicking the Babinski and “triple flexion” responses; however, this is not a common presentation). Unlike most other movement disorders, which are abolished during sleep,

a40

Movement Disorders W

Non-Parkinsonian Movement Disorders

PLMS activity appears with the onset of sleep. The movements usually are associated with sleep disturbances ranging from full awakenings to minimal electroencephalographic (EEG) arousals, and the percentage of movements associated with any such sleep disruption can vary from 0% to 100% but usually is about 35%. Patients are unaware of all but the most prominent movements and arousals, and the movement activity can vary greatly from night to night, making it difficult to diagnose PLMD by patient history alone. Bed partner reports of leg kicking can be helpful, and if periodic movements are carefully timed, the diagnosis may be made. The movements generally have a duration of 0.5 to 5 seconds (most patients average 2 seconds) and a repetition interval of 5 to 90 seconds (most patients repeat at 20- to 40-second intervals). The limbs are immobile between episodes. The amplitude of the movements can be crudely measured on the polysomnogram (PSG) by comparing the electromyogram (EMG) in the anterior tibialis muscles during voluntary contractions while awake with the EMG bursts in the same muscles during sleep. However, because volitional muscle activation varies, there is no reliable way to calibrate the EMG output for all patients; some patients may have repeated arousals in association with very small EMG bursts that are difficult to distinguish from background noise. Perhaps these recording problems account for cases in which the apparent movements are too few in number to explain a particular patient’s daytime sleepiness. Indeed, the PSGs (all-night sleep electroencephalograms) of some hypersomniacs without leg movements show numerous arousal and subarousal EEG patterns with the same periodicities seen when leg movements are present, thus implying that the movements are only an epiphenomenon of a fundamental central nervous system (CNS) disturbance during sleep; some clinicians believe that these nonmovement arousals (sometimes called a-intrusions) are equal in impact to the disturbance of sleep seen in full-blown PLMD. Conversely, there are patients with PLMS who have very large numbers of leg movements but few or no EEG arousals. These patients may have less prominent daytime fatigue, but some may develop degenerative arthritis. Some patients have very violent kicks and may injure their bed partners or themselves. (Two patients with PLMS in our clinic developed knee injuries while asleep, eventually needing surgery.) The distribution of leg movements over the various sleep stages can vary; some patients have the largest amounts of leg movement activity in stages 3 to 4,but most have the maximum activity in stage 2. One study showed the relationship between U S and PLMS in nine members of one family; the leg movements were recorded in wakefulness and sleep and showed a periodicity similar to that seen in PLMS, with the intermovement intervals gradually increasing as the patients became drowsy and entered stage 2 sleep; the authors concluded that RLS and PLMS are two clinical manifestations of the same CNS dysfunction. When PSG recordings are scored, the sleep stages are delineated first so that leg movements can be assessed according to the sleep stage in which they occur (including brief periods of wakefulness). Leg movements associated with the end of an apnea or hypopnea are thought to be hypoxia-induced and are counted separately because they may be abolished by treatments for sleep apnea. It is useful to note the number of times a leg movement is followed by a full awakening, usually defined as the appearance or an occipital alpha rhythm (8 to 12 Hz) for at least 60 seconds; an incomplete awakening, alpha rhythm for 15 to 60 seconds; or an arousal, which can be defined as the appearance of occipital alpha activity

for 3 to 15 seconds. (Occasionally, there are large amounts of generalized 7- to 11-Hz activity during NREM sleep-the so-called alpha-delta pattern-in patients with the fibrositis-fibromyalgia syndrome, although these patients can have alpha-delta without PLMS.) Furthermore, it may be difficult to differentiate some normal features of NREM sleep from subtle arousal patterns: prolonged “spindle-beta’’ (12 to 18 Hz) accelerations, bursts of delta (1 to 3 Hz) activity, and K complexes. Also note that the more recently described cyclic alternating pattern (CAP), described by Terzano et al, accounts for much of the above periodic sleep-related EEG activity, whether associated with physical movement or not. Subtle arousals can be surmised when a physiologic event such as a leg movement is closely associated with a vertex V wave or K complex, EEG phenomena that are known to occur normally when externally applied stimuli disturb sleep. Carskadon et al. found that PLMS is common in “normal” older adults, and even though their subjects complained of neither nocturnal insomnia nor daytime sleepiness, there was a substantial amount of daytime sleepiness on objective testing (Multiple Sleep Latency Test); Coleman remarked that this indicates that a sleep-wake complaint is very subjective. Indeed, patients with PLMD may present with either insomnia (sleep maintenance type) or hypersomnia. (It should be noted that sleep maintenance insomnia usually is associated with a physiologic sleep disorder, whereas sleep onset insomnia is most often associated with a psychological or psychiatric condition.) This looks like a paradox, but working diagnoses usually are based on presenting complaints, even though objective (PSG or Multiple Sleep Latency Test) findings may not fully explain the patient’s symptoms. Indeed, the line distinguishing insomniacs from hypersomniacs is blurred on close examination: Both groups have poor-quality sleep of which they are aware to various degrees, and the primary difference is the ability of patients with insomnia to maintain alertness (appropriately in the daytime but too well at night), whereas the patients with hypersomnia have similarly poor-quality sleep at night and much more difficulty staying awake in the daytime. Restless Legs Syndrome. The diagnosis of restless leg syndrome ( U S ) was formerly based on the obligatory presence of disagreeable sensations usually before sleep onset, as well as the presence of observable leg movements. New NIH criteria* remove the latter requirement and focus the major effort on uncovering whether there is an urge to move the legs (which, by implication, adds back the possibility of an observer witnessing overt movements). In either case, the old or the new approaches place a heavy burden on patient and physician in requiring precise descriptions of the core symptoms, thus placing a hurdle in the path of the diagnosis of this common debilitating disorder. However, the increasing availability of multilingual questionnaires and validated forms to be used by patients and clinicians as diagnostic and severity-assessment instruments should begin to alleviate this problem. *NIH Criteria (Allen RP, et al): 1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. (Sometimes the urge to move is present without the uncomfortable sensations and sometimes the arms or other body parts are involved in addition to the legs.) 2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting. 3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. 4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. (When symptoms are very severe, the worsening at night may not be noticeable but must have been previously present.)

Chapter 133

Movement Disorders in Sleep and Restless Legs Syndrome (Ekbom’s Syndrome)

The sensations usually are deep-seated, bilateral and limited to the lower legs but can involve the thighs and rarely may be unilateral or involve the arms or other parts of the body. Sometimes, the words used-itching, tingling-suggest the dysesthesias of peripheral neuropathy, whereas at other times the patient describes severe pains in the legs, suggesting sciatica, diabetic nerve infarction, or radiculopathy caused by root encroachment. [AUof these are potential causes of secondary RLS, which sometimes can be alleviated by removal of the underlying cause-such as a renal transplant in a patient with uremic-induced RLS-but usually the RLS is best treated by one of the “standard treatments” (see TREATMENT section below). Indeed, before a diagnosis of primary RLS can be made-and although it is likely that some patients, especially those with the common diabetic or uremic neuropathies, could have both primary RLS and a neuropathy at the same time-for most purposes (and particularly genetic studies) it is necessary to be fairly certain that none of the “secondary” causes are present)]. The disorder can begin at any age and may wax and wane over the years, even remit entirely for lengthy periods. In primary RLS, which are mostly familial cases, there may be earlier onset in each successive generation (so-called “anticipation”). The inheritance pattern may be autosomal dominant, but the variable penetrance can make cases from small families appear to be sporadic until a detailed family history is obtained (including data on nocturnal movements). There is a tendency for exacerbation in times of stress, and many women with U S may have their initial bout during the latter half of (usually their first) pregnancy. The restlessness or discomfort begins toward evening and increases further with sitting or lying down, making television or movie watching difficult. The symptoms are nearly always relieved by walking or pacing or by exercise of any kind, including stretching, cycling, swimming, and running. However, when the patient sits back down, the symptoms tend to return quickly unless the exercise has been extensive. Montplaisir et al. have developed simple laboratory methods to diagnose RLS using only surface EMG electrodes applied to the anterior tibialis muscles during a 30-minute evening recording. This test was called the suggested immobilization test (SIT) because patients were asked to sit on a stretcher or bed with eyes open and try to remain motionless. This method yielded positive results (periodic EMG bursts on the recordings) in about 67% of patients if recorded on two consecutive nights. To increase the sensitivity of testing, the forced immobilization test (FIT) was developed. This test is similar to the SIT except that patients sit on the stretcher with their legs tied down in the extended position. Three quarters or more of patients with RLS also have PLMS in sleep, as demonstrated by PSG. However, patients with RLS have been shown to exhibit periodic leg movements while awake if they are closely observed after being asked to avoid voluntary leg movements, such as during a SIT or FIT. The periodicity often is briefer in the awake state (typically 15 seconds apart) than during sleep (usually 20- to 40-second intervals, as previously described for PLMS). Montplaisir et al. showed that the average intermovement interval in familial RLS or PLMS with insomnia lengthens from 24 seconds in stage 1 sleep to 35 seconds upon entering stage 2 of sleep. Patients with severe RLS or PLMS may not be able to sleep at all through most of the night, but those who are able to sleep usually can enter stage 2 within 30 to 60 minutes, and although there may be abundant periodic leg movements, their sleep usually is no worse than the average patient with PLMS

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alone, and there is a tendency for the patient with RLS to have fewer leg movements toward morning. Some of the severely afflicted patients are phase-delayed; that is, they stay awake for several hours, then fall asleep when the leg movements have completed the presumptive circadian cycle. These patients may then sleep later into the morning to catch up on the number of hours they need, whereas still others are unable to obtain even 4 to 5 hours total sleep per night, often because they must arise for work. Indeed, without the societal influence requiring a job for survival (most of those jobs starting early in the morning), patients with advanced RLS and delayed sleep phase syndrome (the need to stay up late due to the leg movements and the resultant need to sleep late the next morning to get sufficient total sleep) would probably be able to gain enough sleep to function normally if environmental factors were arranged to allow them to do so. As with PLMD, patients with RLS may complain of either insomnia or excessive daytime sleepiness. The patients with RLS and excessive daytime sleepiness often are older, but young adults with it may need more therapeutic effort because employability may be an issue. Excessive daytime sleepiness was studied by Coleman et al. in a small group of older patients with PLMD; the number of arousals per hour of sleep correlated with the subsequent day’s degree of sleepiness as measured on the Multiple Sleep Latency Test. Another study showed differences in the sleep disruption patterns of insomniac and hypersomniac patients with PLMD; the sleepy patients had longer histories of poor sleep (average 22.4 versus 14.3 years) with more total arousals that were short in duration and concentrated in clusters. More recently, reduced hypocretin 2 (orexin) levels have been found in the CSF of RLS patients. This substance, secreted in the lateral posterior hypothalamus, is one of the most alerting neurotransmitters ever discovered and is the same substance found reduced (with much lower levels) in narcolepsy. (Narcolepsy patients have one of the highest incidences of PLMS, after RLS.) The cause of this finding is unknown. Coleman et al. looked at the final diagnosis among patients with sleep disorders whose PSGs showed PLMS; in one early study of 441 sleep clinic patients, they found more than 40 (total) periodic movements in 19% of insomniacs, 15% of patients with sleep apnea, 10% of narcoleptics, 12% of patients with other hypersomnias, and 9% of patients with other disorders, including parasomnias and sleep-wake schedule disorders. This seemed to indicate either that PLMS is a nonspecific finding among patients with a variety of sleep complaints, or that PLMS may be a contributing factor in many different sleep disorders. The latter concept is still today supported by the fact that some patients with daytime hypersomnolence have “only” PLMS as a sleep-disturbing factor on their PSGs (although increasing recognition of other PSG/EEG phenomena, such as Terzano’s “CAP” activity mentioned earlier, may yet account for much of this). In addition, several studies show an increased incidence of PLMS in narcolepsy, but other studies dispute the importance of the finding or show no increase. However, no matter how sleepy, patients with an ICSD diagnosis of PLMD do not have the EM-onset sleep tendency that is diagnostic of narcolepsy. Secondary RLS (but not necessarily PLMD or PLMS alone) are associated with iron deficiency anemia (whether due to heme loss, malabsorption, or chronic diseases causing low erythropoietin, especially uremia), neuropathies such as diabetes, amyloid or uremia, and normal pregnancy.

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Fibromyalgia or fibrositis syndrome has been related to PLMS and alpha-delta sleep. The latter involves the appearance of large amounts of a activity during deep NREM sleep (stages 3 and 4, often called 6 sleep) and can be found in patients with other disorders, including hypersomnolence, eating disorders, and schizo-affective disorders. Some patients with fibrositis may initially respond to small doses of chlorpromazine or amitriptyline, but antipsychotics in such patients can cause severe akathisia and PLMS, and tricyclics may worsen both daytime sleepiness and PLMS. A small study of patients with atypical depression found that each had PLMS. Other disorders in which PLMS or RLS may play a part include attention deficit hyperactivity disorder (pediatric and adult forms), migraine, toxemia of pregnancy, epilepsy, premenstrual syndrome, and pseudodementia. Treatment of the sleep problem in each of these disorders may be helpful, but larger, controlled studies are needed to confirm these findings.

EPIDEMIOLOGY PLMS and RLS together may affect 5 to 15% of the population, but the incidence of PLMS increases with age and is most prevalent in older adults (see Coleman et a1 1983). A survey of healthy seniors over age 60 found PLMS in 57%, although one half had fewer than five movements per hour. In other studies, PLMS and RLS incidences of 37% to 53% have been found among sleep disorder patients over 60 years of age, and 18% in one study had PLMS or RLS as their primary diagnosis, whereas longitudinal follow-up showed an increasing prevalence of nocturnal movements with aging. More recently, large scale studies have begun to uncover evidence that, after sleep apnea, RLS/PLMD/PLMS may contribute additionally to the morbidity/mortality burdens stemming from hypertension and cerebro-cardiovascular disease. On the other end of the age spectrum, children as young as 1 year have been noted to have PLMS, but they usually have a strong family history of RLS. Among patients of all ages, 3% to 26% of insomniacs and 1% to 12% of hypersomnolent patients can be diagnosed with PLMD or RLS. Given the high prevalence among older adults, the rate of sleep complaints seems low compared with that of younger age groups. Perhaps many seniors accept the prevailing geriatric stereotype of slowed function or lowered expectations of sleep quality. Increasing efforts are being made to communicate to the primary care provider the high level of variability and subtlety in RLS symptoms in the hope that the contributed component to the costly and severe comorbidity rates may be reduced.

CAUSES Montplaisir et al. noted an elevation of dopamine metabolites in the CNS and suggested that dopamine receptors may be reduced in sensitivity in these disorders. His genetics group’s more recent announcement (Rouleaux et al) of a link to chromosome 12q in a series of large Quebec families may close this loop because the gene that codes for neurotensin, an agent that alters sensitivity at dopamine receptors, is located near the linkage locus (as is the putative analog of the important Drosophila circadian gene “timeless”) although no mutations have been discovered. The outstanding recent advancement in understanding the pathophysiology of RLS and PLMS comes from Allen and Earley at Johns Hopkins, where the role of iron metabolism has been largely elucidated. They have shown that cerebrospinal fluid and post-

mortem substantia nigra tissue transferrin levels are high and ferritin levels are low in most patients, suggesting a failure of Fe++ transport into the central nervous system. Because iron acts as an important cofactor for tyrosine hydroxylase, the enzymatic ratelimiting step in dopamine synthesis, it stands to reason that any impairment in its availability centrally can lead to deficient production of dopamine. This would also explain why erythropoietin alleviates RLS in patients on renal dialysis (who can have both iron deficiency and neuropathy as exacerbating factors for their RLS). As mentioned earlier, PLMS is almost invariably present in cases of familial RLS, although it is now becoming more and more doubtful that the two entities are driven by identical mechanisms despite the striking similarity of their periodicity and clinicoanatomical localization. Askenasy et al. thought that PLMS and RLS in patients with Parkinson’s disease result from basal ganglia dysfunction, but this conclusion was based on improvement from levodopa. Wechsler et al. showed that patients with PLMS have hyperexcitable blink reflexes, somatosensory evoked responses, long-latency motor responses, and H reflexes, indicating possible pontine dysfunction. However, PLMS may still be either the cause-through sleep deprivation-or the result of such hyperexcitability. Referring to Smith’s work on the Babinski-lie appearance of the lower extremities during the movements of PLMS, Walters and Hening questioned whether there is pyramidal tract dysfunction in PLMS, causing a release of central inhibitory activity. The antigravity muscles of the legs (gastrocnemii, quadriceps, glutei) can overpower the opposing muscles, causing contractures in immobilized patients when a stroke or spinal cord lesion blocks upper motor neuron outflow. There may be an inherent imbalance between opposing muscle groups requiring the smaller, weaker still muscles to undergo greater amounts of exercise, and this need may be genetically greater in patients with PLMS or RLS, such that internal mechanisms supervene whenever daytime activity levels have been insufficient. Exercise in normal subjects has been shown to improve stage 3 and 4 sleep which may suppress PLMS by inhibiting the central drive for PLMS, thereby also reducing the symptoms of RLS. In two women accustomed to 5 hours of strenuous exercise daily, abrupt reduction of such effort (one due to injury, the other due to pregnancy-related “cultural norms”) caused marked PLMS and sleep disruption leading to daytime hypersomnolence within a week. By extension, it is possible that in older adults the deterioration in stages 3 and 4 sleep and the great prevalence of PLMS are both caused by age-related reductions in exercise levels. This does not account for the occasional case of severe PLMS found in young adults or children, but such earlyonset cases probably result from genetic factors. Coleman et al. noted that patients with PLMS may have altered circadian rhythms and postulated that this might be an underlying causative factor in PLMS. RLS symptoms also show a marked circadian pattern, with most patients having maximum restlessness during the evening and first part of the night. It has been suggested that these disorders may be caused by dysfunction of the circadian rhythm pacemaker in the suprachiasmatic nucleus. The suprachiasmatic nucleus is well supplied with y-aminobutyric acid (GABA) receptors, perhaps explaining the response to benzodiazepines, and also valproate, which is thought to enhance activity at these receptors. Another intriguing aspect of the circadian hypothesis is the known association of the daily temperature curve with the sleep-wake cycle; because many patients with RLS (and

Chapter 133 W

Movement Disorders in Sleep and Restless Legs Syndrome (Ekbom’s Syndrome)

PLMS?) note cold feet, this suggests altered thermoregulation in the hypothalamus, perhaps in turn caused by suprachiasmatic nucleus dysfunction. Some argue that instead of causing poor sleep, PLMs may be a normal phenomenon. Bixler et al. found a 6% incidence of PLMs (with a PSG showing at least 3 clusters of 30 or more consecutive leg movements) in a normal population (mean age, 40 years). However, their subjects had arousals with only 10% of the leg movements. This may explain why there were no sleep complaints; patients with insomnia or hypersomnolence usually have arousals in association with more than 30% of the leg movements.

TREATMENT Only since the early 1980s have effective pharmacologic treatments for PLM and RLS emerged. Initially only drugs that acted at the GABA receptor (including the benzodiazepines, baclofen and, more recently, valproate), the benzodiazepines having been the most commonly used treatment for RLS until the discovery of dopaminergic therapy in the mid- 1980s. As sleep-inducing medications in the treatment of insomnia, benzodiazepines in general, and more recently clonazepam in particular, have seen widespread use among psychiatrists treating various affective disorders, including depression. Indeed, because PLMD and RLS cause 15% of insomnia, there may well be many undiagnosed patients with PLMD or RLS who are fortuitously receiving this treatment. However, hypersomnolent patients with PLMD may have great difficultywith the sedative effects of benzodiazepines, even at very small dosages. The other major problem with benzodiazepines is the gradual development of tolerance to the beneficial effects. This can be a vexing problem when attempts are subsequently made to withdraw the medication because the underlying insomnia will be severely exacerbated. Other withdrawal effects include tremors, headaches, nausea, and seizures (all partly brought out by the sleep disruption and the “denervation hypersensitivity” of the GABA receptor). This could account for patients who are addicted and cannot tolerate being weaned. Indeed, patients with PLMD and RLS (and other patients with chronic severe sleep disturbances) may gravitate toward benzodiazepines when obtainable (or to alcohol as an alternative) and then develop addiction after initially obtaining relief. Because there is no clear mechanism of action for benzodiazepines other than sedative and hypnotic effects and no evidence that the leg movements are significantly reduced, the search has continued for more effective, less problematic therapies. Baclofen was found effective in one study, but interestingly, it did not decrease the leg movements and seemed to improve sleep by decreasing the number of arousals associated with the leg movements. One problem with this drug is its short half-life. Another class of agents that affects GABA receptors but has not been formally studied in PLMD is the barbiturates, including phenobarbital, among the most widely prescribed sleep agents for decades. Ekbom found phenobarbital helpful only in milder cases, mainly as a sedative, and again, the problems of tolerance and abuse are well recognized with this class of drugs. Valproate is a medication whose mechanism of action is not fully understood, but studies have suggested that its anticonvulsant property involves enhancement of GABA receptor activity. This medication is not known to produce addiction, and tolerance to its antiepileptic effects has not been seen. Valproate has been used as

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a sleep-inducing agent in Europe. Valproate in low to moderate dosages at bedtime improves nocturnal sleep and daytime alertness in 40% of patients with PLMD. Patients with PLMS and hypersomnolence may be extremely sensitive to the usually mild sedative effects of valproate, so small dosages given only at bedtime, aiming for a low serum level in the morning, may work best. Patients who return with high levels may complain of excessive morning fatigue, headaches, and moodiness, probably related to a “hangover.” However, in some patients after a few weeks it may be appropriate to increase the dosage to maintain the beneficial effect. Caution concerning the weight gain potential is advised, especially with higher doses of valproate. The most effective medications for RLS and PLMD are the dopaminergic agents levodopa, pergolide, pramipexole, and ropinirole. The slow-release form of levodopa or carbidopa has been beneficial for patients with RLS and also in intractable cases of PLMD. Studies by Coleman et al. originally speculated that levodopa might be an exacerbating factor for PLMS, but work by Montplaisir et al. demonstrated that the effects of the short-acting form last only 2 hours, after which there is rebound, causing exacerbation of the PLMD. Therefore, regular levodopa or carbidopa may work for patients whose symptoms occur only at bedtime but is suboptimal for patients with RLS or PLMD whose worst sleep occurs in the latter half of the night, when bouts of leg movement activity increase in intensity in the lighter stages of NFEM sleep. For these patients, one slow-release 50/200-mg tablet at bedtime is a major improvement in therapy because this form lasts 4 to 6 hours, especially if its effects are prolonged by entacapone (a catechol-o-methyl transferase inhibitor), allowing most patients to experience a better night’s sleep. This long-acting combination form is also a boon to patients with RLS and diurnal leg symptoms that begin early in the day. Indeed, many patients experience their first morning RLS symptoms only after initiating an evening dose of levodopa, as a rebound phenomenon (so-called augmentation). Rebound is more severe with higher daily dosages of levodopa and can be counteracted by using the long-acting form in evenly divided 24-hour dosing schedules and adding medications with alternative mechanisms of action to the regimen to reduce the total daily levodopa intake. The current drugs of first choice for treating RLS are pramipexole and ropinirole, often in dosages far below those that are effective for Parkinson’s disease, the only current indication for these two dopamine agonists (each with D3- as well as D2receptor-activating abilities). These two agents appear to be the best-tolerated of all available agents, although reports of patients falling asleep suddenly while driving have caused concern. Most of these patients may have been taking large parkinsonian dosages and may have been sleep deprived, but it is advisable to warn patients about this possibility when prescribing one of them for the first time. Another long-acting dopaminergic agent is pergolide, in starting dosages of 0.05 to 0.1 mg, usually given at bedtime. Bupropion is touted as a dopaminergic-serotonergic antidepressant and in daily dosages of 75 to 150 mg may be helpful when levodopa or carbidopa is not tolerated. In any case, for depressed patients with RLS, it is a good alternative to tricyclic and selective serotonin reuptake inhibitor antidepressants because members of both of these classes may exacerbate RLS or PLMD. (Of the other antidepressants, only trazodone and monoamine oxidase inhibitors are tolerable to patients with US.) Pemoline, methylphenidate, and D-amphetamine have long

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been used as daytime stimulants in patients with hypersomnolence, and each may act as dopaminergic agonist. Although some patients who take stimulants report improved nocturnal sleep quality, it is not known how many of these patients have PLMD or RLS; in any case, most patients develop insomnia if the stimulant dosages are high enough. Patients with narcolepsy have a 10% to 75% incidence of PLMS (increasing with advancing age). Valproate, levodopa, or 6-hydroxybutyrate produces better-quality nocturnal sleep, leading to a decrease in daytime sleepiness, potentially allowing reductions in stimulant dosage. Opiates (including propoxyphene) can be very helpful in PLMD and RLS; codeine was used in one study, and despite the potential for tolerance and abuse, the authors state that their patients tended to follow the prescribed regimens. Compared with valproate, levodopa, or benzodiazepines, the opiates have a longer and better record of safety in pregnancy and may be especially useful when PLMD or RLS become severe early in the first trimester. Adrenergic blockers have limited use in patients with sleep disorders. An occasional patient with PLMD may respond to an a-adrenergic blocker such as phenoxybenzamine. Studies have shown a moderate but not necessarily long-lasting response to the P-blocker propranolol in RLS, akathisia, and narcolepsy. Clonidine, an a,-adrenergic agonist, has been used in RLS. Serotonergic agents such as L-tryptophan and 5hydroxytryptophan have been used with rare success in RLS but have not been found useful in PLMD. Other therapies useful in treating RLS that have not been clearly shown to work for patients with PLMD include iron and folate (both helpful in RLS even in the absence of a deficiency), vitamin E, vasodilators, and aldehydes, but none of these is currently in widespread general use, although clearly any patient with RLS and anemia should be evaluated and treated appropriately. Indeed, it is becoming clear that RLS may well be associated with a central deficiency of iron in nearly all cases. Aside from valproate, another anticonvulsant that has been tried in PLMD and RLS is phenytoin. Carbamazepine has been shown to work in mild RLS but is not in widespread use. Patients with PLMD or RLS sometimes are awakened by leg cramps, but most patients with recurrent nocturnal cramps do not have PLMD. Nevertheless, quinine, long used for nocturnal cramps, is sometimes used to treat patients with PLMD, but there is no evidence to support its use for either RLS or PLMD. Other drugs that can bring out or exacerbate RLS or PLMD include lithium, caffeine, terbutaline, and nifedipine (all calcium channel blockers are suspect; they can cause parkinsonism and akathisia, probably by reducing dopaminergic neurotransmission). As mentioned earlier, antipsychotic neuroleptic drugs commonly cause akathisia, which is similar to RLS but has a

different circadian pattern and can be associated with a sleep disturbance that may also be similar to that of PLMD. In treating PLMD, it must always be kept in mind that subtle forms of sleep apnea may cause the clinical appearance of periodic leg movements on PSG without obvious changes in respiration or oxyhemoglobin saturation. Therefore, in cases where the PLMD seems intractable to all medications, a trial of nasal (continuous positive airway pressure) or a dental device (a “snore guard”) may be warranted if snoring has been a concomitant.

SUGGESTED READINGS Allen RP, Hening WA, Montplaisir J, Picchietti D, Trenkwalder C, Walters A and members of the IRLSSG. Restless Legs Syndrome: Diagnosis criteria, special considerations, and epidemiology. Report from the diagnosis and epidemiology workshop at NIH, summer, 2002 The Atlas Task Force of the American Sleep Disorders Association. EEG arousals: scoring rules and examples. Sleep 16:174-184, 1992 The Atlas Task Force of the American Sleep Disorders Association: Recording and scoring leg movements. Sleep 16749-759, 1993 Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol41:639-645, 1997 Coleman RM, Bliwise DL, Sajben N et ak Epidemiology of periodic movements of sleep, pp. 217-229. In Guilleminault C, Lugaresi E (eds): SleeplWake Disorders: Natural History, Epidemiology,and Long-Term Evolution. Raven Press, New York, 1983 Diagnostic Classification Steering Committee, Thorpy MJ, Chairman:

International Classification of Sleep Disorders: Diagnostic and Coding Manual. pp. 69-71, 29 1-293. American Sleep Disorders Association, Rochester, MN, 1990 Ehrenberg B L Sleep Pathologies associated with nocturnal movements, pp. 582-593. In: Joseph AB, Young RR (eds): Movement Disorders in Neurology and Neuropsychiatry, 2/e. Blackwell Scientific, Boston, 1999

Ekbom KA: Restless leg syndrome. Neurology 102368-873, 1960 Montplaisir J, Godbout R, Pelletier G, Wames H: Restless legs syndrome and periodic limb movements during sleep, pp. 589-597. In Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine. WB Saunders, Philadelphia, 1994 Rechtschaffen A, Kales A, eds. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. U.S. Department of Health, Education, and Welfare, Public Health ServiceNational Institutes of Health, National Institute of Neurological Diseases and Blindness, Neurological Information Network, Bethesda, MD, 1968

Terzano MG, Parrino L, Sherieri A, Chervin R, Chokroverty S, Guilleminault C, Hirshkowitz M, Mahowald M, Moldofsky H, Rosa A, Thomas R, Walters A. Consensus Report: Atlas, Rules, and Recording Techniques for the Scoring of Cyclic Alternating Pattern (CAP) in Human Sleep. Sleep Medicine 2:537-555, 2001 Walters A, Hening W Clinical presentation and neuropharmacology of restless legs syndrome: a review. Clin Neuropharmacol 10:225-237, 1987

Chapter 134

Stiff-Man Syndrome

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134 Stiff-Man Syndrome Kathleen McEvoy

Stiff-man syndrome is a rare motor function disorder characterized by involuntary stiffness of axial muscles and superimposed painful muscle spasms. The cause is unknown, but there are clinical and laboratory associations with autoimmune diseases, and it is becoming increasingly apparent that stiff-man syndrome may form a spectrum of diseases with some types of encephalomyelitis. In addition, some cases of the syndrome may be paraneoplastic. Whether these atypical cases of stiff-man syndrome are varying manifestations of the same pathologic entity or phenotypically similar but pathophysiologically distinct from typical stiff-man syndrome remains to be defined. Stiff-man syndrome is also known as Woltman-Moersch syndrome, acknowledging the neurologists who first recognized and described this condition in the 1950s. They published a report of 14 patients with progressive and fluctuating rigidity and spasms seen over a 35-year period at the Mayo Clinic. In the years after this report, numerous other patients were recognized throughout the world. By 1990, about 100 patients had been reported in the literature.

EPIDEMIOLOGY AND THE AT-RISK POPULATlON Stiff-man syndrome is clearly rare, but its true prevalence cannot be known because of poor ascertainment. Diagnosis can be made only if it is suspected, and physician recognition of this rare and unusual disorder is very low, especially in the primary care setting. Misdiagnosis as a psychiatric disorder is common. Because stiff-man syndrome can be a devastating and sometimes lifethreatening condition when untreated, its recognition is critical. The index of suspicion for diagnosis of stiff-man syndrome should be elevated in certain patient populations, particularly those with a personal or family history of organ-specific autoimmune diseases or organ-specific autoantibodies. Women may be more likely to develop the syndrome. The age of onset of symptoms usually is in the fifth decade of life but ranges from the third through at least the seventh decade, with cases in children rarely reported. No antibody-positive cases have been reported in children.

SYNDROME RECOGNITION Clinical Manifestations Typical stiff-man syndrome is well characterized by the diagnostic criteria laid out by Lorish et al. (1989): a prodrome of stiffness and rigidity in axial muscles; slow progression of stiffness to include proximal limb muscles, making volitional movement and ambulation difficult; a fixed deformity of the spine; superimposed episodic spasms precipitated by sudden movement, jarring, noise, and emotional upsets; normal findings on motor and sensory examinations; normal intellect; and typical electromyographic findings of continuous muscle activity abolished by intravenous diazepam or a positive therapeutic response to oral diazepam. Although these criteria remain valid for diagnosing typical

stiff-man syndrome, reflex asymmetry and enhancement are common, and extensor plantar responses may be seen in otherwise typical patients. Symmetry of stiffness is the rule, to which there are exceptions. The spinal deformity is a most helpful feature in recognizing stiff-man syndrome and distinguishing it from common back pain. Symptoms usually develop over a period of months, beginning in the low back muscles, producing pain and stiffness, and also deformity of the spine, with exaggerated lumbar lordosis. Paraspinal muscle spasm is pronounced, and lumbar range of motion is severely limited. Lordosis usually is maintained even with forward bending, which is done almost completely at the hips. Abdominal muscles often are rigid. Many patients describe abdominal protuberance, which is really caused by the spinal deformity. After months or years, paraspinal hypertrophy develops and may be striking. Whereas the muscular activity generally is noted to abate during sleep, the spinal deformity may become fixed and persistent. In some patients, the muscular hyperactivity and spinal deformity are more rostral, producing cervical tightness and hunching of the shoulders. In most patients, disease is predominant at one level so that either the lumbar or cervical level is symptomatic. Stiffness and rigidity may extend to the anterior neck muscles, but trismus is not seen in typical stiff-man syndrome, and would suggest the possibility of tetanus as the cause of muscle stiffness. Stiffness and simultaneous contraction of agonists and antagonists may spread to the proximal extremities. In lumbar patients, this produces a characteristic stiffness of gait not unlike that of Frankenstein’s monster. Ambulation is slow and difficult and may be punctuated by freezing episodes. Falls are common. Postural reflexes are overridden by stiffness, so the patient falls like a tin soldier, and the risk of fracture is high. Fear of falling exacerbates the gait disorder because emotional stimuli potentiate the abnormal muscle stiffness. Most patients experience increased stiffness in social situations or in public places. Stressful situations and exposure to cold temperatures also aggravate stiffness and spasms. Not surprisingly, any activity requiring truncal flexibility is performed slowly and awkwardly, if at all. This includes arising from chairs, getting out of bed, tying shoes, and arising from a fall. Mobility and ability to perform activities of daily living may be severely limited. This and the aggravation of symptoms in public places or social situations render many patients essentially housebound. Painful muscle spasms are a universal feature of stiff-man syndrome, and they are generally more amenable to treatment than the underlying stiffness and rigidity. Their absence in an untreated patient renders the diagnosis suspect. The spasms occur primarily in axial muscles but may spread to involve the limbs as well. They may arise spontaneously but usually are induced by movement, startle, or emotional stimuli. Common examples include an unexpected tap on the shoulder, the sound of a doorbell or telephone, or excessive activity producing back pain. These

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spasms may be strong enough to break bones and to bend the pins used for repair. Autoimmune Associations

The autoimmune pathogenesis of stiff-man syndrome is strongly supported by the presence of antibodies to glutamic acid decarboxylase (anti-GADS) or anti-islet cell antibodies (antiICAs) in most patients, the common presence of other organspecific autoimmune diseases or autoantibodies in stiff-man syndrome patients and first-degree relatives, and the response to immunosuppressive therapy. The target of autoimmune attack within the central nervous system is not known with certainty, nor is it known whether the antibodies detected are pathogenic or merely markers of disease. Passive transfer of the syndrome to animals via patient serum has not yet been demonstrated, and there is no animal model of the disease. Anti-GAD antibodies have been detected in significant numbers of patients reported to have stiff-man syndrome in several series. Anti-ICAs are nearly identical to anti-GADS, with differences only in the N-terminal epitopes, and are adequate as a screening test for the diagnosis. This antibody is present in low titer in many patients early in the course of development of type I diabetes mellitus. Anti-ICAs are present in high titer in the majority of patients diagnosed with typical stiff-man syndrome in recent years at the Mayo Clinic, independent of the presence of diabetes. Titers have not fallen with time and are present in patients with long-standing stiff-man syndrome. This antibody is very rare in people with neither diabetes nor stiff-man syndrome but may occasionally be detected in intermediate titers in patients with multiple autoimmune endocrinopathies. Recent reports describe a new antibody in patients with breast cancer and stiff-man syndrome. Most patients with autoimmune stiff-man syndrome harbor other autoantibodies, most commonly antithyroid antibodies. Many have other autoimmune diseases, as do their first-degree relatives. Type I diabetes is present in approximately 30% of patients. Most patients have antimicrosomal thyroid antibodies, and some have had clinical autoimmune thyroid disease, either Hashimoto’s or Graves’s. Other autoimmune endocrinopathies and organ-specific autoimmune diseases from the thyrogastric cluster of autoimmunity may be seen, including pernicious anemia, vitiligo, premature ovarian failure, premature gray hair, autoimmune adrenal failure, and myasthenia gravis. The presence of anti-GAD or anti-ICA, other autoantibodies, or other autoimmune diseases in the patient or family help to support the diagnosis of stiff-man syndrome in a patient with the appropriate clinical presentation but are not necessary for the diagnosis. An association with epilepsy has been postulated but is not supported by the literature. Stiff-man syndrome often is misdiagnosed as a psychiatric disorder. Until recent years, there was doubt in the medical community as to the existence of the syndrome. In fact, many patients with it do have coexisting psychiatric conditions, generally anxiety or affective disorders, and some overuse alcohol and other medications, in part to control their disease. The combination of the unusual nature of the symptoms, the limited findings on neurologic examination despite significant disabilities in function and gait, the lack of findings on routine laboratory testing, the exacerbation by emotional stimuli, the frequency of accompanying anxiety or affective disorder, and

probably also the relative frequency of the disease in women all contribute to the common error of attributing symptoms solely to psychiatric disease. Even the efficacy of treatment with benzodiazepines may be taken to support this error in diagnosis.

Other Laboratoy Testing

The diagnosis of stiff-man syndrome is made on clinical grounds based on the patient history and examination results. The clinical index of suspicion is raised in patients with known tendencies to autoimmune disorders. The presence of anti-GADS or anti-ICAs strongly supports the diagnosis in patients with appropriate signs and symptoms. Other laboratory testing may provide specific support for the diagnosis of stiff-man syndrome but largely rules out other diseases. Electrophysiologic testing in stiff-man syndrome includes routine electromyography (nerve conduction studies and needle electrode examination), as well as specialized surface electrode studies documenting the pattern of muscle activity in axial and limb muscles and the response to stimuli. Nerve conduction study results generally are normal, including long loop reflexes. Routine electromyographic testing shows continuous activation of normalappearing motor unit potentials in affected muscles despite attempts to relax. Surface electrode demonstration of widespread continuous muscle activity in axial muscles is important as a tool to document that inability to relax is not caused simply by discomfort from the recording needle. Additional studies may be done to document simultaneous activation of agonists and antagonists in limbs and exaggerated response to startle stimuli in many patients. Brain and spinal imaging typically is normal, as is spinal fluid examination. Occasional patients show inflammatory cerebrospinal fluid (CSF) changes, including mild pleocytosis, elevated immunoglobulin G index, or oligoclonal bands. These changes may be more likely in atypical patients, such as those with cerebellar signs, and may represent an inflammatory phase in the development of stiff-man syndrome or, in some cases, true encephalomyelitis.In such patients, as in those with inflammatory changes on magnetic resonance imaging, it is particularly important to exclude demyelinating disease.

ATYPICAL SYNDROME FORMS Atypical forms of stiff-man syndrome may be seen. Some patients have findings that are otherwise typical of the syndrome except for the presence of mild brainstem or cerebellar signs such as ophthalmoparesis, nystagmus, or dysmetria. Jerking stiff-man syndrome, or stiff-man syndrome with prominent myoclonic jerks, has been described. The presence of significant sensory disturbance or significant primary sphincter dysfunction suggests an alternative diagnosis, such as demyelinating disease, other causes of myelopathy, or central nervous system disease. Symptoms of stiff-man syndrome usually develop over a period of months. More rapid onset-a period of 6 to 8 weeks or less-suggests encephalomyelitis as the underlying cause. In these cases, other neurologic manifestations are commonly present, especially brainstem or cerebellar signs. Anti-GAD antibodies have been detected in patients with pathologically proven encephalomyelitis with rigidity.

Chapter 134

Encephalomyelis with Rigidity The pathogenic mechanisms of typical stiff-man syndrome are not known with certainty. Some forms of encephalomyelitis may produce progressive stiffness and rigidity. Since the original description of the syndrome, several cases have been reported with clinical features highly suggestive of stiff-man syndrome but with additional focal neurologic signs atypical for the diagnosis, including cerebellar signs, oculomotor disturbances, facial or bulbar weakness, extensor plantar responses, vertigo, or epilepsy. Autopsies have shown inflammatory infiltrates in the gray matter of the spinal cord and brainstem, with perivascular lymphocytic infiltration and microglial proliferation. These cases were called progressive encephalomyelitis with rigidity. Anti-ICA and antiGAD antibodies have been detected in several nondiabetic patients with confirmed encephalomyelitiswith rigidity. In a patient with symptoms of stiff-man syndrome, the possibility of underlying encephalomyelitis is suggested by any of the following: onset of symptoms over less than 6 to 8 weeks, the presence of fever or clouding of consciousness, inflammatory CSF changes, or focal neurologic signs.

Paraneoplastic Stiff Man Syndrome Most stiff-man syndrome is not paraneoplastic. Thorough evaluations and long follow-up reveal no evidence of cancer in most patients. In a few cases, the syndrome has been associated with carcinoma; however, most well-documented cases have features suggestive of underlying encephalomyelitis, as outlined earlier. Antibodies against a separate antigen and a distinct clinical picture, with predominantly proximal lower extremity rather than axial involvement, have been described in patients with stiff-man syndrome associated with breast cancer.

DIAGNOSIS The overlap between the clinical entities of typical stiff-man syndrome, progressive encephalomyelitis with rigidity, and paraneoplastic stiff-man syndrome suggests that stiff-man syndrome, as originally described by Moersch and Woltman, may be part of a spectrum of disease, with the syndrome perhaps resulting from a more confined form of spinal encephalomyelitis. Occasional focal neurologic signs and CSF changes might then be expected even with typical stiff-man syndrome, and additional focal signs, a more hlminant onset, and more inflammatory CSF would be the rule in more extensive cases of encephalomyelitis. Paraneoplastic inflammation might produce still a different distribution of involvement. Alternatively, stiff-man syndrome and progressive encephalomyelitis with rigidity may be different diseases with similar signs and symptoms. The diagnosis of typical stiff-man syndrome remains primarily clinical, using the diagnostic criteria as previously outlined, with support from serologic and electrophysiologic tests. Further testing, including magnetic resonance imaging and spinal fluid examination, may be necessary to exclude other neurologic disease. The time course of the slow progression should be longer than 8 weeks. A clinical classification of stiff-man syndromes might be extended beyond typical stiff-man syndrome to include cases of atypical stiff-man syndrome that have focal neurologic signs and cases that are atypical in that they have focal neurologic

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signs and also either rapid onset and progression of symptoms or myoclonus. A differentialdiagnosis should include multiple sclerosis, other causes of myelopathy, extrapyramidalsyndrome including Parkinson’s disease, bilateral frontal lobe dysfunction (e.g., caused by hydrocephalus, vascular disease, trauma, or malignancy), degenerative disorders producing spasticity, tetanus, other causes of primary muscle stiffness or continuous muscle fiber activity such as Isaac’s syndrome, and other orthopaedic or rheumatologic causes of reduced spinal range of motion.

MANAGEMENT For nearly a decade after stiff-man syndrome was first described, there was no known effective treatment for this disorder. In 1963, Howard discovered the efficacy of diazepam, and benzodiazepines have remained a mainstay of treatment. As in other autoimmune disorders, although pharmacologic manipulations may be directed at the physiologic defect (e.g., benzodiazepines for stiff-man syndrome, anticholinesterase drugs for myasthenia gravis), immunosuppressive therapy may be necessary for optimal management. In recent years, immunosuppression has proven effective in some cases; however, despite a combined approach to treatment with both directly neuroactive drugs and immunosuppressive agents, symptomatic control sometimes is marginal. Patient education and supportive care are essential.

Phannacologic Manipulation of Spinal Mechanisms of Stiffness Diazepam was the first drug shown to be effective in stiff-man syndrome, and it has been the most widely used. Its efficacy is unquestionable. The exact mechanism by which it relieves stiffness and spasms in stiff-man syndrome is not known, but it is believed to act at the spinal level via the y-aminobutyric acid receptor system to reduce abnormal motor activity. Whereas modest antianxiety dosages of diazepam are of some benefit and often have been administered even before diagnosis, patients with stiff-man syndrome often need and tolerate very large dosages. Many patients take 40 to 60 mg/day, a few take more than 100 mg/day, and dosages greater than 300 mg/day have been reported. A reasonable starting dosage is 5 mg three times a day, but rapid escalation may be needed. Equivalent dosages of other benzodiazepines are also effective. Sedation may occur transiently but usually is not a dose-limiting side effect. Mood and personality changes are common and often limit the dosage. Abuse and dependence on these and other agents may develop in stiff-man syndrome, despite claims to the contrary. Care should be taken to ensure that the drugs are being used to treat symptoms of stiff-man syndrome rather than anxiety per se. Baclofen is also efficacious in stiff-man syndrome. As with benzodiazepines, very large dosages may be needed, sometimes more than 100 mg/day. An initial dosage of 5 mg twice or three times a day may be increased every few days as tolerated. Because strength is normal in stiff-man syndrome, there is no unmasking of underlying muscle weakness, as may be seen in multiple sclerosis or other forms of spasticity. Dosage therefore is limited by other side effects, mainly sedation. Intrathecal administration allows high spinal levels with much lower brain levels and therefore is an attractive consideration in this syndrome. Initial

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rn Non-Parkinsonian Movement Disorders

experience with intrathecal baclofen is promising. Although the pump implantation and drug titration entail risk, expense, and effort, the benefits may be significant. Sodium valproate in anticonvulsant dosages and vigabatrin may also provide at least modest benefit. Alcoholic beverages relieve symptoms, but medicinal use is not recommended, especially because affective disorders and substance abuse are common in stiff-man syndrome. Pharmacologic manipulation of spinal mechanisms of stiffness often provides less than satisfactory control of stiff-man syndrome, at least with oral administration. Spasms may be eliminated, but relieved stiffness and improved mobility often are possible only with high dosages and significant medication side effects. Intrathecal baclofen may circumvent this, but it is expensive, invasive, somewhat cumbersome, and not generally available. Immunosuppression therefore is often indicated.

Immunosuppressionand Related Therapies Corticosteroids and azathioprine are clearly effective in reducing disease activity in stiff-man syndrome. Isolated reports of response to corticosteroids antedate the discovery of antibodies in stiff-man syndrome and even the suspicion that the syndrome was autoimmune. The possibility of a direct effect on mechanisms of stiffness has been raised. The comparable efficacy of other immunoactive treatments suggests that any direct effect of steroids on syndrome-related stiffness must be small. Prednisone may be administered in a regimen similar to that used in myasthenia gravis. Initial dosages of 60 mg/day generally take effect within a few weeks. A switch or rapid taper to alternate-day therapy and then a slow taper of the dosage usually is well tolerated. Experience thus far is too limited to predict the lowest tolerated dosage, especially because many patients are concurrently treated with azathioprine. Unlike myasthenia gravis, in which immunosuppression often obviates for anticholinesterase medications, stiff-man syndrome seldom responds so well to immunosuppression that diazepam can be withdrawn. Some side effects of corticosteroid treatment are of particular concern in stiff-man syndrome. Diabetes mellitus is present in about 30% of these patients; this complicates corticosteroid treatment but is not an absolute contraindication. Steroid-induced osteoporosis may increase the risk of fractures caused by falls. If intrathecal baclofen is to be used, the higher infection risk with any immunosuppression is of concern. Azathioprine appears to be an effective steroid-sparing agent in stiff-man syndrome and may allow steroids to be tapered completely. Again following the pattern of treatment of myasthenia, an initial dosage of 50 mg once per day may be increased over 1 month to 2 to 2.5 mg/kg/day in three divided doses. Liver enzymes and a complete blood count must be checked weekly for the first month and monthly thereafter. A normal level of thiopurine methyltransferase activity in patients’ red blood cells ensures that they are not among the 1 in 300 who are severely deficient in this enzyme, which participates in azathioprine metabolism. However, a normal level of thiopurine methyltransferase does not rule out the possibility of severe leukopenia or hepatic dysfunction. Hepatic intolerance usually occurs early, within the first week. The white blood cell count may drop at any time. High steroid dosages may falsely elevate the white blood cell count early in the course of azathioprine treatment. As steroids are tapered, the leukopenia becomes apparent. About 5% of people are intolerant

of azathioprine because of a febrile serum sickness type of response. Others note gastrointestinal upset, which may respond to dividing the daily dosage into six rather than three doses. The long-term risk of promoting the development of neoplasms with azathioprine appears to be very small and is almost certainly less than the overall risks of prolonged steroid treatment. Plasma exchange is effective in some cases and has rescued some severely affected patients from crises. Other patients do not improve with plasma exchange but may still respond well to steroids and azathioprine. Experience with intravenous immunoglobulin G in stiff-man syndrome is limited but promising. Nonpharmacologic treatments may significantly augment the effects of pharmacotherapy in stiff-man syndrome. Physiatric intervention may provide symptomatic relief of muscle discomfort and stiffness, as may aids and instruction in mobility and gait safety. Stretching exercises benefit some patients. Behavioral medicine and biofeedback may also be helpful in managing the psychological factors that can aggravate symptoms. Good patient education allows patients and their families to understand the organic nature of the syndrome and the role of stress and psychological factors. As in other rare disorders, patients very much appreciate the chance to speak with others suffering from the same disorder. In addition to managing stiff-man syndrome itself and watching for side effects and complications of treatment, treating physicians must be vigilant for development of associated conditions, such as diabetes and multiple endocrine failure.

SUMMARY The diagnosis of stiff-man syndrome has been primarily clinical, supported by electrophysiologic findings. Clinical criteria for diagnosis therefore have necessarily been strict and exclusive to ensure accurate diagnosis of the specific syndrome. A number of neurologic and musculoskeletal disorders can resemble the syndrome in some aspects. Differentiation from demyelinating disease is essential. Diazepam and other drugs that act on the y-aminobutyric acid receptor system are effective in stiff-man syndrome. Anti-GADS and anti-ICAs have been found in many patients with stiff-man syndrome, lending support to the autoimmune hypothesis. Immunosuppression with corticosteroids or azathioprine ameliorates symptoms in most patients. Plasma exchange sometimes is helpful. With the advent of improved neuroimaging to exclude demyelinating or structural disease, and with serologic testing to support the diagnosis of stiff-man syndrome in questionable cases, we are now able to reapproach the issue of defining the diagnosis of stiff-man syndrome and may consider a wider spectrum of clinical manifestations and causes, including primary autoimmune stiff-man syndrome, stiff-man syndrome associated with encephalomyelitis, paraneoplastic stiff-man syndrome, and atypical clinical manifestations.

SUGGESTED READINGS Auger RG: AAEM mini-monograph diseases associatedwith excess motor unit activity. Muscle Nerv (in press) Lorish TR, Thorsteinsson G, Howard FM: Stiff-man syndrome updated. Mayo Clin Proc 64:629, 1989 McEvoy KM: Stiff-man syndrome. Semin Neurol 11:3, 1991

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BEHAVIORAL NEUROLOGY

135 Examining Mental State Sandra Weintraub The purpose of the mental state examination in neurology is to detect and characterize cognitive and behavioral abnormalities resulting from brain disease. Although several standardized mental state tests are available, there is no single all-purpose test. Existing tests do not sample the full range of cognitive and behavioral domains, and there are no standard measures of such symptoms as prosopagnosia, semantic processing deficits, and impaired judgment. Another limitation of available mental state screening tests is that they are too easy for most people of normal intelligence with a high school education but too difficult for those with limited education. This is especially problematic for the early detection of dementia associated with aging. For these reasons, it is important that the mental state examination be guided by principles of neurobehavioral organization and that the clinician possess a flexible array of instruments and procedures at several levels of difficulty to test the nature of presenting symptoms. In this chapter, a theoretical approach to neurobehavioral organization is outlined. This perspective structures the examination of mental state, its interpretation, and synthesis of findings. Domains of mental function are defined, and selected procedures to test their integrity are described. General principles that apply to the examination of all types of neurobehavioral disorders, including those caused by neurodegenerative diseases of the brain, are discussed.

NEUROCOGNlllVEAND BEHAVIORAL ORGANIZATION The backbone of the mental state examination consists of a limited number of cognitive and behavioral domains defined by studies in human psychology and brain science: arousal, mood, motivation, attention, language, perception, reasoning, executive functions, and comportment. Each of these domains encompasses distinct types of mental processes, and each has been well characterized with respect to its neuroanatomic substrates. Identifying the domain of the primary clinical symptoms, therefore, serves to identify the neuroanatomy of the disorder, while the symptom history, the patient’s past history, and the remainder of the neurologic examination identify its nature (i.e., vascular, neoplastic, neurodegenerative, infectious, or toxic or metabolic). For example, primary amnesia detected on examination only predicts damage to limbic networks. A subacute onset and symptoms of malaise suggest encephalitis as a possible cause; insidious onset and gradual progression suggest a neurodegenerative disease with affinity for limbic regions, such as Alzheimer’s; acute onset and a cardiac history are more consistent with cerebrovascular accident. 850

To interpret the examination of mental state, it is necessary to subscribe to a model of how behavior and cognition are organized in the brain. One such model, proposed by Mesulam, offers a practical framework to guide the examination and interpretation of the findings. According to this model, mental domains can be divided into two large classes. “State-dependent’’ domains are mediated by diffusely projecting neuroanatomic networks of the type that constitute the major neurotransmitter projection pathways. This anatomic arrangement supports neural activity that rapidly modulates the general information processing state, or tone, of the brain. Arousal and many aspects of attention, mood, and motivation are supported by this type of anatomic organization. In contrast, “channel-dependent” domains are supported by large-scale neuroanatomic networks consisting of distinct groups of distributed cortical epicenters and their monosynaptic, reciprocal cortico-cortical connections. Each of these networks also incorporates connections with distinct subcortical components in the thalamus and striatum. Language, visual and auditory perception, explicit memory, and highly integrative functions such as comportment, judgment, reasoning, and executive functions are mediated by this second type of anatomic organization. This proposed system of neurobehavioral organization leads to the first important practical principle governing anatomic localization of mental state abnormalities: primary deficits in channeldependent domains predict damage to discrete anatomic networks in the brain; primary deficits in state-dependent domains are not similarly localizable. Identifying the primary domain of impairment can be challenging because there are no pure tests of each domain. For example, even a seemingly simple test such as mental calculation is multifactorial from the perspective of the component operations and neural machinery enlisted in the actual performance of this task. Concentration, auditory language comprehension, working memory, arithmetic knowledge, and speech production are all components of performance, and each represents a different domain of mental functioning. A patient’s inability to carry out mental calculation could result from failure in any one of these components. The interpretation of failure (and subsequent predictions of the anatomic locus of disease) would be very different if the responsible deficit were aphasia rather than a problem with working memory and attention, or with numerical reasoning. Therefore, if the clinician wants to know whether a patient can do mathematical computation, it might be best to test this more directly with paper-and-pencil calculations, eliminating many of the confounding variables.

Chapter 135

STRUCTURE AND INTERPRETATIONOF THE EXAMINATION OF MENTAL STATE

The major neurocognitive and behavioral domains that structure the examination of mental state are depicted in Figure 135-1. Each domain is assessed with different tests. Although these domains are not hierarchically organized in the brain, it is heuristically useful to sequence the examination in a hierarchical manner and to apply this sequence to the interpretation of findings. Deficits provide two kinds of information. First, if primary, they are of localizing value. Secondly, a deficit in one domain can impede performance in others, leading to “secondary deficits.” For example, a primary anomia can interfere with accurate word retrieval on tests of verbal learning, despite normal retentive memory. These facts lead to a second important general principle in the examination of mental state: primary deficits in one domain can interfere with performance on tests in other domains not themselves directly affected by the primary disease process. An application of this principle follows. If a patient fails tests of attention and tests of all other domains, there are two possible interpretations: the deficit in attention, a state-dependent function, is primary and the only true deficit, interfering with performance of all other tests and yielding the appearance of more widespread deficits; or the deficits in each domain are all truly primary. If the first alternative is correct, then discrete network localization is not possible, and the remainder of the workup is to

FIG. 135-1. A framework for the examination of mental state, based on major domains of mental functioning. Even though tests of mental state are intended to target a single domain, performance may rely on other domains as well. Deeper shades of gray indicate that performance at each level depends on several layers of mental processing. For example, performance of verbal and nonverbal learning and memory tests requires normal language, visual perception, and drawing skills, and the levels of arousal, attention, and motivation must be sufficient to support task completion. Therefore, failure to recall a list of words can be interpreted as evidence of primary amnesia only if the other domains enlisted in performance are functioning normally. This framework can be used to analyze each task with respect to its component domains and also to interpret the pattern of task failure at the conclusion of the examination.

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search for factors that interfere with the projection networks (e.g., toxic or metabolic or white matter disease); if the second is true, then the search turns to diseases that cause multifocal cortical or subcortical damage. To decide between the alternatives, it is necessary to test each domain in a manner that controls for the attentional deficit. For example, to demonstrate normal retentive memory in the inattentive patient, it is necessary to reduce the attentional load by either repeatedly drilling information before testing recall or by limiting the amount of information to be initially learned (e.g., three words instead of five). PRINCIPLES OF TEST SELECCION

There are many instruments, procedures, and clinical maneuvers that can be used to evaluate mental state. Most seasoned clinicians use a routine set of procedures for which they have internalized standards over many years of experience that allow them to judge the presence and severity of observed deficits. The specific tests that are used in the mental state examination are not as important as the principles that direct their use and interpretation. Two general principles apply to test selection: Each test should contain as few component processes as possible so that it is easier to interpret the source of failure. As in the example given earlier, written calculation is a more direct test of acalculia than mental calculation because the latter could also be disturbed by impaired working memory or diminished arousal. However, written calculation itself becomes an undesirable test of this function in a patient with dysgraphia. The examiner must have a thorough understanding of the processes engaged by any given test. Each task used in the mental state examination should be analyzed with reference to the domains it actually enlists (outlined in Fig. 135-1) to understand the possible sources of failure. Tests should be appropriate for the patient’s level of education, cultural background, and level of life accomplishment. Patients differ with respect to the premorbid level of skill each brings to the examination. Intellectual capacity, education, socioeconomic background, and cultural factors each can influence performance independently, in the absence of brain disease. Therefore, for each domain tested, the clinician should come prepared with tasks at several levels of difficulty: easy, intermediate, and hard. For example, to test persistence without introducing other variables, serial sevens may be appropriate for a patient with a college education, and counting backwards or forwards by ones or even tapping a finger for a minute, would be more appropriate for a patient with a fourth grade education.

Some strategies for bedside and office examination, including clinical case examples, are described in the following sections. Table 135-1 provides a list of procedures and tests for each domain that range in their relative level of difficulty. Even if examination time is limited, every effort should be made to sample all domains to identify where the primary deficit resides and its secondary impact on other parts of the examination. For more comprehensive and precise measurement of mental abilities, including comparison of the patient’s performance against age- and education-relevant norms, it is desirable to have the patient undergo assessment by a skilled clinical neuropsychologist.

rn TABLE135-1. Primary Domains, Test Procedures, and Repercussion of Primary Deficits Domains (Components)

Description

Test Procedures

Repercussion of Primary Deficits.

WAKEFULNESS/ AROUSAL

Level of alertness/consciousness

Rate level of arousal (normal, drowsy, stuporous, comatose, hypervigilant)

Experienced mood Abiliky to sustain behavioral output, cooperate with exam

Assess from interview and observation: euthymic, dysphoric, hypomanic, etc.; labile or restricted affect, normal range; abulic, cooperative

Pervasive; affects performance on all tasks; reduces reliability of other findings for purposes of localization Pervasive; depression, mood instability, or poor cooperation invalidates test results; may lead to underestimating integrity of other domains; reduces reliability of other findings.

Sustained attention and detection of important events; tied to level of arousal

Auditory Continuous Performance: Present up to 300 letters (total of 5 minutes) in random sequence at the rate of one per second, 30 targets ("A") interspersed Digit Span: Present strings of random digits of increasing length, 2 trials at each length; span is longest string that can be repeated without error

(State dependent) MOOD/MOTNATION

(State dependent)

ATCENTION

(State-dependent) Vigilance

Span

Amount of information immediately grasped for further processing; linked to arousal

Perseverance

Sustained behavioral output; closely linked to motivation

Series Generation Tasks: Count back 20 to 1 (easy); recite months in forward then reverse sequence (intermediate); serial sevens (hard)

Response Inhibition

Inhibition of responsesto extraneous or distracting stimuli

Stroop Interference Test: Motor Go No Go procedure

Spontaneous Speech

Self-generated and responsive conversation

Auditory Comprehension

Understanding spoken language, including grammar and word meaning

Repetition

Verbatim repetition of speech

Note articulation, melody, rate (fluency), word-finding pauses, paraphasias, grammaticality in conversation and in speech elicited from a description of a scene or common task ("Describe how you would make a sandwich.") Ask questions that can be answered "Yes" or "No": Do dogs fly? Is a coffee pot alive? If a tiger is killed by a lion, is the lion alive? Is the tiger alive? Ask the patient to repeat: The red book is on the table. No ifs, ands, or buts.

Naming

Oral labeling of visually presented objects

Reading Comprehension

Comprehension of printed words (not necessarily able to read aloud)

Writing

Writing spontaneously and to dictation

Pervasive; affects performance on all tasks

Limits quantity of information intake, e.g., fewer story elements or words can be learned on memory tests, or grasped for language comprehension or repetition tasks Patient gives up easily; diminished spontaneous recall on memory tests; "pseudoneglect" on drawing and cancellation tests due to failure to persist at task Patient may respond impulsively in general, giving rise to high error rate despite presenred capacity

LANGUAGE

Show patient a watch and ask to name parts: face, hands, stem, crystal, band, clasp Present the following sentence and ask the patient to pick the correct word to complete it "The man drove his car down the to work." accelerator wheel road town Ask patient to write a spontaneous sentence and one to dictation; check for spelling, grammar

Even mild aphasia interferes with all tasks that rely on speech output (e.g., story or word list recall, digit span, similarities, orientation, etc.) Interferes with performance of all tasks that require comprehension of oral instructions Inabilityto repeat word lists and stories on memory tests; difficulty with digit span task despite normal attention Difficulty providing similarities or recalling specific words after a delay interval Difficulty performing tasks with printed instructions, written stimuli Difficulty performing tasks where writing is a component (eg., calculations, memory recall)

VlSUAySPATW PERCEPTION

Object/Form Perception Spatial Perception

Perception and discrimination of objects and geometric forms Perception of spatial orientation and direction

SPATIAL DISTRIBUTION OF AlTENnON LEARNING AND EXPLICIT MEMORY

Symmetric distribution of attention within both visual fields Acquisition of new information; retention over time; spontaneous recall; recognition

EXECUTIVE FUNCllONS

Complex mental operations involved in reasoning decisionmaking, planning, forethought, etc.

COMPORTMENT

Knowledge and application of rules of social conduct, judgment, insight

Ask if pairs of objects, faces, colors are the same or different Ask if pairs of angles are same or different Ask patient to reach for objects Paper-and-pencil visual target cancellation tasks Three Words Three Shapes Test; Drilled Word Span procedure Drill any information before testing recall after a delay of at least 5 minutes Obtain information from an informant who knows the patient well and note examples of impairments in real life activities Obtain information from an informant who knows the patient well

Y

Ways in which primary deficits interfere with performance on tests not specifically targeted by those tests.

Difficulty on drawing tasks, naming tasks. Difficulty on tasks requiring a spatial judgment Difficulty processing information/ stimuli in the unattendedfield May forget task instructions

Disruptive in daily living activities but may also interfere with planning any sequence of activities on tests in other domains (eg., any multiple choice response task) Most apparent in daily living although may be apparent in patient's lack of social graces -

Chapter 135

TESTING STATE-DEPENDENT DOMAINS Wakefulness, Mood, Motivation Wakefulness (or arousal) is at the basis of all conscious mental activity. Diminished arousal influences performance of tests in all other domains, despite the absence of a primary disturbance in those domains. The level of wakefulness or arousal should be documented before testing. If it is sufficiently impaired, it may be advisable to postpone the examination. The presence of a deficit in arousal reduces the extent to which failure on tests of any other domain represents a primary deficit in that domain or can be reliably localized. Diminished arousal implies interference with the major neurotransmitter projection systems, including the cholinergic pathways from the nucleus basalis and brainstem reticular activating system, serotonergic pathways from the raphe nucleus, noradrenergic pathways from the locus coeruleus, dopaminergic pathways from the substantia nigra and ventral tegmentum, and histaminergic pathways from the hypothalamus. Mechanisms of injury that interfere with these pathways and thereby cause a primary disturbance in all statedependent domains include alterations of the physiologic milieu via a toxic or metabolic disorder, structural damage to their origins, and extensive multifocal structural injury throughout the cerebral cortex or white matter that effectively disrupts cortical modulation by these systems. Mood is the patient’s current feeling state, and affect is the means whereby mood is conveyed in facial and body gestures and tone of voice. It is important to differentiate between the experience of mood and its conveyance. Some patients with focal, right-sided cerebral lesions may lose the ability to convey mood with facial and body gestures, resulting in a mismatch between feelings and appearance. Some patients with bilateral cerebral disease may display pseudobulbar affect or emotional incontinence, an exaggerated display of emotion that lacks the accompanying feeling state. Motivation is the capacity to initiate and sustain goal-directed behavior. A disturbance of motivation often is seen in the form of apathy or, in extreme cases, abulia. These symptoms and decreased initiative and impersistence should be differentiated from depressed mood. Similar to a disturbance of arousal, a disturbance of mood or diminished motivation can also lead to the impression of widespread cognitive deficiencies. Frequent “Don’t know” responses in the abulic patient should be followed up with prompting or cueing because encouragement may overcome the inertia. For example, a patient with abulia secondary to a toxic encephalopathy responded “Don’t know” to most questions asked of him. He denied knowledge of current news events. However, when cued with the name of a celebrity, he provided detailed information about the person and the event. His initial economy of mental effort was overcome by adapting the testing procedures to circumvent a lack of initiative. This method allowed us to conclude that there was no primary defect of memory and therefore no evidence of medial temporal involvement.

The domain of attention comprises several different processes that target internal and external stimuli in the service of current behavioral goals and drives. Not all aspects of attention are state dependent. However, even those that engage other neuroanatomic networks, such as working memory and response inhibition, are discussed in this section because they contribute to setting the

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overall information processing state within which the examination is conducted. Vigilance, or the maintenance of attention over time, is one component closely linked to the level of arousal. The continuous performance paradigm, in which the patient is asked to detect a particular target (e.g., the letter “A”) occurring repeatedly among a random series of similar stimuli (e.g., other letters) over at least 5 minutes, is one test of this aspect of attention. The digit span is a measure of the immediate span of attention. Normally, people under 65 can repeat a string of six to seven digits. A reduced digit span signifies a limitation on the amount of information that can be processed. For example, a patient with a digit span of four was able to immediately repeat only four items from a ten-item list with which she was presented. After a delay of 10 minutes, however, she recalled all four items. Although an absolute score of four is not considered normal for delayed recall on this test, it nevertheless indicated that she did not have a primary disturbance of retentive memory. Working memory is the capacity for holding information available for brief time intervals to process or manipulate it further. Reciting a string of digits in reverse sequence or reversing the sequence of the months of the year are tasks that tap working memory. Patients with working memory deficits can be easily distracted and may appear forgetful when they are having difficulty holding information long enough for it to be transferred to a more permanent store. Working memory is one component of attention that involves prefrontal cortex. Perseverance, or persistence, is the ability to sustain behavioral output and a coherent stream of thought. Reciting the months in reverse sequence is an intermediate-level test of perseverance that also tests working memory. The patient should first be asked to recite the months in forward sequence. The difference in time to complete both tasks can indicate whether there is a problem with perseverance. Typically, the forward sequence takes 5 to 8 seconds, and the reverse sequence may take twice as long without error. Generation of word lists over a 60-second interval (i.e., words that begin with a specific letter or that belong to a single semantic category) is also useful as a test of perseverance unless the patient has anomia or limited educational experience. Impersistence is reflected in an inability to sustain measured output. Perseveration, the repetition of elements within a task or of a previously appropriate response that is no longer relevant, is another symptom of impaired perseverance. Persistence depends on the level of arousal but may be selectively impaired by prefrontal cortex damage. Patients with impaired attention often are easily distracted. Some also are unable to inhibit an overt response to the distracting stimulus. Response inhibition is another component of attention that can be affected selectively by lesions of the frontal lobe. This function can be tested with a simple bedside adaptation of the “go-no go” procedure or the Stroop interference procedure (Fig. 135-2). In both tasks, competing and usually automatic response tendencies are first established. Normal performance requires the inhibition of one of the responses. In the “go-no go” procedure, the patient is asked to place one hand palm down on a table surface and to raise and quickly lower the index finger in response to a single loud tap of the examiner’s pencil. The patient is instructed not to respond if the examiner delivers two taps in quick succession. After a few practice trials, the examiner then delivers a random series of one or two taps. Deficits in response inhibition are manifested as errors of commission (i.e., lifting the finger in response to the “no go” signal).

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FIG. 135-2. A modification of the Stroop procedure. First ask the patient to read aloud the color words (white, black, and grey). Next,

ask the patient to name the colors in the middle box. Finally, ask the patient to name the colors of the ink of the words in the bottom box. The classic stimuli for this task are the colors red, green, and blue. However, this variation lends itself to being easily reproduced and brought to bedside.

Arousal, mood, motivation, and all aspects of attention are essential for complex mental activity. A primary deficit in any one of these domains has a ripple effect throughout the examination, even to the extent that other findings may be invalidated. Thus, caution must be exercised in interpreting findings in patients with primary impairments in these domains. The localizing value of symptoms in other domains is diminished in the presence of primary impairment in any of the state-dependent domains. The differential diagnosis of primary impairments in state-dependent domains is lengthy and, except in rare instances, does not implicate a single focal cortical lesion. Structural damage to components of the frontal network can also give rise to selective disturbances in attention and motivation because of its extensive connectivity with other areas of association cortex. TESTING CHANNEL-DEPENDENT DOMAINS Language Current notions of the neural control of language make obsolete the designation of aphasia as “receptive” or “expressive.” It is now understood that distinct components of language processing, namely morphosyntactic, semantic, lexical, and phonological, are modulated by different subsectors of the left cerebral neuroanatomic network supporting language and its connections with extralanguage brain regions. Lesions in the language network, therefore, can selectively impair one type of processing across all modalities of input and output. Traditional testing of language focuses on the integrity of different modalities of language use (i.e., auditory comprehension, repetition, reading comprehension, speaking, writing), but it is also necessary to specify the nature of the deficit. For example, a patient may meet classic criteria for the diagnosis of Broca’s aphasia, which specifies that comprehension is intact. However, lesions associated with Broca’s aphasia often interfere with

grammatical processing, and so comprehension of word order and words that convey syntactic information (i.e., prepositions, morphological endings) also is usually impaired despite preserved comprehension of nouns. To conclude that comprehension, or receptive language, is preserved in such a patient therefore would not be accurate. Speech is evaluated for articulation, melody, pitch, fluency, rate, grammaticality, and evidence of word-finding difficulty. Fluency in part is determined by the number of words uttered per unit time, or phrase length. Phrase length can range from one word per utterance (nonfluent) to seven or more (fluent). Fluency is also affected by the presence of dysarthria. Auditory comprehension should be tested with items requiring only a “yes” or “no” response, eliminating other factors such as speech or motor output (e.g., “DO dogs fly?”). Grammatical comprehension can be tested with questions such as “Do you put on your shoes before your socks?” A patient with a syntactic processing deficit may correctly answer the first question but not the second. Lengthy questions may exceed a patient’s immediate attention span, and commands that require a physical action may not be carried out despite preserved comprehension if apraxia is present. Reading comprehension can be tested by asking the patient to silently read a short sentence from which a word is missing and to select the missing word from four choices (Table 135-1). Repetition is tested by having the patient repeat a grammatically complex but short sentence, such as “No ifs, ands, or buts.” Writing is usually impaired in the same manner as speech in the patient with aphasia. An isolated disturbance of writing, or agraphia, however, may be a common manifestation of impaired attention in the acute confusional state. Naming of objects is a very sensitive test of the integrity of the language system because it is affected by lesions almost anywhere in the language network. An effort should be made to present less common items for naming, such as parts of objects (i.e., lapel of a jacket, hem of a skirt, crystal of a watch, eraser of a pencil). Naming deficits can represent a failure of access to the lexicon or may also occur with a disturbance of semantic processing. Visual or spatial perception deficits can interfere with naming and must be ruled out before failure to name on visual confrontation is interpreted. Visual agnosia can be differentiated from naming failure if the patient is able to name the item by tactile exploration. Modality-specific naming deficits (e.g., tactile anomia) are rare but can be tested by eliciting naming in response to objects presented visually, tactually, and auditorily. The melodic features of speech production, or prosody, can be selectively affected by lesions in the right cerebral hemisphere. Such alterations may make a patient incapable of conveying affect through tone of voice or using prosody as a device to lend emphasis in conversation. For example, depending on the conversation that precedes this utterance, saying “Margo plays the piano” or “Margo plays the piano” bears different referential meaning. If the preceding statement were “Does Margo play the harp?” then the latter prosodic pattern would be appropriate in response. Asking the patient to repeat sentences that vary in their emphasis or affective tone can serve as a test of this function. Aphasia can be localized to damage to the left perisylvian region of the brain. Further precision may be possible based on the clinical nature of the aphasia. Thus, nonfluent speech with preserved semantic comprehension often is associated with damage to Broca’s area and surrounding cortex. However, because of the nature of large-scale networks, the lesion may be located in a less expected portion of the network, such as the thalamus or

Chapter 135 W

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even Wernicke’s area. In addition to the localizingvalue of aphasia, its presence necessitates testing the integrity of other domains with methods that bypass the aphasia (i.e., using nonverbal materials and pantomime to demonstrate to the patient the expected task performance). Visual Perception

Constructions often are used to assess visual perception. However, constructions also enlist other mental domains. Failure to draw a clock, copy a cuhe, or assemble puzzles, for example, can reflect executive function deficits in the presence of normal perception. Thus, it would be inaccurate to conclude that impaired constructions imply parietal lobe damage. However, if an alert, attentive, and cooperative patient cannot decide whether one geometric figure is in the same plane as another or whether two angles are similar (Fig. 135-3), then localization to networks involved in visual perception is more reliable. Prosopagnosia, the inability to recognize familiar faces, can be differentiated from a more basic facial discrimination problem by having the patient judge whether two photographs depict the same person. A disturbance of the spatial distribution of visual attention in the form of hemispatial neglect can be measured in the visual modality with target cancellation tasks (Fig. 135-4).Note the point of origin of the patient’s search. Patients with right cerebral lesions may begin on the right side of the page and search in an erratic fashion, even in the absence of clinical neglect. Deficits in visual perception and hemispatial neglect interfere with performance of all tests that entail visual inspection or reproduction of designs and figures. Hemispatial neglect can be localized to one sector of a large-scale network for the spatial distribution of attention. Persistent right-sided hemispatial neglect often is a sign of bilateral lesions. Disorders of spatial perception usually are associated with damage to the visual pathways that are directed dorsally to the parietal lobe, the “where pathways.” The

FIG. 135-3. (A) Object sorting task. Ask the patient to divide the objects into two groups, each characterized by a distinctive feature. Once this has been done, ask the patient to think of another way to divide the objects into two different groups. One strategy is to group all the ovals and all the hexagons. The other strategy is to group all the white objects and all the black objects. (B) Test for spatial perception. One of the fwe angles to the right of the vertical line must be matched to the sample on the left.

FIG. 135-4. Performance of a patient with left-sided hemispatial neglect on the visual target cancellation test of Weintraub and Mesulam. The task is to circle all the& The density of targets and their irregular arrangement is helpful in detecting subtle neglect when other similar measures may not be as sensitive.

classic disturbance of spatial perception seen in Balint’s syndrome, for example, is a result of biparietal damage. Disorders of object and color perception imply damage to the ventrofugal visual pathways, the “what pathways.” Prosopagnosia and some forms of visual object agnosia are associated with lesions in the lingual and fusiform gyri of the inferior temporo-occipital area and in the lateral and mesial aspects of temporal cortex.

Explicit Retentive Memory Orientation (e.g., to place, time, examiner’s identity) and the ability to learn new information and retain it over time are key elements of retentive memory. Knowledge of current news or personal events is an informal measure of the integrity of explicit memory. “Three Words-Three Shapes” is a simple bedside procedure to test learning, retention, and retrieval of verbal and nonverbal material in the visual modality (Fig. 135-5). After copying the six stimuli, without forewarning, the patient is asked to immediately reproduce them (incidental recall). If five of the six stimuli are recalled (defined as criterion level of learning) delayed recall can be tested 5, 15, and 30 minutes later (or at other intervals as time permits). If the patient recalls fewer than five from incidental memory, the examiner re-exposes the original stimuli for a 30-second interval, after which the patient is asked to immediately draw them again (study-recall trial). Drilling proceeds in this manner until at least five items are reproduced or five study-recall trials are exhausted. This procedure is necessary to ensure that the information for which retention will be tested has first been acquired and to control for the impact of poor attention. Then delayed recall is tested as described earlier. After the final delayed recall trial, multiple-choice recognition can be tested. The number of items recalled after each delay is a measure of the rate of forgetting, which is accelerated in the amnestic syndrome. The drilled word span procedure can also be used to test learning and recall. Select a list of words equal in length to the

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BehavioralNeurology and Epilepsy Confusional State Primary Deficit Inattention

Behavioral Neurology

Probable Alzheimer's Disease Primary Deficit: Amnesia

a

B

Comportment, Executive Functions, and Reasoning

B

D

differentiating primary amnesia from memory failure secondary to attentional and motivational deficits. The amnestic syndrome is characterized by normal immediate recall and impaired delayed recall (i.e., rapid forgetting) in the context of a normal level of attention and motivation and normal language and perception. It is a sign of damage to the limbic system that is almost always bilateral. Patients with primary amnesia are not able to recall information after even brief distraction and after a delay interval. Inattentive patients may have difficulty initially learning information but then can retain it over time (Fig. 135-5). Occasionally, however, severely inattentive or abulic patients may be unable to spontaneously retrieve information despite remembering it, and this is often confirmed by normal recognition.

D

FIG. 135-5. Three Words-Three Shapes Test. After copying the three words @ride, hunger, and stution) and the three designs, incidental recall is tested, followed by testing of delayed recall. Left column: Sample taken from a 75-year-old woman in an acute confusional state caused by medication effects. Right column: Sample taken from a 64-year-old man with a progressive decline in memory subsequently autopsy-confirmed as Alzheimer's disease. (A) Copy; (B) incidental recall; (C) recall after three additional study-recall trials for the confused patient to reach criterion, and only one such trial for the amnestic patient; (0) spontaneous recall after a 30-minute delay. The confused patient took more trials to learn the stimuli but then retained them well after the delays. The amnestic patient needed only one additional trial to learn the stimuli but then forgot the information over time. In the first instance, there was no evidence of a primary disturbance of memory. In the second, primary amnesia accounted for test performance.

patient's digit span minus one (i.e., the word span). Drill these words until the patient can repeat them successfully three times in a row. If the patient still has difficulty with this list length, drop to a level at which the list is repeated without error. Test recall after a 60-second interval without distraction. Poor performance at this point indicates that the patient is internally distracted or lacks motivation. If recall is less than perfect, repeat the drilling procedure. Then, test recall after another 60 seconds filled with a distracting activity, and again after 3 minutes. Multiple-choice recognition is tested after the final delayed recall trial. Recall after each delay interval with distraction is a measure of retention and retrieval. Recognition testing can determine whether there is a deficit in retrieval. This procedure is especially helpful in

These domains are made up of mental processes that orchestrate behavior and make it adaptable to the social setting and moment-to-moment contingencies. Comportment consists of behaviors that support social interaction and the ability to alter behavior based on the social context. Executive functions are mental processes that organize and sequence behavior and guide decision making and the ability to act appropriately in uncertain or unexpected circumstances. Reasoning is the ability to abstract categoricalsimilarities and to move flexibly from one point of view to another in arriving at a solution to a problem. Impairments in these domains are among the most common in clinical practice. Testing judgment and reasoning in the clinician's office is exceedingly difficult. Asking a patient what should be done in the event of a fire in a movie theater is a useful measure of judgment only if the patient provides the wrong answer. A correct answer may only indicate conventional knowledge of the appropriate response and does not guarantee that the patient would act appropriately in the real situation where there are many contingencies and alternative options. A patient's insight into his or her own symptoms, decisionmaking ability, and reasoning about everyday issues and health care decisions can provide clues about the integrity of these domains. More reliable information about the patient's judgment, social behavior, and decision-making ability may need to be obtained by questioning family members or other informants. In general, with the patient's permission, the examiner should always seek corroboration from an informant because many forms of brain disease interfere with insight and adequate self-perception of symptoms. Proverb interpretation is commonly used as a test of reasoning, but it may not be suitable in patients with limited education. Moreover, responses to familiar proverbs may be highly overlearned. Reasoning tests that emphasize categorization and mental flexibility, such as object-sorting tasks (Fig. 135-3), can be used to demonstrate primary deficits in this domain. Deficits in executive functions may have a pervasive influence on performance of tests that entail organization and sequencing. For example, a patient with a disturbance of executive functions performed very poorly on a test that required matching a photograph of a face with one of six alternative choices. Because there was no other evidence that this patient had a primary disturbance of visual perception, the examiner adapted the testing procedure to prevent impulsive responses by exposing only one face at a time and asking whether it matched the stimulus face. With that adaptation, the patient demonstrated normal facial

Chapter 135

discrimination and the examiner reaffirmed a primary disturbance of executive functions. The frontal lobes and their extensive connections with other cortical and subcortical regions (frontal network) provide the neuronal substrate for these complex behaviors. The extensive connectivity of the frontal lobes helps to explain why many multifocal brain diseases (e.g., toxic and metabolic encephalopathy, multiple bilateral strokes, hydrocephalus) result in so-called frontal symptoms in the absence of structural injury to the frontal lobes. SUMMARIZING AND INTERPRETINGTHE EXAMINATION

At the completion of the examination, the clinician can review the patient’s performance and rank the domains in order of the level of impairment in each normal or mildly, moderately, or severely impaired. In many instances it is possible to pinpoint one primary domain of impairment. In others, there may be multiple domains of impairment. In yet others, a single deficit may interfere with performance of tests in other domains that themselves are not primarily involved. The clinician must determine whether there is one or more primary deficits and what the relative contribution of each is to the overall clinical picture. Reference to the hierarchy outlined in Fig. 135-1is helpful in this regard. Once the clinical profile is established, the neuroanatomic localization follows. Table 135-2 outlines some common neurobehavioral syndromes and their associated clinical profdes and neuroanatomic localization. The principles of examination and interpretation outlined in this chapter apply not only to patients with focal cerebral lesions but also to those with developmental syndromes and neurodegenerative diseases. Developmental syndromes, such as dyslexia and the social-emotional processing disorder, can be quite selective in terms of anatomic and behavioral specificity. Similarly, in early stages of neurodegenerative disease, pathology can be highly anatomically selective, giving rise to fairly behaviorally focal deficits that can be identified with the clinical profile approach outlined in this chapter. EXAMINING FOR DEMENTIA IN OLDER ADULTS

Rapid developments in the study of Alzheimer’s disease have refined clinical methods for detecting dementia and differentiating it from age-related cognitive change. The use of mental state screening tests has become common in the primary care setting. Instruments such as the Mini Mental State Examination and the

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Blessed Dementia Scale and qualitative rating scales such as the Clinical Dementia Rating and the Global Deterioration Scale have all improved the quantification of dementia severity. These instruments are very helpful, once dementia is detected, to stage disease and track changes over time. However, as public awareness of the implications of mental decline with aging increases, patients are seeking medical assessment earlier in the course of illness, at a time when only mild cognitive change, and not dementia, may be present. Because screening instruments are insensitive to the earliest changes, it is advisable to have the patient undergo neuropsychological assessment that is more likely to detect subtle abnormalities of mental state. Such evaluation is conducted with the understanding that test scores play only a small role in the clinical neuropsychologist’s contribution to the assessment of dementia. For example, forms of dementia in which memory, language, and visual perception are not impaired, such as frontal lobe dementia, are more likely to be detected with specialized testing and interview techniques than on the routine mental state examination or even after administration of many standardized tests. The principles of examining mental state and interpreting the findings, outlined earlier, also apply to the evaluation of the patient with the progressive mental state changes of neurodegenerative or vascular dementia. The goal remains to identify the primary domain of impairment. This is easy to do in the very earliest stages of disease because it is now well established that most degenerative brain diseases tend to target specific brain regions at the onset. However, this may be more difficult once the disease has progressed to involve multiple cortical areas and multiple domains. Even in that circumstance, though, the examiner can assess the relative degree of impairment among the domains. Thus, the clinical syndrome of probable Alzheimer’s disease includes deficits in memory and other cognitive functions, but the memory deficits typically are more salient and continue to remain more pronounced than other deficits until late stages of illness. The challenge in identifjmg primary domains of impairment is well illustrated in the examination of a patient with primary progressive aphasia, a dementia syndrome in which language progressively deteriorates in the absence of other cognitive deficits for at least 2 years. Because memory testing usually relies on language, the examiner must demonstrate the integrity of memory by other means. Nonverbal recall tests offer one method. Gathering information about daily living activities that imply the presence of normal memory may provide the only means in the severely aphasic patient. One patient with severe language

w TABLE 135-2. Profiles of Common Neurobehavioral Syndromes on Mental State Testing RUMIN NNROC~GNIIM DOMINS

Syndrome

Aphasia syndrome Hemispatial neglect B a h t syndrome Acute confusional state Dyslexia Probable Alzheimer‘s disease Primary progressive aphasia Depression Schizophrenia

Attention

Mood

Language

Complex Visual Perception

Explicit Memory

Reasoning/ Comportment

UnderlyingAnatomy

Left perisylvian Right frontal, parietal, cingulate Bilateral occipito-parietal # 0 0 0 0 Frontal lobe or frontal network # Left perisylvan # Medial temporal (limbic), parietal # 0 0 Left perisylvian # # d 0 0 Transmitter projection systems # # Frontal network #, Primary domain of impairment +, Impairment may be present due to overlap in neuroanatomical networks subserving affected domains or to the multifocal nature of the causative disease agent 0,Performance on tests of this domain may suffer secondary to primary impairment

+

+

#

+

+

+

+

# #

+

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comprehension and speech deficits traveled by air to Chicago from his home in New York and negotiated ground transportation to make his doctor’s appointment without assistance. In the case of frontotemporal dementia, the entire mental state examination might be normal, with the only evidence of abnormality coming from information from a family member or friend about changes in the patient’s characteristic behavior.

SUMMARY The examination of mental state unfolds in a dynamic interaction between the examiner and patient, driven by a firm understanding of psychological principles of behavior, the demands that even simple tasks make on mental processing, and principles of neurobehavioral organization. The selection of tests depends on how well each can test the examiner’s hypothesis about the nature of the mental state abnormality and by factors determined by the individual patient’s background. The detection of a clinical profile of primary and secondary deficits and areas of preserved functioning leads to identification of the anatomic networks affected by the disease. This profile can also be helpful in educating patients and those who care for them and in designing appropriate interventions to augment functional status.

ACKNOWLEDGMENTS Work on this chapter was supported in part by Alzheimer’s Disease Core Center grant AG13854 to Northwestern University, Chicago, Illinois. The author wants to thank Dr. Gabriel Uger and Dr. Gulustu Kaptanoglu for their critical reading of the manuscript and Caralynn Nowinski for technical assistance.

SUGGESTED READINGS Herndon RM (ed): Handbook of Neurologic Rating Scales. Demos Vermande, New York, 1997 Lezak M: Neuropsychological Assessment. 3rd Ed. Oxford University Press, New York, 1995 Mesulam MM Attention, confusional states and neglect. pp. 174-256. In Mesulam MM (ed):Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Mesulam MM: Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. pp. 1-120. In Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Mesulam MM. The human frontal lobes: transcending the default mode through contingent encoding. pp. 8-30 In Stuss DT, Knight RT (eds): The Frontal Lobes. Oxford University Press, New York, 2002 Salmon DP, Thal LJ, Butters N, Heindel WC Longitudinal evaluation of dementia of the Alzheimer type: a comparison of 3 standardized mental status examinations. Neurology 4 0 12251230, 1990 Spreen 0, Strauss E A Compendium of Neuropsychological Tests. Oxford University Press, New York, 1998 Tombaugh TN, McIntyre NJ: The Mini-Mental State Examination: a comprehensive review [see comments]. J Am Geriatr SOC40922-935, 1992

Weintraub S: Neuropsychological assessment of mental state. pp. 121-173. In Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. Oxford University Press, New York, 2000 Weintraub S , Mesulam MM: Four neuropsychological profiles of dementia. In Boller F, Grafman J (eds): Handbook of Neuropsychology.Vol. 8. Elsevier, Amsterdam, 1993

136 Evaluation of Patients with Dementia Bruce H. Price and Martin A. Coldstein DEFINING DEMENTIA Dementia is a clinical syndrome, not a specific diagnosis; therefore, it can be produced by a wide variety of causes. Dementia can be defined as a sustained or progressive decline in cognition or comportment caused by chronic brain dysfunction. It can be reversible or irreversible, dramatically progressive or indolent, and can be characterized by isolated or multiple cognitive deficits. Occurring via acute or more commonly insidious onset mental decline, dementia gradually interferes with activities of daily living (ADLs) appropriate for age and background. In many ways dementia diagnosis and management are at the epicenter of revolutionary advances in basic and clinical neuroscience. In contrast to conditions that impede intellectual development, dementia involves the loss of acquired cognitive abilities. Dementia is therefore distinguished from mental retardation by the requirement that a patient’s function has declined from a previously higher capacity. A diagnosis of dementia implies cognitive impairments that compromise personal, social, or vocational function and persist for a minimum of several months. Deficits can occur in any

combination of comportmental, cognitive, affective, and perceptual domains. Several authors specify that impairment involve at least three of the following functional capacities: attentional matrix, language, memory, visuospatial skills, executive abilities, and personality. Although memory loss sometimes is considered a prerequisite to diagnosis, amnesia is neither ubiquitous nor necessarily prominent in all forms of dementia. Furthermore, cognitive and social abilities can be differentially affected by dementia; patients with severe but focal cognitive deficits can retain their functional independence, whereas those with mild impairments affecting socially critical functions may need extensive supervision. Table 136-1 provides the current international criteria standard for the diagnosis of dementia; Table 136-2 summarizes core components of the widely used Diagnostic and Statistical Manual, Fourth Edition, (DSM-IV) diagnostic criteria. Dementia severity can be gauged in social terms as well as by nature and degree of cognitive impairments. Dementia is considered mild when the affected person continues to conduct basic activities such as dressing, grooming, eating, and toileting without assistance. Patients with moderate dementia depend partially on

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comprehension and speech deficits traveled by air to Chicago from his home in New York and negotiated ground transportation to make his doctor’s appointment without assistance. In the case of frontotemporal dementia, the entire mental state examination might be normal, with the only evidence of abnormality coming from information from a family member or friend about changes in the patient’s characteristic behavior.

SUMMARY The examination of mental state unfolds in a dynamic interaction between the examiner and patient, driven by a firm understanding of psychological principles of behavior, the demands that even simple tasks make on mental processing, and principles of neurobehavioral organization. The selection of tests depends on how well each can test the examiner’s hypothesis about the nature of the mental state abnormality and by factors determined by the individual patient’s background. The detection of a clinical profile of primary and secondary deficits and areas of preserved functioning leads to identification of the anatomic networks affected by the disease. This profile can also be helpful in educating patients and those who care for them and in designing appropriate interventions to augment functional status.

ACKNOWLEDGMENTS Work on this chapter was supported in part by Alzheimer’s Disease Core Center grant AG13854 to Northwestern University, Chicago, Illinois. The author wants to thank Dr. Gabriel Uger and Dr. Gulustu Kaptanoglu for their critical reading of the manuscript and Caralynn Nowinski for technical assistance.

SUGGESTED READINGS Herndon RM (ed): Handbook of Neurologic Rating Scales. Demos Vermande, New York, 1997 Lezak M: Neuropsychological Assessment. 3rd Ed. Oxford University Press, New York, 1995 Mesulam MM Attention, confusional states and neglect. pp. 174-256. In Mesulam MM (ed):Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Mesulam MM: Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. pp. 1-120. In Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Mesulam MM. The human frontal lobes: transcending the default mode through contingent encoding. pp. 8-30 In Stuss DT, Knight RT (eds): The Frontal Lobes. Oxford University Press, New York, 2002 Salmon DP, Thal LJ, Butters N, Heindel WC Longitudinal evaluation of dementia of the Alzheimer type: a comparison of 3 standardized mental status examinations. Neurology 4 0 12251230, 1990 Spreen 0, Strauss E A Compendium of Neuropsychological Tests. Oxford University Press, New York, 1998 Tombaugh TN, McIntyre NJ: The Mini-Mental State Examination: a comprehensive review [see comments]. J Am Geriatr SOC40922-935, 1992

Weintraub S: Neuropsychological assessment of mental state. pp. 121-173. In Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. Oxford University Press, New York, 2000 Weintraub S , Mesulam MM: Four neuropsychological profiles of dementia. In Boller F, Grafman J (eds): Handbook of Neuropsychology.Vol. 8. Elsevier, Amsterdam, 1993

136 Evaluation of Patients with Dementia Bruce H. Price and Martin A. Coldstein DEFINING DEMENTIA Dementia is a clinical syndrome, not a specific diagnosis; therefore, it can be produced by a wide variety of causes. Dementia can be defined as a sustained or progressive decline in cognition or comportment caused by chronic brain dysfunction. It can be reversible or irreversible, dramatically progressive or indolent, and can be characterized by isolated or multiple cognitive deficits. Occurring via acute or more commonly insidious onset mental decline, dementia gradually interferes with activities of daily living (ADLs) appropriate for age and background. In many ways dementia diagnosis and management are at the epicenter of revolutionary advances in basic and clinical neuroscience. In contrast to conditions that impede intellectual development, dementia involves the loss of acquired cognitive abilities. Dementia is therefore distinguished from mental retardation by the requirement that a patient’s function has declined from a previously higher capacity. A diagnosis of dementia implies cognitive impairments that compromise personal, social, or vocational function and persist for a minimum of several months. Deficits can occur in any

combination of comportmental, cognitive, affective, and perceptual domains. Several authors specify that impairment involve at least three of the following functional capacities: attentional matrix, language, memory, visuospatial skills, executive abilities, and personality. Although memory loss sometimes is considered a prerequisite to diagnosis, amnesia is neither ubiquitous nor necessarily prominent in all forms of dementia. Furthermore, cognitive and social abilities can be differentially affected by dementia; patients with severe but focal cognitive deficits can retain their functional independence, whereas those with mild impairments affecting socially critical functions may need extensive supervision. Table 136-1 provides the current international criteria standard for the diagnosis of dementia; Table 136-2 summarizes core components of the widely used Diagnostic and Statistical Manual, Fourth Edition, (DSM-IV) diagnostic criteria. Dementia severity can be gauged in social terms as well as by nature and degree of cognitive impairments. Dementia is considered mild when the affected person continues to conduct basic activities such as dressing, grooming, eating, and toileting without assistance. Patients with moderate dementia depend partially on

Chapter 136

TMLE 136-1. ICD-10 Criteria for the Diagnosis of Dementia Impairment of short- and long-term memory (more accurately of anterograde memory) At least one of the following: Impairment of abstract thinking Impairedjudgment Other disturbance of higher cortical function Personality change Memory impairment and intellectual impairment causing significant social and occupational impairment Absence of occurrence exclusively during the course of delirium Either of the following: Evidence of an organic factor causing impaired memory and intellect Impaired memory and intellect cannot be accounted for by any nonorganic mental disorder Adapted from InternationalClassification of Disease.

others for these activities, and in severe stages these functions must be provided by caregivers. The same terms are used to describe the severity of neuropsychological deficits in dementia (e.g., mild, moderate, severe memory loss). To identify the underlying disease process causing a dementia, all aspects of the patient’s medical history, family history, and clinical examination (medical, neurologic, psychiatric) must be considered, along with appropriate laboratory investigations. Dementia features such as age at symptom onset, nature and severity of cognitive and behavioral deficits, and progression pattern are considered in evaluating the differential diagnosis of a dementia. Neuropathologic examination of the brain at autopsy usually conclusively establishes the nature of the underlying disorder and constitutes the gold standard against which accuracy of antemortem diagnosis is measured. The neuroanatomic, neurohistologic, and neurochemical underpinnings of dementia vary depending on specific causes. Most dementing processes preferentially involve certain cell types or neurotransmitter systems. Consequently, not all mental faculties

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are affected simultaneously. Cognitive profile often is dictated more by neuroanatomic lesion site than by specific histopathology. Several dementias reflect direct damage to cortical association areas (e.g., asymmetrical cortical degeneration). In other cases, dysfunction is secondary to impairment of interconnected subcortical areas such as basal ganglia, thalamus, and limbic structures. Disruption of white matter pathways, whether multifocal (as in multiple sclerosis) or confined to single areas such as the genu of the internal capsule (as in strategic infarct dementia), can critically slow or disconnect neocortical areas, thereby resulting in dementia. Degeneration of brainstem or basal forebrain nuclei that normally provide specific neurotransmitters to cerebral cortex can also contribute to dementia, particularly when involvement includes cholinergic or monoaminergic systems.

EPIDEMIOLOGY The overall prevalence of dementia is about 10% in patients over 65. Prevalence increases almost exponentially with age, from an estimated 2% in those under 65,8% to 25% in those 65 to 85, and 25% to 40% in those 85 and older. Prevalence is slightly greater in women than men. The incidence of dementia is more pertinent to diagnosis. Between ages 65 and 75, the number of new cases is less than 1:lOO per year. After age 75, yearly incidence rises to at least 2:lOO. In the East Boston study, yearly incidence of Alzheimer’s disease (AD) alone rose to 8.4 per 100 in individuals older than 85. In the Rotterdam study, a population-based prospective cohort study among almost 8000 subjects over age 55, overall prevalence was 6.4% and overall incidence was 1 per 100 person-years. Both prevalence and incidence increased strongly with age; typical incidence estimates for age 65, 75, and 95 were 1 per 1000, 1 per 100, and 1 per 10 person-years, respectively. It is estimated that one in six men and almost one in three women will suffer from dementia at some point.

TAU 136-2. Selected DSM-IV Dementia Criteria Dementia of the Alzheimer‘s type

Vascular dementia

Development of multiple cognitive deficits manifested by: Memory impairment One or more of the following: Aphasia Apraxia Agnosia Executive dysfunction The cognitive deficits in criteria A1 and A2 cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning The course is characterized by gradual onset and continuing cognitive decline The cognitive deficits in criteria A1 and A2 are not caused by any of the following: Other CNS conditions Systemic conditions Substance-induced conditions The deficits do not occur exclusively during the course of a delirium Development of multiple cognitive deficits manifested by Memory impairment One or more of the following: Aphasia Apraxia Agnosia Executive dysfunction The cognitive deficits in criteria A1 and A2 cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning Focal neurologic signs and symptoms or laboratory evidence indicative of cerebrovascular disease are judged etiologically related to the disturbance The deficits do not occur exclusively during the course of a delirium

Adapted from Diagnostikand StatistjcalManual of Mental Disorders, Fourth Edition.

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Behavioral Neurology

TMLE 136-3. Classifying Cognitive Dysfunction Cognitive Impairment

Primary or Secondary Process

Potential Reversibili

Examples

Encephalopathy Dementias

Secondary Secondary

Usually reversible Sometimes reversible Irreversible Irreversible

Toxic or metabolic B,, deficiency Creutzfeldtdakob disease Alzheimer's disease

Primary

DlFFERENTIATlNC DEMENTIA FROM OTHER MENTAL DISORDERS

When a patient is referred for assessment of cognitive decline, the first necessity is to differentiate dementia from other psychiatric disease, focal neurologic syndromes, and confusional states (Table 136-3). A principal goal of initial clinical evaluation is to find a treatable cause. Although there can be much phenomenologic overlap (e.g., subdural hematoma can manifest as delirium or as a reversible dementia), clinicians need to consider the following questions: Does this patient meet criteria for a dementia? If the patient is demented, is it secondary to a potentially reversible cause? If irreversible, what type of dementia is it? Although only about 10% to 15% of dementias are reversible, and only a fraction of these are completely reversible, the possibility of reversing or at least arresting the disorder by appropriate treatment justifies careful diagnostic investigation. Risk of missing a treatable dementia mandates screening investigation for reversible causes. Diagnosis is important in some cases for purposes of genetic counseling or for alerting family members and medical personnel of risk of an infectious etiologic process. DelirSum/EncephalopaUly/Acute Confusional State Several terms are applied to acute or subacute sensorium disturbance; delirium, encephalopathy, and acute or subacute confusional state are essentially equivalent clinically and can be used interchangeably. The sine qua non clinical feature of delirium is a clouded sensorium (see Chapter 139). Although dementia involves cognitive impairment in the context of an awake patient with a clear sensorium, acute confusional states often are misdiagnosed as dementia (Table 136-4). Patients with delirium commonly experience fluctuations in levels of consciousness, with consequent gross attentional impairments; in contrast, patients with dementia often have nearly normal attention spans throughout mild and moderate stages of illness. Abnormalities of level of consciousness

rn TMLE 136-4. Contrasting Features of Delirium and Dementia Feature

Delirium

Dementia

Onset Course Duration Attention

Acute or subacute Fluctuating Limited Impaired

Language Speech Visual hallucinations Tremor Myoclonus Electroencephalogram

Incoherent Slurred, dysarthria Common Common Common Prominent abnormalities (e.g., encephalopathic triphasic waves)

Insidious Persistent Chronic Intact until more advanced stages More coherent Usually intact Uncommon Uncommon Variable Minimal changes (e.g., slowing)

are unusual in dementia until the disorder is far advanced. Another key distinction between delirium and dementia is time course. Delirium by definition is acute or subacute, its onset occurring over hours to days. Amnedc Syndromes

Amnesia, a disorder of memory, can occur as a component of a multifaceted mental status change, such as delirium or dementia, or as an isolated abnormality. When occurring as an isolated cognitive deficit, it is sometimes clinically useful to consider amnesia as a distinct nosologic category (see Chapter 142 for detailed discussion).

Aging Although cognitive deficits in older adults often are attributed to aging, it is important to emphasize that normal aging is not associated with dramatic declines in recent memory or other cognitive functions. Aging is associated with increased susceptibility to a variety of medical disease processes, but major mental decline is not the natural course of old age. Although interpretation of what is normal cognitive aging is complicated by daunting methodologic issues, cognitive functions that should remain preserved over the lifespan include temporal orientation, immediate attention, vocabulary, and most visuospatial skills; delayed recall in healthy older adults can be preserved into the tenth decade. Mild age-related decrements involve difficulties with sustained attention, visual greater than verbal memory recall, confrontation naming, mental flexibility, and response speed. Episodic memory declines with age, but semantic, implicit, procedural, recognition, and working memory remain largely intact. Furthermore, mild age-related cognitive decrements may be counterbalanced by improvements in vocabulary, judgment, insight, and wisdom. In sum, normal cognitive aging, even into the ninth decade, is compatible with independent living. It is therefore inaccurate to attribute significant memory complaints or other cognitive impairment merely to consequences of normal aging. We summarize consensus opinion regarding normal agerelated cognitive changes in Table 136-6.

rn TABLE136-5. Medication Classes Often Associated with Encephalopathy Cholinergic antagonists Benzodiazepines Barbiturates Narcotics H, antagonists P-Blockers Sympathomimetics Digoxin Dopamine antagonists Dopamine anonists

Chapter 136

TABLE 136-6. Cognitive Changes Associated with Normal

Aging Finding with Functional Domain Attention

Normal Aging

Sustained Selective

Memory

Language Executive function Visuospatial function

Registration Short-term Long-term Working Syntax Naming Integration Planning Response inhibition Perceptual Constructional

Processing speed

Presenred into eighth decade Presenred into ninth decade Presenred Declines Presenred Impaired Presenred Gradual decline Declines Declines Declines Declines Declines Gradually progressive slowing

Evaluation of Patients with Dementia

861

APPROACH TO DIAGNOSIS Recognizing Dementia Barriers to detecting dementia in routine practice are formidable. Patients rarely seek medical attention for their symptoms; in fact, a lack of insight into the symptoms is a common feature of the early stages of the disorder. Assessment of dementia often is driven by family concerns, but this can be inefficient. Family members often delay bringing the person with symptoms of dementia to a physician. Reasons for delay include lack of ongoing contact with a failing older adult or lack of appreciation of the patient's loss of function and physician failure to respond to family concerns. Furthermore, physicians too often do not perform mental status examinations adequate for early dementia detection. Consequently, physicians detect dementia only occasionally in the absence of specific patient or family complaints. History from a collateral source, adequate mental status examination, and a competent neurologic examination are paramount to an accurate dementia diagnosis (Table 136-10).

rn TABLE 136-7. Mild Cognitive Impairment Criteria Memory complaint, preferably corroborated by an informant Objective memory impairment Normal general cognitive function Not demented

w TABLE136-8. Relative Alzheimer's Disease Incidence Rates, General Population Versus Patients with Mild Cognitive Impairment Dementia Incidence Rate Patient Population

per Year

General population

0.2%

Ages 65-69 Ages 85-89 Patients with mild connitive imoairment

Mild Cognbe Impairment

The diagnosis of mild cognitive impairment (MCI) has been the subject of increasing clinical and empiric attention. Although MCI is reviewed in Chapter 142, we briefly mention it here because the diagnosis becomes a consideration in the differential diagnosis of cognitive impairment and carries significant implications for long-term patient monitoring. Table 136-7 summarizes current criteria for MCI. The significance of MCI diagnosis is underscored by results of meta-analyses indicating that patients characterized as being cognitivelyimpaired but not meeting clinical criteria for dementia have a high risk of progressing to dementia in general and AD in particular (Table 136-8). The American Academy of Neurology (AAN) recently issued practice parameter guidelines for detecting MCI in the context of such epidemiologic data strongly suggesting MCI's relevance to early detection of dementia; the major recommendations are summarized in Table 136-9.

W

3.9% 6%-25%

TABLE 136-9. AAN Practice Recommendationsfor

Monitoring Patients with Mild Cognitive Impairment Patients with mild cognitive impairment should be recognized and monitored for cognitive and functional decline because of their higher risk for subsequent dementia. General cognitive screening instruments (eg., mini-mental status exam [MMSEI) are useful for detecting dementia when used in patient populations with suspected cognitive impairment (eg., caused by age or presence of memory dysfunction). Neuropsychologicalbatteries are useful in identifying patients with dementia, particularly when administered to a population at higher risk of cognitive impairment. Adapted from Peterson RC, Stevens JC, tanguli M et al: Practice parameters: early detection of dementia: mild cognitive impairment (an evidence-basedreview). Neurology 56:1133-1142,2001

rn TABLE136-10. Sample Schema for Initial Approach to Dementia Differential Diagnosis D

l

m

~G~ ~ A~R Ac~ ~ E I I I ~ C S

Histoy

Examination and Diagnostics

Syndrome

Presentation within weeks or months of symptom onset Motor abnormalities developing with cognitive impairment Alterations in judgment and social behavior Prominent anterograde amnesia of gradual onset Vascular disease

Seizures, headaches, unexplained motor abnormalities Extrapyramidal signs

Rapidly progressive dementia

Executive deficit exceeds anterograde amnesia Relative absence of extracognitive signs

Dementia associated with extrapyramidal features Frontotemporal dementia Alzheimer's disease

Focal lesions on imaging: infarcts

Vascular dementia

862 W TABLE 136-11.

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w Behavioral Neurology

AAN Practice Parameters for Using

Diagnostic Criteria Sets for Dementia Dementia Tvpe

Diamostic Criteria Set

Practice Parameter

General Alzheimer‘s disease

DSM-IIIR and DSM-IV NINCDS-ADRDA for probable AD DSM-IIIR for DAT Hachinski Ischemic Index Consortium for DLB

Routine guideline Routine guideline

Vascular dementia

Optional

Optional Dementia with Lewy bodies (DLB) Frontotemporal deConsensus diagnostic Optional criteria mentia Rapidly progressive Clinical criteria for O D Guideline Abbreviations: AD, Alzheimer‘s disease; UD, Creutzfeldt-Jakobdisease; DAT, dementia Alzheimer type; DSM, Diagnosticand Statistical Manual of Mental Disorders; NINCDS-ADRDA, National Institute of Neurologic, Communicative Disorders and Stroke-AD and Related Disorders Association. Adapted from Knopman DS, DeKosky ST, Cummings JL et al: Practice parameter: diagnoses of dementia (an evidence-based review). Neurology 56:1143-1153,2001

Consensus Criteria and Practice Guidelines Specific individual diagnostic criteria sets have been formulated for most of the major categories of dementia to facilitate diagnostic standardization. How reliably these criteria sets are able to establish a neuropathologically correct diagnosis is addressed in detail for each dementia subtype’s respective section in this volume. In general, criteria of probable AD have good sensitivity for neuropathologic AD but less optimal specificity. Diagnostic criteria for vascular dementia (VAD), dementia with Lewy bodies (DLB), and fronto-temporal lobar dementia (FTLD) do not as neatly correspond to neuropathologic phenotypes; although there are strong clinical-pathologic relationships for these disorders in the majority of patients, many patients present with atypical or nonspecific symptom constellations. The most widely used general diagnostic criteria for dementia are based on definitions contained in the National Institute of Neurologic, Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDS-ADRDA)Work Group and the DSM-IV. The DSM-IIIR definition of dementia was demonstrated to have good to very good reliability; the closely related NINCDS-ADRDA and DSM-IV definitions of dementia have not as yet been subjected to assessment reliability. The AAN issued a revised practice parameter for the diagnosis of dementia in May 2001; recommendations regarding use of diagnostic criteria sets are summarized in Table 136-11.

Diagnostic Workup Patient History. In general, most patients with dementia do not refer themselves. Relatives or associates usually note onset first. Referrals can often occur in crisis settings (e.g., on Monday mornings after a family reunion or Friday afternoons when a family is seeking a weekend respite). Table 136-12 covers the major areas of potential impairment that should be reviewed with a reliable informant (relative or close friend) in a dementia assessment. Detecting dementia in its early stages can be difficult. Routine activities may be less taxing than coping with change; therefore, disruption of ADLs may not be as apparent. The uninformed family can accept “senility” as a normal aging pattern. Highly functioning patients may be able to mask signs of dementia for a protracted time. Most mental status examinations have a ceiling

effect. Results within normal range may still reflect great decline compared with the person’s superior baseline talents. Preexisting asymptomatic lesions in the limbic and association cortex can become symptomatic with normal aging. A detailed patient history can help narrow the differential diagnosis (Table 136-13). Because cognitive impairment must be measured against that person’s baseline, his or her highest degree of formal education, life achievements, and premorbid personality traits should be established first. The family is often but not always a more reliable historian than the patient. Family members may disagree as to time of onset, initial deficits, and sequence of events. Some tend to

H TABLE 136-12.

Dementia Symptoms in Newly Diagnosed (Mild) Patients

Impaired orientation to time, place, person, or situation Impaired recent memory Asking the same question several times over a 5- to 10-minute period Forgetting recent events within a few hours or days Forgetting recent conversations Misplacing items repeatedly Forgetting names of familiar friends or family members Problems with finding words, loss of conversational skills Impaired judgment Loss of interest or inability to perform hobbies or chores, including Use of telephone Managing finances (e.g., checkbook, taxes, bills) Shopping Meal preparation Housekeeping Driving (having accidents, getting lost) Occupational activities Alterations in mood or behavior, such as Subtle changes in interpersonal relationships New-onset anxiety New-onset depression Agitation in the form of paranoia, irritability, or delusional or illogical thinking

TABLE 136-13. Patient History Survey Highest degree of formal education, life achievements, baseline personality traits Impact of decline on activities of daily living Work performance Financial accountability Walking, driving Grocery shopping Household chores Repetition of conversations Misplacement of personal belongings When did cognitive difficulties begin? What was the initial feature? Were the changes abrupt or insidious in onset? Did they resolve, persist without change, or worsen over time? In what sequence were deficits noted? Changes in self-care, personality, behavior Altered language, including word-finding difficulties, paraphasias, diminished fluency, comprehension, or writing Ataxia, incontinence, seizures Underlying illnesses, current medications History of poor nutrition, head trauma, cardiac disease, strokes, atherosclerotic risk factors, subarachnoid hemorrhage, meningitis Exposure to alcohol, illicit drugs, industrial toxins, human immunodeficiency virus, Lyme, syphilis Family history of dementia (e.g., Alzheimer‘s, Pick‘s, Huntington’s, Parkinson’s diseases; spinocerebellar degenerations; Tay-Sachs disease? Confirmed by laboratory tests or brain biopsy? Past or present depression in the patient or patient‘s family

Chapter 136 H Evaluation of Patients with Dementia

863

TABU 156-14. Distinguishing Features of Major Dementia Origins Feature

History

Association

Homosexuality IV drug use Hemophilia Blood transfusion

Human immunodeficiency virus dementia

Family history Headache Vital signs

General examination Cranial nerves

Hypothermia Hypertension Hypotension Bradycardia Meningismus Jaundice Kayser-Reischer rings Papilledema Argyll Robertson pupils Ophthalmoplegia Pseudobulbar palsy

Motor

Tremor Asterixis Myoclonus Rigidity

Chorea Other

Gait apraxia Polyneuropathywith hyporeflexia

use calendar events to date onset, but subtle decline preceding these events often can be elicited. After further reflection, usually during follow-up examination, a more accurate history may be forthcoming. A detailed travel, substance abuse, and sexual history is essential to identify specific pathologic risk factors. Past history of depression in the patient or family suggests a need for further inquiries regarding the possibility of a current mood disorder. Given their genetic implications, a family history of Alzheimer’s, Huntington’s, Parkinson’s disease, or spinocerebellar degeneration obviously influences investigation. Pattern recognition in the differential diagnosis of dementia is essential. For example, a patient with insidious onset of progressive amnesia over months to years suggests the possibility of AD. Language involvement in AD is common, but language impairments are unusual in normal pressure hydrocephalus. Subacute onset with rapid deterioration accompanied by myoclonus, pyramidal, and extrapyramidal signs is more typical of Creutzfeldt-Jakob disease (CJD). A previously fastidious person who over months to years suffers decline in personal hygiene, comportment, and planning with relative sparing of recent memory and language is more likely to have Pick‘s disease. Table 136-14 outlines clinical features helpful in organizing an effective diagnostic approach to dementia. Physical Examination. A thorough physical assessment, including a comprehensive neurologic examination, must be performed on all patients undergoing dementia evaluation.

Huntington’s disease Wilson‘s disease Brain tumor Chronic subdural hematoma Hypothyroidism Multi-infarct dementia Hypothyroidism Hypothyroidism Chronic meningitis Acquired hepatocerebral degeneration Wilson’s disease Brain tumor Chronic subdural hematoma Neurosyphilis Progressive supranuclear palsy Multi-infarct dementia Progressive supranuclear palsy Parkinson’s disease Wilson’s disease AIDS dementia complex Acquired hepatocerebral degeneration Creutzfeldt-Jakob disease AIDS dementia complex Acquired hepatocerebral degeneration Creutzfeldt-Jakob disease Progressive supranuclear palsy Wilson‘s disease Huntington’s disease Wilson’s disease Normal pressure hydrocephalus Neurosyphilis B,, deficiency AIDS dementia complex

Associated Neurologic Deficits. Recognition of associated elementary neurologic deficits can guide dementia differential diagnosis and subsequent investigations (Table 136-15). Impaired visual or auditory acuity can be misinterpreted by patients and their families as cognitive decline. On occasion, it is rewarding to witness the dramatic effects of improved sight and hearing. Normal elementary neurologic examination results in the context of dementia favor Alzheimer’s, Pick‘s, or nonspecific neurodegenerative diseases. Pseudobulbar affect suggests multiple deep lacunae or motor neuron disease, such as amyotrophic lateral sclerosis. Gait abnormalities suggest Parkinson’s disease, frontal network dysfunction, or normal pressure hydrocephalus. Visual field cuts, hemiparesis, and hemineglect are most consistent with cortical infarcts, but adult polyglucosan body disease can present this way as well. Supranuclear gaze paresis suggests progressive supranuclear palsy. Fasciculations, distal atrophy, and bulbar signs in the context of a frontal network dementia point to motor neuron disease. Choreiform movements are not seen in every patient with Huntington’s disease, particularly in those with onset after age 60. Cerebellar signs in the context of dementia constitute a different set of considerations. Mental Status and Neurocognitive Examination. The mental status examination helps corroborate a history of cognitive impairment or establish impairment in the absence of a good history in most forms of dementia. The mental status examination helps to determine whether it is the level or the content of consciousness that is impaired and whether cognitive dysfunction

864

Behavioral Neurology and Epilepsy W

Behavioral Neurology

rn TABLE136-15. Dementias Associated with Noncognitive Neurologic Deficits Abnonnali

Associations

Pseudobulbar affect

Bilateral strokes Demyelinating diseases Motor neuron diseases Parkinson's disease Vascular dementias Normal pressure hydrocephalus Neurosyphilis Progressive supranuclear palsy Tay-Sachs disease Huntington's disease Parkinson's disease Creutzfeldt-Jakob disease Wilson's disease Striatonigral degeneration Mass lesions Cortical strokes Brain abscess Adult polyglucosan body disease Progressive supranuclear palsy Wernicke-Korsakoff encephalopathy Stroke Progressive supranuclear palsy Multiple sclerosis Motor neuron disease Parkinson's disease Paraneoplasia Stroke Motor neuron disease (e.g., amyotrophic lateral sclerosis) Parkinson's disease with dementia Tay-Sachs disease Hallemorden-Spatz disease Parkinson's disease Progressive supranuclear palsy Huntington's disease Wilson's disease Striatonigral degeneration Metachromatic leukodystrophy Vitamin B,, folate deficiencies Thyroid disease Neoplasia Paraneoplasia Creutzfeldt-Jakob disease Paraneoplasia Spinocerebellar degeneration Tay-Sachs disease Gerstmann-Strausslerdisease Hallemorden-Soatz disease

Gait and station

Adventitial movements

Visual fields

Extraocular movements Dysarthria

Pyramidal and motor system

Extrapyramidal

Sensory

Cerebellar

utility for determining dementia origin are summarized in Table 136-16.

Because up to 20% of patients referred for evaluation of intellectual deterioration may have causes that are reversible (e.g., B,, deficiency) or carry potential for preventing of further deterioration (e.g., secondary prevention of vascular dementia progression with antihypertensives or aspirin), the need to avoid missing such diagnoses is imperative. Therefore, selecting which diagnostic investigations to perform becomes the challenge of balancing adequate investigation of dementia cause while minimizing unnecessary testing burden and cost to the patient. A variety of guidelines have been formulated to inform this process; Table 136-17 summarizes the most recent AAN practice parameter recommendations. Psychometrics and Neuropsychological Testing. Formal neuropsychological testing, with far greater diagnostic sophistication and standardized age-related norms, is significantly more precise and quantitatively informative than routine cognitive evaluation procedures (eg., mini-mental status examination). Specific tests of attentional matrix, frontal network functions, memory, language, and visuospatial abilities provide invaluable diagnostic profiles. Such testing also helps clarify possible contributions of normal aging, encephalopathy, and psychiatric disease.

TABLE 136-16. Investigations with Potential Utility in Dementia Diagnosis Blood

Cerebrospinal fluid

is global or circumscribed. To determine the scope of the cognitive dysfunction, various spheres of cognition are tested in turn. These include memory, language, parietal lobe functions (pictorial construction, right-left discrimination, localization of objects in space), and frontal lobe executive or diffuse cerebral cortical functions (judgment, abstraction, thought content, and the ability to perform previously learned acts). Essential components of a proper mental status examination are reviewed in detail in Chapter 135. laboratory Investigations. Dementia is a clinical syndrome principally diagnosed by clinical examination. In determining cause, and most importantly reversible cause, certain diagnostic tests are necessary. Given the many potential dementia origins, many tests are conceivably applicable, and an array of biochemical, hematologic, microbiologic, radiologic, electrophysiologic, and nuclear medicine investigations are available for investigating the cause of a dementia. Laboratory investigations with potential

Urine Biopsy Ophthalmologic screening Electrophysiologic

Radiologic

White blood cell count, hemoglobin and h e matocrit, platelets, differential, mean corpuscular volume Electrolytes Blood urea nitrogen, creatinine, liver function tests Prothrombin time, partial thromboplastin time, fibrinogen Erythrocyte sedimentation rate, antinuclear antibody B,2, folate Ceruloplasmin Lyme, VDRL, human immunodeficiency virus Serum drug levels Heavy metal screen Homocysteine, methylmalonic acid ApoE2.3.4 alleles AP42 peptide, Tau protein, PS-1 HD trinucleotide repeat Protein, cytology, VDRL, Lyme, AFB/viral/ fungal us Protein 14-3-3 Cysticercosis Ab AP42 peptide Tau protein UA

Neme Brain Slit lamp (e.g., Kayser-fleischer rings), pigmentary changes Electrocardiogram Electroencephalogram Muscle Small bowel CXR

Structural imaging magnetic resonance imaging gadolinium Functional imaging (single photon emission computed tomography, positron emission tomography) Multiple inventories

*

Neuropsychological testinn Abbreviations: VDRL Venereal Disease Research Laboratories test; AB, antibody; AFB, acid fast bacteria; CXR. chest x-ray; CXS. cultures; PS- 1, presenilin-1; U& urinalysis. ~~

Chapter 136

Evaluation of Patients with Dementia

865

TMIE 136-17. Summary AAN Practice Guidelines for Diagnostic Evaluation of Dementia Diagnostic Investigation

Practice Parameter

Blood

B,, assessment should be included in routine assessment.

Metabolic Endocrine Infectious

CSF

Structural neuroimaging (0,MRI) Linear or volumetric Cr or MRI Functional neuroimaging

Single photon emission computed tomography Positron emission tomography

Genetic testing

Hypothyroidism should be included in routine assessment. Unless patient has a specific risk factor or evidence of prior syphilitic infection, screening in patients with dementia is not justified. There are no CSF biomarkers recommended for routine use in diagnosing AD. Protein 14-3-3 is recommended for confirming or rejecting the diagnosis of UD. Routine use in all patients. Not recommended for routine use. Not recommended for routine use (absence of demonstrated superiority to clinical criieria). Not recommended for routine use. Apolipoprotein E not recommended for routine use in suspected AD. Not recommended for patients with suspected DLB or UD. Testing for tau mutations is not recommended for routine evaluation in oatients with m D .

Abbreviations: AD, Alzheimer‘s disease; UD, Creutzfeldt-Jakob disease; CSF, cerebrospinal fluid; 0, computed tomography; DLB, dementia with Lewy bodies; m D , frontotemporal lobar dementia; MRI, magnetic resonance imaging. Adapted from Knopman DS, DeKosky ST, Cummings JL et al: Practice parameter: diagnoses of dementia (an evidencebased review). Neurology 56:1143-1153,2001

Among degenerative dementias, three patient groups can be grossly identified via principal deficits found on neuropsychological profile: those with amnesia; aphasia, agnosia, or apraxia; and motivation and comportment. The majority of patients with primary amnesia will be found, on postmortem examination, t o have had AD. The second group can demonstrate a mixture of disorders, with a preponderance of Alzheimer’s and vascular elements. Pathology in the third group is more heterogeneous but often includes frontotemporal dementias. Structural Neuroimaging STANDARDSTRU~RAL.Neuroimaging can be an essential aid in

diagnosing structural causes of cognitive dysfunction and demonstrating key findings supportive of a specific dementia origin. One study found the possibility of detecting a clinically significant but covert (i.e., no noncognitive signs or symptoms indicating lesion’s presence) structural lesion (e.g., neoplasm, subdural hematoma [SDH], normal pressure hydrocephalus [NPH]) to be approximately 5%. Table 136-18 summarizes some structural neuroradiographic findings potentially associated with cognitive dysfunction. Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans can be extraordinarily powerful diagnostic aids.

They are easy, safe tests that can detect most intra-axial and extra-axial lesions. Recent AAN practice guidelines include structural neuroimaging with a noncontrast CT or MRI scan as a routine component of the initial evaluation of patients with dementia. CT generally provides adequate data for evaluating atrophy, ventricular system integrity, most hemorrhages (epidural, subdural, subarachnoid, intraparenchymal), and mass effects (e.g., of tumors, abscesses). Consequently, CT usually is adequate to exclude most structurally evident causes of cognitive dysfunction. Although CT usually yields adequate screening data, MRI’s capacity for multiplanar views and multiple imaging sequence modalities provides vastly more information about potential vascular, neoplastic, inflammatory, and infectious causes of cognitive impairment. Sagittal MRI is especially useful for demonstrating the selective lobar atrophies of certain dementia origins (e.g., the focal atrophy attendant to frontotemporal dementias, e.g., knifelike atrophy of the anterior third of the superior temporal gyrus in Pick‘s disease). And only gadoliniumenhanced MRI is truly adequate for ruling out certain serious and potentially treatable conditions (e.g., leptomeningeal disease). Despite promising utility of structural neuroimaging in the assessment of dementia, problems with interpretation are

a TMLE 156-18. Potential Findings on Structural Neuroimaging Associated with Cognitive Dysfunction Svndrome

lmaninn Modalii

Examde NeuroradionraDhic Finding

Subdural hematoma

cr

Normal pressure hydrocephalus Tumor

MRI T2 0,MRI Cr/MRI + contrast

Convexity hypodensity Convexity signal intensity Communicating hydrocephalus Variably enhancing mass lesion, single or multiple White matter signal intensities Lacunar lesions Cortical hypodensity Cortical signal intensity Cortical hyperdensity Cortical signal hypointensity Selective frontotemporal atrophy f Temporal or generalized atrophy Bilateral caudate atrophy Cystic putamenal lesions

Vascular dementia

Small vessel disease Large vessel disease

MRI T2, FLAIR

Subcortical white matter Subcortical gray matter Ischemic

Cr,MRI Cr

Hemorrhagic

Cr

MRI FlAlR MRI GE Frontotemporal lobar dementia Alzheimer‘s disease Huntington’s disease Wilson’s disease Abbreviations: CT,computed tomography; MRI, magnetic resonance imaging.

Cr,MRI Cr,MRI Cr,MRI CT, MRI

866

Behavioral Neurology and Epilepsy

Behavioral Neurology

common. Some patients with dementia can have completely normal structural scans; sulcal widening and ventricular dilation are found in many cognitively intact older adults; some nondemented patients can have multiple lesions without cognitive impact; degree of atrophy is not a reliable predictor of dementia severity; hippocampal atrophy is nonspecific (has also been reported in patients with hypoxia; traumatic brain injury; alcoholism; schizophrenia; and 30% of asymptomatic older adults); and T2 pulse sequence abnormalities on MRI are extremely nonspecific and bear an unclear relationship to type and severity of dementia. Therefore, as with all other tests, structural neuroimaging data must be interpreted within clinical context, bearing in mind these caveats. QUANTITATIVE STRUCTURAL. The hippocampal formation, parahippocampal gyrus, and temporal lobe in general are among brain regions most consistently and crucially implicated in neurodegenerative dementias, especially AD, even at an early stage. Indeed, presymptomatic hippocampal atrophy on MRI has been demonstrated in asymptomatic individuals at risk of autosomal dominant AD. In clinically diagnosed AD of moderate severity, MRI-based volumetric measurements show a reduction of up to 40% in the size of the hippocampus, amygdala, anterior temporal lobe and thalamus. But can structural neuroimaging-based measurements usefully discriminate patients with probable AD from normal older adults? One prospective study of quantitative CT using autopsyconfirmed diagnostic standards found that a medial temporal lobe width falling below the 5th percentile was 95% sensitive but only 40% specific for AD. Several studies without neuropathologic confirmation have reported the utility of medial temporal lobe atrophy, particularly hippocampal or entorhinal atrophy, for the dinical diagnosis of AD. In differentiating clinically diagnosed AD (NINCDS-ADRDA criteria) from normal older adults, the sensitivities of various medial temporal atrophy measures on CT or MRI range from 77% to 92%, with specificities ranging from 49% to 95%. Measurement of the hippocampal formation is arguably more sensitive than temporal lobe measurements in separating controls from people with AD. Neuropsychological assessments of recent memory are highly correlated with visually rated hippocampal atrophy, and hippocampal volume loss is strongly associated with neurofibrillary pathology in AD. Determination of the rate of change of hippocampal atrophy may be of diagnostic value but is unlikely to be of use in clinical practice. Given the proximity of temporal structures to skull bone, artifact hampers CT assessment; MRI provides better visualization of the medial temporal lobes, including the hippocampus. Furthermore, MRI capacity to provide coronal images, in a plane perpendicular to the long axis of the hippocampus, reduces artifact secondary to volume averaging. Normative data for volumetric measurements of the hippocampus and parahippocampal structures are available for comparison. Although automated volumetric techniques are more reliable, they are not widely available. Despite these promising findings, there are no studies determining the added value of hippocampal, entorhinal, or temporal volume measurement once a clinical diagnosis of dementia is made. Combining volumetric data with other potentially informative markers (e.g., apolipoprotein E [APO-E] genotyping, functional neuroimaging) may improve diagnostic accuracy. For clinical purposes, volumetric measurements are helpful but not necessary; visual inspection usually is sufficient.

Functional Neuroimaging Single Photon Emission Computed Tomography (SPEq.

Because perfusion abnormalities in certain dementias often reflect pathologic changes underlying cognitive decline, SPECT has been widely used to investigate dementia. The classic appearance of AD on SPECT is bilateral temporoparietal hypoperfusion. Two SPECT studies with autopsyconfirmed diagnoses examined the value of SPECT in the differential diagnosis of dementia. For differentiating AD from non-AD dementia, hypoperfusion in the temporoparietal lobe was reported to be 86% to 95% sensitive and 42% to 73% specific. Some studies combining assessment of hippocampal atrophy on structural neuroimaging with cerebral blood flow studies on SPECT have yielded sensitivity and specificity rates exceeding 90% in discriminating patients with AD from normal controls. Although encouraging, these figures are not consistently better than those obtained by diagnosis with established clinical criteria; the sensitivity of SPECT alone remains lower than that of clinical diagnosis. Although sensitivity increases as dementia severity worsens, pretest probability of AD also rises. The added value of SPECT is greatest for a positive test among patients with mild dementia in whom there was substantial doubt about the diagnosis of AD. Because frontal hypoperfusion with relative sparing of posterior cortex is characteristic of frontal lobe dementias, SPECT can sometimes be helpful in distinguishing frontotemporal lobar dementias (FTLD) from other dementias. Although temporoparietal hypoperfusion on SPECT is common to both AD and dementia with Lewy bodies (DLB), occipital hypoperfusion is more common in DLB. However, this finding remains insufficiently specific to be relied on for diagnosis. In vascular dementia, SPECT often reveals a scattered or patchy pattern, reflecting the variable localization of vascular-based insults. Despite the promising findings reviewed here, SPECT is generally not recommended in the routine diagnostic evaluation of cognitive impairment. Positron Emission Tomography (Pn). Like SPECT, PET is able to demonstrate functional abnormalities correlating with structural changes. However, PET has the added potential diagnostic value of quantifying neurotransmitter (e.g., cholinergic) and other neurochemical changes. For example, a direct comparison of PET and SPECT in their ability to differentiate AD from vascular dementia (VA) revealed higher diagnostic accuracy for PET regardless of dementia severity. PET scans in AD can demonstrate a characteristic but nonspecific bilateral temporoparietal hypometabolism. A sensitivity of 90% and specificity of 80% are reported when a composite metabolic ratio of affected to unaffected areas is used. In a study of dementia cases undergoing PET and later autopsy confirmation, visual interpretation of PET scans yielded a sensitivity of 93% and a specificity of 63%. FDG-PET may be superior to MRI measures of hippocampal atrophy because cerebral glucose metabolism changes antedate onset of memory decline but MRI hippocampal changes do not. PET may be helpful in distinguishing FTD from AD. Many patients with FTD show hypoperfusion of anterior cerebral cortex with relative sparing of posterior cortex. Like SPECT, despite the potential for significant diagnostic power, the decision to perform a PET scan on a patient being evaluated for cognitive decline must be made on a case-by-case basis. PET scanning appears promising for use as an adjunct

Chapter 136

to clinical diagnosis, but further prospective studies with PET are needed to establish its diagnostic value beyond a competent clinical diagnosis. Therefore, PET is generally not recommended in the routine diagnostic evaluation of cognitive impairment. Serum Genetic Markers. We briefly consider representative dementia subclasses individually. AD. In a large neuropathologically confirmed cohort of patients with dementia, apoliproprotein E4 assay slightly increased the positive predictive value of an AD diagnosis. Relative to the neuropathologic diagnosis of AD, the sensitivity of clinical diagnosis of AD was 92%, whereas sensitivity of having at least one APO-E4 allele was only 65%. In patients with clinical diagnosis of AD, the addition of APO-E testing increased the positive predictive value of a clinical diagnosis of AD by approximately 4% (from 90% to 94%) if an APO-E4 allele was present. In patients with a clinical diagnosis of non-AD, the absence of an APO-E4 allele increased the negative predictive value by 8% (from 64% to 72%). FTLD. A high prevalence of tau mutations was found in a Dutch population (17.8% of all FTLD cases and 40.3% of all familial FTLD cases). However, the diagnostic and prognostic yield from screening of sporadic cases of suspected FTLD for known tau gene mutations is likely to be very low and not routinely recommended. UD. Although familial CJD has been linked to a number of different mutations in the prion gene, and a polymorphism at one codon has been shown to be more common in sporadic CJD, there is no evidence that genetic analysis of the prion gene is of value in diagnosing suspected CJD. In sum, no serum genetic markers are recommended for the routine differential diagnosis of dementia. However, as etiologic mechanisms of dementia are further elucidated, genetic marker assays represent a promising diagnostic strategy. Cerebrospinal Fluid (CSF) Analysis. Although lumbar puncture generally is not indicated in the routine evaluation of clinically typical cognitive impairment, CSF analysis can be an important part of the investigation of atypical dementing processes warranting investigation for evidence of infection, inflammation, demyelination, neoplasia, or paraneoplastic disease, as well as searching for certain markers of neurodegenerative processes. Sensitivityof CSF P-amyloid (1-42) level as a diagnostic marker for AD is high. Reduced P-amyloid (1-42) in CSF of patients with AD compared with normal older adults has been repeatedly observed in multiple studies. In post hoc analyses, moderate sensitivities (78% to 92%) and specificities (81% to 83%) have been achieved in distinguishing patients with AD from normal older adults. Therefore, CSF P-amyloid (1-42) analyses may be of value in the clinical diagnosis of AD, especially in the early course of the disease, when drug therapy may have the greatest potential for being effective but clinical diagnosis is difficult. Unfortunately, it remains unclear whether CSF P-amyloid (1-42) retains diagnostic usefulness in patients with very mild AD. CSF tau is significantly elevated in AD, including early in the AD disease process. Furthermore, this elevation is stable over time, with a low intraindividual variation on repeated sampling. CSF tau can have sufficient sensitivity and specificity to differentiate AD from normal aging and depression, as demonstrated in a large community-based series of consecutive patients with AD. In another study, CSF tau distinguished AD from normal controls with 80% to 97% sensitivity and 86% to 95% specificity. However, CSF tau is found in patients with other neurodegenerative diseases

Evaluation of Patients with Dementia

867

and even nondegenerative neurologic conditions (e.g., stroke). Still, CSF tau assay may be useful in supporting an AD diagnosis early in the disease process when symptoms are vague and clinical diagnosis is difficult. Nevertheless, although sensitivity and specificity of CSF tau measurements appear good, there are no studies that determine the benefits of CSF tau over a precise clinical diagnosis. In contrast to patients with AD who demonstrate elevated CSF tau, patients with FTLD show a significant decrease in CSF tau concentration. CSF analysis for paraneoplastic antibodies in identifymg paraneoplastic limbic encephalitis can be invaluable in attempting to diagnose such a protean and elusive pathologic process. CSF analysis for protein 14-3-3, along with neuroimaging, has revolutionized the diagnosis of CJD. CSF protein 14-3-3 immunoassay has a reported sensitivity of up to 96% and specificity up to 99% for CJD diagnosis among dementia patients who have not had a stroke within one month of testing. Some studies have demonstrated CSF 14-3-3 as superior to electroencephalography (EEG) or MRI in identifymg CJD. However, other neurologic conditions (e.g., stroke, viral encephalitis, paraneoplastic disorders) can yield false positive results, and a negative 14-3-3 immunoassay does not absolutely rule out CJD. Electroencephalogram (EEG). Although utility of routine EEG in the differential diagnosis of dementia is questionable, EEG remains an inexpensive and noninvasive probe of brain function and can help support a specific dementia diagnosis. For example, EEG remains helpful in the diagnosis of CJD, and a correlation has been found between slow-frequency EEG band power and glucose metabolism in vascular dementia, correlating with specific regional metabolic differences. Furthermore, studies using quantitative EEG (qEEG) to predict timing of major clinical events (e.g., loss of ADLs, incontinence, death) have suggested potentially useful associations between voltage change lateralities and disease progression. As previously described, differentiating delirium from dementia is a primary task in the initial assessment of cognitive change. Although the distinction usually is clear-cut clinically, EEG can be useful in detecting a subtle delirium. Delirium characteristics on EEG include slowing or dropout of posterior dominant rhythm, generalized theta or delta slow-wave activity, poor background rhythm organization, and loss of EEG reactivity to eye opening and closing. These are paralleled by qEEG findings of increased absolute and relative slow-wave (theta and delta) power, reduced ratio of fast-to-slow band power, reduced mean frequency, and reduced occipital peak frequency. In alcohol and sedative withdrawal, EEG findings can include voltage attenuation and beta activity prominence. However, despite these fairly robust associations, specificity of EEG and qEEG findings in delirium relative to EEG changes in normal aging and dementia remains suboptimal. Brain Biopsy. Brain biopsy usually is the diagnostic investigation of last resort. The procedure carries several potential drawbacks: Specific histologic diagnosis is not always obtainable, false-positive and false-negative results occur, multiple potential complications (e.g., seizures) can subsequently develop, and anesthesia can worsen the patient’s mental state. However, in certain circumstances, when other diagnostic efforts fail, biopsy can be unavoidable and potentially life-saving (e.g., defining neoplastic disease). Sometimes, alternative disease-affected tissue targets can be considered (e.g., small bowel biopsy may obviate brain biopsy in the diagnosis of Whipple’s disease).

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Behavioral Neurology

THE IMPORTANCE OF ACCURATE DIAGNOSIS TO CLINICAL MANAGEMENT Although careful diagnosis is always the foundation of highquality clinical management, thorough and accurate diagnosis is imperative for a syndrome as complicated, nuanced, and protean as dementia. This is further accentuated by the frequent need to engineer a multidisciplinary management team, provide family education and support, and prognosticate with reasonable precision. Functional characterization of dementia stages can be clinically helpful. Patients with mild dementias are capable of many ADLs. Those with moderate involvement usually need some level of direct daily assistance. Patients with advanced disease need nearly total assistance. Serial neurologic and neuropsychological monitoring after initial evaluation often clarify disease nature and course. Sudden deterioration after gradual decline suggests “beclouded dementia,” a dementia worsened by superimposed toxic, metabolic, or systemic insults. Autopsy verification establishes definitive diagnosis. Besides providing a basis for further understanding the pathophysiologies of dementias, the finality of diagnosis can help families achieve closure, move on, and understand possible genetic implications. We are entering a remarkable new era in the diagnosis and management of dementia. Dementias regarded as hopeless in the recent past are approached more optimistically. Emerging neurobiologic developments such as new neurotransmitter modulators, pathogenic enzyme inhibitors, genetic recombinant replacement therapies, and the decision-making empowerment bestowed by genetic counseling methods now mandate meticulous attention to dementia diagnosis. The assessment of dementia is no longer a sterile, hopeless intellectual exercise. It now takes a diligent effort that offers increasing hope to many patients and their families.

SUGGESTED READINGS

Desmond DW, Moroney JT, Sano M et al: Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke (33)922542262,2002

Freter S, Bergman H, Gold S et ak Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort. CMAJ 159(6):657-662, 1998

Gifford DR, Holloway RG, Vickrey B G Systematic review of clinical prediction rules for neuroimaging in the evaluation of dementia. Arch Intern Med 160( 18):2855-2862,2000 Goldman W, Price JL, Storandt M et al: Absence of cognitive impairment or decline in preclinical Alzheimer’s disease. Neurology 56( 1):361-367, 200 1

Ihl R, Brinkmeyer J: Differentialdiagnosis of aging, dementia of the Alzheimer type, and depression with EEG-segmentation. Dement Geriatr Cogn Disord Switzerland 10(2):6449, 1999 Knopman DS, DeKosky ST, Cummings JL et al: Practice parameter: diagnosis of dementia (an evidence-based review). Neurology 5 6 1143-1153,2001

Lyketsos CG, Lupez 0, Jones B et ak Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288( 12):1475-1483,2002 Patterson CJ, Gauthier S, Bergman H et al: The recognition, assessment, and management of dementing disorders: conclusions from the Canadian Consensus Conference on Dementia. CMAJ 160(S12):S1-15, 1999

Petersen RC, Stevens JC, Ganguli M et ak Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology 56:1133-1142, 2001 Quinn J, Kaye J: The neurology of aging. Neurologist 7(2):98-112, 2001

Scheltens P Early diagnosis of dementia. J Neurol 246(1):16-20, 1999

Steffens DC, Morgenlander J C Initial evaluation of suspected dementia: asking the right questions. Postgrad Med 106(5):72-76, 79-80,82-83, 1999

Van Crevel H, van Goo1 WA, Walstra GJM: Early diagnosis of dementia: which tests are indicated? What are their costs? J Neurol 24673-78, 1999

Zekry D, Hauw JJ, Gold G Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr SOC50(8):1431-1438, 2002

Breteler MM, Ott A, Hofman A The new epidemic: frequency of dementia in the Rotterdam study. Haemostasis 28(3-4):117-123, 1998

137 Alzheimer’s Disease: Diagnosis, Pathophysiology,

and Treatment Kirk R. Daffner MAGNITUDE OF THE PROBLEM Alzheimer’s disease (AD) is the major cause of dementia in the United States and constitutes a significant and growing health care problem. The prevalence of AD has risen steadily as the average age of the population has increased. It has been estimated that up to 10% of Americans age 65 and older suffer from the disease, and for the population age 85 and older estimates of the prevalence have been as high as 47%. As many as 4 million Americans may suffer from AD, at a cost of more than $100 billion per year for

their care. Based on current estimates, if no effective preventive measures are developed, in 50 years there will be as manv as 14 million patients witi AD in the‘ United States alone.

CLINICAL PROFILE Neurodegenerative diseases such as AD must be understood as having a clinical and pathologic dimension. It is extremely rare to have access to brain tissue to make a pathologic diagnosis in living patients. The approach adopted has been to identify clinical

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Behavioral Neurologyand Epilepsy

Behavioral Neurology

THE IMPORTANCE OF ACCURATE DIAGNOSIS TO CLINICAL MANAGEMENT Although careful diagnosis is always the foundation of highquality clinical management, thorough and accurate diagnosis is imperative for a syndrome as complicated, nuanced, and protean as dementia. This is further accentuated by the frequent need to engineer a multidisciplinary management team, provide family education and support, and prognosticate with reasonable precision. Functional characterization of dementia stages can be clinically helpful. Patients with mild dementias are capable of many ADLs. Those with moderate involvement usually need some level of direct daily assistance. Patients with advanced disease need nearly total assistance. Serial neurologic and neuropsychological monitoring after initial evaluation often clarify disease nature and course. Sudden deterioration after gradual decline suggests “beclouded dementia,” a dementia worsened by superimposed toxic, metabolic, or systemic insults. Autopsy verification establishes definitive diagnosis. Besides providing a basis for further understanding the pathophysiologies of dementias, the finality of diagnosis can help families achieve closure, move on, and understand possible genetic implications. We are entering a remarkable new era in the diagnosis and management of dementia. Dementias regarded as hopeless in the recent past are approached more optimistically. Emerging neurobiologic developments such as new neurotransmitter modulators, pathogenic enzyme inhibitors, genetic recombinant replacement therapies, and the decision-making empowerment bestowed by genetic counseling methods now mandate meticulous attention to dementia diagnosis. The assessment of dementia is no longer a sterile, hopeless intellectual exercise. It now takes a diligent effort that offers increasing hope to many patients and their families.

SUGGESTED READINGS

Desmond DW, Moroney JT, Sano M et al: Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke (33)922542262,2002

Freter S, Bergman H, Gold S et ak Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort. CMAJ 159(6):657-662, 1998

Gifford DR, Holloway RG, Vickrey B G Systematic review of clinical prediction rules for neuroimaging in the evaluation of dementia. Arch Intern Med 160( 18):2855-2862,2000 Goldman W, Price JL, Storandt M et al: Absence of cognitive impairment or decline in preclinical Alzheimer’s disease. Neurology 56( 1):361-367, 200 1

Ihl R, Brinkmeyer J: Differentialdiagnosis of aging, dementia of the Alzheimer type, and depression with EEG-segmentation. Dement Geriatr Cogn Disord Switzerland 10(2):6449, 1999 Knopman DS, DeKosky ST, Cummings JL et al: Practice parameter: diagnosis of dementia (an evidence-based review). Neurology 5 6 1143-1153,2001

Lyketsos CG, Lupez 0, Jones B et ak Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288( 12):1475-1483,2002 Patterson CJ, Gauthier S, Bergman H et al: The recognition, assessment, and management of dementing disorders: conclusions from the Canadian Consensus Conference on Dementia. CMAJ 160(S12):S1-15, 1999

Petersen RC, Stevens JC, Ganguli M et ak Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology 56:1133-1142, 2001 Quinn J, Kaye J: The neurology of aging. Neurologist 7(2):98-112, 2001

Scheltens P Early diagnosis of dementia. J Neurol 246(1):16-20, 1999

Steffens DC, Morgenlander J C Initial evaluation of suspected dementia: asking the right questions. Postgrad Med 106(5):72-76, 79-80,82-83, 1999

Van Crevel H, van Goo1 WA, Walstra GJM: Early diagnosis of dementia: which tests are indicated? What are their costs? J Neurol 24673-78, 1999

Zekry D, Hauw JJ, Gold G Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr SOC50(8):1431-1438, 2002

Breteler MM, Ott A, Hofman A The new epidemic: frequency of dementia in the Rotterdam study. Haemostasis 28(3-4):117-123, 1998

137 Alzheimer’s Disease: Diagnosis, Pathophysiology,

and Treatment Kirk R. Daffner MAGNITUDE OF THE PROBLEM Alzheimer’s disease (AD) is the major cause of dementia in the United States and constitutes a significant and growing health care problem. The prevalence of AD has risen steadily as the average age of the population has increased. It has been estimated that up to 10% of Americans age 65 and older suffer from the disease, and for the population age 85 and older estimates of the prevalence have been as high as 47%. As many as 4 million Americans may suffer from AD, at a cost of more than $100 billion per year for

their care. Based on current estimates, if no effective preventive measures are developed, in 50 years there will be as manv as 14 million patients witi AD in the‘ United States alone.

CLINICAL PROFILE Neurodegenerative diseases such as AD must be understood as having a clinical and pathologic dimension. It is extremely rare to have access to brain tissue to make a pathologic diagnosis in living patients. The approach adopted has been to identify clinical

Chapter 137 W Alzheimer‘s Disease: Diagnosis, Pathophysiology, and Treatment

profiles that provide accurate estimates of the likelihood of underlying neuropathology. Patients with a clinical diagnosis of probable AD have a very high probability of having the plaques and tangles that define AD pathologically. Likewise, patients who have underlying Alzheimer’s pathology have the greatest risk of developing the clinical syndrome of probable AD. Probable AD presents clinically as an insidiously progressive illness in which memory decline is one of the salient features. Family members may note that the patient is increasinglyforgetful of appointments, names, and events, repeats the same stories or questions, and tends to misplace items. Early in the course of the disease, mental state testing tends to reveal preserved autobiographic information, variable recall of recent events, and subtle disorientation. Even in the mildest cases, acquisition of bits of information that exceed digit span is impaired. There is difficulty retrieving newly learned information even after short delays. Patients with such symptoms tend to perform better with recognition memory tasks. Over time, patients exhibit increasing problems with learning new information and even recognizing simple material. In addition to memory deficits, patients with probable AD also tend to exhibit disruptions in executive functions, language, and visual spatial abilities. Disturbance in complex attention (controlled information processing, response selectivity and inhibition, and divided attention) often is the first nonamnestic function to be affected. Studies have indicated that impairment of executive function is very strongly associated with the amount of care a patient needs, even after controlling for overall dementia severity. Language impairments are also extremely common. Patients tend to have naming difficulties and empty fluent speech, consistent with features of anornic, transcortical sensory, or Wernicke’s aphasia. The ability to generate lists of words based on semantic category (e.g., animals, grocery items) often is impaired. The addition of such a task to mental state tests has been shown to enhance diagnostic accuracy. Many patients exhibit abnormalities in visuospatial functioning, both the visuoconstructive (e.g., drawing cubes or intersecting pentagons) and visuoperceptual (e.g., matching the angles made by pairs of lines) aspects and are at risk of experiencing spatial disorientation. Table 137-1 summarizes clinical, imaging, biologic, and pathologic aspects of probable AD. Workup for a patient suspected of having Alzheimer’s disease should follow the guidelines reviewed in Chapter 136. A good history from a reliable informant about the patient’s baseline and changes in cognitive and behavioral status is invaluable. A detailed mental state examination, as reviewed in Chapter 135, is essential

TMLE 137-1. Probable Alzheimer‘s Disease: Summary Clinical Presentation

Pathophysiologic Information

Insidiously progressive decline in cognitive and functional status Major memory problems Disrupted executive functions, language, visuospatial functions Nonfocal neurologic examination

MRI/CT scans: generalized atrophy, loss of hippocampal volume SPECT: hypoperfusion in temporoparietal f frontal regions Genetics: chromosome 14.1.21 (autosomal dominant), chromosome 19 (APOE) Pathology: plaques and tangles most common Prominent distribution of pathology: limbic regions and association cortex

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for establishing a patient’s current level of cognitive functioning and for illuminating a profile of salient deficits. Most challenging is to identify patients who are in the very earliest stages of the illness, when many of their basic activities of daily living are not clearly disrupted. As much as possible, a person’s current abilities should be compared with his or her own premorbid baseline functioning and not only with reported conventional norms for a particular age. It is essential to follow such patients longitudinally to establish a clearly progressive course. Although there is disagreement about the cost-effectiveness of clinical neuroimaging in dementia workups, computed tomography (CT) or magnetic resonance imaging (MRI) can rule out lesions such as strokes or tumors that may account for or contribute to a patient’s cognitive decline. Scattered foci of increased T2 signal or even more definitive areas of infarction should not automatically yield a diagnosis of vascular dementia, especially in patients whose clinical profile points to a progressive amnestic dementia. Patients presumed to have a vascular dementia often are found to have coexistent Alzheimer’s pathology. Also of note, several studies have suggested that in patients with underlying AD pathology, even a few subcortical lacunar infarcts can markedly reduce their cognitive and functional status. NEWER DIAGNOSTIC APPROACHES There is strong evidence that the pathologic process of Alzheimer’s disease precedes the development of a clinical dementia by years to decades. As prospects have grown for developing treatments that may slow the underlying disease process, there has been increasing interest in being able to diagnosis AD in its very early or preclinical stages. It has been shown that community-dwelling older adults who exhibit significant impairment in memory are at high risk of developing a clinical dementia over the ensuing 2 to 5 years. This observation has helped to define the category of mild cognitive impairment (MCI), which includes individuals not currently demented but who, for example, score greater than 1.5 standard deviations below norms for memory (see Chapter 142). MFU morphometric analysis of the medial temporal lobe structures has demonstrated significant focal atrophy in patients with probable Alzheimer’s disease and those in preclinical stages. Functional neuroimaging with, for example, single photon emission computed tomography (SPECT) has suggested that the most typical pattern in probable Alzheimer’s disease is bilateral temporoparietal hypoperfusion, with a variable degree of additional bifrontal perfusion abnormalities. Older adults in the preclinical stages of the illness appear to exhibit hypoperfusion of medial temporal, anterior and posterior cingulate, and thalamic regions. Several markers in the cerebrospinal fluid (CSF) may also have diagnostic utility. Compared with that of nondemented controls, the CSF of patients with probable AD tends to have a high level of the tau protein and a low level of amyloid-P peptide (AP). This CSF pattern yields a high specificity (0.81 to 0.95) but only modest sensitivity (0.60 to 0.85). Patients with AD also tend to have an elevated CSF neuronal thread protein, with a reported sensitivity of 0.62 to 0.89 and specificity of 0.88 to 0.95. The value of CSF markers for very early or preclinical diagnosis remains to be determined. CSF proteins are not measured routinely. Currently, genetic markers play a limited role in diagnosing most cases of AD. Autosomal dominant forms of AD (caused by mutations on chromosome 1,14, or 21) only account for a very small proportion of the illness. Their importance lies not in their frequency (which is quite low) but in the information that has been provided to

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Behavioral Neurology

neuroscientists about the pathophysiology of AD. The APOE4 genotype (coded by chromosome 19) is common among patients with AD (about 40% have one or more E4 alleles), but does not serve as a diagnostic test. APOE4 is most appropriately viewed as a susceptibilitygene that increases the risk of a lower age of onset of AD and whose influence occurs in a dose-dependent fashion. A recent study involving a large population of individuals suggested that APOE genotyping in combination with established clinical criteria can improve the specificity of diagnosis. DIAGNOSTIC CRITERIA The salient feature of the most commonly observed dementia syndrome in older adults is a progressive decline in memory that occurs in combination with other cognitive deficits such as executive dysfunction, language impairments, or visual-spatial compromise. On a pathologic plane, this clinical syndrome is most often associated with the plaques and tangles that pathologically define AD. The National Institute of Neurological and Communicative Disorders and StrokeAlzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) Work Group codified the clinical criteria associated with a high likelihood of Alzheimer’s pathology. Criteria for probable Alzheimer’s disease include the presence of dementia, progressive worsening of memory and other cognitive functions, deficits in two or more areas of cognition, no disturbance of consciousness, age of onset between 40 and 90, and the absence of systemic or central nervous system disorders that could account for the dementia. Use of these clinical criteria has yielded diagnostic accuracy in autopsy series of greater than 80%. Other neuropathologic causes of this pattern of progressive amnestic dementia cited in the literature that are much less common than AD include dementia with Lewy bodies, Pick‘s disease, and focal, nonspecific neuronal degeneration. The cognitive profile seen most typically in AD is consistent with the distribution of pathology in this disease and wellestablished brain-behavioral relationships. In the early stages of the illness, pathologic changes, especially the accumulation of neurofibrillary tangles, tend to involve limbic regions and over time spread to neocortical areas. The temporolimbic system has been shown to play a central role in memory processing. Thus, pathology in this region helps to explain the salient memory disturbance observed in Alzheimer’s disease (see Chapter 142). PATHOLOGY AND PATHOPHYSIOLOGY

AD is characterized pathologically by senile plaques (composed of dystrophic neurites and a central core of extracellular deposits of AP), neurofibrillary tangles (composed of paired helical filaments that contain an abnormally phosphorylated protein), significant loss of neurons, and diminished synaptic density. The limbic system and multimodal association areas are particularly ravaged, with the relative sparing of primary motor and sensory cortex.

Although the cholinergic system, arising from the basal forebrain, is significantlydisrupted, many other neurotransmitter systems are damaged as well. Given the wide range of pathology affecting multiple ascending neurotransmitter systems and multifocal areas of cortex involved in different aspects of cognition, it is not surprising that simple pharmacologic interventions for Alzheimer’s disease (e.g., with cholinesterase inhibitors) have had only limited efficacy. According to the amyloid cascade hypothesis (a dominant theory in AD research), AP plays a central role in the pathogenesis of the disease. Based on this model, AD results from excessive production or diminished clearance of AP. This 40- to 42-aminoacid protein is produced through the cleavage of P-amyloid precursor protein (APP) by proteases that have been designated p-secretase and y-secretase. It has been theorized that excessive AP leads to progressive neuronal damage, perhaps through inflammatory and oxidative injury. Increasing neuronal dysfunction and cell death are the source of progressive functional decline and dementia. According to this account, tau abnormalities do not occur early in the pathophysiologic process of AD. Among the strongest pieces of evidence supporting the central role of AP is the observation that the known genetic factors that predispose to AD are associated with an increase in AP peptides or plaques. Table 137-2 summarizes the key chromosomes involved in AD. Many believe that the merits of the amyloid cascade hypothesis will be put to the test through clinical trials involving y-secretase or p-secretase inhibitors that presumably will decrease AP production or immunization with AP, which may inhibit the formation of amyloid plaques and promote their clearance. TREATMENT STRATEGIES Treatment goals for AD are similar to those for any of the dementing illnesses and include the following: eliminating or managing other conditions that contribute to the further decline of a patient’s cognitive and functional status, ameliorating or treating cognitive symptoms, managing or treating behavioral symptoms, slowing the rate of disease progression, delaying the onset of the illness (note that a 5-year delay in onset of symptoms would reduce the number of AD cases by 50%), and preventing disease development. Table 137-3 summarizes treatments that are available, those have been tried without success, and those in current or anticipated clinical trials. Neurologists need to be advocates for their patients with probable AD whose medical problems may be overlooked or undertreated. Patients with probable AD, even very early in the illness, have very low cognitive reserve. They cannot tolerate additional insults to their central nervous system. As noted, among patients with a similar degree of underlying AD pathology, those who have even seemingly subtle subcortical lacunar strokes have been shown to exhibit much greater impairment in cognitive and functional status. We favor aggressive management of concomi-

TABLE137-2. Genetic Factors Predisposing to Alzheimer‘s Disease: Relationship to the P-Amyloid Phenotype Chromosome 21 19 14 1

Gene Defect

Age of Onset

Ap Phenotype

PAPP mutation APOE4 polymorphism Presenilin-1 mutations Presenilin-2 mutations

50s 60s and older 40s and older 50s

7 Production of total AP peptides or of AP, peptides 7 Density of AP plaques and vascular deposits 7 Production of AD, peptides Production of AO., DeDtides

Adapted from Selkoe DJ: The pathophysiology of Alzheimer‘s disease. In Scinto LFM, Daffner KR (eds): Early Diagnosis of Alzheimer‘s Disease. Humana Press, Totowa, NJ, 2000

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TABLE137-3. Potential Treatments for Patients with Alzheimer's Disease Twe of Treatment

Medication

status

Comment

Cholinesterase Inhibitors

Tacrine (Cognex) Donepezil (Aricept) Rivastigmine (Exelon) Galantarnine (Reminyl) Metrifonate Hupenine A Milameline 58202026 Vitamin E Selegiline Acetyl-1 -carnithe Propentofylline Prednisone Cox II inhibitors Hydroxychloroquine NSAIDs AIT-082 Nerve Growth Factor Gene Therapy ySecretase Inhibitors P-Secretase Inhibitors Memantine Ampalex Ampakines Injected AP Nasal AP Passive Immunization with AP antibodies Ginkgo Estrogen

FDA approved FDA approved FDA approved FDA approved

The approved cholinesterase inhibitors are for symptomatic, treatment of cognitive and behavioral problems

Statins

Trials under way

Cholinergic Agonists Cerebroprotective Agents

Anti-Inflammatory Agents

Neurotrophic Factors Altering APP Processing to Reduce P-Amyloid Formation Excitatory Neurotransmitter Modulators Vaccine

Other Agents

Withdrawn ADCS study planned No proven efficacy Potential benefit Potential benefit No proven efficacy ? efficacy No proven efficacy No proven efficacy No proven efficacy On-going study No proven efficacy Phase I Phase I trials planned On-going study Phase I1 Phase I1 trial planned Phase II-HALTED No trial currently No trial currently Potential benefit No proven efficacy

? Neuroprotective glial cell modulator Ongoing Primary Prevention Study (NIA) of Naproxen and Celecoxib

Ongoing study of alternative dosages

NMDA antagonist AMPA receptor modulator AMPA receptor modulator Immune-mediated amyloid clearance

Ongoing Primary Prevention Study (Women's Health Initiative)

ADCS =Alzheimer's Disease Cooperative Study; NIA = National Institute on Aging.

tant medical conditions such as cerebrovasculardisease, endocrine disorders, sleep disturbance, pain, and side effects from various medications. The current standard of care for probable AD is to offer patients a trial of a cholinesterase inhibitor to try to ameliorate their symptoms. In general, studies of cholinesterase inhibitors have indicated that patients on these agents show mild but statistically significant improvement compared with patients on placebo in terms of cognitive measures and clinical assessment of global function. Neuropsychiatric symptoms (e.g., hallucinations, apathy, restlessness) also have tended to improve. Relative benefits can continue over several years, and treatment has tended to delay placement of patients into nursing homes. The first U.S. Food and Drug Administration (FDA)-approved cholinesterase inhibitor, tacrine, was frequently associated with elevated liver function test

values and gastrointestinal distress. Subsequent agents have been much better tolerated and include donepezil, rivastigmine, and galantamine. In absence of impartial head-to-head trials, there is limited evidence that one of these agents is more efficacious than another. Preliminary evidence suggests that if one of these medications is not beneficial to a particular patient, another one may prove helpful. Table 137-4 summarizes the dosing schedule and other features of these medications. Many dementia experts would also recommend treatment with vitamin E, a well-tolerated antioxidant. In one study, after adjusting for Mini-Mental State Examination scores at the start of the trial, researchers found that vitamin E delayed the development of severe dementia or death. Although the trial dosage was 2000 IU per day, many clinicians are prescribing lower dosages (e.g., 800 IU). Ginkgo biloba has also been shown to mildly

TABLE137-4. Currently Available Medications Medication

Dosage

Major Side Effects

Comment

Donepezil (Aricept)

Start: 5 mg Objective: 10 mg Increase to 10 mg after 4-6 wk Start: 1.5 mg bid Objective: 6 mg bid Increase by 3 mg -q2wk Start: 4 mg bid Objective: 12 mg bid Increase by 8 muday -q4wk 400-1 000 IU bid 40 mg tid Herbal (over-the-counter)

Gastrointestinal distress

Once-per-day dosing

Gastrointestinal distress

? Impact of its butyl cholinesterase activity on -1 disease progression

Gastrointestinal distress

? Impact of its modulation of nicotinic receptor on -1 disease progression

Increased risk of bleeding at very high dosages No major side effects Well tolerated

Well tolerated; may slow disease progression

Rivastigmine (Exelon) Galantarnine (Reminyl) Vitamin E Ginkgo biloba Huperzine A

N

2x/day (1 00 mg G 5 mg donepezil)

872

BehavioralNeurology and Epilepsy W Behavioral Neurology

TABLE157-5. Neuropsychiatric and Behavioral Problems

in AD Depression Apathy Hallucinations and sensory misperceptions Delusions and memory distortions Agitation and aggressiveness Wandering and restlessness Incontinence

improve cognitive status and functional assessment by caregivers and thus is another therapeutic option. Much excitement has been generated about a possible vaccine for AD utilizing AP peptides, which in mouse models of AD has been shown to promote the clearance of amyloid plaques and in some studies to improve cognitive function. Passive immunization with monoclonal antibodies to AP also have had promising results in mouse models of the disease. Unfortunately, clinical trials in humans of active immunization have been halted because of concerns about the development of treatment-related CNS inflammation. Efforts are underway to better define immune responses elicited by vaccines in order to improve their safety profile and augment understanding of the pathophysiological mechanisms underlying AD. Early trials also have begun for the y-secretase inhibitors, which theoretically should reduce the burden of AP. Epidemiologic studies have raised the possibility that treatment with estrogen, nonsteroidal anti-inflammatory drugs, and (cholesterol-lowering) statins may reduce the probability of developing a dementing illness. To date, clinical trials with anti-inflammatory agents (e.g., prednisone) and estrogen have been disappointing in patients who already carry the diagnosis of probable AD. Prospective studies are under way to help to determine whether these agents can play a role in preventing or delaying the onset of the disease. BEHAVIORAL ISSUES AND THEIR MANAGEMENT

Although the cognitive abnormalities in AD tend to be emphasized, changes in affect, personality, and behavior also are major problems for patients and their caregivers. Table 137-5 lists the most common neuropsychiatric and behavioral issues associated with AD. Fifteen to twenty percent of patients with AD develop symptoms of major depression, most often early in the course of their illness. Because depression may further erode daily functioning and cognitive performance, it is reasonable to have a low threshold for initiating treatment. However, medications for depression must be used judiciously, clearly identifylng target symptoms and watching closely for side effects. Selective serotonin reuptake inhibitors tend to be preferable to tricyclic antidepressants because of their low anticholinergicside effects. In general, it makes sense to avoid drugs with long half lives (e.g., fluoxetine hydrochloride) and to initiate therapy with low dosages. Delusions or fixed false beliefs are also common in AD, occurring in up to 40% of cases, probably more often in midcourse. They often involve the patient’s conviction that someone is stealing from them, that they are not in their own home, or that their spouse is not faithful. Hallucinationshave been reported in approximately 25% of patients with AD. Psychotic symptoms in AD have been associated with a more rapidly deteriorating course. Patients who become agitated or aggressive, especially if this represents a change from or marked exacerbation of their baseline state, may be suffering from a superimposed

toxic-metabolic process. An important service we can perform for our patients is to ensure that intercurrent illnesses or problems are ruled out (Table 137-6). These include infection, medication side effects, pain, constipation, sleep disturbance, or additional medical problems such as cardiac ischemia. Table 137-7 summarizes strategies to manage agitation and other behavioral problems. CONCLUSIONS

AD and the other degenerative dementias should be viewed as chronic illnesses. Rewards to clinicians come from supporting a patient and his or her family through the different stages of the illness. It is essentialto establish a therapeutic relationship with the caregiver and, when possible, the patient. Educating families and caregivers about the illness can enhance their empathy for the patient, increase their tolerance for a range of maladaptive behaviors, establish more realistic expectations, and allow them to prepare for the future. It is important to ensure that the home environment is safe (e.g., limited access to dangerous appliances or utensils) and to establish daily routines for the patient. Table 137-8 summarizes potential social and behavioral interventions. Typically, disruption of routines leads to confusion and to a deterioration in functional status. When unwanted behaviors emerge, it is worthwhile to review the context in which they arose to see whether simple manipulations of the patient’s schedule or environment may be beneficial. It is important to rule out

w TABLE157-6. Conditions to Identify and Treat Infections Medication side effects Metabolic disturbance Organ failure or disease Endocrine abnormalities Pain Sleep disturbance Constipation Cerebrovascular disease

W

TABLE 157-7. Treatment Strategies for Agitation and Behavioral Problems

Nonohamacolonic Amroaches

Phannacolonic Aimroaches

Rule out intercurrent illness and problems (e.g., infection, pain, constipation, sleep disturbance) Ensure a safe environment (limited access to dangerous utensils, appliances) Establish daily routines Limit noise levels Monitor schedule of light and darkness Use gentle distraction (move attention to something else) Calm, soothing approach Cueing Involvement in activities Improve sensory fidelity, if possible (hearing, vision)

Stabilizing anticonvulsant agents Valproic acid Cabapentin (particularly if the patient is also having problems with sleep or pain) Selective serotonin reuptake inhibitors (e.g., sertraline or citalopram) Sedating agents (e.g., trazodone) (although diminished arousal can make mental state worse) Avoid benzodiazepines in general (although on occasion medications such as lorazepam and oxazepam prove beneficial) Neuroleptics Low dosages of risperidoneas effective as haloperidol with fewer side effects. Olanzapine (especially if the patient is not sleeping at night) Quetiapine

Chapter 138

TMLE 157-8. Social and Behavioral Interventions lntewention

Potential Course of Action

Ensure a safe home environment Optimize cognitive abilities

Occupational and physical therapy consultation; home assessment Consider cognitive rehabilitation consultation early in the course: compensatoly strategies (memorization, organizational aides); teaching caregivers cueing and other ways to be helpful Consider power of attorney and guardianship early in the course when the patient is more able to express his or her wishes Education of families about the illness can Enhance empathy for the patient Increase tolerance for a range of maladaptive behaviors Establish more realistic expectations Allow preparation for the future Very high incidence of depression among caregivers Social work Alzheimefs Association (support groups)

Plan for the future

Support and educate caregivers

intercurrent illnesses or problems if a patient demonstrates a more rapid decline in status and exhibits what has been called a beclouded dementia. Communication with the patient’s internist and other physicians is crucial. Support for caregivers, the lifelines of our patients, is essential. Caregiver involvement with local chapters of the Alzheimer’s Association can help reduce the isolation and psychological burden. Social work input also can be extremely helpful to caregivers by increasing services at home, finding appropriate day programs, providing supportive counseling, and reviewing long-term plans for the patient. Studies suggest that such intervention can delay nursing home placement by an average of 6 months.

Non-Alzheimer Dementias

873

We have the tools to provide thoughtful care to our patients with probable AD. Fortunately, we are also approaching a new era in our understanding and treatment of AD. Our knowledge of the basic biology of the disease has grown tremendously. We are nearing the threshold of being able to identify the illness earlier and treating the underlying disease process much more effectively. Combining these new scientific advances with long-standing principles of humane care will help our patients to maintain as much independence and dignity as possible.

SUGGESTED READINGS Doody RS, Stevens JC, Beck C et ak Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:115&1166, 2001

Evans DA, Funkenstein HH, Albert MS et ak Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA 262:2551-2556, 1989 Growdon JH, Rosser M (eds): The Dementias. Butterworth-Heinemann, Boston, 1998 Knopman DS, DeKosky ST, Cummings JL et al: Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:1143-1153, 2001 Mayeux R, Sano M: Treatment of Alzheimer’s disease. N Engl J Med 341(22):1670-1 679, 1999

Scinto LFM, Daffner KR (eds): Early Diagnosis of Alzheimer’s Disease. Humana Press, Totowa, NJ, 2000 Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:23-31, 1999 Terry RD, Katzman R, Bick K L Alzheimer’s Disease. 2nd Ed. Raven Press, New York, 1999 Weintraub S, Mesulam MM: Four neuropsychological profiles in dementia. pp. 253-282. In Boller F, Spinnler H (eds): Handbook of Neuropsychology. Vol. 8. Elsevier, Amsterdam, 1993

138 Non-Alzheimer Dernentias Martin A. Goldstein and Bruce H. Price Although Alzheimer’s disease (AD) is the most common cause of dementia, as many as one third of cases have other causes. It is therefore important to include consideration of non-Alzheimer dementias during assessment of cognitive impairment.

DIFFERENTIAL DIAGNOSIS OF NON-AUHEIMER DEMENTIA CAUSES Familiarity with the clinical presentations of non-Alzheimer dementias facilitates their early identification and therefore can be crucial to successful management of this diagnostic class, which includes reversible and partially reversible syndromes. Table 138-1 lists major dementia types, and Table 138-2 gives estimated prevalences of dementia types derived from retrospective case reviews. Many of these syndromes are addressed in detail in other chapters.

Differentiation between cortical and subcortical dementia profiles can be clinically useful but often anatomically oversimplified because dysfunction is rarely limited to cortical or subcortical regions. Deficits tending to be caused by subcortical disease include slowed and inefficient cognitive processing and alterations in personality, mood, and behavior. Parkinson’s disease, Huntington’s disease, Wilson’s disease, progressive supranuclear palsy, normal pressure hydrocephalus, demyelinating diseases, leukodystrophies, and acquired immunodeficiency syndrome (AIDS)dementia are representative of this subtype. Other disorders such as CreutzfeldtJakob disease (CJD), diffuse Lewy body disease, or neurosyphilis can equally involve both cortical and subcortical structures. Amnesia, cognitive disorganization, and impaired visuospatial skills can be caused by either cortical or subcortical lesions. Table 138-3 contrasts clinical features of cortical and subcortical dementias, and Table 138-4 summarizes subcortical dementia causes.

Chapter 138

TMLE 157-8. Social and Behavioral Interventions lntewention

Potential Course of Action

Ensure a safe home environment Optimize cognitive abilities

Occupational and physical therapy consultation; home assessment Consider cognitive rehabilitation consultation early in the course: compensatoly strategies (memorization, organizational aides); teaching caregivers cueing and other ways to be helpful Consider power of attorney and guardianship early in the course when the patient is more able to express his or her wishes Education of families about the illness can Enhance empathy for the patient Increase tolerance for a range of maladaptive behaviors Establish more realistic expectations Allow preparation for the future Very high incidence of depression among caregivers Social work Alzheimefs Association (support groups)

Plan for the future

Support and educate caregivers

intercurrent illnesses or problems if a patient demonstrates a more rapid decline in status and exhibits what has been called a beclouded dementia. Communication with the patient’s internist and other physicians is crucial. Support for caregivers, the lifelines of our patients, is essential. Caregiver involvement with local chapters of the Alzheimer’s Association can help reduce the isolation and psychological burden. Social work input also can be extremely helpful to caregivers by increasing services at home, finding appropriate day programs, providing supportive counseling, and reviewing long-term plans for the patient. Studies suggest that such intervention can delay nursing home placement by an average of 6 months.

Non-Alzheimer Dementias

873

We have the tools to provide thoughtful care to our patients with probable AD. Fortunately, we are also approaching a new era in our understanding and treatment of AD. Our knowledge of the basic biology of the disease has grown tremendously. We are nearing the threshold of being able to identify the illness earlier and treating the underlying disease process much more effectively. Combining these new scientific advances with long-standing principles of humane care will help our patients to maintain as much independence and dignity as possible.

SUGGESTED READINGS Doody RS, Stevens JC, Beck C et ak Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:115&1166, 2001

Evans DA, Funkenstein HH, Albert MS et ak Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA 262:2551-2556, 1989 Growdon JH, Rosser M (eds): The Dementias. Butterworth-Heinemann, Boston, 1998 Knopman DS, DeKosky ST, Cummings JL et al: Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:1143-1153, 2001 Mayeux R, Sano M: Treatment of Alzheimer’s disease. N Engl J Med 341(22):1670-1 679, 1999

Scinto LFM, Daffner KR (eds): Early Diagnosis of Alzheimer’s Disease. Humana Press, Totowa, NJ, 2000 Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:23-31, 1999 Terry RD, Katzman R, Bick K L Alzheimer’s Disease. 2nd Ed. Raven Press, New York, 1999 Weintraub S, Mesulam MM: Four neuropsychological profiles in dementia. pp. 253-282. In Boller F, Spinnler H (eds): Handbook of Neuropsychology. Vol. 8. Elsevier, Amsterdam, 1993

138 Non-Alzheimer Dernentias Martin A. Goldstein and Bruce H. Price Although Alzheimer’s disease (AD) is the most common cause of dementia, as many as one third of cases have other causes. It is therefore important to include consideration of non-Alzheimer dementias during assessment of cognitive impairment.

DIFFERENTIAL DIAGNOSIS OF NON-AUHEIMER DEMENTIA CAUSES Familiarity with the clinical presentations of non-Alzheimer dementias facilitates their early identification and therefore can be crucial to successful management of this diagnostic class, which includes reversible and partially reversible syndromes. Table 138-1 lists major dementia types, and Table 138-2 gives estimated prevalences of dementia types derived from retrospective case reviews. Many of these syndromes are addressed in detail in other chapters.

Differentiation between cortical and subcortical dementia profiles can be clinically useful but often anatomically oversimplified because dysfunction is rarely limited to cortical or subcortical regions. Deficits tending to be caused by subcortical disease include slowed and inefficient cognitive processing and alterations in personality, mood, and behavior. Parkinson’s disease, Huntington’s disease, Wilson’s disease, progressive supranuclear palsy, normal pressure hydrocephalus, demyelinating diseases, leukodystrophies, and acquired immunodeficiency syndrome (AIDS)dementia are representative of this subtype. Other disorders such as CreutzfeldtJakob disease (CJD), diffuse Lewy body disease, or neurosyphilis can equally involve both cortical and subcortical structures. Amnesia, cognitive disorganization, and impaired visuospatial skills can be caused by either cortical or subcortical lesions. Table 138-3 contrasts clinical features of cortical and subcortical dementias, and Table 138-4 summarizes subcortical dementia causes.

874

Behavioral Neurology and Epilepsy H Behavioral Neurology

TABU158-1., Differential Diagnosis of Dementia Causes in Adults Degenerative disorders

Vascular dementias

Myelinoclastic disorders

Traumatic conditions Neoplastic dementias

Hydrocephalic dernentias

Alzheimer's disease Frontotemporal dementias Dementias associated with movement disorders

Pick's disease

Parkinson's disease Dementia with Lewy bodies Huntington's disease Progressive supranuclear Pain/ Spinocerebellar degeneration Idiopathic basal ganglia calcification Striatonigral degeneration Motor neuron disease Hallervorden-Spatz disease Lacunar state (multiple subcortical infarcts) Binswanger's disease Mixed cortical and subcortical infarctions Mitochondria1encephalopathies (e.g., MELAS) CADASIL Demyelinating Multiple sclerosis Marchiafava-Bignarni disease Dysmyelinating Metachromatic leukodystrophy Adrenoleukodystrophy Cerebrotendinous xanthornatosis Ceroid lipofuscinosis (Kufs's disease) Polyglucosan body disease Tay-Sachs disease Subdural hematoma Dementia pugilistica Meningioma (especially subfrontal) Gliorna Metastatic lesions Leptorneningeal disease Paraneoplastic Communicating Normal pressure hydrocephalus Noncomrnunicating Aqueductal stenosis lntraventricular neoplasm lntraventricular cyst Basilar meningitis

Inflammatory conditions

Infectionrelated dementias

Metabolic disorders

Endocrinologic disorders Toxic exposures Psychiatric disorders

Systemic lupus erythematosus Temporal arteritis Sarcoidosis Sjogren-Larsson syndrome Granulomatous arteritis Syphilis Lyme disease Herpes encephalitis Chronic meningitis (tuberculosis, fungal) Brain abscess Progressive multifocal leukoencephalopathy Whipple's disease HIV encephalopathy CreuMeldt-Jakob disease Cerstrnann-Straussler disease Subacute sclerosing panencephalitis Hypoxia Hypercapnia Uremia Hepatic encephalopathy Anemia Vitamin deficiency states (B,, folate, niacin) Porphyria Hypoglycemia Wilson's disease Thyroid Adrenal Parathyroid Alcohol-related syndromes Other substance abuse Heavy metals Industrial solvents Depression Mania Schizophrenia Conversion reactions

SECONDARY DEMENTIAS H TABLE138-2. Estimated Prevalences of Common Causes of Dementia Culled from Clinical and

Epidemiologic Series Dementia Type

Relative Prevalence

Percentage Range

Alzheimef 50 25-75 Cerebrovascular" 15 5-30 l e v body 15 5-30 5 Other neurodegenerative 2-20 Alcohol-related 5 2-15 Toxic or metabolic 2 1-15 2 Neoplastic 1-10 Infectious 2 1-5 Acquired hydrocephalus 1-5 2 1 Post-traumatic 1-3 1 1-2 Miscellaneous aMixedAlzheimer and cerebrovascular represent a large proportionof each group's composition.

Potentially Reversible Secondary Dementias

Meta-analyses of dementia studies have revealed at least potential reversibility in approximately 13% of patients (see Table 138-5). The most common causes of reversible dementias are depression and iatrogenic (e.g., adverse drug effect),which together constitute about 50% of reversible dementias. Metabolic disorders are next, followed by normal pressure hydrocephalus. Other causes have indistinguishably small prevalences. Primary Psychiatric Disturbances DEPRESSION. Dementia and depression often are comorbid and can appear remarkably similar. Between 20% and 55% of older

adults with depression develop cognitive impairment phenomenologically consistent with a dementia syndrome; this has commonly been called pseudodementia but is more correctly called the

Chapter 138 W

Non-Alzheimer Dementias

875

TABLE138-3. Distinguishing Characteristics of Cortical and Subcortical Patterns of Dementia Function ~

Cortical Dementia

Subcortical Dementia

Normal Dysnomia Variable aphasias Poor insight Poor judgment Reduced abstraction impaired impaired Anterograde amnesia Agnosia Spared until late impaired Present Less common Disinhibition Apathy or abulia Cerebral cortex

Slowed Spared

~~

Psychomotor speed Language Executive function Memory

Recent

Retrieval and recall Recognition

Remote Motor Visuospatial Agnosias Depression Comportment Neuroanatomy

rn TABLE138-4. Major Causes of Subcortical Dementia Diseases of Subcortical Crav Matter

Diseases of white Matter

Parkinson's disease Huntington's disease Progressive supranuclear palsy Small vessel vascular disease

Small vessel vascular disease Multiple sclerosis Head injury Hydrocephalus Binswanger's encephalopathy HIV

dementia of depression or depression-related cognitive impairment (DRCI). Meta-analytic investigations demonstrate that new antidepressants not only treat depression comorbid with dementia but can also improve cognitive function, suggesting a high prevalence of superimposed DRCI among patients with dementia in general. Patients with DRCI are more likely to complain of memory and concentration problems than patients with degenerative dementia. Also in contrast to patients with degenerativedementia, those with depression can do reasonably well on formal mental status testing when depression-related confounds such as motivation and attention are minimized. Careful bedside mental status or neuropsychological assessment is necessary to establish dementia in a patient with both depressive affective symptoms and cognitive deficits. Although recall is impaired in both dementia and DRCI, depressed patients usually have preserved recognition, whereas patients with an amnestic degenerative dementia have impaired recognition and more intrusion errors. Cognitive testing in depression reveals performance variability and impaired attention with insufficient effort during memory encoding. Examiner tenacity at ensuring successful encoding of short-term memory items is essential to distinguish the memory epiphenomenon of depression-related attention impairment from a primary memory disturbance. Key differences often can be elicited in language functions, which are generally preserved in DRCI but often become impaired in a degenerative dementia. Similarly, apraxias, visuospatial deficits, and gross executive dysfunction, common features of degenerative dementias, are seen only in the most severe forms of DRCI.

Poor problem solving, global slowing impaired Preselved No temporal gradient Early involvement Normal Less significant or absent More common Apathy Subcortical structures Dorsolateral prefrontal cortex

Of note, depression can be an early symptom of several degenerative dementing processes. Despite initial improvement via antidepressant therapy, almost half of older adults with depression-related cognitive dysfunction develop irreversible degenerative dementias within 5 years. Patients with depression unaccompanied by cognitive impairment develop dementia at rates more comparable to that of the general population. Once a single episode of depression complicated by cognitive impairment is documented and treated in an older adult, that patient should be monitored closely for signs of relapse and incipient dementia thereafter. Regrettably, neither clinical features nor currently available biological markers reliably differentiate older adults with a primary dementia from those with DRCI. Nevertheless, consensus heuristics, summarized in Table 138-6,can sometimes be helpful when used cautiously.

Structural NORMAL PRESSURE HYDROCEPHALUS (NPH). Normal pressure hydrocephalus (NPH) can be a structural cause of dementia that is potentially treatable by surgery. A diagnosis originally pioneered by Adams, Hakim, and Fisher, NPH classically presents as a triad of gait apraxia, urinary urgency or incontinence, and mental status changes. Usually developing in late middle or old age, psychomotor slowing combines with cognitive findings suggestive of a mixed cortical and subcortical dementia. Importantly, parkinsonism, sensory complaints, and depression may be associated findings.

TAW15116 Example secondaly Causes'of Dementia cah?PON

Examole

Psychiatric Structural

Pseudodementia of depression Normal pressure hydrocephalus Subdural hematomas Wilson's disease Hypothyroidism Obstructive sleep apnea Vasculitis intracranialtumors Chronic meningitis Medication enceDhalooathv

Metabolic Endocrinologic Respiratory Inflammatory Neoplastic infectious iatrogenic

876 TABU 158-6.

Behavioral Neurologyand Epilepsy

Behavioral Neurology

Distinguishing Features of Dementia and Depression-Related Cognitive Impairment

Dementia

Insidious onset Progressive deterioration No history of depression Patient typically unaware of deficits, does not complain of memory loss Somatic complaints uncommon Variable affect Few vegetative symptoms Impairment often worsens at night Neurologic examination and lab studies often abnormal

Depression-Related Cognitive Dvsfunction

Abrupt onset Plateau of dysfunction History of depression Patient aware of and may exaggerate deficits, often ;om- plains of memory loss Somatic complaints or hypochondriasis common Depressed affect Prominent vegetative symptoms Impairment usually not worse at night Normal examination, normal lab studies

Some patients, especially those with hydrocephalus from meningitis or subarachnoid hemorrhage, can improve after ventriculoatrial, ventriculoperitoneal, or lumboperitoneal shunting. In idiopathic NPH, about half of patients experience sustained improvement, and about one third have a good or excellent response to shunting. Complications of shunting occur in about one third of patients and can include shunt infection, subdural hematoma, and shunt malfunction necessitating revision. NPH is reviewed in detail in Chapter 16. Subdural hematoma (SDH) is the most SUBDURAL HEMATOMA. readily treatable intracranial mass lesion that can cause cognitive dysfunction. Patients aged 50 to 70 years are most commonly affected. The most common precipitating factor is head trauma, which can often be minor. Factors increasing the risk of head trauma or severity of resulting SDH include alcoholism, cerebral atrophy, epilepsy, use of anticoagulants, ventricular shunts, and long-term hemodialysis. SDH is bilateral in about one sixth of cases. Clinical Manifestations. SDH can be clinically quiescent without overt symptoms evident for months. Headache is the most common initial symptom. Neurologic signs including cognitive dysfunction (ranging from mild nonspecific confusion to significant dementia) and contralateral hemiparesis are the most common findings, followed by papilledema and extensor plantar responses. Although seizures are uncommon, they can signal a previously undetected SDH. Diagnostic Investigations. SDH usually can be visualized on noncontrast computed tomography as an extraaxial crescentshaped hypodensity. Usually involving a portion of or, less commonly, an entire cerebral convexity, SDH can also occur above and below the tentorial dural regions. When SDH is convexity based, ipsilateral obliteration of cortical sulci is seen. If it is large, mass effects such as ventricular compression can occur. Neuroimaging should be carefully reviewed for evidence of bilateral subdural collections. Age of SDH can be estimated on computed tomography by evolution of the subdural defect from hyperdense (bright), representing presence of recently accumulated blood, progressing through successive shades of gray, culminating in isodense collections for which contrast infusion may be needed to visualize. Management. Symptomatic hematomas should be surgically evacuated. However, management can be complicated when SDH, especially bilateral SDH, is associated with significant cerebral

atrophy, as is common in older adults, because evacuation can result in recurrent bleeding as atrophy-related tensile forces on subdural space complicate healing. NEOPLASTIC.Brain tumors manifesting solely via progressive cognitive impairment are uncommon. Nevertheless, certain slowgrowing intracranial neoplasms occurring in strategic locations (e.g., frontal or temporal meningioma or low-grade glioma) can be a curable cause of secondary dementia. When otherwise clinically covert (i.e., in the absence of noncognitive neurologic signs), the threshold for performing screening neuroimaging becomes key (see Chapter 136). Metabolic. Almost any metabolic abnormality can affect cerebral function to such an extent as to cause cognitive dysfunction. Most of the major types are reviewed in other sections of this volume devoted to metabolic causes of acute confusional states, such as metabolic deliria (e.g., hepatic encephalopathy). Here we summarize a prototypical example of a metabolic disturbance associated with chronic cognitive dysfunction (i.e., a secondary dementia). WILSON'SDISEASE.Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder of copper metabolism that produces neurologic and hepatic dysfunction. Prevalence of WD is approximately 30 per million population. A gene defect has been localized to the long arm of chromosome 13. Pathogenesis involves decreased binding of copper to the transport protein ceruloplasmin, resulting in excessive amounts of circulating unbound copper, eventually depositing in a variety of tissues, most notably brain, liver, kidney, and cornea. Although the average age of onset is 11 years for patients presenting with hepatic dysfunction and 19 years for those with neurologic manifestations, the disease can remain clinically covert until the sixth decade. Ocular and hepatic abnormalities are the most prominent nonneurologic complications of WD. Kayser-Fleischer rings, pathognomonic for WD, are bilateral brown corneal rings resulting from copper deposition and are present in almost all patients with neurologic involvement. The rings are sometimes subtle, detectable only by slit lamp examination. Hepatic involvement can take the form of an asymptomatic rise in liver enzymes, hepatitis, or jaundice; if involvement is chronic, cirrhosis can ensue, with portal hypertension-related complications. Neurologic manifestations reflect disproportionate involvement of the caudate, putamen, cerebellum, and cortex. Signs can include facial grimacing, dysarthria, dysphagia, hypokinesia, abnormal postures, rigidity, resting or postural tremor, choreiform movements, and ataxia. There is a tendency for a dystonic or parkinsonian picture with hyperreflexia and extensor plantar responses to predominate with disease onset before age 20 and for older patients to exhibit tremor, chorea, or ballismus. A wingbeating tremor is a common late manifestation. Seizures sometimes occur. The cognitive impairment of WD is consistent with a subcortical dementia profile marked by generalized thought process slowing, concentration impairment, and secondary memory deficits. Research has been performed to distinguish whether the visuomotor task slowing found in WD is more a product of motor involvement than cognitive deficiency; specially designed neuropsychological batteries controlling for manual dexterity effects confirm motor defect-independent slowing. Psychomotor impairment in WD may result from disrupted cortico-basal ganglionic connections. Associated psychiatric signs include affective, person-

Chapter 138

ality, and behavioral changes; psychoses, including hallucinations, are more rare presentations. Diagnostic testing reveals decreased serum copper (less than 80 pg/dL), low ceruloplasmin levels (less than 20 mg/dL), elevated 24-hour urinary copper excretion (more than 100 pg/24 hours), and abnormal liver function tests. Neuroimaging often demonstrates bilateral cortical and basal ganglia atrophy, with compensatory ventricular dilation. Inconsistently present and unusual characteristics visualizable on structural neuroimaging are basal ganglia cystic degeneration and cavitary necrosis. Liver biopsy reveals marked excess copper and cirrhosis. The principal differential diagnosis based on clinical symptoms is Huntington's disease. Management includes copper chelation by penicillamine and restriction of dietary copper. Treatment response can take months; serial serologic assays and slit lamp examinations can be used to track progress. Treatment is lifelong. Most patients treated early can expect a complete or nearly complete recovery. Siblings of affected patients should be screened for WD with neurologic examination including slit lamp evaluation and serum ceruloplasmin levels. Endocrine Disorders. Multiple endocrinologic disturbances can contribute to cognitive dysfunction. We focus on two prototypical endocrinopathiesknown to cause reversible dementias. HYPOTHYROIDISM. In addition to being a cause of an acute confusional state, hypothyroidism (myxedema) can cause a reversible global dementia characterized by generalized cognitive slowing and nonspecific memory impairment. Common psychiatric signs include depression sometimes complicated by psychotic features including paranoia and hallucinations. Associated neurologic manifestationscan be helpful in suggesting hypothyroidism as an underlying cause of a dementia. Symptoms can include headache, tinnitus, paresthesias, and generalized weakness. Signs include delayed relaxation of deep tendon reflexes, hearing impairment, and typical stigmata of hypothyroidism (e.g., dry skin, pretibial myxedema). Thyroid function tests usually confirm diagnosis. Cognitive dysfunction usually reverses significantly with thyroid hormone replacement. HYPOCORTISOUSM. Patients with severe or chronic adrenal insufficiency can present with mild to moderate cognitive impairment (5% to 20%), depression (20% to 40%), or psychosis (20% to 40%). At least partial reversibility of hypocortisolism-related dementia via exogenous steroid repletion is the rule. Nutritional Disorders VITAMIN B,, DEnaENcv. Vitamin B,, (cyanocobalamin) defi-

ciency can produce many neurologic complications including cognitive dysfunction ranging from a mild confusional state to severe dementia or psychosis (megaloblastic madness). Although presenting symptoms are most commonly caused by anemia, neurologic abnormalities can precede development of macrocytic anemia. Potential neurologic symptoms include peripheral neuropathy, subacute combined degeneration of the spinal cord, nutritional amblyopia (visual loss), distal paresthesias, gait ataxia, bandliie tightness around the trunk or limbs, and Lhermitte's sign (electric shock-like sensation along spine precipitated by rapid neck flexion). Associated leukopenia or thrombocytopenia can signal disease presence via infection andlor bleeding respectively. Like the acute confusional state associated with B,, deficiency, the dementia of B,, deficiency can occur with or without hematologic manifestations. The dementia consists of global

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cognitive dysfunction with generalized slowing, impaired concentration, and memory disturbance. Psychiatric disturbances often are prominent and include depression, mania, and psychosis. Diagnostic clues include glossitis, yellow skin discoloration, and cutaneous hyperpigmentation. Spinal cord involvement is manifested by impaired vibratory and joint position sense, sensory ataxia, spastic paraparesis, extensor plantar responses, decreased deep tendon reflexes (especially in the legs), and urinary retention. Laboratory investigations reveal low B,, level (important to check because folate deficiency can cause the same set of hematologic abnormalities), macrocytic anemia, leukopenia with hypersegmented neutrophils, and thrombocytopenia with giant platelets. Schilling's test helps identify the cause of the B,, deficiency (the most common cause of B,, deficiency is pernicious anemia). Serum methylmalonic acid and homocysteine can also be useful measures. Both are elevated in B,, deficiency, but by better indexing tissue vitamin stores they can demonstrate relative deficiency when serum B,, levels are still normal. Some patients, particularly older adults, with normal B,, levels but elevated serum methylmalonic acid can manifest neuropsychiatric abnormalities, including cognitive impairment. Treatment of patients with such covert B,, deficiency often can produce at least partial improvement. WERNICKE'S ENCEPHALOPATHY AND KORSAKOFF'S SYNDROME. Wernicke's encephalopathy (WE) is produced by thiamine (vitamin B,) deficiency, a condition associated most commonly with alcoholism-related nutritional deficiency, but can be a component of many other syndromes involving nutritional compromise (e.g., hyperemesis gravidarum, cancer). Pathologically, WE is characterized by neuronal loss, demyelination, and gliosis in periventricular gray matter regions. Structures most commonly involved include medial thalamus, mammillary bodies, periaqueductal gray matter, and cerebellar vermis, as well as oculomotor, abducens, and vestibular nuclei. Onset of WE typically is abrupt but can be insidious. The classic syndrome comprises the triad of ophthalmoplegia, ataxia, and encephalopathy. However, in one postmortem study, the complete triad had been present in only one third of patients with Wernicke-related lesions found on autopsy. The most common ocular abnormalities are nystagmus, VI nerve palsy, 111 nerve palsy, horizontal gaze palsy, and vertical gaze palsy. Ataxia is typically cerebellar, primarily affecting gait; this can be aggravated by peripheral neuropathy-related sensory ataxia. Cognitive examination reveals global confusion with defective immediate and recent memory. Most patients have peripheral neuropathy (often both WE- and alcohol-related) with absent ankle jerks. Hypothermia and hypotension may occur, presumably secondary to hypothalamic involvement. Pupillary abnormalities, including mild anisocoria, and sluggish light reactivity are occasionally seen. Untreated, WE can progress to stupor and coma. Treatment entails prompt thiamine administration. Parented thiamine is continued for several days to ensure repletion of tissue stores. Ocular abnormalities usually begin to improve within days, ataxia and confusion within weeks. Ophthalmoplegia, vertical nystagmus, and acute confusion are generally reversible, usually within 1 month. However, horizontal nystagmus and ataxia resolve completely in only about 40% of cases. The major long-term complication of WE is alcohol amnestic disorder, commonly known as Korsakoff's syndrome. Korsakoff's syndrome is primarily a memory disorder of anterograde greater than retrograde capacity; other cognitive functions including

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TABLE138-7. General Features of Vascular Dementias History

Physical examination Neuroimaging

Onset of cognitive deficit associated with a stroke Symptomatic improvement after acute event Abrupt onset Stepwise deterioration Focal findings (e.g., hemiparesis, hemianopia) Infarct above tentorium Cognitive impairment corresponding to infarct foci seen on imaging

language are not usually affected. Severe disorientation usually is a consequence of recent memory impairment. Confabulation and impaired insight are common. Inflammatory Disorders. A variety of inflammatory disorders can affect cognitive function. Primary (e.g., primary CNS angiitis) and systemic vasculitides (e.g., Churg-Strauss vasculitis), granulomatous disorders (e.g., neurosarcoidosis), and other autoimmune syndromes (e.g., Hashimoto's encephalitis) can contribute to cognitive dysfunction. These are especially important to identify because the associated dementias can be at least partially reversible with anti-inflammatories (e.g., steroids), immunosuppression (e.g., azathioprine), immunotherapy (e.g., intravenous y-globulin, IV immunoglobulin), and plasmapheresis. See detailed discussion of these syndromes under separate headings in this volume.

Secondary Dementias: Usually Irreversible Vascular Dementias. Strokes, small and large, ischemic and hemorrhagic, cortical and subcortical, together are the second most common cause of dementia, accounting for up to 10% of late-life mental decline. After stroke, 20% to 25% of patients are demented. Diagnostic criteria for vascular dementia are more controversial than those for other dementia subtypes. The term vascular dementia implies presence of a clinical syndrome (dementia) caused by a specific disorder (cerebrovascular disease). Table 138-7 summarizes the features of vascular dementia. Diagnostic criteria for vascular dementia still must be validated by systematic clinicopathologic study. Until such criteria are better refined, vascular dementia is best conceptualized as a secondary dementia (i.e., cognitive dysfunction of brain injury secondary to cerebrovascular disease). Vascular dementia criteria currently in use include the State of California AD Diagnostic and Treatment Centers Criteria (the California criteria), the National Institute of Neurologic Disorders and Stroke, the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria, the Hachinski Ischemic Score (HIS), and those found in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSMIV).In studies comparing clinical diagnoses and neuropathologic findings, the NINDS-AIREN and the California criteria (as well as DSM-IIIR) had very low sensitivity but high specificity. A retrospective study using HIS was the only analysis in which diagnosis of vascular dementia appeared both sensitive and specific. The diagnosis of vascular dementia is supported by sudden onset of cognitive impairment in two or more domains, stepwise deterioration, asymmetries on neurologic examination, neuroimaging evidence of stroke, and presence of cerebrovascular risk

factors. The incidence of vascular dementia has declined over the last 2 decades, perhaps as a consequence of more effective stroke prevention. It is generally assumed that risk factors for vascular dementia are similar to those for stroke, with arterial hypertension and atherosclerotic disease leading factors. Vascular dementia can take several forms, as outlined in Table 138-8.

Marked differences in clinical presentation of these variants make it inappropriate to regard vascular dementia as a unitary diagnostic entity. Rather, vascular dementia represents a group of dementia types sharing the general common pathogenesis of brain injury secondary to derangement of cerebrovascular functional or structural integrity. A pleomorphic nature thereby arises from variations in type and location of cerebrovascular pathology. Abrupt onset of cognitive impairment supports a diagnosis of vascular dementia but by itself is not diagnostic. Vascular dementia characteristically progresses in a stepwise fashion, with new episodes of minor or major deterioration reflecting additional vascular events. Therefore, the temporal relationship between documented stroke and onset of cognitive impairment is key. The shorter the time difference between the two, the more vascular dementia should be considered as the cause. Multiple small infarctions of subcortical white matter pathways, disconnecting circuitry between cognitively important cortical centers, causes a leukoencephalopathy previously called Binswanger's disease. The resulting clinical situation has been likened to a highway damaged by potholes: destinations remain intact, but travel between these destinations is slowed. In these and other forms of vascular dementia, cognitive changes can be accompanied by abnormalities of motor and sensory functions that are often spared in the early stages of degenerative disorders such as AD. In the majority of patients assessed for dementia, an exclusive diagnosis of vascular dementia can rarely be made. Instead, clinicians are often confronted with patients having some vascular features together with a history that otherwise seems more compatible with a diagnosis of AD. Although epidemiologic studies are limited by diagnostic uncertainties, they suggest that stroke increases the risk of dementia. Recent neuropathologic analyses offer perspective on the difficulty of correctly diagnosing cerebrovascular pathology in dementia. Rather than considering vascular dementia as present or absent, these studies distinguished between presence of any vascular lesions and pure vascular pathology (where vascular pathology was both sufficient to account for cognitive symptoms

TABLE 138-8. Categories of Vascular Dementia Category

Clinical Presentation

Lacunar infarctions

Progressive dementia, focal deficits, apathy, frontal lobe syndrome, possibly absent history of clinically recognized strokes Sudden-onset aphasia, agnosia, anterograde amnesia, frontal lobe syndrome Stepwise appearance of cognitive and motor deficits Progressive dementia with remote or concurrent history of stroke Dementia, apathy, agitation, bilateral corticospinal and bulbar signs

Single strategic infarctions Multiple infarctions Mixed AD-vascular dementia White matter infarctions Binswanger's disease

Chapter 138 H Non-Alzheimer Dementias

and unaccompanied by other pathology). Although at least some vascular pathology existed in more than 40% of dementia cases coming to autopsy, pure vascular pathology accounted for dementia in only approximately 10%. Approximately 10% to 15% of autopsied dementia cases show a combination of Alzheimer and cerebrovascular pathology. One prospective autopsy series of patients with clinically diagnosed dementia found that dementia could not be attributed to the effects of cerebrovascular disease alone in any of the patients studied; 87% were found to have AD, either alone or in combination with cerebrovascular disease. All patients with cerebrovascular disease at autopsy had some concomitant neurodegenerative disease. Such clinical and pathologic admixtures are a common presentation for cerebrovascular disease. Therefore, clinicians should maintain a high index of suspicion for AD or other neurodegenerative processes in patients with dementia, even in the presence of documented cerebrovascular disease. Treatment of vascular dementia consists primarily of identifying and correcting predisposing cerebrovascular risk factors. The overall rate of progression can be slow compared with that of other causes of dementia, even spanning several decades, but some patients suffer from an accelerated evolution. Cerebral Autosomal Dominant Arteriopathy Subacute Infarcts and Leukoencephalopathy (CADASIL). CADASIL is an

increasingly recognized clinicopathologic syndrome. CADASIL causes subcortical lacunar infarction and dementia in more than 80% of cases. CADASIL can appear very similar to hypertensive microvascular disease (Binswanger's disease). Signs and symptoms of CADASIL tend to appear between ages 40 and 60, but changes are apparent on magnetic resonance imaging (MRI) much earlier. Approximately 30% of patients have migraines with aura; mood disorders are common. Neuropathologic findings include smooth muscle hypertrophy in small arteries, demyelination, gliosis in subcortical white matter and basal ganglia, and involvement of the corpus callosum. Given the autosomal dominant hereditary basis of this disease, family history is key. CADASIL is associated with a notch3 family gene on chromosome 19. Neoplastic Disease. Dementia secondary to cancer is mentioned earlier as a potentially reversible secondary dementia; here we discuss a specific irreversible cancer-related dementia. Paraneoplastic limbic encephalitis (PLE) is a rare disorder characterized by variably progressive cognitive and affective changes; less often, focal motor and sensory signs can occur. PLE is both an inflammatory and degenerative disorder of certain CNS gray matter regions occurring as a rare complication of a non-CNS cancer. Symptoms typically precede diagnosis of the underlying cancer. Symptoms usually develop over the course of several weeks. The disorder is characterized by profound impairment of recent memory corresponding to inability to learn new information (i.e. anterograde amnesia). Attention and registration are unaffected, and remote memory is less impaired. Confabulation occurs in some cases. Affective symptoms, especially anxiety and depression, are common early features. Hallucinations are a variable feature. The primarily amnestic syndrome sometimes progresses to a global dementia. Depending on the extent to which gray matter regions outside the limbic system are involved, cerebellar, pyramidal, bulbar, and peripheral nerve disturbances can coexist with cognitive, affective, and behavioral symptoms. Seizures, including complex partial or generalized, sometimes occur. MRI can reveal abnormal signal intensity in the medial temporal lobes. Diffuse slowing or bitemporal slow waves and

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spikes are sometimes seen on electroencephalogram (EEG). CSF often demonstrates a modest mononuclear pleocytosis and mildly elevated protein. Serologic tests for detecting paraneoplastic antineuronal antibodies have become increasingly available. Excluding other potentially treatable disorders is of primary importance before settling on a diagnosis of PLE. Korsakoffs syndrome, also marked by antero-grade amnesia, should especially be considered since patients with cancer are susceptible to nutritional deficiency (previously stated under Korsakoffs). PLE can be static, progressive, or even remitting. No specific treatment is available except management of the underlying cancer. Radiation. The effects of radiation therapy on the brain can be extremely variable in type and time of onset; late effects, on the order of 10 years after treatment, are known. Clinical expression depends in part on type (e.g., focal beam or whole brain) and amount of radiation. MRI often demonstrates significant leukoencephalopathy. Infectious Dementias. Chronic CNS infectious processes can sometimes cause dementia as a primary manifestation; we briefly describe some major types. VIRAL ENCEPHALITIDES. Viral encephalitis is caused by viral infection of brain parenchyma, producing neuronal and glial degeneration, inflammatory infiltration, edema, and tissue necrosis. Viral encephalitis occurs worldwide, with a higher incidence in tropical regions. Between 1000 and 2000 cases per year in the United States are reported by the Centers for Disease Control. Investigators fail to identify an etiologic agent in up to 75% of presumed viral CNS infection cases. Indeed, the confusing term aseptic meningitis attests to the historic difficulty of definitively isolating an etiologic agent in presumed viral meningitides. Amplification of viral nucleic acids from CSF, as done by the polymerase chain reaction (PCR), for example, has greatly improved diagnosis of several acute, subacute, and chronic viral CNS infections. PCR has become the method of choice for rapid noninvasive diagnosis of herpes simplex virus (HSV) encephalitis; other herpes viruses that can now be diagnosed reliably include cytomegalovirus, varicella-zoster virus, Epstein-Barr virus, and human herpesvirus 6. In AIDS, PCR can help differentiate lesions caused by human immunodeficiency virus (HIV) itself or by opportunistic infections such as progressive multifocal leukoencephalopathy caused by JC virus or cytomegalovirus-related complications. Herpes €rtcepho/itis. HSV causes the most common form of sporadic, potentially fatal encephalitis in children older than 6 months and adults worldwide; herpes encephalitis is addressed in detail in Chapter 65. H/K Up to 70% of patients with HIV develop neurologic complications. Although neurologic disease typically occurs in the context of other AIDS-defining illnesses, neurologic signs can herald AIDS in up to 20% of patients with HIV. The spectrum of neurologic disorders that complicates HIV- 1 infection is extremely diverse. CNS complications can be divided into those caused by HIV infection itself and those caused by HIV-related secondary factors (e.g., opportunistic infections consequent to HIV-induced immunosuppression). HIV-related cognitive disorders are discussed in detail in Chapter 75. hawurns CreuMeM-hkob Disease.

SLOW VIRUS

CJD is one of the slow virus infections, also known as prion diseases after the presumed infectious agent and as transmissible spongiform encephalopathies

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(TSE), after the histopathologic changes associated with these infections. CJD is the most common human TSE. A new variant of sporadic CJD probably caused by the same agent as bovine spongiform encephalopathy was first described in 1996. Variability in CJD diagnostic criteria sets relying solely on clinical manifestations has led to different incidence rates in different series. CJD occurs primarily as a sporadic illness but also emerges in small family clusters. Sporadic CJD has an annual incidence of about one per million in the general population and occurs randomly worldwide. Inherited CJD has an annual incidence of about 1 per 10 million in the general population. Sporadic CJD is most often diagnosed in patients aged 50 to 70 years; there is generally an equal sex distribution. Although presumably dormant for many years, once clinically expressed, CJD produces a rapidly developing, progressive dementia that can be clinically variable. Initial complaints in approximately one third of patients are constitutional, consisting of fatigue, disordered sleep, or decreased appetite. Another third have nonfocal neuropsychiatric features at onset (eg., confusion or atypical behaviors). The remainder can present with prominent signs of corticospinal and extrapyramidal dysfunction, including gait disturbance and rigidity, as well as focal neurologic features, including ataxia, visual loss, aphasia, hemiparesis, or focal amyotrophy, sometimes leading to an erroneous initial clinical impression of stroke or motor neuron disease. Diagnosis becomes clearer with onset of cognitive decline and startle myoclonus to abrupt sound or touch. Pyramidal, extrapyramidal, and cerebellar signs eventually occur in the majority of patients. Seizures, especially myoclonic, occur in up to 20% of patients. Table 138-9 summarizes the principal clinical features of sporadic CJD. Although seizures are not a common complication of slow virus infection, there can be characteristic electroencephalographic changes. Early in the course of sporadic CJD, the EEG may show nonspecific slowing. Later, periodic, biphasic or triphasic, synchronous sharp wave complexes are superimposed on a slow background rhythm in 60% to 80% of cases on single EEG recordings. These characteristic complexes may disappear as myoclonus subsides in the terminal phase of the disease. Periodic triphasic complexes have shown a sensitivity and specificity of 67% and 86%, respectively, for CJD detection; if repeated recordings are obtained, more than 90% of patients may show periodic complexes within 12 weeks of onset. Until recently, diagnosis of CJD depended on clinical symptoms, characteristic EEG pattern (periodic sharp wave complexes),

W TAW 158-9.

Incidence of Neurologic Features of Sporadic CreuMeldt-Jakob Disease

Sign or Symptom Memory loss Behavioral disturbance Other neuropsychiatric dysfunction Myoclonus Cerebellar ataxia Pyramidal signs Periodic electroencephalographiccomplexes Extrapyramidal signs Visual disturbances Lower motor neuron signs

Frequency (%) 100

57 73 78

71 62 60

56 42 12

Adapted from Brown P et al: Human Spongiform encephalopathy. Ann Neurol35(5): 513-529,1994

and brain biopsy assessment. The introduction of 14-3-3 CSF protein Western blot immunodetection has greatly improved diagnostic accuracy (sensitivity up to 99% and specificity up to 96%). MRI demonstrates a characteristic “cortical ribboning” on diffusion-weighted imaging (DWI). Definitive diagnosis still entails identification of abnormal prion protein or related neuropathology in brain tissue obtained by biopsy or autopsy. However, with typical clinical presentation, rapid course, EEG showing periodic complexes, presence of 14-3-3 protein in CSF, and abnormal DWI MRI, the diagnosis of CJD is reasonably certain. Diagnostic criteria for new variant CJD derived from 35 confirmed deaths have indicated a median duration of illness of 14 months and median age of 29 years. In all cases, psychiatric symptoms such as depression, anxiety, and withdrawal were followed within a median of 6 months by neurologic symptoms such as dysesthesias and paresthesias. In some cases, neurologic symptoms were not accompanied by neurologic signs. Terminal stages of the disease typically have been characterized by progressive loss of function leading to akinetic mutism. Except for a case involving a young woman who is believed to have acquired new variant CJD while living in the UK, there have been no reported cases of new variant CJD in North America. CJD is uniformly fatal, with progression to death within 12 to 18 months of symptom onset. Management is supportive; there is no cure. Chapter 79 reviews prion diseases in further detail.

PRIMARY COGNITIVE DISORDERS Mild Cognitive lmpainnent Some older adults exhibit age-related memory deficits (previously called age-associated memory impairment or isolated memory impairment) but are not considered to have dementia because their general intellect is preserved and there is no significant impairment in activities of daily living. Patients with mild cognitive impairment (MCI) can have memory dysfunction similar to that of patients with mild AD, but the balance of their cognitive functions are similar to those of healthy age-matched controls. Although MCI has been thought to be a possible precursor to AD, dementia may not inexorably occur, even after many years of observation. The hypothesis that MCI, particularly impairment in episodic memory (because this cognitive system is affected earliest and most profoundly by AD), represents an early stage of AD has been a subject of increasing study. Positron emission tomography scans of patients with MCI demonstrate a pattern of hypometabolism more closely resembling that of patients with AD than that of a healthy elderly control group. Retrospective studies of nondemented nondepressed patients have revealed that memory loss alone rarely progresses to dementia at least 2 years after follow-up monitoring. But dementia risk is significantly higher among patients with clear cognitive impairment beyond memory loss. That is, nondemented patients with memory loss and impairment in at least one other cognitive domain, thereby meeting criteria for MCI but not yet meeting criteria for dementia, are more likely than those with age-normal memory impairment alone to develop AD. The annual conversion rate of MCI to frank dementia is estimated to vary from 12%to 15%. This is greater than the overall age-adjusted dementia incidence rate but still leaves many patients without dementia after up to 5 years of follow-up. Hippocampal

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TABLE 158-10. Clinical Features of Frontal-Variant Frontotemporal Lobar Dementia Core diagnostic features

Supportive diagnostic features

Insidious onset and gradual progression Early decline in social conduct Early impairment in personal conduct Early emotional blunting Early loss of insight Behavior Decline in personal hygiene Mental rigidity Distractibility and impersistence Hyperorality and dietary changes Perseverativeand stereotyped behavior Utilization behavior Speech and language Altered speech output (reduced, aspontaneous, or pressured) Stereotypy Echolalia Perseveration Mutism Physical signs Primitive reflexes With or without incontinence Hypokinesia With or without rigidity With or without tremor Investigations Neuropsychology Impaired executive tasks Absence of amnesia, aphasia, visuospatial dysfunction Electroencephalography Normal Neuroimaging Frontal or frontotemporal structural and functional abnormalities

atrophy has been shown to predict conversion to dementia in patients with MCI. There is also some preliminary evidence that CSF measures of AD-related pathology (e.g., CSF tau and P-amyloid) might predict dementia conversion among patients with MCI. Age is a strong predictor of conversion from MCI to dementia. In summary, there is converging evidence (e.g., psychometric, neuroimaging, neurogenetic) that MCI is characterized by a symptom pattern and prognosis that, though remaining benign in many cases, increasingly appears to exist within the same disease spectrum as other neurodegenerative cognitive disorders such as AD. Because even a minimum MCI-to-dementia conversion rate of 12% would in 5 years result in approximately 60% of patients with MCI converting to dementia, vigilant monitoring of patients with MCI is prudent.

Non-AD Neurodegenerative DementEas Identifymg a specific neurodegenerative dementia can sometimes seem as much art as science. However, with detailed clinical assessment, accurate diagnosis is possible (e.g., one study of interclinician reliability and diagnostic criteria validity for neurodegenerative dementias found near-perfect interrater agreement for diagnosing AD, frontotemporal lobar dementias, and progressive supranuclear palsy). Use of multiple diagnostic criteria for cortical and subcortical dementias increases clinical diagnostic accuracy. We will briefly review diagnostically relevant characteristics of the primary non-AD neurodegenerative dementias. Frontotemporal Lobar Dementias. Certain forms of degenerative disease disproportionately affect circumscribed areas of the frontal or frontotemporal cortex, producing a variety of clinical syndromes diagnostically grouped under the term fiontotemporal lobar dementia (FTLD). Although it is the third most common cause of degenerative cortical dementia after AD and dementia with Lewy bodies (DLB); (some epidemiologic studies place FTLD second), FTLD is much less common than AD, DLB, and vascular

dementia, especially in very old patients with dementia. Nevertheless, FTLDs are important to recognize because although insidious in onset, they usually progress to severe disability and sometimes fatality; their symptoms can mimic those of other disease states (particularly primary affective psychiatric disturbance); and management needs are very different from those of other dementias. Two histopathologic substrates primarily affecting frontal or temporal cortex underlie most FTLDs: microvacuolar change (frontal lobe degeneration type) and astrocytic gliosis with or without Pick bodies. Although the generic term FTLD refers to progressive circumscribed frontotemporal degeneration, distinct clinical syndrome phenomenology is determined primarily by neuropathologic distribution. Based on such differential neuroanatomic involvement, three prototypic neurobehavioral syndromes are recognized frontal-variant FTLD (fvFTLD; predominantly frontal pathology), semantic dementia (SD; predominant anterior temporal pathology), and primary progressive aphasia (PPA); mixed frontal, superior temporal). We briefly review each of these later in this chapter. Useful diagnostic criteria sets for FTLDs, with high interrater reliability (sensitivity and specificity up to 97%), have been formulated (e.g., Lund-Manchester groups). The American Academy of Neurology consensus criteria for FTLDs (an adaptation of the Lund-Manchester criteria) are presented for individual FTLD subtypes in Tables 138-10 through 138-12; common features of all major FTLDs are summarized in Table 138-13. Because of the complexity of the symptom and pathologic spectra of FTLDs, optimal evaluation and management entails cooperation across four disciplines: neurology, psychiatry, neuropsychology, and neuroimaging. fvFTLD is the FRONTAL VARIANTFRONTOTEMWN LOBARDEMENTIA. most common FTLD. Functional neuroanatomic division of the frontal lobe into three separate regions-medial, orbitobasal, and dorsolateral-provides a conceptual basis for organizing fvFTLD symptoms. For example, abulia can be associated with medial frontal-anterior cingulate involvement, social disinhibition and impulse dyscontrol with orbitobasal involvement, and executive

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TABLE158-11. Clinical Features of Semantic Dementia Core diagnostic features

Supportive diagnostic features

Insidious onset and gradual progression Language disorder characterized by Content-impoverished but fluent speech Impaired naming and comprehension Semantic paraphasias Perceptual disorder characterized by associative agnosia (impaired recognition of object identity) Preserved perceptual matching and drawing reproduction Preserved single word repetition Preserved ability to read aloud and write orthographically regular words Speech and language Idiosyncratic word usage Surface dyslexia or dysgraphia Speech pressure Absence of phonemic paraphasias Behavior Loss of sympathy and empathy Narrow preoccupations Parsimony Physical signs Akinesia, rigidity, tremor Absence or late primitive reflexes Investigations Neuropsychology Profound semantic loss Preserved phonology, syntax Electroencephalography Normal Neuroimaging Anterior temporal abnormalities

T M L E158-11. Diagnostic Features of Primary Progressive Aphasia Core diagnostic features

Supportive diagnostic features

Insidious onset and gradual progression Nonfluent spontaneous speech with at least one of the following Agrammatism Phonemic paraphasias Anomia Speech and language

Behavior Physical signs Investigations

Neuropsychology Electroencephalography Neuroimaging

Stuttering or oral apraxia Impaired repetition Alexia, agraphia Late mutism Preservation of word meaning Early preservation of social skills Late behavioral changes similar to frontotemporal lobar dementias Late contralateral primitive reflexes Akinesia, rigidity, tremor Nonfluent aphasia Absence of severe amnesia Normal or minor asymmetrical slowing Dominant hemisphere frontotemporal abnormality

TABLE138-15. Features Common to All Frontotemporal Lobar Dementia Syndromes Supportive features Exclusion features

Relative exclusion features

Onset before 65 Family history of similar disorder in first-degree relative Pseudobulbar palsy, muscular weakness or wasting, fasciculations History Abrupt onset lctal events Head trauma related to onset Exam Early severe amnesia Spatial disorientation Logoclonic, festinant speech Loss of train of thought Myoclonus Corticospinal weakness Cerebellar ataxia Choreoathetosis Investigations Neuroimaging Multifocal lesions Predominant postcentral structural/functional deficit Lab CNS involvement by one or more of the following: Metabolic disorder Inflammatory disorder Infectious disorder History Chronic alcoholism Vascular disease Examination Hypertension

Chapter 138 H Non-Alzheimer Dementias

TABLE138-14. Clinical Features of Dementia with Lewy

Bodies Spontaneousextrapyramidal features Marked fluctuations of alertness Recurrent visual hallucinations Syncope and episodes of transient unresponsiveness Unprovoked falls Neuroleptic sensitivity Systematic delusions Nonvisual hallucinations

(e.g., organization, planning) dysfunction with dorsolateral prefrontal cortex involvement. Symptom admixtures commonly occur with disease progression. Personality alteration is prominent but highly variable, ranging from reduced volition and affective blunting to aggression and gross social inappropriateness. Such marked behavioral disturbances can be erroneously attributed to primary psychiatric disease, often prompting initial patient presentation to a psychiatrist. For example, progressive apathy can be mistaken for depression. Alternatively, contextually inappropriate ebullience and impaired judgment can mimic the manic phase of bipolar disorder. Multiple potential behavioral changes can manifest. Activity often becomes stereotyped. Rituals (e.g., eating same food at the same time every day), verbal and ideational perseveration (e.g., repeated use of same catch-phrase), and behavioral perseveration (e.g., watching the same video over and over) are common. Speech output often becomes abridged, sometimes culminating in mutism (often associated with an amotivational or hypokinetic state), although episodic speech excess and pressure can occur in some patients with fvFTLD and prominent disinhibition. Patients often display a food preference change (increased sweets), and behavioral features of Kliiver-Bucy syndrome (e.g., hypersexuality, hyperorality) often occur. The term dysexecutive syndrome has been applied to the constellation of cognitive deficits in fvFTLD. Dysfunction routinely involves cognitive domains including attention, abstraction, planning, organization, problem solving, judgment, and mental flexibility. Primary elements of language, perception, and spatial function are well preserved. Typically not significantly amnesic, patients usually are well oriented. Memory deficits tend to be a secondary epiphenomenon of frontal regulatory disturbances (i.e., inattention with consequent encoding deficiency, defective strategies for learning and retrieval) rather than manifestations of a primary anterograde amnesia. Executive deficits typically are more evident in inert, avolitional patients than in overactive, disinhibited patients. Poor insight regarding these impairments sadly complicates patient management. Pick’s disease is the primary form of fvFTLD. A distinctive but inconsistent neuropathologic correlate of Pick’s disease is the Pick body-a basophilic intraneuronal inclusion-affecting prefrontal cortex and anterior temporal lobes including mediotemporal limbis structures. Atrophy involving frontotemporal cortex and subjacent white matter is severe, ultimately producing “knifeedge” gyri (ulegyria) in these regions, with abrupt transitions between mildly and severely involved sectors (e.g., between the anterior and posterior segments of the superior temporal gyrus). Neuropsychological testing plays an essential role in fvFTLD evaluation. Simple cognitive screening tests, such as the MiniMental State Exam, lack sensitivity for early signs of executive

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dysfunction and therefore are unreliable for detecting and monitoring fvFTLD. Useful neuropsychological tests are the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency challenge. Test profiles typically reveal frontal system deficits, including attention, verbal fluency, abstraction, and executive function. Quantifiable tests involving decision making and risk taking, which are better able to detect orbitobasal frontal function, have been developed. Anterograde memory performance is variable; patients with fvFTLD tend to do worse on spontaneous recall than on recognition tasks. Non-temporally graded remote memory loss can occur late in the disease course. The most striking neuropsychological finding is how well subjects perform on tests of visuospatial ability, particularly when organization aspects are minimized. Structural neuroimaging usually demonstrates bilateral and symmetrical frontal atrophy. However, this is not universal, especially early in the disease process. Functional imaging may be more sensitive for early diagnosis of fvFTLD. Of functional imaging modalities commonly available, 99Technetium single photon emission computed tomography probably is the most sensitive and can detect frontal hypoperfusion before atrophy is evident. FTLDs w m WWLY LANGUAGE DISTUR~ANCE (FTLD-LD). As with other FTLD diagnostic subdivisions, controversy exists regarding nosologic classification of FTLDs whose primary symptoms involve language disturbance. The syndrome initially was suggested by Pick, and Mesulam’s 1982 report of patients with gradually progressive dysphasia within the context of otherwise preserved intellect and insight sparked contemporary interest in the phenomenon commonly called primary progressive aphasia. Although language disturbances in such FTLD-related dysphasias are heterogeneous, two distinct clinical prototypes can be identified semantic dementia (SD) and primary progressive aphasia (PPA). It is important to recognize patients with FTLD-related dysphasias because such patients can be mistakenly diagnosed with stroke, neoplasm, or even AD because of the focal nature of their deficit (i.e., isolated language impairment). Histopathologyunderlying primary aphasias is varied Pick’s or AD-like aphasias are most common; less common neuropathology includes lipofuscinosis, gliosis, and spongiform changes. In general, language impairment remains an isolated but increasingly severe aphasia in about half of cases; the balance eventually progress to a more global dementia. Temporal Lobe Variant FTLD: Semantic Dementia. SD involves progressive dysnomia and word comprehension impairment in the context of fluent, grammatical speech (it is therefore grossly similar to Wernicke’s aphasia). There is preservation of repetition and ability to read aloud and write orthographicallyregular words (i.e., words whose phonemes follow regular rules of spelling representation). Patients can also display associative agnosia (impaired understanding of visual percepts); therefore, there is loss of meaning for both verbal and nonverbal elements. Patients with semantic dementia typically complain of wordfinding difficulty. Though often painfully aware of their worsening expressive vocabulary,patients often are unaware of their impaired comprehension. Because syntactic and phonologic language structures remain intact, clinical signs are subtle in early stages. Although behavioral symptoms are generally absent or minimal at presentation, fvFTLD-lie features can emerge at later disease stages.

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Behavioral Neurology and Epilepsy

Behavioral Neurology

Patients with SD demonstrate significant impairment on semantic memory tests. This is most apparent on tasks involving verbal output, such as category fluency tests, picture naming, and verbal definition tasks. Although able to read and write words with regular spelling-to-sound correspondence, patients with SD have difficulty reading and writing orthographically irregular words. This pattern, known as surface dyslexia or dysgraphia, has been attributed to loss of semantic support for pronunciation or spelling of irregular words. Episodic memory is spared, although quantitative assessment reveals impaired recall of more distant life events (a reversal of the usual temporal gradient of AD). Structural neuroimaging reveals anterior temporal neocortical atrophy, with inferior and middle temporal gyri predominantly affected. Asymmetries of temporal involvement reflect relative severity of impairment for verbal versus visual concepts (word meaning versus object recognition). Functional changes on single photon emission computed tomography usually precede detectable structural alterations, demonstrating dominant greater than nondominant temporal hypoperfusion. Primary Progressive Aphasia. PPA is a disorder of expressive language, characterized by effortful speech production, with phonologic and grammatical errors. Comprehension is well preserved. The language disorder occurs in the absence of impairment of other cognitive domains, although behavioral changes of fvFTLD may emerge late in the disease course. Patients present with complaints of speech dysfluency and distortion or word-finding difficulty. The pattern of cognitive deficits in primary progressive aphasia is in many ways the mirror image to that in semantic dementia. Patients perform well on tests of semantic memory except those involving phonologic competence. Although conversational speech is severely disrupted, anomia is mild. Structural neuroimaging usually reveals predominant left Sylvian fissure widening with atrophy of the insula, inferior frontal, and superior temporal lobes. NONSPECIFIC FTLDs. Frontal lobe dementias with nonspecific pathologic changes and atypical clinical symptom sets represent a loose category undergoing evolving nosologic description. For overview purposes, as a means of distinguishing these primary degenerative dementias, we simply call them nonspecific FTLDs. Nonspecific FTLDs often have cognitive and comportmental disturbances similar to Pick‘s disease. Both Pick’s and nonspecific FTLDs tend to have somewhat earlier average ages of onset (50 to 65 years) than AD, with longer survival times. Both disorders tend to occur within families; chromosome 17 abnormalities are being elucidated. A particularly virulent form of nonspecific FTLD occurs in combination with motor neuron disease of the kind seen in amyotrophic lateral sclerosis; memory can remain intact until late in the course of this variant but overall prognosis is poor, with progression to death in as few as 6 to 18 months. Despite the distinct clinical and investigative profiles of FTLDs, differentiation of this large class of non-AD dementias from AD can be diagnostically challenging. One study found that only stereotypy, changes in eating preference, disinhibition, and poor social awareness reliably separate FTLD from AD. Posterior Cortical Atrophy (PCA). PCA is a lobar dementia characterized by initial disturbances of visual perception and integration. Involvement of the occipitoparietal region produces visuospatial, attentional, and linguistic disturbances with relative sparing of personality, insight, and memory until late in the disease. PCA is sometimes called the visual variant of AD. Progression to a global dementia occurs in most cases.

Dementias Associated with Motor Disorders. Several forms of dementia involve the basal ganglia and their neocortical and subcortical projections. Consequently, these are associated with extrapyramidal movement disorders. PARKINSON’S DISEASE (PD). An estimated 30% to 40% of patients with PD develop dementia as part of their illness. It is thought that dementia in PD is underrecognized because of phenomenologically overwhelming problems with motor disturbances. PD-related dementia is characterized by psychomotor slowing, executive dysfunction, memory impairment, and visuospatial disturbances, as well as an increased propensity for depression. PD-related dementia is reportedly more common in patients with asymmetrical onset of parkinsonism affecting the nondominant side and accentuated gait disturbance relative to tremor. Cognitive symptoms may respond partially to dopaminergic pharmacotherapy in the early stages of the illnesses but tend to become refractory as the disease progresses and dementia becomes more severe. Recognition of dementia in PD is important because it is managed differently than dementia in AD. Therefore, a working knowledge of the clinical features of PD is essential. Both history and neurologic examination contribute to making a diagnosis of PD. A history of gait or balance problems, tremors, and extrapyramidal findings defines the movement disorder. Diagnostic criteria specifically for dementia in PD are evolving, as is the terminology. For example, some experts refer to the disorder that results when dementia and extrapyramidal signs and symptoms occur simultaneously as Parkinsonian dementia, or dementia associated with extrapyramidal disease. Psychometric testing may show slightly better recent memory and slightly worse executive functions than typical AD, but the pattern is nonspecific. For further discussion of cognitive changes associated with PD, see Chapter 118. DEMENTIA WITH L w BODIES. DLB probably is the second most common type of degenerative dementia after AD. DLB has clinical features that diagnostically overlap with AD and PD. Lewy bodies are eosinophilic intracytoplasmic inclusions that were originally described in the brainstem (substantia nigra) of patients with PD but occur with slight ultrastructural differences in cerebral (neocortical and paralimbic) neurons in several disorders. Despite its prevalence, clear consensus has not yet been reached regarding terminology, neuropathologic criteria, or clinical symptoms; universally accepted diagnostic criteria remain to be validated. DLB has been defined clinically by the presence of dementia, gait and balance disorder, prominent hallucinations and delusions, sensitivities to traditional antipsychotics, and fluctuations in alertness. Many studies investigating the accuracy of DLB diagnostic criteria against neuropathologic findings found high specificity (e.g., 94%) but low sensitivity (e.g., 34%). Heterogeneity of clinical presentation of DLB can yield low interrater reliability. Hallucinations, delusions, and affective disturbance all occur significantly more often in DLB, but can also occur in AD. Lack of specificity of DLB clinical diagnosis may be attributable to a similar amount of spontaneous extrapyramidal disturbance in DLB and non-DLB dementia. Prominent deficits in attention, visuospatial skills, and relative sparing of memory are neuropsychological features of DLB. However, neuropsychologic tests do not reliably differentiate DLB from AD or VAD. Also, even though patients with DLB tend to demonstrate less temporal lobe atrophy on MEU than do patients with AD, and more hypoperfusion in the occipital lobe on SPECT, neuroimaging has not proven successful in differentiating DLB from AD. Clinical presentation of DLB usually includes cognitive, affective, and motor components. Cognitive dysfunction can range

Chapter 138

from fluctuating impairment to sustained dementia. A superimposed fluctuation in alertness can sometimes mimic a deliriumlike component. Variable permutations of DLB-associated depressive features can include neurovegetative derangement, dysthymia, and psychomotor agitation. Delusions, if present, are typically depression congruent. The characteristic motor disturbance is parkinsonism, often with prominent bradykinesia. The parkinsonism, with or without resting tremor, occurs either spontaneously or in response to treatment with dopamine antagonists. Other features can include hallucinations, which tend to be complex and visual in nature, and frequent falling. In general, patients with DLB have greater visuospatial impairment and executive dysfunction than patients with AD. Rapid eye movement ( E M ) sleep is often disturbed Muscle tone normally decreases in REM sleep, but when patients with DLB attain REM sleep they do not become atonic. The result is that patients with DLB sometimes have a worrisome capacity to act out their dreams (i.e., develop REM sleep disorder). Lewy bodies are widely distributed in the cerebral cortex and substantia nigra in DLB. In contrast, Lewy bodies usually are confined to the substantia nigra in PD. Lewy bodies can occur with or without neuritic plaques or neurofibrillary tangles. Lesions that appear to be most relevant to cognitive decline in DLB are cortical Lewy bodies, Lewy-related neurites, senile plaques, neurofibrillary tangles, neuronal and synaptic loss, spongiform change, and cholinergic deficits. It is possible to operationally classify patients with cognitive decline and cortical Lewy bodies into three main groups: cortical DLB, cortical DLB with plaques, and cortical DLB with plaques and tangles; frequent overlap occurs. Approximately 25% of autopsied cases of AD have substantial numbers of Lewy bodies in both the brainstem and the neocortex. This clinical entity, sometimes called the Lewy body variant of AD, often is associated with increased senile plaque counts but usually lacks sufficient neurofibrillary tangles to meet criteria for a formal diagnosis of AD. However, the histopathology of DLB, PD, and AD can overlap, and a subgroup of patients can simultaneously meet criteria for DLB, PD, and AD. The diagnosis of DLB has several important implications for patient management. As neuroleptic use becomes a complicated process in any dementia with comorbid parkinsonism (because neuroleptic-related dopamine blockade can worsen parkinsonian motor disturbance), this caution becomes imperative in DLB. Patients with DLB often are exquisitely sensitive to neuroleptics, which can precipitously worsen the overall clinical profile. Other important management issues include making caregivers aware that hallucinations are common and that impaired postural stability and falling necessitates added supervision. Cholinesterase inhibitors have shown some efficacy for DLB-related cognitive and behavioral symptoms. PROGRESSIVE SUPRANUCLEAR PALSY (PSP). About 7% of patients with parkinsonian motor abnormalities suffer from progressive supranuclear palsy, a disorder affecting volitional vertical eye movements early in its course. PSP causes a dementia similar to that of PD in 50% to 75% of affected patients. PSP is the most common “dementia with parkinsonism” after DLB. Typical clinical findings in PSP are impaired vertical (downward) eye movements together with axial (truncal) postural disturbances and bulbar dysfunction. Recent studies suggest that PSP is a recessive disorder, in linkage dysequilibrium with the tau gene, rather than a sporadic disease. HUNTINGTON‘S DISEASE (HD). HD is a progressive, eventually fatal neuropsychiatric disease occurring in 5 to 10 per 100,000 in the

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general population. A prototypical genetically based neurodegenerative disorder, HD is inherited as an autosomal dominant trait with complete penetrance. One third of patients with HD have psychiatric changes at onset, and an even greater number suffer cognitive decline. Executive dysfunction and memory impairment are cardinal features of the dementia of HD. Patients with HD display core deficits in frontal corticosubcortical circuits, which yield a multitude of cognitive deficits. Meta-analyses of HD cognitive studies indicate that patients with HD are most deficient on tests of delayed recall, followed by performance deficits on measures of memory acquisition, cognitive flexibility, abstraction, manual dexterity, sustained attention and verbal skills. See Chapter 126 for additional information about HD. Spinocerebellar Degenerations. Dementia can sometimes be a feature of inherited ataxias. The most common autosomal recessive form, Friedreich‘s ataxia, is characterized by early onset of gait ataxia, sensory deficits, and areflexia; cognitive deficits are sometimes present. The large and heterogeneous group of autosomal dominant forms of inherited ataxias, now collectively called spinocerebellar ataxias, can also sometimes include a component of sustained or progressive cognitive impairment. Dementia can also occur in the etiologically heterogeneous Ramsay Hunt syndrome, marked by the clinical dyad of progressive ataxia and myoclonus, and the less common dyssynergia cerebellaris myoclonica. Cortico-Basal Ganglionic Degeneration (CBGD). CBGD is a rare neurodegenerative disease, beginning during the sixth decade or later, marked by asymmetrical rigidity and postural disturbances that may predispose to falls. Focal myoclonus and tremors are occasionally associated features. Apraxias are characteristic of the dementia of CBGD and are usually apparent before cognitive dysfunction in other domains. Approximately 60% of patients experience “alien limb syndrome,” a phenomenon in which the affected limb assumes positions or carries out actions disconnected from the patient’s awareness. CBGD often is associated with asymmetrical cortical atrophy affecting the frontoparietal neocortex, with attendant reductions of cerebral metabolism in that region. Neuropathologic findings include patchy neuronal loss and gliosis in the cerebral cortex and substantia nigra, as well as a characteristic intraneuronal nigral inclusion body. CBGD typically progresses to global dementia; death usually ensues within 5 to 10 years. There is no known treatment. Motor Neuron Disease-Related Dementias. In the course of their disease, certain patients with FTLD develop clinical features compatible with a motor neuron disease (FTLD-MND). Previous reports have suggested that the functional pattern is similar in FTLD and FTLD-MND. However, some neuropathologic studies suggest greater involvement of medial temporal regions in FTLD-MND than in FTLD. Positron emission tomography scans of patients with FTLD and FTLD-MND suggest comparable frontal and lateral temporal hypometabolism in FTLD and FTLD-MND, but greater impairment of medial temporal lobe activity in FTLD-MND. This has prompted investigators to theorize a functional continuum between classic MND, FTLDMND, and FTLD. SUGGESTED READINGS Beghuis JP, Uldall KK, Lalonde B: Validity of two scales in identifying HIV-associated dementia. J Acquir Immune Defic Syndr 21(2): 1 3 6 140, 1999

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Bozeat S, Gregory CA, Lambon MA et al: Which neuropsychiatric and behavioral features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 69:178-186, 2000 Bozoki A, Giordani B, Heidebrink JL et al: Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol 58(3):411-416, 2001 Breteler MM, Ott A, Hofman A The new epidemic: frequency of dementia in the Rotterdam study. Haemostasis 28(3-4):117-123, 1998 Brie1 RC, McKeith IG, Barker WA et ak EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 66(3):401-403, 1999

Collins S, Boyd A, Fletcher A et al: Creutzfeldt-Jakobdisease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. J Clin Neurosci 7(3):203-208, 2000 Freter S, Bergman H, Gold S et al: Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort. CMAJ 159(6):657-662, 1998

Garraux G, Salmon E, Degueldre C et al: Medial temporal metabolic impairment in dementia associated with motor neuron disease. J Neurol Sci 168(2):145-150, 1999 Gomez-Tortosa E, Ingraham AO, Irizarry MC et al: Dementia with Lewy bodies. J Am Geriatr SOC46(11):1449-1458, 1998 Gregory CA, Serra-Mestres J, Hodges J R Early diagnosis of the frontal variant of frontotemporal dementia: how sensitive are standard neuroimaging and neuropsychologicaltests? Neuropsychiatry Neuropsychol Behav Neurol 12(2):128-135, 1999 Gultekin SH, Rosenfeld MR, Voltz R et ak Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings, and tumor association. Brain 123(7):1481-1494, 2000 Hardy J: Genetic dissection of neurodegenerative disease. Clin Neurosci Res l(1-2):134-141, 2001 Hodges J R Frontotemporal dementia (Pick‘s disease): clinical features and assessment. Neurology 56(S4):6-10, 2001 Iddon JL, Pickard JD, Cross JJL et ak Specific patterns of cognitive impairment in patients with idiopathic normal pressure hydrocephalus and Alzheimer’s disease: a pilot study. J Neurol Neurosurg Psychiatry 67~723-732, 1999

Ihl R, Brinkmeyer J: Differential diagnosis of aging, dementia of the Alzheimer type, and depression with EEG-segmentation. Dement Geriatr Cogn Disord 10(2):64-69, 1999 Leys D, Pasquier F, Parnetti L Epidemiology of vascular dementia. Haemostasis 28(3-4):134-150, 1998 Litvan I, Hutton M. Clinical and genetic aspects of progressive supranuclear palsy. J Geriatr Psychiatry Neurol 11(2):107-114, 1998

Looi JC, Sachdev PS: Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 53(4):670-678, 1999 Lopez OL, Litvan I, Catt KE et al: Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 53 (6):1292-1 299, 1999

Lowe J, Dickson D: Pathologic diagnostic criteria for dementia associated with cortical Lewy bodies: a review and proposal for a descriptive approach. J Neural Transm 51:lll-120, 1997 Lund and Manchester Groups: Consensus statement: clinical and neuropathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry 4416-418, 1994 Meyers BS: Depression and dementia: comorbidities, identification, and treatment. J Geriatr Psychiatry Neurol 11(4):201-205, 1998 Miller BL, Gearhart R Neuroimaging in the diagnosis of fronto-temporal dementia. Dement Geriatr Cogn Disord 10(S1):71-74, 1999 Neary D, Snowden JS, Gustafson L et ak Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:15461554, 1998

Nolan KA, Lino MM, Seligman AW et al: Absence of vascular dementia in an autopsy series from a dementia clinic. J Am Geriatr SOC 46(5):597404, 1998

Nyenhuis DL, Gorelick PB Vascular dementia: a contemporary review of epidemiology,diagnosis, prevention, and treatment. J Am Getriatr SOC 46( 11):1437-1448, 1998

Papka M, Rubio A, Schiffer RB: A review of Lewy body disease, an emerging concept of cortical dementia. J Neuropsychiatry Clin Neurosci 10(3):267-279, 1998 Patterson CJ, Gauthier S, Bergman H et al: The recognition, assessment, and management of dementing disorders: conclusions from the Canadian Consensus Conferenceon Dementia. CMAJ 160(S12):S1-15, 1990

Pinner G, Johnson H, Bouman WP et ak Psychiatric manifestations of normal-pressure hydrocephalus. Int Psychogeriatr 9(4):465-470, 1997 Poser S, Mollenhaeur B, Kraubeta A et ak How to improve the clinical diagnosis of Creutzfeldt-Jakobdisease. Brain 122( 12):2345-2351, 1999 Salloway S, Hong J: CADASIL syndrome: a genetic form of vascular dementia. J Geriatr Psychiatry Neurol 11(2):71-77, 1998 Scheltens P, Hijdra AH: Diagnostic criteria for vascular dementia. Haemostasis 28(3-4):151-157, 1998 Van Kooten F, Koudstaal PJ: Epidemiology of post-stroke dementia. Haemostasis 28(3-4):124-133, 1998 Zakzanis K K The subcortical dementia of Huntington’s disease. J Clin Exp Neuropsychol 20(4):565-578, 1998

139 Confusional States and Metabolic Encephalopathy Michael Ronthal Confusion (delirium) may be defined as a disorder of higher cognitive function characterized by loss of the normal coherent stream of thought or action. The label delirium often is used synonymously with confusional state. It is useful to reserve the former for agitated patients with autonomic instability and hallucinations as part of their confusion. Delirium therefore would be a good description for patients in alcoholic withdrawal and adequately describes the clinical picture in delirium tremens. Although the young are not immune, major risk factors for the development of a confusional state include age and the presence of

an underlying mild preexisting cognitive defect. Patients aged 65 and older account for more than 48% of all inpatient days of hospital care in the United States. Delirium develops in 20% to 30% of hospitalized patients. Each year delirium complicates hospital stays for more than 2.3 million people. Thirty to seventy percent of patients with confusion are not diagnosed by their health care providers, and many physicians remain oblivious to the fact that an acute confusional state is a n emergency and may signify the presence of a life-threatening illness. Reported hospital mortality rates for patients with confusion range from 10% to 65%, 2 to 20 times those of control patients.

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Bozeat S, Gregory CA, Lambon MA et al: Which neuropsychiatric and behavioral features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 69:178-186, 2000 Bozoki A, Giordani B, Heidebrink JL et al: Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol 58(3):411-416, 2001 Breteler MM, Ott A, Hofman A The new epidemic: frequency of dementia in the Rotterdam study. Haemostasis 28(3-4):117-123, 1998 Brie1 RC, McKeith IG, Barker WA et ak EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 66(3):401-403, 1999

Collins S, Boyd A, Fletcher A et al: Creutzfeldt-Jakobdisease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. J Clin Neurosci 7(3):203-208, 2000 Freter S, Bergman H, Gold S et al: Prevalence of potentially reversible dementias and actual reversibility in a memory clinic cohort. CMAJ 159(6):657-662, 1998

Garraux G, Salmon E, Degueldre C et al: Medial temporal metabolic impairment in dementia associated with motor neuron disease. J Neurol Sci 168(2):145-150, 1999 Gomez-Tortosa E, Ingraham AO, Irizarry MC et al: Dementia with Lewy bodies. J Am Geriatr SOC46(11):1449-1458, 1998 Gregory CA, Serra-Mestres J, Hodges J R Early diagnosis of the frontal variant of frontotemporal dementia: how sensitive are standard neuroimaging and neuropsychologicaltests? Neuropsychiatry Neuropsychol Behav Neurol 12(2):128-135, 1999 Gultekin SH, Rosenfeld MR, Voltz R et ak Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings, and tumor association. Brain 123(7):1481-1494, 2000 Hardy J: Genetic dissection of neurodegenerative disease. Clin Neurosci Res l(1-2):134-141, 2001 Hodges J R Frontotemporal dementia (Pick‘s disease): clinical features and assessment. Neurology 56(S4):6-10, 2001 Iddon JL, Pickard JD, Cross JJL et ak Specific patterns of cognitive impairment in patients with idiopathic normal pressure hydrocephalus and Alzheimer’s disease: a pilot study. J Neurol Neurosurg Psychiatry 67~723-732, 1999

Ihl R, Brinkmeyer J: Differential diagnosis of aging, dementia of the Alzheimer type, and depression with EEG-segmentation. Dement Geriatr Cogn Disord 10(2):64-69, 1999 Leys D, Pasquier F, Parnetti L Epidemiology of vascular dementia. Haemostasis 28(3-4):134-150, 1998 Litvan I, Hutton M. Clinical and genetic aspects of progressive supranuclear palsy. J Geriatr Psychiatry Neurol 11(2):107-114, 1998

Looi JC, Sachdev PS: Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 53(4):670-678, 1999 Lopez OL, Litvan I, Catt KE et al: Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 53 (6):1292-1 299, 1999

Lowe J, Dickson D: Pathologic diagnostic criteria for dementia associated with cortical Lewy bodies: a review and proposal for a descriptive approach. J Neural Transm 51:lll-120, 1997 Lund and Manchester Groups: Consensus statement: clinical and neuropathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry 4416-418, 1994 Meyers BS: Depression and dementia: comorbidities, identification, and treatment. J Geriatr Psychiatry Neurol 11(4):201-205, 1998 Miller BL, Gearhart R Neuroimaging in the diagnosis of fronto-temporal dementia. Dement Geriatr Cogn Disord 10(S1):71-74, 1999 Neary D, Snowden JS, Gustafson L et ak Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:15461554, 1998

Nolan KA, Lino MM, Seligman AW et al: Absence of vascular dementia in an autopsy series from a dementia clinic. J Am Geriatr SOC 46(5):597404, 1998

Nyenhuis DL, Gorelick PB Vascular dementia: a contemporary review of epidemiology,diagnosis, prevention, and treatment. J Am Getriatr SOC 46( 11):1437-1448, 1998

Papka M, Rubio A, Schiffer RB: A review of Lewy body disease, an emerging concept of cortical dementia. J Neuropsychiatry Clin Neurosci 10(3):267-279, 1998 Patterson CJ, Gauthier S, Bergman H et al: The recognition, assessment, and management of dementing disorders: conclusions from the Canadian Consensus Conferenceon Dementia. CMAJ 160(S12):S1-15, 1990

Pinner G, Johnson H, Bouman WP et ak Psychiatric manifestations of normal-pressure hydrocephalus. Int Psychogeriatr 9(4):465-470, 1997 Poser S, Mollenhaeur B, Kraubeta A et ak How to improve the clinical diagnosis of Creutzfeldt-Jakobdisease. Brain 122( 12):2345-2351, 1999 Salloway S, Hong J: CADASIL syndrome: a genetic form of vascular dementia. J Geriatr Psychiatry Neurol 11(2):71-77, 1998 Scheltens P, Hijdra AH: Diagnostic criteria for vascular dementia. Haemostasis 28(3-4):151-157, 1998 Van Kooten F, Koudstaal PJ: Epidemiology of post-stroke dementia. Haemostasis 28(3-4):124-133, 1998 Zakzanis K K The subcortical dementia of Huntington’s disease. J Clin Exp Neuropsychol 20(4):565-578, 1998

139 Confusional States and Metabolic Encephalopathy Michael Ronthal Confusion (delirium) may be defined as a disorder of higher cognitive function characterized by loss of the normal coherent stream of thought or action. The label delirium often is used synonymously with confusional state. It is useful to reserve the former for agitated patients with autonomic instability and hallucinations as part of their confusion. Delirium therefore would be a good description for patients in alcoholic withdrawal and adequately describes the clinical picture in delirium tremens. Although the young are not immune, major risk factors for the development of a confusional state include age and the presence of

an underlying mild preexisting cognitive defect. Patients aged 65 and older account for more than 48% of all inpatient days of hospital care in the United States. Delirium develops in 20% to 30% of hospitalized patients. Each year delirium complicates hospital stays for more than 2.3 million people. Thirty to seventy percent of patients with confusion are not diagnosed by their health care providers, and many physicians remain oblivious to the fact that an acute confusional state is a n emergency and may signify the presence of a life-threatening illness. Reported hospital mortality rates for patients with confusion range from 10% to 65%, 2 to 20 times those of control patients.

Chapter 139

After 1 month, median rates of institutionalization and mortality are 44% and 16%, respectively. After 6 months the rates are 36% and 26%, respectively. When attempting to elicit the history, it soon becomes apparent that the patient is distractible and inattentive. These two signs are consistently present in all confused patients. Conversely, distractibility and inattention do not always imply confusion but are often encountered in the course of daily living. What leads to the diagnosis of confusion is the inability of the patient to interact with the examiner in an orderly, goal-directed, and coherent fashion, making it impossible to stay on track. When attention is low, distractibility is high. Some patients are agitated and hyperactive. Inattention in these patients is a global dysfunction and does not imply a loss of directed attention to hemibody or hemispace. One cause of global inattention is dysfunction of the subcortical arousal mechanisms in the brainstem; failure in this system may result in drowsiness, progressing to coma. However, this syndrome is not the subject of this chapter; rather, dysfunction in the supratentorial compartment is explored. PSYCHOLOGY OF AlTENTIONAL SYSTEMS Basic attentional mechanisms function at a subconscious level to allow normal cognitive and motor function. The system has survival value and is present in humans and animals during consciousness. The following characteristics can be defined.

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PATHOPHYSIOLOGY OF CONFUSION A confused patient is distracted by trivial stimuli yet fails to react to stimuli of importance. He or she may suddenly shift attention at an inappropriate moment yet may maintain attention after it has become inappropriate. We are not dealing with a simple rise or fall in the arousal level but rather a more profound disruption of the normal hierarchy of rules. Action and thought lose their normal coherence, the patient responds in an inappropriate manner, and the line of thinking becomes jumbled.

PHYSICAL SIGNS As in any syndrome of disordered function, the diagnosis is made on the basis of examination and the eliciting of physical signs; here the signs are to be found in the mental status examination. Not all patients exhibit all the signs described, but at various times one or more of the following signs is found. A good research and clinical instrument to help with the diagnosis is the Confusion Assessment Method (CAM). This has been shown to be sensitive, specific, reliable, and easy to use. Four key features of delirium are defined

Acute onset and fluctuating course Inattention Disorganized thinking Altered level of consciousness

All confused patients are inattentive. Usually a few simple tests of Selectivity We are subject at all times to multiple external and internal environmental stimuli. If effective learning or action is to take place, only a limited number of these can be handled at any particular moment. Thus the predatory animal tracking prey must pay selective attention to the trail at the expense of many other surrounding stimuli. The nursing mother selects stimuli originating from her newborn infant at the expense of other environmental cues.

Coherence Coherence is the ability to maintain selective attention over time.

the attentional system suffice to establish abnormalities. Tests of attention are discussed in Chapter 135. Repeating months or days of the week backward, counting forward in threes, and repeating seven numbers forward or five backward are good screening tests. Loss of Coherence Loss of coherence is established upon attempting to elicit a consecutive history. The dialogue becomes bizarre; the topic shifts abruptly, or the patient may persist with a topic long since thought abandoned. Fragments of the program of action are preserved, but although individual movements are executed correctly, the overall program is lost. This represents one kind of ideational apraxia, as originally described by Hugo Liepmann.

Disorders of Memory

Distractibility Although selectivity and coherence allow effective thought and action, other coincident and simultaneous stimuli must be monitored at the same time. The animal must be capable of screening the environment and have a set of rules to determine the criteria that lead to a shift of focus. Thus, at a cocktail party, one is capable of a one-on-one conversation; the background bustle is filtered out. Yet if one’s name is spoken softly, one’s attention shifts automatically to the sound. The rules for distraction are complex and depend on the immediate state of the animal and on previous learning.

Although patients usually are amnestic for the episode of confusion when they recover, memory is sometimes distorted rather than lost during the confusional state. A paramnesia is an error of memory in which the answers to the questions are incorrect but the elements of the correct answer are present. Geographic paramnesia is the most common. Here the patient, when asked for orientation, may state that he or she is in another city or town yet may correctly identify the building or hospital. When confronted with the previous answer, he or she may claim to be in the “branch office” in the other town.

Propagation of Error Universality The monitoring system must register as many environmental stimuli as possible.

Once the error has been made, the patient persists in the delusion and brings other environmental elements into apparent coherence. For example, the patient may interpret the stand to which the

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intravenous infusion apparatus is attached as being a lamp in his or her living room. Inattentionto Environmental Stimuli

In true amnestic syndromes, the patient is hyperattentive to environmental cues and relies on them to function. The confused patient, in the example just mentioned, will deny that he or she is in a hospital or doctor’s office, even though the evidence is abundant. Occupational Jargon

The patient may use language reminiscent of his or her workplace. Occasionallythe patient speaks in military or legalistic style. When asked to name, say, a pair of spectacles, he or she may describe them as “an optical instrument for the purpose of increasing visual acuity.” Isolated or Predominant Disturbance of Writing

Spoken language usually is well preserved, although occasional anomia or neologisms may be seen. Conversely, writing often is disrupted, sometimes severely. Writing may degenerate to a scrawl; it often does not stay on the line but moves upward, and there are often perseverations of loops. The deficit cannot be ascribed to an aphasia but rather represents a breakdown in writing secondary to the basic attentional deficit. Unconcern4 t h or Denial of Illness

Confused patients may be fully aware of their illness but show unconcern or denial, a feature shared with patients who have right hemisphere lesions but are not confused. Unconscious Humor or Playful Behavior

Confused patients often are unintentionally funny. The apparent wit is the chance result of an incoherent stream of thought that results in the apposition of incongruous or inappropriate phrases and ideas. One patient who believed that he was at home, when confronted with the undeniable evidence of another patient in the next bed, thought for an instant and stated, “I’m going to charge him rent!” Gait Disorder

This is probably the most frequently missed sign: having established the diagnosis of confusion, we rarely get the patient up to walk. The gait disorder may be nonspecific in type, but occasionally asterixis may involve the lower limb muscles, resulting in sudden loss of tone with a sudden lurch downward. Hyperactivity

The patient may be hyperactive to the point of needing four-point restraints. He or she may be described as “wild” or “psychotic” and may be admitted to a psychiatric ward in “delirium.” Delirium tremens is one such hyperactive form of confusional state or encephalopathy characterized by the appearance of formed hallucinations, sometimes of animals, which may elicit fear.

CAUSES OF CONFUSION Intoxication The most common cause of a diffuse encephalopathy or confusional state is some sort of “brain intoxication.” The toxin may be exogenous (e.g., alcohol, street drugs, or pharmaceutical preparations), or it may be endogenous (e.g., organ failure or some other dysmetabolic state). Drug or alcohol withdrawal may be the precipitant. Failure of almost any of the body systems is a possible cause of confusion and must be assiduously sought. Sepsis-acute, subacute, or chronic-in any anatomic organ is a likely culprit. In these patients, treatment of the underlying systemic illness or withdrawal of the exogenous toxin is the treatment of the disordered cognitive state. It should be appreciated that recovery of brain function may be delayed for some days and sometimes weeks after correction of the causative abnormality. Patients with borderline or very mild dementia are particularly vulnerable to metabolic or toxic encephalopathy. In the presence of severe inattention and confusion it may not be possible to establish a true baseline, and it is only after recovery that the fixed or progressive deficits can be established. Some authors have called this vulnerable brain syndrome with confusion “beclouded dementia.” At the bedside, the clue to an intoxication is the presence of asterixis or, more rarely, multiple myoclonus. Cerebrospinal Fluid Pleocytosis

The presence of cells in the spinal fluid is a potent cause of confusion. The cells may be red cells, white cells, bacteria or some other infecting agent, or even malignant cells. A spinal tap is mandatory in the workup of these patients, even when a metabolic abnormality is suspected. Seizure

Patients may be confused either as part of a partial seizure or in the postictal state. On occasion anticonvulsant drugs themselves may be the culprit, but ordinarily confusion secondary to a seizure disorder responds to anticonvulsants. Because the seizure may not be immediately clinically apparent at the bedside, an electroencephalogram is part of the essential workup of these patients. Pain

Poor pain control in the postsurgical patient has been correlated with a higher incidence of confusion. Environmental Stressors

Sensory deprivation, particularly blindness as in cataract surgery, immobilization and forced restraint, and interference with circadian rhythms as in the intensive care unit are common contributing factors. Head Injury

Confusion may be the presenting syndrome immediately after an injury. It may be transient, as after a minor concussion, or it can be prolonged as part of the recovery phase of more serious injuries. Because there may be no clear history of head injury, a

Chapter 139

careful examination of the skull and scalp are essential in evaluating these patients. Structural Brain Lesions An acute or fairly rapidly progressive structural brain lesion may be the cause. These lesions, whether caused by stroke, focal inflammatory processes, or surgery, usually are found in the right hemisphere. The elementary examination may or may not demonstrate left body signs, and an imaging procedure sometimes is the only way to demonstrate the focal pathology. As noted earlier, all confused patients are inattentive, and it has been suggested with fairly good evidence that the right hemisphere is dominant for the function of attention. The predominance of right hemisphere lesions in this subgroup of patients therefore may reflect a disturbance of the basic underlying attentional matrix. It has been argued that confusion cannot be diagnosed in patients with left hemisphere lesions because they are aphasic. With sophisticated neuropsychological testing it can usually be shown, even in the presence of aphasia, that the patient is attentive and does not lack coherence. Multifocal brain disease, whatever the cause, is a potent cause of confusion. Patients with lesions of the undersurface of either the right or left occipital lobe may present with a hyperactive confusional state, sometimes to the degree that they may need physical restraint. In such cases it is impossible to examine the visual fields, and imaging is the only way to demonstrate the lesion. Focal lesions in the parahippocampal-fusiform-lingualgyri on either side of the brain probably are focal lesions in agitated confusional states. Agitation may also occur after infarction in the right middle cerebral artery territory.

rn Confusional States and Metabolic Encephalopathy

TABU159-1. Common Causes of Confusional States and the Appropriate Tests Cause

Sie

Test

Infection

Urinary tract Lung or bronchi

Urinalysis or culture Sputum analysis, radiograph Spinal tap Spinal tap As appropriate Spinal tap Blood or urine toxic screen

Meninges Brain Other organ Meningeal irritation Toxin

Exogenous Endogenous Renal Respiratory Cardiac Liver Endocrine Porphyria Withdrawal Alcohol Barbiturate

Blood urea nitrogen and creatinine Blood gases Examination, radiograph, ultrasound Liver function tests As appropriate Urine screen

Electrolyte screen Calcium Magnesium PH Glucose Red cell transketolase

Electrolyte disorder

Vitamin deficiency

Blood level Other system dysfunction Seizure Migraine Stroke Miscellaneous

As appropriate Electroencephalogram Occult neoplasm Blood diseases Space-taking lesion Postooerative state

WORKUP Confusional state or diffuse encephalopathy are simply labels used to describe a clinical syndrome. That syndrome, as can be seen from the preceding discussion, has many causes. The true test of the astute clinician is to find and treat the cause. The cause may be as mundane as a urinary tract infection or as obscure as an inborn error of metabolism that becomes apparent at a time of stress. The workup therefore may be long, arduous, and expensive. Many confused older adults are treated with multiple medications, and careful consideration and pruning of the drug list may be the most valuable intervention one can offer. Table 139-1 lists some common causes of confusional states and the appropriate tests. All patients should undergo a blood screen for organ failure, a workup for sepsis, an imaging process, an electroencephalogram, and a spinal tap for the reasons given earlier. A urine and blood toxic screen are added in suspicious circumstances. Some confused patients may need a more extensive workup; searching for the cause is a challenge to diagnostic skill. It might be argued that a complete and extensive workup including brain imaging, spinal fluid examination, and electroencephalogram is not cost-effective for the majority of patients in whom the cause of confusion is a systemic disease, organ failure, or exogenous toxin. It should not take longer than 24 hours to complete the basic workup for these conditions. In patients who are febrile without obvious source, are immunocompromised, have known vascular risk factors, have background cancer, or have obvious focal signs, specific neurologic studies should be done immediately as part of the workup.

889

Imaging study Imaging study Complete blood cell count Imaging study

TREATMENT The prime concern of the treating physician is to establish the cause of the confusional state and treat appropriately. That having been said, primary prevention and symptomatic treatment are also important. Education, support, reorientation, anxiety reduction, and preoperative medical assessment can be modestly successful in preventing confusion in young and old surgical patients, but often not in older medical patients. Identification and prevention of risk factors can be rewarding. In one recent study, cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration were evaluated as risk factors, and the intervention was provided by a trained interdisciplinary team consisting of a geriatric nurse specialist, two specially trained elder life specialists, a certified therapeutic recreation specialist, a physical therapy consultant, a geriatrician, and trained volunteers. The incidence of delirium was 9.9% in the intervention group and 15% in the usual care group. The total number of days of delirium was 105 in the intervention group and 161 in the usual care group. Symptomatic treatment is best provided by a sitter who will prevent wandering. Although this may be economically difficult, restraints may make the situation worse and can lead to agitation. A quiet and nonstimulating environment may have a calming effect; ambient noise and bright lights should be toned down.

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Agitation necessitates drug therapy; neuroleptic dosages should be monitored carefully if side effects are to be minimized. A suggested starting dosage is 0.25 to 0.5 mg haloperidol repeated up to four times in the first 24 hours. The newer antipsychotics have fewer parkinsonian side effects and may become the treatment of choice: risperidone 0.5 mg/day with a maximum of 4 mg and quetiapine 25 mg with a maximum 300 mg/day are good candidate drugs, but the results of controlled trial are awaited. Although widely used, anxiolytics have not been studied carefully. Lorazepam 0.5 mg/day up to 4 mg/day may be effective and has a shorter half life than diazepam. A benzodiazepine would be the drug of choice for alcohol or drug withdrawal-related confusional states. Antidepressants have been reported to be of some symptomatic benefit. Trazodone, beginning with 25 mglday and increasing to a maximum of 300 mg/day, is about as effective as haloperidol but with fewer side effects. Anecdotal reports support the use of fluvoxamine, fluoxetine, and sertraline. CHRONIC CONFUSION On occasion, especially after an acute right hemisphere stroke, the patient becomes confused and does not recover. The basic defect of attention persists, and the patient lapses into a chronic confusional state. It might be argued that these patients are essentially demented. The essential difference between dementia and chronic confusional state is that the dementia is progressive, and the chronic confusional state is static.

Chedru F, Geschwind N: Writing disturbances in acute confusional states.

Neuropsychologia 10343-353, 1972 Cole MG, Primeau F, McCusker J: Effectiveness of interventionsto prevent delirium in hospitalized patients: a systematic review. Can Med Assoc J 155(9):1263-1268, 1996 Devinsky 0, Bear D, Volpe BT: Confusional states following posterior cerebral artery infarction. Arch Neurol45160-163, 1988 Geschwind N Disorders of attention: a frontier in neuropsychology. Philos Trans R SOCLond B Biol Sci 298:173-185, 1982 Gnanamuthu C Confusional states and seizures: when are they related? Postgrad Med 84:149-158, 1988 Inouye SK Delirium in hospitalized older patients: recognition and risk factors. J Geriatr Psychiatry Neurol 11:118-125, 1998 Inouye SK, Bogardus ST, Charpentier PA et ak A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 340669-676, 1999 Lipowski ZJ: Delirium (acute confusional states). JAMA 258: 1789-1792, 1967 Mesulam MM: Attentional networks, confusional states, and neglect syndromes. pp. 174-256. In Mesulam M M Principles of Behavioral Neurology. 2nd ed. Oxford University Press, New York, 2000 Mesulam MM, Waxman SO, Geschwind N, Sahin TD: Acute confusional states with right middle cerebral artery infarctions. J Neurol Neurosurg Psychiatry 3984-89, 1976 Mulalley W, Ronthal M, Huff K, Geschwind N Chronic confusional state. N J Med 86541-544, 1989 Pousada L, Leipzig RM: Rapid bedside assessment of postoperative confusion in older patients. Geriatrics 4559-64, 66, 1990 Ribby KJ, Cox KR: Development, implementation and evaluation of a confusion protocol. Clin Nurse Specialist 10(5):241-247, 1996 Schmidley JW,Messing RO: Agitated confusional states in patients with right hemisphere infarctions Stroke 15:883-885, 1984

SUGGESTED READINGS Amit R Acute confusional state in childhood. Childs New Syst 4:255-258, 1988

140 Speech and Language Disorders Howard S. Kirshner Speech and language disorders have long attracted interest. Historically, they were the first higher functions to be directly associated with a specific area of the brain. In addition, human communication is the function that sets us apart most clearly from the animals. Speech and language disorders provide a window on the mind-body connection and link neurology to cognitive psychology, linguistics, and philosophy. For neurologists, speech and language disorders also have practical implications. They are among the most common of serious neurologic maladies. About 20% of strokes produce language disturbance, and a greater number affect speech articulation. Language deficits are common in patients with traumatic brain injuries, brain tumors, dementias, neurodegenerative diseases, and infections of the nervous system such as acquired immunodeficiency syndrome. Disorders of communication frustrate patients and families and challenge the abilities of physicians. In recent years, knowledge about language and the brain has expanded greatly. New developments include brain imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), which provide a simultaneous view of

brain pathology to be correlated with behavioral study, and the functional imaging modalities of positron emission tomography, single photon emission computed tomography, and functional MRI, all of which provide a map of the functional activation of cortical areas during behavioral activities and tasks in both patients with aphasia and normal subjects. Finally, electrical mapping of the language cortex via direct electrical stimulation or transcranial magnetic stimulation, in preparation for epilepsy surgery, has provided an independent window on the organization of language in the brain. Cognitive neuroscientists and linguists have developed sophisticated linguistic models and test paradigms of the cognitive operations involved in language function. All of these advances have contributed to our understanding of language, building on the foundation based on studies of patients with strokes and other focal brain pathologies over the past 150 years. MOTOR SPEECH DISORDERS Motor speech disorders are abnormalities of the motor production of speech, or articulation, in the absence of abnormal language.

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Agitation necessitates drug therapy; neuroleptic dosages should be monitored carefully if side effects are to be minimized. A suggested starting dosage is 0.25 to 0.5 mg haloperidol repeated up to four times in the first 24 hours. The newer antipsychotics have fewer parkinsonian side effects and may become the treatment of choice: risperidone 0.5 mg/day with a maximum of 4 mg and quetiapine 25 mg with a maximum 300 mg/day are good candidate drugs, but the results of controlled trial are awaited. Although widely used, anxiolytics have not been studied carefully. Lorazepam 0.5 mg/day up to 4 mg/day may be effective and has a shorter half life than diazepam. A benzodiazepine would be the drug of choice for alcohol or drug withdrawal-related confusional states. Antidepressants have been reported to be of some symptomatic benefit. Trazodone, beginning with 25 mglday and increasing to a maximum of 300 mg/day, is about as effective as haloperidol but with fewer side effects. Anecdotal reports support the use of fluvoxamine, fluoxetine, and sertraline. CHRONIC CONFUSION On occasion, especially after an acute right hemisphere stroke, the patient becomes confused and does not recover. The basic defect of attention persists, and the patient lapses into a chronic confusional state. It might be argued that these patients are essentially demented. The essential difference between dementia and chronic confusional state is that the dementia is progressive, and the chronic confusional state is static.

Chedru F, Geschwind N: Writing disturbances in acute confusional states.

Neuropsychologia 10343-353, 1972 Cole MG, Primeau F, McCusker J: Effectiveness of interventionsto prevent delirium in hospitalized patients: a systematic review. Can Med Assoc J 155(9):1263-1268, 1996 Devinsky 0, Bear D, Volpe BT: Confusional states following posterior cerebral artery infarction. Arch Neurol45160-163, 1988 Geschwind N Disorders of attention: a frontier in neuropsychology. Philos Trans R SOCLond B Biol Sci 298:173-185, 1982 Gnanamuthu C Confusional states and seizures: when are they related? Postgrad Med 84:149-158, 1988 Inouye SK Delirium in hospitalized older patients: recognition and risk factors. J Geriatr Psychiatry Neurol 11:118-125, 1998 Inouye SK, Bogardus ST, Charpentier PA et ak A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 340669-676, 1999 Lipowski ZJ: Delirium (acute confusional states). JAMA 258: 1789-1792, 1967 Mesulam MM: Attentional networks, confusional states, and neglect syndromes. pp. 174-256. In Mesulam M M Principles of Behavioral Neurology. 2nd ed. Oxford University Press, New York, 2000 Mesulam MM, Waxman SO, Geschwind N, Sahin TD: Acute confusional states with right middle cerebral artery infarctions. J Neurol Neurosurg Psychiatry 3984-89, 1976 Mulalley W, Ronthal M, Huff K, Geschwind N Chronic confusional state. N J Med 86541-544, 1989 Pousada L, Leipzig RM: Rapid bedside assessment of postoperative confusion in older patients. Geriatrics 4559-64, 66, 1990 Ribby KJ, Cox KR: Development, implementation and evaluation of a confusion protocol. Clin Nurse Specialist 10(5):241-247, 1996 Schmidley JW,Messing RO: Agitated confusional states in patients with right hemisphere infarctions Stroke 15:883-885, 1984

SUGGESTED READINGS Amit R Acute confusional state in childhood. Childs New Syst 4:255-258, 1988

140 Speech and Language Disorders Howard S. Kirshner Speech and language disorders have long attracted interest. Historically, they were the first higher functions to be directly associated with a specific area of the brain. In addition, human communication is the function that sets us apart most clearly from the animals. Speech and language disorders provide a window on the mind-body connection and link neurology to cognitive psychology, linguistics, and philosophy. For neurologists, speech and language disorders also have practical implications. They are among the most common of serious neurologic maladies. About 20% of strokes produce language disturbance, and a greater number affect speech articulation. Language deficits are common in patients with traumatic brain injuries, brain tumors, dementias, neurodegenerative diseases, and infections of the nervous system such as acquired immunodeficiency syndrome. Disorders of communication frustrate patients and families and challenge the abilities of physicians. In recent years, knowledge about language and the brain has expanded greatly. New developments include brain imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), which provide a simultaneous view of

brain pathology to be correlated with behavioral study, and the functional imaging modalities of positron emission tomography, single photon emission computed tomography, and functional MRI, all of which provide a map of the functional activation of cortical areas during behavioral activities and tasks in both patients with aphasia and normal subjects. Finally, electrical mapping of the language cortex via direct electrical stimulation or transcranial magnetic stimulation, in preparation for epilepsy surgery, has provided an independent window on the organization of language in the brain. Cognitive neuroscientists and linguists have developed sophisticated linguistic models and test paradigms of the cognitive operations involved in language function. All of these advances have contributed to our understanding of language, building on the foundation based on studies of patients with strokes and other focal brain pathologies over the past 150 years. MOTOR SPEECH DISORDERS Motor speech disorders are abnormalities of the motor production of speech, or articulation, in the absence of abnormal language.

Chapter 140

Patients with motor speech disorders can comprehend both spoken and written language, and their speech output, if comprehensible at all, can be transcribed into normal language. These disorders include dysarthrias, disorders of speech articulation; dysphonias, abnormalities of voice; apraxia of speech; and stuttering.

Dysarthrias Dysarthrias involve the abnormal articulation of sounds or phonemes, especially distortions of consonant sounds, errors in the place of articulation, voicing, or opening of the velum. For example, a “p” sound and a “b” sound differ only in the initial voicing of the “p”; a dysarthric patient might consistently substitute “b” for “p.” Dysarthrias can be caused by mechanical difficulty in the larynx or vocal cords or by neurologic diseases. Neurogenic dysarthrias are classified into six categories: flaccid, spastic (and unilateral upper motor neuron), ataxic, hypokinetic, hyperkinetic, and mixed. Flaccid dysarthria is associated with lower motor neuron disorders affecting the bulbar muscles, neuromuscular junction, cranial nerves, or brainstem anterior horn cells. Examples include polymyositis, myasthenia gravis, and bulbar poliomyelitis. Flaccid dysarthria is characterized by breathy, nasal speech, with consonant errors. Spastic dysarthria is seen in patients with bilateral lesions of the motor cortex or corticobulbar tracts, such as in bilateral strokes. The speech has a harsh, strain-strangle quality, with slow rate, low pitch, and imprecise consonants. A lesser variant of spastic dysarthria, called unilateral upper motor neuron dysarthria, is a similar speech pattern but usually less severe, associated with a unilateral upper motor neuron lesion such as in stroke. This may be the most common type of dysarthria encountered by neurologists. Ataxic dysarthria, or scanning speech, associated with cerebellar disorders, involves irregular or slow rhythm of speech, with pauses and abrupt explosions of sound and abnormal or excessively equal stress on every syllable. Hypokinetic dysarthria, seen in Parkinson’s disease, is associated with decreased and monotonous loudness and pitch, increased rate with occasional pauses, and some consonant errors. Hyperkinetic dysarthria, seen in such diseases as Huntington’s disease and dystonia musculorum deformans, is characterized by excessive variation in rate, loudness, and timing, with distorted vowels. In dystonia, hyperkinetic dysarthria can also include harsh, strainstrangle speech with imprecise consonants. The final category, mixed dysarthria, involves combinations of the other types. Common causes include multiple sclerosis, which often combines spastic and ataxic characteristics, and amyotrophic lateral sclerosis, which links spastic and flaccid elements. With practice, a clinician can use speech patterns to confirm suspected neuroanatomic diagnoses.

Speech and Language Disorders

rather than distorted, as in dysarthria. The misarticulations increase with polysyllabic words that require multiple consonant shifts. Difficulty with initial consonants makes the speech hesitant and groping. Errors are inconsistent from one attempt to the next, in contrast to the more regular distortion of phonemes seen in dysarthria; for example, a patient attempting to repeat the word “artillery” five times might produce five different utterances. Apraxia of speech is rare in isolated form, but it often contributes to the aphasic deficit of Broca’s aphasia. Speech apraxia as part of an aphasia is defined by the inconsistent articulatory errors in the presence of preserved comprehension and by the patient’s ability to write better than speak. Lesions producing apraxia of speech often appear to involve the insula of the left hemisphere. Stuttering

Stuttering is an often hereditary disorder characterized by initial pauses and dysfluency of speech production, without other articulatory or language disorders. Stuttering usually is a childhood, developmental disorder, but a close imitation can occur in acquired brain lesions, including strokes or brain injury in either hemisphere. APHASIAS Language disorders, or aphasias, are defined as abnormalities of symbolic communication, or language, acquired as a result of brain disease. This definition distinguishes aphasias from motor speech disorders, from congenital or developmental language disorders (often called dysphasias), and from psychiatric thought disorders. Psychotic patients express bizarre, illogical language content in well-articulated, syntactically correct sentences; the abnormality lies in thought, not in its expression in language. Aphasia is diagnosed by a six-part bedside language evaluation (Table 140-l),used in conjunction with a neurologic history and examination. The first test item, spontaneous speech, can be ascertained during the clinical interview. Automatic sequences, such as the days of the week, are helpful in provoking speech output. The most important variable is fluency, the free-flowing quality of the utterances. The presence of articulatory errors or dysarthria should be noted, along with circumlocutions, wordfinding pauses, and paraphasic errors. These errors can be of the literal or phonemic type, involving substitution of an incorrect sound (“ben” for “pen”) or of the verbal or semantic type, involving substitution of an incorrect word (“spoon” for “fork”). Jargon speech is so replete with paraphasic errors that the meaning is unclear. Naming is evaluated with objects, body parts, colors,

m TAW 110-1. Bedside Language Examination

Dysphonias Dysphonias, or disorders of voicing, are part of dysarthria. Hoarseness can result from laryngitis or a paralyzed vocal cord. Neurogenic dysphonias include the breathy voice of myasthenia gravis and the whispered voice of Parkinson’s disease.

Apraxia of Speech Apraxia of speech is an inability to program sequences of phonemes, especially consonants. Consonants are substituted

891

Speech expression Spontaneous speech Automatic sequences Naming Auditory comprehension Repetition Reading Aloud Comprehension Wriiing Spontaneous Dictation Coovinn

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and parts of objects. Auditory comprehension is tested by asking the patient to follow spoken commands of one, two, and three steps. Care must be taken to exclude hearing loss, motor paralysis, or apraxia as the cause of a failure to follow commands; if doubt exists, comprehension can be tested by yeslno questions or by commands that require only a pointing response. Repetition is tested with polysyllabic words and phrases such as “Methodist Episcopal,” which are sensitive to dysarthria, and with sentences, especially grammatically complex, unfamiliar phrases such as “no ifs, ands, or buts,” which are sensitive to aphasia. If apraxia of speech is suspected, the patient is asked to repeat polysyllabic words such as “artillery” or “catastrophe” five times. Reading is tested by asking the patient to follow printed commands or to read paragraphs for meaning. Writing, the final element, is tested by spontaneous generation of sentences, writing to dictation, or copying. Muteness, or absence of speech, can be difficult to interpret. A mute patient may be aphasic but may suffer instead from severe dysarthria, a frontal lobe syndrome such as abulia or akinetic mutism, a basal ganglia disorder such as parkinsonism, a psychiatric disorder such as catatonia, or a mechanical disorder of the larynx. It is helpful to have some language production to analyze before diagnosing aphasia. In general, a mute aphasic cannot write or comprehend language normally. The physician uses the bedside language examination, together with the neurologic examination, to localize diseases in the nervous system. The history provides clues as to the cause of the disorder. For example, the sudden onset of fluent aphasia indicates an embolic stroke to the inferior division of the left middle cerebral artery, whereas a slowly developing anomia may indicate an early dementia or a left hemisphere brain tumor. More detailed examination of language function can be obtained by consultation with a speech and language pathologist or neuropsychologist. Standard language testing batteries such as the Boston Diagnostic Aphasia Examination or the Western Aphasia Battery are helpful in quantitating a language deficit, supporting a syndrome classification, and following progress during rehabilitation. Finally, neurodiagnostic and brain imaging studies confirm the medical diagnosis. CT scanning and MRI detect brain lesions such as strokes or brain tumors. Positron emission tomography and single photon emission computed tomography show the metabolic activity or blood flow of brain regions; activation of these regions can be studied during language tasks.

Handedness and Cerebral Dominance Approximately 99% of right-handed patients and most lefthanded patients have relative left hemisphere dominance for language. Both autopsy studies and measurements based on CT

and MRI scans have shown anatomic brain asymmetries, especially a larger superior temporal plane in the left cerebral hemisphere. Left hemisphere language dominance appears to be genetically programmed because temporal lobe asymmetries are found even in newborns and in illiterate people. Further knowledge of language dominance is emerging from testing of patients with epilepsy in preparation for surgical resection; the areas important for language are determined by the Wada test, in which sodium pentobarbital is injected into the internal carotid artery, or by intraoperative stimulation mapping of the language cortex. Such mapping has produced somewhat more variable localizations for the classic language centers than traditional, autopsy-based or even CT scan-based localization from stroke patients. Occasionally, aphasia develops in right-handed patients with right hemisphere lesions (“crossed aphasia”). Aphasia in lefthanders may be seen with lesions of either hemisphere but most commonly the left. Recent studies have shown less difference in initial language profiles or ultimate recovery between right- and left-handers than previously thought. Atypical syndromes occasionally are seen in left-handers, such as preserved comprehension in a patient with a large left hemisphere lesion, suggesting right hemisphere comprehension ability.

Classification and Diagnosis Aphasias have been classified into eight traditional syndromes: Broca’s, Wernicke’s, global, conduction, anomic, and three transcortical aphasias. In addition, two single-modality deficits, aphemia and pure word deafness, and syndromes of alexia and agraphia deserve attention. Finally, a newer category, subcortical aphasia, has emerged, based on subcortical lesion localization on brain imaging studies. Broca’s Aphasia. Broca’s aphasia is characterized by nonfluent speech, varying from mutism to hesitant, struggling efforts to speak (Table 140-2). The patient utters the principal, contentcarrying words, mainly nouns and verbs, of a sentence, omitting pronouns, prepositions, and articles, a phenomenon called telegraphic speech or agrammatism. Patients hesitate on names but often can indicate some knowledge of the word (tip-of-the-tongue phenomenon). Repetition is effortful and slow. Auditory comprehension is adequate for simple conversations and commands but breaks down on complex grammatical constructions, which are also difficult for the patient in expressive speech. Reading often is more affected than auditory comprehension. Writing is impaired, even with the nonparalyzed left hand. Patients with Broca’s aphasia are aware of their deficits, often becoming frustrated and depressed. The lesions of Broca’s aphasia involve the left frontal lobe, classically the posterior portion of the inferior frontal gyrus, anterior to the motor face area. Small lesions of Broca’s area permit

TMLE 140-2. Language Features of the Eight Classic Aphasias Syndrome

Broca’s Wernicke’s Global Conduction Anornic TCMA TCSA MTCA

Speech

Naming

Comprehension

Repetition

Nonfluent Anornic Mild Hesitant Fluent Paraphasic Poor Paraphasic Anornic Nonfluent Poor Poor Fluent f Impaired Normal Poor Fluent Anornic Normal Normal Nonfluent & Impaired Normal Normal Fluent Paraphasic Poor Normal Normal Nonfluent Poor Poor Abbreviations: MTCA, mixed transcortical aphasia; TCMA, transcortical motor aphasia; TCSA, transcortical sensory aphasia.

Reading

Writing

Mild Impaired Poor k Impaired Normal Impaired Poor Poor

Poor Poor spelling Poor f Impaired Normal & Impaired Poor spelling Poor

*

Chapter 140

nearly complete recovery, whereas larger left frontoparietal lesions produce an early global aphasia that evolves gradually into Broca’s aphasia. Associated damage in the subcortical and periventricular white matter (especially the periventricular white matter and subcallosal fasciculus) may be necessary to produce lasting loss of expressive speech. Aphemia is a transitory syndrome of muteness or nonfluent speech, with preserved writing and comprehension. Some authorities equate aphemia with isolated apraxia of speech. Lesions involve the face area of the motor strip, sometimes with extension into the inferior frontal gyrus and underlying white matter. Wernicke’s Aphasia. In contrast to patients with Broca’s aphasia, patients with Wernicke’s aphasia speak fluently, but with empty phrases, circumlocutions, and paraphasic errors of both literal and verbal type (Table 140-2). Naming may provoke bizarre, paraphasic substitutions. Auditory comprehension is severely impaired. Reading is affected much like auditory comprehension, but some patients show sparing of one or the other modality. Writing is well formed but contains spelling and word choice errors; in mild cases, writing may be a sensitive clue to the diagnosis of Wernicke’s aphasia. Patients with Wernicke’s aphasia usually are not depressed, but they may be unaware of their deficits and may become angry when not understood. Motor and sensory findings usually are absent, although some have right hemianopia. The lesion typically involves the classic Wernicke’s area in the left posterior superior temporal gyrus. Destruction of most of Wernicke’s area appears necessary for lasting loss of comprehension, but there is often associated damage in the supramarginal and angular gyri. Pure word deafness is a rare syndrome of inability to understand or repeat spoken language, in the absence of expressive language difficulty or deafness for nonverbal sounds. Classically, pure word deafness results from bilateral temporal lesions that disconnect Wernicke’s area from both auditory cortical areas. The syndrome also occurs with unilateral left temporal lesions. Global Aphasia. Global aphasia may be thought of as the sum of Broca’s and Wernicke’s aphasia, a loss of all six major language functions (Table 140-2). Spontaneous speech is nonfluent or mute, and the patient cannot name, repeat, understand, read, or write. Most patients have extensive left hemisphere damage and profound neurologic deficits of right hemiplegia, right hemisensory loss, and right hemianopia. When less severe deficits involve all language functions, the syndrome is called mixed aphasia. Conduction Aphasia. Conduction aphasia is a less common language syndrome in which repetition is affected out of proportion to other language modalities (Table 140-2). Speech is fluent but may be interrupted by pauses to correct literal paraphasic errors. Auditory comprehension is intact. Conduction aphasia was traditionally explained as a disconnection between Wernicke’s and Broca’s areas. Others have explained the repetition difficulty as a deficit of auditory verbal immediate memory. Lesions involve either the left temporal lobe, without destruction of Wernicke’s area, or the inferior parietal lobule. Anomic Aphasia. Anomic aphasia is a selective deficit of naming. Speech is fluent, except for word-finding pauses and circumlocutions, and the other language modalities are intact. This syndrome is less localizing than other types of aphasia. Anomic aphasia is seen with focal lesions of the left temporal or inferior parietal region and is often the last stage in recovery of language in almost any type of aphasia. Anomia is also common in encephalopathies, aging, and dementia.

H

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Transcortical Aphasias. The transcortical aphasias have in common the preservation of repetition. The word transcortical refers to disruption of areas of the association cortex (Lichtheim called these the “area of concepts”) that project onto the perisylvian language cortex, rather than of the language cortex itself. Transcortical motor aphasia (TCMA) resembles Broca’s aphasia in that there is marked dysfluency or difficulty initiating speech, but the patient with TCMA repeats normally. The lesions of TCMA spare Broca’s area but involve the adjacent left frontal cortex, medial frontal cortex, or subcortical white matter. Strokes causing transcortical motor aphasia generally are within the territory of the anterior cerebral artery, so the syndrome is relatively specific. Transcortical sensory aphasia resembles Wernicke’s aphasia except for the sparing of repetition. The lesions involve the posterior left temporo-occipital region or the temporal lobe itself; Boatman et al. found that stimulation of adjacent cortical areas in the left superior temporal region could produce either Wernicke’s or transcortical sensory aphasia. This syndrome also occurs in Alzheimer’s disease. Mixed transcortical aphasia, also called the syndrome of the isolation of the speech area, resembles global aphasia except that repetition is not only spared but may be excessive or palilalic. Some patients mimic and learn new song lyrics or complete poems if given the first lines. Reported cases have had large, watershed infarctions sparing the perisylvian language area or advanced dementing illnesses. Subcortical Aphasias. Unlike the other aphasia syndromes, subcortical aphasias are diagnosed by the location of the brain lesion rather than by language features. In recent years, aphasia syndromes increasingly have been associated with subcortical lesion sites. First, lesions of the left thalamus produce fluent aphasia, usually with better comprehension and repetition as compared with Wernicke’s aphasia. Patients may fluctuate between periods of drowsiness, with severe aphasia, and periods of alertness, with improved language function. Second, lesions of the left putamen, anterior limb of internal capsule, and caudate nucleus produce syndromes of dysarthria and nonfluent speech, with less abnormality of phrase length and repetition as compared with Broca’s aphasia. This atypical Broca-like aphasia is sometimes called the anterior subcortical aphasia syndrome. Lesions extending into the deep temporal white matter or temporal isthmus may impair comprehension, producing subcortical equivalents of Wernicke’s and global aphasia. Alexias and Agraphias. Because reading and writing are elementary language functions, acquired disorders of reading and writing should be considered aphasias, as opposed to congenital or developmental reading disorders, usually called dyslexias. The interesting disorders of acquired alexia and agraphia will be missed unless the neurologist takes care to test reading and writing. Alexia with agraphia is an acquired illiteracy, with intact spoken language modalities except for anomia and mild fluent, paraphasic speech (Table 140-3). The syndrome is associated with focal lesions of the left angular gyrus. Associated deficits include Gerstmann’s syndrome of agraphia, inability to calculate, right-left confusion, and finger agnosia, an inability to name or point to specific fingers on the patient’s or examiner’s hand. Pure alexia without agraphia (Table 140-3) is an isolated inability to read. The lesions involve the left posterior cerebral artery territory, including the left medial occipital and medial temporal lobes and the splenium of the corpus callosum. Some patients have difficulty naming colors. Most have at least a partial right hemianopia. Another common association is with decreased ability to encode new information (short-term memory loss),

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TABE 140-5. Language Features of the Classic Alexias Feature

Alexia with Agraphia

Fluent, often paraphasic

Speech Naming Repetition Comprehension Reading

+ Impaired

Writing Associated signs Localization

Severely impaired Right hemianopsia Left angular gyrus

Normal Intact or mildly impaired Severely impaired

Pure Alexia Without Agraphia

Normal Color anomia Normal Intact Impaired. f sparing of letters Normal Right hernianopsia Left occipital lobe, splenium

explained by damage to the hippocampus and adjacent medial temporal structures. Pure alexia has been explained as a disconnection between the intact right occipital visual cortex and the left hemisphere centers for decoding of visual language symbols. Alexia is also seen as part of the language deficit of aphasia (aphasic alexia). The alexia of Broca’s aphasia is called the third alexia. Neurolinguists have described four separate patterns of alexia: deep, phonologic, surface, and letter-by-letter alexia. Letter-by-letter alexia is identical to the syndrome of pure alexia without agraphia. Both deep and phonologic alexia involve the visual recognition of whole, familiar words, without the ability to decode graphemes into phonemes; surface dyslexia involves the opposite ability to convert graphemes laboriously into phonemes, without any recognition of words or phrases at a glance. The agraphias, like the alexias, can be divided into the rare pure agraphias and agraphia associated with aphasia. Agraphias have also been classified into deep, phonologic, and surface varieties. Language in Dementias. Aphasia usually is the result of focal, destructive lesions of the brain, but language disturbances also occur in acute encephalopathies and dementias. In probable Alzheimer’s disease, language deteriorates along a generally predictable gradient: naming of people and objects is deficient early in the course, along with simplification of discourse and language content; reading, writing, and auditory comprehension deteriorate during the middle stages; and in the terminal phase, articulation and expressive speech begin to fail. In linguistic terms, semantics fail first, then syntax, and finally phonology. A less common pattern of language deterioration with aging is called primary progressive aphasia. These disorders, though variable, often begin with loss of fluency in patients who may not develop a generalized dementia for several years. This syndrome is seen in patients with Pick’s disease, corticobasal degeneration, and a family of diseases called frontotemporal dementia. Only very rarely does a progressive, nonfluent aphasia turn out to be associated with Alzheimer’s disease.

communication deficit of right hemisphere lesions, although not strictly meeting the definition of aphasia, is socially disabling to patients, hindering readjustment to family and work environments. Recovery and Therapy

Patients with aphasia from acute brain injury or stroke improve spontaneously for several months. The aphasia type often changes during recovery; global aphasia evolves into Broca’s aphasia, and Wernicke’s aphasia may recover toward the profile of conduction or anomic aphasia. As mentioned earlier, anomic aphasia often is the last stage of recovery from any aphasia. Early recovery of language function may involve resolution of edema or reactivation of partially damaged tissue in the language cortex, but later recovery probably requires the reorganizationof new cortical areas for language function in either adjacent left hemisphere or analogous right hemisphere regions. The work of Heiss and colleagues in Germany indicates that right hemisphere activation on positron emission tomography scans always predicts incomplete recovery, and only left hemisphere activation permits full restitution of language capability. In general, such recovery is much more complete in children than in adults. Speech therapy, carried out by trained speech and language pathologists, aims to facilitate language recovery by a variety of methods. In traditional therapy, repeated practice is carried out to improve performance in the major communication modalities of speech, auditory comprehension, reading, and writing. The therapist focuses on specific language operations that are deficient, working first in an artificial language task and then applying these functions to communication in the real world. Repeated drills and stimulus-response paradigms are performed. A number of new speech therapy techniques have been developed. Melodic intonation therapy entrains musical intonation into speech, theoretically involving the right hemisphere in speech production. Visual action therapy uses simple gestures to convey meaning. Computer techniques originally developed for primate communication have enabled even severely aphasic patients to combine pictures of nouns and verbs, creating simple sentences that can be printed or transmitted to a voice synthesizer. Other augmentive speech devices permit simple, stereotyped language expression. Finally, pharmacologic agents are beginning to be used in language rehabilitation. Bromocriptine, a dopamine agonist used in Parkinson’s disease, increases speech production in some patients with transcortical motor aphasia. Amphetamines have also been used to facilitate language improvement; a research trial is in progress. Although the medical profession often considers speech therapy an unproved treatment, large, randomized trials have clearly established that speech therapy is effective in promoting better communication in aphasic patients, and several meta-analyses have also confirmed the efficacy of speech therapy.

Language and the Right Hemisphere

The right hemisphere, although dominant for language in only a small minority of people, plays an important role in communication. The elements of communication most affected by right hemisphere disease are prosody, or cadence and intonation of speech, and pragmatics, or practical, extralinguistic messages that normal speakers convey. Patients with right hemisphere disease sound flat in their intonation, and they may fail to comprehend emotional nuances, irony, sarcasm, and humor in the speech of others. They understand what is said but not how it is said. The

SUGGESTED READINGS Albert ML, Bachman DL, Morgan A, Helm-Estabrooh N Pharmacotherapy for aphasia. Neurology 382377-879, 1988 Alexander MP, Benson DF The aphasias and related disturbances. pp. 1-58. In Joynt RJ (ed): Clinical Neurology. Vol. 1. JB Lippincott, Philadelphia, 1993 Alexander MP, Naeser MA, Palumbo CL: Broca’s area aphasia: aphasia after lesions including the frontal operculum. Neurology 40:353-362, 1990

Chapter 141

Alexander MP, Naeser MA, Palumbo CL Correlation of subcortical CT lesion sites and aphasia profiles. Brain 110:961-991, 1987 Appell J, Kertesz A, Fisman M: A study of language functioning in Alzheimer’s patients. Brain Lang 22:23-30, 1982 Bakar M, Kirshner HS, Wertz R T Crossed aphasia: functional brain imaging with PET or SPECT. Arch Neurol 53:102&1032, 1996 Basso A, Farabola M, Pia Grassi M et al: Aphasia in left handers: comparison of aphasia profiles and language recovery in non-righthanded and matched right-handed patients. Brain Lang 38:233-252, 1990

Benson DF, Ardila A Aphasia: a clinical perspective. Oxford University Press, New York, 1996 Boatman D, Gordon B, Hart J et ak Transcorticalsensory aphasia: revisited and revised. Brain 123:1634-1642, 2000 Dronkers N F A new brain region for coordinating speech articulation. Nature 384:159-161, 1996 Duffy J R Motor speech disorders: substrates, differential diagnosis, and management. Mosby, St. Louis, 1995 Heiss WD, Kessler J, Thiel A et al: Differential capacity of left and right hemispheric areas for compensation of poststroke aphasia. Ann Neurol 45:430438, 1999

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Kirshner HS: Behavioral Neurology: Practical Science of Mind and Brain, 2nd ed. Butterworth Heineman, Boston, 2002. Kirshner HS: Handbook of Neurological Speech and Language Disorders. Marcel-Dekker, New York, 1995 Kirshner HS, Alexander M, Lorch MP, Wertz RT Disorders of speech and language. Continuum 5:l-237, 1999 Kirshner HS, Casey PF, Henson J, Heinrich JJ: Behavioral features and lesion localization in Wernicke’s aphasia. Aphasiology 3:169-176, 1989 Ludlow CL, Rosenberg J, Salazar A et ak Site of penetrating brain lesions causing chronic acquired stuttering. Ann Neurol 22( 1):60-66, 1987

Ojemann G A Conical organization of language. J Neurosci 11:2281-2287, 1991

Posner MI, Petersen SE, Fox PT, Raichle M E Localization of cognitive operations in the human brain. Science 2401627-1631, 1988 Weintraub S, Rubin NP, Mesulam M: Primary progressive aphasia: longitudinal course, neuropsychological profiles, and language features. Arch Neurol47:1329-1335, 1990 Wertz RT, Weiss DG, Aten LJ et ak Comparison of clinic, home and deferred language treatment for aphasia: a VA cooperative study. Arch Neurol 143:653-658, 1986

141 Higher-Order Visual Impairments Michael P. Alexander Higher-order visual impairments are those that cannot be accounted for by deficits in visual acuity, visual fields, o r gaze mechanisms. Most higher-order visual impairments are caused by lesions in visual association cortex (Brodmann’s areas 18 and 19) or by the outflow from those regions to multimodal association cortex in the temporal lobe (particularly area 37) and hippocampus or in parietal lobes (particularly areas 7, 39, and 40). The clinical approach to these impairments is facilitated by the fact that the higher-order deficits are readily divided along three separate dimensions. The first dimension is lesion laterality. Damage to the left hemisphere causes deficits in processing visual stimuli for language content or associations. Deficits in processing visual material for some spatial relations, for some perceptual properties, and for some aspects of emotional content usually are caused by right hemisphere lesions. The second dimension is dorsal-ventral. Damage to the ventral (inferior) visual association cortex and pathways impairs discrimination and identification of stimuli: the “what” system. Damage to the dorsal (superior) visual association cortex and pathways impairs attentional, spatial, and kinesthetic analyses: the “where” system (Table 141-1).The third dimension is the scale of visual attention. Attention can be paid to large components of a visual array, such as overall configuration, sometimes called global attention or a “floodlight.” Attention can also be paid to small items within a visual array, such as specific letters or faces, sometimes called local attention or a “spotlight.” In normal subjects under normal conditions, visual attention may be a composite of the two or switch between them, either unconsciously o r consciously, as when searching for a face in a crowd. Damage to the left visual association cortex, particularly dorsal, reduces sensitivity to high spatial frequency (local o r detailed) properties of stimuli. Damage to the right reduces sensitivity to

low spatial frequency (global or configurational) aspects of stimuli. These differences in scale of attention underlie some of the characteristic findings of lateralized lesions: the markedly different error patterns in drawing and other spatial manipulations of visual stimuli and the very asymmetrical clinical manifestations of hemifield spatial neglect after right or left brain lesions. This chapter reviews the common higher-order deficits, attempting to place them in relation to the three dimensions just outlined. For each disorder, clinical assessment methods, treatment strategies (if any), and natural history are discussed.

TABLE141-1. Classification of Higher-Order Visual Impairments According to Whether the Lesion Is in the Superior or Inferior Visual Association Cortex Inferior (Temporo-Occipital Cortex) Visual System Disorders

Pure alexia Object agnosia Prosopagnosia

Left occipitotemporal Bilateral inferior occipitotemporal Large left inferomedial occipitotemporal Bilateral inferior occipitotemporal Large right inferomedial occipitotemporal

Superior (Parieto-Occipital Cortex) Visual System Disorders

Neglect Visually guided movements Balint‘s syndrome Primary dressing disorder (“dressing apraxia”) Ideational apraxia Visuoconstructive disorders

Contralateral parieto-occipital (left neglect more severe) Contralateral parieto-occipital Bilateral parieto-occipital Right superior parieto-occipital Left parietal Either left or riaht oarietal

Chapter 141

Alexander MP, Naeser MA, Palumbo CL Correlation of subcortical CT lesion sites and aphasia profiles. Brain 110:961-991, 1987 Appell J, Kertesz A, Fisman M: A study of language functioning in Alzheimer’s patients. Brain Lang 22:23-30, 1982 Bakar M, Kirshner HS, Wertz R T Crossed aphasia: functional brain imaging with PET or SPECT. Arch Neurol 53:102&1032, 1996 Basso A, Farabola M, Pia Grassi M et al: Aphasia in left handers: comparison of aphasia profiles and language recovery in non-righthanded and matched right-handed patients. Brain Lang 38:233-252, 1990

Benson DF, Ardila A Aphasia: a clinical perspective. Oxford University Press, New York, 1996 Boatman D, Gordon B, Hart J et ak Transcorticalsensory aphasia: revisited and revised. Brain 123:1634-1642, 2000 Dronkers N F A new brain region for coordinating speech articulation. Nature 384:159-161, 1996 Duffy J R Motor speech disorders: substrates, differential diagnosis, and management. Mosby, St. Louis, 1995 Heiss WD, Kessler J, Thiel A et al: Differential capacity of left and right hemispheric areas for compensation of poststroke aphasia. Ann Neurol 45:430438, 1999

Higher-Order Visual Impairments

895

Kirshner HS: Behavioral Neurology: Practical Science of Mind and Brain, 2nd ed. Butterworth Heineman, Boston, 2002. Kirshner HS: Handbook of Neurological Speech and Language Disorders. Marcel-Dekker, New York, 1995 Kirshner HS, Alexander M, Lorch MP, Wertz RT Disorders of speech and language. Continuum 5:l-237, 1999 Kirshner HS, Casey PF, Henson J, Heinrich JJ: Behavioral features and lesion localization in Wernicke’s aphasia. Aphasiology 3:169-176, 1989 Ludlow CL, Rosenberg J, Salazar A et ak Site of penetrating brain lesions causing chronic acquired stuttering. Ann Neurol 22( 1):60-66, 1987

Ojemann G A Conical organization of language. J Neurosci 11:2281-2287, 1991

Posner MI, Petersen SE, Fox PT, Raichle M E Localization of cognitive operations in the human brain. Science 2401627-1631, 1988 Weintraub S, Rubin NP, Mesulam M: Primary progressive aphasia: longitudinal course, neuropsychological profiles, and language features. Arch Neurol47:1329-1335, 1990 Wertz RT, Weiss DG, Aten LJ et ak Comparison of clinic, home and deferred language treatment for aphasia: a VA cooperative study. Arch Neurol 143:653-658, 1986

141 Higher-Order Visual Impairments Michael P. Alexander Higher-order visual impairments are those that cannot be accounted for by deficits in visual acuity, visual fields, o r gaze mechanisms. Most higher-order visual impairments are caused by lesions in visual association cortex (Brodmann’s areas 18 and 19) or by the outflow from those regions to multimodal association cortex in the temporal lobe (particularly area 37) and hippocampus or in parietal lobes (particularly areas 7, 39, and 40). The clinical approach to these impairments is facilitated by the fact that the higher-order deficits are readily divided along three separate dimensions. The first dimension is lesion laterality. Damage to the left hemisphere causes deficits in processing visual stimuli for language content or associations. Deficits in processing visual material for some spatial relations, for some perceptual properties, and for some aspects of emotional content usually are caused by right hemisphere lesions. The second dimension is dorsal-ventral. Damage to the ventral (inferior) visual association cortex and pathways impairs discrimination and identification of stimuli: the “what” system. Damage to the dorsal (superior) visual association cortex and pathways impairs attentional, spatial, and kinesthetic analyses: the “where” system (Table 141-1).The third dimension is the scale of visual attention. Attention can be paid to large components of a visual array, such as overall configuration, sometimes called global attention or a “floodlight.” Attention can also be paid to small items within a visual array, such as specific letters or faces, sometimes called local attention or a “spotlight.” In normal subjects under normal conditions, visual attention may be a composite of the two or switch between them, either unconsciously o r consciously, as when searching for a face in a crowd. Damage to the left visual association cortex, particularly dorsal, reduces sensitivity to high spatial frequency (local o r detailed) properties of stimuli. Damage to the right reduces sensitivity to

low spatial frequency (global or configurational) aspects of stimuli. These differences in scale of attention underlie some of the characteristic findings of lateralized lesions: the markedly different error patterns in drawing and other spatial manipulations of visual stimuli and the very asymmetrical clinical manifestations of hemifield spatial neglect after right or left brain lesions. This chapter reviews the common higher-order deficits, attempting to place them in relation to the three dimensions just outlined. For each disorder, clinical assessment methods, treatment strategies (if any), and natural history are discussed.

TABLE141-1. Classification of Higher-Order Visual Impairments According to Whether the Lesion Is in the Superior or Inferior Visual Association Cortex Inferior (Temporo-Occipital Cortex) Visual System Disorders

Pure alexia Object agnosia Prosopagnosia

Left occipitotemporal Bilateral inferior occipitotemporal Large left inferomedial occipitotemporal Bilateral inferior occipitotemporal Large right inferomedial occipitotemporal

Superior (Parieto-Occipital Cortex) Visual System Disorders

Neglect Visually guided movements Balint‘s syndrome Primary dressing disorder (“dressing apraxia”) Ideational apraxia Visuoconstructive disorders

Contralateral parieto-occipital (left neglect more severe) Contralateral parieto-occipital Bilateral parieto-occipital Right superior parieto-occipital Left parietal Either left or riaht oarietal

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SYNDROMES OF IMPAIRED IDENTIFICATION OF COMPLEX VISUAL STIMULI: THE ” W H A T SYSTEMS Disorders of identification are produced by lesions in the ventral visual association cortex and its pathways. Pure Alexia

Pure alexia is the acquired inability to read despite preservation of adequate vision (acuity, fields, and attention) and preservation of other language capacities (thus, “pure” alexia or alexia without agraphia). Pure alexia is caused by lesions in the language-dominant (usually left) hemisphere’s occipitotemporal lobes (Table 141-2). It is not specific to any cause and may be seen after infarcts, hemorrhages, tumors, abscesses, and even focal degenerative disorders. Most cases in clinical practice are caused by left posterior cerebral artery territory infarctions. It has long been proposed that pure alexia is a disconnection of visual input from the language competent left temporal lobe. The disconnection is variably characterized as anatomic or psychophysiologic. The anatomic disconnection is straightforward. The most common lesion anatomy of pure alexia is a large medial occipitotemporal lesion producing right hemianopia and damaging the ventral, posterior callosal projections. This prevents processed visual information from passing from the right inferior association cortex to the left, at least via the most efficient pathways, thus impairing extraction of language information. White matter lesions subjacent to that area can also cause alexia by disrupting the input of left and right, visual association cortex into a critical cortical region for visual-language processing, with or without producing a right visual field deficit. Lesions in the left inferior occipitotemporal junction (areas 37 and 19) can also produce alexia, identifjmg that area as the critical site for visual-language associations. It is probably more accurate to characterize the disconnection as a disruption of language-specific visual information processing and cast it in different terms. There are a series of partially nested neural systems in the ventral left occipital and temporal lobes that progressively extract and code visual features distinct for letters and words. Damage to these systems or to the pathways linking them or carrying visual information to them impair reading without otherwise affecting language. There is abundant evidence from positron emission tomography and functional magnetic resonance imaging activation studies in normal subjects to support the existence and location of these systems. They operate at high spatial frequency. They require very rapid processing. In some patients pure alexia may be caused by an inability to process

W

TABLE141-2. Pure Alexia

Examination Oral reading Single letters Words Connected text Words Forced-choice comprehension Commonly associated signs Right visual field defect Color anornia Verbal mernorv deficits

the letter specific operations quickly enough to assemble words from letter stimuli. Few cases of “pure” alexia are totally pure. Right hemianopia is common, caused by damage to the geniculocalcarine pathways or calcarine cortex. Anomic aphasia is also common, although usually mild, reflecting damage to inferior temporal gyrus. A particularly severe color-naming deficit may be observed. The general naming deficit may be much more severe with visual presentation of objects than with either tactile presentation or spontaneous speech, so-called optic aphasia or visual anomia. Large lesions may produce object agnosia. Lesions that involve the hippocampus, parahippocampal gyrus, or the deep medial temporal white matter cause significant memory problems. The alexia is independent of any of these associated deficits. Patients are aware of their hemianopia and reading impairment but may be less aware of the associated deficits. Alexia testing is straightforward: Present stimuli in an uncrowded field to eliminate attentional, perceptual, and scanning problems. Begin with single letters and move to single words and then short, connected text. Ask the patient to read targets aloud. If unsuccessful, present an array of four to six written stimuli (letters or words) and ask the patient to point to them as you name them. Any patient complaining of alexia must be evaluated for other language deficits, especially writing, and for visual recognition or at least naming to visual presentation of other stimuli (e.g., colors, common objects). The same approach can be followed (naming colors or objects to visual presentation and then pointing to a specified color or object in an array of four to six; if impaired at the latter, naming objects that are palpated or described). Patients with severe pure alexia cannot read or recognize single letters, although they may still recognize iconic written stimuli, such as advertising signs, traffic signs, menu items, or their own names. When forced to choose between written words, they can show considerable capacity to recognize words. Certain classes of words are more readily recognized, even in the complete absence of ability to read the word aloud or indicate any recognition of its meaning. Emotionally charged words, proper names, and the names of highly imageable, concrete objects seem particularly likely to survive. Patients often are unaware that they have this recognition capacity. Improvement follows a typical course. Letter recognition improves, and as it does, patients begin to read letter by letter, assembling words by slowly reading off the letters. This becomes faster, and they seem to recognize entire short words. With more improvement, the letter-by-letter strategy will not be evident to an observer except on very long and unfamiliar words. At this point, the patient is no longer truly alexic, but reading is such an effort that it is rarely pursued. Furthermore, any impairment in verbal memory from medial temporal damage will make it almost impossible for the patient to recall what he or she so effortfully reads. Treatments are unproven. Superficial similarities in patients with pure alexia probably hide differences in the level of processing impairment. Most treatments have been attempted on only single patients and are of unknown general efficacy. If the patient cannot read single letters, there may be no reasonable treatment. Letter-by-letter reading improves with simple practice. Patients probably should use visually uncrowded text with well-marked margins. The content of the reading material should be familiar to the patient so that he or she does not have to struggle additionally for meaning beyond the individual words. Rapid, forced-choice word selection tasks may help the patient improve word recogni-

Chapter 141 W

tion without resorting to the laborious letter-by-letter strategy. Recall that therapy should be tempered if the patient also has verbal memory deficits. Object Agnosia

Object agnosia is characterized by an inability to recognize common objects despite adequate acuity and despite preserved capacity to recognize the objects through palpation or description. There are two prototypical forms of visual agnosia. In apperceptive agnosia, patients are unable to recognize objects, but they complain of impaired vision, not impaired recognition. Their corrected acuity is reduced, and visual fields are very hard to establish but usually are fullto perimetry techniques. They are able to recognize colors and movement. The usual cause of apperceptive agnosia is anoxia or carbon monoxide poisoning, and the lesion anatomy therefore has been laminar necrosis of the striate cortex. The agnosia is not specifically a deficit in recognition of well-perceived stimuli. It is a form of elemental perceptual impairment that precludes recognition. Patients with associative visual agnosia more accurately meet the defining criteria for agnosia. The patients complain of impaired recognition, not impaired vision. The usual cause is infarction, but traumatic contusions, tumors, and focal degenerative disorders have been described. The usual lesion anatomy is bilateral lesions in inferior temporo-occipital association cortex, but large left temporo-occipital lesions may also produce associative agnosia (Table 141-3). Depending on the lesion configuration, associated signs are somewhat variable. Patients with bilateral lesions usually have superior altitudinal visual field deficits. Disturbed color vision (achromatopsia) and impaired facial recognition (prosopagnosia) are common. If lesions extend into the medial temporal structures, including hippocampus, there may be significant memory impairments. Alexia and anomic aphasia may be present, depending on the extent of the left-sided lesion. Patients with large unilateral left lesions present a clinical problem of distinguishing agnosia from several boundary syndromes (Fig. 141-1). Very large left occipitotemporal lesions produce alexia and anomic aphasia and, as described earlier, may produce optic aphasia, in which patients recognize objects, are able to describe their use, usually recognize their names and can name them from a description, but are unable to name them from vision alone. In contrast, patients with object agnosia are unable to identify an object presented visually and thus be unable to describe its use or match it to its name. It is uncertain whether there is an unambiguous boundary between these syndromes. Many allegedly agnosic patients have been able to select a named object from an array, suggesting that the problem is not only visual recognition but also name retrieval or else that the visual recognition problem is only partial and facilitated by selection from limited possibilities (top-down facilitation.) Another boundary condition for associative agnosia is semantic amnesia or multimodal agnosia. Associative visual agnosia should be marked by preserved recognition and knowledge of objects in any format except visual. Thus, patients could define a described object, describe a named object, provide information about the object’s use, construction, and common location, and name an object placed in their hands. However, many patients with large left-sided lesions, usually large posterior cerebral artery infarctions, are unable to recognize an object through any sensory route (multimodal agnosia) or to provide any associated commonly

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TMLE 141-5. Associative Visual Agnosia Examination Objects Naming Identification by description Categorization Matching to name Commonly associated signs Bilateral lesion Superior attitudinal visual field defect Prosopagnosia Achromatopsia Amnesia Left lesion Right visual field defect Alexia Anomic aphasia Semantic memory deficits Verbal memory deficits

known information about the object (semantic amnesia). Although rare, this loss of semantic knowledge has been described after herpes encephalitis or posterior cerebral artery territory infarctions. Loss of semantic memory is a hallmark of Alzheimer’s disease and the subtype of frontotemporal dementia now called semantic dementia, which may be synonymous with one form of Pick’s disease. It is believed that the posterior association cortices house the mechanisms critical to semantic knowledge. Agnosia testing is designed to define the level of recognition impairment and its modality specificity (Table 141-3). The patient is shown simple objects or pictures of objects (visually more challenging) and asked whether he or she can name them. If so, the patient may be simply anomic and therefore is asked to describe the object’s function. If not, the patient is anomic but should be asked to name it from description and palpation. This resolves whether the patient has a general anomia, visual anomia, or both. If he or she cannot provide any associated information about an object but can name it with tactile input, the patient should be asked to point to the named object in an array. If he or she can, the patient presumably has simply a very severe lexical-semantic deficit. If he or she cannot, the patient should be asked to sort objects or pictures into natural categories. If the patient cannot, he or she has definite agnosia, but categorization through other modalities should be probed (“Is a hammer a carpentry tool?” “ISa camel a type of fish?”).If impaired, he or she has multimodal agnosia and general semantic knowledge loss. Cases of visual agnosia and all of its boundary conditions have produced abundant information about how the brain organizes knowledge, in part by the sensory modality through which it is experienced and in part by the abstract (and verbal) categories. There are critical cortical regions for modality-specific and modality-independent associational networks. The exact neural structure of semantic systems is controversial. There is convincing evidence that different semantic domains (e.g., proper names, faces, letters) have regionally specific organizations. It is less clear whether the modality of access to semantic knowledge (e.g., sounds, vision, description) actually contains modality-specific knowledge or only delivers distinctive information to a single associative semantic system. Patients with isolated visual object agnosia have been used to argue for the former. Multimodal loss of semantic knowledge in dementias or after structural temporal lesions has been used to argue for the latter. Treatments of visual agnosia, multimodal agnosia, and semantic memory loss have not been reported. Many patients improve.

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Patient shown an object or a picture of an object

Unable to name but describes and/or gestures its correct use

Unable to name or to describe or gesture its correct use

I

ANOMIA

AGNOSIA

No improvement if allowed to hold object or to hear object

Correctly names palpated objects or described objects

I

I

Multimodal agnosia

Visual agnosia

Unable to answer questions of common knowledge about object

Severe semantic knowledge impairment ("semantic amnesia")

No improvement if allowed to hold object or to hear object

Correctly names palpated objects or described objects

141-1mnowchart showingthe method by which agnosia may be distinguished from boundary syndromes that may resemble it.

1 Multimodal anomic agnosia

Visually specific anomia ("optic aphasia")

Unable to recognize correct name or match object to its name

Severe lexical impairment ("two-way naming" disorder)

Patients with bilateral inferior occipitotemporal lesions may be left with recognition deficits in areas that are particularly demanding perceptually: distinguishing faces and recognizing photographs, line drawings, or video clips. Patients with large left-sided unilateral lesions continue to have more clear-cut visual-language deficits (alexia and optic aphasia) and general language deficits (anomic aphasia) and less perceptual recognition impairment.

Prosopagnosia is defined by an inability to recognize familiar faces despite preservation of adequate acuity. Prosopagnosia usually is caused by bilateral lesions in inferior temporo-occipital cortex, most commonly infarcts. It has also been described in patients with focal progressive atrophy of the right temporal lobe, probably a variant of frontotemporal dementia. Patients with infarcts have

superior altitudinal visual field deficits (Table 141-4).Achromatopsia is also commonly seen. Depending on lesion extent in medial temporal regions, there may be considerable memory impairment. Some patients have only large right temporooccipital lesions. They usually have left hemianopia and impaired topographic memory. With either lesion configuration, impairments in other perceptually demanding visual discriminations have been reported, most notably a farmer unable to distinguish between the cows in his dairy herd. Note that prosopagnosia can be considered a modality-specificloss of knowledge. Normal rapid facial recognition appears to be a global perceptual task. In normal subjects the right hemisphere is faster and more reliable at recognizing familiar faces than the left. Permanent prosopagnosia is less common after unilateral right lesions than after bilateral injuries. This suggests that the right ventral occipitotemporal association cortex may be the critical processing node but that in

Chapter 141

most patients the left posterior association cortex can extract enough perceptual information for recognition, even if slowly. Testing for prosopagnosia takes some planning. Because it is a visual modality-specific deficit, the examiner must be careful to provide only visual information. Magazine pictures or family pictures are useful. If real people (i.e., family members) are used for testing, they must be cautioned not to speak or to wear distinctive clothing. This is not a test of perception that happens to use faces. It is a test of recognition of familiar, known faces. Patients with bilateral lesions may be anomic, but descriptions of the target’s occupation, relationship, and so on suffice to eliminate prosopagnosia. Semantic memory deficits can be differentiated from prosopagnosia by performance on strictly verbal tasks. A patient with prosopagnosia will have abundant knowledge of named people. No treatment has ever been proposed. Patients with large bilateral lesions usually improve through a stage of profound object agnosia. Perhaps because it is perceptually more demanding, facial recognition usually recovers less well than object agnosia, but the relative recoveries depend on lesion site, size, and laterality. Some patients have recovered from prosopagnosia but remained unable to recognize emotional expressions. ACHROMATOPSIA

Achromatopsiais the loss of color vision in a preserved visual field. It is usually caused by the same infarction in the inferior occipital lobes. It is often accompanied by prosopagnosia or alexia. It has been described as a migraine aura. It can be demonstrated in just the field contralateral to a ventral occipital lesion or in the entire spared field of patients with bilateral lesions. Patients with unilateral achromatopsia often are not aware of the problem. When bilateral, patients complain that their vision is bleached out or washed out or that illumination always seems poor. Damage to the occipitotemporalgyri (lingual and fusiform) causes contralateral achromatopsia. There is usually a superior visual field deficit with achromatopsia in the preserved inferior field. With rightsided lesions, prosopagnosia usually is present at least transiently. With left-sided lesions, alexia usually is present. With the demonstration in nonhuman primates that visual cortex is not simply a stepwise visual pattern analyzer, that different regions in the visual cortex have specific capacities to analyze particular aspects of a visual stimulus, an explanation became available for acquired color blindness. The color-specific region of visual cortex (V4) in experimental animals is the analogue of the lingual gyrus region in humans. Functional activation in positron emission tomography studies has also

TMLE 141-4. Prosopagnosia Examination Famous and familiar faces Naming Identificationby description Categorization Matchingto name Commonly associated signs Bilateral lesion Superior attitudinal visual field defects Achromatopsia Amnesia Right lesion Left visual field defed Topographic amnesia

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identified the occipitotemporal regions as specifically tuned to color extraction. No treatment has been proposed. SYNDROMES OF IMPAIRED VISUAL AllENTlON

The disorders that result from impaired visual attention are produced by lesions in the dorsal visual association cortex and its outflow to parietal and frontal lobes and by lesions in parietal heteromodal association cortex. Directed attention is a very complex operation that uses a network including structures far from visual cortex. Neglect

Failure to attend to stimuli in extrapersonal space constitutes neglect. Neglect can be seen in either right or left hemispace after lesions in the contralateral hemisphere. Left hemispatial neglect is much more severe than right hemispatial neglect after comparable lesions, one of many pieces of evidence that the right hemisphere is dominant for attentional functions. Neglect may be seen after any structural lesions of any cause. Within the hemisphere, neglect can been seen with dorsolateral frontal, dorsolateral striatal, anterior cingulate, posterior thalamic, or parietal lesions. The manifestationsand mechanisms of neglect differ for these different lesion sites. Large lesions, damaging more than one of those regions, produce the most severe neglect. In clinical practice large infarctions in middle cerebral artery territory produce the most dramatic neglect. Large posterior cerebral artery territory infarctions involving posterior thalamus and occipital cortex also produce very dramatic neglect. The associated signs may be varied, depending on lesion size and site. However, neglect is independent of visual field deficits. Any combination of field deficits and neglect can be seen, depending on lesion site. Testing for neglect is readily accomplished at the bedside with paper and pencil. Although not the cause of or necessary for neglect, primary sensory deficits, including sensory extinction, should be defined. Among the many proposed tests of neglect, line bisection and line (or object) cancellation are most easily performed and sensitive. For line bisection the patient can be given a sheet of paper, presented in the midline, with numerous horizontal lines of various lengths distributed to the right and the left of the paper’s midline. Neglect is measured as systematic deviation from the midline. For cancellation tasks, the patient is given a sheet of paper with randomly arrayed lines or objects and told to mark each line or designated target object. Failure to cancel lines in parts of space defines neglect. Neglect may be apparent in other tests. When reading aloud, the patient may fail to read one end of each line of text. When the patient is quickly shown compound words (e.g., doghouse), one side of the word may be omitted. If the patient is asked to copy complex figures, the copy may start far to one side with failure to copy or disproportionate miscopying of one side. For all tests of neglect, patients with right-sided lesions show much more left neglect than patients with comparable left-sided lesions show right neglect. Patients with parietal lesions seem to show neglect because they fail to pay attention to contralateral hemispace. Thus, when a competing stimulus is present in right space, attention turns to the right. Patients with dorsolateral frontal and dorsolateral striatal lesions appear to show neglect because they fail to move attention to the contralateral hemispace. As long as stimuli are available to draw attention, the patient may move into the impaired hemispace. Only if the task requires the patient to generate his or her

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Behavioral Neurology

own strategy to move attention (e.g., on copying tasks) will evidence of neglect emerge. For parietal or frontal lesions, left hemispatial neglect is always much more noteworthy than right neglect after comparable lesions. Functional imaging studies have demonstrated that the distribution of attention to low-frequency features of a stimulus depends on right parietal lobe. This may account for the patient’s inability to cast a “spotlight” that includes all portions of a stimulus. Many aspects of the visual processing of neglected left field stimuli are normal in patients with neglect, even neglect combined with hemianopia. Patients with neglect are sensitive to center of mass, optic illusions, motion, and word meaning in the neglected fields as long as testing for awareness does not depend on conscious reporting of the left side of a stimulus. Overt demonstration of neglect is influenced by the target’s background and the visual context of testing. These preserved capacities are presumed to occur preattentively and represent automatic operations of the visual system. Treatment of left hemispatial neglect has been attempted in a variety of ways. The primary motivation for these treatments has been the frequent observation that left hemineglect is a significant factor in a bad functional outcome after rehabilitation for stroke. Treatments have been both direct and compensatory. In direct treatments, microcomputer presentation has been used to direct attention to the impaired side before presentation of stimuli. Patients can also be given practice in directing gaze in the horizontal plane to specific points in the impaired hemifield. Compensatory treatments are all techniques of providing a perceptual anchor in the neglected hemispace, such as a brightly colored marker down the left margin of books or on the bathroom mirror, with the patients instructed to always look to the marker. Both techniques seem to improve patients’ function in test circumstances and perhaps in self-care activities. The vestibular system can be stimulated to direct gaze, and presumably attention, into the neglected field with caloric or optokinetic input. Passive stimulation (vibration) and active movement of the left side, when possible, also appear to increase attention to the left side of space. Each of these techniques ameliorates neglect, but the effects are short-lived, and no practical applications have been devised. Right hemispatial neglect recovers quickly. Left hemispatial neglect, in addition to being more severe, is much slower to recover. Several studies of patients with stroke indicate that most recovery occurs within 4 to 6 weeks of onset. Patients with persistently severe neglect 4 weeks after onset may have incomplete long-term recovery and often do very poorly in rehabilitation. In Massachusetts, for example, only visual fields and acuity are considered relevant to driving, but patients with any degree of hemispatial neglect, regardless of their visual fields, should not drive. Significant neglect also probably precludes cooking at open stovetops and using power tools.

Visually Guided Movement As noted earlier, the superior visual association systems are involved in mechanisms of hemispatial attention (detection of the presence of a stimulus, its distance, and its direction of movement), not in mechanisms of visual recognition. This is commonly expressed as the view that dorsal visual systems (occipitoparietal) are concerned with the “where” of an object, and the ventral visual systems (occipitotemporal) are concerned with the “what” of an object. One implication of that dichotomy is that the parieto-occipital regions are concerned with generating movements toward a

detected object. This could involve eye movements to obtain fixation (the better to facilitate discrimination in the ventral systems) or limb movements to capture the object. For eye movements, active fixation must be disengaged, presumably by frontal to occipital projections, allowing new fixations to be made. For limb movements, there must be a cerebral representation of location that allows for size (large objects at a distance occupy the same retinal space as small objects that are near) and movement and that can represent space in both visual and kinesthetic forms so that rapid movement to a visually detected point can occur. The superior parietal lobe contains cells that serve this purpose, and projections to frontal cortex guide these movements. White matter pathways in the parietal lobe between the frontal gaze center (area 8) and the occipital gaze center (area 19) allow the fixation changes. AU these mechanisms work only in contralateral space, depending on parietal callosal connections to drive movement of limbs to a target in the field contralateral to the arm used (i.e., the left arm into right space). Damage to these parietal systems produces a deficit in directing gaze toward an object in space contralateral to the lesion and a deficit in directing the hand toward the object. These two deficits disappear as soon as the object is in central fixation because now both hemispheres have spatial information and guide the limbs. The deficits in eye movement are well known to clinicians, especially for patients with right brain lesions, as gaze preference, poor fixation or tracking into the impaired field, and impaired optokinetic nystagmus. The limb movement deficit, often called impaired visually guided reaching or optic ataxia, is not as well known because all bedside reaching tasks are done to a fixated target. If the patient is forced to reach to a target in the peripheral field, he or she will be unable to direct movement to the target. This is easily tested at bedside. First, proprioceptive deficits and visual field loss must be assessed. If they are absent, visually guided reaching can be tested by having the patient maintain central fixation on the examiner’s nose and then asking him or her to reach to a fingertip held a few degrees into the impaired side of space. Most patients, and in fact most neurologists, are amazed at how easily this is normally accomplished on the intact side. Any structural lesion in the posterior parietal lobe may produce these deficits. Because the superior parietal lobule (area 7) is particularly critical for visually guided reaching, the usual middle cerebral artery territory infarction may not cause a problem. Most reported cases have been tumors, penetrating trauma, spontaneous hemorrhages, or high watershed infarctions. They do not cause hemiparesis, hemiproprioceptive loss, or hemianopia, so the specific reaching deficit can be demonstrated. There is no known treatment for these deficits, but their prognosis generally is favorable because of the instantaneous correction produced by central fixation once gaze is appropriately directed. The same techniques described as direct treatment of neglect may be useful in accelerating recovery.

Balint‘s Syndrome Balint’s syndrome represents the effects of bilateral parietal lesions in which central visual fixation cannot compensate because neither hemisphere can generate normal visual attention or visual control of movement. Thus, it is as though patients have bilateral neglect, attending only to what is at fixation, neglecting nonfixated targets on either side. Furthermore, they may be trapped in fixation, unable to direct gaze volitionally to any other target. Finally, they have severe bilateral optic ataxia, even to targets in

Chapter 141

fixation, because neither hemisphere can represent location or spatially guided movement. These three elements-visual inattention, so-called psychic paralysis of gaze, and optic ataxiaconstitute Balint’s syndrome. Some patients have partial inferior altitudinal visual field defects. The disorder requires bilateral parietal lesions. Most reported cases have been through-and-through gunshot wounds or butterfly gliomas, but bilateral posterior parietal strokes, often watershed type, also can produce Balint’s syndrome. No treatment has been suggested. The prognosis is quite poor, and patients may actually function better if blindfolded because they will rely on proprioception exclusively.

RELATED DISORDERS OF SPATIAL-MOTOR CAPACITY Several cognitive disorders related to visuospatial impairments are not usually considered in this context and should be mentioned briefly.

Limb Praxis Apraxia is almost universally covered in papers on aphasia for several reasons. First, both are common after left-sided brain lesions, and they commonly co-occur. Second, both have a communicative intent, at least as praxis is usually tested. Third, both apraxia and aphasia are viewed as related to handedness. In the context of this chapter, it is important only to note that praxis involves learning to use the arm and hand for a large number of tasks. The constraints of the tasks are spatial and kinesthetic, not communicative. Throwing a ball entails activating a series of movements designed to bring the hand and fingers to a particular point where the ball can serve as a substitute for the hand to travel to a point specified in visual space. Stirring a cup of coffee is highly restricted by the spatial limits of the cup and the implications of that space for the restrictions of movement. Ideomotor apraxia is the inability to carry out learned movements in response to request or imitation. Limb praxis, as usually tested, probes the preservation of the movement patterns unconstrained by space or by the use of actual objects. Deficits in these movement patterns usually are ameliorated by spatial cues (such as a real object). Patients with ideational apraxia may be able to demonstrate correct movement patterns but cannot place them correctly in space. Thus, they cannot actually throw a ball, stir a cup, and so on. This has been called tool-use apraxia but is now considered the most transparent manifestation of ideational apraxia. Patients may have either apraxia in isolation or both ideational apraxia and ideomotor apraxia. Others may have such severe ideomotor apraxia that they do not even improve with the context of an actual object. Lesions can be in the praxis-dominant parietal lobe, usually the left, at least in right-handers, or they can be anywhere in the projections from the parietal lobe to the motor systems that control the movement, whether of the ipsilateral or contralateral hand. In fact, large corona radiata lesions often produce the most persistent ideomotor apraxia of the left hand associated with right hemiparesis. Ideational apraxia is also associated with lesions in the praxis-dominant hemisphere, usually large and including superior parietal lobe and deep white matter. These are the brain regions that code the neural basis for learned movements and also for the proper placement of the movements in space. The clinical assessment is straightforward. Once the patient’s comprehension is established, he or she is asked to pretend to carry out a number of learned movements. If the patient fails, he

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or she is given actual objects to use. Nurses and therapists usually are aware of isolated ideational apraxia before neurologists. No treatment is known. Ideational apraxia has major implications for self-care. The prognosis usually is good, especially for very familiar movements of everyday care.

Dressing Apraxia Most patients who are unable to dress themselves fail for neurologically mundane reasons, severe weakness, visual neglect, or confusion. A very small number have trouble dressing because they cannot represent the spatial, kinesthetic components of visually guiding their limbs into the clothes. This is a primary dressing disorder (dressing upruxiu is a confusing term). Lesions producing this deficit are found in the right superior parietal region. No treatment has been suggested, but selecting clothes that are not visually confusing and laying them out in a manikin-like manner are helpful. The prognosis usually is favorable. Patients with Balint’s syndrome have both ideational apraxia and dressing apraxia.

DrawSng lmpainnents The topic of drawing impairments is too complex to address completely. Nevertheless, it should be clear that parieto-occipital lesions would produce deficits that would make drawing or copying difficult. Lesions of either hemisphere produce disturbances in these visuoconstructive tasks. The tasks entail at a minimum integration of movement with perception, complete attention to the entire visual target, and the ability to direct attention to subcomponents of the target. Patients with left parieto-occipital lesions usually conserve the overall design of the target (low spatial frequency), whether drawing from memory or copying. Probably because of coincident neglect and inability to register the configuration of the entire target, right posterior lesions produce much worse drawings and constructions than left posterior lesions. Patients with right-sided lesions may lose the overall design, attempting to place individual, well-constructed subparts (reflecting high spatial frequency) without respect to the total configuration. Patients with right-sided lesions may also start from the middle of the object and work to the right, never or incompletely returning to the left side. These differences in visuoconstructive deficits can be brought out by having the patient draw familiar but complex figures from memory (e.g., house, flower) and copying novel, complex geometric figures. This part of the examination, combined with neglect tests, takes no more than a few minutes and may be a much clearer window into the patient’s deficits than any other testing. There is almost no information about natural history of constructional impairments. The purpose of treatment would not be clear, and no specific treatments have been proposed.

CONCLUSION The clinical classification follows from answering four questions: Is there an impairment of visual discrimination or recognition? Is there an impairment in visual attention? Is there a deficit in visuospatially controlled movement (eye movements, limbs, or whole body)? Is the deficit demonstrated with language-based or non-languagebased tasks?

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Behavioral Neurology

The higher-level visual processing disorders have been extraordinarily informative vehicles for constructing theories of how the brain carries out complex mental operations. Although some parts of these fascinating scientific questions have been addressed here, the primary focus has been clinical. In clinical practice these disorders are not uncommon, and this chapter has summarized the causes and clinical settings in which they are encountered and the most direct strategies of bedside diagnosis. To the extent that they are treatable, current treatment strategies have been reviewed.

SUGGESTED READINGS Benson DF, Greenberg J P Visual form agnosia. Arch Neurol 20:82-89, 1969

Coslett HB, Saffran E Simultanagnosia. Brain 114:1523-1545, 1991 Damasio AR, Benton AL: Impairment of hand movements under visual guidance. Neurology 29:170-174, 1979 Damasio A, Damasio H: The anatomical basis of pure alexia. Neurology 33~1573-1583, 1983

Damasio AR, Damasio H, Van Hoesen GW Prosopagnosia:anatomic basis and behavioral mechanisms. Neurology 32:331-341, 1982 Damasio AR, Yamada T, Damasio H: Central achromatopsia: behavioral, anatomic, and physiologic aspects. Neurology 30:1064-1071, 1980 DeRenzi E: Disorders of Space Exploration and Cognition. Wiley, Chichester, UK, 1982

DeRenzi E Prosopagnosia in two patients with CT scan evidence of damage restricted to the right hemisphere. Neuropsychologia24385389, 1986

DeRenzi E, Lucchelli F: Ideational apraxia. Brain 113:1173-1188, 1988 D’Esposito M, McGlinchey-Berroth R, Alexander MP et ak Dissociable cognitive and neural mechanisms of unilateral visual neglect. Neurology 43~2638-2644, 1993 Feinberg T, Heilman KM, Rothi LG Multimodal agnosia after unilateral left lesion. Neurology 36864-867, 1986 Halligan PW, Marshall JC: Figural modulation of visuo-spatial neglect: a case study. Neuropsychologia 29:619428, 1991 Henderson VW, Friedman RB, Teng EL, Weiner JM: Left hemisphere pathways in reading: inference from pure alexia without hemianopia. Neurology 35:962-968, 1985 Hodges JR, Patterson K, Oxbury S, Funnell E Semantic dementia. Brain 115:1783-1806, 1992

Marshall RS, Lazar RM, Krakauer JW, Sharma R Stimulus context in hemineglect. Brain 121:2003-2010, 1998 Mesulam MM: A cortical network for directed attention and unilateral neglect. Ann Neurol 10:309-325, 1981 Petersen SE, Fox PT, Posner MI, Raichle ME Activation of extrastriateand frontal cortical areas by visual words and word-like stimuli. Science 2491041-1044, 1990

Ro T, Rafal RD: Perception of geometric illusions in unilateral neglect. Neuropsychologia 34:973-978, 1996 Tyler HR Abnormalities of perception with defective eye movements. Cortex 4154-177, 1968 Zeki S: A century of cerebral achromatopsia. Brain 113:1727-1777, 1990

142 Disorders of Memory Ronald C. Petersen Memory complaints are common in clinical practice, especially as the patient population ages. Memory is an essential cognitive function, and even a mild impairment can disrupt one’s professional and social life. Occasionally memory disorders are the patient’s sole complaint and can be very disabling. Among cognitive complaints, memory dysfunction is the most common problem brought to the clinician’s attention, yet it can be perplexing to evaluate. The clinician must determine the following: Does a memory problem exist? What is the anatomic site of the problem? What is the mechanism of the disorder? What treatments are available?

DOES A MEMORY DISORDER EXIST? This can be a difficult question to answer. Patients and families often attribute any type of cognitive or emotional disorder to a memory problem. It is as if memory function is the final common pathway for a variety of cognitive complaints. The clinician must be certain that the patient is not referring to difficulties with attention, concentration, naming, or language. For example, it is typical for an older patient to complain of word-finding difficulties and attribute this to a poor memory. A major problem exists in the memory literature with respect to terminology. Memory functions are complex, so various terms

have developed over the years to describe different aspects of learning and recall performance. Although several sets of terminology relating to multiple theoretical models have evolved over the years, there are certain commonalties among the various theoretical approaches. These features can be appreciated by considering a classic amnestic syndrome such as that resulting from bilateral amygdalohippocampectomies or the alcoholic Wernicke-Korsakoff syndrome. In these examples, the primary cognitive dysfunction is one of impaired learning or acquisition of new information. The neurologic process thought to be disrupted in this disorder is consolidation or the actual formation of a more permanent memory trace. Failure of the consolidation process is also known as anterograde amnesia, referring to the inability to lay down new memories after the onset of the memory disorder. In dramatic cases of the amnestic syndrome, the clinician may spend much time interviewing and examining the patient with a seemingly normal interpersonal interaction. The clinician may then leave the room to return 5 minutes later and find the patient unaware of the previous interview or of having met the clinician. This dramatic amnesia results from a failure of consolidation. In the typical amnestic syndrome, information acquired before the onset of the memory disorder is variably recalled. Typically, older memories may be better preserved than more recently experienced events. This gradient may reflect an ongoing consolidation failure in recent days and months that may degrade the more recently acquired information. When a patient does not

902

BehavioralNeurology and Epilepsy

rn

Behavioral Neurology

The higher-level visual processing disorders have been extraordinarily informative vehicles for constructing theories of how the brain carries out complex mental operations. Although some parts of these fascinating scientific questions have been addressed here, the primary focus has been clinical. In clinical practice these disorders are not uncommon, and this chapter has summarized the causes and clinical settings in which they are encountered and the most direct strategies of bedside diagnosis. To the extent that they are treatable, current treatment strategies have been reviewed.

SUGGESTED READINGS Benson DF, Greenberg J P Visual form agnosia. Arch Neurol 20:82-89, 1969

Coslett HB, Saffran E Simultanagnosia. Brain 114:1523-1545, 1991 Damasio AR, Benton AL: Impairment of hand movements under visual guidance. Neurology 29:170-174, 1979 Damasio A, Damasio H: The anatomical basis of pure alexia. Neurology 33~1573-1583, 1983

Damasio AR, Damasio H, Van Hoesen GW Prosopagnosia:anatomic basis and behavioral mechanisms. Neurology 32:331-341, 1982 Damasio AR, Yamada T, Damasio H: Central achromatopsia: behavioral, anatomic, and physiologic aspects. Neurology 30:1064-1071, 1980 DeRenzi E: Disorders of Space Exploration and Cognition. Wiley, Chichester, UK, 1982

DeRenzi E Prosopagnosia in two patients with CT scan evidence of damage restricted to the right hemisphere. Neuropsychologia24385389, 1986

DeRenzi E, Lucchelli F: Ideational apraxia. Brain 113:1173-1188, 1988 D’Esposito M, McGlinchey-Berroth R, Alexander MP et ak Dissociable cognitive and neural mechanisms of unilateral visual neglect. Neurology 43~2638-2644, 1993 Feinberg T, Heilman KM, Rothi LG Multimodal agnosia after unilateral left lesion. Neurology 36864-867, 1986 Halligan PW, Marshall JC: Figural modulation of visuo-spatial neglect: a case study. Neuropsychologia 29:619428, 1991 Henderson VW, Friedman RB, Teng EL, Weiner JM: Left hemisphere pathways in reading: inference from pure alexia without hemianopia. Neurology 35:962-968, 1985 Hodges JR, Patterson K, Oxbury S, Funnell E Semantic dementia. Brain 115:1783-1806, 1992

Marshall RS, Lazar RM, Krakauer JW, Sharma R Stimulus context in hemineglect. Brain 121:2003-2010, 1998 Mesulam MM: A cortical network for directed attention and unilateral neglect. Ann Neurol 10:309-325, 1981 Petersen SE, Fox PT, Posner MI, Raichle ME Activation of extrastriateand frontal cortical areas by visual words and word-like stimuli. Science 2491041-1044, 1990

Ro T, Rafal RD: Perception of geometric illusions in unilateral neglect. Neuropsychologia 34:973-978, 1996 Tyler HR Abnormalities of perception with defective eye movements. Cortex 4154-177, 1968 Zeki S: A century of cerebral achromatopsia. Brain 113:1727-1777, 1990

142 Disorders of Memory Ronald C. Petersen Memory complaints are common in clinical practice, especially as the patient population ages. Memory is an essential cognitive function, and even a mild impairment can disrupt one’s professional and social life. Occasionally memory disorders are the patient’s sole complaint and can be very disabling. Among cognitive complaints, memory dysfunction is the most common problem brought to the clinician’s attention, yet it can be perplexing to evaluate. The clinician must determine the following: Does a memory problem exist? What is the anatomic site of the problem? What is the mechanism of the disorder? What treatments are available?

DOES A MEMORY DISORDER EXIST? This can be a difficult question to answer. Patients and families often attribute any type of cognitive or emotional disorder to a memory problem. It is as if memory function is the final common pathway for a variety of cognitive complaints. The clinician must be certain that the patient is not referring to difficulties with attention, concentration, naming, or language. For example, it is typical for an older patient to complain of word-finding difficulties and attribute this to a poor memory. A major problem exists in the memory literature with respect to terminology. Memory functions are complex, so various terms

have developed over the years to describe different aspects of learning and recall performance. Although several sets of terminology relating to multiple theoretical models have evolved over the years, there are certain commonalties among the various theoretical approaches. These features can be appreciated by considering a classic amnestic syndrome such as that resulting from bilateral amygdalohippocampectomies or the alcoholic Wernicke-Korsakoff syndrome. In these examples, the primary cognitive dysfunction is one of impaired learning or acquisition of new information. The neurologic process thought to be disrupted in this disorder is consolidation or the actual formation of a more permanent memory trace. Failure of the consolidation process is also known as anterograde amnesia, referring to the inability to lay down new memories after the onset of the memory disorder. In dramatic cases of the amnestic syndrome, the clinician may spend much time interviewing and examining the patient with a seemingly normal interpersonal interaction. The clinician may then leave the room to return 5 minutes later and find the patient unaware of the previous interview or of having met the clinician. This dramatic amnesia results from a failure of consolidation. In the typical amnestic syndrome, information acquired before the onset of the memory disorder is variably recalled. Typically, older memories may be better preserved than more recently experienced events. This gradient may reflect an ongoing consolidation failure in recent days and months that may degrade the more recently acquired information. When a patient does not

Chapter 142

recall information learned before the time of injury or ictal event, this is called retrograde amnesia. Although these abnormalities in memory function are prominent, patients with the amnestic syndrome have preserved general intellect, attention, and language. These preserved functions allow patients to carry on a reasonably normal conversation in the immediate time frame, but when patients are asked to recall information encountered in the recent past, they have great difficulties. In this sense, the amnestic syndrome is a rather pure disruption of memory function.

Information ProcessingModel Why does the amnestic syndrome occur? This question can be addressed by invoking an information processing model. Most information is received in the brain through sensory processing systems and is stored for a brief period of time in these systems. These processing networks initially are modality specific and then converge to bring together information regarding a perceptual event from a variety of sensory modalities. The sensory information is held in a temporary register that depends on attention and serves the function of holding the information for subsequent processing. As is shown in Figure 142-1, the temporary processing register is of limited capacity, and the information persists in this store for only a short period of time (seconds).While information is in this temporary register, some of it is selected for further processing, dependent on the experience of the individual and the requirements of the learning situation. For example, if one were to process information regarding a soft drink can, certain visual features of its shape, color, and size would be held in a visual information register briefly. If the can were held in the hand, somatosensory information also would be retained, and if one manipulated the can to hear the sound of bending aluminum, auditory information would also be held in a register for a brief period of time. AU this information ultimately would coalesce, but in its initial processing phase it would be held in the modalityspecific stores. This limited-processing temporary store can be assessed clinically by asking patients to recite digit spans such as telephone numbers. Typically, most people can process up to seven independent items of information and hold them for up to a minute without rehearsal. However, if the material is not rehearsed or further encoded, the information decays rapidly. The actual learning process entails encoding this information in terms of previous experiences and transferring it to a more

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permanent memory register. This transfer process, previously called consolidation, is the primary site of dysfunction in most organic amnesias. In the amnestic syndrome, patients are able to recite a normal digit span but are unable to transfer information from this temporary store to a more permanent memory register. The transfer of information from the temporary store to the more permanent register can be assessed by providing the patient with a list of items, such as words, that exceeds the immediate memory span of approximately seven units or by requiring the patient to recall the information after a delay interval filled with intervening activities that prevent rehearsal. For example, to use the latter technique the clinician could present five or six words to patients and ask them to remember the words over a series of three or four learning trials. The clinician could then engage in other activities for perhaps 15 minutes and ask the patient to try to recall the five or six words after the 15-minute delay. This technique can be useful to the clinician for assessing this critical aspect of information processing involved in consolidation. Figure 142-1 presents a schematic of this information processing model and provides some terminology that corresponds to various aspects of the scheme and tasks that can be used to assess the various aspects of processing. Most investigators accept these features of memory function as universal but use a variety of terms to discuss these concepts in various theoretical models. Some of the more commonly used terms in various theoretical discussions of memory are defined in this chapter.

Psychological-Anatomic ProcessingModel One of the problems for the clinician in assessing memory disorders concerns the terminology and the literature. Many terms are used to describe various aspects of memory function. A popular model for memory has been proposed and refined by Dr. Larry Squire and colleagues at the University of California at San Diego. Figure 142-2 shows a modification of his model with putative anatomic loci for these functions. Most memory complaints clinicians deal with in the office setting concern declarative or explicit memory functions. This type of memory is accessible to the patients through conscious mechanisms, whereas the nondeclarative aspects of long-term memory generally are not accessible to consciousness. When patients complain of memory problems, they are referring to declarative or explicit memory processes as shown in Figure 142-2, and the anatomic substrate for

I'

Temporary Store

FIG. 142-1. Information processing scheme depicting a temporary store and a more permanent store. For each store, alternative terms in various theoretical models and office testing procedures are indicated.

Disorders of Memory

n Permanent Store

PrimaryMemory Working Memory

Long-term Memory Secondary Memory Recent, Remote Memory E#=, Semantic

Digit Span 3 or 4 Word Lists

Delayed Recall

Short-term Memory

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Long-term memory i

I Declarative I

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FIG. 142-2. Model of memory including declarative and non-declarative memory processes as proposed by Dr. Larry Squire. (Adapted with permission from Squire LR: Memory and Brain. Oxford University Press, 1987.)

these disorders is likely to involve medial temporal lobe and limbic system structures. Figure 142-2 can be interpreted in the context of the following glossary.

Glossary Short-Term Memory. This terms refers to the limitedcapacity temporary storage buffer shown in Figure 142-1. It has a finite capacity, and information remains in the store for a brief period of time (seconds to a minute) without rehearsal. This type of store would hold a telephone number for a short time. It reflects an attentional rather than a memory process. This term often is used loosely in clinical practice and, without a specific definition, should be avoided. Long-Term Memory. This aspect of memory function refers to the more permanent large-capacity memory store also outlined in Figure 142-1. Long-term memory usually refers to our knowledge base of previously learned information. Occasionally, this store is divided into two components: recent memory and remote memory. These terms are defined imprecisely along a temporal dimension, with recent memory typically referring to memories hours to days in duration and remote memory referring to distant

past memories of many years. However, these terms are not specific. Primary Memory. This term is similar with respect to retention duration to the concept of short-term memory. Primary memory refers more to the processing nature of this type of memory than to the actual storage function. It tends to deemphasize a precise temporal gradient and describes the type of processing performed on material held in the temporary store. Secondary Memory. In a similar fashion, this term refers to memory processes that support retention across long retention intervals. It is somewhat similar to the long-term memory notion but emphasizes the processes involved in the storage and retrieval of previously learned information rather than the temporal dimension. Working Memory. This term refers to material held in primary memory on which further elaboration is done. This concept refers to the selection of material in the temporary store for further processing and encoding into the more permanent memory store. Working memory refers to encoding processes and the use of strategies for facilitating consolidation. This is a dynamic aspect of memory and can be impaired in attentional disorders.

Chapter 142

Episodic Memory. This term refers to memory for events that are related to a specific spatial or temporal context. There is no temporal dimension to this type of material; rather, this concept incorporates the specific situation in which an event was remembered. For example, when a person tries to learn a list of words in a particular setting, this material would be referred to as existing in episodic memory. This type of memory is severely affected in pathologic processes involving the medial temporal lobes and diencephalic structures and is impaired in most organic amnesias. Semantic Memory. This term typically is used in contrast to episodic memory to refer to information that is stored in the more permanent knowledge base without any reference to the specific learning context. For example, information that we have learned about a concept such as gravity would be incorporated into our semantic memory store despite the fact that we do not remember the specific context in which we acquired this information. This type of information forms our knowledge of the world and is resistant to disruption in many memory disorders. Declarative Memory. This refers to memory that is directly accessible to consciousness and is also significantly affected in most organic amnesias. Declarative memory refers to recently experienced information about which we are aware and often remember the circumstances in which it was learned. Damage to medial temporal and diencephalic structures can disrupt this type of memory. Procedural Memory. In contrast to declarative memory, this form of memory refers to skills and procedural operations. Certain overlearned motor skills and mechanical sequences are part of procedural memory. This type of memory often is spared in many organic amnesias and presumably involves structures in the basal ganglia rather than the medial temporal lobe or diencephalic structures. Encoding. Encoding is the acquisition or learning of new information. In particular, this term refers to the actual psychological representation of the new information with respect to previously learned material. That is, the new information is encoded with respect to the person’s knowledge of the world. Retrieval. This term refers to the spontaneous reproduction of information stored in the long-term or permanent memory store. That is, once information has been encoded or learned and it is recalled at a later point in time, the item often is referred to as being retrieved. This requires accessing previously learned information (i.e., one’s knowledge of the world) to reproduce the information. Recognition. This term refers to the matching of a piece of information to a previously experienced event. That is, in contrast to retrieval, where the item is reproduced spontaneously from memory, in recognition a newly presented item is matched with a previously learned or experienced piece of information. In this sense, it is useful at identifylng previouslylearned items as a means of testing memory. In this form of memory test, the to-beremembered items are presented to the person along with distractor items, and the person is asked to identify the correct items. A multiple-choice test is an example of a recognition exercise. Summary. As one can see, there are many terms that refer to multiple aspects of memory function. These terms are not mutually exclusive and at times refer to very similar concepts. The individual differences among the terms emanate from the theoretical background from which they are derived and pertain to one theoretical model or another. Each of these terms can be useful in

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specific instances, but the overall concept of temporary and more permanent memory stores ultimately may be more useful. Does a Memory Problem Exist?

Based on the information presented in this conceptual frame, the clinician can then decide whether the patient’s problem involves memory primarily or other cognitive functions. If the patient appears to be describing a failure of consolidation with preservation of attention, language, and other cognitive processes, then it is likely that the clinician is dealing with an organic memory disorder, and an evaluation is appropriate.

WHAT IS THE SITE OF THE PROBLEM? To a certain extent, the information processing scheme outlined in Figure 142-1 has anatomic analogues. For example, as is shown in Figure 142-3, the primary sensory receiving areas and the unimodal (modality-specific) association areas corresponding to each sensory modality provide the substrate for the input processing of sensory information. Superimposed on this sensory processing scheme are attentional functions, which are largely subserved by frontal and subcortical structures. One role of attention in sensory processing is to preserve the incoming information in the temporary holding store. In addition, certain association areas in the right hemisphere (temporoparietal and frontal association areas) may also contribute to the selective preservation of information in these temporary memory registers. After initial processing in the primary sensory and unimodal association areas, the information is elaborated upon and transferred through multimodal association areas residing largely in temporoparietal and frontal regions. These areas combine the individual modality-specific aspects of the stimulus to be remembered and further enrich the elaboration of the information. Using the example of a soft drink can cited earlier, all the properties of the individual modalities such as the visual, somatosensory, and auditory aspects of the can itself would coalesce into the multimodal sensory areas to provide a richer perception of the individual sensory experiences. The soft drink can not only would have visual features of a cylinder of a certain size but also would have somatosensory features of a smooth object and auditory features of an aluminum can. The information is then transferred from the multimodal association areas to the limbic system, largely through the entorhinal cortex and parahippocampal regions (Fig. 142-3). The experience is then processed through the perforant pathway of the entorhinal cortex into the hippocampal formation and limbic system, which is the anatomic basis for major aspects of the consolidation process. It is important to realize that the information is not stored in the hippocampal formation and limbic system but rather is processed in these regions and ultimately transferred back to cortical association areas where the neural networks exist, which embody the remembered information. The actual neural representation of the information to be remembered is diffusely distributed in neocortical regions, and these areas correspond to the more permanent aspects of storage in the information processing model. This interaction between the association areas and the limbic system is a dynamic process, with the remodeling of information in the more permanent stores taking place regularly. Consequently, memory should be viewed as a dynamic process with constant reorganization of information rather than as a passive system of storage of facts and information.

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FIG. 142-3. Anatomic localization of the flow of information from sensory association areas to temporolimbic structures for memory acquisition. (0) Somatosensory association area; (b) auditory association area; (c) visual association area.

Returning to our soft drink can example, it is at the point of the limbic system involvement that the soft drink can takes on meaning as a soft drink can based on our previous knowledge. In addition, if we have had previous personal experiences with certain types of soft drink cans, these aspects of the sensory event are brought to bear on remembering this particular perceptual event. In this model, although many areas of cortex and subcortical regions are involved in acquisition, the temporolimbic system is the critical focus of much of the consolidation activity. The clinician needs to focus on the temporolimbic system as a site of impairment in most organic amnesias with significant acquisition or consolidation defects. Most commonly encountered amnestic syndromes involve dysfunction of these structures. In summary, when encoding or acquisition processes are primarily involved, the most likely structures implicated are the medial temporal lobe including the entorhinal cortex, perforant pathway, hippocampal formation, thalamus, hypothalamus, surrounding third ventricular structures, basal forebrain, and multiple interconnecting pathways. Most disease processes that affect memory significantly involve these structures anatomically or pharmacologically. For severe memory disorders, the involvement must be bilateral. However, unilateral lesions can give materialspecific deficits such as verbal or nonverbal processing difficulties. The anatomic localization of retrieval processes is less clear but probably involves some aspect of limbic system processing as well as other regions of the cerebral cortex such as the prefrontal cortex. This region may be involved in attention and retrieval strategy generation, whereas the temporoparietal neocortex, in-

cluding higher-order association areas, may be where the neural networks that embody the material to be remembered reside. These structures subserve the anatomic localization of the more remote memories or knowledge base and consequently are preserved except in the setting of diffuse or advanced disease processes.

WHAT I S THE MECHANISM OF THE DISORDER? As with all neurologic disorders, the temporal course of the development of the symptoms is of paramount importance. This factor, coupled with other features of the history such as head trauma, alcohol use, concomitant cancer, vascular disease, or psychiatric illnesses, may all give the clinician insight into possible mechanisms (Table 142-1). Acute Memory Loss

From a temporal perspective, if the memory disturbance has come on acutely, the clinician should consider a vascular cause. Because many of the central limbic structures that subserve memory are in the distribution of the vertebrobasilar arterial system, these structures should be investigated. For example, ischemia to the medial temporal lobes or the thalamus can present with the acute onset of a memory impairment. Other conditions that can produce an acute memory loss include transient global amnesia, about which the precise mechanism is not known, but presumably some type of temporary dysfunction of these critical structures is involved. In certain other

Chapter 142

medical contexts, hypoxia, hypoglycemia, migraine, intracerebral hemorrhages (particularly resulting from anterior communicating artery aneurysm rupture), drug ingestion, or toxic exposure could produce an acute memory loss. In addition, psychogenic causes of amnesia must be considered in the appropriate context. Initially, an imaging study may be helpful to evaluate a possible infarct, hemorrhage, mass, or infection. A head computed tomography (CT) scan with and without contrast is helpful initially. However, a negative scan does not rule out all considerations because many of the structures involved in memory function may not be visualized well by CT because they reside in close proximity to the calvaria of the middle cranial fossa, which can produce artifacts on CT. Magnetic resonance imaging (MFU) may be preferred because of its increased sensitivity to detect small lesions in critical structures. Recently, MRIs using certain acquisition procedures have been particularly useful at detecting lesions, including atrophy in the medial temporal lobe region. If an infarct is detected in the thalamus, medial temporal lobe, or limbic system structures, then an investigation of the cause of this event, as discussed in Chapters 28 and 29, must be considered. If the patient complains of multiple acute episodes of memory loss, a complex partial seizure disorder of temporal lobe origin must be considered and pursued. As mentioned, if there is a history of head trauma or psychiatric disease, then these causes must be evaluated as well. Occasionally, transient ischemic attacks of the vertebrobasilar artery circulatory system can present with memory impairment, although usually other neurologic symptoms also occur. Transient global amnesia is a distinctive condition involving a pure amnestic problem of short duration. Typically patients with transient global amnesia cannot lay down any new memories for a period of several hours and have a retrograde amnesia of variable extent. The patient otherwise looks well and is neurologically intact. However, because of their inability to consolidate new information, they ask the same question repeatedly because they are unable to retain the answer that was given to them previously. The precise cause of this condition is not known, but it probably involves medial temporal lobe and limbic system structures on a transient basis. Other causes of temporary dysfunction of the temporolimbic system must be considered also, such as ischemia or a seizure disorder, but if there are no other features of these alternative conditions, transient global amnesia may be the best explanation.

TAW 142-1. Onset of Memory Disorders mme

Cause

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Seconds to minutes

Subacute

Days to weeks

Chronic

Months to years

Vascular‘ ischemic Hemorrhagic Transient global amnesia* Seizure disorder‘ Migraine* Hypoxia infectious inflammatory Metabolic Toxic Neoplastic Degenerative Neoplastic Deficiency state Psychiatric

‘Can be episodic

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Finally, nonorganic or psychogenic conditions can present with an acute memory loss. Often these amnesias have certain features that distinguish them from organic memory problems. Typically, a retrograde amnesia is a prominent feature of the symptom complex, often in the setting of preserved learning and acquisition (i.e., no anterograde amnesia). These patients may claim to have forgotten their names, family information, and occasionally emotionally laden experiences. Although prominent isolated retrograde amnesia cases have been reported in association with brain injury, they are uncommon. In evaluating suspected nonorganic amnesias, the patient’s performance often provides clues. The patient may give inconsistent responses on tests, fail easier memory tasks such as recognition tests, and perform normally on free recall. Patients may forget information that is distinctly resistant to loss, such as personal identity. However, the clinician should also seek supporting psychiatric evidence for nonorganic amnesias before concluding that the memory deficit has no organic basis. Subacute Memory Loss A subacute (days to weeks) evolution of a memory disorder would raise the consideration of infectious, inflammatory, toxic, or metabolic causes. Other features of the history and examination should alert the clinician to consideration of infectious causes and possible cerebrospinal fluid analysis. Herpes simplex encephalitis must be considered, especially in the setting of altered cognition with seizures because this is a treatable condition. Some inflammatory conditions may present with a memory disorder including multiple sclerosis, central nervous system sarcoidosis, and Sjogren’s syndrome. Finally, in the appropriate clinical context, meningeal carcinomatosis or limbic encephalitis can present with a memory impairment, although usually with additional cognitive and neurologic findings. As always, a psychiatric explanation should be considered.

Chronic Memory Loss Finally, if the memory disorder has evolved over months to years, a degenerative disorder such as Alzheimer’s disease becomes much more likely in the appropriate age group. Other considerations include a neoplasm, particularly of the limbic system, deficiency state such as thiamine, or psychiatric conditions including depression. In a degenerative disease such as Alzheimer’s disease, acquisition processes and retrieval processes are affected early and may be the only manifestation of disease in the initial stages. Later, however, other cognitive functions become impaired, and memory is no longer an isolated defect. Occasionally, distinctions are drawn between predominantly cortical dementias, such as Alzheimer’s disease, and predominantly subcortical dementias, such as those seen in Parkinson’s disease, Lewy body dementia, vascular disease, progressive supranuclear palsy, or multiple sclerosis. In subcortical dementias, it is often more difficult for the patient to encode the material, but once it has been learned, it is recalled reasonably well, especially with cues. In cortical dementias such as Alzheimer’s disease, learning is impaired despite adequate effort, and recall with cues is also significantly impaired. The subcortical dementias may also have impaired attention, which contributes to the learning difficulties.The cortical-subcortical distinction must be made with some caution because there is often significant overlap. Investigations of chronic memory disorders include imaging studies, MFU

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FIG. 142-4. Theoretical transition from normal aging through mild cognitive impairment to dementia in people who are ultimately destined to develop dementia. (Adapted from Neurologist 1:326344, 1995, with permission.)

or CT scan, and laboratory studies more typical of those associated with a dementia evaluation, as discussed in Chapter 136. Degenerative Memory Disorders of Aging: Mild Cognitive Impairment

Although memory disorders can wcur in patients of any age, most of these problems present in older patients. The clinician often is faced with a patient who asks, “Am I developing Alzheimer’s disease?” In the setting of mild forgetfulness in an older patient, this can be a perplexing question. In recent years, a great deal of research has been done on the concept of mild cognitive impairment. Mild cognitive impairment is regarded as a transitional state between normal aging and Alzheimer’s disease, as depicted in Figure 142-4. Presumably, people who develop Alzheimer’s disease do so over many years. The transition can be gradual. Mild cognitive impairment is defined by the criteria outlined in Table 142-2. The ultimate diagnosis of mild cognitive impairment is clinical. Essentially, these patients have a memory impairment that is out of proportion to what would be expected for their age and education, yet they are not demented. These patients are functioning independently in the community and do not appear impaired. However, when the patient is tested in a more rigorous setting, a memory impairment is apparent and significant. From a historical standpoint, these patients tend to forget important information more often than they have in the past. The casual forgetfulness for people’s names or locations of car keys probably is not significant, but forgetting an important event or appointment may be significant. For example, if a person is having difficulty remembering doctors’ appointments or social engagements to which he or she is committed, this may be meaningful. In particular, if this represents a change from the person’s previous behavior, and this is apparent to those who know the patient well, this may be of sufficient concern to merit an evaluation. Because the diagnosis of mild cognitive impairment is clinical, neuropsychological testing can be very helpful but is not definitive.

TABLE142-2. Clinical Criteria for Mild Cognitive Impairment

Memory complaint, preferably corroborated by an informant Objective memory impairment on clinical testing Largely preserved general cognitive functions Essentially normal activities of daily living Not demented

Ultimately, the clinician must decide who may qualify for this diagnosis. The recognition of this transitional state can be important because patients who meet these criteria have a 10% to 15% annual risk of going on to meet criteria for clinical Alzheimer’s disease. This figure is in contrast to normal subjects of the same age, who develop Alzheimer’s disease at a rate of 1% to 2% per year. No pharmacologic treatments have been demonstrated to be efficacious for mild cognitive impairment. However, counseling as to the nature of the condition and the likelihood of progression over subsequent years can be very useful to subjects for the purposes of future planning. Several clinical trials for mild cognitive impairment are currently under way involving 4000 to 5000 subjects worldwide. The American Academy of Neurology has recently endorsed the concept of mild cognitive impairment through an evidence-based review of the literature. They have published a practice parameter that recommends that clinicians identify, evaluate, and follow patients with a mild cognitive impairment because they are at a greater risk of developing Alzheimer’s disease. As the field evolves, effective treatments may be developed to forestall this progression.

EVALUATION OF MEMORY DISORDERS History The history from a patient with a memory disorder can be very important. Typically, the history should focus on the recall of recent events rather than recall of remote memories that may be preserved. In the course of taking a history, the patient can be asked about recent events in the news, including events of the past few days or significant news items of recent months, such as natural disasters, major crimes, or prominent political events. This line of questioning presumes that the patient has been exposed to these events and a family member can be asked to corroborate these items. Typically most people are aware of major weather events such as hurricanes, earthquakes, or floods that are commonly in the news. If a person is a sports fan, recent events can be tested by asking about performance of the patient’s favorite teams. These questions are meant to assess the acquisition of significant information most people would demonstrate if they have been exposed to the events. Often patients with memory problems are vague about the answers to these questions and provide little detail. The clinician needs to be certain that the patient is attentive and does not have a significant language problem (aphasia) when

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assessing memory. Many people, as they age, are aware of word-finding problems, usually for names of people. They often attribute such problems to a failing memory, and this condition must be assessed because some naming deficits are a part of normal aging and represent a retrieval failure for previously learned information rather than an acquisition or learning problem. Occasionally in taking a history from a patient, certain details of the history itself may be lost. The clinician can get an impression of the severity of the problem by asking the patient to recount events of the past day or two in terms of travel, activities with family members, or how they got to the clinician’s office. Though not necessarily quantitative, these questions can reveal the possibility of a significant memory problem. Mental Status Evaluation An accurate mental status examination is an essential component

of evaluating someone with a memory disorder. As indicated, it is important to determine whether memory is in fact impaired or other cognitive deficits contribute to the problem. A complete discussion of mental status testing is found in Chapter 135. The clinician can use one of the standard mental status examinations available, such as the Mini-Mental State Exam or the Short Test of Mental Status, but must be aware of the limitations of these instruments. These tests usually use three- or four-word lists with a short recall interval and may underestimate early memory deficits. Alternatively, if the patient has difficulty with delayed recall with three or four words, there is probably a significant memory problem. The Short Test of Mental Status also assesses an element of learning by taking into account the number of trials the subject needs to learn the four words accurately. In general, office testing of memory should include sets of verbal and nonverbal materials that are presented over several learning trials. This will give an index of learning or acquisition. A several-minute delay, usually 15 to 30 minutes, should be interposed to assess delayed recall. Recent evidence indicates that in addition to acquisition deficits, delayed recall performance may be a sensitive index of early impairment. Based on the findings of the clinician in the office, specific recommendations can be made to the neuropsychologist for more extensive memory testing. The mental status examination should also include evaluation of attention and language functions (Chapters 139 and 140) to be certain that the patient is not significantly inattentive, leading to poor learning or acquisition, or that the patient does not have a significant aphasia with profound anomia. If the patient performs reasonably well in the general assessment of cognitive function but performs poorly with respect to acquisition or delayed recall, then

the clinician needs to pursue an investigation of the cause of the problem. Inconsistencies or a depressed affect may alert the clinician to psychiatric contributions to the cognitive impairment such as those found in depression. It may be helpful to augment the cognitive components of the mental status examination with an inventory of psychiatric symptoms. NeuropsychologicalTesting

Neuropsychological testing can be viewed as an extension of the mental status examination. The same principles involved in evaluating mental status in the office can be used in interpreting the results of neuropsychological testing. In general, the clinician is interested primarily in the results of the memory tests. The testing should involve acquisition of verbal material that exceeds the primary memory capacity and requires the transfer of information from the temporary memory store to the more permanent memory store. This usually involves multiple learning trials of a list of 10 to 15 words. A delay of approximately 15 to 30 minutes should be interposed between the final acquisition trial and a later recall test. The clinician should assess the patient’s ability to generate a learning curve, that is, improve recall on each successive learning trial. Ultimately the patient should recall more than five or six items over the several learning trials. That is, one should see evidence that the patient has transferred some information from the temporary memory store to the permanent memory store. As shown in Figure 142-5, learning curves can take on characteristic features of underlying disorders. Ideally, performance on these instruments should be assessed relative to age- and education-appropriate norms. After the delay interval, free recall for the material should be assessed, and retrieval performance of at least 50% of the initially acquired material should be achieved. However, this will vary with the age and education of the patient as well. Some neuropsychological learning instruments also involve the use of semantic cueing and facilitated recall. These measures are meant to assess the patient’s ability to use provided acquisition strategies and subsequent recall through the use of these semantic cues. These can be very sensitive tools to detect very early memory impairments involving damage to medial temporal lobe structures. An analogous set of nonverbal materials such as a complex geometric figure should be used as well. There are various instruments for assessing the learning and recall of visuospatial materials. The same principles as applied to verbal learning should be used to assess nonverbal recall. As with the mental status examination, neuropsychological testing should also assess other aspects of cognitive function including attention, language, visuospatial skills, higher reasoning

Normal

FIG. 142-5. Hypothetical learning curves in normal aging, Alzheimer‘s disease, and depression. The significant differences pertain to the slopes of the learning curves and the relation of performance on delayed recall to the final learning trial.

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processes, praxis, and constructions. This will help the clinician determine whether memory is the sole cognitive function impaired or is impaired out of proportion to other mental abilities. It will also help the clinician determine whether other cognitive functions such as attention and language are having an impact on memory performance, thereby necessitating qualification of the memory test results. The combination of the clinician’s history, mental status examination, general neurologic examination, and neuropsychological testing should provide adequate information for a determination of a memory deficit. Occasionally, if performance is equivocal, some of the tests may need to be repeated at an appropriate interval using alternate test forms to determine the stability of the findings. Evaluations of Memory Disorders (Table 142-3) Neuroimaging. If memory function is the primary cognitive disorder affected, limbic system structures must be imaged. A CT scan with and without contrast is helpful, but MRI is more sensitive. Because the relevant structures often are difficult to

visualize on CT images, MRI evaluating temporal lobe structures, the thalamus, basal forebrain, and interconnecting pathways can be particularly useful. Occasionally contrast agents are helpful in bringing out subtle lesions or characterizing possible infarctions. In some instances, functional imaging scans such as positron emission tomography or single photon emission computed tomography are helpful in delineating certain memory disorders. In the early course of some diseases, structural changes may not be evident, and a functional impairment may be the only imaging index of impairment. To a certain extent, these scans are limited by the resolution of the particular instrument, but with improved spatial resolution, these techniques are becoming increasingly sensitive at evaluating medial temporal lobe structures. Because of their limited availability and expense, they should be reserved for selected cases. Electroencephalogram. Because complex partial seizure disorders of temporal lobe origin can present with episodic memory disturbances and occasional persistent memory deficits, an awake and asleep electroencephalogram may be necessary to assess a possible epileptogenic cause of the memory disorder. Careful attention must be paid to seizure foci in the medial temporal and

H TAW 142-3. Evaluation of Memory Disorders Imaging studies

CT MRI PET, SPECT Electroencephalogram Cerebrospinal fluid analysis Microbiology Gram stain Bacterial cultures Fungal cultures AFB cultures Viral cultures PCR: herpes simplex encephalitis, 6. burgdorferi Chemistry Protein Glucose VDRL FTA-Abs IgG index Oligoclonal bands Cell count Cytology Blood studies Chemistry group including glucose Hematology group Sedimentation rate Vitamin B,, Thyroid function studies Toxicology screen Alcohol level Optional ANA ENA Heavy metal screen HIV Lyme serology Copper Ceruloplasmin Anticardiolipin antibody Lupus anticoagulant Anti-Purkinje cell antibody Antineuronal nuclear antibody Arterial blood gas Abbreviations: AFB, acid-fast bacillus; ANA, antinuclear antibodies; CT,computed tomography; EN& extractable nuclear antigens; FIA-Abs, fluorescent treponemal antibody-absorption; HIV, human immunodeficiency virus; IgC, immunoglobulin C; MRI, magnetic resonance imaging; PCR. polymerase chain reaction; PET, positron emission tomography; SPECT, single photon emission computed tomography; VDRL, Venereal Disease Research Laboratory.

Chapter I42

inferior frontal region with this examination. The medial temporal lobe structures, including the amygdala and hippocampus, are among the most epileptogenic structures in the brain, and because they subserve memory, occasionally a subtle complex partial seizure disorder can be the cause of a memory deficit. This study ideally is done with sleep deprivation. Laboratory Evaluation. As indicated earlier, a variety of laboratory studies that assess various processes that are not necessarily specific for a memory dysfunction but can affect cognitive performance must be considered. Tests that can be considered in the appropriate clinical context include a chemistry group, hematology group, sedimentation rate, B,,, folic acid, thyroid function studies, antinuclear antibody, extractable nuclear antigen, 24-hour urine for heavy metals, human immunodeficiency virus, Lyme serology, toxicology screen, alcohol level, copper, ceruloplasmin, anticardiolipin antibodies, lupus anticoagulant, anti-Purkinje cell antibodies, paraneoplastic autoantibodies, and an arterial blood gas. In addition, a cerebrospinal fluid analysis for possible bacterial, fungal, mycobacterial, or viral infections, cell count, total protein, glucose, syphilis serology, immunoglobulin G index, immunoglobulin G synthesis rate, oligoclonal bands, and polymerase chain reaction for herpes simplex virus or Borrelia burgdorferi along with a cytologic examination for neoplastic cells can be considered. All of these tests must be evaluated in the appropriate clinical context, and as indicated earlier, vascular studies may be necessary as well as other evaluations for systemic diseases. Psychiatric Consultation. In the appropriate clinical context, a psychiatric consultation can be useful. Because many psychiatric conditions that may account for or contribute to a memory disorder are treatable, this aspect of the evaluation should be considered. The psychiatrist should be particularly attentive to disorders of mood and anxiety.

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laboratory monitoring. More recently, three additional drugs have been approved donepezil, rivastigmine, and galantamine. These last three drugs produce a modest effect on the symptoms of Alzheimer’s disease, e.g., memory impairment, and can also have positive behavioral effects. Cholinesterase inhibitors have potential side effects including an increase in gastrointestinal motility and theoretically heart rhythm effects or possible increase in bronchial secretions if a person has chronic obstructive pulmonary disease. These drugs can interact with other medications given for anesthesia. A variety of other drugs that work through other mechanisms have been used, such as adrenergic agents, serotonergic compounds, peptides, nootropics, calcium channel antagonists, and antioxidants. Most of these have been studied in the context of Alzheimer’s disease. Occasionally agents designed to augment catecholaminergic functioning have been helpful in treating attention and memory disorders. Compounds such as methylphenidate and bromocriptine have been successful occasionally in some conditions in which attention is the primary cognitive function impaired. Occasionally memory is affected in depression, so treatment of the primary underlying psychiatric disorder can secondarily augment memory function. Some of the newer antidepressants such as fluoxetine, sertraline, and paroxetine can be helpful. These may be activating and may augment attention, which secondarily improves memory. In addition, psychotherapy can be helpful in the appropriate context. The pharmacologic treatment of memory disorders is in its infancy, and a great deal remains to be learned about successful drug treatments. At present, a few drugs are available for altering certain neurotransmitter systems, and new drugs are being investigated. Behavioral Treatments

TREATMENT If a treatable cause of a memory impairment is disclosed during the evaluation of the imaging or laboratory tests, the offending process should be treated. For example, if a seizure disorder is found, appropriate antiepileptic drugs can be used. Similarly, if a neoplasm, infarct, or inflammatory process or an infection such as herpes simplex encephalitis is identified, strategies aimed at treating the underlying disorder should be considered. Often, however, a specific cause is not found or a single insult has occurred, and the patient is left with a significant memory problem. The two major approaches to treating memory disorders involve pharmacologic agents or behavioral measures. The overall state of treatment of these disorders is not particularly advanced, so most of the measures are meant to be palliative. Phannacologic Treatments

Most of the drugs designed to aid memory are modulators of one or more neurotransmitter systems. Because the cholinergic system is intimately involved in attention and memory functions by virtue of its projections in the limbic system, most of the early work on memory disorders has involved drugs designed to enhance cholinergic function. The U.S. Food and Drug Administration (FDA) has approved several drugs for treating Alzheimer’s disease. All of the currently available drugs are cholinesterase inhibitors. The first drug approved by the FDA was tacrine. This drug is no longer used to any significant extent because of the necessary

Most of the behavioral treatments for memory and other cognitive disorders occur in the setting of the treatment of traumatic brain injury. From a practical standpoint, patients with memory disorders can be taught to use external aids such as schedule books, diaries, and watch alarms or to keep a notepad and thereby circumvent many of the problems arising from memory disorders. Alternatively, internal strategies such as mental imagery, semantic elaboration, and mentally retracing one’s steps can also be useful. Often these techniques take training and effort for patients to become skillful at them. Some claim that cognitively impaired people may be incapable of mastering these complex mnemonic strategies. However, in certain instances these techniques can be helpful. Recently, several computer-assisted techniques have been developed to help patients learn new cognitive skills. Some patients can achieve success at acquiring domain-specific knowledge for learning job-related skills. For example, some amnesic patients can be taught the vocabulary and techniques necessary to operate a computer. In certain training settings, cognitive rehabilitation can be successful at enhancing memory and other cognitive functions.

Memory disorders are common in clinical practice, and their identification,evaluation, and treatment can be very rewarding for both the patient and the clinician. Principles of memory function can be applied to the assessment and evaluation of patients with a

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memory disorder. Certain anatomic structures are known to be involved in various types of memory disorders, and the evaluation of these structures can be revealing. If a particular problem is disclosed through the evaluation process, remedial steps can be made. Alternatively, treatment strategies involving certain drugs and behavioral techniques can be helpful to patients with memory disorders. ACKNOWLEDGMENTS I would like to thank Donna Asleson for her superb secretarial assistance in preparing this manuscript. Preparation of this chapter was supported by grants from the National Institute on Aging, AG 06786 and AG 16574.

SUGGESTED READINGS Folstein MF, Folstein SE, McHugh PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198, 1975 Gazzaniga M (ed): New Cognitive Neurosciences. 2nd Ed. MIT Press, Boston, 2000

Jack CR Jr, Petersen RC, Xu YC et al: Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology 49786794, 1997 Kokmen E, Smith GE, Petersen RC et ak The Short Test of Mental Status: correlations with standardized psychometric testing. Arch Neurol 48~725-728, 1991 Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Petersen RC (ed): Mild Cognitive Impairment. Oxford University Press, New York, 2003 Petersen RC, Smith GE, Waring SC et ak Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303-308, 1999 Petersen RC, Stevens J, Ganguli M et ak Practice parameter: early detection of dementia: mild cognitive impairment. Neurology 56:1133-1142, 200 1 Squire LR Memory and Brain. Oxford University Press, New York, 1987 Squire LR, Kandel E R Memory: From Mind to Molecules. Scientific American Library, New York, 2000 Tulving E, Craik FIM (eds): The Oxford Handbook of Memory. Oxford University Press, New York, 2000 Yanagihara T, Petersen RC (eds): Memory Disorders: Research and Clinical Practice. Marcel Dekker, New York, 1991

143 Learning Disabilities and Attention Deficit

Hyperactivity Disorder in Adults Dorene M. Rentz

Learning disabilities and attention deficit hyperactivity disorder (ADHD), once the domain of child practitioners, have become common diagnostic and treatment issues for the practicing adult neurologist. This chapter is intended to clarify the current understanding of various learning disorders as they persist into adulthood and provide basic tools for assisting in the diagnosis and treatment of these conditions. DEFINITIONS

In 1988 the National Joint Committee on Learning Disabilities (NJCLD) established a widely accepted definition that reads, “a learning disability is a general term that refers to a heterogeneous group of disorders manifested by significant difficulties in the acquisition and use of listening, speaking, reading, writing, reasoning, or mathematical abilities. These disorders are intrinsic to the individual, presumed to be due to central nervous system dysfunction, and may occur across the life span. Problems with self-regulatory behaviors, social perception and social interaction may exist with learning disabilities but do not by themselves constitute a learning disability. Although learning disabilities may occur concomitantly with other handicapping conditions, for example sensory impairment, mental retardation, serious emotional disturbance or with extrinsic influences (i.e., cultural differences, and insufficient or inappropriate instruction), they are not the result of those conditions or influences.”

The important contribution of the NJCLD definition is that learning disabilities are neurologically based and may extend into adulthood. However, contrary to this definition, a growing body of evidence suggests that problems with self-regulatory behaviors, social perception, and social interactions may be primary developmental learning disorders as well. This chapter presents this broader spectrum of learning and attention disorders as they persist in adulthood. In accordance with the NJCLD, important preliminary data about a patient should be clarified before a diagnosis of learning or attention disorder is considered. First, the clinician should investigate whether the complaint is lifelong. Developmental problems with attention, reading, or social emotional processing emerge early in childhood. When patients claim symptom onset occurred in late adolescence or adulthood, it is likely that the attention or learning difficulties may be related to other causes rather than a developmental disorder. Second, the clinician should also ensure that there was adequate academic instruction. Although standardized education is taken for granted, there are situations in which education is substandard or children do not receive basic instruction because of lack of opportunity (i.e., they were kept from attending school or transferred to other schools at critical educational junctures). The clinician needs to determine whether, given the opportunity, the patient could learn the requisite skills. Third, did the complaints emerge primarily in the context of a medical illness or sensory or psychiatric disorder?

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memory disorder. Certain anatomic structures are known to be involved in various types of memory disorders, and the evaluation of these structures can be revealing. If a particular problem is disclosed through the evaluation process, remedial steps can be made. Alternatively, treatment strategies involving certain drugs and behavioral techniques can be helpful to patients with memory disorders. ACKNOWLEDGMENTS I would like to thank Donna Asleson for her superb secretarial assistance in preparing this manuscript. Preparation of this chapter was supported by grants from the National Institute on Aging, AG 06786 and AG 16574.

SUGGESTED READINGS Folstein MF, Folstein SE, McHugh PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198, 1975 Gazzaniga M (ed): New Cognitive Neurosciences. 2nd Ed. MIT Press, Boston, 2000

Jack CR Jr, Petersen RC, Xu YC et al: Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology 49786794, 1997 Kokmen E, Smith GE, Petersen RC et ak The Short Test of Mental Status: correlations with standardized psychometric testing. Arch Neurol 48~725-728, 1991 Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Petersen RC (ed): Mild Cognitive Impairment. Oxford University Press, New York, 2003 Petersen RC, Smith GE, Waring SC et ak Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303-308, 1999 Petersen RC, Stevens J, Ganguli M et ak Practice parameter: early detection of dementia: mild cognitive impairment. Neurology 56:1133-1142, 200 1 Squire LR Memory and Brain. Oxford University Press, New York, 1987 Squire LR, Kandel E R Memory: From Mind to Molecules. Scientific American Library, New York, 2000 Tulving E, Craik FIM (eds): The Oxford Handbook of Memory. Oxford University Press, New York, 2000 Yanagihara T, Petersen RC (eds): Memory Disorders: Research and Clinical Practice. Marcel Dekker, New York, 1991

143 Learning Disabilities and Attention Deficit

Hyperactivity Disorder in Adults Dorene M. Rentz

Learning disabilities and attention deficit hyperactivity disorder (ADHD), once the domain of child practitioners, have become common diagnostic and treatment issues for the practicing adult neurologist. This chapter is intended to clarify the current understanding of various learning disorders as they persist into adulthood and provide basic tools for assisting in the diagnosis and treatment of these conditions. DEFINITIONS

In 1988 the National Joint Committee on Learning Disabilities (NJCLD) established a widely accepted definition that reads, “a learning disability is a general term that refers to a heterogeneous group of disorders manifested by significant difficulties in the acquisition and use of listening, speaking, reading, writing, reasoning, or mathematical abilities. These disorders are intrinsic to the individual, presumed to be due to central nervous system dysfunction, and may occur across the life span. Problems with self-regulatory behaviors, social perception and social interaction may exist with learning disabilities but do not by themselves constitute a learning disability. Although learning disabilities may occur concomitantly with other handicapping conditions, for example sensory impairment, mental retardation, serious emotional disturbance or with extrinsic influences (i.e., cultural differences, and insufficient or inappropriate instruction), they are not the result of those conditions or influences.”

The important contribution of the NJCLD definition is that learning disabilities are neurologically based and may extend into adulthood. However, contrary to this definition, a growing body of evidence suggests that problems with self-regulatory behaviors, social perception, and social interactions may be primary developmental learning disorders as well. This chapter presents this broader spectrum of learning and attention disorders as they persist in adulthood. In accordance with the NJCLD, important preliminary data about a patient should be clarified before a diagnosis of learning or attention disorder is considered. First, the clinician should investigate whether the complaint is lifelong. Developmental problems with attention, reading, or social emotional processing emerge early in childhood. When patients claim symptom onset occurred in late adolescence or adulthood, it is likely that the attention or learning difficulties may be related to other causes rather than a developmental disorder. Second, the clinician should also ensure that there was adequate academic instruction. Although standardized education is taken for granted, there are situations in which education is substandard or children do not receive basic instruction because of lack of opportunity (i.e., they were kept from attending school or transferred to other schools at critical educational junctures). The clinician needs to determine whether, given the opportunity, the patient could learn the requisite skills. Third, did the complaints emerge primarily in the context of a medical illness or sensory or psychiatric disorder?

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Learning Disabilitiesand Attention Deficit Hyperactivity Disorder in Adults

Although developmental learning and attention disorders can coexist with other medical, sensory, or psychiatric illnesses, the clinician needs to clarify the primary diagnosisto determine which symptoms should be treated. To assist in this diagnosis, medical and school records and employment histories are very helpful when trying to determine whether the current complaint is developmental in nature or the result of another medical, neurologic, or psychiatric process. Finally, the clinician should be sensitive to cultural background and not diagnose a learning or attention disorder when the difficulty in academic or occupational performance may be related to issues of inadequate English language skills or cultural diversity. This chapter begins with the diagnosis and treatment of ADHD in adulthood. Persistent developmental disorders of language, nonverbal processing and comportment will also be addressed. Each section will cover diagnosis, etiology, genetics, assessment strategies and treatment.

AHENTION DEFICIT HYPERACTIVITY DISORDER IN ADULTHOOD ADHD, characterized by inappropriate levels of inattention, impulsivity, or hyperactivity, was believed to be a childhood syndrome in which the symptoms diminished with age. Early studies were retrospective and claimed that the rate of ADHD declined from 0.8% at age 20 to 0.05% at age 40. However, recent prospective longitudinal studies have shown that 30% to 60% of children diagnosed with ADHD will manifest the full clinical syndrome in adulthood. Unfortunately, many adults being evaluated today were not diagnosed in childhood. If untreated, the adolescent and young adult with ADHD are at risk for school and occupational failure, emotional difficulties, poor peer relationships, and trouble with the law. If properly treated, most patients with ADHD live productive lives and cope reasonably well with their symptoms. DiagnosticCriteria

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) emphasizes the diagnostic heterogeneity of ADHD and describes three subtypes in childhood inattentive, hyperactive-impulsive, and combined type (Table 143-1). In childhood, the core clinical features usually include motoric hyperactivity, restlessness, distractibility, and behavioral impulsivity. In adulthood, a history of childhood symptoms is prerequisite, but the exact diagnostic profile for adult ADHD remains unclear. Table 143-2 lists the symptoms that have been reported in adult ADHD. However, ADHD may change over the lifespan from a mixed inattentive and hyperactive type to the predominantly inattentive form. The symptoms can vary and overlap with other diagnoses; therefore, the clinician should keep several issues in mind. For example, a common misconception is that attention deficits are constant and pervasive in all areas of a person’s life. In fact, it is the inconsistency of attention that often is the problem. Adults with ADHD can rigorously focus attention on tasks of personal interest to them but fail to direct and sustain attention to other environmentally or socially important details, events, or ideas. This “maldistribution” of attention creates problems distinguishing relevant from irrelevant details and determining which of the available items competing for their attention is most important. This leads to problems prioritizing and organizing many essential aspects of vocational and personal life. Consequently,

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TMU 143-1. Diagnostic Criteria for Attention Deficit Hyperactivity Disorder

A. Either (1) or (2): 1. Six (or more) of the following symptoms of inattention have per-

sisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention a. Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities b. often has difficulty sustaining attention in tasks or play activities c often does not seem to listen when spoken to directly d. Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) e. Often has difficulty organizing tasks and activities f. Often avoids, dislikes, or is reluctant to engage in tasks that entail sustained mental effort (such as schoolwork or homework) g. Often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) h. Is often easily distracted by extraneous stimuli i. Is often forgetful in daily activities 2. Six (or more) of the following symptoms of hyperactivity-impulsivity have persisted from at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity a. Often fidgets with hands or feet or squirms in seat b. Often leaves seat in classroom or in other situations in which remaining seated is expected c. Often runs about or climbs excessively in situations in which it is appropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) d. Often has difficulty playing or engaging in leisure activities quietly e. is often ”on the go” or often acts as if “driven by a motor“ f. Often talks excessively Impulsivity g. Often blurts out answers before questions have been completed h. Often has difficulty awaiting turn i. Often interrupts or intrudes on others (e.g., butts into conversations or games) B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years. C. Some impairment from the symptoms is present in two or more settings (e.g., at school or work and at home). D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning. E. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder and are not better accounted for by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, or personality disorder). Code based on type: 3 14.01 Attention-Deficit/Hyperactivity Disorder, Combined Type: if both criteria A1 and A2 are met for the past 6 months 3 14.00 Attention-Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: if criterion A1 is met but criterion A2 is not met for the past 6 months 314.01 Attention-Deficit/HyperactMty Disorder, Predominantly Hyperactive-Impulsive Type: If criterion A2 is met but criterion A1 is not met for the past 6 months. Coding Note: For patients (especially adolescents and adults) who currently have symptoms that no longer meet full criteria, ”In Partial R e mission“ should be specified. From American PsychiatricAssociation Staff Diagnosticand Statistical Manual of Mental Disorders. 4th Ed. American PsychiatricAsssociation, New York, 1995, with permission.

adults with the inattentive ADHD type report disruptive interpersonal relationships, marital instability, and academic and vocational success that are below expectations for their intelligence. Adults diagnosed with the hyperactive-impulsive subtype, on the other hand, have a greater incidence of antisocial behaviors and psychoactive substance use disorders. Higher rates of psychological maladjustment, psychosomatic concerns, and behavioral problems are common in all subtypes of ADHD.

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rn TABLE145-2. Ten Basic Symptoms of Adult ADHD Inattentlon: Manifested by the inability to keep one's mind on conversations, reading materials, or tasks. Symptoms of inattention cause forgetfulness and the losing or misplacing of things. Learning and memory problems: Result from poor concentration or distractibility, which interfere with the ability to learn new information, and poor retrieval of previously learned material. Disorganization: Results in the inability to complete tasks, thus interfering with performance on the job, running a household, or completing schoolwork. Switching from one task to another in a haphazard fashion before one task is complete is a common occurrence. Impulsivity: Common symptoms include talking before thinking things through, interrupting conversations, impatience (e.g., while driving), impulse buying. impulsive decision making, and abrupt initiation or termination of relationships or employment opportunities. In contrast, people with ADHD exhibit excessive focus or hyperfocus on activities of interest. Affective lability: Usually described as antedating adolescence and in some instances extending as far back as the patient can remember; manifested by rapid transitions from a normal mood to depression or excitement. H o t temper, explosive, short-lived outbursts: A hot temper, "short fuse," or "low boiling point" is common with outbursts usually followed by quick calming down. People with ADHD are easily provoked or constantly irritable. Temper problems interfere with personal relationships. Emotional overreactivity: The inability to take ordinary stress in stride without overreacting. Motor hyperactMty: Manifested by restlessness and the inability to relax or persist in sedentary activities (e.g., watching movies or television, reading the newspaper). People with ADHD are always on the go and tend to be dysphoric when inactive. ImpairmentsIn abstract reasoning: Delayed or impaired development of certain forms of abstract thinking is common. For example, a person with ADHD may interpret a statement literally that was clearly intended as a metaphor, often inviting ridicule. They have difficulty developing an internal sense of conviction or forming opinions about controversial issues. They may also find it difficult to see a problem from a different angle or to adopt another person's point of view. They sometimes lack insight or objectivity. D d a e n u r in social and interpersonal skills: Adults with ADHD often are at a disadvantage in social situations. They may not attend to interpersonal verbal and nonverbal social cues, which can be irritating and even offensive to others. They have trouble following shifts in the conversation and may withdraw rather than appear socially awkward. Those who are impulsive typically lack skills in self-regulation and inhibition. Their comments may seem irrelevant and even intrusive. Adapted from Wender (1998).

Although comorbid disorders of mood and anxiety are common in ADHD, some people with ADHD have features of mood lability that are qualitatively and quantitatively different from primary mood disorders. People with ADHD may experience frequent shifts throughout the day between boredom and excitement. Impulsivity usually is characterized as thoughtless and short-lived. For example, running a traffic light, interrupting others in conversation, talking before thinking, impulse buying, and hasty decision making are commonly reported. Anger outbursts are episodic and transition rapidly from quick explosions to immediate calming. Depression usually is described as brief and related to real-life difficulties. Neurovegetative features are uncommon. Interpersonal relationships in ADHD are not necessarily idealizing, denigrating, or intense. Suicidal preoccupations, self-injurious behavior, identity disturbances, feelings of emptiness, and fears of being abandoned are not typical. If intense mood states cycle, persist, or disrupt interpersonal relatedness, the clinician should consider a comorbid mood or personality disorder in addition to a diagnosis of ADHD. Finally, disruptions in attention can be caused for other reasons, including medications, drugs, alcohol, sleep disturbance, systemic illness, cardiac and pulmonary diseases, and neurologic disorders. Therefore, a comprehensive medical and neurologic

evaluation is helpful to ensure that the condition is developmental and not the result of other treatable conditions. Etiology

The underlying neural and pathophysiologic substrates for ADHD remain to be defined. However, an emerging neuropsychological and neuroimaging literature suggests that frontostriatal dysfunction is the disorder's underlying neural substrate, and catecholamine dysregulation is its underlying pathophysiologic substrate. Studies of patients with ADHD using magnetic resonance imaging (MRI) reveal reductions in total cerebral volume, subtle anomalies in caudate, pallidum, and corpus callosal size and shape, and reductions in right frontal areas. These data are consistent with a positron emission tomography (PET) study that identified abnormalities of cerebral metabolism in the prefrontal and premotor areas of the frontal lobe in adults with ADHD who had children with ADHD. Genetics and Prevalence

Growing evidence from family genetic, twin, and adoption studies suggests that ADHD is largely genetic but in part is shaped by interaction with the environment and other psychological and social factors. Family studies of ADHD have shown that relatives of ADHD children are at high risk for ADHD, comorbid psychiatric disorders, school failure, learning disability, and impairments in intellectual functioning. Twin studies of ADHD children found a concordance rate of 50% among monozygotic twins, compared with 33% for dizygotic same-sex twins. Adoption studies reveal that adoptive relatives of children with ADHD are less likely to have ADHD or associated disorders than are the biological relatives of children with ADHD. ADHD is less prevalent in females, but females share with their male counterparts the prototypical features of the disorder (e.g., inattention, impulsivity, and hyperactivity). They also share high rates of school failure and high comorbidity with mood and anxiety disorders and learning disabilities. However, aggression and conduct disorder are more prevalent in males than females with ADHD (1O:l).The overall ratio of male to female is 2:l.Some believe that ADHD may be underidentified in girls. Assessment

A comprehensive assessment of medical, neurologic, psychiatric, and neuropsychological factors is needed to determine the underlying cause of attention problems in adults. A neurologist, neuropsychologist, or psychiatrist can make the diagnosis if these factors have been explored sufficiently. Neuropsychologicaltesting, although not required, is valuable for supporting the clinical diagnosis and identifylng comorbid learning disabilities or subtle deficits in information processing. The information from the neuropsychological examination can monitor the effectiveness of medications and other nonpharmacologic treatment decisions. To meet DSM-IV criteria, the symptoms of inattention and hyperactivity must occur before age 7.This requires a retrospective recollection of symptoms from childhood. The best-known scale for retrospectively assessing childhood symptoms of ADHD in adults is a self-report inventory, the Wender Utah Rating Scale (WURS; Ward et al, 1993). Shown in Figure 143-1,the WURS originally consisted of 61 items (Wender, 1971) but has been reduced to 25 items, making it quick and easy to administer at the

Chapter 143 H Learning Disabilities and Attention Deficit Hyperactivity Disorder in Adults

time of the evaluation. Research studies have demonstrated that the WURS can successfully distinguish patients with ADHD from a nonpatient comparison group and patients with unipolar depression. More specifically, a cutoff score of 36 or higher

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correctly identified 96% of adults with ADHD (i.e., sensitivity) and 96% of normal subjects (i.e., specificity). When the cutoff score was set at 46 or greater, the WURS was able to successfully discriminate 86% of patients with ADHD, 81% of those with

FIG. 143-1. Abbreviated Wender Utah Rating Scale (WURS). (Adapted from Ward, 1993.)

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This form should be filled out by mother (or father, if mother is unavailable). Name

Date

Your Name

Relationship

Listed below are items concerningchildren’s behavior and the problems they sometimes have. Read each item carefully and decide

how much you think you were bothered by these problems when your child was between 6 and 10 years old. Rate the amount of the problem by circling the number in the column that best describes your child at that time.

Behavior

Not at All

Just a Little

Pretty Much

Very Much

FIG. 143-2. Wender Parent‘s Rating Scale. (Adapted from Ward, 1993.)

unipolar depression, and 99% of the normal controls. A discriminant validity study suggested that an important subtest on the WURS is the School Problems in Childhood, which alone correctly identified 72% of patients with a clinical diagnosis of ADHD. A Parents Rating Scale was developed as a modification of the 10-item Conners (1973) Abbreviated Rating Scale used by teachers to diagnose ADHD in childhood. Scores of 12 or greater on the Parents Rating Scale (Fig. 143-2) placed children above the 95th percentile of childhood “hyperactivity.”The WURS has also been used to distinguish responders from nonresponders to methylphenidate and to measure treatment effect in adults. The mean WURS scores for patients who responded to methylphenidate was 70.3 (SD= 12.5), whereas those with mean WURS scores of 59.7 (SD= 15.6) did not. A major limitation of using self-report inventories, such as the WURS, is the tendency for patients to exhibit a response bias that endorses items supporting the diagnosis of ADHD. On the other hand, neuropsychological assessment measures performance directly. Neuropsychological test performance is able to confirm

deficiencies in frontostriatal networks affected by ADHD and measure change during treatment. Seidman et al ( 1998) identified specific neuropsychological tasks sensitive to ADHD in adults, which included impairments in auditory sustained attention or vigilance on the Continuous Performance Test, executive components of verbal learning on the California Verbal Learning Test, and written arithmetic when compared with controls matched for similar levels of education and IQ. However, these adult subjects showed milder neuropsychological impairments than those reported in children with ADHD using an identical neuropsychologicalbattery. Surprisingly, impairments were not found on other measures sensitive to attention deficits such as the Stroop, Wisconsin Card Sort Test, and Rey-Osterrieth Complex Figure, although these are usually impaired in ADHD children. They also did not show significant impairments on the Freedom-from-DistractibilityIndex from the Wechsler Adult Intelligence Scale, which has been consistently reported in pediatric samples. The source of the apparent discrepancy between pediatric and adult neuropsychological

Chapter 143

Learning Disabilities and Attention Deficit Hyperactivity Disorder in Adults

findings is unclear. Seidman et al (1998) speculated that transient lags in brain maturation could lead to prominent neuropsychological deficits in childhood ADHD that become milder with age. They also considered that their sample, which was self-referred, could represent a higher-functioning subgroup of grown-up children with ADHD who did well and therefore avoided the extreme dysfunction associated with ADHD such as addiction and antisocial personality. Seidman et al believe that neuropsychological competencies might play a critical role in determining the psychosocial outcomes of ADHD adults. Finally, a comprehensive neuropsychological assessment is invaluable in the college setting, where many cases of ADHD are first diagnosed. Circumscribed academic problems associated with ADHD sometimes lead to the clinical misinterpretation that students are cultivating an alibi for their poor academic skills or limited effort. However, ADHD-related academic problems that first manifest in college are more likely to be caused by environmental factors such as the academic difficulty of a particular university, loss of family structure that supported academic success at lower grade levels, or the absence of individualized educational services. Treatment

Treatment of adult ADHD is symptomatic, not curative, but may offer life-changing opportunities to patients with the disorder. Successful treatment for most adults with ADHD involves an integrated approach, which includes medication, psychotherapy, relaxation training, and cognitive remediation strategies. Pharmacologic interventions alone, though effective, work best in conjunction with other behavioral therapies. Seven target symptoms have been identified in the pharmacologic treatment of ADHD, including hyperactivity, inattention, mood lability, temper outbursts, disorganization, stress, and impulsivity. Table 143-3 summarizes medications for treating ADHD. The most effective medications for reducing these target symptoms are stimulants such as amphetamines, methylphenidate, and pemoline. Studies have shown that amphetamines and methylphenidate are equally effective, but individual patients may do better on one than the other. Potential side effects associated with stimulant medications include sleep disturbance, appetite suppression, nervousness, increased tics, and palpitations. Pemoline has rarely been linked to fatal hepatic failure. As with all stimulant medications, pulse, blood pressure, and sleep disturbances should be caremy monitored. Another concern is the potential abuse of stimulants, which limits their use in substance-

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abusing patients. Some people with ADHD find that short-acting stimulants wear off and opt for longer-acting preparations. Some patients with ADHD, particularly those with underlying dysphoria, benefit from a stimulating antidepressant such as bupropion. However, improvement of ADHD symptoms is not as effective as with stimulants. Some health-conscious adults are reluctant to take medication or respond poorly to it, creating a demand for nonpharmacologic approaches to ADHD treatment. Relaxation training is one approach that holds promise and has been highly effective in other diagnostic populations, particularly patients with chronic hypertension. However, unmedicated patients with ADHD have great difficulty learning and practicing the exercises. One solution may be to learn the relaxation techniques while on medication and then gradually reduce the medication while monitoring ADHD target symptoms. Psychotherapy should focus on understanding what ADHD means for the patient and the ramifications that the disorder has for all aspects of life (i.e., vocational, educational, social, sexual, and psychological). Adults with ADHD often have a profound feeling of inadequacy and low self-esteem. The psychotherapist must confront the deep sense of shame, humiliation, and frustration that comes with years of repeated failure and negative feedback because neurologic symptoms have been attributed to lack of will, laziness, or personal character defects. The goal of treatment is to help the patient identify dysfunctional behavior (i.e., arriving late for appointments, switching topics, and interrupting conversations), accept responsibility for that behavior, and develop strategies for change. Replacing feelings of helplessness and frustration with a sense of control and discarding maladaptive techniques that are no longer necessary are critical for a patient with ADHD. However, it is important to note that different psychological problems may surface when ADHD symptoms remit, and psychotherapeutic intervention would help the patient manage other issues as they emerge. Another important adjunct to medications and psychotherapy is cognitive remediation strategies. These strategies focus on simple techniques that are taken for granted by non-attentionimpaired people. Writing down essential information, asking for repetition, asking speakers to present information more slowly, breaking down tasks into small, simple steps, working in a quiet space, and learning to do one thing at a time are a few of the useful strategies recommended. College students with ADHD often need school-based accommodations to address specific academic problems. Once the diagnosis is documented, students with learning disabilitiesshould

TABLE 143-3. Medications Used in to Treat ADHD Medication

Available Fonnr

Duration of Action

Methylphenidate (Ritalin, Methylin) Dextroamphetamine (Dexedrine) Dextroamphetamine (DextroStat) Dexmethylphenidate (Focalin) Methylphenidate (Ritalin-SR) Methylphenidate (Metadate ER, Methylin ER) Methylphenidate (Metadate CD) Pemoline (Cylert)

Tablet: 5, 10,20 mg Capsule: 5 mg Tablet: 5,lO mg Tablet: 2.5,5, 10 mg Tablet: 20 mg Tablet: 10,20 mg Capsule: 20 mg Tablet: 18.75,37.5,75 mg Chewable tablet: 37.5 mg Tablet: 5,7.5, 10, 12.5, 15,20, 30 Capsule: 5, 10, 15 mg Capsule: 18,36,54 mg Capsule: 10, 20, 30 mg

Short-acting Short-acting Short-acting Short-acting Intermediate-acting Intermediate-acting Intermediateacting Intermediate-acting

Amphetamine-dextroamphetamine (Adderall) Dextroamphetamine (Dexedrine, Spansule) Methylphenidate (Concerta) AmDhetamine-dextroamDhetamine (Adderall XR)

Intermediate-acting Intermediate-acting Long-acting Long-acting

Effective Duration (hr)

1-4 1-6 1-6

N/A 3-8 3-8 6-8 7-9 6-8 6-8 12

N/A

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TMLE 143-4. Suggested Academic Accommodations for Adult College Students with Dyslexia or ADHD Extended time or untimed examinations, including standardized testing Testing in a separate room to eliminate distractions A reader to assist with interpretingtest questions Modified test format (e.g., multiple choice instead of essay) Oral examinations when written test scores do not reflect the student's knowledge Take-home examinations when necessary Audiotaped exams as an alternative to the use of a reader or oral exams Use of a word processor with spelling and grammar checks during all written assignments and tests Preferential seating close the front to enhance attention during classroom lectures Permission to tape classroom lectures Access to notes from another student or the professor Assistance from a note taker if notes are not available Tutoring in specific course content when needed An academic advisor who can reduce the number of courses in a semester that stress weak areas such as heavy reading courses and substitute other courses that are more experiential and applied Waiver of course requirements when tutoring or other accommodations are not sufficient Reduction in required number of courses per semester Extendedtime to complete degree Attendance at a study skills course or workshop Regular conferenceswith professors to review progress Tutoring should focus on Advanced reading skills including identifying the main idea and scanning for key terms Advanced writing skills including idea development, organization, use of an outline, and proofreading Study skills, which include planning how to attack reading and writing assignments, memorization, scheduling, organization strategies, and self-monitoring techniques Cognitive strategies to improve motivation and to overcome procrastination

consult their academic advisor or the coordinator of learning disability services to obtain the necessary accommodations. It may seem obvious, but students should be reminded that a pill cannot teach skills or information that has not been acquired; it can only enhance the ability to learn them. Tutoring to improve reading efficiency and written expression often is needed for optimal academic performance. Orton-Gillingham approaches and VisualizingNerbalizing Techniques by Nancy Bell are helpful for adults with ADHD. Table 143-4 provides a list of commonly granted academic accommodations recommended by neuropsychologists for adults returning to college. Occupational problems are common for adults with ADHD and usually consist of getting to appointments or meetings on time, fulfilling task expectations in a timely manner, organizing, and prioritizing. Under Title 1 of the Americans with Disabilities Act (ADA), employers are prohibited from discrimination against people with physical or mental limitations, including those with ADHD or other learning disabilities, who may be qualified for a job if reasonable accommodations are provided. The definition of reasonable accommodations includes a modification in the work environment or in the job itself that will allow a person to successfully perform a specific job or job function. For the patient with ADHD, successful accommodations are ones that will assist in organizing tasks, reduce distractions that may lower performance, spell out expectations, and provide clear work instructions. Table 143-5 provides a list of accommodations that both the employer and employee may implement.

Summary Prospective, longitudinal follow-up studies provide compelling evidence of the continuation of ADHD into adulthood. However, the issue of how many cases persist is not completely resolved. The symptoms of ADHD that continue into adulthood include inattention, disorganization, distractibility, and impulsivity, which contribute to academic and occupational failure. A multimodal treatment approach provides the best prognosis for overcoming the disabling symptoms of ADHD in adulthood and enhances the possibility of vocational and interpersonal success.

NONVERBAL LEARNING DISABILITY Nonverbal learning disability (NLD), also known as social emotional processing disorder (SEPD) and right hemisphere learning disability (RHLD), is a neurodevelopmental disorder, presumably of the right hemisphere, usually diagnosed in children who do not acquire the nonverbal skills necessary to master the environment. Problems in telling time, reading maps, following directions, performing mathematics, and understanding humor and the nonverbal gestures of others often alert parents and teachers to the potential diagnosis of NLD. However, many people with NLD may not be recognized in childhood because scholastically they tend to perform in the average or above-average range in verbal abilities. People with NLD who are proficient in verbal skills often are successful in academic life and go on to acquire advanced degrees. However, the social impairments common in NLD interfere with interpersonal relatedness and occupational success, causing them to experience social rejection and to work at jobs well below their academic accomplishments. These consistent failures to achieve contribute to chronic feelings of depression and low self-esteem. The following sections describe the features of NLD as they persist in adulthood and the associated treatments that might be helpful.

TMLE145-5. Accommodationsfor ADHD in the Workplace Break tasks into parts and set personal deadlines for each part so that the whole task will be completed on time. Use brief notes to assist in staying focused during meetings. Use a notebook to take notes that highlight what needs to be remembered at meetings, including meetings with supervisors. Don't be afraid to ask for repetition to hear the information again. Ask for frequent and specific feedback on meeting performance expectations. If needed, ask for a modified work schedule and job restructuring. Use breaks to get physical movement and exercise to help refresh concentration. Keep workspace orderly and clean to reduce distraction and help maintain focus. Set aside 15 minutes at the end of the day to plan work for the next day. Keep a day planner with you at all times. Place tasks on the "to do" list for a specific day. Leave early for work, interviews, appointments, and meetings. Do not become diverted unless there is an emergency. Listen to others at meetings and take 10 seconds before making an immediate response, especially if feeling argumentative or negative. Be positive and avoid impulsive responses. Take a time out if feeling frustrated or angry. Avoid interpersonal conflicts. Give vourself time to cool down and focus on what is imDortant. Adapted from a publication of the National Center for Law and Learning Disabilities.

Chapter 143

Learning Disabilities and Attention Deficit Hyperactivity Disorder in Adults

Diagnostic Criteria

Because the right hemisphere plays a critical role in environmental adaptation and social adjustment, the most disabling symptoms of adults with NLD are related to the inability to monitor their behavior and integrate the affective response of others with whom they interact. The following are major symptoms that characterize adult NLD: Nonverbal Communication Impairments. The inability to interpret and express the paralinguistic (nonverbal) aspects of communication such as prosody (voice inflection), facial expressions, gestures, caresses, body stances, and the other nonverbal subtleties of social discourse interferes with the development of interpersonal relationships and the ability to exercise appropriate social judgment. Speech usually is unmodulated and monotone and often perceived as angry, threatening, or uninterested when no such intent is implied. Eye contact, facial expressions, and body gestures that accompany speech are notably absent or excessive and exaggerated. It is thought that those who develop some capacity to appreciate social scenarios usually apply learned templates of nonverbal communication acquired over repeated trials. However, any novelty to a social event renders people with NLD unable to respond appropriately in the moment. Social and Emotional Processing Deficits. People with NLD often are shy, socially immature, and isolated because they cannot appreciate or understand the emotions and nonverbal interplay that underscore the social environment. Many of them describe themselves as loners, having few or no friends. In part, the failure to develop social competence arises from the inability to perceive another person’s emotional state or point of view. Therefore, adults with NLD lack the ability to empathize and adopt a sympathetic attitude toward others. They also have difficulty matching their social skills to the demands of a particular situation, such as knowing the difference between appropriate behaviors at a baseball game and appropriate behavior at a formal dinner party. This failure to acquire social graces ultimately interferes with interpersonal relationships and occupational achievement and leads to further social rejection, extreme shyness, and introversion. Motor Incoordination. Clumsiness and poor athletic skills are common and often result in frequent fracture injuries and body bruising. Reported neurologic deficits include asymmetrical body formation and left sided abnormalities on elementary neurologic examination, such as upper motor neuron signs (hyperreflexia, increased tone, extensor and plantar responses), facial weakness, increased deep tendon reflexes, posturing during complex gait, and slower performances on timed motor tests. These motor and coordination deficits make it difficult for many patients with NLD to gracefully gesture, walk, or compete in sports. Cognitive Impairments. Neuropsychological findings reveal difficulties in spatially directed attention, visuospatial perception, geographic orientation, and mathematics, in contrast to highly developed verbal skills. These problems interfere with acquiring abilities such as reading maps, following directions, operating computers, performing certain mathematical operations, and performing tasks that require any type of eye-hand coordination. The arithmetic difficulties in NLD are in spatial organization, misreading of visual detail, procedural and operational errors, and visual motor skills for aligning the computations correctly. Some patients with NLD have problems distinguishing differences in

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shapes, sizes, amounts, and lengths. Poor organization and aversions to novelty are also reported. Problem solving usually involves overreliance on rote responses and trial-and-error approaches. Adults with NLD also have difficulty adapting previously learned operations to slightly different problems. Finally, patients with NLD have attention deficits that may be misdiagnosed as ADHD. Obviously, treatment for the attention deficits will not relieve the more disabling symptoms of social relatedness common to patients with NLD. Affective and Psychiatric Disturbance. Chronic depression and anxiety, including inpatient hospitalization, are common psychiatric issues for adults with NLD. These findings are consistent with the hypothesis that the right hemisphere may play a mediating role in the expression of sadness in some forms of depression. Some patients with NLD have also been identified early in life as having “adjustment problems” or a schizoid personality. Etiology NLD is a neurodevelopmental disorder thought to arise from congenital or early-acquired damage to the right hemisphere. The most commonly accepted cause of NLD is a genetically determined lag in cerebral maturation or prenatal or perinatal cortical damage. In the sample of patients with NLD described by Weintraub and Mesulam (1983), the origin of the disorder was related to infantile hemiplegia on the left side of the body, perinatal insults, early-onset seizure disorder, and genetic predisposition to developmental dysfunction of the right hemisphere. Studies have shown that the right hemisphere may also provide the primary neuroanatomic substrate for the spatial distribution of attention. This large-scale network has its principal anatomic components in the prefrontal and posterior parietal cortices and the cingulate gyrus regions, which regulate both shifts of attention and accompanying shifts of gaze. Dysfunction of components to this anatomic network may also be responsible for deficits in receptive and productive aspects of paralinguistic communication, including eye contact, gesture, and facial expression seen in NLD. Thalamic dysfunction related to visual-spatial input and the expression of emotion has also been implicated. Finally, some pediatric specialists speculate that NLD may represent a milder form of neurodevelopmental disorder along the continuum of childhood autism, pervasive developmental disorder, schizoid personality disorder, and Asperger’s syndrome. Symptoms common to these disorders overlap with NLD, but further studies are needed to understand the relationship between these conditions. Genetics

There are no formal genetic, twin, or adoption studies of NLD, but family histories have noted academic learning disabilities, social maladjustment, and severe psychiatric illness in first-degree relatives. Assessment

The neurologic assessment of NLD entails particular attention to body asymmetries and to the paralinguistic aspects of communication. As mentioned earlier, asymmetrical body formation, left-sided abnormalities such as upper motor neuron signs (hyperreflexia, increased tone, extensor plantar response), facial

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Behavioral Neurology and Epilepsy H Behavioral Neurology

weakness, increased deep tendon reflexes, posturing during complex gait, and slower performances on timed motor tests are commonly seen in NLD. Close examination of affective and attitudinal prosody, facial expressions, and gestures are essential. The neuropsychological assessment should examine verbal and nonverbal discrepancies (i.e., those seen on Verbal and Performance Scales of the Wechsler Adult Intelligence Scale-111) and deficiencies in arithmetic in contrast to reading and spelling skills. Specific tests such as the Profile of Nonverbal Sensitivity (PONS) test, the Ekman Faces, and Riggio’s Social Skills Inventory target directly the nonverbal and social deficits seen in NLD. Treatment Children treated with tricyclic antidepressant medications showed improvement not only in symptoms of depression but also performance on right hemisphere tasks. Traditional psychopharmacologic approaches are also effective in patients who have disturbing anxiety or other psychiatric symptoms. Therapy for patients with NLD can take traditional and nontraditional forms including social skills training, group therapy, occupational guidance, and education about their deficits. Role playing to help develop appropriate interaction skills and incorporate learned templates for interpreting the emotional discourse of others is also helpful.

DYSLEXIA IN ADULTHOOD Dyslexia is a neurodevelopmental disorder of reading in people who otherwise possess normal intelligence and thinking. Most cases of dyslexia are diagnosed in childhood because fundamental problems in reading are first noted in school. Therefore, this chapter focuses on the persistent features of dyslexia in adulthood rather than the initial assessment. Diagnosis Reading involves two processes: phonologic awareness (i.e., the ability to identify the sound structure of words) and orthographic awareness (i.e., the representation of spoken language by letters and spellings). It was once thought that more experienced readers develop a direct visual (orthographic) route by which the letters of a word are mapped directly onto the reader’s lexicon or internal dictionary by which meaning is accessed. However, studies of reading in adults indicate that a phonologically mediated route in which letters are first mapped onto the sounds or phonology of a word and then routed to the lexicon for meaning persist across the lifespan for all readers, whether experienced or beginners. Converging evidence from various research studies indicates that the reduced ability to identify the sound structure of words (i.e., phonologic awareness) is the primary deficit responsible for dyslexia, and these phonologic processing impairments persist throughout the lifespan. As children, those with dyslexia have difficulty with naming letters, associating letters with sounds of speech, and sounding out new or unfamiliar words. In adolescence and adulthood, the characteristics of dyslexia that persist are slower reading rate, spelling deficits, diminished naming, and the inability to process rapid sound sequences that can interfere with the auditory language processing. Etiology Dyslexia affects 15% to 20% of the school-aged population of both boys and girls and does not remit in adulthood. Dyslexia has been

associated with gross anatomic and cytoarchitectonic abnormalities disproportionately affecting the left hemisphere. A range of neurobiologic investigations using postmortem brain specimens, brain morphometry, functional brain imaging, and electrophysiology suggests that there are differences in the temporo-parietooccipital brain regions between people with dyslexia and those who are not reading impaired. For example, the autopsy studies of Galaburda and colleagues (1990) reported an unusual symmetry in the planum temporale, neuronal migration anomalies of the cerebral cortex, anomalies in the magnocellular layers of the lateral geniculate nucleus, and anomalies (e.g., reductions in cell size) in the medial geniculate nucleus in the brains of dyslexic people, in contrast to normal readers. Using a functional MRI task to explore the phonologic impairment in dyslexia, Shaywitz et al (1998) found differing brain activation patterns in dyslexic readers that suggested relative underactivation in posterior regions of Wernicke’s area, the angular gyrus, and striate cortex and relative overactivation in anterior regions such as the inferior frontal gyrus. In a recent voxel-based MR study of 16 men with dyslexia, Brown et al (2001) also found decreases in gray matter, most notably in the left temporal lobe and bilaterally in the temporal parietal and occipital junction but also in the frontal lobe, caudate, thalamus, and cerebellum. Thalamic dysfunction has also been implicated as impeding the allocation of hemispheric attentional resources. These studies suggest that there are widely distributed morphologic differences affecting several brain regions associated with dyslexia.

Dyslexia tends to run in families, and researchers have attempted to identify the genes responsible. In one study of 36 Norwegian family members of whom 11 had dyslexia, researchers were able to pinpoint the location of a new gene to a section of chromosome 2. The research team named the new gene DYX3. Another linkage study of 96 families containing at least two siblings with dyslexia (totaling 877 people) found evidence of a dyslexia susceptibility gene on chromosome 6q linked to deficits in phonologic awareness, phonologic coding, spelling, and rapid automated naming speed. Another study of 140 families found a locus on chromosome 3 also associated with deficits in three essential components of reading, namely phonologic awareness, rapid naming, and verbal short-term memory. Other studies have found associations with chromosomes lp, 7, and 15 for reading and spelling deficits. Advances have been made in understanding the genetic contribution to dyslexia, but further work must be done. Dyslexia affects three times as many males as females and is equally prevalent in people from different ethnic and socioeconomic backgrounds. A proportion of patients with dyslexia (12% to 25%) also has ADHD.

During childhood, treatment focuses on remediation. Systematic and highly structured programs that explicitly teach phonologic awareness are most successful. In these programs, children are taught to identify rhyming and nonrhyming word pairs, blend isolated sounds to form words, and segment a spoken word into its individual sounds. There are no known studies as to the success of these programs in adults. The most helpful strategies for dyslexia in adulthood usually focus on educational and occupational

Chapter 145

Learning Disabilities and Attention Deficit Hyperactivity Disorder in Adults

accommodation. Adult dyslexics may have good word recognition but suffer from the phonologic deficit that makes reading less automatic, more effortful, and slow. College students with dyslexia need extra time to read information or listen to lectures or conversations. This extra time allows them to decode each word to understand the higher-order meaning of that word. Many of the accommodations listed in Table 143-4 are relevant for college students with dyslexia. With such accommodations, many students with dyslexia are successfully completing advanced degrees in a variety of disciplines.

Prognosis Results from one longitudinal study that evaluated dyslexic readers from kindergarten to late adolescence found that children with dyslexia do not spontaneously remit, nor do they demonstrate a lag in catching up in the development of reading skills. Rather, adults who had dyslexia as children continue to display reading and spelling problems. This same study indicated that there is no increased prevalence of legal trouble, alcohol or tobacco use, or increase in conduct or attention problems between good and poor readers.

COMPORTMENTALLEARNING DISABILITY Price et al(1990) first introduced the concept of a comportmental learning disability (CLD) that affected conduct, moral judgment, insight, foresight, and abstract reasoning. Anderson et al (1999) described two adults with early prefrontal cortex lesions who also exhibited impaired development in social and moral competency. Although more research is needed to substantiate whether the behavioral dysfunction resulting from early damage to frontal networks constitutes a learning disorder, a definition and description will be provided.

Unlike patients with acquired damage to frontal networks in adulthood, comportmental learning disability is a presumed neurodevelopmental disorder that selectively interferes with the acquisition and development of complex comportmental skills, formal operational thought, social conduct, and moral judgment. The predominant symptoms include impulsive behavior, immaturity, irresponsibility, the inability to learn from past experience, diminished insight, immersion in the present, lack of drive and curiosity, irritability when crossed, social isolation, and the absence of enduring friendships. The impulsive behavior of CLD often is triggered by an immediate stimulus without consideration of the long-range consequences. For example, one subject reported in Price et al (1990) was walking by a gas station where he saw an unattended taxi with keys in the ignition. He jumped in the car and drove off with the hose still in the gas tank, only to be captured several blocks later. This lack of premeditation, remarkable clumsiness in committing crime, and the absence of any predisposing factors in the social background distinguish CLD from conduct or antisocial personality disorders. Other associated features of CLD include the inability to feel remorse, empathy, or fairness toward others and a tendency to feel victimized when caught. Despite these severe deficits of comportment, judgment, and insight, most people with CLD have no problems with language, memory, or visuospatial skills.

92 1

Etiology Congenital or early acquired damage to a neural network involving bilateral prefrontal cortex and limbic systems is believed to underlie the poor integration of thought with emotion seen in CLD. The critical areas reported by Anderson et al(1999) included dysfunction in the medial prefrontal cortices (which can be caused by either direct cortical damage or white matter undercutting) and the sparing of at least one dorsolateral prefrontal sector. The extent to which frontal lobe lesions underlie deviant and criminal behavior in the general population is difficult to surmise. Of interest, studies have shown that juveniles condemned to death had histories of head trauma, electroencephalographicabnormalities, and poor performances on tests of reasoning and mental flexibility. Assessment

Assessment includes a detailed history from several sources including parents, school, and criminal records. In most instances, behavioral difficulties are noted in childhood and do not respond to parental discipline. In the cases presented in Price et a1 (1990), neurologic examination did not demonstrate frontal release signs. MRI revealed bilateral frontal lesions. One also had a mild ex vacuo enlargement of the right lateral ventricle and the other had dilation of the frontal horns. The cases in Anderson et al (1999) had focal damage to prefrontal regions and no evidence of damage in other brain areas. In all cases, neuropsychological examination of overall intelligence was in the average to low average range. Other neuropsychological abnormalities implicated frontal network compromise. Specific tests that measure attention, organization, mental flexibility, response inhibition, and abstract problem solving are helpful, including Trailmaking Test B, Stroop Interference, Wisconsin Card Sort Test, Word List Generation, and Proverb Interpretation. Questions requiring social and moral reasoning and role-taking ability are also helpful in determining the neuropsychological deficits of CLD. Treatment

Despite parental guidance, relevant instruction, and extensive exposure to appropriate social behavior in the home and school, people with CLD usually fail to acquire complex social knowledge or self-governance over their behavior. Programs aimed at correcting inappropriate behavior during adolescence and young adulthood have also failed. Anderson et al (1999) speculated that other neural systems could be recruited for learning and processing social knowledge. They suggested using cognitive-behavioralstrategies that rely on a different balance of punishment and reward contributions in conjunction with neuromodulators such as serotonin and dopamine. Treating other comorbid conditions might also be helpful. However, to date, psychotherapy, behavioral methods, and medications have had limited benefit. Prognosis

Early bilateral damage to the frontal lobe may leave permanent uncompensated deficits that persist into adulthood. It appears as if bilateral frontal lesions acquired early in life are more difficult to compensate for than acquired damage in adulthood.

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Behavioral Neurology and Epilepsy

H

Behavioral Neurology

SUMMARY This chapter delineated the characteristics of learning and attention disorders in adulthood. In most cases, the neurologic, neuropsychological, emotional, and behavioral sequelae experienced in childhood persist in adults. Multimodal approaches are the most efficacious in the treatment or accommodation of these disorders. If treated, many people with persistent symptoms of ADHD and childhood learning disabilities are capable of living full and productive lives.

SUGGESTED READINGS Anderson SW, Bechara A, Damasio H et ak Impairment of social and moral behavioral related to early damage in human prefrontal cortex. Nature Neurosci 2:1032-1036, 1999 Barkley RA: Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. Guilford, New York, 1992 Biederman J: Attention-deficivhyperactivitydisorder: a life-span perspective. J Clin Psychiatry 59(Suppl 7):4-16, 1998 Biederman J, Milberger S, Farone SV et ak Family-environment risk factors for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 523464470, 1995 Bigler ED: The neurobiology and neuropsychology of adult learning disorders. J Learn Disabil 25:487-506, 1992 Brown WE, Eliez S, Menon V et ak Preliminary evidence of widespread morphological variations in the brain in dyslexia. Neurology 56781783,2001 Bush G, Frazier JA, Rauch SL et ak Anterior cingulate cortex dysfunction in attention-deficivhyperactivitydisorder revealed by fMRI and the counting Stroop. Biol Psychiatry 45: 1542-1 552, 1999 Conners CK Rating scales for using drug studies with children. Psychopharmacol Bull 9:24-85, 1973 Felton RH, Nalor CE, Wood FB: Neuropsychological profile of adult dyslexics. Brain Lang 39485-497, 1990 Galaburda AM, Rosen GD, Sherman GF: Individual variability in cortical organization: its relationship to brain laterality and implications to function. Neuropsychologia 28:529-546, 1990 Hallowell EM, Ratey JJ: Driven to Distraction. Recognizing and Coping with Attention Deficit Disorder from Childhood through Adulthood. Guilford, New York, 1995 Heiligenstein E, Guenther G, Levy A Psychological and academic functioning in college students with attention deficit hyperactivity disorder. J Am Coll Health 47181-185, 1999 Manoach DS, Weintraub S, Daffner KR, Scinto LFM: Deficient antisaccades in the social-emotional processing disorder. Neuroreport 8:901905, 1997

McCann BS, Scheele L, Ward N, Roy-Byme P: Discriminant validity of the Wender Utah Rating Scale for attention-deficitlhyperactivity disorder in adults. J Neuropsychiatry Clin Neurosci 12:240-245, 2000 Myklebust H R Nonverbal learning disabilities: assessment and intervention. pp. 85-121. In Myklebust HR (ed): Progress in Learning Disabilities. Vol. 111. Grune & Stratton, New York, 1975 Price BH, Daffner KR, Stowe RM, Mesulam M M The comportmental learning disabilities of early frontal lobe damage. Brain 113:1383-1393, 1990 Rourke BP The syndrome of nonverbal learning disabilities: developmental manifestations in neurological disease, disorder and dysfunction. Clin Neuropsychol 2:293-330, 1988 Seidman LJ, Biederman J, Weber W et ak Neuropsychological function in adults with attention-deficit hyperactivity disorder. Biol Psychiatry 44260-268, 1998 Semrund-Clikeman M, Hynd G: Right hemispheric dysfunction in nonverbal learning disabilities:social, academic and adaptive functioning in adults and children. Psycho1 Bull 107:196-209, 1990 Shaffer D: Attention deficit hyperactivity disorder in adults. Am J Psychiatry 151:633-638, 1994 Shaywitz S E Current concepts, dysleha. N Engl J Med 338:307-312, 1998 Shaywitz SE, Fletcher JM, Holahan JM et al: Persistence of dyslexia: the Connecticut Longitudinal Study at Adolescence. Pediatrics 104:13511359, 1999 Shaywitz SE, Shaywitz BA, Pugh KR et al: Functional disruption in the organization of the brain for reading in dyslexia. Proc Natl Acad Sci 95:2636-2641, 1998 Spencer T, Biederman J, Wilens T, Faraone S: Is attention-deficit hyperactivity disorder in adults a valid disorder? Harvard Rev Psychiatry 1:326-335, 1994 Ward MF, Wender PH, Reimherr FW: The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder. Am J Psychiatry 150885-890, 1993 Weinstein CS: Cognitive remediation strategies: an adjunct to the psychotherapy of adults with attention-deficit hyperactivity disorder. J Psychother Pract Res 3:44-57, 1994 Weintraub S, Mesulam MM: Developmental learning disabilities of the right hemisphere: emotional, interpersonal and cognitive components. Arch Neurol40463-468, 1983 Weiss G, Hechtman L Hyperactive Children Grown Up: ADHD in Children, Adolescents and Adults. 2nd Ed. Guilford, New York, 1993 Wender PH: Attention-deficit hyperactivity disorder in adults. Psychiatr Clin North Am 21(4):761-774, 1998 Wender PH: Minimal Brain Dysfunction in Children. Wiley, New York, 1971 Wender PH: Pharmacotherapy of attention deficit hyperactivity disorder in adults. J Clin Psychiatry 59(Suppl. 7):76-79, 1998

SECTION

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EPILEPSY

144 Epilepsy in Children Gregory L. Holmes

Epilepsy is one of the most common neurologic problems in childhood. Children with seizures differ from adults in a number of ways, including the type of epileptic syndrome, prognosis, and therapy. In this chapter some of the unique features of seizures in children are discussed. The history and neurologic examination remain the cornerstone of epilepsy diagnosis. It is important to determine by history whether the patient had a seizure and, if so, what type. The clinician evaluating the child with a history of a paroxysmal disorder must differentiate a seizure disorder from other episodic disorders such as breath-holding attacks, syncope, night terrors, and movement disorders such as tics and choreoathetosis. A careful history or observation of the event usually is sufficient to distinguish seizures from nonepileptic events. For example, breath-holding attacks invariably are preceded by an upsetting event that causes the child to cry. Night terrors occur during slow-wave sleep, as opposed to nocturnal seizures, which typically occur during transitions between wakefulness and sleep. If there is uncertainty about the diagnosis, it is usually better to withhold treatment and wait for another attack before embarking on an extensive evaluation and initiation of antiepileptic drugs (AEDs). The electroencephalogram (EEG) can be useful in supporting the clinical suspicion of epilepsy. Epileptiform activity is defined as any paroxysmal discharges containing spikes or sharp waves, either localized or generalized. Spikes are transient electrical events lasting less than 70 msec. They typically have a biphasic or polyphasic form, exceed the amplitude of the background activity in the region, and usually are followed by a surface-negative slow wave. Sharp waves have a duration of 70 to 200 msec and, like spikes, are clearly delineated from background activity. Generalized epileptiform discharges consist of spike-and-wave, sharp-andslow waves, and multiple spikes. Epileptiform activity on the EEG is rarely diagnostic of epilepsy. For example, in large studies of normal children, up to 9% have epileptiform activity on EEG. Conversely, a normal EEG does not rule out the possibility of epilepsy because patients with well-documented seizures may have normal EEGs. This is particularly important when dealing with partial seizures. It is not uncommon for children with either simple or complex partial seizures to have a normal EEG, sometimes even during the ictal event. The yield of the EEG is increased by recording during sleep, hyperventilation, and photic stimulation. If the record is normal, sleep deprivation may be useful.

Once the diagnosis of a seizure disorder is established, the clinician should determine the seizure type. The classification of the seizures is given in Chapter 145. The next step is to try to determine whether the child has an epileptic syndrome. A syndrome is defined as a cluster of signs and symptoms customarily occurring together. Identification of an epileptic syndrome may allow the physician to determine inheritance risk for other family members. In addition, syndrome identification helps determine the type of evaluation that is necessary, the appropriate therapy, and the prognosis. Epilepsy is defined as two or more unprovoked seizures. Seizures that occur only in association with fever, head trauma, hypoglycemia, or an intracranial infection are considered provoked seizures. The child who has multiple seizures induced by fever would not be considered to have epilepsy. In this chapter the common clinical and electroencephalographic features of childhood seizures and the epilepsies are discussed (Table 144-1). When the epileptic conditions occur predominantly or exclusively in children, recommendations regarding drug therapy are provided. PARTIAL SEIZURES IN CHILDREN Partial seizures in children can vary from those that are quite benign to more malignant conditions. Partial seizures often generalize, and most generalized tonic-clonic seizures are partial seizures that secondarily generalize. Often the generalization occurs so quickly that the focal onset is not seen.

Simple Partial Seizures The signs or symptoms of the simple partial seizure depend on the focus of the seizure. Seizures involving the motor cortex commonly consist of rhythmic to semirhythmic clonic activity of the face, arm, or leg. There is usually no difficulty in diagnosing this type of seizure. Seizures with somatosensory, autonomic, and psychic symptoms (hallucinations,illusions, dkjja vu) may be more difficult to diagnose. Psychic symptoms usually occur as a component of a complex partial seizure (CPS).

Complex Partial Seizures Complex partial seizures (CPSs), formerly called temporal lobe or psychomotor seizures, are one of the most common seizure types 923

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BehavioralNeurology and Epilepsy

Epilepsy

TAW 144-1. Epileptic Syndromes:Typical ElectroencephalographicFeatures and Treatment Srndrome

Electroencephalographic Features

Treatment

Febrile convulsions

Variable

West syndrome (infantile spasms)

Hypsarrhythmia, modified hypsarrhythmia

Partial seizures

Focal spikes or sharp waves

Benign rolandic epilepsy (benign partial epilepsy with centrotemporal spikes)

High-voltage centrotemporal spikes activated by sleep

Childhood absence Juvenile absence Lennox-Gastaut syndrome

Generalized spike-and-wave Generalized spike-and-wave Slow (<2.5-Hz) spike-and-wave activity

Juvenile myoclonic epilepsy

Rapid (3.5- to 6-Hz) generalized spike-wave activitv

Oral diazepam at time of fever, rectal diazepam for prolonged seizure Adrenocorticotropic hormone, prednisone; vigabatrin (if child has tuberous sclerosis) Carbamazepine, gabapentin, lamotrigine, levetiracetam, phenytoin, tiagabine, topiramate, zonisamide, valproate Carbamazepine, gabapentin, lamotrigine, leve tiracetam, phenytoin, tiagabine, topiramate, zonisamide, valproate Ethosuximide, lamotrigine, valproate Lamotrigine, valproate Lamotrigine, topiramate, valproate, zonisamide Lamotrigine, valproate, zonisamide

encountered in both children and adults. CPSs, though commonly beginning in the temporal region, may start elsewhere. The clinical manifestations vary as a function of the seizure onset. CPSs may be preceded by a simple partial seizure, which may serve as a warning to the patient (i.e., aura) of a more severe seizure. It is important to recognize that the aura may enable the clinician to determine the cortical area in which the seizure is beginning. Common auras in children include fear, a rising sensation in the abdomen, dizziness, or a feeling that cannot be described. By definition, all patients with CPSs have impaired consciousness; thus the patient does not respond to commands or responds in an abnormally slow manner. Although CPSs may be characterized by simple staring and impaired responsiveness, behavior usually is more complex during the seizure. Automatisms (involuntary motor activity) are common during the period of impaired consciousness in CPSs. Automatic behavior is quite variable and may consist of activities such as facial grimacing, gestures, chewing, lip smacking, snapping fingers, and repeating phrases; the patient does not recall this activity after the seizure. Although variable, CPSs usually last from 30 seconds to several minutes. In contrast, absence seizures usually last less than 15 seconds. Most patients have some degree of postictal impairment, such as tiredness or confusion. CPSs may arise in a variety of locations. Temporal lobe onset, especially in mesial structures (hippocampus and amygdala) often begins with an aura, followed by staring and automatic behavior such as chewing, swallowing, and aimless movements of the hands. CPSs beginning in the frontal lobe are more likely to have prominent motor components such as tonic posturing or clonic activity. In addition, these seizures often are nocturnal and short in duration. CPSs can be caused by a variety of factors, including tumors, trauma, congenital abnormalities, vascular malformations, and infection. A history of a prolonged febrile seizure early in life is often obtained. Although some children with CPSs may outgrow their seizure, some patients have seizures that are poorly controlled and continue into adulthood. When seizures are medically intractable, surgery should be considered.

Benign Rolandic Epilepsy Benign rolandic epilepsy (BRE), also called benign partial epilepsy with centrotemporal spikes, is an epileptic syndrome characterized

by nocturnal generalized seizures and diurnal partial seizures arising from the lower rolandic area. The disorder is associated with a striking electroencephalographic pattern consisting of midtemporal-central spikes. BRE is a familial disorder with an apparent autosomal dominant pattern with variable penetrance. Siblings of children with BRE may have a similar electroencephalographic pattern but never develop seizures. The patient may present with either nocturnal generalized tonic-clonic seizures or daytime simple partial seizures. The syndrome is called rolandic epilepsy because of the characteristic clinical and electroencephalographic feature of partial seizures involving the region around the lower portion of the central gyrus of Rolando. The characteristic features of BRE include an aura of tingling or numbness in the oral-buccal cavity, speech arrest caused by motor involvement of the mouth, preservation of consciousness, excessive drooling, and tonic or tonic-clonic activity of the face. In nocturnal seizures the initial event typically is clonic movements of the mouth with drooling. Generalization to a tonic-clonic seizure is common in nocturnal seizures. The initial focal component of the seizure may be brief, and it is surmised that this portion of the seizure may not be seen by the parents. The disorder is characterized by a distinctive, dramatic electroencephalographic pattern. The characteristic interictal electroencephalographiccorrelate is a distinct high-amplitude, usually diphasic spike with a prominent following slow wave in the rolandic region. The disorder has an excellent prognosis, with almost all children having a remission of the disorder by age 16 years. Interestingly, despite the dramatic electroencephalographic features, the EEG is not predictive of when the child will go into remission.

Evaluation of Children with Partial Seizures All patients with partial seizures, whether simple or complex, should have an EEG, which should include periods of sleep and wakefulness, hyperventilation, and photic stimulation. The EEG, though not diagnostic of epilepsy, can provide supporting evidence for the diagnosis. Focal spikes and sharp waves, called epileptiform activity, suggest an epileptic region. Patients with BRE should have spikes in the midtemporal or central region. Although patients with active BRE should always have an abnormal EEG, the lack of epileptiform activity does not eliminate

Chapter 144

the possibility of other types of partial seizures. For example, patients with CPSs beginning in the mesial aspects of the temporal lobe (hippocampus or amygdala) often have normal EEGs. Patients with BRE and normal neurologic examinations need no further diagnostic tests. Other patients with simple or complex partial seizures should have neuroimaging to rule out a structural lesion such as a tumor. Although computed tomography (CT) scanning usually can rule out a malignant lesion, magnetic resonance imaging (MRI) is more sensitive for scar tissue and congenital brain anomalies.

Treatment of Children with Partial Seizures In the recent past it was not unusual for children or adults to be placed on both phenytoin and phenobarbital for their first generalized tonic-clonic seizure or partial seizure. However, an increasing number of physicians are deciding not to treat the first seizure with AEDs.In a prospective study, 238 children with a first unprovoked seizure were closely followed for a mean of 30 months by Shinnar and colleagues. Most of the children were not treated with AEDs. Subsequent seizures occurred in only 36%. The cumulative risk of recurrence was 60% at 36 months in children with a history of a static neurologic insult (called remote symptomatic by the authors) compared with 36% in children with an idiopathic seizure. The EEG was the most important predictor of recurrence in children with idiopathic seizures. Children with an idiopathic seizure and a normal EEG had a cumulative recurrence risk of 26% at 36 months. Age at the time of the first seizure and duration of the seizure did not affect recurrence risk. This study of largely untreated children demonstrated that the recurrence risk after a first unprovoked seizure is low. Many factors must be considered when deciding whether to start AED therapy, and each child must be evaluated individually. However, in view of the risk encountered with AEDs, in most children it is reasonable to wait for a second seizure before subjecting the child to years of drug therapy. In the case of BRE, where the prognosis is uniformly good, some clinicians do not recommend treatment until the child has had three or even more seizures. In children a variety of drugs are effective in treating partial seizures, including the established drugs carbamazepine, valproate, and phenytoin. Though not studied extensively in children, gabapentin, lamotrigine, levetiracetam, topiramate, tiagabine, and zonisamide also appear to be effective. Unfortunately, there have been no large studies directly comparing these drugs in partial seizures. GENERALIZED SEIZURES IN CHILDREN

Generalized seizures are those that begin suddenly, without warning, and involve bilateral cortical structures from onset. Seizure severity varies from dramatic generalized tonic-clonic seizures to more subtle absence seizures.

Generalized Tonlc-Clonic Seizures As noted earlier, most generalized tonic-clonic seizures are partial

seizures that generalize. Children who have primary generalized tonic-clonic seizures usually have other types of generalized seizures such as absence or myoclonic. Typically these patients have normal development and neurologic examinations and have

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a positive family history for epilepsy. EEGs typically demonstrate generalized spike-and-wave bursts.

Absence Seizures Formerly called petit mal, typical absence seizures usually are characterized by an abrupt cessation of activity and a change of facial expression, with a blank gaze. The seizures are short, rarely lasting more than 30 seconds, and are never associated with an aura or postictal impairment. Typical absence seizures almost always begin during childhood, with the usual age of onset between 3 and 6 years. Although they occasionally continue into adulthood, they are most prevalent during the first 10 years of life. In the majority of patients with typical absence seizures, the neurologic examination is normal. Hyperventilation is a very useful technique when typical absence seizures are suspected. Three minutes of hyperventilation in an untreated child is likely to induce an absence seizure. Photic stimulation, usually administered during the EEG, may also precipitate an absence seizure. The electroencephalographicsignature of a typical absence seizure is the sudden onset of 3-Hz generalized symmetrical spike- or polyspike-and-slow wave complexes. A normal EEG during the awake and sleep states as well as during hyperventilation and photic stimulation in an untreated child makes the diagnosis of absence epilepsy very unlikely. There are three syndromes in which absence seizures are one of the seizure types: childhood absence (pyknolepsy) epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy (JME). Pyknolepsy describes typical absence seizures (i.e., both simple and complex) in children between the ages of 3 years and puberty who are otherwise normal. There is a strong genetic predisposition, and girls are more frequently affected. The absences are very frequent, occurring at least several times daily, and tend to cluster. The absences may remit during adolescence, but generalized tonicclonic seizures may develop. Juvenile absence epilepsy begins around puberty and differs from pyknolepsy in that the seizures are more sporadic, and generalized tonic-clonic seizures somewhat more common. JME is a familial disorder that typically begins in the second decade of life and is characterized by mild myoclonic seizures, generalized tonic-clonic or clonic-tonic-clonic seizures, and occasionally absence seizures. The myoclonic seizures usually are mild to moderate in intensity and involve the neck, shoulders, and arms. The movements involve an entire extremity or body part rather than an isolated muscle contraction. They can occur either singularly or repetitively and may cause the patient to drop objects. They are generally bilateral, although they are sometimes asymmetrical with changing left-right accentuation. Rarely, the jerks may involve the legs and cause the patient to fall to the ground. The interictal EEG in this disorder is reported to be distinctive and easily distinguished from other forms of generalized epilepsies. The characteristic interictal feature of the EEG is the fast (3.5- to 6-Hz) spike-and-wave and multiple spike-andwave complexes. This pattern contrasts with the 3-Hz spike-andwave complexes seen in classic absence and the slow (1.5- to 2.5-Hz) spike-and-wave complexes seen with atypical absence seizures. Atypical absence seizures are characterized as having a less abrupt onset or cessation, more pronounced changes in tone, and longer duration than typical absence. They usually begin before 5 years of age and are associated with other generalized seizure types and mental retardation. The ictal EEG is more heterogeneous,

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showing 1.5- to 2.5-Hz slow spike-and-wave or polyspike-andwave discharges that may be irregular or asymmetrical. The interictal EEG usually is abnormal, with slowing and multifocal epileptiform features. Patients with a history suggestive of childhood absence epilepsy, juvenile epilepsy, or JME with typical electroencephalographic findings and normal neurological examinations do not need any additional evaluation. Children with atypical absence seizures often have Lennox-Gastaut syndrome (LGS), a disorder that necessitates more extensive evaluations, including MRI and metabolic testing. Treatment of Primary Generalized Seizures

Because of the very high recurrence risk, it is recommended that any child presenting with absence seizures begin treatment immediately. In children presenting with a single primary generalized tonic-clonic seizure it is reasonable to wait until the second seizure to begin therapy. Valproate, ethosuximide, and lamotrigine are most commonly used to treat absence seizures. In patients who also have generalized tonic-clonic seizures, valproate or lamotrigine is the drug of choice. Infantile Spasms

Infantile spasm, or West syndrome is a unique and often malignant epileptic syndrome confined to infants. The usual characteristic features of this syndrome are tonic or myoclonic seizures, hypsarrhythmic EEGs, and mental retardation. Infantile spasms are an age-specific disorder beginning only in children during the first 2 years of life. The spasms can be classified into three major groups: flexor, extensor, and mixed flexor-extensor types. Flexor spasms consist of flexion of the neck, trunk, arms, and legs. Spasms of the muscles of the upper limbs result either in adduction of the arms in a self-hugging motion or in adduction of the arms to either side of the head with the arms flexed at the elbow. Extensor spasms consist of a predominance of extensor muscle contractions, producing abrupt extension of the neck and trunk with extensor abduction or adduction of the arms, legs, or both. Mixed flexor-extensor spasms include flexion of the neck, trunk, and arms and extension of the legs or flexion of the legs and extension of the arms with varying degrees of flexion of the neck and trunk. Infantile spasms often occur in clusters, and the intensity and frequency of the spasms in each cluster may increase to a peak before progressively decreasing. On the basis of history, physical examination, and laboratory studies, cases of infantile spasms have been conventionally classified into those in which there is no apparent preceding neurologic disorder or identified etiologic factor (idiopathic) and those in which a prior, presumptively responsible pathologic event or disorder is demonstrated (symptomatic cases). The majority of infants who have infantile spasms have developmental delay, neurologic deficits, or both before the onset of the spasms; unfortunately, even in children with normal development before the onset, the disorder is associated with slowing or regression of development. Infantile spasms usually are associated with markedly abnormal EEGs, the most common of which is hypsarrhythmia. This pattern consists of high-amplitude slow waves mixed with spikes and sharp waves. The electroencephalographic background activity is disorganized and chaotic. A large number of etiologic factors have

been associated with infantile spasms. These include hypoxicischemic injuries, tuberous sclerosis, congenital brain anomalies, infection, and head injury. Almost any agent that can harm the brain has been associated with infantile spasms. Why some children with these conditions develop spasms is unclear. The evaluation of a child with infantile spasms should include an MRI to look for a congenital anomaly, evidence of tuberous sclerosis or a congenital infection, metabolic evaluation, and a spinal tap. Although recommendations for treatment of infantile spasms are controversial, the most common therapy is adrenocorticotropic hormone (ACTH). Standard AEDs such as carbamazepine, phenytoin, and phenobarbital usually are not effective. Vigabatrin, a drug not marketed in the United States, can be highly effective in infantile spasms, particularly in children who have tuberous sclerosis. The drug is associated with retinal degeneration and necessitates close ophthalmologic follow-up with periodic electroretinograms. ACTH also is associated with significant side effects. Although some children rapidly respond to ACTH and develop normally, a significant number of infants continue to have spasms or develop other seizure types. Some infants progress into LGS. Because of the poor prognosis in most infants with infantile spasms, there recently has been interest in early surgical treatment. In some infants, regional cortical abnormalities have been resected with resolution of the spasms. Positron emission tomography has been used in some centers to help identify these regional abnormalities. Unfortunately, only a few children with infantile spasms have an identifiable focal lesions.

Lennox-Castaut Syndrome

LGS is a mixed seizure disorder in which tonic seizures are a major component, with a slow spike-and-wave electroencephalographic pattern. The syndrome always begins in childhood, and most children have mental retardation. Patients with the LGS typically have very frequent seizures: A mixture of seizure types is the rule in LGS. The most common are tonic, tonic-clonic, myoclonic, atypical absences, and head drops, which are a form of atonic, tonic, or myoclonic seizures. Tonic seizures are a major component of this syndrome. They are typically activated by sleep and may occur repetitively throughout the night. The sine qua non of the electroencephalographic findings in LGS is the slow spike-and-wave discharge superimposed on an abnormal, slow background. The slow spike-and-wave or sharpand-slow-wave complexes consist of generalized discharges occurring at a frequency of 1.5 to 2.5 Hz. Although sleep increases the frequency of the discharges, hyperventilation and photic stimulation rarely activate these discharges. As with infantile spasms, LGS is associated with a variety of etiologic agents that cause brain injury. The evaluation of the child should include an EEG, MRI, a spinal tap and metabolic screening. Treating children with LGS is very difficult because the seizures often are refractory to AEDs. When possible, the physician should avoid treating the child with multiple AEDs because this typically leads to drug toxicity without satisfactory treatment. Valproate, lamotrigine, and topiramate appear to be the most efficacious drugs in treating this disorder. Although felbamate is also effective, the risk of aplastic anemia and hepatotoxicity prohibits its use as a first-line therapy. In patients with medically intractable seizures, corpus callosotomy or vagal nerve stimulation may be useful.

Chapter 144

Febrile Seizures A febrile seizure is a seizure occurring in infancy or childhood that occurs between 3 months and 5 years of age in association with a fever but without evidence of intracranial infection or defined cause. Febrile seizures must be differentiated from epilepsy, which is characterized by recurrent, afebrile seizures. However, patients with epilepsy often are more susceptible to seizures during fever. Unfortunately, when a child has a seizure with fever, there is no definitive way to determine whether the seizure is secondary to the fever or is the first manifestation of epilepsy. The first febrile seizure in the majority of children occurs before 3 years, with the average age of onset between 18 and 22 months. Most studies have demonstrated a higher incidence in boys. Febrile seizures may be of any type, although they are usually generalized tonic-clonic. Febrile seizures are associated with a very low mortality rate. When deaths do occur they are usually secondary to the agent causing the fever or antecedent neurologic disorder. Prospective studies have shown a very low incidence of acquired motor or intellectual abnormalities after a febrile seizure. Although few children who experience febrile seizures develop epilepsy, many children experience recurrences of febrile seizures. Approximately a third of the children have at least one recurrence. Three-fourths of recurrences take place within 1 year of the first febrile seizure and 90% within 2 years. Recurrence risk is not uniform for all children with febrile seizures. The most important factor appears to be age of onset of the first febrile seizure. The younger the child at the first attack, the more likely are further febrile seizures. Although children who have one or more febrile seizures are at greater risk of developing epilepsy, the risk is quite small. The risk of developing epilepsy appears to be increased by several factors. If the febrile seizure duration is greater than 15 minutes, occurs more than once in 24 hours, or has focal features, the risk increases significantly. When evaluating a child with febrile seizures the physician must first determine whether there is an underlying illness that warrants immediate, specific treatment. The most urgent diagnostic decision is whether to do a lumbar puncture. One of the earliest signs of meningitis may be a seizure, which, like a febrile seizure, usually is short and generalized tonic-clonic in type. Although meningitis usually results in meningismus, in patients under the age of 2 years clinical signs of meningitis may be minimal or absent. In the absence of specific clinical indications, there is little evidence in the literature indicating that other tests are helpful in determining the cause of seizures associated with fever. Although often ordered by physicians, serum glucose, calcium, blood urea nitrogen, and electrolytes are not routinely recommended. Brief, single, self-limited febrile seizures from which the child fully recovers are seldom caused by conditions such as hypoglycemia or toxins. Unless the physical examination points to a possible structural lesion, a CT or MRI scan is not warranted in evaluating febrile seizures. Somewhat surprisingly, the EEG has not been found to be useful in evaluating a child with febrile seizures. Although there remains some controversy, most authorities believe that the EEG is a poor predictor of either febrile or afebrile seizure recurrence. Because febrile seizures are benign events, there are few compelling reasons to place the child on chronic AEDs because all the AEDs have side effects. Although most studies demonstrate

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that phenobarbital is effective in reducing recurrence risk, the behavioral disturbances seen in some children taking the drug limit its usefulness. Valproic acid, though effective, carries a risk of hepatic and pancreatic dysfunction. Other AEDs such as carbamazepine and phenytoin are not effective in reducing seizure frequency. An effective way to reduce recurrence risk is to administer diazepam, 0.3 mg/kg every 8 hours when the child has a fever or appears to be developing an illness. This form of intermittent therapy has proven to be effective in reducing but not eliminating febrile seizure recurrences because parents may not know the child has a fever until after the seizure. In addition, diazepam can result in significant lethargy and irritability. Another alternative is to prescribe rectal diazepam for use if the child has a febrile seizure lasting more than 5 minutes. Rectal diazepam significantly reduces the likelihood of the child developing status epilepticus or having a second febrile seizure.

-drawing

AntEeplleptlc Drugs in Children

In general, once a child goes 2 years without a seizure, the physician should consider withdrawing AEDs. Although certain factors such as age at onset greater than 12 years, a positive family history, slowing on the EEG before AED withdrawal, a symptomatic origin, abnormal neuroimaging, and mental retardation increase the risk of recurrence, even in these children the physician and parents may want to consider withdrawing AEDs. A withdrawal period of 6 to 8 weeks is recommended. SUGGESTED READINGS Appleton RE: The role of vigabatrin in the management of infantile epileptic syndromes. Neurology 43(Suppl 5):S21-S23, 1993 Berg AT, Shinnar S: The risk of seizure recurrence following a first unprovoked seizure: a metaanalysis. Neurology 41:965-972, 1991 Dreifuss FE, Rosman NP, Cloyd JC et al: A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 338:18691875, 1998 Duchowny M, JayakarP, Resnick T et al: Epilepsy surgery in the first three years of life. Epilepsia 39:737-743, 1998 Dulac 0, N'Guyen T: The Lennox-Gastaut syndrome. Epilepsia 34(Suppl 7):S7-S17, 1993 Fanvell JR, Lee YJ, Hirtz DG et ak Phenobarbital for febrile seizures: effects on intelligence and on seizure recurrence. N Engl J Med 322:364-369, 1990 Felbamate Study Group in Lennox-Gastaut Syndrome: Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 328:29-33, 1993 Genton P, Dravet C Lennox-Gastaut and other childhood epileptic encephalopathies. pp. 2355-2366. In Engel J Jr, Pedley TA (eds): Epilepsy: A Comprehensive Textbook. Lippincott-Raven, Philadelphia, 1997 Gross-Tsur V, Banin E, Shahar E et ak Visual impairment in children with epilepsy treated with vigabatrin. Ann Neurol 48:60-64, 2000 Motte J, Trevathan E, Arvidsson JFV et ak Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med 337:1807-1812, 1997 Pearl PL, Holmes GL Absence seizures. pp. 219-231. In Pellock JM, Dodson WE, Bourgeois BFD (eds): Pediatric Epilepsy. Diagnosis and Treatment. Demos, New York, 2001 Rantala H, Putkonen T Occurrence, outcome, and prognostic factors of infantile spasms and Lennox-Gastaut syndrome.Epilepsia 40286-289, 1999

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Rosman NP, Colton T, Labazzo J et al: A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 329:79-84, 1993 Shinnar S, Berg AT, Moshk SL et ak Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol354:534-545, 1994

Snead OC 111, Benton JW, Myers G L ACTH and prednisone in childhood seizure disorders. Neurology 33:966-970, 1983 Wyllie E, Comair YG, Kotagal P et al: Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 44:740-748, 1998

145 Diagnosis and Classification of Epilepsy Edward B. Bromfield Epilepsy, a tendency toward recurrent unprovoked seizures, is among the most common of neurologic conditions, affecting 0.5% to 1.0% of the population at any given time. Furthermore, up to 10% of individuals at some time in their lives experience at least one seizure, either provoked or unprovoked. These high prevalence rates are related to the fact that epilepsy is not a specific disease but rather a symptom of brain dysfunction, a final common pathway of many different cerebral insults. Because of the variety of causative conditions and clinical manifestations, classification systems are necessary for appropriate diagnosis and treatment. SEIZURES AND SEIZURE CLASSIFICATION

Physiologically, an epileptic seizure is an uncontrolled, abnormally synchronous discharge of a collection of neurons. This excessive discharge causes a transient abnormality in brain function, the specific nature of which is determined by the brain regions involved. For example, motor cortex typically produces stiffening or rhythmic jerking of the corresponding limb; somatosensory cortex, tingling or “electricity”; primary visual cortex, flashing lights or spots; auditory cortex, ringing or buzzing; and olfactory or gustatory regions, hallucinations of smell or taste. Cortical association areas may give rise to more complex phenomena such as formed hallucinations in the appropriate modalities, and limbic cortex may produce emotional experiences or memory phenomena (e.g., vivid recall of a specific event or dkja vu experience). Because the pathophysiologic process is one of too much rather than too little neuronal activity, epileptic brain dysfunction often takes the form of what Hughlings Jackson called positive symptoms. Negative symptoms, such as paralysis or sensory loss, are much less common in epileptic seizures than in processes that lead to decreased neuronal activity, such as brain ischemia. (An exception is speech arrest, a negative sign that is common when consciousness is lost or altered in complex partial seizures,whereas aphasic seizures are uncommon.) If enough of the brain is involved in the abnormally synchronous discharge, consciousness is lost, and the patient is unable to report any further phenomena. Seizures that spread from one hemisphere to the other often impair consciousness. Automaticappearing movements such as chewing, swallowing, or picking with one’s hands are commonly seen after consciousness is lost. If most or all of the cerebrum is involved, a stereotypic event known as a generalized tonic-clonic seizure (also known as grand mal or major motor seizure or generalized convulsion) occurs. This

consists of widespread stiffening (tonic phase, an increase in muscle tone) followed by rhythmic jerking (clonic phase). The entire event seldom takes longer than 2 minutes. Return to normal mental state occurs gradually over minutes to hours, during the phase of postictal recovery. Implicit in this description is the paradigm of a seizure starting locally and then spreading throughout the brain, with successive impairments reflecting the involvement of additional brain regions. This sequence applies to partial seizures, which may occur without or with loss of consciousness (simple or complex partial seizure) and may or may not culminate in a generalized tonic-clonic seizure (partial seizure secondarily generalized). For classification purposes, consciousness is defined operationally as the ability to respond appropriately to the environment or to remember events during any time period in which response is impaired because of a motor or language disturbance. Seizures may also be primarily generalized, that is, involve the entire cerebrum apparently simultaneously without evidence of focal onset. Such seizures can take the form of a tonic-clonic convulsion or be less severe. A primarily generalized seizure that consists only of brief staring is called an absence seizure (formerly petit mal). A myoclonic seizure consists of a single rapid movement or series of such movements. When generalized, these are bilateral, although not always symmetrical. Clonic seizures are manifested by rhythmic, repetitive jerking movements. Generalized tonic seizures consist of sudden stiffening, usually in an abnormal but symmetrical posture. Tonic-clonic seizures typically have tonic and clonic phases, as described earlier. Atonic seizures result in sudden loss of muscle tone and falling or, in milder form, head nods or jaw drops. (Sudden falls may also occur with myoclonic, tonic, or clonic seizures if legs are involved.) The following is a simplified version of the International Classification of Epileptic Seizures, last revised in 1981. I. Partial seizures (seizures beginning locally) A. Simple partial seizures (consciousness not impaired) Motor Somatosensory or special sensory Autonomic (e.g., rising epigastric sensation, flushing) Psychic-cognitive (e.g., d6ja vu, fear, aphasia) B. Complex partial seizures (consciousness impaired) Beginning as simple partial seizures (see above) With impairment of consciousness at onset C. Partial seizures secondarily generalized (can start as simple, complex, or simple evolving to complex partial)

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Rosman NP, Colton T, Labazzo J et al: A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 329:79-84, 1993 Shinnar S, Berg AT, Moshk SL et ak Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol354:534-545, 1994

Snead OC 111, Benton JW, Myers G L ACTH and prednisone in childhood seizure disorders. Neurology 33:966-970, 1983 Wyllie E, Comair YG, Kotagal P et al: Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 44:740-748, 1998

145 Diagnosis and Classification of Epilepsy Edward B. Bromfield Epilepsy, a tendency toward recurrent unprovoked seizures, is among the most common of neurologic conditions, affecting 0.5% to 1.0% of the population at any given time. Furthermore, up to 10% of individuals at some time in their lives experience at least one seizure, either provoked or unprovoked. These high prevalence rates are related to the fact that epilepsy is not a specific disease but rather a symptom of brain dysfunction, a final common pathway of many different cerebral insults. Because of the variety of causative conditions and clinical manifestations, classification systems are necessary for appropriate diagnosis and treatment. SEIZURES AND SEIZURE CLASSIFICATION

Physiologically, an epileptic seizure is an uncontrolled, abnormally synchronous discharge of a collection of neurons. This excessive discharge causes a transient abnormality in brain function, the specific nature of which is determined by the brain regions involved. For example, motor cortex typically produces stiffening or rhythmic jerking of the corresponding limb; somatosensory cortex, tingling or “electricity”; primary visual cortex, flashing lights or spots; auditory cortex, ringing or buzzing; and olfactory or gustatory regions, hallucinations of smell or taste. Cortical association areas may give rise to more complex phenomena such as formed hallucinations in the appropriate modalities, and limbic cortex may produce emotional experiences or memory phenomena (e.g., vivid recall of a specific event or dkja vu experience). Because the pathophysiologic process is one of too much rather than too little neuronal activity, epileptic brain dysfunction often takes the form of what Hughlings Jackson called positive symptoms. Negative symptoms, such as paralysis or sensory loss, are much less common in epileptic seizures than in processes that lead to decreased neuronal activity, such as brain ischemia. (An exception is speech arrest, a negative sign that is common when consciousness is lost or altered in complex partial seizures,whereas aphasic seizures are uncommon.) If enough of the brain is involved in the abnormally synchronous discharge, consciousness is lost, and the patient is unable to report any further phenomena. Seizures that spread from one hemisphere to the other often impair consciousness. Automaticappearing movements such as chewing, swallowing, or picking with one’s hands are commonly seen after consciousness is lost. If most or all of the cerebrum is involved, a stereotypic event known as a generalized tonic-clonic seizure (also known as grand mal or major motor seizure or generalized convulsion) occurs. This

consists of widespread stiffening (tonic phase, an increase in muscle tone) followed by rhythmic jerking (clonic phase). The entire event seldom takes longer than 2 minutes. Return to normal mental state occurs gradually over minutes to hours, during the phase of postictal recovery. Implicit in this description is the paradigm of a seizure starting locally and then spreading throughout the brain, with successive impairments reflecting the involvement of additional brain regions. This sequence applies to partial seizures, which may occur without or with loss of consciousness (simple or complex partial seizure) and may or may not culminate in a generalized tonic-clonic seizure (partial seizure secondarily generalized). For classification purposes, consciousness is defined operationally as the ability to respond appropriately to the environment or to remember events during any time period in which response is impaired because of a motor or language disturbance. Seizures may also be primarily generalized, that is, involve the entire cerebrum apparently simultaneously without evidence of focal onset. Such seizures can take the form of a tonic-clonic convulsion or be less severe. A primarily generalized seizure that consists only of brief staring is called an absence seizure (formerly petit mal). A myoclonic seizure consists of a single rapid movement or series of such movements. When generalized, these are bilateral, although not always symmetrical. Clonic seizures are manifested by rhythmic, repetitive jerking movements. Generalized tonic seizures consist of sudden stiffening, usually in an abnormal but symmetrical posture. Tonic-clonic seizures typically have tonic and clonic phases, as described earlier. Atonic seizures result in sudden loss of muscle tone and falling or, in milder form, head nods or jaw drops. (Sudden falls may also occur with myoclonic, tonic, or clonic seizures if legs are involved.) The following is a simplified version of the International Classification of Epileptic Seizures, last revised in 1981. I. Partial seizures (seizures beginning locally) A. Simple partial seizures (consciousness not impaired) Motor Somatosensory or special sensory Autonomic (e.g., rising epigastric sensation, flushing) Psychic-cognitive (e.g., d6ja vu, fear, aphasia) B. Complex partial seizures (consciousness impaired) Beginning as simple partial seizures (see above) With impairment of consciousness at onset C. Partial seizures secondarily generalized (can start as simple, complex, or simple evolving to complex partial)

Chapter 145

11. Generalized seizures (bilaterally symmetrical and without local onset) A. Absence Typical (petit mal) Atypical B. Myoclonic C. Clonic D. Tonic E. Tonic-clonic (grand mal) F. Atonic 111. Unclassified epileptic seizures (inadequate or incomplete data)

More detailed descriptions are provided in Table 145-1. By allowing careful correlation of clinical and electrographic seizure phenomena, the development of long-term videoelectroencephalographic (EEG) recording was one of the key factors behind revision of the classification. Currently, this technique is generally reserved for especially difficult cases, so that diagnosis typically depends primarily on history and interictal EEG findings. Other than those with motor manifestations, simple partial seizures can be diagnosed only on the basis of the patient’s history, supported in many cases by electroencephalogramshowing interictal epileptiform activity or neuroimaging showing a plausible causative lesion. For complex partial seizures, the patient’s history should be supplemented by that of other observers. Descriptions of automatisms, defined as complex behaviors of which the patient has no awareness or memory, and other evidence of altered consciousness are extremely important.

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The term aura, coined initially by Galen for the “breeze” that some patients felt just before their seizures, currently refers to whatever the patient recalls experiencingbefore consciousness is lost, that is, the simple partial seizure that precedes a complex partial or secondarily generalized event. Interictal physical examination and neuroimaging studies can indicate focal or global abnormalities that may predispose to seizures but are only indirectly relevant to diagnosis and classification. Several conditions may present with events resembling either partial or generalized seizures. These include cerebral ischemia, syncope, migraine, movement disorders, sleep disorders, metabolic disturbances, and psychiatric conditions, which are discussed elsewhere in this volume. There are several characteristic features related to onset, progression of symptoms, stereotypy, duration, and postictal changes that help to distinguish seizure types from each other and from nonepileptic events. Almost all seizures begin abruptly; indeed, it is their very unpredictability that is responsible for much of the associated functional impairment. Although some patients can have a prodromal feeling lasting hours or more, the seizure itself usually is sudden. Although certain psychosocial or lifestyle factors, most commonly sleep deprivation and, less often, stress, may increase the likelihood of seizures occurring on a given day, most seizures have no clear precipitant. Furthermore, the sequence of events that follows seizure onset is stereotyped for a given patient. Certain sequences tend to be stable even across patients; a symptom that can be associated with simple partial seizures, such as abdominal upset or dkja vu, probably is not epileptic in origin if it follows rather than precedes alteration in consciousness. In generalized

TABU 145-1. Selected Clinical and Electroencephalographic Features of Different Seizure Types Seizure Type

Clinical Features

Typical Duration

Postictal Period

lnterictal Electroencephalogram

Simple partial

Motor, somatosensory, special sensory, autonomic, or psychic symptoms Altered consciousness, often beginning with stare and followed by automatisms; may be immediately preceded by simple partial Simple or complex partial seizure followed by tonic posturing evolving to repetitive, bilateral muscle contractions Arrest of activity, staring with loss of awareness; may have subtle tonic, clonic, myoclonic, or atonic features; automatisms occur rarely Altered awareness, perhaps incomplete; variably abrupt onset and cessation Sudden isolated or multiple jerks, usually involving upper > lower body, restricted or extensive Rhythmically repetitive myoclonic jerks, usually with altered consciousness Bilateral tonic posturing, usually involvingtrunk and face; loss of consciousness Tonic posturing followed by clonic jerking bilaterally Altered awareness and loss of muscle tone accompanied by sudden fallinn or. when milder. . head nod-or jaw drop

10-1 80 sec

Mild and brief if any

15-300 sec

Highly variable (none to many minutes)

Spikes or sharp waves over appropriate area, with or without associated slowing Same as above

30-1 20 sec (exclusive of partial seizure at onset)

Minutes to hours

Same as above

5-20 set

None

Generalized 2.5-4/sec spike wave or multiple spike and slow wave complexes

5- 180 sec

Variable

<1 sec if isolated

None

Slow (<2.5 Hz) spike wave or multiple spike and slow wave complexes, abnormal background Multiple spike and slow wave complexes

Variable

Variable

Generalized spike wave or multiple spike and slow wave complexes

5-20 sec; may cluster

Seconds to minutes

30-1 20 set

Minutes to hours

Generalized spike wave or multiple spike and slow wave complexes; bursts of multiple spikes Generalized discharges as above

Seconds; rarely > 1 min

Variable

Complex partial

Partial secondarily generalized Absence (typical)

Absence (atypical) Myoclonic Clonic Tonic Tonic-donic Atonic

Slow spike wave, multiple spike and slow wave complexes, a b normal background

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tonic-clonic seizures, the clonic movements almost always slow progressively before they stop. Duration of seizures is also surprisingly consistent across patients for a given seizure type (Table 145-1). Simple partial seizures last seconds to a few minutes, and complex partial seizures usually last slightly longer. The duration of either primarily or secondarily generalized tonic-clonic seizures is rarely longer than 2 minutes. Bilateral tonic posturing or clonic movements usually (though not always) are associated with loss of consciousness. Another characteristic of motor activity arising from an epileptic mechanism is that it generally cannot be stopped by stimulation or gentle restraint. Finally, postictal confusion or somnolence is characteristic of most seizures manifested by loss of consciousness. (Exceptions are typical absence seizures and certain complex partial seizures, especially those of frontal lobe origin.) Although ictal EEG recording with synchronized video is the gold standard for seizure classification, routine interictal studies can also be extremely helpful. As discussed in Chapter 20, the majority of patients prone to partial or generalized seizures eventually show a confirmatory interictal epileptiform abnormality, particularly if sleep is obtained. Often, a focal interictal EEG abnormality is the only indicator that a generalized tonic-clonic seizure was actually a partial seizure that secondarily generalized. Clinical features that can contribute to this diagnosis include symptoms compatible with a simple partial seizure immediately preceding loss of consciousness, a witnessed complex partial seizure before generalization, or a postictal (Todd’s) paralysis. As described elsewhere in this book, this distinction has implications for treatment. CLASSIFICATION OF EPILEPSY SYNDROMES

Although alternatives have been proposed (see Luders et al., 1993), the International Classification of Epileptic Seizures summarized earlier has achieved wide acceptance and application. The task of classifying epileptic syndromes, though equally important clinically, has been more difficult. The schema proposed in 1989 by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE)remains the standard, but it is being revised (see Engel, 2001). As in any other medical discipline, a syndrome is a collection of signs and symptoms that go together; in the case of the epilepsies, syndrome definitions may include seizure types, age of onset, presumed cause, physical characteristics, neurologic status, family history, and EEG and neuroimaging findings. Certain syndromes are sufficiently well characterized to provide reliable information about prognosis and response to treatment. Epileptic syndromes may be broadly grouped along two dimensions, regarding presumed cause (idiopathic versus symptomatic) and seizure type (partial versus generalized). Idiopathic, as used here, refers to the absence of an identifiable underlying brain insult and in general implies a genetic cause. A genetic cause may be present without a positive family history, as family members may have the trait (sometimes apparent on electroencephalogram) without the clinical syndrome, and in other patients the syndrome may result from a spontaneous mutation or from a specific combination of genes. Symptomatic refers to the presence of a specific brain insult thought to predispose toward recurrent seizures. The equivalent terms primary and secondary have been dropped because of the potential confusion with the concept of primarily and secondarily generalized seizures. Cryptogenic refers to cases in which a specific

insult is presumed but not identified. An abbreviated and slightly modified form of the international classification follows. I. Partial epilepsies and syndromes (also called focal, local, or localization-related) A. Idiopathic (with age-related onset) Benign epilepsy with centrotemporal spikes Childhood epilepsy with occipital paroxysms Primary reading epilepsy B. Symptomatic Chronic progressive epilepsia partialis continua of childhood Syndromes with seizures precipitated by sensory stimuli or activities (reflex epilepsies) Temporal lobe epilepsies (mesial and lateral) Frontal lobe epilepsies (multiple subareas) Parietal lobe epilepsies Occipital lobe epilepsies 11. Generalized epilepsies and syndromes A. Idiopathic (with age-related onset, in order of age) Benign neonatal familial convulsions Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with grand mal seizures on awakening Other idiopathic generalized epilepsies Reflex epilepsies with generalized seizures B. Cryptogenic or symptomatic Infantile spasms Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic absences C. Symptomatic; many inborn errors of metabolism and congenital malformations 111. Epilepsies and syndromes undetermined whether focal or generalized A. With both generalized and focal seizures B. With unclassifiable seizures IV. Special syndromes A. Situation-related seizures Febrile convulsions Isolated seizures or isolated status epilepticus Seizures precipitated by acute systemic metabolic or toxic disturbance These and other syndromes are described in Chapter 144 and in several of the Suggested Readings. Some of the more important syndromes are listed in Table 145-2, which may better highlight the relationships between them. Briefly mentioned in the table is

TABLE145-2. Selected Epilepsy Syndromes ORIGIN

Seizure Type

Idiopathic (Primary)

Partial

Benign rolandic epilepsy Autosomal dominant nocturnal frontal lobe epilepsy

Generalized

Childhood absence epilepsy Juvenile mvoclonic epilepsv

Symptomatic (Secondary)

Temporal lobe Frontal lobe Parietal lobe Occipital lobe Lennox-Gastaut svndrome

Chapter 145

the unusual but conceptually important group of syndromes known as reflex epilepsies, which may be either idiopathic or symptomatic and either partial or generalized. These are not simple reflex responses, as the term implies, but refer to reproducible elicitation of seizures by stereotyped sensory stimuli or activities. In selected patients, seizures may be precipitated by such elementary stimuli as flashing lights or such complex activities as reading or eating. Of particular interest to the adult neurologist are the several (presumed) symptomatic partial epilepsies, particularly temporal and frontal. Temporal lobe epilepsies typically include simple partial seizures characterized by autonomic, psychic, or certain special sensory phenomena. Examples are a rising epigastric sensation, sudden fear, deja vu, unpleasant olfactory or gustatory hallucinations, or visual distortions of size or distance. (However, none of these is pathognomonic for temporal lobe origin.) Complex partial seizures arising from the temporal lobe often begin with a motionless stare followed by oroalimentary automatisms and later by a postictal state gradually resolving over minutes. Secondary generalization occurs but usually with only a minority of seizures. Other clinical features often include a history of febrile seizures, onset in childhood or adolescence, and temporal discharges on electroencephalogram. Associated personality traits have been demonstrated in some studies, but their diagnostic usefulness is controversial (see Chapter 149). Lesions are not typically visualized on neuroimaging, although careful magnetic resonance imaging analysis often shows signs of hippocampal sclerosis, and interictal positron emission tomography studies demonstrate unilateral temporal lobe hypometabolism. Response to medical treatment often is unsatisfactory, but surgery may be an excellent option in appropriately selected candidates (see Chapter 148). Temporal lobe epilepsies are the most common epilepsy syndromes seen in adults. Frontal lobe epilepsies have been increasingly recognized in recent years because of improvements in neuroimaging and intracranial EEG studies. Although the clinical distinction from temporal lobe syndromes is not always clear, complex partial seizures associated with frontal lobe pathology typically are shorter in duration, more often lack postictal confusion, and are more prone to secondarily generalize. Isolated simple partial seizures occur less often, and motor manifestations are more common and dramatic, sometimes leading to diagnostic confusion with psychogenic episodes. Seizures often occur several times a day, especially during sleep, and may evolve into status epilepticus. EEG findings may be normal or nonspecifically abnormal, even ictally (when artifact often obscures the tracing). For patients whose seizures are not controlled by medication, the likelihood of surgical success is less than in the case of temporal lobe epilepsies unless a resectable structural lesion is present. The frontal lobes are very large and include a variety of functionally distinct areas, including primary and supplementary motor, cingulate, frontopolar, orbitofrontal, dorsolateral, and opercular regions. Delineating characteristics of seizures arising from each of these areas is an active area of study. Occipital and parietal lobe epilepsies are less common than frontal and especially temporal lobe syndromes. The expected contralateral visual or somatosensory phenomena do not always occur, and rapid spread to other areas may mimic seizures of temporal or frontal origin. Forced contraversion of head or eyes, at times with retained consciousness, is common in occipital lobe epilepsies, as is a history of migraine. Because of proximity to the posterior frontal lobe, parietal lobe seizures often include motor phenomena, and language disturbances are typical if the seizure

Diagnosis and Classification of Epilepsy

931

arises in the dominant hemisphere. Structural lesions are often but not always seen. Advances in genetics have led to the definition of new idiopathic partial epileptic syndromes, such as familial temporal lobe epilepsy and autosomal dominant nocturnal frontal lobe epilepsy. Like most idiopathic syndromes, these tend to be more responsive to treatment than the symptomatic or cryptogenic partial epilepsies. These syndromes and several others probably will appear in the next revision of the International Classification of the Epilepsies and Epileptic Syndromes. The most important idiopathic generalized syndrome seen in adults is that of juvenile myoclonic epilepsy. Although onset typically occurs in adolescence, the syndrome remits in less than 20% of cases. The cardinal symptom, that of bilateral but not always symmetrical rapid jerks, often is not remarked upon by the patient without specific questioning. Rare patients actually have unilateral myoclonus, though usually involving either side at different times, which may further obscure the diagnosis. In many cases, myoclonic seizures have been occurring for years before the patient comes to medical attention, most often at the time of his or her first generalized tonic-clonic seizure. The patient may regard the morning myoclonus as merely shakiness or nerves. In other patients, however, myoclonus involving the lower extremities can result in sudden falls or injuries. In addition to myoclonic and generalized tonic-clonic seizures, a substantial minority of patients with juvenile myoclonic epilepsy also have absence seizures, clinically similar to but less frequent than those associated with childhood absence epilepsy. Another important feature of juvenile myoclonic epilepsy is extreme sensitivity to sleep deprivation and alcohol; lifestyle adjustments in these areas are important adjuncts to drug therapy. Examination and imaging studies are normal, but electroencephalogram usually demonstrates generalized spike wave or multiple spike and slow wave complexes, often faster than 3 Hz. Photosensitivity, manifested by an abnormal EEG response or even a clinical seizure during strobe light stimulation, is also common. Response to medical treatment usually is excellent, although, as noted, relapse is common if medications are withdrawn after a seizure-free period.

USE OF SEIZURE AND SYNDROME CLASSlFlCATlON IN TREATMENT DECISIONS Of nearly two dozen drugs marketed for epilepsy in the United States, fewer than 10 are commonly used. On the basis of animal testing, clinical experience, and a few large, controlled clinical studies, a rough consensus has been reached regarding drugs of choice for specific seizure types and syndromes. In general, drugs that are effective in treating partial seizures, such as phenytoin and carbamazepine, are also effective for generalized tonic-clonic seizures but not for other generalized seizures. Valproate can be used for almost all seizure types and is especially helpful in the idiopathic generalized syndromes with more than one seizure type, such as juvenile myoclonic epilepsy; although effective for partial seizures, it is regarded by some as a second choice in partial epilepsies. Barbiturates are still in use, mainly for partial and generalized tonic-clonic seizures; the phenobarbital precursor primidone is also an important alternative to valproate for juvenile myoclonic epilepsy. Ethosuximide is the most selective antiepileptic drug, ineffective for partial or generalized tonic-clonic seizures but highly efficacious in treating absence seizures. Benzodiazepines can be useful in treating myoclonic and some other seizure types. All approved newer drugs have shown efficacy against

932

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Epilepsy

partial seizures, including those that secondarily generalize; felbamate and lamotrigine, and probably topiramate and zonisamide, are also useful against generalized seizures including myoclonic and absence. More detail regarding drug treatment is provided in Chapter 146. As discussed in Chapter 148, consideration for surgery is highly dependent on accurate syndrome classification, particularly as regards localization of the seizure focus. Finally, for the rare syndromes in which seizures occur only or mainly in response to a specific activity or stimulus, therapy sometimes can be based on behavioral techniques. In general, then, accurate diagnosis and classificationprovide the foundation for effective treatment.

SUGGESTED READINGS Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30:389, 1989

Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised clinical and electrographic classification of epileptic seizures. Epilepsia 22:489, 1981 Dam M, Gram L Comprehensive Epileptology. Raven, New York, 1991 Engel J Jr:A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 42796, 2001 Engel J Jr: Seizures and Epilepsy. FA Davis, Philadelphia, 1989 Liiders HO, Burgess R, Noachtar S: Expanding the international classification of seizures to provide more localizing information. Neurology 43:1650, 1993 Prasad AN,Prasad C, Stafstrom CE Recent advances in the genetics of epilepsy: insights from human and animal studies. Epilepsia 4013291352, 1999 Wyllie E: The Treatment of Epilepsy: Principles and Practice. 3rd ed. Lippincott Williams & W i n s , Philadelphia, 2001

146 Medical Treatment of Seizures Steven C. schachter Over the past 15 years, the concept of optimum therapy has evolved from complete control of seizures despite side effects and without regard for psychosocial problems to treatment that enables the patient to lead a life consistent with his or her capabilities. During that time, an unprecedented number of antiepileptic drugs (AEDs) and a device were developed for treating partial seizures, giving renewed hope to patients with suboptimal quality of life because of seizures or medication side effects. As a result, many patients who were unable to function to the best of their abilities because of seizures or medication side effects can now anticipate a full and useful life with the help of new medications and epilepsy surgery. Designing and implementing a management plan to optimize the quality of life for the patient with epilepsy requires an accurate, objective measurement of the patient’s seizure types, frequency, and severity; medication side effects; and psychosocial problems. This is an ongoing, often lengthy process that requires a working knowledge of available AEDs, AED pharmacokinetics, drug interactions, and drug side effects.

INITIATING TREATMENT Chronic therapy is not necessary if a first seizure is provoked by factors that resolve, such as a seizure caused by transient hypotension or an iatrogenic drug reaction. Although AED treatment generally is not started until after the second seizure, it may be appropriate to initiate AED therapy after the first seizure if the patient is considered to be at high risk for recurrence. Risk factors for recurrent seizures include a history of brain insult (e.g., head injury, stroke, encephalitis), a brain lesion on neuroimaging studies, lateralizing abnormalities on neurologic examination, a partial seizure as the first seizure, and an electroencephalogram with epileptiform abnormalities. Additionally, certain types of

seizures are more likely to recur, such as absence and myoclonic seizures.

TREATMENT STRATEGIES The first step is to establish the seizure type(s) within the framework of the seizure classification of the International League Against Epilepsy, as discussed in Chapter 145. Most patients experience more than one type of seizure (e.g., complex partial and secondary generalized), and identification of seizure types helps in selecting AED therapy. Direct questions often are necessary to probe for identification of seizure triggers, such as sleep deprivation, alcohol intake, and stress, because measures to limit exposure to these triggers may successfully augment AED therapy. Complete seizure control with minimal side effects can be achieved in approximately 40% to 60% of patients with singledrug therapy; with combinations of anticonvulsants, only an additional 10% to 15% of patients can expect seizure control without significant side effects. Even before therapy has begun, the physician should enlist the additional cooperation of the patient’s significant others in tracking seizure frequency and severity. By encouraging the patient to keep track of seizures, seizure triggers, and medications on a calendar, the clinician can ascertain whether seizures correlate with triggers such as stress or menses and also monitor compliance with the AED regimen. If the patient experiences any side effects, he or she can record the time of day they occur. Similarly, the clinician should monitor AED serum levels if an AED is started or stopped, if an AED dosage is changed, or if the patient experiences side effects or increased seizures. Table 146-1 shows the recommended initial treatment for the different types of seizures. If one AED is unsuccessful because of ineffectiveness or side effects, then a second AED may be tried. In general, it is preferable to maintain a patient on a single AED.

932

Behavioral Neurologyand Epilepsy

Epilepsy

partial seizures, including those that secondarily generalize; felbamate and lamotrigine, and probably topiramate and zonisamide, are also useful against generalized seizures including myoclonic and absence. More detail regarding drug treatment is provided in Chapter 146. As discussed in Chapter 148, consideration for surgery is highly dependent on accurate syndrome classification, particularly as regards localization of the seizure focus. Finally, for the rare syndromes in which seizures occur only or mainly in response to a specific activity or stimulus, therapy sometimes can be based on behavioral techniques. In general, then, accurate diagnosis and classificationprovide the foundation for effective treatment.

SUGGESTED READINGS Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30:389, 1989

Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised clinical and electrographic classification of epileptic seizures. Epilepsia 22:489, 1981 Dam M, Gram L Comprehensive Epileptology. Raven, New York, 1991 Engel J Jr:A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 42796, 2001 Engel J Jr: Seizures and Epilepsy. FA Davis, Philadelphia, 1989 Liiders HO, Burgess R, Noachtar S: Expanding the international classification of seizures to provide more localizing information. Neurology 43:1650, 1993 Prasad AN,Prasad C, Stafstrom CE Recent advances in the genetics of epilepsy: insights from human and animal studies. Epilepsia 4013291352, 1999 Wyllie E: The Treatment of Epilepsy: Principles and Practice. 3rd ed. Lippincott Williams & W i n s , Philadelphia, 2001

146 Medical Treatment of Seizures Steven C. schachter Over the past 15 years, the concept of optimum therapy has evolved from complete control of seizures despite side effects and without regard for psychosocial problems to treatment that enables the patient to lead a life consistent with his or her capabilities. During that time, an unprecedented number of antiepileptic drugs (AEDs) and a device were developed for treating partial seizures, giving renewed hope to patients with suboptimal quality of life because of seizures or medication side effects. As a result, many patients who were unable to function to the best of their abilities because of seizures or medication side effects can now anticipate a full and useful life with the help of new medications and epilepsy surgery. Designing and implementing a management plan to optimize the quality of life for the patient with epilepsy requires an accurate, objective measurement of the patient’s seizure types, frequency, and severity; medication side effects; and psychosocial problems. This is an ongoing, often lengthy process that requires a working knowledge of available AEDs, AED pharmacokinetics, drug interactions, and drug side effects.

INITIATING TREATMENT Chronic therapy is not necessary if a first seizure is provoked by factors that resolve, such as a seizure caused by transient hypotension or an iatrogenic drug reaction. Although AED treatment generally is not started until after the second seizure, it may be appropriate to initiate AED therapy after the first seizure if the patient is considered to be at high risk for recurrence. Risk factors for recurrent seizures include a history of brain insult (e.g., head injury, stroke, encephalitis), a brain lesion on neuroimaging studies, lateralizing abnormalities on neurologic examination, a partial seizure as the first seizure, and an electroencephalogram with epileptiform abnormalities. Additionally, certain types of

seizures are more likely to recur, such as absence and myoclonic seizures.

TREATMENT STRATEGIES The first step is to establish the seizure type(s) within the framework of the seizure classification of the International League Against Epilepsy, as discussed in Chapter 145. Most patients experience more than one type of seizure (e.g., complex partial and secondary generalized), and identification of seizure types helps in selecting AED therapy. Direct questions often are necessary to probe for identification of seizure triggers, such as sleep deprivation, alcohol intake, and stress, because measures to limit exposure to these triggers may successfully augment AED therapy. Complete seizure control with minimal side effects can be achieved in approximately 40% to 60% of patients with singledrug therapy; with combinations of anticonvulsants, only an additional 10% to 15% of patients can expect seizure control without significant side effects. Even before therapy has begun, the physician should enlist the additional cooperation of the patient’s significant others in tracking seizure frequency and severity. By encouraging the patient to keep track of seizures, seizure triggers, and medications on a calendar, the clinician can ascertain whether seizures correlate with triggers such as stress or menses and also monitor compliance with the AED regimen. If the patient experiences any side effects, he or she can record the time of day they occur. Similarly, the clinician should monitor AED serum levels if an AED is started or stopped, if an AED dosage is changed, or if the patient experiences side effects or increased seizures. Table 146-1 shows the recommended initial treatment for the different types of seizures. If one AED is unsuccessful because of ineffectiveness or side effects, then a second AED may be tried. In general, it is preferable to maintain a patient on a single AED.

Chapter 146 W Medical Treatment of Seizures

TABU 146-1. Recommended Pharrnacologic Treatment

for Different Seizure Types Second-Line or Adjunctive Therapy

Seizure Type

Initial Therapy

Primary generalized tonicclonic seizures

Valproate Phenytoin Oxcarbazepine* Carbamazepine Phenytoin Oxcarbazepine

Lamotrigine Carbamazepine* Topiramate Partial seizures with or Valproate without secondary Gabapentin generalization Lamotrigine Tiaga bine Topiramate Levetiracetam Zonisamide Absence seizures Valproate Lamotrigine Ethosuximide Myoclonic seizures Valproate Lamotrigine Mixed seizures (myoclonic Valproate Lamotrigine and tonic-clonic) Topiramate 'Oxcarbarepine (OXC) is a keto-analogueof carbamazepine(CBZ). OXC is less likely than CBZ to cause drug interactionsor be affected by hepatic dysfunction. In addition, rash occurs less frequently with OXC than with C B I as do other side effects such as drowsiness, dizziness, headache, double vision, nausea, vomiting, and ataxia. Hyponatremia is more commonly seen with OXC than with CBZ, although patients rarely are symptomatic

When the initial medication is determined to be ineffective, the second drug should be titrated to therapeutic level or dosage before the first AED is tapered. As previously stated, combinations of AEDs may be necessary in some patients. Almost all combinations of medications have been tried, although certain combina-

933

tions should be avoided, such as phenobarbital, primidone, and diazepam, because all three drugs are central nervous system (CNS) depressants. Side effects are a major cause of medication intolerance and noncompliance. Table 146-2 shows the common and rare side effects of the most prescribed AEDs. Information on the contraindications for each medication is available to the clinician from the manufacturer and should be consulted before prescribing. The AEDs differ in how easily and rapidly a loading dose can be administered, as shown in Table 146-3. This consideration is particularly important for patients with frequent seizures. Table 146-3 also presents the likely mechanism of action for each AED. Table 146-4 gives pharmacokinetic information, including frequency of dosing, number of days needed to achieve steady state, and frequency of initial monitoring (serum levels, liver function tests, renal function tests, and complete blood counts). The information presented in Table 146-4 applies to adults; therefore, physicians who treat children with epilepsy should consult prescribing information for correct dosing regimens. NONCOMPLIANCE WITH ANTIEPILEPTIC DRUG THERAPY When a patient's seizures are uncontrolled, the clinician must consider whether the patient is noncompliant, which is the most common reason for incomplete seizure control. Up to half of patients treated for epilepsy may not take their medications as directed, and more than half of patients seen in emergency rooms

TABU 146-2. Common and Rare Side Effects of Antiepileptic Drugs Neurotoxic Side Effects

Rare Idiosyncratic Reactions

Gingival hypertrophy, body hair increase, rash, lymphadenopathy

Confusion, slurred speech, double vision, ataxia, neuropathy (with long-term use)

Tegretol, Carbatrol

Nausea, vomiting. diarrhea, hyponatremia, rash, pruritus, fluid retention

Drowsiness, dizziness, blurred or double vision, lethargy, headache

Valproate

Depakote

Weight gain, nausea, vomiting, hair loss, easy bruising

Tremor

Felbamate

Felbatol

Gabapentin Primidone, phenobarbital

Neurontin Mysoline

Nausea, vomiting. anorexia, weight loss None known Nausea, rash

Ethosuximide

Zarontin

Nausea, vomiting

Insomnia, dizziness, headache, ataxia Somnolence, dizziness, ataxia Alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, dependence Sleep disturbance, drowsiness, hyperactivity

Agranulocytosis, Stevens-Johnson syndrome, aplastic anemia, hepatic failure, dermatitis or rash, serum sickness Agranulocytosis, Stevens-Johnson syndrome, aplastic anemia, hepatic failure, dermatitis or rash, serum sickness, pancreatitis Agranulocytosis, Stevens-Johnson syndrome, aplastic anemia, hepatic failure, dermatitis or rash, serum sickness, pancreatitis Aplastic anemia, hepatic failure

Lamotrigine

Lamictal

Rash, nausea

Dizziness, somnolence

Tiagabine

Gabitril

N/A

Topiramate

Topamax

Anorexia, weight loss

Oxcarbazepine

Trileptal

Levetiracetam

Keppra

Nausea, vomiting, hyponatremia, rash Anorexia

Zonisamide

Zonegran

Anorexia

Dizziness, weakness, ataxia nervousness, tremor, somnolence Confusion, cognitive slowing, dysphasia, dizziness, fatigue, paresthesias Drowsiness, dizziness, headache, double vision, ataxia Somnolence, dizziness, headache, nervousness Dizziness, ataxia, fatigue, somnolence, confusion

Drug

Trade Name

Systemic

Phenytoin

Dilantin

Carbamazepine

Side Effects

Unknown Agranulocytosis, Stevens-Johnson syndrome, hepatic failure, dermatitis or rash, serum sickness Agranulocytosis, Stevens-Johnson syndrome, aplastic anemia, dermatitis or rash, serum sickness Stevens-Johnson syndrome, hypersensitivity syndrome N/A Nephrolithiasis N/A N/A Nephrolithiasis

954

BehavioralNeurology and Epilepsy rn Epilepsy

TABLE146-3. Loading and Initial Dosing and Mechanism of Action of Antiepileptic Drugs Intravenousloading Dosage

Oral loading and Maintenance Dosage

Mechanism of Action

Dilantin

15 rng/kg (not more than 50 mg/min)

15 mg/kg in 3 divided doses over 9-1 2 hours; 5 mg/kg/day maintenance

Carbamazepine

Tegretol, Carbatrol

N/A

Valproate

Depakote

Start at 2-3 rng/kg/day in 2 divided doses; increase dosage every 3-5 days to 10 mg/kg/day in 3 divided doses; dosage may need to be further increased to 15-20 mg/kg/day after 2-3 months because of hepatic autoinduction 15 mg/kg/day in 3 divided doses; increase by 5-1 0 mg/kg/day every week as needed and tolerated

Blocks sodium-dependent action potentials; reduces neuronal calcium uptake Blocks sodium-dependent action potentials; reduces neuronal calcium uptake

Cabapentin

Neurontin

Ethosuximide

Zarontin

N/A

Barbiturates

Mysoline (primidone)

Lamotrigine

Lamictal

90-1 20 mg every 10-15 min as needed to maximum of 1000 mg N/A

Tiagabine

Cabitril

Topiramate

Topamax

Oxcarbazepine

Trileptal

Levetiracetam

Keppra

Zonisamide

Zonegran

D w

Trade Name

Phenytoin

300 mg first day, 300 mg bid second day, 300 mg tid third day; increase as needed to 1800 mg/day in 3 divided doses 20-40 mg/kg/day in 1-3 divided doses 1-5 mg/kg/day

For patients taking an enzyme-inducing AED, 25 mg bid titrated upward by 50-mg increments every 1-2 weeks as needed; for patients taking valproate, 25 rng every other day with increases of 25-50 mg every 2 weeks as needed to a maximum of 500 mg/day; maximum dosage used in U.S. open-label drug trials 700 rng/day 4-1 0 mg/day; increase 8-1 2 mg/day every 4 weeks until 20-60 mg/day maintenance in 2-4 divided doses 25-50 mg/day; increase 25-50 mg/day every 1-2 weeks until 100-1 000 mg/ day maintenance in 2 divided doses 150-300 mg/day; increase 300 mg/day every 3-5 days until 900-2700 rng/day maintenance in 2-3 divided doses 1000 rng/day; increase by 1000 mg/day every 2 weeks until 1000-4000 mg/day in 2 divided doses 100 rng/day; increase by 100 rng/day every 2 weeks until 400-600 mg/day in 1-2 divided doses

Reduces high-frequency neuronal firing; (?) blocks sodiumdependent action potentials; enhances CABA effects on CNS Unknown

Modifies low-threshold or transient neuronal calcium currents Prolongs CABA-mediated chloride channel openings; decreases CNS excitability Inhibition of voltage-dependent sodium channels, resulting in decreased release of the excitatory neurotransmitters glutamate and aspartate

Inhibits neuronal and glial reuptake of CABA Blocks sodium-dependent action potentials; attenuates kainateinduced responses; enhances CABAergic transmission Blocks sodium-dependent action potentials; reduces neuronal calcium uptake Not known Blocks voltage-dependent sodium and T-type calcium channels; inhibits release of excitatorv neurotransmitters

Abbreviation: CAB& y-aminobutyric acid.

because of recurrent seizures are noncompliant. Clinicians should suspect noncompliance if a patient does not accept the diagnosis, has limited financial means, has difficulty tolerating side effects, or forgets when or how to take medication because of frequent seizures or associated memory impairment. As is true of patients with other chronic illnesses, compliance on the part of patients with seizures decreases with increasingly long intervals between clinic visits and increasingly complicated medication regimens. Serum levels may help to monitor compliance, but the clinician should be aware that these levels might vary if medications are stored in or near a humid environment, if the patient takes generic medications from different manufacturers, or if there is a significant change in the patient’s weight. Furthermore, serum levels may fluctuate during the day, particularly those for valproate, and may vary for women during the menstrual cycle.

SIDE EFFECTS For most patients, monotherapy enhances compliance, provides a greater therapeutic window, and is more cost-effective than combination therapy; that is, there are usually fewer side effects, idiosyncratic reactions, and teratogenic effects, and no risk of AED interactions. Within the first 6 months of AED therapy, systemic toxicity and neurotoxicity are as likely to contribute to medication failure as lack of efficacy. As shown in Table 146-2, the neurotoxic effects of commonly used AEDs include diplopia, nystagmus, dysarthria, ataxia, incoordination, tremor, sedation, mood alteration, dizziness, headache, and cognitive impairment. The extent to which patients complain about side effects (e.g., cognitive side effects) depends on the patient’s level of functioning and perception of the physician’s willingness to listen. Detailed

Chapter 146 H Medical Treatment of Seizures

935

rn TABU 146-4. Pharrnacokinetic Information for Antiepileptic Drugs Frequency of Dosing

Frequency of Initial Monitoring

Therapeutic level (Irg/mL)

5-15 3-10

Qd or bid Bid, tid, or qid

2-3 weeks 3,6,9 weeks

10-20 4-12

6-1 8

2-4

Bid or tid

1-2 weeks

50-1 50

See package insert for detailed instructions None

32-1 37 2-3

Qd, bid, or tid Qd or bid Bid

2-3 weeks 3-4 weeks

40-1 00 10-40

None

Not established

Bid, tid, qid Bid Bid, tid

None None None (except sodium every 2-4 weeks in patients at risk for hyponatremia) None None

Not established Not established Not established

D w

Percentage Bound to Plasma Protein

Elimination Half-life (h)

Phenytoin Carbamazepine

90 70-80

15-30 11-1 7 (chronic

Valproate

60-95 (decreases

lime to Steady State (days)

therapy) with serum levels over 100 pg/rnL) Felbamate

25

20-23

5-10

Bid or tid

Cabapentin

0

5-7; increases with

1-2

Tid

decreased creatinine clearance (see prescribing information) Ethosuximide Phenobarbital Lamotrigine

0 40-60 50-55

40-50 30-50 10-15 with enzyrne-

6-1 2 16-2 1 5-1 5

inducing AEDs*; 40-60 with valproate Tiagabine Topiramate Oxcarbazepine

96 9-1 7 40

5-9 20-24 8-1 0

3 5-7 3-4

<10 Levetiracetam 7-8 Zonisamide 40-60 50-68 *Such as carbamazepine, phenytoin, and phenobarbital,

3-4 12-14

neuropsychologicaltesting (see Chapter 135) may help determine whether a patient’s complaint of memory loss or trouble concentrating is medication related and also whether a patient is functioning up to full potential. Adding an AED to an existing AED, that is, changing a patient from monotherapy to polytherapy, may increase AED side effects. For example, adding carbamazepine to phenytoin offers little benefit over either drug alone and may increase mean total phenytoin serum levels by 35% and decrease phenytoin clearance by 37%. The effects of adding one AED to another are outlined in Table 146-5. Combinations of anticonvulsants and other types of medications may also cause side effects. For instance, giving propoxyphene or erythromycin to a patient who is taking carbamazepine often elevates carbamazepine levels. The common AED-non-AED interactions are shown in Table 146-6.

Bid Qd, bid

Not established Not established

For patients who have peak level side effects from a particular AED, the usual strategy is to modify the medication regimen or treatment schedule to minimize side effects while maximizing seizure control and compliance, such as spreading out the dosage, using more frequent, smaller doses over the day. The physician should attempt to correlate drug serum levels with the patient’s side effects before abandoning that medication. Specifically, levels should be obtained when a patient is experiencing side effects and then compared with levels when the patient is free of symptoms. This comparison may help to prove a cause-and-effect relationship. Serum levels that are associated with neurotoxicity vary from one patient to another and may occur within the therapeutic range. Free serum phenytoin and valproate levels have clinical significance in managing patients with low albumin levels or patients who are taking multiple drugs that are tightly protein-

TABU 146-5. Common Antiepileptic Drug Interactions CarbamareDine

Phenvtoin

Valproate

Lamotrixine

Neurontin

Phenobarbital

AEDs that increase AED levels

Valproate Felbarnate (increases carbamazepine epoxide)

Felbamate

Valproate

None

Valproate

AEDs that decrease AED levels

Phenobarbital Phenytoin Primidone Felbamate

Valproate Diazepam (these may increase free and/or total phenytoin levels) Ethosuximide Felbamate Carbamazepine

Carbamazepine

Phenytoin Carbarnazepine

None

Carbarnazepine

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TABLE146-6. The Common AED Drug-non-AED Drug Interactions Carbamazepine

Phenytoin

Valpmate

Phenobarbital

Drugs that increase AED levels and/or enhance effects

Erythromycin Cimetidine Propoxyphene lsoniazid Calcium channel blockers fluoxetine valproate (may increase free level)

Aspirin Dicumarol

Antihistamines Tranquilizers Corticosteroids MA0 inhibitors Arnitriptyline lrniprarnine

Drugs that decrease AED levels

Warfarin Doxycycline Theophylline Haloperidol Oral contraceptives

Chlorarnphenicol Dicurnarol Disulfiram Tolbutarnide lsoniazid Phenylbutazone Aspirin Chlordiazepoxide Phenothiazines Estrogens Halothane Methylphenidate Sulfonarnides Trazadone Cirnetidine lsoniazid Chronic alcohol use

bound and should be multiplied by 10 to approximate the effective total serum level. In women with catamenial exacerbation of seizures, serum AED levels should be checked in the premenstrual period and compared with midcycle levels because anticonvulsant levels tend to drop during menses. When AEDs are withdrawn, special caution is warranted. Abrupt discontinuation of an AED may increase the risk of seizures and status epilepticus. Withdrawal from CNS depressants, such as phenobarbital and the benzodiazepines should be accomplished over weeks to months. A full discussion of the teratogenicity of AEDs is beyond the scope of this chapter. In general, women who take an AED have twice the risk of bearing a malformed infant. The risk is even higher for women who take multiple AEDs or who have a personal or family history of malformations. Features of the fetal anticonvulsant syndrome include limb abnormalities, craniofacial abnormalities, and growth and development abnormalities. Women planning a pregnancy should begin to take folic acid, 0.4 mg/day, before conception and throughout pregnancy. Women with a previous pregnancy complicated by a fetal malformation, such as a neural tube defect, should take 1 to 4 mg/day of folic acid and probably should avoid valproate and carbamazepine. Congenital malformations have been reported in association with all of the older AEDs; clinical experience with felbamate, gabapentin, lamotrigine, tiagabine, oxcarbazepine, levetiracetam, and zonisamide has not been sufficient to determine risk. As in every clinical situation, the physician must weigh the riskfbenefit ratio for treating epilepsy in a pregnant woman. NONPHARMACOLOGICTHERAPY Vagus Nerve Stimulation Vagus nerve stimulation (VNS) is approved for use as adjunctive therapy for adults and adolescents over 12 years of age whose partial onset seizures are refractory to antiepileptic medications. In practical terms, patients whose seizures continue to significantly interfere with their quality of life despite at least three trials of properly selected and dosed AEDs and who are otherwise not good candidates for resective cerebral surgery should be considered for VNS treatment.

As of early 2001, nearly 10,000 patients had been implanted with the Neurocybernetic Prosthesis VNS system worldwide. The system consists of a programmable signal generator that is implanted in the patient’s left upper chest; a bipolar VNS lead that connects the generator to the left vagus nerve in the neck; a programming wand, which uses radiofrequency signals to noninvasively communicate with the generator; and handheld magnets, which are used by the patient or caretaker to manually turn the stimulator on or off. The mechanism of action of VNS is uncertain. It has no effect on hepatic metabolic processes, serum concentrations of AEDS, or laboratory values and has no clinically significant effect on vagally mediated physiologic processes as measured by Holter monitoring, pulmonary function tests, and serum gastrin levels. The surgical approach to implanting the Neurocybernetic Prosthesis system is similar to performing a carotid endarterectomy or implanting a cardiac pacemaker. Most centers hospitalize patients for the implantation, although some centers perform the procedure as day surgery. The implantation procedure usually lasts approximately 1 hour and typically is carried out under general anesthesia to minimize the possibility that a seizure will affect the operation; however, others do the procedure using regional cervical blocks. Within the first 2 postoperative weeks, ramping up of the output current is initiated by the physician and adjusted to patient tolerance. A typical treatment regimen consists of adjusting the current output to a 30-Hz signal frequency with a 500ysec pulse width for 30 seconds of on time and 5 minutes of off time. Once programmed, the generator delivers intermittent stimulation at the desired settings until any additional programming instructions are received. In addition, the patient or a companion may activate the generator by placing the supplied magnet over the generator for several seconds; in some patients this may interrupt a seizure or reduce its severity if administered at the onset of the seizure. Approximately one-third of patients have a 50% or greater reduction in seizure frequency in association with VNS therapy. Improvement may not be seen for weeks to months after stimulation begins, for unknown reasons. Patients rarely become seizure free but in some cases may be able to reduce concomitant medications without significant loss of seizure control.

Chapter 146

Common treatment-related side effects are hoarseness, throat pain, coughing, dyspnea, and paresthesias. There have been no reported cognitive, sedative, visual, affective, or coordination side effects.

PSYCHOSOCIAL ISSUES The comprehensive treatment of patients with epilepsy includes dealing with the psychosocial aspects of this disorder. Even patients with infrequent seizures may be significantly affected by their disorder, particularly with regard to employment, driving, and insurance. Depression is particularly common. The physician should look for psychological and social problems that adversely affect the patient’s quality of life. This process begins with a complete psychosocial history, including previous psychiatric illness or treatment, education, employment, driving, insurance, interpersonal relationships, and attitude toward having epilepsy. A number of questionnaires have been developed for this purpose that supplement the psychosocial history and provide a quantifiable means of assessing and following patients as pharmacotherapeutic and psychosocial interventions are implemented. Uncovering a source of psychosocial stress may enable the clinician to reduce the impact of that stress on the patient, which in turn may help reduce seizure frequency.

DISCONTINUATIONOF TREATMENT The decision whether to discontinue seizure treatment is difficult because there is no reliable way to prospectively identify patients who will remain seizure free after discontinuing their treatment. Factors associated with an increased risk of seizure recurrence off drug therapy include known structural brain pathology (e.g., brain tumor, congenital anomaly, cerebral contusion), seizure onset after age 12 years, severe epilepsy before the start of drug therapy, specific epilepsy syndromes (especially juvenile myoclonic epilepsy), and multiple seizure types. Even patients with no risk factors who are seizure free for a number of years have a higher risk of seizure recurrence than the general population. Because this risk cannot be known exactly for any given patient and because the timing of seizure recurrence cannot be predicted, many patients elect to continue AED therapy rather than to risk recurrent seizures. Other patients are willing to take the chance of recurrent seizures because of AED-related side effects or the stigma associated with taking seizure medications. Therefore, the decision to taper and discontinue AEDs must be made on an individual basis, weighing the potential risk of seizure recurrence after discontinuing therapy against the patientperceived problems associated with continuing therapy.

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If the decision is made to withdraw therapy, carbamazepine and CNS depressants such as phenobarbital and the benzodiazepines should be discontinued gradually over weeks to months to minimize the likelihood of withdrawal seizures. Other drugs may be tapered over days to weeks. There are no general guidelines about driving restrictions during and after AED taper. Some clinicians suggest that patients refrain from driving until they have been seizure free off of medication therapy for the same interval of time that their state requires them to be seizure free before driving again.

CONCLUSIONS In most patients with epilepsy, an accurate seizure diagnosis and the appropriate selection and use of antiepilepticdrugs will lead to therapeutic success. In the remaining patients whose epilepsy is refractory because of ongoing seizures, medication side effects, or psychosocial issues, clinicians should carefully modify the treatment until the situation has resolved. In selected cases, nonpharmacologic treatments, such as vagus nerve stimulation, may be appropriate. Patients should be referred to support groups, individual or family counseling, educational guidance, and stress reduction techniques when appropriate. As new drugs with known mechanisms of action are introduced, the range of options for patients will further increase, and a rational approach to polypharmacy may emerge. Until then, cautious use of medications alone and in combination will minimize side effects and enable patients to achieve their potential within the limits of current therapy. As Lennox and Markham wrote more than 40 years ago, physicians who treat patients with epilepsy must “match modern drug and surgical therapy with practical sociopsychological therapy.”

SUGGESTED READINGS Kaneko S, Battino D, Andermann E et ak Congenital malformationsdue to antiepileptic drugs. Epilepsy Res 33(2-3):145-158, 1999 Kwan P, Brodie ME Early identification of refractory epilepsy. N Engl J Med 342(5):314-319,2000 knnox WG, Markham CH: The sociopsychological treatment of refractory epilepsy. JAMA 152:169&1694, 1953 Pellock JM: Standard approach to antiepileptic drug treatment in the United States. Epilepsia 35:Sll-S18, 1994 Schachter S C Advances in the assessment of refractory epilepsy. Epilepsia 34S2PS30, 1993 Schachter SC, Schmidt D Vagus nerve stimulation. Martin Dunitz, London, 2001

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147 Status Epilepticus Frank W Drislane

Fortunately, most epileptic seizures stop within minutes. If a patient has continuous seizures or does not recover between recurrent seizures that are so frequently repeated or so prolonged as to create a fixed and lasting condition, this is considered status epilepticus (SE). Traditionally, the term has been used after 30 minutes of continuous or repetitive seizures without recovery. With concern for eventual neuronal damage caused by SE, especially with generalized convulsions, several investigators have argued that 5 or 10 minutes should be the criterion for clinical diagnosis and decision making, and treatment should certainly begin by this time. SE has been recognized for centuries, but until the last few decades the term has been applied primarily to generalized convulsive seizures. Just as there are many types of epileptic seizures, there are many forms of SE. The simplest classification is that of convulsive or nonconvulsive status, but a description of syndromes based on partial (focal) or generalized seizure onset provides more insight into pathophysiology and clinical management (Table 147-1). GENERALIZED CONVULSIVE STATUS EPILEPTICUS Generalized convulsive status epilepticus (GCSE) is the most dramatic, dangerous, and best studied form of SE. It is potentially life-threatening but treatable in most cases, so it is important for the clinician to understand the causes, electrophysiology and pathophysiology, course, and consequences of GCSE. Having a plan for medical management and pharmacotherapy is crucial. Convulsive SE is readily recognizable. GCSE may start with focal or complex partial seizures but often begins with a generalized convulsion. Convulsions recur, and most last but a few minutes, with intervals of persistent unresponsiveness. Each convulsion may begin with a tonic phase with tensing of extensor

TMLE 147-1. Types of Status Epilepticus Generalized Generalizedtonic-clonic: grand mal, may be secondarily generalized from a focus Absence: petit mal, spike wave stupor Myoclonic Tonic: Pediatric; often with Lennox-Gastaut syndrome Clonic: Infants Partial (focal) onset Simple partial Motor: epilepsia partialis continua Sensory: rare, or rarely diagnosed; can be visual, olfactory Autonomic Psychic: fear, emotional content Aphasic Complex partial: includes impairment of consciousness Special types Neonatal and pediatric: includes electrographic status epilepticus of sleep, infantile spasms Subtle status

muscles and forced expiration, followed after several seconds by a clonic phase with gradually slowing clonic movements. Both phases usually are bilateral and symmetrical, although there may be a focal onset with head or eye deviation even without a unilateral motor onset in the limbs. Consciousness is impaired, at least from the time of tonic seizures. Less often, movement is continuous. In this case clonic movements eventually diminish, often with replacement by repetitive jerking movements of the eyes, eyelids, or facial muscles alone, sometimes with intermittent limb jerking. This constitutes subtle SE and implies continuing epileptic brain activity with a progressive decoupling of electrical and motor systems. Most estimates of the incidence of convulsive SE suggest about 60,000 cases each year in the United States, but population-based surveys suggest that it may occur a few times as often. The incidence of other forms of SE is even less well known. Convulsive SE is not a disease itself but rather a life-threatening manifestation of some underlying cause. Table 147-2 lists several causes of SE and combines results of several studies. Causes vary tremendously in different populations. For example, alcohol and drug-related SE generally are more common in studies from urban hospitals. Causes or precipitants of convulsive SE also differ in patients with known epilepsy compared with those presenting with acute, new illness. Table 147-2 focuses on adult cases. Congenital abnormalities and infection play a more important role in children, and SE is more common in children. Often, there is an interaction between acute systemic illness and earlier neurologic disease, including prior epilepsy and other earlier neurologic insults. Prior epilepsy often is assumed but is actually the case in about one third of patients with SE; 1% of patients with epilepsy have an episode of SE in a given year. Anticonvulsant withdrawal often is assumed in patients with prior epilepsy, although this may be less common than presumed. Physician-changed medication regimens may cause withdrawal seizures as often as patient noncompliance. Infections may have a direct role in epileptogenicity, but several antibiotics can also precipitate seizures and alter anticonvulsant metabolism. Newly added anticonvulsants may also alter the metabolism of others and lead to subtherapeutic levels of prior medications. The epidemiology of convulsive SE provides several important clinical lessons. First, there is usually an identifiable cause of SE, and this should be sought. Trauma, new or old vascular disease, metabolic derangements, drug toxicity (whether prescribed or recreational), and infection not only help to explain the SE but often determine the subsequent course and must be identified to be treated appropriately. Alcohol abuse and benzodiazepine withdrawal are other common contributors. Second, there is often more than one cause or precipitant; medication withdrawal, infection, or sleep deprivation may add to an earlier illness and precipitate convulsive SE. In some series, up to 50% of patients have either an infection or a recent medication change. Conversely, even in acute illness convulsive SE occurs more often in people with prior neurologic deficits. Third, despite the many known causes, patients may present with SE as the first sign of neurologic

Chapter 147 W

TABU 147-2. Causes of Status Epilepticus Percentage of Patients

Factor

Anticonvulsant withdrawal 25 Alcohol withdrawal 25 Cerebrovascular (including stroke, anoxia, hemorrhage) 22 Metabolic (acute encephalopathy, e.g., hypoglycemia, 22 systemic infection) Trauma 15 Drug toxicity 15 Central nervous system infection 12 Tumor 8 Congenital lesion 8 Prior epilepsy 33 No cause found 30 Percentagesadd up to more than 100% because of multiple causes (e.g., a patient with a congenital lesion and chronic epilepsywith anticonvulsant withdrawal or infection). Figures estimated from several sources.

disease. This is especially true in children, in whom up to 10% of initial seizures may be SE, particularly with febrile seizures. Convulsive SE can lead to numerous complications (Table 147-3). Autonomic changes can be severe and include hypertension, tachycardia, arrhythmias, diaphoresis, hyperthermia, and vomiting. Many of these changes are caused by increased sympathetic nervous system activity and circulating catecholamines. Hyperthermia may be a result of the excessive convulsive muscle contractions and a hypothalamic effect. The electrocardiogram may show conduction abnormalities or ischemic patterns. Autonomic dysfunction and cardiac arrhythmias may explain much of the mortality of SE and some other cases of unexplained sudden death in patients with epilepsy. Cerebral blood flow (CBF) and metabolism are elevated in early SE but decline eventually, and the excessive metabolic rate of discharging neurons may outstrip the oxygen and glucose supply. As seizures continue, autoregulation of CBF may break down, and this may contribute to cerebral edema, particularly in children. Many physiologic changes of early SE appear to reverse after about 30 minutes, with subsequent hypotension, hypoxemia, hypoglycemia, and increasing acidosis and hyperkalemia. Hypotension and bradycardia may be worsened by anticonvulsants and other medications. Cardiac arrhythmias may be precipitated by lactic acidosis and catecholamines. Hypotension or volume depletion may complicate medical and metabolic disorders or lead to venous stasis and even cerebral venous thrombosis.

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SE prompts cortisol and prolactin release, although prolactin stores may become exhausted and levels return to normal in prolonged SE. Leukocytosis and spinal fluid pleocytosis may occur, but this should not be attributed to the SE itself until infection or other inflammation have been excluded. Aspiration pneumonia is common if the airway is not protected. Respiratory failure probably is caused more often by medications than by SE itself. Nervous system complications of SE may include subsequent intellectual impairment. However, studies in this area generally are retrospective and include primarily patients who have had prolonged status, those with prior and substantial neurologic and intellectual impairment, and those on several anticonvulsants. SE may also prompt an exacerbation of a patient’s prior epilepsy. Finally, SE may lead to new chronic recurrent seizures; new epilepsy may follow 20% to 40% of episodes of SE and may be considered a consequence of the SE. In many cases, however, both the SE and the subsequent epilepsy may be caused by one or more underlying abnormalities rather than solely by the SE. Abundant experimental animal evidence shows that convulsive SE leads to neuronal damage caused directly by the neuronal epileptic activity. Systemic complications, especially hypotension, respiratory failure, and hypoxia, worsen the prognosis and contribute to cerebral damage. The cellular activity of SE releases excitatory amino acids, which are neurotoxic in excessive amounts. Experimental work using convulsant agents and electrical stimulation suggests that SE can cause hippocampal damage and subsequent recurrent seizures. Such neuronal injury is more difficult to substantiate in humans. At least after GCSE, there is evidence of hippocampal neuronal loss and atrophy, although it is unknown whether this follows other forms of SE. Experimental electrical stimulation produces similar damage after about 30 minutes, the same time at which human homeostasis appears to deteriorate during convulsive SE. Thus, both clinical and experimental data implicate 30 minutes as a critical time before which convulsive status should be interrupted. (Clinically, one should not wait for this to occur before treating.) Patients may also exhibit an orderly sequence of electroencephalographic (EEG) changes in SE, including discrete seizures, then merging seizures and eventual interruptions by flat periods (with markedly diminished voltage), and, finally, periodic discharges. Clinical convulsions abate as the electroencephalogram progresses. Patients in later EEG stages have seizures particularly refractory to the usual anticonvulsant medications and have a worsened prognosis. This suggests that these EEG signs of SE warrant

TABU 147-3. Complications of Status Epilepticus

Systemic Cardiac: hypertension, tachycardia (reversing after 30 min), arrhythmias, cardiac arrest Pulmonary: apnea, respiratory failure, hypoxia, neurogenic pulmonary edema, aspiration pneumonia Autonomic: fever, sweating, hypersecretion (including tracheobronchial), vomiting Metabolic: hyperkalemia, hyperglycemia, then hypoglycemia; volume depletion, venous stasis, and possible thrombosis Endocrine: increased prolactin and cortisol Other: leukocytosis, cerebrospinal fluid pleocytosis,vertebral and other fractures, physical injury, rhabdomyolysis, renal failure Brain Neuronal damage similar to that of hypoxia, hyperthermia: cortical layers 3 and 5,cerebellum, and hippocampus Cerebral edema, raised intracranial pressure Cortical vein thrombosis Neurologic sequelae .

Increased seizure frequency, recurrent status epilepticus Decreased cognitive function (?) May lead to recurrent seizures, epilepsy Drug effects; increased exposure to anticonvulsants

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aggressive treatment as the sign of continuing and damaging SE even if there are no associated motor phenomena. The electroencephalogram can show whether comatose patients are in a postictal state or still having seizures. This concern about ongoing nonconvulsive seizures after apparent control of GCSE often is pertinent. About 5% to 10% of patients with severe head injury or nontraumatic coma who undergo continuous EEG monitoring have evidence of ongoing SE without any motor manifestations. Similarly, several studies have found that 15% to 20% of patients who were thought to have had GCSE controlled by medications were still in nonconvulsive status when EEG testing was carried out. Despite the many complications, the disease underlying GCSE is the most important prognostic factor. No morbidity or mortality figure is worth reporting without a precise description of the population studied. Overall, however, the mortality rate has declined in recent decades and, with reasonable treatment, should be below 2% from the SE itself. The mortality rate of the condition causing GCSE may be substantially higher. Anoxia, stroke, drug toxicity, central nervous system infection, and severe metabolic derangements predict a worse outcome. Tumors and head injury vary in prognostic gravity depending on the series. SE caused by alcohol abuse or drug withdrawal has a better outcome. A long duration of SE, especially with systemic complications of hypothermia and hypotension, and delayed effective treatment also worsen outcome. Patients unresponsive to initial treatment with one or two anticonvulsants (patients with refractory SE) have a worse prognosis. It has become increasingly clear that SE is almost two different conditions in patients with prior epilepsy and in those with a new diagnosis. Patients with prior epilepsy and those with a precipitation by anticonvulsant or other medication withdrawal do far better. This may be because of earlier detection and diagnosis, partial treatment from earlier anticonvulsants, or the absence of acute insults that worsen the prognosis in other patients. Children also fare much better than adults; older patients often are susceptible to underlying illnesses with a higher morbidity and mortality. Clinical lessons also emerge from the pathophysiology and prognostic studies of convulsive SE. First, the longer the SE, the more refractory it becomes and the more neuronal damage occurs. Second, although systemic factors including hypotension, hypoxia, and acidosis may add to the neurologic complications, some damage appears to accrue from the synchronized discharging neural activity itself. Persistent EEG discharges generally are an indication for treatment. Therefore, the electroencephalogram is necessary when convulsions have ended and patients have not awakened. Third, clinical and experimental data suggest that 30 minutes of convulsive SE is a critical duration in neurologic function and probably in prognosis. This figure is far less certain in other, particularly nonconvulsive, forms of SE. OTHER TYPES OF STATUS EPILEPTICUS Convulsive SE is rarely a diagnostic problem, but other forms of SE may present less dramatically on general medical or surgical wards or even in outpatient settings, and diagnosis becomes more important. Management often is similar but less urgent. Other forms of SE can be divided into generalized seizures and those with a partial or focal onset.

Generalized Forms of Status Epilepticus Absence (Petit Mal). Terminology in this area is confusing, with descriptions of spike wave stupor and epileptic twilight states. Absence status implies generalized epileptiform EEG discharges (Fig. 147-1). Because of the difficulty of detection, it is hard to know how often absence status occurs. It may be one fourth as common as convulsive SE. It typically occurs in patients with prior genetic primary generalized epilepsy, but patients may be otherwise healthy, seizure-free, and off medication for years. It may present to the office physician as confusion and limited responsiveness in an older person with a remote history of epilepsy and no recent treatment, sometimes with infection or other systemic illness. Older patients have more de now absence SE. Metabolic and pharmacologic precipitants exist, and benzodiazepine withdrawal is particularly common. Persistent epileptic unresponsivenesswith generalized EEG discharges also explains some persistent coma after generalized convulsions. Onset of absence SE may be sudden or gradual. Patients may be awake, walking, and talking (even as the electroencephalogram shows ongoing epileptiform discharges), although they are often confused. Motor activity may be preserved but clumsy. There is occasionally some blinking or sporadic myoclonus. Absence SE can persist for days or weeks without recognition. A history of earlier epilepsy is suggestive. It is entirely possible that most cases are missed, although the diagnosis is readily confirmed by electroencephalogram. The electroencephalogram may show generalized 3-Hz epileptiform discharges, although some seizure activity may be secondarily generalized from a focus. Especially in younger patients with primary generalized epilepsies, benzodiazepine treatment often is immediately successful. Valproic acid may be more efficacious in preventing recurrences. Most patients return to normal, although recurrence of absence SE is common. In older patients and those with a less certain cause, the response to anticonvulsants can be delayed. The typical absence status of patients with prior epilepsy is not lifethreatening, although occasional episodes end with a generalized convulsion. Myoclonic Status Epilepticus. Myoclonic status epilepticus (MSE) also occurs in several forms. The most severe is that following anoxia, essentially always a fatal condition. Persistent myoclonus caused by a severe encephalopathy without MSE is potentially reversible. The electroencephalogram helps to determine whether myoclonus is the marker of an encephalopathy (with sporadic, nonrhythmic sharp wave discharges) or part of MSE (with electrographic seizure activity). The former has a better prognosis. At least after anoxia, MSE is best considered the sign of a severely damaged brain rather than a treatable epileptic condition. MSE may have motor manifestations limited to subtle status, also an ominous sign after anoxia. MSE as a manifestation of generalized epilepsies such as juvenile myoclonic epilepsy, on the other hand, may include prolonged epileptic myoclonus without loss of consciousness. The electroencephalogram shows generalized polyspike and slow wave discharges with a normal background between episodes. Episodes may go on for hours (with preserved consciousness), but the prognosis is excellent given the prior normal neurologic function. Similarly, patients can return to baseline in the MSE of progressive myoclonus epilepsies, although this may be part of a progressive debilitating neurologic disease in the long run. In all of these

Chapter 147 H Status Epilepticus

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FIG. 147-1. Electroencephalogram of a 33-year-old woman with a history of epilepsy, now ambulatory and speaking but confused at the time of an office visit; approximately 3-Hz generalized spike and slow wave discharges with a frontal and central emphasis.

conditions the electroencephalogram can help distinguish MSE from encephalopathies with less rhythmic abnormalities. Tonic Status Epilepticus. Tonic SE is rare and is seen primarily in children, particularlywith Lennox-Gastaut syndrome. Treatment of the potentially injurious seizures often is frustrating, as is the associated mental retardation. Rarely, benzodiazepines have been cited as triggering tonic status. Tonic (and atonic) SE is distinctly uncommon in adults and certainly in those with normal neurologic function interictally. Similarly, another form of SE, generalized clonic SE, is a pediatric condition. Clonic activity often is of low amplitude; both sides of the body usually are involved but may move asynchronously. Status Epilepticus wlth a Partlal (Focal) Origin Epilepsia Partialis Continua. The most readily recognized focal SE is continuous regular muscle jerking, or epilepsia partialis continua (EPC). EPC signifies involvement of motor cortex. Focal SE implies focal pathology, and tumors, acute vascular disease (such as vasculitis or new strokes), and infectious diseases, particularly encephalitis, are among the most common causes. Old epileptogenic lesions can be activated by a new metabolic, infectious, or other stress, such as hyponatremia or renal failure. Nonketotic hyperglycemia is particularly common. Trauma and mitochondrial disorders are other possible causes, and occasionally children with Rolandic epilepsy have continuous motor symptoms with a presumed genetic origin. EPC is also seen in progressive lesions such as a Rasmussen’s encephalitis, possibly caused by a “smoldering” viral infection and generally limited to

children and adolescents. Most episodes of focal SE do not generalize. Whether EPC leads to significant neuronal damage is controversial. Partial Status Epilepticus Without Motor Activity. Other forms of partial status without motor activity are rarely diagnosed. It is unclear whether the neural substrates involved are less vulnerable to epileptic processes or whether this is a failure in diagnosis. One example is aphasic status, in which patients may appear similar to those with Wernicke’s aphasias of embolic vascular origin, although many are not as fluent. Continuous EEG discharges are almost always in the left hemisphere, particularly in posterior temporal (or frontal) areas. Simple speech arrest is more common but is not, strictly speaking, an aphasia. Speech arrest occurs in many different types of seizures, particularly those of frontal lobe origin. Persistent visual hallucinations and eye movements may be seen with occipital SE. Prolonged sensory symptoms, including autonomic symptoms, can also occur in partial SE, but ictal discharges may be difficult or impossible to record. A high index of suspicion, ready use of the electroencephalogram, and a response to anticonvulsants are the keys to diagnosis and treatment. Complex Partial Status Epilepticus. Complex partial status epilepticus (CPSE) implies an impairment of consciousness from seizures with a focal origin, sometimes called fugue states or psychomotor status. Confusion is the most common symptom. A sudden alteration in behavior, particularly in a patient with prior epilepsy, should raise this possibility. Although the diagnosis often is invoked to explain bizarre behavior, it is relatively uncommon,

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Epilepsy

especially in patients without known epilepsy. Some patients may have complex partial seizures with a prolonged postictal phase. CPSE may be continuous or include frequent discrete seizures without recovery between them. CPSE can go on for weeks. The usual site of origin is assumed to be mesial temporal structures with limbic connections, but implanted electrode recording has shown that frontal lobe onset is common. The electroencephalogram may show the seizure clearly (though less likely in frontal areas without implanted electrodes) or may have just persistent focal slowing. Seizures may spread rapidly, and nonconvulsive SE with generalized discharges (“absence SE”) may actually arise from a focus. CPSE can be very difficult to distinguish from absence SE. Patients with CPSE may exhibit more bizarre behavior during seizures, leading to confusion with psychiatric disease or metabolic encephalopathies with delirium. CPSE must be stopped, but not as urgently as GCSE. Most CPSE responds rapidly to anticonvulsants, but it may recur even with adequate therapy. Nonconvulsive Status Epilepticus. Nonconvulsive status epilepticus (NCSE) includes many of the syndromes described earlier in this chapter. Most patients have generalized, absence SE; fewer have CPSE. SE with simple partial sensory or autonomic symptoms and all SE without convulsions are included in NCSE. Most classification systems separate NCSE into absence SE, with continuous, generalized epileptiform discharges on the electroencephalogram, and CPSE, with continuous or recurrent discrete complex partial seizures. Altogether, NCSE probably constitutes about 25% of all SE. Whatever the EEG type, patients may present with confusion or even coma, and many cases are missed or misdiagnosed at the beginning or even permanently. There is a great failure of diagnosis. NCSE is common after convulsions or GCSE that have appeared to come under control with anticonvulsant treatment but with the patient still unresponsive. Although some patients have been treated successfully based on clinical suspicion, the electroencephalogram is crucial in confirming the diagnosis and in assessing the response to treatment. There is little evidence of permanent neurologic damage from NCSE in humans, but several patients with prolonged CPSE have had lasting memory deficits, and NCSE can lead to injuries or generalized convulsions. Treatment probably is somewhat less urgent than with GCSE, but the illness still has morbidity and should be diagnosed and treated promptly. Electrographic Status Epilepticus. There are also patients with electrographic status epilepticus (ESE) in whom the significance of the continuous epileptic discharges on electroencephalogram is unknown or controversial. Children with ESE during sleep may have no clear clinical concomitant, but most have mental retardation and epilepsy. Many have markedly impaired language function. In waking, they tend to be healthier than those with Lennox-Gastaut syndrome. Medications may improve the electroencephalogram without affecting overall health, cognition, or behavior. ESE during sleep can be associated with neuropsychologic regression after previously normal development. ESE may also be seen in adults, in some cases representing absence SE or after GCSE. In some other cases it may be an unexpected finding in patients with severe medical illnesses and encephalopathies. Some of these patients have subtle motor phenomena, but in others coma is the only manifestation. Diagnosis rests on the electroencephalogram. Anticonvulsant treatment can be helpful in some patients but may be unrewarding in others, primarily because of the severe underlying illness.

TREATMENT As in all areas of medicine, effective treatment is facilitated tremendously by the correct diagnosis. Convulsive SE is rarely a diagnostic difficulty, but NCSE, including that occurring after generalized seizures, may be difficult to recognize and may be missed altogether. Conversely, not all that shakes and responds poorly to medication is SE (Table 147-4). Movement disorders, including chorea, myoclonus, tremors, and tics, have all been treated as SE, with potentially greater harm from the treatment than from the disease. Pseudostatus is particularly troublesome. Further complicating diagnosis, these nonepileptic episodes often occur in patients who have epileptic seizures as well. Out-of-phase limb movements and more complicated vocalizations correlate with nonepileptic spells. Iatrogenic morbidity is common in these patients, and spells may persist until treatment causes respiratory arrest. Recurrence is common. Psychiatric management is appropriate but not always successful. Clinical Evaluation

The history often provides some reason for SE (Table 147-2). A history of trauma, drug overdose, alcohol use, medical illness, stroke, or epilepsy may be available through family members, companions, medical bracelets, and personal possessions. Physical examination focuses on the underlying cause of SE and localization of the neurologic abnormality. Vital signs are crucial given the cardiovascular complications; respiratory failure is an occasional complication of SE but more often results from medications. The general examination can show signs of infection (by fever, nuchal rigidity, or skin lesions) or systemic illness such as kidney or liver disease. Signs of head injury or coagulopathy are also important. The neurologic examination also assesses whether seizures are continuing in subtle ways. Laboratory Studies

Appropriate laboratory studies include a search for metabolic abnormalities, particularly of sodium, calcium, magnesium, and glucose; kidney, liver, and coagulation assays are also important. Toxicology screen, anticonvulsant levels, and arterial oxygen tension often are helpful, but treatment must begin before levels

W

TABLE147-4. Differential Diagnosis of Apparent Status Epilepticus

With prominent motor abnormalities Movement disorders: myoclonus, tremors, chorea, tics, dystonia Structural disease: decerebrate, decorticate posturing Psychiatric:pseudoseizure/convenion, acute psychosis Usually ”nonconvulsive“ Epilepsy-related: postictal state, periodic lateralized epileptiform discharges, with acute structural lesions Acute encephalopathies Toxic: drug and alcohol related Metabolic (e.g., hypoglycemia, delirium related to drugs, alcohol, or infection) Psychiatric: catatonia, acute psychosis Sleep disorders: narcolepsy, cataplexy, parasomnias Syncope: cardiac, vagal, hypovolemia, medication toxicity Vascular: strokes, transient ischemic attacks Head injury: stupor, coma, amnesia Transient global amnesia

Chapter 147

are known. The blood gas and prolactin level can be useful in the consideration of pseudoseizures. Women of childbearing age should have a pregnancy test, in part for counseling with regard to the effects of SE and medications on the fetus. When pregnant, women should be assessed for eclampsia. Urgent computed tomography scans or magnetic resonance imaging are prompted by concerns about head injury, an asymmetric neurologic examination, or seizures with a focal origin. Any source of infection must be found. Lumbar puncture is mandatory with any suggestion of central nervous system infection or when SE is of unknown cause or difficult to control. GCSE is diagnosed without an electroencephalogram, and treatment begins without it. An electroencephalogram is necessary for diagnosis of NCSE, although treatment may begin based on clinical suspicion. An electroencephalogram is mandatory when a patient does not recover after initial treatment because it may be impossible to ascertain clinically whether the patient is postictal or still seizing. Medical Management

Treatment begins as in other emergencies, with attention to airway, breathing, and circulation. Patients with GCSE or coma from other forms of SE usually need intubation, at least for airway protection. Physical safety and prevention of further injury must be ensured. A soft oral airway is reasonable, but forced insertion or use of hard objects is not. Thiamine and a bolus of 50% glucose should be infused after establishment of a reliable normal saline intravenous line. Cardiac monitoring should continue, looking for arrhythmias and ischemia. The aims of medical management include normalization of blood pressure, volume status, temperature, ventilation, and oxygenation. Magnesium is appropriate for alcoholic or malnourished patients; hypomagnesemia may worsen seizures, although magnesium is not an anticonvulsant. Drug overdoses may prompt gastric emptying or even hemodialysis.

AnticonvulsantTherapy The choice of anticonvulsant medications in SE is still controversial. Few studies have compared different medications, and it is important to stress that most describe GCSE alone. The generalized nonconvulsive status that follows clinical convulsions probably should be considered a continuation of convulsive SE and just as much of an emergency as GCSE. Other forms of SE are of less certain morbidity and urgency. Almost all published protocols and guidelines refer to GCSE; differences regarding other forms of SE will be pointed out. Medication use is generally similar, if less urgent. Nevertheless, other forms of SE can lead to convulsions, and a casual approach is inappropriate. A recent, controlled, rigorous trial of anticonvulsant medication regimens for GCSE tested four regimens: phenytoin 18 mg/kg, lorazepam 0.1 mg/kg, phenobarbital 15 mg/kg, and diazepam 0.15 mg/kg followed by phenytoin 18 mg/kg. With clinically evident (or overt) SE, control of seizures by the first drug administered ranged from 44% to 65%, with the lorazepam treatment the only one with statistical superiority. Rather than trying to choose the best anticonvulsant for all cases of SE, it may be more useful to consider medications in two classes. One is that of very rapidly acting anticonvulsants, largely limited to benzodiazepines, which often are necessary for the interruption of SE, especially when the physiologic and pathologic consequences of GCSE are imminent. Benzodiazepines are invalu-

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able in interrupting continuous seizures but may not be necessary when seizures are discrete, even with incomplete recovery. The other medications (particularly phenytoin and phenobarbital but also most other anticonvulsants) work less rapidly but provide continued protection against the reemergence of SE and are almost always necessary after the first few minutes. The goal must be to stop continuous convulsions or other symptoms and to interrupt continuing EEG discharges. Phenytoin. Phenytoin may be the most frequently used anticonvulsant for SE but is often given in inadequate doses. Its major disadvantage is the long time of a loading infusion (Table 147-5), although it may be beneficial before reaching therapeutic levels. The advantage of minimal sedation from medication alone is generally overstated but may be pertinent with head trauma, hemorrhage, or raised intracranial pressure, where it is important to monitor alertness. Patients with GCSE are unconscious, and the most immediate concern is stopping the seizures. In the absence of acute structural lesions phenytoin may be successful alone in as many as 80% of patients with GCSE. It can then become a long-term maintenance medication without changing or adding drugs. Patients may need adjunctive benzodiazepines to interrupt convulsions if they occur during the phenytoin infusion. Many neurologists use phenytoin as the primary treatment of GCSE, sometimes after initial interruption of convulsions with a benzodiazepine. A usual loading dose is 15 to 18 mg/kg, but 20 mg/kg is preferable before concluding that phenytoin is insufficient. It should be given by intravenous bolus or in saline solution at a maximum rate of 50 mgminute; it may precipitate in glucose solutions. Intramuscular phenytoin is poorly absorbed and should not be used. Conduction defects, while rare, are the most worrisome cardiac toxicity, but hypotension is not rare. Cardiac monitoring is appropriate during phenytoin infusion. Older adults or patients with cardiac disease may not tolerate phenytoin as well as phenobarbital. Acute toxicity is more closely related to the infusion rate than to total dose; patients with possible complications may tolerate greater doses in slower infusions. Fosphenytoin. Fosphenytoin a new prodrug that is cleaved by serum phosphatases rapidly to phenytoin. The prodrug’s greater solubility in saline obviates the propylene glycol carrier used for phenytoin and may avoid much of the toxicity. Fosphenytoin can be given three times as fast (150 mg phenytoin equivalent/ minute). The faster administration and diminished toxicity make fosphenytoin preferable to phenytoin in the setting of SE. It has been demonstrated to cause fewer episodes of venous thrombosis and less tissue damage near the infusion. It may cause fewer cardiac arrhythmias, although this has not been shown conclusively yet. Phenobarbital. Phenobarbital is often used if phenytoin is insufficient. It is often avoided for fear of sedation, but its advantages include a lack of cardiac toxicity until very high dosages are reached. Aside from phenytoin, it is the major anticonvulsant available intravenously for longer-term management. Up to 20 mdkg is reasonable. Loading is faster than with phenytoin, but its lipid solubility is lower and brain penetration slower. Nevertheless, phenobarbital may act quickly, even before typical therapeutic levels are established. In addition, although some SE may be refractory to phenytoin, high enough doses of phenobarbital will control almost all seizures. Very high dosages necessitate artificial ventilation and may cause hypotension, but they may be tolerated better than expected. Sedation is expected

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TABLE147-5. Anticonvulsant Properties in Status Epilepticus Treatment Medication

Dosages

Kinetics

Comrlications

Comment

Phenytoin

15-20 mJkg <50 mg/min Maintenance level ? 20 pg/mL 15-20 mg phenytoin equivalent& 4 5 0 mg equivalent/min 10-20 mg/kg 4 0 0 mg/min Maintenance level ? 40 pg/mL 10 mg (0.1 5 mg/kg) Repeat ql5min; up to ? 40 mg; <5 mg/min

Effect in 10-30 min Peak effect: 1 hr Eliminationtl12: 24-48 hr Converts to phenytoin in minutes

Cardiac arrhythmias Hypotension Phlebitis, tissue necrosis at IV site Fewer side effects (proven for infusion site)

Bolus lasts 6-24 hr Best for following level of consciousness Worse for cardiac disease Faster loading than with phenytoin

Effect in 5-20 min Peak in 1 hr Elimination2 lf: 120 hr

Respiratory depression, hypotension (possible synergy with benzodiazepines)

Effect in 1-2 min Peak 20-30 min Metabolite tl12:36 hr

Lorazepam

5-10 mg (0.1 mg/kg) <2 mg/min

Effect 2-5 min Peak 15-30 min Elimination tl12: 12-1 5 hr

Sedation, respiratory depression, hypotension Recurrent seizures as it wears off Same as diazepam; less sudden

Valproic acid

Load: 20-40 mg/kg; <6 me/ kg/min; Maintenance: 5 mg/kg/hr Load: 3-5 mg/kg Maintenance: 1-5 mg/kg/hr

Effect time uncertain Serum tl12: -10 hr

Few; hypotension is rare

Effect: minutes Elimination t,12: 20-40 hr

Respiratory depression More severe hypotension Hypothermia

Midazolam

Load: 0.2 mg/kg bolus Maintenance: 0.1 -0.6 me/ kJhr

Effect: 3-5 min Peak 30 min Elimination t,,2: 1.5 hr

Same as diazepam

Propofol

Load: 1-2 mg/kg over 5 min Maintenance: 2-1 0 ma/ kJhr

Effect: 2-4 min Cleared rapidlv; seizures recur 5-1’0 min

Sedation, resolves quickly Lipid load

Slower than benzodiazepines Depression of consciousness can be prolonged after loading Very rapid interruption of convulsions Must be followed by maintenance anticonvulsants More prolonged protection, up to 12 hr, against seizure recurrence No active toxic metabolites No major sedation Can be used as maintenance, PO Uniformly effective High mortality caused by underlying disease Duration of treatment unknown (? 24 hr) Very rapid Possibly the best IM drug Seizure recurrence if stopped quickly Rapid control and cessation without prolonged sedation; should be tapered

Fosphenytoin

Phenobarbital

Diazepam

Pentobarbital

-

with high doses, but levels below 40 pg/mL should not produce prolonged coma. Phenobarbital has been compared favorably with a combination of diazepam and phenytoin in one prospective trial; clinical response was faster with phenobarbital. Barbiturates and benzodiazepines may be particularly likely to cause respiratory depression and hypotension when used together. Diazepam. Diazepam can interrupt convulsive SE rapidly but should not be used alone. Usual practice is to administer 10 mg intravenously over a few minutes, repeating if necessary. Rectal administration has been effective, particularly in children. Intramuscular diazepam is absorbed slowly. Diazepam is very lipid soluble, enters the brain rapidly, and may have an anticonvulsant effect within a minute. Nevertheless, it redistributes to many tissues, and its central nervous system effect declines in 20 to 30 minutes; recurrent seizures or SE are common when longer-acting anticonvulsants are not used concomitantly. Repeated doses may lose effectiveness but produce metabolites with prolonged elimination half-lives and potential toxicity, including prolonged coma. Continuous infusion of diazepam (generally 4 to 8 mg/hour) is often discussed for the management of SE but is rarely practiced, probably because the best doses have not been established clearly, and rapid acute tolerance may develop. Continuous infusion should be used only in intensive care units. Iatrogenic apnea can occur suddenly; it is often ascribed to seizures or to “tongue swallowing.”

Benzodiazepines (BDZs) are particularly effective in typical absence SE, and subsequent longer-term anticonvulsants may be unnecessary. For patients with continuous generalized discharges and coma, however, they are not as efficacious. Diazepam is a very common first treatment for SE, but conservative management would limit it to patients with continuing convulsions or those having another convulsion during infusion of a maintenance medication. Different reviews have found diazepam effective in 38% to 83% of SE. Lorazepam. Lorazepam has several advantages over diazepam. It may be rapid enough to interrupt seizures quickly and s t i l l have a more prolonged anticonvulsant effect; some believe that it satisfies the requirements for both the acute interruption of SE and prolonged protection against recurrence. Initial doses typically are 5 to 10 mg intravenously. Its lipid solubility is half that of diazepam, and its brain penetration is slower, but it is still rapid. Its effect declines less rapidly than that of diazepam, and it has no active, troublesome metabolites. Many epileptologists prefer lorazepam because of its favorable pharmacokinetics, but direct comparative studies are few. A double-blind, randomized trial found lorazepam marginally more effective than diazepam in controlling SE, with an onset of action not significantly different. Adverse effects are similar to those of diazepam, though perhaps less sudden. Lorazepam may provide 12 hours of anticonvulsant effect, but acute tolerance may occur and reduce its maintenance value.

Chapter 147 w

Clonazepam. Clonazepam appears to be similar to other BDZs and is popular in Europe but is not available in intravenous form for SE treatment in the United States. Valproic Acid. Valproic acid is a standard oral anticonvulsant, also available in rectal and intravenous forms for SE treatment. Intravenous valproate may be loaded with 20 to 40 mg/kg over 5 to 10 minutes, sometimes followed by a continuous infusion of 5 mg/kg/hour. Hypotension appears to be infrequent. Its effectiveness has not been compared with that of other medications, but it appears very promising. Rectal doses of 17 mg/kg have been recommended. Peak concentrations may lag by hours, and the effect may be even more delayed. Many patients never achieve therapeutic levels by this route. Enteral valproate may also be a useful adjunct in the long-term treatment of refractory or intermittent SE and is helpful in preventing the recurrence of absence SE. Carbamazepine. Enteral carbamazepine may be useful in long courses of refractory seizures, but the drug is not available intravenously or helpful acutely in SE. Paraldehyde. Paraldehyde has fallen out of favor in clinical trials but remains a popular alternative, especially in patients with allergies to other anticonvulsants and those in whom intravenous access is limited. A dose of 5 to 10 mL may be given rectally, mixed with mineral oil. Intramuscular use yields a faster effect but may produce sterile abscesses. The physical preparation is important because of its rapid decomposition and reaction with plastic and rubber tubing. Its onset of action is slower than for medications described earlier. The effective half-life of paraldehyde is 6 hours. It may be more effective for SE prompted by alcohol withdrawal, but this has not been studied well. Oral administration in the setting of possible aspiration can lead to serious pulmonary toxicity. It is no longer available widely. Its unpleasant smell accounts for some of its unpopularity. Lidocaine. Lidocaine can have a rapid effect without significant respiratory depression. Several reports describe success in focal motor SE. At higher doses, however, it can also cause convulsions and must remain a last resort. Newer Anticonvulsants. Felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide are not currently available intravenously and have not been studied well for SE.

Therapy for Refractoy Status Epilepticus When SE does not respond to initial anticonvulsants, it is considered refractory SE and warrants more aggressive treatment. In such a case, GCSE may have continued for 30 minutes, or another form of SE is considered refractory. Definitive treatment may come in several forms. Pentobarbital. Pentobarbital (or thiopental) can provide a definitive treatment for refractory SE. Short-acting barbiturates are rapid but necessitate intensive care unit treatment. Loading doses of 3 to 5 mg/kg followed by infusion of 1 to 3 mg/kg/hour are typical; some studies suggest that many patients need at least 3.5 mg/kg/hour. Effectiveness is measured as the effect on the electroencephalogram, with an attempt to eliminate seizures or aim for a burst suppression or flat record; most reviewers seek a burst suppression pattern. The half-life of pentobarbital is approximately 20 hours but may be extended at higher levels. Accordingly, prolonged coma after pentobarbital treatment should not be attributed to a “burnt out” brain before the medication has had time to dissipate. Pentobarbital levels are more useful to

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indicate residual toxicity than they are in assessing therapeutic effect. All SE should be suppressible with adequate pentobarbital dosages, but hypotension is very common. Usually, volume replacement and low doses of vasopressors are sufficient. Myocardial function and temperature regulation can be impaired. Most reports of pentobarbital use show a very high mortality, usually attributed to the severe underlying diseases causing SE refractory enough to necessitate pentobarbital. An advantage of pentobarbital, besides its invariable effectiveness when used in large enough doses, is a reduction of cerebral metabolism and blood flow. The infusion is also easy to adjust. The optimal duration of barbiturate-induced coma has not been established. Recommendations range from 4 to 72 hours; at least 24 hours may be helpful. Patients probably should have therapeutic levels of two other anticonvulsants before pentobarbital withdrawal. Midazolam. Midazolam has proved successful in some particularly refractory cases of SE after failure of other BDZs and phenytoin. In such cases it may avoid some adverse effects of barbiturate-induced coma. A single bolus of 0.2 mg/kg (10 to 15 mg) can be given intravenously or intramuscularly and produces an effect within 5 minutes by either route. One or two boluses may be followed by an infusion of 0.1 to 0.6 mg/kg/hour. Midazolam may be the best medication for SE when an intramuscular route is needed, and its long-term continuous infusion may be preferable to that of diazepam or lorazepam because the other BDZs have longer half-lives and may build up lasting effects. After prolonged administration (over days) midazolam’s half-life and sedating side effects may be prolonged. Unfortunately, some patients do not respond to midazolam, and others may develop tachyphylaxis, as with other BDZs. Its high lipid solubility makes it extremely rapidly acting, but the half-life is also very short (elimination half-life, 1.5 hours); this confers a risk for potentially troublesome recurrences of SE when the medication is discontinued. EEG monitoring is necessary to assess its effectiveness and to monitor for seizures after discontinuation. For out-of-hospital emergencies, 10 mg of midazolam in a 2-mL solution may be given buccally with efficacy similar to that of rectal diazepam. When intravenous access is available, it is unclear that midazolam has any advantages over lorazepam, the typical and standard initial intravenous BDZ. Propofol. Propofol, an intravenous nonbarbiturate anesthetic, is extremely lipid soluble and rapid acting. Typical rcgimens include loading with 1 to 2 mg/kg and maintenance with 2 to 10 mg/kg/hour, adjusting to seizure control by clinical observation and electroencephalogram. Its advantages include coming from a different class of medications and the rapid onset and offset of action. However, this last consideration suggests that rapid taper can lead to recurrent seizures or SE. Propofol has been associated with seizure precipitation in a few cases and causes a very high lipid load. Severe respiratory depression, hypotension, metabolic acidosis, and nonepileptic involuntary movements have been reported. Nevertheless, it can be effective when other medications have failed. Trials comparing it with other agents such as barbiturates have included few patients and were unable to demonstrate a difference in efficacy. inhaled Anesthetics. Anesthetics are less well studied and far less convenient but may have a role in patients allergic to pentobarbital or other definitive treatments. Most increase cerebral blood flow, a theoretical disadvantage. Isoflurane may be the most effective anesthetic with the least cardiovascular effect in the setting of SE. Halothane is used frequently, but isoflurane may produce a burst suppression EEG tracing with less severe

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cardiovascular morbidity. Both may necessitate vasopressors. Nitrous oxide does not appear effective. Enflurane can precipitate convulsions.

NonadconvulsantTreatments Neuromuscular Blocking Agents. Neuromuscular blocking agents eliminate motor activity, but they are not anticonvulsants. They may provide false reassurance when SE continues on an electrical and metabolic basis. They can help when excessive movement impairs oxygenation, acid-base balance, or temperature regulation, but adequate dosages of anticonvulsants, including pentobarbital, benzodiazepines, or propofol, will obviate these problems. Steroids, Osmotic Agents, Surgery. Steroids and osmotic agents may be used to treat cerebral edema that results from prolonged SE, particularly in children, but efficacy has not been established. Rarely, a persistent seizure focus causing refractory partial SE may be resected surgically. Summary. Most medication trials for SE have studied patients with generalized convulsive SE. The same medications may treat other forms of SE. Intravenous benzodiazepines usually interrupt absence SE, and subsequent treatment may be unnecessary. For partial or nonconvulsive SE, valproate and carbamazepine can be valuable, although the response may take days; rarely are pentobarbital or anesthetics necessary in such cases. In children, phenobarbital often is preferred to phenytoin for reasons of absorption, efficacy, and longer-term side effects.

Electroencephalography Electroencephalogram use in SE depends on the seizure type and vigor of treatment. It is generally unnecessary during generalized convulsions but is mandatory when motor activity has ceased and the patient has not returned to normal; one needs to know whether seizure activity is continuing. The electroencephalogram is also necessary in assessing medication effect with high dosages of anticonvulsants, particularly with pentobarbital, midazolam, and propofol. Certainly, with neuromuscular blocking agents, the electroencephalogram is needed to determine whether SE has been treated at all. Protocol

Protocols for treating SE emphasize cardiorespiratory support in acutely ill patients followed by one of several orders of standard anticonvulsants, often emphasizing diazepam, lorazepam, phenytoh, and phenobarbital. Rather than choose one protocol for all patients, it might be best to keep in mind the following principles: Be sure of the diagnosis. Distinguish from myoclonus, other movement disorders, decerebrate posturing, and pseudoseizures. Blood gases and electroencephalogram may be helpful. After 30 minutes of recurrent seizures without recovery, the patient is clearly in SE. Even 5 to 10 minutes of intermittent seizure activity is likely to continue and should be interrupted. It is reasonable to assume the same urgency when convulsions are continuous for more than 2 minutes because few single seizures last this long. Determine the cause of SE through history, examination, and appropriate laboratory tests.

Direct attention to airway, respiration, blood pressure, and cardiac rhythm. Most patients with GCSE need intubation. Patients with other forms of SE often do not. Establish an intravenous line with saline, thiamine, and glucose. Antibiotics are given when infection is considered. Blood should be drawn for metabolic studies, anticonvulsant levels, and toxic screens. Rapidly acting anticonvulsants (i.e., benzodiazepines) are often the initial treatment. The Veterans’ Administration study provides support for using 5 to 10 mg of lorazepam first, and BDZs are particularly appropriate if GCSE continues beyond 5 minutes of continuous seizures or if there is a concern about NCSE between convulsions. They should certainly be used when GCSE has lasted 30 minutes, when convulsions are continuous, when convulsions occur during the infusion of phenytoin or phenobarbital, or when other drugs have not been successful. A long-acting medication is necessary. Phenytoin is the most frequently used maintenance medication and should be given in saline at 50 mg/minute, with attention to the cardiogram, to a dose of 15 to 20 mg/kg rather than the commonly used 1000 mg. Fosphenytoin at 150 phenytoin equivalents/minute, to the same total dose, is preferable in SE. Phenobarbital is more often used for children and for older adults or those with cardiac rhythm disturbances, at 10 to 20 mg/kg, up to 100 mg/min, with attention to blood pressure. Definitive treatment with pentobarbital, midazolam, or propofol should be used after 30 to 45 minutes or if the aforementioned agents are unsuccessful. This should be done in the intensive care unit after intubation and with EEG monitoring. Induction with pentobarbital is done with 3 to 5 mg/kg and an attempt to eliminate epileptiform activity on the electroencephalogram; many proceed to burst suppression EEG tracings. The maintenance dose is 1 to 5 mg/kg/hour as needed to control seizures and attain the desired EEG recording. Midazolam is given in 10- to 15-mg intravenous or intramuscular boluses, sometimes followed by a continuous infusion. Propofol is loaded intravenously as 1 to 2 mg/kg over 5 minutes, followed by an infusion of 2 to 10 mg/kg/hour, as adjusted to the clinical and EEG response. A few groups have found much higher dosages of lorazepam or phenobarbital to be reasonable alternatives for refractory SE. When used, pentobarbital, midazolam, or propofol might be discontinued after 24 to 48 hours, assuming that clinical and electrographic seizures have ceased and that two longeracting anticonvulsants are at high therapeutic levels. Attention is given to complications such as hypothermia, acidosis, hypotension, rhabdomyolysis, renal failure, infection, and cerebral edema. Maintenance medications must be chosen and established at therapeutic levels. Continued reassessment of clinical and EEG activity, as well as attention to the diagnosis and medical complications, is necessary until the patient returns to normal. Continuous reassessment of the patient’s clinical condition and electroencephalogram are necessary, as is continued reevaluation of the diagnosis and medication effectiveness. When SE does not respond to treatment as expected, attention should refocus along

Chapter 148

several lines. First, be sure the diagnosis of SE was correct. Second, the underlying cause is crucial, and SE can continue especially when trauma, hemorrhage, or infections such as encephalitis remain untreated. Third, medications often are given in inadequate doses, such as the 1000 mg phenytoin infusion. Fourth, medication absorption may be insufficient if there are problems with intravenous access or if the medication is given by another route. Finally, SE may be treated successfully and then recur, most often because of inadequate attention to maintenance levels of longer-acting anticonvulsants or lack of treatment of the underlying disease. SUGGESTED READINGS Barry E, Hauser WA Status epilepticus: the interaction of epilepsy and acute brain disease. Neurology 43: 1473-1478, 1993 Drislane Fw: Presentation, evaluation, and treatment of nonconvulsive

status epilepticus. Epilepsy Behav 1:301-314,2000 Fountain NB, Adams RE: Midazolam treatment of acute and refractory status epilepticus. Clin Neuropharmacol 22:261-267, 1999

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Hauser WA Status epilepticus: epidemiologic considerations. Neurology 4O(S~ppl2):9-13, 1990 Lothman EW The biochemical basis and pathophysiology of status epilepticus. Neurology 4O(Suppl 2):13-23, 1990 Lowenstein DH, Bleck T, Macdonald RL: It’s time to revise the definition of status epilepticus. Epilepsia 40:12&122, 1999 Meldrum BS, Horton RW Physiology of status epilepticus in primates. Arch Neurol 28:l-9, 1973 Schomer DL Focal status epilepticus and epilepsia partialis continua in adults and children. Epilepsia 34(Suppl 1):29-36, 1993 Tomson T, Lindbom U, Nilsson BY: Nonconvulsive status epilepticus in adults: thirty-two consecutive patients from a general hospital population. Epilepsia 33:829-835, 1992 Treiman DM, Meyers PD, Walton NY et al: A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 339792-798, 1998 Van Ness PC: Pentobarbital and EEG burst suppression in treatment of status epilepticus refractory to benzodiazepines and phenytoin. Epilepsia 31:61-67, 1990 Walton Ny: Systemic effects of generalized convulsive status epilepticus. Epilepsia 34(Suppl 1):54-58, 1993

148 Surgical Treatment of Epilepsy Donald L. Schorner A surgical approach to epilepsy is considered when a patient has a medically intractable form of partial epilepsy. Partial seizures are those that have a focal neocortical onset. Focal neocortical seizures may remain focal and either affect consciousness, in which case they are considered to be complex partial seizures, or not, in which case they are considered to be simple partial seizures. Alternatively, focal onset seizures may spread or secondarily generalize, in which case they may be difficult to distinguish from primary generalized seizures. A surgical approach aims to remove the smallest volume of brain that is essential to initiate and generate the seizures. This area is called the epileptic zone. When there is an identifiable lesion, removing the lesion and some of the surrounding brain is necessary to inhibit convulsive activity. The goal of surgery in most cases of partial onset epilepsy, either with or without an identifiable lesion, is to produce a cure. However, in certain types of seizures, specifically those associated with drop attacks or sudden periods of atonia, another procedure, a callosotomy, aims only to reduce the frequency of these devastating events. About 10% to 15% of the population experiences a convulsion at some time. A smaller percentage of that group are prone to recurrent seizures and therefore are diagnosed with epilepsy. In the United States, the incidence of all types of epilepsy is estimated to be between 0.7% and 1.0%. That means that between 2.0 and 2.8 million people have recurrent seizures, or epilepsy. Somewhere between 40% and 60% of people with epilepsy have partial or focal onset seizures. This represents 800,000 to perhaps more than 1.6 million people. Some studies suggest that even with the newer medications, more than 30% of this latter group will never achieve what is considered good control with medication, let alone achieve a cure. This leaves 250,000 to 500,000 people with poorly controlled forms of partial epilepsy. Of this group, it is estimated that 30% would benefit from a surgical procedure. This translates

to approximately 75,000 people in the United States, who, if chosen properly, have a potentially surgically amenable or treatable form of partial epilepsy. Approximately 5000 new cases are added to this number every year. Given the fact that only 3000 and 3500 patients are surgically treated on a yearly basis in this country, we are not even keeping pace with the newly added cases, let alone dealing with an almost 20-year backlog of cases. Although there are many difficulties in approaching patients with partial epilepsy surgically, the most immediate need is the better recognition by the primary care physician that such an approach is reasonable. Additionally, patients and their families need to be educated about the role of surgery in treating epilepsy, and whenever possible they need to be seen and evaluated by a team of experienced professionals. Although there are probably enough facilities available in the United States to make this form of treatment a more viable and more frequently used alternative, the insurance industry has overlooked its long-term importance. Often the payoff of successful surgery is the patient’s return to a productive position in society. This, in turn, has significant psychosocial and fiscal ramifications for all.

IDENTIFYING THE POPULATlON AT RISK

In 1975 McNaughton and Rasmussen wrote, “Without doubt, the proper evaluation and selection of patients for surgical management of the symptom, epilepsy, is the most important single factor in determining the success or failure of this form of treatment in reducing the seizure tendency.” In the United States, most patients presenting with epileptic seizures are seen and treated by pediatricians, internists, and general physicians. Most patients with new-onset seizures have a routine electroencephalographic evaluation and some form of imaging study performed. Most

Chapter 148

several lines. First, be sure the diagnosis of SE was correct. Second, the underlying cause is crucial, and SE can continue especially when trauma, hemorrhage, or infections such as encephalitis remain untreated. Third, medications often are given in inadequate doses, such as the 1000 mg phenytoin infusion. Fourth, medication absorption may be insufficient if there are problems with intravenous access or if the medication is given by another route. Finally, SE may be treated successfully and then recur, most often because of inadequate attention to maintenance levels of longer-acting anticonvulsants or lack of treatment of the underlying disease. SUGGESTED READINGS Barry E, Hauser WA Status epilepticus: the interaction of epilepsy and acute brain disease. Neurology 43: 1473-1478, 1993 Drislane Fw: Presentation, evaluation, and treatment of nonconvulsive

status epilepticus. Epilepsy Behav 1:301-314,2000 Fountain NB, Adams RE: Midazolam treatment of acute and refractory status epilepticus. Clin Neuropharmacol 22:261-267, 1999

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Hauser WA Status epilepticus: epidemiologic considerations. Neurology 4O(S~ppl2):9-13, 1990 Lothman EW The biochemical basis and pathophysiology of status epilepticus. Neurology 4O(Suppl 2):13-23, 1990 Lowenstein DH, Bleck T, Macdonald RL: It’s time to revise the definition of status epilepticus. Epilepsia 40:12&122, 1999 Meldrum BS, Horton RW Physiology of status epilepticus in primates. Arch Neurol 28:l-9, 1973 Schomer DL Focal status epilepticus and epilepsia partialis continua in adults and children. Epilepsia 34(Suppl 1):29-36, 1993 Tomson T, Lindbom U, Nilsson BY: Nonconvulsive status epilepticus in adults: thirty-two consecutive patients from a general hospital population. Epilepsia 33:829-835, 1992 Treiman DM, Meyers PD, Walton NY et al: A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 339792-798, 1998 Van Ness PC: Pentobarbital and EEG burst suppression in treatment of status epilepticus refractory to benzodiazepines and phenytoin. Epilepsia 31:61-67, 1990 Walton Ny: Systemic effects of generalized convulsive status epilepticus. Epilepsia 34(Suppl 1):54-58, 1993

148 Surgical Treatment of Epilepsy Donald L. Schorner A surgical approach to epilepsy is considered when a patient has a medically intractable form of partial epilepsy. Partial seizures are those that have a focal neocortical onset. Focal neocortical seizures may remain focal and either affect consciousness, in which case they are considered to be complex partial seizures, or not, in which case they are considered to be simple partial seizures. Alternatively, focal onset seizures may spread or secondarily generalize, in which case they may be difficult to distinguish from primary generalized seizures. A surgical approach aims to remove the smallest volume of brain that is essential to initiate and generate the seizures. This area is called the epileptic zone. When there is an identifiable lesion, removing the lesion and some of the surrounding brain is necessary to inhibit convulsive activity. The goal of surgery in most cases of partial onset epilepsy, either with or without an identifiable lesion, is to produce a cure. However, in certain types of seizures, specifically those associated with drop attacks or sudden periods of atonia, another procedure, a callosotomy, aims only to reduce the frequency of these devastating events. About 10% to 15% of the population experiences a convulsion at some time. A smaller percentage of that group are prone to recurrent seizures and therefore are diagnosed with epilepsy. In the United States, the incidence of all types of epilepsy is estimated to be between 0.7% and 1.0%. That means that between 2.0 and 2.8 million people have recurrent seizures, or epilepsy. Somewhere between 40% and 60% of people with epilepsy have partial or focal onset seizures. This represents 800,000 to perhaps more than 1.6 million people. Some studies suggest that even with the newer medications, more than 30% of this latter group will never achieve what is considered good control with medication, let alone achieve a cure. This leaves 250,000 to 500,000 people with poorly controlled forms of partial epilepsy. Of this group, it is estimated that 30% would benefit from a surgical procedure. This translates

to approximately 75,000 people in the United States, who, if chosen properly, have a potentially surgically amenable or treatable form of partial epilepsy. Approximately 5000 new cases are added to this number every year. Given the fact that only 3000 and 3500 patients are surgically treated on a yearly basis in this country, we are not even keeping pace with the newly added cases, let alone dealing with an almost 20-year backlog of cases. Although there are many difficulties in approaching patients with partial epilepsy surgically, the most immediate need is the better recognition by the primary care physician that such an approach is reasonable. Additionally, patients and their families need to be educated about the role of surgery in treating epilepsy, and whenever possible they need to be seen and evaluated by a team of experienced professionals. Although there are probably enough facilities available in the United States to make this form of treatment a more viable and more frequently used alternative, the insurance industry has overlooked its long-term importance. Often the payoff of successful surgery is the patient’s return to a productive position in society. This, in turn, has significant psychosocial and fiscal ramifications for all.

IDENTIFYING THE POPULATlON AT RISK

In 1975 McNaughton and Rasmussen wrote, “Without doubt, the proper evaluation and selection of patients for surgical management of the symptom, epilepsy, is the most important single factor in determining the success or failure of this form of treatment in reducing the seizure tendency.” In the United States, most patients presenting with epileptic seizures are seen and treated by pediatricians, internists, and general physicians. Most patients with new-onset seizures have a routine electroencephalographic evaluation and some form of imaging study performed. Most

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often the latter is a magnetic resonance image. If these two studies are normal, the nonneurologist treating physician decides whether to treat. If the patient continues to have recurrent seizures for more than 3 months after adequate trials with at least one anticonvulsant drug, he or she should be referred to a neurologist. Most practicing neurologists are capable of reevaluating such a patient. The neurologist first confirms that the continuing events are epileptic. If they are, he or she identifies reasonable medical alternatives or any psychosocial factors that, if dealt with successfully, would help with control. Most neurologists are comfortable prescribing additional anticonvulsant medications in a controlled fashion and dealing with some of the known psychosocial factors. However, if the patient is still having seizures after several additional medical trials, he or she should be considered for formal evaluation at an epilepsy center. Epilepsy centers are multidisciplinary diagnostic and treatment units. Patients usually are first screened by an epileptologist. Most epilepsy centers try to coordinate their efforts with those of the referring physician. Any surgical approach must be weighed in the context of the refractoriness of the seizures to medication, the identification of a focal onset of events, an understanding of the natural history of the specific seizure syndrome, if identifiable, and the impact that the workup, surgery, and postoperative care will have on the patient and his or her family. Refractoriness is a difficult concept to define. At a minimum, patients should have clinical breakthrough seizures while on adequate medications. The events must be disturbing enough that the patient’s lifestyle is adversely affected by their occurrence. Consider a patient who has only an occasional nocturnal generalized seizure occurring at intervals of 4 to 8 weeks. The consequence of those seizures is profound fatigue the next day. That fatigue may constitute refractoriness if it adversely affects the patient’s economic independence or social or psychiatric wellbeing. Some patients may have complex partial seizures reduced by medication to simple partial events. In some cases, the simple partial seizures may be manifested by minor unpleasant smells or a feeling of nausea, but in other cases they may be associated with profound feelings of dread and doom that makes the person distraught and anxious for many hours or days. In the first case, the person may be willing to live with these experiences, but in the other case the person may find them so disturbing that surgery becomes a real alternative. Also, many patients are adversely affected by their anticonvulsant medicines and would consider a surgical approach if it meant fewer medicines, lower dosages of medicines, or possible withdrawal from drugs altogether. Initially, the epileptologist makes every attempt to identify a seizure syndrome (see Chapter 145) to gain an understanding of the expected natural history of the disorder. For instance, it is important to identify the benign syndromes such as rolandic or occipital epilepsy, which have an excellent long-term prognosis. In such cases, surgery would be inappropriate. By contrast, in mesial temporal sclerosis, if the patient is refractory to medicines, the natural history would support an early and more aggressive surgical approach. In the cases of symptomatic partial epilepsy, in which seizures are secondary to a structural lesion, the lesion and the epilepsy must be treated together. With the advent of improved imaging and electroencephalographic recording techniques, many patients can be defined as having an identifiable syndrome early in their treatment and receive appropriate counseling. Compliance with medication is another major problem in identifying the refractory patient. For a patient to be deemed medically refractory, there must be clear, well-documented trials

in which several appropriate anticonvulsant medications have failed to produce control.

INVESTIGATION OF SURGICAL PATIENTS Figure 148-1 illustrates the approach used at our institution to evaluate how to proceed with potential surgical patients. History

It is important to review with the patient and family members the history of the onset and course of the patient’s seizures. It is worth noting the first event and the circumstances surrounding it, such as head injury, fever or infection, loss of sleep, unusual stress, and exposures to drugs or toxins. The subsequent evolution of the seizure disorder is equally important in assessing the natural history and outlining the historical response to medications and their side effects. It is always worth checking original data obtained early in the course of the disorder, including neurologically relevant findings, physical abnormalities, abnormal imaging studies, or electroencephalograms (EEGs), if available. Also, if available, the early imaging studies should be reviewed and compared with more recently acquired ones to determine whether there has been a change. It is also important to note any abnormalities or changes in the psychosocial or educational-developmental history that may give clues to medication side effects or the presence of a progressive neurologic disorder. The epileptologist will obtain detailed developmental histories. Questions about early development not only detail a retrospective account of the patient’s birth and development history but also give the physician a sense of the family’s response to the disorder. This serves two purposes. First, in attempting to define any seizure syndrome, it is important to note trends in biologically related patients and their families. These observations are relevant not only in identifying and learning about other family members with specific syndromic forms of epilepsy but also in defining other conditions that have familial tendencies in which epilepsy may or may not have a role. In the latter case, the symptoms may be misdiagnosed as seizures. Potential confounding disorders include bipolar disorder, seasonal affective disorder, or schizophrenic disorders. Second, this type of detailed history lays the groundwork for the personal and family counseling that will be necessary before surgery can be attempted. A better understanding of the patient’s past responses to his or her seizures and the family’s reaction are necessary in preparing the patient to deal positively with anger, frustrations, and fears and to develop realistic expectations for a surgical procedure. For instance, if a patient’s surgical procedure is successful and he or she has no more seizures postoperatively but remains in an overprotected environment, the patient may not be significantly better, from a psychosocial or educational perspective, for having undergone surgery. A corollary to this observation is that many successful surgical patients end marriages that were based on their illness or on their role as a “sick person.”

Physical Examination The physical examination includes a general examination looking for major medical problems such as cardiac murmurs or arrhythmias and significant neurocutaneous stigmata that would indicate an underlying hereditary familial disorder in which the epilepsy may play only a small part. The neurologic examination should be

Chapter 148 H Surgical Treatment of Epilepsy

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FOCAL CORTICAL EXCISIONS History Exam

Recurrent Seizures Documented Clinical Trials Compliant and Willing Patient

-

Further Clinical Trials Counseling

Start Phase I Investigations

EEG consistent focal ictal onset Radiology - focal or suspicious area Neuropsychology focal deficit consistent with EEG and radiology

-

Psychological Counseling Pre-Op Nursing - Teaching

A4

1

Wada Testing

Controlled Stop Evaluation Stop Evaluation

t

ISurgery 1

FIG. 148-1. Flowchart showing the evaluation and decision-making process that would ultimately lead to a focal cortical resection for seizure of temporal or frontal lobe origin. Phase I electroencephalographic investigations are noninvasive, whereas phase II investigations entail the use of at least one type of invasive electrode.

detailed. Subtle differences in cortical sensory function must be tested, subtle motor coordination asymmetries identified, and subtle reflex asymmetries documented. These become more important in trying to find corresponding imaging abnormalities or relevant electroencephalographic findings. Investigative Testing Electroencephalography is one of the mainstays in presurgical evaluation. Baseline electroencephalographic studies are important in noting the presence of interictal epileptic activity. If present, it is important to note whether the discharges are consistently focal, multifocal, or generalized in appearance. Slowing on the EEG, either focal or generalized, is an important finding. Focal slowing suggests a structural abnormality that may correlate with seizure onset. This finding may be helpful in directing specialized imaging studies. Generalized slowing may reflect either a more widespread disease process or an effect that is secondary to medication. When considering a patient for focal cortical resection, however, the most important electroencephalographic data is that which is recorded during an event. The electroencephalographic onset of a seizure usually occurs before the patient is aware of the event. If the electroencephalographic changes occur after the patient is aware of the onset of the seizure, the EEG may not be showing the area of onset but rather an area into which the epileptic physiologic event has spread. To enhance the spatial resolution capability of the EEG, sphenoidal electrodes often are used when looking for focal onset in the inferior temporal region (Fig. 148-2)or posterior inferior frontal area. Because of the risk of activating secondary epileptic sites or

inducing prolonged status epilepticus states, it is generally considered better to record spontaneous seizures that occur without alterations in medication dosing or associated behavioral manipulations. If seizure frequency is such that it would be statistically unlikely to capture an event while doing telemetered electroencephalographic recording, drugs can be withdrawn in a controlled fashion and environment. Advances in technology allow computer-assisted detection of seizures and interictal epileptic abnormalities (Fig. 148-3).This allows the investigator to find abnormalities that might otherwise go unseen. It is necessary to capture several typical seizures on EEG before making a decision regarding the completeness of this part of the evaluations. It is also reasonable to record the patient’s behavior on video. If there is a clear focal onset seen on the EEG that correlates with the onset of the clinical activity and the events are typical for the patient, this part of the evaluation can be considered complete. If no such clear correlation is seen, the patient may be a candidate for more invasive electroencephalography (discussed later in this chapter). Parallel to the EEG, patients usually undergo imaging procedures. The most helpful studies are done with magnetic resonance techniques. TI- and T2-weighted images with coronal, anteroposterior, and sagittal views should be obtained. Obvious lesions and malformations are looked for depending on the seizure semiology. Evidence of sclerosis is looked for in mesial temporal regions and in frontal areas when appropriate clinically (Fig. 148-4).Thin cuts are also useful when looking for subtle cortical migration abnormalities where congenital asymmetries are noted. Special T2-weighted sequences (e.g., fluid attenuated inversion recovery [FLAIR] sequences) further improve the yield when looking for

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A

FIG. 148-2. This patient experienced multiple events in which he had a warning of an ascending sense of nausea followed by loss of consciousness, during which he repeated the words "deja vu" but did not actually have that as a sensation. The arrow indicates the physiologic onset of the ictus or onset of the electrical seizure activity. There is rhythmic delta activity starting at 17:32:35 (A), followed by an attenuation of activity at 17:33:19 (B), followed by rhythmic 2- to 6-Hz spikes at 17:33:39 (C).

migration abnormalities. Gadolinium enhancement is also useful when trying to define vascular or neoplastic abnormalities. Magnetic resonance volumetric studies of the hippocampal regions are done frequently when evaluating patients with hippocampal onset seizures. If an atrophic hippocampus can be demonstrated with this technique and it is coincident with the site of seizure onset, the patient is likely to have an excellent long-term response to the surgical removal of that area and is likely to have little additional cognitive deficit from the removal. Targeted magnetic resonance spectroscopy also may have prognosticating significance. If there is a clear decrease in the N-acetylaspartate) content and an increase in the lactate concentration confined to the region suspected as the site of seizure initiation and this area can be included in the surgical removal, there is reason to suspect that the patient may also have a good outcome from the surgical removal. Dynamic imaging testing is another frequently used procedure in some centers. These techniques include single photon emission

computed tomography (SPECT), positron emission tomography (PET) (Fig. 148-5), and functional magnetic resonance imaging (fMRI). In all three techniques, it is important to know the state of the patients while they are being studied. The results, if obtained during the seizure, show direct or indirect consequences of increased neuronal activity focally. These changes may be manifest by increased blood flow as noted through SPECT or PET techniques, increased metabolic activity as demonstrated on specific forms of PET scans, or changes in the oxyhemoglobin to deoxyhemoglobin ratios seen on MRI. The opposite findings are seen if the study is done during an interictal period, with a few minor exceptions. The colocalization of these studies to the electroencephalographic localization of seizure onset is a prerequisite for surgery in some centers. Detailed neuropsychological testing is done preoperatively to assess general level of cognitive capability and to assess for focal areas of inadequate performance. In patients undergoing evaluation for focal cortical resections, an additional localizing finding is

Chapter 148

a deficit in cognitive performance that colocalizes to the same region as the EEG and imaging procedures. The neuropsychologist can also provide counseling relevant to the surgical and postoperative care and addresses the patient’s anxieties about the procedure. Identifymg major psychiatric disorders is important because the presence of major psychosis or suicidal depression is considered by many centers to contraindicate surgery. If these disorders are identified and successfully treated or managed, many patients can continue their surgical evaluation. The neuropsychologist addresses issues related to the family or work that must be resolved before an operation. The neuropsychologist is responsible for assessing hemispheric specialization for memory and language. This is confirmed, when necessary, by a Wada test, which involves injecting small doses of sodium amytal into the carotid artery (intracarotid amytal procedure) while assessing cognitive function during the time of transient medication-induced deficit. lnvasive EECs Occasionally the scalp-based recording of seizure onset does not afford sufficient information to make a surgical decision. Under

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those conditions, an invasive EEG may be helpful. A variety of electrodes are tailored to provide information based on the specific surgical questions. For example, the foramen ovale electrode may be the least invasive of the invasive electrodes. It is placed through the foramen ovale and directed along the mesial aspects of the temporal lobe in the epidural space. These electrodes can remain in place for many weeks. Recordings often are coupled with surface or scalp electrodes or more invasive electrodes. Recording with these electrodes is useful in localizing seizures that are suspected of originating in mesial temporal structures. Although this electrode is less invasive, the major complication, tic douloureux, is common. Epidural pegs also are less invasive with respect to brain penetration. Multiple electrodes can be placed through small twist drill holes. Their recording contacts are on the epidural surface. Both hemispheres can be investigated through this procedure. Because the electrodes are inside the skull, recordings show higher amplitude and much less artifact than scalp recordings do. These electrodes are useful in investigating suspected frontal or central seizure foci. Electrode strips or grids can be placed either by Burr holes or through a craniotomy. From the patient’s perspective, this is invasive. However, very little neocortical damage occurs with

FIG. 148-2 Continued There is rhythmic delta activity starting at 17:32:35 (A), followed by an attenuation of activity at 17:33:19 (B), followed by rhythmic 2- to 6-Hz spikes at 17:33:39 (C). Illustration continued on following page

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C

FIG. 148-2 Continued There is rhythmic delta activity starting at 17:32:35 (A), 17:33:19 (B), followed by rhythmic 2- to 6-Hz spikes at 17:33:39 (C).

these procedures. These electrodes are useful in investigating patients in whom lateral neocortical onset of seizures is suspected and in whom the hemisphere of onset can be identified. An additional advantage of the grid array of electrodes is that it allows the investigator to stimulate the brain and identify eloquent cortex before planning a surgical procedure. Depth electrodes are perhaps the most invasive of the electrodes used for recording purposes. These electrodes are placed so that they penetrate the brain substance and usually are targeted for deep limbic sites. They are most helpful in investigating patients in whom, with surface and sphenoidal electrodes, seizure onset cannot be clearly determined but the events are believed to be of limbic origin. Because each of the electrodes has multiple contacts, the physiologic evolution of the seizure can be reasonably detailed. Today most epilepsy centers use depth electrodes primarily to investigate suspected deep mesial frontal or orbital frontal seizure onset, although there are still occasional temporal cases in which they are appropriate.

followed by an attenuation of activity at

SURGICAL STRATEGIES Focal Excision of Epileptic Tissue. Temporal Lobe The focal excision of epileptic tissue of the temporal lobe is the most frequently performed procedure for epilepsy and accounts for 60% to 70% of the focal removals. The decision to operate is outlined in Figure 148-1. If a patient with temporal lobe onset seizures makes it to the surgical procedure, the most frequently performed operation is a corticoamygdalohippocampectomy.There is wide variation in this procedure between epilepsy centers. A few centers perform a standardized en bloc removal in which 5 to 6 cm of the nondominant temporal lobe and up to 5 cm of the dominant hemisphere temporal lobe is removed. The measurement is made from the tip of the temporal fossa along its lateral extent. Variable amounts of mesial tissue are removed. Some centers remove only mesial structures, leaving the lateral temporal neocortex intact, the so-called amygdalohippocampectomy.However, most centers tailor their procedure to the patient’s physiology.

Chapter 148 W Surgical Treatment of Epilepsy

Removal may be more or less on lateral or mesial aspects, depending on seizure physiology. The more lateral removals are done primarily in patients with temporal neocortical seizure onset, and more significant mesial removals are done in patients in whom mesial sclerosis is found. Results of this type of surgery are quite good, with an overall success rate between 80% and 90%. Success is measured in terms of seizure frequency reduction, and half of the patients who have a positive response are seizure-freeor have rare auras. The other half of those responders have significant improvement in seizure frequency, having only perhaps a few auras or rare seizures. Of the patients undergoing this procedure, 10% to 20% do not benefit significantly. If patients respond, cognitive improvement often is noted. This improvement in cognitive functioning may result from a number of factors. The absence of seizures probably allows the patient to better formulate new memories. The reduction in medication coincident with seizure control also allows improved attention and cognition.

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Frontal Removals

Focal cortical excisions are done frequently for seizures of frontal lobe origin. The epileptic zones that are approachable are primarily in the area of the prerolandic dorsolateral cortex and anterior mesial frontal cortex. Because seizures that originate in these areas often have rapid secondary generalization, investigations often include depth electrode studies. The outcome for focal frontal removals does not seem to be as good as for temporal removals. Overall success is 60% to 70%, compared with 80% to 90% for temporal cases. The responders, like patients with temporal lobe seizures, also have noted cognitive improvements for the same reasons.

Mulple

and

These procedures are considered reasonable alternatives for patients with regional or hemisphere-wide seizure onset and

FIG. 148-3. A computer-based program for automated detection of interictal spike activity captured multiple sleepenhanced epileptic spike and wave discharges seen from the right inferior temporal leads Sp2 and more broadly from the right inferior temporal surface where there is a zone of isopotentiality between Sp2 and T4. Phase-reversing discharges are noted by arrows.

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Subplal Transections Patients with clear focal seizure onset from essential cortical areas such as the primary motor or sensory cortex or language areas such as Broca’s or Wernicke’s area may be candidates for this procedure. In these cases, subpial sectioning of the cortex is carried out at 5-mm intervals with a blunted knife that passes around the gyrus transverse to the axis of the gyrus. This procedure sections the gray matter connections that run horizontally and, in turn, connect functional columns to each other. It is believed that this prevents the functional columns from being pathologically synchronized and leading to a clinical event. Overall, the functional state of the column remains intact. The procedure is not common, but the majority of patients undergoing this procedure have had a significant reduction in seizure frequency and very little or no worsening of their functional capacity. Lesionectomy

In patients with identifiable lesions, the area of epileptogenesis usually is near or surrounding the lesion. However, this must be

FIG. 148-4. This coronal view TI -weighted magnetic resonance image for a patient with right temporal lobe-onset seizures shows a small and sclerotic-appearing hippocampus. The entire right temporal lobe also appears shrunken compared with the normal left side.

concomitant severe neurologic impairment. Many of these patients have had early damage to a hemisphere or to multiple lobes within one hemisphere and have associated hemiparesis, loss of visual field, and sensory deficit. Multiple disorders are encountered when dealing with this subpopulation of surgical patients. The most common disorder seen may be the chronic progressive encephalitis described by Rasmussen. Other origins include the Sturge-Weber syndrome and hemimegalencephaly. Children presenting with infantile spasms and the hypsarrhythmia electroencephalographic pattern, with lateralized or localized PET abnormalities, are considered candidates for this procedure if they fail medication trials. The procedure includes either multiple lobectomies or an entire hemispherectomy. The latter may be either complete or modified. In the modified approach, both the frontal and occipital poles are left in place with their pial blood supply untouched. However, they are deafferented by undercutting the neocortex through its underlying white matter. The cortex, though left intact, is nonfunctional. It is believed that this approach reduces the long-term sequelae of hemosiderosis described by early investigatorswho performed the total hemispherectomy. The outcome from this procedure in many cases is dramatic. Overall, about 75% of patients undergoing this procedure become seizure-free or develop medical tractability. There is often a significant improvement in behavior and occasionally an improvemerit in cognition and in the hemiparesis* In with infantile spasms and the hYPsarrhflhmic elearoencePhalograPhic pattern, there may often be dramatic improvement in cognition and neurologic development.

FIG. 148-5. This fluorodeoxyglucose PET study shows an area of significantly decreased metabolic activity in the region of the right temporal lobe that is prominent along the mesial border (arrows). This corresponded to the site of electroencephalographic origin of seizures in this patient (same as noted in Figs. 148-2 and 148-3). He went on to have a successful mesial temporal lobe removal and cure of his seizures.

Chapter 149

confirmed during the presurgical evaluation. If the lesion were in the anterior or middle temporal lobe, the surgical approach would be to tailor the temporal lobectomy to include the lesion and epileptogenic zone. However, if the lesion is nontemporal, the surgical approach must take into account whether the epileptic zone and the lesion itself can be removed surgically without interfering significantly with function. Outcome measures for lesionectomy take into account both epilepsy control and the treatment specific for the lesion. The surgical outcomes with respect to epilepsy are very similar to responses for focal cortical removals; that is, temporal lobe removals tend to give better results than frontal removals. The excision of the lesion and the response to that procedure relate directly to the pathology of the lesion itself.

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important factor in determining the outcome. Although this approach may be expensive, the financial, emotional, and cognitive benefits may far outweigh the initial investment. The evaluation is best done in a major epilepsy center. SUGGESTED READINGS Berkovic S, Howell RA, Hay DA et al: Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol43:435-445, 1998 Blume HW,Schomer D L Surgical approaches to epilepsy.Annu Rev Med 39~301-313,1988 Briellmann RS, Jackson GD, Torn-Broers Y, Berkovic S: Causes of epilepsies: insights from discordant monozygous twins. Ann Neurol 49:45-52, 2001 Cendes F, Lopes-Cendes I, Andermann E, Andermann F Familial temporal lobe epilepsy: a clinically heterogeneous syndrome. Neurology 50554-557, 1998

Callosotomy Callosotomy is the only epilepsy surgical procedure that is never considered to be curative. At best, this procedure is palliative. It is considered when the patient’s seizures predominantly take the form of drop attacks. This type of seizure is seen in patients who have widespread brain pathology and multiple seizure types. Drop attacks remain resistant to medications, although with some of the newer drugs there have been some successes. Drop attacks often are associated with repeated head and body injury. The callosotomy often is done as a two-step approach. In eligible patients an anterior two-thirds callosotomy section is done initially. In most cases, this is sufficient, and no further procedure is necessary. Leaving the posterior third of the callosum intact seems to reduce some of more the unusual cognitive complications noted in the early description of this technique. The posterior third of the callosum can be sectioned in a separate setting if the anterior two-thirds section has failed. If this procedure is successful in controlling the drop attacks, patients often show some improvement in their cognitive abilities. More importantly, it seems to improve long-term outcome and reduce some of the difficulties of caring for these patients.

Connelly A, Jackson GD, Duncan JS et al: Magnetic resonance spectroscopy in temporal lobe epilepsy. Neurology 441411-1417, 1994 Hardimann 0, Burke T, Philips J et al: Microdysgenesia in resected temporal neocortex: incidence and clinical significance in focal epilepsy. Neurology 38:1041-1047, 1988 Luders H O Epilepsy Surgery. Raven, New York, 1992 Mathern GW, Babb TL, Vickery BC et ak The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain 118:105-118, 1995 Mosewick RK, So EL, O’Brien TJ et ak Factors predictive of outcome of frontal lobe epilepsy surgery. Epilepsia 41:843-849, 2000 Olivier A Surgery of frontal lobe epilepsy. Adv Neurol66321-348, 1995 Salanova V, Andermann F, Rasmussen T et ak Parietal lobe epilepsy: clinical manifestations and outcomes in 82 patients treated surgically between 1929 and 1988. Brain 118:607-627, 1995 Spencer S: The relative contributions of MRI, SPECT and PET imaging in epilepsy. Epilepsia 35(Suppl):S72-S89, 1994 Weiser HG, Engel J Jr, Williamson PD et ak Surgical remedial temporal lobe syndromes. pp. 49-63. In Engel J Jr (ed): Surgical Treatment of the Epilepsies. 2nd Ed. Raven, New York, 1993 Zentner J, Hufnagal A, Ostertum B et ak Surgical treatment of extra temporal epilepsy: clinical, radiologic, and histopathologic findings in 60 patients. Epilepsia 361072-1080, 1996

CONCLUSION Surgical approaches to medically intractable forms of epilepsy are underused. Proper patient selection may be the single most

149 Epilepsy and Behavior Shahram Khoshbin To the practicing neurologist, the issue of epilepsy and behavior presents two distinct complex and difficult management problems: diagnosis and management of cognitive and behavior changes in patients with different types of epilepsy and diagnosis and management of patients presenting with behavioral symptoms or symptom complexes akin to those seen in epileptic patients but without classic idal or electroencephalographic manifestations of seizures. The latter has been called temporolimbic dysfunction because the manifestations of these symptoms and symptom

complexes are similar to those described in the literature as being associated with complex partial epilepsy or focal lesions in the temporal lobe, the frontal lobe, the limbic system, and their connections. Although these problems have been recognized since antiquity and have been the subject of numerous anecdotal reports and small and large prospective and retrospective studies, for a number of reasons, including the multifactorial origins of behavioral symptoms, varied theories of pathophysiology, and methodologic difficulties in carrying out behavioral research, they

Chapter 149

confirmed during the presurgical evaluation. If the lesion were in the anterior or middle temporal lobe, the surgical approach would be to tailor the temporal lobectomy to include the lesion and epileptogenic zone. However, if the lesion is nontemporal, the surgical approach must take into account whether the epileptic zone and the lesion itself can be removed surgically without interfering significantly with function. Outcome measures for lesionectomy take into account both epilepsy control and the treatment specific for the lesion. The surgical outcomes with respect to epilepsy are very similar to responses for focal cortical removals; that is, temporal lobe removals tend to give better results than frontal removals. The excision of the lesion and the response to that procedure relate directly to the pathology of the lesion itself.

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important factor in determining the outcome. Although this approach may be expensive, the financial, emotional, and cognitive benefits may far outweigh the initial investment. The evaluation is best done in a major epilepsy center. SUGGESTED READINGS Berkovic S, Howell RA, Hay DA et al: Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol43:435-445, 1998 Blume HW,Schomer D L Surgical approaches to epilepsy.Annu Rev Med 39~301-313,1988 Briellmann RS, Jackson GD, Torn-Broers Y, Berkovic S: Causes of epilepsies: insights from discordant monozygous twins. Ann Neurol 49:45-52, 2001 Cendes F, Lopes-Cendes I, Andermann E, Andermann F Familial temporal lobe epilepsy: a clinically heterogeneous syndrome. Neurology 50554-557, 1998

Callosotomy Callosotomy is the only epilepsy surgical procedure that is never considered to be curative. At best, this procedure is palliative. It is considered when the patient’s seizures predominantly take the form of drop attacks. This type of seizure is seen in patients who have widespread brain pathology and multiple seizure types. Drop attacks remain resistant to medications, although with some of the newer drugs there have been some successes. Drop attacks often are associated with repeated head and body injury. The callosotomy often is done as a two-step approach. In eligible patients an anterior two-thirds callosotomy section is done initially. In most cases, this is sufficient, and no further procedure is necessary. Leaving the posterior third of the callosum intact seems to reduce some of more the unusual cognitive complications noted in the early description of this technique. The posterior third of the callosum can be sectioned in a separate setting if the anterior two-thirds section has failed. If this procedure is successful in controlling the drop attacks, patients often show some improvement in their cognitive abilities. More importantly, it seems to improve long-term outcome and reduce some of the difficulties of caring for these patients.

Connelly A, Jackson GD, Duncan JS et al: Magnetic resonance spectroscopy in temporal lobe epilepsy. Neurology 441411-1417, 1994 Hardimann 0, Burke T, Philips J et al: Microdysgenesia in resected temporal neocortex: incidence and clinical significance in focal epilepsy. Neurology 38:1041-1047, 1988 Luders H O Epilepsy Surgery. Raven, New York, 1992 Mathern GW, Babb TL, Vickery BC et ak The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain 118:105-118, 1995 Mosewick RK, So EL, O’Brien TJ et ak Factors predictive of outcome of frontal lobe epilepsy surgery. Epilepsia 41:843-849, 2000 Olivier A Surgery of frontal lobe epilepsy. Adv Neurol66321-348, 1995 Salanova V, Andermann F, Rasmussen T et ak Parietal lobe epilepsy: clinical manifestations and outcomes in 82 patients treated surgically between 1929 and 1988. Brain 118:607-627, 1995 Spencer S: The relative contributions of MRI, SPECT and PET imaging in epilepsy. Epilepsia 35(Suppl):S72-S89, 1994 Weiser HG, Engel J Jr, Williamson PD et ak Surgical remedial temporal lobe syndromes. pp. 49-63. In Engel J Jr (ed): Surgical Treatment of the Epilepsies. 2nd Ed. Raven, New York, 1993 Zentner J, Hufnagal A, Ostertum B et ak Surgical treatment of extra temporal epilepsy: clinical, radiologic, and histopathologic findings in 60 patients. Epilepsia 361072-1080, 1996

CONCLUSION Surgical approaches to medically intractable forms of epilepsy are underused. Proper patient selection may be the single most

149 Epilepsy and Behavior Shahram Khoshbin To the practicing neurologist, the issue of epilepsy and behavior presents two distinct complex and difficult management problems: diagnosis and management of cognitive and behavior changes in patients with different types of epilepsy and diagnosis and management of patients presenting with behavioral symptoms or symptom complexes akin to those seen in epileptic patients but without classic idal or electroencephalographic manifestations of seizures. The latter has been called temporolimbic dysfunction because the manifestations of these symptoms and symptom

complexes are similar to those described in the literature as being associated with complex partial epilepsy or focal lesions in the temporal lobe, the frontal lobe, the limbic system, and their connections. Although these problems have been recognized since antiquity and have been the subject of numerous anecdotal reports and small and large prospective and retrospective studies, for a number of reasons, including the multifactorial origins of behavioral symptoms, varied theories of pathophysiology, and methodologic difficulties in carrying out behavioral research, they

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have remained controversial. Specifically, correlation between these symptom complexes and epilepsy, particularly temporal lobe epilepsy, has not been clearly established. However, patients suffer from significant morbidity because of these symptom complexes. In this chapter we discuss neuropsychiatric behavioral disorders presumed to be related to epilepsy with an emphasis on management rather than pathophysiology. In treating patients with epilepsy, it is helpful to keep a general view of the disorder in the form of what we shall call the patient care diamond (Fig. 149-l), with major aspects of patients’ problems constituting the different points of the diamond with reciprocal relations between each point. In this section, we particularly emphasize the symptoms related to reciprocal relationships between seizures and psychiatric symptoms and those behavioral symptoms related to the use of antiepileptic drugs and surgical treatment of epilepsy. The overview considers the following: Behavioral changes and seizures can be separate but related manifestations of the same underlying disorder. Abnormal behavior can develop as a result of partial inhibition or enhancement of activity in neighboring or distant regions of the brain (postictal and interictal symptoms). Seizures as a behavior can be positively or negatively reinforced, resulting in other behaviors mimicking seizures (pseudoseizures) or abnormal psychological adaptation (personality disorders). The unpredictable and disruptive nature of seizures produces psychological stress. Behavioral abnormalities can be a result of a chronic illness with its social limitations and cultural stigmatization. Cognitive and behavioral abnormalities can be secondary to the effects of treatment with anticonvulsant drugs. Many pathophysiologic mechanisms have been suggested to explain these reciprocal relationships. Mechanisms underlying the epileptic focus and ictal behavioral manifestations related to these focal lesions (such as paroxysmal depolarizing shift) are now well understood. There is also good evidence for propagation of these focal dysrhythmias to adjacent and distant areas via excitatory and inhibitory circuits, causing additional behavioral manifestations. However, mechanisms underlying symptoms not temporally related to the ictal discharge have been less clearly understood. Suggestions have been made of processes such as hyperconnectivity or misconnectivity. Some aspects of the animal model of kindling have provided interesting possible mechanisms for these spatially and temporally distant manifestations.

CLASSIFICATION OF BEHAVIORAL CHANGES Many recent studies have used psychiatric classificationsof disease to address these behavioral manifestations. Although the symptoms seen in patients with epilepsy or temporolimbic dysfunction do not exactly correspond to the criteria set for these diagnoses in the different versions of the Diagnostic and Statistical Manual, this classification offers a practical model for the practicing clinician. The major categories are as follows: Cognitive disorders (disorders of attention, memory, and learning) Psychoses (ictal, interictal, and forced normalization) Affective disorders (depression, mania, and bipolar symptoms) Anxiety disorders (panic attacks and phobias) Personality disorders (hypergraphia, hyperreligiosity, viscosity, altered sexuality, and aggressivity) Pseudoseizures (somatoform disorders and conversion) Hypothalamic disorders (neuroendocrine disorders and eating disorders [anorexia]) Symptoms in each of these categories can be seen in different stages in relationship to the seizure and can be grossly classified as shown in Table 149-1.

TABLE 149-1. Stages of Seizure Symptoms Relationship to Seizure

Stage

SvmDtoms

Temporal

Prodromal

Long duration, noted 2-3 days before seizure Brief duration Alterations of consciousness Motor automatisms Sensoly disturbances Autonomic symptoms From immediately after to 1-3 days after seizure Confusion Intermittent, episodic, or persistent, associated with the epileptic focus After cessation of seizures and normalizationof EEG Remission when EEG shows recurrence of abnormalities

lctal

Postictal Nontemporal

lnterictal Forced normalization

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COGNITIVE DISORDERS In both the pediatric and the adult populations, major issues of management related to cognitive difficulties are raised. Complaints are primarily of attention, concentration, and memory problems. As with other symptoms, in the evaluation of cognitive disorders multiple factors must be considered biologic factors (cognitive function as a result of the site of the original lesion or as a result of clinical and subclinical seizures), psychiatric factors (as a result of affective disorders, primarily depression), iatrogenic factors (side effects of antiepileptic medication), and social factors (secondary to lack of educational opportunities and school environment acceptability of the seizure patient). For the younger patient in school, issues surrounding learning can be evaluated by direct contact with the school or the school psychologist, although many studies have shown lower global intelligence in patients with epilepsy. This is certainly not true for all forms of epilepsy. Earlier age of onset of seizures and frequency of generalized seizures have been correlated with lower intelligence quotient (IQ). Neuropsychological testing, specifically the Wexler Intelligence Scale for Children and the Wechsler Adult Intelligence Scale for the older patient, are the two most commonly used tests in the evaluation of these patients. Memory disorders are the most common cognitive complaint of patients. Laterality has been considered, although most patients with memory complaints show bilateral-temporal foci; as expected, problems with verbal memory are more prominent in patients with left temporal lesions. In patients who complain of memory problems, the electroencephalogram (EEG) is helpful to rule out the possibility of frequent subclinical discharges. Sedation and cognitive difficulties secondary to anticonvulsant drugs should also be considered. Attempts to use monotherapy and to use lower dosages of antiepileptic medication help to improve memory function. Some of the new anticonvulsants have been associated with word-finding difficulty, particularly topiramate. On the other hand, levetiracetam was originally used as a cognition-enhancing drug before it became available as an anticonvulsant. However, this effect was quite mild. Language dysfunction, mostly in the form of word-finding difficulty, is another common cognitive disorder. Word-finding difficulty is more prevalent among patients with left temporal lesions. However, patients with right temporal lesions seem to have language difficulties, mainly as a result of aprosody. Clearly, achievement in school and college may be affected by the speed of responding to timed tests (slowed reaction time). Patients who because of frequent subclinical seizures or antiepileptic drug side effects have slowed responses and abnormalities on routine vigilance tests. To improve the patient’s academic performance, the physician could request that additional time be provided to the patient when taking timed tests. Clearly, patient advocacy by the physician is the most effective intervention technique in this case. In younger children with school difficulty, neuropsychological testing by an experienced educational neuropsychologist may be needed to assess the possibility of specific learning disabilities.

PSYCHOSIS The oldest and one of the most controversial correlations of abnormal behavior in epilepsy is with psychosis. Many investigators have questioned the correlation between seizures and psy-

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chotic symptoms. However, a number of studies have shown an unequivocal increase in the prevalence of psychosis among epileptic patients. To distinguish the behavioral abnormality of interictal psychosis from functional psychosis, the term schizophrenia-like psychoses of epilepsy has been used. Certain findings have been considered to be more common among patients with epilepsy who show psychosis. These are lefthandedness or ambidexterity, left-sided or bilateral temporal foci, and left hemisphere tumors or other structural lesions, especially in women. As in other behavioral disorders, psychosis can be seen during the prodromal, ictal, and postictal periods in temporal relation to the seizure, or interictally. Interictal psychosis is suspected in the epileptic patient who develops persistent hallucinations and paranoid delusions, with an onset in middle age. Certain factors are more prevalent in ictal and postictal psychosis, where hallucinations are mostly olfactory and gustatory. In the interictal psychosis, visual and auditory hallucinations are more prevalent, particularly visual hallucinations. These hallucinatory experiences usually are stereotypic as opposed to functional psychosis. In both ictal and interictal psychoses, affect is preserved as opposed to the flat affect seen with functional psychosis. The sensorium usually is cloudy in ictal psychosis and clear in interictal psychosis. The presence of autonomic signs and symptoms and motor automatisms are indicative of ictal psychosis. The EEG in patients with postictal or ictal psychoses usually is positive, showing epileptogenic discharges. However, with interictal psychosis, negative EEGs and borderline findings are more common. Psychosis associated with normalization of the EEG and reduction or remission in clinical seizures has been called “forced normalization,” described by Landolt (1958). This is not a very common phenomenon; however, it is reminiscent of the old observation of antagonism between psychosis and epilepsy, when an improvement in psychosis was noted when seizures are more frequent and when seizure control resulted in worsening of psychosis. This observation led to Von Meduna’s use of electroconvulsive therapy in psychosis. Psychosis can be seen with all forms of epilepsy. However, most studies have shown a higher prevalence among patients with complex partial seizures, specifically patients with left-sided temporal lesions. Also, history of early cerebral lesions, birth trauma, perinatal encephalopathy, or infections in childhood are more prevalent among patients with epilepsy and psychosis. Certain chromosomal anomalies, such as Klinefelter’s syndrome, have been associated with both seizures and psychosis. Prolonged fugue states with wandering and multiple personalities in patients with complex partial seizures have been the subject of a number of anecdotal reports.

Management Treatment of psychosis, whether interictal or ictal and postictal, still entails the use of neuroleptic medication. However, because most neuroleptic drugs are known to induce seizures, there has been a reluctance to treat psychosis vigorously. Haloperidol, in dosages not to exceed 6 mg/day, and molindone, not to exceed 225 mg/day, have been helpful. Some reports have suggested that B,, and folate deficiency is more common among patients with psychosis, and this deficiency should be corrected during therapy. Carbamazepine has been the anticonvulsant drug of choice in these patients. The addition of benzodiazepines such as clonazepam has been helpful in some patients with interictal psychosis. However, it has been reported that benzodiazepine withdrawal

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could itself trigger a psychotic episode in patients with epilepsy. In surgical series, conflicting results have been seen with regard to psychosis. Some series show an improvement in the ictal and postictal psychotic periods. There have also been indications for what is known as postoperative psychosis, which seems to occur in patients who have a family history of psychiatric disease. The newer anticonvulsants have been difficult to judge in their effect when used in patients with a diagnosis of psychosis or psychosis associated with epilepsy. Levetriacetam, vigabatrin, and zonisamide may have psychotic symptoms as part of their untoward effects. Although it appears to be as effective as carbamazepine, lamotrigine, still has significant side effects.

increased risk of suicide, especially family history of depression, presence of interictal psychosis, history of repeated suicide attempts, and left-sided lesions. Mania is not uncommon among patients with epilepsy. Patients usually exhibit hypomanic episodes, sometimes called “epileptic excitement” in the literature. These episodes usually are seen postictally. An association with right temporal lobe foci has been made in these cases. Bipolar illness is also more common among patients with temporal lobe epilepsy, creating yet another difficult point of differential diagnosis. Here, the EEG can be very useful in distinguishing atypical bipolar disease from temporal lobe epilepsy.

ANXIETY DISORDERS

Management

Ictal fear is one of the most common symptoms of complex partial seizures. When present, it has been associated with increasing prevalence of interictal behavioral disorders and psychopathology. Prodromal anxiety is also quite common. Prolonged periods of heightened anxiety are seen in the postictal period. Interictally, patients report anxiety as frequently as depressive episodes. Panic attacks also occur with greater frequency among patients with epilepsy and are clinically difficult to distinguish from complex partial seizures. Many studies have tried to distinguish between the two disorders. Hyperventilation, which may occur with both disorders, may result in symptoms in patients with panic that one usually associates with seizures, such as loss of consciousness, dizziness, and depersonalization. Panic attacks, as opposed to seizures, are associated with family history of neuroses and history of childhood phobias, are usually slow in buildup, and last longer than seizures. Panic attacks can also be precipitated by provocation tests, and motor automatisms seen with seizures usually are not seen with panic. Phobias have also been reported in patients with epilepsy. Most patients with frequent seizures may exhibit agoraphobia. Phobias for sharp objects and driving may be a result of concern about self-injury during a seizure.

Tricyclic antidepressants have been known to reduce seizure threshold and therefore should be used with caution, although in our experience, in regular therapeutic dosages an increase in seizures is not usually seen. Amitriptyline, imipramine, and doxepin have been the most frequently used. Fluoxetine and monoamine oxidase inhibitors have also been known to produce seizures and therefore do not necessarily offer a better alternative. Lithium, especially at toxic levels, has been strongly associated with seizures and epileptiform discharges on the EEG. Carbamazepine, valproate, and phenytoin are believed to be superior to barbiturates in treating patients with depressive symptoms. In general, monotherapy is preferred in these patients. Of the new anticonvulsants, lamotrigine and oxcarbazepine have been used to treat patients with epilepsy and clinical depression with some success.

Management

Benzodiazepines, particularly clonazepam but also clorazepate, lorazepam, and alprazolam have been used; carbamazepine and propranolol have also been used with some success. In our experience, buspirone has been a very effective antianxiety medication when benzodiazepines could not be used. AFFECTIVE DISORDERS As in the other behavioral manifestations, depression in epilepsy is

multifactorial. Ictal depression usually is sudden in onset and resolves spontaneously. However, both prodromal and postictal depression have been reported to last 2 or 3 days. Interictal depression is seen in association with the other interictal disorders, and the prevalence seems to be higher among patients with complex partial seizures, with a suggestion of a predominance of left temporal focus on EEG. The issue of suicide and epilepsy has received much attention in the literature. Studies claim that the rate is 5 to 25 times higher than in the general population. These patients usually overdose on anticonvulsant drugs. A number of factors should warn against

PERSONALITY DISORDERS The issue of interictal personality disorders has been the subject of much controversy. The diagnosis is difficult clinically, and standard neuropsychological tests for personality disorders, such as the Minnesota Multiphasic Personality Inventory, fail to measure some of the traits known to be associated with epilepsy. Some of these personality characteristics may actually constitute a positive aspect in the life of a patient, such as deepened philosophical interests and hypergraphia, whereas others may be the causes of morbidity and social maladjustment, such as altered sexuality, aggressivity, and tendency to adhere to certain thoughts and actions (viscosity). It is also clear that these symptoms and symptom complexes are not present in all patients with epilepsy, and although primarily associated with complex partial seizures, they are seen in only a small percentage of patients with temporal lobe epilepsy. References to these symptoms have been present in the literature for many years. They became the focus of recent attention since the report of Waxman and Geschwind (1974) on hypergraphia in patients with temporal lobe epilepsy. Subsequently, these authors described a symptom complex of varied and interesting personality characteristics, including religiosity, deep concern with religious and philosophical issues, feelings of deepened emotionality, hyposexuality, viscosity, and aggressivity. Certain aspects of this cluster appear to be opposite to symptoms observed in animals with bilateral temporal lobectomies manifesting placidity and hypersexuality, known as the Kliiver-Bucy syndrome. Bear and Fedio (1977) devised a new personality inventory to quantify the presence of these symptoms in patients with temporal lobe epilepsy. This personality inventory has been

Chapter 149

used in many different studies with mixed results as to the prevalence of these symptoms, individually or in clusters, in patients with different forms of epilepsy. The original syndrome described by Geschwind, constituting hypergraphia, hyperreligiosity, altered sexuality, aggressivity, and viscosity, has been recognized in the behavioral neurology literature as Geschwind's syndrome since our original reference to the presence of this syndrome in the case of Dutch painter Vincent Van Gogh. Hypergraphia

Compared with disorders of spoken language, disorders of writing are less explored in the neurologic literature. The correlation between agraphia and aphasias was made much later than the original descriptions of aphasias. However, disorders of writing in psychiatric disease have been long recognized, specifically compulsive writing in schizophrenia. Studies comparing hypergraphia in patients with schizophrenia and temporal lobe epilepsy have shown a greater prevalence of this symptom among patients with epilepsy. Waxman and Geschwind's article brought attention to this interesting symptom in patients with temporal lobe epilepsy. They described extensive writing with attention to great detail and multiple repetitions and also indicated an association with religiosity and deep philosophical interests. Patients uslially make copious notes and keep detailed diaries. They also show great interest in writing fiction and poetry, again usually with great attention to detail and tendency to repetition. Hypergraphia has been reported to be of sudden onset in some hospitalized patients after surgery for epilepsy, and the patients describe a compulsion and urge to write. These patients describe more frequently ictal symptoms of ecstasy, elation, and dkja vu. Electroencephalographic studies in patients with hypergraphia shows the presence of bitemporal abnormalities; however, there is a predominance of right-sided foci. Religiosity

Commonly associated with hypergraphia, an unusual and deep interest in religion has been described in patients with complex partial seizures. Ictal religious auras and more prolonged feelings of ecstasy associated with religious aspects have been reported in the prodromal phase and during ictus. Interictal symptoms have been described during times of increased seizure frequency and also in periods of forced normalization as sudden religious conversions and periods of heightened interest in religion in patients previously not so inclined. Other associated personality traits are hypermoralism,deep philosophical interests, and feelings of personal destiny. Anticonvulsant treatment has not been known to affect these symptoms, but changes in hypergraphia and religiosity have been seen after temporal lobectomy. viscosity

Patients with temporal lobe epilepsy have been reported to have a tendency to engage in long conversations and verbal exchanges, showing an inability to terminate and perceive messages and cues for termination of such exchanges from others. In certain cases, the speech may be without informational content, and circumstantiality has been described. Viscosity has been noted to be more prevalent among patients with left temporal foci.

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ALTERED SEXUALITY Hyposexuality is common among patients with epilepsy. However, unless the physician inquires, patients usually exhibit a lack of concern and do not complain. Both female and male patients report not only lack of sexual activity but also reduction in masturbation and sexual fantasy. Prevalence of infertility is higher among epileptic patients, and in men with frequent seizures, impotence has been reported, with improvement in both drive and potency after anticonvulsant therapy and after lobectomy. Women report failure to reach orgasm; however, this may be associated with the use of some anticonvulsants, particularly barbiturates and benzodiazepines. Hypersexuality has also been reported, particularly in temporal lobe epilepsy. Reports of exhibitionism, masochism, transvestism, and fetishism have all been anecdotal. Abnormalities of sex hormones, including gonadotropins, testosterone, estrogen, and progesterone have been reported in all forms of seizures, particularly temporal lobe epilepsy. Association between these abnormalities and hyposexuality, and also an increased prevalence of homosexuality among patients with complex partial seizures, has been postulated. Ictal sexual excitement (orgasmic seizures) is rare and is seen mostly in women. However, masturbatory behavior is seen ictally as well as postictally in both sexes. Management

Ictal and postictal sexual symptoms, as well as interictal complaints of decreased libido, seem to improve with anticonvulsant therapy. In patients with hyposexuality, barbiturates and benzodiazepines should be avoided. Marriage counseling, psychotherapy, and group therapy should be offered to the patients.

ACCRESSWITY The issue of aggression and epilepsy has received a great deal of attention, both in the early literature and in the most recent studies. In the prodromal stage, most patients and their families report increased irritability and, at times, explosive behavior, but this is quite different from the more common reports of rage and explosive behavior seen during the ictus or in the immediate postictal period, usually associated with restraining the patient during motor automatisms. The latter usually are nondirected and brief, and the patient may be amnestic for these events. However, interictally, an increase in irritability, aggressivity, and an intermittent rage reaction similar to the so-called episodic dyscontrol syndrome are noted, and patients have periods of heightened anxiety and irritability during which minor provocations may result in directed explosive behavior disproportionate to the situation. These episodes are also seen in periods of forced normalization. The issue of ictal aggression in epilepsy has been the subject of a detailed review by the Committee on Violence and Epilepsy, which found ictal aggression to be extremely rare. Self-mutilatory behavior and suicidal attempts by violent means have been seen during ictus and postictally, particularly in temporal lobe epilepsy, but these are less common in epileptics than among patients with psychosis. Electroencephalographic studies in prison populations have shown a higher incidence of abnormalities. Most of these studies were done at a time when certain nonspecific electroencephalographic patterns were still considered abnormal because of

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the lack of large normal population studies. The validity of these original studies is now in question. However, among patients with temporal lobe epilepsy exhibiting aggressivity, a higher prevalence of left temporal discharges and evoked potential abnormalities lateralizing to the left hemisphere have been reported.

Management Carbamazepine and clonazepam have been used to treat interictal aggressivity. We have used propranolol successfully in these patients in addition to an anticonvulsant regimen. When aggressivity has been associated with periods of mania, lithium has also been prescribed. However, lithium levels must be monitored carefully in patients with epilepsy, and this treatment is generally discouraged. Tricyclic antidepressants have also been used in some of these patients. In children, barbiturates ought to be avoided, and there is some indication that some of the new anticonvulsants such as gabapentin and topiramate may result in increased irritability and aggressivity, similar to behavior associated with barbiturates. As with all other behavioral syndromes, the clinician should consider that aggressive behavior has multifactorial origin, and the patient’s background, family history, and social milieu should be considered. Individual counseling, psychotherapy, and group therapy should be offered to these patients.

PSEUDOSEIZURES The presence of psychogenic seizures in patients with epilepsy, especially those with onset in childhood, has been reported in both generalized as well as partial and complex partial seizures. This presents a diagnostic difficulty and produces problems with management, leading to polytherapy in patients who report continuation of seizures despite adequate control of epileptic fits. Many recent reports have tried to outline clinical means of distinguishing pseudoseizures from epileptic fits. These have been aided by the use of closed-circuit TV monitoring now available in most EEG laboratories. Behavioral seizures should be suspected when patients with frequent daily seizure episodes show persistently normal electroencephalographic findings and when the patient reports frequent seizures but this does not correspond to the family’s report of frequency of seizures. In generalized seizures, atypical movements, such as alternating movements of the limbs, flailing of the arms, side-to-side movements of the head, grimacing, pelvic thrusts, exaggerated opisthotonus, flailing movements before a tonic spasm, and persistent lack of movement (unresponsiveness longer than 5 minutes) in a patient with no other neurologic signs indicate pseudoseizures. When generalized seizures are not followed by confusion and autonomic signs, pseudoseizures should be considered. However, the distinction of psychogenic seizures in patients with complex partial epilepsy is far more difficult than in generalized seizures. Inpatient evaluation with closed-circuit TV monitoring and telemetry may be needed for these patients. We have found that with the increased availability of portable video cameras, one could request family members to make video recordings of the events taking place at home. A review of these tapes has made it increasingly easy to distinguish psychogenic seizures. Admitting the patient to the hospital for long-term monitoring may be the most effective way to determine whether behavioral seizures are present. Careful monitoring of the behavior during seizures is the first step in distinguishing pseudoseizures from epileptic fits. However, cau-

tion is necessary because in cases of frontal lobe epilepsy, some of the behaviors just mentioned may be seen. The use of special electrodes, either minimally invasive such as nasopharyngeal leads or gradually more invasive such as sphenoidal and even placement of subdural grids or depth electrode recording, may be used to diagnose frontal lobe epilepsy. Magnetic resonance imaging (MFU) and ictal single photon emission computed tomography (SPECT) have also been shown to be helpful in these difficult cases. Prolactin levels obtained within 15 minutes after a seizure, if showing a twofold increase over baseline, may be helpful. In some epilepsy centers, enolase levels can also be used up to 30 minutes after a seizure. Careful ictal and postictal examinations, including looking for a positive extensor-plantar response, is also helpful. Placebo induction of seizures, which is tried in some epilepsy centers, raises obvious ethical issues. Psychopathology seen with patients with pseudoseizures ranges from conversion disorders to factitious (Munchausen syndrome) to malingering. An early history of physical and sexual abuse and history of frequent seizures in childhood have been associated with all of the above. Individual psychotherapeutic intervention is needed in these patients, and monotherapy is preferred in anticonvulsant therapy.

EVALUATING BEHAVIORAL DISORDERS IN EPILEPSY Electroencephalography Electroencephalography remains the mainstay of evaluation of patients with epilepsy, although interictal EEG, if positive, can only support the diagnosis. Presence of epileptiform abnormalities can be quite helpful. A normal EEG does not rule out correlation between behavior and seizures because most mesial temporal foci cannot be seen on a regular surface EEG. However, caution must also be used in overinterpreting some of the atypical findings seen in electroencephalography, which in large normative studies have been found to be present in patients with no complaints of seizures or behavioral disorders. In this regard, findings of 14 and 6 positive spikes and psychomotor variants and benign epileptiform transience of sleep, which previously were considered signs of abnormality, have now come into question. After sleep deprivation, special EEG electrode placements such as nasopharyngeal electrodes, sphenoidal electrodes, and maxillary electrodes clearly increase the yield of findings in patients with mesial temporal lesions. However, EEG and closed-circuit TV monitoring have been particularly helpful in evaluating the behavioral aspects of epilepsy. Monitoring units are now available in most centers, and evaluating patients with high morbidity caused by their behavioral symptoms in these centers is quite cost effective. Computerized processing of electroencephalographic data and evoked potentials to form probability maps provide a sensitive method for evaluation of functional disorders. In addition, they allow comparison to maps of large normal populations. However, because of excessive statistical manipulation of the raw data, artifacts abound. However, in combination with standard EEG and other functional studies such as positron-emission tomography (PET), SPECT, and functional MRI (WRI),these techniques increase the sensitivity in diagnosis of seizure-related behavior.

Neuroimaging Neuroimaging studies have been most helpful in diagnosing epilepsy and also have elucidated the changes underlying behav-

Chapter 149 W

ioral aspects. MRI is clearly a preferred technique to computed tomography (CT) in evaluating patients with epilepsy and behavioral disorders. The lack of bone artifact and the availability of coronal and sagittal sections allow better evaluation of the temporal lobes. MRI detect mass lesions, especially small, lowgrade tumors, and small vascular malformations. Also, areas of cortical dysplasia can be evaluated with greater accuracy than with other techniques. In evaluating behavioral changes, ventricular size, and most recently through use of thinner slices and special angles of the coronal section, volumetric measurements of the hippocampal region have been quite useful. Bilateral nonspecific increase in T2-weighted signal intensity in the hippocampal region and the white matter adjacent to these areas have also been reported in patients with temporal lobe disorders. fMRI, which is still in its infancy, may soon become the most sensitive test in evaluating behavioral disorders. Rapid succession acquired MRI slices show signal changes caused by variations in the oxygenation state of venous vasculature during functional activation. PET and SPECT have demonstrated interictal changes of hypometabolism in patients with complex partial seizures. Hypermetabolism is seen during the seizure and at times in association with a surrounding area of hypometabolism in complex partial seizures. Both PET and SPECT show areas of hypoperfusion, not only surrounding the area of the ictus but also at distant areas, giving further evidence of the distant effects of the epileptic focus.

BEHAVIORAL DISORDERS AND QUALITY OF LIFE IN EPILEPSY Recently, different scales for assessing quality of life in patients with epilepsy have been devised, similar t o those for other chronic neurologic illnesses. These scales address the issues affecting the whole patient, especially the psychosocial aspects, which are of great importance in evaluating behavioral symptoms. As more data from these studies become available, prognostic evaluation and therapeutic mediation in all aspects of behavioral disorders related to epilepsy will become more accurate and will allow a reevaluation of the controversial aspects of behavior and epilepsy.

SUGGESTED READINGS Bear DM, Fedio P Quantitative analysis of interictal behaviour in temporal lobe epilepsy. Arch Neurol 34454-486, 1977 Blumer D Hypersexual episodes in temporal lobe epilepsy. Am J Psychiatry 126:1099-1106, 1970 Delgado-Escueta AV, Mattson RH, King L et al: Special report: the nature of aggression during epileptic seizures. N Engl J Med 305:711-716, 1981

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Devinsky 0 Clinical uses of the quality of life in epilepsy inventory. Epilepsia 34(suppl4):S39-S44, 1993 Flor-Henry P Psychosis and temporal lobe epilepsy: a controlled investigation. Epilepsia 10363-395, 1969 Geschwind N Pathogenesis of behaviour changes in temporal lobe epilepsy. In Ward A, Penry J, Purpura D (eds): Epilepsy. Raven Press, New York, 1983 Henry TR, Mazziotta JC, Engel J: Interictal metabolic anatomy of mesial temporal lobe epilepsy. Arch Neurol 50:582-589, 1993 Herzog AC, Russell V, Vaitukaitis J L Neuroendocrine dysfunction in temporal lobe epilepsy. Arch Neurol 39:133-135, 1982 Janszky J, Szucs A, Halasz P et ak Orgasmic aura originates from the right hemisphere. Neurology 58:302-304,2002 Khoshbin S: Seizure disorders. pp. 730-743. In Branch WT (ed): Office Practice of Internal Medicine. WB Saunders, Philadelphia, 1994 Khoshbin S: Van Gogh‘s malady and other cases of Geschwind’s syndrome. Neurology 36(suppl 1):213-214, 1986 Khoshbin S, Kim DH: Cortical auditory evoked potential mapping in females with panic disorder. Neurology 39(suppl 1):226, 1989 Khoshbin S, Levin AL: Cortical evoked potential mapping in the episodic dyscontrol syndrome. Neurology 36(suppl 1)348-349, 1986 Khoshbin S, Levin L, Milrod L et al: Cortical evoked potential mapping in complex partial seizures. Neurology 34(suppl):219, 1984 Kwan P, Brodie MJ: Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 357:216-222, 2001 Landolt H: Serial encephalographic investigations during psychotic episodes in epileptic patients and during schizophrenic attacks. pp. 91-133. In de Hass L (ed): Lectures on Epilepsy. Elsevier, Amsterdam, 1958 Meierkord H, Will B, Fish D et ak The clinical features and prognosis of pseudoseizures diagnosed using video-EEG telemetry. Neurology 41:1643, 1991 Saygi, S, Katz A, Marks DA et al: Frontal lobe partial seizures and psychogenic seizures: comparison of clinical and ictal characteristics. Neurology 42:1274, 1992 Schomer DL, O’Connor M, Spiers P et al: Temporolimbic epilepsy and behavior. pp. 373-405. In Mesulam MM (ed): Principles of Behavioral and Cognitive Neurology. 2nd Ed. Oxford University Press, New York, 2000 Slater E, Beard AW The schizophrenia-like psychoses of epilepsy. Br J Psychiatry 109:95-150, 1963 Stevens J R Neuropathology of schizophrenia. Arch Gen Psychiatry 39:1131-1139, 1982 Taylor D C Sexual behavior and temporal lobe epilepsy. Arch Neurol 21:510-516, 1969 Waxman SG, Geschwind N Hypergraphia in temporal lobe epilepsy. Neurology 24629436, 1974 Zaidi A, Clough P, Cooper P et al: Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol 36181-184, 2000

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Disorders of Sleep Jean K. Matheson

Sleep is an active, clinically important behavior that is associated with important physiologic changes in most organ systems. These changes have a temporal organization that is under cerebral influence. Sleep disorders may represent a primary disorder of mechanisms regulating sleep or failure of a specific organ system manifesting in a unique way during sleep. Sleep complaints should not be ignored or treated empirically with pharmacologic agents. More often than not, disordered sleep is a symptom of underlying disease. PHYSIOLOCY

Rapid eye movement (REM) and non-REM (NREM) are the two sleep states. REM sleep was discovered by Aserinsky and Kleitman in the early 1950s. By waking subjects during REM, they also established that vivid dreaming occurs during this state. Soon thereafter, Dement recognized that episodes of REM sleep alternate with NREM sleep in cycles lasting approximately 90 minutes throughout the night. Recordings derived from electroencephalograms (EEGs), electro-oculograms to determine eye movements, and electromyograms (EMGs) of chin tone are necessary to distinguish sleep states. Polysomnography is the technique used to record multiple physiologic variables during sleep. In clinical practice several other physiologic measures typically are recorded, including respiratory effort from the chest and abdomen, oral and nasal air flow, cardiac rhythm, and electromyographic activity in the anterior tibialis muscles of the legs. NREM sleep is divided into four stages (I-IV). The waking EEG with the eyes closed reveals the characteristic a-rhythm, which is a posteriorly predominant 8- to 12-Hz rhythm that attenuates with eye opening. Stage I sleep is characterized by the gradual disappearance of the a-rhythm, which is replaced by slower, 2- to 7-Hz activity and some fast 12- to 14-Hz low-voltage activity. Stage I1 is distinguished by the presence of spindles (bursts of 12to 14-Hz activity, lasting at least 0.5 seconds, with a spindle appearance) and K complexes (high-voltage biphasic negative and positive waves best seen at the vertex, often associated with spindles). Stages I11 and IV are defined by the presence of high-voltage slow-wave activity of 2 Hz or less. An epoch of 30 seconds is measured: If 20% to 50% of the record shows high-voltage slow-wave activity, it is called stage 111; more than 50% high-voltage slow-wave activity is called stage IV. Stages I11 and IV often are described together as slow-wave sleep or delta 962

sleep. Delta sleep can be characterized as deep sleep because during this stage subjects are difficult to arouse. Detailed dreaming does not occur, but subjects awakened during this sleep stage have reported “thinking.” The normal subject descends in an orderly progression through the four NREM sleep stages. Delta sleep appears 30 to 45 minutes after sleep onset. The first REM period follows this delta sleep, about 70 to 90 minutes after sleep onset. The polysomnogram during REM shows dramatic changes. A sudden loss of electromyographic activity is seen in the chin muscles, which reflects generalized skeletal muscle atonia. Except for the eye muscle sphincters, and respiratory muscles, the subject is paralyzed. Rapid eye movements occur in phasic bursts. The EEG shows mixed frequencies similar to those of stage I and waking. Characteristic “sawtooth” waves sometimes appear on the EEG during eye movements. Respiration and heart rate are irregular. The first REM period is short, approximately 10 minutes. The end of the first REM period completes the first sleep cycle. Thereafter NREM continues to alternate with REM; the healthy young adult goes through four to six cycles (Fig. 150-1). Sleep architecture is the organization of sleep stages and cycles. The normal young adult spends approximately 5% of the night in stage I, 50% in stage 11, 12% in stage 111, 13% in stage IV, and 20% in REM. Delta sleep is concentrated in the first third of the night, whereas REM episodes become progressively longer later in the night. Delta sleep decreases as a function of age, but REM percentage is stable after early childhood. Of the newborn’s daily 17 to 18 hours of sleep, 50% is REM. Children and early adolescents sleep 10 to 11 hours. Most adults prefer to sleep 7 to 8 hours a day, but sleep needs vary. Short sleepers are classified as people who feel adequately rested with less than 6 hours of sleep; long sleepers need more than 9 hours. Sleep efficiency is defined as the time spent asleep divided by the time spent in bed. Sleep efficiency decreases in old age as both the number of arousals and the time spent in bed increase. This does not necessarily represent normal aging. Arousals usually have a cause. If there are frequent external or internal sleep disrupters, the sleep patterns change. After arousal, the patient develops stage I sleep, followed by stage I1 sleep, repetitively, and the percentages of delta sleep and REM sleep decrease. Drugs can also inhibit REM and delta sleep. Monoamine oxidase inhibitors and tricyclic antidepressants, for example, decrease the percentage of REM sleep dramatically. Alcohol and caffeine increase arousal. If patients are deprived of either REM or delta sleep, rebound usually

Chapter 150 CHILOREN

nOUASOFSLEEP

FIG. 150-1. Sleep architecture. REM sleep alternates with NREM in

cycles approximating 90 minutes in all age groups. Delta sleep is prominent in childhood and decreases in older adults as awakenings and wake time increase. (From Kales A, Kales JD: Sleep disorders: recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med 290:487, 1974, with permission.) is seen on recovery nights. REM rebound can be intrusive and frightening, with an abundance of vivid dreams. Chronic partial sleep deprivation results in inattentiveness during monotonous tasks, performance variability, slowed reaction time, memory impairment, mood deterioration, irritability, and even mild paranoia. Evidence is accumulating that even low levels of sleep restriction can induce important dysfunction of a number of endocrine systems. One important recent study showed impaired glucose tolerance, decreased thyrotropin, and increased cortisol in short-term sleep restriction to 4 hours a night. REM sleep and NREM sleep differ physiologically. REM sleep is characterized by both phasic and tonic changes in physiology. The drop in baseline EMG correlates with a tonic change. Rapid eye movements correlate with phasic changes. Tonic physiologic changes also include impaired thermoregulation, hypotension, bradycardia, increased cerebral blood flow and intracranial pressure, increased respiratory rate, and penile erection. Intercostal and upper airway muscles become atonic, but the diaphragm maintains activity. Phasic changes include vasoconstriction, increased blood pressure, tachycardia, and further increases in cerebral blood flow and respiratory rate. During NREM, the physiologic state is more stable, but blood pressure, heart rate, cardiac output, and respiratory rate decrease. The functional anatomy of sleep is complex and not yet resolved. Recent evidence has shown that neurons of the ventrolateral preoptic nucleus (VLPO) are sleep active and sleep promoting, confirming old observations that lesions in this area induced insomnia. These neurons express y-aminobutyric acid (GABA) and the neuropeptide galanin and are reciprocally connected to monoaminergic arousal systems, especially the

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histaminergic tuberomammillary nucleus of the posterior hypothalamus. It is likely that separate sets of neurons in the region of VLPO are important in independent control of both NREM and REM sleep. Neurons known to be critical for generating REM sleep are also found in the lateral pons and adjacent midbrain, including the cholinergic cells of the pedunculopontine and lateral dorsal tegmental nuclei. Physiologic components of REM sleep such as muscle atonia or cardiovascular changes can be dissociated in lesion experiments in animals, indicating that this sleep state represents a coordinated interaction between multiple cell populations and neurotransmitters. GABA, acetylcholine, glycine, and glutamate are important transmitters in brainstem cells that are maximally active in REM ( E M - o n cells). Monoaminergic neurotransmitters inhibit REM, and brainstem neurons producing norepinephrine, epinephrine, and serotonin are essentially inactive during REM sleep (EM-off cells). Hypocretin (also called orexin), a recently discovered neuropeptide produced by neurons in the lateral hypothalamus, appears to play a key role in maintaining wakefulness. Abnormalities of this peptide system induce excessive sleepiness in narcolepsy. Hypnogenic substances have been isolated, including prostaglandin D,, delta sleepinducing peptide, muramyl dipeptides, and interleukin-1, but how they promote sleep is unknown. Attention has recently focused on adenosine, a degradation product of adenosine triphosphate, because injections of adenosine into the brain promote sleep. In addition, the concentration of adenosine gradually increases during prolonged waking, and the sleep-promoting effects of adenosine are blocked by the adenosine antagonist caffeine. Chronobiology is the science of the temporal organization of physiologic processes. Circadian rhythmicity of multiple physiologic variables,with a period close to 24 hours, is seen in almost all living organisms, even in the absence of environmental cues. Sleep, body temperature, and melatonin secretion by the pineal gland are examples of these rhythms. This internal rhythmicity has long suggested an underlying endogenous "clock" that can be influenced by external cues, especially light. There is extensive anatomic and physiologic evidence that the suprachiasmatic nucleus of the hypothalamus, which receives direct input from the retinohypothalamic tract, is the major anatomic location of this circadian clock. A major breakthrough in the understanding of the circadian system is the recent discovery of a set of clock genes that participates in transcription-translation feedback loops that generate oscillations of close to 24 hours in fungi, plants, insects, and mammals. In mammals, these clock genes are expressed in the suprachiasmatic nucleus and in many other tissues, especially the retina. For many years the period of the human circadian pacemaker was reported to be 25 hours. New evidence, with better attention to the influence of environmental lighting, indicates that the human period is actually closer to 24 hours. The current estimate of the human circadian period is reported to be 24.18 hours.

SLEEP DISORDER CLASSlFlCATlON In 1972 the Association of Sleep Disorders Centers established a diagnostic classification system of sleep and arousal disorders. The nosology unified clinical definitions across medical and research disciplines. The disorders were classified by presenting complaint, rather than by cause, into four major categories: disorders of initiating and maintaining sleep, or insomnias; disorders of excessive somnolence; disorders of the sleep-wake schedule; and dysfunctions associated with sleep, sleep stages, or partial arousal

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(parasomnias). This organization is helpful in approaching differential diagnosis. However, for statistical and research purposes the classification is inadequate because one disorder may present with more than one symptom. Therefore, the classification was revised in 1990 as the International Classification of Sleep Disorders (ICSD; Table 150-1) and is now based on broadly defined pathophysiologic mechanisms rather than presenting symptoms. The major divisions of the ICSD classification are the dyssomnias, parasomnias, sleep disorders associated with medical and psychiatric disorders, and proposed sleep disorders. DYSSOMNIAS The dyssomnias are primary sleep disorders that produce either difficulty initiating and maintaining sleep or excessive daytime sleepiness. Within the classification of the dyssomnias, the sleep abnormalities must be fundamental to the disorder. Psychiatric and medical disorders that influence sleep as only one component of the clinical presentation are not included in the ICSD definition of dyssomnia. The dyssomnias are further divided into three groups: the intrinsic, the extrinsic, and the circadian rhythm sleep disorders. Intrinsic sleep disorders are thought to originate within the body (e.g., narcolepsy or obstructive sleep apnea). Extrinsic sleep disorders originate outside the body (e.g., poor sleep hygiene or environmental disruption). Circadian rhythm sleep disorders represent disorders in timing of the sleep-wake cycle within the 24-hour day. Difficulty Initiating and Maintaining Sleep (Insomnia) Inability to sleep may take the form of prolonged initial latency to sleep, recurrent nocturnal awakenings, or early morning awakening without the ability to return to sleep. Insomnia is an extremely common complaint that causes high levels of frustration and significant misery. For reasons that are inexplicable, insomnia often is trivialized by the clinician and treated pharmacologically without attention to the underlying cause of the complaint. Inability to initiate or maintain sleep is a symptom that must be explored with the same approach the clinician uses to assess other medical complaints. As in most disorders, a careful history is the most useful diagnostic tool. (See Table 150-2, which reviews the basic components of a sleep history.) Exploring the patient’s daily schedule in an orderly fashion often is particularly revealing. A sleep log helps document patterns that suggest specific disease. The schedule of daily activities gives insight into the patient’s personality and discloses habits that contribute to poor sleep hygiene. All medical history is relevant, and illnesses that are well known to cause nocturnal arousal are particularly important (e.g., gastroesophageal reflux, arthritis, congestive heart failure, snoring). A family history of sleep disorder and history of childhood sleep behavior is useful. A review of drug use is critical, including prescription medications, home remedies, caffeine, alcohol, and illicit drugs. Excessive Daytime Sleepiness Excessive daytime sleepiness is defined as the tendency to fall asleep inappropriately when sedentary. Patients with excessive daytime sleepiness may or may not demonstrate hypersomnolence (i.e., excessive sleep during a 24-hour period). Patients with chronic disorders of excessive daytime sleepiness often accept sleepiness as normal. The clinician should look for a history of

excessive daytime sleepiness in any situation presenting as chronically reduced performance, including dementia or depression, or in situations suggesting episodic inattention, such as automobile accidents. Instead of sleepiness, many patients cite blackouts, forgetfulness, poor concentration, automatic behavior, or amnesic spells. Children may have poor school performance or behavioral problems. These situations necessitate the taking of a sleep history that includes questioning whether sleeping occurs during sedentary activities, social activities, driving, and eating. Sleepiness must be distinguished from fatigue (i.e., a sense of tiredness without the tendency to fall asleep inappropriately) and disorders of consciousness secondary to encephalopathy. On careful study most patients with excessive daytime sleepiness prove to have either sleep-disordered breathing or narcolepsy.

Intrinsic Sleep Disorders “Psychophysiologic insomnia is a disorder of somatized tension and learned sleep-preventing associations that results in a complaint of insomnia and associated decreased functioning during wakefulness.” (This definition and those that follow are taken from the ICSD Diagnostic and Coding Manual and appear in quotation marks.) Such patients usually do not have evidence of underlying psychiatric disease, but they may be highly focused on their insomnia. Overconcern with the process of going to sleep is alerting, induces increased tension, and becomes a sleeppreventing association. The precipitant for this disorder may be a period of acute insomnia associated with an external stress (adjustment sleep disorder, described later in this chapter). A characteristic pattern emerges: inability to obtain satisfactory sleep for a few nights induces fear that another sleepless night will follow. Patients report that they feel alert as soon as they try to initiate sleep. They toss and turn, watch the clock, and become frustrated and angry that they are unable to sleep. Often, sleep is better in a new environment free of the usual external sleep-onset associations. Psychophysiologic insomnia can be treated with relaxation techniques in combination with methods that decondition the patient’s negative associations with sleep onset. A technique known as stimulus-control therapy, proposed by Bootzin, is highly effective. The patient is instructed to go to bed only if sleepy; use the bed only for sleeping and sexual relations, not as a place to read, write, or watch television; get up and leave the bedroom if sleep is not obtained within 10 to 15 minutes and engage in a nonstimulating activity until sleepiness is perceived; repeat this step as many times as necessary throughout the night; maintain a fixed schedule of awakening each morning; and not nap during the day. “Sleep state misperception is a disorder in which a complaint of insomnia or excessive sleepiness occurs without objective evidence of sleep disturbance.” Underestimation of the actual amount slept is common in insomniacs. Some patients complain of absolute lack of sleep. Polysomnographic recording reveals a normal sleep latency, a normal number of arousals and awakenings, and normal sleep duration, but the patient perceives poor or absent sleep. This disorder must be distinguished from the phenomenon of paradoxical improvement in sleep during overnight recording in the sleep laboratory, which occurs in patients with psychophysiologic insomnia. In the latter disorder, sleep may improve in a novel environment, including the sleep laboratory, and this improvement is appreciated by the patient. Many patients who report near

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TABU 150-1. International Classification of Sleep Disorders 1. Dyssomnias

A. Intrinsic sleep disorders

3. Sleep disorders associated with mental and psychiatric disorders A. Associated with mental disorders 1. Psychoses 2. Mood disorders 3. Anxiety disorders 4. Panic disorders 5. Alcoholism B. Associated with neurologic disorders 1. Cerebral degenerative disorders 2. Dementia 3. Parkinsonism 4. Fatal familial insomnia 5. Sleep-related epilepsy 6. Electrical status epilepticus of sleep 7. Sleep-related headaches C. Associated with other medical disorders 1. Sleeping sickness 2. Nocturnal cardiac ischemia 3. Chronic obstructive pulmonary disease 4. Sleep-related asthma 5. Sleep-related gastroesophageal reflux 6. Peptic ulcer disease 7. Fibrositis syndrome 4. Proposed sleep disorders 1. Short sleeper 2. Long sleeper 3. Subwakefulness syndrome 4. Fragmentary myoclonus 5. Sleep hyperhidrosis 6. Menstrual-associated sleep disorder 7. Pregnancy-associatedsleep disorder 8. Terrifying hypnagogic hallucinations 9. Sleep-related neurogenic tachypnea 10. Sleep-related laryngospasm 1 I.Sleep choking syndrome

1. Psychophysiologic insomnia 2. Sleep state misperception 3. Idiopathic insomnia 4. Narcolepsy 5. Recurrent hypersomnia 6. Idiopathic hypersomnia 7. Post-traumatic hypersomnia 8. Obstructive sleep apnea syndrome 9. Central sleep apnea syndrome 10. Central alveolar hypoventilationsyndrome 1 1. Periodic limb movement disorder 12. Restless legs syndrome 13. Intrinsic sleep disorder not otherwise specified B. Extrinsic sleep disorders 1. Inadequate sleep hygiene 2. Environmental sleep disorder 3. Altitude insomnia 4. Adjustment sleep disorder 5. Insufficientsleep syndrome 6. Limit-setting sleep disorder 7. Sleep-onset association disorder 8. Food allergy insomnia 9. Nocturnal eating (drinking) syndrome 10. Hypnotic-dependent sleep disorder 1 1. Stimulant-dependent sleep disorder 12. Alcohol-dependent sleep disorder 13. Toxin-induced sleep disorder 14. Extrinsic sleep disorder not otherwise specified C. Circadian rhythm sleep disorders 1. Time zone change (jet lag) syndrome 2. Shift work sleep disorder 3. Irregular sleep-wake pattern 4. Delayed sleep phase syndrome 5. Advanced sleep phase syndrome 6. Non-24-hour sleep-wake disorder 7. Circadian rhythm sleep disorder not otherwise specified 2. Parasomnias A. Arousal disorders I. Confusional arousals 2. Sleepwalking 3. Sleep terrors B. Sleep-wake transition disorders 1. Rhythmic movement disorder 2. Sleep starts 3. Sleep talking 4. Nocturnal leg cramps C. Parasomnias usually associated with REM sleep 1. Nightmares 2. Sleep paralysis 3. Impaired sleep-related penile erections 4. Sleep-related painful erections 5. REM sleep-related sinus arrest 6. REM sleep behavior disorder D. Other parasomnias 1. Sleep bruxism 2. Sleep enuresis 3. Sleep-related abnormal swallowing syndrome 4. Nocturnal paroxysmal dystonia 5. Sudden unexplained nocturnal death syndrome 6. Primary snoring 7. Infant sleep apnea 8. Congenital central hypoventilationsyndrome 9. Sudden infant death syndrome 10. Benign neonatal sleep myoclonus 1 1. Other parasomnia not otherwise specified From Thorpy M1: ICSD-International Classification of Sleep Disorders: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee, American Sleep DisordersAssociation, Rochester, MN, 1990,with permission.

absence of sleep are mistakenly treated with hypnotic medications for years, without improvement. The existence of this disorder underscores the usefulness of polysomnographic evaluation of patients with chronic sleep complaints. Sometimes patients report sleepiness that cannot be verified on

objective testing with the multiple sleep latency test (MSLT); this may be a sleep state misperception. However, sleepiness is more difficult to measure than the presence or absence of sleep. “Idiopathic insomnia is a lifelong inability to obtain adequate sleep that is presumably due to an abnormality of the neurological

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TABLE150-2. Basic Components of the Sleep History What problems do you have with your sleep? When did these problems start? Do you have a bedpartner? Does your bedpartner complain about any aspect of your sleep? What is your job? Do you work shifts? What time do you go to bed on workdays? On days oft? What time do you wake on workdays? On days oft? On average how many hours do you sleep? Do you wake on your own, or do you use an alarm clock? Do you oversleep past your planned wake up time? Do you feel rested when you wake? Do you nap during the day? Are these naps planned? Are your naps refreshing? Do you dream during short naps? How long does it take you to fall asleep at night? If you have difficulty getting to sleep, what do you think is the cause? Do you worry about not being able to get to sleep? What do you do when you cannot sleep? Have you ever used sleeping pills?When? How long? Does it take you longer to fall asleep on workdays than on days off? Is it easier or more difficult to fall asleep when you are away from home? Do you wake up during the night?How often? When? What do you think wakes you up during the night? Do you have difficulty returning to sleep when you wake during the night? What do you do if you cannot return to sleep? Are you sleepy during the day? Do you fall asleep during the day or evening when you do not intend to? If yes, when under what circumstances do you fall asleep? Have you ever fallen asleep, or nearly fallen asleep, while driving? Have you ever had an automobile accident that you think was caused by your sleepiness? Do you snore? How loudly? Does your bedpartner leave the room because of your snoring? Does anyone notice that you stop breathing in your sleep? Do you wake gasping for air? If you wake unable to breathe, can you speak? Do you have hypertension? Are you overweight? What is your collar size? if excessively sleepy: Have you ever had a sensation of weakness in your knees or face brought on by laughter, excitement, anger, or sadness? Do you ever see dreamlike images just before you fall asleep or when you are sleepy? Do you ever have any other unusual sensations as you fall asleep such as hearing a voice, having the feeling that something is crawling on you, or that you are flying? Have you ever had the sensation that you cannot move as you are falling asleep or waking up? Do you ever perform activities automatically, without conscious attention to the task? Do you have uncomfortable sensations in your legs when you are trying to sleep or when you are sitting quietly? Is this discomfort more prominent in the evening? Do your legs twitch when you are trying to sleep or when you are sitting quietly? Does anyone else notice that your legs twitch or move when you are asleep? Does anything unpleasant happen to you during your sleep? Describe what happens. Do you scream or yell out in your sleep? Do you wake with a sensation of panic? Have you ever walked in your sleep? Were you a bedwetter as a child? Do you ever wet the bed now? Do you have frightening dreams frequently? Have you ever injured yourself or anyone else during your sleep? Do you think that you act out your dreams? Has anyone ever told you that you run, kick, or punch during your sleep? Document: Caffeine, amount and timing Alcohol, amount and timing Illicit drugs Herbal preparations Light exposure (with particular attention to evening and morning) Exercise schedule Work schedule Medications Medical and psychiatric history Review of systems Family history, including snoring and restless legs Social historv

control of the sleep-wake system.” This disorder may also be called childhood-onset insomnia. Unlike “short sleepers,” who feel rested despite short sleep durations, patients with this disorder complain of chronically poor performance because of poor sleep. Polysomnographic evaluation reveals increased sleep latency, decreased efficiency, and increased arousals, but the cause of the sleep disruption is not apparent. Because of the chronicity of the disorder, patients often develop secondary sleep disorders such as psychophysiologic insomnia and hypnotic dependence. There is no effective treatment except directing attention to conditions that may aggravate the underlying insomnia. “Narcolepsy is a disorder . . . characterized by excessive sleepiness that typically is associated with cataplexy and other REM sleep phenomena such as sleep paralysis and hypnagogic hallucinations.” Narcolepsy was first defined as a distinct disorder in 1880 by Gelineau, who described the syndrome as a “rare, little known neurosis characterized by imperative need to sleep.” It is now known that the disorder is not rare. The prevalence is estimated at 2 to 16 in 10,000 persons. The onset of symptoms occurs typically in the second or third decades, and both sexes are equally affected. A family history is noted in approximately one third of cases. The discovery of E M sleep was followed by the finding that patients with narcolepsy have abnormal REM physiology. It is now accepted that the major manifestations of narcolepsy represent a disorder of control mechanisms that regulate REM sleep. Episodes of REM occur at the wrong time, intruding on wakefulness, and the physiologic components of this sleep state dissociate and appear independently. These major symptoms are known as the narcolepsy tetrad excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Few patients report all of these symptoms, especially in the early stages of the disorder, but almost all patients have evidence of excessive daytime sleepiness. The cardinal symptom of narcolepsy is excessive daytime sleepiness, and approximately 10% of patients complain of this symptom alone. The tendency to sleep inappropriately may have a gradual or an abrupt onset. History taking typically reveals that patients remember brief lapses of attention in sedentary situations years before presentation to a physician. With time, sleepiness is evident in clearly inappropriate situations, such as driving, attending business conversations, eating, or engaging in sexual intercourse. Patients often are able to recognize impending drowsiness and take measures to alert themselves. Irresistible sleep attacks are characteristic, however, and tend to occur when the urge to sleep has been delayed. Two features are unique to the naps of narcoleptics: Dreaming during naps is common, and brief naps of 5 to 10 minutes duration are remarkably refreshing. Cataplexy is a sudden, usually brief loss of muscle tone induced by emotion. The presence of cataplexy is considered diagnostic of narcolepsy, but only 60% to 80% of patients experience this symptom, and it may occur years after the onset of sleepiness. Rarely, cataplexy is the presenting symptom of the disorder. Idiopathic cataplexy without sleepiness may exist but is poorly described. Laughter and anger are the most common precipitants, but the emotional trigger may be specific to the patient. The weakness that develops usually involves the muscles of the face or the supporting muscles of the legs; it may be so mild as to give only the sense that the face will not move properly or so profound as to cause a sudden fall. The appearance of facial tremulousness can be confused with seizure activity. Occasionally, patients have difficulty speaking. Consciousness is maintained during a cataplectic episode, but prolonged episodes may be immediately followed by

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REM sleep. Cataplexy is the result of sudden skeletal muscle atonia sparing extraocular eye movements and diaphragm. Deep tendon reflexes are absent during the episode. This atonia is similar to that which occurs during normal REM sleep. Cataplexy thus seems to represent a dissociation of normal REM phenomena, occurring inappropriately during waking. In hallucinations occurring at the onset of sleep, called hypnagogic hallucinations, the sensory perceptions associated with normal dreaming occur during perceived wakefulness. These hallucinations are a manifestation of the sudden onset of inappropriate and dissociated REM sleep. Hallucinations may involve any sensory system and often are visual, auditory, or vestibular. Sleep paralysis is an inability to move skeletal muscles voluntarily during sleep-wake transitions. Normal subjects may experience the sensation on awakening from REM, but narcoleptics typically complain of sleep paralysis at sleep onset. The episodes can be associated with extreme fear, especiallywhen they are associated with threatening hypnagogic hallucinations. Sleep paralysis is another manifestation of REM-related atonia. Two other symptoms are typical of narcolepsy: automatic behavior and disrupted nighttime sleep. Patients with automatic behavior complain that they perform complex, often routine activities “automatically,” with partial amnesia and evidence of inattention during the behavior. “Microsleeps” or poor attentiveness caused by sleepiness may be the source of this behavior. Just as patients have difficulty maintaining alertness because of intrusion of sleepiness during the day, narcoleptics complain of inability to maintain sleep at night. The narcoleptic’ssleep tends to be punctuated by frequent awakenings and vivid dreams. Periodic movements in sleep syndrome and sleep apnea are more common in narcolepticsand contribute to this poor sleep quality. Cataplexy, hypnagogic hallucinations, and sleep paralysis are episodic symptoms that may resolve, but automatic behavior, poor memory, and disturbed sleep often worsen with age. The degree of sleepiness remains constant over the years. Recent discoveries provide compelling evidence that dysfunction of the hypocretin (Hcrt) peptide system is involved in the neurobiology of narcolepsy. The hypocretin peptides (Hcrt-1 and Hcrt-2, also known as orexin-A and -B) are wake-promoting neurotransmitters derived from a common precursor, preprohypocretin. Hcrt cells are found predominantly in the posterior lateral hypothalamus and have widely projecting excitatory inputs to arousal systems, especially brainstem regions that promote wakefulness and suppress REM sleep. In 1999, a mutation of the Hcrt receptor 2 gene was discovered in genetically narcoleptic dogs. Shortly thereafter, mice with a null mutation of the preprohypocretin gene were noted to display features consistent with narcolepsy. A postmortem analysis of brains from narcoleptic humans showed a reduction in the number of Hcrt neurons with associated gliosis in the hypothalamus. One atypical, early-onset human narcoleptic has been identified with a mutation of the preprohypocretin gene, but no other mutations in this gene or in the genes coding for the hypocretin receptors have been identified in humans. The association of certain human leukocyte antigen (HLA) alleles with this apparent loss of hypocretin neurons suggests the possibility of an autoimmune mechanism, but none has yet been proven. Most narcoleptics, carry the HLA allele HLA-DQB1*0602, which appears to confer susceptibility to the disorder. This association holds best for patients with convincing cataplexy, of whom 85% to 95% test positive for HLA-DQBl*0602. Although

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HLA-DQB1-0602 is seen in 12% to 38% of the normal population across many ethnic groups, narcolepsy affects only 0.02% to 0.18% of the general population. Most monozygotic twin pairs are discordant for narcolepsy, suggesting that environmental factors are likely to be involved in the pathogenesis. Polysomnographic studies in narcoleptics demonstrate two major features: excessive daytime sleepiness, as measured by multiple daytime naps; and the tendency to develop REM sleep within minutes of sleep onset in daytime and nocturnal recordings. Normal patients do not show sleep-onset REM unless they are sleep deprived, have an abnormal sleep-wake cycle, or are withdrawing from REM-suppressing medication. Recordings during periods of cataplexy and sleep paralysis show the sudden onset of muscle atonia characteristic of REM sleep. Occasionally narcolepsy or cataplexy occurs in association with other neurologic disorders, in which case the condition is called symptomatic narcolepsy. Both narcolepsy and cataplexy have been described in patients with tumors in the region of the third ventricle and upper brainstem. Cataplexy has also been described in Niemann-Pick disease. Occasionally narcolepsy is said to follow head trauma and encephalitis. The diagnosis of narcolepsy is secure if excessive daytime sleepiness is associated with unequivocal cataplexy. The diagnosis can be confirmed with polysomnographic studies, and these are especially helpful in patients without a clear history of cataplexy. The current electrophysiologic standard of diagnosis is the MSLT, which measures the tendency to sleep and the type of sleep the patient obtains in four or five brief naps scheduled throughout the day. The mean latency to daytime sleep usually is less than 5 minutes. Confirmation of the diagnosis of narcolepsy requires that a minimum of two daytime naps demonstrate REM sleep. A polysomnogram on the night preceding the MSLT is necessary to exclude sleep deprivation as a cause of short daytime latencies and sleep-onset REM and to identify other sleep disorders. Drugs that are known to influence sleep latency or REM sleep, such as antihistamines, antidepressants, or stimulants, cannot be present or recently discontinued. Because sleep-onset REM may be seen in a number of clinical settings including sleep deprivation, drug use, and circadian rhythm disorders, the MSLT cannot be interpreted without careful attention to the clinical context. The pharmacologic treatment of narcolepsy relies on the use of central nervous system (CNS) stimulant medication. The most commonly used medications include methylphenidate, modafinil, and dextroamphetamine. Pemoline was previously used extensively for this disorder but is no longer an acceptable first-line medication because of reports of fatal liver toxicity. The goal of treatment with stimulant medication is to use the lowest effective dosage of stimulant medication that will maintain adequate alertness to perform day-to-day activities. Methylphenidate and dextroamphetamine act primarily to increase the availability of norepinephrine and dopamine in CNS by blocking uptake and increasing release. Methylphenidate and dextroamphetaminedemonstrate side effects consistent with their sympathomimetic properties. Cardiovascular side effects are dose dependent and may be relative contraindications in patients with heart disease or hypertension. Sinus tachycardia may limit dosage adjustment, even in healthy young patients. Both methylphenidate and amphetamines have high abuse potential and may induce a toxic psychosis when used in excess. However, intentional abuse tends to be unusual in the narcoleptic population. Efficacy of these drugs is similar, but methylphenidate has fewer side effects and less abuse potential than dextroamphetamine. Recommended dosages

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of both methylphenidate and dextroamphetamine are 5 to 60 mg, but prescribing practices vary widely. A regimen that works well for many patients is one in which a stable dosage of a long-acting preparation of methylphenidate or dextroamphetamine is supplemented by the short-acting preparations of the same drug for activities necessitating increased alertness, typically once or twice a day. The excessive use of short-acting medications often induces periods of relative withdrawal that exacerbate underlying symptoms. Stimulants used late in the day may increase nocturnal sleep deprivation and, therefore, paradoxically increase excessive daytime sleepiness. Modafinil, a novel stimulant medication with an unknown mechanism of action, was introduced into the United States in 1999 specifically to treat narcolepsy. The major benefits of this drug are absence of cardiovascular stimulating effects, low abuse potential, and long duration of action. Modafinil also produces less interruption of nocturnal sleep than either methylphenidate or amphetamines. The most common side effect is headache, which may be transient. The drug’s metabolism renders hormonal birth control unreliable, which is an important concern in this young population. The dosage for narcolepsy is typically 200 to 400 mg given as a single or divided dose. Cataplexy often resolves or improves dramatically with treatment of excessive daytime sleepiness with either methylphenidate or dextroamphetamine. However, modafinil is ineffective for cataplexy. When cataplexy remains symptomatic despite treatment with stimulants, drugs with specific anti-cataplectic activity may be added to the patient’s regimen. Traditionally, cataplexy has been treated with antidepressant medications that demonstrate reuptake inhibition of serotonin and norepinephrine. In clinical practice the most effective drugs among the antidepressants are clomipramine, protriptyline, and venlafaxine. Recently, sodium oxybate, also known as gamma hydroxybutyrate, was approved for use in cataplexy. The mechanism of action of this drug is unknown; it is a potent CNS depressant. Clomipramine is typically used in a single dose before sleep because it is sedating and long acting. Protriptyline is alerting and has the advantage that it may be used episodically before expected social triggers. Venlafaxine is well tolerated and avoids the anticholinergic side effects that limit the use of clomipramine and protriptyline. Sodium oxybate is taken before sleep and repeated during the night; its use is highly controlled because of the high risk of side effects when abused. Nonpharmacologic techniques include the use of strategic napping. Brief naps during the day, during periods of maximum fatigue, or before periods of needed alertness decrease sleepiness and the total daily dosage of stimulant medication. Attention is directed to maintaining nocturnal sleep by avoiding stimulant drugs, caffeine, and alcohol in the evening. Because patients with narcolepsy have a higher incidence of sleep-disordered breathing than normal subjects, the clinician should remain vigilant to the possibility that sleep-disordered breathing is contributing to excessive daytime sleepiness and should treat that disorder appropriately. “Recurrent hypersomnia is a disorder characterized by recurrent episodes of hypersomnia that typically occur weeks or months apart.” Kleine-Levin syndrome is the prototype of these disorders. This is usually thought of as a disorder of young men, but young women are also affected, with a male-to-female sex ratio of 3:l. In a large series, median age of onset was 16.0 for men and 19.5 for women. Daily sleep durations of 18 to 20 hours are associated with behavioral abnormalities including hyperphagia and lack of sexual inhibition. During periods of wakefulness, the patient appears

apathetic and irritable. Delusions and hallucinations occasionally occur. EEGs may show background slowing and bursts of high-voltage slow waves. Spontaneous remission is typical. A thorough neurologic evaluation is appropriate to exclude structural abnormalities of brain. “Idiopathic hypersomnia is a disorder of presumed central nervous system cause that is associated with a normal or prolonged major sleep episode and excessive sleepiness consisting of prolonged (1-2 hours) sleep episodes of non-REM sleep.” This disorder has also been called n o n - E M narcolepsy and CNS hypersomnolence. Patients demonstrate excessive sleepiness on the MSLT, but there is no evidence of sleep-onset REM. The all-night polysomnogram should not show nocturnal disruption induced by sleep-disordered breathing, leg movements, or other causes. Psychiatric and medical conditions that might contribute to sleepiness are absent. Therefore, the diagnosis is one of exclusion. However, a group of these patients, when restudied, have been shown to demonstrate subtle evidence of sleep-disordered breathing that has been called upper airway resistance syndrome. Brain tumors, especially those in the region of the third ventricle, may induce sleepiness as a primary symptom. Magnetic resonance imaging or computed tomography of the brain is an appropriate screening technique in patients whose hypersomnia is unexplained. “Posttraumatic hypersomnia is excessive sleepiness that occurs as a result of a traumatic event involving the central nervous system.” Subtle derangements of neurologic function often follow head trauma, and there may be disruption of usual sleep patterns. However, it is critical to exclude life-threatening conditions such as subdural hematoma and atlantoaxial dislocation. The latter condition has been associated with sleep attacks that may be secondary to brainstem ischemia or involvement of medullary respiratory centers. “Obstructive sleep apnea syndrome is characterized by repetitive episodes of upper airway obstruction that occur during sleep, usually associated with a reduction in blood oxygen saturation.” “Central sleep apnea syndrome is characterized by a cessation or decrease of ventilatory effort during sleep usually with associated oxygen desaturation.” “Central alveolar hypoventilation syndrome is characterized by ventilatory impairment, resulting in arterial oxygen de-saturation that is worsened by sleep, which occurs in patients with normal properties of the lung.” Obstructive sleep apnea inexplicably was not identified as a clinical entity until 1965, when Gastaut described repetitive obstructive apneas in obese, somnolent patients with cardiovascular abnormalities. Since that time sleep-disordered breathing has emerged as an important clinical problem with varied clinical presentations that affects multiple organ systems. The absence of attention to this disorder during the medical training of a large percentage of currently practicing physicians has contributed to continued delay in the appreciation of its importance. The most salient features of the sleep-disordered breathing syndromes are sleep-related respiratory irregularity, oxygen desaturation, sleep disruption, and excessive daytime sleepiness. Much confusion exists in the evolving terminology. Initial clinical descriptions focused on the presence of obstructive or central apneas. An apnea is defined as absence of air flow for a period of 10 seconds. The apnea is called obstructive if evidence exists of continued respiratory effort. Central apnea is characterized by absence of respiratory effort throughout the 10-second episode. Although the underlying pathophysiology may be different, the outcome is similar, and the repetitive presence of either type of apnea can

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cause arousals and oxygen desaturation. The presence of five apneas per hour of sleep was initially defined as necessary to establish the presence of both syndromes. However, it has become clear that either incomplete obstructions or central hypoventilatory episodes without apnea, both called hypopneas, are also important in causing similar physiologic changes and symptoms. Therefore, the term sleep-disordered breathing is used as a more accurate description of a phenomenon often characterized by a combination of respiratory patterns. However, specific characterization of the predominant abnormalities during sleep remains important in understanding the individual pathophysiology and in designing treatment. Ironically, the term obstructive sleep apnea syndrome may now refer to a disorder characterized by recurrent airway obstructions during sleep, resulting in functional impairment, even if true apnea is not present. Even recurrent arousals induced by increased airway resistance are now accepted as evidence of a form of sleep-disordered breathing, sometimes called upper airway resistance syndrome. Sleep-disordered breathing is a ubiquitous problem. An epidemiologic study of employed men and women aged 30 to 60 years generated estimated prevalences of 9% for women and 24% for men using the definition of a minimum combined apnea/ hypopnea index of 5 per hour of sleep. The prevalence of sleep apnea syndrome, defined as an apnea/hypopnea index of at least 5, associated with daytime sleepiness, is 2% for women and 4% for men in the same group (as noted by Young et al. in 1993). The prevalence in older age groups is thought to be significantlyhigher. Prevalence rates for children are unknown, but the disorder is not uncommon in this age group. Most sleep-disordered breathing comes about through repetitive upper airway obstruction caused by collapse at the level of the pharynx, usually at the soft palate or posterior to the base of the tongue. The mechanism of collapse is complex. Sleep relaxes upper airway dilator muscles and impairs reflexes that are critical to maintaining airway patency against the negative pressures induced by the chest wall muscles. Anatomic narrowing because of tonsils, low soft palate, macroglossia, vascular congestion, fat, or structural abnormalities such as micrognathia predisposes to collapse. Dilator muscle activity is inhibited by alcohol and sedating drugs such as benzodiazepines. Conditions that induce pharyngeal motor or sensory impairment such as myasthenia, muscular dystrophy, stroke, or other brainstem disorders can be predisposing factors. Any cause of increased airway resistance, such as nasal congestion, may induce a compensatory increase in negative pressure in the thorax that promotes further narrowing of the flexible upper airway above. Patients with predominantly obstructive events usually come to medical attention because of excessive daytime sleepiness, often after an episode of sleep while driving or at work. However, difficulty initiating or maintaining sleep may be the presenting complaint. Often, apneas are noted by the bedpartner in association with loud chronic snoring or gasping. Obesity, especially with increased neck girth, is a strong risk factor but need not be present, particularly in patients with structural abnormalities of the upper airway. Morning headache, inattentiveness with memory complaints, and pseudodepression are common neurologic symptoms. Hypoxia contributes to nocturnal seizures, and sleep deprivation may induce poor seizure control in patients with epilepsy. Polycythemia may indicate severe nocturnal hypoxia with daytime hypoxia. Impotence and enuresis are seen, more often in patients with severe disease. Systemic and pulmonary hypertension, nocturnal arrhythmias, and right heart failure are accepted

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cardiovascular consequences. There is solid evidence that sleepdisordered breathing, even with low apnealhypopneas indices, is an independent risk factor for developing hypertension. Similarly, data from 6,424 patients in the Sleep Health Heart Study showed that mild sleep-disordered breathing is associated with significantly increased self-reported heart failure, stroke, and coronary artery disease. Central sleep apnea episodes are seen as the manifestation of several forms of respiratory pathophysiology. Typically episodes are categorized as those occurring in association with normocapnia or hypocapnia, and those associated with hypercapnia. Normocapnic or hypocapnic central episodes include CheyneStokes (or periodic) breathing, idiopathic central apnea, and high-altitude periodic breathing. These disorders follow from the fact that control of breathing is highly dependent on the chemical responses to P a , and, to a lesser extent, Po,. The set point for response to P a , increases variably at sleep transition, meaning that a higher Pco, is tolerated. If the patient’s P a , is lower than this new set point, an apnea follows. Hypoxia or transient wakefulness induced by the apnea can transiently increase the PIX, responsiveness, inducing a brief period of hyperventilation and a P a , that again falls below threshold values for sleep. Some patients with idiopathic central sleep apnea have been found to show higher CO, sensitivity at baseline, resulting in chronically lower Pco,s that remain close to the apnea threshold during sleep. Delays in the feedback loop can induce instability, and this instability is thought to be the mechanism that underlies Cheyne-Stokes respirations in the presence of congestive heart failure (delayed circulation time) and a diverse group of CNS disorders. At altitude, hypoxia-induced hyperventilation results in P a , s lower than the set point. In all of these settings, periods of central apnea also predispose to obstruction. In part the obstruction occurs because absence of airflow contributes to airway collapse and probably because central input to the upper airway muscles is desynchronized in relation to chest wall and diaphragmatic activation. Combined episodes of central and obstructive apnea are called mixed apneas. The coexistence of obstructive central apneas and mixed apneas in the same patient is common. Central sleep apnea associated with hypercarbia is uncommon and is a form of hypoventilation. Bilateral medullary lesions from tumor or infarct, syringobulbia, and surgical cordotomy represent lesions in the pathways involved in automatic breathing that are known to induce this type of central apnea. Autonomic dysfunction including Shy-Drager syndrome (multisystem atrophy) familial dysautonomia, and diabetic neuropathy induces chemoreceptor dysfunction and failure of respiratory control that result in central apneas. Hypoventilation and central sleep apnea may also be seen in neuromuscular disease, inducing severe respiratory muscle dysfunction such as phrenic nerve paralysis, myopathies, myasthenia gravis, and motor neuron disease. The mechanism in these diseases of peripheral neuromuscular disease represents more than end organ failure and is not well understood. Patients with central sleep apnea syndrome usually present with difficulty initiating and maintaining sleep and nocturnal restlessness. In the case of hypercapnic central sleep apnea, signs of respiratory failure, including cor pulmonale, often are present. Central sleep apnea with a Cheyne-Stokes pattern is a common cause of disrupted sleep in older adults and in patients with congestive heart failure. A wide variety of neurologic disorders predispose to the Cheyne-Stokes breathing pattern, including stroke and degenerative diseases. Diagnosis of sleep-disordered breathing entails all-night poly-

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somnography. Severity of disease is measured by degree of sleep disruption, oxygen desaturation, cardiovascular abnormalities associated with apneas, and respiratory events per hour of sleep (apnea/hypopnea index). Constant positive airway pressure (CPAP) is the mainstay of treatment for obstructive sleep apnea and for some patients with predominantly central apneas. Airway pressure acts as a pneumatic splint to maintain upper airway patency during sleep. The appropriate CPAP pressure typically is determined during a night of polysomnography, but auto-titrating devices can be used if access to a laboratory is limited. Patient acceptance of positive pressure devices has improved as the technology of the machines and nasal and oral masks has evolved; for many, the response to treatment is dramatic. CPAP’s effectiveness in central sleep apnea is not entirely understood, but many of these patients have some degree of obstruction that exacerbates the tendency to breathe periodically. Bilevel positive airway pressure (BiPAP) is a similar technique that allows independent manipulation of inspiratory and expiratory pressures, as well as timed oral and nasal pressure ventilation. BiPAP sometimes is better tolerated in purely obstructive apnea and is used especially in patients with neuromuscular weakness and central sleep apnea. Intermittent positive-pressure volume ventilation delivered by mask is another option in more severe cases of neuromuscular weakness and hypoventilation. Periodic breathing may respond to low-flow oxygen, especially if hypoxia or congestive heart failure is present. Severe oxygen desaturation in patients with obstructive sleep apnea can be treated with oxygen, especially if there is intolerance to CPAP. Custom-made oral appliances that are designed to reposition the mandible or hold the tongue forward are recommended for obstructive sleep apnea in patients who are unwilling or unable to use positive-pressure devices. Obstructive sleep-disordered breathing improves with removal of alcohol and sedating drugs that decrease upper airway tone. Protriptyline, a stimulating tricyclic, can be used to increase daytime alertness and upper airway tone. Acetazolamide is helpful in some patients with central sleep apnea, presumably because the drug-induced metabolic acidosis lowers the CO, set point during sleep. In the obese patient weight loss is always advised, but success generally is not long-lived. When upper airway anatomic abnormalities are present, surgical correction is considered depending on the patient’s age, tolerance of positive pressure, and complexity of surgery. Tonsillectomy is beneficial in those with prominently enlarged tonsils, and this treatment is generally accepted in younger patients. Uvulopalatopharyngoplasty, a surgical technique that removes the uvula, soft palate, and any tonsillar tissue present, has had disappointing efficacy that is significantly lower than that of positive pressure. “Periodic limb movement disorder is characterized by periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep.” “Restless legs syndrome is a disorder characterized by disagreeable leg sensations, usually prior to sleep onset, that cause an almost irresistible urge to move the legs.” Restless legs is a term that refers to an extremely annoying, aching, crawling sensation affecting predominantly the legs when sedentary, especially when trying to initiate sleep. A circadian pattern exists, with maximum symptoms in the evening. The subject feels the overwhelming urge to continually move the legs to abort the sensation. Almost all patients with restless legs syndrome have another disorder, periodic limb movement disorder (also called periodic leg movements or nocturnal myoclonus). Periodic limb movement disorder may also exist without the complaint of restless legs.

These patients show recurrent, periodic leg jerks involving flexor muscles of the legs, analogous to the triple-flexion response. Upper extremity movements may also occur. Leg twitches occur approximately every 20 to 40 seconds episodically throughout the night. Hundreds of leg jerks may occur, unknown to the patient but often witnessed by the bedpartner. The repetitive movements result in arousal. Patients with these disorders may present with difficulty initiating and maintaining sleep or excessive daytime sleepiness. Restless legs syndrome often is familial. Both periodic limb movements and restless legs syndrome can be exacerbated and possibly induced by drugs, especially selective serotonin uptake inhibitors. The other most important risk factors are low ferritin levels (below 4 nglml), peripheral neuropathy, and uremia. Periodic limb movements frequently accompany other primary sleep disorders, including sleep apnea and narcolepsy. Often, no cause is discovered. Restless legs and periodic leg movements respond dramatically to the dopaminergic agonist pramipexole in low dosages, starting at 0.125 mg, given 1 to 2 hours before symptom onset. Pergolide also is effective but more difficult to use because of nausea and slow dosage titration. Levodopa-carbidopa can be used but should be avoided if possible. Levodopa-carbidopa often induces a syndrome described as augmentation in which symptoms begin to appear at an earlier hour with increased severity over time, Progressive increase of medication dosages in response exacerbates the syndrome. In contrast to levodopa-carbidopa, augmentation is rarely seen with dopaminergic agonists. When dopaminergic drugs are not adequately effective or poorly tolerated, gabapentin is the next best choice. This drug is particularly effective in patients with underlying painful neuropathy. Codeine sometimes is effective in low dosages and seems to have a mechanism of action independent of pain control. Clonazepam is somewhat effective in this disorder, but tolerance limits its usefulness. Judicious combination therapies using these medications can be more effective than monotherapy in difficult patients. Iron deficiency should be investigated and treated aggressively.

Extrinsic Sleep Disorders “Inadequate sleep hygiene is a sleep disorder due to the performance of daily activities that are inconsistent with the maintenance of good quality sleep and full daytime alertness.” Many daily behaviors are inconsistent with obtaining good-quality sleep. Frequent daytime napping, inattention to maintenance of regular sleeping hours, caffeine, nicotine, and alcohol are the most common offenders. Poor sleep secondary to this or another disorder may perpetuate the maladaptive habits. For example, insomniacs often insist on maintaining caffeine intake or daytime naps to counteract the effects of sleep deprivation. The presence of at least one of the following behaviors is necessary for the diagnosis of inadequate sleep hygiene by ICSD standards: daytime napping at least two times each week; variable wake-up times or bedtimes; frequent periods (two to three times per week) of extended amounts of time spent in bed; routine use of products containing alcohol, tobacco, or caffeine in the period preceding bedtime; scheduling exercise too close to bedtime; engaging in exciting or emotionally upsetting activities too close to bedtime; frequent use of the bed for unrelated activities (e.g., television watching, studying); sleeping on an uncomfortable bed (e.g., poor mattress, inadequate blankets); allowing the bedroom to be too bright, too stuffy, too cluttered, too hot, too cold, or in some other way nonconductive to sleep; performing activities demanding high levels of concentration shortly before bed; and

Chapter 150 rn Disorders of Sleep

allowing such mental activities as thinking, planning, and reminiscing to occur in bed. “Environmental sleep disorder is a sleep disturbance due to a disturbing environmental factor that causes a complaint of either insomnia or excessive sleepiness.” External physical factors are temporally associated with the development and resolution of the sleep complaint. Older adults appear to be at more risk for this disorder. Attention to the quality of the sleep environment may avoid needless trials of hypnotic medication. Perhaps nowhere is this more apparent than in the hospital setting. “Altitude insomnia is an acute insomnia, usually accompanied by headaches, loss of appetite and fatigue, that occurs following ascent to high altitudes.” This insomnia is associated with a periodic respiratory pattern caused by low inspired oxygen pressure. Arousals are associated with the hyperventilatory phase of the periodic breathing. “Adjustment sleep disorder represents sleep disturbance temporally related to acute stress, conflict, or environmental change causing emotional arousal.” Inability to initiate sleep in the face of an acute stressor is a nearly universal experience. Occasionally the opposite is true: patients note excessive sleepiness in response to a stressful situation. Symptoms generally are short lived and resolve with removal of the stressor. “Insufficient sleep syndrome is a disorder that occurs in an individual who persistently fails to obtain sufficient nocturnal sleep required to support normally alert wakefulness.” A large percentage of the population suffers from self-imposed sleep deprivation. Sleep logs help document the disorder for the patient who is often unwilling to recognize the problem. A history reveals that symptoms resolve during vacations and weekends when sleep duration increases. Symptoms resolve if the patient chooses to prolong nocturnal sleep. “Limit setting disorder is a predominantly childhood disorder that is characterized by the inadequate enforcement of bedtimes by a caretaker, with resultant stalling or refusal to go to bed at an appropriate time.” The disorder is characterized by persistent struggle between the caretaker and child, with sleep disruption for both. Irregular sleep-wake cycles may develop. The disorder resolves with the institution of firm limits. The underlying psychosocial factors that may foster the lack of limit setting are multiple and deserve exploration. “Nocturnal eating (drinking) syndrome is characterized by recurrent awakenings with the inability to return to sleep without eating or drinking.” This disorder occurs predominantly in early childhood and is associated with breast or bottle-feeding. Consuming large amounts of fluid during the night contributes to repeated awakenings because of excessive urination. An adult variant of this disorder is unusual but striking in its presentation. Patients wake fully and engage in uncontrolled binge eating without evidence of similar behavior during daytime hours. “Hypnotic-dependentsleep disorder is characterized by insomnia or excessive sleepiness that is associated with tolerance to or withdrawal from hypnotic medications.” Hypnotic medications are to be avoided whenever possible. The benzodiazepines and benzodiazepine receptor agonist drugs are the safest sleepinducing medications but should be reserved for short-term use in patients with transient, usually situationally-induced insomnia. Hypnotics are discouraged for several reasons. The underlying cause of the insomnia may be masked or exacerbated, as in sleep-disordered breathing. Tolerance to the benzodiazepines develops with regular use, and the medication becomes ineffective, resulting in dosage escalation. Half-lives of the benzodiazepines

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and their active metabolites vary widely. Drugs with long half-lives result in accumulation and impaired performance during waking, especially in older adults. Withdrawal effects are more evident with shorter-acting drugs. Rebound insomnia follows withdrawal, leading the patient to overestimate the underlying sleep disorder. “Stimulant-dependent sleep disorder is characterized by a reduction of sleepiness or suppression of sleep by central stimulants and resultant alterations in wakefulness following drug abstinence.” Stimulants are an obvious cause of difficulty initiating and maintaining sleep, but they can easily be overlooked if not pursued in the history. Caffeine is the most common stimulant, in the form of coffee, tea, soft drinks, or chocolate. Decongestants and bronchodilators are often forgotten offenders. Nonamphetamine stimulants prescribed for attention deficit disorder and narcolepsy (such as pemoline and methylphenidate) may produce insomnia as a major side effect, usually because of dosing too late in the day. Prolonged periods of sleeplessness followed by excessive sleep are seen in amphetamine and cocaine abuse. “Alcohol-dependent sleep disorder is characterized by the assisted initiation of sleep onset by the sustained ingestion of ethanol that is used for its hypnotic effect.” Alcohol usually results in fragmentation of sleep and frequent arousal, contrary to the popular belief that it helps induce sleep. Alcohol also exacerbates sleep-disordered breathing. Many patients become alcohol dependent in attempting to treat insomnia of other origins with nocturnal alcohol. Instead, alcohol exacerbates the problem. Circadian Rhythm Sleep Disorders The activities of modern society allow marked variations in the patterns of day-to-day activity. Air travel and shift work are common. Nighttime activities are no longer limited by darkness. Continuous activity with the potential for disrupting sleep-wake cycles is particularly evident in the hospital setting. When the timing of sleep is disrupted, the patient is said to have a circadian rhythm sleep disorder. “Time zone change (jet lag) syndrome consists of varying degrees of difficulties in initiating or maintaining sleep, excessive sleepiness, decrements in subjective daytime alertness and performance, and somatic symptoms (largely related to gastrointestinal function) following rapid travel across multiple time zones.” “Shift work sleep disorder consists of symptoms of insomnia or excessive sleepiness that occur as transient phenomena in relation to work schedules.” An abrupt change in the sleep schedule induced by travel across time zones or a change in work shift results in transient disorders of the sleep-wake cycle. Circadian rhythms are out of phase with the imposed sleep schedule. Subjects note difficulty in initiating and maintaining sleep and sleepiness during waking hours. Schedules that result in an advance of the sleep cycle, such as eastward flight, are more poorly tolerated. It may be easier to delay rather than advance bedtime because the circadian period in humans is slightly longer than 24 hours. Symptoms resolve after circadian rhythms entrain to the new schedule, which may take more than a week. If the sleep-wake cycle changes constantly because of travel or shift work no entrainment occurs, and the circadian rhythm disorder persists. “Irregular sleep-wake pattern consists of temporally disorganized and variable episodes of sleep and waking behavior.” The sleep pattern of the patient with an irregular sleep-wake cycle is erratic. Unlike in non-24-hour sleep-wake syndrome, sleep logs reveal no underlying periodicity. This disorder usually occurs in patients with developmental abnormalities of the brain. Prolonged

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illness with enforced bed rest and absence of attention to daily routines may be precipitating factors. Patients complain of chronic fatigue. Neither sleep nor wakefulness is well maintained. This disorder is treated by external reinforcement of a normal sleep-wake cycle, but it usually recurs. “Delayed sleep phase syndrome is a disorder in which the major sleep episode is delayed in relation to the desired clock time that results in symptoms of sleep-onset insomnia or difficulty in waking at the desired time.” Patients habitually adopt a late bedtime and wake late in the day. The amount of sleep and its quality are normal. The patient is symptomatic when attempts to advance the bedtime to an earlier hour fail. These patients appear to be less able to advance their circadian rhythms to reset the body’s natural tendency to delay endogenous rhythms or to compensate for occasional schedule changes. As noted in the next paragraph, evidence suggests that the underlying mechanism of disorders associated with displacement of sleep phase in relation to the 24-hour day may be a genetically determined abnormality in length of the underlying circadian period. Bright-light therapy is the most effective treatment for delayed sleep phase. Patients are exposed to bright light in the range of 2500 to 10,000 lux during morning hours, which advances endogenous rhythms and allows earlier sleep onset. “Advanced sleep phase syndrome is a disorder in which the major sleep episode is advanced in relation to the desired clock time, that results in symptoms of compelling evening sleepiness, an early sleep onset, and an awakening that is earlier than desired.” In rodents, insects, and fungi, mutations that alter the length of the circadian period lead to advances or delays in daily rhythms. A recent report of a family with autosomal dominant advanced phase syndrome led to the discovery of a single point mutation in the human homolog (hPer2) of the Drosophila clock gene Per2. Advanced sleep phase disorder is commonly seen in older adults, and it has been postulated that the circadian period may shorten with age, but shortening of the period with normal aging has not been demonstrated. Patients with advanced sleep phase syndrome alone generally do not complain of the disorder. When symptoms are bothersome, patients can be treated with progressive delay of bedtime or bright-light therapy in the evening. “Non-2Chour sleep-wake syndrome consists of a chronic steady pattern comprised of 1- to 2-hour daily delays in sleep onset and wake times.” Patients with this disorder present with what appears to be an erratic sleep-wake cycle. However, sleep logs demonstrate that there is a non-24-hour periodicity in the sleep-wake cycle. This disorder mimics the prolongation of the sleep cycle that can be seen in experimental environments in which subjects are isolated from time cues and are said to be “freerunning.” Patients who do not attend to environmental cues, including the blind, may develop this syndrome. PARASOMNIAS The term parasomnia refers to undesirable physical events that occur during sleep or are exacerbated by sleep. These phenomena often are sleep stage-specific. Subdivisions of the parasomnias are the arousal disorders, the sleep-wake transition disorders, (3) the parasomnias usually associated with REM sleep, and the other parasomnias. Arousal Disorders

The term disorders of arousal refers to behaviors characterized by confusion and automatic behavior after sudden arousal from delta

sleep. Broughton established the uniqueness of these disorders in a classic paper in 1968. He noted that arousal from delta sleep in both normal subjects, and to an exaggerated extent in patients with this disorder, was associated with body movements, autonomic activation, mental confusion and disorientation, automatic behavior, relative nonreactivity to external stimuli, poor response to efforts to provoke behavioral wakefulness, amnesia for many intercurrent events, and fragmentary recall of dreamliie mentation. The tendency to arouse spontaneously from delta sleep tends to be a familial trait, with first presentation in childhood and resolution by adolescence. However, episodes may occur for the first time or recur with greater severity in adolescence or adulthood. Stress, sleep deprivation, and any factors that may contribute to sleep disruption can exacerbate the problem. Sleep apnea and alcohol are common causes of adult recurrence. Occasionally, seizure activity may induce the arousal. There is a long-standing debate as to the contribution of emotional factors. Anxiety, depression, and obsessive-compulsive personality may be overrepresented in this patient population, but at least half of the patients show no diagnosable psychiatric disorder. “Confusional arousals consist of confusion during and following arousals from sleep, most typically from deep sleep in the first part of the night.” These episodes are most commonly seen in forced arousals from delta sleep, particularly in patients with a family or personal history of sleepwalking or sleeptalking and in children under age 5. Amnesia for the events during the arousal is typical. This is predominantly a problem for people such as physicians who are called at night and must react appropriately. “Sleepwalking consists of a series of complex behaviors that are initiated during slow wave sleep and result in walking during sleep.” Sleepwalkers characteristically arouse during the first third of the night from delta sleep, leave the bed in a confused state, and perform complex, automatic acts. Some episodes of sleepwalking are initiated by sleep terror, in which case the behaviors exhibited may be violent as the subject tries to combat a perceived threat. More routine behaviors, such as eating and urinating, may be performed in a remarkably stereotyped fashion idiosyncratic to the subject. The patient may awaken during the behavior embarrassed and bewildered. Most often the patient returns to bed and has no memory of the episode. Patients are at risk of injuring themselves and their bedpartners. The typical inability to awaken the patient fully and stop the behaviors is particularly frightening and dangerous to the bedpartner. Attacks specifically directed at the bedpartner are common and can raise difficult legal issues. Murders have been committed in this context. Care must be taken to secure the sleep environment to prevent falling from heights. Occasionally dangerous objects, such as knives and guns, must be made inaccessible. “Sleep terrors are characterized by a sudden arousal from slow wave sleep with a piercing scream or cry, accompanied by automatic and behavioral manifestations of intense fear.” Typically, the person arouses within the first 2 hours of sleep, sits bolt upright, and screams. Marked tachycardia, mydriasis, and sweating may be evident. The subject is agitated, confused, and difficult to console or arouse fully. Dream recall is not detailed, but a single terrifylng image, such as a demon, insect, or intruder, may be reported. Generally sleep is resumed in a few minutes, with amnesia for the entire event. Occasional parasomnic episodes with typical family and personal histories do not warrant further evaluation. The distinction between these disorders and an EM-related nightmare usually can be made on the basis of history. In the latter, the patient can recount detailed dream activity, whereas in the dis-

Chapter 150

orders of arousal, only fragmentary images or fears are recalled. Motoric activity associated with detailed dream recall indicates REM behavior disorder rather than sleepwalking. Atypical features may suggest nocturnal seizure. Polysomnographic study and sleep-deprived full-montage EEGs are recommended in patients with violent behavior, frequent disruptive episodes, atypical clinical features, or excessive daytime sleepiness. Polysomnograms may confirm sudden arousal from delta sleep, even in the absence of an episode; some sleep laboratories induce arousal with a buzzer to precipitate the clinical syndrome. More importantly, the polysomnogram may identify another cause of arousal, such as sleep apnea, that precipitates the behavior in the predisposed patient. Seizure activity, although not frequent, may induce arousal, or seizure itself may mimic the clinical syndrome. The first line of treatment is removal of the possible underlying precipitants of arousal or delta sleep rebound, or both. Improved sleep hygiene helps, with avoidance of sleep deprivation, irregular sleep-wake cycles, caffeine, and alcohol. Stress reduction by relaxation techniques appears to be useful. Hypnosis has been tried with success. Coincident sleep apnea should be treated, even if not severe. The mainstay of treatment for recurrent injurious or disruptive episodes is clonazepam, given before sleep. Many patients use the medication intermittently in settings that are dangerous, embarrassing, or known to precipitate their episodes. Clonazepam and other benzodiazepines appear to increase the arousal threshold. Sleep-Wake Transition Disorders “Rhythmic movement disorder comprises a group of stereotyped, repetitive movements involving large muscles, usually of the head and neck, which typically occur immediately prior to sleep onset and are sustained into light sleep.” This disorder is predominantly recognized as head banging or rocking in children, with onset at about 6 months and resolution, in most cases, by age 4.Persistence into adulthood is sometimes seen. “Sleep starts are sudden, brief contractions of the legs, sometimes also involving the arms and head, which occur at sleep onset.” Also called hypnic jerks, these episodes often are associated with the sensation of falling and are considered normal unless they occur so frequently as to interfere with sleep onset. When episodes are disruptive, sleep-onset epilepsy should be considered. Periodic limb movement disorder may induce arousal at sleep onset, but the movements are less generalized, and polysomnographic study reveals persistent movements during sleep. ParasomnZas Usually Associated with REM Sleep “Nightmares are frightening dreams that usually awaken the sleeper from REM sleep.” Because nightmares occur during REM sleep, the subject arouses easily and has detailed dream recall. Episodes typically occur in the last half of the night, when REM is more predominant. The episodes may be recurrent in the same night, reflecting the periodicity of REM. Sleep-onset nightmares reflect abnormal REM sleep, as in narcolepsy or drug withdrawal states. Many believe that occasional nightmares are a normal occurrence in childhood. In adults, recurrent nightmares may represent underlying psychiatric disorders, especially anxiety, depression, and post-traumatic stress disorder. The contribution of medications should always be considered, especially antidepressants that cause REM suppression followed by REM rebound on withdrawal, centrally acting antihypertensives, and antiparkinso-

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nian drugs. Physiologic disruptions occurring during REM sleep such as sleep-disordered breathing or arrhythmia may also induce nightmares. “Sleep paralysis consists of a period of inability to perform voluntary movements either at sleep onset (hypnagogic or predormital form) or upon awakening either during the night or in the morning (hypnopompic or postdormital form).” Sleep paralysis represents a partial arousal or entry into REM sleep such that the atonia of REM sleep is present, but the cerebral cortex is awake. This is a common symptom of narcolepsy, especially at sleep onset. Normal subjects may have occasional episodes of sleep paralysis on awakening. A familial disorder has been described with sleep-onset sleep paralysis without other features of narcolepsy. Sleep paralysis is particularly common in patients taking REM-modifymg drugs, especially monoamine oxidase inhibitors. “REM sleep-related sinus arrest is a cardiac rhythm disorder that is characterized by sinus arrest during REM sleep in otherwise healthy individuals.” Asystole may be prolonged, lasting as long as 9 seconds. This arrhythmia shows response to anticholinergic drugs. Most patients have been treated with artificial pacemakers because the natural history of the disorder and the risk of sudden death are unknown. “REM sleep behavior disorder (RBD) is characterized by the intermittent loss of REM sleep EMG atonia and by the appearance of elaborate motor activity associated with dream mentation.” REM sleep behavior disorder was first described clinically in 1986, but lesion experiments in cats predicted the possibility of the disorder as early as 1965. In this disorder the usual atonia associated with REM is incomplete. As a result, patients are able to enact dreams without awakening from REM. Dream mentation also changes, and patients usually complain of frightening or violent dreams. The accompanying motor activity can be injurious to the patient or bedpartner and bring the problem to clinical attention. Exhibiting behaviors similar to those in the cat model, patients typically run, punch, kick, or leap from bed. Vocalization consistent with the dream activity is usual. The patient may be able to correlate detailed dreaming with the witnessed motoric behavior. Sometimes the patient is able to incorporate ongoing conversation and activity into the dream, giving rise to the misperception that he or she is confused or hallucinating. Underlying dementia or acute illness may impair the patient’s ability to report the perception of dreaming, or the observer’s willingness to listen to that report, resulting in misdiagnosis. The disorder often is mistaken for “sundowning” or, because of the violent quality of the dreams, post-traumatic stress disorder. REM behavior disorder occurs most frequently in older men with a mean age of 60. Approximately half of the patients reported have had a known neurologic disease at diagnosis. Early reports documented various neurologic diseases such as unspecified dementia, Parkinson’s disease, multisystem atrophy, and stroke. Over time it has become clear that RJ3D often precedes clinical signs or symptoms of some degenerative diseases, especially Parkinson’s disease and dementia with Lewy bodies, by years. In one large study of patients with known RBD, of the patients in that group who were known to have Parkinson’s disease, RBD symptoms had developed before parkinsonism in 52%, by a median of 3 years. The prevalence of RBD in populations of patients with known Parkinson’s disease is reported as approximately 15%. The combination of degenerative dementia and RBD is highly correlated with the diagnosis of dementia with Lewy bodies, based on clinical and pathologic criteria. Polysomnographic studies have demonstrated RBD in more than 90% of patients with multisystem atrophy. Medications, especially antide-

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pressants, including selective serotonin uptake inhibitors, tricyclics, and monoamine oxidase inhibitors, as well as drug withdrawal, can induce the syndrome, especially in patients predisposed to the disorder because of underlying neurologic disease. Clinical descriptions consistent with this disorder were noted in patients with alcohol withdrawal years before the syndrome of REM behavior disorder was described. The diagnosis can be confirmed unequivocally if a full polysomnographic study is available. During episodes of REM sleep excessive tone and movements are noted, usually correlated with some manifestation of the clinical behavior. For unclear reasons clonazepam (0.5 to 2.0 mg before sleep) is remarkably effective in treating REM sleep behavior disorder and results in resolution or significant attenuation of the clinical symptoms in most cases.

The patient may fall asleep easily but wake a few hours later, alert and unable to return to sleep. This can be the earliest symptom apparent to the patient. Sleep studies in some of these patients demonstrate an earlier-than-normal REM latency and increased phasic REM activity early in the night. By contrast, the sleep in bipolar depressive disease is characterized by prolonged periods of inability to sleep during the manic phase and excessive sleep during the depressive phase. Most actively psychotic patients have difficulty maintaining sleep, but some may be hypersomnolent at the onset of their psychosis. Patients with panic disorder may wake suddenly at night with panic; polysomnographic evaluation sometimes is useful to distinguish these episodes from sleep terror, and nocturnal seizure must be considered. The treatment of sleep disorders of psychiatric cause is directed toward treating the underlying illness. Improvement in sleep is often a sensitive measure of the effectiveness of treatment.

Other Parasomnias

“Sleep bruxism is a stereotyped movement disorder characterized by grinding or clenching of teeth during sleep.” This is a common disorder that is often attributed to stress, but the underlying pathophysiology is not known. Bruxism results in disrupted nocturnal sleep, temporomandibular joint dysfunction, damage to teeth, and morning headache. Damage caused by bruxism is inhibited by the use of a nocturnal tooth guard. Underlying sleep-disordered breathing seems to exacerbate the disorder and may warrant treatment. “Sleep enuresis is characterized by recurrent involuntary micturition that occurs during sleep.” Bedwetting after the age 5 years is considered abnormal. There may be a delay in toilet training without the development of continence during sleep, called primary enuresis. Secondary enuresis is the development of bedwetting after toilet training is complete. Symptomatic enuresis is secondary to underlying medical disease (e.g., urogenital disorder, nocturnal seizure, or sleep apnea). Some cases of enuresis follow arousal from delta sleep, but enuresis may occur in any sleep stage. If no underlying medical cause is identified, the disorder is treated with bladder training, behavioral techniques, and (if these fail) imipramine. “Nocturnal paroxysmal dystonia is characterized by repeated dystonia or dyskinetic (ballistic, choreoathetoid) episodes that are stereotyped and occur during NREM sleep.” Both short- and long-lasting episodes have been described and appear to have different mechanisms. Short episodes often respond to carbamazepine. Brief episodes of stereotyped dystonic, choreoathetoid, or ballistic movements may be associated with mumbling or crying. Episodes arise from all stages of NREM sleep. EEGs during the episodes are reportedly without evidence of seizure activity. However, a history of known generalized seizures is present in many of the patients, and recent cases suggest frontal lobe epileptic foci. Long-duration episodes have been observed in one patient who later developed Huntington’s disease. “Sudden unexplained nocturnal death syndrome (SUND) is characterized by sudden death during sleep in healthy young adults, particularly of Southeast Asian descent.”

MEDICAL AND PSYCHIATRIC SLEEP DISORDERS Conditions Associated with Mental Disorders

Disordered sleep is typical of most psychiatric disorders. Unipolar depression characteristically presents with a disorder of initiating and maintaining sleep, most commonly early morning awakening.

Conditions Associated with Neurologic Disorders Cerebral Degenerative Disorders, Dementia, Parkinsonism.

Sleep disruption is a prominent but not well studied symptom in all degenerative diseases of brain. Patients with degenerative disease of brain are at particular risk of sleep-disordered breathing because of Cheyne-Stokes respirations, abnormal chest wall and upper airway muscle tone, brainstem dysfunction, and sedating medications. The resulting hypoxemia can contribute to episodes of nocturnal confusion. In the disorders involving motor systems, sleep fragmentation also occurs secondary to rigidity, tremor, myoclonus, and periodic limb movements. Brainstem involvement induces REM sleep abnormalities, including the REM sleep behavior disorder. Circadian rhythm disorders are common and probably represent derangement of neurologic control mechanisms, coupled with the secondary effects of disrupted sleep and medication. Sleep-Related Epilepsy. Seizures are facilitated by sleep, particularly stage I1 sleep. Hypoxia secondary to sleep apnea also precipitates seizures. Grand ma1 seizures are suggested by falls from bed, incontinence, bitten tongue, and morning confusion. In a patient with known seizure disorder, paroxysmal nocturnal behaviors of any sort are best considered seizure activity until proven otherwise. Atypical seizures with symptoms only during sleep may represent difficult diagnostic problems. Some types of seizure disorders, especially complex partial seizures with temporolimbic symptoms, closely mimic sleep terrors and sleepwalking. Episodic nocturnal wandering is a syndrome that may be indistinguishable from the disorders of arousal, but it usually has atypical features. The wandering tends to be less goal directed and organized than typical sleepwalking. Speech tends to be unintelligible. Automatisms may be noted. Rather than clustering in the first third of the night, when delta sleep is abundant, episodes often recur frequently in the same night or appear late. There is a high prevalence of interictal electroencephalographic abnormalities in these patients, and episodes respond to anticonvulsants. A variety of paroxysmal nocturnal autonomic symptoms have been ascribed to the partial epilepsies, including breathing abnormalities, arrhythmias, and flushing. Standard polysomnography includes a limited electroencephalographic montage that is inadequate for evaluating seizure disorders. A full electroencephalographic montage with polysomnographic monitoring or electroencephalographic telemetry must be used when the diagnosis is in doubt. Sleep-Related Headaches. Cluster headache is a severe unilateral orbital headache associated with ipsilateral rhinorrhea

Chapter I50 W

and tearing. The headache is often nocturnal and appears to be exacerbated specifically by REM sleep. Chronic paroxysmal hemicrania, a similar headache disorder that is more common in women and responsive to indomethacin, is also REM-related. Increased blood flow and hypoxemia during REM may be etiologic factors. Most patients note that migraine is improved by sleep, but occasionally the reverse is true. Sleep-related headache may be the presentation of raised intracranial pressure, exacerbated by the supine posture and episodic elevation in intracranial pressure during REM sleep. Morning headache is typical of sleep apnea syndrome and bruxism.

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SUGGESTED READINGS Boeve BF, Siber MH, Fermon TJ, et al: Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy.Mov Disord 16(4):622-630,2001 Bootzin RR, Engle-Friedman M, Hazelwood L Insomnia. pp. 81-115. In Lewinsohn PM, Teri L (eds): Clinical Geropsychology, New Directions in Assessment and Treatment. Pergamon, New York, 1983 Broughton RJ: Sleep disorders: disorders of arousal? Science 159:1070, 1968

Czeisler CA, Duffy JF, Shanahan TL, et al: Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284(5423):2177-2181, 1999

Conditions Associated with Other Medical DErorders Just as medical illness disrupts the quality of life during the day, it also affects sleep maintenance. A careful consideration of possible systemic disease is important in every patient with a sleep disorder. Almost every disease, at some point in its course, may disrupt sleep. Most painful disorders cause nocturnal arousal, especially arthritis and peptic ulcer disease. Insomnia may be the presenting complaint of congestive heart failure with nocturia, paroxysmal nocturnal dyspnea, or arousal secondary to Cheyne-Stokes respirations. Pulmonary dysfunction is exacerbated during sleep and predisposes patients to sleep-disordered breathing. Sleep disruption is particularly prominent in hyperthyroidism and uremia.

PROPOSED SLEEP DISORDERS “Menstrual-associated sleep disorder is a disorder of unknown cause, characterized by a complaint of either insomnia or excessive sleepiness, that is temporally related to the menses or menopause.” Premenstrual excessive sleepiness is a sometimes dramatic disorder that appears within the first 2 years after menarche. Periodic episodes of hypersomnolence tend to occur 6 to 10 days before the onset of menses. The disorder is treated successfully with birth control pills. Menopausal insomnia is characterized by recurrent awakenings, often associated with hot flashes or night sweats. Premenstrual insomnia is common, characterized by difficulty in initiating and maintaining sleep; it is often associated with other symptoms attributed to the premenstrual syndrome. “Sleep-related laryngospasm refers to episodes of abrupt awakenings from sleep with an intense sensation of inability to breathe, and stridor.” The disorder is frightening but usually benign. Otolaryngologic examination reveals no abnormality. The disorder tends to recur several times and then resolve. It is more common in smokers and patients with esophageal reflux. Sleep apnea and upper airway disorders must be considered. Rarely, nocturnal seizure is the cause.

Guilleminault C, Pool P, Motta J, Gillis AM: Sinus arrest during REM sleep in young adults. N Engl J Med 311:1006, 1984 Jones CR, Campbell SS, Zone SE, et ak Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 5(9):1062-1065, 1999 King DP, Takahashi J S Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci 23:713-742, 2000 Kryger MH, Roth T, Dement W Principles and Practice of Sleep Medicine. 3rd Ed. WB Saunders, Philadelphia, 2000 Mahowald M W , Ettinger MG Things that go bump in the night: the parasomnias revisited. J Clin Neurophysiol 21 19, 1990 Mignot E Genetic and familial aspects of narcolepsy. Neurology 50(2 Suppl 1):S16-22, 1998 Phillipson EA, Bradley TA Clinics in Chest Medicine. Breathing Disorders in Sleep. WB Saunders, Philadelphia, 1992 Saper CB The sleep switch hypothalamic control of sleep and wakefulness. Trends Neurosci 24( 12):726-731, 2001 Scbenck CH, Bundlie SR, Patterson AL, Mahowald MW Rapid eye movement behavior disorder. JAMA 257:1786, 1987 Shahar E, Whitney CW, Redline S, et ak Sleep-disordered breathing and cardiovascular disease: cross-sectionalresults of the Sleep Heart Health Study. Am J Respir Crit Care Med 163(1):19-25, 2001 Siege1 JM: Narcolepsy: a key role for hypocretins (orexins). Cell 98 (4):409-412, 1999

Spiegel K, Leproult R, Van Cauter E, et ak Impact of sleep debt on metabolic and endocrine function. Lancet 354(9188):1435-1439, 1999 Thorpy MJ: Handbook of Sleep Disorders. Marcel Dekker, New York, 1990 Thorpy MJ: ICSD-International Classification of Sleep Disorders: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee, American Sleep Disorders Association, Rochester, MN, 1990

Toh KL, Jones CR, He Y, et ak An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291(5506):10401043,2001

Young T, Palta M, Dempsey J, et ak The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328:1230, 1993

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PSYCHIATRIC AND SOCIAL ISSUES IN NEUROLOGIC PRACTICE

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Psychiatric Issues in Neurologic Practice Barry S. Fogel and Melissa Frumin

ANXIETY AND PANIC Symptoms of anxiety are nearly universal among patients seen in neurologic practice, but the manifestations of anxiety differ widely between patients. Anxiety, or behavior caused by anxiety, often represents a complete or incomplete form of an anxiety disorder. Anxiety disorders, the most prevalent mental disorders in the general population, are readily treated once diagnosed. This section of the chapter addresses the following themes: identification of anxiety in neurologic patients, assessment of the anxious patient, general management, and pharmacologic treatment. Recognition and Characterization of Anxiety The cognitive experience of anxiety is one of worry, fear, or apprehension, often accompanied by irritability or difficulty concentrating. The somatic experience of anxiety may include restlessness or a keyed-up feeling, fatigability, muscle tension, palpitations, sweating, trembling, dyspnea, choking sensations, chest discomfort, nausea, dizziness, paresthesias, and hot or cold feelings. Symptoms often are linked to hyperventilation or to overactivity of the sympathetic nervous system. The behavioral manifestations of anxiety may include seeking reassurance or comfort, avoiding a fearful stimulus, inhibition of action, physical hyperactivity, explosive behavior or speech in response to personal or environmental irritation, or repetitive speech or action. In a given patient, one or another dimension of anxiety (cognitive, affective, or behavioral) may predominate. The predominance of a particular dimension of anxiety may result from disorder-specific or patient-specific factors. Typically, behavioral manifestations are the most salient features of phobias and obsessive-compulsive disorder, whereas somatic manifestations predominate in panic disorder. Patients with dementia or severe mental retardation may display somatic or behavioral manifestations of anxiety but be unable to generate or express the cognitions associated with worry or apprehension. In particular, agitation in cognitively impaired patients in institutional settings can be a behavioral manifestation of anxiety. Patients who are unaware of their own feelings may similarly complain of or display somatic symptoms of anxiety while denying worry or stress. Such patients may reveal their anxiety behaviorally by showing unusual rigidity in their approach to dealing with their medical problems. Anxiety may be well founded given the patient’s objective 976

situation, or it may be completely endogenous. Often, there is a combination of causal factors. Emotional reactions to illness tend to follow the patient’s historical pattern of stress response, a pattern influenced by his or her level of trait anxiety or “neuroticism.” Moreover, the cognitive and behavioral details of anxiety disorders can incorporate concerns related to neurologic disease, as when a patient with agoraphobia and epilepsy insists that she cannot go out alone because she might have a seizure. Anxiety-related phenomena obviously warrant further assessment when they appear to be a major source of the patient’s distress or disability or when they interfere with the efforts of the patient, the physician, or caregivers to deal with the patient’s neurologic disorder. When a patient has symptoms in excess of objective neurologic findings, amplification of neurologic symptoms by anxiety should be considered when the patient has some definite symptoms of anxiety, and the neurologic symptoms are amplified concurrently with an aggravation of those symptoms. Thus, aggravation of headache by anxiety would be supported by its worsening at a time of muscle tension and worry. However, because anxiety disorders are highly prevalent in the general population, the mere presence of anxiety symptoms or an anxiety disorder should not be taken uncritically as an explanation for neurologic symptoms in excess of findings. Diagnosis The goals of initial assessment of the anxious patient are to determine whether the patient has an immediate, remediable cause for the anxiety such as pain or misinformation; whether there is a medical condition (e.g., hyperthyroidism) or an exogenous substance (e.g., caffeine) causing or aggravating the anxiety symptoms; whether the patient has an anxiety disorder; whether the patient has some other primary psychiatric disorder that can cause anxiety; and whether there is relevant history to guide management or treatment. The inquiry about discomfort or worry is straightforward in the cognitively intact patient; in those with impaired cognition or communication, pain and discomfort may be inferred from the patient’s facial expression and movements. In the office setting, the relative or other caregiver who accompanies the cognitively impaired or aphasic person may be able to assist. Exogenous Factors. The most common exogenous causes of anxiety in office practice are caffeine and alcohol. As few as two

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cups of coffee or the equivalent daily can be sufficient to produce clinically significant symptoms of anxiety in predisposed individuals, and patients do not necessarily make the connection between their caffeine habit and their anxiety symptoms. Alcohol, consumed in moderate to heavy quantities in the evening, can be associated with anxiety symptoms and elevated blood pressure the next day. Other common causes are sympathomimetic decongestant drugs, theophylline preparations taken for lung disease, and rebound anxiety from short-acting benzodiazepines.A wide range of prescription drugs, over-the-counter drugs, and herbal preparations can cause anxiety, nervousness, or insomnia in a small proportion of patients who presumably have a pharmacodynamic vulnerability to those agents. For most of these substances, the temporal relationship of the symptoms and the use of a drug or herbal remedy permits the diagnosis. In some cases, a trial of discontinuation of the suspected agent may be needed to settle the issue. Endocrinologic and Neurologic Assessment, Although numerous systemic diseases can produce symptoms of anxiety, only the endocrine disorders commonly present with anxiety: Hyperthyroidism, hypercortisolism, and hyperparathyroidism all can do so. For this reason, a screen of thyroid function, electrolytes, and calcium is part of the medical assessment for persistent symptoms of anxiety. Assessment of anxious patients for more unusual endocrine conditions, such as pheochromocytoma and insulinoma, is not routine. The neurologic disease that most often presents with dramatic anxiety symptoms is partial epilepsy; fear is the most common ictal emotion, and there is much overlap between the phenomenology of panic attacks and the phenomenology of partial seizures with ictal fear. Evaluation for epilepsy is indicated for recurrent episodic anxiety with lateralized symptoms, alteration of consciousness or memory, or severe postattack fatigue or headache. Patients with apparently typical panic attacks should be evaluated for epilepsy upon presentation if there is no personal history of anxious traits and no family history of anxiety disorders; if there is a personal or family history of epilepsy or seizures; or if there is a personal history of traumatic brain injury, stroke, or another focal brain insult. There are well-documented cases of antiepileptic drugs suppressing seizures with ictal fear, leaving “panic attacks” as a residual; the “panic attacks,”which represent aborted seizures, may cease with more aggressive antiepileptic drug therapy. In the absence of these conditions, it is reasonable to defer extensive neurologic assessment until standard treatment for panic disorder has been tried and found insufficient. Although it usually does not present with anxiety, Parkinson’s disease is associated with a higher prevalence of anxiety symptoms and anxiety disorders. Other movement disorders associated with a higher prevalence of anxiety disorders are essential tremor and Tourette’s syndrome. In the early stages, the abnormal movements of these conditions sometimes are misattributed to anxiety. If an anxiety disorder is to be diagnosed later in the course, the neurologist should take care to indicate to the patient that this is a second diagnosis, not a psychiatric explanation of the patient’s neurologic disorder. Tourette’s syndrome is specifically associated with obsessive-compulsive disorder and attention deficit and hyperactivity disorder. Nonparoxysmal anxiety symptoms are common in patients in the early stages of degenerative neurologic diseases, in which the patient experiences symptoms of dysfunction of the central nervous system but examination and test results are still negative or equivocal. These symptoms, if not caused by direct effects of the

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degenerative disease on subcortical or limbic structures, may be a reaction to an altered sense of self or to functional impairment or may reflect conscious worry about the diagnosis.

Symptoms After excluding immediate concerns and exogenous causes of anxiety, the assessment proceeds to an inventory of symptoms of anxiety in the cognitive, somatic, and behavioral domains, determining how long the patient has been symptomatic and whether the symptoms are associated with distress, impaired function, or self-imposed limitations. An anxiety disorder is present when symptoms are persistent or recurrent and of sufficient severity or multiplicity to have functional consequences. Important distinctions between anxiety disorders are made according to whether the patient has panic attacks, avoidant behavior, obsessive thoughts, or compulsive rituals and whether the anxiety symptoms are linked to a specific traumatic event. The corresponding anxiety disorders are panic disorder, phobias (agoraphobia, social phobia, and various specific phobias), obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD) with anxious mood. Multiple anxiety symptoms lasting 6 months or more without these distinguishing features suggest a diagnosis of generalized anxiety disorder. Clinically significant anxiety that occurs in close relation to a major life stressor may represent an adjustment disorder (i.e., a reaction to acute stress that temporarily exceeds the person’s ability to cope). A history of significant anxiety symptoms preceding the stressor suggests that a patient with stress-related anxiety actually suffers from a relapse or aggravation of a preexisting anxiety disorder rather than an adjustment disorder. The anxiety disorders are distinguished from other psychiatric disorders in which anxiety may be a symptom but for which other symptoms are more prominent and define the syndrome. Anxiety and depression often occur together. Depression can occur as a complication of an anxiety disorder, anxiety can occur as a symptom of a depressive disorder, and an anxiety disorder and depressive disorder can occur simultaneously. From the therapeutic viewpoint, however, it is particularly important to determine whether the patient suffers from clinically significant depression because this implies differences in treatment strategy, prognosis, and the risk of suicide. The two symptoms that most clearly distinguish depression from anxiety as the primary diagnosis are anhedonia (loss of the capacity to experience pleasure or enjoyment) and apathy (loss of interest, motivation, or emotional reactivity). Other symptoms infrequently seen in anxiety disorders unaccompanied by depression are psychomotor slowing, significant short-term weight changes, early morning awakening, and intense feelings of guilt and self-punishment. Anxiety caused by early dementia is distinguished from a primary anxiety disorder by cognitive impairment disproportionate to the patient’s level of anxiety. Anxiety secondary to thought disorder is discussed later in this chapter under “Thought Disorders”; the distinguishing feature is disorganization of thinking beyond the mild distractibility and inattentiveness that often accompany anxiety. Finally, anxiety may be a prominent symptom of bipolar disorder. Diagnosis of mania usually is not difficult, but the diagnosis of patients with milder or atypical manic symptoms can be subtle. Distinctive clinical features not usually seen in anxiety disorders that should raise a suspicion of bipolar disorder include

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a positive family history of bipolar disorder, acceleration of movement (rapid speech can be caused by anxiety alone), decreased need for sleep (as opposed to insomnia with complaints of tiredness), increased libido, and grandiosity. A marked increase in anxiety after treatment of anxiety with an antidepressant drug should raise the suspicion of bipolar disorder, which often is aggravated by antidepressants. General Management

If the patient’s anxiety appears related to physical discomfort or a remediable concern, such as a need for more medical information, these concerns are addressed concretely. When possible, exogenous substances that aggravate anxiety are eliminated. In the case of caffeine, a slow taper usually is better tolerated than abrupt withdrawal, which can cause headaches and influenza-like aches and pains. When alcohol is thought to contribute, the patient is asked to abstain for a specific time period to assess the contribution of alcohol to the symptoms; this may avert defensiveness about whether drinking is excessive. If a patient has anxiety directly related to a recent stressor and not associated with long-term problems with anxiety, the patient is likely to benefit from psychosocial interventions to help him or her deal with the stressor. These interventions include formal psychotherapy, support groups, pastoral counseling, or counseling by the physician or a member of the clinical care team. The choice of intervention is based on the patient’s preferred style of coping and the resources available locally. Psychotherapy from a mental health professional usually is preferable when it appears that the patient has personal concerns beyond the evident stressor; support groups or counseling by the clinician often are satisfactory when the main issues are related to coping with a neurologic disease. Pharmacologic therapy for symptoms of anxiety should be considered if there is significant insomnia, irritability, or disruption of daily activity by anxiety. Benzodiazepines are the usual drug of choice in this situation. However, some patients, often those with highly intellectual or action-oriented coping styles, do not tolerate the mild sedation associated with benzodiazepines. For them, less sedating antianxiety drugs (e.g., buspirone) are preferable even if insomnia is a presenting complaint. Panic Disorder. Patients with panic disorder usually respond best to a combination of psychological and pharmacologic therapy. Initially, the patient should be educated as to the benign significance of panic attacks, their origin in overactivity of the sympathetic nervous system, and their controllability with medication, if desired. If the attacks are frequent and uncomfortable, treatment can be initiated with a benzodiazepine; clonazepam is particularly effective, with alprazolam being an alternative for those who find clonazepam too sedating. For longer-term therapy, a tricyclic antidepressant or serotonin reuptake inhibitor (SSRI) is gradually substituted for all or part of the benzodiazepine dosage. After pharmacologic therapy is offered, the patient is taught a relaxation method for coping with the panic attacks. Effective methods include deep breathing, progressive muscular relaxation, self-hypnosis, visualization, and biofeedback. The patient should be offered books and other educational materials that explain the symptoms of anxiety and emphasize their benign nature. Patients who cannot achieve adequate suppression of panic attacks despite educational approaches and a trial of a benzodiazepine and an SSRI or tricyclic antidepressant in usual therapeutic dosage should be placed on a trial of a drug effective for partial epilepsy. Patients who do not want pharmacologic therapy, or

whose panic attacks have an apparent relationship to specific interpersonal conflicts, should be referred to a psychotherapist with expertise in treating panic. Phobias. Patients with specific phobias must be repeatedly exposed to the feared stimulus to extinguish the fear. The usual treatment is to teach the patient a method of relaxation and then expose the patient to progressively stronger stimuli while the patient practices the relaxation technique. Exposure is supplemented with education. People with fears of flying, for example, are taught about the principles of aviation and the basis of flight safety. When there is only an occasional need to confront the feared stimulus, a benzodiazepine or P-blocker can be given in anticipation of exposure to help control symptoms. Patients with agoraphobia or social phobia usually need an SSRI, tricyclic, or monoamine oxidase inhibitor (MAOI) antidepressant in addition to the techniques for specific phobias. Socially maladroit patients may need formal social skill training to address the realistic basis for their avoidance of social interaction. Obsessive-Compulsive Disorder. Patients with obsessivecompulsive disorder respond specifically to drug therapy with serotonin reuptake inhibitors. Compulsive rituals also respond to behavior therapy in which patients practice inhibiting their compulsive behavior, using relaxation procedures to cope with the anxiety that emerges when they refrain from performing the ritual. Post-Traumatic Stress Disorder. Patients with PTSD almost always need psychotherapy that addresses the traumatic event and its significance for the patient. There are convincing case series of patients who have been helped by specialized forms of psychotherapy, such as hypnosis or eye movement desensitization response therapy, who had not benefited previously from less specific psychotherapy. Because the symptoms of PTSD are extremely wide-ranging, the pharmacotherapy of PTSD tends to focus on whatever symptoms are most severe, distressing, or disabling. The only medication currently approved by the U.S. Food and Drug Administration for treating PTSD is sertraline, an SSRI. Sertraline, and probably all of the other SSRIs, are efficacious for relieving PTSD symptoms that overlap with symptoms of other anxiety disorders and with chronic depression. True mood instability in PTSD may respond to mood-stabilizing agents such as lithium, divalproex sodium, carbamazepine, and lamotrigine. Recurrent panic attacks in patients with PTSD may be treated initially with a benzodiazepine; in the longer term, an antidepressant such as an SSRI is preferable because of a lesser risk of tolerance and dependence and fewer cognitive side effects. When patients with PTSD present with severe, violent agitation, effective behavioral control is most readily obtained with a combination of a benzodiazepine and a high-potency neuroleptic. Pharmacologic Treatments Benzodiazepines. Benzodiazepines are the mainstay of short-term pharmacologic therapy for anxiety. They offer the benefit of almost immediate action. The only significant medical contraindication is severe pulmonary disease with hypoventilation. However, two common situations in neurologic practice warrant precautions. First, patients with gait disturbance can become significantly more unsteady on benzodiazepines. Their gait should be reassessed after starting a benzodiazepine and again after steady state is reached with continued dosing. Second, patients with cognitive impairment, and especially patients with frontal system dysfunction, can show significant disinhibition on

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the benzodiazepines. Behavior should be reassessed after the initial dose and again at steady state. For treating anxiety in the context of an adjustment reaction, any benzodiazepine will do, but current fashion favors intermediate-acting agents without active metabolites (e.g., clonazepam or oxazepam). However, longer-acting agents such as diazepam may be more convenient and economical if the dosage is kept low and one is alert to accumulation, as steady state may not be reached for more than a week. For treating panic attacks, clonazepam and alprazolam are preferred because they appear to suppress panic attacks better than other benzodiazepines, at dosages that have equal effect on anticipatory anxiety. Optimum dosages of benzodiazepines for treatment of anxiety in neurologic patients vary widely for several reasons. First, there is wide variation in benzodiazepine metabolism in the general population and even more variation among people with chronic diseases. Second, patients who have received antiepileptic drugs or antispasticity agents may be pharmacodynamically tolerant to some of the effects of benzodiazepines. Third, regional brain disease can influence drug response, as when frontal system disease increases the risk of disinhibition. See Table 151-1 for typical dosage ranges. To determine the optimum dosage of a benzodiazepine for a given symptom in a given patient, start with a small initial dose. If the first dosage is ineffective, a slightly higher dosage is given the next time, until the patient receives noticeable benefit. The minimum beneficial dosage is given repeatedly until the pharmacologic steady state is reached; the situation is then reassessed. Dosages are adjusted repeatedly until the desired effect is obtained. In this way, the minimum dosage to control symptoms is approached from below. Patients who are responsible and cognitively intact may titrate benzodiazepine dosage for themselves within parameters specified by the physician. Antidepressants. Almost all chronic anxiety disorders can be treated with antidepressants rather than benzodiazepines, although the onset of therapeutic action is slower. Patients who are intolerant of the sedation or ataxia produced by benzodiazepines may prefer antidepressants, particularly the serotonin reuptake inhibitors. However, when these drugs are used for anxiety disorders, they should be started at dosages well below the usual recommended dosages for depression because they can transiently aggravate anxiety symptoms if they are started at standard antidepressant dosages. Typical starting dosages are paroxetine 5 to 10 mg/day or sertraline 12.5 to 25 mg/day. In patients with a history of extreme sensitivity to medication, fluoxetine liquid can be used because it permits titration from an extremely low starting dosage (e.g., 2 mg/day). Once it is established that a dosage is tolerated, increases can be made every 2 to 3 days until symptoms are relieved or the full antidepressant range is reached. Buspirone. Buspirone, a serotonin- 1A partial agonist, is effective for generalized anxiety but not for phobia or panic. It is less effective than benzodiazepines for the autonomic symptoms of anxiety, and, as with the antidepressants, several weeks of continued dosage may be needed to attain maximal effectiveness.

TABU 151-1. Typical Dosage Ranges for Benzodiazepines Alprazolam 0.25 to 1.O mg tid to qid Clonazepam 0.25 to 1.O mg qhs to bid Lorazepam 0.25 to 1.O mg tid Oxazepam 10 to 30 mg tid DiazeDam 2 to 10 mn ahs to tid

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The chief advantage of buspirone is that for some patients, it is both effective and essentially free of side effects. When side effects do occur, they commonly are dizziness, tinnitus, or gastrointestinal upset, not sedation or ataxia. The drug is safe in patients with chronic lung disease and hypoventilation, and it can be given safely to people with a history of alcohol abuse. Effective use of buspirone is based on appreciating its widely variable pharmacokinetics, which result partially from a large first-pass effect. Therefore, some patients obtain therapeutic or adverse effects on as little as 10 mg/day, and others need 60 mg/day or more to obtain any noticeable effect. Patients therefore must be instructed to start with 5 mg twice a day and raise the dosage in 5-mg increments every 1 or 2 days until they obtain a therapeutic benefit, experience limiting side effects, or reach a dosage of 20 mg three times per day. The therapeutic dosage should then be maintained for at least 4 weeks to attain maximum benefit. The long titration period and latency for effect makes benzodiazepine therapy necessary in the interim for most patients with clinically significant anxiety. Patients who have been treated with benzodiazepines in the past rarely report satisfactory relief of anxiety from buspirone alone. However, concurrent administration of buspirone can make possible satisfactory relief at a lower dosage of benzodiazepines than would otherwise be needed. This strategy is particularly useful when concurrent neurologic disease makes the patient vulnerable to ataxia and falls at the dosage of benzodiazepines needed to control anxiety with single-drug therapy. A drawback of buspirone for many patients is its high cost. This is a particularly significant problem for patients who metabolize the drug rapidly because high dosages are needed for efficacy. For those with rapid metabolism and without prescription drug coverage, the cost may be prohibitive. Neuroleptics. Anxious or agitated patients who voice paranoid, highly suspicious, or angry accusatory ideas may benefit from neuroleptic treatment even if they do not suffer from a full-blown psychosis. Patients with early dementia, epileptic hyperemotionality, or unstable personalities may fit this clinical pattern, particularly when under stress. Drugs of choice in this situation are neuroleptics with some intrinsic sedating or anxiolytic effect, given at low dosages, well below those used to treat schizophrenia. Options include risperidone 0.5 to 1 mg once or twice a day, olanzapine 2.5 to 5 mg once a day at bedtime, and ziprasidone 20 mg at bedtime. High-potency nonsedating agents such as haloperidol may be less satisfactory in this situation because of their relative lack of anxiolytic effect and the risk of akathisia. Akathisia, an irresistible impulse to move the limbs and often the whole body, is one of the most common extrapyramidal effects of neuroleptics. In an anxious patient the physical restlessness and inner tension of akathisia may be wrongly attributed to a worsening of anxiety. The onset of symptoms after starting or raising the dosage of neuroleptics should raise suspicion of this syndrome. Acute akathisia can be treated with 50 mg of intravenous diphenhydramine or 2 mg of intravenous benztropine. Longer-term P-blockers (e.g., propranolol 20 mg three times a day) are a more satisfactory treatment, should continuation of the neuroleptic be clinically necessary. Duration of Treatment. When benzodiazepines are given for relief of situational anxiety, they should be tapered gradually when the crisis is over and the patient is coping well. In fact, most patients given benzodiazepines for true situational anxiety taper themselves, and a reluctance to do so suggests that there may be an underlying anxiety disorder. Duration of therapy for patients with

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anxiety disorders follows from the natural history of anxiety disorders. Some patients relapse and remit, and others have a chronic course. When benzodiazepines or antidepressants are given for an anxiety disorder, the patient should be continued on the drug until free of symptoms, or adequately relieved, for at least 3 months. At that point, a gradual taper of the drug can be attempted. If symptoms recur, the patient is put back on the minimum dosage necessary to control symptoms for another 3 months, and a taper is tried again. Long-term maintenance should be considered if symptoms recur on each of three attempts to taper medication. Psychotherapy should be tried in cognitively intact patients with anxiety and residual symptoms or disability despite drug treatment, before one accepts the need for lifetime maintenance pharmacotherapy. The psychotherapies efficacious for anxiety disorders differ according to the specific disorder treated. Cognitive or behavioral therapy directly addressing control of the symptoms is particularly efficacious for obsessive-compulsive disorder and phobias. Formal relaxation training via progressive muscular relaxation, meditation, or biofeedback can be efficacious for generalized anxiety whether or not it reaches the threshold for diagnosis of generalized anxiety disorder. Among the anxiety disorders, insight-oriented psychotherapy probably is most efficacious for PTSD, generalized anxiety, and obsessional thinking without compulsive rituals. MOOD DISORDERS Mood disorders, especially depression, are the most common psychiatric complication of chronic neurologic disease. The prevalence of clinically significant depression in clinical neurologic populations has been estimated at 30% to 50% among stroke patients, 10% to 20% among patients with Alzheimer’s disease, 27% to 54% among patients with multiple sclerosis, 40% among patients with Parkinson’s disease, and more than 33% among survivors of severe traumatic brain injury. Depressive phenomena can aggravate the primary symptoms of neurologic disorders or make them less bearable to the patient. Furthermore, patients may seek neurologic consultation or treatment for neurologic symptoms of depression, such as cognitive impairment or somatic pain, particularly of the head, back, or neck. Because of the ubiquity of depression, its recognition and initial treatment have become part of the usual outpatient neurologic practice. This section of the chapter reviews the symptoms of depression and mania, assess-

= TMLE 151-2. Symptoms of Depression Unintentionalweight loss or gain of greater than 5% over 1 month or 10% over 6 months Alteration in sleep patterns, most commonly insomnia with early morning awakening or multiple awakenings, associated with daytime fatigue Psychomotor retardation (i.e., slowing of speech and movement relative to the patient‘s baseline) Agitation (excessive non-goal-directed movements, e.g., hand wringing, picking at oneself, pacing) Fatigue or loss of energy Feelings of worthlessness, inferiority, shame, or guilt Trouble concentrating or remembering recent events or recently learned material Impaired decision making (indecisiveness, impulsive decision making, or poor judgment) Recurrent thoughts of death, suicide, or self-injurious behavior The facial expression of depression, a pained expression with furrowed brow and contraction of the corrugator muscle of the forehead

TABLE 151-3. Symptoms of Mania Grandiosity or inflated self-esteem Decreased need for sleep Talkativeness Erratic thought or speech patterns or jumping from topic to topic Distractibility Agitation Increased goal-directed behavior Excessive involvement in pleasurable but potentially dangerous activities (impulsive travel, sexual escapades, high-risk investments)

ment of patients with suspected mood disorder, general management, and pharmacologic treatment.

Symptoms

Depression. The cardinal symptoms of depression are depressed mood and loss of interest or pleasure in life activities. However, the term depressed is not always accepted as an accurate description of the mood by patients with depression; some prefer to describe their mood as irritable, sad, discouraged, or negative. Other patients complain of, or acknowledge, a loss of interest or pleasure while denying any negative mood. Patients’ descriptions of their moods are influenced by cultural and personality factors and by the effects of brain diseases. In particular, patients with right hemisphere damage often deny depressed mood even when their caregivers see them as visibly depressed, and the patients acknowledge a loss of interest and pleasure. In clinically significant depression, the cardinal symptoms are accompanied by persistent distress or by mood-related impairment in social, occupational, physical, or cognitive functioning. Table 151-2 summarizes the symptoms of depression. Patients usually have some combination of the associated symptoms. The concurrence of five or more symptoms of depression (any of those in Table 151-2 with the exception of facial expression) for most of the time over a 2-week period is the syndrome of major depression. Clinically significant depression need not meet diagnostic criteria for major depression. Patients with chronic neurologic disease can have a small number of depressive symptoms whose intensity makes them clinically important. For example, if one of the symptoms is suicidal thinking, the depression is clinically significant regardless of the total count. Moreover, the persistence of depressive symptoms over time can contribute substantiallyto disability and distress even when the symptoms of depression as such do not appear to be severe. Mania. The cardinal symptom of mania is elevated, expansive, or irritable mood. A manic episode consists of such a mood persisting for 1 week or more, producing impairment in social or occupational function, disruption of relationships, or behavior resulting in hospitalization, and accompanied by a combination of associated symptoms. See Table 151-3 for the associated symptoms. For diagnosis, the patient must have at least three of the associated symptoms if the mood is elevated or expansive and at least four if the mood is irritable. Psychotic symptoms-grandiose or persecutory delusions, hallucinations, or belief in a special relationship with God or with a famous person-are common in mania. What distinguishes them from the psychotic symptoms of schizophrenia is the total pattern of symptoms and history. The content of delusions in mania may be indistinguishable from the content of delusions in other psychotic disorders. Paranoid thinking in particular is not specific to any diagnosis.

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The diagnosis of a hypomanic episode entails a duration of 4 days, a similar number of associated symptoms, and a lesser degree of functional impairment. Psychotic features such as delusions and hallucinations are, by definition, not compatible with a diagnosis of a hypomanic episode. As with depression, patients with neurologic diseases can have clinically significant hypomanic phenomena that fall short of diagnostic criteria for a hypomanic episode. For example, elevated, expansive, or irritable moods, accompanied by an accelerated rate of speech and action, can occur as a consequence of the illnesses or complications of treatment listed in Table 151-4. Bipolar Disorders. Mood disorders comprise a range of conditions, partially of genetic origin, in which patients have episodes of major depression, mania, or hypomania, combinations of depressed and hypomanic symptoms, or chronic symptoms of depression or hypomania falling short of a full syndrome for a major depressive episode or hypomanic episode. The more common mood disorders include major depressive disorder, bipolar (manic-depressive) disorder, and dysthymic disorder (a chronic depressed mood that lasts at least 2 years). Patients who present with a history of depression may suffer from a disorder in which episodes of depression alternate with manic symptoms that may or may not reach the threshold for the diagnosis of hypomania. These conditions, called bipolar spectrum conditions, include bipolar I1 disorder (recurrent major depressive episodes with hypomanic episodes) and cyclothymic disorder (multiple episodes of subsyndromal depressive and hypomanic periods, occurring over a span of 2 years or more). When a patient can identify two distinct abnormal mood states, one of which has a faster rate of movement, thought, or speech than the other, it is highly likely that the patient has one of the bipolar disorders. The clinical importance of recognizing bipolarity is that moodstabilizing drugs are almost always needed for the success of long-term treatment. Bipolar patients who present with depression may initially do well on antidepressants but then start to cycle between depression and mania or hypomania. Alternatively, they can develop an abnormal mood state with some features of both depression and mania occurring simultaneously. If a mood stabilizer is part of the treatment, this is less likely to happen, and a stable remission is more probable. Depressive Symptoms in Neurologic Patients. Neurologic patients with impaired insight into their physical or cognitive deficits, such as those with frontal system or right hemisphere disease, also have impaired awareness of their own affective states. When the physician is assessing such patients for depressive symptoms, the observations of people close to the patient usually are needed to supplement the history. Also, systematic inquiry about the associated symptoms of depression may yield many positive symptoms even though depressed mood is denied or minimized. Patients with’ aphasia and related communication problems may have difficulty articulating their mood. Such patients can be given a simple visual analogue scale of mood with a happy face at one end and a sad face at the other and can be asked to describe their usual mood over the past week or at the time of the interview. TMLE 151-4. Organic Causes of Hypomania Right hemisphere damage from stroke, tumor, or demyelinating disease Dementing illnesses Dopamine agonist treatment for Parkinson’s disease Antidepressant or stimulant therapy

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Patients’ responses on the visual analogue scale have shown remarkable validity when tested against depression rating scales completed by caregivers. The visual analogue scale should be oriented vertically to avoid false results caused by hemineglect or hemianopsia. When depressive symptoms are elicited, both the physician and the patient may be tempted to attribute some symptoms to the patient’s neurologic or systemic illness or to a normal emotional response to symptoms or disability. Such efforts tend to be unreliable because symptoms such as sleep disturbance or weight changes are multiply determined, and the presence of a specific medical problem does not exclude depression as an aggravating factor. Moreover, emotional reactions to physical illness deserve clinical attention if they persistently interfere with a patient’s functional capacity or ability to participate fully in his or her medical or rehabilitative treatment. Pain as a Depressive Symptom. Pain itself is not regarded as an associated symptom of depression. However, depressed mood and its accompanimentsare strongly associated with chronic pain, both in clinical samples and in the general population. In chronic pain samples, patients usually report that the pain preceded the depression or that the onset was simultaneous. The relationship between pain and depression in clinical practice appears to be circular. Increased pain leads to increased depression, which leads to increased pain or decreased tolerance of whatever pain is present. There is little evidence that depression causes pain in the absence of a painful condition such as osteoarthritis, radicular disease, migraine, or tension headache. However, the latter conditions are so common that the presentation of depression as back, neck, or head pain is an everyday occurrence. Diagnostically, however, the patient is most accurately seen as having two diagnoses: a somatic disease causing the pain and a mood disorder aggravating the pain. Depression and Grief. The symptoms of normal bereavement overlap extensively with the symptoms of clinical depression. Whereas delusional guilt, suicide attempts, and incapacitating psychomotor retardation are not part of normal bereavement, almost every other depressive symptom can occur, including death wishes and hallucinations of the lost person. Grief over lost function, as can occur in a patient recovering from a stroke or a spinal cord injury, produces very similar symptoms. Grief becomes a clinical problem when its symptoms lead to a major loss of function, interfere with the patient’s self-care or compliance with medical treatment, or are unbearable to the patient. In addition, psychosis and suicidal behavior define grief as a clinical problem. Grief that becomes problematic in this way, so-called complicated bereavement, is in essence a mood disorder and is assessed and treated accordingly. When it is unclear whether a patient’s bereavement will be complicated, closer medical follow-up is indicated until the situation declares itself.

Diagnosis Assessment begins with a categorization of the patient’s syndrome based on his or her history of mood changes. If the chronology of the symptoms is unclear from the medical history, the patient or caregiver can be asked to draw a graph showing fluctuation of mood above and below normal over the time since the onset of mood changes and also indicating major life events. The history distinguishes between patients with depressive symptoms only and those who also have had manic or hypomanic symptoms. The latter need different pharmacologic treatment and have a different

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prognosis. The history also reveals whether the depression has been chronic, episodic but persistent, or recent and apparently reactive to a life stress or illness-related problem. Detailed chronology of the relationship between the course of the patient’s neurologic illness, drug treatments, and mood symptoms should help establish whether the mood symptoms are directly linked to disease activity or to a specific medication. The historical review also includes a detailed alcohol and drug history, if this was not obtained earlier. If the patient is actively drinking alcohol or abusing drugs or has just recently abstained after prolonged use, a mood disorder should not be diagnosed based on current symptoms. A confident diagnosis of a primary mood disorder entails the persistence of the mood syndrome after 1 or more months of total abstinence. Patients are assessed for evidence of psychosis. Manic patients usually volunteer their grandiose or persecutory delusional thoughts or readily answer questions about their unusual perceptual experiences. Depressed patients may not volunteer symptoms of psychosis and need direct questioning regarding concerns about guilt, persecution, or “voices,” particularly of a critical or punitive character. Patients should be assessed for current suicidal ideas or plans. The patient’s list of medical problems and medications are reviewed for entities that can cause or aggravate mood disorder. If the patient has a new onset of major depression with weight loss and is middle-aged or older, appropriate screening is done for cancer. Often the patient is on medications sometimes associated with mood disturbance but without a clearly established connection to major depression, such as P-blockers or digoxin. These medications rarely are a sole cause of clinically significant depression, but they can worsen depressive symptoms so that they become more distressing or disabling. Whereas the diagnosis of a drug-induced depression should not be made unless the drug is the primary or sole cause of the mood disturbance, there often is practical benefit in discontinuing the suspect drug and, if necessary, substituting a therapeutically equivalent agent with lesser effect on the central nervous system. Patients’ level of insight into their mood disturbance is assessed, as are general cognitive capacities, including memory and abstract reasoning. If the patient has suicidal ideas or plans or preoccupations with death, the reasons for not acting on them are elicited.

Patients with psychotic features or active suicidal ideas are referred to a psychiatrist for specialized treatment. When feasible, decisions about immediate treatment of psychosis with neuroleptics and hospitalization for the patient’s protection are made collaboratively with the psychiatrist who will assume responsibility for treatment. Patients with mood disorders of lesser severity may appropriately be treated by the neurologist. Treatment by the neurologist may be preferable when depression or hypomania complicates or coincides with a chronic neurologic disease already being treated or when a primary depression has presented with a headache or back or neck pain and the patient is more comfortable being treated in a purely medical context. New Diagnoses of Depression. Patients diagnosed with depression for the first time need education about the diagnosis and its meaning. They should be told that they suffer from a disturbance of brain and endocrine physiology that has both

mental and physical symptoms and that can be helped with medical treatment. If the patient has presented with a specific complaint such as back pain, an explanation is offered of how the physiologic changes of depression can aggravate the pain or make its pain less bearable. If the depression is related temporally to a specific external stress, bereavement, or aggravation of physical illness, the concept of depression as a form of stress response is emphasized (e.g., when stress exceeds the capacity to cope or makes an excessively prolonged demand on coping resources, the syndrome of depression may develop). If the depression is accompanied by specific and treatable problems such as radicular pain, treatment for both the depression and the somatic problem are offered at the same time. Almost all patients with clinically significant depression are offered education and antidepressant drug therapy. Also, patients are referred for psychosocial therapy according to their situation. If the patient is coping with a new diagnosis of a major chronic neurologic disease, a referral for individual psychotherapy is offered, as is information about support groups for patients and families. If the patient is dealing with grief, appropriate secular or religious support is offered. If the patient has an evident emotional or interpersonal conflict related to the depression, the patient is referred to a psychotherapist for at least brief psychotherapy. If the patient is chronically depressed, longer-term individual or group psychotherapy can work additively or even synergistically with drug therapy. Recurrent Depression. Patients with recurrent depression do best with maintenance antidepressant drug therapy and psychotherapy to address the maladaptive beliefs and interpersonal behaviors that lead to depressed moods or that create unhappy situations to which a depressed mood is a predictable reaction. Two critical points concerning maintenance drug therapy are that the dosage needed to maintain a remission is the same as that needed to induce one and that therapy must be continued indefinitely. These points run counter to the beliefs of many clinicians, so one should verify that a relapse did not occur because of a well-meaning effort to taper the antidepressant dosage. If patients have had adequate maintenance dosages of antidepressant drugs and have relapsed despite compliance with the regimen, they should be treated with an antidepressant drug of a different therapeutic class. Patients who have not received psychotherapy should be referred to a psychotherapist; those who were treated in the past but did not establish rapport with the therapist should be offered a referral to a different one. Hypomanic Symptoms. Patients with hypomanic symptoms may decline treatment because they may find their elevated mood and increased energy adaptive or enjoyable. However, when there is a history of crashes into depression or of bad judgment while hypomanic, this history should be thoroughly discussed with patients when attempting to persuade them to take mood stabilizers. One explains that mood-stabilizing treatment does not prevent normal happiness but only the excessive and risky expansiveness of hypomania. If the patient has hypomania as a consequence of a specific lesion such as a right temporal stroke or tumor, mood-stabilizing medication can be described to the patient or family as routine treatment to prevent adverse consequences of the lesion. Hypomania can disrupt cognitive performance because it impairs attention, concentration, and executive function. Many such patients can be persuaded to take mood stabilizers because they can enhance cognition. Another reason why patients resist treatment for hypomania is that they have had adverse effects of mood stabilizers in the past.

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Polyuria, weight gain, and tremors from lithium are particularly common complaints. It is not unusual to encounter patients whose sole prior treatment has been with lithium and who are not aware of the broader range of treatment options now available. Neurologists in particular can confidently initiate and monitor trials of mood-stabilizing antiepileptic drugs. Pharmacologic Therapy Pharmacologic therapy for primary mood disorders has been well established by a large number of controlled clinical trials. By contrast, few studies have been done of antidepressants in specific populations with neurologic disease and mood disorders. The studies that have been reported in neurologic populations have used tricyclic antidepressants, drugs that are now less preferred for treating depression in primary care because of their greater systemic toxicity than the SSRIs. The recommendations given here are an extrapolation from studies done in populations without gross brain disease. Major Depression. The most effective treatment for major depression with prominent weight loss and sleep disturbance is tricyclic antidepressants unless the patient has electrocardiographically confirmed heart block or has known or expected intolerance of anticholinergic effects. (A baseline electrocardiogram is standard practice before tricyclic therapy is initiated.) The secondary amine tricyclics, nortriptyline and desipramine, are preferred to the tertiary amines amitriptyline and imipramine because they have fewer anticholinergic and hypotensive effects and because their blood levels are more easily monitored. Starting dosage in a frail, older, or chronically ill patient is 10 mg of nortriptyline at bedtime or 10 mg of desipramine two or three times a day; the dosage is increased gradually as tolerated. The dosage is raised until symptoms are relieved; until limiting side effects of sedation, orthostatic hypotension, or confusion, tachycardia, or other anticholinergic effects develop; or until typical therapeutic dosages are reached (50 to 75 mg of nortriptyline at bedtime or 50 mg of desipramine two or three times a day). A blood level of the drug is obtained at that point unless the patient is in complete remission and free of side effects. The usual therapeutic levels are 50 to 150 ng/mL for nortriptyline and more than 120 ng/mL for desipramine. Nortriptyline levels have a therapeutic window; increasing the level beyond 150 ng/mL can reduce therapeutic benefits. In contrast, the therapeutic response to desipramine increases with levels beyond 120 ng/mL, so it is rational to seek a higher blood level if a patient has an incomplete response. However, the applicability of these therapeutic ranges to very old patients has not been established. Patients who are younger and without systemic illness tend to need higher dosages to attain a given blood level, as do those who smoke or those who have been on enzyme-inducing antiepileptic drugs, such as carbamazepine or phenytoin. However, there is substantial variability in the rate of metabolism of tricyclics at any age; occasionally an older adult needs more than 300 mg per day of desipramine or more than 100 mg per day of nortriptyline to attain a therapeutic level. When pushing dosages above conventional limits it is advisable to obtain a follow-up electrocardiogram on the higher dosage because some patients have significant levels of tricyclic metabolites with cardiac side effects. These metabolites are not measured by usual blood level assays. If the patient cannot take tricyclics or cannot tolerate them and has depression with insomnia and weight loss, alternative therapies are venlafaxine, mirtazapine, and nefazodone. Venlafaxine’s

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most common side effects are sedation, sweating, and hypertension. Although it occasionally causes orthostatic hypotension, it does not have quinidine-like effects that aggravate heart block. The starting dosage is 25 mg two or three times a day; the dosage is raised gradually, with a recommended maximum dosage of 100 mg three times a day, although occasional patients tolerate and benefit from dosages as high as 150 mg three times a day. Mirtazapine often causes weight gain and sleepiness; these effects can be desirable in patients with major weight loss and insomnia. Mirtazapine may be started at 15 mg at bedtime and raised gradually as needed and tolerated, to a maximum of 45 mg twice a day. Nefazodone often causes sedation and less often causes gastrointestinal upset but is largely free from major systemic side effects. However, it does inhibit metabolism of many drugs, notably carbamazepine. If the drug is given to a patient on carbamazepine, the blood level of carbamazepine should be monitored and the dosage reduced as necessary. Nefazodone is started at 50 mg per day; it is gradually raised as high as 600 mg/day in two to four doses, with most of the dosage given after 6

P.M.

Patients with weight loss and sleep disturbance less prominent than their depressed or irritable mood are treated initially with SSRIs (citalopram, fluoxetine, paroxetine, and sertraline); fluvoxamine, also an SSRI, is efficacious for depression but is approved by the U.S. Food and Drug Administration only for obsessivecompulsive disorder. All of these drugs have shown equal efficacy in clinical trials, but any given patient may do better on one than another, from the standpoint of both efficacy and tolerability of side effects. SSRIs may be especially effective for chronic depression and for the chronic irritable states that can accompany limbic epilepsy or Parkinson’s disease. Whereas the SSRIs have few serious systemic side effects, they can cause apathy or sedation and can produce neuromuscular side effects and involuntary movements including tremors, myoclonic jerks, akathisia, restless leg syndrome, and cramps. Agitation is not uncommon, and hypomania can occur in patients with no prior history of bipolar disorder. Patients with preexisting brain disease may be more sensitive to these side effects. Commonly occurring and of great concern to many patients are the sexual side effects of the SSRIs, which include decreased libido and delayed or inhibited orgasm. SSRIs can disrupt the menstrual cycle or cause breast enlargement. Finally, they have an unpredictable effect on sleep. They can cause hypersomnia, insomnia, or a characteristic syndrome of extreme sleepiness in the mid- to late afternoon. Rapid eye movement sleep latency is increased, but vivid dreams can occur later in the night. Starting dosages are kept low to assess tolerance before advancing to a more typical antidepressant dosage. Starting dosages in neurologic patients should be lower than the usual starting dosages recommended by the manufacturer. All drugs can be given once a day. Typical starting dosages are citalopram 10 to 20 mg, fluoxetine 5 to 10 mg, paroxetine 5 to 10 mg, sertraline 12.5 to 25 mg, and fluvoxamine 12.5 to 25 mg. The dosage is increased gradually to a maximum of four times the manufacturer’s recommended minimum dosage (i.e., fluoxetine 80 mg, sertraline 200 mg, paroxetine 80 mg, fluvoxamine 200 mg), with the exception that citalopram, having fewer side effects than the others, may be pushed to a dosage of 100 to 120 mg if a patient tolerates the drug and has a partial response to a conventional dosage. Meaningful blood levels are not available for clinical use. However, most patients either respond or develop limiting side effects before reaching the maximum dosages listed. The SSRIs have inhibiting effects on the cytochrome p-450 system and

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therefore can increase drug levels of antiepileptic drugs primarily metabolized by the liver. Levels of carbamazepine and phenytoin should be rechecked after concurrent therapy with an SSRI is initiated. If an SSRI relieves a depression that significantly affects the patient’s functioning, its side effects should be treated to enable the patient to remain on the drug. If a patient’s depression responds to an SSRI but the patient develops a tremor, the tremor should be suppressed with either a benzodiazepine or with a lipophilic P-blocker such as propranolol or metoprolol, at dosages similar to those that would be used for essential tremor. Akathisia usually responds to a P-blocker as well. Myoclonic jerks, if disruptive, can be suppressed with a small dosage of clonazepam (e.g., 0.5 to 1.0 mg/day), usually given at bedtime. SSRI-induced restless leg syndrome responds to a dopamine agonist or to gabapentin, as is observed in the idiopathic form. All of these effects are more likely to occur in patients with deficiency of calcium or magnesium; if dietary deficiency of these minerals is suspected, supplements should be prescribed. For apathy complicating otherwise effective treatment with an SSRI there are several choices: dextroamphetamine, methylphenidate, bupropion, and pramipexole. Dosages of these drugs are similar to those used for their primary indications. Decreased libido can be restored in some cases by a dopamine agonist or testosterone. Inhibited orgasm can be treated with cyproheptadine or sildenafil taken before sexual activity. However, none of the treatments for sexual side effects has been proven efficacious by controlled clinical trials. Patients with depression characterized by prominent apathy need especially careful diagnostic assessment for such entities as metabolic encephalopathy (e.g., hepatic, hypothyroid), sleep disorders (especially obstructive sleep apnea), and early Parkinson’s disease. If these entities have been excluded, one drug to consider is bupropion, a particularly stimulating antidepressant. Bupropion is started at 75 mg twice a day. If it is tolerated without excessive nervousness or agitation, it is raised to 75 mg three times a day and eventually, in small steps, to a maximum of 150 mg three times a day. The most feared but rare side effect of bupropion is seizures; the risk is approximately 0.4% at 450 mg/day for patients without specific risk factors for seizures. The risk rises substantially if more than 150 mg is taken at one time; patients should be cautioned not to make up missed doses. The controlled-release preparation of bupropion theoretically should have a lower seizure risk than the standard preparation, but this has not been established clinically. If the drug is to be tried in patients with risk factors for seizures, such as those with a history of significant traumatic brain injury, consider giving a nonsedating antiepileptic drug concurrently. Other stimulating antidepressants include desipramine, protriptyline, and fluoxetine, the latter being the most stimulating SSRI. MAOIs are effective broad-spectrum antidepressants with substantial antianxiety and antiphobic effects and, in the case of tranylcypromine, a substantial stimulating effect because amphetamine is one of its active metabolites. Many physicians avoid these drugs because of fear of a hypertensive crisis and the belief that MA01 therapy is incompatible with surgery or with a normal diet. However, recent studies have established that only a small number of foods pose a significant danger of adverse interactions with MAOIs and that anesthesia can be safe in patients on MAOIs if appropriate precautions are taken. The risk of hypertension can be reduced by advising patients against the use of any over-the-

counter medication without prior physician clearance, by stating in the medical record that the patient is “allergic” to meperidine and dextromethorphan, by advising the patients to monitor their blood pressure at home, and by having patients carry a small supply of 80-mg verapamil tablets, to be taken if a sudden, severe headache develops or blood pressure rises substantially after they eat an unfamiliar or contraindicated food. Between 5% and 10% of patients treated with antidepressant drugs develop hypomania or a milder state of euphoria or irritability. In addition, a substantial proportion of those with preexisting cognitive impairment develop confusion. If hypomania, euphoria, or severe irritability develops on an antidepressant, the drug should be withdrawn while a mood-stabilizing drug is started. If the patient continues to have depressive symptoms severe enough to warrant drug treatment, an antidepressantcan be reinstituted. If a patient with cognitive impairment develops confusion on an antidepressant, the drug usually should be stopped. Confusion developing on a tricyclic does not rule out future successful treatment with a SSRI. However, the rate of upward dosage titration should be particularly slow in patients with a history of antidepressant-induced confusion. If depression has responded dramatically to an antidepressant, cognitive impairment is only mildly exacerbated, and there are peripheral anticholinergic side effects, a trial of a cholinesterase inhibitor (e.g., donepezil, starting with 5 mg per day), is reasonable. Dosage may be increased slowly until all peripheral anticholinergic effects have resolved. Patients treated for major depression with one of the aforementioned agents may have a partial response to treatment, with enough benefit to warrant continuation of the drug but with enough residual symptoms to pursue further treatment. Augmentation of antidepressant treatment can be tried in this situation. Addition of lithium, 300 mg daily to three times a day, is a well-establishedoption in this situation. Triiodothyronine(TJ, 25 to 50 pg per day, is another consideration. If the patient is on an SSRI, the addition of bupropion to the regimen, in usual antidepressant dosage, may be efficacious. Unless a patient has severe, intolerable side effects, antidepressants should not be discontinued abruptly after a month or more of treatment. Abrupt withdrawal of SSRIs can produce profound irritability, anxiety, and moodiness. Abrupt withdrawal of tricyclics can produce weight loss and insomnia as well as mood changes. Withdrawal of venlafaxine can be a profoundly unpleasant experience, so much so that a switch to an SSRI and withdrawal of the latter may be prudent. Suicidal ideation and actions may accompany the sudden mood changes associated with abrupt antidepressant withdrawal; for this reason patients’ complaints of discomfort in this context warrant a prompt response. Patients beginning SSRI therapy or complaining of SSRI side effects should be warned about the danger of abrupt withdrawal. Hypomania and Bipolar Conditions. Patients with hypomania, or with a history of hypomania and depression, need mood-stabilizing medication. The first mood-stabilizing medication of proven benefit was lithium, which remains the treatment of choice for bipolar disorder with prolonged manic and depressive episodes. It was subsequently discovered that carbamazepine and valproate were effectivefor bipolar disorder and might be superior to lithium for patients with mixed manic and depressive symptoms or with rapid alternation between hypomania and depression. The efficacy of antiepileptic drugs for mood disorders is not predicted by any electroencephalographic finding. The blood

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levels at which the drugs are effective for mood disorders is roughly the same as their therapeutic levels for the treatment of epilepsy, except that valproate levels of up to 150 pg/mL may be effective and tolerated in treating acute mania. More recently, lamotrigine, gabapentin, and topiramate have been suggested as alternative therapies for bipolar conditions. At the time of this writing, the efficacy of these drugs for bipolar disorder has not yet been confirmed by controlled clinical trials. However, there is sufficient support for their efficacy in selected cases to warrant their consideration if a patient does not respond to or tolerate the conventional agents. Finally, atypical neuroleptics (olanzapine, quetiapine, and risperidone) have mood-stabilizing actions even when the patient has no psychotic symptoms. Of the three, the evidence of efficacy is greatest for olanzapine. The mood-stabilizing antiepileptic drugs also may be effective for fluctuating or unstable moods in patients with gross brain disease, including those recovering from traumatic brain injury or encephalitis, those with static encephalopathies, and those with dementia. Their use for this purpose is supported by multiple case series and a few controlled trials. Guidelines for the clinical use of the antiepileptic drugs are found in Chapter 146. Lithium is given to patients with gross brain disease on a two- or three-times-daily schedule, aiming for a blood level of 0.6 mE/L; occasional patients need and tolerate levels of up to 1.0 mE/L. Higher levels than that often are intolerable to patients with impaired brain function, even though such levels may fall within published therapeutic ranges for patients with bipolar disorder. The starting dosage for a patient with impaired brain function but without kidney disease is 300 mg twice a day. Lithium clearance is linked to creatinine clearance, and dosage must be reduced in patients with renal insufficiency. Both diuretics and nonsteroidal anti-inflammatory drugs raise lithium levels by increasing its resorption in the proximal tubule; lithium dosage must be reduced accordingly. Lithium levels should be checked frequently until the patient reaches a steady state. The workup before lithium is initiated consists of tests of kidney and thyroid function and an electrocardiogram. Renal insufficiency, thyroid disease, and sinus node dysfunction are all relative contraindications to lithium. Ongoing treatment is monitored with thyroid and kidney function tests every 3 to 6 months to screen for the development of hypothyroidism (a reversible side effect occurring in about 10% of patients) and renal insufficiency. Lithium probably does not aggravate renal problems when used at a conservativeblood level, but renal status has a profound effect on lithium clearance, so it must be monitored. Patients on lithium, or their responsible caregivers, must be aware that lithium levels rise rapidly with dehydration and that the therapeutic index of lithium is very low. Therefore, the drug should be temporarily discontinued if the patient develops vomiting or diarrhea or if there is any question of dehydration caused by decreased oral intake, unusual heat, or intercurrent systemic disease. If a patient on lithium develops confusion or a coarse tremor, neurotoxicity of lithium may be the cause. The drug should be discontinued temporarily and a lithium level should be checked. Patients receiving mood-stabilizing medications may develop major depression, even though they are protected from hypomania. Antidepressantscan be added to the regimens of such patients. Duration of Therapy. Major depression tends to recur; continuation of treatment beyond the relief of symptoms minimizes the risk of recurrence. Treatment for a first episode of major

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depression should be continued for 6 to 9 months; an effort to taper and discontinue the antidepressant can be made at that time. If the patient has a recurrence of symptoms, the medication is resumed at a therapeutic level for another 3 months, and withdrawal is attempted again, with a similar approach. If a patient has failed three attempts to taper antidepressants, longterm maintenance therapy should be offered. There is no evidence that dosages for long-term maintenance are different from those for initial treatment of the depression. Bipolar disorder is regarded as a chronic illness, necessitating long-term drug therapy for optimal outcome. However, some cases clearly “burn out” after several years of cycling. The natural history of hypomanic phenomena after gross brain disease is not known. The decision to discontinue mood-stabilizing medication in a case of primary bipolar disorder should be made in consultation with a psychiatrist. When mood stabilizers are used to control hypomania or mood fluctuations related to a gross brain lesion, they are continued until the physician finds it appropriate to see whether the patient can do without them. Practically, the mood stabilizersused are antiepileptic drugs whose continued use may be justified as prevention for focal seizures. In this situation, the drugs are continued as long as one would continue the antiepileptic drug therapy for its conventional indication. PERSONALITY DISORDERS AND REACTlON TO DISEASE Neurologic diseases pose unique challenges to patients’ coping and self-image. In some cases, there are visible stigmata of disease, as in Tourette’s syndrome or muscular dystrophy. In others, the disease is invisible but disabling, as in poorly controlled epilepsy. Coping with these disorders challenges patients with normal personality traits. When patients with maladaptive or rigid personality traits face the stress of neurologic disease, they often develop overt mental or behavioral symptoms. This section of the chapter deals with stress and coping, personality types and disorders in neurologic practice, and practical management strategies. Stress and Coping

Illness creates stress for patients through symptoms, disruption of life routines, changes in appearance or function, effects on interpersonal relations, and occupational or economic consequences. Illnesses force patients to change their behavior in ways contrary to their habits and inclinations. When confronted with the stress of illness, patients use coping mechanisms: a combination of conscious and unconscious strategies for dealing with the stress or for excluding it from awareness. Highly adaptive coping mechanisms involve handling the situation in a way that maximizes the patient’s satisfaction of legitimate needs and averts preventable conflicts and problems. These mechanisms include anticipation of problems (e.g., participation in patient education or studying the disease), affiliation with others (e.g., support group participation, sharing problems with family and friends), self-assertion (e.g., advance directives), self-observation, humor regarding the situation, and altruism (e.g., assisting others with the same illness or participating in clinical trials). At the opposite end of the spectrum are coping mechanisms that may exclude some painful thoughts from consciousness, but do so at the expense of problem solving, and that may endanger one’s health or network of supportive

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relationships. Such mechanisms include denial, projection (i.e., blaming), acting out (e.g., behaving in a violent, self-destructive, or provocative manner), apathetic withdrawal, help-rejecting complaining, and passive aggression (e.g., noncompliance with treatment accompanied by excuses). Overt problems with depression and anxiety may develop when the stress of illness exceeds the patient’s ability to cope. Patients with more adaptive coping mechanisms are able to tolerate more stress for a longer period of time, but if stress is sufficiently severe or prolonged, most patients develop emotional symptoms. Patients display maladaptive coping behavior either because it is habitual for them or because they have newly adopted the behavior. This can happen when stress exceeds their capacity to cope in their accustomed manner or because cognitive impairment (e.g., delirium or dementia) or a disturbance of mood or thought content (depression, anxiety, paranoid ideas) has temporarily impaired their adaptive function. A common pattern is seen in patients with relapsing-remitting illnesses, such as multiple sclerosis or systemic lupus, wherein the patient shows more adaptive coping when in remission than during acute exacerbations. Side effects of medications can cause a loss of adaptive coping via either cognitive impairment or disturbances of mood or thought content. Whereas coping styles, like personality, are generally stable over time, specific coping mechanisms can be learned or strengthened with practice. The habit of learning about one’s illness and of anticipating problems can be promoted by effective patient education. Affiliation, self-observation, and self-assertion can be strengthened by experiences in support groups or by counseling of the patient together with his or her caregivers. Negative coping through such mechanisms as denial and blaming sometimes can be attenuated by psychotherapy if the patient can be engaged in a relationship sufficiently trusting to permit confrontation of these usually maladaptive behaviors. When patients are not motivated to change behavior that significantly compromises their neurologic treatment, education of the family or other caregivers may enable behavior change through modification of the physical or social environment. Because maladaptive coping can be triggered by stress, more effective coping can be promoted by managing the amount of stress that the patient faces in a given period of time. Practical methods for regulating stress include adequate pain control and patient-specific pacing of diagnostic and therapeutic procedures. Some patients prefer a rapid workup or course of treatment “to get it over with; others prefer to space out procedures and treatments. Similarly, some patients want to know the results of tests immediately rather than wait for an appointment and their doctor’s personal interpretation. Formal relaxation exercises and structured physical exercise also have stress-reducing effects. It is important to individualize the relaxation method and the exercise prescription. Patients may fail at one approach and succeed at another. Personality Types and Disorders Personality traits are characteristic, stable patterns of behavior and interpersonal interaction. Personality types are constellations of traits that occur together often enough to be recognizable by clinicians. Personality disorders are stable, lifelong constellations of personality traits that are sufficiently rigid and maladaptive that they cause the patient significant distress or impairment and are recognized as deviating from patterns recognized within the

patient’s culture as normal or acceptable. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), of the American Psychiatric Association recognizes 10 such personality disorders (see Table 151-5). These personality disorders are grouped into three clusters. Paranoid, schizoid, and schizotypal personalities (cluster A) share the feature of oddness or eccentricity. Antisocial, borderline, histrionic, and narcissistic personalities (cluster B) share the feature of being dramatic, emotional, or erratic. Avoidant, dependent, and obsessive-compulsive personalities (cluster C) include the feature of becoming highly anxious if they are prevented from coping in their usual style. Clinical classification of personality disorders into categories is limited by overlap between categories and general problems of reliability. However, the more general assignment of a patient into one cluster or another is reliable enough to have some utility in planning clinical management strategies. Recent theoretical work has associated the clusters of personality disorders with specific neurotransmitter imbalances or physiological disturbances. Cluster A personalities have shown a subtle disorder of saccadic eye movements that is typical of people with schizophrenia. Cluster B personalities have shown markers of abnormal serotonergic transmission. In addition to these personality disorders, neurologists often recognize characteristic personality types associated with dysfunction of particular brain systems. Specifically, patients with frontal system lesions may show a personality characterized by impulsiveness, poor judgment and planning, and shallowness of affect, or one characterized by apathy and indifference. Patients with irritative temporal lobe lesions may show hyperemotionality and a viscous interpersonal style. Personality disorders are determined partly by neurobiology and partly by early life experience. Definite genetic factors have been established for schizotypal personality and antisocial personality. Borderline personality is strongly associated with traumatic early life experiences, particularly of physical or sexual abuse. Genetic studies suggest that schizotypal personality and schizophrenia occur in the same families, as do obsessive-compulsive

TABLE151-5. Classification of Personality Disorders Cluster A Paranoid personality disorder: a pattern of distrust and suspiciousness; interpreting others’ motives as malevolent Schizoid personality disorder: a pattern of detachment from social relationships and a restricted range of emotional expression Schizotypal personality disorder: a pattern of acute discomfort in close relationships, cognitive or perceptual distortions, and eccentricities of behavior Cluster B Antisocial personality disorder: a pattern of disregard for and violation of the rights of others Borderline personality disorder: a pattern of instability in interpersonal relationships, self-image, and affects and marked impulsivity Histrionic personality disorder: a pattern of excessive emotionality and attention-seeking Narcissistic personality disorder: a pattern of grandiosity, need for admiration, and lack of empathy Cluster C Avoidant personality disorder: a pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation Dependent personality disorder: a pattern of submissive and clinging behavior related to an excessive need to be taken care of Obsessive-compulsive personality disorder: a pattern of preoccupation with orderliness, perfectionism, and control From American PsychiatricAssociation: Diagnostic and Statistical Manual of Mental Disorders. 4th Ed. American Psychiatric Association, Washington, DC.

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personality and obsessive-compulsive disorder. Avoidant personality is associated with social phobia. Patients with cluster B personality disorders have a high incidence of major depression and substance abuse. They are more likely than those with normal personalities or with cluster A or C personality disorders to engage in suicide attempts or selfinjurious behavior. Personality Types and Disorders in Neurologic Practice. In the setting of clinical practice, formally diagnosing personality disorders is far less relevant than recognizing patients with rigid or maladaptive personality traits that compromise their neurologic treatment or impair their functioning in the face of neurologic disease. Moreover, neurologists can comprehend the general characteristics and themes of these patients’ behavior. If a reliable psychiatrist or psychologist has formally diagnosed a personality disorder, his or her diagnosis can be a useful guide to what to expect from the patient. When a patient presents a persistent or recurrent pattern of troublesome interpersonal behavior, a personality disorder or a personality trait disturbance is in the differential diagnosis. The nature of the patient’s interpersonal problem suggests the specific diagnosis. When the impression of a personality disorder is formed on the basis of current behavior, further information about the patient’s past behavior is needed to confirm the diagnosis. Relevant data can come from the educational, occupational, military, marital, and social history. These data can be elicited or collected de novo by the neurologist but often are available from the primary care physician, a social agency, or a mental health professional that the patient has seen in the past. Patients with cluster A diagnoses tend to be mistrustful; they can become uncomfortable if the neurologist shows excessive familiarity or concern or presumes a collaborative relationship. The forced intimacies of hospitals, rehabilitation centers, and nursing homes similarly cause these patients emotional distress. Under stress, they may become overtly paranoid or even delusional. Their life history typically shows a paucity of intimate relationships and avoidance of social activities; their pattern of interests may include some odd preoccupations. Patients with antisocial, borderline, or histrionic personalities have life histories characterized by drama and instability, typically with many broken or unsatisfactory relationships. Despite past disappointments, they often have unrealistic expectations about the clinicians or institutions that treat them. Narcissistic personalities view themselves as special and therefore entitled to special treatment. Patients with these cluster B personalities bring their personality traits to the attention of the neurologist by making demands or by challenging rules. Although initially they may be charming or engaging, they eventually become a burden to the practitioner when they explicitly or implicitly demand special treatment and explicitly or implicitly threaten bad consequences if limits are set. Disappointment of their expectations can trigger angry outbursts, self-injurious behavior, or other forms of acting out of their emotions. Patients with cluster C diagnoses come to the attention of the neurologist through some form of noncompliance with treatment or through demands for special attention. However, their noncompliance results from anxiety or avoidance rather than from anger, and special requests arise not from a sense of entitlement but from needs to assuage their anxiety. Thus, a patient with an avoidant personality may fail to attend educational groups despite a need for information, one with a dependent personality may make many calls to the office to reconfirm instructions, or one

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with an obsessive-compulsive personality may need to review the diagnosis and therapeutic recommendations in exhaustive and exhausting detail. Their life histories suggest that their characteristic style of avoidance, dependence, or compulsiveness began in their school years and continued as a feature of their marital relations and work or military experience. Patients with personality syndromes caused by frontal system disorders are brought to the attention of the neurologist by family members or other caregivers who are concerned about the patient’s poor judgment, self-neglect, or impulsive or socially inappropriate behavior. Typically, the behavior had its onset after the acquisition of a specific frontal system lesion, or it came on insidiously in association with cognitive impairment, as in cases of frontotemporal dementia. Patients with personality change caused by frontal system disorders might or might not be aware of their troublesome behavior. If they do acknowledge their personality changes, they tend to underestimate their significance. Patients with a temporal lobe personality syndrome caused by a focus of abnormal brain electrical activity present with excessive emotional intensity. They may write long notes to their neurologists. They show viscosity: by having difficulty being brief about any topic. It can be difficult to get such patients to leave the office at the end of a visit. Their behavioral syndrome has developed gradually over the course of years, usually in parallel with the course of complex partial epilepsy. Occasional patients show the same syndrome with signs of temporal lobe disorder on electroencephalogram or brain imaging but without overt seizures. Presenting symptoms include headaches or anxiety, or the patient may present for an unrelated neurologic problem (e.g., multiple sclerosis, stroke) and turn out to have this syndrome.

Management

AU maladaptive personality traits and coping mechanisms are aggravated by anxiety and by pain and discomfort. When a patient first is perceived as being “difficult,” realistic sources of anxiety and worry should be identified and addressed to the extent feasible. Patients with personality disorders usually have trouble tolerating frustration or disappointment. Therefore, their appointments should be scheduled on days and at times when the neurologist is likely to be punctual. If possible, sufficient time should be allowed for the appointment to minimize any sense of hurry. Paranoid, Schizoid, and Schizotypal Personalities. Patients with paranoid, schizoid, or schizotypal personalities should be treated in a cool, polite, and professional manner that avoids excessive warmth or familiarity. Because these patients often are uncomfortable in conversations, they should be given written information about their diagnosis and treatment and should be encouraged to ask questions in writing if concerns arise after the appointment. When the diagnosis is known, it may be helpful to use questionnaires to follow the course of illness or response to treatment. When patients with these personalities become overtly paranoid under stress, they should be treated with neuroleptic drugs. The atypical neuroleptics (olanzapine, risperidone, quetiapine, and ziprasidone) are the drugs of choice because of less frequent extrapyramidal side effects. Also, patients with severe cluster A disorders should be treated preventively with low dosages of atypical neuroleptics to help them cope with the specific stresses that can be expected to trigger paranoid symptoms (e.g., surgery that causes disfigurement, severe pain, forced intimacy caused by prolonged hospitalization or rehabilitation). In explaining the

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prescription, patients can be told that the drug may help them organize their own thoughts, or the purpose can be related to the patients’ own descriptions of their emotional distress (e.g., “to help with nervousness”). Antisocial, Borderline, Histrionic, and Narcissistic Personalities. Patients with dramatic and often manipulative personali-

ties can lead physicians to deviate from their own usual practice style. At times this can begin before the physician recognizes what is happening. As soon as the patient’s personality type is recognized or the physician realizes that he or she is treating the patient in an unusual way, three principles should be applied. First, all communications should be exceedingly clear and unambiguous. If a family member, a friend, a social agency, or another clinician is involved in the patient’s treatment, they should be communicated with directly and should be given exactly the same message as the patient regarding diagnosis and treatment. Second, the usual rules of one’s practice regarding prescriptions and refills, telephone calls, billing, appointment length, and other details should be observed without deviation or modification. Third, if patients impose on the physician or behave unacceptably in the office, limits should be set firmly but without anger. When patients with these personalities become overwhelmed by stress, they may develop a brief psychosis or an intense anxiety state. Management of the former situation is described later in this chapter under “Thought Disorders.” Intense anxiety in a patient with one of the dramatic personality disorders is best treated with a low dosage of an atypical neuroleptic (e.g., 2.5 mg of olanzapine or 0.5 to 1.0 mg of risperidone). Even though patients may request benzodiazepine antianxiety drugs, these agents are risky because they can reduce inhibitions. The prescription of the neuroleptic in these circumstances can be explained to the patient as a treatment for overwhelming anxiety. On occasion, the demands of patients with antisocial, borderline, or narcissistic personalities simply cannot be met, as when a patient wants the physician’s cooperation with a disability claim the physician does not support or when a patient demands refillable prescriptions for drugs that often are abused. When the patient will not accept the physician’s limits and responds with an angry attack on the physician, the patient should be told that such behavior is not acceptable in the physician’s practice. A referral to another physician is offered, and the encounter is documented in the record. The patient may threaten litigation, but this should not influence the limit-setting approach. Avoidant, Dependent, and Obsessive-Compulsive Penonalities. Patients with avoidant personalities present problems in

neurologic practice by being noncompliant with diagnostic tests, medications, rehabilitation, or other prescriptions such as exercise or diet. Patients’ fear of failure or humiliation leads them to avoid situations in which they might be judged, and they consciously or subconsciously fear that clinicians are judging their “performance.” The symptoms of the avoidant personality overlap with those of social phobia and are exacerbated by depression. Mobilizing the avoidant patient’s cooperation begins by identifying and treating depression if it is present; SSRIs are the usual drugs of choice. Patients’ fear of failure is explained to them and is then mitigated by making the task hard to fail. For example, medication regimens are simplified, and physical therapy programs are broken up into segments so small that it is difficult for the patient to fail at them. Patients with dependent personalities may fail to solve illnessor treatment-related problems despite adequate intelligence because their characteristic style is to be helpless until an authority

figure tells them what to do. A pragmatic approach to medical treatment with such personalities is to identify a support person on whom the dependent patient can lean; the support person then is educated about the illness and its treatment. The dependent person who has become socially isolated may attempt to develop an emotional dependency on the physician. In the short term, this can be managed by scheduling more frequent appointments; telephone calls between appointments should be discouraged except in true emergencies. In the longer term, a psychotherapist or social worker can be engaged to assist the patient in finding social supports unrelated to medical treatment. Patients with obsessive-compulsive personalities may have difficulty making treatment decisions because of indecisiveness, or they may take up the physician’s time with excessively detailed questions. Such patients’ needs for information should be met realistically with handouts and with suggestions for books, support groups, and Web sites. If they are truly paralyzed by indecision yet must make a choice of medical treatments, useful interventions include referral for short-term psychotherapy and a trial of an SSRI. The latter may be especially efficacious if the patient has not tried these medications before. Both interventions are framed as efforts to help patients deal with the unpleasant experiences of anxiety or depression that interfere with their ability to make a good decision. “Frontal Lobe” Personalities. Managing personality syndromes caused by frontal system dysfunction entails working simultaneouslywith the patient and the family or other caregivers. The family must learn to set limits and provide cues without anger or condescension, understanding that the patient’s behavior is strongly determined by environmental cues. If patients have some capacity for insight, they are educated about their need for external cueing to function at their best. Their feelings of humiliation about their need to be monitored and cued by others must be acknowledged empathically. ”Temporal Lobe“ Personalities. In dealing with personality syndromes caused by temporal lobe dysfunction, the neurologist should not overreact to the patient’s intensity, particularly when feelings of anger or despair are expressed. Patients’ feelings can be very deep yet be transient and not have the diagnostic significance they would have in a setting of primary mental illness. The transient nature of some of the patient’s more painful feelings can be pointed out. If behavioral viscosity is a problem, patients can be taught to recognize it as a feature of their illness rather than a moral defect. If they are able to acknowledge this, they may not be badly offended if the neurologist is firm about ending visits or telephone calls or about limiting replies to the patients’ written communications.

Somatizationand Amplification of Illness As suggested earlier in this chapter, under “Anxiety and Panic” and “Mood Disorders,” patients with depression or anxiety disorders may amplify the physical symptoms of systemic or neurologic disease. This amplification of symptoms can be alleviated, at least in part, by effective treatment of the mood or anxiety disorder. Patients with personality disorders may amplify somatic symptoms on a different basis, necessitating a different management strategy. Patients with personalities in the odd cluster may incorporate medical diagnoses or somatic diagnoses into idiosyncratic beliefs about themselves or their bodies. If these beliefs lead to significant distress or disability, an effort should be made to

Chapter 151

reduce their intensity. Directly challenging patients’ odd beliefs is not effective. If the beliefs are delusional or nearly so, a trial of neuroleptic therapy can be considered, as discussed later in this chapter under “Thought Disorders.” If the beliefs are strongly held but open to objective test, a trial of an SSRI should be considered. SSRIs have been shown efficacious for treating body dysmorphic disorder, a condition in which the patient has a strong conviction of a bodily defect disproportionate to any objective finding. Patients with personality disorders in the dramatic cluster may amplify symptoms or exaggerate diagnoses because their illnesses and symptoms function as claims on the attention of others. To extinguish amplification of symptoms, the attention given to the patient should depend as little as possible on the intensity of complaints or the drama with which they are expressed. Patients with this type of symptom amplification often belong to families in which illness complaints serve an important communicative function. Family therapy sometimes can enable such families to communicate more straightforwardly, with the benefit of reduced somatic complaints. Patients with avoidant personalities may amplify symptoms because their symptoms function as an excuse for an actual or feared poor performance. Because such patients have a strong need to use illness or disability as an excuse, it usually is futile to expect complete resolution of neurologic symptoms or disability, regardless of their cause. The efficacy of any treatment, neurologic or psychiatric, should be monitored by objective signs, not by patients’ comments on how bearable they find their symptoms. Patients with dependent personalities, like those with dramatic personalities, may amplify symptoms because they function as a claim on the attention and care of others. Management is similar. Patients with obsessive-compulsive personalities may amplify symptoms by expressing them in exhaustive (and exhausting) detail. This may pose difficulties for the neurologist in monitoring treatment response. Global self-ratings of symptoms, such as the visual analogue pain scale, are superior methods for getting useful feedback from such patients. THOUGHT DISORDERS Disordered thinking, as inferred from disordered speech and behavior, is the characteristic abnormality of schizophrenia and related psychotic disorders. It is also a feature of delirious states, an expression of several of the drug-induced encephalopathies, a potential complication of dementia, and a feature of the more severe forms of mood disturbance, both manic and depressive. Thought disorder usually is accompanied by impaired selfmonitoring and consequently by impairment in everyday func-

TMLE 151-6. Thought Disorder Strong behavioral evidence of thought disorder Hallucinationsin any sensory modalii Delusions Disorganized speech not accounted for by aphasia Disorganized or bizarre behavior Markedly abnormal motor behavior not accounted for by a movement disorder (odd posturing, stereotyped movements, prominent mannerisms, prolonged immobility, purposeless hyperactivity) Mild evidence of thought disorder Vagueness and obscurii of speech Idiosyncratic associations Affect incongruouswith the situation or subject of the conversation Suspiciousness Unusual beliefs held with great intensity

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TABU151-7. Differential Diagnosis of a Thought Disorder Brief psychotic disorder (extreme activation of association areas by extraordinary stress, mediated in part by catecholaminesand cortisol) Chronic temporal lobe seizures (temporal lobe hyperactivity and hypoactivity with secondary effects on association cortex) Delirium and dementia (diffuse cortical dysfunction) Drug-induced psychoses, includingthose associated with amphetamines, cocaine, and phencyclidine (diffuse or frontotemporal dysfunction caused by altered neuromodulation or neurotransmission) Mood disorders (impaired executive function caused by altered monoamine modulation) Schizophrenia (frontotemporal dysfunction caused by genetic, neurodevelopmental, and possibly infectiousfactors) Wernicke‘s aphasia (posterior temporal lobe lesion)

tion. Symptoms of thought disorder often can be alleviated with neuroleptic (antipsychotic) medication. For this reason, the recognition of thought disorder has particular importance for determining the pharmacologic treatment of patients with disturbances of mood or behavior. This section of the chapter reviews symptoms of thought disorder, assessment of the patient with thought disorder, management of the neurologic outpatient with thought disorder, pharmacologic treatment, and strategies for managing psychosis in dementia and in Parkinson’s disease. Symptoms

Thought disorder may present with abnormal content of thinking, abnormal process of thinking, or a combination. Strong evidence of these abnormalities of thinking, as inferred from the patient’s speech and behavior, are included in Table 151-6. The presence of hallucinations can be inferred either from the patient’s report of hallucinations or from observed behavior suggesting a response to a hallucinated voice or other sensory experience. Similarly, delusions may be expressed either in words or in actions based on the delusions. Abnormal thinking can manifest in milder forms with symptoms that suggest but do not confirm the presence of a thought disorder. Paranoid thinking often accompanies thought disorder, but it can occur in the presence of otherwise normal thought processes. Assessment

The presence of thought disorder implies dysfunction of cortical association areas; when the patient acts on disordered thinking, there is an additional inference of impaired executive control functions. The differential diagnosis of thought disorder includes conditions that directly or indirectly influence the function of cortical association areas and executive control functions (see Table 151-7). Assessment begins with establishing the full set of mental and behavioral symptoms from which the patient suffers, including mood symptoms and cognitive signs such as disorientation and memory loss. The mental status examination often shows some cognitive impairment in the patient with current symptoms of thought disorder, so the examiner’s aim is to determine whether the disturbance of speech and behavior is disproportionate to whatever cognitive impairment is found. Thought disorder disproportionate to cognitive impairment is evidence of a primary psychotic disorder (e.g., schizophrenia or mania) rather than delirium or dementia. The medical and drug history provides evidence for or against psychosis caused by metabolic disturbance or an exogenous agent.

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However, laboratory testing and drug screening often are necessary to completely exclude the diagnosis of a drug-induced psychosis or metabolic encephalopathy because the symptoms of exogenous and endogenous psychotic disorders do overlap. The diagnosis of psychosis caused by a focal cortical lesion entails both demonstration of the lesion and compatibility of the mental syndrome with the known effects of the lesion. The psychosis associated with Wernicke’s aphasia is a paranoid state with irritability. The psychosis typically associated with longstanding and poorly controlled temporal lobe seizures is characterized by paranoid thinking and hallucinations, with relative preservation of the capacity for interpersonal relationships and emotional expression. It is usually easy to diagnose psychosis caused by extraordinary stress (brief psychotic disorder) because the stressor is known and the patient does not have a history of a chronic mental illness or dementia. Characteristically, a patient with a brief stress-induced psychosis shows confusion, perplexity, emotional turmoil, and affective lability. The patient clearly is not accustomed to the symptoms. If a patient presents (usually brought by concerned relatives) with an acute change in mental status and evidence of thought disorder, a history of recent trauma or major stress should be asked about. A patient with a chronic thought disorder may experience a worsening of symptoms in connection with stress; distinctions from a brief psychotic disorder are that the symptoms are typical of the patient’s chronic condition and that the patient may show familiarity and a relative lack of concern about them. A thought disorder not explained by neurologic or systemic disease, exogenous agents, or severe stress is either a primary psychotic disorder such as schizophrenia or a mood disorder with psychotic features. To diagnose a mood disorder with psychotic features, definite evidence of depression or mania should be present in the history or on the examination. When the content of abnormal thought is congruent with the mood state (e.g., delusions of guilt in depression, a belief of unlimited wealth in mania), the thought disturbance is regarded as a complication of the mood disorder. The presence of psychotic features reflects greater severity of illness or a loss of the executive function of self-monitoring. Mood-congruent delusions are likely to resolve completely with successful treatment of the mood disorder. When the content of abnormal thought in a patient with a mood disorder is mood-incongruent or bizarre, the patient may be suffering from a psychosis with combined features of schizophrenia and a mood disorder. This condition usually is diagnosed as schizoaffective disorder, but in practice there are fuzzy boundaries between schizoaffective disorder, schizophrenia with comorbid depression, and mood disorder. Treatment is substantially the same regardless of the choice of diagnostic label. However, in the latter two conditions psychotic symptoms can persist despite normalization of mood. Persistent symptoms of thought disorder associated with impairment in social or occupational function and lasting more than 6 months suggest the diagnosis of schizophrenia. Schizophrenia is a chronic disorder of brain function with heterogeneous manifestations. Some patients present primarily with so-called negative symptoms of impaired range and intensity of emotional expression, impaired initiation of goal-directed behavior, and impaired productivity of thought and speech. Others show dramatic positive symptoms of hallucinations, delusions, paranoid ideas, and bizarre behavior. Patients can have chronic negative symptoms with intermittent episodes of positive symptoms or may have mainly one type of symptom throughout the course of

their disorder. Brain imaging and clinical neurophysiology have linked positive symptoms to abnormal temporal lobe function and negative symptoms to frontal system impairment. The median age of onset of schizophrenia is in the early 20s for men and in the late 20s for women, but there is wide variability, with the illness presenting after age 40 in approximately 25% of patients. Such late-onset cases are more likely to present to neurologists because of the appropriate suspicion that new-onset thought disorder later in life may be a sign of gross brain disease. Full evaluation for gross brain disease is appropriate for patients with symptoms typical of schizophrenia and less than 6 months’ duration of illness. Patients who present with a long-standing psychotic disorder typical of schizophrenia do not need brain imaging or a lumbar puncture unless additional features in the history or neurologic examination suggest another diagnosis. Electroencephalography should be considered whenever there are unexplained and rapid fluctuations in symptoms; a typical seizure history may be hard to elicit from an actively psychotic patient. Patients with long-standing temporal epilepsy can develop a psychosis resembling schizophrenia but lacking major impairment in executive function, in which social behavior and the capacity to relate to others usually are preserved. This condition should be recognized because it warrants treatment that combines antiepileptic and antipsychotic medications. Finally, because unrecognized medical conditions can aggravate schizophrenia, an especially complete general medical evaluation is always necessary. A psychotic disorder distinct from schizophrenia can develop in middle age or later life that is characterized by nonbizarre delusions and little additional evidence of thought disorder or dementia. Patients with this condition, called delusional disorder, have a fixed false belief. Typical beliefs include delusions that one’s partner is unfaithful, the delusional conviction that one suffers from a particular somatic disease, delusions of persecution, and delusions of romantic involvement with a person, usually of high status, with whom there is no actual connection. Delusional disorder is not associated with the general impairment in social functioning that is typical of schizophrenia. Patients with delusional disorder may have an excess of white matter abnormalities on magnetic resonance imaging and may show mild impairment of executive cognitive functioning on neuropsychological testing, but they do not suffer from dementia.

Once a patient is identified as having a thought disorder, management strategy depends on the context in which the neurologist is seeing the patient. If the patient is receiving psychiatric care or will be referred to a psychiatrist, the main goals of the neurologist are to exclude brain disease, systemic disease, or exogenous agents as causes of the thought disorder and to identify concurrent neurologic conditions in need of treatment. If the patient has been treated with neuroleptic drugs, the neurologic assessment should include assessment for drug-induced movement disorders. The full neurologic evaluation of the patient with a psychotic disorder who is under psychiatric care includes magnetic resonance imaging of the brain and electroencephalography. The former offers the most definitive exclusion of frontotemporal anatomic lesions, and the latter screens the patient for paroxysmal brain electrical activity that may be relevant to subsequent treatment for the psychosis. An antiepileptic drug should be considered as an adjunct to a neuroleptic when a patient with psychosis has epileptiform features on electroencephalogra-

Chapter I51

phy and the psychosis has been poorly responsive to standard neuroleptic treatment. Although controlled trials have not been done, there is extensive clinical experience supporting this practice. Because of the relevance of this treatment combination, an electroencephalogram should be obtained when a patient with a chronic psychosis does not respond to an adequate dosage and duration of neuroleptic treatment. When a thought disorder arises in a patient who will be continuing in treatment with the neurologist for dementia, epilepsy, Parkinson’s disease, or another brain disease, the neurologist must first decide whether to involve a psychiatrist and, if so, how to divide responsibility between the neurologist and the psychiatrist. If care is to be divided, an explicit decision should be made regarding who will prescribe which drugs and who will be responsible for monitoring treatment response and side effects. Patients with mood disorders with psychotic features usually should be referred to a psychiatrist because severe mood disorders warrant aggressive biologic treatment, possibly including electroconvulsive therapy. Patients with delusional disorders tend to resist direct confrontation about their delusions and may also resist referral to a psychiatrist. They may be more accepting of neuroleptic medication prescribed by the neurologist. When neuroleptic medication is initiated in the context of neurologic care, the patient and the family may better accept the prescription if the goal of treatment is expressed in terms relevant to the patient’s subjective concerns. Thus, for example, patients with schizophrenia may initially accept medication if they are told that the drugs may help them organize their own thoughts better or reduce the voices that are bothering them. Ultimately, continuation of therapy must be based on fully informed consent by the patient, including discussion of the diagnosis. The comprehensive management of schizophrenia goes beyond the training of the typical neurologist. The social and occupational impairments associated with the disorder and its usual early onset necessitate a complex mix of family education, vocational rehabilitation, social skill training, and counseling that focuses on practical problem solving, education about the illness, selfmonitoring, and coping with impairments and disabilities. In addition, many patients need supportive environments separate from family members to attain their highest possible level of independence and well-being. Comprehensive management of psychotic complications of chronic neurologic disease begins with education of the patient and family and provision or arrangement of assistance in addressing practical problems in coping with the illness that increase the patient’s level of stress. Comprehensive psychiatric assessment can help identify priorities for psychological or environmental intervention, so it is valuable even when the diagnosis is not in doubt and the neurologist is committed to providing principal care for the patient. Specific advice on management strategy should be requested from the psychiatrist at the time of the referral, and the purpose of the referral should be explained clearly to the patient. Phannacologic Therapy Neuroleptics. Neuroleptic (antipsychotic) medications are the primary drug therapy for thought disorder. The neuroleptic drugs comprise several distinct pharmacologic classes, but all share the property of blocking dopamine receptors in both the striatum and the frontal and limbic cortex. Their benefits for the treatment

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of psychotic symptoms (thought disorder) have been attributed primarily to their effect on limbic and frontal cortical dopamine receptors. The effect of the drugs on striatal dopamine receptors is responsible for their many adverse effects on the motor system. See Table 151-8 for typical daily dosages of neuroleptics for the ongoing treatment of schizophrenia or a related psychosis. Typical neuroleptic agents are distinguished from one another by their potency in blocking dopamine receptors and by the extent of their actions on other neurotransmitter receptors such as the muscarinic cholinergic receptors. The less potent agents tend to be more anticholinergic and to also have antihistaminic and a-adrenergic blocking properties. Atypical neuroleptic agents have significantly different pharmacodynamics that include simultaneous blockade of D2 dopamine and S2 serotonin receptors. The current choice of atypical neuroleptics includes clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Although all are effective, clozapine may work when no other typical or atypical neuroleptic does. This may be related to the fact that clozapine, compared with other neuroleptics, shows less binding to striatal D2 dopamine receptors and greater binding to limbic and cortical D3, D4, and D5 receptors. Among the other atypical neuroleptics, the choice usually is dictated by the drugs’ differing side effect profiles. Olanzapine usually causes weight gain and can cause glucose intolerance, whereas ziprasidone can cause weight loss. Risperidone is most likely to produce extrapyramidal side effects; quetiapine is least likely. Clozapine is the only atypical neuroleptic that does not cause or aggravate parkinsonism. Unfortunately, it can cause bone marrow suppression, and for this reason very frequent monitoring of blood counts is needed. In addition, it may cause or aggravate seizures at the upper end of its therapeutic dosage range. All of the typical neuroleptic agents can cause drug-induced parkinsonism, with the incidence highest with the more potent, less anticholinergic agents. They have fallen out of favor for chronic use as the atypical neuroleptics have been adopted as first-line drugs. However, for treating acute, severe psychosis and agitation, parenteral forms of typical neuroleptics still have a role. Neuroleptic drugs have both immediate and delayed effects on thought disorder. Almost immediately, patients may show a reduction in such symptoms as agitation, emotional lability, and overtly paranoid behavior. Disorganized speech may become more coherent within hours to days. Resolution of delusions and hallucinations can occur in hours to days when they are acute symptoms of recent onset, as can be encountered in delirium or stress-related psychosis. Long-standing delusions, as occur in schizophrenia or delusional disorder, may take several weeks to improve and may not resolve completely. Resolution of delusions associated with mood disorder tends to occur synchronously with the restoration of normal mood. The negative symptoms of

W TABLE 151-8. Ongoing Treatment

of Schizophrenia

For ongoing treatment of schizophrenia or a related psychosis (e.g., the schizophrenia-likepsychosis of temporal lobe epilepsy), typical daily dosages of neurolepticsare Clozapine: A wide range, between 25 and 300 mg bid. Titration should be slow. Olanzapine: 2.5 mg qd to 10 mg bid. Quetiapine: 25 mg qd to 200 bid. Risperidone: 0.5 to 3 mg bid. Beyond 6 mg per day the drug begins to lose its atypical character, and the incidence of extrapyramidal effects rises significantly. Ziwasidone: 20 ma ad to 20 ma tid.

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schizophrenia, which usually do not improve substantially with typical neuroleptic therapy, can improve with the atypical neuroleptics, especially clozapine. When they do respond, symptoms improve over weeks to months of therapy. Neuroleptics are given as primary or sole therapy for schizophrenia, delusional disorder, and brief psychosis, for psychotic symptoms of delirium or dementia, and for psychotic states induced by drugs, metabolic disturbances, or gross brain disease. Neuroleptics are given together with mood-stabilizing drugs for mania or mixed manic-depressive states with psychotic features. They are combined with antidepressants to treat major depression with delusions. The psychosis of temporal lobe epilepsy is treated with neuroleptics in combination with antiepileptic drugs. Choice and Dosage. Neuroleptic dosage differs according to the purpose of neuroleptic therapy. For acute behavioral emergencies in younger and otherwise healthy adults, neuroleptics are given every hour until the patient is behaviorally stable; transfer to the care of a psychiatrist usually is arranged simultaneously. Typical dosages are 5 mg/hour of haloperidol or 5 mg/hour of thiothixene either orally or parenterally. The neuroleptic is combined with a benzodiazepine (e.g., 1 to 2 mg of lorazepam each dose) for more rapid behavioral control. For acute behavioral emergencies in older or frailer patients, the dosage increments are haloperidol 0.5 to 1.0 mg per dose with lorazepam 0.5 to 1.0 mg. In patients with dementia, many clinicians avoid using lorazepam with haloperidol for emergencies because of a concern that lorazepam will induce or worsen a confusional state. However, lorazepam may substantially reduce the total amount of haloperidol needed, and it confers some protection against extrapyramidal reactions. In patients with mild to moderate dementia and continual rather than reactive agitation, a reasonable strategy is to try combined treatment and then drop the lorazepam if confusion develops or worsens. If a patient benefits from neuroleptics but is repeatedly nonadherent to prescriptions, it may be appropriate to prescribe a depot form of a neuroleptic on a monthly basis. At present only the typical neuroleptics fluphenazine and haloperidol are available in a depot preparation. However, depot risperidone is under development and may become available during the lifespan of this edition. The superiority of atypical agents would warrant using depot risperidone most of the time once it becomes available. For treatment of a chronic mild thought disorder, such as a delusional disorder with minimal effects on everyday functioning or low-grade paranoid symptoms in early dementia, a low dosage of a neuroleptic may suffice. For this purpose the lower end of the ranges described usually shows some effectiveness. Frail patients may only tolerate dosages below the lower end of the usual range, but they may nonetheless benefit from the treatment. The atypical neuroleptic drug clozapine currently has a unique place in treating psychosis. It is the single most effective agent for thought disorder and the one most likely to relieve negative symptoms of schizophrenia; it also has the fewest extrapyramidal side effects and the lowest risk of tardive dyskinesia and neuroleptic malignant syndrome. However, it carries a 1% risk of agranulocytosis and a 3% to 5% risk of seizures. For this reason, it is not prescribed routinely to patients with psychotic disorders. However, clozapine is indicated for schizophrenia poorly responsive to conventional therapy, for schizophrenia with drug-induced movement disorders of unacceptable severity, and for psychosis in Parkinson’s disease. When used for schizophrenia, a typical dosage of clozapine is 300 to 500 mg/day, titrated slowly. When used for the psychosis of Parkinson’s disease, the dosage is much lower,

beginning with 6.25 mg per day and occasionally getting as high as 50 mg. Patients on clozapine must have white blood cell counts weekly during the first 6 months of treatment and every two weeks thereafter. The drug is discontinued if the white blood cell count falls below 3000/mm3. Because of the seizure risk, patients with known epilepsy or risk factors for seizures (e.g., history of traumatic brain injury) should be treated with an antiepileptic drug concurrently. Phenytoin or valproate is preferred; carbamazepine is avoided because of concern about additive bone marrow suppression. Neurotoxicity. During the first several days after starting neuroleptic therapy, patients are at risk of developing extrapyramidal motor symptoms. The risk is greatest when typical neuroleptics are prescribed. Younger patients, particularly young men, may develop acute dystonia. This usually involves the neck, with torticollis or opisthotonus. All patients are at risk of drug-induced parkinsonism. Some patients develop typical rest tremors, but rigidity and akinesia without noticeable tremor also can develop and are more likely to go undetected if muscle tone and voluntary movement are not systematically checked. In particular, axial tone should be checked by moving the neck through a passive range of motion. Acute dyskinesia, involving either the orofacial region or the extremities, also occurs, although less commonly than drug-induced parkinsonism. Akathisia is common and, when subtle, can be mistaken for anxiety, agitation, or the purposeless hyperactivity of psychosis. Typically, the patient with akathisia reports physical discomfort if he or she attempts to remain still. With the exception of akathisia, the acute extrapyramidal disorders respond to antiparkinson medication. Dopamine agonists, either amantadine 100 mg two or three times a day, bromocriptine 2.5 mg daily to 5 mg three times a day, or pramipexole 0.25 mg to 1 mg three times a day, are more effective for rigidity and akinesia than anticholinergic antiparkinson drugs. Parented anticholinergic agents (e.g., benztropine 2 mg, trihexyphenidyl5 mg, or diphenhydramine 50 mg) are immediately and decisively effective for acute dystonia. Akathisia usually responds to propranolol, typically at a dosage of 20 to 40 mg three times a day. Some patients with movement disorders caused by neuroleptics can be withdrawn from antiparkinson drugs after several weeks of neuroleptic therapy, without recurrence of the motor symptoms and signs. If withdrawal of antiparkinson drugs is attempted, the patient should be reexamined for recurrent signs and questioned about his or her everyday functioning. Not all patients with psychotic disorders complain of their movement disorders, even when the signs are evident and the disorder is functionally relevant. Subtle extrapyramidal symptoms are a common reason for patients not to adhere to their prescriptions for neuroleptics. This problem has not disappeared with the advent of atypical neuroleptics. Although the atypical neuroleptics are much less likely than the typical ones to cause florid extrapyramidal symptoms, they may cause subtle symptoms distressing to patients and less likely to be recognized because of their subtlety. Use of neuroleptics for more than a few months is associated with the risk of movement disorders that persist after the neuroleptics are withdrawn. These late complications of neuroleptic therapy, the tardive movement disorders, include tardive dyskinesia (TD), tardive dystonia, and tardive akathisia. The dyskinesias include choreoathetosis, buccolingual movements, blepharospasm, respiratory dyskinesia, and dysphagia caused by dyskinesia of the larynx and pharynx. Tardive dystonia usually

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involves flexion-extension movements of the trunk, torsion dystonia is less common. Tardive akathisia resembles acute akathisia. Advanced age, female sex, diabetes, and alcoholism are risk factors for the tardive movement disorders, as is preexisting gross brain disease and a psychiatric diagnosis other than schizophrenia. Tardive movement disorders tend to remit over months to years if neuroleptics are withdrawn, with an average of 50% improvement at 9 months. However, a substantial number of patients have permanent symptoms. The pathophysiology of TD appears to involve oxidative stress caused by the disinhibition of glutamatergic neurons as a consequence of dopamine blockade in the striatum. There is no treatment of general efficacy. Symptoms can be suppressed by dopamine blockers, but this may aggravate the underlying condition. A switch to clozapine can permit spontaneous recovery because of clozapine’s minimal blockade of striatal D2 receptors. The dopamine-depleting drugs tetrabenazine and reserpine often can ameliorate the movements, but they may be poorly tolerated because they cause fatigue, apathy, and depression. Vitamin E has shown efficacy at 1600 IU per day in one controlled clinical trial. Individual patients in case histories have responded to a wide range of medications, including benzodiazepines, calcium channel blockers, and buspirone. Supplementation of calcium and magnesium in the diet of the patient with TD is rational because low levels of either are associated with greater motor side effects and because patients with psychosis often have poor diets. The neurologist treating tardive movement disorders usually must undertake systematic trials to find the most effective and best-tolerated treatment. The most life-threatening neurologic side effect of neuroleptic therapy is the neuroleptic malignant syndrome. It is characterized by severe tremulous rigidity, autonomic instability, hyperthermia, and delirium. The patient appears to have an acute encephalopathy, and the most conspicuous laboratory finding is an elevated creatine kinase. Risk factors for the disorder include male sex, agitation, concurrent lithium therapy, and the presence of an unrelated cause of fever. Untreated, the disorder can lead to widespread rhabdomyolysis, myoglobinuria, and death. Treatment begins with transfer of the patient to an intensive care unit and discontinuation of the neuroleptic, hydration, and control of temperature and blood pressure. This is followed by specific therapies: dantrolene, used intravenously as for malignant hyperthermia, or a direct dopamine agonist. Options include bromocriptine, pergolide, pramipexole, and ropinirole. Dosing should be aggressive in view of the emergent nature of the condition. For example, a typical starting dosage of bromocriptine in a case of neuroleptic malignant syndrome is 5 mg every 8 hours.

Special Therapeutic Skations Psychosis in Dementia. When treating psychosis in dementia, the aims are to improve the patient’s everyday function and reduce the burden on caregivers. Therefore, neuroleptic therapy should aim to contain paranoid behavior, hallucinations, and agitation but to avoid adding disabling parkinsonian symptoms to the patient’s preexisting cognitive impairments. Office-based outpatient monitoring of neuroleptic therapy for psychosis in dementia should include an overview of the patient’s functional dependencies and the caregiver’s burdens at each visit. Because of the need to avoid extrapyramidal effects, atypical neuroleptics are preferred. The initial dosage of a neuroleptic should be very low to avoid overshooting the optimum dosage.

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Typical dosages are olanzapine 1.25 to 2.5 mg at bedtime, quetiapine 25 to 50 mg at bedtime, and risperidone 0.25 to 0.5 mg at bedtime. The drugs are given at night to take advantage of the sedative effects. If there is no adverse or therapeutic effect at the initial dosage, the dosage can be increased in increments of similar size every 2 to 3 days until there is improvement in the target symptoms or until extrapyramidal symptoms develop. Drug therapy should be maintained for at least 4 weeks at the minimum dosage that produces an early therapeutic action or at the highest dosage that can be given without problematic motor side effects. Then, the overall balance of positive and negative effects of neuroleptic therapy should be assessed, to permit an informed decision about whether to continue it or to adjust the dosage. If a neuroleptic relieves delusions and hallucinations at a given dosage, leaving a persistent problem with insomnia or agitation, the latter problem should be treated with nonneuroleptic therapy. Options for treating insomnia include the sedating antidepressants nefazodone, mirtazapine, and doxepin, all given at the lower end of their dosage range. In addition, the hypnotic drugs zolpidem and zaleplon may be tolerated despite the common belief that it is unwise to give hypnotic agents to older adults. Patients should be observed carefully for their first few nights on a new hypnotic to see whether they will awaken in the middle of the night ataxic and confused. If this occurs the hypnotic is unacceptable because of the heightened risk of falls. Residual agitation after neuroleptic treatment can be treated with an SSRI,buspirone, a P-blocker, or valproate. Psychosis in Parkinson’s Disease. The occurrence of delusions, hallucinations, paranoid ideas, and other psychotic symptoms in Parkinson’s disease often limits effective levodopa therapy in the late stages of the disease. Reducing levodopa dosage or substituting direct agonists for part of the levodopa occasionally helps but usually has no benefit for mental status except at the cost of worsening motor disability. In this situation, treating the drug-induced psychosis with clozapine may permit relief of psychosis with maintained or even improved motor function. Clozapine treatment for Parkinson’s disease with psychosis is most likely to be beneficial when the patient is not demented or has only mild cognitive impairment. Treatment should begin at a very low dosage of clozapine (e.g., 6.25 mg/day). If the drug is tolerated, dosage can be increased at weekly intervals until there are limiting side effects (usually sedation or anticholinergiceffects) or the patient has relief of psychotic symptoms. Dosages rarely need to exceed 50 mg/day. Some improvement in motor disability is common, perhaps because of the drug’s strong anticholinergic effects. The other atypical neuroleptics, although they are less likely to cause drug-induced parkinsonism in patients with schizophrenia, are likely to aggravate the motor symptoms of Parkinson’s disease. None of them is a viable substitute for clozapine in advanced Parkinson’s disease with drug-induced psychosis. Psychotic Symptoms in Limbic Epilepsy. When a patient with limbic epilepsy develops a schizophreniformpsychosis, drug therapy is similar to that for schizophrenia. A specific atypical neuroleptic should be chosen based on tolerability of side effects because all are similarly effective. More important than the choice of neuroleptic is optimal management of the seizures themselves. Barbiturates and primidone should be avoided because of sedation and cognitive dulling. Vigorous efforts should be made with rational drug combinations or even surgery to control the seizures because persistent seizure activity appears to be related to the development and maintenance of psychosis. When patients are on

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multiple-drug regimens that include a neuroleptic, antiepileptic drug levels should be rechecked after changes in the psychotropic regimen because of the possibility of drug interactions. Other patients with limbic epilepsy do not have a chronic psychosis but have emotional hyperintensity and idiosyncratic thinking that intermittently reaches the point of paranoia or near-delusional conviction. Such patients may suffer distress from their thoughts or alienate employers or social supports with anger and accusations. Low-dose neuroleptic medication may mitigate the symptoms of thought disorder in these patients. Dosages are similar to those used for agitation in dementia.

SUGGESTED READINGS Psychopharmacology in Neurologic Illness Fogel BS: Drug therapy of neuropsychiatry. pp. 223-256. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Wilkins, Baltimore, 1996 Stahl SM: Essential Psychopharmacology. Cambridge University Press, Cambridge, UK, 2000

Anxiety and Panic Charney DS, Nagy LM, Bremmer D et al: Neurobiological mechanisms of human anxiety. pp. 257-286. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Willcins, Baltimore, 1996 Goldberg RJ, Posner DA Anxiety in the medically ill. pp. 165-180. In Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient. Oxford University Press, New York, 2000

Mood Disorders Dubovsky SL, Buzan R: Mood disorders. pp. 479-465. In Hales RE, Yudofsky SC, Talbott JA (eds): American Psychiatric Press Textbook of Psychiatry. American Psychiatric Press, Washington, DC, 1999

Personality Disorders and Reaction to Disease American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th Ed. pp. 297-343. American Psychiatric Association, Washington, DC, 2000 Fogel BS, Stoudemire A Personality disorders in the medical setting. pp. 443-458. In Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient. Oxford University Press, New York, 2000 Green S A Principles of medical psychotherapy. pp. 3-15. In Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient. Oxford University Press, New York, 2000 Ratey JJ: Neuropsychiatry of Personality Disorders. Blackwell Science, Cambridge, MA, 1995

Thought Disorders Jeste DV, Eastham JH, Lohr JB, Salzman C: Treatment of disordered behavior and psychosis. pp. 106-149. In Salzman C (ed): Clinical Geriatric Psychopharmacology. Williams & Wilkins, Baltimore, 1998 Sano M, Marder K, Doonief G: Basal ganglia diseases. pp. 805-825. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Wilkins, Baltimore, 1996

152 Psychosocial Issues in Dementia and Epilepsy Jeffrey M. Robbins and Eileen Salmanson The patient diagnosed with a dementing illness has many needs in addition to the medical management of symptoms. A neurologist can look to the social worker (SW) for help with resources and supportive counseling for the patient and family. Resources may include the placement of a home health aide and a referral to an adult day care program, assisted living facility, or nursing home. Additionally, a variety of support groups may be helpful to family members. In the case of a patient with epilepsy, a variety of patient and family concerns are more appropriately addressed by the SW, ranging from gaining an understanding of the seizure disorder to managing life (job, family, and other relationships) with seizures. SWs refer to and often facilitate a variety of support groups for patients and family members. Responsibility for assessing and addressing the psychosocial needs of the patient with dementia or epilepsy has remained within the domain of nursing until recent years and is now shared with clinical social workers. Such a specialty practice within social work requires a working knowledge of the pathophysiology and pharmacologic treatments of neurologic disorders and the neuropsychological assessment and uses of cognitive and behavioral strategies for patients and family members. Often, the patient with dementia who is referred to the neurologist for assessment needs a referral to a SW for help in understanding the complicated ways in which the patient and the family interact with one another and their milieu as they attempt to manage the course of the illness. It

is thus incumbent on the SW not only to understand the disease process as it affects the patient and the family but also to know the available resources. Similarly, the patient with epilepsy may receive consultation by the neurologist for seizure control strategies, but quality-of-life issues are the main focus of social work. Issues affecting quality of life include compensatory strategies for common problems with memory, cognition, fatigue, seizure management, lifestyle adjustments, and a host of other issues, including those dealing with libido, pregnancy, work, routines of daily living, role reversals, and mental status. These concerns are commonly addressed by the SW or clinical nurse specialist.

PATIENTS WITH DEMENTIA Although many dementing illnesses are addressed in other chapters of this text, this section will use Alzheimer’s disease (AD) as the model for understanding the psychosocial evaluation and implementation of services for patients referred with symptoms of dementia. The following case will be used to illustrate these concepts. Mrs. M., a 79-year-old married woman, was referred for a social work evaluation regarding her symptoms of dementia after having been seen by a behavioral neurologist and neuropsychologist. At the time of referral, Mrs. M. carried the diagnosis of probable AD.

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multiple-drug regimens that include a neuroleptic, antiepileptic drug levels should be rechecked after changes in the psychotropic regimen because of the possibility of drug interactions. Other patients with limbic epilepsy do not have a chronic psychosis but have emotional hyperintensity and idiosyncratic thinking that intermittently reaches the point of paranoia or near-delusional conviction. Such patients may suffer distress from their thoughts or alienate employers or social supports with anger and accusations. Low-dose neuroleptic medication may mitigate the symptoms of thought disorder in these patients. Dosages are similar to those used for agitation in dementia.

SUGGESTED READINGS Psychopharmacology in Neurologic Illness Fogel BS: Drug therapy of neuropsychiatry. pp. 223-256. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Wilkins, Baltimore, 1996 Stahl SM: Essential Psychopharmacology. Cambridge University Press, Cambridge, UK, 2000

Anxiety and Panic Charney DS, Nagy LM, Bremmer D et al: Neurobiological mechanisms of human anxiety. pp. 257-286. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Willcins, Baltimore, 1996 Goldberg RJ, Posner DA Anxiety in the medically ill. pp. 165-180. In Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient. Oxford University Press, New York, 2000

Mood Disorders Dubovsky SL, Buzan R: Mood disorders. pp. 479-465. In Hales RE, Yudofsky SC, Talbott JA (eds): American Psychiatric Press Textbook of Psychiatry. American Psychiatric Press, Washington, DC, 1999

Personality Disorders and Reaction to Disease American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th Ed. pp. 297-343. American Psychiatric Association, Washington, DC, 2000 Fogel BS, Stoudemire A Personality disorders in the medical setting. pp. 443-458. In Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient. Oxford University Press, New York, 2000 Green S A Principles of medical psychotherapy. pp. 3-15. In Stoudemire A, Fogel BS, Greenberg DB (eds): Psychiatric Care of the Medical Patient. Oxford University Press, New York, 2000 Ratey JJ: Neuropsychiatry of Personality Disorders. Blackwell Science, Cambridge, MA, 1995

Thought Disorders Jeste DV, Eastham JH, Lohr JB, Salzman C: Treatment of disordered behavior and psychosis. pp. 106-149. In Salzman C (ed): Clinical Geriatric Psychopharmacology. Williams & Wilkins, Baltimore, 1998 Sano M, Marder K, Doonief G: Basal ganglia diseases. pp. 805-825. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Wilkins, Baltimore, 1996

152 Psychosocial Issues in Dementia and Epilepsy Jeffrey M. Robbins and Eileen Salmanson The patient diagnosed with a dementing illness has many needs in addition to the medical management of symptoms. A neurologist can look to the social worker (SW) for help with resources and supportive counseling for the patient and family. Resources may include the placement of a home health aide and a referral to an adult day care program, assisted living facility, or nursing home. Additionally, a variety of support groups may be helpful to family members. In the case of a patient with epilepsy, a variety of patient and family concerns are more appropriately addressed by the SW, ranging from gaining an understanding of the seizure disorder to managing life (job, family, and other relationships) with seizures. SWs refer to and often facilitate a variety of support groups for patients and family members. Responsibility for assessing and addressing the psychosocial needs of the patient with dementia or epilepsy has remained within the domain of nursing until recent years and is now shared with clinical social workers. Such a specialty practice within social work requires a working knowledge of the pathophysiology and pharmacologic treatments of neurologic disorders and the neuropsychological assessment and uses of cognitive and behavioral strategies for patients and family members. Often, the patient with dementia who is referred to the neurologist for assessment needs a referral to a SW for help in understanding the complicated ways in which the patient and the family interact with one another and their milieu as they attempt to manage the course of the illness. It

is thus incumbent on the SW not only to understand the disease process as it affects the patient and the family but also to know the available resources. Similarly, the patient with epilepsy may receive consultation by the neurologist for seizure control strategies, but quality-of-life issues are the main focus of social work. Issues affecting quality of life include compensatory strategies for common problems with memory, cognition, fatigue, seizure management, lifestyle adjustments, and a host of other issues, including those dealing with libido, pregnancy, work, routines of daily living, role reversals, and mental status. These concerns are commonly addressed by the SW or clinical nurse specialist.

PATIENTS WITH DEMENTIA Although many dementing illnesses are addressed in other chapters of this text, this section will use Alzheimer’s disease (AD) as the model for understanding the psychosocial evaluation and implementation of services for patients referred with symptoms of dementia. The following case will be used to illustrate these concepts. Mrs. M., a 79-year-old married woman, was referred for a social work evaluation regarding her symptoms of dementia after having been seen by a behavioral neurologist and neuropsychologist. At the time of referral, Mrs. M. carried the diagnosis of probable AD.

Chapter 152

One of the first questions the SW must address is whether the diagnosis has been communicated to the patient. If it has not already been addressed, the questions of when, how, and whether this topic is to be introduced becomes a primary issue. Attaching a name to the illness may be extremely helpful to the patient and less emotionally damaging than often assumed. There is a common misperception that it is best to hide the AD diagnosis from the patient for fear that upon hearing this news the patient will become severely depressed and possibly suicidal. Patients with a diagnosis of AD often have accompanying symptoms of depression or dysthymia to begin with. Moreover, their ability to understand the implications of this diagnosis and retain information about it is already compromised. Therefore, it is unlikely that talking about AD will precipitate depression. Finally, there is often a significant difference between the patient’s response to hearing the diagnosis of AD and the family’s response. Accordingly, the SW must tailor the response to the patient’s and family’s concerns. The results of the neuropsychological assessment revealed mild to moderate impairment in the areas of attention, concentration, memory (including deficits in verbal information and visuospatial functioning), and executive functioning. This information cues the SW to the likely clinical manifestations of Mrs. M.’s illness. For example, issues concerning driving, negotiating routine activities of daily life, personal hygiene, and the patient’s ability to communicate effectively were core concerns. An enhanced understanding of these issues helps to pave the way for helping the family learn how to better communicate with the patient and brainstorming strategies to help make Mrs. M.’s life more manageable. How t o communicate effectively and empathically with a person diagnosed with AD may be the SW’s biggest contribution to the overall treatment of the patient and the family. The habilitation model, which teaches effective communication, makes the important point that unlike patients with many other memory disorders, the patient with AD loses information, and it is not retrievable. Thus, the concept of rehabilitation or relearning is not relevant to the issue of effective communication. Whereas the patient’s cognition and memory may decline, the patient’s emotions may remain intact throughout the illness. Helping the family learn how to avoid arguing with and scolding their loved one is critical to successful outcome for the patient and family. At the time of referral Mrs. M. continued to live with her husband of 55 years. Two of her three children lived locally, and one of them was

more involved in caretaking than the other. However, brunt of the caretaking fell on the shoulders of Mrs. M.’s husband, age 80. This abbreviated family history highlights the importance of understanding the dynamic and systemic functioning of the family. Often complex concerns of guilt, burnout, and role changes emerge as issues in social work. Encouraging open dialogue between family members and recruiting those who are less involved to be more engaged in this dialogue often is helpful. It is surprising to discover how often adult children are unaware of the extent to which the nondemented parent is involved in caretaking or the toll it is taking. It is therapeutic and often empowering for children to step in and assume responsibilities that had been performed by the healthy parent. On evaluation, the SW noted that Mrs. M., although having difficulty in a number of domains, retained her sense of dignity and many of her social graces. Her husband, who until a year ago had remained

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involved in his career, had stopped working to assume full-time care of his wife, who was having problems with driving, cooking, and many routine activities of daily life. The impact on the primary family caregiver of the patient with AD has been written about extensively. It is a life-altering experience and often brings with it problems ranging from social isolation and exhaustion to somatic complaints and depression. Therefore, AD can be understood as a family disease with far-reaching consequences for all members. The SW’s concerns were to help Mrs. M. and her family, all of whom were in varying degrees of denial about the severityof her illness, come to terms with the realities of a degenerativeillness; to help them use the resources they needed and to help them retain a sense of hope for the future. This required the SW to instill in all a sense that she knew them, understood them, and could provide help at a pace that was comfortable for them. Introducing the AD diagnosis was extremely helpful to Mrs. M., who had a sense that something was wrong but had no idea what or why. Because Mrs. M. could not fully understand the concept of AD, it was helpful to simply attach a name to something that was problematic for her. Once they saw that sharing this information did not devastate Mrs. M., the family found it easier to talk about AD more freely. Providing a forum for the family to broaden their internal dialogue helped raise the children’s consciousness of what was happening to both Mr. and Mrs. M., allowing them to intervene more readily, including phone consultation with an absent sibling. Although the neuropsychologisthad recommended placement in a nursing home with an AD unit, the SW did not pursue this with the M. family at first. Had she done so, the family probably would have fled treatment. The need to move at a pace that the patient and the family can tolerate is critical to a successful outcome. Rather, the family tried a number of alternatives, including taking turns looking after Mrs. M., hiring a home health aide, and considering adult day program. Only when these alternatives had been tried and failed did Mr. M. agree to consider placement for his wife. With the help of the SW, Mr. M. allowed other family members to help locate a suitable nursing home, and when they decided to facilitate a placement, at the SW’s suggestion, Mr. M. allowed his children to arrange it. This was a major shift in how the family functioned, and this intervention accomplished two important things. First, it helped take the burden of guilt off of Mr. M.’s shoulders by having someone other than himself facilitate a placement, and it helped to further involve other family members in Mrs. M.’s care. Finally, it was important that the SW continue to provide supportive counseling to Mr. M. after his wife’s placement into a nursing home. Although Mr. M. downplayed the helpfulness of his ongoing counseling, claiming, “Talking about this doesn’t really change anything,”it was clear that he used the relationship for reassurance that he and his family had made the correct decision for Mrs. M. and for themselves. It also gave him a forum to focus on the ways in which the course of his wife’s illness affected him. This, in turn, made the acknowledgment of and recommendation for treatment of his depression more understandable and acceptable to Mr. M. This case illustrates the contribution of social work to the assessment and treatment of the patient and family. In this case example, the SW was familiar with the ways in which the patient and the family system were impaired. Interventions were made that helped keep the patient’s dignity intact and helped the family to manage the course of the patient’s illness, involving all of them in the process.

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PATIENTS WITH EPILEPSY

Coping with epilepsy entails some of the same issues as coping with AD. Similarities include loss, limitations, grief, and potential cognitive impairments, including memory. However, there are patterns unique to individuals or families with epilepsy. Some difficulties, such as driving, differ from those of AD because driving can potentially resume with seizure control. The length of time patients must be seizure free before resuming driving varies from state to state. Generally, it is 6 months to a year. This often results in increased dependence on family members, friends, or colleagues for transportation. Changes in employment may be necessary as well. As with AD, the stigma of an epilepsy diagnosis also can be very difficult to tolerate. Younger patients with epilepsy may be teased at school, feel like outcasts, and be misunderstood by peers. The inability to climb ladders alone, to swim alone, and often to travel alone can limit people’s life choices. However, unlike with AD, rehabilitation and the use of compensatory strategies can be effective for people with epilepsy. Compensatory strategies include using an organizer (electronic or otherwise), using other memory aids such as pictures, and listening to others with shared experiences. Clearly, activities with an emotional valence are easier to remember for people with epilepsy. Family members and friends need to be educated about this because relating stories with an emotional valence will be more likely to trigger the patient’s memory. Although seizure control is a goal for the medical staff, many patients may have to learn to live with seizures for the rest of their lives. This can often require intensive psychotherapy and occupational therapeutic strategies for enhancement of self-esteem and confidence. Losses include reduced control, inability to drive, decreased self-esteem, and decreased independence. Assessing where patients fall on the spectrum in Figure 152-1 is key to helping them access their inner strengths and resources and reach out for resources in the community. Case Examples Ruth A. is a 32-year-old woman who has a high position in an insurance company. She came to see the SW in the context of her medical treatment for seizure disorder. Ms. A. was proud of the fact that she could “do it all.” She worked full-time, exercised 2 hours a day doing high-intensity aerobics, cooked all the meals, and shopped for her husband (who was in school obtaining a degree in business). She cleaned her house, had a large circle of friends, and denied any limitations or concerns about her seizure disorder. She was a superachiever, and nothing could keep her down. Although this attitude is admirable, it could impede acceptance of her limitations and put her in danger. Ruth was exhausted all the time, resentful that she was so busy, and unable to accept the need for more rest, sleep, and a more reasonable exercise regimen in an effort to help control her seizures. In contrast Mr. T., who was diagnosed with seizures at age 7, came into the SW’s office claiming that he was unable to do almost anything in his life. He would fall on the dependent side of the spectrum. He had learned the sick role when his parents, “the quintessential watchdogs,” never allowed him to be in any danger. As an adult he was finding himself “in a hole,” unable to get out or to find a meaningful role for himself in society. His learned helplessness has not allowed him to move forward or live a productive life.

Knowing where our patients fall on this spectrum of emotional responses to epilepsy is helpful in knowing how to start assisting

Dependent41 Underachiever

I

:

I

I

;

I

;

I

Independent Superachiever I*

FIG. 152-1. Emotional responses: the spectrum of epilepsy.

them. If patients fall closer to the underachiever end of the spectrum, work would begin by addressing their parents’ fears and treatment of patient (e.g., the patient may have been excused from chores and activities). The initial goal is to teach them safe ways to live a more productive and fulfilling life. Some suggestions may include enjoying activities such as swimming (but never alone), selecting a safe job (e.g., jobs not requiring heavy or dangerous machinery, the use of explosives, or climbing ladders), and finding opportunities close to public transportation. Additionally, women who want to have children should consult with a neurologist and SW before conception to address medical and caretaking concerns. All women of childbearing age should take folic acid supplements. In contrast, those closer to the superachiever end of the spectrum need more counseling on accepting their seizures, getting more rest, reducing caffeine intake, avoiding excessive alcohol, and allowing more rest and reasonable activity. Grieving Process

Health care providers must understand that people with epilepsy and their families need to grieve for actual or perceived losses and limitations. Being unable to control, stop, or predict seizures despite medical treatment may adversely affect the patient’s feelings of productivity, independence, trust, and love. The patient’s perceived loss of control can lead to feelings of being misunderstood or feared, as the following quote demonstrates. “While my first seizures were more terrifying than subsequent seizures because I had no idea what was happening to me, having seizures does not become any easier with familiarity. If anything, each one is a frustrating setback, a reminder that my epilepsy is not under control, an indication that my medication dosage is not sufficient, a signal that I must start over my countdown until the day I may drive again, another reason for my family to worry about me” (Shafer and Salmanson, 1997). Patients with epilepsy exhibit a higher prevalence of selfdestructive behaviors, such as alcohol or drug abuse, to ease their pain because of these losses and limitations. Women may develop eating disorders as a desperate attempt to gain control of their own bodies. Also, mood disorders such as depression are important for all health care professionals to evaluate. The incidence of suicide is four times higher in people with epilepsy than in the general population. Moving Through the Grief Process

The first step in the grieving process is the need to accept the reality of losses and limitations. Inherent is that task is experiencing the pain of those losses. Some people try to cut the grieving process short and move on or avoid it. They may isolate themselves so they do not feel the pain of the limitations or the fear of their seizures. Family members also may be uncomfortable with the grieving process. Unresolved pain or anger can easily return at a later date, manifesting itself as somatic or behavioral problems. Grieving can be a lengthy process, and people can become increasingly aware of their losses over periods of months or years.

Chapter 152 rn Psychosocial Issues in Dementia and Epilepsy

They may resent the need to make accommodations or to modify their activities. The patient’s refusal to make necessary changes in his or her lifestyle or environment must be addressed. By working through the grief, people with epilepsy are more able to reinvest their emotional energy into their relationships and activities. The severity of a person’s epilepsy depends partly on how the patient and family subjectively experience the patient’s seizures. A patient-based seizure severity scale, which incorporates the patient’s perspective on seizures, has been developed as an outcome measure for treatment. Many people with epilepsy focus on seizure control, whereas others hope to control not only their epilepsy but all its consequences. The psychosocial and functional problems that people with epilepsy may encounter can be grouped into three main categories using a model of enforced dependency. These categories are personal care and safety, mobility and social relationships, and community living (Table 152-1). The effect of seizures, medications, psychosocial concerns, and resources must be explored as well as the degree of dependency present.

Sexuality and Couple Issues Couples may find that epilepsy in one partner interferes with intimacy and sexuality. A seizure disorder may make a person feel unattractive and undesirable by altering his or her self-image. Certain antiepileptic medications may cause cosmetic problems, such as coarsened skin, darkened facial hair, or periodontal disease, that may contribute to those negative feelings. Normal behavior during sexual activities, including abnormal breathing, altered facial expression, or stiffening of the body may mimic seizure activity, causing patients or their partners to distance themselves or avoid sexual activity. People with epilepsy often worry that they will have a seizure during sex. It is essential to address the impact of epilepsy on relationships and intimacy. Sexual issues are important to address in couple therapy because sexual behavior is the central manner in which partners bond. Cognitive and behavioral techniques can be particularly rn TAW 152-1. Psychosocial and Functional Aspects of Epilepsy Personal Care and Safety

General safety Seizure first aid Fears and feelings about seizures Activities of daily living Lifestyle modificationsfor seizure control and safety Sleep, rest, and nutritional status Home management Financial ability to provide for self and family Access to health care Mobility

Physical deficits (permanent or temporary) affectingwalking, sitting, stair climbing, traveling, exercising Effects of medicationson movement, coordination, balance, vision Potential for injury and need for safety precautions Ability to driie Availability of accessible alternative transportation Recreational opportunities

Social Relationships and Community Living

View of self and others Cognitive or emotional problems affecting behavior Perceived stigma Education Employment Social skills Social opportunities Sexuality Relationships Housing or independent living Community involvement

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helpful. Simple strategies to enhance communication and intimacy often are the best, such as encouraging couples to set specific times to talk to each other and make dates with each other to enhance their listening. Alternatively, sharing certain thoughts and feelings can be beneficial. Listening to music together can foster a connected feeling, induce relaxation, and reduce stress. Couples can be encouraged to explore creative therapeutic strategies, such as massaging and stroking, allowing patients and their partners to feel cared for and attractive. Referring patients for treatment of medical concerns such as impotence or lack of sexual drive are appropriate additions to psychotherapy. Many people with epilepsy report that stress can precipitate seizures and diminish quality of life. Stress management often can be quite effective. Relaxation exercises, tapes, meditation, biofeedback, and massage can be helpful for some people. Health education often helps people with seizures to take charge of managing their epilepsy in their lives. Encouraging the patient and family to take an active role in the treatment is the first step in the educational process and can enhance treatment success. Health care team members such as the nurse, SW, or psychologist can explore the psychosocial variables and the patient’s and family’s ability to manage the epilepsy as an essential part of any educational program. Support groups and individual therapy should be offered to everyone who has epilepsy to help patients cope with the disorder, regardless of the seizure control. Nursing and social work evaluations may be helpful to look at other factors that can affect seizure control.

M e d i d o n Management If a person cannot remember to take pills or manage a complex regimen, compliance with drug therapy will be erratic and drug efficacy compromised. Before treatment is considered a failure, it is essential to assess whether there is an inability to afford medication or to get to the pharmacy and whether financial and transportation problems must be addressed. Many people are not compliant with medication because of denial and other psychosocial issues. For example, the desire to drink alcohol in a social context may impact medication compliance. These issues must be addressed in a nursing or social work setting for optimum medication management.

Lifestyle Modifications Health care professionals can offer practical supportive help to people in managing their epilepsy. Easily obtainable goals and small, concrete steps can be identified using seizure diaries to measure the amount of change that has occurred or provide feedback to the patient and to allow the clinician to reinforce success. These strategies may be particularly helpful for a patient and family who want to focus on the lifestyle variables that may be affecting seizure control. Lifestyle variables include inactivity, lack of exercise, irregular eating patterns, poor diet, hormonal changes, lack of organizational skills, and stress. Additionally, patients need to be made aware of possible seizure triggers, including sleep deprivation, bright or fluorescent lights, sun-reflecting stainedglass windows, alcohol and nonprescribed medication or illegal substances, and intercurrent illness. Suggestions such as wearing sunglassesto church can help to lessen some patients’ likelihood of having a seizure. Referrals to a nutritionist for a better diet and an, occupational therapist for improved organizational strategies can be helpful.

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TABU 152-2. Resource Guide Alzheimer‘s Association 919 Notth Michigan Avenue, Suite 1 1000 Chicago, IL 6061 1-1676 800-272-3900

http://www.alz.org Epilepsy Foundation of America 4351 Garden City Drive Landover, MD 20785-2223 800-332-1000

http://www.efa.org National Council on Aging 409 Third Street SW, Suite 200 Washington, DC 20024 202-479-1200

impairments, including memory loss. The differences are that patients with epilepsy can work on improving their quality of life with better education about seizure management, compensatory strategies (e.g., improved organizational skills), and improved medication regimen to control seizures. Although the quality of life of patients with AD also can be improved with medication, education, and compensatory strategies, the responsibility lies mainly with caregivers. Caregivers must understand how to relate to patients by redirecting, assuming increased responsibility, and understanding that the patient is not going to be the same again. Families and significant others of patients with epilepsy and AD should meet with SWs to address these issues and to learn about helpful resources in the local community such as the Epilepsy Foundation or the Alzheimer’s Association (Table 152-2).

http://www.ncoa.org

SUGGESTED READINGS

Support Croups Support groups are a useful treatment approach for many people. Groups may be offered by many institutions that specialize in epilepsy services, or they can be community based. Support groups can foster a sense of empowerment and validation. Sharing with others living with the losses and limitations of epilepsy can be curative. If the psychosocial impact of epilepsy is not treated adequately, decreased self-esteem, incompetence, loss of self-identity, isolation, impaired social skills, and increased dependence can result. Motivation is the single most important variable in individual and family counseling. The SW’s goals are to foster a sense of security and trust and to help families tolerate discomfort. Education about epilepsy, family counseling, cognitive and behavioral techniques, and sexual concerns must be provided. SUMMARY Patients with epilepsy and patients with AD share some common experiences. They both face loss, grief, limitations, and cognitive

Edwards J: When Memory Fails: Helping the Alzheimer’s and Dementia Patient. Plenum, New York, 1994 Heimlich H: Camp experiences and attitudes toward epilepsy: a pilot study. J Neurosci Nurs 33(1):57-64, 2001 Kennedy PA, Schelbert G: Practical issues and concepts in vagus nerve stimulation: a nursing review. J Neurosci Nurs 33:105-111, 2001 Ween MR Symptoms of depression in adolescentswith epilepsy. J Child Fam Nurs 23:124-126, 2000 Kwan I, Ridsdale L, Rolins D: An epilepsy care package: the nurse specialist’s role. J Neurosci Nurs 32(3):145-152, 2000 Kynger H: Compliance of adolescents and chronic disease. J Clin Nurs 9(4):545-546, 2000 Powell LS: Alzheimer’s Disease: A Guide for Families. Perseus Publishing, Cambridge, MA, 1993 Raia P, Koenig-Coste J: Habilitation therapy: realigning the planets. Alzheimer’s Association of Eastern Massachusetts Newsletter 14(2):3, 12-14, 1996 Shafer P, Salmanson E: Psychosocial aspects of epilepsy. pp. 91-109. In Schachter S, Schomer D (eds): The Comprehensive Treatment and Evaluation of Epilepsy. Academic Press, San Diego, 1997 Worden Bereavement. Semin Oncol 12:472-475, 1985

153 Evaluation of Competence in the Medical Setting Michael Mufson The clinical issues surrounding the evaluation of competence in the medical setting form an intriguing and challenging area in psychiatry and neurology. Although evaluating a patient’s capacity to make decisions about his or her medical care and to give informed consent for treatment most often falls to the psychiatrist, it should be an area familiar to all neurologists as well. The problem of decision making capacity in patients deemed incompetent is not trivial. Each year increasing numbers of people are incapacitated by Alzheimer’s disease, vascular dementia, and human immunodeficiency virus encephalopathy. If we add patients with moderate to severe mental retardation, other forms of dementia, post-traumatic brain injury, and alcoholic-related

amnestic syndrome, the number of potentially incompetent patients is in the millions. In addition to these groups of patients, those who enter the hospital and become encephalopathic, with periods of severely impaired cognition rendering them temporarily incapacitated, form another large population in which the question of competence surfaces. In brief, the problem of how to evaluate a patient’s capacity to provide informed consent and to make decisions about his or her own health care is very common and necessitates that the clinician have a working knowledge of the fundamental concepts of competency and decision-making capacity. The clinician should also understand how a capacity evaluation is performed.

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TABU 152-2. Resource Guide Alzheimer‘s Association 919 Notth Michigan Avenue, Suite 1 1000 Chicago, IL 6061 1-1676 800-272-3900

http://www.alz.org Epilepsy Foundation of America 4351 Garden City Drive Landover, MD 20785-2223 800-332-1000

http://www.efa.org National Council on Aging 409 Third Street SW, Suite 200 Washington, DC 20024 202-479-1200

impairments, including memory loss. The differences are that patients with epilepsy can work on improving their quality of life with better education about seizure management, compensatory strategies (e.g., improved organizational skills), and improved medication regimen to control seizures. Although the quality of life of patients with AD also can be improved with medication, education, and compensatory strategies, the responsibility lies mainly with caregivers. Caregivers must understand how to relate to patients by redirecting, assuming increased responsibility, and understanding that the patient is not going to be the same again. Families and significant others of patients with epilepsy and AD should meet with SWs to address these issues and to learn about helpful resources in the local community such as the Epilepsy Foundation or the Alzheimer’s Association (Table 152-2).

http://www.ncoa.org

SUGGESTED READINGS

Support Croups Support groups are a useful treatment approach for many people. Groups may be offered by many institutions that specialize in epilepsy services, or they can be community based. Support groups can foster a sense of empowerment and validation. Sharing with others living with the losses and limitations of epilepsy can be curative. If the psychosocial impact of epilepsy is not treated adequately, decreased self-esteem, incompetence, loss of self-identity, isolation, impaired social skills, and increased dependence can result. Motivation is the single most important variable in individual and family counseling. The SW’s goals are to foster a sense of security and trust and to help families tolerate discomfort. Education about epilepsy, family counseling, cognitive and behavioral techniques, and sexual concerns must be provided. SUMMARY Patients with epilepsy and patients with AD share some common experiences. They both face loss, grief, limitations, and cognitive

Edwards J: When Memory Fails: Helping the Alzheimer’s and Dementia Patient. Plenum, New York, 1994 Heimlich H: Camp experiences and attitudes toward epilepsy: a pilot study. J Neurosci Nurs 33(1):57-64, 2001 Kennedy PA, Schelbert G: Practical issues and concepts in vagus nerve stimulation: a nursing review. J Neurosci Nurs 33:105-111, 2001 Ween MR Symptoms of depression in adolescentswith epilepsy. J Child Fam Nurs 23:124-126, 2000 Kwan I, Ridsdale L, Rolins D: An epilepsy care package: the nurse specialist’s role. J Neurosci Nurs 32(3):145-152, 2000 Kynger H: Compliance of adolescents and chronic disease. J Clin Nurs 9(4):545-546, 2000 Powell LS: Alzheimer’s Disease: A Guide for Families. Perseus Publishing, Cambridge, MA, 1993 Raia P, Koenig-Coste J: Habilitation therapy: realigning the planets. Alzheimer’s Association of Eastern Massachusetts Newsletter 14(2):3, 12-14, 1996 Shafer P, Salmanson E: Psychosocial aspects of epilepsy. pp. 91-109. In Schachter S, Schomer D (eds): The Comprehensive Treatment and Evaluation of Epilepsy. Academic Press, San Diego, 1997 Worden Bereavement. Semin Oncol 12:472-475, 1985

153 Evaluation of Competence in the Medical Setting Michael Mufson The clinical issues surrounding the evaluation of competence in the medical setting form an intriguing and challenging area in psychiatry and neurology. Although evaluating a patient’s capacity to make decisions about his or her medical care and to give informed consent for treatment most often falls to the psychiatrist, it should be an area familiar to all neurologists as well. The problem of decision making capacity in patients deemed incompetent is not trivial. Each year increasing numbers of people are incapacitated by Alzheimer’s disease, vascular dementia, and human immunodeficiency virus encephalopathy. If we add patients with moderate to severe mental retardation, other forms of dementia, post-traumatic brain injury, and alcoholic-related

amnestic syndrome, the number of potentially incompetent patients is in the millions. In addition to these groups of patients, those who enter the hospital and become encephalopathic, with periods of severely impaired cognition rendering them temporarily incapacitated, form another large population in which the question of competence surfaces. In brief, the problem of how to evaluate a patient’s capacity to provide informed consent and to make decisions about his or her own health care is very common and necessitates that the clinician have a working knowledge of the fundamental concepts of competency and decision-making capacity. The clinician should also understand how a capacity evaluation is performed.

Chapter 153

Because capacity evaluation in the clinical setting always relates to specific clinical situations, this chapter is organized around illustrative case histories that raise the major questions of capacity and competence in the neurologic setting. The key legal terms are defined in Table 153-1,and the key aspects of assessing capacity are outlined in Table 153-2.

COMPETENCE: THE LEGAL CONCEPT It is important for the physician to understand that competence is a legal concept. Determination of a person’s competence is

TMLE 155-1. Key Legal Terms Involved in Evaluating

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adjudicated by a court, not made by the doctor. Many types of competence are recognized by the law in the civil arena. These include competence to make a will (testamentary capacity), competence to give informed consent for medical treatment, competence to give consent to psychiatric hospital admission, competence to enter into contracts, and competence to act in a fiduciary or professional capacity. Each of these areas of competence is associated with specific capacity criteria that are assessed by a judge in a court setting. The ultimate legal judgment of competence is made by the court. It is also important to point out that a person may be assessed as lacking capacity for one task but still not be assessed as globally incompetent (i.e., in need of a guardian); he or she may retain decision making capacity for other tasks.

Capacity and Competence Capacity: A person’s ability in a task-specific situation to communicate choice, understand relevant information about the choice, and weigh risks and benefits of choice. The person is able to engage in reasoning about the choice in a logical fashion. Competency: Ability to understand or act reasonably. Competence is a context-dependent term with criieria specific to the function being evaluated. Competence is task specific, and a person may be judged competent for one task and incompetent for another. It is not necessarily a static state and can change as a person’s underlying medical condition changes. When a person is found to be incompetent by a court, guardianship or conservatorship may be granted. A person who is assessed to be generally incompetent for all legal purposes is considered globally incompetent. There are many types of competence in the cMl arena (e.g., competence to parent, competence to provide informed consent for treatment, competence to enter into a contract, competence to write a will). Competence is determined (adjudicated) by a judge in a court proceeding. Full guardian: When a guardian is appointed to make decisions about the ward’s personal health, safety, and welfare, guardianship is described as limited to the person only. Guardianship of the person and estate is called full guardianship. Guardian ad litem: A person appointed by the court to protect the interests of the ward in a legal proceeding. Guardianship: A guardian is a person appointed by the court who is given the power and charged with the duty of managing the rights and property of another person (the ward). The court requires evidence of incompetence of the ward wherein he or she is incapable of handling his or her affairs. The guardian‘s authority is limited to the areas of decision making in which the ward is adjudicated as incompetent Health care proxy: A document by which one person gives another person the authority to make health care decisions. The health care proxy is used when the person handing over the authority becomes incapable of making health care decisions. Limited guardian: Also known as a conservator; has limited powers and duties with regard to the ward, specifically managing financial affairs but allowing the ward to make personal decisions. Living will: A declaration by a person in writing, executed while competent, to set forth directions regarding medical treatment including treatments the person wants to accept or refuse. Specific treatments listed for refusal may include cardiac resuscitation and ventilatory support; the living will may include a health proxy designation clause. Power of attorney: A legal instrument in writing by which a person, as principal, appoints another as his or her agent and confers on that agent the authority to perform specified acts or kinds of acts on behalf of the principal. The person holding the power of attorney can then act as agent to third parties with whom the agent deals and use the power of attorney as evidence of authority to do so. Representativepayee: A person or agency who accepts payment from an entitlement program on behalf of the ward and is authorized to manage those payments. A person need not have a guardian or be incompetent to have a representative payee; the standard is whether a representative payee is judged to be in the person’s best interest. Temporary guardian: A permanent guardian can take months to obtain. If an emergency arises and a guardian is needed immediately, the probate court may appoint a temporary guardian. Guardianship is limited to address a specific potential harm; the temporary guardian is appointed to address actions necessary to avoid the occurrence of the specific harm. Ward: A person the law regards as incapable of managing his or her own affairs and over whom or over whose property a guardian is appointed.

Case I:Dementia with SpecHpc lncapaclty but Not Global

Incompetence A 74-year-old man was admitted to the hospital for increasing cognitive decline. A medical evaluation and neurologic consultation led to a presumptive diagnosis of early Alzheimer’s disease. The patient was living alone in his apartment, and his children were concerned about his ability to live independently. He wandered occasionally but could find his way home, and although his home was unkempt there was no evidence of or history of him being unsafe. Medical staff and family recommended transfer to a nursing home. The patient refused, demanding to go home, and expressed ideation that people were plotting against him to take his home away. A psychiatric consultation was requested to assess the patient’s capacity to refuse placement and to assess whether guardianship proceedings should be initiated in court. The neuropsychiatric evaluation revealed an alert, spry man. He understood why he was in this hospital, and although he downplayed his intellectual deficits, he admitted that his memory was failing. Formal mental status testing revealed deficits in recent and remote memory. However, the patient retained insight into the fact that others were concerned about him and that eventually he might need placement, but at present he was determined to live at home as long as possible. He understood the risks of this decision and the reasons why others disagreed with his choice. He was able to retain information about the staff recommendations and to discuss his choice and why he disagreed. His cognitive impairments did not interfere with his decision-making capacity about placement. He acknowledged that his fears arose from feeling alone and isolated, but he showed no delusional ideation. He agreed that in the context of his failing memory he should have power of attorney granted to his children because he was having difficulty organizing his finances. The psychiatric assessment documented that the patient had the capacity to refuse placement, and the family was told that there was no evidence of such severe cognitive impairment to warrant a guardianship proceeding. It was recommended that they monitor his functioning and obtain power of attorney, with his consent, so they could help manage finances and legal affairs as needed. The issue of placement would have to be reassessed when there was evidence of cognitive decline that interfered with his capacity to function independently. At that time, guardianship proceedings would be necessary.

Comment This case illustrates the complex nature of capacity evaluations. Despite cognitive decline and emergence of acute paranoia, this man retained capacityto make a fundamental decision about his life. On the

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other hand, the increasing cognitive decline interfered with other capacities (e.g., financial affairs), and the psychiatrist instructed the family to become involved and to act as a surrogate in that particular area of the patient’s life. It was recommended that guardianship was not appropriate at this particular time. The most common issues neurologists must address revolve around a person’s ability to make decisions about health care, to give informed consent to treatment (or to refuse treatment), and to decide whether to return home or go to a nursing facility. Competence and the evaluation of competence grow out of the fundamental principle that a person has a right to privacy, self-determination, and autonomy. This is eloquently stated in the law in the well-known legal decision from 1914 articulated by Justice Cardozo in a consent case: “Every human being of adult years and sound mind has a right to determine what shall be done to his own body; and a surgeon who performs an operation without his patient’s consent commits an assault, for which he is liable in damages.” In another landmark decision (Nutunson v. mine, 1969) the Kansas Supreme Court ruled, “Anglo American Law starts with the premise of thorough ongoing self determination. It follows that each man is considered to be master of his own body, and he may, if he be of sound mind, expressly prohibit the performance of life-saving surgery, or other medical treatment. . . . The law does not permit him [the doctor] to substitute his own judgment for that of the patient by any form of artifice o r deception.” Therefore, the key clinical question most often revolves around whether the patient is of sound mind when making a decision. This capacity to make decisions is to be distinguished from competence in that capacity assessment can be done by a psychiatrist or other physicians, whereas competence is decided by the court, which uses the evaluation of the patient’s capacity as performed by the physician to determine whether the patient needs a guardian. The task of assessing capacity most often falls to psychiatrists because the comprehensive mental status evaluation as it relates to decision making is the key element of assessing a person’s capacity. From a legal perspective, however, performing this evaluation is not the purview of psychiatry alone, and a neurologist can perform the assessment if he or she is comfortable doing so and is familiar with the principles of evaluating decision-making capacity (see Chapter 135 on the mental status examination).

EVALUATING DECISION-MAKING CAPACITY When a patient refuses treatment, refuses placement in a nursing home, or demands discharge from a hospital against medical advice, the question often arises as to whether the patient is “competent” to make such decisions (i.e., lacks capacity to make such a decision). This often occurs when there is cognitive impairment or a psychiatric disorder impairing judgment and the clinician raises questions about whether there is substantial impairment of decision-making capacity. As noted earlier, the law is clear that as long as the patient is of “sound mind” (i.e., has the capacity to make decisions), he o r she has the right to do so, even to the point of making what the physician considers to be a wrong decision.

Case II:Retaining the Right to Make the Wrong Choice A 47-year-old woman was admitted to the hospital for the evaluation of headache. The neurologicworkup revealed a subarachnoid hemorrhage.

The patient consented to admission procedures and hospitalization. After the first 24 hours the patient refused to be on bed rest, demanding to be allowed to walk around and smoke cigarettes. She also refused systemic antifibrolysin therapy and demanded to be released home if she could not ambulate. A psychiatric consultation was requested to assess the patient’s capacity to refuse treatment and to sign out of the hospital against medical advice. The consultation revealed a patient with mild inattention. However, she was able to understand the diagnosis and appreciate the need for acute medical care and the risks of refusing treatment (including rebleed and death), and she expressed her refusal clearly and consistently over several evaluations during the morning. Psychiatric examination revealed a long history of suspiciousness and isolated social behavior but no delusional ideation or history of psychosis. There was no evidence that her mild cognitive impairment or suspiciousness interfered with her capacity to refuse treatment or choose to be discharged. After consultation with the hospital attorney it was determined that the patient had the right to refuse treatment if she could not be persuaded to stay. Despite attempts by the psychiatrist to provide emotional support and address her fears and anxieties, the patient would not change her mind, and she was discharged home against medical advice.

This case illustrates the point made in Brock and Wartman’s article, “When Competent Patients Make Irrational Choices.” Although this woman was making a decision that from a neurologic standpoint was inappropriate, if not irrational, she retained the right to make the wrong decision. Because she did not lack capacity to make treatment decisions, she had the right to refuse treatment. Although she was mildly cognitively impaired, suspicious, and socially isolated, she did not have evidence of impaired judgment that interfered with her decision-making capacity to refuse treatment. She clearly stated her position, appreciated the risks and benefits of her refusal of treatment, and therefore was discharged against medical advice. How is decision-making capacity evaluated in the medical setting? Technically the patient’s capacity to make decisions is based o n how the law defines such legal standards. Although different jurisdictions may differ on specifics, there are general principles that cover most cases. These are best summarized by Applebaum and Grisso, who describe the essential components of competence standards (Table 153-2).

TABLE 155-2. Assessing a Person‘s Capacity to Make Decisions About Medical Care

Although the legal standards for adjudicating competence vary from state to state, general standards fall into the following categories: rn Ability to communicate choices: The person must be able to express his or her choice and communicate that choice. rn Understanding of relevant information: The person must be able to understand information about the proposed treatment, remember the information, and show that he or she can be a part of the decision-making process. Appreciation of the significance of the information and its consequences: The person must understand the consequences of treatment refusal and the risks and benefits of accepting or refusing treatment. rn Manipulating information rationally: The person must be able to engage in reasoning as it applies to making treatment decisions (e.g., use logical processes, weigh treatment decisions, and rationally manipulate information about treatment decisions). Adapted from Applebaum PS, Grisso T: Assessing patient‘s capacity to consent to treatment. N Engl J Med 319(5):1635-1638, 1988.

Chapter 153

A wide variety of neurologic conditions can impair a person’s capacity to make or express decisions. These include the aphasias, dementias, encephalopathies, mental retardation, and traumatic head injury with intellectual deficit. Psychiatric conditions that may impair decision making include the wide variety of psychotic disorders, delusional disorders, depressive disorders and acute adjustment disorders with emotional disorganization and severe anxiety. In any of these situations the patient may lose the capacity to make a specific decision. However, it is important to note that none of these disorders per se means that the patient has lost the ability to make decisions and therefore is not competent. Rather, when the disorder impairs decision-making capacity for a specific task or decision, the patient becomes incapacitated and needs to be treated as such by having a substitute decision maker involved or, if the patient is globally incapacitated, by having a guardianship proceeding initiated in court.

THE FORMAL ASSESSMENT OF DECISION-MAKING CAPACITY AND OBTAINING INFORMED CONSENT The assessment of decision-making capacity begins with noting whether the patient can express his or her decision. This can be a complicated assessment if the patient has a nonfluent aphasia. The patient may understand language, but because it is impossible to assess his or her ability to reason and understand risks and benefits, the patient may be found to lack decision-making capacity in the medical-legal context. The patient must be able to do more than assent with a “yes” or “no” or a nod of the head. The evaluator must be able to assess the patient’s capacity to manipulate information in a complex fashion as it pertains to providing informed consent.

Case 111: The Loss of Decision-Making Capacity in Context of a Stroke and Aphasia A 55-year-old man suffered a middle cerebral cerebrovascular accident. After the stroke he developed a nonfluent aphasia. His speech was nonfluent, and he could not produce meaningful sentences. His comprehension of spoken language was limited to nodding “yes” or “no” to simple questions, but comprehension of complex ideas appeared significantly impaired but difficult to assess because of the nonfluent aphasia. Reading and writing were impaired as well. Psychiatric consultation was requested to assess the patient’s capacity to consent to treatment. Because of the dense aphasia, the impairment in comprehension, and the patient’s inability to express his thoughts, it was determined that he lacked capacity to provide

informed consent. He had a health care proxy in place before hospitalization, which designated his wife as his proxy. She was then involved in decision making through his hospital course and acted as his surrogate decision maker.

Although it appeared that this patient had an ability to assent to certain decisions, it was found that he could not provide informed consent because of limitations in communication and comprehension. Therefore, decision making was turned over to the health care proxy. The second component the clinician must assess is the patient’s understanding of relevant information about the clinical situation and decision. The patient must be able to comprehend information and remember the information when making the decision.

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This is most often assessed by having the patient answer specific questions, such as, “Please tell me what you understand about your illness. What are the doctors recommending as the best treatment?” The third component is the patient’s capacity to appreciate the information given, to rationally manipulate it, and to weigh the risks and benefits of treatment. Questions that will help define this capacity include, “Can you tell me about what is wrong with you and whether you feel you need treatment?” “Can you tell me what the doctors have explained to you about what the risks and benefits of treatment are?” “Do you know what the treatment alternatives are?” Obtaining informed consent is a two-way street. The physician is obligated to obtain consent by giving the patient specific information in what may be called the informed consent discussion. After this discussion the patient can be assessed to see whether he or she has the capacity to provide informed consent. The informed consent discussion should include a description of the proposed treatment or procedure in language the patient can understand. Second, the patient should be informed about the diagnosis and questions related to the accuracy of the diagnosis. The law requires that the patient be informed of information that any patient in similar circumstances would need to know. The risks and benefits of treatment or procedure should be discussed thoroughly. Treatment alternatives should be reviewed, especially in relation to the proposed treatment. The patient should understand who is the physician with the primary responsibility and who may be performing treatment or procedures. It is the responsibility of the physician providing the treatment to explain to the patient, in language he or she understands, the nature of the recommended procedure and concomitant risks and benefits. This must be done before the capacity evaluation can proceed. If it has not been done, the psychiatrist may ask the surgeon or other health care professional to provide the information to the patient as part of the assessment so it can be reviewed with the patient. Finally, the evaluator should assess whether the patient is able to reason logically with the information at hand and do so consistently over time. The patient should be able to think about what has been told to him or her, weigh the treatment options, understand risks and benefits, and express that decision consistently. Questions such as, “How have you reached your decision?” and “Can you tell me what you have considered in coming to your decision?” are helpful in this regard. If there is a question about memory impairment, evaluations may need to be performed over the course of several hours or longer. Serial evaluations may also be necessary if a patient changes his or her decision from hour to hour to determine whether there is true consistency in the patient’s decision making. These evaluations focus on whether at the time of decision making the patient can recall the relevant information. On the other hand, if a patient’s long-term memory is impaired, he or she may not have the capacity to make a decision several days after the initial informed consent discussion, and a reevaluation is necessary. The most severe memory impairment that interferes with basic understanding renders the patient incapacitated. To summarize, the formal capacity assessment must address whether the patient is able to communicate choice, understand the treatment decision before him or her, appreciate the clinical situation with associated risks and benefits, and rationally manipulate the information as it applies to the clinical situation. In emergencies, when decisions must be made to save the patient’s life and the patient is incapacitated, the physician can

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make choices for the patient. In medical emergencies the patient’s consent is implied by law. If time permits, attempts to contact a surrogate should be made. Emergency care includes conditions necessary to preserve life or prevent serious health impairment. Consultationwith the hospital attorney and chief of staff usually is recommended in these situations. It is also important to note that the capacity to make a decision is not a static concept. It may change with the alteration in the patient’s neurologic condition. This is especially true in encephalopathic states or in states of acute emotional distress. In such instances, sequential evaluations should be done to determine decision-making capacity when the patient is less confused or distressed, at which point decision-making capacity may return. In certain situations family members or friends may help the patient express his or her wishes, reflect on decisions, or reduce anxiety, which may interfere with decision making. These interventions can help optimize the emotional environment, which can result in patients being better able to express themselves in a hospital setting, which often provokes anxiety. Neurologic disorders often create unusual situations that necessitate creative capacity evaluations. For example, if the patient’s memory problems can be compensated for by handwritten materials that can be referred to and thus allow a stable and meaningful expression of the patient’s wishes, such materials should be used. If an aphasic patient can communicate choice by pointing to informative pictures, this would also be a reasonable part of the assessment. The purpose of the assessment is to protect the patient’s autonomy, so the clinician should attempt to explore all avenues possible to allow the patient to show his or her capacity to give informed consent. It is worth stating explicitlythat the patient is presumed to have capacity to make decisions until it is proven otherwise.

THE SUBSTITUTE DECISION MAKER Once the evaluation of decision-making capacity is complete, the clinician can determine whether the patient has the capacity to give informed consent or accept or refuse treatment. If the patient lacks capacity, the clinician must turn to a substitute decision maker. At this point the patient loses his or her autonomy over the specific decision-making capacity, and the clinician involves the surrogate decision maker. If a patient has not completed advance directives, a health care proxy, if designated, becomes the substitute decision maker. If there is no health care proxy, it is common practice to turn to family members next. The formal legal recognition of family members as substitute decision makers for incapacitated patients varies from state to state, but the practice of turning to them is customary. This has been underscored in the Report of the President’s Commission for the Study of Ethical Problems in Medicine, in which this policy was explicitly endorsed. This plan often is written into the hospital’s informed consent policies and procedures. When no family is available, close friends may also be used as decision makers. Capacity evaluations often do not result in an all-or-none determination (i.e., finding that the patient lacks all capacity or retains total capacity). In fact, most evaluations call for clinical judgment that balances the principles of protecting autonomy and protecting the patient from the consequences of bad decisions. This involves clinical judgment based on the findings in the capacity evaluation and in complex cases may necessitate an evaluation from the hospital ethics committee (Fig. 153-1).

If the patient has a health care proxy in place or a durable power of attorney for health care, the proxy becomes the decision maker for the patient, and the clinician involves the proxy in informed consent decisions when the patient is incapacitated. Patients may also have living wills or advance directives in place that express their choices in specific circumstances. These must be reviewed to see whether they are useful in the situation at hand. Although most states recognize advance directives as a legal document, the clinician should consult the hospital attorney or health care attorney if there are any questions about the clarity of the advance directive. The health care proxy should be included in this process if the patient has designated a proxy. If the patient has no health care proxy or advance directives, the clinician should look to family members in accordance with state law. Usually spouses are first in line, followed by adult children, parents, then adult siblings, grandparents, and adult grandchildren. Families can be asked to designate one or two members as decision makers if they want to do so. If there is intrafamilial conflict, the clinician can turn to the medical psychiatry service to conduct a family meeting to see whether a solution can be worked out. If this is not possible, the clinician can turn to the hospital bioethics committee for help in resolving such conflicts. The ethics committee is also a valuable resource if the doctors question the decision of the family member as not being in the patient’s best interest or if the family feels unable to assume the decision-making role.

Case I V Global Incapacity in the Context of a PostTraumatic Brain Injury A 23-year-old woman was admitted to the neurologic service after

falling out a three-story window while intoxicated. She was comatose on admission, and she emerged from coma over a 5-day period. Neurologic evaluation revealed frontal contusion, frontotemporal subdural hematoma, and brain hemorrhage in the right frontal region. After medical and neurosurgical stabilization, the patient appeared emotionally labile, with disorganized thinking and impaired insight. She refused to be transferred to a rehabilitation facility and wanted to go home. A psychiatric evaluation was called to assess the patient’s capacity to make decisions about her care and placement. Psychiatric evaluation revealed a woman with a resolving posttraumatic encephalopathy and frontal lobe syndrome. Symptoms included affective instability, impaired judgment and insight, and thought disorder. Intellectual deficits included impaired memory and concentration. These deficits clearly impaired the patient’s capacity to make decisions about her care and placement. She stated that she was fine now that the doctors were taking care of her and that she was ready to go back to work. She could not understand people’s concern for her and could not discuss the neurologic problems. She had no insight into the risks and benefits of her refusing care or placement. The family was informed that she lacked capacity to give informed consent for treatment or make decisions about placement. Her parents became involved in decision making and were advised to consider obtaining temporary guardianship from the court if no improvement occurred in the upcoming months.

This case illustrates that initiating guardianship proceedings is not necessarily irreversible. Temporary guardianship obtained in court can

Patient has advanced directives

Guardianship initiated in court: temporary or ongoing guardianship

Non acute problem: initiate court proceedings regarding guardianship

1 . 1 Bioethics committee consulted if there is acute problem; also contact hospital attorney

available

in concert with chief of service or convene bioethics committee

If not available

- acutely: attending

Seek alternative

I

I

and/or

Approach family Family used as surrogate for emergency decision

w

Patient does not have advanced directives or health care proxy

On formal assessment patient lacks capacity

Clinician follows directives; if directives are unclear or do not address specific issues at hand, health care mow . I is used as substitute decision maker

I

w

w

I

PSYCHIATRIC CONSULTATION

Clinician questions patient's capacity to make decisions Patient refuses treatment, capacity questioned Disagreement arises among patient, caretaker and/or family

FIG. 153-1. Capacity assessment flowchart.

as substitute decision maker

Health care

J-

No advanced directives but person designated

Proceed with capacity evaluation

Initiating event

Patient's wishes are followed eg: refusal of treatment or signing out AMA. In life threatening situations also contact hospital attorney

patient has capacity to make decisions regarding care

Proceed with capacity evaluation

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Behavioral Neurology and Epilepsy

Psychiatric and Social Issues in Neurologic Practice

be of use until the patient regains decision-making capacity. However, if the patient does not regain this capacity, the guardianship can become permanent. In demented patients the initial guardianship is likely to continue once in place.

If the patient lacks capacity and has no health care proxy and no family, the involvement of the court may be necessary. The court will appoint a guardian, usually an attorney, to be the decision maker for the patient. SUMMARY Evaluating a patient’s capacity to provide informed consent and be involved in decision making relating to his or her health care is a complex clinical problem. All physicians need to be familiar with the legal concept of competence and how that relates to the issues of capacity and decision making in the hospital setting. The clinician should be familiar with the components of the formal assessment of decision-making capacity and know when a psychiatric consultation is necessary to help with this assessment. The legal process of appointing a guardian or turning to a surrogate decision maker has serious implications for a patient’s autonomy and rights. This process should be initiated only when the clinician is convinced that the patient’s capacity for decision

making is severely impaired. Capacity evaluation and the decision to involve surrogate decision makers should always be approached with the dual goal of respecting the patient’s autonomy and judgment while attempting to maximize the patient’s well-being. SUGGESTED READINGS Applebaum PS, Grisso T Assessing patient’s capacities to consent to treatment. N Engl J Med 319:1635-1638, 1988 Brock D, Wartman S: When competent patients make irrational choices. N Engl J Med 322(22):1595-1599, 1990 Buchanan AE, Brock DW Deciding for Others: The Ethics of Surrogate Decision Making. Cambridge University Press, Cambridge, UK, 1990 Drane JH: Competency to give informed consent: a model for making clinical assessments. JAMA 252:925-927, 1984 Grisso T, Applebaum P Assessing Competence to Consent to Treatment. Oxford University Press, Oxford, UK, 1998 Gutheil T, Applebaum P Clinical Handbook of Psychiatry and the Law. Lippincott Williams & Wilkins, Philadelphia, 2000 Hornbostel R Legal and financial decision making in dementia care. pp. 417-432. In Whitehouse P (Ed): Dementia. Philadelphia, F.A. Davis, 1993 Rosner R (ed): Principles and Practices of Forensic Psychiatry. Chapman & Hall, New York, 1994

SECTION

1

BRAIN TUMORS: GENERAL ASPECTS

154 Classification, Epidemiology, and Etiology

of Brain Tumors David Schiff Because of the brain’s intimate relationship to the skull, almost all tumors within the confines of the skull are considered brain tumors. This includes tumors of the brain substance itself, tumors arising from the meninges, tumors of the cranial nerves, tumors of the skull base, and usually tumors involving intracranial glands (the pituitary and pineal glands). Some of these tumors originate elsewhere in the body and metastasize to intracranial contents (secondary brain tumors). Additionally, histologically benign developmental and acquired cysts and malformations in the brain can take on the behavior of a space-occupying lesion and often are considered with tumors. It is important to emphasize that although some entities are clearly histologically and biologically benign, the vital nature of the entire brain often blurs the distinction between benign and malignant. A small, slow-growing, mitotically inactive tumor with little or no metastatic potential may prove lethal if located in a region of the brain that renders it less than totally resectable (Table 154-1). There are more than 100 types of primary brain tumors (Table 154-2). This chapter focuses on the classification and epidemiology of the more common and clinically relevant entities. Many of the entities are discussed further in later chapters.

CLASSIFICATION OF BRAIN TUMORS Primary Brain Tumors

The confusing nomenclature of many primary brain tumors is best understood as a historical consequence of attempts to classify these tumors based on contemporary scientific techniques. Bailey and Cushing published their initial scheme in 1926 based on the premise that tumors could be classified by correlating the light microscopic morphologic features of their cells with those of normal cells at each defined stage of histogenesis. Kernohan, Ringertz, Daumas-Duport, and others focused on the task of trying to predict biological behavior of glial neoplasms based on histology. In 1979, the World Health Organization (WHO) devised their first classification scheme, again based on the concept of grouping tumors according to their normal ontogenic counterparts. In 1993, the WHO published a revised classification, taking advantage of insights gained from immunohistochemistry electron microscopy and molecular biology regarding the origins of some of these tumors. Given these multiple classification schemes, for certain brain tumors, particularly gliomas, it is important to know what system or criteria the neuropathologist is using when he or she assigns a name to a tumor. 1006

Gliomas

As the most common malignant primary brain tumor, gliomas have garnered appropriate emphasis in classification schemes. The term glioma refers to tumors believed to be derived from glial cells (i.e. astrocytes, oligodendrocytes, and ependymal cells) in the central nervous system. For each of these cell types there is a neoplasm that occurs along a spectrum of biologic aggressiveness. The current WHO scheme recognizes three tiers to astrocytic tumors. Astrocytic tumors with increased cellularity and atypia but no mitoses, endothelial proliferation, or necrosis are called astrocytomas. Tumors with mitoses but no endothelial proliferation or necrosis are called anaplastic astrocytomas, and tumors with mitoses and either endothelial proliferation or necrosis are called glioblastomas. (Endothelial proliferation or necrosis in the absence of mitoses rarely if ever occurs.) This grading system reflects widespread acceptance of the criteria proposed by Daumas-Duport in the St. Anne-Mayo grading scheme, in which the presence or absence of these features correlated powerfully with prognosis. Several issues still prove troublesome in the current grading of astrocytic tumors. First, some neuropathologists do not require the presence of mitoses to call a cellular, highly pleomorphic tumor an anaplastic astrocytoma. Second, some neuropathologists adhere to the modified Ringertz classification, in which necrosis was a requirement for a tumor to be called a glioblastoma. Finally, given the frequency of diagnosis by stereotactic biopsy (which gives the neuropathologist a miniscule specimen) and the heterogeneity of some of these tumors, the possibility of undergrading a tumor is very real. Many neuropathologists incorporate radiographic data into their interpretations, noting that a tumor appears to have a necrotic center on computed tomography or magnetic resonance scan and thus may well be a glioblastoma despite the failure of a biopsy to demonstrate necrosis. A few distinct forms of astrocytomas have special names and are not part of this spectrum. Whereas most astrocytomas tend to be diffuse, infiltrating neoplasms, these special forms are generally well localized and thus potentially surgically curable. These include the pilocytic astrocytoma, which tend to occur in children and young adults and have a particular predilection for the cerebellar hemispheres. Another subtype is the subependymal giant cell astrocytoma, usually found in patients with tuberous sclerosis and tending to occur at the foramen of Monro. Gemistocytic astrocytomas are a subtype of diffuse fibrillary astrocytomas with abundant plump eosinophilic cytoplasm that

Chapter 154

TABLE154-1. Most Common Brain Tumors by Location location

Tumor

Cerebral hemispheres

Astrocytoma, grades 1-4 Metastasis Oligodendroglioma Meningioma Primary central nervous system lymphoma Ependymoma Sarcoma Ganglioglioma’ Desmoplastic infantile ganglioglioma” Primitive neuroectodermal tumoP Astrocytoma, especially high-grade Oligodendroglioma Lipoma Ependymoma Central neurocytoma Meningioma Subependymoma Choroid plexus papilloma” Choroid plexus carcinomaa Subependymal giant cell astrocytoma’ Astrocytoma, especially pilocytic“ Colloid cyst Ependymoma Subependymoma Pituitary macroadenoma Craniopharyngioma” Germ cell neoplasm” Meningioma Optic glioma” Astrocytoma, especially pilocytic“ Meningioma Adenorna Craniopharyngioma” Meningioma Germ cell neoplasm” Dermoid cyst Metastasis Germ cell neoplasm” Teratoma” Pineoblastomaa Pineocytoma” Astrocytoma Epidermoid cyst Astrocytoma” Metastasis Metastasis Hemangioblastoma Astrocytoma, especially pilocytic“ Medulloblastoma’ Primary central nervous system lymphoma Acoustic schwannoma Meningioma Epidermoid cyst Schwannoma of other cranial nerves Chemodectoma Choroid plexus papilloma Ependymoma Metastasis Ependymoma” Choroid plexus papilloma’ Subependymoma Meningioma Schwannoma Neurofibroma

Corpus callosum Lateral ventricle

Third ventricle

Suprasellar cistern

Optic chiasm and nerve Pituitary region

Pineal region

Brainstem Cerebellum

Cerebellopontine angle

Fourth ventricle Foramen magnum

’Particularly in children. Modifiedfrom Okazaki H, Scheithauer BW: Atlas of Neuropathology. Cower Medical Publishing, New York, 1988, with permission of the Mayo Foundation.

generally portend a worse prognosis than nongemistocytic astrocytomas. Oligodendrogliomas are another subtype of gliomas and have recently received attention because of their relative chemosensitivity compared with other gliomas. On light microscopy these

Classification, Epidemiology, and Etiology of Brain Tumors

1007

tumors appear as round cells with perinuclear halos (a “fried egg” appearance) and an acutely branching (chicken wire) capillary pattern. The WHO grading system recognizes oligodendrogliomas and anaplastic (or malignant) oligodendrogliomas, the latter characterized by high cellularity, mitoses, and pleomorphism. When such tumors manifest endothelial proliferation or necrosis, they are generally considered glioblastomas (i.e., glioblastomas can arise from oligodendrogliomas as well as from astrocytomas). As with astrocytomas, tumor grade correlates with prognosis. Oligodendrogliomas and astrocytomas are not mutually exclusive; tumors often have some areas more suggestive of oligodendroglioma and other areas resembling astrocytoma. Consequently, both oligoastrocytomas and anaplastic oligoastrocytomas (sometimes called mixed anaplastic gliomas) are well recognized. The final major subcategory of gliomas is the ependymoma, thought to arise from ependymal cells lining the ventricular system. Ependymomas generally are considered low-grade tumors. High cellularity and the presence of mitoses warrant the designation “anaplastic ependymoma.” It is controversial whether anaplastic ependymomas have a markedly worse prognosis than typical ependymomas.

Medulloblastomas Another contentious classification issue concerns medulloblastomas and related tumors. Medulloblastomas are “small blue round cell” embryonal tumors typically arising in children in the roof of the fourth ventricle. Histologically identical tumors arise elsewhere in the brain and depending on their location may be called pineoblastomas, neuroblastomas, or ependymoblastomas. Some taxonomists have argued that all these embryonal tumors, regardless of site, should be classified together as primitive neuroectodermal tumors (PNETs) on the theory that they share a common progenitor cell. Other neuropathologists disagree, arguing that medulloblastomas have a different progenitor cell, in addition to a much more favorable course than these other tumors. In the current WHO framework, medulloblastomas are categorized with other tumors of different sites but similar appearance as embryonal tumors, and the PNET concept is included but deemphasized.

Menindomas As with gliomas, varying grades of malignancy within meningiomas are recognized. In addition to the histologically benign meningioma (which comprises most meningiomas), occasional tumors are called atypical and others malignant (or anaplastic). Atypical meningiomas may have hypercellularity, nuclear pleomorphism, increased mitotic activity, and foci of necrosis. Malignant meningiomas generally contain these features to an even higher degree, although invasion of brain parenchyma or metastasis by a meningioma, even in the absence of these features, warrants the designation malignant. Both atypical and malignant meningiomas are more likely to recur after resection than typical ones. EPIDEMIOLOGY OF BRAIN TUMORS Brain tumors are the second leading cause of neurologic death among adults, after stroke. It is estimated that 35,000 primary brain tumors will be diagnosed in the United States in 2003, of which 13,100 will be fatal. Worldwide, approximately 95,000

W

TABLE154-2. Histologic Classification of Tumors of the Central Nervous System 8.2 Nonvascular mesenchymal tumors and tumor-like lesions 8.2.1 Benign nonvascular tumors 8.2.1.1 Lipoma 8.2.1.2 Lipoma of the internal auditory canal 8.2.1.3 Chondroma and osteochondroma 8.2.1.4 Fibroma and fibromatosis 8.2.1.5 Other benign mesenchymal lesions 8.2.2 Malignant nonvascular tumors 8.2.2.1 Chordoma 8.2.2.2 Chondrosarcoma 8.2.2.3 Mesenchymal chondrosarcoma 8.2.2.4 Rhabdomyosarcoma 8.2.2.5 Fibrosarcoma 8.2.2.6 Malignant fibrous histiocytoma 8.2.2.7 Other sarcomas 9. Tumors of paraganglionic tissue 9.1 Paraganglioma 10. Primary tumors of hematopoietictissue 10.1 Primary central nervous system lymphoma 10.2 Plasmacytoma 10.3 Microgliomatosis 1 1. Tumors of the peripheral nerve sheath 1 1.1 Schwannoma 1 1.2 Neurofibroma 1 1.3 Malignant peripheral nerve sheath tumor 1 1.4Granular cell tumor 12. Melanocytic tumors 12.1 Melanocytoma 12.2 Malignant melanoma 13. Craniopharyngiomas 13.1 Adamantinomatous craniopharyngioma 13.2 Papillary craniopharyngioma 14. Benign cystic lesions 14.1 Colloid cyst of the third ventricle 14.2 Rathke cleft cyst 14.3 Endodermal cyst 14.4 Ependymal (glioependymal) cyst 14.5 Choroid plexus cysts 14.6 Epidermoid and dermoid cysts 14.7 Arachnoid cyst 14.8 Pineal cyst 14.9 Nerve root cyst 14.10 Synovial cyst of spine 14.1 1 Other cysts 15. Tumorlike lesions of maldevelopmental or uncertain origin 15.1 Hypothalamic hamartoma 15.2 Nasal cerebral heterotopia ("nasal glioma") 1 5.3 Meningioangiomatosis 16. Dysgenetic syndromes 16.1 Neurofibromatosis 1 16.2 Neurofibromatosis 2 16.3 von Hippel-Lindau syndrome 16.4 Tuberous sclerosis 16.5 Neurocutaneous melanosis 16.6 Sturge-Weber disease 1 6.7 Mesencephalo-oculo-facial angiomatosis (Wyburn-Mason disease) 16.8 Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) 16.9 Cowden syndrome 17. Reactive and inflammatory masses simulating neoplasia 17.1 Demyelinating disease 17.2 Cerebral infarct 17.3 Radionecrosis 17.4Langerhanscell histiocytosis 17.5 Xanthomatous lesions 17.6 Progressive multifocal leukoencephalopathy 17.7 Sarcoidosis 17.8 Plasma cell granuloma 17.9 Extranodal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) 17.10 Castleman disease 17.1 1 Syphilis (gumma) 17.12 Collagen-vascular diseases 17.13 Amyloidoma 18. Metastatic and secondary neoplasms 18.1 Metastatic carcinoma and sarcoma 18.2 Leukemia 18.3 Secondary malignant lymphoma 18.4 Spinal epidural lymphoma 18.5 lntravascular lymphoma 18.6 LvmDhomatoid " nranulomatosis

1. Tumors of neuroglia and choroid plexus epithelium 1 .I Astrocytic neoplasms 1.1.1 Fibrillary or "diffuse" astrocytic tumors 1.1.1.1 Astrocytoma 1.1.1.2 Anaplastic astrocytoma 1 .I.I.3 Glioblastoma multiforme 1.1.1.4 Cliosarcoma 1 .I .I .5 Protoplasmic astrocytoma 1.1.1.6 Granular cell astrocytic neoplasms 1 .I .I .7 Gliomatosis cerebri 1.1.1.8 Meningeal gliomatosis 1.1.2 Other astrocytic tumors 1 .I2.1 Pilocytic astrocytoma 1.1 2.2 Pleomorphic xanthoastrocytoma 1.1.2.3Subependymal giant cell astrocytoma (tuberous sclerosis) 1.1.2.4 infantile desmoplastic astrocytoma 1.1.2.5 Gliofibroma 1.2 Oligodendroglial neoplasms 1.2.1Oligodendroglioma and anaplastic oligodendroglioma 1.3 Ependymal neoplasms 1.3.1 Ependymoma and anaplastic ependymoma 1.3.2Subependymoma 1.4 Choroid plexus neoplasms 1.4.1 Choroid plexus papilloma 1.4.2 Choroid plexus carcinoma 1.5 Gliomas of mixed composition 1.5.1 Mixed gliomas 1.6 Other gliomas 1.6.1 ktroblastoma 1.6.2 Granular cell tumor of the infundibulum 2. Neuronal and glioneuronal tumors 2.1 Gangliocytoma and ganglioglioma 2.2 Desmoplastic infantile ganglioglioma 2.3 Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) 2.4 Central neurocytoma 2.5 Dysembryoplastic neuroepithelialtumor 2.6 Other glioneuronal lesions 3. Embryonal tumors 3.1 Primitive neuroectodermal tumor 3.2 Medulloepithelioma 3.3 Neuroblastoma and ganglioneuroblastoma 3.4 Olfactory neuroblastoma (esthesioneuroblastoma) 3.5 Retinoblastoma 3.6 Melanotic neuroectodermal tumor of infancy 3.7 Ependymoblastoma 3.8 Medulloblastoma 3.9 Medullomyoblastorna and melanotic medulloblastoma 3.10 Other embryonal tumors 4. Tumors of the pineal gland 4.1 Pineocytoma 4.2 Pineoblastoma 4.3 Mixed pineocytoma: pineoblastoma and pineal parenchymal neoplasms of intermediate differentiation 4.4 Pineal cyst 4.5 Gliomas 5. Tumors of uncertain origin 5.1 Hemangioblastoma 5.2 Primitive polar spongioblastoma 5.3 Atypical teratoid/rhabdoid tumor 6. Germ cell tumors 7. Tumors of meningothelial cells 7.1 Meningioma 7.2 Atypical meningioma 7.3 Malignant meningioma 8. Tumors of mesenchymal tissue 8.1 Vascular tumors and tumorlike lesions 8.1.1 Vascular malformations 8.1.1.1 Arteriovenous malformation 8.1.1.2 Cavernous angioma 8.1.1.3 Venous malformation 8.1.1.4 Capillary telangiectasis 8.1.1.5 Other vascular lesions 8.1.2Vascular neoplasms 8.1.2.1 Hemangiopericytoma 8.12.2 Hemangioendothelioma 8.1.2.3 Angiosarcoma

*

I

From Atlas of Tumor Pathology, Third Series, Fascicle 10. Burger PC, Scheithauer BW: Tumors of the Central Nervous System. Armed Forces Institute of Pathology, Washington. DC, 1994; with permission.

Chapter 154

people will die from primary brain tumors this year, accounting for 1.8% of all cancer deaths. These figures exclude patients with brain metastases from systemic primary tumors and thus understate the medical impact of brain tumors. Several factors make it difficult to measure the incidence of brain tumors precisely and to compare the findings of different series. These include access to health care, variable access to sophisticated neuroimaging diagnostic techniques including computed tomography and magnetic resonance scans, the optimal dependence of the diagnosis on histologic confirmation, the difficulty of classifjmg certain neoplasms (necessitating availability of expert neuropathologists and standardization of grading among neuropathologists), and the declining autopsy rate (incidentally discovered brain tumors at the time of autopsy are by no means rare). Overall incidence of primary brain tumors ranges from 7.9 to 19.1 cases per 100,000 people per year. The higher figure comes from population-based studies in Rochester, Minnesota; the high autopsy rate and easy access to medical care in this community explain the fact that more than one third of these tumors were asymptomatic. Unsurprisingly, socioeconomically advanced nations report higher incidences than developing countries. For example, in contrast to the high rate of case ascertainment in the United States (63% to 99%), microscopic confirmation is exceedingly exceptional in Algeria. Nonetheless, it is possible that racial variability contributes to differences in incidence rates across populations: Japan, with comparable technological development to Western industrialized countries, has rates of central nervous system cancer that are a third or less of those observed in the United States. The variability in frequency of different primary tumors in different cancer registries underscores differences in case ascertainment in different regions. Across many cancer registries, gliomas account for approximately 50% and meningiomas 28% of primary brain tumors (Table 154-3). In contrast, a study from Rochester over an era beginning before modern neuroimaging but with a 60% autopsy rate found that only 35% of tumors were gliomas and 40% meningiomas. However, two thirds of these meningiomas were diagnosed only at autopsy; thus, gliomas were the most common symptomatic tumor in that series as well. Meningiomas and pituitary adenomas are not uncommonly asymptomatic and detected incidentally, whereas this situation pertains much less often with gliomas and other malignant tumors. Although each biologic type of primary brain tumors has a distinctive descriptive epidemiology, some overall observations may be useful. Data compiled from several tumor registries suggest that peak incidence of primary brain tumors occurs around age 50, although autopsy data from Rochester, Minnesota, suggest that incidence rises continuously with increasing age. The median age of patients with primary brain tumor is about 50 as well. Most studies suggest a small excess of tumors in men (male:female ratio 1.2 to 1.41). Racial variation among brain tumors generally is minor, although some studies have found that blacks have a lower incidence of primary brain tumors than whites, and Japanese have a higher incidence of germ cell neoplasms and craniopharyngiomas. Brain tumors assume particular importance in children because they are the most common solid malignancy and the second leading cause of cancer death (after leukemia). Approximately 1500 cases occur yearly in the United States. Brain cancer rates in children are 2 to 2.5 per 100,000 per year. Some studies suggest these are slightly more common in boys (male:female 1.2:1), and medulloblastomas are twice as common in boys as in girls. In

Classification, Epidemiology, and Etiology of Brain Tumors

1009

contrast to adults, in whom most tumors are supratentorial, most pediatric brain tumors are infratentorial. Moreover, meningiomas are rare in children; when found, they are more likely to be intraventricular, associated with neurofibromatosis, or of the biologically aggressive papillary histology than in adults. Lowgrade supratentorial astrocytomas and medulloblastomas each make up about 20% to 25% of childhood tumors, with cerebellar astrocytomas, high-grade supratentorial astrocytomas, brainstem gliomas, and ependymomas each accounting for about 10%. The incidence of different types of tumors is strongly agedependent. In children under 2, medulloblastomas, ependymomas, and low-grade supratentorial astrocytomas of the visual pathways make up a large fraction of the tumors that are seen, whereas brainstem gliomas and cerebellar astrocytomas are rare (Table 154-4). Some data suggest that the incidence of primary brain tumors is increasing in the United States. For example, using the surveillance, epidemiology, and end results program (SEER) cancer registry, a national cancer database covering approximately one tenth of the country, Greig found that malignant primary brain tumor incidence rates increased between 1973-74 and 1985 187% in patients ages 75 to 79, 394% in patients 80 to 84, and 501% in patients 85 to 89. In the same period, rates varied little in younger patients. Numerous reports have argued that the increase in brain tumors is largely artifactual. The extent of increase caused by changing diagnostic and recording practices is unclear. At this point it appears that much of the increase observed in the 1980s resulted from diagnostic and underreporting bias, but these data and the fact that the increase began before 1970 and continues today suggest that some portion of the increase may be real. This pattern is consistent with the general increase in cancer rates in this century and does not point to an emerging epidemic of brain cancer. Similar trends have been noted in other industrialized countries. The one secular trend clearly established for brain tumors is an increase in primary central nervous system lymphoma (PCNSL) in all age groups and both sexes.

Cllomas High-grade gliomas (glioblastomas and anaplastic astrocytomas) account for approximately two thirds of all gliomas. There are about three or four age-adjusted cases per 100,000 people per year. These tumors show a modest male predominance (M:F ratio approximately 1.2 to 1.6. The median age of patients with high-grade gliomas is 50. In general, lower-grade gliomas strike younger patients; the median age of patients with astrocytomas is 38, ependymoma mid-zos, and oligodendrogliomas the mid-40s. There are several well-defined risk factors for gliomas; however, they account for only a minute fraction of all gliomas: Ionizing radiation: Radiation has been clearly implicated in glioma pathogenesis. Experimentally, radiation has been demonstrated to induce gliomas in primates. Low dosages of scalp radiation in Israeli children produced a 2.6 times higher incidence of gliomas. Additionally, children undergoing whole-brain radiotherapy for acute lymphocytic leukemia, who typically receive about 2000 cGy, have a 22 times higher risk of primary brain tumors, particularly astrocytomas. Ionizing radiation is also a risk factor for intracranial sarcomas. Genetic factors: Several clearly defined genetic syndromes predispose to gliomas.

1010

Neuro-Oncology

Brain Tumors: General Aspects

TABU 154-3. Distribution and Incidence Rates of Primary Brain and CNS Tumors by Histology, CBTRUS 1990-1994 Histology

Total n

Reported Brain Tumors (%)

Mean Age at Diagnosis (years)

Rate (& Sr)

Tumors of Neuroepithelial Tissue

Diffuse astrocytoma (protoplasmic, fibrillaty) haplastic astrocytoma Clioblastoma Pilocytic astrocytoma Unique astrocytoma variants Oligodendroglioma Anaplastic oligodendroglioma Ependyrnoma or anaplastic ependymoma Ependymoma variants Mixed glioma Astrocytoma, NOS Glioma malignant, NOS Choroid plexus Neuroepithelial Benign and malignant neuronal/glial, neuronal, and mixed Pineal parenchymal EmbryonaI/primitive/medulloblastoma

273 885 4695 37 1 94 540 117 420 72 212 1682 546 65 34 216 37 376

1.3 4.3 22.6 1.8 0.5 2.6 0.6 2.0 0.3 1.o 8.1 2.6 0.3 0.2 1 .o 0.2 1.8

47 50 62 17 35 41 46 36 37 40 47 46 22 42 24 28 14

0.15 (0.01) 0.48 (0.02) 2.60 (0.04) 0.27 (0.01) 0.06 (0.01) 0.29 (0.01) 0.07 (0.01) 0.24 (0.01) 0.04 (0.01) 0.12 (0.01) 0.94 (0.02) 0.31 (0.01) 0.04 (0.01) 0.02 (0.00) 0.13 (0.01) 0.02 (0.00) 0.26 (0.01)

1356 1

6.5 0.0

51 36

0.75 (0.02)

4989 73 195

24.0 0.4 0.9

62 39 46

2.63 (0.04) 0.04 (0.01) 0.11 (0.01)

846

4.1

54

0.43 (0.02)

127

0.6

22

0.09 (0.01)

1670 183

8.0 0.9

50 36

0.90 (0.02) 0.11 (0.01)

45

0.2

60

0.02 (0.00)

58 579 8 20,765

0.3 2.8 0.0 100.0

41 63 49 53

0.03 (0.00) 0.29 (0.01) 0.00 (0.ooj 11.47 (0.08)

Tumors of Cranial and Spinal Nerves

Nerve sheath, benign and malignant Other tumors of cranial and spinal nerves

0.00 (0.00)

Tumors of the Meninges

Meningioma Other mesenchymal, benign and malignant Hemangioblastoma Lymphomas and Hemopoietic Neoplasms

Lymphoma Gem Cell Tumors and Cysts

Germ cell tumors, cysts, and heterotopias Tumors of the Sellar Region

Pituitary Craniopharyngioma Local Extensions from Regional Tumors

Chordoma or chondrosarcoma Unclassified Tumors

Hemangioma Neoplasm, unspecified Other Total

Rates are per 100,000 person-years and age-adjusted using the 1970 US. standard population. Abbreviations: CETRUS, Central Brain Tumor Registry of the United States; NOS, not otherwise specified. From Surawia TS, McCarthy BJ, Kupelian V et al: Descriptiveepidemiologyof primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990-1994. Neuro-Oncology 1(1):14-25,1999.

Neurofibromatosis 1 is inherited in an autosomal dominant fashion and is associated with mutation to a locus on chromosome 17 coding for a protein called neurofibromin. Neurofibromin, a putative tumor suppressor protein, has a domain homologous to the GTPase-activating protein family and downregulates rus activity. Fifteen percent of patients with neurofibromatosis 1 develop intracranial gliomas. Most commonly these lesions are low-grade and often have a distinct pilocytic histology. These lesions have a geographic predilection for the optic pathways, hypothalamus, and cerebellum. Tumors of the peripheral nervous system are more common. Neurofibromatosis 2, another autosomal dominant condition, is associated with mutation to a tumor suppressor gene on chromosome 22 whose protein product is called merlin. Neurofibromatosis 2 typically manifests as bilateral acoustic nerve schwannomas and also is associated with schwannomas of other

nerve roots and multiple meningiomas. However, ependymomas and meningiomas are occasionally seen in this condition. The Li-Fraumeni syndrome afflicts families with an autosomal dominant aggregation of osteosarcoma and soft tissue sarcomas, breast cancer, and occasionally gliomas. This syndrome is associated with a germ line mutation within the p53 tumor suppressor gene on chromosome 17, an important tumor suppressor gene often mutated in sporadic human cancers. Turcot’s syndrome is an association between brain tumors (primarily medulloblastomas and gliomas) and colonic polyposis. Turcot’s syndrome consists of at least two distinct inherited conditions. Familial adenomatous polyposis is an autosomal dominant condition caused by a mutation to the adenomatous polyposis coli gene on chromosome 5. The majority of familial adenomatous polyposis-associated brain tumors are medulloblastomas, but gliomas are also reported. The second autosomal

Chapter 154

dominant syndrome linking brain tumors and colonic disease is hereditary nonpolyposis colorectal cancer (HNPCC). Patients with HNPCC have germ line mutations in one of several enzymes involved in DNA nucleotide mismatch repair. Such patients are prone to high-grade gliomas. Tuberous sclerosis is an autosomal dominant condition arising from mutations to chromosome 9 or 16. Although its most common neurologic manifestations, epilepsy and developmental delay, relate to dysplastic lesions, occasional patients develop a unique low-grade tumor adjacent to the foramen of Monro called subependymal giant cell astrocytoma. Von Hippel-Lindau disease is another example of germ line mutation to a tumor suppressor gene, in this case on chromosome 3p. Central nervous system manifestations of this autosomal dominant condition include development of hemangioblastomas (primarily in the cerebellum but also in the spinal cord and rarely elsewhere) and retinal angiomatosis. Basal cell nevus (Gorlin) syndrome is an autosomal dominant condition producing enormous numbers of basal cell nevi and predisposing to development of medulloblastoma. Retinoblastoma is an ocular tumor that occurs in both a sporadic and a familial form. In the familial form, which predisposes patients to bilateral disease, there is germ line loss of R B I , a tumor suppressor gene. Occasional patients with the familial form develop pineoblastoma as well, the so-called trilateral retinoblastoma. Finally, rare pedigrees have been reported in which several members have had gliomas without any of these clearly recognized conditions. The significance of such reports is uncertain. Environmental risk factors for glioma development have been extensively sought. One limitation of most of these studies is that they looked for risk factors for primary brain tumors in general, not for specific histologic types that might have different inciting factors. Additionally, these studies have generally tested multiple hypotheses (i.e., they were “fishing expeditions.”) Given the number of studies and the multiple comparisons, most reported findings are likely to be spurious. Exposure to electromagnetic fields has been proposed as a potential risk factor, and workers in

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the electric utility industry have had a higher incidence of primary brain tumors in some studies. However, these findings have been inconsistent, and there are difficulties in measuring exposure and demonstrating a relationship between increasing exposure and incidence. Diet has also been proposed as a factor; N-nitroso compounds, found in nitrite-preserved meats and fish and in beer, are neurocarcinogens in laboratory animals, especially with prenatal exposure. However, the data in humans are conflicting, and the lack of a good measure to assess total exposure makes such links difficult to prove. Workers exposed to vinyl chloride may have a higher risk of developinggliomas. Despite anecdotal reports of an association between cellular telephone use and brain tumor development, several large controlled studies have failed to demonstrate any greater frequency of brain tumors.

The incidence of meningiomas is difficult to pin down. As noted earlier, the majority of meningiomas are asymptomatic. In fact, 1% to 2% of autopsies reveal a meningioma. The median age of symptomatic meningiomas is 52, and there is a female to male predominance of 2 to 1. The female predominance may be related to the fact that many of these tumors have steroid sex hormone receptors: 70% of meningiomas have progesterone receptors and 30% estrogen receptors. Meningiomas are very rare in children and may be associated with neurofibromatosis I1 or prior cranial irradiation. Some evidence suggests they may be more common among blacks than whites. Environmental exposures have been studied as possible risk factors for meningioma development. The most convincing factor is remote exposure to ionizing radiation. Low dosages of radiation to treat tinea capitis (on the order of 75 to 175 cGy) resulted in a 9.5 times greater incidence of meningiomas in Israeli children. These tumors are always within the prior radiation ports, often are multiple, and are much more likely to be atypical or malignant than usual meningiomas. The latency after radiation may be as short as 5 years or as long as 3 decades. Full mouth dental radiographs give radiation dosages on the order of 100 to 200 cGy

rn TABU151-4. Childhood Primary Brain and CNS Tumor Incidence Rates by Age at Diagnosis (Ages 0-1 9 Years), CBTRUS 1990-1 994 AGE AT

DUGNOSIS (YEARS)

Histology

0-4

5-9

10-14

15-19

Tumors of NeuroepithelialTissue Anaplastic astrocytoma Glioblastoma Pilocytic astrocytoma Ependymoma or anaplastic ependymoma Astrocytoma, NOS Glioma malignant, NOS Benign and malignant neuronal or glial, neuronal, and mixed Embryonal, primitive, or medulloblastoma

0.06 0.10 0.52 0.5 1 0.58 0.43 0.29 0.85

0.1 0 0.08 0.68 0.19 0.50 0.40 0.15 0.78

0.15 0.21 0.57 0.15 0.64 0.2 1 0.23 0.32

0.13 0.19 0.45 0.08 0.32 0.10 0.1 1 0.25

Gem Cell Tumors Germ cell

0.09

0.10

0.23

0.2 1

0.1 1 4.40

0.19 3.80

0.16 3.70

0.07 3.21

Tumors of the Sellar Region Craniopharyngioma

Total’

’Refers to all childhood brain tumors, including histologiesnot listed in this table. AbbreviOtiOns: CBTRUS, Central Brain Tumor Registry of the United States; NOS, not otherwise specified. From Surawia TS, McCarthy 81, Kupelian V et al: Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registty of the United States, 1990-1994. Neuro-Oncology 1(1):14-25, 1999.

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to parts of the brain, and some studies suggest a higher incidence of meningiomas in patients previously undergoing such diagnostic studies. Higher dosages of radiation also predispose to meningioma formation and frankly sarcomatous tumors of bone, dura, or brain parenchyma. Some studies suggest head trauma or a history of boxing as a risk factor for later development of meningioma. Other studies have not supported such an association, and the female predominance of the tumor suggests that this may not be a likely risk factor. An association between meningiomas and breast cancer has also been suggested, although whether these two conditions, both common in middle-aged women, co-exist more often than chance would dictate is uncertain.

Primary Central Nervous System lymphoma PCNSL is the one brain tumor in which an increased incidence over the last few decades is incontrovertible. This neoplasm formerly accounted for 1% or less of all primary brain tumors. For many years it has been recognized that PCNSL, though sporadically striking immunocompetent patients, has a particular predilection for immunocompromised patients. This was initially recognized in congenitally immunocompromised children. With the advent of organ transplantation, the impact on PCNSL was powerful: For example, renal transplant recipients have a 300 times higher incidence of PCNSL than the general population. More recently, the epidemic of human immunodeficiency virus has further contributed, as 5% to 10% of patients dying of acquired immunodeficiency syndrome have PCNSL found at autopsy. Overall, the incidence of PCNSL has increased approximately 12 times over the last two decades. Although increases in human immunodeficiency virus-associated cases undoubtedly contribute, an increase in sporadic, nonviral or transplant-related cases cannot be excluded. PCNSL seems to be made up of at least two separate pathogeneses. In the immunocompromised population, the disease is almost invariably associated with Epstein-Barr virus (EBV) infection. Not only are patients inevitably seropositive for EBV, but EBV generally can be detected in the tumor by immunohistochemistry or polymerase chain reaction (PCR). Similarly, EBV usually can be detected by PCR in the cerebrospinal fluid of affected patients. Presumably the immortalization of B lymphocytes by the virus, in conjunction with the loss of cell-mediated immunity from the underlying immunosuppression, combines with unidentified other factors to contribute to lymphomagenesis. EBV is rarely detected by these techniques in immunocompetent patients with PCNSL; the pathogenesis in these cases remains uncertain. A possible role of human herpesvirus type 8 in some cases has recently been suggested but has not been replicated by others. The median age of immunocompetent patients with PCNSL is 60.

brain metastases were approximately as common as primary brain tumors. However, autopsy studies have shown that these early studies, generally based on hospital records and death certificates, significantly underestimated the frequency of intracranial metastases. Several autopsy surveys of patients dying with systemic cancer have shown that 20% to 25% of such patients harbor intracranial metastases. Applying these estimates to the 563,100 Americans expected to die of cancer this year, there are approximately 110,000 to 140,000 new cases of intracranial metastasis yearly in this country (greatly outnumbering symptomatic primary brain tumors). Intracranial metastases include parenchymal, leptomeningeal, and dural-based metastases, with some patients having a combination of these. Fifteen percent of autopsied patients with cancer have parenchymal metastases, 8% have leptomeningeal metastases, and 9% have dural-based metastases. Lung cancer is by far the most common cause of parenchymal metastases, accounting for almost half of all cases. Breast cancer is the second leading cause, and melanoma, colon, and renal cell carcinoma are also numerically significant contributors. The acute leukemias and non-Hodgkin’s lymphoma are the most common causes of leptomeningeal metastases; breast cancer, melanoma, and lung cancer are the most common offenders among solid tumors. With dural-based metastases, breast cancer, lymphoma, prostate cancer, and neuroblastoma are the most common causes. Viewed differently, the autopsy series suggest that 34% of patients dying with lung cancer will develop intracranial metastases, as will 31% of patients with breast cancer and 73% of those with melanoma. Two thirds of brain metastases of unknown origin arise from primary lung tumors.

SUGGESTED READINGS Bigner DD, McLendon RE, Bruner JM: Russell & Rubinstein’s Pathology of Tumors of the Nervous System. 6th Ed. Oxford University Press, New York, 1998 GreenLee RT, Hill-Harmon MB, Murray T, Thun M: Cancer Statistics 2001. CA Cancer J Clin 51:15-36, 2001 Greig NH, Ries LG, Yancik R, Rapoport SI: Increasing annual incidence of primary malignant brain tumors in the elderly. J Natl Cancer Inst 82:162 1-1624, 1990

Gurney JG, van Wijngaarden E Extremely low frequency electromagnetic fields (EMF) and brain cancer in adults and children: review and comment. Neuro-Oncology 1:212-220, 1999 Posner JB: Neurologic Complications of Cancer. F.A. Davis, Philadelphia, 1995

Radhakrishnan K, Mokri B, Parisi JE et al: The trends in incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurol 37:67-73, 1995 Ries LA, Kosary CL, Hankey BF (eds): Seer Cancer Statistics Review, 1973-1993, National Cancer Institute, Bethesda, MD, 1998 Surawicz TS, McCarthy BJ, Kupelian V et al: Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990-1994. Neuro-Oncology 1:14-25, 1999

BRAIN METASTASES Early studies of the incidence of intracranial metastases (often lumped together under the term bruin metastases) suggested that

Wrensch M, Bondy ML, Wiencke J, Yost M: Environmental risk factors for primary malignant brain tumors: a review. J Neurooncol 17:4744, 1993

Chapter I55

Clinical Presentation and Diagnosis of Brain Tumors

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155 Clinical Presentation and Diagnosis

of Brain Tumors Patrick Y. Wen and Siew Koon Teoh

The presentation and diagnosis of brain tumors is changing with the increasing sophistication of diagnostic tests. As a result of the widespread availability of sensitive imaging techniques such as magnetic resonance imaging (MRI), tumors are being detected at an earlier stage, and patients have increasingly subtle clinical symptoms and signs at diagnosis. This chapter discusses the clinical presentation and diagnosis of brain tumors in general. Chapter 156 discusses the general principles of management of brain tumors, and subsequent chapters will discuss specific tumors in detail.

CLINICAL PRESENTATION Patients with brain tumors typically present with headaches, seizures, nonspecific cognitive or personality changes, and focal neurologic signs. The precise combination of clinical features varies depending on the location, histology, and rate of growth of the tumor. As a result of the widespread availability of sensitive imaging techniques such as MRI, tumors are being detected at an earlier stage, and patients have increasingly subtle clinical symptoms and signs at diagnosis.

Headaches Headaches are the presenting symptom in approximately 35% of patients with brain tumors and develop during the course of the disease in 40% to 70%. The majority of these headaches are intermittent and nonspecific. They are usually dull, nonthrobbing, and often indistinguishable from tension headaches. The headaches often are on the same side as the tumor, although they can also be generalized. Supratentorial tumors usually produce headaches with a frontal location because the majority of supratentorial pain sensitive structures are supplied by the trigeminal nerve. The posterior fossa is innervated by cranial nerves IX and X and upper cervical nerves, and tumors in this area usually result in pain in the occipital region and neck. Occasionally posterior fossa tumors can produce headaches located at the vertex or in the retroorbital region. Certain features of the headache increase the possibility of an underlying tumor (Table 155-1). These include headaches that wake the patient at night or are worse on waking and improve over the course of the day, headaches exacerbated by postural change, coughing, or exercise, headaches of recent onset that are different from the patient’s usual headaches or are greater in severity, the presence of nausea or vomiting, papilledema, or focal neurologic signs. Patients with these features need further evaluation with computed tomography (CT) or MRI. However, in this era of cost containment, it is important to be selective in obtaining cerebral imaging studies for patients presenting with headaches. Most patients with chronic headaches and a normal neurologic examination do not need neuroimaging.

Papilledema Papilledema is important evidence of increased intracranial pressure transmitted through the optical nerve sheath. The incidence of papilledema in older series of patients with brain tumors has been reported to be 50% to 70%. Advances in neuroimaging have resulted in many patients being diagnosed at an earlier stage, and the incidence of papilledema in patients with brain tumor today is probably much lower. In a review of 100 consecutive patients with malignant gliomas who underwent surgery at Brigham and Women’s Hospital in Boston, only 8% had papilledema at the time of diagnosis. Papilledema tends to be more common in children and in tumors that are slowly growing or located in the posterior fossa. It is usually not a useful indicator of increased intracranial pressure in older adults. Papilledema may interfere with optic nerve function and result in transient visual obscurations, especially with maneuvers that briefly increase intracranial pressure such as coughing and sudden postural change. Meningiomas involving the optic nerve may produce optic atrophy in the ipsilateral eye and, by increasing intracranial pressure, result in papilledema in the contralateral eye, giving rise to the Foster Kennedy syndrome.

Seizures Seizures are the presenting symptom in approximately one third of patients with brain tumors and are present at some stage of the illness in 40% to 60% of patients. Approximately half the patients have focal seizures, and the other half have secondarily generalized seizures. Patients with gliomas tend to have a higher incidence of seizures than patients with metastatic brain tumors. In patients with gliomas, seizures occur in 59% of frontal tumors, 42% of parietal tumors, 35% of temporal tumors, and 33% of occipital tumors. Tumors in subcortical areas, such as thalamus and the posterior fossa, are much less epileptogenic. Slowly growing tumors and tumors located near the Rolandic fissure are particularly likely to cause seizures. Approximately 10% to 20% of adult patients with new-onset seizures have brain tumors, and these

TABLE 155-1. Features of a Headache Indicating Possible Need for Cerebral Imaging

Most useful Wakes patient up at night Worse on waking and improves over the course of the day Worse with postural change, coughing, or exercise Less useful features of headache Recent onset Different from the patienrs usual headaches Increased severity Nausea or vomiting Patients with headaches associated with papilledema or focal neurologic signs should always be imaged

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patients should always have CT or MR imaging as part of their evaluation, especially if they also have focal findings on examination or on electroencephalography. Patients with malignant gliomas who present with seizure tend to have a better prognosis, probably because their tumors are diagnosed at an earlier stage. Altered Mental Status Mental status changes are the initial symptom in 15% to 20% of patients with gliomas and are often present in patients by the time of diagnosis. These changes may range from subtle problems with concentration, memory, affect, personality, initiative, and abstract reasoning to severe cognitive problems and confusion. Changes in mentation are especially common in frontal lobe tumors but also occur in patients with increased intracranial pressure from the mass effect of the tumor or hydrocephalus or as a result of gliomatosis cerebri. With increasing intracranial pressure there is also depression of the level of consciousness, resulting in drowsiness and eventually leading to stupor and coma if treatment is not administered. Focal Neurologic Symptoms and Signs

Whereas headaches, seizures, and altered mental status may be seen with tumors in many locations, certain clinical features have specific localizing value. Cortical Tumors. Frontal lobe tumors often are clinically silent initially. As the tumor enlarges there may be personality changes such as disinhibition, irritability, impaired judgment, and lack of initiative (abulia). In addition, there may be hemiparesis, seizures, aphasia, urinary frequency and urgency, and gait difficulties. Gaze preference and primitive reflexes, such as forced grasping and snout, may be present. Meningiomas of the olfactory groove may produce anosmia. Temporal lobe tumors often cause seizures. These include simple partial seizures characterized by olfactory and gustatory hallucinations, dkjja vu, and feelings of fear and pleasure, and complex partial seizures characterized by impairment of consciousness, repetitive psychomotor movements, and automatic behavior. Temporal lobe tumors may also cause memory disturbances, visual field defects (superior quadrantinopsia), and, when the dominant temporal lobe is involved, aphasia. Tumors of the parietal lobe can produce contralateral sensory loss, involving particularly joint position sense, two-point discrimination, stereognosis, and graphesthesia, although other modalities may also be involved. Lesions in the dominant parietal lobe are associated with aphasia, whereas lesions in the nondominant parietal lobe may result in neglect of the contralateral side and the loss of ability to acknowledge deficits (anosognosia). There may also be hemiparesis, homonymous visual defects (or neglect), agnosias, apraxias, sensory seizures, and disturbance of visual spatial ability. Occipital lobe astrocytomas may cause homonymous hemianopsia and, less commonly, visual seizures characterized by lights, colors, and formed geometric patterns. Tumors at the parietooccipital junction may produce visual agnosias such as aprosopagnosia (inability to recognize faces) or Balint’s syndrome. Diencephalic and Brainstem Tumors. Thalamic tumors may produce contralateral sensory loss, hemiparesis, cognitive impairment, and occasionally visual defects and aphasia. Obstructive hydrocephalus occurs commonly and is associated with headache, nausea, vomiting, gait unsteadiness, and urinary incontinence.

Brainstem tumors produce cranial neuropathies, weakness, numbness, ataxia, and occasionally vertigo, nausea, vomiting, and hiccups. As the tumor increases in size there may be compression of the aqueduct or the fourth ventricle, producing hydrocephalus. Pineal Region and Third Ventricular Tumors. Pineal tumors present either with symptoms of hydrocephalus resulting from compression of the third ventricle and aqueduct or with symptoms produced by compression of the tectum of the midbrain. Midbrain compression may result in disturbance of extraocular function including Parinaud’s syndrome, characterized by impairment of upgaze and pupillary light reflex and convergence retraction nystagmus. Occasionally children may present with precocious puberty. Tumors around the third ventricle may produce hydrocephalus. Valsalva maneuvers and positional changes may increase cerebrospinal fluid (CSF) obstruction and lead to severe headaches and occasionally leg weakness and syncope. Tumors in this region may also produce symptoms resulting from hypothalamic dysfunction, autonomic dysfunction, and impaired memory. Cerebellar Tumors. Headaches and ataxia are the two most common symptoms in patients with cerebellar tumors. The headaches may be caused by pressure from the tumor or from hydrocephalus. They are often occipital and associated with nausea, vomiting, and occasionally neck stiffness. Some patients may experience vertigo. Midline cerebellar lesions may produce truncal ataxia, and lesions in the cerebellar hemispheres may cause appendicular ataxia, although the findings often are subtle. Examination may also show nystagmus, hypotonia, and often cranial nerve and corticospinal tract signs from brainstem compression. Head tilt away from the lesion may occur with incipient tonsillar herniation. False Localizing Signs

When tumors produce increase intracranial pressure, shifting of intracranial structures may occur and result in clinical features suggesting involvement of sites distant from the tumor (false localizing signs). Examples include abducens (VIth) nerve palsy resulting from compression of the nerve as it passes forward over the petrous ligament, and compression of the cerebral peduncle by the free edge of the tentorium cerebelli contralateral to a herniating uncus, producing hemiparesis on the same side as the lesion.

DIFFERENTIAL DIAGNOSIS Many conditions producing increased intracranial pressure or progressive neurologic deficits may mimic brain tumors clinically (Table 155-2). These include subdural hematomas, brain abscesses, hydrocephalus, benign intracranial hypertension, progressive multifocal leukoencephalopathy, multiple sclerosis, vascular malformations, cerebral infarctions, and neurodegenerative disorders such as Alzheimer’s disease. Many of these conditions have characteristic radiologic appearances that enable them to be differentiated from brain tumors. However, some of these conditions cannot be distinguished from brain tumors on the basis of their radiologic appearances alone, and a definite diagnosis may require a biopsy. These include some brain abscesses, inflammatory lesions, demyelinating lesions, hamartomas, and congenital anomalies. Even when the imaging characteristics of a lesion are very suggestive of a tumor, a biopsy usually is indicated to obtain

Chapter 155

TABLE155-2. Differential Diagnosis of Brain Tumors Conditions producing increased intracranial pressure or progressive neuro-

logic deficits: Subdural hematomas Hydrocephalus

cvsts

Benign intracranial hypertension Brain abscesses Progressive multifocal leukoencephalopathy Multiple sclerosis CNS vasculitis Vascular malformations Cerebral infarctions Degenerative diseases (e.g., Alzheimer‘s disease) Hamartomas Connenital anomalies (e.n., Chiari malformation)

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often can be differentiated from cerebellar astrocytomas by CT. MRI appearances of tumors tend to be less specific, making similar differentiation with MRI more difficult. The use of contrast enhancement is indispensable in evaluating brain tumors and may help disclose an isodense lesion from the surrounding parenchyma or a hypodense lesion hidden within an area of edema. The introduction of nonionic contrast media has resulted in a significant reduction in serious contrast reactions. Other recent advances in CT scanning include shorter scan times and increased sensitivity of detectors, resulting in decreased radiation dosage. Despite these advances, MRI is being used with increasing frequency because of its greater resolution and sensitivity.

Magnetk Resonance Imaging tissue for precise histologic diagnosis and grading of the tumor because these factors have a significant influence on treatment.

RADIOLOGIC DIAGNOSIS The introduction of CT scanning and more recently MRI have revolutionized the diagnosis and management of brain tumors.

Skull Radiographs Plain skull radiographs are rarely necessary today with the widespread availability of CT and MRI. Occasionally they may be useful in demonstrating calcification, bony erosion, or hyperostosis. Plain films may demonstrate calcifications related to tumors. The presence of calcifications usually indicates a slow-growing tumor. Astrocytomas are the most common calcifying tumors. Although calcifications occur only in approximately 20% of astrocytomas, their overall frequency more than compensates. Other tumors that often calcify are craniopharyngiomas (70% to 80%), oligodendrogliomas (50% to 6O%), ependymomas (50%), ganghogliomas (35%), and meningiomas (10%). Persistent elevation of intracranial pressure can cause erosion of normally calcified structures. In children erosion of the inner table of the skull may lead to a “hammered metal” appearance. Pituitary tumors may produce erosion of the clinoid processes and sellar turcica. Slow-growing tumors, such as meningiomas, may produce hyperostosis of the adjacent skull.

Computed Tomography CT remains a widely used form of neuroimaging for the diagnosis of brain tumors because of its wider availability and lower cost, although MRI is used with increasing frequency. CT scans detect more than 90% of brain tumors. Small tumors (less than 0.5 cm), tumors adjacent to bone (such as pituitary adenomas, clival tumors, and vestibular schwannomas), brainstem tumors, and low-grade astrocytomas may be missed and are better detected by the more sensitive MRI. CT tends to be better tolerated than MRI because of its shorter scanning time and is more sensitive for detecting calcification and bony involvement. Although CT is less sensitive than MRI, the CT appearance of certain tumors may be more specific. For example, small round cell tumors such as medulloblastomas are isodense or hyperdense compared with brain parenchyma before contrast administration, whereas astrocytomas are almost always hypodense. Thus medulloblastomas

MRI is a complex, rapidly evolving modality that has assumed an increasingly important role in diagnosing brain tumors. It is now the preferred modality for the definitive evaluation and follow-up of most brain tumors. MRI has the advantage of being more sensitive than CT, allowing the detection of small tumors that may be missed by CT. It provides much greater anatomic detail in multiple planes and is especially useful for visualizing skull base, brainstem, and posterior fossa tumors. MRI is also superior to CT in detecting hemorrhage and solid and cystic components within tumors and in demonstrating the relationship of the tumors to intracranial vessels. As with CT scans, the addition of contrast agents, such as gadolinium diethylenetriaminepentaacetic acid, to T1-weighted MRI scans greatly increases the sensitivity of the test. MRI is evolving rapidly. Newer imaging sequences are continually being developed, reducing scan times and improving the information obtained from the images. Newer techniques such as magnetic resonance spectroscopy (MRS) and echo planar MRI are now routinely used to image brain tumors. MRS is a noninvasive method that allows direct investigation of tumor metabolism and provides information on the composition and spatial distribution of cellular metabolites. Most MRS studies are done with proton (l-H) or phosphorus-31. With proton MRS, tumors tend to have loss of N-acetyl aspartate (reflecting loss of neurons in the tumor area) and increased choline levels (reflecting active membrane biosynthesis). There is currently great interest in evaluating the usefulness of MRS in noninvasively diagnosing tumors, determining tumor grade, and differentiating tumor from radiation effects (Fig. 155-1). Echoplanar MRI can scan images in less than 100 msec and provide information on tumor perfusion and diffusion and is currently being evaluated for possible use in grading tumors and separating recurrent tumors from radiation change. Echoplanar MRI may also help to differentiate tumor from edema. MR angiography provides a means of displaying blood vessels in the brain in a noninvasive manner. It is increasingly replacing conventional angiography, although angiography has better resolution and is still necessary in certain situations. MRI is also being integrated with advanced image-processing techniques to produce three-dimensional images of brain tumors to aid in surgical planning.

Andography The importance of angiography has diminished significantlywith the availability of CT and MRI. It is no longer used for the routine

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taken up by the brain and tumor cells. These radiopharmaceuticals emit photons that are detected by a rotating gamma camera. Standard tomography reconstruction algorithms are then used to generate cross-sectional images of the brain. Although SPECT is not used in the initial diagnosis of brain tumors, it is increasingly being used to complement information obtained by CT or MRI scanning. Thallium-201 chloride, a potassium analogue that is taken up by viable tumor cells, has been used to differentiate low-grade from high-grade gliomas and to identify residual astrocytoma after radiation therapy. More recently it has been used in combination with technetium-99m hexamethylpropylene amine oxime (''TC HMPAO), a blood flow tracer that crosses the normal blood-brain barrier, to differentiate radiation necrosis from recurrent gliomas.

LABORATORY DIAGNOSIS A number of laboratory tests may contribute to the diagnosis and management of patients with brain tumors. Perimetry FIG. 155-1. Magnetic resonance spectroscopy using proton (1-H) in a patient with a glioblastoma showing the different spectra in areas of normal brain, tumor, and radiation necrosis. The area of tumor shows a high choline and a low N-acetyl aspartate (NAA) peak. (Courtesy of Dr. Lani Lee, Department of Radiology, Massachusetts General Hospital. Reprinted with permission from Wen PY, Teoh SK, Black PM: Clinical, imaging and laboratory diagnosis of brain tumors, pp. 217248. In Kaye A, Laws E (eds):- Brain Tumors. 2nd Ed. Churchill Livingstone, Edinburgh, 2001 .)

Visual fields can be quantitatively evaluated using a combination of Goldmann kinetic perimetry and static perimetry using Humphries visual fields. Measurement of visual fields is especially important in evaluating tumors in the vicinity of the optic chiasm such as pituitary adenomas. Perimetry may be useful in confirming deficits found on examination, detecting subtle changes not found on confrontation, and monitoring the effects of treatment. Electroencephalography

diagnosis of brain tumors. Its role is limited to preoperatively evaluating the vascular anatomy in certain patients (e.g., sphenoid wing meningioma encircling the carotid artery), assessing the patency of venous sinuses in extracerebral tumors (e.g., falx meningioma), embolizing large tumors such as meningiomas, and searching for arteriovenous malformations and aneurysms in patients who present with hemorrhage. However, even for many of these indications MR angiography is increasingly taking the place of conventional angiography. Positron Emission Tomography Positron emission tomography (PET) is a versatile imaging modality that provides dynamic information regarding the metabolism and physiology of the brain and brain tumors. Its use is limited by its high cost, low availability, and low scanner resolution. PET is not used for the routine diagnosis of brain tumors, but it can provide important information complementing that obtained by CT and MR scanning. PET with ( 18F) fluorodeoxyglucose to measure glucose metabolism can be used to noninvasively determine tumor grade in patients with malignant gliomas. PET can also be used to differentiate radiation necrosis from recurrent tumor and study the metabolic effects of chemotherapy, radiation therapy, and steroids on tumor metabolism. Single Photon Emission Computed Tomography Single photon emission computed tomography (SPECT) involves the intravenous administration of radiopharmaceuticals that are

Seizures are the presenting symptom in approximately one third of patients with brain tumors. The presence of focal slow waves and spikes or frank epileptiform activity on electroencephalogram (EEG) may be the first indication of a focal lesion and the need for cerebral imaging. Large tumors producing mass effect and tumors involving the diencephalon may produce asynchronous generalized slowing. However, the EEG often is normal in patients with brain tumors and thus has limited value as a screening test. Audiometry Audiometry is a useful test for the diagnosis of cerebellopontine angle tumors. Ninety-eight percent of patients with acoustic neuromas have sensorineural hearing loss on pure tone audiometry. The most common pattern is high-frequency hearing loss together with reduced speech discrimination. Vestibular testing, including electronystagmography, may be positive in patients with cerebellopontine angle tumors but is rarely needed. Evoked Potentials Evoked potentials have a role in the diagnosis of acoustic neuromas. The brainstem auditory evoked potentials are abnormal in 92% to 96% of patients with acoustic neuromas and are a cost-effective screening test for patients with a low probability of these tumors. The most useful indications of compression of the auditory nerve are prolongation of the wave 1-111 and wave I-V interwave latencies. When wave I cannot be visualized, the

Chapter 155

ear-to-ear difference and the absolute latency of wave V may be useful. Compression of the anterior visual pathway by tumors can reduce the amplitude of visual evoked potentials. However, these tumors usually are diagnosed by MRI, and visual evoked potentials are rarely necessary. Evoked potentials also have an important role in monitoring neurologic function during surgical resection of tumors.

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Evaluation of the hypothalmic-pituitary axis involves measuring hormonal levels in the blood and urine, dynamic testing, and occasionally hormonal sampling of venous sinuses to help localize the tumor (see Chapter 163 on pituitary tumors).

SUMMARY

Cerebrospinal Fluid Analysis CSF examination can be useful in diagnosing certain brain tumors and evaluating the extent of leptomeningeal spread. However, it is important to recognize that lumbar puncture holds definite risks for patients with elevated intracranial pressure and should be avoided in these patients. CSF examination is very useful in patients with primary central nervous system lymphoma (PCNSL). It helps eliminate infections, which are often major considerations in the diagnosis, and may be diagnostic if tumor cells are identified. In patients with acquired immunodeficiency syndrome-related PCNSL, the polymerase chain reaction can be used to detect Epstein-Barr virus DNA in the CSF. The presence of the Epstein-Barr virus DNA in the CSF, together with increased uptake by the tumors of thallium on SPECT scans or ("F) fluorodeoxyglucose on PET scan is highly suggestive of PCNSL. The detection of JC virus DNA by polymerase chain reaction is useful for diagnosing progressive multifocal leukoencephalopathy, which can mimic tumors. A positive cytology may be helpful in the diagnosis of pineal region tumors, which are often difficult to biopsy. CSF examination is important in postoperative staging of patients with medulloblastomas and primitive neuroectodermal tumors because the presence of leptomeningeal disease influences prognosis and treatment. Cytologic examination of the CSF may also be useful in the diagnosis of neoplastic meningitis in patients with metastatic brain tumors and occasionally in patients with gliomas with leptomeningeal spread. CSF cytology is rarely useful in the initial diagnosis of gliomas. Germ cell tumors arising in the pineal region may produce biological markers such as a-fetoprotein, P-subunit of human chorionic gonadotrophin, and placental alkaline phosphatase. The presence of these markers helps in the diagnosis and subsequent follow-up of these germ cell tumors (Table 155-3).

Endocrine Evaluation Tumors in the region of the pituitary gland and hypothalamus may be associated with a variety of endocrine abnormalities.

The diagnosis of brain tumors depends o n careful clinical evaluation of the patient and judicious use of imaging and laboratory tests. Recent advances in imaging techniques have revolutionized the diagnosis of brain tumors and have allowed patients to be diagnosed earlier in their illness. The challenge for the future lies in developing improved methods of diagnosis and ensuring cost-effective evaluation.

SUGGESTED READINGS Carvalho PA, Schwartz RB, Alexander E et al: Detection of recurrent gliomas with quantitative thallium-201Itechnetium-99m HMPAO single-photon emission computerized tomography. J Neurosurg 77: 565-570, 1992

Forsyth P, Posner J: Headaches in patients with brain tumors: a study of 11 1 patients. Neurology 43:1678-1683, 1993 Hustinx R, Alavi A SPECT and PET imaging of brain tumors. Neuroimaging Clin North Am 9:751-766, 1999 Jaekle KA, Cohen ME, Duffner PK Clinical presentation and therapy of nervous system tumors. pp. 1131-1149. In Bradley WG, Daroff RB, Fenichel GM, Marsden CD (eds): Neurology in Clinical Practice. 2nd Ed. Butterworth-Heinemann, Boston, 1996 Kilbanski A, Zervas NT: Diagnosis and management of hormonesecreting pituitary adenomas. N Engl J Med 324:822-831, 1991 Lev MH, Rosen B R Clinical applications of intracranial perfusion MR imaging. Neuroimaging Clin North Am 9:309-331, 1999 Luh GY, Bird CR Imaging of brain tumors in the pediatric population. Neuroimaging Clin North Am 9:691-716, 1999 McKeran RO, Thomas DGT The clinical study of gliomas. pp. 194-230. In Thomas DGT, Graham DL (eds): Brain Tumors: Scientific Basis, Clinical Investigation and Current Therapy. Johns Hopkins University Press, Baltimore, 1980 Nelson SJ: Imaging of brain tumors after therapy. Neuroimaging Clin North Am 9801-819, 1999 Osborn AG: Diagnostic Radiology. Mosby, St Louis, 1994 Pomper MG, Port JD: New techniques in magnetic resonance imaging of brain tumors. Neuroimaging Clin North Am 11:501-525, 2001 Rand SD, Prost R, Li SJ: Proton MR spectroscopy of the brain. Neuroimaging Clin North Am 9379-395, 1999 Ricci PE Imaging of brain tumors. Neuroimaging Clin North Am 9 6 5 1 4 6 9 , 1999

TABLE155-3. Tumor Markers in Patients with Pineal Tumors Tumor Type

AFP

HCG

PLAP

Cerminoma Teratoma Malignant teratoma Undifferentiated germ cell tumor Choriocarcinoma Endodermal sinus tumor Embryonal cell tumor Pineocytoma Pinealblastoma

-

+/-

+

+/+/-

+/+/-

+

-

-

+ -

-

+

+

+/+/-

+/-

+/+/+/-

Abbreviations: AFP. a-fetoprotein; HCC,human chorionic gonadotropin; PLAP, placental alkaline phosphatase.

Stark AA, Bradley WG: Magnetic Resonance Imaging. 3rd Ed. Mosby, St Louis, 1999 Thomas DGT, McKeran RO: Clinical manifestations of brain tumors. pp. 94-12 1. In Thomas DGT (ed): Neuro-oncology. Primary Malignant Brain Tumors. Johns Hopkins University Press, Baltimore, 1990 Weingarten S, Kleinman M, Elperin L, Larson E B The effectiveness of cerebral imaging in the diagnosis of chronic headache. Arch Intern Med 152:2457-2462, 1992 Wen PY Diagnosis and management of brain tumors. pp. 106-127. In Black PM, Loeffler JS (eds): Cancer of the Nervous System. Blackwell Science, Cambridge, MA, 1997 Wen PY, Teoh SK, Black PM: Clinical, imaging and laboratory diagnosis of brain tumors. pp. 217-248. In Kaye A, Laws E (eds): Brain Tumors. 2nd Ed. Churchill Livingstone, Edinburgh, 2001

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156 General Principles of Management of Patients

with Brain Tumors a

Patrick Y. Wen and Naren Ramkrishna

The management of brain tumors requires a multidisciplinary approach involving the close collaboration of physicians from various specialties including neurology, neurosurgery, radiation therapy, medical oncology, internal medicine, psychiatry, neuroradiology, and neuropathology. The management issues can be divided into the definitive treatment of the tumor itself and supportive care. Although neurologists and internists usually are not directly involved in the definitive treatment of brain tumors, they have a crucial role in providing supportive care for these patients. TREATMENT OF BRAIN TUMORS Observation Occasionally, when the patient is asymptomatic and there is strong evidence on radiologic studies that the tumor is benign (e.g., a small convexity meningioma), it may be reasonable to observe the patient closely with serial computed tomography (CT) scans or magnetic resonance imaging (MRI) and consider intervention only if the tumor is enlarging or producing symptoms. For most brain tumors, some form of treatment usually is necessary. As with other neoplasms, the optimal management of brain tumors may involve a combination of treatments including surgery, irradiation, and chemotherapy. By the time a brain tumor produces neurologic symptoms it is usually 20 to 50 g in size (2 to 5 x 10’’ cells). Because of the confined intracranial volume, the tumor usually is lethal when it reaches 100 g (10” cells). With some benign tumors, most or all of the tumor can be removed surgically, allowing the patient to be cured. However, for most malignant brain tumors, complete surgical resection is not possible. Even gross total resection removes only about 90% of the tumor, reducing the tumor burden to 2 to 5 g (2 to 5 x lo9 cells). Radiation therapy may kill up to 2 logs of cells (leaving 2 to 5 x lo7 cells), and chemotherapy may kill an additional log of cells (leaving 2 to 5 x lo6 cells). Unfortunately, current combinedmodality treatment cannot reduce the tumor burden of most malignant brain tumors sufficiently (to 5 x lo5 cells) to allow the body’s immune mechanisms to eradicate the remaining tumor. As a result, treatment for these tumors rarely is curative.

surgery The initial step in treating most brain tumors is surgical resection of as much tumor as is neurologically safe. For some “benign” tumors such as meningiomas, acoustic neuromas, pituitary adenomas, and pilocytic astrocytomas, surgery alone may be curative. Recent advances in surgical techniques including the use of the operating microscope, the Cavitron aspirator, intraoperative ultrasound, laser systems, CT and MR guided stereo-, intraoperative neurophysiologicmonitoring, and intraoperative MRI have greatly improved the safety of surgery. For tumors that cannot be

resected, surgery still has a very important role. In addition to allowing a precise histologic diagnosis to be made, it debulks the tumor, relieving any symptoms resulting from mass effect, and possibly increases the effectiveness of adjuvant therapies by reducing the number of cells that must be treated, altering cell kinetics, and removing radioresistant hypoxic cells and areas of tumor inaccessible to chemotherapy. Stereotactic biopsies should be reserved for deep or critically located tumors that cannot be resected safely.

Radiation Therapy Radiation therapy has an important role in the treatment of all malignant brain tumors and some recurrent benign brain tumors. Ionizing radiation acts as a nonspecific cytotoxic agent by causing DNA damage, either directly or, more commonly, indirectly via generation of free radicals. Cell death usually results from the inability of damaged cells to reproduce and usually is seen during the first or subsequent attempts at division. The amount of radiation that can be delivered to the brain is limited by the tolerance of normal tissue. Current radiation dosages and fiactionation schedules for brain tumors have been developed to take advantage of the greater ability of normal cells to repair DNA damage compared with tumor cells and enables the maximum tolerated dosage to be administered. Typically for malignant gliomas, this is 6000 cGy in 180 to 200 cGy fractions. Unfortunately, most brain tumors are radioresistant, and the maximum tolerated dosages usually are insufficient to completely eradicate the tumors. In an attempt to improve on the results of conventional external beam irradiation, several novel strategies have been developed to selectively sensitize tumors to the effects of radiation using radiosensitizers and altered fractionation schedules. Studies are ongoing, but the results have been disappointing. More promising approaches to improving the effectiveness of radiotherapy are strategies directed at escalating the tumor dosage while biologically or physically limiting the dosage to normal brain. These include the use of stereotacticradiosurgery and fractionated stereotactic radiotherapy. Stereotactic Radiosurgery. This is a technique used to treat small (less than 4 cm) radiographically well-defined tumors with a single high-dose fraction of ionizing radiation in stereotactically directed narrow beams. Radiosurgery can be performed using gamma rays from cobalt-60 sources in gamma knives, x-rays from linear accelerators, or charged particle beams from cyclotrons (Fig. 156-1). These techniques significantly increase the radiation dosage that can be delivered to the tumor bed while sparing normal brain (Fig. 156-2). Radiosurgery has the advantage of being noninvasive, allowing patients with tumors in surgically inaccessible or eloquent areas of the brain or serious coexisting medical illnesses to be treated as an outpatient. Promising results

Chapter 156

W

A

General Principles of Management of Patients with Brain Tumors

B

I019

C

FIG. 156-1. Points of beam entry into the patienfs head with various radiosurgical techniques. (A) Gamma unit. (B) Linear accelerator with multiple noncoplanar converging arcs. (C) Proton beam.

have been achieved with radiosurgery for treating brain metastases, small malignant gliomas, and a variety of benign brain tumors, including skull base meningiomas, acoustic neuromas, and pituitary tumors not involving the optic chiasm. Stereotactic Radiotherapy. This novel technique involves the precise delivery of fractionated radiation to the tumor volume while sparing surrounding brain. It combines the accuracy of stereotactic radiosurgery with the lower toxicity of fractionated external beam irradiation and is a very useful therapy for a variety of brain tumors, including pituitary adenomas and acoustic neuromas.

Chemotherapy Chemotherapeutic agents exert their effects primarily by interfering with cell multiplication. Because cell multiplication is a feature

FIG. 156-2. Diagram showing the isodose curves around a pineal tumor treated with radiosurgery. Note the rapid fall-off in radiation dosage to surrounding structures, including the brainstem.

of many normal cells as well as tumor cells, most chemotherapeutic agents have toxic effects on normal cells, especially those with a high rate of turnover, such as bone marrow. The goal of chemotherapy is to select drugs that inhibit the growth of tumor cells with minimal toxicity to the patient. In addition to the normal problems of drug resistance and toxicity, there are certain problems unique to chemotherapy for brain tumors. The most important of these is the presence of the blood-brain barrier, which limits the passage of water-soluble drugs into the brain. Strategies have been developed to disrupt the blood-brain barrier, using agents such as mannitol, leukotrienes, and RMP-7 to increase the passage of water-soluble drugs into the tumor. Unfortunately, these approaches have had only a modest effect in improving the effectiveness of the chemotherapy. Other strategies to increase the effectiveness of chemotherapeutic agents have included the use of intracarotid injection, administration of the

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chemotherapy before radiation (neoadjuvant therapy), high-dose chemotherapy with autologous bone marrow transplantation, combined chemotherapy with biologic response modifiers and signal transduction inhibitors, and interstitial chemotherapy, in which a biodegradable polymer, impregnated with a chemotherapeutic agent, is implanted into the tumor bed, resulting in prolonged exposure of the tumor to the drug while minimizing systemic toxicity. Studies evaluating these approaches are in progress. Novel Therapies

Recently, a number of promising new approaches for treating brain tumors have been developed and are being evaluated in clinical trials. These include immunotherapy, hormonal therapy, differentiating agents, antiangiogenic agents, inhibitors of invasion, small molecule signal transduction inhibitors, and gene therapy. Participation in Clinical Studies

Progress in the treatment of patients with brain tumors has been very slow. This has resulted partly from the rarity of certain tumors and partly from the widespread nihilism associated with the treatment of brain tumors, resulting in very few patients being enrolled in clinical trials. It is important that physicians treating patients with brain tumors consider enrolling them in clinical trials so that promising new therapies can be evaluated more rapidly. SUPPORTIVE THERAPY

In addition to providing definitive treatment, an important role of physicians treating patients with brain tumors is to provide effective supportive care. The most common problems include treatment of seizures, peritumoral edema, venous thromboembolic disease, and medication side effects. Despite the importance of these issues, there are few formal studies to guide optimal management. Use of Anticonvulsants

Seizures are the presenting symptom in approximately 10% to 40% of all patients with primary or metastatic brain tumors and are present at some stage of the illness in an additional 20% to 45% of patients. The incidence of seizures is higher in primary brain tumors than in metastases. Patients with brain tumors who present with seizures should be treated with one of the standard first-line anticonvulsants. To minimize toxicity, patients should be treated with the lowest effective dosage of the anticonvulsant, and plasma levels should be monitored at the recommended intervals. Polytherapy should be avoided whenever possible. Electroencephalography may be useful if the diagnosis of seizures is in doubt but is not routinely needed for patients who give a clear history of seizures or do not have symptoms suggestive of seizures. In addition to the usual complications of anticonvulsants, patients with brain tumors experience a higher incidence of certain side effects, especially drug rashes. Approximately 20% of patients with glioma treated with phenytoin who undergo cranial irradiation develop a morbilliform rash, and a small percentage develop Stevens-Johnson syndrome. The mechanism is unknown

but may result from depletion of suppressor T cells by the radiation therapy, allowing the development of a hypersensitivity reaction to phenytoin. Stevens-Johnson syndrome has also been described in patients with glioma receiving carbamazepine, whereas patients receiving phenobarbital have a higher incidence of shoulder-hand syndrome. Overall, 23.8% of patients with brain tumors on anticonvulsant therapy experience side effects severe enough to warrant a change in or discontinuation of anticonvulsant therapy. In addition to producing adverse effects, anticonvulsants also have clinically significant interactions with other drugs commonly used in patients with brain tumors. Phenytoin induces the hepatic metabolism of dexamethasone and significantly reduces the half-life and bioavailability of this corticosteroid. Conversely, dexamethasone may also reduce phenytoin levels and thereby affect seizure management. A number of chemotherapeutic agents commonly used to treat brain tumors such as carmustine (BCNU) interact with phenytoin, causing the levels to fall, potentially leading to breakthrough seizures. In addition, the ability of anticonvulsants to stimulate the cytochrome P450 enzyme system markedly accelerates the metabolism of many chemotherapeutic agents, including nitrosoureas, paclitaxel, thiotepa, topotecan, irinotecan, cyclophosphamide, and methotrexate. As a result, the optimal dosage of these chemotherapeutic agents in patients with brain tumors taking enzyme-inducing anticonvulsants often is much higher than in patients not taking enzyme-inducing anticonvulsants. Because the risk of seizures in patients with infratentorial tumors is very small, anticonvulsant therapy usually is not indicated. The prophylactic role of anticonvulsant therapy in patients with supratentorial tumors who have not had a seizure is unknown. Most of these patients are placed on prophylactic anticonvulsant therapy because they are perceived to be at high risk of seizures and because many of these patients will be undergoing surgery. Several small retrospective studies have evaluated the usefulness of anticonvulsant therapy in patients with glioma without a history of seizures and have produced conflicting results. Boarini et al. (1985) studied 68 patients with glioma, of whom 33 received prophylactic anticonvulsants. Seizures occurred in 39% of untreated patients and 21% of patients receiving anticonvulsants. Moreover, patients receiving anticonvulsants had fewer generalized seizures. In contrast, Mahaley and Dudka (1981) studied 59 patients and found that the incidence of seizures was higher (39%) in patients who received anticonvulsants than in patients who did not (28%). Because these studies are retrospective and have small numbers of patients, they have only limited power in detecting a modest protective effect of anticonvulsants. Weaver et al. (1997) conducted a prospective randomized study of prophylactic anticonvulsants in patients with brain tumors who have not had seizures. Of the 100 patients, 40 had primary brain tumors and 60 had metastatic brain tumors. Overall, 26% of patients had seizures. There was no difference in the seizure rate between patients taking anticonvulsants and those who were on no medications. This study was limited by the small number of patients and a high noncompliance rate, but it also did not support the use of prophylactic anticonvulsants in patients with brain tumors. The role of prophylactic anticonvulsant therapy for patients with brain metastases who have not had a seizure is also unknown. Cohen et al. (1988) retrospectively reviewed 160 patients with brain metastases who have not had a seizure and found that

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patients receiving prophylactic anticonvulsant therapy with dilantin had the same frequency of seizures (10%) as patients receiving no treatment. Glantz et al. (1996) subsequently conducted a small prospective, placebo-controlled, randomized study evaluating the efficacy of valproic acid in protecting patients with newly diagnosed brain metastases from seizures. There was no significant difference in the seizure frequency at 7 months between patients receiving valproic acid or placebo, suggesting that prophylactic anticonvulsants may not be effective in these patients. Many patients with brain tumors are treated with anticonvulsants partly because they have had a craniotomy. However, the issue of whether prophylactic anticonvulsant therapy reduces the frequency of seizures after craniotomy is unclear. Early studies such as that of North et al. (1983) found that prophylactic anticonvulsants reduced the frequency of postoperative seizures. However, analysis of their data showed that most of the increased seizure frequency in the patients receiving placebo occurred in the first postoperative week. More recently, Foy et al. (1992) completed a prospective trial involving 276 consecutive supratentorial craniotomy patients (including 50 with meningiomas) who were randomized postoperatively to receive either carbamazepine, phenytoin, or no treatment. There was no difference in the incidence of seizures (37%) or death between the two groups, suggesting that prophylactic anticonvulsant therapy may not be necessary routinely after craniotomy. A meta-analysis of the published trials also found no benefit of prophylactic anticonvulsants after supratentorial craniotomies. Recently, a practice parameter was issued by the Quality Standards Subcommittee of the American Academy of Neurology on the use of prophylactic anticonvulsants in patients with brain tumors. It concluded that the available studies did not show a significant benefit of prophylactic anticonvulsants in patients with brain tumors. It was recommended that in view of the lack of clear evidence that anticonvulsant therapy reduces the incidence of seizures and the potential for adverse effects, routine anticonvulsant therapy in patients with brain tumors who have not experienced a seizure is unnecessary. Possible exceptions to this are patients with brain metastases in areas of high epileptogenicity (e.g., the motor cortex), patients with tumors that often invade the cortex such as melanoma, and patients with both brain metastases and leptomeningeal metastases. These patients probably have a higher incidence of seizures, but there is currently no evidence that prophylactic anticonvulsants are more effective in these subgroups. Patients who do a significant amount of driving usually are placed on prophylactic anticonvulsants, although there are no data to suggest that this practice reduces the incidence of seizures.

Treatmentof Periturnoral Edema The vasogenic edema surrounding many brain tumors contributes significantly to the morbidity associated with the tumors. This edema results from disruption of the blood-brain barrier, allowing protein-rich fluid to accumulate in the extracellular space. Vasogenic edema tends to spread more readily in the white matter extracellular space than in gray matter, possibly because of lower resistance of white matter to flow. The edema may disrupt synaptic transmission, alter neuronal excitability, and contribute to headaches, seizures, and encephalopathy. Because the brain is encased in a rigid cranium, unchecked cerebral edema may result in fatal herniation. The breakdown of the blood-brain barrier within brain tumors is caused by the production of factors such as vascular permeabil-

1021

ity factor/vascular endothelial growth factor, glutamate, and leukotrienes, which increase the permeability of tumor vessels, and by the absence of tight endothelial cell junctions in tumor blood vessels, which develop in response to angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor. Periturnoral edema can be managed adequately with corticosteroids. Occasionally when there is significant intracranial pressure and mass effect, other measures may be needed. Acute Treatment of Increased lntracranial Pressure (ICP). Corticosteroids may take several days to reduce intracranial pressure from peritumoral edema. Some patients who present acutely with significantly increased intracranial pressure may need other measures to lower the intracranial pressure until corticosteroids have had a chance to take effect or until the patient undergoes a craniotomy and debulking procedure. These measures include the following: Elevation of the head of the bed (more than 30 degrees): This displaces cerebrospinal fluid from the intracranial cavity and enhances cerebral venous outflow. Fluid restriction (1 to 1.5 L/day). Osmotic agents: Agents such as mannitol reduce total brain water by creating an osmotic gradient toward the intravascular space. Mannitol usually is given at an initial dosage of 0.75 to 1.0 g/kg, followed by 0.25 to 0.5 g/kg every 3 to 5 hours, aiming for a target osmolality of 300 to 3 10 mOsmlL. The effect of mannitol on ICP usually is achieved within 10 to 30 minutes after administration, with maximal ICP reduction within 20 to 60 minutes. Complications of therapy with osmotic agents include hypokalemia, hypochloremic alkalosis, dehydration, hypotension, nonketotic hyperosmolar state, and rebound intracranial hypertension after prolonged use. Diuretics: These are effective for the short-term treatment of increased ICP, especially when used in combination with osmotic therapy. They produce a mild osmotic diuresis, resulting in an osmotic gradient toward the intravascular space, reduce cerebrospinal fluid formation, and remove sodium and water from the brain. Loop diuretics, such as furosemide (20 to 40 mg), are most commonly used. Administering furosemide 15 minutes after administering mannitol appears to be the most effective in lowering ICP. The main side effects of loop diuretics are electrolyte disturbance and systemic dehydration. Hyperventilation: This is an effective short-term measure used to reduce ICP. It produces hypocarbia and lowers ICP by reducing cerebral blood volume. The reduction in ICP is rapid, although the maximal effect may follow the change in pco2 by 15 to 30 minutes. Usually the pco2 is gradually lowered to 25 to 35 mm Hg to achieve the desired ICP. The ICP gradually returns to baseline despite hyperventilation, making this an effective treatment for increased ICP only in the short term. Corticosteroids. Corticosteroids usually are indicated in any patient with a brain tumor and symptomatic peritumoral edema. The mechanism of action is not well understood. They may produce their antiedema effect by reducing the permeability of tumor capillaries, limiting the leakage of sodium, protein, and water into the peritumoral extracellular space.

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Most patients usually are started on dexamethasone, which has the advantage over other corticosteroids of having little mineralocorticoid activity, reducing the potential for fluid retention and systemic edema. In addition dexamethasone may be associated with a lower risk of infection and cognitive impairment. The usual starting dosage is a 10-mg load, followed by 4 mg four times a day, although there is some evidence that lower dosages may be as effective. Although dexamethasone often is given in four divided doses, its biological half-life is sufficiently long to allow the medication to be administered twice daily. Most patients improve symptomatically within 24 to 72 hours, although neuroimaging studies may not show a decrease in the amount of edema for at least 1 week. In general headaches tend to respond better than focal deficits. If 16 mg of dexamethasone per day is insufficient, the dosage may be increased up to 100 mg/day. Despite the usefulness of corticosteroids, they are associated with a large number of well-known side effects (Table 156-1). The frequency of these complications can be reduced by always using the lowest possible dosage of corticosteroids. Three complications of corticosteroid therapy are of particular concern to patients with brain tumors. These include gastrointestinal (GI) complications, steroid myopathy, and opportunistic infections such as Pneumocystis carinii pneumonitis (PCP). CAsmoimsnw ComPnurnoNs. Most patients with brain tumors receiving corticosteroids are treated with histamine (H,) blockers, proton pump inhibitors, or antacids to prevent peptic ulceration and upper gastrointestinal hemorrhage. However, the relationship between corticosteroids and peptic ulceration and GI bleeding is controversial. The widespread impression that corticosteroids are potentially ulcerogenic originated from observations that stress produced acute ulcers and anecdotal studies suggesting that corticosteroids increase and alter the composition of gastric acid secretion.

TABU 156-1. Complications of Corticosteroid Therapy Common: Behavioral changes, insomnia, myopathy, hallucinations, hiccups, tremor, reduced taste and smell, cerebral atrophy Uncommon: Psychosis, dementia, seizures, dependence, paraparesis (epidural lipomatosis) Thin, fragile skin, purpura, ecchymosis; striae, hirDermatologic sutism; acne, inhibition of wound healing, Kaposi's sarcoma Osteoporosis, avascular necrosis, growth retardaRheumatologic tion, tendinous rupture Increased appetite, abdominal bloating, gastroinGastrointestinal testinal bleeding and perforation, pancreatitis, liver hypertrophy Visual blurring, cataract, glaucoma, exophthalmos, Ophthalmologic uveitis Hypertension, atherosclerosis, arrhythmia (with IV Cardiovascular push) Endocrine and Hyperglycemia, hypokalemia, hypophosphatemia, metabolic hypernatremia, hyperlipidemia, redistribution of body fat (e.g., centripetal obesity, buffalo hump), amenorrhea Polyuria, genital burning (with IV push) Urogenital Miscellaneous Opportunistic infections (including candidiasis, Pneumocystis carinii pneumonia), hypersensitivity reactions, neutrophilia, lymphopenia, night sweats Steroid withdrawal Pseudorheumatism (very common), headache, lethargy, low-grade fever, adrenal insufficiency, Dseudotumor cerebri Adapted in part from DeAngelis IA, Delattre JY, Posner JB: Neurologicalcomplications of chemotherapy and radiation therapy. pp. 437-458. In Aminoff MJ (ed): Neurology and General Medicine. 3rd Ed. Churchill Livingstone,New York, 2001

Neurologic

Theoretically, an association between corticosteroid therapy and peptic ulceration could be established by a prospective randomized clinical trial. However, such a trial is unlikely to occur because of the low incidence of peptic ulceration and the difficulty of recruiting sufficient patients. Several meta-analyses have been conducted evaluating the use of corticosteroids in a variety of diseases to determine whether there is an association between corticosteroid therapy and peptic ulceration and GI bleeding. The results have been conflicting, with some studies showing no significant association between corticosteroid use and upper GI hemorrhage and others showing a small association. At present, the available data do not definitively support an association between corticosteroids, peptic ulceration, and GI bleeding. Even if an association exists, the overall incidence of peptic ulceration and GI bleeding is very low. However, patients with brain tumors often take high dosages of corticosteroids. There are few data concerning the risk of peptic ulceration and GI bleeding or the effectiveness of prophylactic therapy with H,blockers, proton pump inhibitors, or antacids in these patients. Although H,-blockers and proton pump inhibitors are relatively benign, some (e.g., cimetidine) can produce central nervous system (CNS) side effects such as confusion, and most of these drugs are expensive. In the absence of data from clinical studies regarding the efficacy of H,-blockers and proton pump inhibitors in patients with brain tumors, the use of these medications probably should be restricted to the perioperative period and to patients receiving very high dosages of corticosteroids. For most other patients, prophylactic therapy with H,-blockers and proton pump inhibitors probably is unnecessary unless they are at high risk for developing peptic ulceration (i.e., patients with a history of peptic ulcers, those receiving anticoagulation or nonsteroidal anti-inflammatories, and older adults). A less well recognized complication of steroid therapy is perforation of the GI tract. This is often difficult to diagnose because clinical features of peritonitis may be masked by the steroids. GI perforation often can be averted by constipation prevention. A high index of suspicion is also important because early diagnosis improves the outcome of this serious complication. STEROIDMYOPATHY. Myopathy is a common complication of steroid therapy and contributes significantly to the morbidity of patients with brain tumors. The reported incidence of steroid myopathy in patients with brain tumors varies from 2% to 21%, with the largest series reporting clinically symptomatic steroid myopathy in 10.6% of patients. It can often be prevented by using the lowest possible dosage of steroids for peritumoral edema. Steroid myopathy usually occurs with prolonged steroid therapy, with the majority of patients developing weakness between the ninth and twelfth weeks of treatment. There is marked variation of individual susceptibility. Some patients become weak after using a low dosage of steroids for a few weeks, whereas others never develop problems despite receiving large dosages of steroids for months or years. Steroid myopathy has been associated especially with the use of 9-a-fluorinated corticosteroids such as dexamethasone, but the evidence supporting this relationship is weak. Steroid myopathy usually has a subacute onset over several weeks. It is characterized by weakness and wasting in pelvifemoral muscles, especially quadriceps, and eventually may spread to the pectoral girdle, neck, and trunk. Eventually all limb muscles may become weak, but a proximal emphasis persists. Muscle pain is not a feature, and tendon reflexes are preserved.

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Serum creatine phosphokinase, aldolase, and other muscle enzyme levels almost invariably are normal. Electromyography often is unrevealing. Occasionally there may be mild myopathic changes without abnormal irritability or spontaneous discharges. Muscle biopsy results are nonspecific but may show atrophy, involving especially type IIb muscle fibers. The precise pathophysiology of steroid myopathy is unknown. It is likely that steroids exert their effects through inhibition of protein synthesis and increased protein catabolism. Interestingly, the risk of developing steroid myopathy is significantly lower in patients taking phenytoin. The reason for this is unclear but may be caused by the induction of hepatic metabolism of dexamethasone by phenytoin, reducing the effective exposure of muscle cells to the glucocorticoids. Treating steroid myopathy is difficult. Ideally the steroid should be discontinued, but if this is not feasible, the lowest possible dosage should be used. Recovery after stopping steroid therapy can be expected in 2 to 3 months but may be much slower if treatment is continued at a lower dosage. There are anecdotal reports that weakness occurring during treatment with fluorinated corticosteroids improves when the drugs were replaced by an equivalent dosage of nonfluorinated steroid. Animal studies suggest that muscle activity may reduce steroid-induced wasting, raising the possibility that a program of physical therapy may help reduce the severity of myopathy in patients receiving long-term steroid therapy. PNEUMOCYSS CARINIIRuEumoNms. PCP is a fungus capable of causing life-threatening pneumonitis in immunocompromised patients. It is most common in patients with acquired immunodeficiency syndrome but is also being seen with increasing frequency in other immunosuppressed patients such as organ transplant recipients treated with immunosuppressive agents and patients with hematologic malignancies treated with chemotherapeutic regimens. PCP is rare in patients with solid tumors but may occur in these patients in the setting of steroid therapy. There is increasing evidence that patients with brain tumors receiving corticosteroids may be at increased risk of PCP, especially during the steroid taper. The mechanisms by which steroids predispose to the development of PCP are poorly understood but involve suppression of cellular immunity, leading to reactivation of latent infection by Pneumocystis curinii. The paradoxical appearance of PCP during tapering of steroid therapy may result from unmasking Pneumocystis carinii infections that have developed earlier during high-dose steroid administration. Physicians caring for patients with brain tumors receiving steroids should maintain a high index of suspicion for PCP. Although the clinical features of PCP usually are those of an acute diffuse pneumonia, the presentation can be subtle and nonspecific, and the diagnosis should be considered in any patient developing respiratory symptoms. Chest radiographs may demonstrate patchy infiltrates or lobar or cavitary pneumonias. The diagnosis usually is made by visualization of the organism in sputum, fluid obtained by bronchoalveolar lavage, or transbronchial biopsy. Toluidine blue 0, Weigert-Gram, and Grocott-Gomori methenamine-silver nitrate stains are useful for detecting the cyst wall, whereas Giemsa stain detects the internal forms (sporozoites or trophozoites). Immunofluorescent staining of sputum and detection of PCP by polymerase chain reaction may also be helpful. Trimethoprim-sulfamethoxazole (TMP-SMZ) is the treatment of choice for PCP if the patient can tolerate it. The standard dosages are trimethoprim (15 to 20 mg/kg) and sulfamethoxazole (75 to 100 mg/kg) IV or PO for 21 days. This produces response

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rates of 75%. Intravenous pentamidine ( 3 to 4 mg/kg IV daily for 21 days) is as effective as TMP-SMZ but is less often used because it must be administered intravenously and is associated with greater toxicity. Other agents that may be used to treat PCP include trimethoprim and dapsone, trimetrexate and leucovorin, clindamycin, primaquine, and atovaquone. Patients with established PCP may paradoxically benefit from treatment with corticosteroids. The steroids reduce the inflammatory response of the alveolitis and result in clinical improvement and possibly reduced mortality. Because of the risk of PCP, it may be prudent to consider prophylactic therapy against PCP for patients with brain tumors receiving prolonged courses of corticosteroids, especially as steroid therapy is withdrawn. TMP-SMZ is highly effective in preventing PCP. The optimal dosage is not established, but it is effective when administered either as a single dose daily (e.g., 160 mg of trimethoprim plus 800 mg of sulfamethoxazole) or three days a week. Adverse reactions are rare in patients with brain tumors, and the cost is low. For patients with allergic reactions to TMP-SMZ, aerosolized pentamidine, dapsone alone or in combination with pyrimethamine and leucovorin, or atovaquone are effective alternatives. Venous Thromboembollc Disease

Venous thromboembolic disease is common in patients with brain tumors. In one study of patients with high-grade gliomas, all of whom were ambulatory and outside the perioperative period, 19% developed either deep vein thrombosis (DVT) or pulmonary emboli. This risk is 37% to 60% in patients in the postoperative period or those with hemiplegia. The incidence of venous thromboembolic disease is also higher in patients with other types of brain tumors such as meningiomas (72%), brain metastases (20%), and primary CNS lymphoma (18%). The pathogenesis of venous thromboembolism in brain tumor patients is not completely understood. Contributing factors include venous stasis in hemiparetic limbs and release of procoagulant substances and fibrinolytic inhibitors from tumor tissue and surrounding cerebral tissue, leading to subclinical chronic disseminated intravascular coagulation. The optimal therapy for venous thromboembolic disease in patients with brain tumors is unknown. These patients often are perceived to be at greater risk of intracranial hemorrhage with anticoagulation because of the vascularity of the tumors and anecdotal case reports of hemorrhage. Certain metastatic tumors, such a melanoma and choriocarcinoma, may have a particularly high propensity for hemorrhage. Because of the perceived risk of hemorrhage, the majority of patients with brain tumors, DVT, and pulmonary emboli are treated with inferior vena cava (IVC) filtration devices rather than anticoagulation. However, several retrospective studies suggest that the risk of intracranial hemorrhage in anticoagulated patients outside the immediate postoperative period may not be significantlyincreased (0% to 7%). Moreover, a study by Levin et al. (1993) suggests that patients with brain tumors and venous thromboembolic disease treated with IVC filters experience a high percentage of complications (67%) such as recurrent DVTs and postphlebitic syndrome, which severely reduced the quality of life of the affected patients. Because of the high complication rate in patients treated with IVC filters and evidence suggesting that the risk of anticoagulation in these patients is not increased, consideration should be given to

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Brain Tumors: General Aspects

treating venous thromboembolic disease in patients with brain tumors with anticoagulation rather than IVC filters. Rehabilitation. Many patients with brain tumors have significant neurologic deficits and benefit from physical, occupational, and speech therapy. The details of rehabilitation are discussed in greater detail in Chapter 27. Emotional and Psychological Support. The diagnosis of a brain tumor inevitably has a profound and often devastating effect on the patient and their families. An important part of the care of these patients is supplying information about the tumor and the therapeutic options in a compassionate manner and giving emotional and psychological support. Patients and their families often benefit from the help provided by patient support groups, psychiatrists, and societies such as the American Brain Tumor Association (2720 River Road, Des Plaines, IL 60018; phone: 847-827-9910; patient line: 800-886-2282; e-mail: [email protected]), the Brain Tumor Society (124 Watertown Street, Suite 3-H, Watertown, MA 02472; phone: 800-770-TBTS (8287); e-mail: [email protected]), and the National Brain Tumor Foundation (414 Thirteenth Street, Suite 700, Oakland, CA 94612-2603; office line: 510-839-9777; brain tumor information line: 800-934-CURE (2873); e-mail: [email protected]). Terminal Care. Despite some important advances in recent years, the majority of patients with malignant brain tumors eventually die from their disease. When further therapy is no longer possible or not warranted because of the poor quality of the patient’s life, all efforts should be directed toward keeping the patient comfortable and avoiding unnecessary prolongation of suffering.

SUGGESTED READINGS Aguilar D, Goldhaber S Z Clinical uses of low-molecular-weight heparins. Chest 115:1418-1423, 1999 Batchelor T, DeAngelis LM: Medical management of cerebral metastases. Neurosurg Clin 7:435-446, 1996 Boarini D, Beck DW, Van Guilder JC: Post-operative prophylactic anticonvulsant therapy in cerebral gliomas. Neurosurgery 16:290-292, 1985

Cheruku R, Tapazoglou E, Ensley J: The incidence and significance of thromboembolic complications in patients with high grade gliomas. Cancer 68:2621-2624, 1991 Cloughesy TF, Black KL: Peritumoral edema. pp. 107-1 14. In Berger MS, Wilson CB: The Gliomas. Saunders, Philadelphia, 1999 Cohen N, Strauss G, Lew R et al: Should prophylactic anticonvulsants be administered to patients with newly-diagnosed cerebral metastases?A retrospective analysis. J Clin Oncol 6:1621-1624, 1988 Conn HO, Poynard T Corticosteroids and peptic ulcer: meta-analysis of adverse events during steroid therapy. J Intern Med 236:619-632, 1994 DeAngelis LA, Delattre JY, Posner JB: Neurological complications of chemotherapy and radiation therapy. pp. 437-458. In Aminoff MJ (ed): Neurology and General Medicine. 3rd Ed. Churchill Livingstone, New York, 2001

Delattre J, Safai B, Posner JB: Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin. Neurology 383194-198, 1988 Dropcho EJ, Soong SJ: Steroid-inducedweakness in patients with primary brain tumors. Neurology 41:1235-1239, 1991 Eidelberg D: Neurological effects of steroid treatment. pp. 173-184. In Rottenberg DA (ed): NeurologicalComplications of Cancer Treatment. Butterworth-Heinemann, Boston, 1991 Foy PM, Chadwick DW, Rajgopalan N et ak Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy? J Neurol Neurosurg Psychiatry 55:753-757, 1992 Glantz MJ, Cole BF, Forsyth PA et al: Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:1886-1893, 2000 Glantz M, Cole B, Friedberg M et a1 A randomized, blinded, placebocontrolled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors. Neurology 46985-991, 1996 Henson JW, Jalaj JK, Walker RW et ak Pneurnocystis carinii pneumonia in patients with primary brain tumors. Arch Neurol 48:40&409, 1991

Kuijen JMA, Teernstra OPM, Kessels AGH et al: Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis. Seizure 5:291-298, 1996 Lee AYY, Levine MN: Management of venous thromboembolism in cancer patients. Oncology 14:409-421, 2000 Levin JM, Schiff D, Loeffler JS et al: Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 43~1111-1114, 1993

Mahaley M, Dudka L The role of anticonvulsant medications in the management of patients with anaplastic gliomas. Surg Neurol 16399401, 1981

Mamon H, Wen PY, Burns A, Loeffler JS: Allergic skin reactions on anticonvulsant medications in patients receiving cranial radiation. Epilepsia 40:341-344, 1999 North JB, Penhall RK, Hanieh A et al: Phenytoin and postoperative epilepsy. J Neurosurg 58:672477, 1983 Posner JB: Neurologic complications of cancer. FA Davis, Philadelphia, 1995

Schiff D, DeAngelis LM: Therapy of venous thromboembolism in patients with brain metastases. Cancer 73:493498, 1994 Spiro HM: Is the steroid ulcer a myth? N Engl J Med 309:45-47, 1983

Vecht CJ, Verbiest HBC Use of glucocorticoids in neuro-oncology. pp. 199-218. In Wiley RG (ed): Neurological Complications of Cancer. Marcel Dekker, New York, 1995 Weaver S, DeAngelis LM, Fulton D et ak A prospective randomized study of prophylactic anticonvulsantsin patients with primary or metastatic brain tumors and without seizures. Ann Neurol 42:430, 1997 Wen P: The diagnosis and management of patients with brain tumors. pp. 106-127. In Loeffler JS, Black PM (eds): Cancer of the Nervous System. Blackwell Scientific, Boston, 1997 Wen PY, Marks PW: Medical management of brain tumors. Curr Opin Oncol 14(3):299-307, 2002

2

SECTION

SPECIFIC TUMOR TYPES

157 Low-Grade Gliomas Joachim M. Baehring and Fred H. Hochberg

Primary brain tumors, accounting for fewer than 2% of all cancers, are among the most costly to society. Low-grade gliomas represent 10% of these primary tumors. The descriptive names that we apply reflect microscopic appearances and immunohistochemical staining characteristics as well as locations within the nervous system. The terminology is confusing, and the names do not reflect biological behavior, response to therapy, prognosis, or molecular alterations. Astrocytic tumors predominate (diffuse astrocytoma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), followed by oligodendroglial (oligodendroglioma) and mixed glial tumors (oligoastrocytoma). Tumors of mixed glial-neuronal populations also occur (ganglioglioma, desmoplastic infantile astrocytoma, ganglioglioma). Least common are growths in proximity to the ventricles and choroid plexus (choroid plexus papilloma), the ependyma (ependymoma, myxopapillary ependymoma), subependymoma, and neuroepithelial tumors of unknown origin (dysembryoplastic neuroepithelial tumor, chordoid glioma of the third ventricle). Some of these tumors are discussed elsewhere in Part VII of this book. Central to this chapter and to the care of afflicted patients are two tenets. First, low-grude gliorna is a descriptive term and does not imply a benign clinical course. A “benign” infiltrating astrocytoma of the brainstem can lead to disability and death; a similar lesion in the optic chiasm causes blindness, and intramedullary spinal low-grade glioma can produce irreversible paraplegia. Second, because many patients survive their tumors, the clinician must weigh the gains of therapy against the side effects of surgery, irradiation, and chemotherapy.

PATHOGENESIS Despite advances on a molecular level, it remains unclear whether gliomas arise from glial progenitor cells or by degeneration of differentiated cells. What little information is available about the initiating steps of tumor formation comes mostly from investigations of hereditary cancer syndromes. Glial tumors occur in patients with the Li-Fraumeni syndrome (bearing germ line mutations of the TP53 gene), Lynch syndrome type I1 (hMLH1, hMSH2), Turcot’s syndrome (hMLH1, hPMS2), tuberous sclerosis (TS1, TS2), neurofibromatosis (NF1/2), and Cowden’s disease (PTEN). It is likely that these inherited syndromes explain only 10% of low-grade glioma. Noninherited, sporadic low-grade gliomas gain portions of chromosome 7q, and many (40%) show

loss of heterozygosity of microsatellite DNA on chromosome 17p. Whether these changes have prognostic or epidemiologic significance remains to be determined. Certain glioma subtypes are predisposed to specific mutations: 30% of gliomas, especially gemistocyticastrocytomas, but not pilocytic astrocytomas, contain somatic TP53 mutations. Oligodendrogliomas and oligoastrocytomas show loss of chromosome l p and 19q in the absence of TP53 mutations. It is thought that many low-grade gliomas give rise to malignant gliomas and that 90% of the latter were once low-grade gliomas. Indeed, this figure provides a strong rationale for early diagnosis. Malignant degeneration of low-grade gliomas is accompanied by clonal expansion of cells with TP53 mutations and loss of heterozygosity on chromosome 1Oq. Older patients appear at risk of a somewhat different glioblastoma that has not contained a low-grade precursor. These de novo glioblastomas contain genetic alterations in the CDKN2NFWCDK4 pathway, the PTEN gene on chromosome lOq, and amplification of the EGF receptor gene. DIAGNOSIS A careful history and physical examination remain the crucial tools in diagnosis and treatment of the patient with a low-grade glioma. Modern imaging techniques are the basis for diagnosis within weeks of symptom onset and have made surgical intervention less morbid and costly. Certain rules are useful to the clinician. A brain tumor should be considered in all patients with the adult onset of seizures, a new headache or change in quality of a chronic headache, focal neurologic symptoms, or a psychiatric manifestation. The clinical presentation is nonspecific and can be acute (seizure, rarely strokelike, caused by intratumoral hemorrhage) or subacute (slowly progressive headache that is typically worst upon awakening, personality changes, or memory loss).

Imaging studies should be performed in all consultation patients with the aforementioned risk factors even if they were previously reported as normal. Acute or subacute ischemic or hemorrhagic cerebrovascular accidents, extra-axial hemorrhages, hyperacute demyelinating disease, and abscess can mimic the acute presentation of a brain tumor. 1025

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Neuro-Oncology rn Specific Tumor Types

Computed tomography (CT) scans are readily available and useful for emergency room evaluations but do not obviate magnetic resonance imaging (MRI) studies. Gliomas usually can be distinguished from acute infarcts, encephalitides, and brain abscess; low-grade gliomas rarely have hemorrhage or produce mass effect and do not alter radionuclide or positron emission tomography (PET) images. MRI is the most sensitive and specific diagnostic study for a suspected brain tumor. Low-grade gliomas are hypointense to isointense masses on T1-weighted images with intratumoral and surrounding vasogenic edema (hyperintense on T2 or fluidattenuated inversion recovery images). Diffusion-weighted images reveal limited diffusion of protons within the tumor. As a rule gadolinium enhancement within a tumor is a sign of a higher grade in astrocytomas but not oligodendrogliomas. But lack of enhancement is never a guarantee of low grade histology. Indeed, as many as one third of nonenhancing masses contain anaplastic foci, a finding that is particularly germane to patients older than 50 years whose tumors tend to behave aggressively even if they are low-grade gliomas. Although imaging studies do not identify histology, certain clues exist. Cyst formation and calcification indicate growth over years within pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and oligodendroglioma. Intratumoral hemorrhage occurs in some oligodendrogliomas. Infiltration of the cerebral cortex and enlargement of a single gyrus often is seen in oligodendroglioma. Identification of a glioma by its characteristic location sometimes is possible in pilocytic astrocytoma (cerebellum), chordoid glioma (third ventricle), and subependymal giant cell astrocytoma. On a very practical level, the neurologic clinician often is called on to aid in targeting biopsy material. A neurosurgical target of an aggressive focus within tumor can be obtained from the identification of choline excess on single or multivoxel proton spectroscopy and regions of accelerated blood flow on echoplanar cerebral blood volume maps.

Proton magnetic resonance spectroscopy can aid in distinguishing tumor from demyelinative plaque or abscess. Rapidly evolving software will provide higher-resolution maps of the relative concentration of proton-containing molecules within a defined volume of interest. The characteristic pattern of low-grade gliomas is shown in Figure 157- 1. Within 72 hours of a biopsy or open resection, an MRI with gadolinium must be performed to provide the clinician with an anatomic and volumetric baseline against which to evaluate further therapy. PET is a specialized technique using a hospital-based cyclotron and nuclear pharmacy. The technology can assess, within 5 mm of tissue, the glucose or methionine metabolism. Areas of anaplastic degeneration appear with excessive accumulation of fluorodeoxyglucose-18 or methionine. Single photon emission computed tomography uses thallium-201 to measure tumor perfusion in comparison with normal tissue. When the comparative uptake of thallium is less than 1.4, the tumor probably is low grade. Pathology Tissue sampling is still an indispensable diagnostic study and should be attempted whenever possible. Commonly used and least invasive are MRI- or CT-guided stereotactic biopsies, targeted to metabolically active tumor sites. The tissue obtained is seldom larger than 1 mm by 5 mm and may bias the clinician to believe that the core is representative of the entire tumor. Low-grade gliomas do not contain no features that characterize higher grades such as necrosis, new vessel formation (microangiogenesis), cellular pleomorphism, and mitoses. A seemingly benign lesion should always be interpreted within the context of the patient’s age, the number or extent of MRI lesions, and the contrast appearance of the mass. Even if benign under the microscope, a

FIG. 157-1. IH-MR spectrum of a volume of interest located in normal cerebral white matter (left) and in the area of an infiltrating astrocytoma (WHO ll/lV; right). The tumor voxel spectrum shows an increased choline (1) to creatine (2) peak ratio and a markedly decreased N-acetylaspartate peak (3, both characteristics of a neoplasm.

Chapter 157

tumor should be assumed to be more aggressive if it appears radiologically as a necrotic and edematous mass with focal enhancement. The histopathologic classification of brain tumors has been in flux ever since the first classification system. The World Health Organization (WHO) classification of brain tumors (Kleihues and Cavenee, 2000) provides reproducible histologic criteria for diagnosis but lacks universal acceptance and fails to include key information of the clinical appearance, host demography and risk factors, radiologic appearance, data from studies of proliferation markers (Ki-67), and molecular insights. Therefore, a clinical and neuropathologic second opinion appears warranted in many instances. THERAPY

Controversies in the treatment of patients with low-grade gliomas separate clinicians into advocates of early biopsy followed by radiation therapy and proponents of observation. In the absence of randomized prospective trials, our approach is to provide early diagnostic biopsy or gross total resection of low-grade gliomas. Adjuvant radiation or chemotherapy, without proven impact on survival, is reserved for nonresectable symptomatic patients or those with clinical or radiographic evidence of anaplasia. Highdose steroid treatment provides rapid improvement of symptoms caused by vasogenic edema. The patient with symptomatic epilepsy benefits from antiepileptic therapy. SUWY The goal of surgery is to establish a diagnosis, to alleviate symptoms of mass effect, hydrocephalus, hemorrhage, or seizure activity, and to remove potentially more aggressive foci within benign tumors. Stereotactic Biopsy. One third of patients with low-grade gliomas undergo stereotactic biopsy of tumors within eloquent cortex or white matter, the basal ganglia, or the brainstem. Often functional MRI or PET studies are performed to identify eloquent areas of the brain. These studies can be coregistered on threedimensional MRI reconstructions from which biopsy coordinates are drawn. The procedure is safe, obligating the patient to a single day in the hospital and less than 2% risk of seizure, hemorrhage, or infection. In many referral centers, a neuropathologist provides immediate analysis of frozen or smear preparations to confirm the existence of tumor. This is important because up to 10% of apparent neoplasms may actually be of infectious or demyelinative origin. Resection. Few patients appear to benefit from resection of their infiltrating diffuse astrocytoma or partial decompression of a mass. That having been said, resection provides prolonged suMval for oligodendrogliomas and oligoastrocytomas. Widely accepted indications for subtotal resection include increased intracranial pressure, neurologic deficit caused by mass effect or hemorrhage or impending herniation, the presence of necrotic tumor cysts, and uncontrollable seizures. These procedures, increasingly performed with the patient awake and in an operating room offering MRI guidance, commonly improve clinical deficits. In general resection is performed for tumors lying in the poles of the frontal or temporal cortex, but preoperative MRI mapping of both gray and white matter functions has expanded the surgical arena. Aids to the surgeon also include tumor resection based on intraoperative MRI or MRI roadmaps, intraoperative cortical stimulation mapping, and monitoring of somatosensory evoked potentials.

Low-Grade Cliomas

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After diagnosis and therapy, approximately one quarter of recipients of radiation therapy are eligible for decompression of recurrent tumors or the removal of necrotic debris. Radiation Therapy

The role of radiation therapy in the early treatment of low-grade ghomas is controversial. Observation every 4 months is usually indicated. However, radiation is recommended for patients with progressive symptoms or tumor expansion, uncontrolled seizures, or steroid dependence or those whose tumors have undergone focal anaplasia (seen on MRI, PET, or single photon emission computed tomography scans). For these patients we use external beam radiation therapy in fractions of 180 to 200 cGy, 5 days per week, to a total dosage of 50 to 60 Gy. The radiation field includes the area of radiographically identifiable tumor and a margin of 1 to 2 cm. The latter is necessary because of the infiltrative character of most gliomas. For pilocytic astrocytomas that might necessitate radiation, a margin of 0.5 cm is sufficient. Stereotactic radiosurgery is rarely used for low-grade gliomas, although many centers are exploring the role of fractionated stereotactic external beam radiation using gamma knife or linear accelerator technologies. The disinclination to premature radiation therapy reflects the common occurrence of serious long-term adverse effects in survivors of low-grade gliomas. These reactions include acute, early-delayed and late-delayed toxicities. Within 10 days of the start of irradiation patients become fatigued and have altered appetite and sleep patterns as an effect of increased brain swelling and MRI-detected brain edema. There is probably demyelination. Six to 18 months after radiation, contrast-enhancing edematous masses may reflect radiation-induced white matter necrosis poorly distinguished from tumor recurrence."FDG-PET or thallium-20 1 single photon emission computed tomography discloses diminished ligand uptake. The process responds to corticosteroid treatment and may be resected. Additional complications include pan-hypothalamic-pituitary dysfunction or elevated prolactin levels and impotence or amenorrhea.

Chemotherapy Chemotherapy for low-grade gliomas is usually limited to patients whose unresectable tumors are progressively symptomatic or harbor likely anaplastic foci. Radiation therapy should be tried first in those cases unless an oligodendroglial component is present. Chemotherapy may be a logical approach to radiationresistant multifocal low-grade tumors or the neoplastic encephalitis of gliomatosis cerebri. Chemotherapy carries the long-term risk of inducing hematologic malignancies (5% at 5 years) or sterility. Nitrosoureas are the most widely used group of chemotherapeutic agents. They alkylate DNA and produce crosslinks within the DNA double strand. CCNU (1-(2-~hloroethyl)3-cyclohexyl-1-nitrosourea;lomustine) and BCNU (1,3-bis (2chloroethyl) - 1-nitrosourea; carmustine) are the most commonly used agents of this group. They are used either as a single agent or in combination with other chemotherapeutic drugs. Procarbazine is an oral methylating agent. It is used mostly in combination chemotherapy protocols to treat oligodendroglial-containing tumors. The vinca alkaloid vincristine inhibits microtubule assembly, resulting in mitotic arrest. Long-term use produces a large fiber neuropathy. Temozolomide, a derivative of the methylating agent dacarbazine, is a new oral agent used to treat anaplastic glial tumors but is under exploration for lower grades. The combina-

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Neuro-Oncology W

Specific Tumor Types

tion procarbazine, lomustine, and vincristine (PCV) has become standard therapy for oligodendroglial and oligoastrocytic tumors of anaplastic grades and more benign histologies. New approaches including angiogenesis inhibitors (such as thalidomide, penicillamine, and tetracycline analogues), kinase inhibitors (such as the experimental agent imatinib mesylate), and viral vector (adenoviral and herpes viral) gene therapies are being studied. SPECIFIC HISTOLOGIC SUBTYPES Astrocytic Tumors Diffuse Astrocytoma (WHO ll/lV). The cells of the diffuse astrocytomas appear cytologically benign but infiltrate surrounding brain tissue. It is a tumor of young adulthood Symptoms appear either during the first or between the third and fourth decades. It represents fewer than 10% of brain tumors, and there is a slight male predominance. Seizures herald the appearance of a lesion, and a careful history often discloses symptoms of many years or decades. Commonly afflicted are the frontal and temporal lobes of the cerebral hemispheres, where MRI studies reveal poorly demarcated hypointense T1- and hyperintense T2-weighted lesions (Fig. 157-2). Diffusion-weighted images may show limited diffusion, and there is little evidence of enhancement after administration of gadolinium. Surgically resected material contains one of three main subtypes: fibrillary, protoplasmic, and gemistocytic astrocytoma (in order of frequency). The gemistocytic subtype is prone to anaplastic progression usually after 4 or 5 years. Surgery, commonly gross total resection, often is followed by irradiation and rarely chemotherapy. Asymptomatic, nonresectable, diffuse astrocytomas are followed with quarterly and then semiannual MRI scans. The median survival is in the range of 5-7 years. Favorable outcomes follow gross total resection of tumors in young patients. Less than one quarter of patients who undergo gross total resection are likely to relapse after 11 years. Pilocytic Astrocytoma (Juvenile Pilocytic Astrocytoma; WHO I/w. Pilocytic astrocytoma, occurring in the first and second

decade, has an excellent prognosis and is cured by surgery. The

FIG. 157-2. T2-weighted magnetic resonance image of a 32-year-old man who presented to his doctor when he felt off balance after scuba diving. A right frontal nonenhancing mass lesion was identified. Biopsy revealed an infiltrating astrocytoma. He underwent gross total resection. He is being treated for symptomatic epilepsy. . . . Four years after his surgery, the tumor has not recurred.

FIG. 157-3. T I -weighted magnetic resonance image with gadolinium

of a 17-year-old girl. She had experienced almost monthly spells of vertigo and headache over the course of 3 years until a head computed tomogram done after a minor head trauma eventually led to the diagnosis of a cystic, partially nodular enhancing cerebellar mass. The tumor was resected. Histopathologic diagnosis was pilocytic astrocytoma.

tumor probably arises from true astrocytes or subependymal precursors. It accounts for 6% of all primary brain tumors and 85% of infratentorial astrocytomas, most located in the cerebellum (Fig. 157-3). The remainder grow in the hypothalamus, the walls of the third ventricle, the optic pathway, and the brainstem. Pilocytic astrocytoma, usually of the optic nerve, is the most common central nervous system tumor associated with neurofibromatosis type I. The tumor diagnosis is heralded by symptomatic obstructive hydrocephalus, headache, or hypothalamic and pituitary dysfunction. Posterior fossa signs include neck stiffness, head tilt, and incoordination. Unique among low-grade gliomas, the masses enhance with gadolinium and appear in proximity to the ventricle or subarachnoid space. Cysts, focal hemorrhage, and calcification are described. Much of the tumor contains benign features: bipolar (piloid) cells with Rosenthal fibers in addition to microcysts surrounded by protoplasmic astrocytes and eosinophilic granular bodies. Three quarters of patients undergo surgical resection, often to the roof of the fourth ventricle. Radiation therapy is seldom used because the 25-year survival rate is between 50% and 94% after surgical resection. Malignant transformation is unusual and may reflect the effects of prior therapy. Subependymal Giant Cell Astrocytoma (WHO l/lV). Subependymal giant cell astrocytoma (SEGA) should be viewed as a manifestation of tuberous sclerosis and may be unique to that disease. In a detailed search of the Mayo Clinic tissue registry, Shepherd et al (1991) found no patient with SEGA without tuberous sclerosis, although SEGA is reported in only 6.1% of patients afflicted with this phakomatosis. Hydrocephalus emerges before the third decade as tumors in the wall of the lateral ventricles or in the interventricular foramina obstruct cerebrospinal fluid outflow. Epilepsy of long-standing duration may change pattern. The well-circumscribed MRI masses rarely have hemorrhage or calcification but may show subtle enhancement. The tumor cells stain with glial (GFAP) and neuronal (synaptophysin and neuron-specific enolase) markers and may be mixed with large cells that resemble gemistocytic astrocytes, elongated tumor cells, and giant multinucleated pyramidal cells. Surgery is curative and is needed when the masses outgrow the confines of the ventricle.

Chapter 157

Pleomorphic Xanthoastrocytoma (WHO ll/llf). Pleomorphic xanthoastrocytoma is a rare superficial cortical glioma. In young people (two thirds of cases are diagnosed before age 25), seizures preceed diagnosis by 3 years. The cystic masses are in the temporal lobes and extend into the leptomeninges and Virchow-Robin spaces. Pleomorphic xanthoastrocytomas often are cystic but are well demarcated from surrounding tissue. The solid portion of the tumor usually enhances markedly on MRI with gadolinium (Fig. 157-4). On unenhanced TI-weighted images it is hypointense to isointense. The pleomorphic cells vary in size and shape and include single and multinucleated giant cells. The large cells accumulate lipids, hence the term mnthoastrocytorna. There is some uncertainty as to the true aggressive potential of the masses because mitoses and necrosis are seen and malignant forms have been identified. Cells of origin probably are subpial astrocytes. Complete resection is feasible in most patients. Radiation or chemotherapy may be necessary for aggressive or recurrent tumors. The survival is above 80% after 5 and 70% after 10 years, with completely resected lesions faring the best. Anaplastic transformation occurs in 15% to 20% of patients.

Oligodendroglial Tumors Oligodendroglioma (WHO ll/lV). Oligodendrogliomas probably emerge from cells of oligodendrocytic origin (02A progenitor cells), for which a molecular marker has recently been described. No risk factors have been identified, and familial occurrence is anecdotal. Formerly they accounted for fewer than 5% of gliomas, but neuropathologists are recognizing “o1igo”-containing tumors with increasing frequency. The true figure approaches one third of low-grade gliomas. Adults develop seizures between the fourth and sixth decade and are found to harbor masses arising from and expanding a single gyrus. The tumor grows along white matter tracts into basal ganglia and the corpus callosum. In children, thalamic locations predominate. Seizures, headache, and focal neurologic or psychiatric symptoms may precede diagnosis by 1 to 25 years. On MRI, the tumor appears demarcated from surrounding brain and is hypointense on T1- and hyperintense on T2-

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FIG. 157-5. T2-weighted magnetic resonance image of a left frontal low-grade oligodendroglioma in a 33-year-old woman. Generalized seizures were preceded by head pain. The scans revealed infiltration of surrounding cortex and a small cyst. The resected tumor contained more than 5% of cells labeled with MIB-1. procarbazine, lomustine, and vincristine chemotherapy was provided before involved field radiation therapy.

weighted images (Fig. 157-5). When gadolinium enhancement appears, the tumor is no longer low-grade. However, low-grade tumors can contain hemorrhage and calcification and be surrounded by edema. The best microscopic definition of oligodendroglioma lies in the characteristic monotonous “fried-egg” cells that inhabit it. Central round nuclei are surrounded by swollen and pale cytoplasm. Between cells, a “chicken wire” pattern appears, reflecting the reticulin staining of the dense vascular meshwork. Another feature is microgemistocytic cells, which stain with GFAP. Mitoses are rare, and MIB- 1 staining is usually positive in a small percentage of cells. The tumor, along with infiltrative astrocytoma and gliomatosis cerebri, infiltrates normal brain. Gross total resection is recommended when safely feasible, but microscopic infiltrates always remain. Adjuvant radiation therapy immediately thereafter usually is not beneficial. The mean survival time of patients is between 4 and 11 years depending on the histology, extent of resection, and provision of chemotherapy. The clinician should be aware of features that suggest a more aggressive behavior. These include contrast enhancement with gadolinium, the presence of mitoses, and MIB-1 staining rates above 5%. It has become increasingly apparent is that these tumors, either lowgrade or anaplastic, respond to chemotherapy with PCV. Seventy percent of patients with anaplastic oligodendrogliomas completely respond to PCV, with tumor control exceeding 16 months. Tumors with chromosome l p loss or the combined loss of l p and 19q are most likely to respond to these agents or others (BCNU, cisplatin, carboplatinum, or temozolomide). We provide PCV therapy to benign oligodendrogliomas that cannot be resected, are symptomatic, contain more aggressive features, or have demonstrated brain infiltration. It is not clear whether this therapy need be given before radiation is provided, but this has been our approach.

FIG. 157-4. Coronal TI-weighted magnetic resonance image of a

Mixed Gliomas

25-year-old woman with a 3-year history of complex partial epilepsy (auditory illusions, hallucinations) shows an enhancing mass in the superior temporal gyrus on the left side. She undenrvent gross total resection of the tumor, which proved to be a pleomorphic xanthoastrocytoma.

Oligoastrocytoma (WHO ll/lV). These tumors are similar to oligodendroglioma (Fig. 157-6). The oligodendroglia and astrocytic cell types may arise from a single progenitor cell to produce oligodendroglial differentiation adjacent to or intermingled with

1030

Neuro-Oncology rn Specific Tumor Types

has been aided by the use of endoscopic techniques and intraoperative MRI scanning. Mixed Neuronal-GIial Tumors

FIG. 157-6. Left frontotemporal oligoastrocytoma 01-weighted procarbazine, lomustine, and vincristine without gadolinium) in an 18-year-old man who had a generalized convulsion after abuse of an oxycodone-containing analgesic. He underwent subtotal resection.

astrocytic areas. Both components must be present to some degree to confirm the diagnosis of an oligoastrocytoma, but the diagnoses are hazy in the setting of tumors in which one cell type predominates. Therefore, we have assumed that any oligodendroglid component conveys the chemotherapy sensitivity to the entire mass. The true occurrence of this tumor is uncertain because one cell type may predominate, and the clinical and radiographic appearance are not distinguished from infiltrative glioma or oligodendroglioma. An accurate diagnosis of this mixed glial tumor has great clinical significance because oligoastrocytomas share with oligodendrogliomas a notable response to PCV chemotherapy. Oligodendrogliomas and oligoastrocytomas that respond to chemotherapy exhibit chromosome l p and 19q deletions. The current median survival of 4 to 6 years will be altered by future provision of drug therapy to patients with these deletions. Neuroepithelial Tumors of Unknown Origin Chordoid Clioma of the Third Ventricle (WHO ll/lV). Chordoid gliomas usually occur in the third ventricle of adult women. Intracranial hypertension causing lethargy, headache, and ataxic gait and visual difficulties from tumor compression of the optic chiasm are the most common symptoms. As with other tumors in proximity to the hypothalamus (gangliocytoma, pineal area tumors, brain lymphoma, and craniopharyngioma) there may be hypogonadotropic hypogonadism, amenorrhea, hypothyroidism, or fluid balance disorders. Within the third ventricle, probably contiguous with the hypothalamus or suprasellar structures, there appears to be a well-defined mass that enhances on MRI scans with gadolinium. It may contain cysts. The tumor cells, in an epithelioid pattern within a mucoid matrix, stain for GFAP, vimentin, and CD34. The cell of origin probably is ependymal because electron microscopy reveals microvilli and focal basal lamina production. Mitotic activity usually is absent, but infiltrates with lymphoplasmacytic cells are common. Chromosomal and genetic alterations present in other types of gliomas (e.g., TP53 mutations, EGFR amplification) have not been found. The excellent prognosis reflects the extent of surgical resection. Surgery

Persisting precursor elements in the temporal lobes or third ventricle can give rise to ganglioglioma or desmoplastic astrocytoma. Canglioglioma (WHO I/IV or ll/lV). Gangliogliomas contain two cell populations: gangliocytes and mature glial elements derived from primitive bipotential precursors. These tumors contain more glial elements before than seen with gangliocytomas of the third and lateral ventricles. Gangliogliomas usually occur in children and young adults the age of 30 years. They are a common finding in large series of recipients of epilepsy surgery. Seizure durations ranging from 1 month to 28 years have been reported. Also seen are headaches. The temporal lobes (30% to 84%) are a common but not the sole location. On MRI they appear as T1-hypointense masses, with more than half of cases exhibiting gadolinium enhancement (Fig. 157-7). The avascular mass reveals decreased metabolic activity when imaged with '*FDG-PET. Lacking a true capsule, the tumor contains dysmorphic malmigrated neuronal cells and astrocytoma elements containing fibrillary, pilocytic, gemistocytic astrocytes or rarely oligodendroglia. Reactive or degenerative changes include perivascular lymphocytes, calcification, and foci of cortical dysplasia. The benign appearance can give rise to anaplastic changes in 4% to 32% of cases. Cytogenetic and molecular data are unavailable. The treatment is surgical resection followed by radiation therapy for subtotally resected anaplastic tumors or those that progress after surgery. Two thirds of patients survive 4 years, mostly with good quality of life. When anaplastic transformation and recurrence occur, the glial component is affected. At this juncture, it is appropriate to provide radiation therapy. Desmoplastic Infantile Astrocytoma and Canglioglioma (WHO l/lV). Desmoplastic infantile astrocytoma and gan-

glioglioma (DIA and DIG) are rare supratentorial tumors containing two low-grade elements. Manifesting during the first 2 years of life, DIG is more common in boys. DIA has a female predominance. Intracranial hypertension (bulging fontanelles, increased head circumference) reflects compression of brain by this extraaxial mass, which is attached to the dura mater. Seizures may

FIG. 157-7. Ganglioglioma within the right hemisphere of a 36-year-old woman who presented with a secondarily generalized simple partial seizure. The tumor was resected and has not recurred 5 years after surgery. Sagittal T1 -weighted magnetic resonance imaging with gadolinium enhancement.

Chapter 158 H

occur. Subpial astrocytes capable of producing an extensive basal lamina give rise to DIA, which contain large cysts. Attached to these are small, densely cellular superficial nodules that enhance on MRI. There is a predilection for frontoparietal areas. The nodules are firm and contain neoplastic astrocytes-plump, a elongated spindle cells strongly positive on GFAP stains-in dense desmoplastic matrix. The astrocytes are commonly pleomorphic and atypical. DIG contains neuronal elements and exhibits loss of heterozygosity for 17p and 10 q. With either tumor, long-term survival after surgical resection is the rule, so adjuvant treatment is seldom necessary.

SUGGESTED READINGS Ahmed Rasheed BK, Wiltshire RN, Bigner SH, Bigner DD: Molecular pathogenesis of malignant gliomas. Curr Opin Oncol 11:162-167, 1999 Bartolomei JC, Christopher S, Vives K et ak Low-grade gliomas of chronic epilepsy: a distinct clinical and pathological entity. J Neurooncol 34:79-84,1997 Berger MS, Rostomily R C Low grade gliomas: functional mapping resection strategies, extent of resection, and outcome. J Neurooncol 34235-101, 1997 Brat DJ, Scheithauer BW, Staugaitis SM et ak Third ventricular chordoid glioma: a distinct clinicopathologic entity. J Neuropathol Exp Neurol 57~283-290,1998 Daumas-Duport C, Tucker ML, Kolles H et ak Oligodendrogliomas. Part 11: a new grading system based on morphological and imaging criteria. J Neurooncol 34:61-78, 1997 Daumas-Duport C, Varlet P, Tucker ML et ak Oligodendrogliornas.Part I: patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neurooncol 3437-59, 1997 Dirven CMF, Mooij JJA,Molenaar WM: Cerebellar pilocytic astrocytoma: a treatment protocol based upon analysis of 73 cases and a review of the literature. Childs Nerv Syst 13:17-23, 1997 Fortin D, Cairncross GJ, Hammond RR: Oligodendroglioma: an appraisal of recent data pertaining to diagnosis and treatment. Neurosurgery 45:1279-1291, 1999 Freeman CR, Farmer JP, Montes J: Low-grade astrocytornas in children: evolving management strategies. Int J Radiat Oncol Biol Phys 41~979-987,1998 Giannini C, Scheithauer BW, Burger PC et ak Pleomorphic xanthoastrocytoma. What do we really know about it? Cancer 85:2033-2045, 1999

Optic Pathway and Hypothalamic Cliomas

1031

Hakim R, Loeffler JS, Anthony DC, Black PM: Gangliogliomas in adults. Cancer 79127-131, 1997 Hildebrand J, Dewitte 0, Dietrich PY, de Tribolet N: Management of malignant brain tumors. Eur Neurol 38:238-253, 1997 Hill JR, Kuriyama N, Kuriyama H, Israel MA: Molecular genetics of brain tumors. Arch Neurol56439-441, 1999 Kepes JJ: Pleornorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol 3:269-274, 1993 Kleihues P, Cavenee WK: Pathology and genetics of tumours of the nervous system. 2nd Ed. Oxford University Press, Oxford, UK, 2000 Knisely JPS, Haffty BG, Christopher S R Early vs. delayed radiotherapy in a small cohort of patients with supratentorial low grade glioma. J Neurooncol 3423-29, 1997 Linskey ME Glial ontogeny and glial neoplasia: the search for closure. J Neurooncol 345-22, 1997 Louis DN, von Deimling A, Dickersin GR et al: Desmoplastic cerebral astrocytornas of infancy: a histopathologic, immunohistochemical, ultrastructural, and molecular genetic study. Hum Pathol 23:14021409, 1992 McLendon RE, Enterline DS, Tien RD et al: Tumors of central neuroepithelial origin. In Bigner DD, McLendon RE, Bruner JM (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System. 6th Ed. Arnold, 1998 Piepmeyer J, Christopher S, Spencer D et al: Variations in the natural history and survival of patients with supratentorial low-grade astrocytomas. Neurosurgery 38:872-878, 1996 Reifenberger G,Weber T, Weber RG et ak Chordoid glioma of the third ventricle: immunohistochemical and molecular genetic characterization of a novel tumor entity. Brain Pathol9:617-626, 1999 Rumana CS,Valadka AB Radiation therapy and malignant degeneration of benign supratentorial gangliogliomas.Neurosurgery 42:1038-1043, 1998 Selch MT, Goy BW, Lee SP et al: Gangliogliomas. Experience with 34 patients and review of the literature. Am J Clin Oncol 21:557-564, 1998 Shepherd CW, Scheithauer BW, Gomez MR et al: Subependymal giant cell astrocytoma: a clinical, pathological, and flow cytometric study. Neurosurgery 282364-868, 1991 VandenBerg S R Desmoplastic infantile gangliogliorna and desrnoplastic cerebral astrocytoma of infancy. Brain Pathol 3:275-281, 1993 Zentner J, Wolf HK, Ostertun B et al: Gangliogliomas:clinical, radiological, and histopathological findings in 51 patients. J Neurol Neurosurg Psychiatry 57:1497-1502, 1994

158 Optic Pathway and Hypothalamic Gliomas Nancy J. Tarbell and Patrick D. Barnes Optic gliomas are rare and account for approximately 1% to 5% of intracranial gliomas. Their overall incidence is approximately 1 in 105,000 patients. They are most common in children (75% in the first decade and 90% within the first two decades). The location is of significant therapeutic and prognostic importance. Tumors involving the optic nerve alone are associated with a better prognosis than intracranial gliomas involving the optic chiasm and tracts. Tumors involving the optic chiasm often cannot be separated from those arising in the hypothalamus, and for management purposes these tumors generally are considered together.

The occurrence of neurofibromatosis- 1 (NF-1) in patients with optic glioma ranges from 10% to 50%. Conversely, the frequency of optic gliomas in patients with NF- 1 has been estimated at 1% to 5%. However, a 15% incidence of enlargement of the optic nerve o r chiasm o n computed tomography (CT) or magnetic resonance imaging (MRI) has been reported in asymptomatic patients with NF-1. These findings may represent an early optic glioma, gliosis, hamartoma, o r (rarely) neurofibroma. These uncertainties emphasize the need for clinical symptoms or biopsy before initiating treatment in patients with imaging evidence of optic pathway abnormalities.

Chapter 158 H

occur. Subpial astrocytes capable of producing an extensive basal lamina give rise to DIA, which contain large cysts. Attached to these are small, densely cellular superficial nodules that enhance on MRI. There is a predilection for frontoparietal areas. The nodules are firm and contain neoplastic astrocytes-plump, a elongated spindle cells strongly positive on GFAP stains-in dense desmoplastic matrix. The astrocytes are commonly pleomorphic and atypical. DIG contains neuronal elements and exhibits loss of heterozygosity for 17p and 10 q. With either tumor, long-term survival after surgical resection is the rule, so adjuvant treatment is seldom necessary.

SUGGESTED READINGS Ahmed Rasheed BK, Wiltshire RN, Bigner SH, Bigner DD: Molecular pathogenesis of malignant gliomas. Curr Opin Oncol 11:162-167, 1999 Bartolomei JC, Christopher S, Vives K et ak Low-grade gliomas of chronic epilepsy: a distinct clinical and pathological entity. J Neurooncol 34:79-84,1997 Berger MS, Rostomily R C Low grade gliomas: functional mapping resection strategies, extent of resection, and outcome. J Neurooncol 34235-101, 1997 Brat DJ, Scheithauer BW, Staugaitis SM et ak Third ventricular chordoid glioma: a distinct clinicopathologic entity. J Neuropathol Exp Neurol 57~283-290,1998 Daumas-Duport C, Tucker ML, Kolles H et ak Oligodendrogliomas. Part 11: a new grading system based on morphological and imaging criteria. J Neurooncol 34:61-78, 1997 Daumas-Duport C, Varlet P, Tucker ML et ak Oligodendrogliornas.Part I: patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neurooncol 3437-59, 1997 Dirven CMF, Mooij JJA,Molenaar WM: Cerebellar pilocytic astrocytoma: a treatment protocol based upon analysis of 73 cases and a review of the literature. Childs Nerv Syst 13:17-23, 1997 Fortin D, Cairncross GJ, Hammond RR: Oligodendroglioma: an appraisal of recent data pertaining to diagnosis and treatment. Neurosurgery 45:1279-1291, 1999 Freeman CR, Farmer JP, Montes J: Low-grade astrocytornas in children: evolving management strategies. Int J Radiat Oncol Biol Phys 41~979-987,1998 Giannini C, Scheithauer BW, Burger PC et ak Pleomorphic xanthoastrocytoma. What do we really know about it? Cancer 85:2033-2045, 1999

Optic Pathway and Hypothalamic Cliomas

1031

Hakim R, Loeffler JS, Anthony DC, Black PM: Gangliogliomas in adults. Cancer 79127-131, 1997 Hildebrand J, Dewitte 0, Dietrich PY, de Tribolet N: Management of malignant brain tumors. Eur Neurol 38:238-253, 1997 Hill JR, Kuriyama N, Kuriyama H, Israel MA: Molecular genetics of brain tumors. Arch Neurol56439-441, 1999 Kepes JJ: Pleornorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol 3:269-274, 1993 Kleihues P, Cavenee WK: Pathology and genetics of tumours of the nervous system. 2nd Ed. Oxford University Press, Oxford, UK, 2000 Knisely JPS, Haffty BG, Christopher S R Early vs. delayed radiotherapy in a small cohort of patients with supratentorial low grade glioma. J Neurooncol 3423-29, 1997 Linskey ME Glial ontogeny and glial neoplasia: the search for closure. J Neurooncol 345-22, 1997 Louis DN, von Deimling A, Dickersin GR et al: Desmoplastic cerebral astrocytornas of infancy: a histopathologic, immunohistochemical, ultrastructural, and molecular genetic study. Hum Pathol 23:14021409, 1992 McLendon RE, Enterline DS, Tien RD et al: Tumors of central neuroepithelial origin. In Bigner DD, McLendon RE, Bruner JM (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System. 6th Ed. Arnold, 1998 Piepmeyer J, Christopher S, Spencer D et al: Variations in the natural history and survival of patients with supratentorial low-grade astrocytomas. Neurosurgery 38:872-878, 1996 Reifenberger G,Weber T, Weber RG et ak Chordoid glioma of the third ventricle: immunohistochemical and molecular genetic characterization of a novel tumor entity. Brain Pathol9:617-626, 1999 Rumana CS,Valadka AB Radiation therapy and malignant degeneration of benign supratentorial gangliogliomas.Neurosurgery 42:1038-1043, 1998 Selch MT, Goy BW, Lee SP et al: Gangliogliomas. Experience with 34 patients and review of the literature. Am J Clin Oncol 21:557-564, 1998 Shepherd CW, Scheithauer BW, Gomez MR et al: Subependymal giant cell astrocytoma: a clinical, pathological, and flow cytometric study. Neurosurgery 282364-868, 1991 VandenBerg S R Desmoplastic infantile gangliogliorna and desrnoplastic cerebral astrocytoma of infancy. Brain Pathol 3:275-281, 1993 Zentner J, Wolf HK, Ostertun B et al: Gangliogliomas:clinical, radiological, and histopathological findings in 51 patients. J Neurol Neurosurg Psychiatry 57:1497-1502, 1994

158 Optic Pathway and Hypothalamic Gliomas Nancy J. Tarbell and Patrick D. Barnes Optic gliomas are rare and account for approximately 1% to 5% of intracranial gliomas. Their overall incidence is approximately 1 in 105,000 patients. They are most common in children (75% in the first decade and 90% within the first two decades). The location is of significant therapeutic and prognostic importance. Tumors involving the optic nerve alone are associated with a better prognosis than intracranial gliomas involving the optic chiasm and tracts. Tumors involving the optic chiasm often cannot be separated from those arising in the hypothalamus, and for management purposes these tumors generally are considered together.

The occurrence of neurofibromatosis- 1 (NF-1) in patients with optic glioma ranges from 10% to 50%. Conversely, the frequency of optic gliomas in patients with NF- 1 has been estimated at 1% to 5%. However, a 15% incidence of enlargement of the optic nerve o r chiasm o n computed tomography (CT) or magnetic resonance imaging (MRI) has been reported in asymptomatic patients with NF-1. These findings may represent an early optic glioma, gliosis, hamartoma, o r (rarely) neurofibroma. These uncertainties emphasize the need for clinical symptoms or biopsy before initiating treatment in patients with imaging evidence of optic pathway abnormalities.

1032

Neuro-Oncology

Specific Tumor Types

Because of the rarity of this tumor, the diagnostic and therapeutic approaches have been controversial. Anecdotal cases of spontaneous regression have been reported, supporting the view that these tumors may have an indolent course. However, a more aggressive natural history with tumor progression and death has been documented in most long-term reports. Untreated intracranial optic system tumors progress locally or cause death in 75% of patients. Most optic gliomas are slow-growing and histologically low-grade astrocytomas. The occurrence of high-grade astrocytomas or tumors with other histologies is unusual. Rarely, supratentorial low-grade astrocytomas of the chiasmatic and hypothalamic area have been reported to undergo malignant transformation. Hypothalamic tumors have been reported to have a less favorable prognosis than tumors confined to the chiasm. However, with CT and MRI it is now clear that most chiasmic tumors involve the hypothalamus as well. Chiasmal gliomas are further characterized according to their involvement of surrounding structures, including the optic nerves, optic tracts, and hypothalamus (Fig. 158-1).

CLINICAL PRESENTATION, STAGING AND WORKUP Optic chiasm lesions present with unilateral or bilateral loss of vision and often with visual field cuts or hypothalamic dysfunction. Funduscopic examination usually reveals a pale optic disk. Cranial nerve deficits and hydrocephalus may be present. Endocrine dysfunction, particularly precocious puberty, is not uncommon. Typical presenting signs and symptoms are listed in Table 158-1. Visual abnormalities are almost always present. The diencephalic syndrome (emesis, emaciation, and euphoria) may be associated with more posterior tumors centered at the hypothalamus. The clinical presentations of hypothalamic tumors are more varied and include gelastic epilepsy, visual deficits, increased intracranial pressure caused by extension into the third ventricle and foramina of Monro, behavioral changes, and endocrine dysfunction. The history and general physical examination should involve a search for evidence of NF- 1, and the workup should include baseline neuroendocrine studies and formal visual field testing.

TAME158-1. Signs and Symptoms Approximate %

Visual abnormality Visual acuity Field cuts Both Endocrine Precocious puberty Diabetes insipidus Neurologic Ataxia Headache Seizure Macrocephaly Personality change Papilledema Cranial nerve palsy

95 50 25 20

35 30 8 50 15 15 15 10

5 5 5

RADIOLOGIC EVALUATION MRI including contrast enhancement is now preferred to CT for initial and follow-up imaging evaluation (Fig. 158-1). Thin sections through the optic nerves and chiasm allow excellent definition of the extent of disease. Optic gliomas may cause concentric enlargement of one or both optic nerves, an enlarged chiasm, or abnormalities of the optic tracts. Most tumors exhibit contrast enhancement. Neurofibroma occurs rarely in children with neurofibromatosis, appearing as a large eccentric optic nerve mass. The differential diagnosis of a suprasellar mass in a child includes craniopharyngioma, germ cell tumors, ectopic pinealoma, and (in older patients) a pituitary adenoma or meningioma. Serum and cerebrospinal fluid tests a-fetoprotein, and human chorionic gonadotrophin should be performed if germ cell tumors are considered. In patients with NF- 1, dysplastic intensities often are present and may not be readily distinguished from extension of the optic tumor (Fig. 158-1).

THERAPY Controversy over optimal therapy still exists. Alvord and Lofton (1988) reviewed 623 cases in the literature and confirmed that most optic system tumors are low-grade astrocytomas with a variable but nonetheless continuous growth rate.

Surgery Surgery for initial management of intracranial chiasmal and hypothalamic lesions usually is limited to biopsy because resection is not possible without morbidity such as visual impairment and hypothalamic dysfunction. Placement of a ventricular catheter may be needed to relieve hydrocephalus. In special circumstances partial resection may be warranted, such as for exophytic and recurrent tumors. Although a biopsy is indicated in most patients, it may not be necessary in patients with NF-1, progressive symptoms, and characteristic imaging findings.

Radiotherapy Most modern reports using megavoltage radiotherapy document an advantage for patients with progressive chiasmal gliomas. Radiotherapy generally is the treatment of choice for symptomatic chiasmatic and hypothalamic gliomas in older children. The age at which radiation therapy becomes the standard has more recently been raised. Certainly after the age of puberty radiation therapy would be standard. Under age 7 most would recommend chemotherapy first. Between the ages of 7 and 10 years the choice of first treatment is debatable. Many recent series report excellent survival after radiotherapy, generally 90% at 10 years (Pierce et al., 1990; Horwich and Bloom, 1985). However, it is not uncommon for deaths to result from disease progression many years after treatment. This emphasizes the need for long-term follow-up. Visual outcome is an important measure of treatment success for chiasmal or hypothalamic gliomas. After radiotherapy, an improvement in vision is seen in approximately one third of patients, with most patients experiencing visual stabilization (Table 158-2). This success in maintaining or improving vision is possible only if treatment is initiated before severe visual damage has occurred. Therefore, documented visual deterioration is a major indication to initiate therapy promptly.

Chapter 158

Optic Pathway and Hypothalamic Gliomas

1033

FIG. 158-1. A 2-year-old girl with optic hypothalamic astrocytoma. (A) CT shows a nonspecific suprasellar mass (asterisk). (6) Sagittal TI -weighted MRI demonstrates the optic/hypothalamic tumor (usterisk), which markedly enhances with gadolinium (arrows) on the axial T1-weighted MRI (C). (0)Axial proton density and T2-weighted MRI show the optic tract involvement (arrows). In patients with neurofibromatosis-1, such involvement is difficult to distinguish from the dysplastic foci of neurofibromatosis.

Newer techniques such as protons and stereotactic radiotherapy should decrease the late effects of radiation.

Chemotherapy Chemotherapy has been increasingly used. Schmandt and Packer (2001) has updated the results of treatment with vincristine and

actinomycin for recurrent tumors or newly diagnosed optic gliomas in children younger than 6 years of age. This regimen appears to stabilize disease and allows radiotherapy - . to be delayed in most of patients. The use of chemotherapy for young patients (under 7 years of age) may allow a delay in radiotherapy and a reduction in the frequency and severity of radiation sequelae. More recently, national protocols accrue patients to

__

1034

Neuro-Oncology

Specific Tumor Types

rn TABLE158-2. Survival and Visual Response After Radiation Author

Honrvich, 1988

Pierce, 1990

No. of Patients

Control (NoJPatienk)

10-Yr Survey (%)

Vision Improved (%)

29 24

26/29 21/24

93 100

43 30

chemotherapy protocols if patients are less than 10 years old at treatment.

COMPLICATIONS Retrospective studies of long-term radiotherapy complications have been confounded by the fact that many of these children have associated learning disabilities related to NF-1. Pierce et al. (1990) reported some evidence of increased learning disabilities or decreased memory after treatment, in contrast to a smaller number of children who had definite evidence of learning disabilities before radiotherapy. Most but not all of these patients had NF- 1. The occurrence of neurologic abnormalities associated with chiasmal or hypothalamic glioma after treatment is difficult to define. Visual abnormalities and psychological trauma undoubtedly contribute to learning difficulties, but they are difficult to quantify. Neuropsychological testing is recommended before and after treatment to define the cognitive impairment better and to indicate the need for and timing of intervention. Imaging findings of calcifications, white matter abnormalities, and atrophy have been reported in patients after radiotherapy. The clinical significance of these findings remains uncertain in most cases. Neuroendocrine abnormalities may be the consequence of tumor involvement or treatment effects. Therefore, careful endocrine evaluation and monitoring is important not only at presentation but for many years after treatment. This is especially critical for children because hormonal replacement is crucial to normal development. Another reported complication of radiotherapy is Moyamoya syndrome. This syndrome is named for the characteristic angiographic appearance (“puff of smoke”) of arterial collaterals at the base of the brain associated with progressive narrowing of one or both internal carotid arteries; it manifests as repetitive ischemic episodes. Potential late complications after radiotherapy also include hemorrhage and the rare risk of second malignancies. Patients with NF-1 already have a higher risk of malignant tumors, and this risk may increase after radiotherapy.

CONCLUSIONS Gliomas of the optic pathway and hypothalamus present with visual deterioration, endocrine disorders, and neurologic abnor-

malities. These are the most common tumors in children with NF-1. With rare exceptions the course is progressive, albeit variable. Radiotherapy appears to affect disease-free progression and overall survival significantly. Most patients experience improvement or stabilization in vision, demonstrating a clear benefit of radiotherapy for progressive disease. The endocrine and neuropsychological consequences of the tumor and treatment are significant and warrant careful follow-up. Chemotherapy for the young (less than age 7 and perhaps less than age 10) appears warranted to delay radiotherapy.

SUGGESTED READINGS Alvord EC, Lofton S Gliomas of the optic nerve or chiasm. J Neurosurg 68~85-98, 1988

Balcer LJ, Liu GT, Heller G et al: Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Am J Ophthalmol 131(4): 44245,2001

Barnes P, Kupsky W, Strand R Cranial and intracranial tumors. p. 204. In Wolpert S, Barnes R (eds):MRI in Pediatric Neuro-Radiology. Mosby, St. Louis, 1992 Eliason MJ: Neuropsychological patterns: neurofibromatosis compared to developmental learning disorders. Neurofibromatosis 1:17-25, 1988

Haugh RM, Markesbery WR Hypothalamic astrocytoma: syndrome of hyperphagia, obesity, and disturbances of behavior in endocrine and autonomie function. Arch Neurol 40:500-563, 1983 Horwich A, Bloom HJG Optic gliomas: radiation therapy and prognosis. Int J Radiat Oncol Biol Phys 11:1067-1079, 1985 Lewis RA, Gerson LP, Axelson RA et ak Neurofibromatosis: 11. Incidence of optic gliomata. Ophthalmology 91:929-935, 1984 Parsa CF, Hoyt CS, Lesser RL et al: Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol 119(4):516-529,2001 Pierce SM, Barnes PD, Loeffler JS et al: Definitive radiation therapy in the management of symptomatic patients with optic glioma: survival and long-term effects. Cancer 65:45-52, 1990 Schmandt SM, Packer RJ: Treatment of low-grade pediatric gliomas. Curr Opin Oncol 12(3):194-198, 2000 Tao ML, Barnes PD, Billett AL et al: Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome. Int J Radiat Oncol Biol Phys 39(3):579-587, 1997 Wisoff J, Abbott R, Epstein F Surgical management of exophytic chiasmatic-hypothalamic tumors of childhood. J Neurosurg 73:661667, 1990

Chapter 159 W Brainstem Cliornas

1035

159 Brainstem Gliomas Dennis C. Shrieve

Brainstem gliomas are a heterogeneous group of tumors in terms of clinical presentation, histologic grade, and prognosis. The generic term bruinstem glioma refers to neoplasms arising in the rhombencephalon (medulla or pons) or the mesencephalon (midbrain). Tumors of the diencephalon (thalamus or hypothalamus) are included by some authors. Historically these tumors were considered under a single heading because of similarities in presenting symptoms, poor definition on pre-computed tomography (CT) imaging tests, difficulty in obtaining tissue diagnosis, and overall poor prognosis. More recently, advances in neuroimaging and neurosurgical techniques as well as results from cooperative group studies have identified pretreatment characteristics that define distinct prognostic groups.

EPIDEMIOLOGY Primary gliomas of the brainstem account for 10% to 15% of brain tumors in children, resulting in 250 to 300 cases each year in the United States. The incidence in adults is less well documented but probably accounts for less than 5% of primary adult gliomas. Therefore, brainstem gliomas are considered primarily a pediatric brain tumor. Median age at diagnosis in most studies is 5 to 7 years, with no clear male or female predominance. As is the case with other gliomas, the cause is unknown, but there may be an association with known congenital syndromes, most commonly neurofibromatosis.

PATHOLOGY Intrinsic brainstem gliomas are uniformly astrocytic in origin. All grades of astrocytoma may be found at biopsy: pilocytic astrocytoma, ordinary astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. However, prognosis is more closely correlated with appearance on magnetic resonance imaging (MRI) than with histopathology. At autopsy, malignant astrocytoma is uniformly present in patients with diffuse pontine glioma. Because biopsy is unreliable, does not change management or prognosis, and carries a significant risk of serious morbidity, surgical intervention, including biopsy, is not indicated in most patients presenting with diffuse pontine gliomas.

CLASSIFICATION Classification of brainstem gliomas may be made on the basis of tumor location and appearance on MRI scan (Table 159-1). Intrinsic brainstem gliomas are considered unresectable and may involve the midbrain, pons, or medulla alone or may span the entire brainstem. Tumors of the midbrain, with or without thalamic involvement, carry a better prognosis than tumors of the pons or medulla. Exophytic tumors of the dorsal aspect of the medulla or tectal plate or tumors that fd the fourth ventricle are amenable to surgical resection and are nearly uniformly of low-grade histology. Exophytic tumors with more anterolateral extension into the cerebellar pontine angle or posterolateral

extension into the cerebellum are commonly more invasive, high-grade tumors. Tumors may be classified as either diffuse or focal based on MRI appearance. Focal tumors are confined to one anatomic subsite of the brainstem and usually are defined as nonexpansile and less than 2.5 cm in greatest dimension. Diffuse tumors expand the subsite or entire brainstem (Fig. 159-1). Intrinsic tumors of the cervicomedullary junction represent a distinct subclass of brainstem lesions that are amenable to surgical resection and usually are of low-grade histology (Fig. 159-2).

CLINICAL PRESENTATION Most patients present with neurologic symptoms, including cranial nerve deficits, long tract signs, or ataxia. The classic presentation of a patient with an intrinsic brainstem tumor is multiple cranial nerve deficits and contralateral hemiparesis. Although patients may present with isolated cranial nerve findings, multiple or bilateral cranial neuropathies are present in 70%. The most commonly involved cranial nerves are VI and VII, followed by I11 and V. Patients with dorsally exophytic tumors or tumors of the tectum may present with symptoms referable to hydrocephalus caused by obstruction of the fourth ventricle or aqueduct. The duration of symptoms at presentation is of prognostic value. Patients with a shorter history of symptoms have a poorer prognosis than those with a more protracted course. Most modern studies have found that a history of symptoms of 2 months or less is associated with a poorer outcome than a longer history.

DIAGNOSIS Clearly any patient with cranial neuropathy, ataxia, or extremity weakness must be evaluated with whole-brain imaging. MRI with gadolinium is the examination of choice when brainstem glioma is suspected. The definition of the brainstem on axial, coronal, and sagittal sections is far superior to that obtained with CT. Sagittal MRI can be especially helpful in radiotherapy treatment planning.

T ~ L159-1. E Classification of Brainstern Cliornas Intrinsic location Midbrain or diencephalic Pontine or medullary Cervicomedullary MRI appearance Focal Diffuse Cystic Exophytic Tectal Fourth ventricular Anterolateral Poderolateral

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A

B

FIG. 159-1. (A) Diffuse pontine glioma in a 10-year-old boy. The patient received hyperfractionated radiotherapy (1 Cy twice daily to 7,200 cCy). (6)PostradiotherapyMRI showing response to treatment. Despite nearly complete radiographic response the patient died of local failure 15 months after radiotherapy.

DIFFERENTIAL DIAGNOSIS The distinct appearance of a diffuse pontine glioma on MRI scan usually is considered sufficient to make the diagnosis without histologic confirmation. Most institutions do not biopsy such lesions because the procedure is not without risk, the histology is malignant astrocytoma in more than 50% of cases, low-grade

histology does not change management or prognosis, and most patients present acutely and benefit from prompt - treatment. Such patients treated without biopsy make up an extremely poor prognostic group, thus validating this approach. Focal intrinsic brainstem lesions usually are associated with a more protracted history of symptoms, occur more commonly in older patients, and may be approached in a more conservative

A

,

FIG. 159-2. (A) Cervicomedullary tumor in a 4-year-old girl. The tumor was resected, and pathology studies showed pilocytic astrocytoma. (B) Follow-up scan 5 years after surgery showing no evidence of recurrence.

B

Chapter 159 rn BrainsternCliornas

manner. Biopsy usually is recommended because the probability of the diagnosis of low-grade astrocytoma is great and the possibility of the presence of a nonneoplastic process exists. Differential diagnosis of a focal nonexpansive lesion of the brainstem includes vascular malformation, cysticercosis, encephalitis, tuberculoma, arachnoid cyst of the clivus, multiple sclerosis, postinfectious encephalomyelitis, or other nonspecific inflammatory reactions (gliosis) (Fig. 159-3). Exophytic lesions usually are approached surgically for diagnosis as well as resection. These are often low-grade astrocytomas of the brainstem, but the differential diagnosis includes ependymoma and medulloblastoma. These tumors have in common a primary surgical approach. Adjuvant therapies are quite different depending on the histologic diagnosis and age of the patient. TREATMENT The role of surgery in the initial treatment of patients with brainstem glioma is limited. For diffuse pontine gliomas, surgery has no role and biopsy usually is not recommended. Surgery may be indicated for cervicomedullary, focal, cystic, or exophytic tumors. Biopsy (open or CT- or MRI-guided stereotactic) is indicated when the diagnosis of brainstem glioma is in doubt. For most patients radiotherapy is the primary treatment modality. For diffuse lesions radiation fields encompass the entire brainstem with adequate margin around the tumor. For focal lesions, fields may be less extensive, covering the tumor with a 2-cm margin. “Standard” fractionated radiotherapy ( 1.7 to 2.0 Gy/day) was used for many years with poor results. The addition of radiation sensitizers or chemotherapy has not improved survival in patients with poor prognoses. More recently, hyper-

W TMLE 159-2.

1037

Prognostic Factors in Children with Brainstem Cliomas PROGNOSIS

Characteristic

Poor

Better

Duration of symptoms Location Appearance on MRI Age

12 rno

>2

Pons/medulla Diffuse

Midbrain or thalamus Focal

S 6 vr

>6 vr

mo

fractionated radiotherapy has been used by several groups in an attempt to increase the total tumor dosage. Although these trials have resulted in escalation of the total dosage up to 78 Gy, no clear benefit has accrued using this approach. The addition of chemotherapy to either conventional or hyperfractionated radiotherapy in controlled studies has failed to improve outcome. At this time conventional radiotherapy of 54 to 56 Gy in daily fractions of 1.8 to 2.0 Gy must be considered standard therapy. PROGNOSIS Brainstem gliomas are a heterogeneous group of tumors in terms of presenting symptoms, appearance on imaging studies, histology, appropriate workup, therapy, and prognosis. In children, pretreatment characteristics define two distinct prognostic groups (Table 159-2). The most common subtype is the diffuse pontine glioma, associated with a short (less than 2-month) history of symptoms, typically in a younger (less than 7-year-old) patient. This constellation of presenting characteristics is pathognomonic, and biopsy is not warranted. Current treatment would be conventional radiotherapy. Median survival for this group of patients is approximately 1 year, with only rare survivors at 2 years. Focal brainstem lesions proven to be low grade on biopsy carry a much better prognosis. Intrinsic focal brainstem gliomas have up to 80% survival at 5 years after radiotherapy. Other special subtypes such as cervicomedullary tumors and dorsally exophytic lesions of the brainstem or tectum are amenable to surgery, and adjuvant radiotherapy may be withheld until the time of tumor regrowth. Brainstem gliomas in adults are less well characterized by prognostic factors. Overall survival has been reported to be better than in the pediatric group, probably because a higher proportion of poor-risk pediatric patients are entered on treatment protocols. Survival in adults appears to be correlated to histology and is comparable to survival of patients with similar astrocytic tumors of the cerebral hemispheres. SUGGESTLD READINGS Albright AL, Guthkelch N, Packer RJ et al: Prognostic factors in pediatric brain-stem gliomas. J Neurosurg 65:751, 1986 Barkovich AJ, Krischer J, Kun L E Brain stem gliomas: a classification system based on magnetic resonance imaging. Pediatr Neurosurg 1673, 1990

Berger MS, Edwards MSB, LaMasters D et ak Pediatric brain stem tumors: radiographic, pathological, and clinical correlations. Neurosurgery 12298, 1983

Edwards MSB, Prados M: Current management of brain stem gliomas.

FIG. 159-3. Focal lesion of the pons in a 43-year-old woman found on workup for headaches. The lesion was biopsied and found to be inflammatoly with no evidence of tumor. The patient was treated with a short course of steroids, and the lesion regressed slightly over a 6-month follow-up period.

Pediatr Neurosci 13:309, 1987 Edwards MSB, Wara WM, Ciricillo SF, Barkovich AJ: Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. J Neurosurg 8020, 1994

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Epstein F: A staging system for brain stem gliomas. Cancer 56:1804, 1985 Epstein F, Wisoff JH: Intrinsic brainstem tumors in childhood surgical indications. J Neurooncol 6:309, 1988 Freeman CR, Krischer J, Sanford RA et al: Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 27:197-206, 1993 Freeman CR, Krischer J, Sanford RA et al: Hyperfractionated radiation therapy in brain stem tumors. Cancer 68:474, 1991 Freeman CR, Krischer J, Sanford RA et al: Hyperfractionated radiotherapy in brain stem tumors: results of a pediatric oncology group study. Int J Radiat Oncol Biol Phys 15:311, 1988 Freeman CR, Suissa S: Brain stem tumors in children: results of a survey of 62 patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 12:1823, 1986 Halperin EC, Wehn SM, Scott JWet al: Selection of management strategy for pediatric brainstem tumors. Med Pediatr Oncol 17116, 1989 Kretschmar CS, Tarbell NJ, Barnes PD et al: Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. Cancer 72:1404, 1994 Landolfi JC, Thaler HT, DeAngelis LM: Adult brainstem gliomas. Neurology 51:1136, 1998

Levin VA, Edwards MS, Wara WM et al: 5-Fluorouracil and 1-(2chloroethyl)-3-cyclohexyl-l-nitrosourea(CCNU) followed by hydroxyurea, misonidazole, and irradiation for brain stem gliomas: a pilot study of the Brain Tumor Research Center and the Children’s Cancer Group. Neurosurgery 14679, 1984 Mandell LR, Kadota R, Freeman C et al: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a pediatric oncology group phase I1 trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43:959, 1999 Packer RJ, Allen JL, Goldwein JL et al: Hyperfractionatedradiotherapy for children with brainstem gliomas: a pilot study using 7,200 cGy. Ann Neurol 27:167, 1990 Robertson PL, Allen JC, Abbott IR et al: Cervicomedullary tumors in children: a distinct subset of brainstem gliomas. Neurology 44:1798, 1994 Sanford RA, Freeman CR, Burger P, Cohen M E Prognostic criteria for experimental protocols in pediatric gliomas. Surg Neurol30:276, 1988 Shrieve D, Wara WM, Edwards MSB et al: Hyperfractionated radiation therapy for brainstem gliomas in children and adults. Int J Radiat Oncol Biol Phys 24599, 1992 Squires LA, Allen JC, Abbott R, Epstein FJ: Focal tectal tumors: management and prognosis. Neurology 44:953, 1994

160 Malignant Gliomas Patrick Y. Wen, Peter M. Black, and Jay S. LoeMer INCIDENCE In 2001, an estimated 34,000 patients were diagnosed with primary brain tumors in the United States, of which approximately 18,000 were malignant. Malignant gliomas are the most common type of malignant primary brain tumor and account for half the total. They are responsible for most of the 2.5% of cancer deaths caused by primary brain tumors. Approximately 60% to 70% of malignant gliomas are glioblastomas and 20% to 30% are anaplastic astrocytomas, with smaller numbers of anaplastic oligodendrogliomas, anaplastic mixed oligoastrocytomas, and anaplastic ependymomas. This chapter focuses o n glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, and mixed oligoastrocytomas. h a p l a s t i c ependymomas are discussed in Chapter 167.

EPIDEMIOLOGY Malignant gliomas are slightly more common in men than women (1.5:l) and are more common in whites than in African Americans, Latinos, and Asians. Malignant gliomas tend to affect an older population than low-grade gliomas. Whereas low-grade astrocytomas are most common in patients between 20 and 40 years of age, anaplastic astrocytomas and oligodendrogliomas usually occur in patients between 30 and 50 years of age and glioblastomas in patients 50 years or older. The incidence of malignant gliomas may be increasing in older adults. Some studies have shown that between 1973 and 1985 there was a 200%

to 500% increase in the incidence of these tumors in patients 75 years and older. This increase has resulted mainly from improved detection, but a true increase in the number of cases cannot be excluded. Several genetic disorders are associated with an increased incidence of malignant gliomas, including neurofibromatosis type 1 and 2, tuberous sclerosis, Turcot’s syndrome (inherited colonic polyposis associated with astrocytomas and medulloblastomas), and the Li-Fraumeni syndrome, in which families have a dominantly inherited germ line mutation within the p53 tumor suppressor gene on chromosome 17, resulting in a higher incidence of malignant gliomas, breast cancer, sarcomas, and leukemias. In addition to patients with these syndromes, there are also patients with malignant gliomas who have a higher familial incidence of these tumors. The role of environmental factors in the pathogenesis of malignant gliomas is largely unknown. The strongest association is with ionizing radiation. The incidence of gliomas is 2.6 times higher in children treated with low-dose radiotherapy for tinea capitis and 22 times higher in children treated with prophylactic brain irradiation for acute lymphoblastic leukemia. Associations have been reported between vinyl chloride exposure and ingestion of N-nitroso compounds and the development of gliomas, but their significance is unknown. There have also been anecdotal reports suggesting that exposure to electromagnetic radiation may be associated with a higher incidence of gliomas. Several recent large epidemiologic studies have failed to confirm an association between cell phone use and the development of brain tumors.

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Neuro-Oncology

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Specific Tumor Types

Epstein F: A staging system for brain stem gliomas. Cancer 56:1804, 1985 Epstein F, Wisoff JH: Intrinsic brainstem tumors in childhood surgical indications. J Neurooncol 6:309, 1988 Freeman CR, Krischer J, Sanford RA et al: Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 27:197-206, 1993 Freeman CR, Krischer J, Sanford RA et al: Hyperfractionated radiation therapy in brain stem tumors. Cancer 68:474, 1991 Freeman CR, Krischer J, Sanford RA et al: Hyperfractionated radiotherapy in brain stem tumors: results of a pediatric oncology group study. Int J Radiat Oncol Biol Phys 15:311, 1988 Freeman CR, Suissa S: Brain stem tumors in children: results of a survey of 62 patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 12:1823, 1986 Halperin EC, Wehn SM, Scott JWet al: Selection of management strategy for pediatric brainstem tumors. Med Pediatr Oncol 17116, 1989 Kretschmar CS, Tarbell NJ, Barnes PD et al: Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. Cancer 72:1404, 1994 Landolfi JC, Thaler HT, DeAngelis LM: Adult brainstem gliomas. Neurology 51:1136, 1998

Levin VA, Edwards MS, Wara WM et al: 5-Fluorouracil and 1-(2chloroethyl)-3-cyclohexyl-l-nitrosourea(CCNU) followed by hydroxyurea, misonidazole, and irradiation for brain stem gliomas: a pilot study of the Brain Tumor Research Center and the Children’s Cancer Group. Neurosurgery 14679, 1984 Mandell LR, Kadota R, Freeman C et al: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a pediatric oncology group phase I1 trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43:959, 1999 Packer RJ, Allen JL, Goldwein JL et al: Hyperfractionatedradiotherapy for children with brainstem gliomas: a pilot study using 7,200 cGy. Ann Neurol 27:167, 1990 Robertson PL, Allen JC, Abbott IR et al: Cervicomedullary tumors in children: a distinct subset of brainstem gliomas. Neurology 44:1798, 1994 Sanford RA, Freeman CR, Burger P, Cohen M E Prognostic criteria for experimental protocols in pediatric gliomas. Surg Neurol30:276, 1988 Shrieve D, Wara WM, Edwards MSB et al: Hyperfractionated radiation therapy for brainstem gliomas in children and adults. Int J Radiat Oncol Biol Phys 24599, 1992 Squires LA, Allen JC, Abbott R, Epstein FJ: Focal tectal tumors: management and prognosis. Neurology 44:953, 1994

160 Malignant Gliomas Patrick Y. Wen, Peter M. Black, and Jay S. LoeMer INCIDENCE In 2001, an estimated 34,000 patients were diagnosed with primary brain tumors in the United States, of which approximately 18,000 were malignant. Malignant gliomas are the most common type of malignant primary brain tumor and account for half the total. They are responsible for most of the 2.5% of cancer deaths caused by primary brain tumors. Approximately 60% to 70% of malignant gliomas are glioblastomas and 20% to 30% are anaplastic astrocytomas, with smaller numbers of anaplastic oligodendrogliomas, anaplastic mixed oligoastrocytomas, and anaplastic ependymomas. This chapter focuses o n glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, and mixed oligoastrocytomas. h a p l a s t i c ependymomas are discussed in Chapter 167.

EPIDEMIOLOGY Malignant gliomas are slightly more common in men than women (1.5:l) and are more common in whites than in African Americans, Latinos, and Asians. Malignant gliomas tend to affect an older population than low-grade gliomas. Whereas low-grade astrocytomas are most common in patients between 20 and 40 years of age, anaplastic astrocytomas and oligodendrogliomas usually occur in patients between 30 and 50 years of age and glioblastomas in patients 50 years or older. The incidence of malignant gliomas may be increasing in older adults. Some studies have shown that between 1973 and 1985 there was a 200%

to 500% increase in the incidence of these tumors in patients 75 years and older. This increase has resulted mainly from improved detection, but a true increase in the number of cases cannot be excluded. Several genetic disorders are associated with an increased incidence of malignant gliomas, including neurofibromatosis type 1 and 2, tuberous sclerosis, Turcot’s syndrome (inherited colonic polyposis associated with astrocytomas and medulloblastomas), and the Li-Fraumeni syndrome, in which families have a dominantly inherited germ line mutation within the p53 tumor suppressor gene on chromosome 17, resulting in a higher incidence of malignant gliomas, breast cancer, sarcomas, and leukemias. In addition to patients with these syndromes, there are also patients with malignant gliomas who have a higher familial incidence of these tumors. The role of environmental factors in the pathogenesis of malignant gliomas is largely unknown. The strongest association is with ionizing radiation. The incidence of gliomas is 2.6 times higher in children treated with low-dose radiotherapy for tinea capitis and 22 times higher in children treated with prophylactic brain irradiation for acute lymphoblastic leukemia. Associations have been reported between vinyl chloride exposure and ingestion of N-nitroso compounds and the development of gliomas, but their significance is unknown. There have also been anecdotal reports suggesting that exposure to electromagnetic radiation may be associated with a higher incidence of gliomas. Several recent large epidemiologic studies have failed to confirm an association between cell phone use and the development of brain tumors.

Chapter 160

MOLECULAR BIOLOGY There has been significant progress in understanding the molecular biology of malignant gliomas in recent years. As with other neoplasms, combinations of genetic alterations in proto-oncogenes and tumor suppressor genes, together with suppression of apoptotic pathways and deregulation of DNA repair, are thought to be involved. A proto-oncogene is a normal cellular gene that, through overexpression, mutation, or rearrangement, results in a protein that promotes cell growth. Conversely, a tumor suppressor gene is a normal cellular gene that acts to check cell growth but becomes inactivated during tumorigenesis. Malignant gliomas are a heterogenous group of tumors in which a number of pathways involving a variety of genetic alterations in proto-oncogenes and tumor suppressor genes are involved (Figs. 160-1 and 160-2). The genetic alterations that have been reported for astrocytomas include mutations in the p53, PTEN, and retinoblastoma tumor suppressor genes and putative tumor suppressor genes on chromosomes 9p (p16 and ~ 1 4 * ~ 13q, ) , and 19q. Protooncogenes frequently implicated in astrocytomas include the epidermal growth factor receptor (EGFR), MDM2, plateletderived growth factor (PDGF) receptor genes, basic fibroblast growth factor, transforming growth factor alpha, and insulin-like growth factor. It is believed that there are at least two different pathways leading to the formation of glioblastomas (Fig. 160-1). The first

I

1039

Malignant Cliomas

pathway involves mutation in the p53 tumor suppressor gene and overexpression of PDGF at the astrocytoma stage, loss of tumor suppressor genes on chromosomes 9p, 13q, or 19q in the transition to anaplastic astrocytoma, and amplification of EGFR or MDM2 genes or loss of PTEN in the transformation to glioblastoma. Glioblastomas that arise from preexisting low-grade astrocytomas are called secondary glioblastomas. A second de novo pathway does not involve mutations of p53 but instead involves loss of the tumor suppressor gene PTEN or amplification of the EGFR proto-oncogene. These are called primary glioblastomas. The growth factors produced by genetic alterations in malignant gliomas have important effects not only on cell proliferation but also on other aspects of glioma biology. Basic fibroblast growth factor and vascular endothelial growth factors (VEGF) have an important role as angiogenic factors, stimulating the formation of new blood vessels critical for tumor growth. In addition, VEGF alters the permeability of tumor blood vessels, leading to peritumoral edema. The molecular abnormalities in oligodendrogliomas are summarized in Fig. 160-2. Oligodendrogliomas (WHO grade 11) have loss of heterozygosity (LOH) of chromosomes 19q, lp, and 4q and overexpression of EGFR, PDGF, and PDGFR. Progression to anaplastic oligodendrogliomas is associated with deletion of CDKN2a, CDKN2C, LOH 9p, and 1Oq and overexpression of VEGF, CDK4, EGFR, and myc.

I

Differentiated Astrocytes or Precursor Cells P53 mutations

*

PDGF overexpression

EGFR amplijkation or overexpression

Astrocytoma

LOH 19q

MDM2 overexpression

RB alteration p l 6 deletion

LOH lop and 10q LOH 1Oq

PTEN mutation

PTEN mutation PDGFR-a amplijkation

Rb alteration

DCC loss of expression r

Secondary Glioblastoma

Primary Glioblastoma

FIG. 160-1. Genetic pathways in the development of malignant astrocytomas.

1040

Neuro-Oncology

Specific Tumor Types

Oligodendrocytes or Precursor Cells Loss of heterozygosity of chromosome lp

Loss of heterozygosity of chromosome 19q Loss of heterozygosity of chromosome 4q

1

EGFR overexpression PDGFIPDGFR overexpression

Oligodendroglioma (WHO grade 11) Deletion CDKN2A

Amplification of EGFR, MYC,

Deletion CDKN2C

CDK4

Loss of heterozygosity of chromosomes

Overexpression of VEGF

9p and 1Oq

* Anaplastic Oligodendroglioma (WHO grade 111)

FIG. 160-2. Genetic pathways in the development of anaplastic oligodendrogliomas.

CLINICAL FEATURES Malignant gliomas and the associated peritumoral edema produce symptoms by a combination of compression and infiltration of surrounding brain, vascular compression, and increased intracranial pressure. The presenting symptoms for malignant gliomas are similar to those for other brain tumors (Chapter 155). They include headaches (30% to 50%), seizures (30% to 60%), focal neurologic deficits (40% to 60%), and mental status changes (20% to 40%). The headaches often are nonspecific and indistinguishable from tension headaches, although as the tumor enlarges, there may be features of increased intracranial pressure. Seizures occur in 59% of frontal gliomas, 42% of parietal gliomas, 35% of temporal gliomas, and 33% of occipital gliomas. The presentation of patients with malignant gliomas is becoming increasingly subtle as the widespread availability of cerebral imaging allows patients to be diagnosed at an earlier stage. The duration of symptoms tends to be fairly short (weeks or a few months), although patients whose tumors have developed from preexisting low-grade gliomas may have a long history of seizures.

IMAGING OF MALIGNANT GLIOMAS Computed Tomography (cr)and Magnetic Resonance Imaging (MRI) Malignant gliomas have variable appearances radiographically. In general they tend to be less circumscribed than low-grade astro*omas and surrounded with more edema. On CT they appear as hypodense or isodense lesions that enhance with contrast (Figs. 160-3 and 160-4). Glioblastomas often have a central area of necrosis surrounded by a thick enhancing rim of tumor. There is often extensive surrounding edema. On MRI these

FIG, 160-5. 0 scan of a 50-year-old woman with a left frontal glioblastoma, showing a ring-enhancing lesion with a central area of necrosis and surrounding edema. (Reprinted with permission from Black P, Wen PY: Clinical, imaging and laboratory diagnosis of brain tumors. In Kaye A, Laws E (eds): Brain Tumors. Churchill Livingstone, London, 2001.)

Chapter 160

FIG. 160-4. CT scan of a 30-year-old man with a butterfly glioblastoma involving the corpus callosum and both frontal lobes.

Malignant Cliomas

1041

tumors characteristicallyhave low signal intensity on T1-weighted and high signal intensity on T2-weighted images. Tumor cells extend at least as far as the margins of increased T2 signal. The appearance of contrast-enhanced T1 weighted MRIs is similar to that of contrast-enhanced CT scans. These tumors tend to infiltrate along white matter tracts and often involve and cross the corpus callosum (Fig. 160-5). Hemorrhage may be present, but calcificationis uncommon unless the malignant glioma arose from a preexisting lower-grade lesion. Anaplastic oligodendrogliomas have a heterogenous appearance with areas of necrosis, cystic degeneration, hemorrhage, and calcification. Ring enhancement is uncommon and is usually associated with a poor prognosis. Contrast enhancement in malignant gliomas results from extravasation of dye into the extracellular space through a disrupted blood-brain barrier (BBB). Thus it is a manifestation of a disturbed BBB rather than a true measure of tumor extent. By reestablishingthe BBB, corticosteroids can reduce tumor enhancement and lead to the erroneous conclusion that there has been a reduction in tumor size. Although enhancing tumors tend to have a higher histologic grade than nonenhancing tumors, there are frequent exceptions, and caution should be used when relating contrast enhancement to malignancy. Approximately 4% to 10% of glioblastomas do not enhance, whereas a higher percentage of low-grade gliomas show enhancement. Functional imaging techniques such as positron emission tomography (PET)scanning using "F-fluorodeoxyglucose, cerebral blood volume maps using

A

FIG. 160-5. (A) Axial MRI with gadolinium showing left frontal lesion extending to the corpus callosum. This patient was a 36-year-old man who presented with right-side weakness and word-finding difficulties. (B) Axial fluid attenuated inversion recovery (FLAIR) images of the same patient showing the extent of surrounding edema, which contributes to the morbidity of the tumor.

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Neuro-Oncology rn Specific Tumor Types

echoplanar MRI, and MR spectroscopy (MRS) may provide more accurate noninvasive methods of evaluating tumor grade. Postoperative CT or MRI scans obtained to determine the amount of residual tumor to serve as a baseline for gauging response to further treatment should be performed within 4 days of surgery or after 4 to 6 weeks. Postsurgical enhancement typically develops around the fifth postoperative day, peaks after approximately 2 weeks, and may persist for months. In recent years the introduction of new treatment modalities such as stereotactic brachytherapy and radiosurgery, which deliver high focal dosages of radiation to the tumor, have increased the incidence of radiation necrosis. This appears as contrastenhancing lesions with surrounding edema on CT or MRI, developing 4 to 16 months after treatment. The radiologic appearance of radiation necrosis is indistinguishable from tumor recurrence on CT or MR imaging, posing a difficult management problem. Often, a definitive diagnosis can be made only by stereotactic biopsy. Functional imaging with '8F-fluorodeoxyglucose PET, thallium-20l/technetium-ggrn hexamethylpropyleneamineoxime (HMPAO) single photon emission computerized tomography (SPECT), and MRS are noninvasive methods that may be useful in differentiating radiation changes from tumor recurrence in some patients.

Positron Emission Tomography PET provides dynamic information about the metabolism and physiology of brain tumors. It is not used for the routine diagnosis of brain tumors but can provide important information complementing CT and MR scanning. Most PET studies in brain tumors have used "F-fluorodeoxyglucose (FDG) to measure glucose metabolism, which is higher in tumor cells."FDG-PET has been used to determine tumor grade noninvasively in patients with malignant gliomas, localize areas of probable tumor for stereotactic biopsy, differentiate residual tumor after surgery from postoperative changes, study the metabolic effects of chemotherapy, radiation therapy, and steroids on tumor metabolism, identify tumor recurrence, and differentiate radiation necrosis from tumor recurrence.

Single Photon Emission Computed Tomography SPECT is more widely available than PET and may be used to complement information obtained by CT or MRI scanning in patients with brain tumors. Thallium-201 chloride, a potassium analogue that is taken up by viable tumor cells, has been used to differentiate low-grade from high-grade gliomas and to identify residual astrocytoma after radiation therapy. More recently it has been used in combination with technetium-99m hexamethylpropylene amine oxime (201T~ HMPAO), a blood flow tracer that crosses the normal BBB, to differentiate radiation necrosis from recurrent glioma. Magnetic Resonance Spectroscopy

MRS is a noninvasive method that allows direct investigation of tumor metabolism and provides information on the composition and spatial distribution of cellular metabolites. Most MRS studies are done with proton (1-H) or phosphorus-31. With proton MRS, tumors tend to have increased lactate production, loss of N-acetyl aspartate (reflecting loss of neurons in the tumor area), and increased choline levels (reflectingactive membrane biosynthesis).

There is great interest in evaluating the usefulness of MRS in noninvasively diagnosing tumors, determining tumor grade, and differentiating tumor from radiation effects.

DIFFERENTIAL DIAGNOSIS As indicated in Chapter 156, many conditions producing increased intracranial pressure or progressive neurologic deficits may mimic malignant gliomas clinically. These include other brain tumors (especially metastases, primary central nervous system lymphoma, and enhancing low-grade gliomas) and nonneoplastic conditions such as subdural hematomas, brain abscesses, hydrocephalus, benign intracranial hypertension, progressive multifocal leukoencephalopathy, multiple sclerosis, vascular malformations, cerebral infarctions, and Alzheimer's disease. Many of these conditions have characteristic radiologic appearances that differentiate them from malignant gliomas. However, some of these conditions, especially other types of tumor, can be difficult to distinguish from malignant gliomas on the basis of their radiologic appearances alone, and a definitive diagnosis requires histologic examination.

Pathology and Hlstologlc Grading Malignant gliomas are extremely heterogenous tumors characterized by increased cellularity, pleomorphism, mitoses, endothelial proliferation, and necrosis. With anaplastic astrocytomas and glioblastomas arising from astrocytomas, the tumor cells often are glial fibrillary acidic protein positive. The ideal tumor grading system combines the ability to predict behavior and prognosis with reproducibility and minimal interobserver variation. Several grading systems have been proposed for astrocytomas, most using three or four grades of malignancy. Unfortunately, the multiplicity of schemes contributes to a sense of confusion about the grading of astrocytomas and makes comparison of results between different studies difficult. Earlier grading schemes such as the Kernohan systems correlated poorly with patient survival. These systems have been replaced by three grading systems that have prognostic implications: the modified Ringertz system, the St. Anne-Mayo (DaumasDuport) system, and the World Health Organization (WHO) classification (Table 160-1). The modified Ringertz system separates astrocytomas into three histologic grades: astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Patients with anaplastic astrocytomas have a significantly higher 1-year survival (60% to 73%) than those with glioblastoma (35% to 44%). Low-grade astrocytomas consist of a uniform population of glial fibrillary acidic protein positive cells with a mild to moderate increase in cellularity and little nuclear or cytoplasmic pleomorphism. Anaplastic astrocytomas are characterized by marked increase in cellularity, moderate pleomorphism, mitotic figures, and vascular endothelial proliferation (Fig. 160-6). Glioblastomas have areas of necrosis often surrounded by pseudopalisading in addition to the features present in anaplastic astrocytomas (Fig. 160-7). The St. Anne-Mayo (Daumas-Duport) scheme is based on the presence or absence of four histologic criteria: nuclear atypia, mitoses, endothelial proliferation, and necrosis. Grade I tumors have none of the criteria, grade I1 have one, grade I11 have two, and grade IV have three or four criteria present. Median survival for patients with grade 11,111, and IV tumors were 4 years, 1.6 years, and 0.7 years, respectively. Very few patients have grade I tumors. An advantage of this grading scheme is that it is easy to use and

Chapter 160 rn Malignant Cliornas W

1043

TABLE160-1. Astrocytoma Grading Systems

Kemohan

Modified Ringettz

UCSF

SL Anne-Mayo

WHO

Astrocytorna grade 1

Astrocytoma (grade 1)

Mildly anaplastic astrocytoma Moderately anaplastic astrocytoma Highly anaplastic astrocytoma Gemistocytic astrocytoma Glioblastoma rnultiforme

Astrocytoma grade 1

Pilocytic astrocytoma

Grade I

Astrocytoma grade 2

Astrocytorna

Grade I1

Astrocytorna grade 3

Anaplastic astrocytoma

Grade 111

Astrocytoma grade 4

Glioblastoma

Grade IV

Astrocytoma grade 2 Anaplastic astrocytorna (grade 2) Astrocytoma grade 3

Glioblastorna rnultiforme (grade 3)

Astrocytorna grade 4

FIG. 160-6. Anaplastic astrocytoma showing hypercellularii and nuclear pleomorphism.

B

A

FIG. 160-7. (A) Histology of glioblastoma showing extensive areas of necrosis lined by pseudopalisading. (B) Areas of endothelial proliferation. (From Okazaki H, Scheithauer B W Atlas of Neuropathy. Mosby, St. Louis, 1988.)

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interobserver variation is small. The concordance among pathologists who use the St. Anne-Mayo system is reported to be as high as 94%. Currently, the most widely used classification system is that of the WHO. In this classification, pilocytic astrocytomas are grade I, astrocytomas are grade 11, anaplastic astrocytomas are grade 111, and glioblastomas are grade IV. Anaplastic oligodendrogliomas (WHO grade 111) are cellular tumors that may have morphologic features suggestive of oligodendroglial cells with rounded hyperchromatic nuclei, perinuclear halos, and few cellular processes. Usually there is high mitotic activity, marked cytologic atypia, and high mitotic activity. There may also be vascular proliferation and necrosis. Anaplastic oligoastrocytomas contain both oligodendroglial and astrocytic features. Malignant gliomas are extremely heterogeneous, and the histology obtained by stereotactic biopsy is not always representative of the entire tumor. The larger amounts of tissue obtained by surgical resection usually provide a more accurate histologic diagnosis. Even when sampling errors are taken into account, the grading of gliomas based on histologic appearance remains inexact. Although patients with higher grades tend to have a poorer prognosis, the outcome for individual patients within a single grade can be quite variable. Because of these limitations, there is increasing interest in improving tumor grading using techniques to determine the proliferative index of the tumors. These techniques include antibodies against bromodeoxyuridine and Ki-67 (MIB-1 labeling index). Bromodeoxyuridine (BUdR), a thymidine analogue, is administered intravenously at surgery. The proportion of cells labeled with BUdR on histologic sections of tumor provides an indication of the cells in DNA synthesis. This BUdR labeling index (LI) correlates with patient survival. Mean LIs for glioblastoma, anaplastic astrocytoma, and astrocytomas are 9.3%, 4%, and 1%, respectively. Regardless of the pathologic diagnosis, patients with an LI greater than 5% had a much poorer prognosis than patients with LIs below 5%. Similar results have been obtained with antibodies to Ki-67, which labels an antigen in all phases of the cell cycle except Go (MIB-1 index). The Ki-67 or MIB-1 labeling indices have largely replaced BUdR labeling because these tests can be performed with antibodies on paraffin sections and do not necessitate intravenous administration of the agent.

UNCOMMON TYPES OF GLIOMA There are several less common histologic variants of malignant gliomas. Gliosarcomas consist of a sarcomatous component admixed with glioma. This is a variant of glioblastoma and has the same prognosis. Gemistocytic astrocytomas consist of cells with abundant eosinophilic cytoplasm often occurring as foci within more usual fibrillary tumor and have a prognosis similar to that of anaplastic astrocytoma. Gliomatosis cerebri is an uncommon form of malignant glioma characterized by diffuse infiltration of the brain by malignant astrocytes without the formation of a discrete mass. These tumors tend to have a very poor prognosis.

astrocytoma or oligodendroglioma, and a high KPS are favorable prognostic factors. Age: Data from the Brain Tumor Cooperative Group studies show that younger patients live significantly longer than older patients, even when adjusted for other important prognostic factors. Patients under age 40 with glioblastomas have a 50% 18-month survival rate, compared with 20% for those between 40 and 60 and 10% for those over 60. Age may be a more important prognostic factor than even histology. In one recent study, patients under 60 with anaplastic astrocytoma lived longer than those with glioblastoma, but patients over the age of 60 had similar median survival times regardless of the histology. Histology: As previously discussed, patients with anaplastic astrocytomas have a significantly better prognosis than patients with glioblastomas. Median survival for anaplastic astrocytoma is approximately 24 to 36 months, compared with 10 months for glioblastomas. Anaplastic oligodendrogliomas tend to have a better prognosis than anaplastic astrocytomas. The median survival from older studies was approximately 4 years. However, it has become clear that these tumors are chemosensitive, and with aggressive treatment today it is likely that the survival data will improve significantly. Performance status: The prognosis of patients with malignant gliomas decreases as the KPS decreases. Patients with a KPS greater than 70 have a 34% 18-month survival, compared with 13% for those with a KPS less than 60. Other favorable prognostic factors that have been observed with less consistency include a long duration of symptoms before diagnosis, presence of seizures, absence of mental status and personality changes at diagnosis, location of tumor (e.g., frontal and temporal pole), small preoperative tumor size, gross total resection, small postoperative and postradiation tumor size, and blood group 0. The potential use of molecular abnormalities to predict prognosis has not yet been fully realized. However, progress is being made. Patients with anaplastic oligodendrogliomas with the I p and 19q deletions are much more responsive to chemotherapy and have a much better prognosis. Recently it has been shown that the presence of p53 mutations in pediatric brain tumors and the presence of survivin, an antiapoptotic gene, were associated with an adverse prognosis.

TREATMENT As with other neoplasms, the optimal management of malignant ghomas involves cytoreduction through multimodality therapy including surgery, irradiation, and chemotherapy. Interpretation of the results of clinical trials involving patients with malignant gliomas often have been complicated by inadequate patient numbers, absence of appropriate controls, and a failure to take into account prognostic factors, such as patient age and tumor grade, which significantly influence patient survival.

PROGNOSTIC FACTORS Malignant gliomas are a prognostically heterogenous group of tumors. In addition to tumor histology, age at diagnosis and Karnofsky performance status (KPS) are the most important prognostic factors. Young age, a histologic diagnosis of anaplastic

surgery The optimal treatment of patients with malignant gliomas involves surgical resection of as much tumor as is neurologically safe. Stereotactic biopsies should be reserved for deep or critically

Chapter 160

located tumors that cannot be resected safely. The safety of surgery has been greatly improved in recent years by the use of the operating microscope, the Cavitron ultrasonic aspirator, intraoperative ultrasound, laser systems, CT and MRI guided stereotaxy, intraoperative neurophysiologic monitoring, and intraoperative MRI. Operative mortality ranges from 0% to 3% and morbidity from 8% to 14%. In addition to debunking the tumor and relieving any symptoms resulting from mass effect, surgery enables a precise histologic diagnosis to be made and possibly increases the effectiveness of adjuvant therapies by reducing the number of cells that must be treated, altering cell kinetics, and removing radioresistant hypoxic cells and areas of tumor inaccessible to chemotherapy. The role of surgery in prolonging survival remains controversial. Although some studies suggest that patients undergoing resection live longer than those who have only biopsies, suggesting that the extent of resection is important, other studies indicate that survival correlates more closely with the amount of residual tumor seen on postoperative CT or MRI scans than the actual amount of tumor resected. Surgery plays an important role in treating patients with recurrent tumor. In selected patients with a discrete tumor mass, reoperation can increase survival by as much as 9 months. Surgery has also assumed an increasingly important role in the patients who have been treated with stereotactic brachytherapy or radiosurgery. These patients often develop radiation necrosis that is indistinguishable radiologically from tumor recurrence, and surgical biopsy often is needed for definitive diagnosis. In approximately 40% to 65% of patients treated with brachytherapy and 10% to 30% of patients treated with radiosurgery, the areas of radiation necrosis become symptomatic and necessitate surgical resection.

Radiation Therapy Radiation therapy remains the most effective adjunctive therapy to surgery for treating patients with malignant gliomas. The value of radiation therapy was demonstrated by the Brain Tumor Study Group (BTSG) study 69-01 (Walker et al., 1978), which showed that 50 to 60 Gy of whole brain radiotherapy increased median survival in patients with malignant gliomas from 14 weeks after surgery alone to 36 weeks. Subsequent studies confirmed the benefit of radiation therapy and suggested that survival was related to an increase in the dosage of radiation up to 60 Gy. Administration of radiation dosages above 60 Gy at standard fractionation were associated with a significantly higher risk of radiation injury to normal brain tissue. Based on these studies, the recommendation for conventional external beam radiation therapy is 60 Gy in single daily fractions of 1.7 to 2 Gy 5 times a week. This is usually administered to a limited field, which includes the enhancing volume on CT scans together with a 2- to 3-cm margin or a 1-cm margin beyond T2-weighted MRI changes. There appears to be no survival advantage for irradiating the whole brain compared with treating more limited fields, and whole brain irradiation may be associated with a higher incidence of delayed neurotoxicity. In an attempt to improve on the results of conventional external beam irradiation, several novel strategies have been developed to selectively sensitize tumors to the effects of radiation and increase the tumor dosage while biologically or physically limiting the dosage to normal brain. Intensity Modulated Radiotherapy. This is a new advanced conformal delivery system that divides the radiation field into

Malignant Cliomas

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pixel-like small segments. Each segment is independently attenuated by movable leaves, allowing the dosage to different parts of the tumor to be precisely adjusted. Radiosensitizers and Altered Fractionation Schedules. Hypoxic cell sensitizers, pyrimidine analogues, and perfluorochemical emulsions have been used to increase the sensitivity of glioma cells to ionizing radiation with disappointing results. Newer radiosensitizers such as RSR13 appear more promising. With the recent availability of small molecule signal transduction and angiogenesis inhibitors, which may have synergistic effects with radiation therapy, there is renewed interest in the radiosensitization studies for gliomas. Hyperfractionation uses the greater capacity of normal brain tissue to repair sublethal damage compared with glioma cells and involves the administration of several small fractions of radiation a day to a higher total dosage. To date no study has demonstrated a survival advantage using hyperfractionated schedules. Similarly disappointing results have been obtained with accelerated fractionation, which involves administering conventional fraction sizes over a shorter period, reducing the opportunity for tumor cells to repopulate during treatment. Brachytherapy. Most patients with malignant gliomas treated with 60 Gy of standard external beam radiation have persistent disease, and 80% to 100% recur within 2 cm of the primary site. Brachytherapy involves either the placement of radioactive seeds in the wall of the cavity at the time of surgery or the use of stereotactic techniques to place catheters containing radioactive isotopes (e.g., iodine- 125) within brain tumors, enabling tumoricidal dosages of radiation to be delivered to defined volumes while reducing the risk of serious radiation injury to surrounding normal tissues. Stereotactic brachytherapy usually is limited to unifocal, well-defined, supratentorial tumors less than 4 cm in diameter that do not involve corpus callosum, brainstem, or ependymal surfaces. Because of these limitations, only 20% to 30% of patients with malignant gliomas are suitable candidates. These techniques produced only a modest increase in survival and have been largely replaced by stereotactic radiosurgery, which is noninvasive. Stereotactic Radiosurgery. Stereotactic radiosurgery is a technique used to treat small (less than 4 cm) radiographically well-defined tumors with a large single fraction of ionizing radiation using stereotactically directed narrow beams. Like brachytherapy, it significantly increases the radiation dosage delivered to the tumor bed while sparing normal brain. Radiosurgery has the advantage over brachytherapy of being noninvasive, allowing patients with tumors in surgically inaccessible or eloquent areas of the brain or serious coexisting medical illnesses to be treated as outpatients. In uncontrolled studies, patients treated with external irradiation followed by stereotactic radiosurgery delivering approximately 1.2 Gy in a single fraction to the enhancing mass and a 2- to 4-mm margin appear to have slightly improved survival. After radiosurgery, approximately 10% to 20% of patients need reoperation for subsequent radiation necrosis. Stereotactic Radiotherapy. Stereotactic radiotherapy is a novel technique that involves the precise delivery of fractionated radiation to the tumor volume while sparing surrounding brain. It combines the accuracy of stereotactic radiosurgery with the reduced toxicity of fractionated external beam irradiation. Although techniques such as radiosurgery may improve local tumor control, they do not treat tumor cells infiltrating into the surrounding brain. Increasingly, patients are relapsing at distant sites, and there is a growing need for more effective medical

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therapy to complement the advances in surgery and radiation therapy.

Chemotherapy Adjuvant Chemotherapy. Despite more than 20 randomized trials, the role of adjuvant chemotherapy for patients with malignant gliomas remains controversial. Chemotherapy probably has a modest but significant effect in increasing survival when administered after surgery and radiation therapy. In BTSG Trial 69-01 (Walker et al., 1978) the median survival was not significantly prolonged, but at 18 months, 19% of patients receiving carmustine (BCNU), radiation, and surgery were alive, compared with 4% of those receiving surgery and radiation alone. In BTSG Trial 75-01 (Green et al., 1983) the addition of BCNU to surgery and radiation therapy significantly increased median survival from 40 weeks to 50 weeks and increased the percentage of patients surviving 18 months to 24%. A meta-analysis of the major adjuvant chemotherapy trials showed that there was a 10.1% increase in survival at 1 year and an 8.6% increase at 2 years for patients treated with both chemotherapy and radiation compared with radiation alone. The benefit was greater in patients with anaplastic astrocytomas than glioblastomas. Currently, standard therapy for patients with newly diagnosed malignant gliomas involves maximum feasible surgical resection followed by limited-field external beam radiation. Adjuvant chemotherapy is generally recommended for most patients with anaplastic astrocytomas. Its use in patients with glioblastomas remains controversial and is generally limited to younger patients with good performance status. The most commonly used agents include BCNU (200 mg/m’ every 6 weeks for 6 cycles); procarbazine, lomustine, and vincristine (PCV) (lomustine 110 mg/m’ day 1; vincristine 1.4 mg/m’ day 8 and 28; procarbazine 60 mglm’ day 8-21); or temozolomide (150 to 200 mg/m’ days 1 to 5 every 28 days). Other chemotherapeutic drugs have not proved to be any more effective than these agents. The results of standard therapy remain poor. The median survival of patients with glioblastomas is approximately 9 to 12 months, whereas the median survival of patients with anaplastic astrocytomas is 24 to 36 months. Chemotherapy for Recurrent Gliomas. Chemotherapy may have a palliative role in patients with recurrent malignant gliomas. Response rates of 20% to 50% have been reported with a variety of agents, although this is usually not associated with prolonged survival. One approach is to begin with either temozolomide or nitrosourea-based chemotherapy (BCNU or PCV) if the patient has not been treated with these drugs previously. In patients who recur after initial treatment with nitrosoureas and temozolomide, potentially useful agents include irinotecan and carboplatin. When appropriate, patients with recurrent gliomas should be encouraged to participate in ongoing clinical trials so that more effective drug regimens can be developed. Anaplastic Oligodendrogliomas. There is increasing evidence that anaplastic oligodendrogliomas and anaplastic oligoastrocytomas are a special subset of malignant gliomas that are especially sensitive to chemotherapy. Although these tumors generally have been treated with the PCV regimen, it is likely that they will also respond to other alkylating agents. In the largest study to date, the National Cancer Institute of Canada conducted a multicenter phase I1 study of intensive PCV (CCNU 130 mg/m’ day 1, procarbazine 75 mg/mz days 8 to 21, vincristine 1.4 mg/m’ [no maximum] days 8 and 29) for patients with new or recurrent

anaplastic oligodendrogliomas. In this study there was a 75% overall response rate, with 38% complete responses. The time to tumor progression (TTP) for complete responders was greater than 25.2 months and 14.2 months for partial responders (Cairncross et al., 1994). The reason for the sensitivity of oligodendrogliomas to chemotherapy remains unknown. However, there is increasing evidence that response to chemotherapy is associated with allelic loss of chromosomes l p and 19q. It is now possible to predict the most appropriate therapy for specific patients based on their tumor genotype. Patients with loss of both chromosomes l p and 19q have a 100% response rate to PCV chemotherapy and an excellent prognosis (duration of response more than 31 months). These patients could be treated with chemotherapy alone and radiation therapy deferred until there is evidence of recurrent disease. Patients with allelic loss of only Ip also have a high response rate to chemotherapy, but the duration of response is only 11 months. Patients who have an intact Ip and p53 mutations have a 33% response rate to chemotherapy and a 7-month duration of response. Both groups should be treated with chemotherapy followed by radiation therapy. Patients with intact chromosome I p and no p53 mutations respond poorly to chemotherapy and should be treated with radiation therapy alone or enrolled in clinical trials. New Approaches to Chemotherapy. The poor results with conventional chemotherapy have led to the search for new drugs with greater antiglioma activity and strategies to use currently available agents more effectively. Examples of promising agents that are currently undergoing evaluation include irinotecan and oxaliplatin. There is also interest in combining chemotherapeutic agents such as BCNU with drugs such as 06-benzylguanine, which inhibits the DNA repair enzyme 06-alkylguanine-DNA-alkyl transferase, which is responsible for resistance to BCNU. Intra-arterial chemotherapy has been used in an attempt to deliver higher concentrations of drug to the tumor while avoiding systemic toxicities. This approach has produced slightly higher tumor response rates (27% to 60%), but patient survival usually is not significantly prolonged. In addition, intra-arterial administration of agents such as BCNU has been associated with significant ophthalmic and neural toxicity. Attempts have also been made to increase the permeability of water-soluble drugs across the BBB by transient disruption of the BBB with agents such as intra-arterial mannitol. Several studies combining BBB disruption and intra-arterial drug administration have produced slightly higher response rates. However, the usefulness of this approach remains questionable, and agents such as mannitol expose normal brain to higher dosages of chemotherapy, increasing the potential for neurotoxicity. Drugs that are more selective in disrupting the BBB, such as RMP-7, have also been disappointing. There has also been increasing interest in overcoming the resistance of gliomas to alkylating agents by delivering higher dosages accompanied by hematopoietic growth factors and autologous bone marrow transplantation (ABMT). Although several studies with ABMT have shown higher response rates in patients with recurrent gliomas, this has not generally translated into prolonged survival. Moreover significant extramedullary toxicities, such as hepatotoxicity and neurotoxicity, have been observed in some of these studies. Slightly more encouraging results have been observed when ABMT has been used in the adjuvant setting. Many of these studies used only single agents, and it is possible that the use of ABMT with combinations of

Chapter 160 rn Malignant Gliomas

chemotherapeutic agents with nonoverlapping toxicities will be more effective. Interstitial chemotherapy is a more promising approach that involves implanting biodegradable polymers impregnated with a chemotherapeutic agent into the tumor bed. This produces prolonged exposure of the tumor to the drug while minimizing systemic toxicity. Studies in patients with newly diagnosed and recurrent gliomas, in which patients underwent surgery and implantation of polymer wafers impregnated with BCNU (Gliadel) into the tumor bed, showed modest prolongation in survival. In addition to delivering chemotherapy, polymer wafers may also be useful for delivering steroids, antiangiogenic agents, and other novel therapies. Another promising approach is the use of preradiation (neoadjuvant) chemotherapy. Radiation damages the tumor microvasculature, limiting the delivery of drug to the tumor, and, by producing tissue hypoxia and cellular growth arrest, reduces the effectiveness of chemotherapy. Treating patients with chemotherapy before radiation therapy can overcome these problems. Despite these newer strategies, the therapeutic efficacy of radiation therapy and chemotherapy remains limited. This is partly because the final common pathway for cytotoxicity for both chemotherapy and radiotherapy is DNA damage, a nonselective process that occurs in normal as well as neoplastic cells. This results in a low therapeutic ratio that prevents the use of the high dosages of chemotherapy and radiotherapy necessary to completely kill tumor cells. As a result, there has been increasing interest in finding new therapeutic targets for treating gliomas.

New Therapies Immunotherapy. The results of immunotherapy in the past have been disappointing, but the recent availability of more potent cytokines and advances in immunology have led to renewed interest in this form of treatment. Clinical studies with cytokines such as a-and p-interferon and tumor necrosis factor showed only modest antitumor activity. Response rates of 0% to 20% have been reported for a-interferon and up to 50% for p-interferon, although the duration of responses generally was short. Studies of adoptive immunotherapy using interleukin-2 (IL-2) and lymphokine activated killer cells have also been disappointing. Passive immunotherapy with monoclonal antibodies has been limited by significant technical problems including the lack of truly tumor-specific antigens, poor access of the antibodies across the BBB, and the development of neutralizing antibodies. Despite these problems, preliminary studies with radiolabeled humanized antibodies against the tenascin and the epidermal growth factor receptor have shown encouraging antitumor activity. There is also renewed interest in active immunotherapy using dendritic cell vaccines. Antiangiogenerir. Gliomas produce specific angiogenic peptides (e.g., bFGF and VEGF) to stimulate the formation of new blood vessels that are critical for tumor growth. There is increasing interest in angiogenesis inhibition as a new therapeutic strategy for gliomas. Thalidomide, an oral inhibitor of angiogenesis, has modest antiglioma activity. Several more potent inhibitors of angiogenesis have been identified (e.g., VEGF inhibitors such as SU5416 and PTK767) and are being evaluated in clinical studies. Targeted Molecular Therapy. Numerous novel small molecule inhibitors of growth factor receptors and signal transduction have been developed and are in clinical trials. These include inhibitors of the PDGF (e.g., imatinib mesylate), EGFR (e.g.,

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ZD1839), farnesyl transferase inhibitors (e.g., zarnestra), inhibitors of mTOR (e.g., CCI-779), and protein kinase C inhibitors. PKC is a ubiquitous cell membrane-associated second messenger involved in transducing mitogenic signals from the cell surface to the nucleus. Recent studies suggest that inhibition of PKC activity suppresses growth of glioma cell lines. Tamoxifen is a potent inhibitor of PKC that produces a 20% response rate in patients with recurrent gliomas when used at very high dosages (160 to 240 mg/day). More potent inhibitors of PKC have been developed and will be entering clinical trials in the near future. Platelet-derived growth factor (PDGF) probably is involved in autocrine and paracrine loops in the growth of many gliomas. New therapeutic strategies are being developed to disrupt such loops using PDGF inhibitors such as imatinib (STI571, Gleevec). The epidermal growth factor receptor (EGFR) gene is overexpressed in 40% to 50% of glioblastomas, especially in primary glioblastomas. Several inhibitors of EGFR have been developed and are being evaluated in clinical trials. Farnesyl transferase inhibitors and m-TOR inhibitors disrupt signal transduction pathways that are overactive in gliomas and are also being evaluated in trials. Eventually it is likely that more effective therapies will result from a combination of these signal transduction inhibitors with each other or with antiangiogenic agents and chemotherapy. Anti-invasive Agents. The cells of malignant gliomas characteristically invade the surrounding brain. As the understanding of the biology of this invasiveness has improved, drugs have been developed that inhibit critical components of this process such as aVp3 integrins and are being evaluated in trials. Gene Therapy. The rapid advances in molecular biology have resulted in a number of novel therapies for malignant gliomas. One strategy introduces a gene encoding an enzyme that makes tumor cells more susceptible to chemotherapy. In one example of this approach, the herpes simplex thymidine kinase gene is inserted into a replication defective murine retrovirus. Murine fibroblast cell lines can be engineered to constitutively produce these recombinant retroviruses. When these murine fibroblasts are injected into gliomas, proliferating tumor cells become infected by the retroviral vector. These tumor cells produce thymidine kinase and become susceptible to attack by the antiherpes drug ganciclovir. Nondividing brain cells are not infected by the retroviral vectors and remain unaffected by ganciclovir. However, clinical studies using this approach have been disappointing because of the poor efficiency with which tumor cells were transduced with the therapeutic gene. Similar approaches using different therapeutic genes and adenoviral and adenoassociated viral vectors are under way. Many other gene therapy strategies are being evaluated. Among those in clinical trials are the use of viral vectors to replace tumor suppressor genes such as p53, an Elb-deficient adenovirus that replicates in and kills glioma cells with mutated p53 (Onyx virus), and genetically engineered mutants of herpes simplex virus- 1 and re0 virus, which replicate and kill dividing glioma cells but not in nondividing brain cells.

Supporthre Therapy Despite some promising advances in the treatment of malignant gliomas, the prognosis for most of these patients remains poor. In addition to providing optimal treatment for the tumor, an important part of treating these patients is to provide compassionate and effective supportive care. Many of these patients need glucocorticoids to control cerebral edema and anticonvulsants to

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treat seizures (see Chapter 156). The use of prophylactic anticonvulsant therapy for patients with glioma who have not had seizures remains controversial. Although most patients with gliomas are treated with prophylactic anticonvulsants, there is little evidence to support this practice (see Chapter 156 for details). Because of the higher incidence of allergic reactions in patients with brain tumors receiving anticonvulsant therapy (especially phenytoin), their routine use in patients who have not experienced a seizure probably is unnecessary. Many patients with brain tumors have significant neurologic deficits and benefit from physical, occupational, and speech therapy. They may also need the emotional and psychological support provided by patient support groups, social workers, psychiatrists, and the various brain tumor societies (see Chapter 156).

Terminal Care Despite some important advances in recent years, almost all patients with malignant gliomas eventually die of their disease. When further treatment is no longer possible or not warranted because of the poor quality of the patient's life, all efforts should be directed toward keeping the patient comfortable and avoiding unnecessary prolongation of suffering.

Despite intensive research, progress in treating patients with malignant gliomas remains slow. However, recent advances in understanding the biology of gliomas and in gene transfer techniques have resulted in exciting new therapeutic approaches that may lead to improved therapies for patients with malignant 4'iomas.

SUGGESTED READINGS Berger MS, Wilson CB: Textbook of Gliomas. W B Saunders, Philadelphia, 1999 Cairncross JG, Macdonald DR, Ludwin S et al: Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12:2013-2021, 1994 Cairncross JG, Macdonald DR, Ramsay DA Aggressive oligodendroglioma: a chemosensitive tumor. Neurosurgery 3 1:78-82, 1992 Cairncross JG, Ueki K, Zlatesou MC et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 901473-1479, 1998 Chakravarti A, Noll B, Black PM et al: Quantitativelydetermined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol201063-1068, 2002 Fine H A The basis for current treatment recommendations for malignant gliomas. Neuro-Oncology 2O:lll-120, 1994 Galanis E, Buckner J: Chemotherapy for high-grade gliomas. Br J Cancer 82~1371-1380,2000 Green SB, Byar DP, Walker MD et al: Comparison of carmustine, procarbazine and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep 62121-132, 1983 Hoshino T, Ahn D, Prados MD et al: Prognostic significance of the proliferative potential of intracranial gliomas measured by bromodeoxyuridine labelling. Int J Cancer 53:550-555, 1993

Ino Y, Betensky RA, Zlatescu MC et al: Molecular subtype of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res 2839-845, 2001 Kaye AH, Laws ER Jr (eds): Brain Tumors: An Encyclopedic Approach. Churchill Livingstone, London, 2001 Kleihues P, Cavenee WK (eds): World Health Organization Classification of Tumors. Pathology and Genetics. Tumors of the Nervous System. IARC Press, Lyon, 2000 Levin VA, Gutin PH, Leibel S: Neoplasms of the central nervous system. pp. 2100-2160. In DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. 6th Ed. Lippincott, Philadelphia, 2001 Louis DN, Cavenee WK: Molecular biology of central nervous system neoplasms. pp. 2091-2099. In DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. 6th Ed. Lippincott, Philadelphia, 2001 Maher EA, Furnari FB, Bachoo RM et al: Malignant glioma: genetics and biology of a grave matter. Genes Dev 15:1311-1333, 2001 McCormick F Cancer gene therapy: fringe or cutting edge. Nat Rev Cancer 1:130-141, 2001 Nazzarro JM, Neuwelt EA: The role of surgery in the management of supratentorial intermediate and high grade astrocytomas in adults. J Neurosurg 73:331-344, 1990 Packer RJ: Prognostic factors in patients with brain tumors. pp. 275-298. In Salcman M (ed): Neurobiology of Brain Tumors. Williams & Wilkins, Baltimore, 1991 Paleologos NA, Cairncross J G Treatment of oligodendrogliomas: an update. Neuro-Oncology 1:61-68, 1999 Pech IV, Peterson K, Cairncross J G Chemotherapy for brain tumors. Oncology 12:537-547, 1998 Pollack IF, Finkelstein SD, Woods J et al: Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med 346(6):420-427, 2002 Radhakrishnan K, Bohnen NI, Kurland LT Epidemiologyof brain tumors. pp. 1-19. In Morantz RA, Walsh JW (eds): Brain Tumors. Marcel Dekker, New York, 1994 Ram Z, Culver KH, Walbridge S et al: In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res 53:83-88, 1993 Reardon DA, Akabani G, Coleman RE et al: Phase I1 trial of murine I3lI-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:1389-1397, 2002 Salcman M Glioblastoma multiforme and anaplastic astrocytoma. pp. 493-524. In Kaye AH, Laws ER Jr (eds): Brain Tumors: An Encyclopedic Approach. 2nd Ed. Churchill Livingstone, London, 200 1 Scharfen CO, Sneed PK, Wara WM et al: High activity iodine-125 interstitial implant for gliomas. Int J Radiat Oncol Biol Phys 24:583-591, 1992 Shapiro WR: Chemotherapy of malignant gliomas: studies of the BTCG. Rev Neurol 148:428-434, 1992 Sneed PK, Larson DA, Gutin PH: Brachytherapy and hyperthermia for malignant astrocytomas. Semin Oncol 21:186-197, 1994 Walker MD, Alexander E Jr, Hunt WE et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative trial. J Neurosurg 49333-343, 1978 Wen PY, Marks P Medical management of brain tumors. Curr Opin Oncol 14(3):299-307, 2002 Yung WKA: Temozolomidein malignant gliomas. Semin Oncol2227-34, 2000

Chapter 161 W

Primary Central Nervous System Lymphoma

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161 Primary Central Nervous System Lymphoma Craig P. Nolan and Lisa M. DeAngelis

Primary central nervous system lymphoma (PCNSL) is a nonHodglun’s lymphoma limited to the nervous system. It can involve the brain, eyes, leptomeninges, or spinal cord parenchyma. Previously known by a variety of names including microglioma, reticulum cell sarcoma, perivascular sarcoma, and lymphosarcoma, PCNSL represents about 1% of primary cerebral neoplasms. However, among immunocompetent patients, the incidence of this lymphoma has risen threefold in the past two to three decades for no known reason. PCNSL has a predilection for patients suffering from a variety of immunocompromised states including both congenital (Wiskott-Aldrich syndrome) and acquired immunodeficiencies (organ transplant patients), with respective risks of 4% and 2% to 7%. Acquired immunodeficiency syndrome (AIDS), the most common immunocompromised state that predisposes to PCNSL, carries a risk of 12% in some series. PCNSL is associated with late-stage human immunodeficiency virus (HIV) infection, and patients usually have CD4 counts less than 200/mm3and often less than 100/mm3. However, with the introduction of highly active antiretroviral therapy (HAART), there has been a strong decline in AIDS-related PCNSL. This can be attributed to control of the viral infection and relative reconstitution of the immune system with HAART.

CLINICAL FEATURES PCNSL occurs in all age groups, with a peak incidence in the sixth and seventh decades of life. Immunocompromised patients are younger, and the median age of onset among patients with AIDS is 40. There is a slight male predominance among immunocompetent patients; however, 90% of AIDS-related PCNSL occurs in men, comparable to the gender distribution of HIV infection itself. The most common clinical presentation of PCNSL is that of a brain tumor. Because PCNSL is a rapidly growing tumor, symptoms are present in most patients for only weeks before diagnosis. The most common presenting symptoms are cognitive deficits or personality changes that can be attributed to the tumor’s predilection for the frontal lobe and its 30% incidence of multifocality. Lateralizing neurologic deficits appropriate to the involved area and signs of increased intracranial pressure such as headache and nausea are also common (Table 161-1). Although PCNSL is primarily a brain tumor, it may involve all compartments of the central nervous system (CNS), including the spinal fluid, spinal cord, and eye. It usually involves the deep periventricular regions of the brain, allowing access of the tumor into the cerebrospinal fluid (CSF). Leptomeningeal involvement can be demonstrated in 42% of parenchymal PCNSL, but primarily leptomeningeal lymphoma is rare. At autopsy almost all patients have focal microscopic disease in the subarachnoid space overlying areas of brain involvement, but rarely do patients have clinical symptoms suggestive of leptomeningeal disease, such as cranial neuropathies, lumbosacral radiculopathies, or communicating hydrocephalus. Therefore, physicians cannot rely on the

clinical presentation to indicate the presence or absence of subarachnoid spread of the tumor. PCNSL of the spinal cord parenchyma is very rare. It can occur alone or in association with primary brain lymphoma. There have been only isolated case reports of PCNSL occurring in the spinal cord, usually at the thoracic level. Patients typically present with a painless, progressive myelopathy. Magnetic resonance imaging (MRI) with gadolinium is the best means of identifymg the lesion, but the diagnosis rests on histologic confirmation. Occasionally that can be established by examining the CSF for malignant lymphoma cells, but biopsy usually is needed. Unlike lymphomatous involvement of the leptomeninges or spinal cord, ocular involvement is common. It may be the first manifestation of disease or occur at relapse. Patients who develop ocular lymphoma first have a 50% to 80% chance of developing cerebral lymphoma, often years later. Conversely, patients with PCNSL have a 15% to 25% incidence of ocular involvement at diagnosis, and about half of these patients have no visual symptoms. The incidence of ocular lymphoma in AIDS-related PCNSL is unknown, but it has been reported in conjunction with cerebral tumor or as the sole site of disease. Visual symptoms in patients with AIDS may be difficult to interpret because of the high incidence of cytomegalovirus retinitis. Diagnosing ocular lymphoma can be difficult because symptoms often mimic more common benign inflammatory conditions such as uveitis, chorioretinitis, and vitreitis. Often a patient’s visual symptoms are not attributed to ocular lymphoma unless cerebral disease is found, or the disease becomes refractory to antiinflammatory treatment. The most common symptoms are floaters, visual blurring, or segmental visual loss from a retinal detachment caused by a subretinal deposit of lymphoma. Diagnosis often is made on ophthalmologic examination, especially the slit lamp examination, where ocular lymphoma looks like a chronic vitreitis. Ultrasonography reveals nonspecific findings such as choroidal-scleral thickening, widening of the optic nerve, and vitreous debris. Diagnosis can be confirmed by a vitreous biopsy or anterior chamber tap. False-negative biopsies may be seen in patients treated with corticosteroids. Corticosteroids are

TABLE 161-1. Presenting Signs and Symptoms of Primary Central Nervous System Lymphoma (227 Patients)

Focal cerebral deficit (e.g., hemiparesis, visual field defect) Mental status change Increased intracranial pressure (including headache) Cranial nerve palsy Seizure Ataxia/cerebellar syndrome

Percentage of Total

Raw

47

38-79%

37 34

13-63% 14-63%

6 11 9

0-36% 0-23% 0-43%

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the initial treatment of vitreitis; however, an initial response to steroids that later diminishes often is the first indication that the vitreitis is caused by an ocular lymphoma. Ultrasonography reveals nonspecific findings such as choroidal-scleral thickening, widening of the optic nerve, and vitreous debris. Diagnosis can be confirmed by a vitreous biopsy or anterior chamber tap. Falsenegative biopsies may be seen in patients treated with corticosteroids. Definitive treatment includes vitrectomy, ocular radiotherapy, and chemotherapy.

PATHOLOGY

PCNSL is a non-Hodgkin’s lymphoma, typically of the intermediate or high-grade variety. Most are diffuse large cell or large cell immunoblastic. Most exhibit a B-cell immunophenotype, with less than 3% of T-cell origin. Macroscopically, the tumors are deep-seated white matter lesions that may be solitary or multiple. Multiple lesions are more commonly seen in patients with AIDS and occur in 30% to 40% of sporadic cases. Microscopically, the tumors are composed of high-grade neoplastic cells, which have a very characteristic perivascular growth pattern. Tumor cells tend to grow in the perivascular spaces and form concentric rings around vessel walls without invading the vascular lumen (Fig. 161-1). The cells invade the brain parenchyma between blood vessels. Brain infiltration tends to be widespread and at autopsy is always more extensive than suspected on the basis of MRI. Almost 100% of patients with AIDS and half of immunocompetent patients have multifocal tumor at autopsy. Unlike high-grade gliomas, PCNSL in immunocompetent patients lacks vascular proliferation and necrosis. However, necrosis is commonly seen in AIDS-related PCNSL. An additional feature of PCNSL is the presence of reactive lymphocytes among the neoplastic cells. These reactive cells may cause a diagnostic dilemma in samples taken from patients who have received prior corticosteroid therapy; steroids can cause lysis of the malignant B cells, leaving the reactive lymphocytes behind. The resulting paucity of neoplastic cells and the presence of reactive cells often leads to the misdiagnosis of an inflammatory process.

LABORATORY EVALUATION

Because patients with PCNSL present with cerebral neurologic symptoms, the first test most patients undergo is cranial imaging. The radiographic appearance is similar on both computed tomography (CT) and MRI, but MRI is clearly superior to CT. Before contrast administration, PCNSL usually is isodense or hyperdense on CT and isointense on TI-weighted MRI. After contrast administration the lesions enhance prominently and diffusely (Fig. 161-2). The borders of the lesions are indistinct, and the amount of edema is variable. They typically have a periventricular location in the white matter. Unlike malignant gliomas or brain metastases, no central necrosis is seen in immunocompetent patients, although it is a common feature of PCNSL in immunodeficient patients. Radiographically, PCNSL often responds to corticosteroid therapy and may transiently vanish from imaging studies. This can occur within a few days of treatment, and both complete and partial responses have been observed. At diagnosis a variable incidence of positive CSF cytology ranging from 0% to 25% has been reported. When patients are examined routinely and more than one sample is available, we have found that one third of patients have malignant lymphocytes in their CSF and an additional one third have suspicious cells. The CSF shows other nonspecific abnormalities such as an elevated protein in 85% of patients and a lymphocytic pleocytosis in 50%. An increased cell count may be caused by the presence of malignant cells in the CSF or by a reactive lymphocytosis, which may accompany tumor cells or be present in isolation. These reactive T cells are the same phenomenon observed in the tissue samples of PCNSL. Glucose concentration is almost always normal unless extensive leptomeningeal tumor is present, in which case the concentration may be low. DIFFERENTIAL DIAGNOSIS lmmunocompetentPatients

Most patients with PCNSL present with a space-occupying lesion on CT or MRI, and the diagnosis is clear on a biopsy specimen. However, in some situations the diagnosis is extremely difficult or

FIG. 161-1. Microscopic section showing the prominent perivascular growth pattern of PCNSL

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patients with PCNSL have a history of cancer. If brain metastases are diagnosed presumptively on the basis of CT or MRI, patients often receive empiric therapy with palliative whole-brain radiotherapy. When tumor recurs or no systemic cancer becomes evident with further clinical follow-up, the diagnosis of PCNSL may become apparent on CSF examination or subsequent brain biopsy. However, the short course of radiotherapy given for brain metastases has cost the patient the opportunity to receive more definitive and potentially curative treatment with chemotherapy and a less toxic fractionation schedule of radiotherapy.

ImmunosuppressedPatients

FIG.

161-2. Gadolinium-enhanced MRI demonstrating multifocal, periventricular, diffusely enhancing PCNSL in an immunocompetent patient.

is made so by the administration of corticosteroids. Most patients who present with mass lesions on neuroimaging immediately receive corticosteroids before obtaining tissue for diagnosis to reduce perilesional edema and improve neurologic function. Unlike all other brain tumors, PCNSL may shrink and even disappear after corticosteroid administration. This shrinkage is caused by a direct cytotoxic effect by the steroids on the malignant lymphocytesand is mediated by cytoplasmic steroid receptors that are translocated to the nucleus and signal apoptosis. Resolution or significant shrinkage of PCNSL lesions can occur within a few days of steroid administration. However, this response is more common with prolonged steroid use. This response may also be seen in ocular and leptomeningeal lymphoma, and examination of the eyes and CSF after initiation of corticosteroids may result in a false-negative report. However, not all patients with PCNSL respond to corticosteroids in this fashion. Therefore, the absence of tumor regression after corticosteroid administration does not preclude a diagnosis of PCNSL. Furthermore, lesion resolution after steroids should not be used intentionally as a diagnostic test. Other neurologic processes that appear as diffuse contrastenhancing lesions on CT or MRI can also resolve with corticosteroid administration. Acute multiple sclerosis can present with periventricular enhancing lesions that disappear after corticosteroid administration; CNS sarcoid can have a similar appearance. Multiple sclerosis can be particularly difficult to distinguish from PCNSL because both can be accompanied by a CSF pleocytosis and even oligoclonal bands. Another diagnostic pitfall can occur in patients who present with multiple enhancing intracranial lesions that are misdiagnosed as brain metastases. This clinical impression can be substantiated further by the fact that approximately 13% of

The differential diagnosis of PCNSL is different in immunosuppressed patients than in immunocompetent patients. From a practical point of view this section concentrates on the patient with AIDS, although it would apply to any immunocompromised patient with a space-occupying lesion. Although the incidence of PCNSL in the patient with AIDS has decreased since the introduction of HAART, it remains the most common brain tumor seen in this population and the second most common cause of an intracranial lesion. In the patient with AIDS PCNSL does not have the characteristic radiographic features seen in the immunocompetent patient. On CT or MRI, PCNSL usually is a ring-enhancing lesion in patients with AIDS, and a diffusely enhancing mass is rarely seen (Fig. 161-3).This ring-enhancing appearance correlates with the high incidence of tumor necrosis seen pathologically. Because the characteristic radiographic appearance of PCNSL is lacking in patients with AIDS, the lesion is indistinguishablefrom other CNS processes, particularly infection with toxoplasmosis, which remains the most common cause of a cerebral mass in this population. Positron emission tomography (PET) or single photon emission computed tomography (SPECT) may be used to distinguish lymphoma, which is hypermetabolic, from infection, which is hypometabolic. The incidence of leptomeningeal seeding of PCNSL in patients with AIDS is as high as that seen in immunocompetent patients. Lumbar puncture is safe in all patients with PCNSL except those with large posterior fossa lesions and can offer an early and simple means of diagnosis. In patients with AIDS but not in immunocompetent patients, PCNSL is an Epstein-Barr virus (EBV)-driven lymphoma. EBV genome has been detected in almost all patients with AIDS-related PCNSL. EBV DNA is shed into the CSF, so CSF analysis for both cytology and EBV using the polymerase chain reaction (PCR) technique is an essential diagnostic tool. CSF examination also excludes other processes such as infections, including progressive multifocal leukoencephalopathy, which can be detected using PCR for the JC virus. There is 100% diagnostic accuracy for PCNSL when a PET or SPECT scan is hypermetabolic and the CSF is positive for EBV DNA by PCR. This allows a definitive diagnosis in the absence of a brain biopsy. These tests, which are readily available and rapid, have eliminated the earlier approach of treating patients with AIDS and a cerebral lesion with empiric antitoxoplasmosis therapy and reserving brain biopsy for those in whom this therapy fails. Furthermore, if the diagnosis can be established noninvasively, it spares the patient a brain biopsy, which carries a greater risk of intracranial hemorrhage in this population. In addition, if PCNSL is suspected even before tissue confirmation has been obtained, an ophthalmologic examination may also support the clinical impression if lymphocytesare seen in the vitreous.

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B

A

FIG. 161-3. Gadolinium-enhanced MRI demonstrating a ring-enhancing PCNSL in a patient with AIDS. Note the superficial location of the lesion.

Immunocompetent patients with PCNSL do not need an extensive systemic evaluation to search for systemic lymphoma. However, patients with AIDS and systemic lymphoma have a high incidence of extranodal involvement, including CNS disease. A complete evaluation, including body CT scans and bone marrow biopsy, should be performed in all patients with AIDS and PCNSL to ensure that no systemic lymphoma is present, which would markedly change the therapeutic regimen.

TREATMENT lmmunocompetent Patients PCNSL is a highly aggressive neoplasm, and the median survival of immunocompetent patients with supportive care alone is only 3 months. Age at diagnosis and performance status are the most important prognostic factors in patients with PCNSL, regardless of treatment. Older age increases the risk of relapse and shortens survival. Surgical resection does not contribute to survival, and the median is increased to only 4 or 5 months with surgery alone. Surgical resection may also cause neurologic deterioration because of the deep location of most lesions. Cranial radiotherapy (4000 to 5000 cGy) has been the cornerstone of treatment for PCNSL for decades, increasing median survival to 12 to 18 months. Although highly effective at producing a remission, tumor recurs within 1 year after radiotherapy, and 5-year survival is only 3% to 4%. These survival statistics are comparable to those for a glioblastoma multiforme. Unlike malignant gliomas, PCNSL often recurs in regions of the brain remote from the original area of involvement. Relapse usually recurs in the brain, but it may be accompanied by leptomeningeal or ocular recurrence. Furthermore, tumor can recur in either of these locations in the absence of brain relapse. Therefore, patients need a complete neurologic restaging at the time of relapse. In the past 15 to 20 years there has been a growing effort to study the role of chemotherapy in treating PCNSL to im-

prove outcome. Standard chemotherapy regimens for systemic lymphoma have not proved beneficial in treating PCNSL. Cyclophosphamide- and doxorubicin-basedregimens, when combined with radiotherapy, give a median survival comparable to that of radiation alone, although a tumor response to the initial cycles of chemotherapy may be observed. Patients develop rapid brain (and occasionally extensive leptomeningeal)relapse while on these chemotherapy programs. Despite the expected cytotoxic superiority of the agents in the systemic lymphoma regimens, these combinations do not perform as well because the drugs cannot penetrate the intact blood-brain barrier. The drugs reach bulky disease because the blood-brain barrier is disrupted, but they cannot reach areas of microscopic disease situated behind an intact barrier. Thus, while bulky disease may be regressing, microscopic disease continues to grow, resulting in the formation of new tumors. To date, the most successful chemotherapy programs for PCNSL use agents with an intrinsic ability to penetrate an intact blood-brain barrier (e.g., procarbazine, lomustine) or are delivered in dosages that facilitatedrug delivery behind the barrier (e.g., high-dose methotrexate or high-dose cytarabine). High-dose methotrexate is recognized as the single most effective chemotherapeutic drug for treating PCNSL. A wide range of dosages are used in ongoing studies, and to date there are no clear data as to the optimal dosage; however, dosages probably should exceed 1 g/m’ to guarantee CNS penetration. In the 1980s Memorial Sloan-Kettering Cancer Center used a preradiation regimen of high-dose methotrexate (1 g/m’) with intra-Ommaya methotrexate to treat leptomeningeal tumor regardless of CSF cytology. This was followed by whole-brain radiotherapy (4000 cGy) with a boost (1440 cGy) and high-dose cytarabine. The median disease-free survival was 42 months, and long-term follow-up gave a 22% 5-year survival, significantly longer than radiotherapy alone. However, long-term survivors, particularly those over the age of 60 years at diagnosis, suffered significant neurotoxicity characterized by dementia, ataxia, and eventually

Chapter 161

urinary incontinence. Recently, we reported on a protocol to optimize and enhance the chemotherapeutic component of treatment. The methotrexate dosage was increased to 3.5 g/m’ to facilitate penetration into the CNS, and the total number of cycles was increased from two to five. Patients also received procarbazine, a lipophilic agent capable of penetrating an intact blood-brain barrier, and vincristine. Overall median survival was 60 months, giving a 50% 5-year survival. Older patients had similar median survival with or without the addition of radiotherapy: 32 versus 33 months. Twenty-two older patients in the trial deferred radiotherapy to diminish the risk of delayed neurotoxicity. Late neurotoxicity was seen in almost all older patients who received radiotherapy but in none of those treated with chemotherapy alone. We concluded that increasing the methotrexate dosage and adding procarbazine and vincristine improved disease control and overall survival in patients with newly diagnosed PCNSL. In older patients, deferring whole-brain radiotherapy did not compromise overall survival but did reduce treatment-related neurotoxicity. Sandor et al. (1988) investigated the efficacy and toxicity of chemotherapy alone for PCNSL, and many of their patients had ocular lymphoma. Fourteen patients were treated with high-dose methotrexate, thiotepa, dexamethasone, and intrathecal cytarabine and methotrexate. Median progression-free survival was 16.5 months, but patients were successfully salvaged with radiotherapy; the median overall survival has not been reached. McAllister et al. use blood-brain barrier disruption with intra-arterial mannitol followed by intra-arterial methotrexate as well as systemic cyclophosphamide, procarbazine, and dexamethasone. Their goal is to avoid radiotherapy, and chemotherapy is administered monthly for 1 year. In a series of 111 patients (McAllister et al., 2000), 74 patients received chemotherapy alone, without subsequent radiotherapy. Median survival in this group was 40.7 months, clearly superior to that of radiotherapy alone. They report cognitive impairment only in those who received radiotherapy. However, intra-arterial chemotherapy carries a risk of acute complications, such as seizures and increased edema. Furthermore, therapeutic levels of methotrexate in the CSF and CNS can be achieved by conventional high-dose administration. Ocular lymphoma necessitates specific treatment. Ocular irradiation to a total dosage of 3600 to 4000 cGy is effective therapy, producing clinical improvement and regression of cells in most patients. When ocular involvement is present at diagnosis, the ocular radiotherapy must be coordinated with any planned cranial irradiation to avoid overlapping ports. Isolated ocular lymphoma is a particular therapeutic challenge. Ocular radiotherapy is effective, but most patients develop ocular or CNS relapses. Some have advocated concurrent cranial irradiation to reduce the risk of CNS relapse; however, there is no evidence that early brain irradiation reduces cranial recurrence, and the neurologic toxicity of cranial radiotherapy is considerable. Chemotherapy has been used with some success for ocular lymphoma; most drugs penetrate poorly into the vitreous, but high-dose cytarabine and high-dose methotrexate are effective in some patients. In addition, therapeutic levels of both drugs have been achieved in the vitreous. Intravitreal injection of methotrexate has also been used successfully at relapse and is surprisingly well tolerated. Recurrent PCNSL often responds to additional treatment. Radiotherapy is effective if not delivered as part of initial therapy. Additional chemotherapy, particularly using agents previously not administered, can also produce sustained remission that can last for as long as 4 years in some patients. Some investigators have achieved good results using high-dose methotrexate for a second

H

Primary Central Nervous System Lymphoma

1053

time. The efficacy of high-dose systemic chemotherapy supported by autologous peripheral blood stem cell transplantation in patients with recurrent or refractory PCNSL has recently been reported by Soussain et al. (2001). Results could be reported on 20 of 22 patients, and the overall survival rate at 3 years was 63.7%. There was only one transplant-related death, and five patients developed late cognitive impairment. These data are promising but preliminary. IMMUNOSUPPRESSED PATIENTS Treating PCNSL in patients with AIDS is more difficult and less successful than comparable treatment in immunocompetent patients. Whole-brain radiotherapy alone gives a median survival of only 2 to 5 months in HIV-l-infected patients. Although most patients with HIV-related PCNSL respond to radiotherapy with regression of tumor on CT or MRI, death occurs within months, usually from opportunistic infections. Most patients die from systemic infection, but at autopsy almost all patients with AIDS and PCNSL have concurrent CNS infections. The most common include HIV-1 encephalitis, cytomegalovirus encephalitis, toxoplasmosis, cryptococcal meningitis, or multiple infections. These neurologic infections may not be recognized or possible to diagnose before death, but they often contribute to the patient’s poor clinical condition. Many patients with AIDS and PCNSL who have a good radiographic response to treatment do not improve clinically because these other CNS processes are present. This makes assessing antitumor therapy very difficult. Although some patients die of infectious processes, many die of uncontrolled or recurrent PCNSL. The use of chemotherapy in patients with AIDS is complicated by their underlying immunosuppression and reduced ability to tolerate cytotoxic drugs. No large group of patients with AIDS and PCNSL has been treated with combined-modality therapy. However, some patients have been reported who appear to benefit from chemotherapy plus radiotherapy and who have prolonged survival of 2 years or more. Often these are patients who have PCNSL as their AIDS-defining illness, and they have not suffered multiple systemic complications of their HIV- 1 infection. Because combined-modality therapy appears to benefit a subpopulation, any patient with AIDS and PCNSL should be considered for chemotherapy and radiotherapy at diagnosis or enrolled in a clinical trial studying this issue. More recently, there are individual reports of HIV-positive patients with PCNSL whose tumor has responded to antiretroviral and antiviral therapies. These patients strongly suggest that reconstitution of the immune system can control these EBV-driven lymphomas. Unfortunately, some patients are not eligible for aggressive treatment, especially those in poor neurologic condition. These patients are best treated with palliative whole-brain radiotherapy, perhaps delivered in a short-course rapid fractionation schedule. CONCLUSION PCNSL is unique among brain tumors in its responsiveness to systemic chemotherapy. Significant improvement in survival has been observed with combined-modality therapy and the use of systemic chemotherapy. Extended survival has been accompanied by an increased risk of delayed neurotoxicity, particularly in older adults. The continuous development of chemotherapy-based treatment protocols that offer extended suMval and minimize neurotoxicity is essential. Additional clinical trials are necessary to investigatethe efficacy of combined-modalitytherapy with the use

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of systemic chemotherapy and the use of antiretroviral and antiviral therapy in AIDS-related PCNSL. SUGGESTED READINGS Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 16(3):859-863, 1998 Abrey LE, Yahalom J, DeAngelis LM: Treatment of primary CNS lymphoma: the next step. J Clin Oncol 18(17):3144-3150,2000 Ammassari A, Cingolani A, Pezzotti P et ak AIDS-related focal brain lesions in the era of highly active antiretroviral therapy. Neurology 55(8):1194-1200, 2000

Baumgartner JE, Rachlin JR, Beckstead JH et ak Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiencysyndrome. J Neurosurg 73(2):20&211, 1990

Chamberlain MC, Kormanik PA AIDS-related central nervous system lymphomas. J Neurooncol43(3):269-276, 1999 Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119(11):1093-1104, 1993 Guha-Thakurta N, Damek D, Pollack C, Hochberg FH: Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol43(3):259-268, 1999

Herrlinger U,Schabet M, Bitzer M et al: Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol

Herrlinger U,Schabet M, Brugger W et ak Primary central nervous system lymphoma 1991-1997. Cancer 91(1):130-135,2001 Hochberg FH, Miller DC Primary central nervous system lymphoma. J Neurosurg 68(6):835-853, 1988 Ling- SM, Roach M 111, Larson DA, Wara WM: Radiotherapy _ . of primary central nervous system lymphoma in patients with and without human immunodeficiencyvirus. Ten years of treatment experience at the University of California San Francisco. Cancer 73(10):2570-2582, 1994

McAUister LD, Doolittle ND, Guastadisegni PE et ak Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46(1): 5141,2000

Raez L, Cabral L, Cai JP et ak Treatment of AIDS-related primary central nervous system lymphoma with zidovudme, ganciclovir, and interleukin 2. AIDS Res Hum Retroviruses 15(8):713-719, 1999 Sandor V, Stark-Vancs V, Pearson D et ak Phase I1 trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16(9):3000-3006, 1998

Slobod KS, Taylor GH, Sandlund JT et ak Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system. Lancet 356(9240):1493-1494, 2000 Soussain C, Suzan F, Hoang-Xuan K et al: Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol 19(3):742-749,2001

43(3):219-226, 1999

162 Meningiomas Peter M. Black and John K. Park Meningiomas are the most common benign brain tumor and the second most common primary brain tumor overall after ghomas. They account for approximately 15% to 20% of intracranial tumors. The reported incidence of meningiomas is approximately 2.7 per 100,000 population, but autopsy studies indicate that this is probably an underestimate. They are twice as common in women as men, and the peak incidence is in the sixth decade for men and the seventh decade for women. Rarely, meningiomas may occur in children. Meningiomas are more common in patients who have neurofibromatosis or who have been exposed to previous cranial irradiation. The incidence of meningiomas is also slightly higher in patients with breast carcinoma. It has been suggested that head trauma may play a part, but the evidence is not convincing. Approximately 5% to 15% of patients have multiple meningiomas, particularly in association with neurofibromatosis.

ETIOLOGY AND BIOLOGY Meningiomas arise from the arachnoid cap cells, which form the outer lining of arachnoid granulations of the brain (Fig. 162-1) and compress cortex or cranial nerves as they grow. The cause of meningiomas is unknown, but 40% to 80% of these tumors have a loss of genetic material from the long arm of chromosome 22, at a locus separate from the gene for neurofibromatosis-2. Some evidence shows that a second tumor suppressor locus relevant to meningioma formation may be located on chromosome 22q.

Malignant meningiomas are associated with deletion of loci on chromosomes lp, 9q, and 17p. Other deletions may also contribute to the growth of meningiomas. Meningiomas have receptors for sex hormones and other ligands, including progesterone, estrogen, androgen, dopamine, and the P-receptor for platelet-derived growth factor. Analysis of the contributions of these receptors to meningioma growth is intriguing and may have important implications for pathophysiology and future therapies. The presence of hormonal receptors may explain the tendency for some meningiomas to increase in size and become symptomatic during pregnancy. In initial competitive inhibition studies, it appeared that meningiomas had estrogen receptor activity. With more sensitive and specific immunohistochemical and molecular biologic techniques, however, it became clear that estrogen receptors are expressed in only a small percentage of these tumors. In contrast, progesterone receptors are expressed in 70% to 80% of meningiomas. Androgen and dopamine receptors are also expressed in a significant percentage of meningiomas, although in less robust quantities than the progesterone receptor. Dopamine receptors appear to be expressed equally in men and women; androgen receptors, like those for progesterone, are expressed more frequently in women. The platelet-derived growth factor system, which seems important in many brain tumors, is found in abundance in meningioma

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of systemic chemotherapy and the use of antiretroviral and antiviral therapy in AIDS-related PCNSL. SUGGESTED READINGS Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 16(3):859-863, 1998 Abrey LE, Yahalom J, DeAngelis LM: Treatment of primary CNS lymphoma: the next step. J Clin Oncol 18(17):3144-3150,2000 Ammassari A, Cingolani A, Pezzotti P et ak AIDS-related focal brain lesions in the era of highly active antiretroviral therapy. Neurology 55(8):1194-1200, 2000

Baumgartner JE, Rachlin JR, Beckstead JH et ak Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiencysyndrome. J Neurosurg 73(2):20&211, 1990

Chamberlain MC, Kormanik PA AIDS-related central nervous system lymphomas. J Neurooncol43(3):269-276, 1999 Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119(11):1093-1104, 1993 Guha-Thakurta N, Damek D, Pollack C, Hochberg FH: Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol43(3):259-268, 1999

Herrlinger U,Schabet M, Bitzer M et al: Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol

Herrlinger U,Schabet M, Brugger W et ak Primary central nervous system lymphoma 1991-1997. Cancer 91(1):130-135,2001 Hochberg FH, Miller DC Primary central nervous system lymphoma. J Neurosurg 68(6):835-853, 1988 Ling- SM, Roach M 111, Larson DA, Wara WM: Radiotherapy _ . of primary central nervous system lymphoma in patients with and without human immunodeficiencyvirus. Ten years of treatment experience at the University of California San Francisco. Cancer 73(10):2570-2582, 1994

McAUister LD, Doolittle ND, Guastadisegni PE et ak Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46(1): 5141,2000

Raez L, Cabral L, Cai JP et ak Treatment of AIDS-related primary central nervous system lymphoma with zidovudme, ganciclovir, and interleukin 2. AIDS Res Hum Retroviruses 15(8):713-719, 1999 Sandor V, Stark-Vancs V, Pearson D et ak Phase I1 trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16(9):3000-3006, 1998

Slobod KS, Taylor GH, Sandlund JT et ak Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system. Lancet 356(9240):1493-1494, 2000 Soussain C, Suzan F, Hoang-Xuan K et al: Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol 19(3):742-749,2001

43(3):219-226, 1999

162 Meningiomas Peter M. Black and John K. Park Meningiomas are the most common benign brain tumor and the second most common primary brain tumor overall after ghomas. They account for approximately 15% to 20% of intracranial tumors. The reported incidence of meningiomas is approximately 2.7 per 100,000 population, but autopsy studies indicate that this is probably an underestimate. They are twice as common in women as men, and the peak incidence is in the sixth decade for men and the seventh decade for women. Rarely, meningiomas may occur in children. Meningiomas are more common in patients who have neurofibromatosis or who have been exposed to previous cranial irradiation. The incidence of meningiomas is also slightly higher in patients with breast carcinoma. It has been suggested that head trauma may play a part, but the evidence is not convincing. Approximately 5% to 15% of patients have multiple meningiomas, particularly in association with neurofibromatosis.

ETIOLOGY AND BIOLOGY Meningiomas arise from the arachnoid cap cells, which form the outer lining of arachnoid granulations of the brain (Fig. 162-1) and compress cortex or cranial nerves as they grow. The cause of meningiomas is unknown, but 40% to 80% of these tumors have a loss of genetic material from the long arm of chromosome 22, at a locus separate from the gene for neurofibromatosis-2. Some evidence shows that a second tumor suppressor locus relevant to meningioma formation may be located on chromosome 22q.

Malignant meningiomas are associated with deletion of loci on chromosomes lp, 9q, and 17p. Other deletions may also contribute to the growth of meningiomas. Meningiomas have receptors for sex hormones and other ligands, including progesterone, estrogen, androgen, dopamine, and the P-receptor for platelet-derived growth factor. Analysis of the contributions of these receptors to meningioma growth is intriguing and may have important implications for pathophysiology and future therapies. The presence of hormonal receptors may explain the tendency for some meningiomas to increase in size and become symptomatic during pregnancy. In initial competitive inhibition studies, it appeared that meningiomas had estrogen receptor activity. With more sensitive and specific immunohistochemical and molecular biologic techniques, however, it became clear that estrogen receptors are expressed in only a small percentage of these tumors. In contrast, progesterone receptors are expressed in 70% to 80% of meningiomas. Androgen and dopamine receptors are also expressed in a significant percentage of meningiomas, although in less robust quantities than the progesterone receptor. Dopamine receptors appear to be expressed equally in men and women; androgen receptors, like those for progesterone, are expressed more frequently in women. The platelet-derived growth factor system, which seems important in many brain tumors, is found in abundance in meningioma

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FIG. 162-1. Location of the arachnoid cap cells in the arachnoid villi. Meningiomas are thought to originate from these arachnoid cap cells. (From Al-Mefty 0, Origitano TC: Meningiomas. p. 28. In Rengachary SS, Wilkins RH (eds): Principles of Neurosurgery. Wolfe, London, 1994, with permission.)

tissue. The p-form of the receptor is expressed along with the B subunit of platelet-derived growth factor itself, creating the potential for an autocrine loop within meningioma tissue. The precise role of these hormonal and growth factor receptors in the growth of meningiomas is unclear.

be similar to hemangiopericytoma, but in fact is quite different from it because hemangiopericytoma is more a sarcoma than a meningioma and arises from the pericytes around capillaries. Malignant meningiomas are characterized by abundant mitoses, nuclear pleomorphism, necrosis, high nuclear-to-cytoplasmic ratio, loss of normal architecture, and invasion of surrounding

CLASSIFICATION AND PATHOLOGY The characteristic histologic features of meningiomas are whorls that form around a central hyaline material, eventuallycalcify, and form psammoma bodies or interlacing bundles of elongated fibroblastswith narrow nuclei. There is no unequivocal pathologic marker for meningiomas. Epithelial membrane antigen and vimentin are positive in most of these tumors, and glial fibrillary acidic protein and anti-Leu7 are almost always negative. The classification of meningiomas is confusing. An earlier World Health Organization classification divided them into meningotheliomatous (syncytial), fibrous, transitional, psammomatous, and angiomatous types, but this distinction has little prognostic importance (Table 162-1 and Plate 162-1). Presently meningiomas are classified as meningiomas, atypical meningiomas, and malignant meningiomas. Papillary and angioblastic meningiomas are more aggressive variants. Angioblastic meningioma has in the past been thought to

TMLE 162-1. World Health Organization Classification of Meningiomas Class

subtvpe

Predominant Feature

Classic

Meningotheliomatous Fibroblastic Transitional Psammomatous Angiomatous

Angioblastic

Hemangioblastoma

Syncytial cells with lobules Spindle cells with collagen Mixture of above types Exuberant psammoma bodies Abundant sclerosing blood vessels Capillary endothelial cells with lipid stromal cells Poorly differentiated pericytic cells with reticulin Papillary pattern with few anaplastic features Invasion of brain parenchyma metastases

Hemangiopericytoma Aggressive

Papillary

Malignant

Anaplastic

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brain. Aggressive meningiomas contain one or more anaplastic features but do not meet the criteria for malignancy. In 1985 and 1986 Jaaskelainen and colleagues proposed a grading system that is predictive of outcome. This system uses points for loss of architecture, increased cellularity, nuclear pleomorphism, mitotic figures, focal necrosis, and presence of brain infiltration to establish whether a tumor is benign (0 to 2 points), atypical (3 to 6 points), anaplastic (7 to 11 points), or sarcomatous (12 to 18 points). For grade I tumors, the recurrence rate at 5 years is 3%, for grade I1 it is 38%, and for grade 111 it is 78%. Several other methods have been used to help predict the behavior of meningiomas. The bromodeoxyuridine (BdUR) labeling index uses bromodeoxyuridine, a thymidine analogue, that is incorporated into cells undergoing DNA synthesis. The proportion of tumor cells on histologic sections labeled with BdUR (the BdUR labeling index) indicates the proliferative potential of the tumor. Meningiomas with a labeling index of 10/0 have a higher recurrence rate than normal, and for those with an index of 5% or higher, the recurrence rate is 100%. The MIB-1 labeling index, like the BdUR labeling index, indicates the percentage of dividing cells in the tumor specimen. The MIB-1 antibody recognizes Ki-67, an antigen associated with cell proliferation (G,, S, G2,and mitosis) that is absent in quiescent cells (Go).It is easier to perform than the BdUR labeling index and is more widely used.

CLINICAL PRESENTATION Like other brain tumors, meningiomas may present with seizures, headaches, and focal neurologic deficits. Patients often have subtle symptoms for a long period before the meningioma is diagnosed. Increasing numbers of patients are reported with asymptomatic meningiomas discovered by neuroimaging studies performed for unrelated reasons. The precise clinical features vary depending on location. Ninety percent of meningiomas are intracranial, and of these, 90% are supratentorial. Table 162-2 outlines the common sites of meningiomas. Convexity meningiomas usually are located anterior to the central sulcus and may remain asymptomatic until they reach a large size. They typically present with seizures, focal neurologic deficits, or headaches. Falx and parasagittal meningiomas produce similar symptoms, but they often involve the sagittal sinus, making complete resection much more difficult. Large parasagittal meningiomas may result in bilateral leg weakness. Olfactory groove meningiomas often grow to a large size before they become symptomatic because anosmia and mental status changes often are unrecognized. When the tumor becomes very large, visual loss may result from compression of the optic nerves and chiasm.

T m 162-2.Common Locations of Meningiomas Loution

%

Falx or parasagittal

25

Convexity Sphenoid wing Olfactory groove Suprasellar Posterior fossa (petrosal) lntraventricular Miscellaneous (ex.. optic nerve, divus)

20 20 10 10 10 2 3

FIG. 162-2. Axial MRI with gadolinium showing an enhancing meningioma arising in the left sphenoid wing and involving the cavernous sinus and carotid artery. This tumor could not be completely resected and was treated with stereotactic radiotherapy. Follow-up 2 years later showed slight reduction in tumor size.

The presenting symptoms of sphenoid ridge meningiomas vary depending on their exact location. Medial sphenoid ridge meningiomas may involve the cavernous sinus, giving rise to oculomotor palsies and facial numbness (Fig. 162-2). The carotid artery may also be encased by the tumor, preventing complete surgical resection. As the tumor enlarges, the optic nerves may be affected. A large meningioma may produce atrophy of the ipsilateral optic nerve and papilledema in the contralateral optic nerve by increasing intracranial pressure, giving rise to Foster Kennedy syndrome. Posterior fossa meningiomas may produce a wide range of symptoms depending on the structures involved. Meningiomas arising from the petrous bone may compress cranial nerves, especially the eighth nerve, resulting in deafness. Petroclival meningiomas may cause trigeminal neuralgia and hemifacial spasm. Tentorial and foramen magnum meningiomas may produce headaches and symptoms of brainstem compression. Intraventricular meningiomas usually present with headaches resulting from increased intracranial pressure. Intraorbital meningiornas may present with progressive painless visual loss and proptosis. Spinal meningiomas account for less than 10% of meningiomas. They tend to occur in women (female/male ratio, 5:1), usually between ages 40 and 70. They are intradural, extramedullary tumors occurring predominantly in the thoracic spine. Initially they present with back and radicular pain, but as the tumor enlarges and compresses the spinal cord, pyramidal weakness and sensory loss may occur.

Chapter 162

A

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B

FIG. 162-3. (A) Unenhanced axial CT scan showing a large, slightly hyperdense convexity meningioma. (B) Enhanced CT scan showing the tumor enhancing brightly. This tumor was resected completely.

IMAGING In 50% to 60% of patients with meningiomas, plain radiographs may show changes such as calcification and hyperostosis or thinning of the adjacent skull. However, with the availability of computed tomography (CT) and magnetic resonance imaging (MRI), skull radiographs are rarely needed. On noncontrast CT, meningiomas appear as well-defined, hyperdense masses, often with coarse calcification (Fig. 162-3). They have a broad dural base and may expand the adjacent cerebrospinalfluid spaces. The underlying cortex may appear to be buckled from external compression by the tumor. Hyperostotic changes or blistering in the adjacent calvaria may occur. Meningiomas enhance brightly and homogeneously with iodinated contrast. The amount of periturnoral edema is variable and tends to be correlated with angioblastic histology, the presence of hormone receptors, and a high proliferation index. On high-field strength MFU, meningiomas are slightly hypointense on T1 -weighted images and isointense to slightly hyperintense on T2-weighted images. At lower field strengths, they tend to be isointense on T1- and T2-weighted images, so small meningiomas may be missed on noncontrast studies. Therefore, small meningiomas are sometimes better visualized on CT than MRI. Meningiomas often demonstrate a speckled pattern of signal intensity thought to be caused by tumor vascularity, calcification, or cystic foci. Punctate or curvilinear signal voids may be present at the interface of the brain and the meningioma, representing pial vessels at the margin of the tumor. After gadolinium administration, intense enhancement usually is noted, and a tapered projection of enhancement or “dural tail” may be seen at the margin of the tumor (Fig. 162-4). Indistinct margins, marked edema, mushroom-like projections from tumor, invasion deeply into brain, and heterogeneous enhancement all suggest aggressive behavior. However, malignant meningiomas cannot be distinguished with certainty by radiologic

studies. This is important to bear in mind when considering whether a patient should be observed. Three-dimensional reconstruction from MRI can demonstrate the tumor’s relationship to other structures, including cerebral blood vessels, brainstem, and cranial nerves. MR angiography has

FIG. 162-4. Axial MRI with gadolinium showing an enhancing meningioma arising from the left frontal convexity and projecting into the sylvian fissure.

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largely replaced conventional angiography for imaging adjacent blood vessels, although angiography may be necessary when embolization of the tumor is being considered. For convexity meningiomas, MR venography is particularly helpful in evaluating the dural sinuses, which may be invaded by tumor. Preliminary results suggest that positron emission tomography studies may be useful in determining whether a meningioma will recur. In one study, tumors with low glucose utilization (mean 1.9 mg/dL/minute) had a lower risk of recurrence than tumors with a high glucose utilization (mean 4.5 mg/dL/minute).

TREATMENT surgery The primary treatment for meningiomas is surgery. However, some tumors may be asymptomatic, and those that present with seizures only can safely be observed. An approach we find useful is to follow tumors less than 2 cm that are asymptomatic and not associated with edema. In these cases, observation means annual CT or MRI scans with contrast. Surgery takes significant judgment and skill. Total resection usually is possible with tumors of dura, falx, lateral sphenoid wing, frontal base, and cerebellar convexity. Complete resection may not be feasible in tumors involving the sagittal and cavernous sinuses, cerebellopontine angle, clivus (Fig. 162-5), tentorial notch, or optic nerve sheath. However, better understanding of neuroanatomy and improved neurosurgical techniques are allowing many of these lesions to be surgically excised today. The complication rate should be less than 10% for new neurologic deficits in most

meningiomas and the mortality rate less than 4%. These rates may be higher in older adults and patients with skull-based tumors. As discussed later in this chapter, there is an increasing trend to treat patients whose tumor cannot be completely excised with postoperative external beam radiotherapy or radiosurgery after aggressive but subtotal resection. Meningiomas are not always curable even if they appear to have been completely excised. The recurrence rate depends on completeness of removal, site of tumor, and biologic aggressiveness. For apparent complete removal, the recurrence varies from 8% to 20% over 10 years; for patients with obvious residual tumor it is 29% to 55% over a 10-year period. Patients with meningiomas have a higher overall mortality. The cumulative relative survival rates (ratio of observed rate to expected rate) at 1, 5, 10, and 15 years were 83%, 79%, 74%, and 71%, respectively.

Radiotherapy Until recently the use of external beam radiotherapy for meningiomas has been controversial because of concerns about longterm neurotoxicity and conflicting evidence regarding efficacy. Early studies of external beam radiotherapy showed no therapeutic benefit, but several recent studies have shown tumor control rates of 50% to 90% at 10 years. Goldsmith et al. (1994) reported on 140 patients treated at the University of California, San Francisco, between 1967 and 1990. The 5- and 10-year progression-free survival rates were 89% and 77%, respectively. For patients treated after 1980, the 5-year progression-free survival rate was 98%. Only 3.6% of patients experienced complications, which included blindness, necrosis, and death. No second brain tumors were seen. The studies of Goldsmith and others suggest that external beam radiation may have a role in treating selected patients with inoperable, partially resected, and recurrent meningiomas. One of the traditional limitations of external beam radiation has been radiation to surrounding brain. This limitation is now less because techniques of focused radiation have been developed using the linear accelerator or multiple cobalt sources (the gamma knife) that avoid exposure to brain outside the target area. Radiation may be given in one large fraction (stereotactic radiosurgery) or in multiple small fractions (stereotactic radiotherapy). In a review of 127 patients with 155 meningiomas treated with linear accelerator-based stereotactic radiosurgery, Hakim et al. (1998) found that 84% of patients had no tumor progression at a median follow-up time of 22.9 months, and the I-, 2-, 3-, 4-, and 5-year survival probabilities for the group were 90.3%, 82.6%, 73.6%, 70.5%, and 68.2%, respectively. One group reported tumor stabilization after radiosurgery in 38 patients (69%), shrinkage in 16 patients (29%), and enlargement in only 1 patient (2%) with skull base meningiomas over an average follow-up period of 48.4 months. In our own institutional experience, patients with skull base meningiomas have had a 92% control rate and a 34% clinical improvement rate at 28 months. Medical Therapy

FIG. 162-5. Coronal MRI with gadolinium showing a clivus meningioma compressing the brainstern.

As indicated earlier in this chapter, increasing evidence shows that the growth of meningiomas is influenced by hormones and growth factors, raising the possibility of medical therapy for meningiomas. Approximately 30% of meningiomas have estrogen receptors, and 70% to 80% have progesterone receptors. Treatment with antiestrogens such as tamoxifen and medroxyprogesterone acetate has been ineffective. Early pilot studies of the

Chapter 162 rn

antiprogesterone RU-486 showed promising results, but a larger multicenter study failed to show any benefit. Meningiomas express a number of other receptors, including those for dopamine D1, platelet-derived growth factor, epidermal growth factor, and androgens. Antagonists of these receptors inhibit meningioma growth in vitro and may play a role in treating meningiomas. Chemotherapy for malignant meningiomas using standard regimens for soft tissue sarcomas has been uniformly disappointing, although there have been occasional responses reported to interferon-a, possibly as a result of its antiangiogenic activity. There is also interest in using other angiogenesis inhibitors for malignant meningiomas.

Supportive Therapy Corticosteroids are useful for treating peritumoral edema, but they do not change the growth pattern of the tumor and have significant long-term side effects. These include diabetes mellitus, osteoporosis, proximal muscle wasting, and obesity. They should not be used for longer than 1 month at a time unless they are absolutely necessary. Anticonvulsants generally are not necessary for most skullbase meningiomas. The use of anticonvulsants for patients with convexity meningiomas who have not had a seizure remains controversial. Often, these patients are placed empirically on anticonvulsants for 6 to 12 months after the tumor has been resected. However, a study by Foy et al. (1992) suggested that postoperative anticonvulsant therapy may not be necessary. Because patients with meningiomas have a significantly higher risk of venous thromboembolic disease, preventive measures such as pneumatic compression devices and low-dose subcutaneous heparin are important during the perioperative and postoperative periods.

MALIGNANT MENINGIOMAS Malignant meningiomas account for only 12% of meningiomas, but they pose a significant management problem. They have a very high recurrence rate after surgery and generally respond poorly to treatment with radiotherapy, chemotherapy, or hormonal therapy. Unlike other malignant brain tumors, systemic metastases may occur in up to 24% of patients with malignant meningiomas, usually to lung and bone.

SUMMARY The diagnosis and management of meningiomas remain a major challenge to the clinical neurologist and neurosurgeon. With the advent of better imaging techniques, tumors are identified earlier and may be found in asymptomatic patients or patients with only a seizure as the presenting problem. Surgical techniques using the operating microscope, evoked potential monitoring, and improved understanding of anatomy have allowed tumors to be

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resected with better results. Adjunctive radiotherapy appears to have a substantial effect in limiting residual tumor growth, and the use of sex steroids may also have a significant role. The overall care of patients with problematic meningiomas still takes considerable judgment and skill.

SUGGESTED READINGS Al-Mefty 0 (ed): Meningiomas. Raven, New York, 1991 Al-Mefty 0, Origitano T C Meningiomas. p. 281. In Rengachary SS, Wilkins RH (eds): Principles of Neurosurgery. Wolfe, London, 1994 Black PM: Meningiomas. Neurosurgery 32:643-657, 1993 Carroll R, Glowacka D, Dashner K, Black PM: Progesterone receptor in meningiomas. Cancer Res 53:1312-1316, 1993 Cushing H, Eisenhardt L Meningiomas: Their Classification, Regional Behavior, Life History and Surgical End Results. Charles C. Thomas, Springfield, IL, 1938 DeMonte F: Current management of meningiomas. Oncology 983-86, 1995 Foy PM, Chadwick DW, Rajgopalan N et al: Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy? J Neurol Neurosurg Psychiatry 55:753-757, 1992 Glaholm J, Bloom HJG, Crow JH: The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 18:755-761, 1990 Goldsmith BJ, Wara WM, Wilson CB et al: Postoperative irradiation for subtotally resected meningiomas. J Neurosurg 8 0 195-201, 1994 Grunberg SM, Weiss MH, Spitz IM et al: Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 74861-866, 1991 Hakim R, Alexander E, Loeffler JS et al: Results of linear accelerator-based radiosurgery for intracranial meningiomas. Neurosurg 42:446, 1998 Jaaskelainen J: Seemingly complete removal of histologically benign intracranial meningioma: late recurrence rate and facts predicting recurrence in 657 patients. Surg Neurol 26461-469, 1986 JaaskelainenJ, Haltia M, Laasonen E et al: The growth rate of intracranial meningiomas and its relationship to histology. An analysis of 43 patients. Surg Neurol 24165-172, 1985 Kallio M, Sankila R, Hakulinen T et al: Factors affecting operative and excess long-term mortality in 935 patients with intracranial meningioma. Neurosurgery 31:2-12, 1992 Konziolka D, Lunsford LD: Radiosurgery of meningiomas. Neurosurg Clin North Am 3219-230, 1992 Lunsford LD Contemporary management of meningiomas: radiation therapy as an adjuvant and radiosurgery as an alternative to surgical removal? J Neurosurg 80:187-190, 1994 Mahmood A, Caccamo DV, Tomacek D et al: Atypical and malignant meningiomas: a clinicopathologicalreview. Neurosurgery 33955-963, 1993 Mirimanoff RO, Dosoretz DE, Linggood RM et al: Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg 62:18-24, 1985 Schmidek H (ed): Meningiomas and Their Surgical Management. WB Saunders, Philadelphia, 1991 Wilson C B Meningiomas: genetics, malignancy, and the role of radiation in induction and treatment. J Neurosurg 81:66&675, 1994

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163 Pituitary Tumors t

Gary S.Richardson Tumors in the pituitary sella are the most common clinical manifestation of the intersection between neurology and endocrinology. Whereas the most common pituitary tumor, the pituitary adenoma, typically has both endocrine and neurologic manifestations, many pituitary tumors (particularly those without autonomous endocrine function) present with isolated neurologic symptoms. As with other tumors, advances in imaging techniques permit recognition of pituitary tumors at an earlier point in their pathologic evolution, often in advance of clinically apparent neurologic or endocrine manifestations. Indeed, the sensitivity of magnetic resonance imaging (MRI) may have made the incidental pituitary mass the most common clinical presentation of a pituitary adenoma for the neurologist. This trend makes it more important for the neurologist to be familiar with the pathology and presentation of pituitary tumors. The differential diagnosis of a pituitary mass includes a number of pathologic processes and tumor histologies, many of which are reviewed elsewhere in this volume. This chapter provides an overview of pituitary pathology, with an emphasis on the pituitary adenoma, including a discussion of clinical presentation, diagnostic methods, and specific treatment approaches. PITUITARY ANATOMY AND PHYSIOLOGY Normal Anatomy The normal pituitary gland lies in the sella turcica (Fig. 163-1). The gland consists of two parts, the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis). Embryologically, the anterior lobe is derived from Rathke’s pouch, an epithelial extension from the ventral neural ridges. In development, three

components are recognized the pars distalis, which develops into the anterior lobe; the pars intermedius, vestigial in adults but may be the source of some unusual pituitary tumors; and the pars tuberalis, which extends up to envelop the pituitary stalk and the median eminence. Perhaps the most important clinical manifestation of this embryologic origin is the occurrence of cysts arising from remnants of Rathke’s pouch. The posterior pituitary gland arises from a ventral extension of the floor of the third ventricle, which forms the median eminence, the pituitary stalk, and the posterior lobe. The normal human pituitary gland measures approximately 10 x 13 x 6 mm and weighs between 0.5 and 0.9 g. It is significantly larger in girls at menarche and in women during pregnancy and lactation. It is bounded by the bony confines of the sella turcica except superiorly, where the diaphragma sellae, an extension of the dura mater, separates the sella from the suprasellar cistern and the cranial cavity. Important anatomic relationships include the sphenoid sinus anteriorly and inferiorly, the cavernous sinuses laterally, and the optic chiasm superiorly. The posterior pituitary gland arises from the ventral hypothalamus and consists of bundled axons from neurons in the magnocellular regions of the supraoptic and paraventricular hypothalamic nuclei. The normal posterior gland appears as a signal-intense area in the posterior aspect of the sella on T1-weighted MRI (Fig. 163-1). The high signal intensity is thought to represent accumulated secretory product within the s o n s and is decreased in clinical settings in which posterior pituitary hormone is depleted (e.g., diabetes insipidus). Blood flow to the anterior pituitary is greater than for any other organ in the body (approximately 0.8 mL/g/minute). The principal

B

A

FIG. 163-1. (A) Magnified, T I -weighted, sagittal and (B) coronal MRI images of the pituitary gland in a 21-year-old woman referred for evaluation of mild hyperprolactinemia.Although the concave enlargement of the gland is considered to be one sign of a microadenoma, the size and shape of the gland are within normal limits for young women. AP, anterior pituitary gland; BS, brain stem; OC, optic chiasm (at the origin of the optic tracts in the coronal view); PP, posterior pituitary gland; S, pituitary stalk; SS, sphenoid sinus.

Chapter 163

TAUE 163-1. Principal Secretory Products of the Normal

Pituitary Cell Tvve

Seuetorv Products

Somatotroph

Growth hormone Human placental lactogen Prolactin Vasoactive intestinal polypeptide Adrenocorticotropic hormone (corticotropin) P-Lipotropin hormone a-Melanocyte-stimulating hormone Thyroid-stimulatinghormone Luteinizing hormone Follicle-stimulatinghormone Free a-subunit Dynorphin Atrial natriuretic peptide

Lactotroph Corticotroph Thyrotrop h Gonadotroph

source of this blood flow is a portal system arising from the superior hypophyseal artery, including capillary beds in both the median eminence and the pituitary gland itself. The clinical significance of this unusual high-flow and low-pressure vascular supply is that it predisposes the pituitary to infarction when the sella contents expand and compromise blood flow. This occurs in the setting of a pituitary tumor (pituitary apoplexy) or as a consequence of puerperal enlargement of the pituitary coupled with hypotension (Sheehan’s syndrome). Normal Physiology

The anterior pituitary glands consist of five recognized secretory cell types, based on immunohistochemical characterization of their principal secretory products (Table 163-1). Whereas other peptides are found within the normal pituitary, most of these are felt to act as paracrine (local) factors within the gland. Some circumstantial evidence suggests that other pituitary hormones exist, but these have not been convincingly identified. The secretory activity of the anterior pituitary gland is regulated by peptide factors synthesized in the hypothalamus and transported via the hypophyseal portal vasculature. Secretion of most pituitary hormones appears to be regulated primarily by specific stimulatory factors, with inhibitory factors playing a less important role. An exception to this is prolactin, for which inhibitory regulation by dopamine released by cells of the arcuate nucleus of the hypothalamus provides the principal regulatory influence. The significance of this distinction is that any pathologic process that interferes with transport of dopamine to the pituitary can produce clinically significant hyperprolactinemia. This is most commonly seen in the setting of a intrasellar mass that deforms the pituitary stalk. The resulting hyperprolactinemia (stalk syndrome) usually is distinguishable in magnitude from the prolactin elevations produced by prolactinoma (i.e., less than 150 ng/mL) but may still be sufficient to produce clinically significant hypogonadism.

DIAGNOSIS OF PITUITARY TUMORS Prevalence When all histologies are taken together, the prevalence of pituitary tumors is very high. The increased use of sensitive imaging techniques including high-resolution computed tomography (CT) and MRI, particularly with gadolinium enhancement, has made the clinical recognition of pituitary masses much more common

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and has made the approach to the pituitary “incidentaloma” an important clinical problem. In one series of patients receiving CT scans for other reasons, 20% had pituitary lesions greater than 3 mm in diameter. Other estimates for the incidental finding of a pituitary mass on CT or MRI range from 3.7% to 6.5%. Autopsy series generally are consistent with these estimates, demonstrating a prevalence of pituitary microadenomas (less than 10 mm diameter) of 10% to 20%. There was no demonstrable influence of age or gender. In all available autopsy series, incidental macroadenomas (adenomas larger than 1 cm in diameter) are very uncommon, suggesting that the smaller tumors found in the younger patients typically do not progress in size or that larger tumors are consistently recognized clinically. When histology is evaluated, most incidental pituitary tumors found at autopsy are microadenomas, with lesser numbers of cysts, metastases, and infarcts. Differential Diagnosis

A number of pathologic processes can present as a mass within the pituitary sella (Table 163-2). As suggested by the autopsy series described earlier, by far the most common type is the pituitary adenoma, which may account for 10% to 209’0 of all intracranial tumors. The autopsy series suggest that, collectively, metastases are the second most common group of pituitary tumors. Although involvement of the pituitary is common in metastatic disease, presumably reflecting the high blood flow though the gland, most of these tumors are incidental findings. It is unusual for a pituitary presentation to be the first manifestation of metastatic disease. When clinical differentiation is important, the more aggressive malignant tumor is commonly associated with earlier, more complete hypopituitarism, including hypoprolactinemia and diabetes insipidus, without the enlargement of the pituitary sella that typically accompanies slower growing adenomas.

TMLE 163-2. Tumors of the Pituitaly Sella Tumors Pituitaly adenoma Metastasis Breast Leukemia Lymphoma Lung Meningioma Craniophalyngioma Hamartoma Clioma Germinoma and teratoma Dermoid and epidermoid tumors Chordoma Neuroma

cvsts

Rathke’s cleft cyst Arachnoid cyst Inflammation and infection Sarcoidosis Infection Bacterial abscess Tuberculosis Mycotic or viral infection Eosinophilic granuloma Lymphocytic and autoimmune hypophysitis Vascular Aneurysm Carotid or cavernous fistula

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The next most common single histology presenting clinically as a pituitary mass is the craniopharyngioma. The prevalence of these tumors is age dependent. In children, craniopharyngiomas are more common than pituitary adenomas, whereas the frequency decreases sharply in adulthood. Preoperative differentiation of craniopharyngioma from pituitary adenoma can be difficult. Craniopharyngiomas are more likely to be cystic, and half have calcifications, which are more readily identified by CT than by MRI. The typical origination of the craniopharyngioma from cell rests in the pituitary stalk results in a higher frequency of visual field compromise and diabetes insipidus than is seen with pituitary adenomas, and these clinical features can be helpful in the differential diagnosis. Rathke’s cleft cysts are also common findings at autopsy, but they constitute a small percentage of Clinically detected pituitary masses. At the time of clinical presentation, the cysts can be quite large and typically present with headache, hypopituitarism, and visual field disturbances. Although the cystic nature of the tumor is often clear on TI-weighted MRI, the variable content of the mucoid cyst fluid makes the T1-weighted signal characteristics an unreliable diagnostic tool. A variety of other tumor histologies can present in the parasellar region, including glioma, germinoma, and neuroma. Meningiomas are common tumors of the parasellar region, accounting for approximately 10% of all tumors in the area of the chiasm, but they rarely invade far enough into the pituitary sella to be confused radiologically with a pituitary adenoma. Inflammatory and vascular lesions can present as a sellar or parasellar mass. Systemic inflammatory and granulomatous disorders (e.g., sarcoidosis or histiocytosis) may include pituitary presentations. The pituitary stalk is commonly involved, and these disorders must be considered in the differential diagnosis of an enlargement confined to the stalk on MRI. Diabetes insipidus is the most common endocrine manifestation (e.g., Hand-SchtillerChristian disease), and diagnosis is generally possible in the setting of the other systemic manifestations. Occasionally, inflammatory processes are confined to the pituitary. In lymphocytic hypophysitis, a disorder seen exclusively in women (most commonly in the postpartum setting), an autoimmune reaction to the anterior pituitary gland can result in hypopituitarism and a mass on MRI indistinguishable from a pituitary adenoma. In these cases, transsphenoidal biopsy may be necessary to establish the diagnosis. Among vascular lesions, the most important are carotid artery aneurysms. These may extend into the pituitary and appear as an intrasellar tumor on CT scans. Differentiation of this rare presentation is important because of the potential for disaster during attempted trans-sphenoidal resection. MRI is generally sufficient to correctly identify a vascular lesion, although in complicated aneurysms or those with extensive thrombus, an angiogram is occasionally needed.

weighted coronal images with and without gadolinium enhancement. Under normal conditions, this approach allows delineation of the pituitary gland, the pituitary stalk, the optic chiasm, and other important adjacent neural structures (Fig. 163-1). In specific situations, other imaging approaches may be appropriate. The greater resolution of bone allowed by CT scanning makes this approach useful in addressing the question of bony erosion by tumor. Angiography may be necessary to address definitively the possibility of aneurysm presenting as an intrasellar mass. Similarly, modified MRI or CT scanning protocols may be useful in distinguishing the specific tumor types within the sellar region. For example, CT scanning provides improved recognition of calcifications characteristic of craniopharyngioma. Special Studies

Recently the diagnosis of small endocrine tumors has been enhanced by the development of radiologic methods designed to localize endocrinologically active tissue. In petrosal sinus sampling, catheters are positioned bilaterally in the petrosal sinuses to permit simultaneous sampling of blood from both sides of pituitary gland venous drainage. Theoretically, a gradient in hormone concentration between petrosal samples and simultaneous samples from the periphery (e.g., the inferior vena cava) confirms the pituitary origin of hormone overproduction. Similarly, an interpetrosal gradient allows lateralization of the source to one side of the gland. This approach is particularly useful in evaluating patients with suspected Cushing’s disease, in which ectopic sources of hormone excess (e.g., pulmonary carcinoid) can be difficult to distinguish from small pituitary microadenomas that are commonly at the lower limit of reliable MRI detection. The amplitude of the petrosal-peripheral and interpetrosal gradients can be increased by stimulation of corticotropin secretion with ovine corticotropin-releasingfactor, which typically produces an exaggerated response from corticotrope adenomas. Initial work with this method suggested that adequate localizing and lateralizing gradients predicted surgical cure by transsphenoidal resection (or hemihypophysectomywhen tumor could not be found during surgery). However, subsequent data have raised serious questions about the reliability of lateralization, given the variability of venous anatomy, the localization of many tumors to the midline, and the paradoxical reversal of the interpetrosal lateralization gradient after ovine corticotropin-releasing factor stimulation. Whereas some authors recommend routine use of petrosal sampling in patients with suspected Cushing’s disease without unambiguous MRI findings, others argue that the procedure is too difficult to interpret to be of clinical use. Other recent developments include the use of single photon emission computed tomographic scanning in conjunction with radiotracers developed from peptides such as somatostatin to localize extrapituitary remnants of pituitary tumors.

Imaging MRI is now the modality of choice for evaluating the pituitary gland and adjacent structures. The greater resolution of MRI and improved delineation of soft tissue anatomy are needed for sensitive recognition of intrapituitary tumors, particularly those less than 1.0 cm in diameter. In addition, the greater ease with which multiplanar imaging can be accomplished and the absence of ionizing radiation are important advantages of MRI over CT for routine imaging. Typically, MRI scans examining the pituitary are performed using T1-weighted sagittal profiles and thin T1-

CLINICAL PRESENTATION The W u h y Mass The clinical presentation of patients with pituitary tumors can be broadly organized into symptoms of mass effect and symptoms of hormonal excess. With the exception of mild hyperprolactinemia occurring in nonfunctioning tumors, the symptoms of hormone excess occur in patients with functional tumors, and the resultant syndrome depends on the hormone produced. Symptoms arising as a consequence of mass effects of the tumor itself are

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Chiasm Venous Plexus of Cavernous Sinus Internal Carotid Artery Oculomotor Nerve Trochlear Nerve Trigeminal Nerve (Division I) Abducens Nerve rigeminal Nerve (Division II)

FIG. 163-2. Anatomic relationships of the pituitary to adjacent structures. (From Reid R, Quigley M, Yen S: Pituitary apoplexy: a review. Arch Neurol 42371269, 1985, with permission.)

independent of the pathologic process underlying the tumor, except that they are more likely to predominate in nonfunctional tumors, in which the absence of endocrine symptoms makes early detection less likely. Here, the specific anatomic relationships of the pituitary sella and the direction of tumor expansion dictate the nature of the clinical presentation (Fig. 163-2). In addition, the rapidity of tumor growth appears to play an important role. Cranial nerve compromise by a tumor extending laterally into the cavernous sinus is unusual in the setting of slowly expanding lesions such as pituitary adenomas but is more common with rapidly growing tumors such as metastatic carcinoma or after sudden expansion of adenomas in the setting of infarction or hemorrhage (pituitary apoplexy).

Neurologic Manifestations The most common symptom caused by mass effect of an intrasellar tumor is headache. Expansion of the pituitary contents with distention of the diaphragma sellae is the presumed mechanism for headache, which can occur even with smaller (i.e., less than 1 cm) intrasellar tumors. The prevalence of both headache and incidental small pituitary tumors makes the specificity of this association difficult to prove, but a causal relationship is supported by the common finding that larger tumors that have breached the diaphragma sella may paradoxically produce no headache symptoms. Extension of pituitary tumors superiorly results in contact with the optic chiasm and visual field defects. Given the inverted organization of the visual efferents within the chiasm, compression of the chiasm from below results in typical presentation with bilateral superior temporal quadrantanopsia. As compression proceeds, the field defect progresses to bitemporal hemianopsia. The gradual growth of most pituitary tumors results in a subtle progression of the vision loss, and defects commonly are quite advanced at the time of clinical recognition. Lateral extension of pituitary tumors into the cavernous sinus can result in compromise of cranial nerves along their course through the sinus (Fig. 163-2). The most commonly involved nerve is the oculomotor nerve (third), resulting in ophthalmople-

gia, ptosis, and mydriasis. Less commonly, the abducens (sixth) or trochlear (fourth) nerves are involved, producing unilateral oculomotor weakness and diplopia. The first and second branches of the trigeminal nerve also pass through the cavernous sinus near the sella, and involvement of these nerves can present as facial pain or anesthesia. Finally, sympathetic branches traveling with V, may also be compromised, resulting in a central Horner’s syndrome. Other structures within the cavernous sinus, most notably the carotid artery, are occasionally involved by lateral extension of a pituitary tumor. Significant compromise of the carotid artery at this point presents catastrophically,with hemispheric dysfunction and hemiplegia. In the absence of acute hemorrhage or infarction, this usually indicates a more aggressive histology such as metastatic carcinoma. Anterior extension of the tumor into the sphenoid sinus can result in cerebrospinal fluid rhinorrhea and meningitis.

Endocrine Manifestations Endocrine manifestations of secretory pituitary adenomas are discussed later in this chapter. The principal endocrine manifestation of a pituitary mass is hypopituitarism, the mechanism of which is often unclear. Whereas some pituitary deficits presumably arise as a direct consequence of tumor growth and infarction of the normal gland, this mechanism cannot account for the nature of the deficits that are commonly seen. Hormonal deficiency often occurs, although a large portion of the normal gland remains intact. Furthermore, growth hormone deficiency is the most common defect in this setting despite the preponderance of growth hormone-positive cells in the normal pituitary. Finally, significant hormone deficits often are reversed with surgical removal of the tumor. Taken together, these observations suggest that the mechanism responsible for most of the associated hormone deficiency involves interference with communication between the hypothalamus and the anterior pituitary gland, either at the level of the pituitary stalk or though disruption of local paracrine factors whose role in normal hormonal secretion remains incompletely defined.

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Hypopituitarism caused by a pituitary mass can involve any of the pituitary hormonal axes in any combination, but some systems appear to be more vulnerable. Gonadotropin (luteinizing hormone and follicle-stimulating hormone [FSH]) and growth hormone function are affected most often, followed by the thyroid axis (thyroid-stimulating hormone) and then the adrenal axis (corticotropin). Hypoprolactinemia is a rare manifestation of a pituitary mass. As noted earlier, whereas the other anterior pituitary hormones are controlled primarily through stimulation by hypothalamic factors, prolactin is principally under inhibitory control by dopamine. Therefore, the effect of a pituitary mass on this axis is generally to increase prolactin secretion, producing clinical effects of hyperprolactinemia and occasionally mimicking a functional prolactinoma. When hypoprolactinemia is seen, it may indicate destruction of lactotropes by a more aggressive tumor histology (e.g., metastasis) or by infarction. Central diabetes insipidus is also an unusual manifestation of hypopituitarism caused by a pituitary tumor, because the cell bodies responsible for secreting vasopressin are located above the sella in the hypothalamus and are therefore unaffected by intrasellar tumors. Diabetes insipidus is more common in parasellar tumors such as craniopharyngiomas or meningiomas arising at the level of the pituitary stalk or above.

Pituitary Apoplexy Infarction and hemorrhage of the pituitary gland (pituitary apoplexy) is a neurologic emergency. The high metabolic demand of the normal gland, coupled with its tenuous blood supply through a portal (double-capillary) vascular system, predisposes the gland to infarction in situations where blood supply is compromised. Typically, pituitary apoplexy occurs in one of two clinical settings. In the first, pituitary tumors increase both metabolic demand and pressure within the sella, thereby reducing flow through the low-pressure blood supply. When tumor growth produces a critical reduction in blood flow, apoplexy with sudden onset of headache and neurologic symptoms may occur. The previous growth of the tumor and erosion of the bony sella determine the direction and extent of hemorrhage expansion and the nature of the neurologic symptoms. Pregnant women can develop pituitary apoplexy at the time of delivery (Sheehan’s syndrome). In this setting, the pituitary is probably normal (although women with preexisting pituitary tumors may be at increased risk), but the physiologic hypertrophy of the gland associated with pregnancy produces predisposing conditions analogous to those seen with pituitary tumors. At delivery, transient hypotension probably precipitates the crisis, resulting in infarction and neurologic symptoms. With a normal gland and no erosion of the sella, the neurologic manifestations, other than headache, may be subtle or absent, and Sheehan’s syndrome may be unrecognized until hypopituitarism becomes evident after delivery with failure of lactation or postpartum amenorrhea.

Syndromesof Pituitary Hormone Excess The most common pituitary tumors, pituitary adenomas are generally divided into those that secrete excess hormone and those that are nonsecreting. The alternative designation of “nonfunctioning” adenoma is less accurate because many tumors that do not secrete significant amounts of hormone are nonetheless functioning in that they have been shown to produce peptide

hormone or appropriate mRNA when examined using more sensitive methods. Approximately 25% to 30% of patients shown to have pituitary adenomas have no clinically detectable hormone overproduction. These tumors present as a pituitary mass, largely indistinguishable in their clinical manifestations from tumors of other, nonendocrine histology. The remaining 70% to 75% of adenomas are functional, producing specific hormones or hormone fragments in excess, and their clinical presentation typically reflects the specific action of those hormones (Table 163-3).

Hyperproladnemia The most common functional pituitary tumors secrete prolactin (prolactinomas). Clinically significant hyperprolactinemia occurs most commonly as a consequence of prolactin-secreting pituitary adenomas, but a variety of other causes must be considered in the patient with an elevated prolactin level (Table 163-4). As a general rule, a prolactin concentration above 200 ng/mL usually indicates the presence of a prolactin-secreting adenoma because secondary causes of hyperprolactinemia rarely produce levels this high. Hyperprolactinemia of any cause generally presents with hypogonadism, either oligomenorrhea in a woman or oligospermia and impotence in a man. Galactorrhea (nonpuerperal lactation) can occur in both men and women, but is much more common in women with hyperprolactinemia because of the dependence of milk production on costimulation of the breast glandular tissue by estrogen. It is important to note that galactorrhea is present at the time of diagnosis in less than half of patients with hyperprolactinemia caused by a prolactinoma. This is because the sustained hypogonadism (and hypoestrogenemia) produced by the tumor also inhibits milk production.

Acromegaly and Gigantism Growth hormone excess presents clinically as either gigantism or acromegaly, depending on whether the onset of growth hormone overproduction occurs before the closure of the long bone epiphyses. By far the most common cause of acromegaly and gigantism is a pituitary somatotrope adenoma secreting the hormone, but pancreatic islet cell tumors and hypothalamic gangliocytomas producing excessive growth hormone-releasing hormone and secondary pituitary somatotrope hyperplasia have been described. Regardless of mechanism, growth hormone excess leads to overproduction of growth factors such as somatomedin C (insulin-like growth factor 1). Through direct action and via these growth factors, growth hormone excess results in the clinical syndromes in which excessive growth of cartilage and soft tissue produce the typical changes in hands, feet, and facies associated with acromegaly or the elongation of long bones in gigantism. Insulin resistance is also common. Diagnosis of pituitary growth hormone overproduction is most commonly made by demonstrating abnormal failure of the hormone to decrease in response to hyperglycemia (oral glucose load) in the setting of a pituitary abnormality on MRI or CT. Improvements in assays for circulating insulin-like growth factor 1 have permitted increasing reliance on this measure as a screening device and as a means of following therapy. Plasma measurement of growth hormone-releasing hormone should be performed in patients with abnormal growth hormone measurements but no clear pituitary tumor on MRI. Recently, important advances have been made in understanding the pathogenesis of somatotrope adenomas. X-chromosome

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T m 163-3. Laboratory Evaluation of Suspected Secretory Pituitary Adenoma Clinical Syndrome

Laboratory Tests

Procedure

Diagnostic Results

Acromegaly

Somatomedin C (insulin-like growth factor 1) Oral glucose suppression

Random level

More than upper limit of normal for age and sex (varies with assay). CH level >5 p g / ~ (RIA), >I p g / ~(IRMA) at baseline, 1 hr, and 2 hr. >200 ng/mL is diagnostic; 100-200 ng/mL is ambiguous; need to consider renal status, medications (e.g., phenothiazines), pituiiry stalk compression by other pathologic process. Elevated cortisol with loss of normal diurnal variation (i.e., AM level= FM level) and detectable or elevated corticotropin

CH determination at baseline, 1 hr and 2 hr after 1oral glucose load Two determinations

Hyperprolactinemic hypogonadism

Serum proladin

Cushing's disease

Plasma cortisol and corticotropin ( A m )

Moming and evening samples

Overnight dexamethasone suppressiontest

Plasma cortisol at 8 AM after 1 mg dexamethasone at 11 FM the night before

Formal dexamethasone sup pression test

24-hr urine for free cortisol and metabolites (17-hydroxycorticosteroids) at baseline and after low-dose dexamethasone (0.5 mg PO q6h x 8 doses) and highdose dexamethasone (2 mg PO q6h x 8 doses)

Dexamethasone-CRHstimulation test

Dexamethasone 0.5 mg q6h x 8 doses followed by ovine CRH 1 &kg IV at 8 AM; AClH at 0,15,30,45,60, and 120 min after CRH. TSH, with thyroid hormone measures, e.g., free T4 and free T3

Secondary hyperthyroidism

Thyroid function tests

Hypergonadotropic hypergonadism

Reproductive hormone indices

SimultaneousLH and sex steroid determination

(Am).

>5 pg/dL demonstratesinadequatesup pression; multiple false positives (e.g., depression, alcoholism) limit this test to use as weening tool. Lowdose dexamethasone: plasma cortisol >5 pg/dL; urinary free cortisol and 17hydroxycorticosteroids of baseline value with highdose dexamethasone: plasma cortisol d pg/dL; urinary free cortisol and 17-hyd~OxyCOrti~e0%of baselinevalue. Failure to roids 4 suppress with high-dosedexamethasone suggests nonpituiiry Cushing's syndrome (e.g., adrenal tumor). ACTH > 15 pg/mL at any point during the test Elevatedthyroid function tests (free T, and free T J with elevated or normal TSH (21 mTi/L). Elevated LH with normal or elevated testosterone (male) or estradiol (female).

ACTH, adrenocorticotropichormone; CRH, corticotropin-releasing hormone; GH, growth hormone; LH, luteinizinghormone; TSH, thyoid-stimulating hormone.

inactivation studies have established that most of these tumors are monoclonal, arising from a somatic mutation of a single cell. This makes the hypothesized role of abnormal hyperstimulation by hypothalamic growth factors less important, although a contributory role cannot be excluded. A substantial subset (40%) of somatotrope adenomas has been shown to have altered forms of the G, regulatory protein that controls adenylyl cyclase activity, resulting in autonomous growth hormone secretion and cell growth.

Cushlng's D h s r Corticotropin excess is most commonly a consequence of a pituitary adenoma secreting the hormone and in t h i s setting

TABU163-4. Causes of Hyperprolactinemia Functionalpituiiry tumor Pituiiry stalk compression Hypothalamicdisease Primary hypothyroidism Neurogenic factors Pregnancy Medications (e.g., phenothiazines) Cirrhosis Chronic renal failure Sewre stress Idiopathicfactors

constitutes Cushing's disease, named for Harvey Cushing, the neurosurgeon who first described the relationship between the clinical syndrome and a pituitary tumor and who pioneered the trans-sphenoidal surgical approach. The broader term Cwhing's syndrome is used t o describe patients with cortisol excess from any cause (including iatrogenic steroid administration and functional adrenal tumors). The clinical presentation of the patient with Cushing's disease is similar to that of other causes of cortisol excess, with characteristic obesity, muscle wasting, striae, insulin resistance, and hypertension. Hypokalemia is occasionally seen, but this is a mineralocorticoid effect that is usually more prominent in patients with functional adrenal tumors producing aldosterone. As with growth hormone excess and acromegaly, other causes of corticotropin excess must be excluded, including tumors of lung, pancreas, and thyroid that produce corticotropin-releasing hormone, leading to secondary corticotrope hyperplasia. Because the pituitary tumors responsible for Cushing's disease often are quite small and may be at the lower limit of MRI detection, other localization techniques such as petrosal sinus sampling may be needed to exclude extrapituitary causes. Extraordinary elevations of corticotropin can be seen in patients with small cell carcinoma of the lung. The levels of corticotropin in these patients often are sufficient to produce hyperpigmentation and hyperaldosteronism, features rarely seen in the patient with Cushing's disease. Obesity usually is not prominent in these patients, reflecting the opposing impact of other factors produced by the oat cell tumor.

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Classically, the diagnosis of Cushing’s disease is made by demonstrating the failure of cortisol production to decrease in response to exogenous steroid (dexamethasone).The impairment of feedback inhibition in Cushing’s disease is a partial one, such that suppression occurs at higher dexamethasone dosages. This allows differentiation of adrenal tumors, which are more resistant to suppression (Table 163-3). More recently, improved sensitivity in the diagnosis of small tumors has been achieved with stimulation using corticotropin-releasing hormone after dexamethasone suppression.

Secondary Hyperthyroidism The clinical manifestations of thyroid-stimulating hormone hypersecretion are primarily those of hyperthyroidism and are generally indistinguishable from hyperthyroidism of any cause. With modern radioimmunoassays for this hormone, the causal role of the pituitary thyrotrope usually can be recognized by the inappropriate concentrations of the hormone for measured T4 and T,. In contrast to primary hyperthyroidism (e.g., Graves’s disease), in which levels of the hormone are suppressed by the excess thyroid hormones, in secondary hyperthyroidism arising as a consequence of a thyroid-stimulating hormonesecreting pituitary adenoma, levels of this hormone are elevated or inappropriately normal for the concentrations of T, and T,.

Pituitary Hypergonadism Follicle-stimulatinghormone or luteinizing hormone hypersecretion (or both) caused by a functional pituitary tumor occurs more often than was originally reported. With improved gonadotropin assays and MRI scans, this functional tumor is now felt to comprise up to 17% of functional macroadenomas in men. The tumor is more common in men than in women and typically occurs in middle age. Clinical manifestationsof the hypersecretion itself are very subtle. Rarely, testosterone levels are significantly elevated in men with associated complaints of hypersexuality. More typically, sex steroid levels are normal, and, in the absence of clinical symptoms, the tumors present with manifestations of the pituitary mass. Preoperative diagnosis is made based on the presence of normal or elevated gonadal steroids combined with elevated gonadotropins. Many tumors previously thought to be nonsecretory have been shown to secrete one of the subunits of the gonadotropin hormones. Radioimmunoassays specific for the P-subunit, which is unique to each of the three pituitary glycoprotein hormones (thyroid-stimulating hormone, luteinizing hormone, or folliclestimulating hormone), or the &subunit, which is common to all of them, can be secreted in excess by a functional pituitary tumor. The a-subunit is found free in normal plasma, but a function specific to the subunit has not been defined. These secretory tumors are also not associated with a recognizable clinical syndrome, and they typically present with large parasellar masses and symptoms related to the mass effects.

TREATMENT Surgery is the initial treatment of choice for most tumors of the sella and parasellar regions. This is particularly true in the setting of optic chiasm compromise when rapid tumor decompression is necessary to limit or reverse a visual field defect. The exact location of the tumor, its likely histology, and its relationship to anatomic

structures in the region together determine which surgical approach is needed. Tumors within the pituitary sella, and those with limited extraseUar extension, usually can be approached via the trans-sphenoidal route with substantially lower operative morbidity. In experienced hands, this approach has a high success rate and is the initial treatment of choice for most pituitary adenomas. Extension beyond the sella laterally, or superior extension with invasion or entrapment of the optic chiasm, typically necessitates a superior surgical approach through a transfrontal craniotomy. Radiotherapy is an alternative when surgery is not an appropriate initial step. In addition, postoperative radiation is used for certain tumor histologies for which remission and recurrence rates after operative resection can be reduced with combined therapy. Whereas postoperative radiation is still used to treat residual tumor after resection of pituitary adenoma, it is no longer routinely given to patients after resection of nonsecretory adenomas or to those in whom endocrine measures are normal. The improved resolution available with MRI and newer endocrine measures permits an expectant approach in which radiation, and the attendant risk of hypopituitarism, can be reserved for patients with clear evidence of tumor growth or endocrine evidence of recurrent hypersecretion. The applicability of medical therapy for pituitary tumors depends entirely on the tumor histology. Besides chemotherapy, available medical therapy consists of endocrine manipulation of sensitive tumors. Somatostatin, an inhibitory peptide involved in the normal regulation of pituitary hormones, has been adapted for clinical use as octreotide and lanreotide. Administered subcutaneously, these medications have been shown to control growth hormone secretion in patients with acromegaly and to reduce the size and limit the growth of somatotropic tumors. Their principal application is in the control of unresectable residual tumor after surgery or as primary therapy in patients who are not surgical candidates. In addition, somatostatin analogues are now being used preoperativelyto reduce the size of large tumors and improve the results of trans-sphenoidal resection. They have also been used to manage other secretory tumors (e.g., those related to thyroidstimulating hormone), but the response in this setting is more variable, reflecting the inconsistent expression of somatostatin receptors in other functional adenomas. The most widely used medical therapy in this setting uses the oral dopamine (D,) receptor agonists (e.g., bromocriptine, cabergoline, quinagolide) in managing prolactinoma. These drugs are generally effective as a means of limiting prolactin secretion and reducing tumor mass in prolactinomas. The impact on active tumors can be dramatic, and institution of D, agonist therapy is a viable alternative to surgery in the patient with a macroprolactinoma and vision loss. Reduction of tumor size and improvement of the visual fields can occur within hours of starting treatment, but the potential for a poor tumor response dictates that simultaneous preparation for surgical resection be made. In patients with small prolactinomas (less than 10 mm in diameter), the potential for cure with sustained use of D, agonists remains controversial. This is because the natural history of these tumors remains incompletely defined. In macroprolactinomas, bromocriptine has been reported to produce sustained remissions in 5% to 15% of patients after treatment of 5 years. Use of bromocriptine typically is limited by the side effects, most notably nausea and orthostatic hypotension, and by the significant percentage of resistant or incompletely responsive tumors. Newer drugs such as cabergoline and quinagolide have fewer side effects

Chapter 164

and greater ease of use and may have broader efficacy. D, agonists have also been shown to be effective in managing some somatotropic tumors, but the response is much more variable than with prolactinomas, and dopamine receptor agonists are rarely sufficient as the primary treatment in these tumors. SUMMARY Tumors of the pituitary are common and represent an important intersection between neurology and endocrinology. Differential diagnosis of pituitary tumors includes a number of tumor histologies and pathologic processes involving the pituitary sella and the parasellar region. Identification and diagnosis of pituitary tumors has been enhanced by the development of new imaging technology, most notably MRI, which is now the imaging method of choice for tumors in this region. Clinical manifestations of pituitary tumors are divided into manifestations of the tumor’s mass effect and effects of overproduction of specific hormones. Mass effects include neurologic symptoms related to impingement on adjacent structures, induding headache and visual field compromise. Enlargement of a pituitary mass can also produce endocrine deficits. Excessive secretion of pituitary hormones by specific functional adenomas results in recognizable clinical syndromes including acromegaly, Cushing’s disease, and hyperprolactinemia. Treatment of pituitary tumors depends on size and histology, but surgery, typically through the trans-sphenoidal approach, is generally the initial treatment of choice. Medical therapy is also effective in specific settings, most notably in the treatment of prolactinoma, for which dopamine receptor agonists are the treatment of choice.

SUGGESTED READINGS Aron DC, Howlett TA Pituitary incidentalomas. Endocrinol Metab Clin North Am 29( 1):205-221,2OOO Barkan AL: New options for diagnosing and treating acromegaly. Cleve C h J Med 65(7):7-9, 343, 1998

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Boscaro M, Barzon L, Sonino N: The diagnosis of Cushing’s syndrome: atypical presentations and laboratory shortcomings. Arch Intern Med 160(20):3045-3053,2000 Gsponer J, De Tribolet N, D e w JP et ak Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine 78(4):236-269, 1999 Hoybye C, Grenback E, Rahn T et ak Adrenocorticotropic hormoneproducing pituitary tumors: 12- to 22-year follow-up after treatment with stereotactic radiosurgery. Neurosurgery 49(2):91-92, 284-291, 2001 Laws ER, Vance ML, Thapar K Pituitary surgery for the management of acromegaly. Horm Res 53(Suppl3):71-75,2000 Majos C, Coll S, Aguilera C et ak Imaging of giant pituitary adenomas. Neuroradiology 40( 10):651-655,1998 Melmed S (ed): The Pituitary. Blackwell, Cambridge, MA, 1995 Nobels FR, de Herder WW, van den Brink WM et ak Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma. Eur J Endocrinol143(5):615-621, 2000 Onesti ST, Wisniewski T, Post KD: Clinical versus subclinical pituitary apoplexy: presentation, surgical management, and outcome in 21 patients. Neurosurgery 26(6):98&986, 1990 Richardson GS, Black PM: Neuroendocrinology. In Tindall GT, Cooper PR, Barrow DL (eds): The Practice of Neurosurgery. Williams & Wilkins, New York, 1995 Saccomanno K, Bassetti M, Lania A et ak Immunodetection of glycoprotein hormone subunits in nonhctioning and glycoprotein hormonesecreting pituitary adenomas. J Endocrinol Invest 20(2):59-64, 1997 Soule SG, Farhi J, Conway GS et ak The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy. Clin Endocrinol (Oxf) 44(6):711-716, 1996 Thapar K, Laws ER Jr: Pituitary Tumors. pp. 803-856. In Kaye AH, Laws ER Jr (eds): Brain Tumors: An Encyclopedic Approach. 2nd Ed. Churchill Livingston, London, 2001 Touraine P, Plu-Bureau G, Beji C et ak Long-term follow-up of 246 hyperprolactinemic patients. Acta Obstet Gynecol Scand 80(2):162168,2001 Yu R, Melmed S Oncogene activation in pituitary tumors. Brain Path01 11(3):32&341,2001

164 Craniopharyngioma R. Michael Scott Craniopharyngiomas are suprasellar tumors that commonly manifest in childhood. More than 50% of these tumors are diagnosed in patients under the age of 18 years, and the diagnosis in older patients is rare. Craniopharyngiomas are the most common brain tumors of nonglial origin in children, representing approximately 3% to 6% of most patient series. A slight male preponderance is common, but many series report an equal male and female incidence. The biology of these tumors is fascinating. It is generally agreed that the tumor represents an embryonal rest of Rathke’s pouch (the evagination of the oral pharyngeal mucosa through the skull base that is destined to form the anterior pituitary), and it is hypothesized that failure of complete involution of this hypophyseal pharyngeal duct tract leads to development of the craniopha-

ryngioma. The tumor therefore is presumed to be congenital and to have been present and growing since birth. Nevertheless, an adult patient in my series was demonstrated by magnetic resonance imaging (MRI) to have no suprasellar pathology 6 years before the discovery of a tumor that became symptomatic during pregnancy. This suggests that additional stimuli may be important in provoking the growth of vestigial remnants of the hypophyseal pharyngeal duct to form a mass lesion and may account for the occasional presentation of this tumor in the adult. The radiologic and gross appearances of these tumors often are dramatic. They often contain cysts that can assume giant size, insinuating themselves among the structures at the base of the brain or extending throughout the subarachnoid cisterns into the posterior fossa, sylvian fissures, or inferior frontal lobes. Their

Chapter 164

and greater ease of use and may have broader efficacy. D, agonists have also been shown to be effective in managing some somatotropic tumors, but the response is much more variable than with prolactinomas, and dopamine receptor agonists are rarely sufficient as the primary treatment in these tumors. SUMMARY Tumors of the pituitary are common and represent an important intersection between neurology and endocrinology. Differential diagnosis of pituitary tumors includes a number of tumor histologies and pathologic processes involving the pituitary sella and the parasellar region. Identification and diagnosis of pituitary tumors has been enhanced by the development of new imaging technology, most notably MRI, which is now the imaging method of choice for tumors in this region. Clinical manifestations of pituitary tumors are divided into manifestations of the tumor’s mass effect and effects of overproduction of specific hormones. Mass effects include neurologic symptoms related to impingement on adjacent structures, induding headache and visual field compromise. Enlargement of a pituitary mass can also produce endocrine deficits. Excessive secretion of pituitary hormones by specific functional adenomas results in recognizable clinical syndromes including acromegaly, Cushing’s disease, and hyperprolactinemia. Treatment of pituitary tumors depends on size and histology, but surgery, typically through the trans-sphenoidal approach, is generally the initial treatment of choice. Medical therapy is also effective in specific settings, most notably in the treatment of prolactinoma, for which dopamine receptor agonists are the treatment of choice.

SUGGESTED READINGS Aron DC, Howlett TA Pituitary incidentalomas. Endocrinol Metab Clin North Am 29( 1):205-221,2OOO Barkan AL: New options for diagnosing and treating acromegaly. Cleve C h J Med 65(7):7-9, 343, 1998

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Boscaro M, Barzon L, Sonino N: The diagnosis of Cushing’s syndrome: atypical presentations and laboratory shortcomings. Arch Intern Med 160(20):3045-3053,2000 Gsponer J, De Tribolet N, D e w JP et ak Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine 78(4):236-269, 1999 Hoybye C, Grenback E, Rahn T et ak Adrenocorticotropic hormoneproducing pituitary tumors: 12- to 22-year follow-up after treatment with stereotactic radiosurgery. Neurosurgery 49(2):91-92, 284-291, 2001 Laws ER, Vance ML, Thapar K Pituitary surgery for the management of acromegaly. Horm Res 53(Suppl3):71-75,2000 Majos C, Coll S, Aguilera C et ak Imaging of giant pituitary adenomas. Neuroradiology 40( 10):651-655,1998 Melmed S (ed): The Pituitary. Blackwell, Cambridge, MA, 1995 Nobels FR, de Herder WW, van den Brink WM et ak Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma. Eur J Endocrinol143(5):615-621, 2000 Onesti ST, Wisniewski T, Post KD: Clinical versus subclinical pituitary apoplexy: presentation, surgical management, and outcome in 21 patients. Neurosurgery 26(6):98&986, 1990 Richardson GS, Black PM: Neuroendocrinology. In Tindall GT, Cooper PR, Barrow DL (eds): The Practice of Neurosurgery. Williams & Wilkins, New York, 1995 Saccomanno K, Bassetti M, Lania A et ak Immunodetection of glycoprotein hormone subunits in nonhctioning and glycoprotein hormonesecreting pituitary adenomas. J Endocrinol Invest 20(2):59-64, 1997 Soule SG, Farhi J, Conway GS et ak The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy. Clin Endocrinol (Oxf) 44(6):711-716, 1996 Thapar K, Laws ER Jr: Pituitary Tumors. pp. 803-856. In Kaye AH, Laws ER Jr (eds): Brain Tumors: An Encyclopedic Approach. 2nd Ed. Churchill Livingston, London, 2001 Touraine P, Plu-Bureau G, Beji C et ak Long-term follow-up of 246 hyperprolactinemic patients. Acta Obstet Gynecol Scand 80(2):162168,2001 Yu R, Melmed S Oncogene activation in pituitary tumors. Brain Path01 11(3):32&341,2001

164 Craniopharyngioma R. Michael Scott Craniopharyngiomas are suprasellar tumors that commonly manifest in childhood. More than 50% of these tumors are diagnosed in patients under the age of 18 years, and the diagnosis in older patients is rare. Craniopharyngiomas are the most common brain tumors of nonglial origin in children, representing approximately 3% to 6% of most patient series. A slight male preponderance is common, but many series report an equal male and female incidence. The biology of these tumors is fascinating. It is generally agreed that the tumor represents an embryonal rest of Rathke’s pouch (the evagination of the oral pharyngeal mucosa through the skull base that is destined to form the anterior pituitary), and it is hypothesized that failure of complete involution of this hypophyseal pharyngeal duct tract leads to development of the craniopha-

ryngioma. The tumor therefore is presumed to be congenital and to have been present and growing since birth. Nevertheless, an adult patient in my series was demonstrated by magnetic resonance imaging (MRI) to have no suprasellar pathology 6 years before the discovery of a tumor that became symptomatic during pregnancy. This suggests that additional stimuli may be important in provoking the growth of vestigial remnants of the hypophyseal pharyngeal duct to form a mass lesion and may account for the occasional presentation of this tumor in the adult. The radiologic and gross appearances of these tumors often are dramatic. They often contain cysts that can assume giant size, insinuating themselves among the structures at the base of the brain or extending throughout the subarachnoid cisterns into the posterior fossa, sylvian fissures, or inferior frontal lobes. Their

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solid portions often contain calcification,a virtual sine qua non in radiologic diagnosis. These tumors commonly excite reactive change in adjacent brain, and the tumor may become tightly adherent to structures around it, such as the arteries in the circle of Willis, the optic apparatus, and the undersurface of the hypothalamus. The cysts often contain a brownish yellow fluid that has been compared with machinery oil and that may glitter and shimmer because of cholesterol crystals resulting from breakdown of epithelial desquamation; this material may provoke an irritative response and may account for the intense gliosis seen in normal brain adjacent to the tumor. The microscopic appearance of these tumors is also characteristic. They contain a mixture of squamous epithelium, loosely arranged cells, and cystic areas lined by epithelium. The squamous areas can become keratinized, form whorls, and show areas of calcifications or ossification. Their striking histologic picture is very rarely confused with other intracranial neoplasms. The clinical presentation of these patients can be roughly divided into three categories. One of the most common is endocrine dysfunction. Given that most tumors adhere to and displace the pituitary stalk, it is not surprising that this is the case. The endocrinologic symptoms can vary from growth retardation to more overt expressions' of endocrine dysfunction, such as delayed or precocious puberty and diabetes insipidus. Symptoms related to hypothyroidism may be elicited, and menstrual irregularities, impotence, and other symptoms of pituitary dysfunction may be reported in older patients. A second mode of presentation involves visual disturbances. Because of the proximity of craniopharyngiomas to the optic apparatus and the tumor's slow growth, severe visual deficits ranging from bitemporal hernianopsias to unilateral or bilateral blindness may develop without being noted by the patient. The third major category of tumor presentation

A

involves symptoms related to increased intracranial pressure. In craniopharyngioma, intracranial hypertension is almost always caused by obstructive hydrocephalus, which results when the tumor grows upward into the third ventricle, interfering with passage of cerebrospinal fluid through the third ventricle to the aqueduct. These patients develop acute or chronic hydrocephalus with papilledema and all the usual symptoms of increased intracranial pressure, including headache, vomiting, and altered mental status. DIAGNOSIS AND PREOPERATIVE EVALUATION In most patients with craniopharyngioma, the diagnosis is made primarily from the neuroradiologic studies. Before the common usage of computed tomography (CT) and MRI, plain radiographs of the skull were obtained to demonstrate the presence of calcification in the sellar or suprasellar region. The calcium often clumps into discrete areas in the tumor or may be deposited within the walls of cystic portions of the tumor. Currently, the CT scan is the most effective test for demonstrating the presence of calcification in these tumors (Fig. 164-1) and remains a helpful adjunct to diagnosis and surgical planning because calcification is less well seen on MRI, where it appears only as signal voids. MRI imaging is nevertheless the essential study in the preoperative evaluation of these patients. No other study demonstrates so exquisitely the exact anatomic confines of the tumor and the displacement or invasion of the optic apparatus, hypothalamic structures, arteries of the circle of Willis, pituitary stalk, and arachnoid cisterns (Fig. 164-2). The surgeon will be greatly helped in patient evaluation by studies in sagittal, axial, and coronal planes, and gadolinium enhancement is imperative to determine whether cysts are associated with bulk neoplastic tissue.

B

FIG. 164-1. (A) Noncontrast coronal CT scan demonstrating circular intrasellar and suprasellar clumps of calcification (arrowheads) in a craniophalyngioma in an 8-year-old girl. (B) Nonenhanced axial CT scan demonstrating a thin rim of calcification (arrows) bordering a large cystic craniopharyngioma in a 4-year-old girl. The calcifications could not be recognized as such on the MRI of this patient.

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A

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B

FIG. 164-2. (A) T1 -weighted, gadolinium-enhanced sagittal MRI demonstratingan intrasellar and suprasellar mass filling the third ventricle, displacing the brainstem posteriorly and causing massive obstructive hydrocephalus. (B) Protondensity, nonenhanced axial MRI in the same patient The cyst is bright on MRI because of its high lipid content. The encroachment of the tumor cyst on the vessels in the circle of Willis, especially the left anterior and middle cerebral artery, can be clearly visualized, along with invagination of the tumor into the ventral midbrain.

These patients need a thorough endocrinologic evaluation, although if they are ill with increased intracranial pressure or profound visual deficits, there may not be much time available to obtain it. A careful history regarding the presence of symptoms suggesting diabetes insipidus should be obtained, and serum electrolytes and urine-specific gravities should be checked. Morning and evening serum cortisone levels, baseline thyroid function studies, growth hormone levels, and (in adolescent and postadolescent patients) luteinizing and follicle-stimulating hormone levels should be obtained. The endocrine evaluation is important as a baseline to aid in anesthetic management, to anticipate postoperative problems, and to assess treatment morbidity. If possible, patients should receive an ophthalmologic evaluation to determine funduscopic appearance, the presence of peripheral visual field disturbance, and acuity changes. Concern has increased over the past decade because of the neuropsychological deficits that result from this tumor’s compression of the hypothalamus and distortion of limbic system structures, which result in changes in personality, disturbances in eating patterns, and loss of memory; helpful information in this regard could be obtained by neuropsychological testing of the patient before therapy of any type. Unfortunately, because of the urgency of the patient’s symptoms, it is often impossible to obtain these tests until well into the postoperative period. They are important in evaluating the treatment morbidity of this tumor, however, and aid greatly in long-term postoperative management and patient and family counseling.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of tumors that occur in the suprasellar region (causing visual, endocrinologic, and intracranial pressure symptoms) can be problematic. Hypothalamic optic system gliomas infiltrate compress and elevate or occlude the third ventricle. Epidermoid and dermoid tumors are midline tumors that can involve suprasellar structures as well and result in signs and symptoms similar to those of a craniopharyngioma. Hypothalamic hamartomas can cause precocious puberty and present as masses in the suprasellar or interpeduncular cisterns on radiologic evaluation. Giant suprasellar carotid aneurysms can cause mass effect in the suprasellar region and present with rim calcification on radiologic studies. Pituitary tumors can expand the sella and grow upward into the third ventricle, causing endocrinologic deficits and visual disturbances. Rathke’s cleft cysts, another lesion resulting from a residual of Rathke’s pouch, can cause localized suprasellar mass effect along with endocrinologic deficits. Germ cell tumors such as germinoma can present with diabetes insipidus and masses in the suprasellar region. Infectious or inflammatory disorders such as lymphocytic hypophysitis or infundibulitis, sarcoidosis, or histiocytosis X can also mimic certain signs and symptoms of the craniopharyngioma. However, in almost every case, the differentialcan be reduced by careful interpretation of the radiographic studies. The classic findings on CT and MRI described earlier are rarely found in lesions other than craniopharyngioma.

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TREATMENT For decades, the preferred treatment method for craniopharyngioma has been total extirpation of the tumor. The surgery can be extraordinarily challenging because these tumors often adhere to all of the structures with which they come in contact, including the optic apparatus, vessels in the circle of Willis, the pituitary gland and stalk, and the hypothalamus (Fig. 164-3). Injury to any of these structures can result in devastating complications such as stroke, blindness, or permanent endocrine dysfunction. These tumors excite an intense inflammatory response around themselves, possibly because of their cholesterol-laden cyst contents, and the plane of cleavage between tumor and normal brain, optic nerve, or vessels may be difficult to develop. In most series in which total removal has been accomplished, the majority of patients are left with severe endocrinologic deficits. Nearly all patients need medication for diabetes insipidus, and most need treatment for hypothyroidism as well as steroid, growth, and sex hormone deficiency. If surgical removal leads to hypothalamic injury, patients often have significant problems controlling appetite and may become obese and apathetic. Learning disabilities are also common sequelae of surgical excision. These tumors often grow large, and damage to memory and learning centers and to the hypothalamic-pituitary axis may be a significant problem before any form of treatment, as noted earlier. Surgery often is carried out on an urgent basis because of compression of the optic apparatus and visual compromise. However, surgery may fail to reverse preoperative deficits and may occasionally increase them because many of these deficits are caused not only by compression of the optic system but also by vascular compromise of those structures, which tends to worsen when dissection along the optic system affects its vascular supply. In the hands of proficient surgeons, total removal, as determined by postoperative CT or MRI scanning, can be anticipated in approximately 50% to 90% of primary procedures, but only 65% of these patients can be expected to be free of recurrent tumor at 10-year follow-up.

Because of the complications that seem to follow attempts at total removal of craniopharyngioma, some surgeons have resorted to treatment regimens that combine surgery and radiotherapy. Radiotherapy for craniopharyngioma is an effective treatment for these lesions, with 10-year survival figures approaching 90% for patients so treated, either with biopsy alone or with more aggressive surgery. However, radiotherapy has its own set of complications, including endocrinologic dysfunction similar to that seen after surgical excision (although usually to a lesser degree), radiation-induced vasculopathy (with the development of moyamoya syndrome leading to strokes or transient ischemic attacks), learning disabilities, and finally, the induction of second neoplasms such as glioblastoma or meningioma. Patients treated under the age of 3 or 4 seem particularly susceptible to the development of vasculopathy and learning difficulties. In the very young patient whose tumor cannot be totally removed, it is not unreasonable to consider observation alone after surgery, with radiation delayed until the child has reached age 4 or 5 or the tumor begins to regrow. In most series, tumor regrowth occurred by 40 months after the initial operation. Recent advances in radiotherapy such as stereotactic radiotherapy promise to limit exposure of the normal brain to radiation and reduce the deleterious side effects of treatment, but these techniques have been used only for the past 5 to 10 years, and long-term results are just beginning to be obtained. In certain patients in whom residual disease is located in a circumscribed area, stereotactic radiosurgery (or gamma knife or proton beam therapy) can be used to deliver a single dose of high-energy radiation to the lesion to destroy it. These forms of treatment can injure the optic nerves and tracts that are within the treatment beam and cause other cranial nerve dysfunction, however, and they cannot be used where tumor abuts these structures unless permanent visual deficits are already present. When large nonremovable cysts are present, creating mass effect that recurs promptly despite needle or catheter drainage, radioisotopes such as 32Pcan be instilled into the cyst to damage or destroy cyst wall

FIG. 164-3. Right subfrontal exposure of an intrasellar and suprasellar craniopharyngioma, as viewed from the surgeon’s perspective. The frontal lobe is elevated by two retractors (asterisks). The mass is lifting and flattening the right optic nerve (arrows) and displacing the right carotid artery laterally. The right anterior cerebral artery (arrowhead) and the right middle cerebral artery (curved arrow) are also visualized.

Chapter 165

epithelium and diminish or stop the production of cyst fluid. These treatment regimens may be difficult to use because of concerns about correct dosimetry and uniformity of its delivery, particularly in patients in whom prior irradiation has been carried out or when multiple cysts are present. This treatment modality entails precise cannulation of the cyst via an indwelling catheter and a delivery system that must be demonstrated to limit distribution of the isotope to the tumor cyst alone. Similar considerations apply to the use of intracavitary bleomycin, which often reduces cyst size and in certain patients facilitates surgical removal of particularly complex tumor cysts. Bleomycin is a chemotherapeutic agent that has the property of causing craniopharyngioma cysts to shrink, toughen, and thicken. These changes may permit surgical excision of a cyst that otherwise might fragment when its walls are grasped or manipulated.

The craniopharyngioma is a suprasellar neoplasm of congenital origin. It has a characteristic pathologic and radiographic appearance and a common mode of clinical presentation related to signs of endocrine or visual dysfunction or to increased intracranial pressure from obstruction of cerebrospinal fluid flow through the third ventricle. The tumor is optimally treated by surgical excision, either alone or in combination with radiotherapy. Each approach has its advocates, but both have the potential for significant long-term morbidity. Ongoing studies in neuropsychologic outcome and treatment side effects can be expected to shed additional light on this debate over the next several years.

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SUGGESTED READINGS Backlund EO, Axelsson B, Bergstrand CG et ak Treatment of craniopharyngiomas: the stereotactic approach in ten to twenty-three years’ perspective. I. Surgical, radiological and ophthalmologic aspects. Acta Neurochir (Wien) 99:ll-9, 1989 Epstein FJ, Handler MH (eds): Craniopharyngioma: the answer. Pediatr Neurosurg 2l(suppl 1):l-132, 1994 Fischer EG, Welch K, Shillito J et al: Craniopharyngiomas in children: long-term effects of conservative procedures combined with radiation therapy. J Neurosurg 73:534-540, 1990 Hetelekidis S, Barnes PD, Tao ML et ak Twenty-year experience in childhood craniopharyngiorna. Int J Radiat Oncol Biol Phys 27:189193, 1993 Hoffman HJ, DeSilva M, Humphreys Rp: Aggressive surgical management of craniopharyngiomasin children. J Neurosurg 76:47-52, 1992 Pollack IF, Lunsford LD, Slamovits TL et al: Stereotaxic intracavitary irradiation for cystic craniopharyngiomas. J Neurosurg 68:227-233, 1988 Pusey E, Kortman KE, Flannigan BD et ak MR of craniopharyngiomas: tumor delineation and characterization. AJNR k439-444, 1987 R u b JT, Hoffman HJ, Drake JM, Humphreys RF? Suprasellar and sellar tumors in childhood and adolescence. Neurosurg Clin North Am 3:803-820, 1992 Samii M, Tatagiba M Craniopharyngioma. In Kaye AH, et al (eds): Brain Tumors: An Encyclopedic Approach, 2nd Ed. Churchill Livingstone, 2001 Sorva R, Heiskanen D, Perheentupa J: Craniopharyngioma surgery in children: endocrine and visual outcome. Childs Nerv Syst 497-99, 1988

165 Acoustic Neuroma David M. Vernick and John K. Park Named after their most common presenting feature, acoustic neuromas are benign tumors of the eighth cranial nerve. They are actually Schwann cell tumors originating at the transition point where the vestibular nerve becomes a peripheral nerve. Attempts to improve the accuracy of the name have resulted in their being called acoustic neurinomas, acoustic schwannomas, and vestibular schwannomas in some articles. They account for 8% of all adult intracranial tumors and 80% of all cerebellopontine angle tumors. Their overall clinical incidence is about one tumor per 100,000 population per year. In autopsy studies of the temporal bone, the incidence ranges from 0.8% to 2.7%. Most of the difference results from small tumors that presumably lie dormant for years. Acoustic neuromas occur with equal frequency on the superior and inferior branches of the vestibular nerve. They are unilateral, except in cases of the genetic disorder neurofibromatosis type 2 (NF-2), in which they are bilateral. There is no side predilection, nor is there a sex bias. The most common age of presentation is during the fourth and fifth decades, but all ages have been reported. HISTORY By the late 1800s, the diagnosis of cerebellopontine angle tumors was made by the presence of hearing loss, facial numbness, and headache. No diagnostic tests were available to confirm the findings. Audiometric, vestibular, and radiologic testing developed

in the early 1900s allowed earlier and more accurate diagnosis. Unilateral sensorineural hearing loss with decreased discrimination and unilateral decreased caloric response became the main diagnostic findings in patients with acoustic neuromas. Radiology could show widening of the internal auditory canal. Surgery was the best treatment at the time, with radiotherapy being in its infancy, but mortality and morbidity rates ran high. Today the auditory and radiographic techniques have improved dramatically to allow diagnosis of smaller tumors. Treatment options have been refined to reduce the morbidity and mortality rates of therapy markedly. Preservation of facial nerve function and, in small tumors, hearing are now expected results. Despite all the advances, however, the average size of tumors detected has decreased minimally. The average time of onset of symptoms until the diagnosis of the tumor is 4 years. Although benign by histology, acoustic neuromas still present a diagnostic and therapeutic challenge to the physician. PRESENTATION The most common presenting feature of acoustic neuromas is unilateral hearing loss (Table 165-1). This is usually a progressive sensorineuralloss, but,in 10% of cases there is a sudden shift in the hearing. (Only 1% to 3% of all patients with sudden hearing loss have acoustic neuromas, however.) The loss usually is a highfrequency loss but can be almost any configuration and may

Chapter 165

epithelium and diminish or stop the production of cyst fluid. These treatment regimens may be difficult to use because of concerns about correct dosimetry and uniformity of its delivery, particularly in patients in whom prior irradiation has been carried out or when multiple cysts are present. This treatment modality entails precise cannulation of the cyst via an indwelling catheter and a delivery system that must be demonstrated to limit distribution of the isotope to the tumor cyst alone. Similar considerations apply to the use of intracavitary bleomycin, which often reduces cyst size and in certain patients facilitates surgical removal of particularly complex tumor cysts. Bleomycin is a chemotherapeutic agent that has the property of causing craniopharyngioma cysts to shrink, toughen, and thicken. These changes may permit surgical excision of a cyst that otherwise might fragment when its walls are grasped or manipulated.

The craniopharyngioma is a suprasellar neoplasm of congenital origin. It has a characteristic pathologic and radiographic appearance and a common mode of clinical presentation related to signs of endocrine or visual dysfunction or to increased intracranial pressure from obstruction of cerebrospinal fluid flow through the third ventricle. The tumor is optimally treated by surgical excision, either alone or in combination with radiotherapy. Each approach has its advocates, but both have the potential for significant long-term morbidity. Ongoing studies in neuropsychologic outcome and treatment side effects can be expected to shed additional light on this debate over the next several years.

w Acoustic Neuroma

1071

SUGGESTED READINGS Backlund EO, Axelsson B, Bergstrand CG et ak Treatment of craniopharyngiomas: the stereotactic approach in ten to twenty-three years’ perspective. I. Surgical, radiological and ophthalmologic aspects. Acta Neurochir (Wien) 99:ll-9, 1989 Epstein FJ, Handler MH (eds): Craniopharyngioma: the answer. Pediatr Neurosurg 2l(suppl 1):l-132, 1994 Fischer EG, Welch K, Shillito J et al: Craniopharyngiomas in children: long-term effects of conservative procedures combined with radiation therapy. J Neurosurg 73:534-540, 1990 Hetelekidis S, Barnes PD, Tao ML et ak Twenty-year experience in childhood craniopharyngiorna. Int J Radiat Oncol Biol Phys 27:189193, 1993 Hoffman HJ, DeSilva M, Humphreys Rp: Aggressive surgical management of craniopharyngiomasin children. J Neurosurg 76:47-52, 1992 Pollack IF, Lunsford LD, Slamovits TL et al: Stereotaxic intracavitary irradiation for cystic craniopharyngiomas. J Neurosurg 68:227-233, 1988 Pusey E, Kortman KE, Flannigan BD et ak MR of craniopharyngiomas: tumor delineation and characterization. AJNR k439-444, 1987 R u b JT, Hoffman HJ, Drake JM, Humphreys RF? Suprasellar and sellar tumors in childhood and adolescence. Neurosurg Clin North Am 3:803-820, 1992 Samii M, Tatagiba M Craniopharyngioma. In Kaye AH, et al (eds): Brain Tumors: An Encyclopedic Approach, 2nd Ed. Churchill Livingstone, 2001 Sorva R, Heiskanen D, Perheentupa J: Craniopharyngioma surgery in children: endocrine and visual outcome. Childs Nerv Syst 497-99, 1988

165 Acoustic Neuroma David M. Vernick and John K. Park Named after their most common presenting feature, acoustic neuromas are benign tumors of the eighth cranial nerve. They are actually Schwann cell tumors originating at the transition point where the vestibular nerve becomes a peripheral nerve. Attempts to improve the accuracy of the name have resulted in their being called acoustic neurinomas, acoustic schwannomas, and vestibular schwannomas in some articles. They account for 8% of all adult intracranial tumors and 80% of all cerebellopontine angle tumors. Their overall clinical incidence is about one tumor per 100,000 population per year. In autopsy studies of the temporal bone, the incidence ranges from 0.8% to 2.7%. Most of the difference results from small tumors that presumably lie dormant for years. Acoustic neuromas occur with equal frequency on the superior and inferior branches of the vestibular nerve. They are unilateral, except in cases of the genetic disorder neurofibromatosis type 2 (NF-2), in which they are bilateral. There is no side predilection, nor is there a sex bias. The most common age of presentation is during the fourth and fifth decades, but all ages have been reported. HISTORY By the late 1800s, the diagnosis of cerebellopontine angle tumors was made by the presence of hearing loss, facial numbness, and headache. No diagnostic tests were available to confirm the findings. Audiometric, vestibular, and radiologic testing developed

in the early 1900s allowed earlier and more accurate diagnosis. Unilateral sensorineural hearing loss with decreased discrimination and unilateral decreased caloric response became the main diagnostic findings in patients with acoustic neuromas. Radiology could show widening of the internal auditory canal. Surgery was the best treatment at the time, with radiotherapy being in its infancy, but mortality and morbidity rates ran high. Today the auditory and radiographic techniques have improved dramatically to allow diagnosis of smaller tumors. Treatment options have been refined to reduce the morbidity and mortality rates of therapy markedly. Preservation of facial nerve function and, in small tumors, hearing are now expected results. Despite all the advances, however, the average size of tumors detected has decreased minimally. The average time of onset of symptoms until the diagnosis of the tumor is 4 years. Although benign by histology, acoustic neuromas still present a diagnostic and therapeutic challenge to the physician. PRESENTATION The most common presenting feature of acoustic neuromas is unilateral hearing loss (Table 165-1). This is usually a progressive sensorineuralloss, but,in 10% of cases there is a sudden shift in the hearing. (Only 1% to 3% of all patients with sudden hearing loss have acoustic neuromas, however.) The loss usually is a highfrequency loss but can be almost any configuration and may

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recover. In addition to the hearing loss, speech discrimination, the ability to understand words, usually is markedly reduced even when the hearing loss is mild. Only 1% to 3% of all patients with diagnosed tumors have normal hearing. This number probably will increase with the increased sensitivity of magnetic resonance imaging (MRI) scanning in picking up small tumors. Unilateral tinnitus can be an early presenting feature of acoustic neuromas. It is subjective (heard only by the patient) and can be almost any type of sound. Usually it is constant, not pulsatile. Workup may show an asymmetrical hearing loss that accompanies the noise, but audiometry can be normal. Disequilibrium is common in patients with acoustic neuromas but is not a common presenting feature. Because the tumors are slow growing, the body has a chance to compensate for the gradual loss of one peripheral vestibular system. Patients usually have imbalance on questioning, but it is mild to moderate. Acute vertigo is uncommon but can result from a sudden change in the size of the tumor such as from hemorrhage into the tumor. Large

m TAW 16s-1. Presenting Symptoms of Acau Early Late

Hearing loss that is unilateral and may be sudden Tinnitus (unilateral) Disequilibrium Facial hypesthesia or paresthesia Facial spasm or weakness Dysarthria Dysphagia Aspiration Hoarseness Headache Ataxia

tumors may press on the cerebellum or brainstem and cause ataxia late in the course. Other presenting signs are uncommon unless the tumor is large. These result from pressure on adjacent cranial nerves. Hypesthesia or paresthesia of the face can occur with trigeminal nerve involvement. The earliest sign of this is decrease in the corneal reflex. Facial nerve palsy can occur, but more often facial nerve involvement presents with facial twitching. The functions of lower cranial nerves (nerves M, X, and XI), such as speech and swallowing, can be impaired as well, leading to dysarthria, dysphagia, aspiration, and hoarseness. Long tract signs have been seen late in very large tumors. The brainstem can be compressed, or the cerebellar tonsils can herniate through the foramen magnum. Hydrocephalus and death can occur in untreated cases. Asymptomatic cases account for less than 1% of present tumors found. Increased use of MRI may increase this number substantially.

PHYSICAL EXAMINATION After a thorough history has been taken, physical examination, not MRI, should be carried out. Otologic examination shows a normal-appearing ear. Gioss auditory testing should confirm the presence of an asymmetrical hearing loss. Tuning fork testing will confirm this. The Rinne test shows air conduction greater than bone conduction bilaterally. Weber testing lateralizes to the side of the better-hearing ear. Neurologic testing may show some cranial nerve deficits such as an absent corneal reflex or hypesthesia of the face. Facial twitching may be present. Other cranial nerve deficits are uncommon unless the tumor is large. Balance usually is grossly intact in the office.

FREQUENCY (Hz) SPEECH AUDIOMETRY

~ 2 5 2 5 0 5 0 0 1 o o o x K ) o 4 o w B Q o o

LBBREV~LTIONS

SPEECH OISCRIMINATION SCORE LEVEL MASK OWT w m u c1sI CaJdmaC

s

kraddm

Bc Bamrd#awl YQ Y 0 r t w UCL UrronloMCkrl

EAR

MIDDLE EAR MEASUREMENTS TYMPANOMETRY ACOUSTIC REFLEX (HL) SnmlursDoHz

MHr

2KHr

UtHr

1FIG. 165-1. Audiogram of patient with a left acoustic neuroma.

TOLERANCE

Chapter 165

1.52

3.56

5.44

2.04

3.92

1.60

3.80

5.72

2.20

4.12

Acoustic Neuroma

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LEFr I

1x1

V

FIG. 165-2. Brainstem-evoked response audiometry of patient with a left acoustic neurorna.

LABORATORY TESTING Audiometry has been and still is the best initial screening test for diagnosing acoustic neuromas. (Only 5% of acoustic neuromas have a normal auditory evaluation.) Pure tone and speech audiometry should be performed. Test results show an asymmetrical sensorineural hearing loss, usually more prominent in the higher frequencies (Fig. 165-1). mically the speech discrimination score is markedly reduced in the affected ear, being much lower than expected given the degree of hearing loss present. Many other auditory tests have been used historically to try to diagnose acoustic neuromas. These include acoustic reflex testing, impedance audiometry, and Bekesy audiometry. They have all had limited accuracy and diagnostic value. Their utility has diminished with the advent of brainstem-evoked response audiometry. Brainstem-evoked response audiometry should be done in anyone with an unexplained asymmetry in audiometric testing either in pure tone or in discrimination. This test shows abnormalities in 90% to 95% of patients with tumors. Although not all positive tests reflect the presence of a tumor, the test is valuable for screening patients because it is quick, painless, inexpensive, and accurate. Test results show a delay in nerve conduction time on the affected side, reflecting the probable presence of a tumor (Fig. 165-2). Vestibular testing has lost its usefulness as a screening test for diagnosis of acoustic neuromas because of the accuracy of evoked response audiometry. When testing is performed, a decreased or absent caloric response on the affected side may be seen. This information is useful in predicting how dizzy a patient may be postoperatively if surgery is performed. Radiologic imaging has advanced through the years from plain films, polytomograms, posterior fossa myelography, and computed tomography (CT) with contrast agents to MRI. Improved accuracy and patient safety have accompanied the advances. When brainstem testing is abnormal or cannot be done because of the severity of the hearing loss or when suspicion is high, MRI scanning with gadolinium contrast should be performed. It allows

FIG. 166-3. Gadolinium-enhanced magnetic resonance image of acoustic neuroma.

the diagnosisof tumors larger than 1mm in diameter (Fig. 165-3). If a patient cannot tolerate the MRI scan, CT scanning with contrast is almost as accurate. Acoustic neuromas show up on CT and MRI scans as enhancing lesions. CT scans can show widening of the internal auditory canal. A soft tissue mass can be seen in the widened canal, extending into the posterior fossa. This mass enhances with iodinated contrast material.

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TABU 165-2. Probability That an Acoustic Neuroma Is Present in Relation t o Symptoms Svmmms

Probabili

DIFFERENTIAL DIAGNOSES catenow ~~

Classic unilateral asymmetrical senP > 30% High sorineural hearing loss, tinnitus, decreased discrimination Sudden sensorineural hearing loss 5% < P < 30% Intermediate Otherwise unexplained persistent unilateraltinnitus P < 5% Low Isolated vertigo Historically explained unilateral hearing loss, tinnitus Symmetrical hearing loss From Welling BD, Classcock ME 111 et al: Otolaryngology: Head and Neck Surgery. Mosby, St Louis, 1990, with permission.

MRI scans show a soft tissue mass on T1-weighted images, which is brighter than cerebrospinal fluid. With gadolinium contrast, the tumors show up as bright masses. Rare false-positive scans have been reported in small lesions located laterally in the internal auditory canal. These are probably inflammatory lesions that resolve with time. A cost-effective approach to the workup of patients suspected of having an acoustic neuroma was proposed by Welling et al. (Table 165-2 and Fig. 165-4). This approach uses MlU scanning for high-probability situations and brainstem-evoked audiometry testing for screening lower-probability situations.

Although most of the tumors of the cerebellopontine angle are acoustic neuromas, other tumors do occur. Tumors presenting in the cerebellopontine angle include the following: Acoustic neuroma Meningioma Glioma Cholesteatoma Hemangioma Aneurysm Arachnoid cyst Lipoma Metastatic tumor Meningiomas are present 5% to 10% of the time. Cholesteatomas, gliomas, hemangiomas, aneurysms, arachnoid cysts, lipomas, and metastatic tumors are far less common but can present with symptoms similar to those of an acoustic neuroma. Imaging studies can help in the preoperative differential diagnosis. TUMOR GROWTH Acoustic neuromas are slow growing, with an average growth rate of 2 mm/year. Rates as high as 10 mm/year have been seen in a few

Watch Hgh ProbaWity (p > 30%)

Treat

A M ( + ) -RepeatMR

ABR ( -)

0 0 p

-Re-evaluau

Watch MR ( -

)-

Reevaluate

Clinical judgement decision node Chance node dictated by test outcome

= probability estimate FIG. 165-4. Cost-effective workup of patient with possible acoustic neuroma. (From Welling BD, Classcock ME 111 et al: Otolaryngology: Head and Neck Surgery. Mosby, St. Louis, 1990, with permission.)

Chapter 165 W

cases. Up to 40% of cases show no growth or even shrinkage on serial scans. There is no correlation between growth rate and tumor size at presentation. Growth rate tends to be constant over time, but sudden changes in tumor size can occur if there is hemorrhage into the tumor.

NEUROFIBROMATOSIS Two major types of neurofibromatosis-NF- 1 and NF-2-are recognized today. A thorough discussion of these disorders is presented in Chapter 166. The hallmark of NF-2 is bilateral acoustic neuromas. In NF-2, most patients present with the same symptoms as with other acoustic neuromas (i.e., with progressive hearing loss, tinnitus, or disequilibrium). Treatment options are basically the same as with unilateral acoustic neuromas but must be tempered because of the bilateral nature of the losses and the potential deafness that can result. Hearing preservation with surgery is possible but not as common as with the unilateral cases.

CHILDREN Fewer than 20 cases of acoustic neuromas in children younger than 15 years of age have been reported. The ages range from 1 to 14, with a mean age of 9 years. Presenting symptoms often include loss of other cranial nerve function in addition to hearing loss. This is probably because of the larger size of the tumors at the time of diagnosis. This larger size probably reflects lack of consideration of the diagnosis rather than any true biologic difference in the tumor's behavior. Treatment options are the same as for adults.

TREATMENT Once the diagnosis of an acoustic neuroma has been made, treatment options must be discussed. Three major paths of therapy are present: observation, surgery, and radiation therapy. Chemotherapy has not yet made an impact on treatment. Because acoustic neuromas generally are slow growing and up to 40% of them either do not grow or shrink in size, immediate active interventional therapy is not necessary in most cases. Particularly in patients who are older than 65 or who have other significant medical problems, follow-up MRI scans at 6- to 12-month intervals will allow determination of the growth rate of the tumor and prognostic planning before intervention. One contraindication to this wait-and-see approach is in patients with large tumors in whom brainstem compression or hydrocephalus may occur. A second contraindication is in patients with good hearing. Delay in therapy may compromise the chances of hearing preservation. Once the decision to treat a tumor has been made, surgical resection is the recommended initial treatment modality, as determined at a 1991 National Institutes of Health Consensus Development Conference. The approach can be via the translabyrinthine, suboccipital, or middle fossa routes, depending on the size of the tumor and whether hearing preservation is being attempted. In many institutions, this is performed by a team consisting of a neurosurgeon and an otolaryngologist. Postoperative mortality and morbidity rates have been markedly reduced as microsurgical techniques have evolved and intraoperative monitoring has advanced. Facial nerve monitoring during the surgery has markedly reduced the incidence of postoperative facial nerve injuries. Hearing can be preserved in 40% to 50% of cases when the tumor is less than 1.5 cm, the preoperative hearing is better

Acoustic Neurorna

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than 50 dB, and the discrimination is better than 50%. Hospital stays have also decreased secondary to better surgical and anesthetic techniques. Complications such as a cerebrospinal fluid leak occur in 5% to 10% of patients who have undergone a suboccipital approach operation and in less than 5% of those who have undergone surgery via a translabyrinthine approach. Most of these leaks close spontaneously after several days with or without a lumbar drain. Postoperative vertigo is more of an issue with smaller than with larger tumors. Because tumor removal necessitates sacrifice of the vestibular nerves, any function that remains is acutely lost. Small tumors have not destroyed most of the vestibular function and thus leave the patient vertiginous for several days afterward. Mild imbalance usually resolves completely in 3 to 6 months. Injuries of other cranial nerves (V, VI,IX,X, and XI) can occur during tumor dissection. Brainstem stroke and even death can result from injury to the vertebrobasilar circulation. Fortunately, the incidence of these complications has decreased drastically as surgical techniques have improved. In a recent review of the literature, complete tumor removal was achieved in 97% to 99% of patients, normal or near normal facial movements were retained in 94% to 97% of patients with small tumors and 28% to 579/0 of patients with large tumors, and hearing was retained in 45% to 82% of patients with small tumors and good preoperative hearing. Major complications in a single-surgeon series of 1000 patients were tetraparesis in 1 patient, hemiparesis in 10 patients, lower cranial nerve palsies in 55 patients, and cerebral spinal fluid fistulas in 92 patients. Radiation therapy is a possible treatment option for patients with acoustic neuromas 2 to 3 cm in diameter. The optimal mode of radiotherapy is still under investigation, and current options include stereotactic radiosurgery in which a single dose of radiation is delivered or stereotactic radiotherapy in which a dose is fractionated. Cessation of significant tumor growth has been as high as 98% in one series of 162 patients, but longer-term follow-up of these patients is still needed to derive any definitive conclusions. Long-term complications can occur with radiotherapy and include hearing loss and facial nerve injury as well as other major cranial nerve problems. Surgery in patients who do not respond to radiation may be more difficult.

SUMMARY Although benign, acoustic neuromas have challenged physicians throughout history. Advances in the diagnostic and therapeutic fields of audiology, medicine, radiology, radiation therapy, and surgery have greatly improved our ability to detect and treat these tumors. Morbidity and mortality rates have been reduced. However, there is room for even greater success in the years to come.

SUGGESTED READINGS Curtin HD, Hirsch WL Jr: Imaging of ' acoustic neuromas. Otolaryngol Clin North Am 25:553-607, 1992 Gormley WB,Sekhar LN, Wright DC et al: Acoustic neuromas: results of current surgical management. Neurosurgery 41:5&58, 1597 Kondziolka D, Lunsford LD, McLaughlin MR et ak Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 33914261433, 1998 Nedzelski JM, Schessel DA, Pfleiderer A et ak Conservative management of acoustic neuromas. Otolaryngol Clin North Am 25:691-705, 1992 NIH Consensus Development Conference: Acoustic Neuroma, Dec 11-13. 9(4):1-24, 1991

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Roland PS, Glasscock ME, Bojrab DI et al: Normal hearing in patients with acoustic neuromas. South Med J 80:166-169, 1987 Roos K L The neurofibromatoses. Ear Nose Throat J 71512-519, 1992 Samii M, Matthie C Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them. Neurosurg 4011-21, 1997

Selesnick SH, JacklerRK: Clinical manifestationsand audiologic diagnosis of acoustic neuromas. Otolaryngol Clin North Am 2 5 5 2 1 4 5 1 , 1992 Tos M, Thomsen J: Management of acoustic neuromas. Acta Otolaryngol (Stockh) 111:616-632, 1991 Welling DB, Glasscock ME, Woods CI et al: Acoustic neuroma: a cost-effective approach. Otolaryngol Head Neck Surg 103:364-370, 1990

166 The Neurofibromatoses Bruce R. Korf The neurofibromatoses are a set of at least two distinct disorders that have in common a predisposition to formation of tumors of the nervous system, both central and peripheral. These genetically determined disorders have been the subject of intense research in recent years. The discovery of the genes responsible for neurofibromatosis types 1 (NF-1) and 2 (NF-2) has provided insights into pathophysiology that are beginning to suggest new avenues of treatment. Although neither disorder can be cured, both are important to recognize clinically because of the potential for treatment of complications and the need to provide genetic counseling.

CLASSIFICATION OF THE NEUROFIBROMATOSES There are two well-recognized forms of neurofibromatosis, NF- 1 and NF-2. These are contrasted in Table 166-1. NF-1 is the most common form, about 10 times as common as NF-2. The two disorders were not distinguished in earlier literature, but recent genetic studies have confirmed that they are entirely distinct entities. Correct diagnosis is important for clinical care. For example, patients with NF-1 are not at higher risk for vestibular schwannomas, whereas this tumor usually is present in those with NF-2. Conversely, complications such as learning disabilities and optic glioma are found in those with NF- 1 but not NF-2. There are rare patients whose disease does not fit well into the classification scheme of NF- 1 or NF-2. It is possible that there are variant forms of both disorders. Alternatively, there may be other types of neurofibromatosis besides NF- 1 and NF-2, perhaps caused by mutations at other genes yet to be discovered. The disorders in these patients may be better understood as the genetic basis of the neurofibromatoses becomes more thoroughly explored.

TABLE166-1. Comparison of NF-1 and NF-2 NF-1

Frequency Mode of inheritance Features

Chromosome locus Gene product Function

NF-2

1:4000

1 :40,000

Autosomal dominant

Autosomal dominant

Cafe-au-lait spots, neurofibromas, optic gliomas, learning disabilities, malignant schwannomas Chromosome 17

Bilateral vestibular schwannomas, schwannomas, rneningiomas, ependymomas Chromosome 22

Neurofibromin GTPase activating protein

Merlin (schwannomin) Cytoskeletal protein

Abbreviorion: CTPase, guanosine hiphosphatase.

NEUROFIBROMATOSISTYPE I NF-1 is the most common form of neurofibromatosis, occurring in about 1:4000 people. NF- 1 affects people of all racial and ethnic groups worldwide. It is often called von Recklinghausen neurofibromatosis, after the German pathologist who first noted that the characteristic tumors are derived from peripheral nerves. Although NF-1 is sometimes called “Elephant Man’s disease,” it has recently been determined that Joseph Merrick, who was known as the Elephant Man, actually had a different disorder called Proteus syndrome, which is associated with bony and cutaneous overgrowths, epidermal nevi, and caf6-au-lait spots. People with NF- 1 should understand that the physical deformities of the Elephant Man do not occur in neurofibromatosis.

Diagnosis The diagnosis of NF-1 is based on clinical criteria; currently no laboratory test is available. Diagnostic criteria are as follows:

Six or more caf6-au-lait spots larger than 5 mm prepubertal or 15 mm postpubertal Freckles in skin folds such as axillae or groins Two or more neurofibromas or one plexiform neurofibroma Two or more iris Lisch nodules Optic glioma Characteristic skeletal deformity such as tibial dysplasia or sphenoid dysplasia First-degree relative with NF- 1 by these criteria A person who satisfies any two of these criteria is generally agreed to have NF-1. However, many of the features are age dependent, making diagnosis in young children a challenge. Caf6-au-lait macules (Fig. 166-1) most commonly bring the disorder to attention. These are flat, brown spots that generally begin to appear in the early weeks of life and may continue to get darker and increase in number for the first several years. The diagnostic criteria for NF-1 include six or more cafe-au-lait spots larger than 5 mm before puberty or 15 mm after puberty. Almost all people with NF-1 fulfill this criterion, but there is no correlation between the number of cafe-au-lait spots and the severity of NF- 1 or between the location of spots and the location of complications of the disorder. People in the general population may have one or two, or even up to six caf6-au-lait spots and not have NF- 1. There is a rare hereditary trait of multiple cafe-au-lait spots without other signs of NF-1. Another cutaneous diagnostic sign is the occurrence of freckling in intertriginous areas, such as axillae and groins. This

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Roland PS, Glasscock ME, Bojrab DI et al: Normal hearing in patients with acoustic neuromas. South Med J 80:166-169, 1987 Roos K L The neurofibromatoses. Ear Nose Throat J 71512-519, 1992 Samii M, Matthie C Management of 1000 vestibular schwannomas (acoustic neuromas): surgical management and results with an emphasis on complications and how to avoid them. Neurosurg 4011-21, 1997

Selesnick SH, JacklerRK: Clinical manifestationsand audiologic diagnosis of acoustic neuromas. Otolaryngol Clin North Am 2 5 5 2 1 4 5 1 , 1992 Tos M, Thomsen J: Management of acoustic neuromas. Acta Otolaryngol (Stockh) 111:616-632, 1991 Welling DB, Glasscock ME, Woods CI et al: Acoustic neuroma: a cost-effective approach. Otolaryngol Head Neck Surg 103:364-370, 1990

166 The Neurofibromatoses Bruce R. Korf The neurofibromatoses are a set of at least two distinct disorders that have in common a predisposition to formation of tumors of the nervous system, both central and peripheral. These genetically determined disorders have been the subject of intense research in recent years. The discovery of the genes responsible for neurofibromatosis types 1 (NF-1) and 2 (NF-2) has provided insights into pathophysiology that are beginning to suggest new avenues of treatment. Although neither disorder can be cured, both are important to recognize clinically because of the potential for treatment of complications and the need to provide genetic counseling.

CLASSIFICATION OF THE NEUROFIBROMATOSES There are two well-recognized forms of neurofibromatosis, NF- 1 and NF-2. These are contrasted in Table 166-1. NF-1 is the most common form, about 10 times as common as NF-2. The two disorders were not distinguished in earlier literature, but recent genetic studies have confirmed that they are entirely distinct entities. Correct diagnosis is important for clinical care. For example, patients with NF-1 are not at higher risk for vestibular schwannomas, whereas this tumor usually is present in those with NF-2. Conversely, complications such as learning disabilities and optic glioma are found in those with NF- 1 but not NF-2. There are rare patients whose disease does not fit well into the classification scheme of NF- 1 or NF-2. It is possible that there are variant forms of both disorders. Alternatively, there may be other types of neurofibromatosis besides NF- 1 and NF-2, perhaps caused by mutations at other genes yet to be discovered. The disorders in these patients may be better understood as the genetic basis of the neurofibromatoses becomes more thoroughly explored.

TABLE166-1. Comparison of NF-1 and NF-2 NF-1

Frequency Mode of inheritance Features

Chromosome locus Gene product Function

NF-2

1:4000

1 :40,000

Autosomal dominant

Autosomal dominant

Cafe-au-lait spots, neurofibromas, optic gliomas, learning disabilities, malignant schwannomas Chromosome 17

Bilateral vestibular schwannomas, schwannomas, rneningiomas, ependymomas Chromosome 22

Neurofibromin GTPase activating protein

Merlin (schwannomin) Cytoskeletal protein

Abbreviorion: CTPase, guanosine hiphosphatase.

NEUROFIBROMATOSISTYPE I NF-1 is the most common form of neurofibromatosis, occurring in about 1:4000 people. NF- 1 affects people of all racial and ethnic groups worldwide. It is often called von Recklinghausen neurofibromatosis, after the German pathologist who first noted that the characteristic tumors are derived from peripheral nerves. Although NF-1 is sometimes called “Elephant Man’s disease,” it has recently been determined that Joseph Merrick, who was known as the Elephant Man, actually had a different disorder called Proteus syndrome, which is associated with bony and cutaneous overgrowths, epidermal nevi, and caf6-au-lait spots. People with NF- 1 should understand that the physical deformities of the Elephant Man do not occur in neurofibromatosis.

Diagnosis The diagnosis of NF-1 is based on clinical criteria; currently no laboratory test is available. Diagnostic criteria are as follows:

Six or more caf6-au-lait spots larger than 5 mm prepubertal or 15 mm postpubertal Freckles in skin folds such as axillae or groins Two or more neurofibromas or one plexiform neurofibroma Two or more iris Lisch nodules Optic glioma Characteristic skeletal deformity such as tibial dysplasia or sphenoid dysplasia First-degree relative with NF- 1 by these criteria A person who satisfies any two of these criteria is generally agreed to have NF-1. However, many of the features are age dependent, making diagnosis in young children a challenge. Caf6-au-lait macules (Fig. 166-1) most commonly bring the disorder to attention. These are flat, brown spots that generally begin to appear in the early weeks of life and may continue to get darker and increase in number for the first several years. The diagnostic criteria for NF-1 include six or more cafe-au-lait spots larger than 5 mm before puberty or 15 mm after puberty. Almost all people with NF-1 fulfill this criterion, but there is no correlation between the number of cafe-au-lait spots and the severity of NF- 1 or between the location of spots and the location of complications of the disorder. People in the general population may have one or two, or even up to six caf6-au-lait spots and not have NF- 1. There is a rare hereditary trait of multiple cafe-au-lait spots without other signs of NF-1. Another cutaneous diagnostic sign is the occurrence of freckling in intertriginous areas, such as axillae and groins. This

Chapter 166 rn The Neurofibromatoses

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tumors become progressive and symptomatic. Anyone found to have an optic glioma should be examined for other signs of NF-1, although at least 50% of optic ghomas occur in those without neurofibromatosis. Orbital plexiform neurofibroma is a rare complication of NF-1, involving neurofibroma growth in the orbit and upper eyelid. There is usually an associated dysplasia of the sphenoid bone. Orbital plexiform neurofibroma is clinically apparent in the early years of life. It is a congenital lesion that grows during the preschool years. It is clinically recognized as overgrowth of the upper eyelid, downward and outward or inward displacement of the eye, and transmission of venous pulsations to the globe. There may be glaucoma of the affected eye, but neurologic complications are rare. Aside from sphenoid dysplasia, one other bone lesion is characteristic of NF- 1 and represents a diagnostic criterion. This is dysplasia of a long bone, most commonly the tibia. It is a congenital lesion, recognized by anterolateral bowing of the lower leg. There is substantial risk of fracture of the tibia, leading to pseudoarthrosis. The final diagnostic criterion is based on family history. Because NF-1 is inherited as a dominant trait, the existence of an affected first-degree relative satisfies one diagnostic criterion for NF-1. About 50% of cases of NF-1 are sporadic, however, caused by a new mutation. A diagnostic evaluation for NF- 1 consists of physical examination, with careful attention to skin lesions, and an ophthalmologic examination with the slit lamp to look for Lisch nodules. A family history should be obtained, and, if possible, both parents should be examined for signs of neurofibromatosis. Natural Hlrtoy and Management

FIG. 166-1. Multiple cafbau-lait spots in a child with NF-1.

usually begins at around 3 to 5 years of age and, when it occurs, is highly specific to NF-1. It is often the next sign of NF-1 to be found in young children who first present with multiple cafe-aulait spots. Freckling tends to increase with age and may occur throughout the body, lending an appearance of diffuse hyperpigmentation. The neurofibroma is the lesion that gives the disorder its name. Neurofibromas most commonly appear on the skin as small papules, usually having a purplish hue. They may occur at any age but are most commonly seen in late childhood or puberty. Many women note an increase in the size and number of neurofibromas during pregnancy. Neurofibromas can occur any place in the body where there is a nerve. Usually they cause no symptoms other than cosmetic, although rarely symptoms of nerve compression may occur. Three diagnostic criteria involve the eye. Lisch nodules are tan melanocytic hamartomas of the iris. It is necessary to use the slit lamp to identifyLisch nodules and distinguish them from iris nevi, which are not associated with neurofibromatosis. Lisch nodules are specific to NF-1 and occur on at least 95% of patients with NF-1 past 6 years of age. Therefore, they are useful diagnostic markers but do not interfere with vision. Lisch nodules are not a feature of NF-2. Optic glioma, identified as thickening of the optic nerve, occurs in about 15% of children with NF- 1. Only rarely do optic pathway

Important complications of NF-1 are listed in Table 166-2. The overall frequency of severe complications has been overstated in much of the medical literature because severe complications are more likely to bring a person to medical attention or to be published. Studies that have attempted to avoid this bias, including one population-based study, have shown that approximately two thirds of patients with NF-1 have mild involvement, often never needing medical attention. Life expectancy is only slightly shorter, mostly because of malignancy. Much of the medical burden associated with NF- 1 is caused by the neurofibroma. There are three major types of neurofibromas. Cutaneous neurofibromas involve nerve endings in the skin. These usually first appear in late childhood or adolescence and can continue to appear throughout life. They are painless, although some people complain of itching. The number a person will get is

rn TABLE1 6 6 2 . Major Types of Complications of NF-1 ~~S

Cosmetic Impairment, Itching

Neurologic

Nerve compression,spinal cord compression, headache, seizure, learning disability, developmental delay, brain tumor, aqueductal stenosis Orbiil dysplasia, glaucoma, optic glioma Long bone dysplasia, pseudoarthrosis,mandibular dysplasia or cysts, xoliosis, sphenoid wing dysplasia Hypertensioncaused by renal artery stenosis or pheochromocytoma Macrocephaly, short stature Constipation, intestinal obstruction (caused by neurofibroma)

Ophthalmologic Orthopedic Vascular Growth

Gastrointestinal

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Neuro-Oncology

Specific Tumor Types

FIG. 166-2. MRI study of paravertebral neurofibroma involving several nerve roots in the thoracic spine.

unpredictable. Cutaneous neurofibromas sometimes pose a cosmetic problem or may cause discomfort by rubbing against clothing. They can be removed with plastic surgery and probably do not grow back, although new ones can appear at any time. Nodular neurofibromas are neurofibromas attached to major nerves. Often they can be palpated as firm masses below the surface of the skin. These tumors may grow to large size but usually are asymptomatic unless they occur near a bone and cause nerve compression. It is difficult to remove nodular neurofibromas surgically because nerve fibers run through the entire mass, which is different from schwannomas, in which the nerve is displaced by the tumor. Nodular neurofibromas involving nerve roots (Fig. 166-2) can grow across the neural foramen as dumbbell tumors and may cause nerve root compression or compression of the spinal cord. Unexplained pain in a patient with NF-1 should prompt investigation for a nerve root tumor causing referred pain. Tumors of spinal nerve roots are treated surgically. Plexiform neurofibromas are congenital lesions that involve diffuse enlargement of a major nerve and its branches. In infancy, only a subtle soft tissue asymmetry may be noticed, but often these neurofibromas grow rapidly during early childhood. It is rare for a plexiform neurofibroma to appear first in adulthood. Sometimes there is hyperpigmentation of the overlying skin, and early in life this may be the only clue that a plexiform neurofibroma is present deeper inside the body. Plexiform neurofibromas can lead to limb overgrowth (Fig. 166-3), facial deformity, or obstruction of internal organs. The only available treatment is surgical, but it is almost impossible to remove a plexiform neurofibroma completely, so regrowth is common. Neither chemotherapy nor radiation therapy is effective in treating plexiform neurofibromas unless malignant transformation has occurred. Malignant tumors are rare in people with NF-1, occurring in 5% to 10%. Malignant peripheral nerve sheath tumor usually occurs in a preexisting plexiform neurofibroma and presents with sudden growth of a portion of the lesion or unexplained pain. It

is important to realize that growth and pain are common in plexiform tumors and usually do not indicate malignancy. Treatment involves surgery or radiation for local control and chemotherapy. Brain tumors associated with NF-1 include gliomas and optic gliomas. Optic gliomas are common in children with NF-1, but only a small number progress. Progression usually occurs in children aged 4 to 6 years. Gliomas of the orbital portion of the optic nerve lead to vision loss, pain, proptosis, impaired ocular movement, and optic disk swelling. Chiasmatic gliomas (Fig. 166-4) cause visual field deficits, optic atrophy, and hypothalamic disturbance, particularly precocious puberty. Because of the indolent nature of the lesions, treatment should be instituted only after clear demonstration of progression. Biopsy usually is unnecessary, and surgery is indicated only for unilateral orbital tumors that have already caused complete blindness. In the past these were treated by radiation therapy, but currently chemotherapy with vincristine and carboplatin is used as initial treatment. Gliomas can also occur anywhere in the brain at any age. They should be distinguished from areas of enhanced T2-weighted signal seen by magnetic resonance imaging (MRI) in children with NF-1 (Fig. 166-5). These signals are commonly seen in the basal ganglia, internal capsule, brainstem, and cerebellum and are not malignant or premalignant lesions. They tend to disappear with age and may represent areas of abnormal myelination or possibly gliosis. There is evidence that these unidentified bright objects (UBOs) may occur more commonly in children with NF-1 who have learning disabilities. Learning disabilities are common in patients with NF-1, occurring in at least half. There does not appear to be a cognitive profile that is specific to the disorder, and management is the same as for learning disabilities seen in the general population. Only a small proportion have mental retardation. Some children with NF- 1 have attention deficit disorder, with or without hyperactivity, and respond to treatment similarly to those with similar problems

Chapter 166 W The Neurofibromatoses

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in the general population. Other developmental problems, including hypotonia and motor developmental delay, may occur in association with NF-1. Mental retardation occurs rarely, affecting 5% or fewer. Headaches are common in patients with NF-1, particularly in young children. These are often accompanied by abdominal discomfort and probably are migraine headaches. Treatment with migraine prophylaxis, such as P-blocking medications, often is effective. In contrast, seizures are not common in NF-1. It is rare for these to indicate the presence of a structural lesion, even in the case of partial seizures. It is common to find macrocephaly in those with NF-1. Often this is absolute macrocephaly, but sometimes head size is normal, though large in relation to body size. Macrocephaly in NF-1 usually is benign, not associated with cognitive or neurologic problems. Rarely, hydrocephalus may result from aqueductal stenosis. This presents with typical signs of increased intracranial pressure. Many with NF-1 have short stature relative to nonaffected members of their families. No specific neuroendocrine dysfunction is found in most of these patients.

FIG. 166.4 Coronal MRI showing optic glioma of chiasm (arrow).

Routine clinical management for people with NF-1 should include a regular schedule for medical evaluation. This is usually offered once a year or more often if there are active problems. Medical tests, including imaging studies, are best reserved for specific clinical indications. There is no evidence that baseline imaging in the absence of signs or symptoms of neurologic disease is useful in clinical management.

Gendc Counseling

FIG. 166-3. Lower limb overgrowth caused by plexiform neurofibroma. There is pigmentation along the course of the sciatic nerve.

NF-1 is transmitted as an autosomal dominant trait. An affected person therefore has a 50% chance of passing the disorder on to any child. The expression of the disorder tends to vary from person to person in a family, so severity in the next generation cannot be predicted. About 50% of cases occur in the absence of a family history, caused by a new mutation. The mutation rate of the NF-1 gene is about 1:16,000, the highest rate known for any gene. This high mutation rate has been attributed to the large size of the gene and the wide diversity of mutations that can disrupt the function of the gene. Some people have multiple cafk-au-lait spots and other signs of NF-1 involving a restricted region of the body. This is called segmental NF and represents somatic mosaicism for an NF-1 gene mutation. People with segmental NF are at risk of passing an NF-I mutation to an offspring if the mutation is represented in the gem line. Similarly, the unaffected parents of a sporadically affected

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Neuro-Oncology

Specific Tumor Types

FIG. 166-5. Brain MRI showing multiple areas of T2-weighted signal intensity in basal ganglia. The patient had no neurologic symptoms.

child may carry additional mutant germ cells, although their risk of having another child with NF-1 is low. The NF-1 gene is located on chromosome 17 and encodes a protein known as neurofibromin. Neurofibromin functions as a regulator of the RAS protein, which is involved in controlling cell division and differentiation. The mutations responsible for NF- 1 appear to be diverse, making mutation analysis difficult for routine clinical testing. In general, there are no genotype-phenotype correlations, with one exception: Patients with large NF- 1 gene deletions tend to have a complex phenotype of early onset of neurofibromas, dysmorphic facial features, and developmental delay. These deletions can be detected by DNA analysis or fluorescence in situ hybridization on metaphase chromosomes. Polymorphic genetic markers can be used to track the NF-1 gene through a family if two or more generations are affected, enabling prenatal or presymptomatic diagnosis in such cases. Information on the availability of genetic testing can be obtained from the GeneTests database (www.genetests.org).

NEUROFIBROMATOSIS TYPE 2 NF-2 is about one tenth as common as NF-1, occurring in about 1:40,000 people. It can be more difficult to diagnose at an early age but is more commonly associated with severe, often lifethreatening problems.

Diagnostic criteria for NF-2 are listed in Table 166-3. The defining lesion of NF-2 is the presence of bilateral vestibular schwannomas.

Rarely these may present in childhood, but more commonly they become symptomatic after the second decade. The tumors tend to arise from the vestibular branch of the eighth nerve and often present with vertigo or balance problems. Tinnitus and hearing loss occur with growth of the tumors. They are best detected and followed with MRI (Fig. 166-6), although audiograms and auditory brainstem-evoked responses can also reveal their presence. NF-2 should be considered in any patient with a vestibular schwannoma, particularly in those whose tumors present before the third decade. However, it should be remembered that sporadic unilateral vestibular schwannomas are much more common than NF-2. Schwannomas of other cranial nerves, spinal nerve roots, and other peripheral nerves can also occur in patients with NF-2. According to the National Institutes of Health diagnostic criteria, in the absence of bilateral vestibular schwannomas, NF-2 can also be diagnosed in a person with a first-degree relative with NF-2 and some NF-2-related features. These include unilateral vestibular schwannoma, meningioma, glioma (usually of the spinal cord), ependymoma, or cataract. The latter can be a helpful sign of NF-2 in young children and consists of cortical wedge opacities or presenile posterior subcapsular cataracts. Cutaneous manifestations are less common in NF-2 than in NF-1. Some patients have cafk-au-lait spots and rarely may have as many as six. Skin fold freckles are not found in NF-2. Skin tumors may occur in NF-2 but typically are schwannomas rather than neurofibromas. Like NF-1, about one half of cases of NF-2 are sporadic. This presents a problem in diagnosis because many young people with NF-2 have neither bilateral vestibular schwannomas nor a family history of the disorder. Strict adherence to the diagnostic criteria would prevent one from diagnosing NF-2 in a sporadically affected person with unilateral vestibular schwannoma, meningioma, and cataract, for example. NF-2 should be strongly considered in a person having two or more features listed in Table 166-3.

Natural History and Management Unlike NF-1, NF-2 tends to breed true in families in terms of disease severity. Some families have mild manifestations and later age of onset, whereas others have a more fulminant course. In NF-2, death caused by complications of the condition is much more common than in NF-1. In one recent study, the mean age of death was 36.25 years, with a range of 16 to 67 years. Routine clinical care should focus on early detection of complications. Slit lamp examination can detect cataracts in young children at risk of inheriting the disorder. These rarely cause major visual problems but can help in establishing the diagnosis. Audiologic testing should be offered to at-risk patients and repeated every few years. Evidence of hearing loss or symptoms of

Trur 166-3.

of

Bilateral vestibular schwannomas OR

First-degree relative with NF-2 and Unilateralvestibular schwannoma or any two of following features: Schwannoma Meningioma Clioma Cortical wedge opacity or juvenile posterior subcapsular cataract

Chapter 166 W

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cloned and encodes a cytoskeletal protein called merlin or schwannomin. Mutation analysis is under way on a research basis, and is becoming available for diagnostic testing. Laboratory studies have demonstrated that both copies of the NF-2 gene are inactive in tumor cells of schwannomas and meningiomas, supporting the notion that the NF-2 gene functions as a tumor suppressor gene.

SUMMARY AND FUTURE PROSPECTS Although NF-1 and NF-2 have been known as clinical entities for many years, our understanding of the basis for these disorders is recent, since the cloning of the genes. Despite this progress, however, clinical management is currently limited to anticipatory guidance, early symptom detection, symptomatic treatment, and genetic counseling. However, there is hope that increased understanding of the pathogenesis will lead to improved diagnostic tests and advances in therapy. Clinical trials are beginning with RAS inhibitors in NF-1, and angiogenesis inhibitors are likely to be tested in both disorders in the near future. Affected patients can be directed to the National Neurofibromatosis Foundation, 95 Pine Street, 16th Floor, New York, NY 10005 (phone 800-323-7938), www.nf.org; or NF, Inc., 8855 Annapolis Rd., Suite 110, Lanham, MD 20706 (phone 800-942-6825), www.nfinc.org, for additional information. FIG. 166-6. Cadolinium-enhanced MRI from patient with NF-2 showing bilateral vestibular schwannomas (large arrows) and meningioma (small arrow).

vestibular schwannoma should be followed up with MRI, which can also be offered during adolescence and early adult life even in the absence of signs or symptoms because early detection of vestibular schwannoma can help in following the lesion and providing genetic counseling. The standard treatment of vestibular schwannoma is surgery. Small tumors usually are observed without treatment until definite growth or progressive symptoms occur; early surgery may not prevent later symptoms because vestibular schwannomas tend to be multifocal and therefore can regrow after surgery. Major complications related to these tumors include hearing loss and facial nerve damage. Some centers have advocated stereotactic radiosurgery, but it is not clear that the outcome of treatment with this method is different from that of conventional surgery. Spinal schwannomas can lead to nerve root compression or spinal cord compression. It is important to look for these tumors in a person with NF-2 about to undergo surgery for vestibular schwannoma because intraoperative cervical hyperextension can be dangerous in a person with a cervical schwannoma. Treatment of these tumors, and of meningiomas, is surgical. Malignant tumors are rare in NF-2, and nontumor manifestations are likewise uncommon. Canatlc Counseling

NF-2 is transmitted as a dominant trait, like NF-1. Because most of the manifestationsof NF-2 are later in onset, however, it is often difficult to establish the diagnosis in at-risk children. These children are best followed clinically as though affected unless genetic testing can be used to determine that they are not at risk. Currently, genetic linkage analysis can be offered in families with at least two generations of affected people. The NF-2 gene has been

SUGGESTED READINGS DeBella K, Szudek J, Friedman J M Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 105(3 Pt 1):608, 2000 DiMario FJ Jr, Ramsby G, Greenstein R et ak Neurofibromatosis type 1: magnetic resonance imaging findings. J Child Neurol8:32, 1993 Evans DG, Trueman L, Wallace A et ak Genotypelphenotypecorrelations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet 35:450, 1998 Evans DGR, Huson SM, Donnai D et ak A clinical study of type 2 neurofibromatosis. QJM 84603, 1992 Evans DG, Ramsden R, Huson SM et ak Type 2 neurofibromatosis: the need for supraregional care? J Laryngol Otol 102401, 1993 Friedman JF, Gutmann DH, MacCollin M Neurofibromatosis:Phenotype, Natural History and Pathogenesis. 3rd Ed. Johns Hopkins University Press, Baltimore, 1999 Gutmann DH, Aylsworth A, Carey JL et ak The diagnostic evaluation and multidisciplinarymanagement of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51, 1997 Hofman KJ, Harris EL, Bryan RN, Denckla M B Neurofibromatosistype 1: the cognitive phenotype. J Pediatr 124S1, 1994 Hughes RAC, Huson SM (eds): The Neurofibromatoses.Chapman & Hall, New York, 1994 Huson SM, Harper PS, Compston DAS: Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111:1355, 1988 Korf BR Diagnostic outcome in children with multiple cafk au lait spots. Pediatrics 90:924, 1992 Korf BR, Carrazana E, Holmes GL Patterns of seizures observed in association with neurofibromatosis 1. Epilepsia 34616, 1993 Listernick R, Charrow J, Tomita T et al: Carboplatin therapy for optic pathway tumors in children with neurofibromatosis type-1. J Neurooncol45:185, 1999 MacCollin M, Mautner VF: The diagnosis and management of neurofibromatosis 2 in childhood. Semin Pediatr Neurol 5:243, 1998 Martuza RL, Eldridge R Neurofibromatosis 2. N Engl J Med 318684,1988 Mautner VF, Tatagiba M, Guthoff R et al: Neurofibromatosis 2 in the pediatric age group. Neurosurgery 33:92, 1993

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North KN: Neurofibromatosis 1 in childhood. Semin Pediatr Neurol 5:231, 1998

Stumpf DA, Aksne JF, Annegers JF et al: Neurofibromatosis. Arch Neurol 45:575, 1988

North K, Joy P, YuiUe D et al: Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities. Neurology 44878, 1994

Park VM, Pivnick E K Neurofibromatosis type 1 (NF1): a protein truncation assay yielding identification of mutations in 73% of patients. J Med Genet 35:813, 1998

Trofatter JA, MacCollin MM, Rutter JL et ak A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791, 1993 Viskochil D, White R, Cawthon R The neurofibromatosis type 1 gene. Annu Rev Neurosci 16:183, 1993

167 Ependymomas Joao 0.Siffert Ependymomas are tumors of neuroepithelial tissue that arise from the ependymal or subependymal cells surrounding the ventricles and central canal of the spinal cord. Intracranial ependymomas represent approximately 10% of brain tumors in children and less than 3% of intracranial gliomas diagnosed in adults. The mean age at the time of diagnosis is 5 to 6 years, with approximately 60% of children younger than 5 years of age and 4% older than 15 years of age. Spinal cord ependymomas affect primarily adults and account for approximately 75% of all ependymomas and 30% to 60% of all spinal cord tumors in adults. Approximately one third of spinal cord ependymomas are of the myxopapillary histologic type and arise in the filum terminale region. Spinal cord tumors are discussed in more detail in Chapter 172. Ependymomas localize most commonly to the fourth ventricle, where they may extend through the foramina of Luschka and Magendie as well as superiorly through the cerebral aqueduct and inferiorly toward the cervical spine. One third of intracranial ependymomas are localized above the cerebellar tentorium, involving the lateral and third ventricles, as well as the cerebral parenchyma. In the latter case, ependymomas are thought to originate from ependymal cell rests. SIGNS AND SYMPTOMS The localization of ependymomas in the central nervous system dictates the presenting clinical manifestations. Symptoms may precede tumor diagnosis by several months. Posterior fossa tumors, which often lead to obstructive hydrocephalus and increased intracranial pressure, may present with headaches, vomiting, and diplopia. Papilledema is uniformly present in such cases. Tumor compression or invasion of the brainstem leads to cranial nerve palsies and long tract signs. Compression of the cerebellum or brainstem may cause additional signs such as gait ataxia, limb incoordination, and nystagmus. Tumors extending into the cervical spinal canal may produce neck pain and torticollis as the only clinical manifestations. Cerebral hemisphere tumors may lead to visual field deficits, weakness, hyperreflexia, or seizures. Occasionally, patients with either large supratentorial tumors or tumors that obstruct the foramen of Monro and cause hydrocephalus may also present with signs of increased intracranial pressure. Very young children with longstanding hydrocephalus may present with enlargement of the

head, developmental delay, and irritability as sole clinical manifestations. NEUROIMAGING The neuroimaging appearance of ependymomas reflects their heterogeneous pathologic features. Posterior fossa ependymomas typically appear on computed tomographic scan as heterogeneous, often hyperintense, well-circumscribed fourth ventricular masses, commonly associated with hydrocephalus. Supratentorial tumors usually are situated in periventricular regions but may extend into adjacent cerebral parenchyma. In both locations, contrast enhancement is heterogeneous. Cyst formation and calcifications are common. Magnetic resonance imaging (MRI) scans also demonstrate diverse signal intensities, with heterogeneous gadolinium enhancement. In certain cases, the extension of ependymomas through the fourth ventricular foramina, in association with gadolinium enhancement, allows neuroimaging differentiation from medulloblastomas and cerebellar astrocytomas (Fig. 167- 1). Given the potential for subarachnoid tumor dissemination, the initial investigation of patients with ependymoma should also include enhanced spinal MRI scan and cerebrospinal fluid (CSF) cytologic analysis. PATHOLOGY The macroscopic appearance of ependymomas demonstrates solid tumor areas that may contain areas with cysts, necrosis, edema, calcification, or hemorrhage. Microscopically, typical ependymomas consist predominantly of neoplastic ependymal cells that exhibit histologic patterns such as perivascular pseudorosettes and less often the pathognomonic ependymal rosettes (Fig. 167-2). Occasional mitoses, nuclear atypia, and rare foci of necrosis may be seen and are not necessarily indicative of aggressive behavior. haplastic ependymomas, in contrast, are characterized by the presence of significant cellular pleomorphism, necrosis, increased cellularity, frequent mitoses, multinucleation, and giant cells. Most often, anaplastic ependymomas are found in the cerebral hemispheres or in very young children. Nests of ependymal cells in a dense glial fibrillary matrix form subependymomas, another category of ependymal tumors. They are usually found in tissue surrounding the fourth ventricle,

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North KN: Neurofibromatosis 1 in childhood. Semin Pediatr Neurol 5:231, 1998

Stumpf DA, Aksne JF, Annegers JF et al: Neurofibromatosis. Arch Neurol 45:575, 1988

North K, Joy P, YuiUe D et al: Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities. Neurology 44878, 1994

Park VM, Pivnick E K Neurofibromatosis type 1 (NF1): a protein truncation assay yielding identification of mutations in 73% of patients. J Med Genet 35:813, 1998

Trofatter JA, MacCollin MM, Rutter JL et ak A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791, 1993 Viskochil D, White R, Cawthon R The neurofibromatosis type 1 gene. Annu Rev Neurosci 16:183, 1993

167 Ependymomas Joao 0.Siffert Ependymomas are tumors of neuroepithelial tissue that arise from the ependymal or subependymal cells surrounding the ventricles and central canal of the spinal cord. Intracranial ependymomas represent approximately 10% of brain tumors in children and less than 3% of intracranial gliomas diagnosed in adults. The mean age at the time of diagnosis is 5 to 6 years, with approximately 60% of children younger than 5 years of age and 4% older than 15 years of age. Spinal cord ependymomas affect primarily adults and account for approximately 75% of all ependymomas and 30% to 60% of all spinal cord tumors in adults. Approximately one third of spinal cord ependymomas are of the myxopapillary histologic type and arise in the filum terminale region. Spinal cord tumors are discussed in more detail in Chapter 172. Ependymomas localize most commonly to the fourth ventricle, where they may extend through the foramina of Luschka and Magendie as well as superiorly through the cerebral aqueduct and inferiorly toward the cervical spine. One third of intracranial ependymomas are localized above the cerebellar tentorium, involving the lateral and third ventricles, as well as the cerebral parenchyma. In the latter case, ependymomas are thought to originate from ependymal cell rests. SIGNS AND SYMPTOMS The localization of ependymomas in the central nervous system dictates the presenting clinical manifestations. Symptoms may precede tumor diagnosis by several months. Posterior fossa tumors, which often lead to obstructive hydrocephalus and increased intracranial pressure, may present with headaches, vomiting, and diplopia. Papilledema is uniformly present in such cases. Tumor compression or invasion of the brainstem leads to cranial nerve palsies and long tract signs. Compression of the cerebellum or brainstem may cause additional signs such as gait ataxia, limb incoordination, and nystagmus. Tumors extending into the cervical spinal canal may produce neck pain and torticollis as the only clinical manifestations. Cerebral hemisphere tumors may lead to visual field deficits, weakness, hyperreflexia, or seizures. Occasionally, patients with either large supratentorial tumors or tumors that obstruct the foramen of Monro and cause hydrocephalus may also present with signs of increased intracranial pressure. Very young children with longstanding hydrocephalus may present with enlargement of the

head, developmental delay, and irritability as sole clinical manifestations. NEUROIMAGING The neuroimaging appearance of ependymomas reflects their heterogeneous pathologic features. Posterior fossa ependymomas typically appear on computed tomographic scan as heterogeneous, often hyperintense, well-circumscribed fourth ventricular masses, commonly associated with hydrocephalus. Supratentorial tumors usually are situated in periventricular regions but may extend into adjacent cerebral parenchyma. In both locations, contrast enhancement is heterogeneous. Cyst formation and calcifications are common. Magnetic resonance imaging (MRI) scans also demonstrate diverse signal intensities, with heterogeneous gadolinium enhancement. In certain cases, the extension of ependymomas through the fourth ventricular foramina, in association with gadolinium enhancement, allows neuroimaging differentiation from medulloblastomas and cerebellar astrocytomas (Fig. 167- 1). Given the potential for subarachnoid tumor dissemination, the initial investigation of patients with ependymoma should also include enhanced spinal MRI scan and cerebrospinal fluid (CSF) cytologic analysis. PATHOLOGY The macroscopic appearance of ependymomas demonstrates solid tumor areas that may contain areas with cysts, necrosis, edema, calcification, or hemorrhage. Microscopically, typical ependymomas consist predominantly of neoplastic ependymal cells that exhibit histologic patterns such as perivascular pseudorosettes and less often the pathognomonic ependymal rosettes (Fig. 167-2). Occasional mitoses, nuclear atypia, and rare foci of necrosis may be seen and are not necessarily indicative of aggressive behavior. haplastic ependymomas, in contrast, are characterized by the presence of significant cellular pleomorphism, necrosis, increased cellularity, frequent mitoses, multinucleation, and giant cells. Most often, anaplastic ependymomas are found in the cerebral hemispheres or in very young children. Nests of ependymal cells in a dense glial fibrillary matrix form subependymomas, another category of ependymal tumors. They are usually found in tissue surrounding the fourth ventricle,

Chapter 167

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Ependymomas

A

B

FIG. 167-1. Four-year-old girl with headaches and ataxia. (A) Sagittal Tl-weighted MRI scan after gadolinium injection shows minor and irregular enhancement of the fourth ventricular ependymoma (arrow). Note extension of the tumor through the foramen magnum. (B) Axial proton-density MRI scan shows the tumor as a hyperintense mass (usterisk) surrounded by the hypointense CSF within the dilated fourth ventricle. (From Wolpert 5, Barnes PD: MRI in Pediatric Neuroradiology. Mosby, St Louis, 1992, with permission.)

A

~~

~-

FIG. 167-2. (A & B) Histologic features of ependymoma. The figure shows essentially monomorphic neoplastic ependymal cells within a fibrillary background, periiascular pseudorosettes (open arrows), and ependymal rosettes (solid arrows).

B

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occasionally appearing in multiple foci. These tumors tend to have a benign, often asymptomatic course. THERAPY

Surgical resection and radiation therapy are mainstays of treatment for ependymomas. A gross total resection of intracranial ependymomas has been associated with higher survival rates and is the recommended initial treatment. External beam radiation therapy is used as adjuvant treatment after both gross total and partial surgical resections. However, there are two exceptions to the standard of care. Radiotherapy may be deferred in selected patients with completely removed (confirmed by postoperative MRI) “nonanaplastic” supratentorial ependymoma. Patients with spinal cord ependymomas can be cured with a radical surgical removal, and radiotherapy is reserved for the rare cases of recurrence (less than 3%). Patients with disseminated neuraxis disease at the time of diagnosis are treated with full craniospinal radiation. In contrast, patients with low-grade nondisseminated tumors receive involved field radiation only. The use of involved field radiation for patients with nondisseminated disease is based on the observations that tumor recurrence happens typically in the original tumor site. The volume of radiation used for patients with anaplastic nondisseminated tumors is controversial. Those who favor full craniospinal radiation argue that anaplastic tumors are more likely to have CSF pathway dissemination. On the other hand, craniospinal radiation has long-term neurocognitive and endocrine sequelae. When delivered under conventional regimens, total radiation dosages to the original tumor bed greater than 4500 cGy and generally between 5000 and 5500 cGy are thought to be associated with improved outcome. Current three-dimensional and stereotactic planning techniques are more accurate and spare adjacent tissues from unnecessary radiation. The specific role of chemotherapy in treating ependymomas has not been established. Response to chemotherapy in recurrent ependymoma is less than 15%. Cisplatin, etoposide, nitrosourea, and multiple single-agent and multiagent chemotherapy regimens have been tried over the past 20 years. Currently, chemotherapy is used in patients with recurrent ependymoma or in infants in whom radiation is deferred. Given the poor track record of chemotherapy, however, several clinical trials are currently exploring the use of conformal radiotherapy in children older than 1 year.

Adults have longer survival than children. The overall 5-year survival rate in children with ependymomas ranges from 28% to 58% according to different series reported. Factors associated with worse prognosis include young age at presentation (less than 3 years) and subtotal surgical resection, as measured by postoperative enhanced MRI scan. Anaplastic features, particularly large numbers of mitoses and high cellularity, seem to predict a worse prognosis in both children and adults. Recurrence at the primary tumor site constitutes the main pattern of failure, irrespective of pathology, localization, therapy, and age of presentation. Conversely, myxopapillary ependymomas of the spinal cord, although histologically benign, tend to

disseminate in approximately 15% to 20% of patients. Extraneural metastases occur rarely. Local disease control still remains the most important therapeutic goal in attempts to improve survival of patients with ependymomas. SUGGESTED READINGS Allen JC, Siffert J, Hukin J: Clinical manifestations of childhood ependymoma: a multitude of syndromes. Pediatr Neurosurg 28( 1):4955, 1998

Chou PM, Sanz CR, Tomita T, Reyes-Mugica M: Ependymomas in children express the multidrug resistance gene: immunohistochemical and molecular biologic study. Pediatr Pathol Lab Med 16:551-561, 1996

Cohen ME, Duffner PK Brain Tumors in Children. Principles of Diagnosis and Treatment. 2nd Ed. Raven Press, New York, 1994 Constantini S, Allen J C Pediatric and adult primary spinal cord tumors. pp. 658-669. In Black P, Loeffler J (eds): Cancer of the Nervous System. Blackwell Scientific, Cambridge, 1997 Geyer J, Zeltzer P, Boyett JM et al: Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Children’s Cancer Group. J Clin Oncol 12:1607-1615, 1994 Goldwein J, Corn B, Finlay J, Packer R Is craniospinal irradiation required to cure children with malignant (anaplastic) intracranial ependymomas? Cancer 67:276&2771, 1991 Graham ML, Herndon JE 11, Casey JR et al: High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. J Clin Oncol 15(5):1814-1823, 1997 Healey E, Barnes P, Kupsky W, Scott R The prognostic significance of postoperative residual tumors in ependymoma. Neurosurgery 28:666672, 1991

Hukin J, Epstein F, Lefton D, Allen J: Treatment of intracrand ependymoma by surgery alone. Pediatr Neurosurg 29:40-45, 1998 Kleihues P, Burger PC, Scheithauer BW et ak WHO International Histological Classification of Tumors. Histological Typing of Tumors of the Central Nervous System. 2nd Ed. Springer-Verlag, New York, 1994

Kovalic J, Flaris N, Grigsby PW et al: Intracranial ependymoma: long term outcome, patterns of failure. J Neurooncol 15:125-131, 1993 Mork S, Lokn A Ependymoma. A follow-up study of 101 cases. Cancer 40~907-915, 1977

Needle M, Goldwein J, Grass J et ak Improved relapse-free survival in incompletely excised childhood ependymoma with hyperfractionated radiotherapy (HFRT) followed by carboplatin (CBDCA), vincristine (VCR), ifosfamide (IFOS) and etoposide (ETP) chemotherapy. Sixth International Symposium on Pediatric Neuro-Oncology 199479 Robertson PL, Zeltzer PM, Boyett JM et al: Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: a report of the Children’s Cancer Group. J Neurosurg 88(4):695-703, 1998

Russell DS, Rubinstein LJ: Pathology of Tumors of the Nervous System. 5th Ed. Williams & Wilkins, Baltimore, 1989 Salazar OM, Castro-Vita H, Vanhoutte P, Rubin PCN Improved survival in cases of intracranial ependymoma after radiation therapy: late report and recommendations. J Neurosurg 59652459, 1983 Schiffer D, Chi0 A, Cravioto H: Ependymoma: internal correlations among pathological signs. The anaplastic variant. Neurosurgery 29206-210, 1991

Siffert J, Allen J C Chemotherapy in recurrent ependymoma. Pediatr Neurosurg 28(6):314-319, 1998 Sutton L, Goldwein G, Perilongo G et al: Prognostic factors in childhood ependymomas. Pediatr Neurosurg 1 6 5 7 4 5 , 1990-1991 Wolpert S, Barnes PD: MRI in Pediatric Neuroradiology.Mosby, St Louis, 1992

Chapter 168 rn Medulloblastornas

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168 Medulloblastornas Scott L. Pomeroy

Medulloblastomas, the most common malignant brain tumors of childhood, account for approximately 20% of all primary tumors of the central nervous system in children (incidence 0.5:100,000). The tumors arise within the cerebellum and have a nearly 21 male predominance. They are most common in children 5 to 9 years old, with approximately 70% of patients diagnosed before age 20. A smaller incidence peak occurs between ages 20 and 24. The disease is rare after the fourth decade. Bailey and Cushing first described medulloblastomas, hypothesizing that they arise from primitive cells in the developing cerebellum. Recent investigations support their embryonal origin, indicating that most medulloblastomas probably arise from cerebellar granule cell progenitors. More than 90% of patients with the tumors have no known predisposing condition. About 5% of patients have congenital anomalies or inherited genetic syndromes. The most common of these is the basal cell nevus (Gorlin) syndrome, caused by germ line mutation of the gene encoding the Sonic hedgehog receptor PTCH. Medulloblastomas also arise in patients with Turcot’s syndrome, cause by germ line mutation of the adenomatous polyposis coli (APC) gene. Rarely, they occur in patients with ataxia-telangiectasia, xeroderma pigmentosum, or Li-Fraumeni syndrome. For most patients, however, the tumors arise from apparently spontaneous gene mutations within the tumor cells. No environmental influences have been proved to date.

this occurs quite infrequently, radionucleotide bone scanning or bone marrow aspirates must be performed only if pain suggests bony metastasis.

PATHOLOGY At surgery, medulloblastomas are soft and friable, at times with foci of necrosis. Histologidy, they are highly cellular tumors with abundant dark-staining round or oval nuclei and scant, undifferentiated cytoplasm typical of “small round blue cell tumors.” Mitoses and apoptotic cells are abundant. Neuroblastic Homer Wright rosettes can be found in up to 40% of cases. Immunohistochemical analysis demonstrates neuronal markers, including synaptophysin and neuroflament proteins, in the majority of cases. A granule cell-specific transcription factor, Zic, is expressed by a high percentage of medulloblastomas consistent with their granule cell origin, and TrkC, associated with highly differentiated granule cells, is expressed by medulloblastomas with favorable prognosis. Markers of glial lineage, such as glial fibrillary acidic protein, are found less commonly. The desmoplastic variant of medulloblastoma, with dense extracellular matrix between “pale island” nodules as the principal cytoarchitecture, has been associated with a better prognosis.

THERAPY CLINICAL PRESENTATION Medulloblastomasmost commonly present with signs of increased intracranial pressure, which include nocturnal or morning headache, nausea, vomiting, dysfunction of cranial nerve VI with attendant paresis of the lateral rectus muscles causing diplopia, and altered mental status. Approximately three fourths of the tumors arise in the deep cerebellar midline, often within the vermis. One fourth occur in the cerebellar hemispheres, more commonly in adults than children. Because of this l o a h t i o n , truncal ataxia, titubation of the head, and unsteady gait often accompany signs of elevated intracranial pressure. At initial presentation, magnetic resonance imaging (MRI)or computed tomography reveals a contrast-enhancing midline or, occasionally, paramedian tumor, which often distorts or obliterates the fourth ventricle. The enhancement may be heterogeneous, with regions of necrosis, hemorrhage, or cystic changes. Tumor margins often are indistinct because of invasion of the cerebellum or its peduncles or, less often, the brainstem. Because medulloblastoma has a strong tendency to metastasize throughout the central nervous system, contrast-enhanced MRI scanning of the entire neuraxis, including the spine, should always be performed once the diagnosis is established. An example is shown in Figure 168-1. For all patients, the cerebrospinalfluid should be examined for tumor cells by cytologic examination of spinal fluid obtained by lumbar puncture. The tumor less commonly metastasizes outside the nervous system, most often to bone marrow. Because

The first step in treating medulloblastomas is surgical resection to establish diagnosis, relieve mass effect and hydrocephalus, and reduce tumor burden. Gross total surgical removal of tumors that have not infiltrated vital regions such as the brainstem and that are not metastatic at the time of the initial diagnosis has been shown in several clinical studies to improve outcome. Therefore, the goal of surgery should be to remove as much of the tumor as can be accomplished without inflicting incapacitating neurologic deficits such as persistent ataxia or cranial nerve deficits. A disorder of language production has been found to occur after surgery to the midline cerebellum. It is characterized by mutism in association with emotional lability. The most severely affected patients also have varying degrees of inattention and difficulty initiating movements as well as language. These symptoms often resolve over the course of weeks to months, although some patients may not fully recover language skills. Clinical staging is based on amount of residual disease at the primary tumor site and whether there is evidence of metastatic disease. For current treatment protocols in the Children’s Oncology Group, poor risk factors include residual disease greater than 1.5 cm’, the presence of metastases detected by contrast-enhanced MRI scanning, and the presence of malignant cells in cerebrospinal fluid obtained by lumbar puncture. External beam radiation therapy of the cranium and spine, with increased radiation dosage to the tumor site, is the second mode of therapy that has been determined to be effective for medulloblastoma. Current practice standards recommend radia-

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B

A

D

C

FIG. 168-1. Magnetic resonance imaging scans of a 2-year-old boy with the basal cell nevus syndrome and medulloblastoma. (A) A large midline mass (arrows) is evident in this transverse section through the posterior fossa taken without contrast enhancement (B) Enhancement is evident after an intravenous injection of contrast dye. (C & 0) Although no evidence of metastasis was found at the initial diagnosis, 5 months later the patient had multiple enhancing nodules (arrows) in the cerebral hemispheres and in the spinal canal.

Chapter 168

tion dosages of 5400 cGy to the posterior fossa and 3600 cGy applied to the remainder of the cranium and the spine of all high-risk patients. If it can be done without damaging vital neural structures, many centers also include a stereotactic radiosurgery boost to any residual nodules in the original tumor bed. For standard-risk tumors, the current national treatment protocol has decreased the radiation craniospinal dosage to 2400 cGy. Standard-risk protocols in development for the near future may incorporate even lower craniospinal radiation dosages (1800 cGy) and limited radiation fields within the posterior fossa designed to reduce the radiation dosage to the inner ears and the temporal and occipital lobes of the cerebral hemispheres. High-dose multiagent chemotherapy has been accepted as the national standard of care for the treatment of medulloblastomas. The most commonly used agents include lomustine, cyclophosphamide, cisplatin, etoposide, and vincristine. For very young children and babies, chemotherapy has been used to delay radiation, especially of the craniospinal axis, until the child is 3 years old. This approach was developed based on a growing consensus that deleterious effects of radiation on neurocognitive function are most pronounced when the treatment is given during the first 3 years of life. It is too early to know whether the substitution of chemotherapy during these years will have less severe effects on cognitive function. Moreover, a higher incidence of secondary tumors has been documented in children who have survived medulloblastoma chemotherapy treatment as babies. Unfortunately, the prognosis of babies and young children with medulloblastomas remains quite poor. Protocols under development may combine high-dose rnultiagent chemotherapy with full-dose fractionated radiation to the tumor bed only. OUTCOME

The outlook for medulloblastomas has improved significantly in the past 20 to 30 years. Although this may be accounted for, in part, by improvements in neurosurgical technique, increased radiation dosages have had the greatest role in increasing survival rates. Chemotherapyhas added further benefit, allowing reduction of the craniospinal radiation dosage in standard-risk patients as an attempt to improve the morbidity of treatment. Whereas 20% to 50% of patients survived 5 years after diagnosis in the 1960%the 5-year survival rates for children older than 3 years today ranges from 60% to 80%. Babies with medulloblastoma have a poor prognosis, with survival rates of 30% to 40%.

SEQUELAE Although mortality rates have dropped significantly for medulloblastomas, essentially all survivors have life-altering sequelae. The incidence of learning disabilities is very high, and focal neurologic signs, including fine and gross motor deficits, cranial nerve abnormalities, and sensorineural hearing loss often necessitating hearing aids, have been identified in more than 50% of survivors. Hearing loss can continue to progress even 10 years after treatment. Decline of cognitive function has been documented by several groups. Intellectual function loss is highly associated with young age, with decline of up to 50 IQ points documented in some children who have been treated with craniospinal radiation before age 3 years. Cataracts often result from radiation exposure of the eyes. Endocrine abnormalities, especially deficiencies of thyroid and growth hormones, occur in more than 70% of survivors. Several studies have documented that only a minority of survivors

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are fully employed and living independently as a consequence of these many sequelae. SUGGESTED READINGS Bailey P, Cushing H Medulloblastoma cerebelli: a common type of midcerebellar glioma of childhood. Am Neurol Psychiatry 14192,1925 Bergsma D Birth Defects Compendium. Alan R Liss, New York, 1973 Berry MP, Jenkin RD, Colin MB et ak Radiation treatment for medulloblastoma: a 21-year review. J Neurosurg 55:43, 1981 Bloom HGJ, Wallace ENK, He& J M The treatment and prognosis of medulloblastoma in children: a study of 82 verified cases. Am J Roentgen01 10543, 1969 a h e n ME, Duffner PK Brain Tumors in Children. Raven Press, New

York, 1994 Dufher PK, Horowitz ME, Krischer JP et ak Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725, 1993 Dufher PK, Horowitz ME, Krischer JP et ak Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study. Ann NeurolM313, 1998 Evans AE, Jenkin RDT, Sposto R et ak The treatment of medulloblastoma. J Neurosurg 72:572, 1990 Evans G, Burnell L, Campbell R et al: Congenital anomalies and genetic syndromes in 173 cases of medulloblastoma. Med Pediatr Oncol 21:433, 1993

Friede RL: Developmental Neuropathology. Springer-Verlag, Berlin, 1989 Heikens J, Michiels EM, Behrendt H et ak Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma. Eur J Cancer 341592, 1998

Hughes EN, Shillito J, Sallan SE et ak Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. The influence of radiation dose on the pattern of failure and survival. Cancer 61:1992, 1988

Jenkin D, Danjouz C, Gremberg M Subsequent quality of life for children irradiated for a brain tumor before age four years. Med Pediatr Oncol 31:506, 1998

Kadin ME, Rubenstein LJ, Nelson JS: Neonatal cerebellar medulloblastoma originating from the fetal external granular layer. J Neuropathol F q Neurol29583, 1970

Kleihues P, Burger PC, Scheithauer BW Histological Trping of Tumours of the Central Nervous System. Springer-Verlag, Berlin, 1993 Kopelson G, Linggood RM, Kleinman GM: Medulloblastoma in adults: improved survival with supervoltage radiation therapy. Cancer 51: 1334, 1982

Packer RJ, Sutton LN, Elterman R et ak Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:690, 1994 Raimondi AJ, Tomita T: Medulloblastoma in childhood. Acta Neurochir 50127, 1979

Rekate HL, Grubb RL, Aram DM et ak Muteness of cerebellarorigin. Arch Neurol42:607, 1985

Russell DS, Rubenstein L) Pathology of Tumors of the Nervous System. Williams & Willcins, Baltimore, 1989 Siffert J, Young-PoussaintT, Goumnerova LC et ak Neurological dysfunction associated with postoperative cerebellar mutism. J Neurooncol 48:75-81, 2000

Tarbell NJ, Loeffler JS, Silver B et ak The change in patterns of relapse in medulloblastoma. Cancer 681600, 1991 Walter AW, Mulhern RK, Gajjar A et ak SuMval and neurodevelopmental outcome of young children with medulloblastoma at St. Jude Children’s Research Hospital. J Clin Oncol 123720, 1999 Wisoff JH, Epstein FJ: Pseudobulbar palsy after posterior fossa operation in children. Neurosurgery 15707, 1984 Wolpert SM, Bames P D MRI in Pediatric Neuroradiology. Mosby, St Louis, 1992

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169 Pineal Tumors Walter A. Hall and Dennis Y. Wen

Pineal region tumors are rare and account for up to 1% of adult brain tumors and up to 10% of pediatric brain tumors. The incidence of these tumors is higher in Asia, where pineal tumors account for at least 2% of all primary intracranial tumors. In children, pineal tumors are two to three times more common in males than in females, and approximately two thirds present in the second decade of life. PATHOLOGY More than half of pineal region tumors are derived from germ cells, and 14% to 30% are of pineal parenchymal origin (pineocytoma and pineoblastoma). The other lesions that arise in the pineal region include tumors such as astrocytomas, ependymomas, metastatic tumors, meningiomas, and choroid plexus papillomas; vascular malformations; and benign entities such as lipomas, pineal cysts, and arachnoid cysts (Table 169-1). Intracranial germ cell tumors arise from developmental nests of primitive totipotential germ cells and are indistinguishable histologically from tumors that occur in the gonads of young adults. Germinomas account for almost two thirds of pineal region germ cell tumors, with teratomas being one third as common (Fig. 169- 1). Malignant choriocarcinomas,endodermal sinus (yolk sac) tumors, and embryonal carcinomas are one third as common teratomas. Germ cell tumors often have a mixed histologic pattern, making it difficult to establish a definitive diagnosis based on either neuroimaging or the analysis of a small tissue sample (Fig. 169-2). Tumor dissemination in the cerebrospinal fluid (CSF) may occur, but systemic metastasis is uncommon without prior surgical intervention.

TABU169-1. Tumors of the Pineal Region Tumors of germ cell origin Cerminoma Teratoma Dermoid Choriocarcinoma Embryonal carcinoma Endodermal sinus (yolk sac) tumor Tumors of pineal parenchymal origin Pineocytoma Pineoblastoma Tumors of support cells and adjacent structures Astrocytoma Ependymoma Choroid plexus papilloma Meningioma Nonneoplastic cystic and vascular Iesions Pineal cyst Arachnoid cyst Arteriovenous malformation Vein of Calen aneurysm Cavernous malformation

PRESENTING SYMPTOMS Pineal region tumors can present with a variety of symptoms. The deep location of these tumors above the midbrain and their proximity to the CSF pathways can result in some characteristic syndrome complexes. Many patients present with a headache or mental and visual disturbances that can make it difficult to diagnose a pineal region lesion without some form of a neuroimaging study. A detailed neurologic examination should alert the clinician to the possibility of pathology in the pineal region.

Increased lntracranial Pressure Noncommunicating hydrocephalus will occur with obstruction of the aqueduct of Sylvius or with tumor extension into the posterior third ventricle, preventing CSF flow distally. Headaches, lethargy, changes in mental status, nausea, and emesis may result in the presence of CSF blockage. False localizing signs such as a sixth cranial nerve (abducens) palsy with diplopia may develop and papilledema may be present on neurologic examination. Local Mass Effect

Pressure on the tectum of the midbrain, lying inferior to the pineal gland, can cause Parinaud syndrome. Failure of upward gaze is almost invariably present, but the other components of the syndrome such as loss of convergence, pupillary abnormalities, and refractory nystagmus may also be apparent. The oculomotor (third cranial) nerve nucleus may be directly affected, resulting in double vision, and hyperacusis from disturbance of the inferior colliculus can occur with very large lesions. With continued enlargement of the tumor, vertigo and ataxia may develop because of disruption of corticocerebellarpathways, and short-term memory deficits can result from mammillothalamic tract interruption.

InfiltrationSurrounding Structures The more malignant pineal region tumors may infiltrate the adjacent thalamus and cause sensory changes on one side of the body. Continued lateral infiltration into the brain may affect the internal capsule and cause paresis, plegia, and even visual field abnormalities. With hypothalamic infiltration, diabetes insipidus, temperature regulation abnormalities, weight gain, somnolence, and precocious puberty may result. Unilateral thalamic involvement can cause contralateral sensory or motor deficits, with bilateral infiltration causing bilateral symptoms. DIAGNOSTIC STUDIES Neuroimadng The advent of computed tomography (CT) and more recently magnetic resonance imaging (MRI) has allowed clinicians to diagnosis pineal region tumors much more confidently. Skull films usually are unremarkable unless chronic intracranial hypertension

Chapter 169

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B

A

FIG. 169-1. (A) Coronal contrast-enhanced MRI of a 22-year-old man with an enhancing pineal region tumor and associated hydrocephalus. (B) Patient underwent ventricular shunting and radiation therapy with complete resolution of a stereotactic biopsy-proven germinoma. Note the normal ventricular size and disappearance of the enhancing mass after successful treatment.

or a large (more than 1 cm) calcified pineal mass is present. Pineal calcification in a child less than 10 years of age is highly suspicious for a tumor. Although CT demonstrates most lesions, the multiplanar imaging capabilities and the superior soft tissue differentiation

FIG. 169-2. Axial contrast-enhanced CT of a mixed germ cell tumor in the pineal region in a young female patient with marked ventriculomegaly from obstructive hydrocephalus.

afforded by MRI makes this diagnostic modality the test of choice for pineal region lesions. MRI should be obtained with and without intravenous contrast administration. The signal characteristics present with different tissue types may help the neuroradiologist differentiate between teratomas, lipomas, dermoid tumors, and epidermoid tumors. Teratomas contain a mixture of fat, soft tissue, and calcification (present in teeth) compared with lipomas, which have low density on CT and have an increased signal on T1-weighted MRI. On MRI, dermoid tumors possess fat and inhomogeneous areas from dermal structures compared with epidermoid tumors, which can have calcification in the wall of the mass and intracystic material with signal characteristics similar to those of CSF. Germ cell tumors tend to have marked homogeneous enhancement after contrast administration. Tumor infiltration into surrounding structures and tumor dissemination throughout the CSF pathways is well demonstrated on MRI. In evaluating the spinal neuraxis for evidence of tumor spread, usually seen with pineoblastoma, an enhanced spinal MRI is gradually replacing myelography and postmyelography CT. Before considering myelography, it is essential that the presence of CSF blockage be excluded to prevent a postlumbar puncture herniation syndrome. If CSF tumor dissemination is suspected, spinal MFU with gadolinium should be considered and performed before surgical intervention. Cerebral angiography may be necessary to diagnose a vascular lesion in the pineal region such as a vein of Galen aneurysm or arteriovenous malformation. Occasionally, cerebral angiography is necessary to plan the optimal surgical approach to the pineal region lesion. Magnetic resonance angiography may eventually replace conventional angiography for preoperative surgical planning.

Cembrosplnal Fluid Cytology The close proximity of pineal region tumors to the ventricular system may lead to leptomeningeal seeding with the development

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rn TABLE169-1. Tumor Markers Associated with Pineal Tumors Tumor Histolow Cerrninoma Endodermal sinus (yolk sac) tumor Embryonal cell tumor Choriocarcinoma Teratoma

TREATMENT

AFP

6-HCG

PLAP

-

f f

+ f +

-

f f

+ f

-

+

Abbreviations: AFP, a-fetoprotein;p-HCG, &human chorionic gonadotrophin; PLAP, placental alkaline phosphatase.

of symptoms of nerve root or spinal cord compression. Whereas less than 10% of all pineal region tumors seed the subarachnoid space, up to one third of pineoblastomas and nongerminomatous germ cell tumors have been estimated to spread in the CSF. CSF dissemination is associated with a poor prognosis. Analysis of the CSF for tumor cells may be useful in the initial evaluation of a patient for both staging the disease and possibly obtaining a cytologic diagnosis. The diagnostic yield from lumbar CSF cytologic examination is greater than from CSF obtained from the lateral ventricles, either by direct puncture or from obtaining CSF through an already existing ventriculoperitoneal shunt. As previously noted, lumbar puncture is contraindicated in patients with obstructive hydrocephalus to avoid cerebral herniation. However, if CSF is collected it should be analyzed cytologically and for tumor cell markers. CSF obtained after a surgical procedure can result in a false-positive cytologic examination; therefore, CSF should be obtained before surgery if it can be done safely.

Tumor Markers Pineal region tumors of germ cell origin may produce a variety of oncofetal antigens. a-Fetoprotein (AFP) is a glycoprotein normally produced in the yolk sac, fetal liver, or gastrointestinal tract. Tumors derived from yolk sac elements such as endodermal sinus tumors and embryonal carcinomas may produce AFP that can be detected in the serum, in CSF, and on immunohistochemical staining of surgical tissue samples (Table 169-2). Undifferentiated germ cell tumors and malignant teratomas may also express AFP. P-Human chorionic gonadotrophin (P-HCG) is secreted by trophoblastic epithelium of the placenta. P-HCG is expressed in choriocarcinoma and embryonal carcinoma and may be present in other undifferentiated germ cell tumors or malignant teratomas. Pure germinomas rarely secrete any markers, although P-HCG has been detected in up to 10% of germinomas. Placental alkaline phosphatase is a nondiagnostic marker associated with germinomas. Approximately 15% to 20% of pineal tumors secrete markers, and it is unclear whether CSF or serum marker levels are more sensitive for diagnosing a specific type of pineal region tumor. The frequency of mixed histologic types in germ cell tumors of up to 40% makes the use of tumor markers for diagnostic purposes problematic. However, the presence of AFP alone supports the diagnosis of a nongerminomatous tumor. A positive or negative P-HCG level in the blood or CSF does not help direct therapy. The main value of these tumor markers is to determine the effect of therapeutic interventions and to help detect the presence of tumor recurrence. In patients with a pineal region tumor that produces tumor markers, an elevated CSF-to-blood ratio level or another pathologic process, associated with elevated serum AFP and P-HCG levels, should be considered.

suwry For many years, surgery for lesions of the pineal region was associated with considerable neurologic morbidity and mortality. Before 1970, many neurosurgeons recommended treatment of the associated hydrocephalus with ventricular diversion and radiotherapy for the pineal lesion, often without a tissue diagnosis. Advances in microneurosurgical techniques, neuroanesthesia, and neuroimaging in the last three decades have made such an approach unreasonable. In patients with pineal region tumors and associated hydrocephalus, CSF diversion should be performed and a tissue sample obtained for histologic diagnosis and to guide subsequent treatment. The presence of tumor spread into surrounding local neural structures or through the CSF pathways should be determined by suitable imaging studies and by CSF examination, whenever possible (Fig. 169-3). Hydrocephalus may be treated by temporary external ventricular drainage if definitive tumor resection with reestablishment of CSF flow is planned or by permanent ventricular diversion if complete tumor resection with restoration of CSF flow is not possible. There is a potential for systemic tumor dissemination with CSF diversion. With the development of neuroendoscopy, performing a third ventriculostomy has become an accepted procedure for relieving noncommunicating hydrocephalus. It is often possible to biopsy a pineal region mass at the time that the third ventriculostomy is being performed, thereby establishing a diagnosis and relieving hydrocephalus in one single operative procedure. Histopathologic diagnosis may be obtained by either percutaneous image-directed stereotactic needle biopsy or by a variety of open surgical approaches to the pineal region. The mixed histology of many pineal tumors (15%) and the small size of tissue samples obtained with a stereotactic biopsy may result in misdiagnosis caused by sampling error or even nondiagnosis. Nevertheless, stereotactic biopsy is a safe and effective diagnostic procedure, and when there is documented tumor dissemination in the CSF, or CSF AFP levels are elevated, it may be the procedure of choice. Open biopsy allows more accurate tissue sampling and more complete tumor resection, particularly if benign pathology is identified (e.g., dermoid, teratoma, cavernous malformation). Resecting malignant tumors that have decreased sensitivity to adjuvant therapies in the absence of disseminated disease is possible but remains controversial. RadiationTherapy Benign tumors should be treated with surgery alone if resection is possible. Radiation therapy has been used diagnostically when a germinoma was suspected. The tumor is given 20 Gy and the response to radiation measured. If the tumor responded to the radiation, the diagnosis of germinoma was confirmed, and additional treatment to a total radiation dosage of 50 to 55 Gy was administered. This approach is no longer used because tissue can be obtained with acceptable morbidity using neuroendoscopy, stereotactic technique, or microsurgery for open biopsy or resection. When patients have already received external beam radiation therapy to the pineal region, new treatment modalities such as stereotactic radiosurgery may allow a way to further boost

Chapter 169 H Pineal Tumors

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Lesion on MRI with contrast

? l Hydrocephalus

I

No

Yes

Lumar puncture

Ventricular

FIG. 169-3. Management plan for pineal region tumors. I

Germinoma Dermoid Teratoma Low grade astrocytoma

23 Follow

radiation

the primary tumor site to control recurrent disease. The role of radiosurgery for the initial treatment of pineal tumors is under investigation. Germinomas, astrocytomas, and pineocytomas that have not disseminated should receive focal irradiation to the primary site alone. Germinomas in particular are very radiosensitive tumors. Craniospinal irradiation is reserved for patients with documented CSF spread or for prophylaxis in patients with high-grade malignant tumors with a propensity to spread in the CSF such as pineoblastomas and nongerminomatous germ cell tumors.

I

I

I

Embryonal cell Choriocarcinoma Pineoblastoma High grade astrocytoma

Craniospinal radiation 5 chemotherapy

?

radiation chemotherapy

The prognosis for pineal region tumors is related to their histology. Benign tumors such as teratomas can be cured with a complete surgical resection. Germinomas respond to radiation therapy with reported 10-year survival rates of 75%. In contrast, nongerminomatous germ cell tumors do not respond well to treatment, with few patients alive at 5 years.

SUMMARY

Chemotherapy The pineal gland has no blood-brain barrier, and chemotherapeutic agents may be useful for treating a variety of pineal region tumors, particularly germ cell tumors. Germinomas respond to the same chemotherapeutic regimens (cisplatin, vinblastine, and bleomycin) that are used for testicular tumors. Recurrent or disseminated germinomas usually respond to chemotherapy, unlike nongerminomatous germ cell tumors, which do not respond as well. Patients with pineoblastomas may also respond to chemotherapy.

Pineal region tumors are rare and may present with nonspecific signs or symptoms. MRI with and without contrast is the neuroimaging procedure of choice for diagnosing pineal region tumors, and preoperative staging should include analysis of CSF for cytology and tumor markers. Tissue diagnosis is essential to guide future therapeutic intervention and can be accomplished safely using neuroendoscopy, stereotaxis, or open surgery. Resection is indicated for benign lesions and may be useful in localized malignant disease. Subsequent radiation therapy or chemotherapy is directed by the tumor histopathology and the presence of disseminated disease.

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SpecificTumor Types

SUGGESTED READINGS Bruce JN, Stein BM: Surgical management of pineal region tumors. Acta Neurochir (Wien) 134130, 1995 Cho BK, Wang KC, Nam DH et al: Pineal tumors: experience with 48 cases over 10 years. Childs New Syst 14:53, 1998 Choi JU, Kim DS, Chung SS et al: Treatment of germ cell tumors in the pineal region. Childs New Syst 14:41, 1998 Ferrer F, Santamarta D, Garcia-Fructuoso G et al: Neuroendoscopic management of pineal region tumors. Acta Neurochir (Wien) 139:12, 1997

Friedman JA, Lynch JJ, Buckner JC et ak Management of malignant pineal germ cell tumors with residual mature teratoma. Neurosurgery 48:518, 200 1

Herrmann HD, Westphal M, Winkler K et al: Treatment of nongermatous germ-cell tumors of the pineal region. Neurosurgery 34:524, 1994 Horowitz MB, Hall WA Central nervous system germinomas. A review. Arch Neurol48:652, 1991 Huh SJ,Shin KH, Kim IH et al: Radiotherapy of intracranial germinomas. Radiother Oncol 38:19, 1996

Kobayashi T, Kida Y, Mori Y: Stereotactic gamma radiosurgery for pineal and related tumors. J Neurooncol 54:301, 2001 Kreth FW,Schatz CR, Pagenstecher A et al: Stereotactic management of lesions of the pineal region. Neurosurgery 39:280, 1996 Latchaw RE, Johnson DW, Kanal E Primary intracranial tumors: tumors of congenital, pineal, and vascular origin and the phakomatoses. p. 561. In Latchaw RE (ed): MR and CT Imaging of the Head, Neck and Spine. Mosby, St. Louis, 1991 Merchant TE, Sherwood SH, Mulhern RK et al: CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 15:1171, 2000 Pople IK, Athanasiou TC, Sandeman DR et al: The role of endoscopic biopsy and third ventriculostomy in the management of pineal tumours. Br J Neurosurg 15:305, 2001 Schild SE, Scheithauer BW, Haddock MG et al: Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 78:2564, 1996

170 Uncommon Brain Tumors, Skull Base Tumors,

and Intracranial Cysts David Schiff, Liangge Hsu, and Patrick Y. Wen In preceding chapters, the more common brain tumors and some less common malignant brain tumors were discussed. This chapter describes some miscellaneous uncommon brain tumors, skull base tumors, and the more common intracranial cystic lesions that may clinically mimic brain tumors.

UNCOMMON BRAIN TUMORS Ganglion Cell Tumors Gangliogliomas or gangliocytomas are rare tumors containing large mature neurons. These tumors form a spectrum based on their glial cell content. The term gangliocytorna is reserved for lesions consisting of large neoplastic but well-differentiated neurons with minimal glial background; gangliogliomas also contain a neoplastic glial component. Ganglion cell tumors are most common in children and young adults. Eighty percent of these patients are under 30 years of age. They are found most commonly in the temporal lobes but may occur anywhere in the brain. The most common presentation is long-standing epilepsy. Headaches and focal neurologic deficits are less common. Appearance on computed tomography (CT) and magnetic resonance imaging (MRI) often is nonspecific. Typically they appear as poorly enhancing hypodense lesions (Fig. 170-1). Sometimes a contrast-enhancing mural nodule (which may be calcified) is associated with a cyst. Positron emission tomography scans generally demonstrate these tumors to be hypometabolic, although coregistration with MRI scans may demonstrate heterogenous metabolic activity and regions of hypermetabolism compared with white matter. These tumors often are superficially located and may invade the subarachnoid space.

w

Ganglion cell tumors usually are well demarcated and slow growing and are consistent with long survival if surgically accessible. Totally resected tumors do not recur. Even after subtotal resection, the prognosis is good. When gangliogliomas become anaplastic, which occurs in fewer than 10% of tumors, changes in the glial component are thought to be responsible. Radiotherapy usually is recommended for unresectable recurrent gangliogliomas and for subtotally resected gangliogliomas with an anaplastic component. It is generally deferred after subtotal resection of low-grade gangliogliomas. The presence of anaplasia in gangliogliomas is ominous; despite aggressive management such tumors usually are fatal.

Choroid Plexus Tumors Choroid plexus tumors consist of choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). CPPs histologically resemble normal choroid plexus and probably represent local hamartomatous overgrowths. CPCs are aggressive tumors with variable histologic features, including dense cellularity, mitoses, nuclear pleomorphism, focal necrosis, loss of papillary architecture, and invasion of neural tissue. CPPs are very uncommon in children and are even rarer among adults. Most series show a male preponderance. In adults, about 80% are located in the fourth ventricle, with the remainder arising in the cerebellopontine angle. They are almost invariably associated with hydrocephalus as a result of cerebrospinal fluid (CSF) secretion by the tumor itself and obstruction of the ventricular system. Headache is the most common symptom. On CT scan, these tumors often are calcified and show contrast enhancement (Fig. 170-2); differentiation from ependymoma may be difficult. MRI scan may reveal flow voids, reflecting tumor vascularity.

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SpecificTumor Types

SUGGESTED READINGS Bruce JN, Stein BM: Surgical management of pineal region tumors. Acta Neurochir (Wien) 134130, 1995 Cho BK, Wang KC, Nam DH et al: Pineal tumors: experience with 48 cases over 10 years. Childs New Syst 14:53, 1998 Choi JU, Kim DS, Chung SS et al: Treatment of germ cell tumors in the pineal region. Childs New Syst 14:41, 1998 Ferrer F, Santamarta D, Garcia-Fructuoso G et al: Neuroendoscopic management of pineal region tumors. Acta Neurochir (Wien) 139:12, 1997

Friedman JA, Lynch JJ, Buckner JC et ak Management of malignant pineal germ cell tumors with residual mature teratoma. Neurosurgery 48:518, 200 1

Herrmann HD, Westphal M, Winkler K et al: Treatment of nongermatous germ-cell tumors of the pineal region. Neurosurgery 34:524, 1994 Horowitz MB, Hall WA Central nervous system germinomas. A review. Arch Neurol48:652, 1991 Huh SJ,Shin KH, Kim IH et al: Radiotherapy of intracranial germinomas. Radiother Oncol 38:19, 1996

Kobayashi T, Kida Y, Mori Y: Stereotactic gamma radiosurgery for pineal and related tumors. J Neurooncol 54:301, 2001 Kreth FW,Schatz CR, Pagenstecher A et al: Stereotactic management of lesions of the pineal region. Neurosurgery 39:280, 1996 Latchaw RE, Johnson DW, Kanal E Primary intracranial tumors: tumors of congenital, pineal, and vascular origin and the phakomatoses. p. 561. In Latchaw RE (ed): MR and CT Imaging of the Head, Neck and Spine. Mosby, St. Louis, 1991 Merchant TE, Sherwood SH, Mulhern RK et al: CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 15:1171, 2000 Pople IK, Athanasiou TC, Sandeman DR et al: The role of endoscopic biopsy and third ventriculostomy in the management of pineal tumours. Br J Neurosurg 15:305, 2001 Schild SE, Scheithauer BW, Haddock MG et al: Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 78:2564, 1996

170 Uncommon Brain Tumors, Skull Base Tumors,

and Intracranial Cysts David Schiff, Liangge Hsu, and Patrick Y. Wen In preceding chapters, the more common brain tumors and some less common malignant brain tumors were discussed. This chapter describes some miscellaneous uncommon brain tumors, skull base tumors, and the more common intracranial cystic lesions that may clinically mimic brain tumors.

UNCOMMON BRAIN TUMORS Ganglion Cell Tumors Gangliogliomas or gangliocytomas are rare tumors containing large mature neurons. These tumors form a spectrum based on their glial cell content. The term gangliocytorna is reserved for lesions consisting of large neoplastic but well-differentiated neurons with minimal glial background; gangliogliomas also contain a neoplastic glial component. Ganglion cell tumors are most common in children and young adults. Eighty percent of these patients are under 30 years of age. They are found most commonly in the temporal lobes but may occur anywhere in the brain. The most common presentation is long-standing epilepsy. Headaches and focal neurologic deficits are less common. Appearance on computed tomography (CT) and magnetic resonance imaging (MRI) often is nonspecific. Typically they appear as poorly enhancing hypodense lesions (Fig. 170-1). Sometimes a contrast-enhancing mural nodule (which may be calcified) is associated with a cyst. Positron emission tomography scans generally demonstrate these tumors to be hypometabolic, although coregistration with MRI scans may demonstrate heterogenous metabolic activity and regions of hypermetabolism compared with white matter. These tumors often are superficially located and may invade the subarachnoid space.

w

Ganglion cell tumors usually are well demarcated and slow growing and are consistent with long survival if surgically accessible. Totally resected tumors do not recur. Even after subtotal resection, the prognosis is good. When gangliogliomas become anaplastic, which occurs in fewer than 10% of tumors, changes in the glial component are thought to be responsible. Radiotherapy usually is recommended for unresectable recurrent gangliogliomas and for subtotally resected gangliogliomas with an anaplastic component. It is generally deferred after subtotal resection of low-grade gangliogliomas. The presence of anaplasia in gangliogliomas is ominous; despite aggressive management such tumors usually are fatal.

Choroid Plexus Tumors Choroid plexus tumors consist of choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). CPPs histologically resemble normal choroid plexus and probably represent local hamartomatous overgrowths. CPCs are aggressive tumors with variable histologic features, including dense cellularity, mitoses, nuclear pleomorphism, focal necrosis, loss of papillary architecture, and invasion of neural tissue. CPPs are very uncommon in children and are even rarer among adults. Most series show a male preponderance. In adults, about 80% are located in the fourth ventricle, with the remainder arising in the cerebellopontine angle. They are almost invariably associated with hydrocephalus as a result of cerebrospinal fluid (CSF) secretion by the tumor itself and obstruction of the ventricular system. Headache is the most common symptom. On CT scan, these tumors often are calcified and show contrast enhancement (Fig. 170-2); differentiation from ependymoma may be difficult. MRI scan may reveal flow voids, reflecting tumor vascularity.

Chapter 170

m

Uncommon Brain Tumors, Skull Base Tumors, and lntracranial Cysts

FIG. 170-1. A 39-year-old man who presented complex partial seizures. T i -weighted MRI scan show a nonenhancing hypodense ganglioglioma in the right frontal lobe (arrows).

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Similar tumors are rarely found in spinal cord or brain parenchyma (cerebral neurocytomas). Most patients with central neurocytomas are in their third or fourth decades, although no age is entirely exempt. The clinical history usually is brief. Most patients have hydrocephalus and symptoms and signs of increased intracranial pressure at presentation. Thirty percent of patients have visual disturbances, and 25% have impaired cognitive function. Focal neurologic deficits are uncommon. A few patients have presented with intraventricular hemorrhage. The typical CT appearance is a slightly hyperdense intraventricular mass, which enhances moderately with contrast (Fig. 170-3). The majority of central neurocytomas are multicystic and calcified, with a broad-based attachment to the superolateral ventricular wall. They are typically found in the lateral or third ventricle, attached to the septum pellucidum or ventricular wall at the foramen of Monro. They spare the occipital and temporal horns. On MRI, the tumors are slightly hyperintense on both T1and T2-weighted images and enhance with contrast. The optimal treatment of these tumors is complete surgical resection. Often, however, only subtotal resection is possible. Even a subtotal resection is consistent with long-term survival because these tumors usually regrow slowly. A high cell cycle labeling index (i.e., MIB-1 greater than 2%) is associated with a higher risk of recurrence. Reoperation should be considered for symptomatic recurrence. Focal external beam radiotherapy has been documented to shrink residual tumor, supporting a role for radiation in Patients with recurrent or progressive disease. Leptomeningeal dissemination is extremely rare. Several Case reports Suggest that

The treatment for CPP is surgical resection. If completely excised, these tumors are unlikely to recur. Even subtotally resected CPPs usually have a benign course, although malignant transformation to CPC has been reported. Adjuvant radiotherapy is not indicated, but focal external beam radiotherapy may be useful for recurrent tumors that are inoperable. Leptomeningeal seeding may occur with histologically benign tumors. Approximately 10% of all choroid plexus neoplasms are CPCs. Invasiveness usually precludes gross total surgical resection, and leptomeningeal dissemination often occurs. Radiotherapy and chemotherapy have not markedly improved prognosis, and most patients succumb within a few years. CPCs may be hard to distinguish from systemic metastasis (especiallyfrom lung cancer) to the plexus, which occurs more commonly than CPC. Central Neurocytoma

This tumor was not recognized until 1982, when Hassoun et al reported on two patients in their thirties with slowly progressive calcified intraventricular tumors in whom electron microscopic findings of synapses and synaptic vesicles suggested a neuronal lineage. The patients’ age and clinical course, intraventricular tumor location, absence of Homer Wright rosettes, and mature appearance of the cells argued against these being neuroblastomas, an aggressive embryonic parenchymal pediatric tumor. In ensuing years, it became apparent that many tumors previously diagnosed as intraventricular oligodendrogliomas or, less commonly, ependymomas were actually neurocytomas. About one half of all intraventricular tumors in adults are central neurocytomas.

flG. 1 7 0 2 . Axial 0 scan with contrast showing a large enhancing choroid plexus papilloma in the right lateral ventricle (arrow).

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Dysplastic Gangliocytoma of the Cerebellum (LhennitteDudos Disease)

FIG. 170-3. Axial CT scan with contrast showing a slightly enhancing neurocytoma in the left lateral ventricle (arrow). (From Schiff D, Wen P: Uncommon brain tumors. Neurol Clin 13:953-974, 1995, with permission.)

recurrent central neurocytomas may respond to systemic chemotherapy.

DysembyoplasticNeuroepithelialTumors Like the central neurocytoma, dysembryoplastic neuroepithelial tumor (DNT) was only recently recognized. The specific pathologic features of DNTs include their supratentorial cortical location, the presence of neurons, foci of dysplastic cortical organization, multinodular architecture with components resembling astrocytoma, oligodendroglioma or oligoastrocytoma, and a columnar structure oriented perpendicular to the cortical surface. The histogenesis of these lesions is uncertain, but they may arise from the external granule layer of cortex. Patients with DNTs usually present with long-standing, often refractory seizure disorders, which often begin during childhood. These patients generally have normal intelligence and stable neurologic deficits. Rarely, mass effect and increased intracranial pressure are present. CT scans typically show a low-density lesion with little or no ring enhancement. When these tumors are superficial, the overlying calvaria may be deformed, a reflection of their slow growth. On MRI, DNTs appear as a T1-weighted hypointense, T2-weighted hyperintense cortically based lesion focally expanding the cortex. They are usually located in the temporal or frontal lobes. Irrespective of treatment, these tumors generally remain stable in size. Thus, the main indication for intervention is palliation of symptoms, particularly epilepsy that is resistant to medication. Surgically accessible lesions may be resected; lesions in eloquent cortex are best observed. There is no indication for radiotherapy. Malignant transformation occurs only very rarely.

This extremely rare and curious entity is characterized pathologically by loss of normal cerebellar cortical architecture and focal thickening of the folia. Light microscopy reveals abnormal hypertrophic ganglion cells, which superficially resemble Purkinje cells, and there is a reduction of the central cerebellar white matter. This disease typically is diagnosed in adults (average age 34). The most common presentation is a slowly growing cerebellar mass with associated hydrocephalus. Some patients have macrocephaly and mental retardation. It has been found incidentally at autopsy, and rarely it has been associated with sudden death. On CT scan, the lesion is poorly defined and sometimes calcified. MRI shows a nonenhancing, isodense or hypodense lesion on TIweighted images and alternating signal bands on T2-weighted images. The only effective treatment is surgical resection, although a few cases have recurred after apparent gross total resection. Several reports have recently noted an association between Lhermitte-Duclos disease and Cowden’s disease, an autosomal dominant syndrome characterized by facial tricholemmomas, acral keratosis, oral papillomatosis, intestinal polyps, and an increased incidence of breast and thyroid cancer. Cowden’s disease is associated with germ line mutation to the PTEN gene, a tumor suppressor gene on chromosome 10. Lhermitte-Duclos disease may be the central nervous system manifestation of Cowden’s disease. Whether all cases of Lhermitte-Duclos disease harbor germ line PTEN mutations is uncertain, as is the question of whether dysplastic gangliocytomas are best considered hamartomas or neoplasms.

Hemangioblastomas These tumors are most commonly located in the cerebellum, although they may be found in the spinal cord, medulla, and (rarely) the cerebrum. Histologically, they consist of endothelial and stromal cells and closely resemble renal cell carcinoma. About 10% of patients have polycythemia from tumor production of erythropoietin. Tumors may occur sporadically or as part of the autosomal dominant von Hippel-Lindau syndrome. Patients with von Hippel-Lindau syndrome often have multiple hemangioblastomas, which are often asymptomatic. In addition, they may have retinal angiomatosis, renal cell carcinoma, visceral cysts, endolymphatic sac tumors, and adrenal pheochromocytomas. This syndrome is associated with mutations to the VHL gene, a tumor suppressor gene on chromosome 3p. Mutations in this gene are extremely heterogenous and can be detected in 80% of VHL families. Approximately 23% of patients with hemangioblastoma have von Hippel-Lindau syndrome. With more thorough screening and development of gene probes, this incidence may turn out to be an underestimate. Although hemangioblastomas can occur at any age, they are most commonly found in young and middle-aged adults, in whom they account for 7% of posterior fossa tumors. They have a tendency to form cysts with a mural nodule of tumor. The solid tumor nodule enhances homogenously, and flow voids from related blood vessels may be seen with MRI (Fig. 170-4). Hemangioblastomas are well demarcated, and invasion and remote metastasis are rare. Treatment consists of surgical resection of symptomatic lesions. Gross total resection generally is curative, although patients may develop multiple tumors. Radiotherapy,

Chapter 170 rn Uncommon Brain Tumors, Skull Base Tumors, and lntracranial Cysts

FIG. 170-4. Axial T1-weighted MRI with gadolinium showing cystic contrast-enhancing hemangioblastoma in the right cerebellar hemisphere (arrow).

either fractionated external beam or radiosurgery, may be beneficial for unresectable or progressive residual tumors. These hypervascular tumors generally overexpress vascular endothelial growth factor (VEGF), suggesting a potential role for antiangiogenic strategies. SKULL BASE TUMORS Chordoma Chordomas account for roughly 1% of intracranial tumors and arise from the remnants of the embryonic notochord. Despite their origin, they are rare in children and usually present in the fourth to sixth decades. There is a 2:l male preponderance. In adults 50% of chordomas involve the sacrococcygeal region, 35% involve the base of the skull, in the region of the clivus, and 15% are found in the vertebral column. The tumor often is gray or colorless, lobulated, soft, and gelatinous in appearance. There may be areas of calcification, much, and hemorrhage. It usually arises in the midline of the clivus but often extends to one side, growing forward into the nasopharynx and sella turcica, the adjacent cavernous and sphenoid sinuses, or posteriorly and inferiorly into the brainstem. Growth always involves destruction of any restraining bone. Histologically, the neoplastic cells exist in lobulations of variable size within a fibrous connective tissue stroma. Tumor cells, often very pleomorphic with occasional mitotic figures, are

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arranged in solid sheets or along interconnected or isolated strands. Some cells have a homogeneous eosinophilic cytoplasm, which is distinct from intercellular material; others contain various degrees of vacuolation. An extremely vacuolated cell known as the physaliphorous (bubble-bearing) cell is characteristic of the chordoma. Some areas may consist of mesenchymal differentiation, including bone and cartilage. Tumors with cartilaginous foci are less likely to metastasize. Metastasis increases with survival and occurs in 10% to 16% of cases. One biologic variant is the chondroid chordoma, which usually consists of fibrous connective tissue, sparse tumor cells intertwined with cartilaginous foci, immature myxoid elements, and calcification. This form usually occurs in the basioccipital region and carries a longer median survival (20 to 30 years). Dedifferentiation or sarcomatous transformation occurs in 2% to 8% of chordomas. Clivus and sphenoid sinus chordomas usually present with neck pain, headache, and a sensation of nasal obstruction. Visual disturbances caused by involvement of cranial nerves 11, 111, IV, and VI are present in one half of cases. The so-called basisphenoidal chordomas, occurring in the more rostral clivus, usually present with upper cranial neuropathies and endocrine abnormalities secondary to involvement of the diencephalon. In contrast, basioccipital chordomas, arising from the lower clivus at the spheno-occipital synchondrosis, cause mainly lower cranial nerve palsies and long tract signs. MIU of chordoma shows irregular and extensive bone destruction with a mixed pattern of long and short T1- and T2-weighted patterns (Fig. 170-5). CT often is helpful because it can demonstrate the extent of bony destruction. Because of their very slow growth, chordomas usually are large at the time of presentation. The differential diagnosis of chordomas includes chondrosarcoma, mucinous adenocarcinoma, myxopapillary ependymoma, and meningioma. Chordomas usually are treated with a combination of surgery and radiation therapy. In general, chordomas are very difficult to remove completely, and even partial resection may result in significant morbidity because of the deep central location and extent of spread at diagnosis. As a result, postoperative radiation therapy often is necessary to treat residual disease. The results of conventional radiation therapy generally are poor. The proximity of radiosensitivestructures, such as the optic nerve and brainstem, often prevents the delivery of the high dosages of radiation necessary to produce a therapeutic effect. In one study, the local control rate was only 27%, although 85% of patients had palliation of symptoms. Median survival was 62 months (Caton et id, 1996). Local tumor control is essential because salvage therapy after local recurrence is rarely successful. Proton beam therapy and stereotactic radiotherapy allows higher dosages of radiation to be delivered to the tumor while limiting the dosage to surrounding structures, resulting in improved local tumor control. The largest experience has been with proton beam therapy, with which local control rates of 76% at 33 months and progression-free survival of 70% at 5 years and 45% at 10 years have been achieved (Fagundes et al, 1995; Hug et al, 1999). In general, patients with tumor volumes of less than 20 mL have better tumor control than larger tumors. Other favorable prognostic factors are male sex and absence of necrosis on tumor specimens.

Chondrosarcama Chondrosarcomasare malignant cartilaginous tumors that represent roughly 6% of all skull base tumors. They are probably

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A

B

FIG. 170-5. (A) Sagittal T1 -weighted MRI with gadolinium showing chordoma arising from, and eroding, the clivus anterior to the lower brainstem. (19)Axial T2-weighted MRI showing the large chordoma anterior to the brainstem.

derived from the primitive mesenchymal stem cell of the matrix. Most patients present in their third and fourth decades, and there is an equal distribution between the sexes. Whereas a normal neurologic examination is common in patients with chordoma, patients with chondrosarcoma tend to have neurologic deficits. This reflects the tendency of chordomas to originate from the clivus and chondrosarcomas to originate from the temporal bone. Fifty percent of patients present with diplopia caused by cranial nerve palsies, 30% with headaches, 20% with hearing loss, tinnitus, and deafness, and 20% with facial numbness. Roughly two thirds of the skull-based chondrosarcomas occur in the middle cranial fossa (Fig. 170-6), followed by the anterior and the posterior fossa. These lesions are similar to the chordomas in that they are fairly slow growing and locally recurrent with significant bony destruction. Lesions in the parasellar region (the most common site of origin) typically compress optic nerves and disturb hypothalamic-pituitary function. Occasionally, they erupt through the nasal and paranasal sinuses, penetrating the skull base. The degree of histologic anaplasia correlates somewhat with survival, with 5-year survival rates of 90% for grade I as opposed to 40% for grade 111 tumors. The mesenchymal subtype is a more malignant form with a higher tendency for recurrence, metastasis, and increased vascularity. MRI scans of chondrosarcomas show that they commonly extend into the nasopharynx and the upper spinal canal and demonstrate regions of multiple calcifications (“popcorn” areas of calcification). On CT scan, the chondrosarcoma contains regions of multiple calcifications throughout the chondroid matrix and a very irregular pattern of bony destruction and some local thickening of bone with a calcified cartilaginous cap, often combined with irregular bone destruction. Like chordomas, chondrosarcomas are difficult to treat because of their inaccessibility to surgical resection and their overall resistance to radiation therapy. It is unusual for the skull base

chondrosarcomas to metastasize; their course is usually one of local progression. Total gross resection of these lesions has become possible on occasion through the evolution of lateral skull base techniques. Postoperative radiotherapy enhances survival after radical surgical excision. Patients with chordomas or low-grade chondrosarcomas at the base of the skull treated with fractionated high-dose

~~

FIG. 170-6. Axial T1-weighted MRI with gadolinium showing a large chondrosarcoma anterior to the brainstem and extending into the left temporal lobe.

Chapter 170

Uncommon Brain Tumors, Skull Base Tumors, and lntracranial Cysts

postoperative radiation delivered with a proton beam (median tumor dosage 69 cobalt Gy equivalents) have a 10-year local control rate of 98%. Patients with large tumors (more than 75 cc) and cervical spine disease have a higher recurrence rate. Glomus Tumors

Glomus tumors (glomus jugulare or glomus tympanicum) are the most common tumor of the region of the middle ear (Fig. 170-7). This is also the second most common tumor to o m in the temporal bone after the neurilemmoma. Glomus tumors, also known as chemodectomas and paragangliomas, arise from chemoreceptor cells normally found in the adventitia of the jugular bulb just inferior to the floor of the middle ear and in the bony canals that transmit the tympanic branches of the glossopharyngeal and vagus nerves. They also occur in the bone adjacent to the mucosa of the middle ear (glomus tympanicum). These lesions usually present in the sixth decade, although they occasionally occur in patients as young as the midteens. There is a strong (sixfold)predilection for occurrence in women, and most sporadic cases arise in women. There is a definite tendency toward clusters within families, suggesting a genetic predisposition. Transmission is much more likely when the father harbors a glomus tumor than the mother, an example of imprinting. A suspected tumor suppressor gene associated with glomus tumors has recently been identified. Glomus tumors often demonstrate fairly slow growth and tend to extend along planes of low resistance, especially along the carotid artery to the carotid canal into the middle fossa or up to the jugular foramen and hypoglossal canal and posterior fossa. Although in general they demonstrate benign behavior, they can be invasive locally. Because of their extreme vascularity, there is a high propensity toward hemorrhage. They often present with cranial nerve dysfunction, with the facial nerve being most commonly involved. They can also

A

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produce a conductive hearing loss, as well as an obvious mass detected by otoscopic examination of the external auditory canal, or they can present with pulsatile tinnitus. With progressive extension into the base of the brain, they produce fifth, sixth, ninth, and tenth nerve symptoms, as well as long tract signs from brainstem compression and often hydrocephalus. In advanced stages, they demonstrate widespread destruction of the local bony structures, enlarging the jugular foramen and carotid canal, ensuring significant bone destruction. Angiography often reveals their extreme vascularity; these lesions are composed mainly of a very thin wall of vessels within cords of epithelioid cells. Glomus tumors may run a protracted course over decades. One half of these tumors may recur within 3 years of their initial surgical management, and because of their prolonged course, a 5-year survival does not indicate cure. Dissemination throughout the CSF pathways can occur after the tumor has extended intracranially, but metastases to other parts of the body occur in less then 1% of cases. The most common cause of death is from intracranial compression of neural structures caused by extensive intracranial tumor growth. The differential diagnosis often is straightforward because of the location and hemorrhagic tendency of these lesions. Their histologic appearance is characteristic, with small nests of round to polygonal cells, often dispersed around prominent dilated vascular channels. There is some variation in size of chromatin content of these nuclei, with rare mitoses. They usually demonstrate a very complex and extensive network of reticulin because of the intricate pattern of small blood vessels. Surgical management of glomus tumors can be challenging because of the extensive involvement of critical arterial and venous structures as well as cranial nerves around the base of the brain. Because of their extreme vascularity, preoperative embolization of the main arterial supply may reduce bleeding. A cure is possible after complete surgical excision, but there is approximately a 33%

- ~FIG. 170-7. Axial T1-weighted (A) and TZ-weighted (B) MRI showing a right-sided glomus tumor.

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recurrence rate after gross total resection, which indicates invasiveness or the possibility of multicentric origin of this tumor. Fractionated radiation therapy is an effective alternative to surgery in certain patients. It is also useful in providing additional tumor control after subtotal surgical. Complication rates for fractionated radiation therapy and surgical removal are similar. Stereotactic radiosurgery with peripheral tumor dosages in the range of 1500 to 1700 cGy may be useful as a surgical adjunct, whether used several months preoperatively to devascularize the tumor or postoperatively to improve local control. The lower cranial nerves often found adjacent to the tumor capsule generally tolerate radiosurgical dosages of 1500 cGy over small portions of their length (e.g., 2 to 3 cm). Chemotherapy with regimens containing agents such as cyclophosphamide, vincristine, dacarbazine, or doxorubicin may be useful in malignant lesions. Some of these tumors have somatostatin receptors and may respond to octreotide.

Esthesioneuroblastoma Esthesioneuroblastoma, otherwise known as olfactory neuroblastoma, generally originates from olfactory epithelium in the superior aspect of the nasal cavity near the cribriform plate. This tumor is rare and has a very poorly understood embryogenesis. Cells of origin are derived from the neural crest, with a histologic resemblance to childhood neuroblastoma. Esthesioneuroblastomas usually present in adolescents and young adults, although there is a later peak in the sixth and seventh decades. There is no gender predilection. The natural history is one of a fairly slow but insidious course. Presenting symptoms are caused by both the intrinsic high vascularity of the tumor and the location high in the nasal cavity, with pain, epistaxis, and nasal destruction being common presenting symptoms. As the tumor grows, it invades the cribriform plate and extends into the anterior cranial fossa, producing complete anosmia. CT and MRI show an enhancing mass invading surrounding bony structures. Although the lesion does extend intracranially, it remains extra-axial without ever invading the cerebral parenchyma. Angiography reveals mild vascularity, slightly more than is seen with other nasal tumors that may invade the floor of the anterior fossa. Esthesioneuroblastomas usually are treated with surgery and postoperative radiotherapy with favorable results (5-year progression free survival 60% to 80%). The role of chemotherapy is evolving, but agents such as cisplatin and etoposide may be helpful.

INTRACRANIAL CYSTS Dennoid and Epidennoid Cysts These epithelially lined developmental anomalies are thought to arise from inclusion of ectodermal elements during neural tube development. The distinction between dermoids and epidermoids is based on the presence of hair, sweat, and sebaceous glands. Dermoids occur most often in the posterior fossa, especially the midline vermis or fourth ventricle. The suprasellar cistern is another common site. Dermoids may produce symptoms from local mass effect, and rupture of their contents into the CSF can produce a fatal granulomatous meningitis. Cerebellar dermoids sometimes are associated with dermal sinuses of the occiput, which can predispose to bacterial meningitis. On CT scan, they appear as low-density midline lesions; on MRI scan they are

FIG. 170-8. Axial CT scan showing large hypodense epidermoid cyst in the left cerebellopontine angle (arrow). (From Black P, Wen P: Clinical, imaging, and laboratory diagnosis of brain tumors. In Kaye A, Shaw E (eds): Encyclopedia of Brain Tumors. Churchill Livingstone,

Edinburgh,

1995, with

permission.)

identical to lipomas with short TI- and T2-weighted values and minimal contrast enhancement. Treatment of symptomatic dermoids is surgical, although incompletely resected cysts may gradually recur. Intracranial epidermoid cysts are more common than dermoids and occur most often in the cerebellopontine angle and petrous bone. The middle cranial fossa is also a common site. Patients may experience headaches or neurologic deficits from the mass effect of the cysts. Rarely, they develop recurrent aseptic meningitis from leakage of cyst contents. On CT scan, they appear as low-attenuation lobulated masses in characteristic locations (Fig. 170-8). The density is identical to that of CSF, making visualization of these lesions sometimes difficult. On MRI scan, they appear as extra-axial masses with prolonged T1- and T2-weighted values. As with dermoids, malignant transformation into carcinoma has rarely been reported. Treatment is surgical, although their tendency to insinuate along cranial nerves and tissue planes may make gross total resection of posterior fossa epidermoid cysts impossible. Postoperative aseptic meningitis from cyst leakage generally responds to steroids.

Colloid Cysts These are spherical cysts located between the fornical columns in the roof of the third ventricle. They account for approximately 1% of intracranial mass lesions. The incidence of colloid cysts may be increasing as more patients with small, asymptomatic cysts are

Chapter 170

Uncommon Brain Tumors, Skull Base Tumors, and lntracranial Cysts

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found on routine neuroimaging for unrelated symptoms. The derivation of colloid cysts is uncertain, but they probably represent a developmental malformation and not a true neoplasm. Histologically they have an outer fibrous layer and an inner epithelium of ciliated or mucin-producing cells. Because of their location, even small lesions may block the foramen of Monro, producing hydrocephalus. Men and women are affected with equal frequency. They can occur at any age but usually become symptomatic in the third to sixth decades. Most symptomatic patients present with headaches, papilledema, and mental status and gait abnormalities related to hydrocephalus. The classic clinical description of intermittent headaches and drop attacks occurs in only one third of patients. Colloid cysts are isodense or hyperdense on precontrast CT and do not enhance (Fig. 170-9). On MRI scan, they may be hyperintense or have a hypointense center on T2-weighted MRI. With either modality, their location, shape, and lack of enhancement are virtually pathognomonic. Patients with small asymptomatic colloid cysts without evidence of hydrocephalus may be followed by serial examinations and neuroimaging studies. Treatment of symptomatic lesions consists of surgical excision. This is curative but technically challenging, given the intimate relationship to the fornices. Ventricular peritoneal shunts may also be necessary in patients with hydrocephalus.

FIG. 170-10. Axial l2-weighted MRI scan showing large right middle cranial fossa arachnoid cyst, anterior to the temporal lobe (arrow). The cyst fluid typically has the same signal intensity as CSF and appears as a high signal on TZ-weighted images.

Arachnoid Cysts

scan showing hyperdense midline colloid RG. 170-9. Axial in the region of h e third ventride (arrow). The patient had a history of headaches and needed ventriculoperiioneal shunting for hydrocephalus.

These are intra-arachnoid collections of CSF, which account for 1% of intracranial mass lesions. Most of these cysts are congenital, and 75Yo of symptomatic arachnoid cysts occur in children. Arachnoid cysts result from accumulation of CSF within a split or duplicated arachnoid membrane. CSF may accumulate as a result of secretion by arachnoid cells lining the cyst or be trapped as a result of unidirectional flow into the cyst. As the cyst increases in volume, it may produce symptoms by compressing adjacent brain or by obstructing CSF flow. The cysts usually contain clear CSF with normal cell count and protein. Occasionally, the protein content may be elevated if the cyst does not communicate freely with the CSF pathways. Xanthochromia may result from hemorrhage into the cyst. A markedly elevated protein level or pleocytosis should suggest the possibility of a cystic neoplasm rather than an arachnoid cyst. Arachnoid cysts may arise from any part of the nervous system where arachnoid is found. The most common site is the sylvian fissure, where one half of all arachnoid cysts are located. Other sites include the cerebral convexity, interhemispheric fissure, suprasellar cistern, quadrigeminal cistern, cerebellopontine angle, midline of the posterior fossa, and spine. The precise symptoms depend on the location of the cysts. Arachnoid cysts involving the sylvian fissure are more common in men and typically present with headaches, seizures, and less commonly with focal neurolo@c deficits. Subdural hematomas may occur after minor head trauma. Supraseflar cysts usually cause obstructive hydrocephalus and occasionally visual and endocrine dysfunction. Quadrigeminal

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rn Specific Tumor Types

cysts and posterior fossa cysts may also cause hydrocephalus and other brainstem symptoms. The incidence of asymptomatic arachnoid cysts is increasing as more patients undergo neuroimaging procedures for unrelated symptoms. The diagnosis of arachnoid cysts may be made by CT or MRI. O n CT scans, arachnoid cysts appear as nonenhancing, hypodense, extra-axial masses with smooth borders. Large cysts may compress adjacent brain and erode the overlying portion of the skull. Metrizamide CT cisternography and ventriculography may show delayed uptake of contrast in cysts that communicate with the subarachnoid space. MRI is the radiographic study of choice for arachnoid cysts. It allows better visualization of the relationship of the cysts to surrounding neural structures and the underlying pathology of the cyst. On MRI scan, the cyst fluid usually has the same signal characteristics as CSF (low density on T1-weighted and high density on T2-weighted images; Fig. 170-10). The differential diagnosis of arachnoid cysts includes chronic subdural hygromas, infarcts, low-grade gliomas, gangliogliomas, epidermoids, and cerebellar hemangioblastomas. The treatment depends on whether the cysts are producing symptoms. Asymptomatic cysts can be followed with serial examinations and imaging studies. Surgical intervention is indicated in patients with symptoms of increased intracranial pressure, seizures, focal neurologic deficits, or cognitive impairment. The surgical options include craniotomy for partial or complete cystectomy, fenestration into the subarachnoid space, or cyst-peritoneal shunting. Needle aspiration usually provides only temporary benefit and is not a good long-term treatment option.

SUGGESTED READINGS Austin JP, Urie MM, Cardenosa G, Munzenrider J E Probable causes of recurrence in patients with chordoma and chondrosarcomaof the base of skull and cervical spine. Int J Radiat Oncol Biol Phys 25:439-444, 1993

Austin-Seymour M, Munzenrider J, Goitein M et ak Fractionated proton radiation therapy of chordoma and low-grade chondrosarcoma of the base of the skull. J Neurosurg 70:13-17, 1989 Bigner DD, McLendon RE, Bruner JM (eds): Russell & Rubinstein’s Pathology of Tumors of the Nervous System. 6th Ed. Arnold, London, 1998

Brandes AA, Amista P, Gardiman M et ak Chemotherapy in patients with recurrent and progressive central neurocytoma. Cancer 88:169-174, 2000

Camacho A, Kelly PI: Colloid cysts of the third ventricle, pp. 36.1-10. In Rengachary SS, Wilkins RH (eds): Principles of Neurosurgery. Wolfe, London, 1994 Chow E, Reardon DA, Shah AB et ak Pediatric choroid plexus neoplasms. Int J Radiat Oncol Biol Phys 44249-254, 1999 Cirillo SF, Edwards MSB: Intracranial arachnoid cysts. pp. 5 1.1-1 1. In Rengachary SS, Wilkins RH (eds): Principles of Neurosurgery. Wolfe, London, 1994 Daumas-Duport C Dysembryoplastic neuroepithelial tumours. Brain Pathol 3:283-295, 1993

Daumas-Duport C, Scheithauer BW, Chodkiewicz JP et al: Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Neurosurgery 23:545-556, 1988

Debus J, Schilz-Ertner D, Schad L et al: Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys 47:591-596, 2000 Dulguerov P, Calcaterra T Esthesioneuroblastoma: the UCLA experience 1970-1990. Laryngoscope 102:843-849, 1992 Fagundes MA, Hug EB, Liebsch NJ et al: Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse. Int J Radiat Oncol Biol Phys 33:579-584, 1995 Haddad SF, Moore SA, Menezes AH et al: Gangliogliomas: 13 years of experience. Neurosurgery 31:171-178, 1992 Hassoun J, Gambarelli D, Grisoli F et al: Central neurocytoma: an electron-microscopic study of two cases. Acta Neuropathol (Berl) 56:151-156, 1982

Hassounah M, Al-Mefty 0, Akhtar M et al: Primary cranial and intracranial chondrosarcoma. A survey. Acta Neurochir (Wien) 78~123-132,1985

Hug EB, Loredo LN, Slater JD et ak Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg 91:432-439, 1999

Kapadia SB, Janecka I P Olfactory neuroblastoma. In press, 2002 Kapadia SB, Janecka I P Overview of skull base tumors. In press, 2002 Kaye AH, Laws ER Jr: Brain Tumors. 2nd Ed. Churchill Livingstone, London, 2001 Kim DG, Paek SH, Kim IH et al: Central neurocytoma: the role of radiation therapy and long term outcome. Cancer 7 9 1995-2002, 1997 Kleihues P, Cavenee WK WHO Classification of Tumors. Pathology and Genetics. Tumors of the Nervous System. IARC, Lyon, 2000 Krouwer HGJ, Davis RL, McDermott MW et al: Gangliogliomas: a clinicopathological study of 25 cases and review of the literature. J Neurooncol 17:139-154, 1993 Kulkantrakorn K, Awad EE, Levy B et ak MFU in Lhermitte-Duclosdisease. Neurology 48725-731, 1997 Lang FL, Epstein FJ, Ransohoff J et al: Central nervous system gangliogliomas. Part 2: clinical outcome. J Neurosurg 79:867-873, 1993

McGirr SJ, Ebersold MJ, Scheithauer B et al: Choroid plexus papillomas: long-term follow-up of a surgically treated series. J Neurosurg 69843-849, 1988

Miller DC, Lang FF, Epstein FJ: Central nervous system gangliogliomas. Part 1: pathology. J Neurosurg 79:859-866, 1993 Neuman HPH, Eggert HR, Weigel K et ak Hemangioblastomas of the central nervous system: a 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg 70:24-30, 1989 Robinson S, Cohen A R Cowden disease and Lhermitte-Duclos disease: characterization of a new phakomatosis. Neurosurgery 46:371-383, 2000

Rosenberg AE, Nielsen GP, Keel SB et al: Chondrosarcoma of the base of skulk a clinicopathological study of 200 cases with emphasis on its distinction from chordoma. Am J Surg Pathol23:1370-1378, 1999 Rumana CS, Valadka AB, Contant CFL Prognostic factors in supratentorial gangliogliomas.Acta Neurochir (Wien) 141:6349, 1999 Weber PC, Patel S: Jugulotympanic paragangliomas. Otolaryngol Clin North Am D34(6):1231-1240, 2001 Wichmann W, Schubiger 0, von Deimling A et al: Neuroradiology of central neurocytoma. Neuroradiology 33:143-148, 1991

Chapter I71

Brain Metastases

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171 Brain Metastases ~~~

~~

Scott R. Plotkin and Patrick Y. Wen

Cancer remains a common cause of death in the United States, second only to cardiovascular disease. The American Cancer Society estimates that 1.22 million new cases of invasive cancer will be diagnosed annually in the United States. During that time, an estimated 550,000 Americans will die of cancer. Brain metastases are a common complication of cancer and represent an important cause of morbidity and mortality in these patients. About 10% to 30% of adults and 6% to 10% of children with cancer develop intracranial metastases. Among adults, the most common origins of brain metastasis include primary tumors of the lung (50%), breast (15% to 20%), skin (melanoma, lo%), and gastrointestinal tract (5%). In children, the most common sources are sarcomas, neuroblastomas, and germ cell tumors. Not all metastases are clinically significant. Autopsy studies suggest that 25% of patients with cancer have some type of metastasis that escaped detection. Certain tumors almost never metastasize to the brain parenchyma. These include carcinomas of the esophagus, oropharynx, prostate, and nonmelanoma skin cancers. The prevalence of brain metastases has increased in the past three decades. Factors contributing to this increase include the use of magnetic resonance imaging (MRI) to detect clinically silent lesions, improved survival of patients with cancer as a result of more effective systemic therapy, and the aging of the American population. PATHOPHYSIOLOCY Metastasis is a complicated process that involves many steps, some of which are poorly understood at this time. Overall, the most common mechanism of dissemination of tumor cells is hematogenous spread. Certain tumors such as melanoma and breast cancer exhibit tropism for the central nervous system (CNS) and have a higher likelihood of developing metastases in this location. Metastases often are located at the junction of the gray and white matter. This is thought to result from physical factors. Clumping of tumor cells is promoted by progressive narrowing of the arterial supply and by termination of arterial trees at border zone regions. Because physical factors contribute to the deposition of tumor cells, the distribution of metastases occurs in proportion to blood flow. Thus, about 80% of metastases are located in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. However, certain tumors defy this rule. For unclear reasons, metastases from pelvic and gastrointestinal sites are more likely to develop in the posterior fossa (about 50%). CLINICAL MANIFESTATIONS As mentioned previously, about 10% to 30% of patients with cancer develop brain metastases. A diagnostic workup should be initiated when a patient with cancer develops a new neurologic symptom. The majority of patients present with progressive neurologic dysfunction resulting from a gradually expanding tumor mass and the associated edema or, rarely, to the development of obstructive hydrocephalus. Approximately 10% to 20% of

H TABU 171-1. Symptoms and Signs of Brain Metastasis ~Vmptoms

96

Signs

Headache Focal weakness Mental disturbance Gait ataxia Speech difficulty Visual disturbance Sensory disturbance Limb ataxia

49 30 32

Mental status change Hemiparesis Sensory loss Papilledema Gait ataxia Aphasia Visual field cut Limb ataxia DeDressed consciousness

21 12 6

6 6

46 58 59

21 20 19 18 7 6 4

patients present acutely with seizures, and another 5% to 10% present acutely as a result of strokes caused by embolization of tumor cells or invasion or compression of an artery by tumor or hemorrhage into a metastases. Melanoma, choriocarcinoma, and thyroid and renal carcinoma have a particular propensity to bleed. Typical presenting symptoms are listed in Table 171-1. Headache is a common complaint and is reported in about 40% to 50% of patients with brain metastases. It is thought to be caused by elevated intracranial pressure (ICP). The pain usually is worse in the morning and is exacerbated by maneuvers that increase ICP such as coughing or performing Valsalva maneuver. Other signs of increased ICP include vomiting, especially in the absence of nausea, and papilledema. Focal neurologic signs are found in 20% to 40% of patients. Changes in mental status occur in approximately one third of patients. DIFFERENTIAL DIAGNOSIS The differential diagnosis of a mass lesion in a patient with cancer is broad. It includes primary brain tumor, abscess, granuloma, demyelinating lesion, cerebral infarction, radiation necrosis, and postoperative changes. In a study of 54 patients who were thought to have a single metastasis, stereotactic biopsy revealed a different diagnosis in 11% of cases (Patchell et al, 1990). In these cases, the final diagnosis was divided between primary brain tumors and infections. Although the likelihood of establishing an alternative diagnosis falls with the presence of multiple lesions, this study highlights the importance of obtaining pathologic confirmation when the diagnosis is not certain. EVALUATION A contrast-enhanced MRI scan has supplanted CT scan as the standard modality for imaging brain metastasis (Fig. 171-1). MRI is more sensitive than CT for small lesions, particularly within the brainstem and cerebellum. A negative MRI, if of high quality, effectively rules out the diagnosis of brain metastasis. In addition, MRI is better able to distinguish metastatic lesions from alternative diagnoses. Factors that help differentiate metastatic lesions include enhancement with contrast, location near the junction of gray and white matter, the presence of multiple lesions, and the presence of edema.

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I1B

C

FIG. 171-1. Three MRI scans of the same anatomic level of a patient with brain metastases. (A) T2-weighted image showing edema in the right temporal lobe. (6) An unenhanced TI-weighted study showing a mass in the right temporal area and no other definite lesions. (C) A gadolinium contrast-enhanced scan showingthe right temporal lobe mass and two additional

lesions in the left occipital area.

MANAGEMENT GOALS Management of brain metastases can be divided into treatment of symptoms and treatment of the underlying brain lesions. Symptoms that typically necessitate treatment or prophylaxis include mass effect caused by cerebral edema, seizures, and deep venous thromboses. Treatment of the brain metastases includes various modalities such as surgery, radiation therapy (XRT), and chemotherapy.

Symptomatic Treatment Corticosteroids. Corticosteroids are the mainstay for peritumoral edema treatment. They act to reduce the permeability of tumor capillaries and are indicated in any patient with symptoms referable to edema. Dexamethasone is the most widely used corticosteroid. It has a favorable therapeutic profile with minimal mineralocorticoid effect, thereby minimizing the potential for fluid retention. Dexamethasone therapy typically is initiated with a 10-mg loading dose followed by 16 mg/day divided into two to four doses. Clinical improvement typically is noted within 2 to 3 days, although the radiographic appearance of the edema may not improve for up to 1 week. Occasionally, higher dosages may be needed to control symptoms. In these cases, the dexamethasone dosage can be increased to 100 mg/day. In practice, generalized symptoms such as headache respond better than focal neurologic signs such as hemiparesis or aphasia. Adverse effects of glucocorticoids are dose-dependent, so the dosage should be tapered to fit the individual patient’s needs, depending on clinical status. Major adverse effects include myopathy, immunosuppression, glucose intolerance, easy bruising, weight gain, obesity, osteoporosis, hirsutism, abdominal striae, fluid retention, and pneumocystitis pneumonitis. In general, every-other-day dosing is not used to treat peritumoral edema.

Anticonvulsants. Seizures are a common problem for patients with brain metastases. Between 10% and 20% of patients experience a seizure before receiving their diagnosis. An additional 10% to 20% of patients ultimately develop a seizure during their lifetime. In patients who present with seizure the need for anticonvulsant medication is clear. However, physicians differ in the use of prophylactic anticonvulsant medication in patients with brain tumors who have not experienced a seizure. Many physicians choose to use prophylactic anticonvulsants based on the high percentage of patients who eventually develop seizures. However, this potential benefit must be weighed against adverse effects of anticonvulsant medications. These effects include the expense of medication, the inconvenience of monitoring drug levels, and side effects that are more prevalent in patients with brain tumors. Typical side effects may include cognitive impairment, hepatic dysfunction, myelosuppression, and dermatologic reactions such as erythematous rashes and Steven-Johnson syndrome. Furthermore, many anticonvulsant medications affect the cytochrome P-450enzyme system and may alter the metabolism of chemotherapeutic agents used to treat malignancies. The American Academy of Neurology published a practice parameter in 2000 (Glantz et al, 2000) that reviewed the data concerning the use of prophylactic medications in these patients. In studies with either class I or class I1 evidence, there was no evidence to support the use of prophylactic anticonvulsant medication in patients with brain tumors who have not experienced a seizure. Even when patients with subtherapeutic drug levels were excluded from the analysis, there was no positive effect for the use of medication. Therefore, the academy concluded that anticonvulsant medication should be used only in patients with brain metastases who have experienced at least one seizure. Anticoagulants. Venous thromboembolic disease is a common problem in patients with primary and metastatic brain tumors. About 20% of patients with metastatic brain tumors develop evidence of venous thromboembolic disease after diagno-

Chapter 171 rn Brain Metastases

sis of the brain tumor. The chance of developing clinically significant disease is greater in the postoperative period and in patients with hemiplegia. The optimal treatment of patients with brain metastases and thromboembolic disease is not known. In general, there has been a reluctance to use anticoagulant medication in these patients because of the perceived risk of intratumoral hemorrhage. For this reason, many patients are given nonpharmacologic treatments such as inferior vena cava (IVC) filtration devices. However, some studies suggest that this method is associated with significant morbidity in patients with brain tumors. In one study of 49 patients with brain tumors and thromboembolic disease, 42 had IVC filtration devices. In this group, 62% had evidence of complications related to the IVC filters such as new pulmonary embolus, filter thrombosis, or recurrent deep vein thrombosis (Levin et al, 1993). A subsequent study of 42 patients with brain metastases who received prophylactic heparin showed that only 3 of these patients (7%) experienced intracranial hemorrhage (Schiff and DeAngelis, 1994). In 2 of them, the hemorrhage was associated with a supratherapeutic partial thromboplastin time. Several retrospective studies suggest that the risk of intracranial hemorrhage in patients with brain tumors treated with anticoagulation is low. Overall, these studies suggest that anticoagulation outside the postoperative period is associated with fewer complications than ICV filtration devices and is generally safe. Patients with brain metastases with a high incidence of bleeding, such as melanoma and choriocarcinoma, probably should avoid anticoagulation. Definitive Treatment

Treatment of brain metastases is directed at improving neurologic function, improving quality of life, and extending survival. Modalities available for treating brain metastases include surgery, various forms of radiation therapy, and chemotherapy. The specific combination of treatment modalities depends on factors related to the patient (e.g., age, functional status), the primary tumor (e.g., degree of systemic involvement), and the metastases (e.g., size, number, location). Surgev. The goal of surgery is to provide immediate relief of neurologic symptoms of the tumor, to establish a histologic diagnosis, and to provide local control of the metastasis. Selecting patients who will benefit from surgery is an important decision. In general, patients with extensive systemic disease do not benefit from surgery and are not surgical candidates. Other important factors in the decision for surgery include the functional status of the patient, the number of metastases, and the prior response to treatment. The percentage of patients who have a single SINGLEMETASTASIS. metastasis on imaging depends on the modality used. Contrastenhanced CT scans identify a single metastasis in about 50% of patients, whereas MFU identifies a single metastasis in about 33% of patients. Patchell et al (1990) reported the first prospective, randomized study of surgical extirpation in 54 patients with single metastases. Twenty-five patients received surgery plus whole brain radiotherapy (WBRT), and 23 patients received WBRT alone. Histologic examination of the surgical tissue revealed that six patients ( 11%) had nonmetastatic disease. Compared with those who received WBRT only, patients who received surgery plus WBRT had significantly lower rates of recurrence at the original site of

1103

metastasis (20% versus 52%) and longer survival times (40 weeks versus 15 weeks). In addition, they remained functionally independent for a longer period of time. Vecht et al (1993) reported a second prospective, randomized study of surgery extirpation in 63 patients with single metastases. In this study, 32 patients received surgery followed by 40 Gy of WBRT, and 21 received WBRT only. Patients treated with surgery and WBRT survived longer than those treated with WBRT only (10 versus 6 months, respectively). When patients were stratified by activity of extracranial disease, those with inactive disease survived longer than those with active disease (12 versus 7 months). For patients who received both surgery and WBRT, those less than 60 years old survived longer than those older than 60 (1 9 versus 6 months). Patients with active extracranial disease did not benefit from surgery. In contrast to these two studies, a more recent multicenter randomized study conducted by Mintz et al(1996) failed to detect a difference in survival or quality of life between patients who underwent surgery plus radiotherapy and those having radiotherapy alone. This difference may result partly from the fact that this study included patients with a lower baseline median Karnofsky performance score and a higher proportion of extracranial disease. Taken together, these results suggest that the addition of surgical resection to WBRT improves survival in patients with a single metastasis. This benefit appears more significant for patients with stable extracranial disease and for those younger than 60 years of age. MuinBRAN I METASTASES. The majority of patients who present with brain metastases have multiple lesions. Typically, surgery has been offered only to patients with single metastases in surgically accessible locations. In patients with multiple brain metastases, surgery has been reserved for patients with a large lesion producing significant symptoms or impending herniation, patients with two lesions accessible by a single craniotomy, and patients in whom a pathologic diagnosis was necessary. Recently, there has been interest in the role of surgery in patients with multiple lesions. The results of the available studies have been conflicting. Some studies suggest that if in patients with multiple brain metastases all the lesions can be removed, the outcome is significantly improved and comparable to the outcome of patients who underwent surgery for a single lesion. However, other studies have failed to demonstrate a benefit in removing multiple lesions surgically. Patients who undergo surgical RECURRENTBRA NI METASTASES. resection of brain metastases are at risk for recurrence. This problem is estimated to occur in 30% to 50% of patients who undergo gross total resection of their brain tumors. A number of studies have addressed the feasibility of reoperation. Sundaresan et al (1988) reported a series of 21 patients with recurrent brain metastases who underwent reoperation. Patients were selected for reoperation if their performance status was good, their systemic disease was stable, and the brain metastases were surgically accessible. Median survival after reoperation was 9 months. There was no surgical mortality and minimal morbidity. Bindal et al (1995) reported a similar retrospective study of 48 patients who underwent reoperation for recurrent brain metastases. Postoperatively, 75% of patients improved neurologically, and the remainder stabilized. Median survival after reoperation was 11.5 months. There was no operative mortality or morbidity associated with the first reoperation. Twenty-six patients developed a second recurrence, and 17 had a second reoperation.

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Neuro-Oncology H Specific Tumor Types

Median survival for these patients was 8.6 months after second reoperation, as compared with 2.3 months for patients who did not undergo reoperation. Taken together, these studies suggest that reoperation is effective and safe in selected patients with good performance status, stable disease, and surgically accessible lesions. Radlation Therapy. Radiation therapy has been the cornerstone of treatment for brain metastases since 1954, when its efficacy was first reported. Although surgery is an attractive option for some patients, most do not qualify for this intervention. Common exclusion factors include the presence of multiple or inaccessible lesions and poor performance status. In contrast, radiation therapy can be delivered to most patients with a minimum of morbidity and mortality. The main goal of radiation therapy is palliation of neurologic symptoms related to metastases. WHOLE BRAIN RADIOTHERAPY. External beam WBRT typically is delivered to the entire brain down to the bottom of the C2 vertebral body. The effectiveness of WBRT has been studied over the past four decades by the Radiation Therapy Oncology Group (RTOG) with large randomized phase I11 trials. In the first two RTOG reports conducted between 1971 and 1976, the effectiveness of various dosage fractionation schemes was studied. Fractionation dosages varied from 2000 cGy over l week to 4000 cGy over 4 weeks. Symptoms were palliated in 75% to 80% of the patients. Overall median survival was 15 to 18 weeks. Brain metastasis was the cause of death in 40% of patients in both trials. Neither response rates, duration of improvement, nor survival were affected by treatment regimens. Subsequent studies have also failed to show a benefit in using ultra-rapid high-dose irradiation or accelerated fractionation. Earlier studies with radiosensitizers were also disappointing. However, recent studies using gadolinium texaphyrin, RSR #13, and temozolomide have shown slightly more promising results. Overall, there is no consensus regarding the best regimen of WBRT for patients with brain metastases. The available data suggest an equivalence of a wide range of treatment regimens and without a significant advantage of hyperfractionation. There does not appear to be a subgroup of patients who benefit from a particular regimen. Currently, the most common regimen involves treatment with 30 Gy in 10 fractions over 2 weeks. For patients with good prognosis who are likely to survive more than 1 year, more prolonged fractionation (e.g., 40 Gy in 2-Gy fractions) may reduce the long-term morbidity from radiation. POSTOPERII\TIVE WBRT. In patients who undergo surgery for their brain metastases, it has been standard practice to deliver WBRT after surgery. This assumption was based on previous studies that demonstrated functional improvement and survival advantage for patients who received WBRT. However, this assumption was not rigorously addressed until recently, when Patchell et al (1998) completed a randomized trial of postoperative WBRT in 95 patients with brain metastases. All patients underwent surgical resection of a single metastasis as assessed by MRI scan. Forty-nine patients received 50.4 Gy in 28 fractions over 5.5 weeks of postoperative radiotherapy; 46 patients were managed expectantly. Recurrence rates in the brain were significantly lower in the radiation group than in the observation group (18% versus 70%, respectively). This finding was true for both local recurrences (10% versus 46%) and distant recurrences (14% versus 37%). The median time to recurrence was longer in the radiation group than in the observation group (more than 52 weeks versus 27 weeks). Although overall median survival was similar for both groups (48 weeks versus 43 weeks), fewer patients in the radiation group died

of neurologic causes (14%versus 44%). There was no difference in the length of time that patients maintained functional independence. The authors therefore concluded that postoperative radiotherapy was beneficial to reduce neurologic morbidity. However, others have suggested that the lack of benefit for overall survival and functional independence must be weighed against the adverse effects of WBRT such as fatigue, alopecia, nausea, and dementia. REIRRADIATIONFOR RECURRENT DISEASE.In patients with recurrent disease, reirradiation remains a possible option. Patients typically receive 20 to 25 Gy of radiotherapy. Although neurologic improvement was noted in some studies, it was absent in others. Overall, the median duration of response ranged from 2.5 to 2.75 months and the median survival ranged from 2.5 to 4 months, suggesting that reirradiation produces only a very modest benefit. LATETOXICITY.As a result of aggressive treatment for brain metastases, there are an increasing number of long-term survivors. In these patients, late complications of WBRT can be debilitating. These complications include leukoencephalopathy and brain atrophy, leading to neurocognitive deterioration and dementia, brain necrosis resulting in more specific neurologic sequelae depending on the site of necrosis, and communicating hydrocephalus, causing cognitive, gait, and bladder dysfunction. Neuroendocrine dysfunction, such as hypothyroidism, may also occur. The risk of late complications from WBRT is related to total dosage, fraction size, patient age, extent of disease, and neurologic impairment at presentation. Prior or concurrent chemotherapy may also affect the occurrence of late CNS toxicity. If WBRT is to be given, a dosagelfraction schedule should be used that takes into account the overall clinical status of the patient while maximizing the palliation of symptoms and, if appropriate, minimizing the risk of long-term complications. In one retrospective review, 11% of patients treated with postoperative radiation therapy using fractions of 300 cGy or more showed evidence of dementia. Therefore, patients with good prognosis, such as those with single brain metastasis with controlled systemic disease, are best treated with daily fractions of 200 cGy or less to decrease the likelihood of long-term CNS toxicity (e.g., 40 to 45 Gy in 1.8- to 2.0-Gy daily fractions). Stereotactic Radiosurgery. Stereotactic radiosurgery is a technique of external irradiation that uses multiple convergent beams to deliver a high single dose of radiation to a radiographically discrete treatment volume. Radiosurgery can be performed with high-energy x-rays produced by linear accelerators, with gamma rays from the gamma knife and less often with charged particles such as protons produced by cyclotrons. All the stereotactic radiation techniques result in rapid dosage fall-off at the edge of the target volume, resulting in a clinically insignificant radiation dosage to normal nontarget tissue. Metastases usually are small (less than 3 cm) radiographically discrete lesions that are noninvasive, making them ideal targets for radiosurgery. An increasing number of uncontrolled studies confirm the effectiveness of stereotactic radiosurgery in treating brain metastases. Radiosurgery produces local control rates of 73% to 94% and is associated with a 5% to 10% risk of radiation necrosis. The median survival from these series ranges from 6 to 15 months, with an average of 9.4 months. In the largest reported study (Alexander et al, 1995), 248 patients with metastatic brain lesions were treated with radiosurgery. The majority of patients (69%) had a single lesion, and all received WBRT at a median dosage of 30 Gy. Radiosurgery was used to deliver radiation to the center of the lesion at a dosage ranging from 14 to 31 Gy. In these patients, the median survival

Chapter 171

was 9.4 months, with a local control rate of 89%. In multivariate analysis, age greater than 60 and the presence of systemic disease contributed to worse survival. The response was similar with both radiosensitive tumors such as breast cancer and radioresistant tumors such as melanoma. RADIOSURGERY VERSUS SURGERY FOR SINGLEBRAINMETASTASIS. The relative efficacy of both surgery and radiosurgery in the treatment of a single brain metastasis has provoked a debate over which modality should be first-line therapy. Many clinical investigators believe that radiosurgery can act as an alternative to surgical resection in patients with a single small brain metastasis. Moreover, radiosurgery has several potential advantages over surgery. It can be used to treat metastases in surgically inaccessible areas of the brain, such as the brainstem. Because it is a noninvasive procedure that can be performed on an outpatient basis, it is associated with less morbidity than surgery. There is also evidence that radiosurgery may be more cost-effective than surgery. Several retrospective studies suggest that the local tumor control rate and overall survival in patients treated with radiosurgery are comparable to those of patients treated with surgery, although there are other studies indicating that surgical treatment of single brain metastasis may be more effective. The mixed results of these studies highlight the importance of a prospective, controlled trial comparing surgery and radiosurgery. In general, surgery should be performed if the brain metastasis is producing significant mass effect and cerebral edema. For small brain metastases with little surrounding edema, radiosurgery probably is as effective as surgery and less invasive. ROLE OF RADIOSURGERYFOR MULTIPLE METASTASES. The role of radiosurgery after whole brain radiation for multiple metastases is less clear. An early study suggested that the use of radiosurgery in addition to WBRT in patients with two to four metastases significantly improved local tumor control and showed a trend toward improved survival. However, preliminary results from a larger randomized trial (RTOG trial-9508) showed no survival benefit for patients with two or three metastases. ROLEOF WHOLEBRAINRADIOTHERAPY. The role of whole brain radiotherapy in patients treated with radiosurgery is controversial, especially for patients with radioresistant tumors such as melanoma. In the study by Patchell et al (1998), 37% of patients failed in other sites within the brain if they did not receive whole brain radiation. Although some studies have shown improved local control in patients who received whole brain radiation therapy in addition to radiosurgery, overall patient survival generally is not increased. Currently most centers treat patients with brain metastases with both radiosurgery and WBRT and limit the use of up-front radiosurgery alone to cases in which there are no alternatives, such as patients who have received prior high-dose radiation to the head and neck area or those who refuse WBRT. However, several retrospective studies suggest that for selected patients radiosurgery alone may be as effective as the combination of radiosurgery and WBRT, with potentially less morbidity. Randomized studies comparing radiosurgery and the combination of radiosurgery and WBRT are currently under way to assess suMval, quality of life, and cost-effectiveness in patients with newly diagnosed brain metastases. hwuunoNs OF ~ K K U R G E R Y . Acute complications within the first week of treatment are uncommon, occurring in less than 10% of patients. They include seizures, headaches, exacerbation of preexisting neurologic deficits, nausea (especially in patients receiving radiation therapy to the brainstem), and rarely, hemorrhage. The risk of seizures can be reduced by treating patients with

Brain Metastases

1105

anticonvulsants before the radiosurgery procedure. Patients with lesions near the posterior fossa may benefit from premedication with antiemetics. Acute neurologic deficits can be reduced by using dosages less than 30 Gy. Subacute complications occurring within 6 months of treatment consists of alopecia in patients whose scalp received more than 4.4 Gy of radiation and neurologic deterioration caused by necrosis and peritumoral edema. Chronic complications caused by radiation necrosis occur in approximately 8% to 16% of patients. These patients present with increased seizures, headaches, or worsening neurologic deficits. These side effects usually can be treated with corticosteroids. However, 5% to 10% of patients develop severe symptomatic necrosis and may need surgical resection. Cranial nerve palsies are rare and develop in less than 1% of patients. PROGNOSTIC FACTORS.Young patients with good performance status, limited extracranial disease, and one or two small lesions are particularly suited to stereotactic radiosurgery. Poor prognostic factors include poor performance status (less than 70),progressive systemic disease, large tumor size, infratentorial location, and multiple metastases (more than two lesions). The efficacy of radiosurgery appears to be independent of the histology of the lesion. Radioresistant tumors such as renal cell carcinoma, malignant melanoma, and non-small cell lung cancer have statistically the same control rate as other tumors. Brachytherapy. Brachytherapy involves placing a radioactive source in close proximity to a brain tumor. In traditional radiotherapy such as WBRT or radiosurgery, radiation is delivered at a rate of several hundred cGy per minute. In contrast, the rate of delivery of radiation in brachytherapy is low, usually a few cGy/minute. This characteristic is thought to be advantageous because damage to normal tissue is proportional to the dosage rate. Ideally, brachytherapy provides lethal dosages of radiation to neoplastic tissue with minimal damage to normal tissue. Brain metastases have been treated with brachytherapy using radioactive iodine sources (iodine-125) and a photon radiosurgery system consisting of a battery-powered miniature x-ray generator with an attached probe that can be placed stereotactically into a tumor at the time of craniotomy to deliver a single fraction of high-dose radiation. Although preliminary results appear promising, the effectiveness of these approaches awaits more definitive studies. Chemotherapy. The role of chemotherapy for treating patients with brain metastases is limited and generally confined to patients with recurrent metastases who have failed surgery, radiation therapy, and radiosurgery. Traditionally, it had been assumed that the blood-brain barrier prevented chemotherapeutic agents from entering the central nervous system. However, there is evidence that the blood-brain barrier is partially disrupted within brain tumors. Other factors may also contribute to the disappointing results of chemotherapy for brain metastases such as the intrinsic resistance to chemotherapy of many tumors that metastasize to the brain, the use of chemotherapeuticagents designed to penetrate the blood-brain barrier rather than agents known to be most effective against the primary malignancy, and the tendency for brain metastases to develop after the failure of primary chemotherapeutic agents to control systemic disease. Although the overall results of chemotherapy for brain metastases have been poor, a number of uncontrolled studies have demonstrated favorable response rates in brain metastases from chemosensitive tumors such as breast cancer, small cell lung cancer, choriocarcinoma, germ cell tumors, and ovarian cancer (Fig. 171-2). In these patients chemotherapy may have a role as

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Specific Tumor Types

frequency of cerebellar metastases which are associated with an adverse prognosis. Recently, a recursive partitioning analysis of prognostic factors from three RTOG brain metastasis trials was performed and identified three prognostic classes. Class 1 patients with a Karnofsky performance status 70 or higher, less than 65 years of age with controlled primary and no extracranial metastases, had a median survival of 7.1 months. Class 3 patients had a Karnofsky performance status of less than 70 and a median survival of 2.3 months. Class 2 patients included all remaining patients and had a median survival of 4.2 months. Use of this classification may identify patients most likely to benefit from treatment and potentially allows new therapies to be evaluated on homogenous patient groups.

SUGGESTED READINGS

FIG. 171-2. Coronal MRI with gadolinium showing a 46-year-old woman with breast cancer and multiple brain metastases that recurred 7 years after prior whole brain radiation for an occipital metastasis. The patient underwent multiple chemotherapy regimens, and her brain metastases remained stable for the next 24 months.

Alexander E 111, Moriarty TM, Davis RB et ak Stereotacticradiosurgery for the definitive,noninvasive treatment of brain metastases. J Natl Cancer Inst 87:3449, 1995 Batchelor T,DeAngelis LM: Medical management of cerebral metastases. Neurosurg Clin North Am 7435-446, 1996 Bindal RK, Sawaya R, Leavens ME et al: Reoperation for recurrent metastatic brain tumors. J Neurosurg 83:600-604, 1995 Boyd TS, Mehta M P Stereotactic radiosurgery for brain metastases. Oncology 13:1397-1409, 1999 Davey P Brain metastases. Curr Probl Cancer 2359-98, 1999 Gaspar L, Scott C, Rotman M et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745-751, 1997

palliative therapy in patients with recurrent disease after radiotherapy or possibly as initial treatment in patients with small asymptomatic tumors. As newer drugs are introduced, the effectiveness of chemotherapy for brain metastases may improve. Hormonal Therapy. In patients with hormone-responsive tumors, such as breast cancer, there are anecdotal reports of patients responding to hormonal agents such as tamoxifen and megestrol acetate.

PROGNOSIS The median survival of patients with untreated brain metastases is approximately 1month. The addition of steroids increases survival to 2 months, and WBRT further improves survival to 3 to 6 months. Patients with single brain metastases and limited extracranial disease who are treated with surgery and WBRT have a median survival of approximately 10 to 16 months. Favorable prognostic factors include the absence of systemic disease, young age (less than 60 years), good performance status (Karnofsky performance status of 70 or greater), long time to development of metastasis, surgical resection, fewer than three lesions, and possibly response to steroids. Patients with brain metastases as the only manifestation of an undetected primary tumor also have a favorable prognosis, with an overall median survival of 13.4 months. Patients with breast cancer and brain metastases generally have a more favorable prognosis than those with brain metastases from other types of primary tumor. O n the other hand, patients with colorectal carcinoma tend to have a poorer prognosis. This may result from the tendency of these patients to have a higher

Glantz MJ, Cole BF, Forsyth PA et a1 Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 5 4 1886-1893, 2000 Grossman S: NCCN Adult brain tumor guidelines. Oncology 11:237-277, 1997

Lassman AB, DeAngelis LM. Brain metastases. Neurol Clin 2003 (in press). Lesser GJ: Chemotherapy of cerebral metastases from solid tumors. Neurosurg Clin North Am 7527-536, 1996 Levin JM, Schiff D, Loeffler JS et al: Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 43: 11 11-1 114, 1993

Mintz AP, Kestle J, Rathbone MP et al: A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single brain metastasis. Cancer 78:1470-1476, 1996 Patchell R Brain metastases. Handbook of Neurology 25:135-149, 1997

Patchell RA, Tibbs PA, Regine WF et ak Postoperative radiotherapy in the treatment of single brain metastases to the brain. JAMA 280:14851489, 1998

Patchell RA, Tibbs PA, Walsh JWet al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 3223496500, 1990

Posner J B Neurologic Complications of Cancer. F.A. Davis, Philadelphia, 1995

Sawaya R Considerations in the diagnosis and management of brain metastases. Oncology 15:11461158, 2001 Schaefer PW, Budzik RF, Gonzalez RG: Imaging of cerebral metastases. Neurosurg Clin North Am 7:393-423, 1996 Schiff D, DeAngelis LM: Therapy of venous thromboembolism in patients with brain metastases. Cancer 73:493-498, 1994 Shah B, DeAngelis LM Brain metastases. In Schiff D, Wen PY: Cancer Neurology in Clinical Practice. Humana Press, Philadelphia, 2002

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Sundaresan N, Sachdev V, DiGiacinto G Reoperation for brain metastases. J Clin Oncol6:1625-1629, 1988 Vecht CJ, Haaxma-Reiche EM, Noordijk GW et al: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 33583-590, 1993

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Wen PY, Black PM, Loeffler JS: Metastatic brain cancer. In DeVita V, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology.

6th Ed. Lippincott Williams & Wilkins, Philadelphia, 2000 Wen PY, Loeffler JS: Management of brain metastases. Oncology 13:941-961, 1999

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172 Spinal Cord Tumors Chima Ohaegbulam and Marc Eichler This chapter deals with spinal intradural tumors. These fall into two broad groups: intramedullary and extramedullary. Extradural tumors and vascular lesions are discussed in elsewhere in this book. EPIDEMIOLOGY The annual incidence of primary spinal tumors is variously cited as 3 to 10 per 100,000, with a prevalence of about 13 per 100,000. They are much less common than brain tumors, and all intradural spine tumors account for less than 20% of central nervous system (CNS) neoplasms in adults. Of these, less than a third are intramedullary and the rest are extramedullaryor intradural. This ratio is different in the pediatric population, with intramedullary tumors accounting for about half of all the intradural tumors. Of the extramedullary or intradural tumors in adults, the most common are nerve sheath tumors and meningiomas. Nerve sheath tumors are the most common intraspinal lesion in the general population, representing almost a third of all intraspinal masses in some series. They occur with similar frequency in both sexes, with a slight thoracic preponderance, and most commonly in the fourth decade of life. About 80% of meningiomas occur in women, and about 80% are located in the thoracic region. The striking regional predominance does not hold true in men, where there are about equal proportions of cervical and thoracic meningiomas. They are most common around the fifth to seventh decades of life. Of the intramedullary tumors, ependymomas are more common in adults and astrocytomas are more common in children. A variety of other intramedullary tumors are less common, including hemangioblastomas, dermoids, and epidermoids. Most hemangioblastomas are sporadic, occurring typically in young adults, but up to a quarter of patients have evidence of von Hippel-Lindau syndrome. They also tend to be single in about 80% of cases, but multiple lesions are not uncommon. Overall, about 90% of intradural tumors are benign and potentially resectable.

Among children, the most common intramedullary tumors are astrocytomas, of which about one fifth are high grade (anaplastic or ghoblastomas). Neuronal tumors (mostly gangliogliomas) follow closely, with ependymomas generally being the third most common group. Other tumors (oligodendrogliomas, mixed glial tumors, hemangioblastomas) account for a small minority. In adults, ependymomas account for more than half of intramedullary tumors. They are more common in men, with a peak incidence in the fourth decade. About a quarter of the intramedullary tumors are astrocytomas,with fewer than a quarter being high grade (around 10% in several series). Neuronal tumors form the third group, but these are fewer overall than the other less common tumors collectively (including mixed ghal tumors, oligodendrogliomas, hemangioblastomas, and metastases). PATHOLOGY

Astrocytomas These are invariably intramedullary, are largely avascular, and in about half of adult cases have a well-defined plane separating the tumor from adjacent neural tissue. In general, though, they have less well-defined planes than ependymomas. About 10% of astrocytomas are high-grade tumors, whereas the majority are low-grade fibrillary or pilocytic variants.

Almost half of all CNS ependymomas arise in the spinal cord, and of these about half arise from the filum terminale. In the latter location, the myxopapillary type predominates. These tumors may be partially exophytic, and in such cases they have been associated with disproportional elevations in cerebrospinal fluid (CSF) protein and even papilledema. They are generally well circumscribed and avascular, presumably arising from the ependymal lining of the central canal. Histologically, they are typified by sheets of cells with scattered pseudorosettes. The myxopapillary

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Sundaresan N, Sachdev V, DiGiacinto G Reoperation for brain metastases. J Clin Oncol6:1625-1629, 1988 Vecht CJ, Haaxma-Reiche EM, Noordijk GW et al: Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 33583-590, 1993

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Wen PY, Black PM, Loeffler JS: Metastatic brain cancer. In DeVita V, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology.

6th Ed. Lippincott Williams & Wilkins, Philadelphia, 2000 Wen PY, Loeffler JS: Management of brain metastases. Oncology 13:941-961, 1999

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172 Spinal Cord Tumors Chima Ohaegbulam and Marc Eichler This chapter deals with spinal intradural tumors. These fall into two broad groups: intramedullary and extramedullary. Extradural tumors and vascular lesions are discussed in elsewhere in this book. EPIDEMIOLOGY The annual incidence of primary spinal tumors is variously cited as 3 to 10 per 100,000, with a prevalence of about 13 per 100,000. They are much less common than brain tumors, and all intradural spine tumors account for less than 20% of central nervous system (CNS) neoplasms in adults. Of these, less than a third are intramedullary and the rest are extramedullaryor intradural. This ratio is different in the pediatric population, with intramedullary tumors accounting for about half of all the intradural tumors. Of the extramedullary or intradural tumors in adults, the most common are nerve sheath tumors and meningiomas. Nerve sheath tumors are the most common intraspinal lesion in the general population, representing almost a third of all intraspinal masses in some series. They occur with similar frequency in both sexes, with a slight thoracic preponderance, and most commonly in the fourth decade of life. About 80% of meningiomas occur in women, and about 80% are located in the thoracic region. The striking regional predominance does not hold true in men, where there are about equal proportions of cervical and thoracic meningiomas. They are most common around the fifth to seventh decades of life. Of the intramedullary tumors, ependymomas are more common in adults and astrocytomas are more common in children. A variety of other intramedullary tumors are less common, including hemangioblastomas, dermoids, and epidermoids. Most hemangioblastomas are sporadic, occurring typically in young adults, but up to a quarter of patients have evidence of von Hippel-Lindau syndrome. They also tend to be single in about 80% of cases, but multiple lesions are not uncommon. Overall, about 90% of intradural tumors are benign and potentially resectable.

Among children, the most common intramedullary tumors are astrocytomas, of which about one fifth are high grade (anaplastic or ghoblastomas). Neuronal tumors (mostly gangliogliomas) follow closely, with ependymomas generally being the third most common group. Other tumors (oligodendrogliomas, mixed glial tumors, hemangioblastomas) account for a small minority. In adults, ependymomas account for more than half of intramedullary tumors. They are more common in men, with a peak incidence in the fourth decade. About a quarter of the intramedullary tumors are astrocytomas,with fewer than a quarter being high grade (around 10% in several series). Neuronal tumors form the third group, but these are fewer overall than the other less common tumors collectively (including mixed ghal tumors, oligodendrogliomas, hemangioblastomas, and metastases). PATHOLOGY

Astrocytomas These are invariably intramedullary, are largely avascular, and in about half of adult cases have a well-defined plane separating the tumor from adjacent neural tissue. In general, though, they have less well-defined planes than ependymomas. About 10% of astrocytomas are high-grade tumors, whereas the majority are low-grade fibrillary or pilocytic variants.

Almost half of all CNS ependymomas arise in the spinal cord, and of these about half arise from the filum terminale. In the latter location, the myxopapillary type predominates. These tumors may be partially exophytic, and in such cases they have been associated with disproportional elevations in cerebrospinal fluid (CSF) protein and even papilledema. They are generally well circumscribed and avascular, presumably arising from the ependymal lining of the central canal. Histologically, they are typified by sheets of cells with scattered pseudorosettes. The myxopapillary

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variant has a papillary background, with microcystic vacuoles. This variant is especially prone to hemorrhage and can present as unexplained subarachnoid hemorrhage. Although almost all cases of this variant are histologically benign, they can behave in a biologically aggressive manner in younger patients. Though common in intracranial ependymomas, calcification is extremely uncommon in spinal ependymomas.

which contains acid mucopolysaccharides and tissue fluids, spreads apart the axons to produce the fusiform shape of a neurofibroma. They are circumscribed but not encapsulated. Malignant degeneration is an uncommon phenomenon in nerve sheath tumors, occurring in 1% to 10% of cases. These cases have a poor prognosis, and about half occur in patients with neurofibromatosis. Survival rarely extends beyond 1 year.

Hemandoblastomas

CLINICAL PRESENTATION

These are the most vascular intramedullary tumors, although their degree of vascularity varies. They are benign, discrete, well circumscribed, and generally amenable to surgical resection. Histologically, they are composed of endothelial cells intermixed with stromal cells containing fat and hemosiderin. The endothelial cells form masses, cords, and thin-walled blood vessels. Almost half of these tumors in the spinal region are associated with cysts, about two thirds when intramedullary hemangioblastomas alone are considered. The cysts can be very large and are lined with fibrillary neuroglia, similar to those seen in syrinxes. In about one quarter of cases, they are associated with von Hippel-Lindau syndrome.

Tumors of the spine present with varying combinations of pain and neurologic dysfunction (Table 172-1). In general, symptoms precede diagnosis by an average of about 2 years.

Teratomas and Dennoid and Epidermoid Tumors Teratomas are rare and occur in an intramedullary location. Dermoid and epidermoid tumors occur both in an intramedullary location and in the region of the cauda equina. They are generally slow-growing,benign tumors that are usually completely resectable because of their degree of encapsulation. Epidermoid tumors in the region of the cauda have been attributed to lumbar punctures presumably carrying cutaneous tissue into the thecal sac.

These tumors arise from arachnoid cell rests at the exit zones of nerve roots. They adhere to but do not arise from the dura. They are often lateral or ventrolateral to the cord. They are rarely dorsal. They are rarely caudal to the conus. They can often be separated from nerve roots and do not have the same intimate association with them that nerve sheath tumors have.

Nerve Sheath Tumors This group of tumors consists of schwannomas and neurofibromas. They are avascular tumors that arise from the dorsal roots of various segmental levels and can be intimately associated with the matrix of the involved nerve root. This can make sparing the associated nerve roots at surgery difficult. In less than a quarter of cases, they may have a dumbbell configuration when they follow the nerve root through the dural sleeve and foramen, and in these situations they may have larger extradural than intradural components. Rarely (about 1% of cases), the tumor may be entirely intramedullary. Schwannomas are slowly growing tumors composed of Schwann cells. They develop into neoplastic compact interlacing groups associated with fibrous strands. Mitoses are rare. Schwannomas usually are lobular rather than fusiform tumors and appear as masses that project from one side of the nerve. Neurofibromas consist of mixtures of fibroblasts and proliferated Schwann cells between dispersed nerve fibers. Their matrix,

Pain Pain is the cardinal symptom of spinal tumors and often is the only symptom present at the time of diagnosis, although this is more common with intradural extramedullary tumors such as meningiomas and nerve sheath tumors than with intramedullary tumors. Only about two thirds of intramedullary tumors present with pain because of the earlier manifestation of neurologic deficit with these tumors. Tumor compression of the spinal cord is suggested by the development of progressive severe back pain that is increased by coughing, sneezing, straining, and other Valsalva maneuvers. Nocturnal pain is common, and unlike the pain from disc herniations, the pain is often worse while recumbent and is partly relieved by standing or activity. Tumor compression of nerve roots (or plexus), such as with nerve sheath tumors, produces neuralgia or radicular pain. Such pain often is described as a severe, constant burning, sometimes with painful paresthesias or with sharp lancinating pains superimposed, radiating along the course of the involved nerve root or plexus. This pain can also be worse at night and should alert the examiner when this symptom is associated with myelopathy or impaired bowel or bladder function. The skin in the involved dermatome may be tender to the touch. A dermatomal distribution that is unusual for disc herniation should increase suspicion for a spinal cord tumor. Pain may be localized over the back because of local muscle spasm and may be associated with local tenderness as a result. Pain may also be referred to distant sites or have a “funicular” distribution (in the distribution of compressed long tracts of the spinal cord, often described as a cold, unpleasant sensation in the extremity). Other recognized pain syndromes include Lhermitte’s sign with upper cervical cord compression, bandlike pain around the chest or abdomen with thoracic cord lesions (which may be confused with angina pectoris, gallbladder disease, or appendicitis depend-

W TABLE 172-1.

Presenting Signs and Symptoms of Primary Spinal Tumors, Including Extradural Tumors

Sinn or Symptom

Pain Weakness Reflex change Autonomic dysfunction Sensory loss Mass Scoliosis

At Presentation1%)

85-1 00 40-75 35-45 5-20 30-50 15-60 10-70

Chapter 172

ing on side), and sciatica-like pain with lumbar involvement. Worsening of the pain with traction (such as straight leg raising) suggests compression or infiltration of the cauda, roots, or lumbosacral plexus.

Neurologic Dysfunction This is often a late finding with extrinsic compression but can occur earlier with intramedullary tumors. Progression can be arrested but often not reversed by treatment. It occurs as a result of edema, ischemia, or axonal injury. Slow progression is much better tolerated by the spinal cord and more likely to recover in general with treatment. Weakness typically is of an upper motor neuron type, but with cervical tumors a lower motor neuron upper extremity weakness can occur before the onset of symptoms in the legs. Motor dysfunction is more common than sensory loss or autonomic dysfunction. It occurs more often with malignant tumors, with weakness evident in more than half of these at presentation, whereas about a third of benign tumors display neurologic compromise at presentation. Ataxia caused by injury to proprioceptive pathways or spinocerebellar tracts is uncommon at presentation. Spinal cord deficits in general are symmetrical, whereas root symptoms tend to be asymmetrical. Compression of the spinal cord produces a myelopathy with weakness, sensory loss, and spasticity below the level of the lesion. Autonomic dysfunction may manifest as loss of bowel, bladder, or sexual function. Sensory loss my be patchy and involve some modalities more than others. As an example, intramedullary lesions destroying structures near the center of the cord may affect crossing pain and temperature fibers earlier than others. In addition, because of lamellation of the spinothalamic tracts, central lesions may affect lumbosacral fibers last, producing so-called sacral sparing.

SPECIFIC SYNDROMES Lesions of the upper cervical spine or near the foramen magnum sometimes are associated with a unique syndrome of disproportionate loss of position and vibration sense in the upper compared with lower extremities and atrophy of the intrinsic muscles of the hand. This is often accompanied by suboccipital pain. The reasons for this are not fully understood. Brown-Skquard syndrome and somatic pain may arise because of an eccentrically situated extramedullary tumor. Lower cervical and thoracic tumors may also cause a capelike sensory loss and Horner’s syndrome. Rarer neurologic signs include nystagmus and papilledema with upper cervical lesions. Tumors of the lumbosacral or conus medullaris regions affect the parasympathetic innervation of the bladder, bowel, and sexual organs and can lead to pictures of mixed upper and lower motor disorders. They may be mistaken for prostate disorders in men, uterovaginal prolapse in women, and even psychological problems. Tumors of the cauda equina may selectively impair the function of a single dorsal root for several months, leading to a discrete dermatomal syndrome that may be mistaken for a disc prolapse. In younger children, extremity weakness, gait difficulty, deformities of the feet (such as pes cavus or talipes equinovarus), and kyphoscoliosis may lead to orthopedic referral, although they actually result from intraspinal pathology.

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Hydrocephalus has been reported with spinal cord tumors, especially where there is a high CSF protein content. There is a higher association with upper cervical tumors.

DIAGNOSTIC TESTS CSF Studies CSF studies have no role today in diagnosing spinal cord tumors. Historically, a high CSF protein has been associated with the phenomenon of spinal block, and ependymomas in particular have been associated with particularly high CSF protein levels. Ranges for protein reportedly run from 50 mg/dL to more than 2000 mg/dL. Glucose typically is normal except with meningeal tumors. Plain Radiographs Plain films are not typically requested when evaluating these lesions but sometimes show abnormalities in certain cases. Less than 40% of patients with intramedullary tumors have abnormal plain films. Nerve sheath tumors can produce scallopingof vertebral bodies and widening of the neural foramina. Meningiomas also can produce pedicle erosions and widening of the foramina, although not as commonly as with neurofibromas. Intramedullary tumors that cause enough fusiform expansion of the cord can produce erosion of the pedicles or of the posterior surface of the vertebral bodies as well.

Computed Tomography Computed tomography (CT) has largely been supplanted by magnetic resonance imaging (MRI) but is still useful especially where the latter is contraindicated or unavailable or cannot be completed because of patient cooperation. High-resolution scans are acquired before and after the administration of intravenous contrast. MRI

This is now the mainstay of diagnosis of spinal cord tumors. For most spinal imaging, T1- and T2-weighted images are obtained. MRI shows compression or deformation of the cord, enlargement of the cord, masses in or near the cord, edema, or hemorrhage. The tumors often show enhancement with intravenous gadolinium administration. Studies for spinal cord tumor should always be done with and without gadolinium enhancement. Noncontrast MRI can have a very low yield for certain tumors, especially leptomeningeal and secondary tumors, for which even myelography may be more sensitive than noncontrast MRI. Astrocytomas and ependymomas are generally both T1 dark intramedullary lesions on MRI that produce fusiform enlargement of the cord. Figures 172-1 and 172-2 show MRIs of typical lesions. Inhomogeneity may be caused by hemorrhage or cystic components. T2 images are helpful in showing surrounding edema but can make these tumors appear less well defined and larger than on corresponding T1 images (Fig. 172-26). Most of these tumors enhance with gadolinium, although ependymomas appear to enhance more brightly, uniformly, and with sharper margins than astrocytomas. Cysts often are present (more commonly with ependymomas than astrocytomas) and may be intratumoral cavities or rostral or caudal to the tumor. In the latter locations,

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FIG. 172-1. Astrocytoma: high-grade. (A) Sagittal T I -weighted MRI of a cervical high-grade astrocytoma. (B) Sagittal T1-weighted MRI of same tumor after intravenous administration of gadolinium. (C) Sagittal T2-weighted MRI of same tumor. (0)Axial TI -weighted image of same tumor after intravenous administration of gadolinium. Note relative isointensity of lesion on T1-weighted images and enhancement after gadolinium. T2-weighted image shows more extensive signal abnormality than gadolinium enhancing area, probably highlighting areas of edema. Expansion of the cord is well seen in these images, as well as in the axial image shown.

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FIG. 172-2. Ependymoma. (A) Sagittal TI-weighted MRI of a cervical ependymoma. (B) Sagittal Tl-weighted MRI of the same tumor after intravenous administration of gadolinium. (C) Sagittal T2-weighted image of same tumor more clearly shows the inferior tumor syrinx. Note isointensity of lesion on T1-weighted images, with polar cysts. There is bright enhancement after gadolinium administration. This occurs more than with the astrocytoma in Fig. 172-1. This lesion also has sharper borders.

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FIG. 172-3. Myxopapillaryependymomas. (A) Sagittal T1-weighted MRI of a terminal myxopapillary ependymoma. (B) Sagittal T1 -weighted MRI after intravenous administration of gadolinium. (C) Sagittal T2-weighted MRI of the same lesion. (0) Axial T1-weighted image after gadolinium. The axial image shows the large mass filling the spinal canal below the level of the conus medullaris; an axial image at this level typically would contain only free netve roots in CSF. The sagittal images show a fairly typical enhancing extramedullary intradural mass below the level of the conus.

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they are often not of tumorous origin. Cysts appear as low intensity on T1 and high intensity on T2 images (Figs. 172-2B and 172-2C). Myxopapillary ependymomas are most common at the filum terminale (Fig. 172-3). Other features that may help d.istinguish ependymomas from astrocytomas include the following: Ependymomas tend to be more central than astrocytomas. Ependymomas occur far more often in the lower cord and conus than astrocytomas. Ependymomas are more likely to hemorrhage. Hemangioblastomas often are irregular and diffuse on nonenhanced MRI. They may be heterogeneous, reflecting cavities within the tumor. A uniformly enhancing nodule associated with a well-defined cyst strongly suggests hemangioblastomas (see Fig. 172-6A), and enhanced MRI may also reveal small, unsuspected solid tumor nodules elsewhere in the CNS. Teratomas tend to be heterogeneous on MRI. Fatty components with high signal intensity in calcific areas with low signal intensity are well demonstrated with T1- and T2-weighted images. Lipomas share the same imaging characteristics as subcutaneous fat, being bright on T1-weighted images. Melanomas also have a similar appearance. Metastases often are nonspecific in their appearance, with cord widening, increased T2 signal, and contrast enhancement. The diagnosis is suspected in the setting of multiple lesions, especially where there is known primary malignancy elsewhere. The size of the metastasis often is disproportionately small compared with the amount of edema, and these lesions are only rarely associated with cysts. Schwannomas (Fig. 172-4) and neurofibromas have similar appearances on MRI, both tending to be smoothly rounded and well marginated, isointense or slightly hypointense on T1weighted images relative to the cord, with increased T2 intensity and intense enhancement in an extramedullary location. Figure 172-5 shows a meningioma compressing the conus medullaris. Hypodense centers may be present, representing a dense collagenous stroma, and heterogeneous enhancement has been described. Nerve sheath tumors can grow through neural foramina, resulting in a dumbbell shape. The extradural component of these lesions can sometimes be larger than the intradural part. In the cauda equina they may be attached to a nerve root, free from the dura. Meningiomas are also generally rounded and sharply marginated and displace or compress the spinal cord. They are usually isointense on T1-weighted images and isointense or slightly hyperintense on T2-weighted images. Intense uniform enhancement usually is the case. Calcification may result in irregular enhancement and signal voids. Enhancement of a dural tail also suggests a durally based lesion and thus a meningioma. Although nerve sheath tumors and meningiomas can appear very similar, the former tend to be ventrolateral to the cord, are occasionally multiple, may extend through a neural foramen, may have a central focus of decreased signal, and may be attached to a nerve root free from the dura. Meningiomas tend to be posterolateral (except in the cervical spine), usually are solitary, are dural based, and only rarely extend through a neural foramen.

We~osrsPhY Myelography has also been largely supplanted by MRI. It has a role similar to CT in localizing the level and compartment (intradural

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vs. extradural) of the lesion, and it has very limited value for lesion characterization. It classicallyshows fusiform widening of the cord with intramedullary tumors, distinct from extradural tumors that produce an hourglass deformity (with incomplete spinal block) or “paintbrush effect” (with complete block). Intradural or extramedullary tumors produce a “capping” effect with a sharp cutoff (meniscus sign). However, the latter may be enhanced by CT after the myelogram while contrast remains in the thecal sac. CT myelography is the procedure of choice in patients who cannot undergo MRI.

Though not necessary for diagnosis, angiography is sometimes necessary for surgical planning, primarily to identify the artery of Adamkiewicz. Occasionally, uncertainty as to diagnosis after CT and MRI can be resolved by angiography. A hemangioblastoma usually demonstrates a dense homogenous stain lasting from the early arterial phase to the late venous phase, and individual vessels usually are not seen (see Fig. 172-6B). The presence of an early draining vein or dilated feeding arteries suggests the presence of an arteriovenous malformation instead. Embolization of vascular tumors such as hemangioblastomas, meningiomas, and nerve sheath tumors is also a consideration. From a diagnostic point of view, clues to these tumors’ presence may be a vascular blush on a spinal angiogram.

DIFFERENTIAL DIAGNOSIS Vascular lesions, including arteriovenous malformations. Inflammatory myelitis. Figure 172-7 shows a case of neurosarcoidosis involving the spinal cord. Demyelinating disease. Paraneoplastic myelopathy. Diseases of vertebral structures. Syringomyelia.

MANAGEMENT SUWY The first reported resection of an intramedullary tumor of the spinal cord was carried out by Victor Horsley in 1887. It is the mainstay of treatment of these lesions. Several developments in the last few decades have made such operations significantly safer, including the operating microscope, improved preoperative and intraoperative imaging and localization, bipolar coagulation and surgical lasers for controlling bleeding from small vessels while limiting any injury to adjacent neural tissue, and the ultrasonic aspirator for quickly debulking tumor without displacing tumor or injuring adjacent neural tissue. A dorsal approach to the spinal cord typically is needed, with a laminectomy and opening of the dura. Most extramedullary tumors can be resected in this fashion, with due care being taken to avoid too much traction or pressure on the spinal cord. This dorsal approach is useful even for fairly ventral tumors. Occasionally, a tumor that is predominantly ventral to the cord may necessitate a more complex approach. Intramedullary tumors generally necessitate a posterior midline incision into the cord itself, but the general avascularity of

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these lesions and the well-defined planes around them in many cases assist the goal of safe resection. Even tumors involving nearly the entire length of the spinal cord have been resected in this manner, sometimes necessitating multistage operations. Intraoperative monitoring with somatosensory evoked potentials is sometimes used to signal when cord function is affected during tumor removal and might therefore lead to terminating surgery in a subtotal resection if continuing may lead to irreversible injury to adjacent neural tissue.

FIG. 172-4. Schwannoma. (A) Axial TI-weighted MRI of a thoracolumbar region schwannoma. (B) Axial T I -weighted image after intravenous administration of gadolinium. (C) Sagittal T1weighted MRI of the same lesion. (0) Coronal T2-weighted MRI of the same lesion. Note the isointensity of the lesion on the T1 image and very bright enhancement with gadolinium. There is a hypodense center to the lesion, common with nerve sheath tumors. The extradural location of the lesion is well appreciated on the coronal image.

Spinal stability after the operation is a consideration that may necessitate the implantation of hardware after extensive laminectomies to maintain alignment of the spine. With intramedullary tumors in particular, some transient worsening of spinal cord function is not uncommon. This is typically managed expectantly and with the use of steroids and may be especially important in surgery on the cervical cord, where prolonged intubation postoperatively may be necessary to ensure ventilation and airway protection. The same phenomenon will

Chapter 172

also tend to produce some bowel and bladder difficulty after resection of lumbosacral tumors.

Radiation Extramedullary or intradural tumors, most of which are benign, are totally resected and do not necessitate radiotherapy. For intramedullary tumors, initial encouraging reports on the benefit of postoperative radiotherapy have been disputed by several more recent studies. There is mixed evidence at present showing any benefit from radiation therapy in improved recurrence-free survival in patients who have had adequate clinical and MFU follow-up. Most authorities at present do not recommend radiation where there has been total resection of an intramedullary tumor. In many centers, subtotal resection of a tumor also is managed expectantly. Limited resection of a tumor, which is more common with astrocytomas than with ependymomas, is followed up with radiation in many institutions. Germinomas are very radiosensitive, whereas nongerminomatous germ cell tumors are much less so. Generally, more malignant tumors (such as anaplastic astrocytomas and glioblastomas) are radiated, although there are controlled studies documenting the degree of any benefit. Chemotherapy Chemotherapy is used to a much more limited extent than surgery or radiotherapy. The deleterious effects of radiotherapy on the

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developing spinal cord and adjacent spine have made chemotherapy more attractive in children to minimize radiation dosages. For astrocytomas, chemotherapy tends to be used for recurrent or incompletely resected tumors and appears to have benefit with or without additional radiation, although it is most commonly used along with radiation. Vincristine and carboplatin are the most widely used agents, along with etoposide and thiotepa, among other agents. Ependymomas typically have been treated using regimens drawn from the intracranial literature, most commonly applying vincristine, carboplatin or cisplatin, etoposide and ifosfamide. The literature suggests that there is minimal if any benefit to chemotherapy in this context, and the only randomized study of intracranial ependymomas showed no survival benefit with chemotherapy, although response to treatment has been documented in several studies. Chemotherapy is very effective for CNS germ cell tumors, (germinomas and nongerminomatous types). The effective agents include carboplatin and cisplatin, bleomycin, and vincristine. However, only two cases of intramedullary germ cell tumors treated with chemotherapy are reported in the literature, and the chemotherapy was used in combination with surgery and irradiation. Response was transient, and authors in both cases recommended surgery followed by irradiation for these lesions and could not comment on chemotherapy. Only eight patients with intramedullary metastases treated with chemotherapy have been reported in the literature. Intravenous chemotherapy occasionally improves survival, but its overall benefit is limited, especially in the context of disseminated

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FIG. 172-5. Meningioma. (A) Axial TI-weighted MRI of a lower thoracic meningioma after intravenous administration of gadolinium. (B) Sagittal TI -weighted MRI with gadolinium of same lesion. Note the posterolateral relationship of the tumor

to the conus medullaris.

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FIG. 172-6. Hemangioblastoma. (A) Sagittal T1 -weighted MRI after intravenous administration of gadolinium. (B) Selective spinal arteriogram of the cervical region in the same patient. Note the bright enhancement with gadolinium and the cranial area of hypodensity representing a typical polar cyst. There is a dense tumor blush on the arteriogram, which is also typical of hemangioblastomas.

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B FIG. 172-7. Sarcoidosis. (A) Sagittal T1-weighted MRI after intravenous administration of gadolinium. (B) Sagittal T2weighted image of the same lesion. This patient has diffuse enlargement of a long segment of the cord, enhancing with gadolinium and hyperintense on T2-weighted images.

systemic disease. Intrathecal chemotherapy has a role in leptomeningeal metastases but has not been shown to be of any benefit for intramedullary disease. OUTCOMES The prognosis with extramedullary or intradural lesions is generally very good. These are typically benign and can be completely resected, resulting in complete cure. Even patients with significant preoperative deficits generally continue to improve for 18 to 24 months after surgery. Most intramedullary tumors are also benign and resectable. Several technical advances in the last few decades have led to increasing success at complete resection with low operative mortality. Postoperative results generally are most closely related to preoperative neurologic condition. When there are maximal deficits before surgery, the absence of significant recovery tends to be the rule. When there are mild or modest deficits, excellent functional recovery may be expected. Resection of most tumors tends to be complete, with very low recurrence rates. When only a partial resection is accomplished, the subsequent course depends on the growth pattern of the tumor. Recurrence-free survival is generally better with ependymomas than with astrocytomas, being up to 75% at 10 years (with 100%

survival in some series with the former and up to 25% with the latter). The myxopapillary variant fares better than classic ependymomas. Malignant tumors tend to be associated with significant operative morbidity and carry a poor overall prognosis. SUGGESTED READINGS Balmaceda C Chemotherapy for intramedullary spinal cord tumors. J Neurooncol 47(3):293-307, 2000 Eichler ME, Dacey RG Intramedullary spinal cord tumors. pp. 2089-2102. In Bridwell KH, Dewald RL (eds): The Textbook of Spinal Surgery. Lippincott-Raven, Philadelphia, 1996 Greenberg MS: Intramedullary spinal cord tumors. pp. 336-339. In Handbook of Neurosurgery. Greenberg Graphics, Lakeland, FL, 1997 Isaacson S R Radiation therapy and the management of intramedullary spinal cord tumors. J Neurooncol47(3):231-238,2000 McCormick PC, Post KD, Stein BM: Intradural extramedullary tumors in adults. Neurosurg Clin North Am 1(3):591408, 1990 McCormidc PC, Stein B M Intramedullary tumors in adults. Neurosurg Clin North Am 1(3):609430, 1990 Sze G: Neoplastic disease of the spine and spinal cord. pp. 1339-1385. In Atlas SW (ed): Magnetic Resonance Imaging of the Brain and Spine. . Lippincott-Raven, Philadelphia, 1996

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173 Peripheral Nerve Tumors John K. Park Peripheral nerve tumors are uncommon, with an estimated annual incidence of several thousand cases each year. Of the many classification schemes in use, the most practical from a treatment standpoint is to divide them initially into benign or malignant and then subdivide them according to their presumed cell of origin. The most common benign tumors are schwannomas and neurofibromas. Less common tumors include plexiform neurofibromas, neurothekeomas, Pacinian neurofibromas, epithelioid neurofibromas, perineuriomas, ancient schwannomas, and pigmented schwannomas. The most common malignant tumors are malignant nerve sheath tumors, also called neurogenic sarcomas, malignant schwannomas, or neurofibrosarcomas. Additional malignant tumor types include malignant epithelioid schwannomas, neuroepitheliomas, and malignant schwannomas with rhabdomyoblastic or glandular differentiation. Metastatic tumors can also occur in peripheral nerves, with breast and lung carcinomas being the most common primary sources. A careful history and physical examination will suggest the presence of a peripheral nerve tumor. Imaging and electrophysiologic studies can provide useful additional information. When indicated, an experienced peripheral nerve surgeon and neuropathologist should be enlisted to confirm the diagnosis with a minimal degree of morbidity and a maximal likelihood of accuracy. Surgical resection often is curative for benign lesions, but malignant tumors often necessitate adjuvant therapies. When sacrifice of an important motor nerve is necessary to achieve a complete tumor resection, a cable nerve graft should be considered and discussed with the patient preoperatively. Intraoperative nerve stimulation and recording techniques can facilitate surgical decision making and should be used routinely.

CLINICAL DIAGNOSIS A palpable mass associated with pain or paresthesias in the distribution of a peripheral nerve is highly suggestive of a peripheral nerve tumor. Tumors can also present as asymptomatic masses in the absence of any neurologic symptoms or, less commonly, in association with weakness in a specific group or groups of muscles. The rate of growth of the mass, rate of progression of symptoms, presence of constitutional symptoms such as fever or weight loss, history of other cancers, and any trauma or radiation to the region should be elicited. A family history of peripheral nerve tumors or neurofibromatosis should also be sought. Examination of the mass should include notice of any erythema, warmth, or fluctuance in the overlying and surrounding skin. Manipulation often can induce or exacerbate preexisting sensory symptoms, resulting in a positive Tinel's sign. Additionally, the mass will have greater mobility in the direction perpendicular to the axis of the associated nerve than parallel to it. A thorough motor and sensory examination should be performed to determine the degree of neurologic disability resulting from the mass. A comprehensive general examination should also be performed to look for any associated findings, particularly if a diagnosis of neurofibromatosis is suggested.

DIAGNOSTIC TESTING Contrast-enhanced magnetic resonance imaging (MRI) is the radiographic study of choice for a suspected peripheral nerve tumor. The size, shape, and relationship of the mass to adjacent anatomic structures such as neural elements, vascular structures, muscles, bones, and joints can be determined. Benign schwannomas are characteristically elliptical or spherical in shape and are isointense to muscle on TI- and hyperintense on T2-weighted images. They can enhance brightly after intravenous contrast material is administered and often have associated entering, exiting, or circumferentiallydisplaced surrounding nerve fascicles. In contrast, neurofibromas often are fusiform or plexiform in shape. They can also be isointense to muscle on T1- and hyperintense on T2-weighted images, but circumferentially displaced fascicles are rare. Malignant lesions tend to be less circumscribed and can be seen spreading along or across fascia1 planes. Complementary studies include computed tomography scans to evaluate the surrounding bony anatomy, angiograms to assess nearby blood vessel flow and tumor vasculature, and myelograms to determine spinal cord and nerve root compression. Although imaging studies can suggest certain tumor types, a pathologic diagnosis should be sought whenever possible. Imaging studies also can be useful for monitoring asymptomatic and previously resected tumors. Electromyographyand nerve conduction can be useful adjuncts to the history and neurologic examination. They are a secondary means of documenting the degree of neurologic dysfunction either at the time of presentation or over time in patients with lesions managed with watchful waiting. Because their utility in differentiating between the various types of tumors is limited, they are not routinely indicated in patients planning to undergo surgical exploration. BENIGN TUMOR TYPES Schwannoma Schwannomas are the most common nerve sheath tumors and are generally benign. They occur as single or, less commonly, as multiple lesions along a Schwann cell myelinated nerve. The peak incidence is during the fourth and fifth decades of life, but they can occur at any age. Intracranial tumors typically arise in cranial nerves in the transition zone where oligodendroglial myelination ends and Schwann cell myelination begins. The vestibular nerve is the most frequently involved cranial nerve, and tumors are called acoustic neuromas or vestibular schwannomas. The presence of bilateral acoustic neuromas is diagnostic for the inherited disorder neurofibromatosis 11. Intraspinal schwannomas can form on spinal nerve roots, again typically in the myelination transition zone. Larger tumors can have both an intradural and extradural component, resulting in myelopathic or radiculopathic findings, respectively. Extraspinal or distal peripheral nerve schwannomas are most commonly detected as slow-growing asymptomatic masses. They can occur on sensory, motor, or autonomic nerves,

Chapter 173

more often on flexor surfaces. Symptomaticlesions are more likely to present with palpation- or motion-induced pain or paresthesias. Schwannomas arising on nerves within confined anatomic spaces occasionally can cause signs and symptoms secondary to an entrapment syndrome. Pathologically, tumors arise from a single nerve fascicle and typically are smooth and thickly encapsulated. They are eccentrically located, and the remaining fascicles of the parent nerve are displaced to one side or splayed circumferentially. Plexiform schwannomas are a rare exception to this and result from the diffuse schwannomatous transformation of multiple nerve fascicles, commonly in the skin. In general, smaller schwannomas tend to be solid gray-tan masses, whereas larger ones are lobulated, cystic yellow masses. Microscopically, most tumors are made up of two distinctive architectural tissue patterns, Antoni A and Antoni B. Antoni A tissue is made up of tightly packed elongated cells with long, often asymmetrical nuclei. A sharply localized, densely compacted region in which there is palisade-like alignment of nuclei is called a Verocay body. Antoni B tissue, in contrast, is made up of loosely arranged vacuolated cells with round, hyperchromatic nuclei. The significance of these patterns on rate of tumor growth, predisposition to malignant transformation, and overall prognosis is unknown. Additional histologic findings can include cyst formation, interspersion of pyknotic Schwann cell nuclei, overgrowth of collagen, hyahization of tumor vessels, and lack of axons. Immunohistochemical staining commonly reveals reactivity for S-100 protein, Leu-7, and myelin basic protein. The pathologic differentiation of schwannomas from neurofibromas is discussed later in this chapter. Indications for surgical exploration of a presumed schwannoma are increasing size or increasing neurologic symptoms. Intraoperatively, most lesions are found to have a single entering and exiting nerve fascicle. Upon electrical stimulation, this fascicle often no longer passes a nerve action potential and should be removed with the tumor. The remaining nerve fascicles usually are displaced by the tumor, and close attention should be paid to carefully freeing them from the tumor capsule. Complete resection is possible in most cases. Recurrence of completelyresected lesions is uncommon, and incompletely resected lesions should be followed with serial MRI scans to monitor for regrowth. Neudbroma

Cutaneous neurofibromas are seen most commonly as isolated lesions but can also occur in association with neurofibromatosis-1 (NF-1). A further discussion of NF-1 is presented in Chapter 166. The tumors arise from small peripheral nerves in the dermis and elevate the skin as protuberant or pedunculated masses. They are usually asymptomatic, but their prominence can lead to secondary irritation of the overlying skin. They can also be cosmetically disfiguring, particularly given their multiplicity in patients with NF-1. Microscopically, the curved and twisted Schwann cell nuclei usually are dispersed in a wavy matrix of collagen. The Schwann cell processes are poorly discernible, and nerves, blood vessels, lobules of adipose tissue, and cutaneous adnexa are surrounded by the neoplastic cells. Some tumors have a fibroblastic appearance because of the fascicular alignment of tumor cells, whereas others have an areolar appearance because of the predominance of Schwann cells. In contrast to intraneural neurofibromas, the originating nerves of cutaneous lesions usually are unidentifiable.

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Indications for surgical resection include increasing size or worsening symptoms. Stable, asymptomatic lesions should be followed unless they are cosmetically unacceptable because these lesions rarely undergo malignant transformation. Given their superficial location, most lesions typically can be removed completely without any neurologic deficit, and incompletely resected lesions infrequently recur. Intraneural neurofibromas are less common than their cutaneous counterparts and usually occur as a diffuse transformation of a deeper, larger nerve segment and its branches. The term plexiyorrn neurofibrorna is applied to these lesions, and they are usually associated with NF- 1. A less common intraneural neurofibroma subtype occurs as a discrete solitary lesion in the absence of NF-1. Even rarer are segmental neurofibromas, which are limited to a specific anatomic region of the body and are not associated with an inherited disorder. Intraneural neurofibromas have a predilection for the cervical, brachial, and lumbosacral plexuses, but they can occur in the skin as well as a variety of visceral and connective tissue sites. Pathologically, intraneural plexiform neurofibromas have a beaded string appearancewhen small sensory or autonomic nerves are involved. When larger nerves are affected, tumors take on a ropelike appearance with obvious enlargement of the external fascicle. The consistencyvaries from firm to gelatinous to mucoid, and tumors cut in cross-section often have a translucent appearance. Solitary intraneural neurofibromas can resemble schwannomas but are differentiated by their fusiform symmetric nerve expansion and lack of heavy encapsulation. All intraneural neurofibroma subtypes contain nerve fibers integral to the tumor mass. In between the widely dispersed axons are chaotically arranged neoplastic Schwann cells and perineural cells and fibroblasts. The amount of mucopolysaccharide and collagen-rich extracellular matrix varies from tumor to tumor but is consistently greater than the miniscule amounts found in schwannomas. Marked hypercellularity and mitotic activity suggest malignant transformation, whereas nuclear pleomorphism in the absence of these two features is more suggestive of degeneration. Because malignant changes can be focal, multiple regions of the tumor should be surveyed. Immunohistochemical staining is positive for vimentin as well as, in most cases, Leu-7 and S-100. However, the S-100 staining is not as robust as that found in schwannomas. Indications for resection again include increasing size, pain, motor deficit, or sensory deficit. In contrast to cutaneous neurofibroma resection, intraneural neurofibroma resection often leads to neurologic deficit. There should be a low threshold for surgical intervention, however, because 5% to 10% of plexiform neurofibromas undergo malignant transformation.

Neurothekeomas are benign, nodular tumors of the nerve sheath that most commonly occur in children and young adults. They often present as a soft, mobile mass arising in the dermis of the head, neck, or shoulders, but other body parts can also be affected. Other names for this tumor include nerve sheath myxornu, pacinian neurofibroma, and cutaneous neurofibroma. Microscopically, the tumors consist of epithelioid, stellate, or spindle-shaped cells with elongated nuclei and prominent eosinophilic cytoplasms. The cells form discrete lobules and nests separated by well-formed fibrous septae. Nuclear polymorphism and multinucleation are common, but mitotic figures are rare. The variable stroma is myxoid and contains acid mucopolysaccharides.

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The cell of origin is a matter of controversy, with the leading candidates being perineurial cells and Schwann cells. Neurothekeomas should be treated similarly to schwannomas and often are confused with them preoperatively. Resection often is curative because local recurrence is rare.

Perineurioma Perineuriomas are rare benign lesions that typically present as localized masses in the soft tissues of the extremities, most often in adolescents and young adults. They commonly cause a motor mononeuropathy and may in reality be a reactive proliferative process rather than a true neoplastic process. The affected nerve usually is grossly enlarged, often for distances of greater than 10 cm. Microscopically, the majority of the nerve fascicles are hypercellular and composed of onion bulb-like collections of cells about a centrally placed axon. The cells are positive for epithelial membrane antigen and negative for S- 100, indicating a perineurial rather than Schwann cell origin. As with the other benign tumor types, treatment should be dictated by the clinical picture. Complete resection often is curative and can be achieved with minimal neurologic deficit by an experienced peripheral nerve surgeon. Malignant transformation of lesions has not been reported.

MALIGNANT TUMOR TYPES Malignant Peripheral Nerve Sheath Tumor A malignant peripheral nerve sheath tumor (MPNST) is also called a malignant neurofibroma, malignant schwannoma, neurogenic sarcoma, malignant neurilemmoma, or neurofibrosarcoma. The tumor can arise either de novo or secondary to the malignant transformation of a plexiform neurofibroma. Less commonly, the tumor can also result from the transformation of a solitary intraneural neurofibroma or ganglioneuroma but only rarely from a schwannoma or dermal neurofibroma. MPNSTs account for 10% of soft tissue sarcomas and occur with an approximate incidence of 1 in 100,000 in the general population. Approximately 5% of patients with NF-1 develop an MPNST, and 40% to 60% of lesions arise in the setting of NF-1. A previous radiation history is associated with 10% of tumors. The typical tumor presents as a painful expanding mass, and a neurologic deficit in the distribution of the involved nerve is common. Radiographic evaluation of suspected MPNSTs should include an MRI to determine the size and extent of the tumor and to screen for metastases. They often have irregular indistinct margins. Gallium-67 citrate scintigraphy has been reported to be of some benefit in distinguishing benign from malignant lesions in patients with NF-1. Common sites of involvement include the large nerves of the neck and extremities as well as the retroperitoneum, mediastinum, and viscera. Pathologically, the tumor has a firm, fleshy consistency and ranges in color from tan-white to reddish-blue. Softer yellow areas of frank necrosis are common. The microscopic appearance of MPNSTs is variable, and tumors can consist of neoplastic spindle-shaped cells interposed with myxoid and hypocellular zones or cells tightly packed into fascicles in a herringbone pattern. Mitoses and infiltration of tumor cells into the fascicles of the parent nerves are common, as is the growth of cells within the walls of or immediately adjacent to small vessels. Approximately 10% of tumors also have “metaplastic” elements including skeletal muscle, bone, cartilage, and epithelial tissues. An example is a

Triton tumor, which includes elements of a rhabdomyosarcoma and a malignant schwannoma. Although MPNSTs commonly arise from neurofibromas, the proliferating cells were positive for S- 100, Leu 7, and myelin basic protein staining in 56%, 58%, and 42% of cases in one series, indicating a Schwann cell origin. Other tumors were absent for these markers, indicating a “generic” mesenchymal cell origin for MPNSTs. MPNSTs are highly malignant, and 5-year survival rates range from 10% to 50%, with a poorer prognosis in patients with NF-1. Local growth and hematogenously spread metastases, particularly to the lungs, soft tissue, bone, or liver, are common. When an MPNST is suspected, patients should be carefully instructed about the risks, benefits, and alternatives to a radical excision because loss of neurologic function is likely to occur. The preferred initial treatment is complete tumor resection rather than a partial debulking because there is a high risk of local recurrence. Whenever possible, an aggressive resection of the adjoining soft tissue should be performed, with the preservation of uninvolved major nerves, arteries, and veins. If the diagnosis of an MPNST is in doubt or occurs unexpectedly on the frozen section analysis, it may be reasonable to perform a biopsy only, await the results of the permanent section analysis, and return to the operating room at a later date for a definitive resection. If not already performed, a staging workup including a chest, abdomen, and pelvis CT and bone scan should be obtained. Although the local recurrence rate is theoretically lower with the amputation of an involved limb, this is no longer indicated because it does not appear to prevent metastases or improve survival. In most instances, adjuvant radiation or chemotherapy is recommended after surgery.

Secondary Involvement of Peripheral Nerves by Malignant Tumors The most common primary tumors involving the peripheral nerves secondarily are breast and lung carcinomas (Pancoast tumors). They can spread to the brachial plexus by direct extension or by way of the lymphatics. A common presentation is that of a patient with a history of breast or lung carcinoma who has undergone radiation therapy several months previously. The chief complaints are pain in the supraclavicular and arm regions with associated numbness or weakness. The differential diagnosis includes radiation plexitis caused by small vessel injury, tumor involvement of the brachial plexus, or a combination of the two. Clinically, radiation injury commonly induces diffuse symptoms, whereas tumor infiltration often begins initially with numbness, pain, or weakness in the ulnar nerve distribution. Nodular enhancement of the brachial plexus on MRI imaging is highly suggestive of tumor, but diffuse changes are nondiagnostic. Electromyographic studies significant for myokymia suggest radiation plexopathy. Surgical exploration may be warranted if the diagnosis is in doubt or for the relief of symptoms. Removing a compressive nodule of tumor sometimes can relieve symptoms and restore function, but the benefits often are short lived because of the corresponding infiltration of the nerves by tumor cells. In cases of radiation scarring or diffuse tumor infiltration, external neurolysis sometimes can provide pain relief, but recovery of strength or sensation cannot be expected. Other tumor types reported to involve peripheral nerves include prostate cancer, melanoma, pancreatic cancer, and thymoma. Pelvic tumors can affect the lumbar and sacral plexuses, and head and neck tumors can spread to cranial nerves.

Chapter 174 H Metastatic Epidural Spinal Cord Compression

SUGGESTED READINGS Fletcher CD: Peripheral nerve sheath tumors. A clinicopathologicupdate. Pathol Annu 25(1):53-74, 1990 Hajdu SI: Peripheral nerve sheath tumors. Histogenesis, classification, and prognosis. Cancer 72( 12):3549-3552, 1993

Lederman RJ, Wdbourn AJ: Brachial plexopathy: recurrent cancer or radiation?Neurology 34( 10):1331-1335, 1984 Lin J, Martel W: Cross-sectional imaging of peripheral nerve sheath tumors: characteristic signs on CT, MR imaging, and sonography. AJR

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Urich H, Tien RD: Tumors of the cranial, spinal and peripheral nerve sheaths. pp. 141-194. In Bigner DD, McLendon RE, Bruner JM (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System. 6th Ed. Arnold, London, 1998 Wong WW, Hirose T, Scheithauer BW et ak Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 42(2):351-360, 1998 Woodruff J M The pathology and treatment of peripheral nerve tumors and tumor-like conditions. CA Cancer J Clin 43(5):29&308, 1993

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174 Metastatic Epidural Spinal Cord Compression David Schiff and Harry Greenberg Metastatic epidural spinal cord compression (ESCC) is defined as compression of the spinal cord or cauda equina nerve roots from a metastatic lesion outside the spinal dura. It is an important cause of morbidity and mortality in patients with cancer.

EPIDEMIOLOGY Because cancer patients may have unrecognized ESCC or develop ESCC after the decision to forgo diagnostic testing has been made, the incidence of this complication can only be estimated. Both clinical and autopsy studies suggest that the incidence in patients with cancer is at least 5%. Therefore, it is likely that at least 25,000 Americans develop metastatic ESCC each year. The median age at diagnosis of metastatic epidural spinal cord compression has varied from 53 to 63 years. Metastatic tumor from any primary site can produce ESCC, but tumors with a tendency to metastasize to the spinal column account for most cases. Ninety percent of patients with prostate cancer, 74% with breast cancer, 45% with lung cancer, 29% with lymphoma or kidney cancer, and 25% with gastrointestinal cancershave vertebral metastasespresent on autopsy. In most large series, prostate cancer, breast cancer, and lung cancer each account for 15% to 20% of all ESCC cases. Renal cell carcinoma, non-Hodglun’s lymphoma, and multiple myeloma typically each make up 5% to 10% of cases, with the remainder being scattered among tumors of unknown primary site, colorectal carcinoma, sarcoma, and other tumors. In children, sarcomas (especially Ewing’s) and neuroblastomas are the main causes, with germ cell tumors and Hodglun’s disease less common causes.

Whereas most cases of ESCC arise in patients with known cancer, approximately 20% of all cases occur as the initial manifestation of malignancy. Carcinoma of the lung and of unknown primary, non-Hodglun’s lymphoma and multiple myeloma are the most common causes; breast cancer rarely presents in this fashion. Although a careful history and physical examination may suggest the site of the primary tumor, only a minority of these patients have telltale symptoms or signs. Computed tomography (CT)-guided needle biopsy of the epidural mass early in the workup is useful to prove the diagnosis of cancer and to refine the search for likely primary sites. ESCC has a proclivity for certain regions of the spine. In general, approximately 60% of cases occur in the thoracic spine, 30% in the lumbosacral spine, and only 10% in the cervical spine. These percentages are in rough proportion to the combined volumes of the vertebral bodies in each region.

rnOLOGY The epidural space is a true space that lies between spinal cord dura and the bony spinal canal (Fig. 174-1). It contains fat, connective tissue, and a rich paravertebral venous plexus, which drains the vertebrae and intervertebral spaces. The most common mechanism of metastatic epidural spinal cord compression is by hematogenous spread to bone marrow, which results in vertebral body collapse and formation of an epidural mass whose epicenter is anterior to the spinal cord. This hematogenous spread may either be arterial or by retrograde venous spread from the primary site via Batson’s paravertebral plexus. Another mechanism is

Chapter 174 H Metastatic Epidural Spinal Cord Compression

SUGGESTED READINGS Fletcher CD: Peripheral nerve sheath tumors. A clinicopathologicupdate. Pathol Annu 25(1):53-74, 1990 Hajdu SI: Peripheral nerve sheath tumors. Histogenesis, classification, and prognosis. Cancer 72( 12):3549-3552, 1993

Lederman RJ, Wdbourn AJ: Brachial plexopathy: recurrent cancer or radiation?Neurology 34( 10):1331-1335, 1984 Lin J, Martel W: Cross-sectional imaging of peripheral nerve sheath tumors: characteristic signs on CT, MR imaging, and sonography. AJR

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Urich H, Tien RD: Tumors of the cranial, spinal and peripheral nerve sheaths. pp. 141-194. In Bigner DD, McLendon RE, Bruner JM (eds): Russell and Rubinstein’s Pathology of Tumors of the Nervous System. 6th Ed. Arnold, London, 1998 Wong WW, Hirose T, Scheithauer BW et ak Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 42(2):351-360, 1998 Woodruff J M The pathology and treatment of peripheral nerve tumors and tumor-like conditions. CA Cancer J Clin 43(5):29&308, 1993

Am J Roentgen01 176(1):75-82, 2001

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NEUROLOGIC COMPLICATIONS OF SYSTEMIC

174 Metastatic Epidural Spinal Cord Compression David Schiff and Harry Greenberg Metastatic epidural spinal cord compression (ESCC) is defined as compression of the spinal cord or cauda equina nerve roots from a metastatic lesion outside the spinal dura. It is an important cause of morbidity and mortality in patients with cancer.

EPIDEMIOLOGY Because cancer patients may have unrecognized ESCC or develop ESCC after the decision to forgo diagnostic testing has been made, the incidence of this complication can only be estimated. Both clinical and autopsy studies suggest that the incidence in patients with cancer is at least 5%. Therefore, it is likely that at least 25,000 Americans develop metastatic ESCC each year. The median age at diagnosis of metastatic epidural spinal cord compression has varied from 53 to 63 years. Metastatic tumor from any primary site can produce ESCC, but tumors with a tendency to metastasize to the spinal column account for most cases. Ninety percent of patients with prostate cancer, 74% with breast cancer, 45% with lung cancer, 29% with lymphoma or kidney cancer, and 25% with gastrointestinal cancershave vertebral metastasespresent on autopsy. In most large series, prostate cancer, breast cancer, and lung cancer each account for 15% to 20% of all ESCC cases. Renal cell carcinoma, non-Hodglun’s lymphoma, and multiple myeloma typically each make up 5% to 10% of cases, with the remainder being scattered among tumors of unknown primary site, colorectal carcinoma, sarcoma, and other tumors. In children, sarcomas (especially Ewing’s) and neuroblastomas are the main causes, with germ cell tumors and Hodglun’s disease less common causes.

Whereas most cases of ESCC arise in patients with known cancer, approximately 20% of all cases occur as the initial manifestation of malignancy. Carcinoma of the lung and of unknown primary, non-Hodglun’s lymphoma and multiple myeloma are the most common causes; breast cancer rarely presents in this fashion. Although a careful history and physical examination may suggest the site of the primary tumor, only a minority of these patients have telltale symptoms or signs. Computed tomography (CT)-guided needle biopsy of the epidural mass early in the workup is useful to prove the diagnosis of cancer and to refine the search for likely primary sites. ESCC has a proclivity for certain regions of the spine. In general, approximately 60% of cases occur in the thoracic spine, 30% in the lumbosacral spine, and only 10% in the cervical spine. These percentages are in rough proportion to the combined volumes of the vertebral bodies in each region.

rnOLOGY The epidural space is a true space that lies between spinal cord dura and the bony spinal canal (Fig. 174-1). It contains fat, connective tissue, and a rich paravertebral venous plexus, which drains the vertebrae and intervertebral spaces. The most common mechanism of metastatic epidural spinal cord compression is by hematogenous spread to bone marrow, which results in vertebral body collapse and formation of an epidural mass whose epicenter is anterior to the spinal cord. This hematogenous spread may either be arterial or by retrograde venous spread from the primary site via Batson’s paravertebral plexus. Another mechanism is

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Spinal Nerves Section through Thoracic Vertebra

FIG. 174-1. Anatomy of the spinal column and canal at the thoracic level.

spread by direct invasion of tumor through the intervertebral foramina from a paravertebral source. This occurs in 75% of patients with epidural spinal cord compression caused by lymphoma and 15% of patients with metastatic epidural spinal cord compression from other solid tumors.

PATHOPHYSIOLOGY Animal models have been used to demonstrate morphologic features of cord damage and subsequent recovery. After 3 hours of cord compression in cats, selective demyelination without axonal disruption evolves over the subsequent day and continues for 1 week. Most demyelinated fibers show evidence of remyelination by 1 month. If compression is produced slowly over a 48-hour period and maintained for 1 week, recovery from paralysis is still possible, suggesting that demyelination is a more important factor than cord ischemia. With more prolonged compression, cord ischemia and irreversible neurologic changes ensue. Autopsy of humans with ESCC demonstrates vascular congestion, hemorrhage, and edema at the site of cord compression, suggesting that venous occlusion is an important factor in the pathogenesis of cord damage.

CLINICAL MANIFESTATIONS Back pain is the initial complaint in up to 96% of patients with epidural spinal cord compression. It is very unusual for patients with metastatic epidural spinal cord compression to present without pain, but cord compression from lung or renal metastases and lymphoma does so more often than other primary tumors. In large series, the median duration of pain before development of neurologic signs and diagnosis of ESCC typically has been about 2 months. Duration of pain probably is related to rate of tumor

growth rate, being shortest for lung carcinoma and longest for tumors such as breast and prostate carcinoma. The majority of patients have local pain, secondary to stretching of the painsensitive cortical bone and periosteum. Local pain usually is constant, relentlessly progressive, and exacerbated by coughing, sneezing, straining, or exercise. The worsening of pain on recumbency is the most distinctive feature of the pain of ESCC and helps to differentiates it from disc disease. The frequent occurrence in the thoracic spine, an uncommon site for disc disease and spinal stenosis, is another clue that pain may be malignant in origin. Radicular pain is present in 90% of patients with lumbosacral, 79% with cervical, and 55% with thoracic metastatic epidural spinal cord compression. It is often bilateral in the thoracic area and unilateral or bilateral in the lumbosacral and cervical areas. Radicular pain is an important localizing sign. Weakness is present in about 80% of patients with metastatic epidural spinal cord compression at presentation. Approximately 50% of patients are ambulatory, 35% are paraparetic, and 15% are paraplegic at the time of diagnosis. Once weakness is present, progression often is rapid, and urgent investigation and treatment are crucial. Thirty percent of patients with weakness become paraplegic within 1 week. Rate of progression of weakness depends on the tumor growth rate. Weakness usually is bilateral and symmetrical (87%). The degree of weakness and ability to ambulate at the time of diagnosis are the most important predictors of outcome. Bladder and bowel symptoms are often present at the time of diagnosis (57%) and can take the form of frequency, urinary retention, or incontinence. Autonomic disturbance is an unfavorable prognostic sign because it implies bilateral cord or root damage and usually is associated with moderate to severe weakness; isolated bowel or bladder dysfunction is rarely attributable to ESCC. Objective sensory disturbance is found in 78% of patients

Chapter I74 w Metastatic Epidural Spinal Cord Compression

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at the time of diagnosis. The severity of sensory loss almost always mirrors the severity of motor weakness. When a spinal sensory level is present, it is typically one to five levels below the actual level of cord compression; therefore, it is less useful than radicular symptoms or findings for lesion localization. Saddle sensory loss is commonly present in cauda equina lesions, but lesions above the cauda equina often result in sacral dermatomal sparing to pinprick (a finding commonly thought to reflect an intramedullary spinal lesion). Lhermitte’s phenomenon may be seen after administration of radiation or cisplatin but may also occur with an epidural neoplasm. Spinal tenderness to percussion and the presence of visible or palpable spinal deformity should be sought. Limited straight leg raising usually points to an epidural or intradural extramedullary lesion causing root compression; segmental pain and sacral sparing suggest intramedullary disease. Spinal cord, conus medullaris, cauda equina, or peripheral nerve lesions can produce a flaccid areflexic paralysis. If there are cerebral symptoms, magnetic resonance imaging (MRI) of the brain should also be performed to look for concurrent intracranial metastases.

differentiating pain of ESCC from benign causes of back pain is thoracic localization; the benign causes generally occur in the lumbar or cervical spine. The patient whose spine pain worsens with recumbency should not be presumed to have a benign cause.

PREVENTION, RISK FACTORS, AND ASSOCIATED CONDITIONS

Metastatic Disease Without Epidural Extension

To improve clinical outcome, it is important to identify patients early in their illness or who are at high risk for ESCC before the appearance of neurologic symptoms or signs. Patients with malignancy should be advised to inform their physician if they develop new back pain, which is almost always the initial complaint in patients who go on to develop ESCC. High-risk patients include those with known malignancy and recent-onset back pain and those who are not known to have malignancy but who have a new backache that is worse on recumbency or is radicular and that is situated in the thoracic region or associated with spinal tenderness. Radiation therapy usually is the treatment of choice for bony metastases without metastatic epidural spinal cord compression, providing very effective palliation for bone pain and preventing progression of epidural metastases in most cases. In prostate cancer, irradiation of the lumbar spine coincidental to the irradiation of para-aortic nodes and the normally radiated pelvic area prevented or delayed the development of the lumbar spine metastases, which might significantly reduce cauda equina compression. Bisphosphonates such as pamidronate are of proven benefit in reducing pathologic fractures and bone pain in patients with multiple myeloma or breast cancer with lytic bony lesions. Although these studies were not designed to look at ESCC as an endpoint, it is plausible that reducing bony tumor progression and pathologic fractures may help prevent ESCC.

Spinal Epidural Abscess Spinal epidural abscess is an uncommon condition. Predisposing factors include intravenous drug use, vertebral osteomyelitis, and hematogenous infection. Clinical manifestations may be indistinguishable from those of rapidly progressive neoplastic ESCC. Neuroimaging may suggest infection: Epidural abscess is more often posteriorly situated and often will cover multiple vertebral body segments. If there is vertebral collapse from an infective cause, the disc space often is destroyed; metastatic vertebral disease usually spares the disc space. The leading bacterial pathogen causing spinal epidural abscess is Staphylococcus aureus, which accounts for approximately two thirds of cases of bacterial origin; other infectious causes include Mycobacterium tuberculosis, which is responsible for up to 25% of cases.

Vertebral metastases without epidural extension often produce local back pain, which may be severe. The differentiation from ESCC ultimately depends on neuroimaging studies and the absence of radiculopathy or myelopathy.

lntramedullay Spinal Cord Metastases Intramedullary metastases occur about one fifteenth as often as epidural metastases and are most commonly associated with lung cancer. They produce pain, weakness, and numbness similar to ESCC. Unlike ESCC, they often produce a hemicord syndrome of unilateral weakness below the level of the lesion with contralateral diminution of pinprick and temperature discrimination; continued growth results in bilateral spinal cord dysfunction.

Leptomeningeal Metastases Leptomeningeal metastases commonly produce a cauda equina syndrome and occasionally a myelopathy. Local back pain may not be present, but affected patients usually complain of radicular pain. Clinical features usually present that help to differentiate this condition from ESCC include mental status changes, headache, and cranial nerve palsies. The multifocal nature of the radiculopathies is another point against ESCC. MRI in patients with leptomeningeal metastases demonstrates no epidural tumor and may show pathologic meningeal enhancement; cerebrospinal fluid (CSF) examination usually is diagnostic.

DIFFERENTIAL DIAGNOSIS

Plexopathy

Patients with cancer are prone to malignant, non-ESCC causes of back pain and neurologic dysfunction as well as the gamut of nonmalignant causes of these symptoms.

Malignant plexopathy may involve any of the peripheral nerve plexuses. Brachial plexopathy most commonly occurs in breast and lung ‘cancer; lumbosacral plexopathy usually is caused by c o l o r e d and gynecologic tumors, sarcomas, and lymphomas. In most cases, the major feature of malignant plexopathy is severe, unrelenting local or radicular pain. Later, weakness and focal sensory disturbances occur in the distribution of the involved plexuses. In the absence of a palpable mass or ipsilateral extremity swelling, these symptoms can mimic ESCC; in fact, the paraspinal

Musculoskeletal Disease Benign causes of back pain, including muscle spasm, intervertebral disc disease, and spinal stenosis warrant consideration. As mentioned earlier, one feature that is sometimes helpful in

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location of the plexus means that ESCC and malignant plexopathy sometimes coexist. MRI or CT differentiates malignant plexopathy from ESCC.

RadiationMyelopathy Rarely, patients who have received radiation to fields involving the spinal cord develop chronic progressive radiation myelopathy. The total previous radiation dosage and fraction size are important risk factors. The latency after radiotherapy typically is about 1 year. Affected patients usually develop ascending numbness and upper motor neuron findings that often have a hemicord localization, in contrast to ESCC, which typically produces a fairly symmetrical myelopathy. Neuroimaging distinguishes this entity from ESCC.

Other Other disorders can simulate some of the findings in ESCC, including spinal epidural cavernous hemangiomas, spontaneous nontraumatic spinal epidural hematomas related to bleeding diatheses or arteriovenous malformations, benign tumors such as meningiomas and neurofibromas, epidural lipomatosis related to corticosteroid ingestion, extramedullary hematopoiesis, and epidural involvement with rheumatoid arthritis, sarcoidosis, or tophaceous gout. DIAGNOSTICWORKUP The diagnosis of ESCC depends on the demonstration of a neoplastic mass extrinsically compressing the thecal sac. Careful imaging of the thecal sac and epidural space is mandatory for both diagnosis and optimal treatment planning. Definitive imaging of the thecal sac with MRI or myelography may demonstrate multiple lesions that are clinically unsuspected or reveal that a clinically mild lesion is producing radiographically severe cord compression (thereby influencing choice of treatment). Radiologic testing for early diagnosis should be performed in all patients with cancer who develop otherwise unexplained and persistent back pain; signs of a radiculopathyor myelopathymarkedly increase the likelihood of ESCC. Both MRI and myelography are superior to plain radiographs, bone scans, and CT as diagnostic imaging methods. Studies consistently demonstrate that these modalities vastly improve the accuracy of radiation field planning compared with results of clinical examination and plain radiographs.

Plain Radiographs Plain spinal radiographs are the quickest and least expensive study to obtain and are of value in certain situations. In a patient with cancer and back pain, either major vertebral body collapse or pedicle erosion at the level of a radiculopathy predicts a 75% to 83% chance of ESCC on myelogram or MRI. However, false negative plain spinal radiographs occur in 10% to 17% of patients with ESCC. Three factors are primarily responsible for the false negative results. First, at least 50% of bone must be destroyed before a plain radiograph becomes abnormal. Second, metastatic involvement of multiple vertebrae may obscure identification of the clinically relevant lesion. Finally, paraspinal tumor invading through the neural foramen may produce no radiographic abnormality. For example, one third of patients with ESCC from lymphoma have normal spine radiographs.

Bone Scan Radionuclide bone scanning is more sensitive for detecting bony metastasis than plain spinal radiographs. However, bone scans may be negative in neoplasms without increased blood flow or new bone formation, as in multiple myeloma. Other limitations in the diagnosis of ESCC are that increased radionuclide uptake may be seen in numerous conditions other than cancer, scans may be positive at multiple levels, and bone scanning is not informative about thecal sac compression. One retrospective study combined plain radiography and bone scanning retrospectively in a small patient group and concluded that if both studies were negative in a patient with cancer and localized spinal pain, the risk of ESCC was only 2%. If confirmed prospectively, this finding would suggest that certain low-risk patients may safely forgo MRI or myelography. Nevertheless, patients with cancer and myelopathy, radiculopathy, or severe or progressive back pain need to undergo such testing.

Computed Tomography The utility of CT of the spine to evaluate patients for ESCC has been studied. CT does not depict the spinal cord or epidural space clearly. However, in patients with normal bone density, CT depicts metastatic disruption of the bony cortex surrounding the spinal canal, a finding highly predictive of epidural tumor extension. Epidural tumor within the spinal canal may enhance after intravenous contrast administration, facilitating its identification. Disadvantages of CT include its reliance on ionizing radiation and the time needed to obtain images, which limit the length of the spinal canal that can be screened. The availability of MRI has greatly diminished the role of CT in the diagnosis of ESCC. Nonetheless, CT is still occasionally useful when MRI is unavailable or contraindicated.

Myelography and MRI The two definitive means of diagnosing ESCC are myelography (often combined with postmyelogram CT) and MRI. Each provides an image of the thecal sac and delineates epidural neoplasm indenting and encircling the thecal sac. MRI offers several potential advantages over myelography. It produces anatomically faithful images of the spinal cord and intramedullary pathology and is even more sensitive than radionuclide bone scans at identifymg bony metastases (Fig. 174-2). It images the entire thecal sac regardless of whether a spinal subarachnoid block is present. Furthermore, it is not contraindicated with large brain metastases and spares the patient a lumbar puncture. Myelography may be better tolerated by patients in pain because image quality in MRI depends on the patient’s ability to lie still. Myelography permits CSF analysis, which, although not useful for the diagnosis of ESCC, is the cornerstone of the diagnosis of leptomeningeal metastases. In ESCC, CSF examination often reveals an elevated protein (as would be expected with subarachnoid block) with a normal cell count and negative cytology. Postmyelogram CT at the level of thecal sac impingement provides additional anatomic information about the tumor (such as its rostral extent and the presence of a paraspinal component) and usually demonstrates some rostral passage of contrast at the level of high-grade subarachnoid block not appreciated on the myelogram itself. Rarely, patients with complete spinal subarachnoid block deteriorate neurologicallywhen CSF pressure below the block has

Chapter 174

Metastatic Epidural Spinal Cord Compression

1125

Screening for Multiple Deposits Approximately one third of patients with ESCC have multiple epidural tumor deposits on MRI or myelography (Fig. 174-3). Although it remains debatable whether asymptomatic or incidentally detected ESCC should be treated, the presence of multiple sites of ESCC significantly affects prognosis and treatment planning. Most authorities recommend that the entire spine be screened in all patients with ESCC. PROGNOSIS AND COMPLICATIONS

FIG. 174-2. MRI 'can (using the showing Of vertebral involvement, one with ESCC at T8 and another with asymptomatic L3 metastasis.

The severity of weakness at presentation is the most significant prognostic variable for recovery of function. In different series, between 80% and 100% of patients ambulatory at presentation remain so after treatment. Between 30% and 45% of patients who are nonambulatory with antigravity proximal leg function regain ambulation, whereas only 5% of patients who have no antigravity proximal function walk again. The radiobiology of the tumor also plays an important role in response. In one study, 75% of patients with radiosensitive tumors who were nonambulatory but could raise their legs off the bed became ambulatory after radiotherapy, but only 34% of comparable patients with radioresistant tumors became ambulatory after radiotherapy. After treatment, the probability of ambulatory patients surviving 1 year is 0.73, and the probability of nonambulatory patients surviving 1 year is 0.09. Median survival overall for patients with ESCC ranges from 2 to 6 months in different series. Survival by tumor site is shown in Table 174-1. In selected series of paraplegic patients with anterior ESCC treated with anterior decompression and radiotherapy, 50% to 90% of patients had an improvement in motor function. Rapid onset and quick progression are bad prognostic variables. Patients with a preoperative symptom duration greater than 2 months have better postoperative recovery of function than

been reduced by the lumbar puncture (spinal coning). For this reason, it is important to have neurosurgical input when a myelogram is ordered for suspected ESCC. Patients known to have or suspected of having brain metastases should undergo brain CT or MRI before myelogram because of the risk of brain herniation. Surprisingly, MRI has never been proven superior to CT myelography for diagnosing ESCC. Several studies dating from the early years of spinal MRI compared the two modalities and found that they were roughly equivalent in sensitivity and specificity. Given the convenience and widespread availability of MRI, we may not see future comparative studies. Nevertheless, there are occasional cases, particularly with laterally situated lesions, in which CT myelogram demonstrates abnormalities not visualized on MRI. In addition, patients with mechanical valves, pacemakers, paramagnetic implants, and shrapnel remain dependent on myelography. Noncontrast T1- and T2-weighted MRI is generally quite satisfactory to screen for abnormalities in the bone and epidural space. Gadolinium administration may be helpful because most tumors enhance with contrast. Furthermore, the disappearance of contrast enhancement after treatment suggests successful treatment. Typically, radiologists perform Scans in the sagittal Plane, with selected axial images through regions of interest identified on the sagittal images.

FIG. 174-3. MRI Scan (using local spinal cord) showing severe metastatic ESCC with collapse of c 5 vertebral body and severe destruction of posterior elements and local invasion of C4 and C6 vertebral bodies.

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TABU 174-1. Survival Times from Diagnosis of Epidural Spinal Cord Compression in Patients with Common Tumors Treated by Radiotherapy Site

Mean

Standard Deviation

Median

Range

Lung Breast Kidney Prostate Lymphoma or myeloma Other All

3.0 14.0 8.5 11.7 8.6

3.9 12.8 13.4 14.7 14.4

1.5 9.2 3.7 5.1 4.9

0-1 8 0.6-49.3 0.5-70.8 0.2-61.3 0.3-66.5

6.3 8.1

8.2 11.8

3.5 3.1

0.1-28.9 0.4-70.8

From Sorensen PS, Borgesen SE, Rohde K et al: Metastatic epidural spinal cord compression: results of treatment and sunrival. Cancer 65:1502, 1990, with permission.

those with shorter histories. The duration of paraplegia before starting treatment is also important. It has been traditionally taught that when paraplegia is present for more than 24 hours before initiation of treatment, the chances of recovery are slight, although recent reports question this doctrine. In children with metastatic ESCC, prognosis for recovery from complete motor and sensory loss is significantly better than in adults, with 50% becoming ambulatory after surgical decompression and medical therapy. MANAGEMENT

Emergency Measures Patients with cancer, back pain, and an abnormal progressing neurologic examination with myelopathy or radiculopathy should undergo emergency MRI or CT myelography, whichever is the most readily available procedure. Stable patients with uncertain neurologic findings should be scanned urgently over the next 24 hours. While patients are awaiting neuroimaging, they are generally started on corticosteroids. The salutary effects of corticosteroidsin ESCC, first reported in the 1960s, have been demonstrated both in animal studies and in a randomized controlled human trial in which the patients receiving dexamethasone in addition to radiation were more likely to remain ambulatory. One unanswered question is the optimal corticosteroid dosage. Early studies commonly used high dosages of dexamethasone (e.g., a 100-mg intravenous bolus followed by 24 mg every 6 hours). Other series have used a 10-mg bolus followed by 4 to 6 mg every 6 hours. No prospective randomized controlled trials have compared the outcomes with these two regimens. Unrandomized comparison of case series suggests that high- and low-dose dexamethasone are equally efficacious; the risk of serious corticosteroid-related side effects appears significantlygreater in the high-dose corticosteroid group. This must be weighed against the clear superiority of high-dose over low-dose corticosteroids in the setting of acute spinal cord trauma. When the high-dose regimen is chosen, it is important to taper steroids as quickly as tolerated; one common approach is to halve the steroids every 3 days as long as the patient is neurologically stable. Occasional patients can be safely managed without corticosteroids, namely those with small epidural lesions (less than 50% spinal block), stable neurologic examinations, and relative contraindications to corticosteroids. Patients with metastatic ESCC and abnormal neurologic examination with weakness should be monitored at frequent intervals with a neurologic examination. If patients develop a

neurologic deficit during radiation therapy unresponsive to steroid dosage increase, surgery should be considered. If back pain is caused by vertebral involvement with spinal instability and the patient has otherwise limited metastatic disease, spinal stabilization should be considered. Patients with neoplastic spinal cord compression are at a higher risk of deep venous thrombosis and pulmonary embolus. Prophylactic subcutaneous heparin or intermittent pneumatic compression may help reduce morbidity and mortality rates. In the presence of urinary retention or constipation, intermittent or permanent catheterization should be considered, and laxatives or suppositories should be initiated early in the course of admission. Although corticosteroids often are remarkably helpful for pain control, opiates should be prescribed as needed for pain. Care should be taken when nursing patients with paraparesis or paraplegia to prevent pressure sores.

Definitive Management For many years, it was dogma that patients with ESCC needed decompressivelaminectomy before undergoing radiation therapy. In 1978, a retrospective nonrandomized series of 235 patients with metastatic epidural spinal cord compression concluded that radiation therapy alone is as effective as sequential decompressive laminectomy and radiation therapy. This study was instrumental in changing initial therapy for metastatic ESCC from surgery to radiation therapy. There has only been one randomized prospective comparison of laminectomy followed by radiation therapy with radiation therapy alone. This trial failed to reveal any difference between the treatment arms, although the small sample size precluded any definitive conclusion. Recently, a renewed interest in surgery has focused on a directed surgical approach based on the site and level of ESCC.

Radiotherapy The response of epidural metastatic lesions to radiation is well documented. Lymphoma, seminoma, myeloma, Ewing’s sarcoma, and neuroblastoma are very radiosensitive; breast and prostate tumors are moderately so; and melanoma, kidney, colon, and non-small cell lung cancers often are radioresistant. Radiation therapy is still the generally accepted first line of treatment for ESCC in radiosensitive tumors. Its use in radioresistant tumors is more controversial. A large retrospective study reported that radioresistant tumors are as effectively treated with radiation therapy alone as with laminectomy and radiation therapy. The optimal dosage and fractionation regimen for ESCC remains unknown. In fact, there may be no generally optimal plan. Each plan constructed represents a compromise between delivery of the highest dosage achievable to improve tumor control, a desire to achieve palliation as expeditiously as possible, and the intrinsic radiosensitivity of the spinal cord; often a regimen of 30 Gy in 10 fractions is chosen as the best solution. Italian investigators have explored a treatment plan of two large (800-cGy) fractions 1 week apart, with apparent safety and comparable efficacy to more standard schedules. Traditionally, two vertebral bodies above and below the myelographic block have been treated, taking into account other vertebral bodies with documented metastasis. The sensitivity of the spinal cord to radiation limits the prescribed amount of therapy, and the spinal cord dosage should always be calculated as well as the dosage to the involved vertebral body. The incidence of

Chapter 174

permanent radiation injury to the spinal cord directly correlates with the total dosage and fraction size. Spinal cord tolerance has been considered to be between 45 and 50 Gy in 180-cGy fractions, between 35 and 37.5 Gy in 250-cGy fractions, and between 30 and 33 Gy in 300-cGy fractions. The size of the radiation field also plays an important role, and reductions in treatment volume allow a larger dosage.

*"Wry As discussed earlier, decompressive laminectomy has been largely abandoned except when the bulk of tumor is located posterior to the spinal cord or when open biopsy is needed for tumor diagnosis. In the presence of vertebral body collapse, decompressive laminectomy has a 25% risk of major neurologic deterioration, 22% risk of spinal instability, and only 3% recovery of ambulation. The role of surgery is being reevaluated. Surgery is a major undertaking in patients with metastatic disease who have limited life expectancy. Nevertheless, it has been advocated to obtain diagnostic material, to help the rapidly deteriorating patient, to decompress the spinal cord and nerve roots, to correct spinal instability, to relieve pain, and to promote early mobilization. Spinal instability is a potential cause of cord damage and is not affected by radiation therapy. Recently, spinal surgeons, extrapolating from traumatic spinal cord injury and using a similar framework, have divided the bony space into three columns:

Metastatic Epidural Spinal Cord Compression

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anterior column (anterior longitudinal ligament and anterior vertebral body), middle column (posterior longitudinal ligament, posterior vertebral body, and pedicles), and posterior column (facet joints, lamina, and interspinous ligaments). Spinal instability occurs most often if the cortical bone in more than one of three columns is involved, either by tumor or by previous surgery. Technical advances in spinal surgery have led to the development of more aggressive procedures that allow more direct visualization and more thorough tumor resection of ESCC. Given the usual epicenter of epidural metastasis in the vertebral body, these procedures often are called vertebral corpectomy. After exposing the tumor (which sometimes necessitates the assistance of a thoracic or general surgeon), the neurosurgeon or orthopedic surgeon debulks tumor from the vertebral body and epidural space and then stabilizes the spine either with bone grafting or with methylmethacrylate and instrumentation (Fig. 174-4). Patients are mobilized within a few days of the surgery. Case series reported by spinal surgeons suggest substantial value to vertebral corpectomy in carefully selected patients. The largest series published to date reported improvement in 82% of patients in terms of both pain relief and ambulatory status. The overall median survival was 16 months, with 46% alive at 2 years. These excellent results were achieved despite frequent complications, including wound breakdown (probably related to corticosteroids and in some cases prior radiotherapy), stabilization failure, infection, and hemorrhage. The postoperative complication rate was 48%, and 1-month mortality was about lo%,

B

A

FIG. 174-4. Plain radiographs (A) before and (B) after vertebral body resection with anterior and posterior stabilization.

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underscoring that this procedure is a substantial undertaking for the patient. Whether aggressive tumor resection of epidural metastasis followed by radiotherapy improves on the outcome from radiotherapy alone is the subject of an ongoing multicenter phase I11 trial in the United States. Until results of this trial are available, aggressive resection should be strongly considered only in cases with spinal instability or retropulsion of bone within the spinal canal, local recurrence after radiotherapy or clinical deterioration during radiotherapy, or in patients with known radioresistant tumors (e.g., renal cell carcinoma) and minimal or manageable tumor elsewhere. Chemotherapy

There is no a priori reason that chemotherapy cannot be used to treat ESCC; the main limitation is that many of the tumors producing ESCC are not reliably sensitive to anticancer drugs. Epidural lymphoma sometimes is treated successfully with chemotherapy. Hormonal therapy has occasionally been used to treat ESCC from breast or prostate cancer.

Recurrent ESCC Approximately 10% of patients treated with radiotherapy for ESCC eventually develop local recurrence, and another 10% develop a second episode of ESCC distant from the first. Surgical and chemotherapeutic options should be considered in patients with locally recurrent ESCC. Often, however, these patients have exhausted good chemotherapy options and are poor surgical candidates because of widespread bony or visceral disease. When ESCC has recurred locally after a year or more of local control after radiotherapy, a second course of spinal radiation can be administered with reasonable efficacy and safety. The relative infrequency of radiation myelopathy in this setting may result from the generally short life expectancy (i.e., patients may not live long enough to develop radiation myelopathy), from repair of sublethal radiation damage, or from standard estimates of spinal cord radiation tolerance being on the conservative side. SUGGESTED READINGS

Findlay GFG The role of vertebral body collapse in the management of malignant spinal cord compression. J Neurol Neurosurg Psychiatry 50151-154, 1987 Gilbert RW, Kim JH, Posner JB: Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol3:40-51, 1978 Greenberg HS, Kim JH, Posner JB Epidural spinal cord compression from metastatic tumors: results with a new treatment protocol. Ann Neurol 8~361-366,1980 Helweg-Larsen S, Rasmusson B, Soelberg Sorenson P Recovery of gait after radiotherapy in paralytic patients with metastatic epidural spinal cord compression. Neurology 40:1234-1236, 1990 Portenoy RK, Galer BS, Salamon 0 et ak Identification of epidural neoplasms: radiography and bone scintigraphy in the symptomatic and asymptomatic spine. Cancer 64:2207-2213, 1989 Posner JB Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995. Ruff FU, Lanska DJ: Epidural metastases in prospectively evaluated veterans with cancer and back pain. Cancer 1132234-2291, 1989 Schiff D, O’Neill BP, Wang CH, O’Fallon J R Neuroimaging and treatment implications of patients with multiple spinal epidural metastases. Cancer 83:1593-1601, 1998 Schiff D, Shaw EG, Cascino T L Outcome after spinal reirradiation for malignant epidural spinal cord compression. Ann Neurol37:583-589, 1995 Schiff D Spinal metastases. In Cancer Neurology in Clinical Practice. Schiff D, Wen PY (eds). 93-106. Humana Press, Totowa, NJ, 2002 Schiff D: Spinal cord compression. Neurologic clinics, 2003 (In press) Siegal T, Siegal TZ Surgical decompression of anterior and posterior malignant epidural tumors compressing the spinal cord a prospective study. Neurosurgery 173424432, 1985 Sorensen PS, Borgesen SE, Rohide K et ak Metastatic epidural spinal cord compression: results of treatment and survival. Cancer 65:1502-1508, 1990 Sorensen S, Helweg-Larsen S, Mouridsen H, Hansen HH: Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur J Cancer 30A.22-27, 1994 Stark RJ, Henson RA, Evans SyW: Spinal metastasis: a retrospectivesurvey from a general hospital. Brain 105:189-213, 1982 Sundaresan N, Sachdev VP, Holland JF et ak Surgical treatment of spinal cord compression from epidural metastasis. J Clin Oncol 13:23302335, 1995 Young RF, Post EM, King GA Treatment of spinal epidural metastases: randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 53:741-748, 1980

Byrne TN, Waxman S G Spinal Cord Compression: Diagnosis and Principles of Management. FA Davis, Philadelphia, 1998

175 Neodastic Meningitis v I

Stuart A. Grossman The disseminated and multifocal seeding of the leptomeninges by malignant cells is called neoplastic meningitis. This disorder is also called carcinomatous meningitis, leptomeningeal metastases lymphomatous meningitis, or leukemic meningitis, depending on the histology of the underlying disease. Neoplastic meningitis occurs when tumor cells gain access to the cerebrospinal fluid (CSF) and are transported throughout the central nervous system (CNS) by the bulk flow of the CSE This is a serious complication of cancer that results in substantial morbidity and mortality. A high index of

suspicion and early diagnosis and treatment are key to the optimal management of this increasingly common and devastating neurooncologic disorder. ANATOMY AND PHYSIOLOGY The neuraxis of an adult contains approximately 140 mL of CSF in the ventricles and the spinal and cortical subarachnoid space. Approximately five times that much CSF is produced daily by the

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underscoring that this procedure is a substantial undertaking for the patient. Whether aggressive tumor resection of epidural metastasis followed by radiotherapy improves on the outcome from radiotherapy alone is the subject of an ongoing multicenter phase I11 trial in the United States. Until results of this trial are available, aggressive resection should be strongly considered only in cases with spinal instability or retropulsion of bone within the spinal canal, local recurrence after radiotherapy or clinical deterioration during radiotherapy, or in patients with known radioresistant tumors (e.g., renal cell carcinoma) and minimal or manageable tumor elsewhere. Chemotherapy

There is no a priori reason that chemotherapy cannot be used to treat ESCC; the main limitation is that many of the tumors producing ESCC are not reliably sensitive to anticancer drugs. Epidural lymphoma sometimes is treated successfully with chemotherapy. Hormonal therapy has occasionally been used to treat ESCC from breast or prostate cancer.

Recurrent ESCC Approximately 10% of patients treated with radiotherapy for ESCC eventually develop local recurrence, and another 10% develop a second episode of ESCC distant from the first. Surgical and chemotherapeutic options should be considered in patients with locally recurrent ESCC. Often, however, these patients have exhausted good chemotherapy options and are poor surgical candidates because of widespread bony or visceral disease. When ESCC has recurred locally after a year or more of local control after radiotherapy, a second course of spinal radiation can be administered with reasonable efficacy and safety. The relative infrequency of radiation myelopathy in this setting may result from the generally short life expectancy (i.e., patients may not live long enough to develop radiation myelopathy), from repair of sublethal radiation damage, or from standard estimates of spinal cord radiation tolerance being on the conservative side. SUGGESTED READINGS

Findlay GFG The role of vertebral body collapse in the management of malignant spinal cord compression. J Neurol Neurosurg Psychiatry 50151-154, 1987 Gilbert RW, Kim JH, Posner JB: Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol3:40-51, 1978 Greenberg HS, Kim JH, Posner JB Epidural spinal cord compression from metastatic tumors: results with a new treatment protocol. Ann Neurol 8~361-366,1980 Helweg-Larsen S, Rasmusson B, Soelberg Sorenson P Recovery of gait after radiotherapy in paralytic patients with metastatic epidural spinal cord compression. Neurology 40:1234-1236, 1990 Portenoy RK, Galer BS, Salamon 0 et ak Identification of epidural neoplasms: radiography and bone scintigraphy in the symptomatic and asymptomatic spine. Cancer 64:2207-2213, 1989 Posner JB Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995. Ruff FU, Lanska DJ: Epidural metastases in prospectively evaluated veterans with cancer and back pain. Cancer 1132234-2291, 1989 Schiff D, O’Neill BP, Wang CH, O’Fallon J R Neuroimaging and treatment implications of patients with multiple spinal epidural metastases. Cancer 83:1593-1601, 1998 Schiff D, Shaw EG, Cascino T L Outcome after spinal reirradiation for malignant epidural spinal cord compression. Ann Neurol37:583-589, 1995 Schiff D Spinal metastases. In Cancer Neurology in Clinical Practice. Schiff D, Wen PY (eds). 93-106. Humana Press, Totowa, NJ, 2002 Schiff D: Spinal cord compression. Neurologic clinics, 2003 (In press) Siegal T, Siegal TZ Surgical decompression of anterior and posterior malignant epidural tumors compressing the spinal cord a prospective study. Neurosurgery 173424432, 1985 Sorensen PS, Borgesen SE, Rohide K et ak Metastatic epidural spinal cord compression: results of treatment and survival. Cancer 65:1502-1508, 1990 Sorensen S, Helweg-Larsen S, Mouridsen H, Hansen HH: Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur J Cancer 30A.22-27, 1994 Stark RJ, Henson RA, Evans SyW: Spinal metastasis: a retrospectivesurvey from a general hospital. Brain 105:189-213, 1982 Sundaresan N, Sachdev VP, Holland JF et ak Surgical treatment of spinal cord compression from epidural metastasis. J Clin Oncol 13:23302335, 1995 Young RF, Post EM, King GA Treatment of spinal epidural metastases: randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 53:741-748, 1980

Byrne TN, Waxman S G Spinal Cord Compression: Diagnosis and Principles of Management. FA Davis, Philadelphia, 1998

175 Neodastic Meningitis v I

Stuart A. Grossman The disseminated and multifocal seeding of the leptomeninges by malignant cells is called neoplastic meningitis. This disorder is also called carcinomatous meningitis, leptomeningeal metastases lymphomatous meningitis, or leukemic meningitis, depending on the histology of the underlying disease. Neoplastic meningitis occurs when tumor cells gain access to the cerebrospinal fluid (CSF) and are transported throughout the central nervous system (CNS) by the bulk flow of the CSE This is a serious complication of cancer that results in substantial morbidity and mortality. A high index of

suspicion and early diagnosis and treatment are key to the optimal management of this increasingly common and devastating neurooncologic disorder. ANATOMY AND PHYSIOLOGY The neuraxis of an adult contains approximately 140 mL of CSF in the ventricles and the spinal and cortical subarachnoid space. Approximately five times that much CSF is produced daily by the

Chapter 175

Neoplastic Meningitis

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FIG. 175-1. Anatomy of the leptomeninges. (Modified from Crossman SA, Moynihan TJ: Neoplastic meningitis. Neurol Clin North Am 9:843-856, 1991, with permission.)

choroid plexus in the lateral, third, and fourth ventricles. CSF flows through the CNS in a predictable fashion. It leaves the fourth ventricle through the foramina of Magendie and Luschka, traverses the spinal subarachnoid space, returns to the basilar cisterns, and passes over the cortical convexities into the superior sagittal sinus via the arachnoid granulations (Fig. 175-1). CSF flow along these pathways results from the continuous production of CSF and alterations in pressure within the subarachnoid space that result from arterial pulsations, changes in position, and Valsalva maneuvers.

INCIDENCE Neoplastic meningitis was once thought to be rare and was uncommonly diagnosed before death. However, leptomeningeal metastases are now recognized with increasing frequency as a result of heightened awareness of the diagnosis, new neuroimaging techniques, and improved survival in some systemic malignancies. In large series, most patients with neoplastic meningitis have breast cancer (11% to 64%), lung cancer (14% to 29%), or melanoma (6% to 18%). It is currently estimated that leptomeningeal disease occurs in 5% of patients with breast cancer, 9% to 25% with small cell lung cancer, 23% with melanoma, 5% to 29% with non-Hodgkin’s lymphomas, and 11% to 70% with leukemias. Autopsy studies demonstrate that 19% of patients with cancer and neurologic complications have meningeal involvement and that concomitant intraparenchymal or epidural metastases are common. Patients with lymphomas are at highest risk if they have bone marrow, testicular, or extranodal sites involved and if the tumors have a diffuse, lymphoblastic, or Burkitt’s histology. Although neoplastic meningitis usually occurs in patients with advanced and progressive systemic cancer, it can present as the first manifestation of a malignancy.

PATHOGENESIS Tumor cells most commonly gain access to the subarachnoid space by direct extension from preexisting CNS tumors (epidural, subdural, or intraparenchymal) or preexisting systemic tumors

that advance along nerve roots to gain access to the subarachnoid space, or by hematogenous dissemination via arachnoid vessels or choroid plexus. Direct extension is best exemplified by the leptomeningeal involvement associated with some primary brain tumors. Ependymomas, pineoblastomas, and medulloblastomas, which are contiguous with the CSF, often involve the CSF. However, symptomatic leptomeningeal disease is less common with intraparenchymal astrocytic brain tumors. Metastatic tumors can also reach the meninges by direct extension. Patients with solid tumors and neoplastic meningitis often have cerebral, cerebellar, or epidural metastases, which can provide direct access to the leptomeninges. The leukemias provide a model for hematogenous dissemination to the leptomeninges. These malignant cells traverse the walls of the superficial arachnoid veins and surrounding adventitia en route to the CSF. They migrate through arachnoid vessels, seed the choroid plexus, and extend into the leptomeninges from hemorrhagic brain infarcts. This pattern of tumor dissemination into the leptomeninges has also been noted in solid tumors. Patients with small cell lung cancer and isolated leptomeningeal disease have been found to have tumor filling the Virchow-Robin spaces with perivascular extension, perineural and perivascular lymphatic involvement, invasion of endoneural and perineural sheaths of the intervertebral foramina, and choroid plexus involvement. Solid tumors may also enter the subarachnoid space through the venous plexus of Batson, perivenous spread from bone marrow metastases, or direct extension along nerve sheaths. The latter has been noted in patients with squamous cell carcinoma of the head and neck. Once malignant cells gain access to the CSF, they spread along the surface of the meninges of the brain and spinal cord. Exfoliated cells are carried by the flow of the CSF to distant regions of the CNS. Tumor deposits on leptomeningeal surfaces invade subpial parenchyma, penetrate spinal nerve roots, and produce masses in the subarachnoid space. The basilar cisterns, posterior fossa, and cauda equina are most commonly affected. Gravity may be responsible for the high risk of symptomatic involvement in these areas.

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TMLE 175-1. Signs and Symptoms of Neoplastic Meningitis Sixns and SvmDtoms

Cause

Increased intracranial pressure Focal neurologic - abnormalities

CSF flow abnormalities Parenchymal invasion in Virchow-

Encephalopathy

Robin space or along spinal cord Direct invasion of nerves in subarachnoid space Occlusion of penetrating pial blood vessels Interference with normal CNS metabolism

Abbreviations: CNS, central nervous system; CSF, cerebrospinalfluid. Modified from Crossman SA, Moynihan TJ: Neoplastic meningitis. Neurol Clin North Am 9:843-856, 1991, with permission.

CLINICAL PRESENTATION AND DIAGNOSIS Neoplastic meningitis may become clinically apparent in several ways (Table 175-1). Patients often present with signs and symptoms of increased intracranial pressure and hydrocephalus. These occur as a result of obstruction of normal CSF flow pathways. CSF flow abnormalities have been identified in up to 70% of patients with neoplastic meningitis using radionuclide CSF flow scans. Leptomeningeal tumor can also invade underlying brain and spinal parenchyma, nerve roots, and vessels that supply the CNS. These lesions can cause focal neurologic deficits or seizures. Some patients present with a diffuse encephalopathy, which may be secondary to tumor-induced changes in brain metabolism or regional cerebral blood flow. A high index of suspicion is needed to make an early diagnosis of leptomeningeal metastases. The diagnosis should be considered if signs and symptoms suggest multifocal CNS involvement. Multiple cranial nerve palsies that result in diplopia, dysphagia, dysarthria, and hearing loss are common presenting complaints. Headache, changes in mental status, back or radicular pain, incontinence, lower motor neuron weakness, and sensory abnormalities are often reported. Most patients have a combination of cranial nerve, cerebral, and spinal signs and symptoms at the time of diagnosis. LABORATORY STUDIES CSF examination is the most useful laboratory test for diagnosing neoplastic meningitis (Table 175-2). Only 3% of patients with leptomeningeal metastases have a completely normal lumbar puncture. Positive CSF cytology is found in approximately 50% of patients with this disorder on the initial lumbar puncture and in 85% of patients who undergo multiple diagnostic spinal taps. The

TABLE175-2. Diagnostic Tests for Neoplastic Meningitis Test

Parameter

Lumbar puncture

7 Pressure (50%)

~

~~~~

BIOCHEMICAL MARKERS Numerous biochemical markers have been studied in the CSF of patients with neoplastic meningitis. Unfortunately, their utility is limited by poor sensitivity and specificity. Carcinoembryonic antigen (CEA), a high-molecular-weight glycoprotein produced by colon, breast, ovarian, bladder, and lung cancer cells, is not normally detectable in the CSF. A number of studies have demonstrated that an elevated CSF CEA level, in the absence of a markedly elevated serum level, is specific for carcinomatous meningitis. This biomarker is not useful in patients with lymphomatous meningitis. CSF CEA levels tend to decline with successful therapy and can rise in patients before other findings of leptomeningeal relapse are evident. Studies of CSF P-glucuronidase, lactate dehydrogenase, and P,-microglobulin have been disappointing. Elevations of these markers are not specific for neoplastic meningitis, often fluctuate widely, and can be elevated as a consequence of antineoplastic therapy. As a result, they are rarely of use in diagnosing or monitoring this disorder. RADIOLOGIC STUDIES Radiologic studies are important in diagnosing neoplastic meningitis. Contrast-enhanced computed tomography or magnetic resonance imaging scans of the brain are routinely obtained in patients with cancer and worrisome neurologic signs or symptoms. These scans identify most intraparenchymal lesions and provide an estimate of the risk of herniation after lumbar puncture. Approximately one half of patients with neoplastic meningitis have abnormal imaging results. Some radiologic findings, such as multiple subarachnoid mass lesions, are virtually diagnostic of neoplastic meningitis. Others, such as those with hydrocephalus without an identifiable mass lesion, are consistent with or suggestive of the diagnosis. Meningeal enhancement is of limited utility in the early diagnosis of leptomeningeal malignancy. Contrast enhancement of the basilar cisterns or cortical convexities usually is seen with advanced leptomeningeal involvement when the CSF cytology is likely to be positive. In addition, it is commonly associated with infections, inflammatory diseases, trauma, subdural hematomas, intracranial hypotension, and recent neurosurgical procedures, making it a nonspecific finding.

t Protein (75%)

k Glucose (40%)

Myelography or spinal MRI Brain CT or MRI

CSF cytology is much more likely to be positive in the lumbar region than in the ventricle of the same patient with documented leptomeningeal involvement. A positive CSF cytology is virtually diagnostic of leptomeningeal metastases. However, differentiating reactive from malignant lymphocytes can be difficult and may lead to false-positive cytologies in patients with viral infections of the CNS. Elevations in opening pressure or CSF protein and a pleocytosis are common but nonspecific abnormalities. A low CSF glucose can occur with CNS infections or leptomeningeal metastases.

First cytology result positive (50%) One of
Abbreviations: CT,computed tomography; MRI, magnetic resonance imaging. Modified from Grossman SA, Moynihan TI: Neoplastic meningitis. Neurol Clin North Am 9:843-856, 1991, with permission.

TREATMENT The goals of treatment in patients with neoplastic meningitis are to improve or stabilize the neurologic status of the patient and to prolong survival. Fixed neurologic deficits, such as paraplegia or cranial nerve palsies, usually do not improve with therapy, although a diffuse encephalopathy may resolve dramatically. Without therapy, the median survival of patients with this disorder

Chapter 175

TABLE 175-3. Standard Therapy for Neoplastic Meningitis

Radiation therapy to sites of symptomatic and bulk disease lntrathecal chemotherapy Methotrexate (10 mg twice weekly) Thiotepa (1 0 mg twice weekly) Cytarabine (90 mg/week) Optimal treatment of systemic disease Modified from Crossman SA, Moynihan TJ: Neoplastic meningitis. Neurol Clin North Am 9:843-856, 1991, with permission.

is 4 to 6 weeks, and death usually results from progressive neurologic dysfunction. Occasionally patients with indolent tumors live significantly longer even without therapy. Appropriate therapy for neoplastic meningitis often provides effective local control. As a result, many patients succumb to systemic rather than neurologic complications of their neoplasm. Treatment of neoplastic meningitis must encompass the entire nervous system because tumor cells are disseminated widely by CSF flow (Table 175-3). Radiation should be administered to symptomatic regions of the neuraxis and to bulk disease identified on neuroimaging studies. Intrathecal chemotherapy is directed at subclinical leptomeningeal deposits and tumor cells floating in the CSF. Craniospinal irradiation is of limited benefit in solid tumors, which are not exceptionally radiosensitive. In addition, this is time-consuming and myelosuppressive, especially in patients who have received prior antineoplastic therapy. High dosages of systemically administered cytarabine, methotrexate, or thiotepa can yield therapeutic concentrations of these agents in the CSF for short periods of time. However, the systemic toxicities of these agents prohibit twice-weekly dosing, making this an inadequate approach for established leptomeningeal metastases. Intrathecal chemotherapy usually is administered through an implanted subcutaneous reservoir and ventricular catheter (SRVC) (Fig. 175-2). These devices are associated with little

Neoplastic Meningitis

1131

morbidity or mortality when placed by an experienced neurosurgeon. Intraventricularly administered drugs reach the CSF reliably. They may also be more uniformly distributed and associated with a higher response rate and longer remissions than drugs administered in the lumbar CSF. Use of the SRVC is also less painful than repeated lumbar punctures. However, even when an SRVC is in place, periodic lumbar punctures are needed to determine the response to intraventricular chemotherapy. This is necessary because the ventricular CSF cytology is much less likely to be positive than a specimen taken from the lumbar region at the same time. In addition, the normal ventricular CSF glucose level is higher and the protein concentration is lower than in lumbar samples. CSF flow abnormalities are common in patients with neoplastic meningitis. Radionuclide ventriculography in patients with neoplastic meningitis has shown that up to 70% have ventricular outlet obstructions, abnormal flow in the spinal canal, or impaired flow over the cortical convexities. As a result, patients with neoplastic meningitis should undergo radionuclide ventriculography to determine whether they have serious CSF flow disturbances. These can affect the distribution, efficacy, and toxicity of intrathecal chemotherapy and are potentially reversible with radiation therapy. A limited number of antineoplastic agents are suitable for intrathecal administration. Fixed dosages of these agents should be administered because the volume of CSF is not a function of surface area in adults. Although combination chemotherapy has led to substantial improvements in the treatment of systemic cancers, combination intrathecal regimens have yet to demonstrate superiority to any single intrathecal agent. Methotrexate is the most widely used and thoroughly studied agent for intrathecal administration. Ten milligrams of preservative-free methotrexate mixed in artificial CSF or saline usually is given twice weekly for eight treatments or until the CSF

FIG. 175-2. CSF circulation in a patient with an Ommaya reservoir. (Modified from Crossman SA, Moynihan TJ: Neoplastic meningitis. Neurol Clin North Am 92343-856, 1991, with permission.)

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Neurologic Complications of Systemic Cancer

clears. This is commonly followed by weekly and then monthly maintenance therapy if the patient remains free of progressive disease. These treatments result in therapeutic concentrations (more than M) that persist for 48 hours. Serum levels peak at lo-’ M and fall slowly. The low but prolonged systemic concentrations of this cycle-active agent may result in significant myelosuppression. With this treatment approach, approximately 50% of patients stabilize or improve, but the median survival remains under 6 months even in patients with responsive malignancies. Intrathecal cytarabine, a synthetic pyrimidine nucleoside, is commonly used in patients with leukemic and lymphomatous meningitis. This agent has limited activity in most solid tumors. The half-life of cytarabine is short in the serum but longer in the CSF because of the low levels of cytidine deaminase in the CSF. An intrathecal dosage of 30 mg daily for 3 days results in therapeutic concentrations (more than 4 x lo4 M) for more than 72 hours. The systemic toxicities of intrathecal cytarabine are minimal because of the drug is rapidly deaminated in the systemic circulation. Response rates in leukemic meningitis range from 50% to 70%. Cytarabine encapsulated in multivesicular lipid particles (DepoCyt) is available for intrathecal injection. The duration of tumor exposure is markedly longer than that of the unbound cytarabine. Clinical trials demonstrate that DepoCyt improves complete response rates in patients with leptomeningeal lymphoma and may also affect survival. Benefit in solid tumors is much more modest. Chemical arachnoiditis (headache, nausea, vomiting, and fever) are common after intrathecal administration of DepoCyt and necessitate the concomitant administration of oral dexamethasone. The usual dosage of DepoCyt is 50 mg intrathecally every 2 weeks. Thiotepa, a potent alkylating agent with activity in many solid tumors, can be administered intrathecally. It is stored as a sodium salt and should be mixed with sterile water instead of artificial CSF to avoid injecting a hypertonic solution into the subarachnoid space. A randomized phase 111 trial comparing intrathecal thiotepa and methotrexate demonstrated identical survival with these agents. However, thiotepa appeared to be associated with fewer overall and neurologic toxicities than methotrexate. TREATMENT-RELATED TOXICITIES

Significant toxicities can accompany therapy for neoplastic meningitis. These can result from placement of the SRVC and the administration of radiation and intrathecal chemotherapy. The primary toxicities seen with the SRVC include perioperative complications, migration of the ventricular catheter tip into adjacent brain tissue, or infections of the device. Many of the infections are secondary to Staphylococcus epidermidis and can be treated with local antibiotics rather than removal of the SRVC. Radiation for leptomeningeal disease can be fairly myelosuppressive. Myelosuppression is common if the treatment portals are large, the patient is receiving systemic antineoplastic therapies, or the marrow reserve is compromised by prior antineoplastic therapies or tumor in the bone marrow. Intrathecal methotrexate can result in acute arachnoiditis and seizures, which are associated with high CSF levels. Long-term intrathecal methotrexate administration, especially after cranial irradiation, almost invariably results in radiologic and clinical manifestations of treatmentinduced leukoencephalopathy. These white matter changes are initially seen in asymptomatic patients on routine neuroimaging

studies. However, patients subsequently develop progressive neurologic signs and symptoms, which can be fatal. Although the pathogenesis of this toxicity has not been determined, recent data suggest that it may result from direct toxicity to neurons with secondary demyelination. Mucositis and myelosuppression from intrathecal methotrexate can be prevented with the systemic folinic acid administration. The acute and chronic toxicities of intrathecal cytarabine and thiotepa are less well characterized. NEW THERAPEUTIC APPROACHES

Several new intrathecal chemotherapeutic agents or delivery techniques are being evaluated to improve the efficacy or reduce the toxicity of therapy for neoplastic meningitis. Those in clinical trials include 4-hydroxycyclophosphamide,an active metabolite of cyclophosphamide, and antibodies conjugated to radioactive isotopes. THERAPEUTIC DECISIONS

Many clinicians are hesitant to treat patients with neoplastic meningitis. Therapy can result in significant neurologic toxicities, fixed neurologic deficits rarely improve, most patients have extensive and progressive systemic disease, and survival, even with therapy, can be short. However, prompt evaluation of patients with cancer and neurologic signs and symptoms can result in a diagnosis of neoplastic meningitis before serious and permanent neurologic disabilities occur. A similar approach is recommended in evaluating epidural metastases, in which a late diagnosis is often associated with permanent paraplegia. An early diagnosis of epidural metastases and prompt, appropriate therapy provides excellent local control, allowing most patients to die of progressive systemic disease with intact spinal cord function. Similarly, early diagnosis and treatment of leptomeningeal disease should provide excellent local control. Once the diagnosis of leptomeningeal metastases is made, several factors should be considered in deciding how aggressive treatment should be (Table 175-4). Patients with an excellent performance status, an indolent systemic cancer that is potentially responsive to treatment, and minimal or no evidence of systemic disease should be considered for aggressive therapy. On the other hand, in patients with multiple, serious, fixed neurologic symptoms, a poor performance status, and extensive disease from a poorly responsive tumor, deficits are unlikely to benefit from therapy. Ideal treatment candidates should begin radiation to bulk and symptomatic sites of disease, and placement of an SRVC should be

TABLE175-4. Factors Influencing Treatment Decisions

in Neoplastic Meningitis

Features of tumor Extent of systemic tumor Degree of fixed neurologic deficits Performancestatus of patient

Good Treatment Candidate

Poor Treatment Candidate

Indolent Treatment responsive Absent None

Aggressive Resistant Widespread Multiple, serious

Normal

Confined to bed

Modified from Grossman SA, Moynihan TJ: Neoplastic meningitis. Neurol Clin North Am 9:843-856, 1991, with permission.

Chapter 175

considered. A CSF flow scan should be performed to obtain information on the distribution of intraventricularlyadministered drugs. Local radiation should be administered to sites of abnormal CSF flow. Intrathecal chemotherapy should be accompanied by optimal management of the patient’s underlying systemic malignancy. Patients who are poor candidates for aggressive therapy may benefit from radiation therapy to symptomatic sites or supportive measures only. Local radiation therapy and a trial of intrathecal chemotherapy delivered by lumbar puncture may be appropriate in patients who are intermediate candidates. This approach allows time for the natural course of the disease to be manifest before committing to a more aggressive or conservative approach.

CONCLUSIONS Neoplastic meningitis is a serious complication of systemic malignancies that appears to be increasing in frequency. Although it occurs with almost any malignancy, it is recognized most often in patients with breast cancer, lymphomas, and small cell cancer of the lung. A high index of suspicion is needed to make the diagnosis of leptomeningeal metastases. A careful history and physical examination usually reveal signs and symptoms that indicate involvement of more than one area of the CNS. The diagnosis of neoplastic meningitis is made by a positive CSF cytology, subarachnoid metastases identified on radiologic studies, or a compelling history and physical examination combined with an abnormal but not diagnostic examination of the CSF. Treatment should include radiation therapy to symptomatic areas of the CNS, intrathecal chemotherapy, and optimal therapy of the systemic cancer. Careful selection of patients for aggressive therapy is indicated. Despite the potential toxicities of therapy, many patients receive substantial palliation, some live for more than 1 year, and most die of systemic tumor progression without symptomatic recurrence of their leptomeningeal metastases. New efforts are under way to decrease the toxicity and improve the efficacy of antineoplastictherapy for this devastating complication of cancer.

SUGGESTED READINGS Blaney SM, Poplack D G Neoplastic meningitis: diagnosis and treatment considerations. Med Oncol 17:151-162,2000 Bleyer WA, Drake JC, Chabner BA Neurotoxicity and elevated cerebrospinal fluid methotrexate concentration in meningeal leukemia. N Engl J Med 289770-773, 1973 Chamberlain M C Neoplastic meningitis: a guide to diagnosis and treatment. Curr Opin Neurol 13:641448, 2000

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Chamberlain MC, Sandy AD, Press GA: Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology 40:435-438, 1990 Esteva FJ, Soh LT, Holmes FA et ak Phase I1 trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chernother Pharmacol46:382-386, 2000 Gilbert MR, Harding BL, Grossman S A Methotrexate neurotoxicity: in vitro studies using cerebellar explants. Cancer Res 492502-2505, 1989 Glantz MJ, Jaeckle KA, Chamberlain MC et al: A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 53394-3402, 1999 Glass JP, Melamed M, Chernik NL, Posner JB Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology 29:1369-1375, 1979 Grossman SA, Finkelstein DM, Ruckdeschchel JC et ak Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. J Clin Oncol 11:561-569, 1993 Grossman SA, Spence A Management of leptomeningeal metastases: National Comprehensive Cancer Network guidelines. Oncology 13: 144-152, 1999 Grossman SA, Trump DL, Chen DC et ak Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. An evaluation using “indium-DTPA ventriculography.Am J Med 73:641447, 1982 Gutin PH, Weiss HD, Wiernik PH, Walker MD: Intrathecal N, N’, N”-triethylenethiophosphoramide [thio-TEPA (NSC 6396)] in the treatment of malignant meningeal disease: phase 1-11 study. Cancer 38:1471-1475, 1976 Jaeckle KA, Phuphanich S, Bent MJ et al: Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 84157-163,2001 Kerr JZ, Berg S, Blaney SM: Intrathecal chemotherapy. Crit Rev Oncol Hematol37227-236, 2001 Kesari S , Batchelor T T Leptomeningealmetastases. Neurologic Clinics (in press) Mason WP: Leptomeningeal metastases. In: Schiff D, Wen PY (eds): Cancer Neurology in Clinical Practice. Humana Press, Philadelphia, 2003 Murry DJ, Blaney S M Clinical pharmacology of encapsulated sustainedrelease cytarabine. Ann Pharmacother 341173-1 178, 2000 Shapiro WR, Young DF, Mehta BM: Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293:161-166, 1975 Sze G, Soletsky S, Bronen R, Krol G MR imaging of the cranial meninges with emphasis on contrast enhancement and meningeal carcinomatosis. Am J Neuroradiol 10965975, 1989 Twijnstra A, Ongerboer de Visser BW, van Zanten AP Diagnosis of leptomeningeal metastasis. Clin Neurol Neurosurg 89:79-85, 1987 Wasserstrom WR, Glass JP, Posner JB Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 49759-772, 1982 Zimm S, Collins JM, Miser J et ak Cytosine arabinosidecerebrospinalfluid kinetics. Clin Pharmacol Ther 35:82&830, 1984

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rn Neurologic Complications of Systemic Cancer

176 Neurologic Complications of Chemotherapy Patrick Y. Wen

Neurologic complications are seen with increasingly frequency in patients with cancer as a result of aggressive antineoplastic therapy and prolonged patient survival. These complications may result from the direct toxic effects of the drug on the nervous system or indirectly from metabolic encephalopathies,infections, or cerebral vascular disorders induced by the drugs. It is important to recognize these complications because they may be confused with metastatic disease and because they may result in significant disability, necessitating that the drug be discontinued before irreversible damage occurs (Table 176- 1). In this chapter the neurologic complications of the more commonly used chemotherapeutic agents, hormones, biologic agents, monoclonal antibodies, and signal transduction inhibitors used to treat patients with cancer will be discussed. CHEMOTHERAPY Drugs That Commonly Cause Neurotoxlcity Cisplatin. Cisplatin is an alkylating agent often used in the treatment of ovarian, testicular, small cell lung, and head and neck cancers. NEUROPATHY. The main neurotoxicity of cisplatin is an axonal neuropathy affecting predominantly large myelinated sensory fibers. The neuropathy usually occurs with dosages greater than 400 mg/m2 and is characterized by numbness, paresthesias, and occasionally pain in the extremities. Proprioception is impaired and reflexes are lost, but pinprick, temperature sensation, and power often are spared. Nerve conduction studies show decreased amplitude of sensory action potentials and prolonged sensory latencies, compatible with a sensory axonopathy. Surd nerve biopsy shows both demyelination and axonal loss. The primary site of damage is the dorsal root ganglion, but the peripheral nerve is also affected. After cessation of chemotherapy, the neuropathy may improve and even return to normal after many months. The main differential diagnosis is a paraneoplastic neuropathy and a neuropathy associated with autoimmune disorders such as Sjogren's syndrome. Paraneoplastic neuropathies tend to be progressive despite discontinuation of cisplatin and involves all sensory fibers. There is no treatment for cisplatin neurotoxicity, but amifostine partially protects peripheral nerves from cisplatin, and a double-blind placebo-controlled study suggested that the adrenocorticotropic hormone (4-9) analogue Org 2766 may prevent cisplatin neurotoxicity. Laboratory studies suggest that nerve growth factor and neurotrophin-3 may be useful in preventing cisplatin-induced neuropathies. Arterial infusions of cisplatin in the extremities or neck may produce focal neuropathies. Autonomic neuropathies have also been rarely observed. CRANIALNEUROPATIIIES. Cisplatin may cause ototoxicity, leading to high-frequency sensorineural hearing loss and tinnitus. The toxicity is caused by peripheral receptor (hair loss) in the organ of Corti and is dose-related. Audiometric hearing loss is present in

4

74% to 88% of patients receiving cisplatin, and symptomatic hearing loss occurs in 16% to 20% of patients. Cranial irradiation probably increases the likelihood of a significant hearing loss. The hearing loss tends to be worse in children, although they have a slightly greater ability to improve after the drug has been stopped. Cisplatin may also cause a vestibulopathy, resulting in ataxia and vertigo. Rarely, cisplatin may result in optic neuritis and retinopathy. This is more common after intracarotid administration of the drug. SPINAL CORD INVOLVEMENT (LHERMITTE'SSIGN). This symptom, characterized by paresthesias in the back and extremities with neck flexion, is seen in 20% to 40% of patients receiving cisplatin. Patients tend to develop this after weeks or months of treatment. Neurologic examination usually is normal, and Lhermitte's sign usually resolves spontaneously several months after the drug has been discontinued. It is thought to result from transient demyelination of the posterior columns. Very rarely, a true myelopathy has been reported. UNCOMMON ComwianoNs. Rarely, cisplatin may produce an encephalopathy resulting in seizures and focal neurologic symptoms, including cortical blindness. The encephalopathy is associated with reversible abnormalities in the white matter of the occipital, parietal, and frontal lobes and clinically resembles the reversible posterior leukoencephalopathy syndrome. The encephalopathy tends to be more common after intra-arterial administration of the drug. It has to be distinguished from a metabolic encephalopathy that may result from water intoxication caused by prehydration or from renal impairment, hypomagnesemia, hypocalcemia, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that may follow treatment with cisplatin. Cisplatin can also cause late vascular toxicity, resulting in strokes. Other rare complications include taste disturbance and a myasthenic syndrome. Methotrexate. This is a dihydrofolate reductase inhibitor used to treat a wide range of cancers including leukemias, lymphomas, choriocarcinoma, breast cancer, central nervous system (CNS) lymphoma, and leptomeningeal metastases. The clinical expression of its neurotoxicity is determined by the dosage, route of administration, and use of other therapeutic modalities, such as irradiation, with overlapping neurotoxicities. INTRATHECAL M~OTREXATE TOXICITY. Aseptic meningitis is the most common neurotoxicity associated with intrathecal methotrexate therapy. This complication occurs in approximately 10% of patients, although some series have reported incidences as high as 50%. It begins 2 to 4 hours after the drug is injected and may last for 12 to 72 hours. The clinical features are indistinguishable from those of other types of chemical meningitis and consist of headaches, nuchal rigidity, back pain, nausea, vomiting, fever, and lethargy. The cerebrospinal fluid (CSF) shows a pleocytosis and an elevated protein. These symptoms resemble bacterial meningitis but occur too soon after injection of the drug to be caused by an infection. The symptoms usually are self-limited and warrant no

Chapter 176 W

Neurologic Complications of Chemotherapy

1135

w TMU 176-1. Neurologic Complications of Cancer Therapy Acute Encephalopathy

Seizures

Headaches

Neuropathy

Asparaginase 5-Azacitidine Carmustine (IA and HD) Cisplatin Cytosine arabinoside (HD) Etoposide Fludarabine 5-Fluorouracil Clucocorticoids Hexamethylmelamine lfosfamide Interferons Interleukin-2 Methotrexate Procarbazine Tamoxifen Thiotepa (HD) Vinca alkaloids

Asparaginase Carmustine Busulphan (HD) Cisplatin Dacarbazine Etoposide 5-Fluorouracil lfosfamide Interferons Interleukin-2 Methotrexate Nitrogen mustard Pentostatin Vinca alkaloids Teniposide

Asparaginase Cytosine arabinoside (IT) Etoposide fludarabine Clucocorticoids Hexamethylmelamine Interferons Interleukin-2 Mechlorethamine Methotrexate (IT) Retinoic acid Tamoxifen Temozolomide Thiotepa (IT)

Vaxulopathy and Stroke

Carmustine (IA) Cisplatin Fludarabine Tamoxifen Taxanes

5-Azacitidine Carboplatin Cisplatin Cytosine arabinoside Etoposide 5-fluorouracil Cemcitabine Hexamethylmelamine lfosfamide Interferon-a Oxaliplatin Procarbazine Purine analogs fludarabine Cladribine Pentostatin Suramin Taxol Taxotere Teniposide Vinca alkaloids

Dementia

Carmustine (ID and HD) Carmofur Cytosine arabinoside 5-fluorouracil Levamisole Interferon-a Fludarabine Methotrexate

Asparaginase Carmustine (IA) Cisplatin (IA) Doxorubicin Estramustine Methotrexate Aseptic Meningitis

Cytosine arabinoside (IT) Methotrexate (IT) Levamisole

Acute Cerebellar Syndrome

Cytosine arabinoside 5-fluorouracil Hexamethylmelamine Procarbazine Vinca alkaloids Abbreviations; I& intra-arterial; IT, intrathecal; HD,highdose.

specific treatment. Aseptic meningitis can be prevented to some extent by injecting methotrexate with hydrocortisone or taking dexamethasone orally. Some patients who developed aseptic meningitis have been retreated with methotrexate without subsequent problems. Transverse myelopathy is a much less common complication of intrathecal methotrexate characterized by back or leg pain followed by paraplegia, sensory loss, and sphincter dysfunction. The symptoms usually occur between 30 minutes and 48 hours after treatment but may occur up to 2 weeks later. The majority of cases show clinical improvement, but the extent of recovery is variable. This complication is more common in patients receiving concurrent radiotherapy or frequent treatments of intrathecal methotrexate. . Rarely intrathecal methotrexate may produce an acute encephalopathy, subacute focal neurologic deficits, neurogenic pulmonary edema, and sudden death. Accidental overdosage of methotrexate (more than 500 mg) usually results in myelopathy, encephalopathy, and death. The use of rapid CSF drainage, ventriculolumbar perfusion, high-dose leucovorin, and alkaline diuresis has allowed occasional patients to survive. HIGH-DOSE MEIHOTREXATE NEUROTOXIW.High-dose methotrexate may cause acute, subacute, or chronic neurotoxicity. Acute high-dose methotrexate neurotoxicity is characterized by somnolence, confusion, and seizures within 24 hours of treatment. Symptoms usually resolve spontaneously without sequelae.

Visual Loss

Cranial Neuropathy

Carmusthe (IA) Cisplatin Vincristine MveloPathv

Methotrexate (IT) Cytosine arabinoside (IT) Thiotepa (IT)

Weekly treatments with high-dose methotrexate may produce a subacute strokelike syndrome characterized by transient focal neurologic deficits, confusion, and occasionally seizures. Typically the disorder develops 6 days after high-dose methotrexate, lasts 15 minutes to 72 hours, and resolves spontaneouslywithout sequelae. MRI scans and CSF usually are normal, but the electroencephalogram shows diffuse slowing. Methotrexate may be subsequently administered without the encephalopathy recurring. The pathogenesis of this syndrome is unknown but may be related to reduced cerebral glucose metabolism. Chronic leukoencephalopathy has also been reported in a number of patients after high-dose methotrexate. LEUKOENCEPHALOPATHY. The major delayed complication of methotrexate therapy is a leukoencephalopathy. Although this syndrome may be produced by methotrexate alone, it is exacerbated by radiotherapy, especially if the latter is administered before or during methotrexate therapy. The clinical features are characterized by the gradual development of cognitive impairment months or years after treatment with methotrexate. This may range from mild learning disabilities to severe progressive dementia, together with somnolence, seizures, ataxia, and hemiparesis. Computed tomography and magnetic resonance scans show cerebral atrophy and diffuse white matter lesions. Pathologic lesions range from loss of oligodendrocytes and gliosis to a necrotizing leukoencephalopathy. The clinical course is variable. Many patients stabilize or improve after discontinuation of the methotrexate, but the course is progressive in some patients and may lead to death. No effective

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Neuro-Oncology # Neurologic Complicationsof Systemic Cancer

treatment is available. The cause of the leukoencephalopathy is unknown. It is possible that cranial irradiation may potentiate the toxic effects of methotrexate or disrupt the blood-brain barrier, allowing high concentrations of methotrexate to reach the brain. Oxaliplatin. Oxaliplatin is a third-generation platinum complex that has activity against cisplatin-resistanttumor cells in vitro. Its main use has been in treating colon cancer. Neuropathy remains the dose-limiting toxicity, although severe neuropathy is rare at conventional dosages and tends to improve after therapy is discontinued. Suramin. Suramin inhibits the binding of a number of growth factors to their receptors, including platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-@ It also inhibits DNA polymerases and glycosaminoglycan catabolism. Suramin is used mainly to treat refractory prostate cancer. It causes a severe peripheral neuropathy in 10% of patients. There are two patterns of neuropathy: an inflammatory demyelinating neuropathy resembling GuillainBarrC syndrome clinically, which may improve after the drug is discontinued, and a distal axonal sensorimotor polyneuropathy. Some patients develop proximal weakness and paresthesias in the face and extremities, followed by more generalized weakness. The neuropathy usually improves after the drug is discontinued. Initially it was thought that the development of neuropathy correlated with blood levels of suramin above 350 pg/mL, but more recent studies have failed to demonstrate this association. Taxanes (Paclitaxel pax011 and Docetaxel [Taxotere]).

These agents are used to treat a variety of cancers including ovary, breast, and non-small cell lung cancers. They contain a plant alkaloid that inhibits microtubule function, leading to mitotic arrest. Paclitaxel produces a dose-limiting peripheral neuropathy that occurs in 60% of patients receiving 250 mg/mz. The neuropathy is predominantly sensory and affects both large and small fibers. Symptoms usually begin after 1 to 3 weeks of treatment. Patients develop burning paresthesias of the hands and feet and loss of reflexes. The neuropathy often does not progress despite continued treatment, and there have been reports of patients improving with continuing therapy. Some patients develop arthralgias and myalgias beginning 2 to 3 days after a course lasting 2 to 4 days. Less commonly, Tax01 can result in motor neuropathies that affect predominantly proximal muscles, perioral numbness, and autonomic neuropathies. Rarely, paclitaxel causes seizures or transient encephalopathies or phantom limb pain in patients with prior amputation. Neuropathies are less common with docetaxel, but some patients develop sensory and motor neuropathies similar to those caused by paclitaxel. Docetaxel can occasionally produce Lhermitte’s sign. The neurotoxic effects of paclitaxel and docetaxel increase when they are combined with cisplatin. Nerve growth factor prevents the neuropathy in mice and is being evaluated in clinical trials. Vinca Alkaloids. Vincristine is a vinca alkaloid used to treat many cancers including leukemia, lymphomas, sarcomas, and brain tumors. Its main toxicity is an axonal neuropathy resulting from disruption of the microtubules within axons and interference with axonal transport. The neuropathy involves both sensory and motor fibers, although small sensory fibers are especially affected. Almost all patients have some degree of neuropathy, which is the dose-limiting toxicity. The earliest symptoms usually are paresthesias in the fingertips and feet. Muscle cramps are also quite common. These symptoms may occur after several weeks of treatment or even after the drug has been discontinued and progress for several months before improving. Children tend to

recover more quickly than adults. Initially objective sensory findings tend to be minor compared with the symptoms, but loss of ankle jerks is common. Occasionally there may be profound weakness, with bilateral foot drop and wrist drop, and loss of all sensory modalities. This occurs especially in older patients who are cachectic, patients who have received prior radiation to the peripheral nerves, or those who have preexisting neurologic diseases such as Charcot-Marie-Tooth neuropathy. Vincristine may also cause focal neuropathies. Neurophysiologic studies show a primarily axonal neuropathy. Although there are anecdotal reports that glutamine may help some patients with vincristine neuropathy, there is generally no effective treatment. Autonomic neuropathy is common in patients receiving vincristine. Colicky abdominal pain and constipation occur in almost 50% of patients, and rarely paralytic ileus may result. All patients receiving vincristine should receive prophylactic stool softeners and laxatives. Less commonly, patients may develop impotence, postural hypotension, and atonic bladders. Vincristine occasionally may cause cranial neuropathies. The most common nerve to be involved is the occulomotor nerve, resulting in ptosis and ophthalmoplegia. Other nerves that may be involved include recurrent laryngeal nerve, optic nerve, facial nerve, and auditory nerve. Vincristine may also cause retinal damage and night blindness. Some patients may experience jaw pain and parotid pain. Rarely, vincristine may cause SIADH, resulting in hyponatremia, confusion, and seizures. CNS complications unrelated to SIADH may also occur. These include seizures, encephalopathy, transient cortical blindness, ataxia, athetosis, and parkinsonism. The related vinca alkaloids vindesine and vinblastine have less neurotoxicity. This may be related to differences in lipid solubility, plasma clearance and terminal half-life, and different sensitivities of axoplasmic transport. Vinorelbine is a semisynthetic analogue of vinblastine that is being increasingly used for patients with breast and lung cancer. Like vincristine, vinorelbine inhibits microtubule assembly but has less affinity for neural tissue and therefore was predicted to be less neurotoxic. Vinorelbine use is associated with mild paresthesias in about 20% of patients. Severe neuropathy is rare but appears to be more common in patients treated previously with paclitaxel. Drugs That Occasionally Cause Neurotoxicity Carboplatin. Carboplatin is an alkylating agent used for a variety of cancers including ovarian, cervical, testicular, lung, and head and neck. Unlike with cisplatin, peripheral neuropathy and CNS toxicity occur only rarely at conventional dosages. However, intra-arterial carboplatin may produce strokelike syndromes and retinal toxicity. Cytosine Arabinoside. This is a pyrimidine analogue used to treat leukemias, lymphomas, and neoplastic meningitis. This agent has little neurotoxicity when used at conventional dosages. High dosages (3 g/m’ every 12 hours) cause an acute cerebellar syndrome in 10% to 25% of patients. Patients above age 40 with abnormal liver or renal function and underlying neurologic dysfunction or those receiving more than 30 g of the drug are especially likely to develop cerebellar involvement. Typically, the patient develops somnolence and occasionally encephalopathy 2 to 5 days after completing treatment. Immediately afterward the patient develops cerebellar toxicity. This may range from mild ataxia to inability to sit or walk unassisted. Rarely patients may

Chapter 176

experience seizures. The pathologic changes are localized to the cerebellum, where there is widespread loss of Purkinje cells. In some patients the cerebellar syndrome resolves spontaneously, but it is permanent in others. No specific treatment is available, but avoidance of very high dosages of the drug has led to a decline in the incidence of this syndrome. High-dose cytosine arabinoside may occasionally cause peripheral neuropathies resembling the Guillain-Barre syndrome, brachial plexopathy, encephalopathy, lateral rectus palsy, and an extrapyramidal syndrome. Intrathecal administration of cytosine arabinoside produces high levels of drug in the CSF for at least 24 hours and is used to treat neoplastic meningitis. It can cause a transverse myelopathy similar to that seen with intrathecal methotrexate. Rarely, it can also cause aseptic meningitis, encephalopathy, headaches, and seizures. 5-Fluorouracil. 5-Fluorouracil (5-FC) is fluorinated pyrimidine that disrupts DNA synthesis by inhibiting thymidylate synthetase. It is used to treat many cancers, including colon and breast cancers. An acute cerebellar syndrome can occur in approximately 5% of patients. This usually begins weeks or months after treatment and is characterized by the acute onset of ataxia, dysmetria, dysarthria, and nystagmus. These symptoms usually resolve completely after the drug is stopped. The development of a cerebellar syndrome may be partly explained by the fact that 5-FU readily crosses the blood-brain barrier, with the highest concentrations being found in the cerebellum. Rarely 5-FC can cause encephalopathy, optic neuropathy, eye movement abnormalities, Parkinsonian syndrome, peripheral neuropathy, or seizures. Patients with decreased dihydropyrimidine dehydrogenase activity are at a higher risk of developing severe neurologic toxicity after 5-FU chemotherapy. The combination of 5-FC and levamisole used to treat colon cancer has been rarely associated with the development of an encephalopathy and ataxia resulting from multifocal demyelinating lesions in the periventricular white matter. The cause of these lesions is unknown, and they usually improve with steroids and discontinuation of the drugs. The importance of recognizing this syndrome is that the cerebral lesions may be mistaken for brain metastases. The administration of 5-FC and other drugs may also increase the incidence of neurotoxicity. The coadministration of 5-FC and allopurinol, PAM, doxifluridine, carmofur, and tegafur have all been reported to cause encephalopathies and cerebellar syndromes. Ifosfamide. This is an analogue of cyclophosphamide, with similar systemic toxicities. Unlike cyclophosphamide, it can also produce an encephalopathy in 20% of patients. The encephalopathy begins hours or days after administration of the drug and usually resolves completely after several days. This encephalopathy is thought to result from accumulation of chloracetaldehyde, one of the breakdown products of ifosfamide. Patients at higher risk for the encephalopathy include those with renal dysfunction, low serum albumin, prior treatment with cisplatin, and previous encephalopathy with ifosfamide. There have been reports that methylene blue may be useful in preventing or treating ifosfamide encephalopathy by inhibiting monoamine oxidases. For most patients no specific treatment is necessary, and the encephalopathy usually improves with time. Ifosfamide may also rarely cause seizures, cerebellar ataxia, weakness, cranial nerve dysfunction, and an extrapyramidal syndrome.

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Nitrosoureas. The nitrosoureas (carmustine, lomustine) are lipid-soluble alkylating agents that rapidly cross the blood-brain barrier and are used to treat brain tumors, melanoma, and lymphoma. These drugs generally have little neurotoxicity when used at conventional dosages. High-dose intravenous carmustine used in the setting of autologous bone marrow transplantation can cause an encephalomyelopathy and seizures that develop over a period of weeks to months after the drug is administered. Intra-arterial carmustine produces ocular toxicity and neurotoxicity in 30%to 48% of patients. Patients often complain of headache and eye and facial pain, and retinopathy and blindness may occur. The neurotoxicity includes confusion, seizures, and progressive neurologic deficits. Imaging and pathologic studies show findings similar to those of radiation necrosis confined to the vascular territory perfused by the carmustine. Concurrent radiotherapy may increase the neurotoxicity of intracarotid carmustine. Injection of the drug above the origin of the ophthalmic artery reduces the incidence of ocular toxicity but increases the neurotoxicity. Procarbazine. This is a weak monoamine oxidase inhibitor that probably acts as an alkylating agent. It is used to treat lung carcinoma, lymphoma, and brain tumors. At normal oral dosages it can cause a mild reversible encephalopathy and neuropathy and rarely psychosis and stupor. Procarbazine also potentiates the sedative effects of narcotics, phenothiazines, and barbiturates. Intravenous and intracarotid procarbazine produces a severe encephalopathy. Asparaginase. This is used mainly to treat acute lymphocytic leukemia. Neurotoxicity with asparaginase is rare, but it affects coagulation and may cause hemorrhagic and thrombotic complications including sagittal sinus thrombosis and cerebral infarction. These complications typically occur after several weeks of treatment. Patients usually present with seizures, headaches, or focal deficits. Asparaginase may also produce a reversible encephalopathy. The related pegylated (PEG)-asparaginase has similar neurotoxicity. Thalidomide. Thalidomidewas introduced in Europe in 1954 as a sedative-hypnotic agent but was withdrawn in 1961 because of the high incidence of limb malformations in children of women who took the drug. In 1998, the drug was approved by the U.S. Food and Drug Administration to treat erythema nodosum leprosum. In preclinical studies, thalidomide has shown potent antiangiogenic effects. Based on this property, it has been used in clinical trials for multiple myeloma, gliomas, Kaposi's sarcoma, and breast cancer. The most common side effect is somnolence, affecting approximately 50% of patients. Many patients develop tachyphylaxis to this side effect and report decreased somnolence after 2 or 3 weeks. Peripheral neuropathy occurs in 3% to 32% of patients and does not appear to be dose-related. Seizures have occurred in a minority of patients with gliomas and a history of seizures.

Drugs That Rarely Cause Neurotoxicity Anthracycline Antibiotics (Doxorubicin, Daunorubicin, Mitoxantrone). Apart from accidental intrathecal injection, which can cause a myelopathy and encephalopathy, these agents have little neurotoxicity. Doxorubicin can cause arrhythmias and cardiomyopathies, and this may result in cerebrovascular complications. Busulfan. This drug has little neurotoxicity at standard dosages, but high-dose therapy can cause seizures.

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Capecitabine (Xeloda). This is metabolized to its cytotoxic form, 5-FU, by the enzyme thymidine phosphorylase and is used to treat breast cancer. Neurologic complications are uncommon, but some patients experience paresthesias, headaches, dizziness, and insomnia. Chlorambucil. This usually has little neurotoxicity but can cause an encephalopathy and seizures when taken in very high dosages. Etoposide (VP-16). This is a topoisomerase I1 inhibitor used to treat lung cancer, germ cell tumors, and refractory lymphoma. It generally has little neurotoxicity, even in high dosages. Rarely it can cause a peripheral neuropathy, mild disorientation, seizures, transient cortical blindness, or optic neuritis. Fludarabine and Cladribine. Fludarabine is an inhibitor of DNA polymerase and ribonucleotide reductase that is used to treat chronic lymphatic leukemia, macroglobulinemia, and indolent lymphomas. Neurotoxicity is uncommon, but it can cause headaches, somnolence, confusion, and paresthesias at low dosages and seizures, visual loss, paralysis, and coma at high dosages. Cladribine (2-~hlordeoxyadenosine),a related drug used for Waldenstrom's macroglobulinemia,has little neurotoxicity at conventional dosages but can produce a paraparesis at high dosages. Gemcitabine. This is a deoxycytidine analogue used to treat pancreatic cancer, but it also has activity against other tumors, including breast cancer and small cell lung cancer. Neurotoxicity is uncommon, but up to 10% of patients experience mild paresthesias, and, rarely, more severe peripheral and autonomic neuropathies have been described. Hydroxyurea. This is an antimetabolite used to treat resistant chronic myelogenous leukemia and certain solid tumors including melanoma, ovarian carcinoma, trophoblastic neoplasms, and cervical, head and neck, and prostate cancers. Rarely it can cause headaches, drowsiness, confusion, and seizures. Mechlorethamine (Nitrogen Mustard). This is an alkylating agent used to treat Hodgkin's lymphoma and malignant pleural effusions. It may rarely cause sleepiness, headaches, and weakness. At high dosages used for bone marrow transplantation, it has been reported to cause confusion and seizures. Mithramycin. This is used to treat refractory hypercalcemia and may cause headaches, lethargy, and irritability, These side effects tend to be dose dependent. Mitomycin-C. This is an alkylating agent used to treat carcinomas of the gastrointestinal tract, breast cancer, and head and neck malignancies. It has been associated with an encephalopathy caused by thrombotic microangiopathy. Pentostatin (Deoxycoformycin). This adenosine deaminase inhibitor is used to treat a variety of leukemias, including hairy cell leukemia. At low dosageslethargy and fatigue are common. Higher dosages can cause a severe encephalopathy, seizures, and coma. Retinoic Acid. All-trans-retinoic acid, which is used to treat promyelocytic leukemia, can rarely cause pseudotumor cerebri and multiple mononeuropathies. Temozolomide. This is an alkylating agent related to imidazotetrazines with activity against malignant gliomas and melanoma. Forty percent of patients receiving the drug experience headaches, but serious neurologic complications are rare. Teniposide (VM-26). This is a topoisomerase inhibitor used to treat acute lymphoblastic leukemia, Kaposi's sarcoma, and cutaneous T-cell lymphoma. It has rarely been associated with paresthesias, fatigue, somnolence, and seizures. Thioguanine. This antimetabolite is used to treat leukemia and brain tumors. It can rarely cause loss of vibratory sense and ataxia.

Thiotepa. This is an alkylating agent occasionally used to treat leptomeningeal metastases. Rarely, intrathecal thiotepa causes a myelopathy. High intravenous dosages of thiotepa can produce an encephalopathy that can be fatal.

HORMONAL THERAPY Aminoglutethimide. This inhibits the synthesis of steroid hormones and is used to treat breast carcinoma, adrenocortical carcinoma, and ectopic Cushmg's syndrome. It often causes mild lethargy and rarely may cause vertigo and ataxia. Anastrozole (Arimidex). This is an aromatase inhibitor (inhibitor of estrogen) used for postmenopausal women with hormone receptor-positive advanced breast cancer. It can cause weakness and back pain. Corticosteroids. Corticosteroids often are used in patients with cancer for a variety of reasons. They reduce peritumoral edema in patients with primary and secondary brain tumors and spinal cord edema in patients with epidural spinal cord compression. Corticosteroids also have a direct cytolytic effect against neoplastic lymphocytes and are used to treat leukemias and lymphomas. High-dose corticosteroids often are given with chemotherapy to reduce nausea and vomiting, and low dosages are used to improve the appetite and sense of well-being in some patients with cancer. The side effects of prolonged steroid therapy are well known (See Table 156-1in Chapter 156).The incidence of complications increases with higher dosages and prolonged therapy, but there is also significant variation in individual susceptibility. The systemic side effects include a Cushingoid appearance, truncal obesity, hirsutism, acne, impaired wound healing, striae, easy bruising and capillary fragility, immunosuppression, hypertension, glucose intolerance, electrolyte disturbance, fluid retention, peripheral edema, increased appetite, gastrointestinal bleeding, osteoporosis, avascular necrosis, growth retardation, cataracts, glaucoma, and visual blurring. The neurologic complications of corticosteroids are summarized in Table 176-2.The most common complication is steroid myopathy. This is characterized by weakness of the proximal muscles affecting primarily the hip girdle. Patients typically complain of difficultygetting up from a chair or climbing stairs. In severe cases, the pectoral girdle and neck muscles may also be involved. Steroid myopathy tends to occur after prolonged use of high dosages of steroids, but there is significantvariation in patient susceptibility, and some patients will develop a myopathy after using low dosages of steroids for a short period. Electromyography usually is normal, and creatine kinase levels usually are not elevated. Corticosteroids often produce alterations in mood. An improved sense of well-being, anxiety, irritability, insomnia, diffi-

W

TAW 176-2. Neurologic Complications of Corticosteroids Common

Uncommon

Myopathy Visual blurring Tremor Behavioral changes Insomnia Reduced taste and olfaction Cerebral atrophy

Psychosis Hallucinations Hiccups Dementia Seizures Dependence Epidural lipomatosis Neurooathv

Chapter 176

culty concentrating, and depression are all common. Occasionally, patients may develop steroid psychosis. This usually takes the form of acute delirium, but the psychosis may resemble mania, depression, or schizophrenia. Other common neurologic complications of corticosteroids include tremors, visual blurring, reduced sense of taste and smell, and cerebral atrophy on neuroimaging studies. Rare complications include hiccups, dementia, seizures, and cord compression as a result of epidural lipomatosis. Steroid withdrawal can also produce a variety of symptoms that can be quite disabling. These include headaches, lethargy, nausea, vomiting, anorexia, myalgia and arthralgia (pseudorheumatism), fever, abdominal pain, postural hypotension, pseudotumor, and panniculitis. Estramustine. This is used to treat prostate cancer and may occasionally cause headaches and cerebrovascular complications. Letrozole (Femara). This is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) used to treat breast cancer. It can cause headaches, insomnia, and arthralgias. Leuprolide Acetate (Lupron). This is a gonadotropinreleasing hormone analogue used to treat prostate cancer and refractory breast cancer. Neurologic complications are uncommon, but it can cause headaches, dizziness, and paresthesias. Mitotane (OF-DDD). This drug, which suppresses adrenocorticosteroid production and is cytotoxic to adrenal cortical cells, is used to treat adrenocortical carcinoma. It produces lethargy, sedation, and dizziness in 40% of patients. Octreotide (Sandortatin). This is a long-acting analogue of somatostatin used to treat carcinoid tumors, vasoactive intestinal peptide secreting tumors, and certain pituitary adenomas. It can cause headaches, dizziness, and rarely seizures. Tamoxifen (Novaldex). This is an antiestrogen that is used to treat breast cancer. It can produce retinopathy, encephalopathy, and ataxia, especially when used in high dosages. Other antiestrogens and antiandrogens such as flutamide usually are not associated with neurotoxicity. Toremifene Citrate (Fareston). This is an antiestrogen used to treat breast cancer. Neurologic complications are uncommon, but patients may experience dizziness, depression, tremor, blurred vision, and ataxia.

BIOLOGICAGENTS In recent years there has been increasing interest in using biologic agents to treat cancers. Often, they are used in combination with conventional chemotherapeutic agents. a-Interferon. This is used therapeutically in a number of cancers including hairy cell leukemia, Kaposi's sarcoma, and myeloma. Systemic toxicities include flulike symptoms and myelosuppression. The flulike symptoms tend to be worse at the onset of therapy and usually improve with time. Neurotoxicity tends to be dose related and includes headaches, confusion, lethargy, hallucinations, and seizures. These are usually reversible, but occasionally a permanent dementia or a persistent vegetative state may result. Rarely, a-interferon has been associated with occulomotor palsy, sensorimotor neuropathy, brachial plexopathy, and polyradiculopathy. Patients treated with interferon a-2b may have 'a higher incidence of neuropsychiatric complications. Intrathecal administration of a-interferon has been evaluated for treating meningeal and brain tumors, multiple sclerosis, amyotrophic lateral sclerosis, and progressive multifocal leukoencephalopathy. An acute reaction usually is seen within hours of the

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first injection and consists of headache, nausea, vomiting, fever, and dizziness. The symptoms usually resolve over the next 12 to 24 hours. A severe encephalopathy develops in a significant number of patients within several days of the onset of treatment. This is dose dependent and tends to be worse in patients who have received cranial irradiation. p- and y-Interferon. These have neurotoxicities similar to those of a-interferon, although intrathecal P-interferon appears to be better tolerated. Interleukin-2. This has been used alone and in combination with lymphokine activated killer (LAK) cells and tumorinfiltrating lymphocytes to treat a number of cancers, especially renal cell carcinoma and melanoma. Neuropsychiatric complications occur in 30% to 50% of patients. These include cognitive changes, delusions, hallucinations, and depression. In addition, there have been reports of transient focal neurologic deficits, acute leukoencephalopathy,and brachial neuritis. Interleukin-2 has been administered directly into the tumor bed to treat gliomas and can cause significant cerebral edema. Interleukin-4. This as been associated with headaches. Colony-Stimulating Factors (granulocyte colony-stimulating factor [C-CSF], granulocyte-macrophage colony-stimulating factor [CM-CSq). These are used to increase the granulocyte

count and reduce the incidence of infections in patients with nonmyeloid tumors receiving chemotherapy. Musculoskeletal symptoms such as cramps and bone pain occur commonly. Rarely they may cause fatigue and headaches. GM-CSF has also been reported to cause confusion and neuropathies. Erythropoietin (Procrit, Epogen). This is used to stimulate red cell production. Some patients may experience fatigue, dizziness, and paresthesias, but serious neurologic complications have not been described. Oprelvekin (Neumega). This is a platelet growth factor used to prevent severe chemotherapy-inducedthrombocytopenia. Neurologic complications are uncommon, but some patients complain of headaches, dizziness, insomnia, and paresthesias.

MONOCLONAL ANTIBODIES Cemtuzumab Ozogamicin (Mylotarg). This is an antibodytargeted chemotherapeutic agent used in patients with CD33+ acute myelogenousleukemia. It can cause headaches and dizziness. Rituximab (Rituxan). This is a genetically engineered chimeric murine-human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. It is used to treat low-grade or follicular .' B-cell lymphoma. Neurologic complications are uncommon, but some patients complain of headaches, myalgia, dizziness, or . paresthesias. Iodine-131 Tositumomab (Bexxar). This is a radiolabeled immunoglobulin G-2a murine monoclonal antibody directed against the CD20 antigen. In addition to the cytotoxic effects induced by the antibody, the presence of iodine-131 results in focused targeting of beta radiation to the tumor and surrounding tissue. To date, it has been used primarily to treat relapsed or refractory non-Hodgkin's lymphoma. Iodine-131 tositumomab is well tolerated. A minority of patients experience headache or myalgia, and a few develop hypothyroidism. Trastuzumab (Herceptin). This is a humanized antip185(HER2) monoclonal antibody used alone or in combination with chemotherapeutic agents in patients with HEWneuoverexpressing metastatic breast cancer. Rarely, patients experience headaches, dizziness, and insomnia after infusion of the antibody.

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SIGNAL TRANSDUCTION INHIBITORS lmatinib (ST1571, Cleevec). Imatinib is a protein-tyrosine kinase inhibitor of the Abl tyrosine kinase and the receptors for platelet-derived growth factor (PDGF) and stem cell factor c-kit. It has been shown to have significant activity in patients with chronic myelogenous leukemia (CML) and c-kit-expressing gastrointestinal stromal tumors. CNS side effects are uncommon, but there have been isolated reports of patients with confusion, cerebral edema, and papilledema. ~

OTHER AGENTS Amifostine. This is a thiophosphate cytoprotectant agent used to reduce renal toxicity associated with cisplatin. There is also evidence that it may reduce the neurotoxicity of many chemotherapeutic agents, including cisplatin. Neurologic complications are uncommon, but amifostine may cause hypotension and lead to syncope, and there have been rare reports of seizures. Denileukin Difitox (Ontak). This is a fusion toxin used to treat cutaneous T-cell lymphoma expressing the CD25 component for the interleukin-2 receptor. The most common complication is a vascular leak syndrome, but some patients experience myalgias, dizziness, paresthesias, nervousness, confusion, and insomnia. Pamidronate (Aredia). This is a bisphosphonate used to treat hypercalcemia and bony metastases. Approximately 2% of patients experience insomnia, sleepiness, or abnormal vision.

SUGGESTED READINGS DeAngelis LA, Delattre JY,Posner JB: Neurological complications of chemotherapy and radiation therapy. pp. 437458. In Aminoff MJ (ed): Neurology and General Medicine. 3rd Ed. Churchill Livingstone, New York, 2001 Delattre JY, Vega F, Chen Q: Neurologic complicationsof immunotherapy. pp. 267-293. In Wiley RG (ed): Neurologic Complications of Cancer. Marcel Dekker, New York, 1995

Denicoff KD, Rubinow DR, Papa MZ et al: The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 107:293-300, 1987 Feinberg WM, Swenson MR Cerebrovascular complications of Lasparaginase therapy. Neurology 38:127-133, 1988 Forsyth PA, Cascino TL Neurologic complications of chemotherapy. pp. 241-266. In Wiley RG (ed): Neurologic Complications of Cancer. Marcel Dekker, New York, 1995 Hammack JE, Cascino TL Chemotherapy and other common druginduced toxicitiesof the central nervous system in patients with cancer. pp. 481-514. In Vecht CJ (ed): Handbook of Clinical Neurology. Elsevier, Amsterdam, 1998 Herzig RH, Hines JD, Herzig GP et al: Cerebellar toxicity with high dose cytosine arabinoside. J Clin Oncol 5:927-932, 1987 Keime-Guibert F, Napolitano M, Delattre p.Neurologic complications of radiotherapy and chemotherapy. J Neurology 245:695-708, 1998 La Rocca RV, Meer J, Gilliatt RW et al: Suramin-induced polyneuropathy. Neurology 40:954-960, 1990 Legha SS: Vincristine neurotoxicity. Pathophysiology and management. Med Toxic01 1:421-427, 1986 Lipton RB, Apfel SC, Dutcher JP et al: Tax01 produces a predominantly sensory neuropathy. Neurology 39368-373, 1989 Meyers CA, Scheibel RS, Forman AD: Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 41:672477, 1991 Paleologos N Complications of chemotherapy. pp. 439-460. In Biller J (ed): Iatrogenic Neurology. Butterworth-Heinemann, Boston, 1998 Phillips P C Methotrexate toxicity. pp. 115-134. In Rottenberg DA (ed): Neurological Complications of Cancer Treatment. ButterworthHeinemann, Boston, 1991 Phillips PC, Reinhard CS: Antipyrimidine neurotoxicity: cytosine arabinoside and 5-fluorouracil. pp. 97-114. In Rottenberg DA (ed): Neurological Complications of Cancer Treatment. ButterworthHeinemann, Boston, 1991 Posner JB: Side effects of chemotherapy. pp. 282-310. In Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995 Rottenberg DA (ed): Neurological Complications of Cancer Treatment. Butterworth-Heineman, Boston, 1991 Wen PY CNS complications of cancer therapy. In Schiff DS, Wen PY: Cancer Neurology. Humana Press, Philadelphia, 2003 (in press) Wen PY Neurologic Complications of Chemotherapy MedLink Neurology, San Diego 2003

177 Neurologic Complications of Radiation Therapy Edward J. Dropcho The central nervous system (CNS) was once considered to be resistant to high-energy radiation. With patients living longer after CNS radiotherapy and with the advent of sensitive neuroimaging techniques, it has become clear that the limits of tolerance of the CNS must be revised downward. Table 177-1 summarizes the adverse effects of irradiation on the nervous system.

ACUTE ENCEPHALOPATHY Brain injury by therapeutic irradiation has traditionally been classified according to its time of onset into acute, early delayed, and late forms. The acute reaction to cranial radiation therapy

(RT) usually occurs during the first several days of treatment and consists of headache, nausea, fever, somnolence, and worsening of preexisting focal symptoms. Acute RT encephalopathy tends to occur more often and to be more severe among patients with large intracranial masses and in patients who receive large (greater than 300 cGy) daily dosage fractions of whole-brain RT. Increased cerebral edema is the most likely cause of symptoms, but this may not be apparent on computed tomography (CT) or magnetic resonance (MR) scans. Acute toxicity generally responds well to increased dosages of dexamethasone. Patients with large primary tumors o r multiple metastases should be pretreated with dexamethasone for 24 to 72 hours before cranial RT is initiated.

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SIGNAL TRANSDUCTION INHIBITORS lmatinib (ST1571, Cleevec). Imatinib is a protein-tyrosine kinase inhibitor of the Abl tyrosine kinase and the receptors for platelet-derived growth factor (PDGF) and stem cell factor c-kit. It has been shown to have significant activity in patients with chronic myelogenous leukemia (CML) and c-kit-expressing gastrointestinal stromal tumors. CNS side effects are uncommon, but there have been isolated reports of patients with confusion, cerebral edema, and papilledema. ~

OTHER AGENTS Amifostine. This is a thiophosphate cytoprotectant agent used to reduce renal toxicity associated with cisplatin. There is also evidence that it may reduce the neurotoxicity of many chemotherapeutic agents, including cisplatin. Neurologic complications are uncommon, but amifostine may cause hypotension and lead to syncope, and there have been rare reports of seizures. Denileukin Difitox (Ontak). This is a fusion toxin used to treat cutaneous T-cell lymphoma expressing the CD25 component for the interleukin-2 receptor. The most common complication is a vascular leak syndrome, but some patients experience myalgias, dizziness, paresthesias, nervousness, confusion, and insomnia. Pamidronate (Aredia). This is a bisphosphonate used to treat hypercalcemia and bony metastases. Approximately 2% of patients experience insomnia, sleepiness, or abnormal vision.

SUGGESTED READINGS DeAngelis LA, Delattre JY,Posner JB: Neurological complications of chemotherapy and radiation therapy. pp. 437458. In Aminoff MJ (ed): Neurology and General Medicine. 3rd Ed. Churchill Livingstone, New York, 2001 Delattre JY, Vega F, Chen Q: Neurologic complicationsof immunotherapy. pp. 267-293. In Wiley RG (ed): Neurologic Complications of Cancer. Marcel Dekker, New York, 1995

Denicoff KD, Rubinow DR, Papa MZ et al: The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 107:293-300, 1987 Feinberg WM, Swenson MR Cerebrovascular complications of Lasparaginase therapy. Neurology 38:127-133, 1988 Forsyth PA, Cascino TL Neurologic complications of chemotherapy. pp. 241-266. In Wiley RG (ed): Neurologic Complications of Cancer. Marcel Dekker, New York, 1995 Hammack JE, Cascino TL Chemotherapy and other common druginduced toxicitiesof the central nervous system in patients with cancer. pp. 481-514. In Vecht CJ (ed): Handbook of Clinical Neurology. Elsevier, Amsterdam, 1998 Herzig RH, Hines JD, Herzig GP et al: Cerebellar toxicity with high dose cytosine arabinoside. J Clin Oncol 5:927-932, 1987 Keime-Guibert F, Napolitano M, Delattre p.Neurologic complications of radiotherapy and chemotherapy. J Neurology 245:695-708, 1998 La Rocca RV, Meer J, Gilliatt RW et al: Suramin-induced polyneuropathy. Neurology 40:954-960, 1990 Legha SS: Vincristine neurotoxicity. Pathophysiology and management. Med Toxic01 1:421-427, 1986 Lipton RB, Apfel SC, Dutcher JP et al: Tax01 produces a predominantly sensory neuropathy. Neurology 39368-373, 1989 Meyers CA, Scheibel RS, Forman AD: Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 41:672477, 1991 Paleologos N Complications of chemotherapy. pp. 439-460. In Biller J (ed): Iatrogenic Neurology. Butterworth-Heinemann, Boston, 1998 Phillips P C Methotrexate toxicity. pp. 115-134. In Rottenberg DA (ed): Neurological Complications of Cancer Treatment. ButterworthHeinemann, Boston, 1991 Phillips PC, Reinhard CS: Antipyrimidine neurotoxicity: cytosine arabinoside and 5-fluorouracil. pp. 97-114. In Rottenberg DA (ed): Neurological Complications of Cancer Treatment. ButterworthHeinemann, Boston, 1991 Posner JB: Side effects of chemotherapy. pp. 282-310. In Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995 Rottenberg DA (ed): Neurological Complications of Cancer Treatment. Butterworth-Heineman, Boston, 1991 Wen PY CNS complications of cancer therapy. In Schiff DS, Wen PY: Cancer Neurology. Humana Press, Philadelphia, 2003 (in press) Wen PY Neurologic Complications of Chemotherapy MedLink Neurology, San Diego 2003

177 Neurologic Complications of Radiation Therapy Edward J. Dropcho The central nervous system (CNS) was once considered to be resistant to high-energy radiation. With patients living longer after CNS radiotherapy and with the advent of sensitive neuroimaging techniques, it has become clear that the limits of tolerance of the CNS must be revised downward. Table 177-1 summarizes the adverse effects of irradiation on the nervous system.

ACUTE ENCEPHALOPATHY Brain injury by therapeutic irradiation has traditionally been classified according to its time of onset into acute, early delayed, and late forms. The acute reaction to cranial radiation therapy

(RT) usually occurs during the first several days of treatment and consists of headache, nausea, fever, somnolence, and worsening of preexisting focal symptoms. Acute RT encephalopathy tends to occur more often and to be more severe among patients with large intracranial masses and in patients who receive large (greater than 300 cGy) daily dosage fractions of whole-brain RT. Increased cerebral edema is the most likely cause of symptoms, but this may not be apparent on computed tomography (CT) or magnetic resonance (MR) scans. Acute toxicity generally responds well to increased dosages of dexamethasone. Patients with large primary tumors o r multiple metastases should be pretreated with dexamethasone for 24 to 72 hours before cranial RT is initiated.

Chapter 177 W

TAW 177-1. Adverse Effects of Irradiation on the Nervous

System Cerebral injury Acute Early delayed Delayed Focal necrosis Diffuse injury Neuroendocrine effects Optic neuropathy Cranial neuropathies Spinal cord injury Transient myelopathy Delayed progressive myelopathy Motor neuron syndrome Peripheral nerve injury Cerebrovascular damage Radiation-inducedtumors

EARLY DELAYED ENCEPHALOPATHY Early delayed encephalopathy typically consists of headache, somnolence, or deterioration in preexisting deficits occurring within the first few months after the completion of whole-brain or limited-field RT. Corticosteroids usually produce symptomatic improvement, but the syndrome resolves after several weeks with or without corticosteroids. Early delayed encephalopathy is of particular clinical importance among patients with primary brain tumors because its clinical and radiographic features are indistinguishable from those of tumor recurrence or progression. During the 2 to 6 months after completing RT, CT or MR scans in as many as one third of patients with gliomas show worsening edema and mass effect with or without new contrast enhancement, which subsequently improve. Another form of early delayed encephalopathy is the somnolence syndrome, which occurs in 40% to 60% of children with leukemia after 1800 to 2400 cGy of prophylactic whole-brain RT. The syndrome occurs 3 to 8 weeks after completion of RT and consists of drowsiness, nausea, irritability, and less commonly fever or transient papilledema. The somnolence syndrome probably is more common and more severe in children younger than 3 years old. Symptoms resolve without sequelae within 3 to 6 weeks. Corticosteroids hasten recovery and may also prevent the syndrome if given during the course of RT. Children who develop the somnolence syndrome do not have a higher risk of delayed cognitive impairment.

FOCAL CEREBRAL NECROSIS Delayed neurotoxicity can occur several months to 10 or more years after cranial RT. This may take the form of focal necrosis or diffuse cerebral injury. Focal cerebral necrosis may occur after whole-brain or limited-field RT given for primary or metastatic brain tumors and after incidental irradiation of the brain during treatment of pituitary adenomas or other extraneural tumors of the head and neck. The incidence of cerebral necrosis after 5000 cGy or more is generally quoted as 3% to 5%, but many patients with brain tumors do not live long enough to be at risk for developingthis delayed complication. Among 12-month survivors with malignant gliomas after standard fractionated RT, the incidence of focal necrosis is approximately 10%. The incidence of

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symptomatic focal cerebral necrosis after stereotactic radiosurgery (gamma knife) or interstitial radio-iodine brachytherapy is approximately 5% to 15% or 50% to 60%, respectively. There are several formulas for calculating RT dosage equivalents based on total dosage, daily dosage fractions, and treatment duration to allow comparison of the radiobiologic effect of different treatment regimens and to establish dosage thresholds for cerebral RT necrosis. These dosimetric analyses of cerebral necrosis have led to several general conclusions. First, the RT dosage per daily fraction is an important determinant of the risk of cerebral necrosis. Second, the risk of cerebral necrosis as a function of the RT dosage equivalent forms a sigmoid curve. Above a critical exposure level, small increments in dosage lead to a significantly higher risk of cerebral necrosis. Third, with “safe” RT regimens the risk of cerebral necrosis is very low, but there is probably no absolute therapeutically effective dosage threshold below which cerebral necrosis cannot occur. Focal RT in patients with primary brain tumors is most often located in close proximity to the tumor, even in patients who received a high dosage of RT to nearby brain tissue. Cerebral necrosis affecting both frontal lobes, temporal lobes, or brainstem is likely to occur after RT for pituitary tumors or for nasopharyngeal carcinoma. Cerebral necrosis predominantly involves the white matter, with relative sparing of cerebral cortex and deep gray matter. In extreme cases there are confluent foci of coagulative necrosis of all parenchymal elements. Demyelination and loss of oligodendrocytes are present in less severely affected areas, with variable axonal loss, axonal swellings, focal calcifications, fibrillary gliosis, and scattered perivascular infiltrates of mononuclear cells. Extensive vascular changes are a nearly constant feature of focal cerebral necrosis, including fibrinoid necrosis or hyaline thickening of vessel walls, thrombosis of small vessels, proliferation of adventitial fibroblasts, hyaline transudates surrounding affected vessels, and formation of telangiectasias. The clinical presentation of focal cerebral necrosis typically is that of a subacute space-occupying lesion occurring with a peak onset 15 to 18 months after completion of RT; the latent period may rarely be as short as 4 months or as long as 7 years. CT or MR scans show a mass lesion with a combination of edema and patchy or ring enhancement. Neither the clinical features nor the routine neuroimaging studies distinguish cerebral necrosis from recurrent or progressive tumor. Definitive diagnosis of cerebral necrosis therefore entails pathologic confirmation, although in patients with malignant gliomas there is often an intermingling of active tumor with areas of cerebral necrosis, so that stereotactic brain biopsy may yield a nonrepresentative tissue sample. Other neuroimaging techniques may be useful in diagnosing RT necrosis but have limitations. Recurrent anaplastic gliomas usually show increased uptake of fluorodeoxyglucose on positron emission tomography (PET) scans. However, interpretation of fluorodeoxyglucose PET scans often is confounded by limited spatial resolution, the frequent intermingling of tumor cells with small areas of necrosis, difficulty in distinguishing tumor signal from normal grey matter, and occasional hypermetabolic areas of necrosis. Single photon emission computed tomography (SPECT) has also been used to distinguish recurrent tumor from RT necrosis. Like PET imaging, SPECT scanning is limited by spatial resolution and carries a significant rate of false-positive and false-negative results. MR spectroscopy is an increasingly used method for distinguishingtumor progression from RT necrosis; at this time it is not clear whether MR spectroscopy is better than PET or SPECT.

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Dexamethasone or other glucocorticoids produce at least partial clinical and radiographic improvement in most patients with cerebral necrosis. This improvement usually is temporary or patients become steroid dependent, but exceptional patients maintain their improvement even after the steroids are discontinued. There are anecdotal reports of clinical and radiographic improvement in patients anticoagulated with heparin or warfarin or treated with hyperbaric oxygen. Surgical debutking of necrotic brain tissue may be beneficial in patients who do not show adequate response to conservative measures and who have a focal accessible mass lesion. DIFFUSE CEREBRAL INJURY IN ADULTS

The most common neurotoxic effect of cranial RT at any patient age is not focal necrosis but diffuse cerebral injury. For adults with glioblastoma multiforme or other malignant primary brain tumors, only a small minority survive long enough for delayed diffuse cerebral injury to become an issue. Among patients surviving longer than 18 months, serial CT or MR scans in the majority show diffuse cortical atrophy, ventricular dilation, and signal abnormalities in the hemispheric white matter. These changes may worsen over time. The severity of radiographic changes is correlated to the volume of brain irradiated and to the total RT dosage. Some but not all patients with glioma and these radiographic abnormalities develop clinically important cognitive impairment. There is not a very strong correlation between the severity of abnormalities in neuroimaging studies and the presence or severity of clinical neurologic and neuropsychologic deficits. Up to one half of adults with malignant gliomas are unable to return to their premorbid employment and functional status because of moderate to severe neurocognitive deficits not attributable to direct tumor effects. Neuropsychological testing in these patients demonstrates particular difficulties with tasks necessitating attention or problem solving. The most severely affected patients develop progressive dementia and prominent gait disturbance reminiscent of normal pressure hydrocephalus, but few patients benefit from ventriculoperitoneal shunting. Several autopsies of patients with malignant gliomas and symptomatic diffuse injury have shown marked cerebral atrophy with diffuse demyelination and spongiform changes in the hemispheric white matter but with relative preservation of axons and blood vessels. Patients older than 50 years at diagnosis appear to be more likely to develop diffuse cerebral injury than younger patients. A potentiating effect of nitrosoureas or other chemotherapy on the neurotoxic effect of RT has been postulated but not proved. Focal cerebral necrosis is a rare complication of whole-brain RT given for brain metastases because patients generally receive less than 4000 cGy and few patients survive long enough to be at risk. At least one half of patients who survive more than 1 year after whole-brain RT for brain metastases develop abnormalities on serial CT or MR scans, including diffuse cerebral atrophy, ventricular enlargement, and abnormal signal in the periventricular white matter. Most patients with abnormal neuroimaging studies do not have gross neurologic deficits or cognitive impairment, but a small proportion develop a disabling syndrome of progressive dementia, psychomotor retardation, and gait disturbance appearing 6 to 18 months after whole-brain RT. The incidence of RT dementia has been estimated at 2% to 5% among all patients given whole-brain RT for brain metastases and as high as 20% of patients who survive more than 12 months. A

disproportionately high percentage of reported patients with RT dementia received unconventional whole-brain RT regimens, with daily dosage fractions greater than 300 cGy. Autopsies in a few of these patients have shown diffuse injury to myelin sheaths with relative preservation of axons and blood vessels. Ventriculoperitoneal shunting produces a temporary and partial improvement in a minority of patients, but to date there is no reliable way to predict which patients would benefit from a shunt. Patients with small cell lung carcinoma who receive prophylactic whole-brain RT for brain metastases are also at risk of diffuse cerebral injury. Mild to moderate diffuse cerebral atrophy and signal abnormalities in hemispheric white matter are present on CT or MR scans in a majority of patients with small cell lung cancer who survive more than 1 year after prophylactic RT. These abnormalities often become progressively worse on serial imaging studies. Gross neurologic deficits are uncommon, but a high percentage of patients tested have impairment of memory and cognitive functions. Some patients develop progressive dementia with gait disturbance. Severe cognitive impairment probably is more likely to occur in patients who receive high daily dosage RT fractions or concomitant systemic chemotherapy during prophylactic RT. DIFFUSE CEREBRAL INJURY IN CHILDREN

The developing brain is clearly more sensitive to irradiation than the adult brain. Serial CT or MR scans show diffuse cerebral atrophy and signal abnormalities in hemispheric white matter in up to one half of children with primary brain tumors after 2500 to 4000 cGy whole-brain RT. A distinctive pattern of calcifications called mineralizing microangiopathyalso occurs in up to one third of these patients. The calcificationsappear most commonly in the basal ganglia, dentate nuclei, and cerebral gray-white matter junction, sometimes as early as 3 months after whole-brain RT, and often become progressively larger and more numerous over time. Children who receive hyperfractionated RT for brainstem glioma may develop multiple enhancing lesions and abnormal white matter signal distributed in the RT field. Prospective studies of disease-free survivors of childhood primary brain tumors have demonstrated significant declines in mean IQ scores within 2 years after whole-brain RT. Neurobehavioral problems and learning disabilities after whole-brain RT often are present in children whose full-scale IQ still lies in the normal range. These abnormalities include maladaptive behavior, shortterm memory loss, attention deficit disorders, visual perceptual difficulties, and impaired fine motor coordination, reflected in poor school performance and the need for special education. Among children who receive whole-brain RT for medulloblastoma or other brain tumors, the two main factors that determine the severity of cognitive impairment are the RT dosage and the age when RT is administered. Cognitive decline is more common and more severe in children given whole-brain RT before 3 years of age. Significant cognitive impairment and learning disabilities are less common among children who receive RT to a limited brain volume rather than to the whole brain, although impaired intellectual function may still occur after limited-field RT directed at the posterior fossa or diencephalon. Prophylactic whole-brain RT (1800 to 2400 cGy) and intrathecal methotrexate given to children with acute lymphoblastic leukemia carry a significant risk of producing diffuse cerebral injury. The most common findings on serial CT or MR scans after CNS prophylaxis are diffuse cerebral atrophy or white matter

Chapter I77

changes, present in 25% to 50% of patients. In some patients the radiographic changes appear at the end of treatment and subsequently improve. CT scans show intracerebral calcifications (mineralizingmicroangiopathy) appearing within 5 years of RT in up to one third of long-term survivors. Mineralizing microangiopathy does not occur in patients who receive intrathecal methotrexate but no cranial RT. Most neuropsychological studies of childhood leukemia survivors have demonstrated a risk of delayed cognitive impairment after CNS prophylaxis. The severity of neuroimaging changes does not correlate very well with the results of neuropsychological testing, except that patients with intracerebral calcifications are more likely to have cognitive impairment than patients with cerebral atrophy or normal scans. The mean full-scale IQ scores of survivors who received whole-brain RT generally remain in the average range but are less than the IQ of controls or show a decline on serial testing. Performance IQ is more likely to be affected than verbal IQ. Children may have significant neuropsychological dysfunction and learning disabilities despite IQ scores in the average range. Significant cognitive impairment is more likely to occur after 2400 cGy whole-brain RT than 1800 cGy, is more common after a combination of whole-brain RT and methotrexate than with methotrexate alone, and is more common among children given CNS prophylaxis before 6 years of age than in older children. Children who receive treatment for overt meningeal leukemia have a higher risk of cognitive impairment than children who are given prophylactic treatment. In addition to cognitive impairment, some patients with mineralizing microangiopathy have neurologic deficits such as seizures, motor signs, or gait impairment. The most devastating neurologic syndrome occurring in survivors of childhood leukemia is delayed leukoencephalopathy, which generally begins insidiously with personality changes, confusion, or somnolence 4 to 24 months after CNS prophylaxis. Some children show neurologic stabilization or improvement after cessation of methotrexate treatments, but many suffer a progressive course that, in the most severe cases, leads to profound dementia, spastic quadriparesis, seizures, and coma. Leukoencephalopathy is not limited to children receiving CNS leukemia prophylaxis; it may also occur in adults who receive whole-brain RT and intrathecal methotrexate for CNS lymphoma or for leptomeningeal metastases from solid tumors. CT or MRI scans early in the course show decreased attenuation of deep hemispheric white matter with patchy areas of contrast enhancement, followed by diffuse atrophy, ventricular dilatation, and intracerebral calcifications. The pathology of leukoencephalopathy features multiple foci of coagulative necrosis disseminated throughout the hemispheric white matter. In addition to demyelination and severe loss of oligodendrocytes, striking axonal fragmentation and axonal swellings are present within and around the necrotic loci. Vascular changes such as fibrinoid necrosis and fibrin extravasation may be present but are not common or severe. These changes often coexist with mineralizing microangiopathy. The exact pathogenesis of leukoencephalopathy remains unknown, but there is little doubt that the neurotoxic effects of cranial RT and methotrexate are synergistic.Leukoencephalopathy occasionally occurs after intrathecal or high-dose intravenous methotrexate without cranial radiotherapy, but whole-brain RT clearly increases the likelihood of developing leukoencephalopathy many times. The risk of developing leukoencephalopathy increases in several settings: after high cumulative dosages (intrathecal plus

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intravenous) of methotrexate, when the methotrexate is given during or after the whole-brain RT, when whole-brain RT and methotrexate are given for therapy of overt leukemic or carcinomatous meningitis rather than for prophylaxis, and in patients with abnormalities of cerebrospinal fluid flow that result in delayed clearance of methotrexate from the CNS. NEUROENDOCRINE EFFECTS The hypothalamic-pituitary axis is clearly sensitive to cranial RT. In children, the most common neuroendocrine sequela is growth failure. Irreversible biochemical growth hormone deficiency is present in up to 90% of children within 12 months after irradiation of primary brain tumors, with clinical growth failure occurring in 50% to 90%. This occurs in children receiving whole-brain RT as well as those irradiated for medulloblastoma or other posterior fossa tumors, in whom the RT ports encompass the posterior hypothalamus. Other factors contributing to short stature in some of these children include precocious puberty, poor nutrition, systemic chemotherapy, and failure of vertebral body growth after spinal axis RT. Children receiving prophylactic RT for CNS leukemia prophylaxis often have biochemical growth hormone deficiency but generally have normal growth rates. Most children are euthyroid after whole-brain RT but show elevated thyroid-stimulating hormone levels or an exaggerated response to exogenous thyrotropin-releasing hormone. Clinical hypothyroidism is more likely to occur among children who receive craniospinal axis RT because the thyroid gland is included in cervical spine RT ports. In contrast with children, hypothyroidism is the most common neuroendocrine sequela of cranial RT in adults. Free thyroxine levels are low in up to two thirds of long-term survivors after whole-brain RT for primary brain tumors; stimulation tests indicate defective hypothalamic thyrotropin-releasing hormone production as the primary abnormality. Mild to moderate hyperprolactinemia is found in 50% to 75% of adults irradiated for primary brain tumors. Hyperprolactinemia may be accompanied by impotence in men and decreased libido in both sexes. Oligomenorrhea in women probably reflects a combination of hyperprolactinemia and gonadotropin-releasing hormone deficiency. The pituitary-adrenal axis is spared in both children and adults. Diabetes insipidus is inexplicably rare. OPTIC NEUROPATHY Radiation injury to the optic nerve and chiasm most often occurs in patients treated for tumors of the orbit or paranasal sinuses, pituitary adenomas, or craniopharyngiomas, and less commonly occurs after whole-brain RT for primary or metastatic brain tumors. Optic neuropathy may also occur after stereotactic radiosurgery in patients treated for pituitary adenoma or meningioma. The median latency period from RT to the onset of symptoms is 12 to 18 months, without a clear relationship between the RT dosage and latent interval. RT regimens using a high daily dosage fraction probably carry an increased risk of subsequent optic neuropathy. The pathology of RT-induced optic neuropathy is a nonspecific mixture of axonal loss, demyelination, gliosis, and microvascular changes. Patients with RT-induced optic neuropathy generally present with painless monocular or binocular loss of acuity or visual field constriction. Funduscopic examination initially shows optic nerve head swelling with hyperemic disks, telangiectasias, hemorrhages,

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cotton wool spots, and narrowed retinal arterioles. Fluorescein angiography shows retinal capillary nonperfusion. Less commonly, the fundus may appear normal if the main injury is to the retrobulbar optic nerve. Visual field deficits include central scotoma, altitudinal loss, or quadrantic loss. MR scanning shows patchy enhancement of one or both optic nerves and occasionally of the optic chiasm. The optic nerves may also be slightly enlarged. Most patients with RT optic neuropathy deteriorate rapidly over several weeks and are left with irreversible, severe bilateral vision loss and optic atrophy. Partial spontaneous improvement occurs in a small minority. There are anecdotal reports of partial improvement with corticosteroids or hyperbaric oxygen, although most patients do not respond to any treatment.

OTHER CRANIAL NEUROPATHIES Other than optic neuropathy, hypoglossal palsy is the most common RT-induced cranial neuropathy, occurring 2 to 10 years after treatment of primary head and neck tumors. The probable mechanism is entrapment of the nerve by fibrosis. Less common is unilateral palsy of the vagus nerve, spinal accessory nerve, or multiple lower cranial nerve palsies. Some patients with RTinduced bulbar palsy have myokymia and neuromyotonic electromyographic discharges in multiple muscles innervated by the lower cranial nerves. Cranial nerves 11 to VII seem resistant to ordinary external photon beam RT but may be injured by proton beam irradiation of pituitary tumors. Hearing loss is a common complication of cranial RT but is generally caused by a conductive loss or by cochlear damage rather than by damage to the auditory nerve itself.

TRANSIENT MYELOPATHY The most common form of RT-induced spinal cord injury is a transient syndrome occurring in at least 10% of patients after craniospinal axis RT for primary CNS tumors or after incidental irradiation of the cord for treatment of lymphoma or extraneural tumors of the head, neck, or thorax. The risk of transient myelopathy is higher in patients receiving more than 4000 cGy to the spinal cord and in patients receiving high daily dosage fractions. Transient myelopathy occurs after a latent period of 1 to 30 months after the completion of RT, with the peak onset at 3 to 6 months. The syndrome consists solely of paresthesias or “electric shock” sensations radiating down the spine (Lhermitte’s sign) and often extending down the limbs as well. These symptoms often are precipitated by neck flexion or physical exertion. Patients rarely report other symptoms and almost never show objective signs of myelopathy. MRI scans and myelography are normal. The syndrome resolves gradually over several months. Affected patients are not at higher risk for developing severe delayed myelopathy. Transient myelopathy is generally believed to be caused by demyelination of the posterior columns, but there is no neuropathologic proof of this.

DELAYED PROGRESSIVE MYELOPATHY Most patients who develop delayed severe RT myelopathy received incidental irradiation of the spinal cord as part of treatment for extraneural primary carcinomas of the lung, esophagus, head, and neck or of lymphoid tumors. Less common are patients in whom the spinal cord itself is targeted in treatment of a glioma or as part of craniospinal axis RT for medulloblastoma. The reported

incidence figures for delayed RT myelopathy range from 1% to 12% but are probably misleading because many patients do not survive long enough to be at risk for developing this complication. There appear to be bimodal incidence peaks after latent intervals of 12 to 14 months and 24 to 28 months. Exceptional patients have latent intervals as short as 3 months or as long as 10 years after RT. The earliest symptoms of delayed RT myelopathy usually are numbness or dysesthesias in the legs, followed by weakness and sphincter dysfunction, with the upper level of cord dysfunction ascending to lie within the irradiated area. A Brown-SCquard pattern is fairly common early in the course. In most patients, the neurologic deficit progresses over weeks to months in a steady or (less commonly) stepwise fashion, leading to paraplegia or quadriplegia in at least 50% of patients. The clinical features of RT myelopathy do not reliably distinguish it from spinal metastases (extradural or intramedullary), paraneoplastic necrotizing myelopathy, or myelopathy caused by intrathecal chemotherapy. The cerebrospinal fluid in delayed RT myelopathy usually is normal but may contain slightly elevated protein level or a mild pleocytosis. MR scans usually show enlargement of the affected cord and abnormal high signal intensity on T2-weighted images. Most patients have abnormal intramedullary contrast enhancement, either in a streaky or less commonly a ringenhancing pattern. The MR abnormalities often extend beyond the RT ports and generally persist for several months, followed by spinal cord atrophy in long-term survivors. MR scanning cannot absolutely distinguish RT myelopathy from recurrent spinal cord glioma, intramedullary spinal cord metastasis, or paraneoplastic myelopathy. The histopathology of delayed RT myelopathy features a varying combination of changes in white matter and microvasculature. White matter is characteristically more severely affected than gray matter. Coalescing foci of demyelination and axonal degeneration are accompanied by wallerian degeneration above and below the necrotic zones. Vascular changes are variably present and include fibrinoid necrosis of the vessel walls, hyaline thickening and obliteration of lumens, telangiectasias, extravasation of hyaline material, and perivascular lymphocytic cuffing. In some cases the vascular changes are mild compared with the degree of demyelination and parenchymal necrosis. The risk of developing delayed RT myelopathy is largely but not entirely dependent on the total RT dosage and size of the daily dosage fraction. The spinal cord, like the brain, is more sensitive to large dosages per fraction than many other tissues. The best current data indicate that given in once-daily fractions of 200 cGy or less, the risk of delayed RT myelopathy is less than 0.5% for a total dosage of 4500 cGy and 5% for total dosages of 5700 to 6100 cGy. Unexplained differences in individual sensitivity result in the occurrence of delayed RT myelopathy in a very small percentage of patients who receive a “safe” RT regimen. There is no evidence of differential susceptibility between regions of the spinal cord, nor is there a clear relationship between the length of spinal cord irradiated and the risk of delayed myelopathy. Anecdotal reports suggest a potentiating effect of concomitant chemotherapy on the risk of developing RT myelopathy, but this has not been well studied. Treatment options for patients with severe RT myelopathy are very limited. Some patients show stabilization or partial improvement on corticosteroids. There are reports of partial improvement or stabilization after anticoagulation with heparin and warfarin or after hyperbaric oxygen.

Chapter 177 W Neurologic Complications of Radiation Therapy

MOTOR NEURON SYNDROME A rare syndrome of selective damage to lower motor neurons may occur in patients undergoing spinal RT for medulloblastoma, lymphoma, or germ cell tumors. Patients present with subacute, unilateral, or bilateral leg weakness beginning 4 to 14 months after completion of RT. Examination shows bilateral asymmetrical muscle.atrophy,fasciculations,normal or decreased muscle stretch reflexes, flexor plantar responses, and no sensory or sphincter involvement. In most patients, the syndrome progresses slowly over several months and then stabilizes but does not improve. Motor and sensory nerve conduction velocities are normal, and there is electromyographic evidence of diffuse denervation including lumbar paraspinal muscles. In a few published cases spine MR scans were normal. It is not clear whether the primary site of injury in these patients is anterior horn cells, proximal motor axons, or motor roots.

PERIPHERAL NERVE INJURY Effects of radiation on peripheral nerves, especially the brachial plexus, are discussed in Chapter 173.

CEREBROVASCULAR DISEASE The most common deleterious effect of RT on the cerebral vasculature is development of occlusive disease of major extracranial or intracranial vessels. Stenosis or occlusion of the extracranial carotid arteries can occur after cervical or supraclavicular RT given for lymphomas, carcinomas of the breast or thyroid, or a variety of other head and neck tumors. Amaurosis fugax, transient ischemic attacks, or cerebral infarcts occur after an interval of 6 months to 50 years after RT; the median latent period is approximately 15 to 20 years. Arteriograms show disease limited to the RT ports, including such unusual sites as the proximal common carotid artery and the internal carotid artery distal to the common carotid bifurcation. The reported morbidity of carotid endarterectomy or bypass grafting in these patients is low, despite the frequent presence of periarterial fibrosis. There are no definite data comparing the merits of treatment with surgery, antiplatelet agents, or warfarin. RT-induced occlusive disease of intracranial vessels manifesting as stroke or transient ischemic attack may occur after irradiation of the region of the circle of Willis for a variety of tumor types. Onset of cerebrovascular symptoms usually occurs within 5 years of RT but can be delayed for 10 years or more. The most common angiographic findings are narrowing or occlusion of the supraclinoid internal carotid artery or proximal middle cerebral artery. Vasculopathy after RT during early childhood (usually for optic pathway or hypothalamic glioma, craniopharyngioma, or other suprasellar tumors) often shows a moyamoya pattern. Children with optic gliomas and type 1 neurofibromatosis may be at especially high risk for this complication. Clinical manifestations in these children include multiple strokes, recurrent transient ischemic attacks, headache, seizures, and progressive cognitive impairment. The vascular pathology resembles that of idiopathic or primary moyamoya syndrome and features intimal fibrosis and marked proliferation of endothelial and myointimal cells. Some patients benefit from extracranial-intracranialbypass surgery or other revascularization procedures. Symptomatic or asymptomatic intracranial hemorrhages occurring distant from the tumor site may occur 2 to 20 years after

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a wide dosage range of cranial RT for primary brain tumors, pituitary tumors, or leukemia prophylaxis. Vascular lesions associated with these hemorrhages include aneurysms or multiple foci of small-caliber vessels or telangiectasiaswith thickened walls and perivascular hemosiderin. These vasculopathies are more common after cranial RT given during childhood than in adults. Multiple lacunar lesions on MR scans may appear within several years after RT in children, especially if RT is given before 5 years of age. The lesions usually are clinically silent and not correlated with strokelike events or cognitive decline. Complicated migraine with unilateral headache and transient focal deficits has been reported in children after whole-brain RT for primary tumors.

RADIATION-INDUCED TUMORS An increasing number of case reports and epidemiologic studies indicate that tumorigenesis can be a sequel not only of therapeutic dosages of cranial RT given for brain tumors but also of much lower dosages of brain irradiation. The most common radiotherapy-induced intracranial tumors are meningiomas, gliomas, schwannomas, and sarcomas. Meningioma after cranial RT for primary brain tumors occurs after a median latency of approximately 15 years. Meningiomas have also occurred after prophylactic whole-brain RT for childhood leukemia. RT-induced meningiomas do not show any unusual distribution of histologic subtypes, but they do have a higher than expected degree of cellular anaplasia and are more likely to recur after surgery compared with sporadic meningiomas. Low-grade or anaplastic gliomas have been reported after cranial RT in a number of settings, including long-term survivors of medulloblastoma, pituitary adenomas, suprasellar tumors, and patients irradiated for extracranial diseases. The mean latent period to diagnosis of RT-induced ghomas is approximately 10 years, with no clear correlation between the latency and either the radiotherapy dosage or the patient’s age when irradiated. Approximately 75% of post-RT gliomas are glioblastoma multiforme or anaplastic astrocytoma. There are no distinctive histologic features of the tumors and no striking differences in clinical behavior compared with malignant gliomas in general. Approximately 40% of reported RT-induced gliomas occurred in long-term survivors of childhood leukemia who received prophylactic whole-brain RT. Gliomas are the most common nonhematologic tumors occurring as second neoplasms in leukemia survivors, with an estimated incidence of 1% to 2%. The risk of developing glioma may be higher among children with leukemia who receive cranial RT before age 6 years. Sarcoma of the skull base, calvaria, or dura is a rare complication of RT for primary brain tumors, pituitary tumors, or leukemia prophylaxis. Tumors include osteosarcoma, fibrosarcoma, or malignant fibrous histiocytoma. Clinical outcome is poor.

SUGGESTED READINGS Anderson VA, Godber T,Smibert E et ak Cognitiveand academic outcome following cranial irradiation and chemotherapyin children: a longitudinal study. Br 7 Cancer 82:255-262, 2000 Archibald YM, Lunn D, Ruttan LA et al: Cognitive functioning in long-term survivors of high-grade glioma. J Neurosurg 80247-253, 1994 Asai A, Matsutani M, Kohno T et ak Subacute brain atrophy after radiation therapy for malignant brain tumor. Cancer 63:1962-1974, 1989

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Behin A, Delattre J-T Neurologic sequelae of radiation therapy of the nervous system. In Schiff D, Wen PY (Eds.). Cancer Neurology in Clinical Practice. Humana Press, Totowa, 2003 (in press) Bitzer M, Topka H: Progressive cerebral occlusive disease after radiation therapy. Stroke 26131-136, 1995 Constine LS, Woolf PD, Cann D et ak Hypothalamic-pituitarydysfunction after radiation for brain tumors. N Engl J Med 328:87, 1993 Cross NE, Glantz MJ: Neurologic complications of radiation therapy. Neurol Clin 2003 (in press) Crossen JR, Garwood D, Glatstein E, Nevwelt EA: Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 12627442, 1994 DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789-796, 1989 De Carolis P, Montagna P, Cipulli M et al: Isolated lower motoneuron involvement following radiotherapy. J Neurol Neurosurg Psychiatry 49:7 18-7 19, 1986

Fonseca R, O'Neill BP, Foote RL et ak Cerebral toxicity in patients treated for small cell carcinoma of the lung. Mayo Clin Proc 74461-465, 1999 Glantz MJ, Burger PC, Friedman AH et ak Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 4420202027, 1994

Grill J, Renaux VK, Bulteau C et ak Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 45:137-145, 1999

Jankovic M, Brouwers P, Valsecchi MG et al: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. Lancet 344224-227, 1994 Larson JJ, Ball WS, Bove KE et ak Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children. J Neurosurg 88:51-56, 1998 Ricci PE, Karis JP, Heiserman JE et ak Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography? AJNR Am J Neuroradiol 19407-413, 1998 Roman DD, Sperduto PW Neuropsychologicaleffects of cranial radiation: current knowledge and future directions. Int J Radiat Oncol Biol Phys 3 1 :983-998, 1995

Salvati M, Artico M, Caruso R et ak A report on radiation-induced gliomas. Cancer 67:392-397, 1991 Schultheiss TE, Kun LE, Ang KK, Stephens Lc:Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31:1093-1112, 1995

Strojan P, Popovic M, Jereb B: Secondary intracranial meningiomas after high-dose cranial irradiation: report of five cases and review of the literature. Int J Radiat Oncol Biol Phys 48:65-73, 2000 Valk PE, Dillon WP: Radiation injury of the brain. AJNR Am J Neuroradiol 12:45-62, 1991 Young WC, Thornton AF, Gebarski SS, Cornblath W. Radiation-induced optic neuropathy: correlation of MR imaging and radiation dosimetry. Radiology 1853904-907, 1992

178 Paraneoplastic Svndromes Josep Dalmau and Francesc Graus When patients with cancer develop neurologic symptoms, metastasis usually is the cause. Other neurologic complications result from infections, vascular and metabolic disorders, and neurotoxicity from chemotherapy and radiation therapy. This chapter focuses on the remote effects of cancer on the nervous system, o r neurologic disorders of unknown cause that are more common in patients with cancer than in the general population. We refer to these disorders as paraneoplastic syndromes throughout this chapter. The incidence of these syndromes is unknown and varies between studies depending on how the paraneoplastic syndrome is defined, the type of neurologic evaluation used for study (i.e., clinical examination alone or associated with electrophysiologic studies), and the care with which other possible causes of neurologic disability are excluded (i.e., advanced neoplastic disease, weight loss). Clinically significant paraneoplastic syndromes occur in less than 1% of patients (Table 178-1). Most of these disorders develop before the diagnosis of cancer, so these patients usually are first seen by neurologists. Because similar syndromes can develop in patients without cancer, the likelihood that a disorder is paraneoplastic depends on the type of syndrome (Table 178-2), the clinical exclusion of an underlying tumor, and for some disorders the presence of characteristic autoantibodies (Table 178-3). In many patients with paraneoplastic disorders the neoplasm is small, remains localized throughout the course of the disease, and is

rn TABLE 178-1. Paraneoplastic Syndromes Affecting the Nervous System Paraneoplasticsyndromes of the central nervous system Paraneoplasticcerebellar degeneration Paraneoplasticencephalomyelitis(limbic encephalitis,brainstem encephalitis,myelitis)" Paraneoplasticstiff man syndrome Paraneoplasticopsoclonus-myoclonus Paraneoplasticnecrotizing myelopathy Motor neuron syndromes (amyotrophic lateral sclerosis, subacute motor neuronopathy, upper motor neuron dysfunction) Visual paraneoplastic syndromes (cancer-associatedretinopathy, melanoma-associated retinopathy, optic neuritis) Paraneoplasticsyndromes of the peripheral nervous system Paraneoplasticsensory neuronopathy Acute polyradiculoneuropathy (Cuillain-Barre syndrome) Brachial neuritis Vasculitis of the nerve and muscle Subacute or chronic sensorimotor peripheral neuropathy Sensorimotorneuropathies associated with plasma cell dyscrasias (myeloma, Waldenstram's macroglobulinemia) Autonomic neuropathy Neuromyotonia Paraneoplasticsyndromes of the neuromuscularjunction and muscle Lambert-Eaton myasthenic syndrome Polymyositis or dermatomyositis Acute necrotizing myopathy Carcinoid myopathy Cachectic myopathy "Can include cerebellar symptoms, autonomic dysfunction, and sensory neuronopathy.

1146

Neuro-Oncology

Neurologic Complications of Systemic Cancer

Behin A, Delattre J-T Neurologic sequelae of radiation therapy of the nervous system. In Schiff D, Wen PY (Eds.). Cancer Neurology in Clinical Practice. Humana Press, Totowa, 2003 (in press) Bitzer M, Topka H: Progressive cerebral occlusive disease after radiation therapy. Stroke 26131-136, 1995 Constine LS, Woolf PD, Cann D et ak Hypothalamic-pituitarydysfunction after radiation for brain tumors. N Engl J Med 328:87, 1993 Cross NE, Glantz MJ: Neurologic complications of radiation therapy. Neurol Clin 2003 (in press) Crossen JR, Garwood D, Glatstein E, Nevwelt EA: Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 12627442, 1994 DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789-796, 1989 De Carolis P, Montagna P, Cipulli M et al: Isolated lower motoneuron involvement following radiotherapy. J Neurol Neurosurg Psychiatry 49:7 18-7 19, 1986

Fonseca R, O'Neill BP, Foote RL et ak Cerebral toxicity in patients treated for small cell carcinoma of the lung. Mayo Clin Proc 74461-465, 1999 Glantz MJ, Burger PC, Friedman AH et ak Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 4420202027, 1994

Grill J, Renaux VK, Bulteau C et ak Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 45:137-145, 1999

Jankovic M, Brouwers P, Valsecchi MG et al: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. Lancet 344224-227, 1994 Larson JJ, Ball WS, Bove KE et ak Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children. J Neurosurg 88:51-56, 1998 Ricci PE, Karis JP, Heiserman JE et ak Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography? AJNR Am J Neuroradiol 19407-413, 1998 Roman DD, Sperduto PW Neuropsychologicaleffects of cranial radiation: current knowledge and future directions. Int J Radiat Oncol Biol Phys 3 1 :983-998, 1995

Salvati M, Artico M, Caruso R et ak A report on radiation-induced gliomas. Cancer 67:392-397, 1991 Schultheiss TE, Kun LE, Ang KK, Stephens Lc:Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31:1093-1112, 1995

Strojan P, Popovic M, Jereb B: Secondary intracranial meningiomas after high-dose cranial irradiation: report of five cases and review of the literature. Int J Radiat Oncol Biol Phys 48:65-73, 2000 Valk PE, Dillon WP: Radiation injury of the brain. AJNR Am J Neuroradiol 12:45-62, 1991 Young WC, Thornton AF, Gebarski SS, Cornblath W. Radiation-induced optic neuropathy: correlation of MR imaging and radiation dosimetry. Radiology 1853904-907, 1992

178 Paraneoplastic Svndromes Josep Dalmau and Francesc Graus When patients with cancer develop neurologic symptoms, metastasis usually is the cause. Other neurologic complications result from infections, vascular and metabolic disorders, and neurotoxicity from chemotherapy and radiation therapy. This chapter focuses on the remote effects of cancer on the nervous system, o r neurologic disorders of unknown cause that are more common in patients with cancer than in the general population. We refer to these disorders as paraneoplastic syndromes throughout this chapter. The incidence of these syndromes is unknown and varies between studies depending on how the paraneoplastic syndrome is defined, the type of neurologic evaluation used for study (i.e., clinical examination alone or associated with electrophysiologic studies), and the care with which other possible causes of neurologic disability are excluded (i.e., advanced neoplastic disease, weight loss). Clinically significant paraneoplastic syndromes occur in less than 1% of patients (Table 178-1). Most of these disorders develop before the diagnosis of cancer, so these patients usually are first seen by neurologists. Because similar syndromes can develop in patients without cancer, the likelihood that a disorder is paraneoplastic depends on the type of syndrome (Table 178-2), the clinical exclusion of an underlying tumor, and for some disorders the presence of characteristic autoantibodies (Table 178-3). In many patients with paraneoplastic disorders the neoplasm is small, remains localized throughout the course of the disease, and is

rn TABLE 178-1. Paraneoplastic Syndromes Affecting the Nervous System Paraneoplasticsyndromes of the central nervous system Paraneoplasticcerebellar degeneration Paraneoplasticencephalomyelitis(limbic encephalitis,brainstem encephalitis,myelitis)" Paraneoplasticstiff man syndrome Paraneoplasticopsoclonus-myoclonus Paraneoplasticnecrotizing myelopathy Motor neuron syndromes (amyotrophic lateral sclerosis, subacute motor neuronopathy, upper motor neuron dysfunction) Visual paraneoplastic syndromes (cancer-associatedretinopathy, melanoma-associated retinopathy, optic neuritis) Paraneoplasticsyndromes of the peripheral nervous system Paraneoplasticsensory neuronopathy Acute polyradiculoneuropathy (Cuillain-Barre syndrome) Brachial neuritis Vasculitis of the nerve and muscle Subacute or chronic sensorimotor peripheral neuropathy Sensorimotorneuropathies associated with plasma cell dyscrasias (myeloma, Waldenstram's macroglobulinemia) Autonomic neuropathy Neuromyotonia Paraneoplasticsyndromes of the neuromuscularjunction and muscle Lambert-Eaton myasthenic syndrome Polymyositis or dermatomyositis Acute necrotizing myopathy Carcinoid myopathy Cachectic myopathy "Can include cerebellar symptoms, autonomic dysfunction, and sensory neuronopathy.

Chapter 178

TAW 178-2. Neurologic Syndromes That Suggest a Paraneoplastic Origin Lambert-Eaton myasthenic syndrome Subacute cerebellar syndrome Subacute sensory neuropathy Opsoclonus-myoclonus (pediatric population) Subacute autonomic dysfunction (postural hypotension, gastrointestinal immotility) Derrnatomyositis” Subacute encephalomyelitis Subacute retinopathy Subacute limbic encephalopathy Subacute motor neuronopathy and atypical motor neuron disease ‘In older population.

difficult to demonstrate even with thorough periodic clinical and radiologic studies. For most paraneoplastic syndromes the pathogenesis is unknown. However, in some disorders the patient’s serum and cerebrospinal fluid (CSF) contain antibodies directed against neuronal proteins expressed by the associated tumor (Table 178-3). It is believed that the ectopic expression of these proteins leads to the development of an immunologic response against the tumor that cross-reacts with the nervous system, resulting in the paraneoplastic disorder. This autoimmune hypothesis has been proven for the Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis, and neuromyotonia, but for other paraneoplastic syndromes the role of the antibodies in the pathogenesis of the disease remains unclear. Clinically, identifylng these antibodies is important for two reasons: Their detection confirms the paraneoplastic origin of the neurologic dysfunction, and their characterization directs the search for the tumor to one or a few organs. However, similar paraneoplastic syndromes may develop without the presence of antibodies; this situation almost always occurs when the associated tumor is different from the typical histologic type involved in the antibody-related disorder. For example, the anti-Hu antibody is almost always detected in the serum of patients with paraneoplastic sensory neuronopathy (PSN) and small cell lung cancer (SCLC), but the antibody is rarely present in PSN associated with other tumors. Conversely, some paraneoplas-

Paraneoplastic Syndromes

1147

tic disorders may be mediated by antibodies that are not detected by currently available techniques. Non-immune-mediated mechanisms such as competition for an essential substrate (i.e., carcinoid myopathy) or viral infection (i.e., subacute motor neuronopathy) have been proposed as the cause of other paraneoplastic disorders. For most paraneoplastic syndromes, particularly those involving the central nervous system, treatment usually is unrewarding. In a few instances prompt identification and treatment of the tumor or the paraneoplastic disorder may result in stabilization or improvement of the neurologic symptoms. A general diagnostic approach to a patient with neurologic dysfunction of possible paraneoplastic origin is shown in Table 178-4. Paraneoplastic neurologic syndromes can involve any part of the central or peripheral nervous system, including neuromuscular junction and muscle (Table 178-1). Some syndromes are limited to one area of the nervous system (paraneoplastic cerebellar degeneration, PCD), but the same type of symptoms may be observed as part of a more widespread syndrome (paraneoplastic encephalomyelitis, PEM) or in associationwith other paraneoplastic disorders (PCD and LEMS). Even when symptoms appear limited to one area of the nervous system (PCD), minor signs of dysfunction of other regions usually are present (corticospinal tract involvement, mild cognitive dysfunction). PARANEOPLASTIC SYNDROMES OF THE CENTRAL NERVOUS SYSTEM ParaneoplasticCerebellar Degeneradon

Patients with PCD typically develop rapid progressive symptoms that evolve, over weeks or months, to a severe pancerebellar dysfunction. Symptoms include truncal and appendicular ataxia, dysarthria, and nystagmus. The main pathologic hallmark is extensive loss of Purkinje cells, accompanied by proliferation of Bergmann astrocytes in the molecular layer, loss of granule cells, and sometimes inflammatory infiltrates in the deep cerebellar nuclei. Gynecologic tumors, breast cancer, lung cancer, and lymphomas are the most commonly associated neoplasms. Pure subacute cerebellar dysfunction in adult patients should be considered paraneoplastic until another cause is demonstrated.

I Antibodv

Associated Cancer

Svndrome

Anti-Hu Anti-Yo Anti-Ri Anti-Tr

SCLC, other Gynecologic, breast Breast, gynecologic, SCLC Hodgkin’s lymphoma

Encephalomyelitis, sensory neuronopathy Cerebellar degeneration Cerebellar ataxia, opsoclonus Cerebellar degeneration

Anti-CRMP3 (CV2) and anti-CRMPS Anti-Ma proteins”

SCLC, other

Encephalomyelitis, cerebellar degeneration

Testicular germ cell tumors and other neoplasms Breast Thymoma, others SCLC Thymoma SCLC Melanoma

Limbic, brainstem encephalitis, cerebellar degeneration Stiff man syndrome Neuromyotonia LEMS Myasthenia gravis CAR MAR

Anti-amphiphysin Anti-VCKCb Anti-VCCCb Anti-acetylcholine receptop Anti-recoverin (CAR) Anti-MAR

Antigens, lmmunohlstochemicaland Western Blot ReactMy All neuronal nuclei; 35-40 kDa Cytoplasm Purkinje cells; 34, 62 kDa Neuronal nuclei of the CNS; 55,80 kDa Cytoplasm neurons, Purkinje spiny dendrites Clial cells, neurons; 66 kDa (anti-CRMP3) and 62 kDa (anti-CRMPS) Neuronal nuclei and cytoplasm; 39, 42 kDa Synaptic vesicle protein; 128 kDa Several VCKCs Presynaptic P/Q type VCCC Postsynaptic acetylcholine receptor Retinal photoreceptors, 23 kDa Bipolar cells of the retina, unknown antipen

%tibodies limited to Ma2 (also called anti-Ta antibodies) usually associatewith limbic and brainstem encephalitis and germ cell tumors. Antibodies directed at Mal, Ma2, and Ma3 usually associate with brainstem encephalitis, cerebellar degeneration and several types of cancer (e.g., lung, breast, ovafy). b e s e antibodies are also identified in the nonparaneoplasticform of the syndrome. Abbf?vhtions: CAR, cancer-associatedretinopathy; CRMP, collapsin responsemediatorprotein; LEMS, Lambert-Eatonmyasthenic syndrome; MAR, melanoma-associatedretinopathy; SCLC, small cell lung cancer; VGCC, voltagegated calcium channel; VCKC, voltagegated potassium channel.

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Neuro-Oncology H Neurologic Complications of Systemic Cancer

w TABLE178-4. Diagnostic Approach to a Patient with Neurologic Dysfunction of Possible Paraneoplastic Origin Known Cancer

Cancer Not Known

1) Rule out metastatic complications: MRI of involved site, CSF cytology, and appropriate tumor markers (e.g., CEA)

1) Workup for cancer detection:

2) Rule out nonmetastatic complications: toxic effects of chemotherapy and radiation therapy, metabolic and nutritional deficits, coagulopathy, infection, post-traumatic nerve injury 3) Study of CSF for cells, IgC index, oligoclonal bands 4) Examine serum and CSF for paraneodastic antibodies

chest CT,pelvic exam, mammography, serum tumor markers (i.e., CEA, CA-125), body PET scan 2) Study of CSF for cells, IgC index, oligoclonal bands, cytolow

3) Examine serum and CSF for

paraneoplastic antibodies 4) Follow up and search for cancer if #2 and #3 are positive

Abbreviations: CW, carcinoembryonicantigen; CSF, cerebrospinal fluid; 0, computed

tomography; IgG, immunoglobulin G; MRI, magnetic resonance imaging; PET, positron emission tomography. Modified from Posner JB: Paraneoplastic syndromes. p. 353. In Neurologic Complications of Cancer. F A Davis, Philadelphia, 1995, with permission.

PCD can develop in association with several paraneoplastic antineuronal antibodies (Table 178-3), although the absence of antibodies is not uncommon. The most common and wellcharacterized antibody-associated PCD is defined by the presence in serum and CSF of an antibody called anti-Yo that reacts with 34- and 62-kDa proteins expressed in the cytoplasm of Purkinje cells and tumor, usually gynecologic or breast cancer. If the presence of a tumor is not known, patients with anti-Yo positive PCD should undergo breast and pelvic examination, mammography, pelvic computed tomography (CT), and measurement of the ovarian tumor antigen CA- 125. Positron emission tomography (PET) studies may uncover neoplasms not detectable by other tests. If no malignancy is revealed, repeat mammography, pelvic examination under anesthesia, and, in the appropriate clinical setting, uterine dilation and curettage should be considered. Anti-Yo antibodies have been identified in a few male patients with PCD and cancer of the salivary gland, lung, and esophagus. PCD develops in association with a large variety of neoplasms. However, when neoplasms other than breast and gynecologic tumors are involved, patients are anti-Yo negative. Patients with predominant truncal ataxia and ocular movement abnormalities may harbor an antibody called anti-%. In this subset of patients the tumor usually is breast cancer or, much less often, gynecologic, bladder, or SCLC. Opsoclonus often is present in the early stages of the disease and may evolve toward flutter or resolve. In addition to PCD, these patients may develop dementia, mixed peripheral neuropathy, and axial rigidity and myoclonus. Treatment with steroids and immunosuppressants (cyclophosphamide) may improve the neurologic disorder. PCD may be the presentation of anti-Hu-associated PEM. In this case, PCD should be considered a fragment of PEM because the cerebellar dysfunction rarely persists as the main neurologic symptom. When PCD is the only or predominant dysfunction, anti-Hu antibodies usually are absent even when the associated tumor is SCLC. Patients with PCD associated with Hodgkin’s disease develop antibodies (called anti-Tr) to an antigen expressed in the cytoplasm of Purkinje cells and neurons of the molecular layer of the cerebellum. The identity of the antigen is unknown. These

patients usually are younger (20 to 40 years) than other patients with PCD. The neurologic disorder may develop before or after the diagnosis of the lymphoma, sometimes heralding tumor recurrence. Treatment of the lymphoma usually results in a rapid decrease of antibody titers and is sometimes associated with neurologic improvement. Other antineuronal antibodies associated with PCD are shown in Table 178-3. A subset of patients with SCLC develop PCD associated with LEMS; most of these patients do not harbor antineuronal antibodies other than those directed to the voltagegated calcium channels (VGCCs) that cause LEMS. Usually, patients develop LEMS or PCD before the tumor is diagnosed. Unless LEMS develops first, its diagnosis may be overlooked. In two patients with cerebellar degeneration, antibodies to the metabotropic glutamate receptor la (mGluRla) were identified. It is unclear whether the disorder was paraneoplastic because for both patients the history of Hodglun’s lymphoma was remote and the archival tumor tissue did not express mGluRla. For all subtypes of PCD, whether associated with antineuronal antibodies or not, diagnostic tests including head CT and magnetic resonance imaging (MRI) usually are normal in the early stages of the disease and evolve to cerebellar atrophy. Most types of PCD, particularly that associated with anti-Yo antibodies, do not improve but may stabilizewith treatment of the tumor. Autopsies of anti-Yo-positive patients demonstrate complete or near complete loss of Purkinje cells that probably occurs early in the course of the disease. Plasma exchange, intravenous immunoglobulin (IVIg), and immunosuppressants usually are ineffective. In a few patients with tumors other than breast and gynecologic cancers, resection of the tumor has resulted in neurologic improvement.

Paraneoplastic Encephalomyelitis PEM is characterized by clinical signs of dysfunction of various parts of the nervous system and postmortem signs of inflammation within the brain, brainstem, spinal cord, dorsal root ganglia, and nerve roots. The distribution of pathologic findings along the neuraxis is variable, giving rise to several syndromes that can occur alone or in association. Neurologic symptoms of PEM include focal cortical encephalitis, limbic encephalitis, cerebellar degeneration, brainstem encephalitis, myelopathy, and autonomic dysfunction. Many patients with PEM also have symptoms of sensory neuropathy (PSN). PEM and PSN have been reported in association with almost all types of tumors, but in most patients (80%) the underlying tumor is carcinoma of the bronchus, particularly SCLC. The tumor usually remains small, and its metastatic spread is limited to regional lymph nodes; in a number of patients the tumor is not detected until autopsy. The subset of patients with PEM or PSN and SCLC often harbor in their serum and CSF high titers of the anti-Hu antibody. This antibody reacts with protein antigens of 35 to 40 kDa expressed in neurons and SCLC cells. Anti-Hu-associated PEM has a mild predominance in women. Anti-Hu-associated PEM or PSN develops before the diagnosis of the tumor in 80% of patients. Symptoms develop subacutely and progress until stabilization or death in a few weeks or months. Most patients (73%) have signs and symptoms of multifocal involvement of the nervous system; in these patients as well as in patients with unifocal involvement, the predominant disorder is PSN. Table 178-5 indicates the predominant and nonpredominant clinical findings in a series of 71 patients with anti-Hu associated PEM or PSN. PSN is described later in this chapter.

Chapter 178

Limbic encephalopathy predominates in 20% of patients with PEM. Symptoms include confusion, depression, agitation, anxiety, memory deficits, dementia, and partial complex seizures. When limbic encephalopathy develops alone, the anti-Hu antibody may be absent even in patients with SCLC. Motor neuron dysfunction predominates in. 20% of patients with PEM. Almost all patients have signs of involvement of other areas of the nervous system, which allows differentiation from amyotrophic lateral sclerosis (ALS). In general, symptoms start with proximal loss of strength, affecting limbs in an asymmetrical pattern. Neck flexor or extensor weakness may be the initial deficit. Distal involvement of extremities, fasciculations, and muscle atrophy are common. In patients with predominant involvement of the anterior horn or associated PSN, reflexes are decreased or abolished. Other patients have hyperreflexia, clonus, and extensor plantar responses. Symptoms of cerebellar degeneration are predominant in about 15% of patients with PEM. Gait ataxia is the usual presentation, but most patients eventually develop a pancerebellar syndrome. A distinctive clinical feature of these patients compared with other types of PCD is that almost all anti-Hu-positive patients develop signs of severe involvement of other areas of the nervous system. Brainstem encephalopathy develops in one third of patients with PEM, but in only half is it predominant. The most common symptoms include oscillopsia, diplopia, dysarthria, dysphagia, gaze abnormalities (both internuclear and supranuclear [vertical and horizontal]), subacute hearing loss, and facial numbness. Approximately one fourth of patients with PEM develop autonomic nervous system dysfunction. In 10% this is the first and predominant symptom, including postural hypotension, gastroparesis and intestinal immotility, sweating abnormalities, neurogenic bladder, and impotence. Abnormal (sluggish) pupillary response is a common finding. Respiratory or autonomic failure caused by severe neurologic dysfunction is a common cause of death. Routine CSF studies show increased protein concentration or pleocytosis in 80% of the patients; the ratio of CSF to serum IgG is elevated in most, and oligoclonal bands often are detected. If PSN is present, the electrophysiologicfindings suggest dorsal root ganglia involvement. Motor nerve velocities and F wave studies are

rn TABLE178-5. Frequency of Neurologic Symptoms in Patients with Anti-Hu-Associated Sensory Neuronopathy or Encephalomyelitis (N = 71) SVmptom

Frequency(%)

Unifocal Sensory neuropathy Limbic encephalopathy Brainstem encephalopathy Multifocal Sensory neuropathy Cerebellar degeneration Limbic encephalopathy Brainstem encephalopathy Motor neuronopathf Autonomic dysfunction Visual loss

LEMS~ Myoclonus Polymyositis Diffuse enceDhalomvelitis

27 20 6 1 73 54 25 22 31 45 28 1 1 1 1 3

'Includes weakness, fasdculations, and musde atrophy. %e incidence of LEMS probably is underestimated because of the lack of routine eledrophysiologic studies.

Paraneoplastic Syndromes

1149

TAUE178-6. Location and Histologic Diagnosis of Neoplasms in 167 Patients with Anti-Hu-Associated PEM or PSN" Location

n 1%)

Lung SCLCb Non-SCLC X-ray Extrathoracic Prostate Gastrointestinal' Breast Bladder Pancreas ovary Unknown orinin

144 (85.6) 111 15 (neuroendocrine, 4) 18 23 (14.4) 6 (small cell, 1) 6 (small cell, 1 ; neuroendocrine, 3) 3 2 2 (small cell, 1) 2 2

'Data obtained from a study of 200 patients with PEM or PSN. %wee SCLCs coexisted with lung (2) or breast (1) adenocarcinornas. stomach (2), esophagus, gallbladder, colon, and rectum.

normal. In some patients signs of motor denervation secondary to myelitis and anterior horn involvement are also present. Only a minority of patients with anti-Hu-associated PEM develop MRI abnormalities, including atrophy of the cerebellum and, in some patients with limbic encephalopathy, increased signal on T2weighted images involving the medial aspect of the temporal lobes. These MRI abnormalities rarely enhance with contrast and eventually evolve toward medial temporal lobe atrophy. The anti-Hu antibody is the paraneoplastic marker most often identified in patients with PEM or PSN and SCLC. In patients without cancer, the detection of this antibody should prompt the search for an SCLC. Only a few patients with anti-Hu-associated PEM or PSN and tumors other than SCLC have been reported (Table 178-6). If the cancer search, which must include CT or MRI of the chest and bronchoscopy, does not demonstrate the tumor, periodic (every 6 months) clinical follow-ups and CT of the chest are recommended. Whole-body PET scan may show the presence of a tumor when other tests are negative. The anti-Hu antibody may be absent in patients with SCLC and pure or predominant symptoms of limbic encephalopathy and cerebellar degeneration. Treatment with steroids, plasma exchange, IVIg, and immunosuppressants usually is ineffective. If the PEM is not severe, earlier detection and treatment of the tumor may result in mild stabilization and improvement of the neurologic dysfunction. Limbic encephalopathy improves more often than other symptoms of PEM, and this improvement is almost always associated with tumor treatment. Other markers of paraneoplastic encephalitis include antibodies to Ma proteins (Ma1 and Ma2) and antibodies to collapsinresponse mediator proteins 3 and 5 (CRMP3and 5). The presence of serum antibodies exclusively directed to Ma2 is associated with limbic and brainstem encephalitis, and 70% of these patients have germ cell tumors of the testis. A remarkable finding of this disorder is that it may improve or resolve with tumor treatment. The occurrence of antibodies to Ma1 (in addition to Ma2) correlates with more severe and widespread neurologic dysfunction, predominantly affecting limbic region, brainstem, and cerebellum, and several associated cancers have been found (lung, breast, ovary, colon, salivary gland, and germ cell tumors). Antibodies to CRMP3 (also called anti-CV2) and CRMP5 have been reported with a variety of symptoms, including PEM, PCD, optic neuritis, sensorimotor neuropathies, LEMS, and neuromyotonia. The more common tumors are SCLC and thymoma.

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Neurologic Complications of Systemic Cancer

Paraneoplastic Stiff Man Syndrome

Patients with this disorder develop rigidity of the axial muscles with superimposed spasms. Initially, the muscle rigidity affects the lower trunk and legs, but it can extend to the shoulders, upper extremities, neck, and rarely face. Spasms are precipitated by voluntary movement, emotional upset, and auditory or somesthetic stimuli. Progressive muscle rigidity typically results in an exaggeration of the normal lumbar lordosis and abnormal postures. The rigidity disappears during sleep or after local or general anesthesia, suggesting neuronal dysfunction at the spinal or supraspinal level. Electrophysiologic studies show continuous activity of motor units in the stiffened muscles that improves after treatment with diazepam. The serum and CSF of patients with paraneoplastic stiff man syndrome often contain antibodies to amphiphysin I. Another paraneoplastic antigen, called gephyrin, has recently been identified as the target of serum antibodies in a patient with a mediastinal tumor. Stiff man syndrome can occur without a cancer association; 70% of these patients develop type I diabetes and other autoimmune diseases, and the major autoantigen is glutamic acid decarboxylase (GAD). The three target antigens identified in stiff man syndrome (amphiphysin, gephyrin, and GAD) are part of GABNglycine inhibitory synapses. Pathologic studies demonstrate mild perivascular lymphocyte infiltration and loss of motor neurons and interneurons in the anterior horn of the spinal cord. The tumors more commonly associated with paraneoplastic stiff man syndrome are breast and lung cancer. Transient neurologic improvement has been observed with diazepam, clonazepam, and baclofen. Definitive improvement usually is obtained with treatment of the tumor and steroids. ParaneoplasticOpsoclonus-Myoclonus

Opsoclonus is a rare disorder of ocular motility characterized by the presence of spontaneous, arrhythmic, large-amplitude conjugate saccades occurring in all directions of gaze without a saccadic interval. Opsoclonus often is associated with myoclonus, and both can have a paraneoplastic origin. The tumors most often involved include neuroblastoma (in children), lung cancer, particularly SCLC, and carcinoma of the breast. Nearly 50% of children with paraneoplastic opsoclonusmyoclonus (POM) have neuroblastoma, and about 2% of children with this tumor develop POM. Other symptoms include myoclonus of the limbs and trunk, hypotonia, and irritability that cannot be differentiated from nonparaneoplastic POM. In half of the patients POM precedes the diagnosis of neuroblastoma. Symptoms usually fluctuate and may have a prolonged course. Neuroblastoma treatment improves POM in one third of the patients. POM often responds to steroids but may relapse with steroid withdrawal and with intercurrent infections. Spontaneous resolution of POM has been observed. Patients with POM have a better tumor prognosis than patients without paraneoplastic symptoms. In adults, paraneoplastic opsoclonus often develops in association with truncal ataxia, resulting in gait difficulty and frequent falls. Other symptoms include vertigo, dizziness, nausea, vomiting, myoclonus, dysarthria, dysphagia, and diplopia or blurry vision. Less often, patients develop confusion, decreased hearing, proximal muscle weakness, axial rigidity, and paroxysmal spasms, including blepharospasm. Symptoms have sudden onset and reach their peak in 1 to 4 weeks. Spontaneous or therapeutic improve-

ment of opsoclonus usually is followed by ocular flutter and dysmetria. In more than half of the patients, POM precedes the diagnosis of the tumor. The most common offender is SCLC. In women, the detection of the anti-Ri antibody should prompt the search for a breast cancer or a gynecologic neoplasm. In rare instances of brainstem encephalopathy associated with opsoclonus, patients may harbor the anti-Hu antibody. In these patients, a search for SCLC is mandatory. No other antineuronal antibodies indicative of a specific type of tumor have been identified in patients with POM. In general, the CSF shows mild inflammatory changes and may have oligoclonal bands. MRI studies usually are normal but may show hyperintense T2-weighted images in the dorsal midbrain. EEG may be normal or demonstrate generalized slowing of the background activity, without epileptiform activity. There have been clinical responses to immunosuppressants, clonazepam, thiamine, and tumor treatment, but interpretation of these results is confounded by the possibility of spontaneous improvement. Clinical studies suggest that the use of M g and immunotherapy does not result in neurologic improvement unless the tumor is successfully treated.

Paraneoplastic Necmtizing Myelopathy

This rare syndrome has been reported in association with several carcinomas and lymphoma. There is no relationship between the neurologic disorder and the course of the neoplasm. The disorder develops acute or subacutely in the thoracic portion of the spinal cord, with progressive ascending or descending spinal cord deficits. Symptoms include sphincter dysfunction, segmental sensory deficits that may have an ascending progression, and flaccid or spastic paraplegia that evolves to tetraplegia or flaccid paraplegia. Back pain and radicular symptoms are rare. Symptoms progress over days or weeks and eventually result in respiratory failure and death. The CSF shows elevated protein and at times mild pleocytosis but is usually acellular. MRI studies may show enlargement of the spinal cord, T2-weighted abnormalities, and, sometimes, contrast enhancement. There are no biologic markers of this disorder, so a definitive diagnosis cannot be established without postmortem study. There is no effective treatment for paraneoplastic necrotizing myelopathy (PNM). Because PNM is extremely rare, the differential diagnosis should be made with other cancer-associated complications that are more common and treatable. These include leptomeningeal (LM), epidural (EM), and intramedullary (IM) metastasis and postradiation myelopathy (PM). The differential diagnosis between these disorders is facilitated by considering the presence of pain (present in LM, EM, IM and usually absent in PNM), mode of onset (long and insidious for PM, subacute for metastases and PNM), history of radiation therapy (PM occurs within the port of irradiation; regions of overlapping ports should be investigated), initial myelopathic dysfunction (PNM usually starts in the thoracic spinal cord; LM is multifocal; PM often involves the cervical cord after irradiation of head and neck tumors), extension of disease (metastasis to the brain is identified in two thirds of patients with IM), presence of neoplastic cells in the CSF indicative of LM, and MRI of the involved site of the spinal cord, which usually demonstrates EM, LM, and less often IM. In patients with lymphoma and leukemia, a syndrome identical to PNM may be caused by viral infections, particularly of the herpes group, as well as by toxic effects of intrathecal chemotherapy or radiation therapy and more rarely by septic infarcts.

Chapter 178

Paraneoplastic Motor Neuron Syndromes Patients with cancer and motor neuron syndromes can be separated into four groups: those with typical ALS, subacute motor neuronopathy, predominant upper motor neuronopathy mimicking primary lateral sclerosis, and motor neuron dysfunction as a component of PEM (this group has been discussed in the section on PEM). Amyotrophic lateral Sclerosis. Epidemiologic studies have demonstrated no significantly increased incidence of A L S in patients with cancer. However, a few patients with cancer, usually of the lung or kidney, have had remission or improvement of ALS after treatment of the malignancy. In addition, patients with Hodgkin’s disease or other lymphoproliferative disorders can develop symptoms of involvement of upper and lower or only lower motor neurons. In some patients, electrophysiologicstudies demonstrate multifocal conduction blocks. If no tumor is known, patients with ALS, paraproteinemia, and elevated CSF proteins with or without oligoclonal bands should be considered for bone marrow biopsy to rule out a lymphoproliferative disorder. Subacute Motor Neuronopathy. This disorder is characterized by subacute, progressive, painless, often patchy and asymmetrical muscle weakness that is more prominent in the lower extremities. Reflexes are decreased or abolished. There is usually sparing of bulbar muscles; fasciculations are rare. Sensory symptoms, if any, are mild and transitory. The neurologic symptoms may have a benign course, independent of the activity of the neoplasm. The involved tumors are Hodgkin’s lymphoma and, less often, non-Hodgkin’s lymphoma. CSF shows mildly elevated proteins with a normal cell count. Electrophysiologic studies show denervation with normal or mild slowness of motor nerve velocities. Pathologic findings include lower motor neuron degeneration with variable inflammatory infiltrates and patchy areas of segmental demyelination involving spinal roots and brachial and lumbar plexuses. This disorder should be differentiated from a lower motor neuron syndrome secondary to radiation therapy. In these patients the distribution of muscle weakness is more distal, and although symptoms stabilize, they do not improve. The tumor most commonly involved is seminoma. However, patients with Hodgkin’s lymphoma treated with mantle radiation may develop slowly progressive (years) weakness and atrophy involving neck flexors and extensors and proximal muscles of the upper extremities. Characteristically, a strip of atrophy involving paraspinal muscles is also observed. Distal reflexes usually are preserved; sensation is normal. No pathologic studies have been reported. There is no treatment for this disorder. Predominant upper motor neuron dysfunction, mimicking primary lateral sclerosis, has been reported in a few patients with breast cancer. Because no specific paraneoplastic markers have been identified, the association of these disorders may be coincidental.

Vlsual Paraneoplastic Symptoms In patients with cancer, visual symptoms and blindness usually are related to metastatic infiltration of optic nerves by tumor, neurotoxicity from chemotherapy and radiation therapy, and anemia. More rarely, patients develop cancer-associated retinopathy (CAR) and optic neuritis of paraneoplastic origin. Cancer-Associated Retinopathy. CAR is characterized by episodic visual obscurations, light-induced glare, photosensitivity, night blindness, and impaired color vision. Symptoms may begin

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unilaterally but become bilateral within days or weeks and usually precede the diagnosis of the tumor. SCLC is the most common offender. Examination shows peripheral and ringlike scotomata, impairment of visual acuity and color vision, and retinal arteriolar narrowing. Visual evoked responses usually are normal, but the electroretinogram (ERG) demonstrates reduced or flat photopic and scotopic responses, consistent with dysfunction of the cone and rod photoreceptors. CSF usually is normal; in some patients elevated immunoglobulins and pleocytosis have been reported. Head CT and MRI are normal. Pathologic studies demonstrate loss of photoreceptors or ganglion cells, along with infiltrative macrophages with melanin granules and inflammatory infiltrates in the retinal arterioles. The serum of some patients may harbor antibodies that react with antigens contained in photoreceptors and ganglion cells; some of these antigens are also expressed by the tumor (Table 178-3). One of these antigens is a 23-kDa calcium-binding protein named recoverin, which is contained in photoreceptors. CAR rarely improves with treatment. Anecdotal responses have been observed with steroids, plasma exchange, and M g . Melanoma-Associated Retinopathy. This paraneoplastic disorder affects patients with metastatic cutaneous melanoma and presents with shimmering, flickering, or pulsating photopsias that evolve over months to a progressive visual loss. The ERG reveals a markedly reduced B wave in the presence of a normal darkadapted A wave. The patient’s serum usually contains antibodies that react with the bipolar cells of the retina. Parancoplastic Optic Neuritis. This disorder is rarer than CAR. It may develop in isolation but is usually associated with PEM. The onset is subacute with painless, bilateral visual loss. The examination may show papilledema. PARANEOPLASTIC SYNDROMES OF THE PERIPHERAL NERVE Paraneoplastic Sensory Neuronopathy The typical onset of PSN is pain and paresthesias asymmetrically involving one limb, which can be confused with a radiculopathy or multineuropathy. Usually, symptoms progress rapidly (weeks) to involve other extremities and sometimes the face and trunk. Other cranial nerves may be affected, resulting in loss of taste and sensorineural deafness. Eventually, there is severe loss of sensation interfering with walking and movement of the extremities. More than 70% of patients with PSN develop symptoms of involvement of other areas of the nervous system, including muscle weakness, postural hypotension, seizures, or any other symptoms of PEM. There is involvement of all modalities of sensation with predominant deficits of joint position and vibratory sensation. These deficits result in sensory ataxia involving legs (gait ataxia) and arms (pseudoathetotic movements). Deep tendon reflexes are asymmetrically decreased or abolished. When PSN is combined with other signs of PEM, the examination can demonstrate muscle weakness and atrophy, fasciculations (anterior horn involvement), cerebellar and brainstem dysfunction, and memory and cognitive deficits (limbic encephalopathy). Often there are sluggish pupillary reactions and symptoms and signs of autonomic dysfunction (orthostatic hypotension, gastrointestinal immotility, bladder dysfunction, sweating abnormalities). Depending on the area of major involvement, the combination of PEM and PSN can be confused with a multiple mononeuropathy or subacute polyneuritis. In more than 80% of patients with PSN the associated tumor is SCLC. Sensory symptoms usually precede the diagnosis of the

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tumor. In patients with no known cancer, PSN should be clinically suspected when sensory symptoms develop asymmetrically or involve the trunk and cranial nerves. The CSF shows increased proteins with pleocytosis (in general less than 100 cells/dL); oligoclonal bands and increased IgG CSF:serum ratio are common. Electrophysiologic studies demonstrate decreased or abolished somatosensory evoked potentials and action potentials of sensory nerves. Motor conduction studies are normal; signs of motor denervation are absent unless there is a concomitant myelitis with anterior horn involvement. Some patients with PSN also develop peripheral sensorimotor neuropathy. The detection of the anti-Hu antibody in serum or CSF should direct the search for SCLC. If the anti-Hu antibody is negative and studies suggest sensory neuronopathy (DRG involvement), the search for a neoplasm should have a wider spectrum, including other (non-SCLC) lung tumors and breast cancer. To search for the tumor, CT scans of the chest and abdomen and a mammogram should be considered. If the results are negative, a whole-body PET scan may reveal the neoplasm. In rare instances PSN may have a chronic course (6 months to 3 years) and be mild to severe in intensity. In these patients the differential diagnosis must include Sjogren’s syndrome, which may develop with isolated sensory neuronopathy and be negative for Ro (SS-A) and La (SS-B) antibodies. In this setting, the diagnosis of Sjogren’s syndrome is established with a salivary gland biopsy. Patients with carcinoma of the lung and lymphoma can develop an acute sensory neuropathy that may improve spontaneously. In these patients the clinical and electrophysiologicfindings suggest a sensory variant of the Guillain-BarrC syndrome. The treatment of PSN has been discussed in the section on PEM.

Acute Polyradiculoneumpathy Acute paraneoplastic polyradiculoneuropathy identical to the Guillain-Barre syndrome has been reported in association with Hodgkin’s disease. The course of the neurologic syndrome is independent of the lymphoma, and symptoms can develop during active disease or when the patient is in remission. These patients may respond to plasma exchange or IVIg.

Brachial Neuritis Patients with cancer may develop a clinical picture resembling the brachial neuritis observed in patients without cancer. The neoplasm most commonly involved is Hodglun’s lymphoma, and the causal mechanism is unknown. The differential diagnosis must be made between the more common causes of brachial plexopathy, including tumor infiltration, radiation injury, ischemic neuropathy, and traumatic injury of the plexus.

Multineudtisand Vasculstis Only a few patients have been reported with paraneoplastic vasculitic neuropathy, usually associated with carcinoma of the lung, prostate, kidney, endometrium, and lymphoma. Patients are usually older men who develop a painful symmetrical or asymmetrical sensorimotor polyneuropathy, and less often a multiple mononeuropathy. Typically, the erythrocyte sedimentation rate is elevated, and the CSF shows a high protein content. Electrophysiologic findings include axonal degeneration involving motor and sensory nerves. Nerve biopsy studies show intramural

and perivascular inflammatory infiltrates, mainly composed of CD8+ T cells. Similar infiltrates can be found in the muscle of some patients. The course and response to treatment are variable. Steroids and cyclophosphamide have been effective in some patients.

Subacute and Chronic Sensorimotor Neuropathy In patients with cancer, peripheral neuropathy is common, but a paraneoplastic origin is rare. Sensorimotor neuropathy can be caused by chemotherapeutic agents, diabetes, alcoholism, chronic illness, and metabolic and vitamin (BJ deficits. In patients with no known cancer, the development of sensorimotor neuropathy is not often indicative of a paraneoplastic syndrome and has much less significance than the development of subacute sensory neuropathy or cerebellar degeneration (Table 178-2). When sensorimotor neuropathy is paraneoplastic, the most commonly associated tumor is lung cancer. Neurologic symptoms include symmetrical distal paresthesias, numbness, and weakness. Deep tendon reflexes are abolished. Symptoms of neuropathy usually develop after the diagnosis of cancer but sometimes precede the tumor by years. The course usually is slow and progressive; a subacute onset of symptoms raises the possibility of a paraneoplastic origin. Symptoms may have a remitting and relapsing course suggesting chronic inflammatory demyelinating polyneuropathy. CSF studies usually are normal. Nerve conduction studies are consistent with axonal neuropathy, but some patients may have decreased conduction velocities consistent with demyelination. Nerve biopsy commonly shows axonal degeneration and less often segmental demyelination or both. Patients with electrophysiologic signs of demyelinating neuropathy often improve with steroids or IVIg. Patients with breast cancer can develop a slowly progressive sensorimotor neuropathy with predominant sensory symptoms. Initial symptoms include itching and muscle cramps and may precede the tumor diagnosis. Proximal weakness and symptoms suggesting central nervous system involvement, such as hyperreflexia and extensor plantar responses, may be present. Patients usually remain functional. There is no known treatment.

Sensodmotor NeuropathiesAssociated with Plasma Cell Dyscrasias Approximately 10% of patients with peripheral sensorimotor neuropathy of unknown origin have monoclonal gammopathy. Plasma cell dyscrasias associated with peripheral neuropathy include monoclonal gammopathy of uncertain significance, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, cryoglobulinemia, monoclonal gammopathy with solid tumors, monoclonal gammopathy with benign lymph node hyperplasia, y-heavy-chain disease, and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. Patients with myeloma can develop neuropathies in three clinical situations: Osteolytic MM without amyloidosis. In these patients the neuropathy resembles the sensorimotor type seen in patients with carcinoma. The incidence probably is less than 5%. Improvement of MM with chemotherapy is not associated with improvement of neurologic symptoms.

Chapter 178

Osteolytic MM with amyloidosis. The clinical picture is similar to the neuropathy of amyloidosis, characterized by autonomic dysfunction and lancinating and burning dysesthesias. These sensory symptoms predominate over motor deficits. In addition these patients can develop superimposed radicular pain and sensorimotor deficits secondary to involvement of the spine by MM. Treatment of MM does not modify the neurologic symptoms. Osteosclerotic myeloma. Approximately 50% of patients with osteosclerotic MM have symmetrical, distal sensorimotor neuropathy. Motor symptoms predominate and become progressive and disabling unless the osteosclerotic lesion is treated. Electrophysiologicand pathologic studies are similar to those in chronic inflammatory demyelinating polyneuropathy. There are decreased motor nerve conduction velocities with evidence of conduction blocks. Increased proteins in the CSF may result in papilledema. Unlike patients with osteolytic MM, patients with osteosclerotic myeloma are younger, their bone marrow is rarely infiltrated with plasma cells, the renal function is better preserved, and the M components are low in serum and rarely present in urine. Seventy-five percent of these patients have detectable h-light chain with IgG or IgA heavy chains. A radiologic survey always demonstrates a solitary or reduced number of osteosclerotic lesions, which tend to involve the axial skeleton (truncal and proximal long bones) and spare the skull. Patients with osteosclerotic myeloma develop symptoms included in the POEMS syndrome: polyneuropathy, organomegaly (hepatosplenomegaly, lymphadenopathy),endocrinopathy (gynecomastia, impotence, testicular atrophy, low plasma testosterone, low serum thyroxine, high serum estrogen, hyperglycemia), M protein, and skin changes (hirsutism, thickening of the skin, hyperpigmentation, hyperhidrosis). Less often, some of these symptoms are also associated with plasma cell dyscrasias other than osteosclerotic myeloma. Identifymg this disorder is important because treating the osteosclerotic lesions with excision or radiation therapy can improve and reverse the neurologic and systemic symptoms. Patients with Waldenstrom’s macroglobulinemia may develop a demyelinating sensorimotor neuropathy with marked slowing of nerve conduction velocities. Sensory symptoms are prominent. The IgM paraprotein may react with myelin-associated glycoprotein (MAG). A minority of patients have predominant axonal degeneration. Treatment should be directed toward the Waidenstrom’s macroglobulinemia. Patients with anti-MAG antibodies occasionally respond to plasma exchange, IVIg, or rituximab, a monoclonal antibody directed against the B-cell surface membrane molecule CD20. However, most patients need treatment with chemotherapy, including chlorambucil, cyclophosphamide, or fludarabine.

Autonomic Neuropathy Paraneoplastic autonomic dysfunction may occur alone but is more often associated with other paraneoplastic syndromes such as LEMS and PEM or PSN. In PEM and PSN, the autonomic dysfunction may be the first sign of the disorder. If SCLC is the underlying tumor, the anti-Hu serology is positive. Other tumors include cancer of the pancreas or testis, Hodgkin’s and nonHodgkin’s lymphoma, and carcinoid tumor of the lung.

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Symptoms may result from adrenergic or cholinergic nerve dysfunction at the preganglionic or postganglionic level. There are three autonomic problems that may be life-threatening: esophageal and gastrointestinal dysmotility with intestinal pseudoobstruction, cardiac dysrhythmias, and postural hypotension. In some patients treatment of the tumor may stabilize or improve the autonomic symptoms.

The most common causes of cramps in patients with cancer include electrolyte imbalances, nerve compression and infiltration by the neoplasm, peripheral neuropathy, chemotherapy, and radiation therapy. Cramps may also occur in association with a much rarer disorder, namely paraneoplastic neuromyotonia. This disorder results from continuous muscle fiber activity of peripheral nerve origin that can be triggered by voluntary muscle contraction. The involved muscles are hypertrophic, and their spontaneous contraction often is visible as undulating myokymia. Other symptoms include motor weakness and hyperhidrosis. The electromyogram shows fibrillation, fasciculation, and doublet, triplet, or multiplet single-unit discharges that have a high intraburst frequency, with the frequency of the bursts themselves being irregular. These findings are detectable during sleep and general anesthesia, are abolished by curare, and may be unaffected, reduced, or abolished by peripheral nerve block. Thymoma and lung cancer are the tumors more commonly involved. Neuromyotonia is associated with autoantibodies to voltagegated potassium channels (VGKC) that increase the release of acetylcholine and prolong the action potential. Treatment with phenytoin, carbamazepine, diazepam, and plasma exchange can be effective.

PARANEOPLASTICSYNDROMES OF THE NEUROMUSCULAR JUNCTION These syndromes include myasthenia gravis associated with thymoma and LEMS.

Lambert-Eaton Myasthenic Syndrome LEMS is a disorder of neuromuscular transmission characterized by a defect in the presynaptic quanta1 release of acetylcholine in response to a nerve stimulus. About 60% of patients with LEMS have SCLC; neurologic symptoms usually develop before the tumor diagnosis. Patients complain of weakness and fatigability, which appear to be greater than what the examiner finds. Symptoms improve at the beginning of muscle contraction, but prolonged exercise results in muscle discomfort, stiffness, and fatigability. Upper extremities are rarely affected at the onset of the disease, but most patients eventually develop arm weakness. More than 50% of patients have cholinergic dysautonomia, including dry mouth, erectile dysfunction, and blurry vision. On examination, there is proximal muscle weakness, decreased or absent reflexes (particularly in the lower extremities), and mild and transitory (if any) cranial nerve involvement (diplopia, ptosis, difficulty swallowing). In addition to these clinical findings, the diagnosis of LEMS is based on electrophysiologicstudies. Characteristically, nerve conduction studies show reduced amplitude of the compound muscle action potentials, which progressively increase in response to fast rates of repetitive stimulation (20 Hz or greater) or after a short period of maximum voluntary contrac-

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tion. If facilitation of more than 100% occurs in several muscles or if a single muscle shows facilitation of 400% or more, the diagnosis of LEMS is certain. LEMS is the prototype antibody-mediated paraneoplastic disorder. Animals injected with serum or IgG from patients with LEMS develop clinical and electrophysiologic signs of the disease. The antibodies of some patients immunoprecipitate a subtype of VGCC of the presynaptic neuromuscular junction; this property is used as a serologic diagnostic test. The majority of patients with paraneoplastic LEMS improve neurologically with combined treatment of their cancer and therapy specific for LEMS. 3,4-Diaminopyridine produces moderate to marked neurologic improvement in 80% of the patients. Plasma exchange and IVIg provide short-term improvement. Corticosteroids are indicated in patients who do not respond to treatment of the tumor and symptomatic therapy. In patients with complete tumor response or long-term life expectancy, the use of azathioprine as a corticosteroid-sparing medication should be considered. Recurrence of LEMS usually heralds recurrence of the tumor. LEMS can develop in association with other paraneoplastic syndromes such as PCD (usually with no detectable antibodies other than anti-VGCC) and PEM (often with positive anti-Hu serology).

PARANEOPLASTIC SYNDROMES OF THE MUSCLE Polymyositis and Dermatomyosltls Polymyositis (PM) and dermatomyositis (DM) are inflammatory diseases of the muscle, probably autoimmune in nature. The association of PM and DM with cancer is rare, and the existence of paraneoplastic PM is controversial. However, most authors believe that in the older population the association of DM with cancer is more than coincidental. In women the most common tumors are ovarian and breast cancer; in men they are lung and gastrointestinal cancer. Characteristic cutaneous changes and weakness usually precede the identification of cancer. Patients typically present with proximal muscle weakness of subacute onset, elevated levels of serum creatine kinase, and electromyographic evidence of myopathy. Neck flexors and pharyngeal and respiratory muscles are commonly involved; their dysfunction may result in aspiration and hypoventilation and contribute to death. Reflexes and sensory examination are normal. Clinical, electromyographic, and pathologic findings are similar in patients with and without cancer. In some patients, the serum creatine kinase levels are normal. Characteristic skin changes may occur without muscle weakness; these patients may complain of fatigue and myalgias, and MRI studies may show subclinical muscle involvement. Several autoantibodies have been identified in patients with PM or DM; the most specific, anti-Jo-1, is identified in a group of patients with associated interstitial lung disease. Low titer of antinuclear antibodies typical of other connective tissue diseases can also be detected. There are no specific markers indicative of the paraneoplastic origin of DM. Different immune mechanisms appear to be involved in PM and DM. Whereas PM results from cell-mediated cytotoxic mechanisms, DM appears to result from a humoral immunomediated vasculopathy. The course of PM and DM is independent of the malignant disease. Treatment of the tumor may or may not improve the neurologic syndrome. Steroids and other immunosuppressants (azathioprine, cyclophosphamide, methotrexate) have been used

successfully in paraneoplastic and nonparaneoplastic DM. Intravenous immunoglobulin has been proven to be effective in DM refractory to other treatments. Patients with paraneoplastic DM usually die as a consequence of the tumor. Polymyositis can occur as a complication of chronic graft versus host disease (GVHD) that some patients, usually with hematologic malignancies, develop after allogeneic hematopoietic cell transplant. Some of these patients also have skin abnormalities secondary to GVHD that are easily differentiated from dermatomyositis. The polymyositis of these patients responds to prednisone, but treatment should be directed to the GVHD. In patients with solid tumors or hematologic malignancies, opportunistic infections such as toxoplasma can cause a focal or diffuse inflammatory myopathy, which can mimic polymyositis.

Acute Necrotizing Myopathy This rare disorder presents with painful proximal muscle weakness, which rapidly progresses to involve respiratory, pharyngeal, and truncal muscles. The clinical course is rapid and often results in death in the first 12 weeks. In most patients the paraneoplastic disorder precedes tumor diagnosis. Carcinoma of the lung, breast, colon, and bladder is most often associated. Serum creatine kinase is elevated, and there is electromyographic evidence of myopathy. Pathologic studies demonstrate widespread muscle necrosis with mild or no inflammatory infiltrates. There is no effective treatment; in rare instances tumor treatment may result in neurologic improvement.

Carcinoid Myopathy This myopathy typically develops years after the carcinoid syndrome. Symptoms include proximal muscle weakness, fatigability, and cramps. Pathologic studies demonstrate type 2 fiber atrophy with mild or no inflammatory infiltrates. Treatment with cyproheptadine usually is effective.

Cachectic Myopathy Most patients with advanced cancer, as well as other debilitating diseases, develop general muscle wasting and weakness. Pathologic studies demonstrate a predominance of small fiber and grouped atrophy, with no inflammatory infiltrates. Treatment of the underlying disease may reverse the disorder.

SUGGESTED READINGS Alamowitch S, Graus F, Uchuya M et al: Limbic encephalitis and small cell lung cancer: clinical and immunological features. Brain 120:923, 1997 Antoine JC, Cinotti L, Tilikete C et al: [ 18F]Fluorodeoxyglucosepositron emission tomography in the diagnosis of cancer in patients with paraneoplastic neurological syndrome and anti-Hu antibodies. Ann Neurol 48:105, 2000 Antoine JC, Mosnier JF, Absi L et al: Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 627, 1999 Antoine JC, Mosnier JF, Honnorat J et al: Paraneoplastic demyelinating neuropathy, subacute sensory neuropathy, and anti-Hu antibodies: clinicopathological study of an autopsy case. Muscle Nerve 21:850, 1998 Bataller L, Graus F, Saiz A, Vilchez J: Clinical outcome in adult onset paraneoplastic opsoclonus-myoclonus. Brain 124437, 2001

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Butler MH, Hayashi A, Ohkoshi N et ak Autoimmunity to gephyrin in stiff-man syndrome. Neuron 26:307,2000 Dalakas M C Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 325:1487, 1991 Dalakas MC, Illa I, Dambrosia JM et ak A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 3291993, 1993 Dalmau J, Graus F, Rosenblum MK, Posner JB Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 71:59, 1992 Dalmau J, Gultekin SH, Voltz R et ak Mal, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 122:27, 1999 Dalmau J, Posner J B Paraneoplastic syndromes affecting the nervous system. Semin Oncol 24318, 1997 De Camilli P, Thomas A, Cofiell R et ak The synaptic vesicle-associated protein amphiphysin is the 128-kDa autoantigen of stiff-man syndrome with breast cancer. J Exp Med 178:2219, 1993 DeVisser M, Emslie-Smith AM, Engel AG Early ultrastructural alterations in adult dermatomyositis: a quantitative study. J Neurol Sci 94:181, 1989 Digre KB: Opsoclonus in adults. Report of three cases and review of the literature. Arch Neurol 43:1165, 1986 Folli F, Solimena M, Cofiell R et ak Autoantibodies to a 128-kDa synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 328:546, 1993 Forsyth PA, Dalmau J, Graus F et ak Motor neuron syndromes in cancer patients. Ann Neurol 41:722, 1997 Gerl A, Storck M, Schalhorn A et ak Paraneoplastic chronic intestinal pseudoobstruction as a rare complication of bronchial carcinoid. Gut 33:1000, 1992 Graus F, Dalmau J, Valldeoriola F et ak Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin’s disease. J Neuroimmunol7455, 1997 Graus F, Keime-GuibertF, ReiiC R et ak Anti-Hu-associated paraneoplastic encephalomyelitis: Analysis of 200 patients. Brain, 1241138,2001 Gultekin SH, Rosenfeld MR, Voltz R et ak Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123:1481, 2000 Hart IK, Waters C, Vincent A et ak Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia. Ann Neurol 41:238, 1997 Honnorat J, Antoine JC, Derrington E et ak Antibodies to a subpopulation of glial cells and a 66 kDa developmental protein in patients with paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 61:270, 1996 Jacobson DM, Thirkill CE, Tipping SJ: A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 28: 162, 1990 Kelly JJ Jr: Peripheral neuropathies associated with monoclonal proteins: a clinical review. Muscle Nerve 8:138, 1985 Kissel JT, Mendell JR, Rammohan Kw: Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 314:329, 1986 Koh PS, Raffensperger JG, Berry S et ak Long-term outcome in children with opsoclonus-myoclonusand ataxia and coincident neuroblastoma. J Pediatr 125712, 1994 Levin MI, Mozaffar T, Al Lozi MT, Pestronk A Paraneoplastic necrotizing myopathy: clinical and pathological features. Neurology 50:764, 1998 Luque FA, Furneaux HM, Ferziger R et ak Anti-Rk an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol29:241, 1991 Mason WP,Graus F, Lang B et ak Small-cell lung cancer, paraneoplastic cerebellardegeneration and the Lambert-Eaton myasthenic syndrome. Brain 1201279, 1997 Milam AH, Saari JC, Jacobson SG et ak Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci 3491, 1993

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Molinuevo JL, Graus F, ReiiC R et al: Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol M976, 1998 Motomura M, Johnston I, Lang B et al: An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 58:85, 1995 Newsom-Davis J: Lambert-Eaton myasthenic syndrome. Curr Treat Opt Neurol 3:127, 2001 Newsom-Davis J, Mills K R Immunological associations of acquired neuromyotonia (Isaac’s syndrome). Report of five cases and literature review. Brain 116:453, 1993 Oh SJ: Paraneoplastic vasculitis of the peripheral nervous system. Neurol Clin 15:849, 1997 Ojeda VJ: Necrotizing myelopathy associated with malignancy. A clinicopathologic study of two cases and literature review. Cancer 53: 1115, 1984 Oksenhendler E, Chevret S, Leger JM et ak Plasma exchange and chlorambucil in polyneuropathy associated with monoclonal IgM gammopathy. IgM-Associated Polyneuropathy Study Group. J Neurol Neurosurg Psychiatry 59:243, 1995 ONeill JH, Murray NM, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 111:577, 1988 Peterson K, Forsyth PA, Posner JB: Paraneoplastic sensorimotor neuropathy associated with breast cancer. J Neurooncol 21:159, 1994 Peterson K, Rosenblum MK, Kotanides H, Posner JB: Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibodypositive patients. Neurology 42:1931, 1992 Polans AS, Burton MD, Haley TL et ak Recoverin, but not visinin, is an autoantigen in the human retina identified with a cancer-associated retinopathy. Invest Ophthalmol Vis Sci 3481, 1993 Posner JB: Paraneoplastic syndromes. p. 353. In Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995 Rojas I, Graus F, Keime-Guibert F et ak Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 55:713,2000 Ropper AH, Gorson KC Neuropathies associated with paraproteinemia. N Engl J Med 3381601, 1998 Rowland LP, Schneck S A Neuromuscular disorders associated with malignant neoplastic disease. J Chron Dis 16:777, 1963 Rowland LP, Sherman WH, Latov N et al: Amyotrophic lateral sclerosis and lymphoma: bone marrow examination and other diagnostic tests. Neurology 42:1101, 1992 Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 28284, 1997 Saiz A, Minguez A, Graus F et ak Stiff-man syndrome with vacuolar degeneration of anterior horn motor neurons. J Neurol 246:858, 1999 Sanders DB Lambert-Eaton myasthenic syndrome: clinical diagnosis, immune-mediated mechanisms, and update on therapies. Ann Neurol 37563, 1995 Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 3,4-diaminopyridinein Lambert-Eaton myasthenic syndrome. Neurology 54603, 2000 Schold SC, Cho ES, Somasundaram M, Posner JB: Subacute motor neuronopathy: a remote effect of lymphoma. Ann Neurol5:271, 1979 Sigurgeirsson B, Lindelof B, Edhag 0, AUander E Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med 326363, 1992 Sillevis SP, Kinoshita A, De Leeuw B et ak Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 34221, 2000 Solimena M, Folli F, Aparisi R et al: Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322:1555, 1990 Van Lieshout JJ,Wieling W, Van Montfrans GA et ak Acute dysautonomia associated with Hodgkin’s disease. J Neurol Neurosurg Psychiatry 49:830, 1986

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Voltz R, Gultekin SH, Rosenfeld MR et al: A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 340:1788, 1999 Warich-Kirches M, Von Bossanyi P, Treuheit T et al: Stiff-man syndrome: possible autoimmune etiology targeted against GABA-ergic cells. Clin Neuropathol 16214, 1997

Wilson HC, Lunn MP, Schey S , Hughes RA: Successful treatment of IgM paraproteinaemic neuropathy with fludarabine. J Neurol Neurosurg Psychiatry 66575, 1999 Yu Z, Kryzer TJ, Griesmann GE et ak CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 49:146, 2001

179 Neurologic Pain Syndromes in Cancer Patients Julie E. Hammack Cancer pain is an enormous problem worldwide. It has been estimated that at least 70% of patients with advanced cancer report moderate to severe pain during the course of their illness, necessitating the use of opioids. Applying these prevalence rates to U.S. cancer statistics from 2001, 387,380 of the 553,400 patients who were expected to die from cancer and more than 800,000 of those surviving cancer experienced moderate to severe cancerrelated pain during that year. At least 25% of patients with cancer experience neurologic complications related to their malignancies or antineoplastic therapy. Physicians involved in the care of these patients must be especially vigilant to pain because it is the most common presenting symptom of malignant invasion of the nervous system. Indirect effects of malignancy including opportunistic infection, coagulopathy, and paraneoplastic disorders can be associated with pain. Moreover, these cancer-related pain syndromes must be differentiated from pain and neurologic disability resulting from antineoplastic therapies if appropriate treatment is to be administered. This chapter reviews some of the more common pain syndromes associated with malignancy and its treatment. Many of these syndromes involve the nervous system directly; others do so indirectly or not at all but present with symptoms familiar to the consulting neurologist. ESTABLISHING A PAIN DIAGNOSIS There is limited clinical emphasis on cancer pain and its causes in most medical and neurology training programs. As a result, there is an unfortunate tendency to view cancer pain as a single diagnostic entity. In fact, the causes of cancer pain are myriad. Careful medical and neurologic evaluation of each pain complaint is essential to best treat the pain and to prevent otherwise unsuspected complications. A comprehensive pain evaluation in one study revealed a previously undiagnosed cause of pain in 64% of patients (Gonzales et al, 1991). New neurologic diagnoses were made in 36%, and an unsuspected infection was discovered in 4% of patients. As with any medical history, the pain history emphasizes the onset, quality, severity, location, ameliorating and exacerbating factors, and associated symptoms. The patient’s response to previous analgesics and other treatments should be determined, as should the effect of pain on the patient’s level of function and psychological state. The physical examination should include a complete neurologic examination in all patients. Diagnostic studies are directed by historical and physical findings.

CANCER PAIN MECHANISMS Neurologic pain syndromes may be organized into three distinct mechanisms (Table 179-1). The most common is direct tumor invasion of nervous tissue (brain, spinal cord, or peripheral nerve) or adjacent structures, with resulting compression of nervous tissue (i.e., epidural spinal cord compression). Second, cancer treatments (surgery, radiation, and chemotherapy) may injure the nervous system or adjacent structures and produce pain by activation of nociceptors or injury to nervous tissue with deafferentation. Finally, patients with cancer may have pain problems unrelated to cancer or its therapy (migraine headache, carpal tunnel syndrome). Patients in this third category are in a minority, and it is imperative that they be thoroughly evaluated to exclude a cancer-related pain syndrome. Cancer pain may be further subdivided into nociceptive and neuropathic mechanisms. Nociceptive pain is produced by activation of peripheral nerve fibers sensitive to noxious stimuli. The nociceptive stimuli travel through fibers innervating somatic structures (bone, muscle, dura, fascia, skin, blood vessels) or visceral structures (pleura, peritoneum, organ capsules, hollow viscera) when these structures are stretched, obstructed, or otherwise injured. Nociceptive somatic pain is typically well localized, may be sharp or dull, and is made worse by maneuvers that stress the involved structure. Bone metastasis is the most common nociceptive somatic pain syndrome. Visceral nociceptive pain tends to be more diffuse and poorly localized. Depending on the viscera involved, it may be sharp, dull, or colicky. Symptoms and signs of visceral dysfunction (e.g., dyspnea, jaundice, nausea, abdominal distention) typically accompany visceral pain. Neuropathic pain results from direct injury to the central or peripheral nervous system, with subsequent aberrant pain fiber transmission, deafferentation, and reorganization of central sensory processing. Neuropathic pain has unique features including lancination, anesthesia, paresthesias, allodynia, itching, and hyperpathia. Depending on the site of involvement, neuropathic pain follows the referral pattern of a specific peripheral nerve, plexus, root, or sensory tract. Other signs of neurologic dysfunction, including weakness, reflex changes, and autonomic dysfunction, may be present. Many cancer pain syndromes involve more than one of these mechanisms; for instance, epidural tumor produces nociceptive bone pain and neuropathic radicular pain.

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Voltz R, Gultekin SH, Rosenfeld MR et al: A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 340:1788, 1999 Warich-Kirches M, Von Bossanyi P, Treuheit T et al: Stiff-man syndrome: possible autoimmune etiology targeted against GABA-ergic cells. Clin Neuropathol 16214, 1997

Wilson HC, Lunn MP, Schey S , Hughes RA: Successful treatment of IgM paraproteinaemic neuropathy with fludarabine. J Neurol Neurosurg Psychiatry 66575, 1999 Yu Z, Kryzer TJ, Griesmann GE et ak CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 49:146, 2001

179 Neurologic Pain Syndromes in Cancer Patients Julie E. Hammack Cancer pain is an enormous problem worldwide. It has been estimated that at least 70% of patients with advanced cancer report moderate to severe pain during the course of their illness, necessitating the use of opioids. Applying these prevalence rates to U.S. cancer statistics from 2001, 387,380 of the 553,400 patients who were expected to die from cancer and more than 800,000 of those surviving cancer experienced moderate to severe cancerrelated pain during that year. At least 25% of patients with cancer experience neurologic complications related to their malignancies or antineoplastic therapy. Physicians involved in the care of these patients must be especially vigilant to pain because it is the most common presenting symptom of malignant invasion of the nervous system. Indirect effects of malignancy including opportunistic infection, coagulopathy, and paraneoplastic disorders can be associated with pain. Moreover, these cancer-related pain syndromes must be differentiated from pain and neurologic disability resulting from antineoplastic therapies if appropriate treatment is to be administered. This chapter reviews some of the more common pain syndromes associated with malignancy and its treatment. Many of these syndromes involve the nervous system directly; others do so indirectly or not at all but present with symptoms familiar to the consulting neurologist. ESTABLISHING A PAIN DIAGNOSIS There is limited clinical emphasis on cancer pain and its causes in most medical and neurology training programs. As a result, there is an unfortunate tendency to view cancer pain as a single diagnostic entity. In fact, the causes of cancer pain are myriad. Careful medical and neurologic evaluation of each pain complaint is essential to best treat the pain and to prevent otherwise unsuspected complications. A comprehensive pain evaluation in one study revealed a previously undiagnosed cause of pain in 64% of patients (Gonzales et al, 1991). New neurologic diagnoses were made in 36%, and an unsuspected infection was discovered in 4% of patients. As with any medical history, the pain history emphasizes the onset, quality, severity, location, ameliorating and exacerbating factors, and associated symptoms. The patient’s response to previous analgesics and other treatments should be determined, as should the effect of pain on the patient’s level of function and psychological state. The physical examination should include a complete neurologic examination in all patients. Diagnostic studies are directed by historical and physical findings.

CANCER PAIN MECHANISMS Neurologic pain syndromes may be organized into three distinct mechanisms (Table 179-1). The most common is direct tumor invasion of nervous tissue (brain, spinal cord, or peripheral nerve) or adjacent structures, with resulting compression of nervous tissue (i.e., epidural spinal cord compression). Second, cancer treatments (surgery, radiation, and chemotherapy) may injure the nervous system or adjacent structures and produce pain by activation of nociceptors or injury to nervous tissue with deafferentation. Finally, patients with cancer may have pain problems unrelated to cancer or its therapy (migraine headache, carpal tunnel syndrome). Patients in this third category are in a minority, and it is imperative that they be thoroughly evaluated to exclude a cancer-related pain syndrome. Cancer pain may be further subdivided into nociceptive and neuropathic mechanisms. Nociceptive pain is produced by activation of peripheral nerve fibers sensitive to noxious stimuli. The nociceptive stimuli travel through fibers innervating somatic structures (bone, muscle, dura, fascia, skin, blood vessels) or visceral structures (pleura, peritoneum, organ capsules, hollow viscera) when these structures are stretched, obstructed, or otherwise injured. Nociceptive somatic pain is typically well localized, may be sharp or dull, and is made worse by maneuvers that stress the involved structure. Bone metastasis is the most common nociceptive somatic pain syndrome. Visceral nociceptive pain tends to be more diffuse and poorly localized. Depending on the viscera involved, it may be sharp, dull, or colicky. Symptoms and signs of visceral dysfunction (e.g., dyspnea, jaundice, nausea, abdominal distention) typically accompany visceral pain. Neuropathic pain results from direct injury to the central or peripheral nervous system, with subsequent aberrant pain fiber transmission, deafferentation, and reorganization of central sensory processing. Neuropathic pain has unique features including lancination, anesthesia, paresthesias, allodynia, itching, and hyperpathia. Depending on the site of involvement, neuropathic pain follows the referral pattern of a specific peripheral nerve, plexus, root, or sensory tract. Other signs of neurologic dysfunction, including weakness, reflex changes, and autonomic dysfunction, may be present. Many cancer pain syndromes involve more than one of these mechanisms; for instance, epidural tumor produces nociceptive bone pain and neuropathic radicular pain.

Chapter 179

TABU 179-1. Causes of Neurologic Cancer Pain Syndromes Syndromes related to direct or indirect tumor involvement Bone metastases Vertebral syndromes C8-T1 T12-L1 Skull base syndromes Jugular foramen syndrome Clivus syndrome Orbital syndrome Parasellar and middle cranial fossa syndrome Occipital condyle syndrome Dural metastases Meningeal metastases lntraparenchymal metastases Retroperitoneal metastases Pseudotumor cerebri Dural sinus thrombosis Skull or dural metastases Coagulopathy Hyperviscositysyndromes Dehydration and sepsis Superior vena cava obstruction Cerebral hemorrhage Dural, meningeal, intraparenchymal metastases Coagulopathy Cervical, brachial, or lumbosacral plexopathy Peripheral neuropathy Tumor invasion Paraneoplastic Central pain syndromes from brain and spinal cord lesions Syndromes related to antineoplastic therapy Postsurgety Postmastectomy pain syndrome Post-thoracotomy pain syndrome Postamputation pain syndrome Post-radical neck dissection pain syndrome Postradiation therapy Brachial and lumbosacral plexopathy Acute Chronic Radiation myelopathy Radiation-inducedtumors Chemotherapy or other medications Peripheral neuropathy Vinca alkaloids Cisplatin VP-16 Paclitaxel Suramin Misonidazole Hexamethylmelamine Corticosteroids Steroid pseudorheumatism Perineal burning Aseptic necrosis of the humeral and femoral heads Pseudotumor cerebri Phenobarbital pseudorheumatism Headache Retinoic acid Leuprolide Corticosteroids Other Infections Oral and lower gastrointestinal anaerobic bacteria Herpes varicella-zoster Acute and postherpetic neuralgia Pain syndromes unrelated to cancer or its treatment Diagnoses of exclusion after cancer or therapy-related causes have been excluded

PAIN SYNDROMES SECONDARY TO DIRECT TUMOR INVASION Direct tumor involvement of pain-sensitive structures is responsible for pain in at least two thirds of cancer patients with pain. Invasion of somatic, visceral, and neural tissues produces pain

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characteristic to each structure. Visceral pain syndromes are not dealt with at length here, with the exception of pain from involvement of retroperitoneal structures. The reader is directed to sources listed in “Suggested Readings” for a more complete discussion of visceral pain syndromes. The following sections describe some of the more common somatic-nociceptive and neuropathic pain syndromes.

Bone Metastases

Bony metastasis is the most common cause of cancer-related pain. Cortical bone is anesthetic, but the cancellous portion of bone and the investing periosteum are exquisitely pain sensitive when injured or stretched. Bone pain typically is well localized, sharp, and constant. Bone metastases in some locations may produce pain radiating to distant sites. Malignant bone pain is worse when the involved bone is stressed and typically is worse at night, often interfering with sleep. Local production of prostaglandins (e.g., prostaglandin E,) may play a critical role in pain related to bony metastases. Although opioids are the mainstay of therapy for moderate to severe bone pain, corticosteroids and nonsteroidal anti-inflammatory drugs may be useful secondary to their antiprostaglandin effects. Bisphosphonates and calcitonin may also be useful adjuvants in treating refractory pain related to bone metastases or primary bone tumors. Antineoplastic therapy, including radiotherapy, chemotherapy, and sometimes surgery, commonly reduces metastatic bone pain by cytoreduction and a resulting decrease in the pain stimulus. There are a number of well-described pain syndromes secondary to bone metastases. The following are most common. Vertebral Syndromes. The axial skeleton is especially vulnerable to metastatic involvement in patients with solid tumors. The proximity to the spinal cord and other important neural structures makes the early identification of vertebral metastases uniquely important to prevent the development of serious neurologic complications, such as epidural spinal cord compression. Malignant bone involvement typically produces pain located directly over the involved vertebra. This pain is worse with percussion or movements that stress the spine. Malignant spine pain often is worse at night secondary to the elongation of the spine (and stretching of injured periosteum) after several hours of maintaining a reclining posture. The vertebral body and pedicle are the most common sites of metastases. Plain radiograph of the spine may demonstrate sclerotic or lytic lesions, vertebral collapse, and loss of a pedicle (Fig. 179-1). Epidural extension of tumor may impinge on adjacent nerve roots, producing neuropathic pain radiating into the arms (cervical spine), buttocks, or legs (lumbosacral spine) or around the chest or abdomen like a belt or band (thoracic spine). Evidence of a myelopathy may or may not be present with epidural spinal cord compression. One should thus have a high index of suspicion for epidural cord compression in any patient with cancer and persistent spine pain, especially if evidence of root or cord compromise is present; this constitutes a neurologic emergency necessitating high-dose corticosteroids, emergent neuroimaging procedures, and emergent radiotherapy or neurosurgical intervention. Vertebral involvement at some levels produces pain that radiates to distant sites. Metastases to the T12 or L1 vertebrae may produce pain radiating to the iliac crest or ipsilateral sacroiliac joint. This may result in inappropriate imaging of the pelvis or sacrum and failure to diagnose the actual lesion, with resulting epidural progression. C8-T1 vertebral involvement may produce

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FIG. 179-1. Plain radiograph of the thoracic spine demonstrating loss of a pedicle secondary to a metastasis, the so-called winking owl sign (arrow).

pain radiating into the interscapular region, which again may prompt imaging of the inappropriate spinal level. Metastatic involvement of the Cl-C2 vertebrae may simulate a skull base lesion and be associated with atlantoaxial subluxation or odontoid fracture. A severe occipital headache made worse by head movement is characteristic, often with associated torticollis. These patients are at high risk of developing a compressive cervical myelopathy with quadriparesis and sensory loss (usually beginning in the upper extremities), autonomic dysfunction, and respiratory arrest. Expeditious diagnosis and treatment are essential. Magnetic resonance imaging (MRI) and myelography are the most sensitive diagnostic studies. C1-C2 spinal lesions are inherently unstable, and neurosurgical and orthopedic consultations are appropriate in addition to radiotherapy. Skull Base Syndromes. Metastases to the base of the skull produce pain secondary to bony or soft tissue involvement and invasion or compression of neural structures. Cranial nerve dysfunction is common, depending on the site of involvement. JUGULAR FORAMEN SYNDROME.The pain in jugular foramen syndrome is dull and constant and typically refers to the occiput or postauricular region. Occasionally, pain may refer to one or both shoulders. There may be associated sharp lancinating pain (glossopharyngeal neuralgia) in the throat or ear, and on rare occasions syncope is present. The pain may be exacerbated by neck flexion or swallowing if glossopharyngeal neuralgia is present. Deficits of cranial nerves IX, X, and XI are common. CLMJSSYNDROME.Malignant invasion of the clivus produces a vertex headache that is worse with neck flexion. A number of cranial nerves (nerves VI through XII) pierce the dura in the

vicinity of the clivus and thus may be compromised, depending on the location of the metastasis. Usually multiple cranial nerves are involved. Nasopharyngeal carcinoma, chordoma, meningioma, prostate cancer, and breast cancer are the most common malignancies associated with this syndrome. ORBITALSYNDROME.Orbital metastases produce pain that is localized behind the eye, supraorbitally or periorbitally. It is dull and constant and may be worse on lying down or with eye movement. Visual loss, dysfunction of cranial nerves V1, V2,III, IV, and VI, and proptosis are common. PARASELLAR AND MIDDLE CRANIALFOSSA SYNDROME. Involvement of structures within the cavernous sinus produces symptoms that closely parallel those of the orbital syndrome. Proptosis and visual loss are less common, however. Ipsilateral neuropathic facial pain (usually periorbital or maxillary), diminished corneal reflex, and weakened muscles of mastication secondary to gasserian ganglion involvement are common. OCCIPITALCONDYLESYNDROME.Occipital condyle syndrome is characterized by dull, constant occipital pain that is worsened by neck movements. Ipsilateral tongue weakness, fasciculations, and wasting are characteristic and secondary to involvement of the hypoglossal nerve within the hypoglossal canal. Tenderness to palpation of the occiput may be present, as may neck stiffness. On rare occasions, sternocleidomastoid weakness is present. Appropriate imaging procedures for skull base lesions include plain radiograph and bone scan. Computed tomography (CT) with bone windows or MRI, including special skull base, orbital, or cavernous sinus views, usually is needed to delineate the lesion.

Other Causes of Headache Pain-sensitive structures in the head include periosteum, dura, soft tissues (skin, fascia, muscle, adipose tissue), extradural blood vessels, cornea, sclera, uvea, and cranial nerves (especially nerves V, VII, IX, and X). Malignant invasion or stretching of any of these structures produces head pain. Brain parenchyma itself is anesthetic. Brain metastases (parenchymal, leptomeningeal, and dural) are the most common neurologic complication of cancer, occurring in 15% to 20% of patients; headache is the most common presenting symptom. Parenchymal metastases produce head pain secondary to raised intracranial pressure and resulting dural traction. Supratentorial metastases typically produce frontal headache, whereas head pain from infratentorial metastases refers to the occiput, although variation in this referral pattern is common. The headache produced by brain metastases is worsened by maneuvers that increase intracranial pressure, such as cough, Valsalva maneuver, and lying flat. The pain typically is worse at night and may awaken the patient from sleep. Acute, severe headache may occur in the settling of hemorrhage into a cerebral metastasis. Vomiting and somnolence may occur in more advanced cases, indicating traction on brainstem structures secondary to a rostral-caudal herniation syndrome. Focal neurologic defects and seizures are variably present. Leptomeningeal spread of tumor may produce headache by direct dural invasion, raised intracranial pressure (often from communicating hydrocephalus), or invasion of pain-sensitive cranial nerves (nerves V, VII, IX, and X) or cervical roots. Neurologic signs and symptoms at multiple levels of the neuraxis are a cardinal feature of leptomeningeal malignancy, and meningismus may be present. Gadolinium-enhanced MRI and myelography are helpful in diagnosis. Cerebrospinal fluid (CSF) exami-

Chapter 179

nation is the definitive diagnostic test. However, repeated lumbar punctures may be needed to isolate malignant cells. Breast, prostate, lung, and hematologic malignancies may metastasize to the dura and can produce headache from direct stimulation of dural nociceptors or by mass effect and raised intracranial pressure. Dural metastases may hemorrhage, especially if a coagulopathy is present, producing acute or chronic subdural hematomas. Venous sinus occlusion may result from skull or dural metastases, producing pseudotumor cerebri and headache from raised intracranial pressure. Other causes of venous sinus occlusion include L-asparaginase administration (which depletes plasma proteins involved in coagulation and fibrinolysis),polycythemias, paraproteinemias with hyperviscosity syndrome, and other hypercoagulable states. Contrast CT of the head demonstrates no enhancement within the clot-filled superior sagittal sinus, with enhancement of the walls of the sinus (delta sign). MFU of the head has supplanted digital subtraction angiography as the standard diagnostic test for this disorder (Fig. 179-2). Mediastinal tumors causing superior vena cava obstruction produce raised intracranial venous pressure and headache. Retinoic acid, used to treat promyelocytic leukemia and other malignancies, may produce pseudotumor cerebri and headache without venous sinus occlusion. Leuprolide, a gonadotropinreleasing hormone analogue used as an antiandrogen to treat prostate cancer, on rare occasions produces migraine headaches. Cranial neuropathies from extracranial malignant involvement often are painful. Squamous cell carcinoma of skin or oropharynx is notorious for perineural invasion with resulting pain and cranial nerve defects. However, any primary or metastatic tumor may injure somatic or neural structures of the head and neck. Pain syndromes from skull base malignant invasion are described earlier in this chapter. Trigeminal nerve invasion anywhere along its course produces pain referred to the face or ear. Injury to cranial nerves VII, IX, and X commonly produces pain felt in or around the external auditory meatus or helix. Otherwise asymp-

FIG. 179-2. Sagittal noncontrast MRI of the head demonstrating clot within the superior sagittal sinus (arrows).

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tomatic head and neck tumors may present with lancinating pain referred to the ipsilateral ear, tongue, or throat from invasion of branches of cranial nerves IX and X. Hypotension and syncope may be associated with glossopharyngeal nerve involvement from stimulation of chemoreceptive and baroreceptive afferents originating in the carotid sinus and carotid body. Evaluation of any patient with otherwise unexplained ear pain should include a careful examination of the oropharynx and larynx. Herpes zoster virus may remain latent in the trigeminal (cranial nerve V) and geniculate ganglia (cranial nerve VII) and reactivate in immunocompromised patients. Patients with hematopoietic malignancies, especially lymphoma, and those receiving potent immunosuppressant chemotherapy are especially vulnerable. Typically, the infection is heralded by an itching, burning discomfort in the cornea and forehead (V1) or ear and tongue (cranial nerve VII). Erythema of the conjunctiva, forehead, or helix may precede the development of herpetic blisters. Ipsilateral facial nerve weakness may be present with geniculate ganglion herpes zoster infection (Ramsay Hunt syndrome). Herpetic keratitis is a serious complication of trigeminal herpes zoster infection. These patients should be followed closely by an ophthalmologist during the acute phase of infection. Acute herpes zoster infection and postherpetic neuralgia are discussed further later in this chapter.

Visceral Pain Syndromes Injury to organ capsules, pleura, peritoneum, or obstruction of hollow viscera by malignancy typically produces pain and evidence of visceral dysfunction. The full spectrum of visceral pain syndromes is not discussed here. However, the retroperitoneal pain syndrome is occasionally encountered in patients with cancer and back pain. The retroperitoneal space is richly innervated by the celiac plexus and spinal nerves, which may be encased by pancreatic, hepatobiliary, renal, and gastrointestinal tumors and lymphomas. The pain usually is localized to the epigastrium and radiates into the back in 25% to 30% of patients. Alternatively,

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pain from retroperitoneal metastases may be felt exclusively in the upper lumbar spine and flank. Paraspinal retroperitoneal tumors may invade the epidural space via the intervertebral foramina or vertebrae. Neurologic deficits may result from epidural extension or by invasion of the lumbosacral plexus, which is also located within the retroperitoneum. Evidence of visceral dysfunction is variably present depending on the location of tumor within the retroperitoneal space and abdominal cavity. Pain from retroperitoneal tumors usually is worse with extension of the spine (as when lying supine) and is ameliorated by forward flexion. Consequently, many patients report that sleep is possible only while seated (as in a reclining chair) or flexed forward over a table or desk. This pain syndrome is most commonly seen in the setting of pancreatic cancer; therefore, jaundice and weight loss are usual accompaniments. Useful imaging procedures include CT and MRI of the abdomen and pelvis. Selected patients should also have imaging of the spine with MRI or myelography if tumor is noted to invade the vertebra or intervertebral foramen or if symptoms and signs suggest neurologic involvement of the cauda equina.

Neuropathic Pain Syndromes Secondary to Tumor invasion Tumor may infiltrate structures at all levels of the nervous system. Neuropathic pain is variably described as sharp, lancinating, and paroxysmal or dull, gnawing, and constant. Burning, tingling, pins and needles, numbness, squeezing, and stretching are common qualifiers used by patients. Allodynia (the perception of pain when a non-noxious stimulus is applied) is characteristic and causes the touch of garments or bedclothes to be excruciatingly uncomfortable. Itching is an under-recognized feature of neuropathic pain. Weakness, sensory loss, and autonomic dysfunction in the appropriate neural distribution may be present. Brain and spinal cord parenchyma are anesthetic, although stretching (as with raised intracranial pressure secondary to cerebral metastases) or irritation of dural coverings (e.g., leptomeningeal metastases) may produce somatic nociceptive pain. Chronic pain from otherwise anesthetic central nervous system structures may result from disruption and presumed reorganization of central pain pathways. This type of deafferentation pain is rare in patients with brain or spinal cord tumors because they often do not survive long enough for neural reorganization to occur. On rare occasions, a metastasis to the ventral posterior nucleus of the thalamus may produce a neuropathic pain syndrome (Dejerine-Roussy) affecting the contralateral hemibody. Epidural Spinal Cord Compression. Epidural spinal cord compression is a neurologic emergency that presents initially with spine pain in more than 90% of patients. Pain originating from vertebral body involvement may be referred to a site distant from its origin. Thoracic spine metastases are most common and often are associated with bilateral thoracic radicular pain described as a tight band around the chest or abdomen. This may prompt an inappropriate evaluation of the cardiac or gastrointestinal system. Cervical and lumbosacral epidural metastases usually manifest with unilateral radicular pain. Although pain is commonly the first symptom, most patients have some degree of motor, sensory, or autonomic dysfunction at the time of diagnosis. This is regrettable because the neurologic outcome is inversely related to the degree of neurologic deficit at the time of diagnosis. Prompt diagnosis is

FIG. 179-3. Pantopaque myelogram demonstrating a block to flow of contrast within the lumbar spine secondary to epidural cord compression by tumor. Note the collapsed, sclerotic vertebral body.

imperative. Any patient in whom the diagnosis is suspected should receive 100 mg dexamethasone intravenously and undergo plain films of the entire spine (Fig. 179-1) and an MRI or myelogram (Fig. 179-3) with postmyelographic CT. Treatment consists of radiotherapy to the area of epidural involvement, with margins that usually encompass the two vertebrae above and below the level of epidural tumor. Surgery is reserved for those without a tumor diagnosis, for those with radiation-insensitive tumors, and for those with recurrent tumor within a previously radiated field. A simple laminectomy usually is ineffectual because most epidural tumors are located anterior to the spinal cord, which would not be decompressed by such an approach. The favored procedure is a combined anterolateral or posterior approach with vertebrectomy, bone graft, and rod stabilization. Leptomeningeal Metastases. Solid tumors (especially breast, lung, and melanoma) and hematologic malignancies may metastasize to the leptomeninges. Head and spine pain are the most common presenting symptoms. Pain may result from invasion of cranial or spinal nerves, raised intracranial pressure, or direct invasion and irritation of the meninges. Neurologic findings typically are multifocal and localized to more than one level of the central nervous system. Multiple cranial neuropathies and a cauda

Chapter 179 H Neurologic Pain Syndromes in Cancer Patients

equina syndrome are the most common clinical findings, presumably because of the tendency of tumor cells to settle in the basal meninges of the posterior fossa and in the dural sac. Contrast CT and MFU of the head may demonstrate leptomeningeal enhancement and communicating hydrocephalus. Gadolinium-enhanced MRI of the spine usually demonstrates linear enhancement of the cord and roots. Myelography may be normal or show nodular filling defects along the course of the spinal roots. On rare occasions, a complete block to flow of contrast is present. Spinal fluid analysis provides the definitive diagnosis, although cytology may be negative despite repeated examinations. Usually, the CSF protein is elevated and a reactive pleocytosis is present. CSF glucose may be reduced. CSF tumor markers, including carcinoembryonic antigen, P-glucuronidase, P,-microglobulin, and lactate dehydrogenase may facilitate the diagnosis if cytology is negative. Brachial Plexopathy. Brachial plexopathy from direct invasion by apical lung cancer (Pancoast syndrome) or by adjacent cervical lymph nodes involved by metastatic tumor (breast, lung, lymphoma, head and neck cancer) presents most commonly with aching ipsilateral scapular or shoulder pain followed by C8-T1 root distribution neuropathic pain and paresthesia. Lower trunk or medial cord distribution weakness and sensory loss (axilla, medial arm, and ulnar two fingers) is typical. Pain is present at

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diagnosis in more than 95% of patients. Invasion of the upper plexus is less common and presents with aching pain in the shoulder radiating into the thumb and forefinger; weakness is in a C5-C6 root distribution. Symptoms may progress to a panplexopathy from a lower or upper plexopathy. A supraclavicular mass may be palpable and a Tine1 sign (paresthesias felt in the arm and hand) thus elicited. An ipsilateral Horner’s syndrome or the presence of panplexus involvement indicates a high likelihood of extension of tumor into the cervical or upper thoracic epidural compartment with impending epidural cord compression. CT and MRI both adequately visualize the brachial plexus (Fig. 179-4). MRI has the added advantage of visualizing the epidural compartment. In selected cases, electromyography may be helpful to delineate the extent of plexus or root involvement. In previously radiated patients, this syndrome must be distinguished from radiation-induced injury. Lumbosacral Plcxopathy. Pain is present in 98% of patients at the time of diagnosis and is the most common presenting symptom of lumbosacral plexopathy from malignant invasion. Tumor involves the plexus by direct extension in 75%, with remote metastases accounting for the remainder. Sarcomas, lymphomas, and tumors of the colon and genitourinary tract are most commonly implicated. Unilateral, severe, constant or lancinating pain in the buttock or leg is characteristic. There may be associated

A

FIG. 179-4. (A) Coronal and (6) axial MRls through the brachial plexus of two different patients with supraclavicular and axillary adenopathy from lymphoma. Both patients were symptomatic with medial card plexopathies.

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weakness, sensory loss, and reflex changes depending on the segments of the plexus involved. Lower plexus involvement (LPS1) is most common. Differentiation from a lumbosacral radiculopathy may be impossible on clinical grounds. Bowel, bladder, and sexual dysfunction indicate either bilateral plexus involvement or extension of tumor into the spinal canal with an associated cauda equina syndrome. CT and MRI are adequate imaging modalities; neither one has a clear advantage over the other. Myelography or MRI of the spine should be considered in patients with a paraspinal mass, electromyographic evidence of radicular involvement, or bowel, bladder, or sexual dysfunction. Peripheral Neuropathy. Peripheral nerve involvement by tumor is less common than plexus involvement; however, intercostal neuropathies are common with chest wall invasion by lung cancer. Similarly, retroperitoneal tumors may invade spinal nerves, producing radicular-like abdominal pain. Tumors of the limb (e.g., osteogenic sarcoma) may produce solitary or multiple mononeuropathies as a result of local extension. Paraneoplastic neuropathies may be associated with both solid tumors and hematologic malignancies. A subacute sensory neuronopathy (anti-Hu syndrome) is seen in association with small cell lung carcinoma. The clinical presentation is dominated by profound sensory defects, although burning or lancinating neuropathic pain is a common associated feature. Dysautonomia (as manifested by bowel bladder, and sexual dysfunction), xerostomia, and sweating abnormalities may be prominent. Nerve conduction studies reveal absent sensory nerve action potentials but no motor abnormalities. A characteristic serum antibody, anti-Hu, is diagnostic. Multiple myeloma, plasmacytoma, and Waldenstrom’s macroglobulinemia may also be associated with an axonal or demyelinating painful sensorimotor polyneuropathy. PAIN SYNDROMES RELATED TO ANTINEOPLASTIC THERAPY Acute or chronic pain may result from surgery, radiotherapy, or chemotherapeutic agents used to treat cancer. Although pain resulting from malignant invasion is more common, it is important that therapy-related pain be considered in the differential diagnosis of any cancer patient with pain. Pain resulting from cancer treatment probably will necessitate different therapy than that needed for malignant pain and may carry vastly different prognostic implications. Accurate diagnosis of treatment-related pain will prevent inappropriate antineoplastic therapy when metastases or tumor recurrence have been presumed responsible for the pain. Postsurgical Pain Syndromes

Acute postsurgical pain results from injury to somatic, visceral, or neural structures. The features and treatment of this pain are no different in patients with cancer than in the general population undergoing surgery. Therefore, the following discussion is limited to chronic pain syndromes relating to surgery. There are four well-characterizedpostsurgical pain syndromes that result primarily from injury to a peripheral nerve or plexus. Postmastectomy Pain. Postmastectomy pain is a neuropathic pain syndrome occurring in 4% to 10% of women undergoing mastectomy, although it may occur after a simple lumpectomy or thoracotomy. In most cases, the pain results from post-traumatic neuroma formation on the intercostobrachial nerve, a cutaneous sensory branch of Tl-T2. The discomfort is

described variously as a burning, tingling, constricting, constant pain, sometimes with a paroxysmal component in the anterior chest wall, posterior arm, and axilla. The “phantom breast” phenomenon may be present. Sensory loss in the axilla and anterior chest is usual, and there may be marked allodynia. A trigger point may be found along the mastectomy incision. Arm movement typically exacerbates the pain, predisposing to shoulder immobility and adhesive capsulitis (frozen shoulder). Postmastectomy pain usually develops within a few weeks of surgery, although on occasion it may be delayed by as long as 6 months. As a rule, this pain syndrome is not associated with tumor recurrence. Post-Thoracotomy Pain. Post-thoracotomy pain is neuropathic pain, beginning soon after surgery, resulting from traction or section of one or more intercostal nerves with or without neuroma formation. Rib resection or traction on the rib and its neurovascular bundle are the usual mechanisms of injury. Pain is located along the incision, which may display exquisite point tenderness. The pain is described as burning and constricting with or without a lancinating component. Allodynia may be present, making even the light touch of garments unbearably painful. Three groups of patients with post-thoracotomy pain have been identified. The first and largest group are those in whom postsurgical thoracotomy pain resolved by 2 months after surgery. In patients in whom incision pain recurred, all were found to have recurrent tumor. The second group contained patients whose post-thoracotomy pain steadily increased in intensity after surgery. In these patients as well, recurrent tumor and infection were the most likely causes. The third group consisted of patients whose pain was stable or decreasing over a protracted time period (8 months). Unless pain later increased in intensity, this pattern was not associated with recurrent malignancy in most patients. Clearly, a high index of suspicion must be maintained in patients undergoing thoracotomy for malignancy whose incision pain increases in intensity or recurs after the initial postoperative period. A thorough search for infection or recurrent tumor should be made. Postamputation Pain. The amputation of a limb, usually performed to treat sarcoma, may produce two distinct neuropathic pain syndromes. Stump pain is experienced in the distal stump along the incision and usually is secondary to traumatic neuroma formation. Trigger points are common along the incision. Pain is often burning, lancinating, or itching and may make wearing a prosthesis impossible. Treatments include medications commonly used to treat neuropathic pain (tricyclic antidepressants, anticonvulsants), trigger point injection, and sometimes reoperation to resect or transpose the neuroma into muscle or soft tissues. Refitting the prosthesis often is helpful. Phantom pain is a painful sensory experience in which pain localizes to the amputated limb. The phantom limb may be felt to assume unusual positions and may feel swollen or misshapen. Pain often is severe, burning, tingling, or lancinating. Phantom pain is present in most patients in the immediate postoperative period and usually decreases with time. As the pain resolves, the phantom sensation typically shrinks or telescopes into the stump. The recurrence of phantom pain, in the absence of medication changes, should alert the clinician to the possibility of cancer recurrence or stump infection. The frequency of prolonged phantom pain varies widely in the literature. Interestingly, severe phantom pain is more likely to occur if the limb is painful before the amputation. Preoperative epidural lumbar local anesthetic infusion significantly reduces the incidence of phantom pain. Once established, phantom pain may be refractory to even the most aggressive therapies; thus, every effort

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should be made to reduce the incidence by providing optimal preoperative analgesia to patients undergoing amputation. Post-Radical Neck Dissection Pain. Post-radical neck dissection pain follows procedures to remove head and neck tumors and results from sectioning or traction of the cervical plexus and cervical nerves. The cervical plexus is formed by the anterior primary rami of Cl-C4 and is located behind the sternocleidomastoid muscle. Branches of the cervical plexus supply sensation to the skin of the posterior and lateral head and the entire neck to the shoulders. This plexus also supplies part of the external ear. Motor fibers supply the ansa hypoglossi, the spinal accessory nerve, and the nerve innervating the levator scapulae muscle. Pain resulting from cervical plexus injury is described as burning or constricting, with or without a lancinating component, and is generally localized to the sensory distribution outlined earlier. Pain may radiate to the helix of the ear or the external auditory canal. Myofascial discomfort may result from removal of the sternocleidomastoid and strap muscles with an overuse syndrome of the contralateral neck musculature. Shoulder drooping after surgery may produce a traction injury of the suprascapular nerve with aching discomfort over the scapula and weakness of external rotation at the shoulder. Recurrent or escalating pain in a patient after radical neck dissection with or without episodes of syncope (secondary to carotid sinus involvement or glossopharyngeal neuropathy) suggests recurrent tumor or soft tissue infection. The latter may be surprisingly indolent, unassociated with fever, and may respond dramatically to empiric antibiotic therapy directed against oral anaerobes. The diagnosis of soft tissue infection may be difficult in tissues already erythematous and indurated by radiation and surgery. Imaging studies (CT and MRI) assist in making the diagnosis, although they may not differentiate recurrent tumor from infection. Surgical exploration may be appropriate in some instances. PostradiationPain Syndromes

Acutely, radiotherapy may cause a self-limited pain syndrome related to cutaneous or mucosal injury. Oropharynx and esophageal mucositis is seen after radiation of head and neck tumors or cervical spine radiation. Radiation proctitis is a usual cause of rectal pain during or immediately after radiation for pelvic tumors. Viscous lidocaine oral swishes for oral mucositis and a low-fiber diet with use of rectal steroid for proctitis may be all that is needed for relief, although opioids may be needed if pain is more severe. An acute skin reaction during the course of radiation is common and usually is managed with moisturizing lotions and mild analgesics. Avoidance of ultraviolet exposure and use of sun block is said to lessen the risk of skin injury in the irradiated area.

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Necrosis of bone within the radiation field may occur as a delayed phenomenon and be an ongoing source of pain. Rarely, radiationinduced tumors may present many years later and manifest as a painful mass within the previous radiation port. Malignant sarcomas of the nerve sheath may be seen years after radiation to a plexus or peripheral nerve and present with neuropathic pain radiating along the course of the involved nerve or plexus. Radiation-induced meningiomas, sarcomas, and gliomas may occur if the brain was included in the field of radiation. Radiation may damage neural structures, including the brain, spinal cord, root, plexus, and peripheral nerve. With few exceptions, radiation injury to the central nervous system is painless, or pain is mild and overshadowed by the neurologic deficits. Radiation injury to the peripheral nervous system is more often painful. The brachial and lumbosacral plexi are especially prone to radiation injury, presumably because of their proximity to common sites of malignant involvement (e.g., lung, lymph nodes, pelvic organs) and their consequent inclusion in radiated fields. The brunt of radiation-induced injury falls on the cells with the highest rate of turnover: Schwann cells and vascular endothelial cells. The pathologic findings are characterized by demyelinization, hyalinized microvasculature, fibrosis, and sometimes frank necrosis of neural tissue. Radiation Plexopathy. Radiation plexopathy presents from 6 months to 20 years after radiation. Unlike malignant invasion of the plexus, radiation plexopathy is not commonly a painful condition. However, it may produce dysesthesias, sensory loss, and profound weakness, as in malignant plexopathy. The distribution of neurologic deficits may be helpful in clinically differentiating radiation from malignant plexopathy (Table 179-2). Radiationinduced brachial plexopathy most commonly involves the upper trunk or lateral cord (C5-C6 segmental distribution), whereas malignant plexopathy usually involves the medial cord or lower trunk (C8-T1 distribution). The lower trunk and medial cord are protected from the effects of radiation by the overlying clavicle but are more likely to be involved by tumors of the lung apex and malignant involvement of supraclavicular lymph node chain. Lymphedema of the upper extremity is more common in radiation plexopathy secondary to radiation fibrosis and obstruction of lymphatic channels. Electromyography shows myokymic discharges in C5-C6 innervated muscles in radiation plexopathy, although their presence does not exclude recurrent malignancy if the plexus has been previously radiated. Horner's syndrome is common in malignant plexopathy but rare in radiation-induced injury. CT or MRI is helpful in identifymg recurrent tumor, which usually manifests as a circumscribed mass (Fig. 179-4). Imaging in radiation plexopathy is normal or demonstrates nonspecific thickening of tissues with loss of distinct tissue planes. In selected

TMLE 179-2. Differences Between Radiation and Malignant Brachial Plexopathy Malignant

Pain Location of pain Area of involvement Horner's syndrome Lymphedema Eledromyography Computed tomography or magnetic resonance imaging Clinical course

Radiation-Induced

>go%

18%

Shoulder, axilla, medial arm, ulnar two fingers Lower trunk or medial cord Often present Usually absent Decreased sensory and motor action potentials Denervation on needle examination No myokymia Circumscribed mass

Shoulder, lateral arm, thumb and forefinger Upper trunk or lateral cord Absent Often present Decreased sensory and motor action potentials Denenration on needle examination Myokymia present Normal or indistinct tissue planes

Proaressive pain and weakness

Weakness may promess; pain may improve

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cases, surgical exploration may be needed to differentiate the two syndromes. Both radiation-induced and malignant plexopathy may coexist in the same patient, making accurate diagnosis and appropriate management difficult. Table 179-2 summarizes the differences between radiation and malignant brachial plexopathy. An acute reversible plexopathy may be seen during or immediately after a course of radiotherapy encompassing the brachial plexus. This is characterized by aching shoulder pain and paresthesias in the hand and forearm. Transient weakness may be present in C6-C7 innervated muscles. CT and MRI results are normal. Nerve conduction studies may show slowed conduction across the plexus. Needle examination may show reduced recruitment in C6-C7 innervated muscles but usually no motor unit changes. Presumably, this lesion results from acute radiationinduced demyelination. Symptoms typically resolve over weeks to months. This syndrome does not appear to predict the development of delayed radiation injury to the plexus. Severe pain is similarly uncommon in radiation lumbosacral plexopathy, which usually presents with paresthesias, sensory loss, and leg weakness with diminished deep tendon reflexes occurring 1 to 30 years after radiation treatment. Symptoms usually begin in L5-S1 segments and may be bilateral. Patients receiving intrapelvic (intracavitary) or intra-operative radiation (for cervical, uterine, or prostatic malignancies) in addition to external beam therapy may be especially at risk, secondary to the higher dosage of radiation administered and closer proximity to the plexus. Radionecrosis of the pelvic bone may accompany this syndrome. Imaging procedures and electromyography show findings similar to those described in radiation brachial plexopathy. Radiation Myelopathy. Radiation myelopathy typically presents as a Brown-SCquard syndrome with ipsilateral limb weakness and loss to vibration and joint position sense with crossed anesthesia to pinprick and temperature. Pain occurs in less than 30% of patients but may include focal spine pain, burning dysesthesias, lancinating pain, and allodynia below the level of the lesion. Pain in a radicular pattern may also be noted. This entity must be differentiated from epidural, meningeal, or intramedullary spinal cord tumors with MRI of the spine or myelography. PostchemotherapyPain Syndromes A variety of chemotherapy agents produce a painful peripheral

neuropathy, often associated with distal sensory loss and weakness or autonomic dysfunction. Vincristine and other vinca alkaloids commonly produce a sensorimotor peripheral neuropathy that is usually asymptomatic but may produce burning or tingling dysesthesias of the distal extremities associated with allodynia. On occasion, vincristine may produce an acute painful mononeuropathy; acute, severe jaw pain is a common example. Other isolated cranial nerve palsies have been reported. Vinca alkaloids may also cause an acute ileus secondary to autonomic neuropathy. Cisplatin, etoposide, procarbazine, misonidazole (a radiosensitizer), suramin, thalidomide, and paclitaxel are other agents that may produce painful neuropathies. The symptoms resolve partially or completely with discontinuation of the responsible agent in most cases. Occasionally, neuropathic pain may persist, and on rare occasions the symptoms of peripheral neuropathy begin or progress after the chemotherapeutic agent has been stopped. Symptomatic relief of neuropathic pain from these toxic neuropathies may be obtained with adjuvant analgesics (including tricyclic antidepressants and anticonvulsants), opioids, or the use of transcutaneous electrical nerve stimulation.

Corticosteroids are commonly prescribed to patients with cancer as components of chemotherapy regimens, as adjuvant analgesics, as antiemetics, and in treating cerebral or spinal cord edema. Corticosteroids may have a number of psychological and neurologic effects, including psychosis, mania, depression, and hiccups. Several pain syndromes have been attributed to these medications as well. A burning sensation in the perineum is described by more than 50% of patients given large intravenous bolus doses (100 mg) of dexamethasone administered to treat epidural spinal cord compression. The cause is unknown. The burning sensation lasts only minutes, and treatment is neither available nor needed. It is helpful to warn patients of this possible effect before administering high-dose intravenous dexamethasone. Steroid pseudorheumatism is characterized by diffuse myalgias and arthralgias during steroid withdrawal. There are no electromyographic abnormalities and no associated elevation of serum muscle enzymes. This adverse effect does not appear to depend on the dosage, length of therapy, or speed of withdrawal. Steroid pseudorheumatism is especially common in young, muscular patients. Although the exact pathogenesis is unknown, it has been postulated to be secondary to sensitization of joint and muscle nociceptors. Treatment consists of reinstituting steroids at a higher dosage with slower withdrawal. Aseptic necrosis of the femoral or humeral head may follow the intermittent or chronic daily use of glucocorticoids. Pain is localized to the joint or its referral zone (i.e., hip refers to the knee, shoulder refers to the elbow) and is exacerbated by weight-bearing and movement of the involved joint. Symptoms usually precede radiographic changes by several weeks. A bone scan is useful in early diagnosis, as is MRI of the involved joint. If diagnosed early, treatment is conservative, with appropriate opioid and nonopioid analgesics and discontinuation of the corticosteroids. Surgical intervention may be needed in patients with joint destruction or poorly controlled pain. Phenobarbital, often used as an anticonvulsant in patients with primary or metastatic tumors to the central nervous system, may cause a pain syndrome characterized by shoulder discomfort and immobility. If diagnosed early, phenobarbital pseudorheumatism resolves with discontinuance of the drug. The pathogenesis is unknown, but signs and symptoms are typical of an adhesive capsulitis. If severe, a superimposed complex regional pain syndrome (reflex sympathetic dystrophy) may develop, leading to a painful, useless limb. Many oncology patients seen by the neurologist are chronically maintained on both steroids and phenobarbital. The differential diagnosis of shoulder and arm pain in these patients should include bone metastases, cervical epidural tumor, brachial plexopathy, aseptic necrosis of the humeral head, and phenobarbital pseudorheumatism. Herpes Zoster Virus Infection Reactivation of latent herpes zoster virus is common in immunocompromised patients, including those receiving intensive chemotherapy with resulting impairment of humoral and cell-mediated immunity. Reactivation in thoracic and lumbosacral dermatomes is more common than cranial involvement. More than 50% of reactivations occur in thoracic dermatomes. Itching, burning, and erythema in the affected dermatomes usually precede the blistering rash. Usually only a few contiguous roots are involved. Involvement is random, although nerve root irritation, as by epidural tumor, may make herpes zoster virus reactivation more likely at that site. Occasionally, weakness in muscles supplied by

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the involved nerve root may occur. Viral dissemination to lung, liver, and brain is a life-threatening complication more likely to occur in the immunocompromised patient. Pain related to herpes zoster virus infection can be acute (within 2 months of the skin eruption) or chronic (greater than 2 months). The acute pain results from inflammation in neural and somatic structures. Chronic pain (postherpetic neuralgia) occurs after the acute inflammation has resolved and is caused by deafferentation resulting from destruction of fibers within the root and dorsal root ganglion. A severe burning, itching, lancinating pain with allodynia and hyperpathia characterizes postherpetic neuralgia. The incidence of postherpetic neuralgia is greatest in older adults, and it may be especially refractory to treatment in this age group. If the zosteriform eruption is present, the antiviral agent famciclovir or acyclovir should be administered. These drugs speed healing, relieve acute pain, and lessen the risk of dissemination. Corticosteroids may also reduce acute pain but should not be used in immunocompromised patients because their use may increase the likelihood of viral dissemination. Neither antiviral agents nor corticosteroids have been shown to reduce the incidence of postherpetic neuralgia in controlled trials. Opioids and nonsteroidal anti-inflammatory drugs should be used without hesitation in acute herpes zoster virus infection when pain is moderate to severe. Local anesthetic blockade of sympathetic fibers supplying the affected dermatomes may provide analgesia in both acute herpes zoster virus pain and postherpetic neuralgia. Other medications with reported analgesic activity in acute herpes zoster virus include levodopa and amantadine, by unknown mechanisms. Tricyclic antidepressants are the first-line therapy for postherpetic neuralgia. They are not effective against the pain associated with acute herpes zoster virus. Amitriptyline, nortriptyline, doxepin, or imipramine is most commonly used for continuous dysesthetic pain. Anticonvulsants (including phenytoin, carbamazepine, valproic acid, and gabapentin) are useful for paroxysmal lancinating pain. A trial of opioids may be indicated in selected, reliable patients when other medications have proved inadequate. These medications may be administered chronically with no significant toxicity and with minimal risk of psychological dependence if closely supervised by a physician. Sympathetic blockade may provide partial analgesia in postherpetic neuralgia, although its precise role in treatment has not been established in controlled trials. Transcutaneous electrical nerve stimulation is occasionally helpful and should be tried in most patients. Topical application of capsaicin, which depletes pain fiber endings of substance P, may occasionally be useful, as may topical lidocaine. Neurosurgical modalities for treating selected patients include spinal cord stimulation, dorsal root entry zone lesioning, and deep brain stimulation. These procedures should be reserved for patients refractory to all other interventions who are experiencing severe, disabling pain.

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CONCLUSION The differential diagnosis of pain in the cancer patient is extremely varied. Just as early, accurate diagnosis is essential to managing any neurologic problem, so it is in pain syndromes in patients with cancer. There is a high frequency of occult neurologic disease in these patients. Pain may be the first symptom of a progressive, disabling neurologic disorder in which early recognition allows prompt and sometimes life- and function-preservingtreatment. In addition to indicating appropriate primary therapy of the underlying malignancy, knowledge of cancer pain mechanisms guides the clinician in selecting the best analgesic, neurosurgical or neuroanesthetic procedure. Moreover, awareness of the presence of pain syndromes resulting from antineoplastic therapy may avoid the mistaken diagnosis of recurrent malignancy and subsequent inappropriate therapy.

SUGGESTED READINGS Bruera E, McDonald N Intractable pain in patients with advanced head and neck tumors: a possible role of local infection. Cancer Treat Rev 70:691492, 1986 Cherny NI: The management of cancer pain. CA Cancer J Clin 50(2):70-116, 2000 Clouston PD, DeAngelis L, Posner J B The spectrum of neurological disease in patients with systemic cancer. Ann Neurol 31:26&273, 1992 Clouston PD, Sharpe DM, Corbett AJ et al: Perineural spread of cutaneous head and neck cancer. Arch Neurol4273-77, 1990 Elliot K, Foley KM: Neurologic pain syndromes in patients with cancer. Neurol Clin 7:333-360, 1989 Foley KM:Pain syndromesin patients with cancer. pp. 59-75. In Bonica JJ, Ventafridda V (eds): Advances in Pain Research and Therapy. Vol. 2. Raven Press, New York, 1979 Forsyth PA, Posner JB: Headache in patients with brain tumors: a study of 1 1 1 patients. Neurology 43:1678-1683, 1993 Gonzales GR, Elliot KJ, Portenoy RK, Foley KM: The impact of a comprehensive evaluation in the management of cancer pain. Pain 47:141-144, 1991 Granek I, Ashikari R, Foley KM: Postmastectomypain syndrome: clinical and anatomic correlates. Proc Am SOCClin Oncol 3:122, 1983 Kanner R, Martini N, Foley KM: Nature and incidence of postthoracotomy pain. Proc Am SOCClin Oncol 1:152, 1982 Kori SH, Foley KM, Posner JB: Brachial plexus lesions in patients with cancer: 100 cases. Neurology 31:45-50, 1981 Kost RG, Strauss S E Postherpetic neuralgia-pathogenesis,treatment, and prevention. N Engl J Med 335(1):3242, 1996 Portenoy RK: Cancer pain: epidemiologyand syndromes. Cancer 63:22982307, 1989 Portenoy RK, Lipton RB, Foley KM: Back pain in the cancer patient: an algorithm for evaluation and management. Neurol 37:134-138, 1987 Solomon L Drug-induced arthropathy and necrosis of the femoral head. J Bone Joint Surg 55:246-261, 1973

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180 Neurologic Complications of Bone Marrow

Transplantation Patrick Y. Wen and Kathryn 1. Swoboda

Bone marrow transplantation (BMT, also called hematopoietic stem cell transplantation) is now well established as a major treatment modality for a variety of disorders, including hematologic malignancies, myelodysplastic syndromes, lymphomas, multiple myeloma, aplastic anemia, Fanconi’s anemia, thalassemia major, sickle cell anemia, chronic granulomatous disease, and several immunodeficiency syndromes including severe combined immunodeficiency syndrome, Chkdiak-Higashi disease, and Wiskott-Aldrich syndrome. More recently, it has shown promise in treating certain metabolic disorders including Gaucher’s disease, amyloidosis, and metachromatic leukodystrophy. It is also being evaluated for solid malignancies and autoimmune disorders. In patients with malignancies, BMT allows the administration of what would otherwise be lethal dosages of chemotherapy. In others, it allows replacement of pathologic marrow or helps correct an existing enzymatic deficiency. In many cases, it offers patients the only chance for cure of their disease. It is estimated that 30,000 to 40,000 BMTs are performed each year worldwide, and the number is increasing by 10% to 20% each year. There are three main types of BMT allogeneic BMT, allogeneic peripheral stem cell transplant, and autologous BMT. In allogeneic BMT, the replacement marrow is obtained from human leukocyte antigen (HLA)-compatible donors. The marrow is then reinfused into the recipient after a myeloablative preparatory (conditioning) regimen that usually includes combinations of chemotherapy and radiation therapy. The infused donor bone marrow rescues the patient from the conditioning-induced bone marrow aplasia. The conditioning regimen varies depending on the underlying disease process and treatment center. Common conditioning regimens include total body irradiation and highdose cyclophosphamide and combinations of high-dose cyclophosphamide and busulfan. Other commonly used agents include etoposide, carmustine, ifosfamide, carboplatin, cytosine arabinoside, and daunorubicin. Recipients are then placed on a variety of immunosuppressive regimens to minimize the chances of rejection or graft versus host disease (GVHD). Strict isolation procedures are necessary in the first 2 to 4 weeks after transplantation until engraftment takes place and marrow function is reestablished. In allogeneic peripheral blood stem cell transplant (PBSCT), donor stem cells are mobilized with chemotherapy and granulocyte colony-stimulating factor, removed by leukapheresis, and infused into the recipient after the appropriate conditioning regimen. PBSCT donors are spared the pain and potential risks of general anesthesia associated with marrow harvesting. Because PBSC grafts contain higher numbers of hematopoietic progenitor cells, T cells, and natural killer cells than bone marrow, engraftment usually is faster. In autologous BMT, the patient’s own marrow or stem cells are harvested, often treated to remove abnormal cells, and then reinfused into the patient after they have been treated with the conditioning regimen. An advantage of autologous BMT is that

complications from GVHD are avoided, and it can be used in a wider population of patients. Despite increasing efficacy of therapeutic regimens and improvements in preventing and treating infectious complications, the morbidity and mortality associated with BMT remain high. Most series have reported neurologic complications in more than half of all transplant recipients, and severe neurologic compromise resulting in death occurs in approximately 5% to 8%. However, recent data suggest that such complications are decreasing, in part because of the increasing percentage of autologous transplants and allogeneic transplants using nonmyeloablative and potentially less toxic conditioning regimens. Potential sources of neurologic injury include cumulative exposure to toxic chemotherapy and radiation treatments, disorders of immunoregulation and immunodeficiency, and central nervous system (CNS) dysfunction secondary to failure of other organ systems. (Table 180-1). The most common neurologic complications are encephalopathy, CNS infections, and cerebrovascular disorders. In general the presence of neurologic complications adversely affects patient survival, reflecting not only the seriousness of most neurologic complications but also the fact that sicker patients with multiple-organ failure and failure of the bone marrow to engraft are more likely to develop neurologic problems.

INFECTION Infection after BMT is common and accounts for 8% to 14% of complications. For the first month after transplantation, the recipient is severely immunocompromised and is susceptible to local and disseminated bacterial, viral, and fungal infections. Before engraftment, strict isolation procedures and prophylactic antibiotic regimens are crucial in ensuring good outcome. The use of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factors, which increase the leukocyte count, have helped to lessen the risk of overwhelming sepsis. Aggressive treatment of fever in an empiric fashion with a stepwise succession of broad-spectrum antibacterial, antiviral, and antifungal agents has also dramatically improved survival and outcome in the immediate post-transplant period. Unfortunately, cellular immunity remains persistently and perhaps indefinitely impaired, necessitating continued vigilance for late parasitic, viral, and fungal infections. For the majority of patients, however, this risk seems to significantly decrease after the first year. CNS complications often occur as a result of overwhelming systemic infections in the first few weeks after transplantation. Disseminated infection can lead to disseminated intravascular coagulation (DIC) or metabolic encephalopathy caused by multisystem organ failure. Endocarditis from a variety of organisms may result in embolic events or mycotic aneurysms, with accompanying ischemic or hemorrhagic complications. Direct CNS involvement caused by meningitis, encephalitis, or abscesses may also occur.

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TABLE180-1. Potential Sources of Neurologic Injury After BMT Infection Primary Meningitis Encephalitis Cerebral abscesses Secondary Sepsis Endocarditis Treatment-related toxicities Primary Headache Seizures Ataxia Neuropathy Myelopathy Leukoencephalopathy Postirradiation somnolence syndrome Sensorineural hearing loss Secondary Metabolic encephalopathy Thrombocytopenia and hemorrhage Nutritional deficiencies Neuropsychiatric and cognitive difficulties Neuroendocrine disorders Thrombotic complications Primary Large or small vessel cerebral arterial thrombosis Cerebral venous sinus thrombosis CNS angiitis Secondary Nonbacterial thrombotic endocarditis DIC Acquired protein C deficiency Hepatic veno-occlusive disease Immune-mediated disorders Acute GVHD Headache Metabolic encephalopathy Chronic GVHD Polymyositis Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) Chronic inflammatory demyelinating polyneuropathy Mononeuritis multiplex Myasthenia gravis Direct CNS involvement (very rare) Abbrewiotions: CNS, central nervous system; DlC, disseminated intravaxular coagulation; CVHD, graft versus host disease.

The incidence of bacterial infections is greatest in the first months after transplantation, in keeping with the expected severe granulocytopenia. A wide variety of organisms have been implicated. Some of the more common include staphylococcus, streptococcus, listeria corynebacterium, bacteroides, clostridium, listeria, klebsiella, enterobacteria, pseudomonas, haemophilus, and rarely nocardia. Meningitis has occurred with and without accompanying systemic infection and may result from contiguous spread from a parameningeal focus such as a sinusitis or otitis. Organisms often are difficult to isolate, and broad-spectrum coverage to include listeria and gram-negative organisms is necessary. In patients who are neutropenic, meningitis or meningoencephalitis may be present in the absence of a significant cerebrospinal fluid (CSF) pleocytosis, and a low threshold for empiric CNS coverage in patients with headache or subtle meningitic features is appropriate. Intracranial bacterial abscesses are surprisingly rare, although they are most likely to be found in the presence of disseminated disease. Viral infections occur less commonly, and usually in the setting of disseminated systemic infection. However, focal reactivation of

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dermatomal herpes zoster is common, and in one series 29% of patients subsequently developed more generalized dissemination. Rarely, postherpetic vasculopathy presenting as stroke has been described, usually after either ophthalmic zoster or disseminated disease. The most common causes of viral encephalitis are herpes simplex type 1 and cytomegalovirus. Occasionally cases may be caused by varicella-zostervirus, adenovirus, Epstein-Barr virus, or the human herpesvirus-6. Symptoms often are atypical, characterized by subacute nonfocal encephalopathy or progressive obtundation in the absence of seizures. CSF studies may be unremarkable or show only a mild pleocytosis or elevated protein. In the case of herpes encephalitis, the typical necrotizing lesions on imaging studies and characteristic frontotemporal electroencephalographic abnormalities may be absent. Polymerase chain reaction studies of CSF may improve the diagnostic yield in such patients, although empiric coverage with acyclovir often is warranted. Spread of viral agents occurs hematogenously from transfused blood products or systemic infection, reactivation of latent virus, or nasopharyngeal or fecal-oral transmission. Cytomegalovirus-negative and irradiated blood products are routinely used in BMT centers in hopes of avoiding the serious morbidity and mortality that can result from such infections. A few cases of progressive multifocal leukoencephalopathycaused by the JC virus has also been described in patients after BMT. Fungal infections reach the CNS via either hematogenous spread or direct extension from cranial sinuses. The most common organism involved is Aspergillus furnigatus, which accounts for 50% to 60% of all CNS infections in some series. CNS aspergillomas and sinonasal disease uniformly necessitate surgical therapy for eradication. However, despite recent advances in combination therapy, invasive Aspergillus often is lethal. Mucormycosis has a similarly poor prognosis, although selected patients with aggressive surgical debridement of sinonasal infection have had a good outcome. These organisms have a propensity for vascular invasion and tissue necrosis, often resulting in intraluminal thrombosis with resultant vascular occlusion, hemorrhage, or embolic phenomena and the formation of necrotizing abscesses. Nasal pain, epistaxis, and sinus congestion are common presenting complaints, with sinus radiographs or computed tomography scans often showing nonspecific sinusitis. Prophylaxis with fluconazole has been disappointing, and infections are rarely eradicated with systemic antifungal therapy alone. Candidal meningitis, meningoencephalitis, and multiple brain abscesses have been reported, as have rare cases of disseminated Torulopsis glabrata, coccidioidomycosis, Cryptococcus neoformans, and Histoplasma capsulaturn. These infections have a better prognosis and are more likely to respond to systemic antifungal therapy. In the future, earlier detection and new combinations of therapy and prophylactic regimens should lead to continued improvements in overall outcome in this group of patients. Parasitic agents have been surprisingly uncommon, considering their frequency in other immunocompromised populations. Pulmonary infections with Pneurnocystis carinii pneumonia are the most common in the category. Cerebral toxoplasmosis may present with focal abscesses or as a diffuse encephalopathy or meningoencephalitis. Stereotactic biopsy of lesions may be diagnostic, although in the case of characteristic imaging studies a trial of empiric therapy often is warranted. Subclinical infections are common in the general population and in most cases are felt to be reactivation of a preexisting infection. CSF and serologic antibody titers are variable and not always helpful, although toxoplasma

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infection is unlikely if the serology is negative. CSF and blood polymerase chain reaction are more helpful in making the diagnosis. TREATMENT-RELATED TOXICITIES Toxicity resulting from the preparatory regimen is to be expected. Acute or chronic effects may occur and often are a result of the cumulative insults of chemotherapy, radiation, and the underlying disease process. Acute effects may include encephalopathy, thrombocytopenia, peripheral neuropathy, sensorineural hearing loss, ataxia, seizures, and nutritional disorders. Later on, leukoencephalopathy, neuroendocrine disorders, neuropsychiatric and cognitive difficulties, and ocular complications may occur. Toxic or metabolic encephalopathy is common and accounts for up to 37% of neurologic complications in some series. This may result from transient effects on renal, cardiac, pulmonary, or hepatic function or from direct CNS toxicity of the treatment regimen itself. Manifestations include confusion, personality changes, hallucinations, tremor, headache, somnolence, or seizures. High-dose cytosine arabinoside has been associated particularly with cerebellar dysfunction and seems to have a selective toxic effect on Purkinje cells. Ifosfamide, which is used with increasing frequency in autologous transplants, particularly in patients with solid malignancies, may cause confusion and hallucinations or, more rarely, seizures and an akinetic mute state. High-dose busulfan may also cause seizures. Cyclosporine and tacrolimus, commonly used as immunosuppressive agents after transplantation to prevent GVHD, has been associated with a wide variety of neurologic toxicities, including headache, tremor, restless legs syndrome, neuropathy, myelopathy, seizures, encephalopathy, focal neurologic deficits, and visual hallucinations. An increasing rate of cortical blindness has been reported in BMT recipients on cyclosporine or tacrolimus. Magnetic resonance imaging characteristically demonstrates increased T2 signal abnormalities in the posterior white matter (posterior leukoencephalopathy), which are entirely reversible with reduction or discontinuation of the drugs. The mechanisms of toxicity leading to this particular clinical presentation are poorly understood. Contributing factors that have been implicated to date include hypomagnesemia, concurrent treatment with highdose steroids, hypertension, hypocholesterolemia, and microangiopathic hemolytic anemia. Leukoencephalopathy is an uncommon complication, occurring in less than 2% of patients undergoing BMT. Unfortunately, it often leads to severe progressive neurologic impairment and death. It seems to occur almost exclusively in those who receive both cranial irradiation and intrathecal chemotherapy. Particularly at risk are those who receive both pre- and posttransplantation intrathecal therapy with cytosine arabinoside or methotrexate. Rare cases have also followed treatment with amphotericin B. Clinical effects include the progressive onset of memory loss, lethargy, slurred speech, ataxia, confusion, dysphagia, and ultimately quadriparesis with decerebrate posturing. Neuroimaging studies and pathology reveal diffuse confluent white matter degeneration and necrosis. In one review of 415 patients after BMT, 7 patients developed leukoencephalopathy. Patients treated with more than 4 doses of intrathecal therapy after transplantation did not have lower rate of CNS relapse, and the risk of leukoencephalopathy increased the number of doses of therapy administered. Methotrexate administered during or after radiation treatment are especially likely to result in serious

neurologic sequelae. The time to onset of symptoms is extremely variable and may occur 1 to 14 months after transplantation, although symptoms usually are apparent in the first 6 months. Postirradiation somnolence syndrome is a reversible phenomenon characterized by transient lethargy, headache, low-grade fever, gastrointestinal disturbances, and depression. It has been commonly observed in children treated for leukemia with prophylactic radiation. However, occasional adults have also been reported. It typically occurs several weeks after transplantation and seems to respond to treatment with steroids and antidepressant therapy. More subtle long-term neuropsychologic and cognitive deficits have not been well studied in adults. They are better documented than those in children, where poor school performance may bring them more quickly to attention. One study of adults receiving BMT found a surprisingly large percentage of patients with significant impairments in a variety of areas. Memory seemed most significantly impaired, and more than 33% of patients scored in the impaired range in this domain. Measures of complex cognitive processing were also notably affected. Again, a history of cranial irradiation and intrathecal chemotherapy were predictors of poor test performance. This study illustrates the need for further research in this area and suggests that cognitive impairment may be an important sequela of BMT. Antibacterial and antiviral agents (e.g., acyclovir) may rarely result in encephalopathy or seizures. Because these agents often are given to critically ill patients, toxicity from these drugs may be difficult to distinguish from the underlying infection or metabolic encephalopathy. Complications involving the spinal cord are rare but may manifest in several ways. Rapidly ascending paralysis and more subtle chronologically progressive forms of myelopathy have been described. Myelopathies have been associated with cyclosporin, methotrexate, and cytosine arabinoside. In other cases, the cause is obscure. Pathologic findings have ranged from spongiotic degeneration preferentially involving the posterior columns to diffuse cord necrosis. Whether these cases represent a synergistic toxic effect of combined chemotherapy, radiation, and borderline nutritional status or a result of other, poorly understood mechanisms is unclear. Rarely, patients may manifest Lhermitte sign, which has been classically associated with demyelinating disease. However, in this population it seems to remit spontaneously and has a benign prognosis. Mild peripheral neuropathies caused by chemotherapy are common, but clinically disabling effects are rare. Patients with leukemia and prior chemotherapy seem more likely to be significantly affected. At least one case of an acute demyelinating polyneuropathy leading to reversible ventilatory failure has been described in a patient with chronic myelogenous leukemia who received high-dose cytosine arabinoside. The clinical course was consistent with Guillain-Barre syndrome. Patients with chronic inflammatory demyelinating neuropathy may develop severe exacerbations during the conditioning regimen for transplant or immediately thereafter. Acute sensorineural hearing loss rarely occurs, but milder deficits probably are common. The use of aminoglycosides to treat post-BMT infection increases the risk of significant injury. Mucositis and gastrointestinal disturbances are common in the first 2 to 3 weeks after transplantation and may lead to a compromised nutritional status. Rarely, Wernicke’s encephalopathy may occur. Although severe examples are rare, milder forms of nutritional deficiencies may be difficult to diagnose, and they

Chapter 180 W

warrant consideration in the absence of other obvious factors. Total parented nutrition often is used during periods of nutritional compromise to offset potential complications. Thrombocytopeniais an expected complication before engraftment of the new marrow in all BMT recipients. Subarachnoid, subdural, and parenchymal hemorrhages sometimes occur and may lead to persistent neurologic compromise or death. Aggressive monitoring and platelet replacement are mandatory, although hemorrhage is not necessarily associated with the degree of thrombocytopenia. Late neuroendocrine abnormalities are also common after transplantation. The combination of total body irradiation and chemotherapy may induce a postmenopausal status in women and azoospermia in men. Thyroid dysfunction develops in up to 40% of patients. In children, growth retardation may occur and sometimes responds to growth hormone replacement. These abnormalities are not clearly predictable, and periodic follow-up is indicated. Ocular complications have become increasingly common as suMval times post-BMT continue to lengthen. Keratoconjunctivitis sicca seems to develop to some degree in the majority of patients after total body irradiation, although it is seen with increased frequency in GVHD. Without proper recognition and treatment, serious complications including blindness may result. Cataracts are common after transplantation, and the risk may exceed 80% after 4 years.

THROMBOTIC COMPLICATIONS Cerebrovascular events are common after BMT. They occur in up to 3% of patients and account for 6% to 28% of neurologic complications. These cerebrovascular complications often are associated with fungal infections. A significant percentage of BMT recipients develop a hypercoagulable state and as a group are prone to a variety of thrombotic complications. The most common clinical manifestations include hepatic veno-occlusive disease, DIC, nonbacterial thrombotic endocarditis (NBTE), and thrombotic or embolic stroke. Superior vena cava and other large vessel thromboses, purpura fulminans, and small bowel infarction caused by microvascular thrombosis have also been observed. The pathogenesis of this hypercoagulability state is not well understood. In the case of NBTE, it has been hypothesized that the preparatory chemotherapy and radiation regimes may damage cardiac endothelium and lead to degenerative changes in the connective tissue of the cardiac valves, thus creating a nidus for thrombosis. A similar mechanism has been proposed for venoocclusive disease, with degeneration of venular endothelium as the originating event. In both of these examples, a significant portion of cases demonstrate concomitant low-grade DIC. The direct infusion of marrow into the bloodstream may play a role in some cases because it contains a large bolus of cells, platelets, and fibrin debris. Alternatively, the subsequent development of an immunemediated process such as GVHD may predispose to ongoing cellular injury and release of thromboplastin into the circulation. Rarely, acquired protein C deficiency has also been implicated. There has also been a report of patients developing cerebral angiitis following BMT. Regardless of the pathogenesis, strokes caused by either embolic or thrombotic events remain an important cause of neurologic morbidity and mortality. Antemortem diagnosis of NBTE is rarely made because cardiac murmurs are unusual and endocardiography often misses small vegetations. Therefore,

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detection of low-grade DIC via the careful monitoring of platelet counts, prothrombin time, fibrinogen levels, and fibrin degradation products may help to prospectively identify patients at risk and aid in prevention.

HEMORRHAGIC COMPLICATIONS Patients with thrombocytopenia, mycotic aneurysms, or relapsed leukemia are at risk of developing subarachnoid hemorrhages. Patients with thrombocytopenia and leukemic infiltrates may also develop subdural hematomas and intraparenchymalhemorrhages. Intraparenchymal hemorrhages may also be caused by infections such as aspergillosis, cerebral venous sinus thrombosis, cyclosporin toxicity, and hemorrhagic transformation of embolic cerebral infarctions.

IMMUNE-MEDIATED DISORDERS Immune-mediated disease in recipients of allogenic BMT is quite common and is one of the primary causes of diminished quality of life and morbidity among long-term survivors. Between 25% and 60% of patients develop some form of GVHD, a disorder believed to result primarily from the reaction of immunocompetent donor lymphocytes to non-HLA-matched host antigens. Humoral mechanisms probably also play a role, as evidenced by the nearly universal deposition of immunoglobulin and complement along the dermal-epidermal junction in chronic GVHD. Given the frequency of systemic involvement, neurologic complications have been surprisingly rare. More often, neurologic dysfunction results from widespread involvement with multisystem organ failure. However, GVHD-associated polymyositis, myasthenia gravis, and, rarely, central and peripheral nervous system involvement may occur. Acute GVHD typically is manifested by rash, hepatic impairment, diarrhea, and abdominal pain. Primary CNS involvement in this syndrome is extremely rare. However, patients who are sick from GVHD have an increased predisposition to infection, stroke, and metabolic encephalopathy. Chronic GVHD is more common in older patients and in those who have had acute GVHD. In both disorders, diffuse lymphocytic infiltration is found in numerous tissues throughout the body. Chronic GVHD shares features with other autoimmune disorders including systemic lupus erythematosus, Sjogren’s syndrome, progressive systemic sclerosis, and lichen planus. In addition to skin changes, it is characterized by multiorgan involvement, including hepatic dysfunction, oral and esophageal mucositis and stricture, sicca syndrome, pulmonary insufficiency, limb contractures, and generalized wasting. A small number of patients have developed polymyositis as the sole or major presenting feature of their disease. Clinically, the syndrome is indistinguishable from idiopathic polymyositis. Muscle biopsies reveal a characteristic monocytic infiltration, with fiber necrosis and active phagocytosis. In some of these cases, the inflammatory infiltrates have been documented to be of donor origin. Infectious causes have not been apparent in these patients, but this bears careful consideration because rare cases of polymyositis have been linked to elevations in toxoplasma immunoglobulin M titers or with various viral agents including coxsackie, influenza, and hepatitis B. Patients with GVHD-associated polymyositis respond to treatment with prednisone or other immunosuppressive therapies. An increasing number of cases of myasthenia gravis in BMT recipients have been described and also seem to occur in

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association with chronic GVHD. These patients meet all criteria for the classic autoimmune-mediated disorder, including proximal and bulbar fatigable muscle weakness, response to cholinesterase inhibitors, decremental response with repetitive nerve stimulation, and the presence of antibodies against the acetylcholine receptor. Discrete thymomas have not been observed, although thymic atrophy has been noted in some cases of GVHD. Some authors have hypothesized that autoantibodies might develop in response to subtle antigenic differences in the acetylcholine receptor between donors and recipient. However, others have noted that the presence of acetylcholine receptor antibodies may significantly precede the onset of clinical disease. In both GVHD polymyositis and myasthenia, the number of patients with the underlying diagnosis of aplastic anemia is greatly increased. Aplastic anemia is well known to have an association with a variety of other autoimmune disorders as well as thymoma. This suggests that the preexisting hematologic disorder somehow predisposes to the later development of these disorders. In one study, acetylcholine receptor antibodies were found in 21 of 51 BMT recipients, especially those with aplastic anemia or acute nonlymphocytic leukemia, but not in other forms of leukemia or with the myelodysplastic Syndromes. The disordered immunoregulation in these patients is complex and warrants further study. Although it its clear that donor cells probably play a role in the genesis of these syndromes, how these cells mediate their influence remains uncertain, and a certain predisposition to their development lies in the host as well. Peripheral nerve involvement has only rarely been associated with GVHD. Several cases of generalized neuropathies have occurred, including acute inflammatory demyelinating polyneuropathies (Guillain-Barrk syndrome) and chronic inflammatory demyelinating polyneuropathies, as well as mononeuropathies and mononeuritis multiplex. Nerve biopsies occasionally show evidence of monocytic perineural infiltrates in the absence of definite clinical symptoms. Although GVHD rarely is implicated in such cases, a high degree of suspicion for an alternative cause of symptoms, particularly infection, should be maintained. Direct CNS involvement secondary to GVHD has been reported in only a few cases. One patient had presumed GVHD related encephalitis with mental status changes, dysphagia, progressive muscle atrophy, and cachexia. The patient was resistant to treatment with methylprednisone, cyclophosphamide, and highdose immunoglobulin and ultimately died of pneumonia more than 3 years after transplantation. Pathologic examination revealed diffuse perivascular lymphocytic infiltrates in meninges and brain parenchyma, similar to those seen in his other organs and in experimental GVHD. Two cases of subacute panencephalitis, with symptoms beginning several months after transplantation in conjunction with GVHD, have been described. An additional case involved an infant with complete heart block and respiratory insufficiency in the absence of pulmonary disease whose brain showed focal lymphohistiocytic infiltrates in the absence of obvious infection.

SECONDARY MALIGNANCY AND DISEASE RECURRENCE Recurrence of the primary disease process or occurrence of secondary malignancy always remains a possibility. In the case of hematologic or lymphoreticular malignancies, the likelihood of CNS recurrence is directly linked to the underlying disease process. For instance, the risk of CNS relapse for acute lymphocytic leukemia is 16% to 20% in most series, whereas the risk of acute

nonlymphocytic leukemia is less than 2%. Secondary malignancies are rare, and the majority do not directly involve the CNS. However, several cases of glioblastoma multiforme have occurred as a second primary neoplasm. Rare cases of Epstein-Barr virus-positive lymphoma involving the CNS have also been reported.

SUMMARY Neurologic complications are common after BMT and occur in more than half of all recipients. Approximately 5% to 6% of patients die as a direct result of these complications. The differential diagnosis often is broad, and careful consideration must be given to a diverse range of factors, including the nature of the primary disease process, the specific preparatory regimen involved, prior exposure to potentially neurotoxic therapies, and current immunocompetence. Becoming familiar with the potential complications and remaining vigilant for neurologic disease that presents in an atypical or subtle manner can greatly facilitate early intervention and lead to improved outcome and quality of life.

SUGGESTED READINGS Amato AA, Bahohn RJ, Sahenk Z Polyneuropathy complicating bone marrow and solid organ transplantation. Neurology 43:1513, 1993 Anfrykowski MA, Schmitt FA, Gregg ME et al: Neuropsychologic impairment in adult bone marrow transplant candidates. Cancer 70:2288, 1992

Antonini G, Ceschin V, Morino S et al: Early neurologic complications following allogeneic bone marrow transplant for leukemia: a prospective study. Neurology 50:1441-1445, 1998 Bleggi-Torres LF, de Medeiros BC, Werner B et ak Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases. Bone Marrow Transplant 25:301-307, 2000 Bolger GB, Sullivan KM, Spence AM et al: Myasthenia gravis after allogenic bone marrow transplantation: relationship to chronic graftversus-host disease. Neurology 361087, 1986 Coplin WM, Cochran MS, Levine SR, Crawford SW Stroke after bone marrow transplantation: frequency, aetiology and outcome. Brain 1241043-1051,2001

Davis DG, Patchell RA: Neurologic complications of bone marrow transplantation. Neurol Clin 6377, 1988 Graus F, Saiz A, Sierra J et al: Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study. Neurology 46:1004-1009, 1996 Hagensee ME, Bauwens JE, Kjos B, Bowden RA: Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center, 1984-1992. Clin Infect Dis 19402-408, 1994 Kramer ED, Packer RJ, Ginsberg J et al: Acute neurologic dysfunction associated with high-dose chemotherapy and autologous bone marrow rescue for primary malignant brain tumors. Pediatr Neurosurg 27~230-237, 1997

Krouwer HGJ, Widjicks EFM: Neurologic complications of hemopoietic stem cell transplantation. In Schiff DS, Wen PY (eds): Cancer Neurology in Clinical Practice. Humana Press, Philadelphia, 2002 Mackey JR, Desai S, Larratt L et al: Myasthenia gravis in association with allogeneic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplant 19939-942, 1997

Maschke M, Dietrich U, Prumbaum M et al: Opportunistic CNS infection after bone marrow transplantation. Bone Marrow Transplant 23: 11671176, 1999 Mohrmann R, Mah V, Vinters HV:Neuropathologic findings after bone marrow transplantation: an autopsy study. Hum Pathol 2 1(6):630, 1990

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Nelson KR, McQuillen MP Neurologic complications of graft-versus-host

diseases. Neurol Clin 6(2):389, 1988 Openshaw H, Hinton DR, Slatkin NE et al: Exacerbation of inflammatory demyelinating polyneuropathy after bone marrow transplantation. Bone Marrow Transplant 7:411, 1991 Openshaw H, Slatkin N E Differential diagnosis of neurological complications in bone marrow transplantation. Neurologist 1:191-206, 1995 Padovan CS, Bise K, Hahn J et al: Angiitis of the central nervous system after allogeneic bone marrow transplantation?Stroke 301651-1656, 1999 Parker P, Chao NJ, Ben-Ezra J et al: Polymyositis is a manifestation of chronic graft-versus-host disease. Medicine 75:279-285, 1996 Patchell RA, White CL, Clark AW et al: Neurologic complications of bone marrow transplantation. Neurology 35:300, 1985 Patchell RA, White CL, Clark AW et al: Nonbacterial thrombotic endocarditis in bone marrow transplant patients. Cancer 55:631, 1985 Snider S, Bashir R, Bierman P Neurologic complications after high dose chemotherapy and autologous bone marrow transplant for Hodgkin’s disease. Neurology 44681, 1994

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Thompson CB, Sanders JE, Flournoy N et al: The risks of central nervous system relapse and leukoencephalopathy in patients receiving marrow transplants for acute leukemia. Blood 62195-199, 1986 Tolkoff-Rubin NE, Hoving GK, Rubin RH: Central nervous system infections. Chapter 10. In Wijdicks EFM (ed): Neurologic Complications in Organ Transplant Recipients. Butterworth-Heinemann, 1999 Trigg ME, Meenzes AH, Giller R et al: Combined anti-fungal therapy and surgical resection as treatment of disseminated aspergillosis of the lung and brain following BMT. Bone Marrow Transplant 11:493, 1993 Walters MC, Sullivan KM, Bernaudin F et al: Neurologic complications after allogeneic marrow transplantation for sickle cell anemia. Blood 86:408-409, 1995

Wen PY, Aleya EP, Simon D et al: Guillain-Barrk syndrome following allogeneic bone marrow transplantation. Neurology 49171 1-1714, 1997

Wiznitzer M, Packer RJ, August CS et al: Neurologic complications of bone marrow transplantation in childhood. Ann Neurol 16569, 1984

18 1 Neurologic Complications of Lymphoma Lawrence Recht The term lymphoma denotes a heterogeneous group of malignant neoplasms derived from lymphoreticular tissues. Approximately 30% of lymphomas are histologically characterized as Hodglun’s disease and distinguished by the presence of characteristic Reed-Sternberg cells; the remainder comprise a diverse group of neoplasms that are classified as non-Hodglun’s lymphoma. From the neurologist’s viewpoint, this subdivision is clinically important because Hodglun’s disease only rarely infiltrates central nervous system (CNS) directly. By contrast, this phenomenon occurs frequently in certain types of non-Hodgkin’s lymphoma. Non-Hodgkin’s lymphomas can be further subdivided according to the tumor’s characteristic pathologic features. However, the terms used often are confusing. In an attempt to allow correlation between the several histologic classifications of non-Hodgkin’s lymphoma, the Working Formulation was developed; from a neurologic perspective, the higher the grade, the more likely the occurrence of direct CNS infiltration (Table 181-1). The neurologic complications of systemic lymphomas can be grouped according to whether they result from direct invasion of tumor or a remote effect of tumor or treatment.

DIRECT CNS INVOLVEMENT BY LYMPHOMA Lymphomas can invade the CNS at any time during the course of the disease; CNS involvement may be present at time of diagnosis, occur during the course of progressive disease, or, most distressingly, be the first sign of a relapse after a complete remission. CNS invasion by lymphoma occurs often in non-Hodgkin’s lymphoma and is one of the more commonly involved extranodal sites; approximately, 10% of these patients develop this complication. In patients with acquired immunodeficiency syndrome, CNS invasion by lymphoma occurs in up to 25%, tends to be more aggressive, and is generally harder to treat than in otherwise normal patients.

Lymphomas produce CNS symptoms directly by some combination of leptomeningeal infiltration, intraparenchymal mass lesions, epidural masses, or infiltration of blood vessels or peripheral nerves. Systemic Lymphoma Direct CNS infiltration is seen almost exclusively in nonHodgkin’s lymphoma; only occasional reports describe its occurrence in Hodglun’s disease. The likelihood of developing CNS involvement varies as a function of the particular non-Hodglun’s lymphoma histology. As a general rule, the more aggressive the grade of lymphoma, the higher the risk of developing leptomeningeal disease (Table 181-1); in the most aggressive lymphomas (i.e., lymphoblastic and small noncleaved cell types), this risk approaches 25%. Involvement of bone marrow or testes or leukemic transformation increases this risk further, as do prior chemotherapy and younger patient age. Most commonly, lymphomas gain access to the CNS via the meninges. Tumor implants are inhomogeneously distributed, being most pronounced at the base of the brain, and spinal cord and lymphoma cells often can be found infiltrating VirchowRobin spaces. Less commonly, parenchymal invasion results in visible intraparenchymal masses. Certain lymphoma types, such as mycosis fungoides, although rarely invading the CNS, seem to result in a disproportionately high incidence of mass lesions.

Meningeal Involvement Meningeal involvement can occur at any time in the lymphomatous disease process; it may be present at time of diagnosis (when it may be clinically asymptomatic), can occur as a manifestation of relapse after a complete remission, or, most commonly, can develop in the setting of progressive systemic disease. It may even

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Nelson KR, McQuillen MP Neurologic complications of graft-versus-host

diseases. Neurol Clin 6(2):389, 1988 Openshaw H, Hinton DR, Slatkin NE et al: Exacerbation of inflammatory demyelinating polyneuropathy after bone marrow transplantation. Bone Marrow Transplant 7:411, 1991 Openshaw H, Slatkin N E Differential diagnosis of neurological complications in bone marrow transplantation. Neurologist 1:191-206, 1995 Padovan CS, Bise K, Hahn J et al: Angiitis of the central nervous system after allogeneic bone marrow transplantation?Stroke 301651-1656, 1999 Parker P, Chao NJ, Ben-Ezra J et al: Polymyositis is a manifestation of chronic graft-versus-host disease. Medicine 75:279-285, 1996 Patchell RA, White CL, Clark AW et al: Neurologic complications of bone marrow transplantation. Neurology 35:300, 1985 Patchell RA, White CL, Clark AW et al: Nonbacterial thrombotic endocarditis in bone marrow transplant patients. Cancer 55:631, 1985 Snider S, Bashir R, Bierman P Neurologic complications after high dose chemotherapy and autologous bone marrow transplant for Hodgkin’s disease. Neurology 44681, 1994

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Thompson CB, Sanders JE, Flournoy N et al: The risks of central nervous system relapse and leukoencephalopathy in patients receiving marrow transplants for acute leukemia. Blood 62195-199, 1986 Tolkoff-Rubin NE, Hoving GK, Rubin RH: Central nervous system infections. Chapter 10. In Wijdicks EFM (ed): Neurologic Complications in Organ Transplant Recipients. Butterworth-Heinemann, 1999 Trigg ME, Meenzes AH, Giller R et al: Combined anti-fungal therapy and surgical resection as treatment of disseminated aspergillosis of the lung and brain following BMT. Bone Marrow Transplant 11:493, 1993 Walters MC, Sullivan KM, Bernaudin F et al: Neurologic complications after allogeneic marrow transplantation for sickle cell anemia. Blood 86:408-409, 1995

Wen PY, Aleya EP, Simon D et al: Guillain-Barrk syndrome following allogeneic bone marrow transplantation. Neurology 49171 1-1714, 1997

Wiznitzer M, Packer RJ, August CS et al: Neurologic complications of bone marrow transplantation in childhood. Ann Neurol 16569, 1984

18 1 Neurologic Complications of Lymphoma Lawrence Recht The term lymphoma denotes a heterogeneous group of malignant neoplasms derived from lymphoreticular tissues. Approximately 30% of lymphomas are histologically characterized as Hodglun’s disease and distinguished by the presence of characteristic Reed-Sternberg cells; the remainder comprise a diverse group of neoplasms that are classified as non-Hodglun’s lymphoma. From the neurologist’s viewpoint, this subdivision is clinically important because Hodglun’s disease only rarely infiltrates central nervous system (CNS) directly. By contrast, this phenomenon occurs frequently in certain types of non-Hodgkin’s lymphoma. Non-Hodgkin’s lymphomas can be further subdivided according to the tumor’s characteristic pathologic features. However, the terms used often are confusing. In an attempt to allow correlation between the several histologic classifications of non-Hodgkin’s lymphoma, the Working Formulation was developed; from a neurologic perspective, the higher the grade, the more likely the occurrence of direct CNS infiltration (Table 181-1). The neurologic complications of systemic lymphomas can be grouped according to whether they result from direct invasion of tumor or a remote effect of tumor or treatment.

DIRECT CNS INVOLVEMENT BY LYMPHOMA Lymphomas can invade the CNS at any time during the course of the disease; CNS involvement may be present at time of diagnosis, occur during the course of progressive disease, or, most distressingly, be the first sign of a relapse after a complete remission. CNS invasion by lymphoma occurs often in non-Hodgkin’s lymphoma and is one of the more commonly involved extranodal sites; approximately, 10% of these patients develop this complication. In patients with acquired immunodeficiency syndrome, CNS invasion by lymphoma occurs in up to 25%, tends to be more aggressive, and is generally harder to treat than in otherwise normal patients.

Lymphomas produce CNS symptoms directly by some combination of leptomeningeal infiltration, intraparenchymal mass lesions, epidural masses, or infiltration of blood vessels or peripheral nerves. Systemic Lymphoma Direct CNS infiltration is seen almost exclusively in nonHodgkin’s lymphoma; only occasional reports describe its occurrence in Hodglun’s disease. The likelihood of developing CNS involvement varies as a function of the particular non-Hodglun’s lymphoma histology. As a general rule, the more aggressive the grade of lymphoma, the higher the risk of developing leptomeningeal disease (Table 181-1); in the most aggressive lymphomas (i.e., lymphoblastic and small noncleaved cell types), this risk approaches 25%. Involvement of bone marrow or testes or leukemic transformation increases this risk further, as do prior chemotherapy and younger patient age. Most commonly, lymphomas gain access to the CNS via the meninges. Tumor implants are inhomogeneously distributed, being most pronounced at the base of the brain, and spinal cord and lymphoma cells often can be found infiltrating VirchowRobin spaces. Less commonly, parenchymal invasion results in visible intraparenchymal masses. Certain lymphoma types, such as mycosis fungoides, although rarely invading the CNS, seem to result in a disproportionately high incidence of mass lesions.

Meningeal Involvement Meningeal involvement can occur at any time in the lymphomatous disease process; it may be present at time of diagnosis (when it may be clinically asymptomatic), can occur as a manifestation of relapse after a complete remission, or, most commonly, can develop in the setting of progressive systemic disease. It may even

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TABLE 181-1. Characteristicsof the Subtypes of Non-Hodgkin‘s Lymphoma According to the Working Formulation, Including Propensity to Invade the Central Nervous System Subiype

Growth Pattern

Incidence of Central Nervous System Invasion

10

Diffuse Follicular Follicular

Rare Rare Rare

5 10 10 20

Follicular Diffuse Diffuse Diffuse

Rare Intermediate Intermediate Intermediate

10 5

Diffuse Diffuse Diffuse

Intermediate High High

Relative Frequency (46)

Low Grade

Small lymphocytic Follicular small cleaved cell Follicular mixed cell

5 25

Intermediate Grade

Follicular large cell Diffuse small cleaved cell Diffuse mixed cell Diffuse large cell High Grade

lmmunoblastic Lymphoblastic Small noncleaved cell

5

be the sole manifestation of non-Hodgkin’s lymphoma, although this is unusual. Moreover, there seems to be a correlation between the presence of intraocular non-Hodgkin’s lymphoma and CNS lymphomatous mass lesions, which may represent a multicentric or metastatic disease process. Any neurologic symptom may be associated with meningeal lymphoma. Most commonly, patients present with symptoms of general CNS dysfunction (i.e., headache, altered mental status), cranial nerve abnormalities (the abducent and facial nerves are most often affected), or spinal cord dysfunction. Because more unusual syndromes can occur, the best approach is to maintain a high index of suspicion and to have a low threshold for performing confirmatory tests when a patient at risk develops neurologic symptoms. The diagnosis of meningeal lymphoma is made most definitively by identification of neoplastic cells in the cerebrospinal fluid (CSF). At least one CSF parameter is abnormal in almost all patients with meningeal involvement. Cytologic examination should yield lymphoma cells in more than 90% of these patients if three examinations are performed and adequate material is obtained. Because meningeal disease may be present at disease onset and associated with no symptoms, all patients with newly diagnosed non-Hodgkin’s lymphoma of intermediate or aggressive histologic subtype should have a lumbar puncture performed as part of their staging procedure. Sometimes, neoplastic cells cannot be identified despite a high index of suspicion. In these situations, other radiographic examinations may be helpful. The appearance of ventricularly based intraparenchymal masses or noncommunicating hydrocephalus on computed tomography or magnetic resonance imaging in a patient with non-Hodgkin’s lymphoma suggests a meningeal process. Similarly, visualizing discrete gadoliniumenhancing nodules on nerve roots in the cauda equina or within the spinal cord itself strongly supports a diagnosis of meningeal disease. Even with these sensitive tests, a diagnosis may still be elusive despite a high degree of suspicion. Determination of P,-microglobulin, analysis of lymphocyte markers, and in vitro gene amplification by polymerase chain reaction to demonstrate chromosome translocations on CSF material are all potentially useful in this situation. The development of meningeal or parenchymal involvement by lymphoma is generally associated with a very poor prognosis. Median survivals after diagnosis generally are measurable in weeks, although this may reflect the failure to control CNS disease

rather than CNS involvement per se. Nevertheless, an aggressive therapeutic approach using some combination of steroids, radiotherapy, and either local or systemic chemotherapy is warranted to minimize or prevent neurologic morbidity. Although symptoms and signs may suggest a focal disorder, the finding of meningeal involvement connotes a diffuse process; therefore, the entire neuraxis must be treated to ensure that all tumor is eradicated. Unlike their effects on most other neoplasms, steroids are more than just palliative when used in lymphoma; sometimes, brisk oncolytic effects can be observed, and even large bulky masses may quickly disappear. Because this is a diffuse disease, radiotherapy ports can be extended to include the entire neuraxis; this can be associated with increased neurologic morbidity, however, and tends to produce myelosuppression, which may limit chemotherapy tolerance. For this reason, a preferred approach combines focal irradiation to areas of maximal involvement with chemotherapy. Focal symptoms such as cranial dysfunction generally are ameliorated, and lymphomatous parenchymal lesions also generally respond. Although systemic chemotherapy with high-dose methotrexate or cytosine arabinoside has been used effectively as a therapy for meningeal lymphoma, most physicians recommend local chemotherapy via intrathecal or intraventricular routes either concomitantly or instead of radiotherapy. Either methotrexate or cytosine arabinoside can be used; lymphomas tend to respond to both agents more often than do other solid neoplasms. Although it has been difficult to demonstrate a clear superiority of intraventricular therapy, use of an Ommaya reservoir combines ease of administration with better penetration into the entire neuraxis. Furthermore, in experienced hands, complication rates are low. With a combined-modality approach, neurologic symptoms can be controlled in approximately 80% of patients, although median survival length is still short, ranging from 1 to 8 months. Favorable prognostic factors are young age, CNS involvement occurring as an isolated event, and combined therapy. Furthermore, when meningeal lymphoma is present at the onset of disease, the outcome is not invariably fatal; up to 25% can attain long-term survival with intensive treatment. Epidural Lymphoma

Approximately 5% of patients with lymphoma develop epidural spinal cord compression secondary to their primary disease; this

Chapter 181 rn Neurologic Complications of Lymphoma

complication occurs with equal frequency in both Hodgkin’s and non-Hodgkin’s disease, although the latter is more commonly found when it occurs as a first disease manifestation. When a presenting symptom, systemic lymphoma may be found during staging procedures, but in a large percentage, the spinal column may be the sole site of involvement. Prognosis for these patients tends to be better than when disease occurs in the setting of established lymphoma; in approximately 20%, evidence of distant disease is never noted, and patients may be cured. Most epidural lesions are diagnosed when extranodal or extensive nodal disease already exists. As with other solid neoplasms, the thoracic cord is most commonly involved; by contrast, lymphomas often spread from paraspinous regions into the epidural space via intervertebral foramina. This results in a radiographically demonstrable complete block despite normal plain spine films, an important point for the clinician to remember in evaluating a patient with lymphoma and spinal cord dysfunction. Presenting signs and symptoms are similar to those produced by other cancers. Although technically symptoms are not an effect of direct CNS infiltration, the common coexistence of epidural and meningeal lymphoma makes the matter moot. Because it will alter the therapeutic approach, it is important to characterize the pathologic process accurately. Therefore, in a patient in whom epidural lymphoma is suspected, a CSF examination (when not contraindicated by complete spinal block) should be performed in addition to imaging of the entire spine. The approach to treating lymphomatous epidural compression is similar to that delineated for other neoplasms. Because the administration of steroids can result in a brisk oncolytic response, however, it is possible to miss a lesion if undue delays occur before diagnostic testing after steroids are started. When epidural lymphoma occurs as the presenting symptom, decompression is indicated, if only to make a diagnosis. Most lymphomatous lesions respond effectively to irradiation, however; surgery is generally reserved for lesions that progress or recur after irradiation. Overall, therapeutic results are generally favorable, and the presence of epidural lymphoma probably does not affect the ultimate prognosis much.

Neoplastk Andoendotheliomatosis (Intravascular lymphoma) Neoplastic angioendotheliomatosis, a rare complication of nonHodgkin’s lymphoma, often produces CNS symptoms. It was originally believed to be a disorder of endothelial cells, but recent immunohistochemical and molecular evidence indicates that the proliferative cells are actually of lymphocytic, primarily B cell origin. Therefore, the condition is more properly called intravascular lymphomatosis or angiotropic large cell lymphoma. Intravascular lymphoma is characterized by the presence of neoplastic cells within the lumina of small and intermediate-size blood vessels. The skin and CNS are preferentially involved. Its clinical features are related to vascular occlusion by neoplastic cells, which accumulate in small arterioles, capillaries, and venules and include progressive multifocal cerebrovascular events, paraparesis, a subacute encephalopathy, and peripheral or cranial neuropathies. Neurologic involvement usually is associated with a rapidly fluctuating clinical course. Because clinical and radiographic features are nonspecific, diagnosis is rarely made during life; when it is suspected, the only definitive method of diagnosis is by brain or meningeal biopsy.

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Anecdotal reports suggest that intravascular lymphomas may respond to steroids, plasmapheresis, or chemotherapy.

Neurolymphomatosis Neurolymphomatosis occurs when peripheral nerves are infiltrated by non-Hodgkin’s lymphoma. It is a rare manifestation of non-Hodglun’s lymphoma that usually results in a rapidly progressive and fatal painful neuropathy that cannot be attributed to chemotherapy, Guillain-Barre syndrome, or a paraneoplastic syndrome. When neurolymphomatosis is confined to the peripheral nerves, the diagnosis can be extremely difficult to make. At autopsy, however, predominant and exclusive infiltration of peripheral nerves is seen. The cause of the neuropathy is unknown. No treatment has been effective.

Should Central Nervous System Prophylaxis Be Administered to Patients wfth Lymphoma? As for the leukemias, early initial therapies for non-Hodgkin’s

lymphoma did not include CNS-directed treatment, and the subsequent development of CNS lymphoma was noted to be significant. Furthermore, it was noted that CNS involvement was more likely to occur in aggressive, extensive non-Hodglun’s lymphoma. When multivariate analyses were performed, the three most important factors predicting CNS invasion were histology (lymphoblasticand small noncleaved cell), younger age (less than 40 years), and advanced stage; the estimated probability of developing meningeal metastases was as high as 60% when all three factors were present. Despite the ability to define a high-risk patient, however, the case for CNS prophylaxis is not as clear-cut as it is in leukemia because isolated CNS relapse is an unusual occurrence in patients with non-Hodgkin’s lymphoma; data from two large trials of the Eastern Cooperative Oncology Group indicate that only 1% of patients with diffuse histiocytic lymphoma (the most common form of non-Hodgkin’s lymphoma) develop isolated CNS relapses. Therefore, because prophylaxis is associated with complications, the morbidities of treatment may outweigh the minimal benefits. Few studies have specifically addressed the benefits of prophylaxis in non-Hodgkin’s lymphoma, and differing conclusions have been drawn. Retrospective studies analyzing large non-Hodglun’s lymphoma patient cohorts suggest that the incidence of CNS involvement is similar whether or not patient receive prophylaxis in the form of radiotherapy or intrathecal chemotherapy. Furthermore, in a recent study comparing intensive chemotherapy with a standard cyclophosphamide, hydroxyurea, vincristine (Oncovin), and prednisone (CHOP) regimen in which CNS prophylaxis was excluded revealed similar survivals and outcomes, suggesting strongly that prophylaxis did not improve outcome.

PARANEOPLASTIC SYNDROMES ASSOCIATED WITH LYMPHOMA Besides directly infiltrating the central and peripheral nervous systems, lymphomas may produce neurologic symptoms via a number of more indirect mechanisms. It is important for the clinician to be aware of these indirect complications, both because they may be treatable and because mistaking them for tumor progression may result in incorrect treatments. Many of these complications are similar to those produced by other cancers and

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are described in other chapters of this book; here, however, the focus is on syndromes that are grouped under the rubric paraneoplastic and exclusively o r predominantly associated with lymphoma (see also Chapter 178). A number of syndromes in patients with cancer have been called paraneoplastic because they are not caused by the cancer or any known treatment, infection, or vascular o r metabolic aberration. In recent years, intensive research into these fascinating syndromes has indicated that many of them probably occur secondary to autoimmune mechanisms. Almost any paraneoplastic syndrome can occur in a patient with lymphoma; certain ones seem especially common, however. A reported association exists between paraneoplastic cerebellar degeneration and Hodgkin’s disease. Another peculiar syndrome that seems almost exclusively associated with lymphoma is subacute motor neuropathy. Seen in both Hodgkin’s disease and patients with non-Hodgkin’s lymphoma, it is usually noted while the patient is in remission, and its manifestations are independent of the underlying neoplasm’s activity. Painless and often patchy weakness of a lower motor neuron variety is encountered; it occurs subacutely and is progressive, and sensory loss is mild. The electromyogram reveals denervation. Pathologically, degeneration of anterior horns and demyelination of anterior nerve roots are seen. The course is benign and generally stabilizes o r improves spontaneously. A syndrome that approximates more closely actual motoneuron disease, with both upper and lower motor neuron signs, has also been recently reported in patients with lymphoma; its occurrence often is associated with a coexistent paraproteinemia. This association is common enough to prompt some researchers to suggest searching for such underlying conditions in all patients with otherwise typical amyotrophic lateral sclerosis. Remote syndromes involving peripheral nerves seem particularly common in patients with lymphoma or related diseases such as myeloma. An acute polyradiculopathy indistinguishable for classic Guillain-BarrC syndrome has been associated with Hodgkin’s disease; it may occur at any stage of the disease. Hodgkin’s disease has also been associated with a painful brachial neuritis that seems to occur more often in the setting of proximate administration of radiotherapy. Finally, a rare association between lymphoblastic lymphoma and myasthenia gravis has been reported, in which elevated antiacetylcholine receptor antibody levels disappeared with successful treatment of the lymphoma.

SUGGESTED READINGS Diaz-Arrastia R, Younger DS, Hair L et ak Neurolymphomatosis: a clinicopathologic syndrome re-emerges. Neurology 42: 1136-1 141, 1992

Fisher RI, Gaynor ER, Dahlberg S et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993 Glass J, Hochberg FH, Miller D C Intravascular lymphomatosis. A systemic disease with neurologic manifestations. Cancer 71:3156-3164, 1993

Haddy TB, Adde MA, Magrath IT:CNS involvement in small noncleavedcell lymphoma: is CNS disease per se a poor prognostic sign? J Clin Oncol 9:1973-1982, 1991 Johnson GJ, Oken MM, Anderson JR et al: Central nervous system relapse in unfavourable-histology non-Hodgkin’s lymphoma: is prophylaxis indicated? Lancet 2:685-687, 1984 Lokich J, Galbo C Leptomeningeal lymphoma: perspectives on management. Cancer Treat Rev 8:103-110, 1981 Mackintosh FR, Colby TV, Podolsky WJ et al: Central nervous system involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer 49586-595, 1982 Malow BA, Dawson DM: Neuralgic amyotrophy in association with radiation therapy for Hodglun’s disease. Neurology 41:440-441, 1991 0”eil BP Neurologic complications of Hodgkin‘s disease and nonHodgkin’s lymphoma. In Schiff D, Wen PY (eds): Cancer in Clinical Practice. Totowa, NJ. Humana, 2003 (in press) Perez-Soler R, Smith TL, Cabanillas F Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type. Cancer 57:971-977, 1986 Perry JR, Deodhare SS, Bilbao JM et al: The significance of spinal cord compression as the initial manifestation of lymphoma. Neurosurgery 32:157-162, 1993

Recht R, Mrugala M: Neurologic complications of hematologic neoplasms. Neurologic Clinics 2003 (in press) Recht L, Straus DJ, Cirrincione C et ak Central nervous system metastases from non-Hodgkin’s lymphoma: treatment and prophylaxis. Am J Med 84:425-435, 1988 Schold SC, Cho ES, Somasundaram M, Posner JB: Subacute motor neuronopathy: a remote effect of lymphoma. Ann Neurol 5:271-287, 1979

Young RC, Howser DM, Anderson T et al: Central nervous system complications of non-Hodgkin’s lymphoma. The potential role for prophylactic therapy. Am J Med 66435-443, 1979 Younger DS, Rowland LP, Latov N et ak Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann Neurol2978-86, 1991

182 Neurologic Complications of Leukemia Kendra Peterson Leukemia is the most common cancer in children and occurs in significant numbers of adults as well. Neurologic disorders in patients with leukemia are common (Table 182-1). They may result from direct leukemic infiltration of the nervous system, may be the indirect consequence of associated vascular events, o r may result from treatment complications. Familiarity with the specific neurologic disorders that occur in patients with leukemia can provide opportunities to prevent untoward complications.

Recognizing and distinguishing the various manifestations when they occur directs appropriate and specific therapy.

DIRECT NERVOUS SYSTEM INVOLVEMENT Leukemia may directly invade any part of the central or peripheral nervous system. Meningeal leukemia is by far the most common manifestation of direct nervous system involvement.

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are described in other chapters of this book; here, however, the focus is on syndromes that are grouped under the rubric paraneoplastic and exclusively o r predominantly associated with lymphoma (see also Chapter 178). A number of syndromes in patients with cancer have been called paraneoplastic because they are not caused by the cancer or any known treatment, infection, or vascular o r metabolic aberration. In recent years, intensive research into these fascinating syndromes has indicated that many of them probably occur secondary to autoimmune mechanisms. Almost any paraneoplastic syndrome can occur in a patient with lymphoma; certain ones seem especially common, however. A reported association exists between paraneoplastic cerebellar degeneration and Hodgkin’s disease. Another peculiar syndrome that seems almost exclusively associated with lymphoma is subacute motor neuropathy. Seen in both Hodgkin’s disease and patients with non-Hodgkin’s lymphoma, it is usually noted while the patient is in remission, and its manifestations are independent of the underlying neoplasm’s activity. Painless and often patchy weakness of a lower motor neuron variety is encountered; it occurs subacutely and is progressive, and sensory loss is mild. The electromyogram reveals denervation. Pathologically, degeneration of anterior horns and demyelination of anterior nerve roots are seen. The course is benign and generally stabilizes o r improves spontaneously. A syndrome that approximates more closely actual motoneuron disease, with both upper and lower motor neuron signs, has also been recently reported in patients with lymphoma; its occurrence often is associated with a coexistent paraproteinemia. This association is common enough to prompt some researchers to suggest searching for such underlying conditions in all patients with otherwise typical amyotrophic lateral sclerosis. Remote syndromes involving peripheral nerves seem particularly common in patients with lymphoma or related diseases such as myeloma. An acute polyradiculopathy indistinguishable for classic Guillain-BarrC syndrome has been associated with Hodgkin’s disease; it may occur at any stage of the disease. Hodgkin’s disease has also been associated with a painful brachial neuritis that seems to occur more often in the setting of proximate administration of radiotherapy. Finally, a rare association between lymphoblastic lymphoma and myasthenia gravis has been reported, in which elevated antiacetylcholine receptor antibody levels disappeared with successful treatment of the lymphoma.

SUGGESTED READINGS Diaz-Arrastia R, Younger DS, Hair L et ak Neurolymphomatosis: a clinicopathologic syndrome re-emerges. Neurology 42: 1136-1 141, 1992

Fisher RI, Gaynor ER, Dahlberg S et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993 Glass J, Hochberg FH, Miller D C Intravascular lymphomatosis. A systemic disease with neurologic manifestations. Cancer 71:3156-3164, 1993

Haddy TB, Adde MA, Magrath IT:CNS involvement in small noncleavedcell lymphoma: is CNS disease per se a poor prognostic sign? J Clin Oncol 9:1973-1982, 1991 Johnson GJ, Oken MM, Anderson JR et al: Central nervous system relapse in unfavourable-histology non-Hodgkin’s lymphoma: is prophylaxis indicated? Lancet 2:685-687, 1984 Lokich J, Galbo C Leptomeningeal lymphoma: perspectives on management. Cancer Treat Rev 8:103-110, 1981 Mackintosh FR, Colby TV, Podolsky WJ et al: Central nervous system involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer 49586-595, 1982 Malow BA, Dawson DM: Neuralgic amyotrophy in association with radiation therapy for Hodglun’s disease. Neurology 41:440-441, 1991 0”eil BP Neurologic complications of Hodgkin‘s disease and nonHodgkin’s lymphoma. In Schiff D, Wen PY (eds): Cancer in Clinical Practice. Totowa, NJ. Humana, 2003 (in press) Perez-Soler R, Smith TL, Cabanillas F Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type. Cancer 57:971-977, 1986 Perry JR, Deodhare SS, Bilbao JM et al: The significance of spinal cord compression as the initial manifestation of lymphoma. Neurosurgery 32:157-162, 1993

Recht R, Mrugala M: Neurologic complications of hematologic neoplasms. Neurologic Clinics 2003 (in press) Recht L, Straus DJ, Cirrincione C et ak Central nervous system metastases from non-Hodgkin’s lymphoma: treatment and prophylaxis. Am J Med 84:425-435, 1988 Schold SC, Cho ES, Somasundaram M, Posner JB: Subacute motor neuronopathy: a remote effect of lymphoma. Ann Neurol 5:271-287, 1979

Young RC, Howser DM, Anderson T et al: Central nervous system complications of non-Hodgkin’s lymphoma. The potential role for prophylactic therapy. Am J Med 66435-443, 1979 Younger DS, Rowland LP, Latov N et ak Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann Neurol2978-86, 1991

182 Neurologic Complications of Leukemia Kendra Peterson Leukemia is the most common cancer in children and occurs in significant numbers of adults as well. Neurologic disorders in patients with leukemia are common (Table 182-1). They may result from direct leukemic infiltration of the nervous system, may be the indirect consequence of associated vascular events, o r may result from treatment complications. Familiarity with the specific neurologic disorders that occur in patients with leukemia can provide opportunities to prevent untoward complications.

Recognizing and distinguishing the various manifestations when they occur directs appropriate and specific therapy.

DIRECT NERVOUS SYSTEM INVOLVEMENT Leukemia may directly invade any part of the central or peripheral nervous system. Meningeal leukemia is by far the most common manifestation of direct nervous system involvement.

Chapter 182 4 Neurologic Complications of Leukemia

H TMIE 182-1. Neurologic Complications of Leukemia Direct nervous system involvement by leukemia Meningeal leukemia Parenchymal leukemia Chloroma Peripheral nerve infiltration Neurologic vascular complications of leukemia Hemorrhagic Blast crisis Thrombocytopenia Disseminated intravascular coagulation Hemorrhagic embolic infarcts Infection (Aspergi//us) Ischemia or infarction Leukocytosis Disseminated intravascular coagulation Cortical vein thrombosis (1-asparaginase) Treatment-related neurologic complications Acute or subacute Radiation-induced Somnolence syndrome Posterior column dysfunction Chemotherapy-induced Meningitis Myelopathy Encephalopathy Cerebellar dysfunction (cytosine arabinoside) Delayed or chronic Cognitive decline or dementia Radiation necrosis Necrotizingleukoencephalopathy Mineralizing microangiopathy Endocrine dysfunction Second malignancies

Meningeal Leukemia

The clinical problem of leukemic infiltration of the meninges has changed over the last several decades. Before the routine use of systemic chemotherapy, meningeal leukemia was only rarely reported. The development of effective combination chemotherapies achieved systemic remission in many patients and allowed longer survival, but subsequent meningeal relapse became common; the incidence of this complication increased 10- to 20-fold between 1947 and 1970. About one half to two thirds of patients successfully treated for systemic leukemia in this period eventually developed central nervous system (CNS) relapse. Most meningeal relapse occurred within the first year of systemic remission, although in rare patients it was delayed for as long as 10 years. Recently, the routine use of CNS prophylactic therapy for many patients with leukemia has once again diminished the incidence of this complication, now to 5% to 10% of patients. Meningeal involvement typically is a late manifestation of leukemia and is rarely detectable at presentation. Meningeal leukemia often occurs in isolation during systemic remission but may herald the onset of bone marrow relapse. The current practice of routine surveillance of the cerebrospinal fluid (CSF) allows subclinical diagnosis of meningeal leukemia in many patients before the development of neurologic symptoms. Meningeal leukemia has been described as a complication of all forms of leukemia, although it occurs more commonly in some types than others. Meningeal involvement is more likely to complicate acute rather than chronic leukemia, lymphocytic rather than nonlymphocytic leukemia, and childhood rather than adult leukemia. Similar to the experience in childhood leukemia, the incidence in adult patients may be increasing as systemic therapies become more effective in maintaining prolonged systemic remission. The rare T-cell lymphocytic leukemias are more prone to

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CNS involvement and more resistant to treatment than the more common B-cell leukemias. There has been some controversy as to the source of leukemic cells in the CNS. Prior hypotheses that leukemic cells arise directly from hematopoietic sources within the CNS (choroid plexus or meninges themselves) or by direct invasion from the bone marrow of the skull have generally been displaced by the view that leukemic cells reach the CNS by hematogenous spread. Pathologically, there is a spectrum of involvement from invasion of the meningeal veins and superficial involvement of the arachnoid, to more extensive perivascular infiltration of the Virchow-Robin spaces and extension into the deep arachnoid, and finally to disruption of the pia-glial membrane and parenchymous infiltration of the brain, cranial nerves, and spinal nerve roots. Hematogenous metastasis to the meninges may occur early in the course of the disease but is ineffectively treated by systemic therapies and therefore may be a reservoir for late relapse. As noted, meningeal leukemia may be asymptomatic and diagnosed only by routine CSF evaluation. When meningeal leukemia is present, symptoms and signs referable to any level of the neuraxis may be present. Most typical are symptoms of elevated intracranial pressure, with headache, nausea, and vomiting and, in younger children, separation of the cranial sutures. Papilledema is present in about one half of patients. Optic nerve and chiasm infiltration may impair vision, and involvement of cranial nerves I11 and VI often causes ophthalmoplegia. Facial weakness caused by involvement of cranial nerve VII is not rare. The lower cranial nerves are involved less commonly. Radicular symptoms resulting from spinal nerve root involvement are uncommon in children but are more common in adults. Rare parenchymal brain infiltration may precipitate seizures or focal deficits. Up to one fourth of children with meningeal involvement by acute lymphoblastic leukemia develop a syndrome of hyperphagia, obesity, and somnolence as a result of hypothalamic infiltration. Computed tomography or magnetic resonance image scans may be normal, although they often reveal mild to moderate increased ventricular size. Contrast-enhanced magnetic resonance imaging may detect diffuse meningeal enhancement and, on rare occasions, focal nodular meningeal deposits. Fluid attenuated inversion recovery (FLAIR) sequences are also helpful in identifying disease in the subarachnoid space. The diagnosis of meningeal leukemia depends on the detection of malignant cells in the CSF. Cytocentrifugation is more sensitive than routine cytology in detecting leukemic cells. Leukemic cells are rarely present if the total CSF white blood cell count is less than 10/mm3.The presence of pleocytosis may be misleading, however, because it may be caused by infection or chemical meningitis after intrathecal chemotherapy or subarachnoid hemorrhage. Other abnormalities may include elevated pressure, mildly elevated protein, and sometimes hypoglycorrhachia. CSF markers such as P,-microglobulin, P-glucuronidase, and polyamine levels are nonspecific but can support a clinical suspicion. Very rarely, patients are treated for meningeal leukemia without a definite pathologic diagnosis, but only when there is strong clinical and supporting laboratory evidence and other meningeal processes have been excluded. CNS prophylactic therapy is now routinely included in the initial treatment regimen of many patients with leukemia, particularly in childhood acute lymphoblastic leukemia and others considered at high risk of CNS relapse. The optimum CNS prophylactic regimen is still being defined. Combination cranial

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radiotherapy and intrathecal methotrexate was used commonly in the past, but because of the resultant neurotoxicity, regimens that exclude cranial radiotherapy and use intrathecal methotrexate alone or combination intrathecal chemotherapies are more commonly used currently. Treatment of meningeal leukemia typically includes multimodality therapy with neuraxis radiotherapy and combination intrathecal and systemic chemotherapy. Response to therapy depends on a number of variables, including the type of leukemia and the stage at which meningeal leukemia is diagnosed. As one might anticipate, patients with subclinical involvement generally respond to therapy more favorably than those with overt disease. Patients who develop meningeal relapse while in systemic remission fare better than those who relapse during initial therapy. Patients who have not received prior cranial radiotherapy respond at relapse better than those who relapse after radiotherapy. Overall, about 20% to 35% of patients treated for meningeal leukemia achieve long-term remission. Parenchymal Leukemia

Parenchymal infiltration of the nervous system occurs either diffusely or as isolated nodular deposits. There is debate as to whether parenchymal leukemic infiltration ever occurs without meningeal involvement. In the majority of cases parenchymal involvement is associated with, and probably results from, direct extension of meningeal disease. Pathologic examination has yielded occasional cases of parenchymal disease without evidence of meningeal disease; this may represent a different pathway of entrance into the CNS other than through meningeal veins or may represent the resistance of parenchymal deposits despite successful treatment of meningeal disease.

Hemorrhage

Intracranial hemorrhage is the most common neurologic vascular complication of leukemia; it is usually intracerebral and less often subdural or subarachnoid. It may occur in a single site or be multifocal. Intracranial hemorrhage may be massive and result in significant neurologic compromise, causing or contributing to death in 10% to 20% of leukemic patients. It may instead be small, subclinical, and diagnosed only on computed tomography or magnetic resonance imaging or at autopsy. Spontaneous intracranial hemorrhage occurs most often in the setting of blast crisis, usually with a total white blood cell count greater than 100,000/mm3. This is associated more commonly with acute myelocytic than with acute lymphocytic leukemia and probably results from direct vascular infiltration by leukemic cells. Intracranial hemorrhage also occurs in the setting of several associated problems: thrombocytopenia, usually with a platelet count of less than 25,000/mm3, associated with either leukemic bone marrow replacement or as a result of chemotherapy; disseminated intravascular coagulation, most often seen in promyelocytic leukemia or associated with sepsis; septic or nonseptic embolic hemorrhagic infarcts; and specific infections such as Aspergillus commonly present with hemorrhagic lesions. Spinal subdural or subarachnoid hemorrhage is a rare complication of leukemia, usually associated with diagnostic or therapeutic lumbar puncture in patients with platelet counts less than 50,000/mm3. Platelet transfusion during and after lumbar puncture may be helpful in avoiding this complication. When it occurs, the condition typically is self-limited, although occasionally surgical decompression may be needed to prevent long-term neurologic compromise. Ischemia and Infarction

Chloroma

Chloromas, so named because of their green color caused by the presence of myeloperoxidase, are rare complications of myelogenous leukemias. They consist of collections of myeloid cells that occur most commonly in skin, liver, and lymph nodes. They may also occur in bone and extend adjacent to bone to affect the nervous system by local compression of spinal cord, nerves, or other structures. On rare occasions, they occur within brain parenchyma, typically as a single mass lesion, although they are occasionally multiple. Chloromas may present with focal neurologic dysfunction but are asymptomatic and noted only at autopsy in as many as one half of affected patients. PeripheralNerve Involvement

Leukemic peripheral nerve infiltration is a very rare event that usually occurs in patients with uncontrolled systemic disease. Patients may present with polyneuropathy or focal infiltration of individual nerves or nerve roots. NEUROLOGIC VASCULAR COMPLICATIONS

Both hemorrhagic and ischemic vascular complications of leukemia occur frequently, either as a direct consequence of the disease or as a result of a number of commonly associated conditions. In some settings, hemorrhagic and ischemic complications occur simultaneously.

Cerebral ischemia and infarction occurs in patients with leukemia as a result of either arterial or venous thrombosis and may present with single, multifocal, or diffuse lesions. Typically, patients present with focal neurologic deficits referable to the involved brain region, although in some settings patients may have global cerebral dysfunction. Recognizing the particular clinical syndrome and associated cause can direct appropriate therapy and prevent additional neurologic injury. Ischemia may result directly from stasis and hypercoagulability in the setting of a significantly elevated white blood cell count. Patients with leukemia are also prone to small vessel thrombosis in the setting of disseminated intravascular coagulation and typically present with fluctuating global encephalopathy or multifocal neurologic signs. Disseminated intravascular coagulation may be difficult to diagnose early in the course because the patient may initially have normal measurable coagulation profiles; with strong clinical suspicion and serial coagulation studies, this diagnosis may be confirmed and then effectively treated with heparin anticoagulation. Cerebral infarction also results from septic embolic events (most often secondary to fungal infection such as Aspergillus) and, less commonly, nonseptic emboli. Embolic infarcts present clinically with focal neurologic deficits or seizures. Cortical vein thrombosis resulting in venous infarcts (and sometimes hemorrhage) occurs as a result of leukemia-induced venous stasis. It may also follow treatment with L-asparaginase chemotherapy, which results in the depletion of plasma proteins. Treatment of cortical vein thrombosis is controversial, but heparin anticoagulationprobably is indicated if hemorrhage is not present.

Chapter 182

Replacement of plasma proteins with fresh frozen plasma has also been advocated in patients treated with L-asparaginase. TREATMENT-RELATED NEUROLOGIC COMPLICATIONS Neurologic complications of radiotherapy and chemotherapy are discussed in detail in Chapters 176 and 177. Some of the vascular complications that result from chemotherapy-induced thrombocytopenia or L-asparaginase-induced thrombosis have already been discussed, and neurologic infections occurring in immunocompromised hosts are covered elsewhere. Highlighted here are some of the specific toxicities related to treatment of leukemia. These can be categorized as acute or subacute or as delayed or chronic complications affecting the brain or spinal cord and result from radiotherapy, intrathecal or systemic chemotherapy, or combination therapy. Acute or Subacute

Acutely, cranial irradiation usually is well tolerated without significant toxicity, except for mild fatigue, headache, and nausea occurring in some patients. Subacute radiation injury is more common and typically presents with a somnolence syndrome sometimes with associated irritability, anorexia, and ataxia, developing a few weeks to months after the completion of treatment. The pathophysiology is thought to be demyelinating and usually is reversible within a few weeks. Corticosteroids may limit the severity and duration of this syndrome. A similar reversible subacute myelopathy may develop after spinal irradiation, often presenting with posterior column dysfunction and Lhermitte sign. The most common neurotoxicity associated with intrathecal chemotherapy is chemical meningitis. Mild cases often are asymptomatic; symptomatic patients develop headache, fever, nausea, and meningismus, usually within 12 hours of treatment. The CSF profile, with elevated protein and granulocytic pleocytosis, may be difficult to distinguish from bacterial meningitis. This is generally a self-limited condition without long-term sequelae. Myelopathy is an uncommon acute complication of intrathecal chemotherapy with either methotrexate or cytosine arabinoside. Patients present with back pain, leg weakness, numbness, and incontinence, usually within a few hours of drug administration. Elevated CSF myelin basic protein in some patients treated with cytosine arabinoside suggests that the initial event in the pathogenesis may be demyelination. Rare pathologic examinations have demonstrated noninflammatory necrosis of the spinal cord. The outcome of this condition is variable; some patients experience complete recovery, whereas others are left with significant neurologic dysfunction. High-dose systemic chemotherapies may also have acute cerebral toxicity. Both high-dose methotrexate and cytosine arabinoside can cause a reversible syndrome of diffuse encephalopathy characterized by somnolence, confusion, or seizures. This usually occurs within a few hours of treatment, although rarely it may be delayed for a few weeks. Subsequent doses of high-dose chemotherapy do not necessarily precipitate the same syndrome. High-dose cytosine arabinoside also causes a pancerebellar syndrome, presenting as ataxia, dysarthria, and nystagmus. Although it is unpredictable in which patients this uncommon syndrome will occur, the incidence is dose-dependent and may occur more commonly in older patients. The cerebellar dysfunction may be

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mild and transient or have devastating permanent neurologic sequelae. When cranial irradiation is combined with intrathecal methotrexate, within hours of initial treatment very rare patients have been reported to develop acute and severe encephalopathy with obtundation, seizures, and increased intracranial pressure. Although usually reversible, in severe cases patients have progressed to coma or even death.

Delayed or Chronic More common and troublesome than the acute and subacute neurologic complications of leukemia treatment are the delayed and chronic complications that can lead to a spectrum of disorders manifested by mild cognitive dysfunction at one extreme to significant morbidity and long-term neurologic dysfunction or death at the other. Computed tomography and magnetic resonance imaging studies have demonstrated radiologic abnormalities in as many as one half of long-term survivors of leukemia, which may or may not represent clinically evident pathology. Radiologic findings include diffuse atrophy, white matter T2weighted hyperintensities that in many patients appear to improve over time, and gray matter calcifications that may become more apparent over time. Radiologic abnormalities are significantly more prevalent in patients who have received cranial irradiation or combination radiotherapy and chemotherapy than in those who have received chemotherapy alone. Cranial irradiation alone can cause cognitive decline or dementia or result in areas of frank brain necrosis, typically delayed for months or years after therapy. The degree of late radiation effects is related to the age of the patient and to the total dosage and fractionation schedule. The mean overall intelligence quotient in irradiated children is 10 to 15 points lower than that of their siblings or of children with leukemia who do not receive radiation. Treatments reported to be of benefit in some patients with late radiation-induced toxicity include anticoagulants, antioxidants, corticosteroids, and pentoxphylline, which decreases serum viscosity. The stimulant methylphenidate may also improve cognitive functioning. When combined with intrathecal methotrexate, cranial irradiation can precipitate potentially the most devastating neurologic complication encountered in this group of patients: necrotizing leukoencephalopathy. The incidence of necrotizing leukoencephalopathy appears to be much greater when methotrexate is administered concurrent with or after radiotherapy and is much less when given before radiotherapy. It is rarely encountered in patients who have received a total radiation dosage of less than 20 Gy. Usually within 6 months of completing treatment, patients present with lethargy, irritability, focal deficits, and seizures. The outcome is variable, with some patients stabilizing or improving and others progressing to obtundation, coma, and death. Pathologically, the white matter lesions demonstrate demyelination, axonal degeneration, and noninflammatory coagulative necrosis. Recognition of this complication in its severe form has prompted revision of treatment protocols for CNS prophylaxis. Most patients are no longer treated with both cranial radiotherapy and intrathecal methotrexate prophylactically. Patients treated with cranial irradiation may also develop a late complication confined to the gray matter, called mineralizing microangiopathy. It is characterized by injury to the walls of the microvasculature, with thrombosis and calcification. The role of chemotherapy in precipitating this condition is unknown. As in

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the other delayed radiation complications, younger children are more prone to this complication than older children o r adults. The typical presentation is a focal neurologic deficit o r seizures, usually milder than the syndrome associated with leukoencephalopathy. Another common delayed treatment-related complication in long-term survivors of leukemia is hypothalamic-pituitary dysfunction. This complication should be screened for periodically so that appropriate hormone replacement can be implemented. In children, growth retardation can occur as a result both of growth hormone deficiency and of the direct effects of radiation o n the axial skeleton. Long-term survivors, especially those treated with radiotherapy, are also prone to develop CNS malignancies, including meningiomas and malignant gliomas.

SUGGESTED READINGS Barcos M, Lane W, Gomez GA et al: An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer 609327437, 1987 Bleyer WA Biology and pathogenesis of CNS leukemia. Am J Pediatr Hematol Oncol 11:57-63, 1989 Bleyer WA Central nervous system leukemia. Pediatr Clin North Am 35~789-814, 1988

Clark AW, Cohen SR, Nissenblatt MJ, Wilson S K Paraplegia following intrathecal chemotherapy. Cancer 50:42-47, 1982 Collins RC, Al-Mondhiry H, Chernik NL, Posner JB: Neurologic manifestations of intravascular coagulation in patients with cancer. A clinicopathologic analysis of 12 cases. Neurology 25:795-806, 1975 Crosley CJ, Rorke BL, Evans A, Nigro M: Central nervous system lesions . in childhood leukemia. Neurology 28:678-685, 1978

Feinberg WM, Swenson MR Cerebrovascular complications of L-asparaginase therapy. Neurology 38:127-133, 1988 Glantz MJ, Burger PC, Friedman AH et al: Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 4420202027, 1994

Haaxma-Riche H. Leukemia. pp. 355-370. In Schiff D, Wen PY (eds): Cancer Neurology in Clinical Practice. Humana Press, New Jersey, 2002

Hansen PB, Kjeldsen L, Dahlhoff K, Olesen B Cerebrospinal fluid beta-2-microglobulin in adult patients with acute leukemia or lymphoma: a useful marker in early diagnosis and monitoring of CNS involvement. Acta Neurol Scand 85:224-227, 1992 Mulhem RK, Friedman AG, Stone PA Neuropsychological status of children with acute lymphoblastic leukemia treated for central nervous system relapse. Am J Pediatr Hematol Oncol 11:106-113, 1989 Ochs JJ: Neurotoxicity due to central nervous system therapy for childhood leukemia. Am J Pediatr Hematol Oncol 11:93-105, 1989 Price RA, Jamieson PA The central nervous system in childhood leukemia. 11. Subacute leukoencephalopathy. Cancer 35:306-318, 1975 Price RA, Johnson PA The central nervous system in childhood leukemia: I. The arachnoid. Cancer 31:520-533, 1973 Recht LR, Mrugala M Neurologic Complications of Hematologic Neoplasms. Neurologic Clinics 2003. In Press. WB Saunders. Walker RW Neurologic complications of leukemia. Neurol Clin 9989999, 1991

Weitzner MA, Meyers CA, Valentine AD: Methylphenidate in the treatment of neurobehavioral slowing associated with cancer and cancer treatment. J Neuropsychiatry Clin Neurosci 7:347-350, 1995

183 Neurologic Complications of Lung Cancer Michael L. Gruber Lung cancer is the leading cause of cancer death for both men and women in the United States. Each year in the United States there are approximately 170,000 new lung cancer cases and 146,000 deaths, accounting for 18% of new cancers in men and 12% in women. Most patients present with advanced disease. The 5-year survival rate is 14%. Non-small cell lung cancers are the most common primary lung tumors and include adenocarcinomas and large cell anaplastic and epidermoid cell types (Table 183-1). Adenocarcinoma is the most common non-small cell lung cancer, and its incidence appears to be increasing. Small cell lung cancer accounts for approximately 25% of primary lung neoplasms and is generally

W TABLE 185-1.

Relative Incidence and Tendency to Metastasize of Primary Lung Cancers

Histologic Type

Incidence (Percentage of All Primay Lung Cancers or Percentage of All Non-Small Cell Primaw Lung Cancers)

Small cell Non-small cell Adenocarcinoma Epidermoid cell Large cell

15-25 75-85 40 30 15

Percentage with Metastasis at Diagnosis 70 40 17 14

nonresectable at the time of diagnosis. Non-small cell lung cancer is more likely to be localized when discovered. Table 183-2 summarizes the possible neurologic complications of lung cancer. The most common of these complications are the result of metastases to the brain, spinal cord, epidural space, and leptomeninges. Metastases to more than one site in the central nervous system occur in 20% of patients. Nonmetastatic neurologic complications include metabolic encephalopathy, infection, cerebrovascular events, symptoms caused by organ failure or complications of therapy, and paraneoplastic disorders.

LOCAL INVASION Local invasion in the thorax can result in compression of the recurrent laryngeal nerve, causing hoarseness, paralysis of the phrenic nerve (producing elevation of the hemidiaphragm and dyspnea), and a Horner’s syndrome caused by sympathetic nerve involvement. Pancoast’s syndrome is seen in 3% of patients with lung cancer. Tumor in the superior sulcus erodes bone and compresses the lower portion of the brachial plexus. The eighth cervical nerve and the first two thoracic nerves usually are affected. This can result in posterior shoulder pain that radiates to the medial aspect of the arm and the fourth and fifth fingers. Numbness of the medial side of the arm, forearm, and hand and weakness and atrophy of the

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the other delayed radiation complications, younger children are more prone to this complication than older children o r adults. The typical presentation is a focal neurologic deficit o r seizures, usually milder than the syndrome associated with leukoencephalopathy. Another common delayed treatment-related complication in long-term survivors of leukemia is hypothalamic-pituitary dysfunction. This complication should be screened for periodically so that appropriate hormone replacement can be implemented. In children, growth retardation can occur as a result both of growth hormone deficiency and of the direct effects of radiation o n the axial skeleton. Long-term survivors, especially those treated with radiotherapy, are also prone to develop CNS malignancies, including meningiomas and malignant gliomas.

SUGGESTED READINGS Barcos M, Lane W, Gomez GA et al: An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer 609327437, 1987 Bleyer WA Biology and pathogenesis of CNS leukemia. Am J Pediatr Hematol Oncol 11:57-63, 1989 Bleyer WA Central nervous system leukemia. Pediatr Clin North Am 35~789-814, 1988

Clark AW, Cohen SR, Nissenblatt MJ, Wilson S K Paraplegia following intrathecal chemotherapy. Cancer 50:42-47, 1982 Collins RC, Al-Mondhiry H, Chernik NL, Posner JB: Neurologic manifestations of intravascular coagulation in patients with cancer. A clinicopathologic analysis of 12 cases. Neurology 25:795-806, 1975 Crosley CJ, Rorke BL, Evans A, Nigro M: Central nervous system lesions . in childhood leukemia. Neurology 28:678-685, 1978

Feinberg WM, Swenson MR Cerebrovascular complications of L-asparaginase therapy. Neurology 38:127-133, 1988 Glantz MJ, Burger PC, Friedman AH et al: Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 4420202027, 1994

Haaxma-Riche H. Leukemia. pp. 355-370. In Schiff D, Wen PY (eds): Cancer Neurology in Clinical Practice. Humana Press, New Jersey, 2002

Hansen PB, Kjeldsen L, Dahlhoff K, Olesen B Cerebrospinal fluid beta-2-microglobulin in adult patients with acute leukemia or lymphoma: a useful marker in early diagnosis and monitoring of CNS involvement. Acta Neurol Scand 85:224-227, 1992 Mulhem RK, Friedman AG, Stone PA Neuropsychological status of children with acute lymphoblastic leukemia treated for central nervous system relapse. Am J Pediatr Hematol Oncol 11:106-113, 1989 Ochs JJ: Neurotoxicity due to central nervous system therapy for childhood leukemia. Am J Pediatr Hematol Oncol 11:93-105, 1989 Price RA, Jamieson PA The central nervous system in childhood leukemia. 11. Subacute leukoencephalopathy. Cancer 35:306-318, 1975 Price RA, Johnson PA The central nervous system in childhood leukemia: I. The arachnoid. Cancer 31:520-533, 1973 Recht LR, Mrugala M Neurologic Complications of Hematologic Neoplasms. Neurologic Clinics 2003. In Press. WB Saunders. Walker RW Neurologic complications of leukemia. Neurol Clin 9989999, 1991

Weitzner MA, Meyers CA, Valentine AD: Methylphenidate in the treatment of neurobehavioral slowing associated with cancer and cancer treatment. J Neuropsychiatry Clin Neurosci 7:347-350, 1995

183 Neurologic Complications of Lung Cancer Michael L. Gruber Lung cancer is the leading cause of cancer death for both men and women in the United States. Each year in the United States there are approximately 170,000 new lung cancer cases and 146,000 deaths, accounting for 18% of new cancers in men and 12% in women. Most patients present with advanced disease. The 5-year survival rate is 14%. Non-small cell lung cancers are the most common primary lung tumors and include adenocarcinomas and large cell anaplastic and epidermoid cell types (Table 183-1). Adenocarcinoma is the most common non-small cell lung cancer, and its incidence appears to be increasing. Small cell lung cancer accounts for approximately 25% of primary lung neoplasms and is generally

W TABLE 185-1.

Relative Incidence and Tendency to Metastasize of Primary Lung Cancers

Histologic Type

Incidence (Percentage of All Primay Lung Cancers or Percentage of All Non-Small Cell Primaw Lung Cancers)

Small cell Non-small cell Adenocarcinoma Epidermoid cell Large cell

15-25 75-85 40 30 15

Percentage with Metastasis at Diagnosis 70 40 17 14

nonresectable at the time of diagnosis. Non-small cell lung cancer is more likely to be localized when discovered. Table 183-2 summarizes the possible neurologic complications of lung cancer. The most common of these complications are the result of metastases to the brain, spinal cord, epidural space, and leptomeninges. Metastases to more than one site in the central nervous system occur in 20% of patients. Nonmetastatic neurologic complications include metabolic encephalopathy, infection, cerebrovascular events, symptoms caused by organ failure or complications of therapy, and paraneoplastic disorders.

LOCAL INVASION Local invasion in the thorax can result in compression of the recurrent laryngeal nerve, causing hoarseness, paralysis of the phrenic nerve (producing elevation of the hemidiaphragm and dyspnea), and a Horner’s syndrome caused by sympathetic nerve involvement. Pancoast’s syndrome is seen in 3% of patients with lung cancer. Tumor in the superior sulcus erodes bone and compresses the lower portion of the brachial plexus. The eighth cervical nerve and the first two thoracic nerves usually are affected. This can result in posterior shoulder pain that radiates to the medial aspect of the arm and the fourth and fifth fingers. Numbness of the medial side of the arm, forearm, and hand and weakness and atrophy of the

Chapter 183 W H TABLE 183-2.

Neurologic Complications of Lung Cancer

Local invasion

Recurrent laryngeal nerve paralysis Phrenic nerve paralysis Sympathetic nerve paralysis Brachial plexus involvement (Pancoast‘s syndrome) Complications of metastasis to Brain Spinal cord Epidural space

Leptomeninges Nonmetastatic complications Metabolic or endocrine Cerebrovascular Central nervous system infections Side effects of treatment Paraneoplasticsyndrome hand may develop. If the stellate ganglion is also involved, a Horner’s syndrome is noted. At times, in previously irradiated patients, symptoms of lower brachial plexus dysfunction are seen. The issue is whether the new symptoms are caused by tumor recurrence or radiation plexopathy. In radiation-induced plexopathy, pain is not a prominent feature, Horner’s syndrome is uncommon, and the upper plexus is more often involved. A magnetic resonance imaging (MRI) scan of the brachial plexus is the diagnostic procedure of choice.

BRAIN METASTASES Primary lung cancer is the most common cause of brain metastasis, accounting for half of all cases. Small cell lung cancer is more likely to metastasize to the brain than non-small cell lung cancer. The apparent increase in the incidence of brain metastases is in large part caused by the rising incidence of lung cancer. The brain often is the first site of recurrence and may be the only site of metastatic disease. Clinically manifested brain metastases occur in 25% to 30% of patients with lung cancer. This is usually seen at the time of systemic relapse, but in 20% of patients, neurologic symptoms precede the discovery of the lung cancer. When the primary cancer is unknown and the patient presents with brain metastases, more than one half eventually prove to have a primary lung tumor. Lung cancer spreads to the brain by hematogenous dissemination through the cerebral arterial circulation. The location of the deposits is related to the blood supply, with 80% of lesions occurring in the cerebral hemispheres (usually at the gray and white matter junction), 17% in the cerebellum, and 3% in the brainstem. The clinical presentation of brain metastasis usually is subacute, developing over days or weeks (Table 183-3). Headache is the most common symptom, and focal weakness and change in mental status are the most common signs. In 2% to 5% of cases, an encephalopathy with depressed mood, agitation, decreased memory, and confusion is seen. Visual field loss, ataxia, and aphasia often occur. Seizures may herald the diagnosis in 15% of patients. Intratumoral hemorrhage and tumor embolus can result in the abrupt onset of neurologic symptoms that at times can resemble a stroke. The number of metastatic brain tumors is best determined by a contrast-enhanced brain MRI scan. The lesions appear as solid or cystic masses that enhance with gadolinium and are surrounded by an area of peritumoral edema. In approximately 50% of cases, there is a single metastatic deposit in the brain. Surgical resection

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of a solitary brain metastasis followed by whole-brain radiotherapy is now the accepted treatment for patients with controlled primary disease. This approach has improved both survival and quality of life. When the diagnosis of lung cancer and a solitary brain metastasis is synchronous,surgical treatment of both tumors may result in a better outcome and, in some cases, a cure. An alternative diagnosis must be considered in the setting of a known primary lung neoplasm and a solitary brain mass. Approximately 11% of patients with cancer and a single brain lesion did not have a metastatic tumor. One half of these patients had potentially reversible infectious or inflammatory conditions and the other one half had astrocytomas. When aggressive therapy is considered, tissue should be obtained for a definitive pathologic diagnosis. The management of brain metastases is evolving with improvement in the control of the primary disease, better imaging techniques, and more aggressive treatment. Surgical resection of multiple metastatic deposits (two or three) can be accomplished safely in a patient with controlled systemic disease and a high Karnofsky performance score. Resection of a large symptomatic tumor can be life-saving even when other lesions are present and may provide the time that is necessary to treat the remaining tumors. Stereotactic radiosurgery is a single high-dose radiation treatment to a small-volume target (less than 3 cm in diameter), using a linear accelerator, gamma knife unit, or proton beam. This allows a precise and very effective delivery of ablative radiation to the metastatic tumor, sparing normal brain tissue. The local control rate is more than 85% in most series. The majority of patients were able to discontinue or reduce their dependence on corticosteroid medication. Radiosurgery may offer lower operative and neurologic morbidity for small lesions that are not located in eloquent areas. In a subset of patients (25% to 35%) whose performance status is good and who have controlled local disease and one to three brain lesions, surgery or stereotactic radiosurgery followed by whole-brain radiotherapy can extend survival and improve quality of ,life. Clinical trials are testing the use of stereotactic radiosurgery without whole-brain radiotherapy to treat brain metastasis. Palliative treatment is reserved for patients with poor Karnofsky performance scores, multiple lesions, or advanced systemic disease. Corticosteroids, anticonvulsants, and whole-brain radiotherapy (30 Gy/lO days) benefit 75% of those treated, resulting in a median survival of 3 to 4 months, with 10% to 15% of patients living 1 year. Whole-brain radiotherapy schedules are best determined by prognosis. Patients with a more favorable outlook (small cell lung cancer) should be treated with smaller fractions over a longer interval (40 Gy/4 weeks) to avoid radiation injury (dementia, endocrinopathy).

TABLE 183-3.Symptoms and Signs of Brain Metastasis Percentage

Sims

Symptoms

Headache Focal weakness Mental or behavioral Seizures Ataxia

ADhasia

53 40 31

Hemiparesis Impaired cognition Unilateral sensory

Percentage ofcases 66

77 27

loss

15 20 10

Papilledema Ataxia

Aohasia

26 24 19

~~

From Posner JB: Management of central nervous system metastases. Semh Oncol 4:81-91, 1977.

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Patients with small cell lung cancer who are complete responders (10% of patients) to initial therapy often are offered prophylactic cranial irradiation in the hope of decreasing the high incidence of brain metastases that are reported to occur in as many as 80% of patients living 2 or more years. However, there is no increase in survival in those treated. Chemotherapy is investigative and is generally used when surgery and radiation fail. There are reports of patients with lung cancer and brain metastases who have had excellent responses to the chemotherapeutic agents commonly used to treat the primary lung tumor. Newer strategies including angiogenesis antagonists and epidermal growth factor receptor antagonists are being explored.

SPINAL CORD METASTASES Lung cancer, responsible for 50% of intramedullary spinal cord metastases, is seen clinically in 1% of patients. The disease is rapidly progressive and is almost always associated with sensory symptoms or signs (sensory level, spine or radicular pain) and weakness. A contrast-enhanced MRI scan is the diagnostic procedure of choice. Radiotherapy may relieve symptoms and prolong life.

EPIDURAL SPINAL CORD COMPRESSION Metastases to the epidural space surrounding the spinal cord and cauda equina are the second most common neurologic complication of systemic cancer. Approximately 18,000 new cases of epidural spinal cord compression occur annually in the United States. In most patients, the tumor metastasizes to the vertebral body or neural arch and extends anteriorly to compress the spinal cord or cauda equina. Lung cancer is the most common cause for epidural spinal cord compression in most series. It is more likely than other malignancies to present with spinal symptoms as the initial manifestation of the disease and generally is seen in the first 6 months. Compression occurs most often at the thoracic level (70%), then lumbar (20%), and least often in the cervical area (10%). In 20% of cases, there are multiple areas of involvement. Therefore, an MRI of the entire spine is the diagnostic study of choice. When MRI is not an option, a complete computed tomography myelogram should be done. Back pain is the presenting symptom in more than 90% of cases and must be differentiated from the pain of degenerative arthritis. Radicular pain helps localize the level of involvement. Most patients have pain for weeks before neurologic symptoms develop. Once weakness occurs, there is a rapid progression to paraplegia with little likelihood (less than 5%) of reversibility. Therefore, prompt investigation is needed in the patient with cancer and back pain. Emergency treatment consists of high-dose steroids (100 mg/day dexamethasone for 72 hours and then taper) and external beam radiotherapy. In patients whose primary disease is controlled, surgery, including vertebral body resection, tumor removal, and stabilization of the spine, should be considered. Laminectomy has little to offer because of the anterior location of the pathology. Radiotherapy is the initial treatment provided in neurologically intact patients (see Chapter 177).

CARCINOMATOUS MENINGITIS Leptomeningealor carcinomatous meningitis is less common than brain metastases or epidural spinal cord compression. There is

widespread infiltration of the meninges, with a predilection for the cisterns, sylvian and hippocampal fissures,and cauda equina. This results in symptoms and signs that reflect involvement of multiple sites in the nervous system. Altered mental status, headache, cranial nerve dysfunction, and radicular pain of cervical or lumbosacral origins are described alone or in combination. The diagnosis should be considered when multiple levels of the neuraxis are involved. Adenocarcinoma of lung and small cell lung cancer are the more common primary tumors that invade the meninges, occurring in 2% to 3% of patients. The presence of malignant cells in the cerebrospinal fluid (CSF) is diagnostic. The yield from the first CSF cytology is 50% but is more than 90% after the third spinal tap. It is important to collect an adequate sample (6 to 10 mL) and deliver the CSF to the cytologist promptly. A contrast-enhanced MRI scan of brain and spine may demonstrate enhancement of the meninges, parenchymal metastases (50% of cases), and hydrocephalus in half of patients. Biopsy of the leptomeninges should be considered when the CSF cytology is negative and a definitive diagnosis is needed. Treatment generally consists of irradiating the symptomatic area and administering chemotherapyvia an Ommaya reservoir or intrathecal injection. High-dose intravenous methotrexate followed by calcium leucovorin rescue is a consideration when CSF flow is compromised (CSF protein very high) or nodular deposits are identified. The median survival of patients who have leptomeningeal metastases and lung cancer is 2 to 4 months, with 10% to 15% living 1 year (see Chapter 168).

NONMETASTATIC COMPLICATIONS Of the nonmetastatic complications of lung cancer, metabolic encephalopathy is the most common and usually is caused by multiple abnormalities rather than a single factor. Abnormalities of fluid and electrolyte balance, hypercalcemia, and hepatic failure are the most common. The earliest symptom is change in mental status, which can be subtle at onset and then progress rapidly to stupor and coma. Asterixis, tremor, and myoclonus often are seen in this setting. Medications that sedate or alter mood should be stopped. Wernicke’s encephalopathy is a consideration in some patients, and thiamine should be provided empirically. The syndrome of inappropriate secretion of antidiuretic hormone is reported in 11% of patients with small cell lung cancer. This is related to the presence of neurosecretory granules and other structures that allow the synthesis of hormones, biogenic amines, and a variety of growth factors. This may lead to confusion and seizures. Cerebrovascular lesions are reported to occur in 15% of patients at autopsy. Marantic or nonbacterial thrombotic endocarditis is the most common cause of brain infarction in the patient with cancer. It is seen most commonly with adenocarcinoma of the lung. On postmortem examination, sterile vegetations are present on the heart valves; they embolize and occlude small and medium-size cerebral arteries. Multiple infarctions are described, some hemorrhagic. The presentation can mimic a cerebral infarction in one third of patients but more often presents with either a nonfocal encephalopathicpicture or evidence of multiplevessel involvement. Transesophageal echocardiography identifies the valvular vegetations. The use of heparin remains controversial. Disseminated intravascular coagulation is seen in both small cell and non-small cell lung cancer. Occlusion of small vessels by fibrin emboli causes an encephalopathy with seizures and transient

Chapter 184

focal signs. Laboratory findings include thrombocytopenia, decreased fibrinogen, elevated fibrin split products, and the presence of d-dimer. The prothrombin and partial thromboplastin times are prolonged. Anticoagulation may benefit some patients. Disseminated intravascular coagulation usually is seen in the final stages of the illness. Other cerebrovascular complications of lung cancer include hemorrhagic brain metastases, ruptured neoplastic aneurysm, superior sagittal sinus thrombosis, and subdural hematoma. Complications of cancer treatment include nervous system injury from radiotherapy, direct toxicity of chemotherapeutic agents, and infectious complications that are most often the result of treatment-induced myelosuppression.

PARANEOPLASTIC SYNDROMES Paraneoplastic syndromes seen in lung cancer include limbic encephalitis, opsoclonus-myoclonus, retinopathy, brainstem encephalitis, subacute cerebellar degeneration, necrotizing myelopathy, subacute sensory neuronopathy, Lambert-Eaton syndrome, and dermatomyositis. Small cell lung cancer is more often associated with these syndromes. Many of these patients have the anti-Hu or anti-CV2 antibodies. It is important to remember that paraneoplastic syndromes are very uncommon and may antedate the discovery of the tumor in one half of cases. Therefore, it is imperative to search for evidence of metastatic disease (see Chapter 178).

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SUGGESTED READINGS Adler JR, Cox RS, Kaplan I et ak Stereotactic radiosurgical treatment of brain metastases. J Neurosurg 76444-449, 1992 Boyd TS, Mehta MP Stereotactic radiosurgery for brain metastases, Oncology 13:1397-1409, 1999 Byrn TN: Spinal cord compression from epidural metastases. N Engl J Med 327:614-619, 1992 Coffey RJ, Flickinger JC, Bissonette DJ et a1 Radiosurgery for solitary metastases. Int J Radiat Oncol 201287-1295, 1991 Graus F, Rogers LR, Posner JB:Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 6416-35, 1985 JeyapalanSA, Henson 7w: Neuro-oncologic complications of lung cancer. In Schiff D, Wen PY (eds): Cancer Neurology in Clinical Practice. Humana Press, Totowa, NJ, 2002 Kelly PJ, Kall BA, Goerss SJ et ak Results of computed tomography based computer-assisted stereotactic resection of metastatic intracranial tumors. J Neurosurg 227-17, 1988 Kristjansen P Should current management of SCLC include prophylactic cranial irradiation. Lung Cancer 10 (Suppl 1):319-329, 1994 Patchell RA, Tibbs PA, Walsh JWet al: A randomized trial of surgery in the treatment of single metastasesto the brain. N Engl J Med 3223494-500, 1990 Posner J: Management of central nervous system metastases. Semin Oncol 481-91, 1977 Posner JB:Surgery for metastases to the brain. N Engl J Med 322:544-545, 1990 Sundaresan N, Sachdev W,Holland JF et ak Surgical treatment of spinal cord compression from epidural metastasis. J Clin Oncol 13:23302335, 1995

184 Neurologic Complications of Breast Cancer Lloyd M. Alderson Breast cancer is diagnosed in more than 150,000 women each year in the United States, making it the most common malignant neoplasm in women. One third of patients with breast cancer ultimately develop metastatic complications, often involving the nervous system. Focal infiltration or compression of neural structures by malignant cells is the most common mechanism, but treatment-associated toxicity and paraneoplastic complications also are common. Most neurologic manifestations appear in patients with advanced systemic disease. However, the median survival of patients with metastatic breast cancer is 2 to 3 years, so the early recognition and aggressive treatment of potentially disabling nervous system complications are crucial to preserving the quality of life. This chapter discusses the clinical presentation, diagnosis, and treatment of the neurologic manifestations of breast cancer. Although many of these issues are common to other cancers, this chapter emphasizes the aspects unique to cancer of the breast.

BRAIN METASTASES Brain metastases are the most common neurologic complication of breast cancer, arising in 25% of all patients with metastatic

disease. Among the cancers that often metastasize to brain, breast is second only to lung as a primary site. Patients with infiltrating ductal histology and patients who are younger (less than 55 years) are at the highest risk of brain metastases. It is rare for brain lesions to be the presenting sign of undiagnosed breast cancer. Brain metastases arise from tumor cells that travel through the arterial circulation, and therefore their distribution reflects the anatomy of the circulatory system of the brain. Lesions most commonly arise near the surface of the brain in the distal fields of the internal carotid arteries. The brainstem is an uncommon site for metastases for most patients with cancer, but magnetic resonance imaging (MRI)-basedstudies suggest that the incidence of brainstem and cerebellar lesions is higher in patients with breast cancer than in patients with other carcinomas. As with other malignancies, brain metastases in patients with breast cancer often are multiple. Only one-half of patients presenting with brain metastases have a single lesion. The average interval between the diagnosis of breast cancer and the development of brain metastases is approximately 33 months. The symptoms of brain metastasis from breast cancer usually develop over weeks. Cerebral hemisphere metastases can produce headache, hemiparesis, seizures, or language disturbance. Confu-

Chapter 184

focal signs. Laboratory findings include thrombocytopenia, decreased fibrinogen, elevated fibrin split products, and the presence of d-dimer. The prothrombin and partial thromboplastin times are prolonged. Anticoagulation may benefit some patients. Disseminated intravascular coagulation usually is seen in the final stages of the illness. Other cerebrovascular complications of lung cancer include hemorrhagic brain metastases, ruptured neoplastic aneurysm, superior sagittal sinus thrombosis, and subdural hematoma. Complications of cancer treatment include nervous system injury from radiotherapy, direct toxicity of chemotherapeutic agents, and infectious complications that are most often the result of treatment-induced myelosuppression.

PARANEOPLASTIC SYNDROMES Paraneoplastic syndromes seen in lung cancer include limbic encephalitis, opsoclonus-myoclonus, retinopathy, brainstem encephalitis, subacute cerebellar degeneration, necrotizing myelopathy, subacute sensory neuronopathy, Lambert-Eaton syndrome, and dermatomyositis. Small cell lung cancer is more often associated with these syndromes. Many of these patients have the anti-Hu or anti-CV2 antibodies. It is important to remember that paraneoplastic syndromes are very uncommon and may antedate the discovery of the tumor in one half of cases. Therefore, it is imperative to search for evidence of metastatic disease (see Chapter 178).

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SUGGESTED READINGS Adler JR, Cox RS, Kaplan I et ak Stereotactic radiosurgical treatment of brain metastases. J Neurosurg 76444-449, 1992 Boyd TS, Mehta MP Stereotactic radiosurgery for brain metastases, Oncology 13:1397-1409, 1999 Byrn TN: Spinal cord compression from epidural metastases. N Engl J Med 327:614-619, 1992 Coffey RJ, Flickinger JC, Bissonette DJ et a1 Radiosurgery for solitary metastases. Int J Radiat Oncol 201287-1295, 1991 Graus F, Rogers LR, Posner JB:Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 6416-35, 1985 JeyapalanSA, Henson 7w: Neuro-oncologic complications of lung cancer. In Schiff D, Wen PY (eds): Cancer Neurology in Clinical Practice. Humana Press, Totowa, NJ, 2002 Kelly PJ, Kall BA, Goerss SJ et ak Results of computed tomography based computer-assisted stereotactic resection of metastatic intracranial tumors. J Neurosurg 227-17, 1988 Kristjansen P Should current management of SCLC include prophylactic cranial irradiation. Lung Cancer 10 (Suppl 1):319-329, 1994 Patchell RA, Tibbs PA, Walsh JWet al: A randomized trial of surgery in the treatment of single metastasesto the brain. N Engl J Med 3223494-500, 1990 Posner J: Management of central nervous system metastases. Semin Oncol 481-91, 1977 Posner JB:Surgery for metastases to the brain. N Engl J Med 322:544-545, 1990 Sundaresan N, Sachdev W,Holland JF et ak Surgical treatment of spinal cord compression from epidural metastasis. J Clin Oncol 13:23302335, 1995

184 Neurologic Complications of Breast Cancer Lloyd M. Alderson Breast cancer is diagnosed in more than 150,000 women each year in the United States, making it the most common malignant neoplasm in women. One third of patients with breast cancer ultimately develop metastatic complications, often involving the nervous system. Focal infiltration or compression of neural structures by malignant cells is the most common mechanism, but treatment-associated toxicity and paraneoplastic complications also are common. Most neurologic manifestations appear in patients with advanced systemic disease. However, the median survival of patients with metastatic breast cancer is 2 to 3 years, so the early recognition and aggressive treatment of potentially disabling nervous system complications are crucial to preserving the quality of life. This chapter discusses the clinical presentation, diagnosis, and treatment of the neurologic manifestations of breast cancer. Although many of these issues are common to other cancers, this chapter emphasizes the aspects unique to cancer of the breast.

BRAIN METASTASES Brain metastases are the most common neurologic complication of breast cancer, arising in 25% of all patients with metastatic

disease. Among the cancers that often metastasize to brain, breast is second only to lung as a primary site. Patients with infiltrating ductal histology and patients who are younger (less than 55 years) are at the highest risk of brain metastases. It is rare for brain lesions to be the presenting sign of undiagnosed breast cancer. Brain metastases arise from tumor cells that travel through the arterial circulation, and therefore their distribution reflects the anatomy of the circulatory system of the brain. Lesions most commonly arise near the surface of the brain in the distal fields of the internal carotid arteries. The brainstem is an uncommon site for metastases for most patients with cancer, but magnetic resonance imaging (MRI)-basedstudies suggest that the incidence of brainstem and cerebellar lesions is higher in patients with breast cancer than in patients with other carcinomas. As with other malignancies, brain metastases in patients with breast cancer often are multiple. Only one-half of patients presenting with brain metastases have a single lesion. The average interval between the diagnosis of breast cancer and the development of brain metastases is approximately 33 months. The symptoms of brain metastasis from breast cancer usually develop over weeks. Cerebral hemisphere metastases can produce headache, hemiparesis, seizures, or language disturbance. Confu-

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sion, apathy, depression, and visual field defects may often go unrecognized as symptoms of cerebral metastases located in less eloquent areas of the brain or of multiple small metastases. In the posterior fossa, metastases can cause occipital headache, ataxia, nausea, vomiting, nystagmus, and diplopia. Ocular metastases occur in almost 5% of patients with disseminated breast cancer and should be considered if visual loss is monocular. When a brain metastasis is suspected, the diagnostic study of choice is a gadolinium-enhanced MFU, which is more sensitive for small lesions than enhanced computed tomography (CT). Lesions typically appear round with thick ring enhancement and edema infiltrating the surrounding white matter. Hemorrhage into a brain metastasis from breast cancer is uncommon. In patients with breast cancer who have a single brain lesion and limited-stage systemic disease, causes other than metastases must be considered. In 10% of patients with breast cancer and an enhancing brain lesion who undergo biopsy or resection, the diagnosis of metastasis is incorrect. Meningioma is associated with breast cancer and should be considered when a brain lesion appears to be dural based. When meningiomas do develop in patients with breast cancer, metastasis into the meningioma is an unusual but well-described phenomenon. Venous and arterial infarctions are also associated with breast cancer and can present as an enhancing parenchymal brain lesion. Patients with newly diagnosed brain metastases from breast cancer often benefit from glucocorticoid administration. Dexamethasone (4 mg every 6 to 8 hours) can give dramatic symptomatic improvement by reducing the edema that surrounds the lesion. The chronic administration of high dosages of dexamethasone (more than 8 mg/day) increases the risk of morbidity from side effects (infection, weight gain, hyperglycemia, muscle atrophy, facial and truncal edema); therefore, the dosage should be tapered in the weeks after diagnosis. In some patients it is difficult to reduce the dexamethasone dosage below 2 mg/day, and they may remain steroid-dependent. Anticonvulsants should be administered to patients who develop seizures. For patients who do not present with seizures, anticonvulsants can be withheld until needed. Phenytoin is the anticonvulsant of choice because of its efficacy, ease of management, and low cost. Physicians should be aware of an increased risk of Stevens-Johnson syndrome in patients who are receiving phenytoin during radiotherapy. Valproic acid, carbamazepine, and phenobarbital are also effective, time-tested anticonvulsants, and the chance of any one of these four controlling seizures is about 70%. It is important to monitor drug levels regularly, particularly during chemotherapy or changes in tamoxifen dosage. Some chemotherapy trials are now excluding patients taking drugs that induce p-450 enzymes in the liver (phenytoin, carbamazepine, phenobarbital). Levetiracetam, topiramate, and lamotrigine are alternatives that have less enzyme-inducing activity (although they are not approved by the U.S. Food and Drug Administration as monotherapy). Finally, because most of these drugs are highly protein bound, patients with hypoalbuminemia may experience symptoms of toxicity even when anticonvulsant levels are within the therapeutic range. Radiation, surgery, and chemotherapy have all been used effectively in combination or alone in the treatment of brain metastases from breast cancer. Whole-brain radiotherapy (WBRT) is recommended for the majority of these patients. Prospective studies suggest that it provides symptomatic improvement in approximately half of the patients and significantly prolongs survival. Radiation is administered either in 3-Gy fractions to a

total of 30 Gy over 10 to 14 days or in 2-Gy fractions to 40 Gy over 4 weeks. Although the benefit of surgery in patients with radioresistant metastases has been convincingly demonstrated, its benefit in patients with breast cancer is less clear. However, in patients with one brain lesion and limited or indolent systemic disease, resection of the lesion can result in long-term local control of disease and improvement in neurologic deficits and can help to control seizures. Surgical resection may also be indicated in the patient with symptomatic progression of brain metastases after radiotherapy. Patients who have been treated with surgery alone have a high rate of failure in distal parts of the brain. Therefore, WBRT should be administered after surgical removal of the lesion. A recent development in the therapy of brain metastases is radiation therapy delivered stereotactically as a single dose using either a gamma knife or a linear accelerator. The radiation is precisely focused to deliver a single dose of 9 to 25 Gy to a sharply defined region of the brain. The indications for radiosurgery are similar to those for surgery. Like surgical resection, radiosurgery provides local control in 85% to 95% of treated metastases while avoiding the risks associated with general anesthesia and craniotomy. With this procedure, there is a small risk the patient will need surgical evacuation of necrotic material 3 to 12 months after treatment. The risk of severe radionecrosis limits this technique to lesions that are 3 cm or less in diameter. It remains controversial how many lesions can be treated with focal radiation and still benefit the patient. Most investigators have excluded patients with four or more metastases. Phase I1 studies suggest that patients treated with focal radiation have a better prognosis, but this may reflect bias created by selection criteria. In a recent phase I11 study, patients with three or fewer brain metastases from lung or breast cancer were randomized to either gamma knife alone, WBRT alone, or gamma knife and WBRT. Survival in the latter two groups was identical, but patients treated with gamma knife had better local control. Unlike most malignancies, breast cancer metastases in the brain often respond to chemotherapy. This is particularly important for the patient with a recurrent or progressive brain lesion who has already received maximum radiotherapy. Uncontrolled studies using a variety of protocols in highly selected patients have demonstrated complete or partial responses in more than 50%. Patients who respond often can be identified after the second course of chemotherapy. Recent phase I1 studies suggest that patients treated with WBRT and temozolomide have a smaller chance of treatment failure in the brain than patients treated with radiotherapy alone, but randomized studies have not confirmed this. Adding chemotherapy to radiotherapy has not been shown to prolong overall survival. The prognosis for patients with newly diagnosed brain metastases from breast cancer remains poor. For all patients, the median survival is 5 to 7 months. Indicators of a poor prognosis include age less than 40, progressive systemic disease, and multiple brain lesions. The median survival for patients with a single brain lesion (treated with either WBRT or radiosurgery) and controlled systemic disease is 11 to 13 months. SPINAL CORD COMPRESSION Breast cancer is the most common primary tumor causing spinal cord compression. Tumor cells travel through the blood to the vertebral bodies, and spinal cord compression occurs when the tumor extends beyond the bone into the spinal canal, displacing

Chapter 184

the thecal sac. Metastatic deposits in the vertebral lamina or pedicle are less common but can also be the origin of epidural disease. Another important cause of spinal cord compression is mechanical deformity of the spinal column associated with vertebral body collapse after replacement of bone by metastatic tumor. Pain is the initial symptom in 95% of patients with cord compression and precedes the diagnosis by at least 1 week in the majority of patients. The pain is midline and localized to the spinal segment involved, and there may be a radicular component. Localized back pain usually is dull and constant and is often more marked with bed rest. This is in contrast to back pain associated with most nonmalignant conditions, which improves with rest. Radicular pain can be sharp and exacerbated by movement. Motor symptoms usually follow pain by several weeks, and the presence of weakness indicates an advanced degree of spinal cord compression. Weakness typically begins in the proximal lower extremities and is associated with hyperactive deep tendon reflexes and an extensor plantar response. These abnormal reflexes are important to help differentiate spinal cord compression from other causes of weakness, such as steroid-induced myopathy, in which reflexes and plantar responses are normal. Sensory symptoms include numbness and paresthesias. A sensory level should be sought because this finding helps to confirm the spinal cord as the site of neurologic injury. Bowel or bladder dysfunction is a late finding in patients with spinal cord compression, but it can be the presenting symptom when there is compression of the conus medullaris from a lesion arising in vertebral bodies T10-Ll. With epidural compression of the conus medullaris or cauda equina, urinary retention often is accompanied by flaccid paralysis of both legs, low back pain radiating into the rectum, and perianal anesthesia. It is important to evaluate patients suspected of having spinal cord compression for the presence of bladder distention secondary to urinary retention. With sensory loss, patients may be unaware of urinary retention, and a history of frequent small voiding may be the only clue that bladder catheterization is needed. Any patient with cancer who develops back pain should be considered to have spinal cord compression until it is proven otherwise. Predictors of which patients will develop spinal cord compression include known bone metastases, metastatic disease at initial presentation, objective weakness, and vertebral body compression fracture. When cord compression is suspected, imaging of the spine must proceed with urgency. Plain films can be useful to identify involved vertebrae. A loss of vertical height in a vertebral body of greater than 50% or the loss of a pedicle strongly suggests epidural spinal cord compression. However, MRI or myelography is needed to define the distribution and severity of disease. MRI is the study of choice, but myelography should be used if a good-quality MRI cannot be obtained. MRI will define compression of the thecal sac and displacement of the cord and help define bony lesions, paraspinal disease, and intramedullary spinal cord tumors. Whether MRI or myelography is used, the entire spinal column must be examined in the initial study. Approximately 80% of patients with spinal cord compression have vertebral metastases distant from the point of compression, and as many as 15% of patients with cord compression have synchronous epidural metastases. Corticosteroids are useful in the immediate management of spinal cord compression. An intravenous bolus of 96 mg dexamethasone, given at the time the diagnosis is suspected, followed by 96 mg/day in four divided doses over the following 3 days is recommended. The drug can then be tapered over the

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following 2 weeks. Radiation is the primary therapy for most patients with breast cancer and spinal cord compression and should be initiated with 8 to 12 hours of making the diagnosis. In the majority of patients, radiation maintains or improves neurologic function and provides pain control. Radiation is administered as a 3- to 5-Gy fraction in each of the first 3 days, followed by 2 Gy daily to a total dosage of 40 Gy. The treatment is given through a single posterior port that includes two vertebral bodies above and below the point of compression. Although most patients with breast cancer and spinal cord compression respond to radiotherapy, surgery is indicated in some situations. In patients with limited-stage systemic disease and symptomatic spinal cord compression from metastatic involvement of a single vertebral body, surgical resection of the lesion followed by radiotherapy can result in long-term local control. Patients for whom radiation has failed or who need stabilization of the spinal column may also need surgery. Finally, surgery may be indicated when spinal cord compression results from vertebral body collapse with posterior herniation of disc fragments into the spinal canal. In patients with inoperable cord compression who cannot be treated with additional radiation, chemotherapy can be effective, particularly in those with responsive systemic disease. The most important determinant of neurologic outcome is the functional status of the patient at diagnosis. In a study of 56 patients with breast cancer and spinal cord compression treated with radiation, 89% had improvement in pain control, 60% of those with motor dysfunction improved, and four of six (67%) with bladder dysfunction improved. Patients who cannot walk at the time of diagnosis of spinal cord compression have a much smaller chance of significant neurologic improvement, emphasizing the need for the physician to be consistently vigilant for cord compression in patients with known breast cancer. However, even in paraplegic patients, radiation should be administered to maintain spinal stability and control pain. LEPTOMENINCEAL METASTASES Malignant cells invade the cerebrospinal fluid (CSF) in approximately 5% of all patients with metastatic breast cancer. The incidence of leptomeningeal metastases (LM) from breast cancer may be rising because of longer survivals afforded by more effective systemic therapies. Malignant cells gain access to the leptomeninges primarily from the blood vessels surrounding the CSF space but can also spread directly from brain or epidural metastases. Malignant cells can then disseminate throughout the neuraxis, infiltrating brain, spinal cord, and nerve roots and block CSF resorption, resulting in communicating hydrocephalus. Symptoms and signs of LM are the result of direct infiltration of malignant cells into nerve tissue or interference with the blood supply. The diagnosis of LM is suggested by the clinical presentation of multifocal dysfunction along the neuraxis. Headache occurs in one third of patients with LM and usually is bifrontal. Mental status changes include lethargy, confusion, and memory loss. Fifteen percent of patients with the condition develop focal or generalized seizures. Other nonlocalizing symptoms include nausea and vomiting, lightheadedness, and diabetes insipidus. The clinical presentation of LM often reflects the involvement of both cranial and spinal nerves. Diplopia and oculomotor palsies are the most common cranial nerve findings, occurring in 20% of patients with the condition. Facial weakness, hearing loss, loss of vision, facial numbness, and tongue weakness are also common. Involvement of the tenth cranial nerve can result in hoarseness and

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dysphagia and can lead to aspiration pneumonia. The majority of patients with LM also have signs referable to a spinal root. Weakness of a lower extremity is more common than of the upper extremity, and most of these patients have reflex asymmetry. Patients rarely complain of sensory symptoms, but paresthesias, sensory loss, or radicular pain can occur. Bowel and bladder dysfunction occurs in approximately 10% of patients with LM. Diagnosis is made by the identification of malignant cells in the CSF. Malignant cells are found in only one half of initial cytologic studies from patients with LMs, but the chance of a positive cytology with three examinations is approximately 80%. The less specific indices of elevated total protein, elevated opening pressure, and decreased glucose concentration suggest LM in the appropriate clinical setting. Vascular endothelial growth factor is elevated in most patients with LM, but the assay is not widely available. It is rare for a patient with LM to have a completely normal CSF. Tumor markers in the CSF of cancer patients suffer from low specificity, but if a marker has been shown to be secreted by the primary tumor of a particular patient, elevated levels in the CSF can be diagnostic in the absence of positive cytology, particularly if the concentration in the CSF exceeds that in the blood. CA 15-3 is a marker of tumor progression in some patients with breast cancer and can be useful in diagnosing LM. Untreated, the course of LM is one of progressive neurologic disability and death in a few weeks. Unlike patients with lung cancer or melanoma, however, more than one half of patients with LM from breast cancer respond to therapy, and some patients survive many months after diagnosis. Intrathecal methotrexate and radiation are the primary therapies. Glucocorticoids can help relieve acute symptoms. Methotrexate is administered in 12-mg doses in preservativefree saline directly into the CSF through a surgically placed ventricular catheter (Ommaya reservoir) or by lumbar puncture. With this dosage of methotrexate, therapeutic concentrations remain in the CSF for 36 to 48 hours. To prevent mucositis and myelosuppression, leucovorin (10 mg) is given every 12 hours for four doses starting 24 hours after treatment. CSF cytology, cell count, and total protein are obtained with each treatment to follow the response to therapy. Methotrexate is given two times weekly for 3 weeks, followed by three weekly treatments and then monthly for 4 months. Cytotoxic CSF concentrations of methotrexate (more than 1 pM) can be achieved with IV therapy, but the response rate is lower. Cytosine arabinoside and thiotepa can also be administered intrathecally as second-line agents. Radiotherapy should be administered to symptomatic and radiographically detected areas of leptomeningeal metastases. A total dosage of 30 Gy to the involved area given over 2 weeks is commonly used. Craniospinal radiation is rarely used because of its toxicity to the bone marrow. The survival of patients with breast cancer and LM depends on their response to therapy. Among patients treated with intrathecal methotrexate, the overall median survival is approximately 12 weeks, but in 50% of patients whose disease responds to therapy (with a clearing of malignant cells from the CSF or a significant reduction in CSF protein), the median survival is longer than 6 months. CRANIAL AND PERIPHERAL NEUROPATHY Cranial Neuropathy

Breast cancer can cause cranial neuropathies by neural compression from metastases to the base of the skull. Breast cancer is by far the most common primary tumor to do this, accounting for 17 of

43 cases in one large study. Cranial neuropathy can also occur as a result of cranial radiation, but in this situation the neuropathy usually is bilateral and symmetrical. A skull base metastasis should be considered when cranial neuropathies can be attributed to a lesion in a single location. Orbital metastases can compress the optic nerve or extraocular muscles and result in pain, proptosis, blurred vision, and diplopia. Involvement of the cavernous sinus or parasellar region results in unilateral frontal headache with ocular paresis without proptosis. With metastases to the temporal bone adjacent to the middle cranial fossa, patients have numbness, paresthesias, and pain in the distribution of the second and third division of the trigeminal nerve. Mental neuropathy can result from metastases to the mandibular bone, and breast cancer is the most common primary tumor among patients with this problem. Ipsilateral hearing loss and facial weakness suggest that the petrous portion of the temporal bone is involved. Patients with bone metastases to the region adjacent to the jugular foramen can present with hoarseness, dysphagia, and pain in the posterolateral pharynx. Finally, metastasis to the occipital condyle results in unilateral occipital and neck pain with weakness of the tongue and sternocleidomastoid. The diagnosis of metastases to the skull is made with plain films, CT with bone windows, and radionuclide bone scan. Leptomeningeal metastases should also be considered, particularly when more than one cranial nerve is involved. The treatment for all of these lesions is focal radiation. Brachial Plexopathy

Sensory and motor symptoms referable to the ipsilateral brachial plexus occur in one half of all patients with breast cancer. Many of these patients have undergone surgery and radiotherapy to the region of the chest wall overlying the brachial plexus, making it difficult to determine whether the symptoms are caused by tumor invasion, radiation-induced brachial plexopathy, or nerve damage at the time of surgery (postmastectomy pain syndrome; Table 184-1). Compression of the plexus by tumor has clinical features that distinguish it from other causes of upper extremity sensory and motor disturbances. Pain is the initial and dominant symptom in 80% of patients with tumor invasion of the plexus, with the pain preceding motor dysfunction by weeks to months. The pain typically involves the posterior aspect of the arm and the fourth and fifth fingers of the hand, consistent with involvement of the lower trunk of the plexus (C8 or Tl). A palpable axillary mass sometimes is present, and tumor may be visualized with MRI or CT of the brachial plexus. Compression of the upper trunk (C5, C6) by metastatic tumor to the cervical lymph nodes is less common than lower trunk involvement in patients with breast cancer. In this case, pain is localized to the lateral shoulder, radial forearm, and thumb. Horner’s syndrome may occur secondary to compression of the paraspinal sympathetic nerves by metastatic tumor in the cervical region. Diagnosis may entail surgical exploration and biopsy of the plexus when tumor invasion is suspected but a mass cannot be demonstrated radiographically. An aggressive diagnostic approach is warranted in the patient who can be treated with radiotherapy to the involved area. The treatment of invasive plexopathy is focal radiation, and pain control improves with treatment in the majority of patients. Narcotic analgesics are also useful in the control of debilitating pain. Radiation-induced brachial plexopathy occurs in 10% of patients receiving radiotherapy to the chest wall. In this condition,

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rn TABLE184-1. Causes of Upper Extremity Pain in Patients with Breast Cancer Initial symptoms Distribution Magnetic resonance imaging or computed tomography Treatment

Metastatic Plexopathy

Radiation Plexopathy

Postmastectomy Pain Syndrome

Aching, severe pain followed by weakness Posterior arm and fourth and fifth digits Axillary mass

Paresthesia and weakness

Burning and constricting pain

Shoulder, radial forearm

Chest wall

Loss of tissue planes

Normal

Analgesics, dorsal root entry zone ablation

Topical anesthetic, analgesics

Radiation, analgesics

the nerves are compressed by radiation-induced fibrosis of the soft tissue surrounding the plexus. These changes often are accompanied by lymphedema in the affected arm. Unlike compressive plexopathy, the typical presenting symptom is paresthesias referable to involvement of the upper trunk or whole plexus. Lower trunk involvement alone is rare. Patients with weakness as the predominant initial symptom of plexopathy are much more likely to have radiation-induced brachial plexopathy than metastatic plexopathy. Symptoms begin soon after radiotherapy is complete, and patients who have received radiation fractions of 2 Gy or more-to a total dosage of 60 Gy or more-are more likely to develop radiation-induced brachial plexopathy than patients who have received a lower dosage. The diagnosis is supported by a CT or MRI study showing loss of the normal tissue planes in the area adjacent to the plexus. In both radiation-induced brachial plexopathy and metastatic plexopathy, electromyography shows motor and sensory neuropathy of axonal type, but myokymic discharges are more common in radiation-induced brachial plexopathy. However, electromyography is rarely a useful diagnostic test for these conditions. There is no effective therapy for radiation-induced brachial plexopathy, and two thirds of patients lose some function of the involved arm with time. Surgical lysis of fibrotic tissue has not been helpful, but surgical ablation of the dorsal root entry zone in affected dermatomes can ease the disabling pain that can accompany radiation-induced brachial plexopathy. Patients with postmastectomy pain syndrome can also present with pain in the upper extremity. The pain results from interruption of the intercostal brachial nerve at the time of surgery. A neuroma develops in the severed nerve ending and may serve as a sensitive trigger point for the pain. Symptoms usually begin within 6 months of surgery, and the pain typically is described as a burning and constricting sensation in the posterior aspect of the arm and axilla, radiating across the anterior chest wall. The pain often is exacerbated by movement and improves with immobilization. Pain may respond to therapies given for other neuropathic pain syndromes (tricyclic antidepressants, anticonvulsants, analgesics, and transcutaneous electrical nerve stimulation), and topical anesthetic agents, such as capsaicin, may also be effective. Two less common causes of neuropathy in the upper extremity are cervical disc herniation and radiation-induced nerve sheath tumors. Disc herniation commonly affects the C7 root in isolation. Nerve sheath tumors can occur as a result of radiation to the chest wall, often with a latency of several years. They can be detected with MRI, but surgical exploration usually is needed to make the diagnosis. Peripheral nerves supplying the lower extremities are much less commonly affected by breast cancer than those supplying the upper extremities. Bone metastases to the pelvis and sacrum can compress the sacral plexus or adjacent nerves, particularly the

sciatic nerve. When bilateral signs or urinary incontinence is present, a careful evaluation for compression of the cauda equina is indicated. CEREBROVASCULAR COMPLICATIONS Cerebrovascular complications are associated with a variety of malignancies, including cancer of the breast. Although the most common cause of hemorrhagic or ischemic infarction in patients with cancer is atherosclerosis, the cancer itself sometimes can cause neurologic dysfunction through direct or indirect effects on the blood, the heart, or the vessels. When stroke occurs in a patient with breast cancer, it can result from one of the paraneoplastic cerebrovascular syndromes. The three most common of these are intravascular coagulation, nonbacterial thrombotic endocarditis, and cerebral venous thrombosis. Early recognition and treatment of patients presenting with these syndromes can prevent further neurologic deterioration. Intravascular coagulation results in fibrin deposits in the terminal branches of multiple cerebral arteries, resulting in small hemorrhagic or ischemic infarctions. Patients commonly present with fluctuating signs of diffuse cerebral dysfunction, such as delirium, stupor, and generalized seizures, signs that are sometimes incorrectly ascribed to metabolic encephalopathy. Symptoms usually precede the laboratory abnormalities of decreased fibrinogen and platelets and elevated split fibrin products. In patients who present with these symptoms and have laboratory evidence of disseminated intravascular coagulation, an evaluation for treatable causes, such as occult infection, should be made. The role of systemic anticoagulation remains controversial. Nonbacterial thrombotic endocarditis occurs in patients with carcinoma of the breast and can precipitate stroke. In this syndrome, an aseptic vegetation, which can form a nidus for emboli to the brain and other organs, develops on the mitral or aortic valve. Patients present with an acute neurologic deficit or may have multiple transient deficits. Involvement of systemic organs is common, but the presenting signs usually are neurologic. Most patients have elevated prothrombin times and decreased platelets, and one third have laboratory evidence of disseminated intravascular coagulation. Echocardiography and cerebral angiography can help make the diagnosis. Patients may improve with successful treatment of the primary tumor, and in patients with limited systemic disease, anticoagulation may prevent additional infarction. Thrombosis in the dural venous sinuses is also associated with breast cancer. The presenting signs and symptoms include headache, seizures, hemiparesis, visual field defects, and mental status changes. Laboratory study results often are normal, but MRI or cerebral angiography demonstrates venous sinus occlusion. In patients with breast cancer, tumor involvement of dural or calvarial structures adjacent to the sinus can precipitate venous

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sinus thrombosis. It is important to identify this condition because the dural metastasis is likely to respond to radiotherapy. Intravenous heparin therapy is also controversial in this syndrome, but the risk of hemorrhage in patients anticoagulated for this problem is low and is probably outweighed by the potential benefits. Tumor embolus is a potential cause of stroke in patients with breast cancer. The embolus originates in the lung, and stroke from this cause carries a particularly grave prognosis.

METABOLIC ENCEPHALOPATHY Diffuse encephalopathy with o r without focal signs can be a prominent sign of many of the neurologic and systemic complications of breast cancer. In the majority of patients, diffuse encephalopathy is the result of multiple metabolic o r nutritional abnormalities related to the underlying cancer. However, focal findings on neurologic examination should prompt a search for a structural brain lesion. Causes of metabolic and toxic encephalopathy in patients with cancer are listed in Table 184-2.

PARANEOPLASTIC SYNDROMES Paraneoplastic syndromes are disorders of unknown cause that occur with increased frequency in patients with cancer. The identification of a neurologic paraneoplastic syndrome is important because the symptoms may precede the diagnosis of cancer by several months, allowing identification of the malignancy at an early stage. In patients with breast cancer, the most common of these rare disorders is subacute cerebellar degeneration. The symptoms are ataxia, dysarthria, nystagmus, and vertigo. MRI of

TABLE184-2. Causes of Encephalopathy in Patients with Breast Cancer Metabolic Hypoxemia Sepsis Hypoglycemia Uremia Electrolyte imbalance Hypercarbia (carbon dioxide narcosis) Hepatic failure Nutritional deficiency Thyroid disorder Toxic Sedative or narcotic intoxication Clucocotticoids Alcohol or other drug overdose Chemotherapeutic agents Anticonvulsants Anticholinernics

the brain fails to show a focal lesion but may demonstrate cerebellar atrophy. Pathologically, there is a striking loss of Purkinje cells. In many of these patients, a circulating antibody (anti-Yo) that binds to proteins shared by breast tumor cells and Purkinje cells can be identified. Another syndrome that occurs in patients with breast cancer is characterized by opsoclonus, ataxia, vertigo, and a vertical gaze palsy. Occasional patients with this latter syndrome harbor an antibody (anti-Ri) that reacts with tumor and neuron proteins. Other paraneoplastic syndromes that have been reported in patients with breast cancer include peripheral neuropathy, dermatomyositis, subacute myelopathy, and parkinsonism with degeneration of the substantia nigra. These syndromes are discussed in Chapter 178.

SUGGESTED READINGS Anderson NE, Rosenblum MK, Posner JB: Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol 24: 559-567, 1988

Boogerd W Neuro-oncologic complications of breast cancer. In Schiff D, Wen PY (eds): Cancer Neurology in Clinical Practice. pp. 309-326 Humana Press Totowa Press, Totowa NJ, 2002 Boogerd W, Hart AA, van der Sande JJ, Engelsman E Meningeal carcinomatosis in breast cancer. Cancer 67: 1685, 1991 Boogerd W, Vos VW, Hart AA, Baris G Brain metastases in breast cancer: natural history, prognostic factors and outcome. J Neurooncol 15:165, 1993

Firlik KS, Kondziolka D, Flickinger JC et a1 Stereotactic radiosurgery for brain metastases from breast cancer. Ann Surg Oncol 7(5):333-338, 2000

Graus F, Rogers LR, Posner JB: Cerebrovascularcomplications in patients with cancer. Medicine 64:16, 1985 Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 25(2):103-119, 1999 Henson JW, Posner JB: Neurological complications. p. 2268. In Holland JF (ed): Cancer Medicine. 3rd Ed. Lea & Febiger, Philadelphia, 1993 Hill ME, Richards MA, Gregory WM et al: Spinal cord compression in breast cancer: a review of 70 cases. BJM 68:969, 1993 Kori S, Foley KM, Posner JB: Brachial plexus lesions in patients with cancer: 100 cases. Neurology 31:45, 1981 Kreusel KM, Weigel T, Stange M et al: Intraocular metastasesof metastatic breast carcinoma in the woman. Ophthalmologe 97(5):342-346, 2000 Lentzsch S, Reichardt P, Wber F et al: Brain metastases in breast cancer: prognostic factors and management. Eur J Cancer 35(4):580-585, 1999

Lu C, Stomper PC, Drislane FW et al: Suspected spinal cord compression in breast cancer patients: a multidisciplinary risk assessment. Breast Cancer Res Treat 51(2):121-131, 1998 Olsen NK, Pfeiffer P, Mondrop K, Rose C: Radiation-induced brachial plexopathy in breast cancer patients. Acta Oncol 27:885, 1993 Solberg A, Bremnes RM: Metastatic spinal cord compression: diagnostic delay, treatment and outcome. Anticancer Res 19( lB):677-684, 1999

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CARDIOLOGY AND CARDIAC SURGERY

185 Neurologic Complications of Cardiac Surgery Jon Brillman From the earliest days of cardiac surgery it has been apparent that neurologic complications were the most serious sequelae of these procedures. Despite improvements in surgical technique and extracorporeal circulation, a variety of neurologic syndromes remain associated with the operations. Technologic advances have made it increasingly possible since the 1980s for older patients (older than 70 years) to undergo coronary artery bypass graft (CABG) operations with low morbidity. The downside of this trend is that these patients have more advanced atherosclerosis and consequently suffer a higher incidence of cerebral sequelae. A large prospective study looking in central nervous system outcomes in more than 2000 patients found an adverse rate of cerebral outcomes in 6.1%.Approximately half have what were described as type 1 outcomes (focal injury, stupor, or coma) and the remainder type I1 outcomes (deterioration in the intellectual function, memory deficit, or seizures). It was certainly not surprising that patients who had adverse outcomes had a higher incidence of lengthy hospital stays, mortality, and nursing home placement. An additional problem has developed because straightforward cases with two- or three-vessel disease are selected for percutaneous coronary interventional techniques, thus postponing the age of referrals for patients with CABG. In addition, coronary bypass procedures seem to be more difficult if the vessels have been dilated or stented. Early reports of neurologic disorders associated with openheart operations were attributed to hypotension and macroembolic events from diseased valves. It is now evident that the major central neurologic complications of stroke and encephalopathy usually are unpredictable and that intraoperative hypotensive episodes or clear-cut embolic sources are not often found. Strokes, which occur with an incidence of 2% to lo%, are now known to result not only from cardiac emboli but from atheromatous emboli from an ectatic, rigid aorta during aortotomy or crossclamping. The coexistence of carotid stenosis with coronary artery disease increases the risk of stroke to a minor degree, and how it should be handled preoperatively is still debated. Severe encephalopathy, characterized by a delay in extubation and emergence from anesthesia, small reactive pupils, and restlessness or agitation, is a serious complication, occurring in 5% to 15% of cases and having a high mortality rate. Despite the fact that patients are on extracorporeal circulation with an artificial pump oxygenator for up to 2 hours, surgical factors may play a more important role in encephalopathy than does extracorporeal circulation. Another issue, yet to be fully defined or explained, is that of minor cognitive changes after cardiopulmonary bypass proce1188

dures. Such changes are found on neuropsychiatric testing in up to 25% of patients (Fig. 185-1). The extent to which these changes affect the lives of the increasingly older population undergoing heart operations is not yet known and is under intense study. This chapter deals with the various neurologic complications in common cardiac operations and discusses what is known about their pathogenesis. The last 5 years have seen increased attention to measures that may prevent neurologic sequelae such as off-pump coronary artery bypass (OPCAB) using composite arterial grafting. STROKE In cardiopulmonary bypass procedures, stroke occurs with an incidence of 0.9% to lo%, depending on whether one examines prospective or retrospective studies. Combination CABG and valve operations have a somewhat higher incidence. Territorial infarcts result from microemboli from diseased valves, left ventricular or atrial thrombi, and atheromatous emboli from a rigid aorta. Watershed strokes caused by hypoperfusion are seen but are rare. A review of the neuroimaging studies in 30 patients who suffered stroke after CABG surgery found that computed tomography scans along with results of six angiograms suggested that most of the infarcts resulted from microemboli from the heart. A retrospective analysis of 126 patients with a history of ischemic stroke who underwent open-heart surgery demonstrated a 13.4% incidence of new strokes or worsening of prior deficits but a small percentage (3.2%) that were moderate or severe in degree. Accordingly, it is recommended that CABG surgery in 54 patients found that the presence of a cervical bruit only slightly increased the risk of stroke (by 2.9%) and that a history of transient ischemic attack, prolonged pump times (more than 2 hours), atrial fibrillation, and congestive heart failure increased the risk of postoperative stroke. Patients with advanced age, hypertension, diabetes, peripheral vascular disease, and pulmonary disease generally pose the highest risk. For reasons that are unclear, it has been reported that female sex is independently associated with a higher risk of postoperative stroke. Despite these studies, the cause of stroke after most cases of CABG surgery often is obscure and usually unanticipated. PreCABG endarterectomy remains a controversial procedure, and the clinician’s judgment remains the most important factor in determining whether it should be carried out in the presence of a carotid bruit or Doppler-demonstrated carotid stenosis. Most recommend that endarterectomy be considered independently of cardiac considerations. That is, if a patient has a surgically accessible carotid stenosis that is more than 70% stenotic and is appropri-

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FIG. 185-1. Graph showing the neurologic deficits

after coronary artery bypass graft surgery. (From Rodewald C: Introduction to the subject. p. 175. In Willner AE, Rodewald D (eds): Impact of Cardiac Surgery on the Quality of Life. Plenum, New York 1990. with permission.)

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ate to the clinical symptoms, an endarterectomy should be performed earlier than the CABG procedure, in accordance with the widely accepted data from the North American Symptomatic Carotid Endarterectomy Trial. Most studies have demonstrated that simultaneous endarterectomy and coronary revascularization procedures produce unacceptable rates of complications, which include stroke and vascular death. Atheromatous emboli from the heart and ascending aorta are emerging as a significant risk for stroke and death in the increasinglyaging population undergoing open-heart surgery and CABG surgery and as an independent risk factor have an odds ratio of 4.5. One group found a high correlation of cerebral atheromatous emboli and severe ascending aortic arteriosclerosis in autopsied patients who underwent cardiac surgery. Others have found that intraoperative echocardiography may be able to identify patients at high risk for emboli from this source. Epiaortic scanning is increasingly being used in larger centers to screen patients who may be stroke prone, including patients who have calcification of the ascending aorta on chest x-ray or on intraoperative direct palpation. If epiaortic scanning becomes standard, this brief and simple procedure in the operating room can guide the surgeon to select alternative areas for aortotomy or elect not to use side-bite clamps, whose application and release have been demonstrated to be sources of microemboli and probable sources of stroke. Clearly, manipulation of a severely arteriosclerotic aorta with an aortotomy and aortic cross-clamping is a significant risk factor for stroke in this group of patients. In the future, surgeons may want to use intraoperative echocardiography to identify portions of the aorta less calcified for the site of aortotomy or placement of cross-clamps. Rare circumstances of hypoperfusion that occur during CABG procedures may lead to watershed infarctions. These are particularly devastating and almost always leave patients significantly impaired. Hypotension is uncommon intraoperatively but certainly may occur under certain circumstances. At least one study has demonstrated that increasing the mean arterial pressure while on bypass may reduce the incidence of postoperative stroke. Avoiding manipulation of the aorta obviously is critical in stroke prevention. The most effective way to achieve this is by OPCAB and composite arterial grafts. Evidence now suggests that the use of arterial grafts rather than venous grafts reduces aortic manipulation and probably will reduce stroke.

8 WEEKS TIME POST SURGERY

12 MONTHS

Surgeons now are acutely aware that post-CABG stroke is associated with 10 times greater mortality and substantial economic burden by doubling hospital stay and cost. Surgeons are now doing whatever is needed to avoid extensive aortic manipulation, including avoiding side-bite clamps and promoting the use of bilateral internal thoracic arteries, the gastroepiploic artery, the inferior epigastric artery, and occasionally radial artery as sources of coronary grafts. Circulating prothrombotic factors are altered during cardiopulmonary bypass, as in the case of elevated levels of fibrinopeptideA and thromboxane B,, but the extent to which this contributes to stroke is as yet unknown. Open-heart procedures for valve replacement pose a special problem because of the possibility of air emboli. Intraoperative transcranial Doppler studies have demonstrated that these emboli are most likely to occur during the redistribution of blood from the heart-lung machine to the patient when the heart is reactivated and begins to eject actively. Air emboli do not cause large vessel occlusions, however, and the evidence suggests that they are more likely to be associated with encephalopathy because of their extreme small size and widespread distribution during cardiopulmonary bypass procedures. Post-CABG stroke is associated with a 10-fold increase in postoperative mortality and doubles the length of hospital stay and cost. OPCAB and multiple arterial donor grafts have already shown to be associated with reduced stroke risk and are likely to be used more in future CABG procedures. HYPOTENSION AND CEREBRAL BLOOD FLOW DURING CARDIOPULMONARY BYPASS PROCEDURES Encephalopathy after cardiopulmonary bypass-both CABG encephalopathy and encephalopathy associated with open-heart procedures-mimics the result of bilateral diffuse frontal lobe ischemia. Because the patient undergoing cardiopulmonarybypass procedures is on extracorporeal circulation for a period that may last 1 or 2 hours, one would suspect that impairment of brain perfusion would be an important mechanism of brain injury. Intraoperative hypotension during these procedures certainly may occur under extreme and unusual circumstances, but it is rare. Indeed, a perusal of the intraoperative records of patients who have suffered encephalopathy after heart surgery rarely reveals

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approach. Under this circumstance, the lower limit of autoregulation appears to be about 30 mm Hg. Although the addition of carbon dioxide during the procedure increases cerebral blood flow, most studies show that there is a corresponding fall in oxygen extraction in the brain and that the vasodilation that may occur may increase the risk of embolic load, which may be a more important factor in neurologic sequelae. Cerebral blood flow, as determined by xenon washout and mean flow velocities as demonstrated by intraoperative transcranial Doppler technique, demonstrate a fall in cerebral blood flow and flow velocities after induction of anesthesia to a slight degree, followed by a rise after hemodilution. During hypothermic cardiopulmonary bypass, however, cerebral blood flow falls at an average of 1% per minute but then rises again during rewarming. Therefore, despite reductions in cerebral flow at moderate hypothermia during cardiopulmonary bypass, neurologic complications as a consequence of this appear to be rare because of intact autoregulation and increased oxygen extraction of the brain. In summary, it appears that hypotension is rarely seen during cardiopulmonary bypass in open-heart and CABG procedures. The decline in cerebral blood flow that occurs during hypothermia seems independent of neurologic outcome after procedures. The increasing number OPCAB procedures probably will not be associated with hypoperfusion.

evidence of hypotension occurring during the procedures. Hypotension perioperatively may be related to left ventricular failure, arrhythmias, or blood loss, but when the patient is on the pump, the circulatory status is controlled by the perfusionist. Nevertheless, if hypotension occurs, it is attributable to decreased peripheral vascular resistance that may result from hemodilution with crystalloid prime, warming of the hypothermic patient, and anesthetic agents. Years of experience and animal experimentation have shown that 50 mm Hg is a safe mean arterial pressure during cardiopulmonary bypass procedures. Figure 185-2 shows that in more than 300 patients studied, only 2% have pressures of less than 50 mm Hg, and most pressures fall well within the safety margin that has been established over the years. In fact, under circumstances of hypothermia with the patient’s body temperature cooled to 27°C or 28OC, 30 mm Hg has been shown to be a mean arterial pressure that is quite safe in terms of cerebral protection. Perfusion flow rates maintained by the perfusionist usually are around 2.2 or 2.4 L/min/m2 of body surface using a roller or centrifugal pump (nonpulsatile or pulsatile flow). Under hypothermic conditions, lower flows, even as low as flow rates of 1.2 to 1.4 Llminutelm’, have been shown to be safe and in fact are believed to be protective by some investigators, reducing the likelihood of cellular edema of the brain. Investigations designed to determine whether hypotension causes postoperative cerebral damage show conflicting results. Some have found that timedependent hypotension (less than 50 mm Hg) tended to impair cerebral function and slow the electroencephalogram. However, Slogoff and colleagues (1982) found no relationship between perfusion pressures, length of cardiopulmonary bypass, and neurologic dysfunction in a large number of patients. Cerebral blood flow is reduced during moderate hypothermic cardiopulmonary bypass (Fig. 185-3). After the induction of hypothermia to moderate levels (28OC), gases such as carbon dioxide go into solution. Therefore, two different strategies have evolved regarding Pco, management during hypothermic cardiopulmonary bypass. The first option of management, which is called a-stat management, maintains the Pco, by 50% and significantly increases cerebral blood flow. However, evidence suggests that neurologic outcome is not altered by this strategy and that cerebral autoregulation is best maintained by using the a-stat

MICROEMBOLI A unique neuropathologic observation by Moody et al. (1990) has provided significant information about the pathogenesis of the cognitive decline after cardiopulmonary bypass procedures. These investigators demonstrated the presence of capillary and small arterial dilations in the penetrating vessels of the brain in patients after cardiac surgery and aortography. Using an alkaline phosphatase stain that reacts strongly with small arterioles and capillaries (5 to 50 pm), a map of the small intracerebral circulation was provided without the disruptive effects of intravascular injection. Millions of these vascular abnormalities, called small capillary arterial dilations, appeared as sausage-like dilations, usually multiple, along the penetrating small vessels with intact capillary or arterial walls and empty lumens (Fig. 185-4). They were

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FIG. 185-4. A medium-size arteriole (arrow) in a patient who underwent cardiopulmonary bypass surgery, showing small capillary arterial dilations. The swollen areas are clear and have intact vascular walls. (From Moody DM, Bell MA, Challa VR et al: Brain microemboli during cardiac surgery or aortography. Ann Neurol 28:477-486, 1 990, with permission.)

thought to represent the ghosts of microemboli that had either dissolved or passed on. The actual composition and source of these emboli remain unknown. The real-time identification of cerebral microemboli may be accomplished by both retinal fluorescein angiography and transcranial Doppler examination. In 1971, emboli were observed in the retina during surgery on bypass. Using a fundus camera, investigators have demonstrated a 100% incidence of microvascular occlusions in the retina with fluorescein angiography, believed to be caused by microemboli (less than 200 ym) during CABG surgery. Because these microvascular occlusions were observed in patients who underwent cardiopulmonary bypass surgery using bubble oxygenators, it was conjectured that the bubble oxygenator was the source of the microemboli. Therefore, oxygenator type plays a role in microembolic events. Accordingly, a brief discussion of the different types of oxygenators and bypass apparatus follows. The basic cardiopulmonary apparatus is shown in Figure 185-5. Deoxygenated blood is drained by gravity from the right atrium into a large reservoir, where it is diluted to approximately 50% of its hematocrit value by crystalloid prime. A centrifugal or roller pump, which produces laminar nonpulsatile flow in most cases, directs the blood through the oxygenator. The blood is then returned to the patient through a 40-ym arterial line filter. Even now, arterial line filters are not always used. Oxygenated blood is circulated through the aortotomy to the various organs. Pumps are present that continually drain the left ventricle so that the surgeon may operate in a bloodless field for the decompressed heart. oxygenators the Oxygen directly into blood using a direct blood%as interface, and the gaseous exchange takes Place at the surface of the bubbles. However, ~ ~ ~ b r a n e oxygenators more closely simulate the capillary-alveolar membrane and therefore are more closely related to pulmonary

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Artery filter

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185-5. Basic cardiopulmonary bypass apparatus. (From Casthely PA: The anatomy of cardiopulmonary bypass. pp. 23-35. In Casthely PA, Bregman D (eds): Cardiopulmonary Bypass: Physiology, Related Complications and Pharmacology. Futura, Mt Kisco, NY, 1991, with permission.)

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capillaries. In this type of oxygenator, a semipermeable membrane is placed between the blood and gas, and microbubbles are not formed. Most institutions that perform cardiopulmonary bypass procedures recognize that membrane oxygenators are less likely to be a source of microbubbles, so bubble oxygenators are in limited use. Transcranial Doppler has proved to be an excellent tool in detecting microemboli, particularly during cardiopulmonary bypass surgery. Using a 2-mHz probe fixed over the temporal window, microemboli varying in size from 50 ym to several hundred micrometers in diameter may be consistently detected. These presumed microemboli have been found by numerous investigators and appear as high-amplitude flow disturbance signals that produce an audible blip and can be clearly distinguished from flow signal and artifact (Fig. 185-6). These signals are often called high-intensity transient signals. Clinically, emboli may be detected in patients who have biomechanical heart valves and are found three to five cardiac cycles after an intravenous injection of air for contrast-enhanced echocardiography. High-amplitude Doppler signals were identified in 54% of patients with mechanical prosthetic heart valves. Similar signals could not be found in patients who had received

biologic prosthetic heart valves. Recent studies have shown that high-intensity transient signals are most common during precannulation; aortotomy; insertion and removal of the aortic cannula, vent, and cardioplegia needle; aortic cross-clamp (total and partial) and clamp removal; defibrillation; and displacement of the heart and other maneuvers. Therefore, the widespread use of membrane oxygenators has removed the threat of many of these events coming from the heart-lung machine, but they still occur in great numbers as a result of surgical maneuvers. Studies have shown that high-intensity transient signals may be correlated with declining cognitive function postoperatively. We have found that neurologic complications with encephalopathic features are most commonly associated in patients who have had more than 60 microembolic events intraoperatively. Higher numbers of microemboli are also associated with neurocognitive decline from preoperative to postoperative intervals in patients who appear to be asymptomatic. Microembolic events occur most commonly as a consequence of surgical maneuvers, particularly cardiac manipulation and aortotomy and cross-clamp application and removal. The emboli that result from these procedures are most likely to result in neurologic symptoms and signs postoperatively. Emboli also occur from the perfusion apparatus, and although greater

Chapter 185 W

numbers of these are associated with neurocognitive decline, they do not appear to be as serious and produce less neurologic dysfunction than those from the surgical technique. The use of membrane oxygenators, arterial line filtration, repeated de-airing of the heart, positioning of the patient, and reduced manipulation of the heart to inspect posterior anastomoses during CABG procedures may well be beneficial in reducing the number of these unwanted events. Because the microemboli are far too small to obstruct cerebral vessels, it is not completely understood how neurologic dysfunction may ensue. Evidence from experimental models in animals suggests that microemboli, which pass through even the smallest circulation, may reduce cerebral blood flow and impair neuron function, as is evidenced by reduced somatosensory evoked potentials. Microemboli therefore occur in large numbers during cardiopulmonary bypass procedures and are readily detected by transcranial Doppler examination intraoperatively. Because significant alterations in cerebral perfusion pressure are rare and poorly correlated with cognitive dysfunction or neurologic sequelae, it is likely that microemboli play a significant role in postoperative neurologic disorders, especially encephalopathy. ~

OTHER POSSIBLE ETIOLOGIC FACTORS The possibility that functional capillary closure in the brain may result from nonpulsatile flow during cardiopulmonary bypass procedures and that this may play a role in neurologic damage must be clarified further. One study found an increase in cerebral blood flow and cerebral metabolic rate for oxygen in 11 randomized patients who were switched from nonpulsatile to

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pulsatile flow using a pump head interrupter. The reversal of the reduction of cerebral flow by the addition of pulsatile perfusion suggests that an increase in cerebral blood flow may result solely from changes in the arterial waveform characteristics. Until now, the role of pulsatile perfusion in preserving brain function was not well understood, and some investigators have found that pulsatile perfusion does not correlate with improved neurologic outcome. Indeed, nonpulsatile or laminar flow is the preferred mechanism of ejecting blood during open-heart procedures. Neuroradiologists have shown interest in patients undergoing cardiopulmonary bypass procedures. Reference has already been made to the pattern of cerebral infarction on computed tomography scanning, and examination of computed tomography scans in stroke patients has confirmed that cerebral infarctions postoperatively are territorial in nature and are not caused by diffuse perfusion deficits. Although diffuse cerebral edema has been demonstrated on magnetic resonance imaging immediately after CABG surgery, the significanceof this is uncertain, and its relation to neurologic or neurocognitive decline is unknown. Other investigators have found no new cerebral lesions on contrastenhanced magnetic resonance imaging after cardiopulmonary bypass. It is likely that further investigations of brain functions such as measurement of high-energy phosphates using magnetic resonance spectroscopy and evaluation of cerebral blood flow and metabolism by position emission tomography scanning will shed further light on brain damage in this group of patients. A systemic inflammatory response syndrome has been demonstrated during cardiopulmonary bypass. This appears to be a nonspecific activation of platelets and leukocytes and obstruction of the microvascular bed. Aprotinin, a serum protease enzyme inhibitor that has powerful anti-inflammatory properties,

FIG. 185-6. Transcranial Doppler monitoring shows a shower of microemboli coinciding with manipulation of the heart during graft inspection near the end of a coronary artery bypass graft procedure.

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has been shown to decrease white cell activation and transmigration and has anti-inflammatory effects similar to that of corticosteroids. Therefore, the syndrome plays some role in postcardiopulmonary bypass procedures, but its role has not yet been fully defined. MARKERS OF BRAIN DAMAGE

With respect to the activities of daily living in this patient population, the significance of the established markers for either cognitive impairment, brain damage, or neuronal damage is uncertain. After a period of time most patients seem to function normally despite the fact that some recent studies have demonstrated that after a period of modest improvement there may be long-term deterioration in intellectual and neurologic function. Of course, the patients undergoing cardiopulmonary bypass procedures are older adults, and cognitive decline is to be expected. Cognitive testing is considered significant if there is one standard deviation or 20% decline from preoperative to postoperative testing. Protein SlOOB is another marker for cerebral injury and can be used as an index of cerebral injury after cardiac surgery. Higher levels of protein SlOOB occur after valve operations and hypothermic circulatory arrest procedures. Others have been unable to demonstrate any correlation between this marker of neuronal injury and cognitive dysfunction. As noted, magnetic resonance imaging in selected patients has demonstrated some diffuse cerebral edema postoperatively. The pathogenesis of this is unclear but may be related to a systemic inflammatory response syndrome. It seems clear that operative techniques and a reduction in the manipulation of the aorta and the graft sites may be more important in the pathogenesis of stroke and even cognitive disorders than the bypass apparatus itself. Accordingly, the technology has now advanced to the point that increasing numbers of OPCAB procedures are being performed with composite arterial grafts, producing a so-called no-touch aortic technique that will undoubtedly lead to better neurological outcomes and long-term survival. Clearly, microemboli have been demonstrated to be reduced in number in patients undergoing OPCAB. Several agents have been studied to provide pharmacologic neuroprotection during coronary artery bypass procedures including thiopental, sufentanil, and calcium channel antagonists. To date, as with several stroke trials, no agent has been found to be beneficial. Because of its anti-inflammatory action, aprotinin has been demonstrated to be a promising agent and continues to be evaluated for its role in cerebral protection. PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF CARDIOPULMONARY BYPASS PROCEDURES

The peripheral nervous system may be damaged in open-heart and CABG procedures. Fortunately, most of the neuropathies and plexopathies that result are transient and reversible. The most common peripheral neurologic injury reported in cardiopulmonary bypass procedures is that of brachial plexus damage. In most cases, the lower trunk or medial cord fibers are involved, as confirmed by clinical and electrodiagnostic evaluation. The mechanism of injury has been reported to be attributable either to traumatic cannulation of the internal jugular vein on the side of the injury or to excessive traction on the brachial plexus

after sternotomy with fracture of the first cervical rib. Ulnar neuropathies, usually reversible after 4 to 6 weeks, are fairly common and result from compression of the nerve at the elbow, particularly during prolonged procedures. Peroneal neuropathies and saphenous neuropathies have also been reported and are caused by either direct compression of the peroneal nerve around the fibular head or stretching of the saphenous nerve. The extent to which hypothermia renders the peripheral nervous system susceptible to damage during these procedures is conjectural, but it is known that both axonal degeneration and myelin breakdown may occur during exposure to extreme cold. An additional problem involving the peripheral nervous system with some more serious consequences is that of hemidiaphragmatic paralysis resulting from phrenic nerve injury, the result of exposure of the phrenic nerve to the topical ice-saline slush that is commonly used to maintain cardiac hypothermia during cardioplegic arrest. In one series, 54% of patients undergoing CABG surgery exhibited abnormal diaphragmatic motion. Postoperatively, phrenic nerve conduction studies demonstrated a high percentage of abnormalities ipsilaterally. Although some degree of diaphragmatic paresis may persist in up to one quarter of patients, it appears to have little morbidity, although prolonged hospital stays have been noted in patients with phrenic nerve injuries. Care to insulate the nerve during these procedures may limit damage to the phrenic nerve. SUGGESTED READINGS Berger MP, Tegeler CH: Transcranial Doppler detection of emboli. pp. 232-241. In Babikian V, Weschler L (eds): Transcranial Doppler Ultrasonography. Clinical and Research Application. Mosby, St Louis, 1993 Blauth CI, Arnold JV, Schulenberg WE et al: Cerebral microembolism during cardiopulmonary bypass: retinal microvascular studies in vivo with fluorescein angiography. J Thorac Cardiovasc Surg 95:668, 1988 Brillman J: CNS complications of coronary artery bypass surgery. Neurocardiology 11:474-495, 1993 Clark RE, Brillman J, Davis D A Microemboli during CABG genesis and effect on outcome. J Thorac Cardiovasc Surg 109:249-258, 1995 Coffey CE, Massey EW, Roberts KB et ak Natural history of cerebral complications of coronary artery bypass graft surgery. Neurology 33:1416, 1983 DeVita MA, Robinson LR, Rehder J et ak Incidence and natural history of phrenic neuropathy occurring during open heart surgery. Chest 1032350, 1993 Gilman S: Neurological complications of open heart surgery. Ann Neurol 28:475, 1990 Hammon J, Stump D, Butterworth J, Moody D: Approaches to reduce neurologic complications during cardiac surgery. Semin Thorac Cardiovasc Surg 13:184-191, 2001 Hanson MR, Bever AC, Furian AJ et ak Mechanism and frequency of brachial plexus injury in open-heart surgery: a prospective analysis. Ann Thorac Surg 36:675, 1983 Harris DNF, Bailey SM, Smith PLC et ak Brain swelling in first hour after coronary artery bypass surgery. Lancet 342:586, 1993 Hise JH, Nipper ML, Schmitker J C Stroke associated with coronary artery bypass surgery. Am J Neuroradiol 12:811, 1991 Lederman RJ, Brever AC, Hanson MR et al: Peripheral nervous systems complications of coronary artery bypass graft surgery. Ann Neurol 12:297, 1982 Moody DM, Bell MA, Challa VR et al: Brain microemboli during cardiac surgery or aortography. Ann Neurol 28:477, 1990 Murkin J: Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 72:S1838-S1844,2001

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Reed GL, Singer DE, Picard EH, DeSanctis RW: Stroke following coronary artery bypass surgery. N Engl J Med 319:1246, 1988 Roach G, Kanchuger M, Mangano C et ak Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 335:1857-1863, 1996 Rodewald G: Introduction to the subject. In Speidel H. Rodewald G (eds): Psychic and Neurologic Dysfunctions After Open Heart Surgery. Thieme, New York, 1980 Slogoff S, Girgis KZ, Keats A S Etiologic factors in neuropsychiatric complications associated with cardiopulmonary bypass. Anesth Analg 61:903, 1982

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Taggart D, Westaby S Neurological and cognitive disorders after coronary artery bypass grafting. Curr Opin Cardiol 16:271-276, 2001 Wareing TH, Dada-Roman VG, Brazilai B et al: Management of the severely atherosclerotic ascending aorta during cardiac operations: a strategy for detection and treatment. J Thorac Cardiovasc Surg 103:453-462, 1992

Willner, Rodewald G Impact of Cardiac Surgery on the Quality of Life: Neurological and Psychological Aspects. Plenum, New York, 1990 Wolman R, Nussmeier N, Aggarwal A et al: Cerebral injury after cardiac surgery. Stroke 30:514-522, 1999

186 Neurologic Complications of Cardiac

Catheterization Cathy A. Sila The first catheterization of the human heart took place in 1929 and by 1956 was the subject of the Nobel prize. Diagnostic or therapeutic catheterization can be performed of the left and right heart. Nearly 2 million catheterizations occur annually for coronary angiography; assessment of cardiac hemodynamics; intracardiac shunting or valvular function; coronary artery angioplasty, stenting, or atherectomy; device closure of septal defects; balloon valvuloplasty; and endomyocardial biopsy. Vascular access to the left heart and coronary arteries is accomplished by percutaneous puncture of the femoral, brachial, or radial artery or by cutdown with direct visualization of the brachial artery. The right heart is accessed via the femoral, brachial, or jugular vein. The rate of serious complications of cardiac catheterization derived from large contemporary databases with more than 400,000 patients include stroke (0.08%), nonfatal myocardial infarction (0.08%), and death (0.1%) caused by myocardial infarction, cardiac arrhythmia, or anaphylaxis. Vascular complications, including arterial stenosis or thrombosis, hematoma, pseudoaneurysm, or arteriovenous fistula formation at access sites are more common (0.5% to 1.5%). CENTRAL NERVOUS SYSTEM COMPLICATIONS Central nervous system complications are primarily the result of embolic stroke, although coronary interventions necessitating fibrinolytic or antithrombotic therapies can also cause intracranial hemorrhage. Diagnostic Coronary Angiography An aggregate, largely retrospective review of 44,880 patients from four large series suggests an average risk of 0.16% for transient or permanent cerebral or retinal neurologic deficits. The risk for children appears to be higher, at 1.3%, with seizures occurring more frequently. Resolution of focal deficits within a few days occurs in more than half of the patients, but visual defects are more likely to persist, and some strokes have been fatal. The symptoms often are acute in onset and suggest a vascular

mechanism. Indeed, embolism of air, catheter-related clot, or atheromatous material dislodged during manipulation of the stiff guidewire are commonly accepted explanations. However, cerebral localization of these events has consistently shown a preponderance for involvement of the posterior circulation. Analysis of the 72 reported cases reveals that only 30% involve the anterior circulation, commonly manifest as hemiparesis, hemisensory deficit, aphasia, gaze preference, or retinal visual defects. There is insufficient information to demonstrate a preponderance of the right or left carotid circulation. At least 53% of reported events clearly implicate the posterior circulation, manifest as brainstem syndromes, hemianopic visual field defects, confusional states with agitation or neglect, or prominent amnestic syndromes. Symptoms of uncertain vascular localization account for the remaining 17%, but when these case histories are carefully reviewed and forced into a posterior-anterior classification scheme, the majority involve binocular visual complaints and mental status changes highly suggestive of posterior circulation involvement. A number of explanations have been offered for the posterior circulation predominance. It was initially suggested that a retrograde brachial approach would be more likely to cause inadvertent right vertebral artery entry or embolization when traversing the subclavian curve, but subsequent series composed predominantly or exclusively of femoral artery catheterizations have confirmed the same magnitude of posterior circulation predominance. Migraine and vasospasm have also been suggested as possible mechanisms because transient visual disturbances are not uncommon during cerebral angiography and occur more often in migraineurs during coronary catheterization. The cause of such evanescent symptoms remains in dispute, although it is unlikely that migraine or vasospasm could account for most of the infarcts. Embolization has been clearly documented as a mechanism and cerebral embolism has been documented during the procedure with transcranial Doppler monitoring. Although most clinical series of cardioembolic stroke have an anterior circulation predominance that reflects the relative supply of the cardiac output, it is most likely that emboli flow within the aorta in a preferential vortex that is determined by catheter placement during advancement, injection, or flushing.

Chapter 186 W

Reed GL, Singer DE, Picard EH, DeSanctis RW: Stroke following coronary artery bypass surgery. N Engl J Med 319:1246, 1988 Roach G, Kanchuger M, Mangano C et ak Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 335:1857-1863, 1996 Rodewald G: Introduction to the subject. In Speidel H. Rodewald G (eds): Psychic and Neurologic Dysfunctions After Open Heart Surgery. Thieme, New York, 1980 Slogoff S, Girgis KZ, Keats A S Etiologic factors in neuropsychiatric complications associated with cardiopulmonary bypass. Anesth Analg 61:903, 1982

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Taggart D, Westaby S Neurological and cognitive disorders after coronary artery bypass grafting. Curr Opin Cardiol 16:271-276, 2001 Wareing TH, Dada-Roman VG, Brazilai B et al: Management of the severely atherosclerotic ascending aorta during cardiac operations: a strategy for detection and treatment. J Thorac Cardiovasc Surg 103:453-462, 1992

Willner, Rodewald G Impact of Cardiac Surgery on the Quality of Life: Neurological and Psychological Aspects. Plenum, New York, 1990 Wolman R, Nussmeier N, Aggarwal A et al: Cerebral injury after cardiac surgery. Stroke 30:514-522, 1999

186 Neurologic Complications of Cardiac

Catheterization Cathy A. Sila The first catheterization of the human heart took place in 1929 and by 1956 was the subject of the Nobel prize. Diagnostic or therapeutic catheterization can be performed of the left and right heart. Nearly 2 million catheterizations occur annually for coronary angiography; assessment of cardiac hemodynamics; intracardiac shunting or valvular function; coronary artery angioplasty, stenting, or atherectomy; device closure of septal defects; balloon valvuloplasty; and endomyocardial biopsy. Vascular access to the left heart and coronary arteries is accomplished by percutaneous puncture of the femoral, brachial, or radial artery or by cutdown with direct visualization of the brachial artery. The right heart is accessed via the femoral, brachial, or jugular vein. The rate of serious complications of cardiac catheterization derived from large contemporary databases with more than 400,000 patients include stroke (0.08%), nonfatal myocardial infarction (0.08%), and death (0.1%) caused by myocardial infarction, cardiac arrhythmia, or anaphylaxis. Vascular complications, including arterial stenosis or thrombosis, hematoma, pseudoaneurysm, or arteriovenous fistula formation at access sites are more common (0.5% to 1.5%). CENTRAL NERVOUS SYSTEM COMPLICATIONS Central nervous system complications are primarily the result of embolic stroke, although coronary interventions necessitating fibrinolytic or antithrombotic therapies can also cause intracranial hemorrhage. Diagnostic Coronary Angiography An aggregate, largely retrospective review of 44,880 patients from four large series suggests an average risk of 0.16% for transient or permanent cerebral or retinal neurologic deficits. The risk for children appears to be higher, at 1.3%, with seizures occurring more frequently. Resolution of focal deficits within a few days occurs in more than half of the patients, but visual defects are more likely to persist, and some strokes have been fatal. The symptoms often are acute in onset and suggest a vascular

mechanism. Indeed, embolism of air, catheter-related clot, or atheromatous material dislodged during manipulation of the stiff guidewire are commonly accepted explanations. However, cerebral localization of these events has consistently shown a preponderance for involvement of the posterior circulation. Analysis of the 72 reported cases reveals that only 30% involve the anterior circulation, commonly manifest as hemiparesis, hemisensory deficit, aphasia, gaze preference, or retinal visual defects. There is insufficient information to demonstrate a preponderance of the right or left carotid circulation. At least 53% of reported events clearly implicate the posterior circulation, manifest as brainstem syndromes, hemianopic visual field defects, confusional states with agitation or neglect, or prominent amnestic syndromes. Symptoms of uncertain vascular localization account for the remaining 17%, but when these case histories are carefully reviewed and forced into a posterior-anterior classification scheme, the majority involve binocular visual complaints and mental status changes highly suggestive of posterior circulation involvement. A number of explanations have been offered for the posterior circulation predominance. It was initially suggested that a retrograde brachial approach would be more likely to cause inadvertent right vertebral artery entry or embolization when traversing the subclavian curve, but subsequent series composed predominantly or exclusively of femoral artery catheterizations have confirmed the same magnitude of posterior circulation predominance. Migraine and vasospasm have also been suggested as possible mechanisms because transient visual disturbances are not uncommon during cerebral angiography and occur more often in migraineurs during coronary catheterization. The cause of such evanescent symptoms remains in dispute, although it is unlikely that migraine or vasospasm could account for most of the infarcts. Embolization has been clearly documented as a mechanism and cerebral embolism has been documented during the procedure with transcranial Doppler monitoring. Although most clinical series of cardioembolic stroke have an anterior circulation predominance that reflects the relative supply of the cardiac output, it is most likely that emboli flow within the aorta in a preferential vortex that is determined by catheter placement during advancement, injection, or flushing.

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Encephalopathic states after coronary angiography often are attributed to sedative and analgesic medications, systemic hypotension, and large volumes of contrast material, although patients with vertebrobasilar distribution ischemia can also present with confusion and memory defects. Transient cortical blindness is a rare complication of angiography occurring in less than 0.05% of patients. The syndrome begins with blurred vision progressing to complete blindness with severe headache and vomiting and may be associated with loss of coordination or limb weakness, aphasia, and confusion. Patients often are hypertensive, and the patchy cortical enhancement on brain computed tomography scan, vascular headache, and hypertension are similar to those seen in hypertensive encephalopathy and eclampsia (Fig. 186-1).

Therapeutic Coronary Catheterization Focal neurologic complications after percutaneous transluminal coronary angioplasty, atherectomy, and stent placement have been recorded in 0.2% to 0.3% of patients and are clinically similar to those seen in diagnostic catheterization patients with presumed similar mechanisms. The observed reduction in complication rates of contemporary series when compared with earlier series probably reflects numerous modifications in catheterization technique, catheter design, and use of antithrombotic drugs. Ischemic or hemorrhagic stroke complicating coronary interventions occurs in less than 1% of patients who receive combination antithrombotic therapy with glycoprotein IIb/IIIa receptor antagonists, heparin, and aspirin. The intracranial hemorrhages

FIG. 186-1. Transient cortical blindness after catheterization. The computed tomography scan demonstrates patchy enhancement of both occipital lobes and the left frontal lobe, suggesting a multifocal breakdown of the blood-brain barrier.

can result from the hemorrhagic transformation of an embolic infarct or from primary intracerebral, subdural, or subarachnoid hemorrhage.

Other Endovascular Procedures Percutaneous balloon valvuloplasty has emerged over the last decade as a nonsurgical treatment for mitral, aortic, and pulmonic valve stenosis in adults and children. The risk of cerebral embolism is 1.4% to 11% for aortic valvuloplasty and 0% to 4.2% for mitral valvuloplasty. Events during aortic valvuloplasty often are highly focal neurologic deficits suggestingbranch embolization. Rare case reports of calcific material on funduscopy or on brain computed tomography implicate valvular debris. The risk of systemic embolization with mitral valvuloplasty appears to be linked with evidence of atrial thrombus that can be dislodged during the procedure. Transesophageal echocardiography should be performed before the procedure to search for evidence of thrombus. Three months of prior anticoagulation to treat potential thrombi has been recommended. Procedural risks of transcatheter closure of atrial septal defect or patent foramen ovale include inability to place the device, device malfunction, or cardiac perforation in up to 15%. Although thrombus can be detected for several weeks after the septal closure device is deployed, the risk of stroke appears to be low at 1% to 2%.

Management of Acute Stroke After Cardlac Catheterization If a focal neurologic deficit with altered mental status occurs within 24 hours of thrombolytic therapy for acute myocardial infarction, the event should be presumed to be an intracranial hemorrhage until proven otherwise. Immediately stopping all thrombolytic, antithrombotic, and antiplatelet therapy, obtaining laboratory coagulation testing, and initiating reversal of the coagulation disturbance should begin while awaiting emergency computed tomography scanning to evaluate the neurologic event because coagulopathy-induced intracranial hemorrhages can rapidly expand within the first 8 hours (Fig. 186-2). Approaches for treating acute ischemic stroke after cardiac catheterization are influenced primarily by the witnessed onset in hospital and any concomitant antithrombotic agents. Intravenous thrombolysis for acute ischemic stroke (by the NINDS protocol) can be considered within 3 hours of symptom onset if aspirin was given or if heparin was used and the activated partial thromboplastin time has normalized. The risk of bleeding at the site of catheterization must be considered and can be minimized if the arterial access site was nontraumatic and in a compressible location. Unusual complications to be aware of include cardiac tamponade from hemorrhage into the pericardium when the stroke is a complication of an acute myocardial infarction and thrombolysis of intracardiac thrombus resulting in cerebral reembolism. However, the safety of thrombolysis for acute ischemic stroke is uncertain in the presence of other antithrombotic regimens such as combination oral antiplatelet therapy or intravenous glycoprotein IIblIIIa receptor antagonists. These patients could be candidates for new endovascular approaches to reperfusion using catheter-based clot retrieval mechanisms and treated efficiently if vascular access has been maintained. If reperfusion strategies are not possible, anticoagulation should be considered to prevent reembolization in the setting of atrial

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FIG. 186-2. Rapid expansion of a coagulopathy-related intracerebral hemorrhage over several hours.

fibrillation or persistent thrombus within the cardiac chambers. The timing of initiation of anticoagulation depends on the size and severity of the cerebral infarct, and the risk of early hemorrhagic transformation must be balanced with the risk of cerebral reembolism.

PERIPHERAL NERVOUS SYSTEM COMPLICATIONS Peripheral nerve injuries usually occur in the setting of vascular injuries either from compression from a hematoma or ischemia from compromise of blood supply from a major limb artery. Direct trauma during dissection or puncture is less common. The risk of any peripheral nerve injury depends on the specific procedure, particularly when antithrombotic therapies are needed. Risk factors include advanced patient age, congestive heart failure, and difficult vascular access, as seen with preexisting peripheral vascular disease, smaller body surface area, or female sex. The frequency of vascular complications varies by specific procedure at 0.5% to 1.0% for diagnostic coronary arteriography, 1.0% to 3.0% for percutaneous coronary interventions with contemporary antithrombotic regimens, and less than 5% for thrombolysis and balloon valvuloplasty. In contrast, the rate of peripheral nerve injury is estimated at 0.01% and usually reported as small case series or case reports. The complication rate increases with the complexity of the intervention, with the highest rates reported for intra-aortic balloon pump counterpulsation support. The contributions to the increased risk are multifactorial and related to manipulation of stiff guidewires, larger sheath size, and need for prolonged sheath placement. Risk of pseudoaneurysm formation and hemorrhage has also been related to the complex antiplatelet and anticoagulant regimens used during stent placement. Femoral Nerve Injuries

Laceration injuries to the femoral nerve usually are caused by punctures at or slightly above the level of the inguinal ligament

before the nerve undergoes extensive branching on its way into the thigh. The symptoms and signs include pain and paresthesias over the anterior thigh and medial calf, weakness and atrophy of the quadriceps muscles, and reduction or loss of the patellar reflex. In milder lesions, burning paresthesias affecting the medial and intermediate femoral cutaneous nerves may occur. Retroperitoneal hematoma formation caused by inadequate hemostasis or concomitant antithrombotic regimens can cause compression of the femoral nerve or lumbar plexus, with respective involvement of the iliacus or psoas muscles. Typically these occur on the side of arterial puncture but have also been described contralaterally where they are presumed to be caused by the anticoagulant regimen alone. Hemorrhage is contained within fascial planes, which produces evolving nerve compressive symptoms commensurate with the rate of bleeding. Slowly evolving hemorrhages may produce insidious onset of symptoms, typically local pain in the groin, flank, or abdomen that typically radiates into the anterior thigh. Spontaneous hip flexion and external rotation may be seen along with pain upon hip movement, which makes psoas weakness difficult to assess. Numbness and paresthesias in the anterior thigh extend into the medial calf along with weakness of the quadriceps muscles and diminution or loss of the patellar reflex. Cutaneous ecchymoses are common, but a palpable mass may be absent. Computed tomography of the pelvis is the most effective method of rapid diagnosis. A confirmed diagnosis of retroperitoneal hemorrhage necessitates discontinuation and reversal of anticoagulation and may warrant surgical exploration in some cases. Pseudoaneurysms of the common femoral artery typically present with a painful, pulsatile groin mass in the absence of neurologic signs. Pseudoaneurysms of the profunda femoral artery may present solely as a compressive femoral neuropathy. Duplex ultrasound scanning is particularly helpful in detecting the presence of blood flow into the perivascular hematoma and can also be used to guide obliteration by direct mechanical compression. Successful obliteration is less likely during anticoagulation but does not necessitate its discontinuation. Direct surgical repair may be necessary if neurologic symptoms are progressive or exacerbated by compressive techniques.

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The lateral femoral cutaneous nerve can be injured by tight hemostatic pressure bandages if compression occurs where the lateral femoral cutaneous nerve passes through o r underneath the upper lateral end of the inguinal ligament. Painful o r burning paresthesias typical of meralgia paresthetica occur and can subside spontaneously. Local nerve blocks may be useful in managing persistent pain. Ischemic monomelic neuropathy of the lower extremity may occur with acute occlusion of the superficial o r common femoral artery. Patients typically complain of severe pain and numbness involving the foot, with decreased sensation and hyperpathia most prominent distally and shading proximally in a stocking pattern. Distal weakness predominantly involving intrinsic foot muscles is also present and may occur in the absence of cutaneous signs of limb ischemia. The electromyographic findings are characteristic, however, and suggest axon loss lesions of motor and sensory nerves supplying the affected distal limb. Although the pattern is also consistent with a peripheral neuropathy, the axon loss is so disproportionate in the affected limb that a coexistent neuropathy should not pose a diagnostic dilemma. Median Nerve Injuries The median nerve in the antecubital region may be directly injured during the dissection needed for brachial artery access, resulting in immediate pain, paresthesia in the median distribution in the hand, and weakness of median nerve innervated hand muscles including the median long flexors and intrinsic muscles of the thumb, radial wrist flexor, and pronator. Hemorrhage into the antecubital space or proximal forearm, if rapid, would produce the same symptoms along with the local pain and obvious swelling. Slowly developing hematomas that cause a gradual increase in intracompartmental pressure can result in insidious median nerve compression with signs and symptoms that may b e more difficult to diagnose. Because of the anatomy of the forearm, hematoma formation is poorly tolerated by the median nerve and warrants early surgical exploration and decompression. Pseudoaneurysm formation of the brachial artery can cause median nerve compression but is rare compared with its counterpart of the femoral artery. The electromyographic manifestation of median nerve injuries at the elbow typically is a main trunk involvement proximal to the origin of the anterior interosseous nerve, pronator teres, and flexor carpi radialis muscles. Median nerve motor and sensory conduction amplitudes were absent o r reduced with little change in conduction velocity. The needle electrode examination reveals fibrillation potentials and motor unit loss in various combinations depending on the severity o r involvement of the particular fibers. Electrodiagnostic studies can be useful in localizing the lesion and determining its severity in all patients. Usually an electromyogram at 3 weeks after the injury is sufficient but in cases where there may be some preexisting neuropathy that might confuse later interpretation, an early electromyographic study at the time of the injury

is useful. Severe axon loss lesions known to be caused by laceration with n o evidence of recovery at 3 weeks should be considered for early exploration and grafting. Compressive lesions with some continuity present should be considered for grafting if there is no significant recovery after 6 months.

SELECTED READINGS Alio J, Esplugas E, Arboix A, Rubio F: Cerebrovascular events in cardiac catheterization. Stroke 241264, 1993 Anstandig J, Wilbourn AJ: Iatrogenic median nerve lesions at the elbow: EMG features in twelve patients. Muscle Nerve 10:647, 1987 Davidson CJ, Skelton TN, Kisslo KB et ak The risk for systemic embolization associated with percutaneous balloon valvuloplasty in adults. Ann Intern Med 108:557-560, 1988 Dawson DM, Fischer EG Neurologic complications of cardiac catheterization. Neurology 27:496-497, 1977 Fischer A, Ozbek C , Bay W, Hamann GF: Cerebral microemboli during left heart catheterization. Am Heart J 137:162-168, 1999 Galbreath C, Salgado ED, Furlan AJ, Hollman J: Central nervous system complications of percutaneous transluminal coronary angioplasty. Stroke 17:616-619, 1986 Ganglani RD, Turk AA, Mehra MR et ak Contralateral femoral neuropathy: an unusual complication of anticoagulation following PTCA. Cathet Cardiovasc Diagn 24176-178, 1991 Jacobs MJ, Gregoric ID, Reul GJ: Profunda femoral artery pseudoaneurysm after percutaneous transluminal procedures manifested by neuropathy. J Cardiovasc Surg 33:729-73 1, 1992 Keeley EC, Grines CL Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol 34:312, 1999

Keilson GR, Schwartz WJ, Recht LD: The preponderance of posterior circulatory events is independent of the route of cardiac catheterization. Stroke 23:1358-1359, 1992 Kennedy W Symposium on catheterization complications. Complications associated with cardiac catheterization and angiography. Cathet Cardiovasc Diagn 8:5-11, 1982 Kosmorsky G, Hanson MR, Tomsak RL: Neuro-ophthalmologic complications of cardiac catheterization. Neurology 3k483-485, 1988 Lockwood K, Capraro J, Hanson MR, Conomy J P Neurologic complications of cardiac catheterization. Neurology 33(Suppl 2):143, 1983 Nishimura RA, Holmes DR, Reeder GS: Percutaneous balloon valvuloplasty. Mayo Clin Proc 65:198-220, 1990 Vi-Mo H, Todnem K, Flling M, Rosland GA Transient visual disturbance during cardiac catheterization with angiography. Cathet Cardiovasc Diagn 12:1-4, 1986 Warfel BS, Marini SG, Lachmann EA, Nagler W Delayed femoral nerve palsy following femoral vessel catheterization.Arch Phys Med Rehabil 741211-1215, 1993

Weissman BM, Aram DM, Levinsohn MW, Ben-Shachar G: Neurologic sequelae of cardiac catheterization. Cathet Cardiovasc Diagn 1 1:577583, 1985

Wijman CA, Kase CS, JacobsAK, Whitehead RE: Cerebral air embolism as a cause of stroke during cardiac catheterization. Neurology 51:31& 319, 1998

Wdbourn AJ, Furlan AJ, Hulley W, Ruschhaupt W. Ischemic monomelic neuropathy. Neurology 33:447-451, 1983

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187 Myocardial Damage and Cardiac Arrhythmias William T. Talman and Patricia H. Davis

Practitioners often confront the effects of the intimate relationship between cardiac and brain function. Although the critical reliance of the brain on normal circulation is obvious, the deleterious effects of neurologic disturbances on cardiac function are less well appreciated. This chapter briefly reviews both the neurologic complications of cardiac disturbances and cardiac complications of neurologic disease, focusing on cardiac arrhythmias as a cause and effect of neurologic conditions. Although this chapter deals exclusively with clinical issues, the reader is referred to reviews of the neuroanatomy and physiology of cardiac control by Talman and Kelkar (1993) and Talman (1997). The heart is capable of generating a normal rhythm and maintaining normal cardiac output in the absence of innervation, but tight coupling of neural and cardiovascular activity plays a significant role in balancing cardiovascular responses to stimuli in health and disease. Despite the brain’s important contribution to normal cardiac function, neural input to the heart may also have detrimental effects. Therefore, neurologic disturbances may induce cardiac abnormalities in anatomically healthy hearts and complicate cardiac dysfunction in diseased hearts. These interactions may have far-reaching implications. Conversely, cardiac disease may lead to some of the same neurologic disorders that themselves could have induced the presenting cardiac abnormalities. Interruption of all parasympathetic and sympathetic input to the heart leads to sinus tachycardia, with a cardiac rate of approximately 90 beatdminute. In addition, the heart no longer demonstrates spontaneous changes in its rate or changes in response to stimuli. Therefore, denervation, as may occur with autonomic neuropathies or in the transplanted heart, may lead to fixed tachycardia. Even if peripheral autonomic input to the heart is intact, imbalances between sympathetic and parasympathetic activity can disturb cardiac rhythm and output. By disturbing the balance, primary neurologic disorders may contribute to potentially dangerous arrhythmias and electrocardiographic changes that may mimic those associated with myocardial ischemia and infarction.

ELECTROCARDIOGRAPHICABNORMALI’IIES An important example of this phenomenon is the electrocardio-

graphic evidence of myocardial ischemia or injury seen in association with numerous central nervous system lesions. Because it may be impossible to differentiate such changes from those of true atherosclerotic disease and because the related cardiac process may predispose to fatal arrhythmias, the affected patient must be treated as if there were a primary cardiac event. The necessity of such care is further reinforced when one recognizes that atherosclerotic coronary disease may coexist with the neurogenic process and may predispose the heart to coronary vasoconstriction and ischemia. Although the electrocardiographic (ECG) changes may occur in the absence of primary cardiac

disease, identifymg the patient in whom that is the case is difficult in the acute setting. The most common ECG abnormalities associated with central lesions are prolongation of the QT interval, ST segment depression, flattening or inversion of the T wave, and U waves. Though less common, some other ECG changes may be even more disturbing. These include elevated, peaked, or notched T waves; ST segment elevation; increased P-wave amplitude; increased QRS voltage; and Q waves. Obviously, such changes might suggest severe metabolic disturbances or ischemic cardiac disease. Their evolution in a manner similar to ischemic changes and occasional elevation of cardiac enzymes in the absence of myocardial infarction further blurs the distinction. It should be clear that physicians would follow a potentially errant diagnostic and therapeutic approach if the only considered explanation for “ischemic” ECG changes and elevated cardiac enzymes accompanying an acute cerebrovascular event were acute myocardial infarction with cerebral embolization. Recognizing that the same changes might occur with a central lesion alone, the physician would be less likely to subject the patient to anticoagulation in the absence of other evidence of cardiogenic emboli. However, ECG changes suggesting ischemia, even in the absence of coronary disease, are associated with significantly higher mortality. Therefore, it is prudent to treat patients for their central disease in a monitored setting until a myocardial infarction has been excluded. The ECG and enzyme changes may result from myocardial injury but not depend on coronary disease. The cardiac injury, like the ECG changes, may partially or totally reverse, leaving only U waves and QT prolongation. No ECG pattern is pathognomonic for a particular central lesion, but some central conditions are more likely than others to produce ECG findings. ECG changes are most commonly seen in patients with subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, or head trauma. Less common causes include brain tumors, meningitis, multiple sclerosis, spinal cord lesions, hydrocephalus, and manipulation of the basal forebrain during neurosurgery. Certain ECG changes, such as prolongation of the ST segment, may increase the patient’s risk of developing cardiac arrhythmias. Both arrhythmias and changes suggesting ischemia are generally considered secondary to excess or imbalanced cardiac sympathetic nerve activity. Arrhythmias, in association with or independent of other ECG changes, may be seen in a variety of disorders, including subarachnoid hemorrhage, head injury, cerebral ischemia, cerebral tumors, and seizures. Even neurosurgical manipulation of the brain may evoke arrhythmias. Central processes that affect the insular cortex seem particularly prone to induce arrhythmias, and right hemispheric events may have a greater arrhythmogenic potential than those of the left hemisphere. Although arrhythmias with central lesions may be transient and benign, some may portend a fatal outcome. The high incidence of sudden death in patients with subarachnoid hemorrhage is caused in large part by fatal ventricular arrhythmias, but this grave

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complication is by no means limited to that condition. It has been seen in patients with intracerebral hemorrhage, strokes, and other central lesions as well.

CARDIAC ARRHYTHMIA AS A CONTRIBUTOR TO NERVOUS SYSTEM DISEASE Of course, cardiac arrhythmias occur much more often as a result of primary cardiac disturbance than as a complication of central or peripheral nervous system disease. When the latter is the case, arrhythmias may affect the nervous system in one of two ways: by altering global cerebral blood flow or by causing embolization of a cardiac thrombus. Arrhythmias that reduce cardiac output may lead to concomitant arterial hypotension. In the absence of cerebrovascular stenosis and with rapid return of cardiac output and blood pressure to normal, this condition is associated with syncope, a transient loss of consciousness without lasting neurologic sequelae. Because patients with such symptomatic arrhythmias have a significant risk of sudden death, they should undergo careful cardiologic evaluation and treatment if the tendency for an arrhythmia is found. The classic presentation in such a case is unprovoked sudden loss of consciousness with little or no warning and without respect to the patient’s position at the time of the event. Palpitations and chest discomfort may certainly occur, but their absence does not preclude an arrhythmia. The same arrhythmia in a patient with a critically stenotic cerebral vessel may lead to signs of focal cerebral ischemia with or without syncope or presyncope. It is very important to keep in mind that syncope is not a sign of cerebral ischemia alone. Therefore, if confronted with a patient who has had transient loss of consciousness, even if left with focal signs, the physician must aggressively seek the cardiac and hemodynamic cause of both events rather than consider the alteration of consciousness secondary to cerebral ischemia.

EMBOLlZATlON FROM THE HEART Another way in which arrhythmias may lead to cerebral ischemia is through embolization from the heart. Atrial fibrillation is the major arrhythmia associated with increased risk of cardioembolic stroke. Currently, nonvalvular atrial fibrillation is the most commonly encountered arrhythmia, and although atrial fibrillation associated with valvular heart disease or thyrotoxicosis also increases the risk of stroke, treatment of patients with atrial fibrillation in these settings is not discussed further in this chapter. Nonvalvular atrial fibrillation is associated with a fivefold increase in stroke risk. The prevalence of atrial fibrillation increases with age from 0.5% at 50 to 59 years of age to 8.8% at 80 to 89 years. The importance of nonvalvular atrial fibrillation as a risk factor also increases with age, so that between ages 80 and 89 years, it contributes to 24% of strokes and thus approaches hypertension (33%) in importance as a risk factor. Although the overall risk of stroke in patients with nonvalvular atrial fibrillation is approximately 5% per year, not all patients with this arrhythmia are at the same risk of stroke. For example, patients under 60 years of age without associated cardiac disease, hypertension, or diabetes (lone atrial fibrillation) have an event rate of 1% per year, whereas those with a prior transient ischemic attack or stroke have a 12% per year event rate. Additional factors that are associated with high stroke risk include a history of systemic embolism, history of hypertension, age over 75 years, poor left ventricular systolic function, rheumatic mitral valve disease, and a prosthetic heart

valve. Moderate risk factors include age 65 to 75 years, diabetes mellitus, and coronary artery disease with preserved left ventricular function. Not all strokes are caused by cardioembolism: About 12% of patients with atrial fibrillation also have 50% or greater internal carotid stenosis on carotid duplex studies. Primary prevention of stroke with anticoagulants in patients with nonvalvular atrial fibrillation has been investigated in five clinical trials. A meta-analysis of these trials has shown that the reduction in stroke risk is 68% (95% confidence interval, 50% to 79%) in patients treated with warfarin. The risk reduction was 84% (95% confidence interval, 55% to 95%) in women and 60% (95% confidence interval, 35% to 76%) in men. The international normalized ratios ranged from 1.5 to 4.0 in these studies; two were double-blind, placebo-controlled trials. The risk of major hemorrhage on warfarin was 1.3% per year, compared with 1.O% per year in the placebo or control group. Results for aspirin therapy are less clear. An American study found that 325 mglday of aspirin was more effective than placebo in preventing stroke, although the effect was not demonstrated in those over age 75. A Danish study did not show a significant effect of 75 mg of aspirin, but patients in this study had a higher mean age. When the results of these two studies were combined, reduction of stroke risk was 36% (95% confidence interval, 4% to 57%). Recent recommendations include use of aspirin for patients less than 65 years with no clinical or echocardiographic evidence of cardiovascular disease. In patients with any high risk factor, adjusted-dose warfarin with an international normalized ratio between 2.0 and 3.0 is recommended unless warfarin is contraindicated (dementia, poor balance, recent bleeding, poorly controlled hypertension, and inability to comply with treatment regimen) or declined by the patient, in which case aspirin is recommended. For patients with one moderate risk factor, either aspirin or warfarin may be used, but for patients with more than one moderate risk factor, warfarin is indicated. Despite these guidelines, several studies have shown that warfarin is underused in clinical practice, particularly in older adults. It is also important to assess whether the patient with nonvalvular atrial fibrillation is a candidate for cardioversion to sinus rhythm. Two clinical trials (Atrial Fibrillation Follow-up Investigation of Rhythm Management and Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation) are addressing whether warfarin therapy plus either rate control alone or conversion to sinus rhythm improves all-cause mortality or stroke risk in older adults with persistent atrial fibrillation. If cardioversion is performed, warfarin therapy should be instituted for 3 weeks before cardioversion for patients in nonvalvular atrial fibrillation for more than 2 days. Alternately, anticoagulation with heparin can be instituted and then a transesophageal echocardiogram performed with immediate cardioversion if no thrombi are seen. Anticoagulation should be continued until sinus rhythm has been maintained for 4 weeks. The therapy of choice in those with nonvalvular atrial fibrillation and a previous transient ischemic attack or stroke is warfarin. Warfarin (mean international normalized ratio 2.9), with a 67% reduction of risk of recurrent stroke, is significantly more effective than aspirin (300 mg), which had a 14% risk reduction. In one trial, the incidence of major bleeding was 2.8% per year on warfarin versus 0.9% per year on aspirin, but there were no intracranial hemorrhages. The optimum time for starting anticoagulation after a recent ischemic stroke in a patient with nonvalvular atrial fibrillation is not clear. There are two clinical trials of anticoagulation with subcutaneous high-dose heparin or

Chapter 188 W

low-molecular-weight heparin within 48 hours after the onset of acute ischemic stroke in patients with atrial fibrillation. Both trials show an increased risk of hemorrhagic conversion with no significant improvement in mortality or functional independence at 3 to 6 months. The risk of recurrent stroke within the first 7 to 14 days in patients with atrial fibrillation is between 2% and 8%, and it may be prudent to delay initiation of warfarin therapy for days to weeks in patients with large infarcts, who are at higher risk of symptomatic hemorrhagic conversion. Future prospects include use of a device for percutaneous left atrial appendage transcatheter occlusion in patients with atrial fibrillation at high risk for stroke who are not suitable candidates for anticoagulation because at least 90% of thrombi form in the left atrial appendage. A pilot study has demonstrated the feasibility of this approach. In summary, acute anticoagulation with heparin or lowmolecular-weight heparin in patients with ischemic stroke and atrial fibrillation is of no proven benefit and is associated with increased risk of hemorrhagic conversion. However, warfarin is the therapy of choice for long-term stroke prevention in patients with nonvalvular atrial fibrillation and other risk factors. For patients with no other risk factors, aspirin is the optimum therapy. However, decisions concerning anticoagulation must be individualized. This is particularly true in older adults, who are at higher risk of intracranial hemorrhage.

SUGGESTED READINGS Albers GW, Dalen JE, Laupacis A et ak Antithrombotic therapy in atrial fibrillation. Chest 119(1 Suppl):194S, 2001 Atrial Fibrillation Investigators: Risk factors for stroke and efficacy of anti-thrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449, 1994

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Berge E, Abdelnoor M, Nakstad PH, Sandset PM: Low-molecular-weight heparin versus aspirin in patients with acute ischemic stroke and atrial fibrillation: a double-blind randomized study. Lancet 355: 1205, 2000 Cheung RTF, Hachinski V: The insula and cerebrogenic sudden death. Arch Neurol57:1685, 2000 European Atrial Fibrillation Trial Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 342:1255, 1993 Kanter MC, Tegeler ELL, Pearce LA et ak Carotid stenosis in patients with atrial fibrillation: prevalence, risk factors, and relationship to stroke. Arch Intern Med 1541372, 1994 Kapoor WN, Karpf M, Wieand HS et al: A prospective evaluation and follow-up of patients with syncope. N Engl J Med 309:197, 1983 Ruff RL, Talman WT, Petito F: Transient ischemic attacks associated with hypotension in hypertensive patients with carotid artery stenosis. Stroke 12:353, 1981 Saxena R, Lewis S, Berge E et ak Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 32:2333, 200 1 Sievert H, Lesh MD, Trepels T et al: Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation. Early clinical experience. Circulation 105:1887, 2002 Stafford RS, Singer D E Recent national patterns of warfarin use in atrial fibrillation. Circulation 97:1231, 1998 Talman WT: The central nervous system and cardiovascular control in health and disease. p. 47. In Low PA (ed): Clinical Autonomic Disorders. 2nd Ed. Little, Brown, Boston, 1997 Talman W, Kelkar P Neural control of the heart. Neurol Clin 11:239, 1993 Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22:983, 1991 Yoon BW, Morillo CA, Cechetto DF, Hachinski V: Cerebral hemispheric lateralization in cardiac autonomic control. Arch Neurol 54:741, 1997

188 Neurologic Complications of Infective

Endocarditis Amy Pruitt

Since William Osler’s detailed description of infective endocarditis in 1885, reports of neurologic complications have appeared regularly. Most authors report a stable distribution of neurologic problems and concur that embolic stroke is the most common neurologic complication. There is also general agreement on the constant frequency of total neurologic complications in about 30% of patients with infective endocarditis, for about one half of whom the neurologic problem is a presenting symptom of the disease. In most series, patients with neurologic complications have a mortality between 1.5 and 3 times that of patients without nervous system involvement. Table 188-1 details the percentage of neurologic complications and mortality in 879 patients from five recent series published since 1978, with patient accrual spanning three decades.

These stable incidence and mortality rates mask an evolving spectrum of conditions predisposing to infective endocarditis, causative organisms, and diagnostic and therapeutic techniques. The practicing neurologist should be familiar with the clinical settings in which infective endocarditis is likely to occur, the differential diagnosis of neurologic conditions resembling infective endocarditis, diagnostic procedures, and management of specific neurologic issues that arise frequently in consultation. This chapter outlines the demographic setting of endocarditis in the 1990s; the frequency, distribution, and timing of neurologic events in different types of native and prosthetic valve endocarditis; and current therapeutic recommendations based on several recently published series and a series of 144 patients from my institution. Although the clinical distinction between acute and

Chapter 188 W

low-molecular-weight heparin within 48 hours after the onset of acute ischemic stroke in patients with atrial fibrillation. Both trials show an increased risk of hemorrhagic conversion with no significant improvement in mortality or functional independence at 3 to 6 months. The risk of recurrent stroke within the first 7 to 14 days in patients with atrial fibrillation is between 2% and 8%, and it may be prudent to delay initiation of warfarin therapy for days to weeks in patients with large infarcts, who are at higher risk of symptomatic hemorrhagic conversion. Future prospects include use of a device for percutaneous left atrial appendage transcatheter occlusion in patients with atrial fibrillation at high risk for stroke who are not suitable candidates for anticoagulation because at least 90% of thrombi form in the left atrial appendage. A pilot study has demonstrated the feasibility of this approach. In summary, acute anticoagulation with heparin or lowmolecular-weight heparin in patients with ischemic stroke and atrial fibrillation is of no proven benefit and is associated with increased risk of hemorrhagic conversion. However, warfarin is the therapy of choice for long-term stroke prevention in patients with nonvalvular atrial fibrillation and other risk factors. For patients with no other risk factors, aspirin is the optimum therapy. However, decisions concerning anticoagulation must be individualized. This is particularly true in older adults, who are at higher risk of intracranial hemorrhage.

SUGGESTED READINGS Albers GW, Dalen JE, Laupacis A et ak Antithrombotic therapy in atrial fibrillation. Chest 119(1 Suppl):194S, 2001 Atrial Fibrillation Investigators: Risk factors for stroke and efficacy of anti-thrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449, 1994

Neurologic Complications of Infective Endocarditis

1201

Berge E, Abdelnoor M, Nakstad PH, Sandset PM: Low-molecular-weight heparin versus aspirin in patients with acute ischemic stroke and atrial fibrillation: a double-blind randomized study. Lancet 355: 1205, 2000 Cheung RTF, Hachinski V: The insula and cerebrogenic sudden death. Arch Neurol57:1685, 2000 European Atrial Fibrillation Trial Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 342:1255, 1993 Kanter MC, Tegeler ELL, Pearce LA et ak Carotid stenosis in patients with atrial fibrillation: prevalence, risk factors, and relationship to stroke. Arch Intern Med 1541372, 1994 Kapoor WN, Karpf M, Wieand HS et al: A prospective evaluation and follow-up of patients with syncope. N Engl J Med 309:197, 1983 Ruff RL, Talman WT, Petito F: Transient ischemic attacks associated with hypotension in hypertensive patients with carotid artery stenosis. Stroke 12:353, 1981 Saxena R, Lewis S, Berge E et ak Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 32:2333, 200 1 Sievert H, Lesh MD, Trepels T et al: Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation. Early clinical experience. Circulation 105:1887, 2002 Stafford RS, Singer D E Recent national patterns of warfarin use in atrial fibrillation. Circulation 97:1231, 1998 Talman WT: The central nervous system and cardiovascular control in health and disease. p. 47. In Low PA (ed): Clinical Autonomic Disorders. 2nd Ed. Little, Brown, Boston, 1997 Talman W, Kelkar P Neural control of the heart. Neurol Clin 11:239, 1993 Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22:983, 1991 Yoon BW, Morillo CA, Cechetto DF, Hachinski V: Cerebral hemispheric lateralization in cardiac autonomic control. Arch Neurol 54:741, 1997

188 Neurologic Complications of Infective

Endocarditis Amy Pruitt

Since William Osler’s detailed description of infective endocarditis in 1885, reports of neurologic complications have appeared regularly. Most authors report a stable distribution of neurologic problems and concur that embolic stroke is the most common neurologic complication. There is also general agreement on the constant frequency of total neurologic complications in about 30% of patients with infective endocarditis, for about one half of whom the neurologic problem is a presenting symptom of the disease. In most series, patients with neurologic complications have a mortality between 1.5 and 3 times that of patients without nervous system involvement. Table 188-1 details the percentage of neurologic complications and mortality in 879 patients from five recent series published since 1978, with patient accrual spanning three decades.

These stable incidence and mortality rates mask an evolving spectrum of conditions predisposing to infective endocarditis, causative organisms, and diagnostic and therapeutic techniques. The practicing neurologist should be familiar with the clinical settings in which infective endocarditis is likely to occur, the differential diagnosis of neurologic conditions resembling infective endocarditis, diagnostic procedures, and management of specific neurologic issues that arise frequently in consultation. This chapter outlines the demographic setting of endocarditis in the 1990s; the frequency, distribution, and timing of neurologic events in different types of native and prosthetic valve endocarditis; and current therapeutic recommendations based on several recently published series and a series of 144 patients from my institution. Although the clinical distinction between acute and

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TABLE188-1. Neurologic Complications of Infective Endocarditis: Comparison of Recent Series MOlflAUW

% Neurologic

Authornear Pruitt et al. (1 978) Salgado et al. (1 989) Cransden et al. (1 989) Kanter and Hart (1991) Pruitt (1 995)

With Neurologic

Wnhout Neurologic

No. Patients

Complications

% Strokeb

Complications

Complications

216 175 178O 166O 144

39 36.5 33 35 29

17 17 7 20 18

58 20.6

20 14.6

35 32

19 13

OSeries included only native valve endocarditis. blxhemic and hemorrhagic strokes are grouped together.

subacute infective endocarditis has been used for many decades, from the neurologist’s perspective, the classification of infective endocarditis according to etiologic agent and underlying condition (native versus prosthetic valve infective) is a more practical formulation and is used in this discussion. EPIDEMIOLOGY Table 188-2 lists the conditions predisposing to infective endocarditis. In 20% to 27% of infective endocarditis cases, no underlying cardiac condition is apparent, whereas among identifiable predisposing conditions, mitral valve prolapse and degenerative changes greatly outweigh congenital heart: disease and rheumatic heart disease. Along with the changing spectrum of underlying cardiac conditions; the age of the affected population is changing. In the recent series from the University of Pennsylvania, the mean ages of patients with and without neurologic complications were similar at 48 and 53, but the range was large (18 to 97) and there was a tendency for a “missing middle,” with patient groups clustering among the old (over age 65) and young adults (under age 40). Other series report a higher mean age, probably reflecting local referral patterns. Risk factors for infective endocarditis include those associated with underlying cardiac abnormalities, patient behavior, and medical and surgical therapies for other conditions. Intravenous drug abuse accounts for an increasing percentage of communityacquired infective carditis and stroke among young adults, whereas 10% to 20% of infective endocarditis cases may be hospitalacquired in patients over age 60. Iatrogenic risk factors include invasive instrumentation of the gastrointestinal and genitourinary tracts and indwelling devices such as arterioarterial fistulae, pacemakers, intra-aortic balloon pumps, and central intravenous catheters. Improved medical treatment of native valve infective endocarditis has led to an increasing population at risk for prosthetic valve endocarditis.

These demographic changes, along with improved medical therapy of systemic malignancy, multiple organ failure, and sepsis, also alter the spectrum of organisms causing infective endocarditis. The distribution of causative organisms varies among institutions with disparate referral patterns, but several generalizations can be made. In native valve endocarditis, streptococci were responsible for up to 90% of infective endocarditis cases in the preantibiotic era. This frequency has declined to around 60% in recent studies. The most common streptococci are those of the viridans group. Group D streptococci, of which Enterococcus faecalis is the most common, account for up to 10% of the cases and are particularly resistant to bactericidal antibiotics. Another group D streptococcus, Streptococcus bovis, observed in association with digestive tract neoplasms, is increasing in frequency. Most recent series have shown an increasing incidence of Staphylococcus aureus infection, particularly among patients abusing intravenous drugs or subjected to recent surgery. S. aureus now accounts for up to 30% of infective endocarditis of cases in some institutions and valves with no apparent preexisting lesions are involved in up to 30% of these cases. Patients with prosthetic valve endocarditis are prone to Staphylococcus epidermidis and S. aureus infections. Other patient populations, particularly older adults with multiple system disease and immunocompromised hosts, display a wider range of causative organisms, including those of the Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kinzella (HACEK) bacterial group and fungal organisms. In heavily pretreated inpatient populations, the incidence of culture-negative endocarditis appears to be rising as well and accounted for 5.5% of cases in my recent experience. From the neurologist’s perspective, it is the increasing incidence of S. aureus and other virulent bacteria, such as enterococci, along with the less common fungi that alters the pace and severity of neurologic complications. Table 188-3 summarizes demographic characteristics,heart valve involvement, and microbiology in my recent series. Pathophysiology

H TAW 188-2.

Distribution of Cardiac Conditions Predisposing to Native Valve Endocarditis

Defect Mitral valve prolapse Congenital heart defects Degenerative changes Rheumatic heart disease Heart disease with no antecedent

Freauenw (Range) 20%-29% 13%-20% 20%-2 1 % 6%-20% 20%-27%

Data from Terpenning MS, Buggy BP, Kaufmann CA: Infective endocarditis: clinical features in young and elderly patients. Am J Med 83:626, 1987; McKinsey DS, Ram TE, Bisno AL: Underlying cardiac lesions in adults with infective endocarditis: the changing spectrum. Am J Med 86:681, 1987; and Aragon T, Sande MA Infective endocarditis. p. 190. In Stein JH (ed): Internal Medicine. 4th Ed. Mosby-Year Book, St Louis, 1994.

The major neurologic manifestations of endocarditis reflect focal, multifocal, or generalized brain malfunction and include stroke (ischemic or hemorrhagic), encephalopathy, and central nervous system (CNS) infection (meningitis, abscess). These complications arise by three major mechanisms: embolization to large and small arteries, infection of brain and meninges, and toxic or immune-mediated injury. Embolism of infected platelethibrin thrombi, the most commonly reported neurologic event in all series, can result in bland infarction, microabscess or macroabscess formation, septic vasculitis, or mycotic aneurysm. These events represent a continuum of processes whose outcome depends on host defense factors, the involved cardiac valve, the

Chapter 188 H Neurologic Complications of Infective Endocarditis

timing and appropriateness of antibiotic therapy, and organism virulence. Continuous bacteremia can produce fever with delirium or metastatic infection of the brain (abscess) or meninges (meningitis). Encephalopathy, the presenting symptom in 27% of older adults with infective endocarditis in one series, poses a complex differential diagnosis, including microabscesses, meningitis, toxic reaction to drugs, and local cardiac complications such as congestive heart failure, perivalvular abscesses, and arrhythmias leading to a low flow state. The continuous antigenic stimulation of infective endocarditis leads to formation of nonspecific humoral antibodies, such as rheumatoid factor and cryoglobulins, and of circulating immune complexes that may play a role in several less common neurologic sequelae, including late aneurysmal rupture and mononeuropathies. Of most concern to the clinical neurologist are those CNS manifestations that precede diagnosis of infective endocarditis. In the series of Gransden et al. (1989), early neurologic events correlated with the causative organism of community-acquired native valve endocarditis. Of neurologic events associated with S. aureus infective endocarditis, 54% occurred at presentation of the disease, whereas only 19% of streptococcal patients experienced early neurologic problems. Salgado and others report that overall, 16% to 23% of neurologic complications occur at presentation, and another 30% occur after initiation of antibiotic therapy but

TAW 188-5. Comparison of Endocarditis Cases with and without Neurologic Complications PAnmm

PKllENTS WIlllOVr

hwunows

Comwunows

(N

= 42Zp

n

Sex Male Female Type of valve Native Prosthetic Valve affected Mitral Aortic Mitral and aortic Tricuspid Anticoagulation Vegetations by echo Organism Staphylococcus aureus Streptococcus viridans Enterococcus Stapbylococcus epidermidis Culture-negative Other Risk factor Intravenous drug use Rheumatic heart disease Nosocomial None identifiable Outcome Improved without surgery Improved, valve replaced Death Due to neurologic complication

(N=

%

n

102)' %

25 12

70 30

70 28

71 29

37 5

88 12

93 9

91 9

21 11 3 2 2 22/39

50 26 7 4.7 4.7 59'

37 20 12 9 10 35/84

37 20 11.7 8.8 10 40.6

18 6 4 2 1 11

43= 14 9.6 4.8 2.4 26'

28 25 18 12 7 12

28 24 17 11.7 6.8 11.7

18 4 5

2

50' 11 14 5.4

28 6 14 9

28 6.1 14 9

16 11 13 6

40 27.5 32' 14

65 24 13

64 23.5 12.7 0

0

"Mean age, 40. bMean age, 53. 'P < 0.05. Data from P ~ i t AA: t Neurologiccomplications of infective endocarditis:a review of an evolving disease and its management issues for the 1990s. Neurologist 1:20-34.1995.

1203

TAW 188-4. Neurologic Complications in 42 Episodes of Infective Endocarditis n

% of

% at

Total

Presentation

Stroke 20 14 7 Cerebral embolism" 9 Single 11 Multiple 3 Hemorrhagic 1 Hemorrhagic on warfarin 6 4.1 2.8 lntracranial hemorrhage 2 Mycotic aneurysm 3 Septic arteritis (?) Subdural hematoma and 1 hemorrhagic infarction Central nervous system infection 3 Brain abscess 4 Meningitis 2 Aseptic 2 Purulent Miscellaneous 1.3 6 4.1 Seizures Paraspinal abscess 1.3 2 1.3 1 Visual obscurations 1 Peroneal palsy 1 Radial palsy 1 Postoperative lower brachial plexopathy 2 Delirium 1 Herpes zoster 1 Opiates "13/20 emboli occurred within 48 hours of presentation at a time of uncontrolled infection (65%). Data from Pruitt AA: Neurologiccomplications of infective endocarditis: a review of an evolving disease and it management issues for the 1990s. Neurologist 1 :20-34.1995.

before bacteriologic cure. In my recent experience, 13 of 20 embolic strokes (65%) occurred with 48 hours of presentation at a time of uncontrolled infection. Of 144 patients with infective endocarditis, nearly one fifth (19%) presented with a neurologic problem, only 3 of whom had no other evidence of infective endocarditis. Table 188-4 summarizes the distribution and timing of neurologic complications of infective endocarditis. Difterentlal Diagnosis

Given the protean neurologic manifestations of infective endocarditis, the neurologist needs to consider the possibility of its presence in many patients. The readily recognizable situation of a febrile patient with focal neurologic deficit and heart murmur represents the minority of case presentations. With a declining frequency of underlying heart disease and a concomitant increase in virulent pathogens, a cardiac murmur may be detected at initial evaluation in only one third of cases. The diagnosis of infective endocarditis should be considered in any febrile patient with a focal neurologic deficit or headache or with an intracranial hemorrhage unexplained by conventional atherosclerotic vascular risk factors. The host and environmental epidemiologic risk factors outlined here should be considered in weighing the possibility of infective endocarditis. Careful questioning of patients with underlying heart conditions should elicit omission of antimicrobial prophylaxis in patients undergoing surgical procedures for whom such treatment is recommended (congenital malformations, prostheses, previous bacterial endocarditis, rheumatic conditions, mitral valve prolapse, and hypertrophic cardiomyopathy). Current recommendations for dental and surgical procedures at high risk for introducing bacteremia include teeth

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cleaning, tonsillectomy, intestinal or respiratory tract procedures, cholecystectomy, cystoscopy and other genitourinary manipulations, hysterectomy, prostate surgery, and vaginal childbirth with evidence of vaginal infection. However, the classic triad of neurologic involvement in infective endocarditis-fever, elevated erythrocyte sedimentation rate, and evidence of CNS embolismcan be seen with atrial myxoma, vasculitis caused by polyarteritis nodosa or other collagen vascular disease, and nonbacterial thrombotic endocarditis. In many of these situations, prior diagnosis of vasculitis or neoplasia is absent. Therefore, blood cultures (at least two, separated by more than several hours) must be obtained in any suspicious clinical setting. In patients who have recently received antibiotics, additional cultures with, when appropriate, media supplemented with P-lactamase may be necessary. Longer incubation times are necessary for fungi and some fastidious bacteria. Although the diagnosis of infective endocarditis rests primarily on clinical and microbiologic data, echocardiography plays an increasing role in early evaluation. Transesophageal echocardiography has proved superior to standard two-dimensional echocardiography for detecting valvular abscesses and evaluating prosthetic valve endocarditis. Echocardiographic data are used as inclusionary criteria for endocarditis in recent series. A patient with a febrile illness and new vegetations on echocardiography should be classified and treated as having infective endocarditis. Several studies have shown an association between demonstrable valvular vegetations and risk of subsequent embolism as well as increased likelihood of valve replacement for congestive heart failure. Recent University of Pennsylvania data show that 74% of patients with cerebral emboli had demonstrable valvular vegetations, whereas only 41% of those without neurologic involvement had positive echocardiographic findings. These figures agree with the composite report by Lutas et al. (1986) of 11 studies in which the embolic rate was 36% for patients with demonstrable vegetations and 15% for those with normal echocardiograms. Vegetations larger than 10 mm are generally associated with a higher incidence of emboli than are smaller lesions (47% versus 19%). Although embolization may decrease the size of vegetations, reembolization is also more common in lesions that initially were larger than 10 mm. The presence of vegetations larger than 10 mm and clinical evidence of embolism may lead to consideration of valve replacement, although at present, further prospective data are needed before management decisions can be based on presence and size of cardiac vegetations. Echocardiographic demonstration of vegetations in fungal and certain prosthetic valve infective endocarditis cases may be an indication for valve replacement. SPECIFIC MANAGEMENT ISSUES

Table 188-5 summarizes the questions most frequently posed to neurologic consultants involved in treating patients with diagnosed infective endocarditis. The following sections of this chapter address these issues, outline current recommendations for management of the most common neurologic complications, and emphasize issues peculiar to prosthetic valve endocarditis. Cerebral Emboli

Cerebral embolism is the most common neurologic complication of native valve endocarditis or prosthetic valve endocarditis. Aggregate data suggest that about 15% of all patients with native valve endocarditis present with brain ischemia and that this

TABLE 188-5. Questions Frequently Posed to Neurologic Consultants Anticoagulation What are the risks and benefits of anticoagulation during an episode of endocarditis? Should anticoagulation be discontinued in patients with prosthetic valve endocarditis? When after an embolic stroke can anticoagulation be reinstituted safely in patients receiving antibiotic therapy for endocarditis? Is there a role for heparin or antiplatelet agents? Cardiac surgery Is there a risk of increasing stroke deficit if the patient needs emergent valve replacement? Should cerebral emboli be an indication for valve replacement? Is there a subgroup of patients who will respond to valve repair surgery and avoid prosthetic valves? Mycotic aneurysms To what extent should a search for aneurysms be undertaken in every patient with endocarditis? What is the proper management of mycotic aneurysms? Antibiotics Does the choice of antibiotics or the duration of therapy change for various neurologic comolications?

complication is extremely uncommon with tricuspid valve endocarditis. In recent series, there is a slight association of mitral valve infection, with a greater risk of cerebral emboli and a much stronger association of cerebral ischemia with causative organism. S. aureus infective endocarditis has been associated with roughly twice the frequency of cerebral embolism compared with that of streptococcal infective endocarditis cases. The incidence of emboli is roughly equal in reports predating and postdating the advent of computed tomography (CT), but there is an increase in detected multiple emboli in the CT era (18% versus 50%). CT is the best diagnostic procedure for the acute investigation of sudden focal neurologic deficit in infective endocarditis and can differentiate bland from hemorrhagic infarctions. Magnetic resonance imaging (MRI) may be useful in follow-up of cerebral emboli and may be more sensitive in demonstrating evolution of microabscesses, cerebritis, and aneurysm formation. Current recommendations call for follow-up MRI if clinically feasible after 1 to 2 weeks of treatment. Emboli tend to cluster at the time of presentation or during uncontrolled infection and may be associated with systemic emboli in nearly one half of cases. Late embolism after infection is controlled occurs largely in patients with prosthetic valves. A bout of cured native valve endocarditis does not change future stroke risk in patients with valvular heart disease. In a group of 140 patients followed for 22 months after bacteriologic cure, 15 developed stroke, 14 of whom had prosthetic valves. In other studies, stroke subsequent to cured infective endocarditis was readily explained by atherosclerotic risk factors, new infective endocarditis, prosthetic valves, or excessive anticoagulation. These data suggest that anticoagulation is not indicated for prevention of recurrent embolic stroke in cured native valve endocarditis. A more pressing question for the neurologic consultant is the role of anticoagulation during an episode of infective endocarditis. In the 1940s, it was argued that anticoagulation would improve antibiotic penetration into infected vegetations and prevent thrombi propagation. More recently, it has been argued that there is no role for anticoagulation in infective endocarditis because valvular vegetations are not propagating thrombi and can break off regardless of anticoagulation, with subsequent risk of cerebral hemorrhage.

Chapter 188 W

Large series emphasizing the role of anticoagulation in producing intracranial hemorrhage in infective endocarditis have given rise to fears about using anticoagulants in the setting of infection. In one large series, one half of the cerebral hemorrhages occurred in the 3% of patients anticoagulated at the time of embolism. Experimental evidence suggests that the “worsening” role of anticoagulants may be particularly pronounced when the cerebral emboli are septic. The data have led to confusing recommendations about instituting anticoagulants after cerebral emboli, withholding anticoagulants in prosthetic valve endocarditis, and reinstituting anticoagulantsduring the course of treatment of infective endocarditis in patients for whom chronic anticoagulation is otherwise indicated. I believe some of the confusion can be resolved by considering the issues of native valve endocarditis and prosthetic valve endocarditis separately. In native valve endocarditis, the recurrence rate of emboli is low after infection is controlled. Because most emboli have occurred within the first 48 hours, particularly with virulent organisms, anticoagulation is of no benefit in preventing recurrent emboli. Should recurrent emboli develop, every effort to control infection should be instituted, including consideration of cardiac surgery for patients with large vegetations, and the neurologist should counsel withholding of anticoagulation until infection is more adequately controlled or, for at least 48 hours, to minimize risk of bleeding into infarcted cerebrum. Should emboli develop in an anticoagulated patient, the neurologist should advise cessation of anticoagulation for 48 hours for similar reasons. On the other hand, the development of native or prosthetic valve endocarditis without emboli does not dictate the cessation of otherwise indicated anticoagulation therapy. Although the platelet-fibrin thrombus is believed to play a role in formation and propagation of vegetations, the role of antiplatelet agents in preventing embolization has not been addressed in a prospective clinical study.

Cardiac Surgery Patients with infective endocarditis come to cardiac surgery for a variety of reasons, and the presence of cerebral emboli may contribute to the decision about timing of valve replacement. The neurologist often is asked about the risk of bleeding into an ischemic stroke during bypass or the effect of nonpulsatile blood flow or hypotension on a recent infarction. What appears clear from various series is that valve replacement is not mandatory for patients with early embolism in the absence of other cardiac indications. If emergent cardiac surgery is needed, several studies have suggested that in patients operated on within a few days of stroke the deficits may worsen. The complication rate in my series was 30% for patients who needed valve replacement within 2 weeks. Another study suggested that emergent valve replacement conferred no special increased risk. Consensus suggests that if the physician has the luxury, he or she should wait until cerebral edema has subsided (at least 5 days). Prosthetic Valve Endocarditis

Patients with bioprosthetic or mechanical valves have a 1%to 4% incidence of infective endocarditis, conventionally divided into late (more than 60 days postoperatively) and early (less than 60 days after valve replacement). Although the incidence of prosthetic valve endocarditis cases in various series reflects hospital referral patterns, aggregate analysis of more than 200 patients in the

Neurologic Complications of Infective Endocarditis

1205

literature suggests that inadequately anticoagulated patients with mechanical valves are at greatest risk of embolism. Therefore, it would not be prudent to advise discontinuation of anticoagulation at the onset of prosthetic valve endocarditis in a high-risk mechanical valve. A recent study suggests that heparin may be safer than warfarin in this population. Of 16 patients treated with heparin, 15 were embolism free. There is general agreement that hemorrhage into embolism confers a high mortality; therefore, it is recommended that if an embolism occurs, anticoagulation should be discontinued for 48 hours, with repeat CT scanning performed before reinstitution of anticoagulation in high-risk valves.

Recommendations for Anticoagulants Recommendations concerning anticoagulation for native and prosthetic valve endocarditis are as follows: The development of native valve or prosthetic valve bacterial endocarditis does not dictate cessation of otherwise indicated warfarin therapy. Anticoagulation is not indicated for preventing recurrent embolic stroke in native valve endocarditis. If a cerebral embolic event occurs in an anticoagulated patient with infective endocarditis, withhold anticoagulant for 48 hours unless the patient has a high-risk prosthetic valve. If fungal endocarditis is present, consider discontinuation of anticoagulation in all but the highest-risk prostheses. Routine initiation of anticoagulation to prevent stroke in bioprosthetic valve endocarditis is not justified. Areas of future study include the role of antiplatelet agents in preventing stroke, confirmation of the encouraging report of heparin’s safety in prosthetic valve endocarditis, and refinement of echocardiographic data about vegetations and cardiac surgery The role of valve repair surgery, used to avoid the long-term risk of prosthetic valves, must be clarified for patients with large vegetations and high embolic risk.

lntracranialHemorrhage Intracranial hemorrhage occurs in 3% to 6% of patients with infective endocarditis. Four mechanisms are responsible: ruptured mycotic aneurysm, septic arteritis, hemorrhagic transformation of initially bland embolic infarction, and, in rare instances, immune complex injury to vasculature resulting in aneurysmal formation months to years after the initial episode of infective endocarditis. Intracranial hemorrhage is associated with a high mortality and represents a spectrum of arterial injury from acute pyogenic necrosis to late rupture of an aseptic aneurysm. Septic arteritis, seen in three cases in my current series, occurs early in the course of virulent organism-related infective endocarditis and may have a higher rate of occurrence when there is purulent meningeal inflammation. Infectious intracranial aneurysms, more commonly known by the Oslerian term mycotic aneurysms, are recognized in 1% to 5% of infective endocarditis cases. The true incidence almost certainly exceeds the diagnosed numbers, as many aneurysms may heal after antibiotic therapy. Typical locations for mycotic aneurysms caused by infective endocarditis are sites where septic emboli are likely to lodge and tend to be more peripheral than those associated with extravascular infectious sources. However, fungal infective

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endocarditis is associated with large proximal aneurysms. The original studies by Molinari et al, (1973) of mycotic aneurysm formation appear confirmed by subsequent neuropathologic investigation. His dog studies suggested that aneurysm formation depended on embolic site, host defenses, and efficacy and timing of antimicrobial therapy. Dogs developed mycotic aneurysms within 3 days if they were untreated, whereas antibiotics delayed the formation of aneurysms by 7 to 10 days or resulted in the formation of brain abscess. Invasion of the vessel wall occurred from the vasa vasorum of the adventitia, with weakening and subsequent rupture. A debate has arisen in the literature about the aggressiveness indicated in the search for mycotic aneurysms. On one hand, it has been argued that all patients with neurologic abnormalities not attributable to systemic toxicity, including cerebrospinal fluid pleocytosis, should undergo four-vessel cerebral angiography and that single accessible lesions in medically stable patients should be excised promptly. Opposing this view are others who emphasize the rarity of mycotic aneurysms, their symptomatic clustering in the early stages of infection, and the extremely low incidence of late rupture after bacteriologic cure of endocarditis. It is not surprising that there is a divergence of opinion, given the conflicting outcomes from large series. In the study by Ojemann and Crowell (1983) of 27 cases followed up with angiography during antibiotic treatment, 8 aneurysms disappeared, 5 decreased, 4 were unchanged, 6 increased, and in 4 cases, new aneurysms formed. Although there is ample documentation that aneurysms heal with antibiotic therapy alone, there is only one systematic study correlating CT and four-vessel angiography. Among the important findings in this study were the high frequency of multiple aneurysms and the high incidence of aneurysms (11 of 35 patients with neurologic signs). However, there were no mycotic aneurysms in patients with normal CT scan results. All 11 patients with aneurysms had abnormal CT scan results. A reasonable conclusion drawn by these authors was that CT is a practical screen for the possibility of aneurysm. These data must be confirmed, however, and the role of MRI and magnetic resonance angiography remains unclear. I prefer a compromise in approach to mycotic aneurysm. Recognizing that for many unfortunate patients with aneurysm, the rupture will occur at presentation or too early in the course for meaningful intervention, I recommend emergent CT for patients with neurologic symptoms. The presence of blood on CT should dictate four-vessel angiography; decisions about emergent surgery will depend on the patient’s medical condition, the location and integrity of the aneurysms, and their multiplicity. Current techniques for excising mycotic aneurysms entail ligation of the affected vessel, and the likelihood of severe neurologic deficit should be weighed in the management decision. Severe persistent headache or sentinel transient embolic symptoms with normal CT scan findings also dictate lumbar puncture. Because minimal aneurysm leakage can result in a focal meningeal reaction, cerebrospinal fluid pleocytosis would sway the decision in favor of four-vessel angiography. Yet to be defined is the role of prophylactic angiography in high-risk patients who need acute valve replacement and short- or long-term anticoagulation. Some authors have advocated angiography in all such patients before surgery because reports of aneurysm rupture perioperatively have raised concern, and the often young patients involved may receive lifelong anticoagulation with mechanical prostheses. It is possible that because one of the mechanisms of aneurysm formation is adventitial invasion, we

should consider patients with S. aureus meningeal reaction at particular risk and study them with angiography prophylactically. However, it is my opinion that available information on the low incidence of late hemorrhage even in this group does not justify routine angiography in this setting. Current recommendations for the management of mycotic aneurysms are as follows: Routine angiography for all patients with meningitis or evidence of cerebral emboli is not justified. The indications for neurosurgical repair must be individualized by organism; aneurysm location, number, and size; and the patient’s medical condition. Serial angiography is indicated for mycotic aneurysms that are being treated medically. Angiography is not recommended before anticoagulation of all patients needing acute valve replacement. Brain Abscess

A continuum exists between ischemic/hemorrhagic cerebrovascular disease in infective endocarditis and CNS infection, depending on host factors, organism, and antibiotic therapy. An increased incidence of radiographically demonstrable cerebritis and microabscess formation is apparent in the MRI era. However, the incidence of macroscopic brain abscess has remained low in all series. Allowing for more sensitive radiographic techniques, however, three abscesses were apparent in my recent series. All developed on antibiotic therapy and resolved without surgical intervention. CT- or MRI-guided needle aspiration proved useful in managing two of these cases. A recent clinicopathologic conference raises caution about superinfection of cerebral embolic infarctions in the setting of central venous line-induced septicemia. A (presumably) initially bland infarction may have been seeded by S. aureus and resulted in the development of brain abscesses months after the patient completed a 17-day course of antibiotics. Patients with “uncomplicated’’ septicemia and recent cerebral infarction may deserve a full infective endocarditis course of antibiotics, and transesophageal echocardiography may disclose vegetations and dictate longer duration of therapy in patients with bacteremia.

Despite earlier detection and better antibiotic therapy, the frequency of neurologic complications of bacterial endocarditis remains high, and patients with neurologic complications are distinguished from those without such sequelae by having more frequent angiographically demonstrable vegetations, a higher frequency of S. aureus as the pathogen, a rising rate of both nosocomial infections and intravenous drug abuse as the underlying risk factors for infective endocarditis, and twice the mortality rate. Mortality from infective endocarditis in the group with neurologic complications is caused by the neurologic problems in about half and by cardiac compromise in the remaining half. The challenge in the diagnosis of patients with infective endocarditis involves an awareness of the evolving spectrum of host factors and organisms. The challenge in management of patients with endocarditis remains the establishment of criteria for identification of the few patients for whom early surgical or medical (anticoagulation) intervention can minimize neurologic morbidity.

Chapter 189

Management Issues Requiring Further Study

Transesophageal Echocardiography. The role of transesophageal echocardiography in defining patients with clinical endocarditis who can have a shorter course of antibiotics, in selecting those who needed full treatment for endocarditis, and in committing certain patients to valve replacement of repair must be developed further. Anticoagulation. The role of heparin in preventing emboli in prosthetic valve endocarditis and the possible role of antiplatelet agents in reducing the risk of cerebral emboli are worthy of further study. Magnetic Resonance Angiography. The sensitivity of magnetic resonance angiography in detecting unruptured mycotic aneurysms must be correlated with conventional angiography.

SUGGESTED READINGS Chun Ty: Current multimodality management of infectious intracranial aneurysms. Neurosurgery 48:1203, 2001 Dajani A S Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 277:1795, 1997 Disalvo G Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 37:1069, 2001 Fowler VG Jr: Infective endocarditis due to Stuphylococcus uureus: 59 prospectively identified cases with follow-up. Clin Infect Dis 28: 106, 1999 Gillinov AM: Valve replacement in patients with endocarditis and acute neurological deficit. Am Thorac Surg 61:1125, 1996 Gouello JP: Nosocomial endocarditis in the intensive care unit: an analysis of 22 cases. Crit Care Med 28:377, 2000 Gransden WR, Eykyn SJ, Leach RM: Neurological presentations of native valve endocarditis. Q J Med 73:1135, 1989 Habib G: Value and limitations of the Duke criteria for the diagnosis of infective endocarditis. J Am Coll Cardiol 33:2023, 1999 Heidenreich PA Echocardiography in patients with suspected endocarditis: a cost-effective analysis. Am J Med 107198, 1999 Heiro M Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med 1601781, 2000 Kanter MC, Hart RG Neurologic complications of infective endocarditis. Neurology 41:1015, 1991

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Kupferwasser LI: Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effects. Circulation 99:2791, 1999 Kupferwasser LI: Diagnosis of culture negative endocarditis: the role of the Duke criteria and the impact of transesophageal echocardiography. Am Heart J 142:126, 2001 Li JS Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 30:633, 2000 Lutas EM, Roberts RB, Devreux RB et ak Relation between the presence of echocardiographic vegetations and the complication rate in infective endocarditis. Am Heart J 112:107, 1986 Mathew 7: Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med 155:1641, 1995 Millar B: Molecular diagnosis of infective endocarditis: a new Duke’s criterion. Scand J Infect Dis 33:673, 2001 Molinari GF, Smith L, Goldstein MN et ak Pathogenesis of cerebral mycotic aneurysms. Neurology 23:325, 1973 Mylonakis E: Infective endocarditis in adults. N Engl J Med 345:13 18,2001 Ojemann J, Crowell RM: Infectious intracranial aneurysms. pp. 225-263. In Ojemann RG (ed): Surgical Management of Cerebrovascular Disease. Williams & Wilkins, Baltimore, 1983 Parrino P E Does a focal neurologic deficit contraindicate operation in a patient with endocarditis?Ann Thorac Surg 6259, 1999 Pruitt AA: Neurologic complicationsof infective endocarditis: a review of an evolving disease and its management issues in the 1990s. Neurologist 1:20, 1995 Pruitt AA, Rubin RH, Karchmer AW et ak Neurologic complications of bacterial endocarditis. Medicine (Baltimore) 57:329, 1978 Roder BL: Neurologic manifestations in Sruphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med 102:379, 1997 Salgado AV, Furlan AJ, Keys TF et ak Neurologic complications of endocarditis: a 12 year experience. Neurology 39:173, 1989 Santoshkumar B Neurologic complications of infective endocarditis observed in a south Indian referral hospital. J Neurol Sci 132139,1996 Tischler MD: The ability of vegetation size on echocardiographyto predict clinical complications: a meta-analysis. J Am SOCEchocardiogr 10562, 1997 Tornos P Infective endocarditis due to Staphylococcus uureus: deleterious effect of anticoagulant therapy. Arch Intern Med 159:473, 1999 Viacosta I: Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 391489, 2002

189 Eclampsia and Hypertensive Encephalopathy Steven K. Feske Preeclampsia-eclampsia,or toxemia of pregnancy, is a multisystem disorder of mid- to late pregnancy, occurring usually between 20 weeks of gestation and several weeks postpartum. Preeclampsia is traditionally characterized by hypertension (HTN), edema, and proteinuria. Progression to a more severe state of toxemia with seizures traditionally defines eclampsia. The term HELLP syndrome was coined by Weinstein in 1982 to describe patients with hemolytic anemia, elevated liver enzymes, and low platelets

occurring during late pregnancy. This syndrome has now been recognized as a severe form of toxemia. Although hypertensive encephalopathy(HTE) may occur in the context of toxemia and is the cause of progression to eclampsia, HTE may also occur in many other clinical contexts in which systemic blood pressure is severely elevated or in which blood pressure is elevated in the setting of damage to cerebral endothelial cells.

Chapter 189

Management Issues Requiring Further Study

Transesophageal Echocardiography. The role of transesophageal echocardiography in defining patients with clinical endocarditis who can have a shorter course of antibiotics, in selecting those who needed full treatment for endocarditis, and in committing certain patients to valve replacement of repair must be developed further. Anticoagulation. The role of heparin in preventing emboli in prosthetic valve endocarditis and the possible role of antiplatelet agents in reducing the risk of cerebral emboli are worthy of further study. Magnetic Resonance Angiography. The sensitivity of magnetic resonance angiography in detecting unruptured mycotic aneurysms must be correlated with conventional angiography.

SUGGESTED READINGS Chun Ty: Current multimodality management of infectious intracranial aneurysms. Neurosurgery 48:1203, 2001 Dajani A S Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 277:1795, 1997 Disalvo G Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 37:1069, 2001 Fowler VG Jr: Infective endocarditis due to Stuphylococcus uureus: 59 prospectively identified cases with follow-up. Clin Infect Dis 28: 106, 1999 Gillinov AM: Valve replacement in patients with endocarditis and acute neurological deficit. Am Thorac Surg 61:1125, 1996 Gouello JP: Nosocomial endocarditis in the intensive care unit: an analysis of 22 cases. Crit Care Med 28:377, 2000 Gransden WR, Eykyn SJ, Leach RM: Neurological presentations of native valve endocarditis. Q J Med 73:1135, 1989 Habib G: Value and limitations of the Duke criteria for the diagnosis of infective endocarditis. J Am Coll Cardiol 33:2023, 1999 Heidenreich PA Echocardiography in patients with suspected endocarditis: a cost-effective analysis. Am J Med 107198, 1999 Heiro M Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med 1601781, 2000 Kanter MC, Hart RG Neurologic complications of infective endocarditis. Neurology 41:1015, 1991

Eclampsia and Hypertensive Encephalopathy

I207

Kupferwasser LI: Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effects. Circulation 99:2791, 1999 Kupferwasser LI: Diagnosis of culture negative endocarditis: the role of the Duke criteria and the impact of transesophageal echocardiography. Am Heart J 142:126, 2001 Li JS Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 30:633, 2000 Lutas EM, Roberts RB, Devreux RB et ak Relation between the presence of echocardiographic vegetations and the complication rate in infective endocarditis. Am Heart J 112:107, 1986 Mathew 7: Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med 155:1641, 1995 Millar B: Molecular diagnosis of infective endocarditis: a new Duke’s criterion. Scand J Infect Dis 33:673, 2001 Molinari GF, Smith L, Goldstein MN et ak Pathogenesis of cerebral mycotic aneurysms. Neurology 23:325, 1973 Mylonakis E: Infective endocarditis in adults. N Engl J Med 345:13 18,2001 Ojemann J, Crowell RM: Infectious intracranial aneurysms. pp. 225-263. In Ojemann RG (ed): Surgical Management of Cerebrovascular Disease. Williams & Wilkins, Baltimore, 1983 Parrino P E Does a focal neurologic deficit contraindicate operation in a patient with endocarditis?Ann Thorac Surg 6259, 1999 Pruitt AA: Neurologic complicationsof infective endocarditis: a review of an evolving disease and its management issues in the 1990s. Neurologist 1:20, 1995 Pruitt AA, Rubin RH, Karchmer AW et ak Neurologic complications of bacterial endocarditis. Medicine (Baltimore) 57:329, 1978 Roder BL: Neurologic manifestations in Sruphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med 102:379, 1997 Salgado AV, Furlan AJ, Keys TF et ak Neurologic complications of endocarditis: a 12 year experience. Neurology 39:173, 1989 Santoshkumar B Neurologic complications of infective endocarditis observed in a south Indian referral hospital. J Neurol Sci 132139,1996 Tischler MD: The ability of vegetation size on echocardiographyto predict clinical complications: a meta-analysis. J Am SOCEchocardiogr 10562, 1997 Tornos P Infective endocarditis due to Staphylococcus uureus: deleterious effect of anticoagulant therapy. Arch Intern Med 159:473, 1999 Viacosta I: Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 391489, 2002

189 Eclampsia and Hypertensive Encephalopathy Steven K. Feske Preeclampsia-eclampsia,or toxemia of pregnancy, is a multisystem disorder of mid- to late pregnancy, occurring usually between 20 weeks of gestation and several weeks postpartum. Preeclampsia is traditionally characterized by hypertension (HTN), edema, and proteinuria. Progression to a more severe state of toxemia with seizures traditionally defines eclampsia. The term HELLP syndrome was coined by Weinstein in 1982 to describe patients with hemolytic anemia, elevated liver enzymes, and low platelets

occurring during late pregnancy. This syndrome has now been recognized as a severe form of toxemia. Although hypertensive encephalopathy(HTE) may occur in the context of toxemia and is the cause of progression to eclampsia, HTE may also occur in many other clinical contexts in which systemic blood pressure is severely elevated or in which blood pressure is elevated in the setting of damage to cerebral endothelial cells.

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This chapter will discuss preeclampsia-eclampsia and hypertensive encephalopathy that occurs in that context.

EPIDEMIOLOGY Preeclampsia affects 3% to 5% of pregnant women, and eclampsia accounts for approximately 50,000 deaths a year worldwide. Risk factors for preeclampsia include nulliparity, poor nutrition, obesity, multiple gestations, age greater than 35 years, extrauterine pregnancy, molar pregnancy, and various conditions that may lead to microvascular disease and placental hypoperfusion, such as maternal HTN, diabetes mellitus, and thrombophilic disorders.

PATHOPHYSIOLOGY The initial cause and pathophysiologic mechanisms that maintain preeclampsia-eclampsia are still poorly understood. Many different possible underlying causes are under investigation, but several features are constant and appear to be fundamental to the disorder. Abnormal placentation results in placental hypoperfusion. In normal placentation, the spiral arteries are remodeled to create a low-resistance system perfusing the intervillous space; this remodeling does not occur normally in preeclampsia. Mothers with preeclampsia exhibit increased vascular tone and reactivity, causing vasospasm and decreased organ perfusion. In general, there is a heightened response to many physiologic mediators of vasoconstriction and a dampened response to many mediators of vasodilation. Patients also exhibit evidence of abnormal endothelial cell function. This alteration in vascular tone and reactivity and endothelial cell dysfunction appear to underlie the HTN and increased vascular permeability that characterize the syndrome. The mechanisms that link the placental insufficiency and the endothelial and vasomotor dysfunction have not been isolated, but many possibilities have been proposed and tested. These include immune mediation of both the placental abnormality and the endothelial and vasomotor dysfunction, genetic factors, and the transfer of oxidative stress from the hypoperfused placenta to the systemic circulation by activated neutrophils and monocytes, by cytokines, or by other factors. HTN, or relative HTN, is present in almost all patients with other features of preeclampsia-eclampsia, and it contributes to its clinical definition. The nature and distribution of the brain lesions in eclampsia are identical to those of hypertensive encephalopathy from other causes as demonstrated by magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) imaging. When HTE occurs in many contexts, such as in chronic hypertensive patients with further acute rises in blood pressure, in patients taking sympathomimetic agents, and during the mass reflex (autonomic dysreflexic response) in quadriplegics, blood pressure elevation typically is great and abrupt. In contrast, in patients with toxemia and in patients with other disorders that damage endothelial cells, such as those with exposure to cyclosporine A, the blood pressure elevations that cause the clinical syndrome may be modest. This observation suggests that endothelial cell dysfunction contributes to the development of HTE in toxemia and that it is not merely secondary to the HTN. It also suggests that hydrostatic factors (elevated systemic blood pressure) and permeability factors (damaged endothelium and hence blood-brain barrier) interact to produce HTE in toxemia and in certain other conditions. Another likely contributor to the development of HTE in the setting of modest blood pressure elevations is a loss of autoregu-

latory control. This also might result from endothelial cell damage. If the normal systemic blood pressure range of autoregulation within which cerebral blood flow is held constant (typically mean arterial blood pressure approximately 60 to 160) is narrowed in toxemia, then patients would be expected to develop rises in cerebral blood flow and cerebral edema at lower pressures (mean arterial blood pressure less than 160). This hypothesis has not been proven. The hemodynamic changes in preeclampsia-eclampsia are complex. Most studies by transcranial Doppler ultrasound find increases in middle cerebral artery flow in preeclampsia and greater increases in eclampsia. However, this finding is variously interpreted as caused by local vasospasm or by dilation of distal resistance arterioles. Also, SPECT studies may find either reduced flow consistent with vasospasm or increased flow consistent with dilation and loss of autoregulatory control. It is likely that both occur. Magnesium has been shown to dampen the increases in middle cerebral flow in preeclampsia-eclampsia. This also could result from an alleviation of vasospasm or from a restoration of autoregulatory competence. The ultimate result of HTN and endothelial cell dysfunction in the brain is vasogenic cerebral edema. The changes of edema are most prominent in the subcortical white matter of the occipital lobes and posterior fossa structures, although lesions may also be seen in the cortex and in other brain regions. This cerebral edema is reversible. However, intraparenchymal hemorrhage and infarction, the latter caused by vasospasm or thrombosis, may cause irreversible focal brain injury. As in other types of HTE, cortical and subcortical brain edema may promote seizures. Therefore, it is the development of cerebral edema that is thought to underlie the traditional clinical marker of eclampsia, seizures. Population studies have addressed whether toxemia is promoted by maternal or fetal factors and whether single or multiple genetic influences are involved. Most data argue for maternal susceptibility, yet several findings suggest fetal influence as well. The lack of concordance between monozygotic twins, the risk of changed paternity (although a finding still in doubt), and the recent finding that risk is higher in partners of fathers whose mothers had preeclampsia all argue for a fetal contribution to susceptibility.

CLINICAL FEATURES Traditional classifications defining preeclampsia and eclampsia are based on the clinical findings of HTN, proteinuria, and edema in the proper clinical context of mid- to late pregnancy or the puerperium (Table 189- 1). Updated classifications, though less precise, acknowledge the great lack of specificity of peripheral edema in pregnancy and, more importantly, allow the consideration of many of the multisystemic disorders that are now known to be a part of toxemia. These disorders include fetal compromise; features of cerebral edema other than seizures, such as headache, encephalopathy with confusion, cortical visual disturbances, and imaging evidence of cerebral edema; and features of the HELLP syndrome without alternative explanations. For clinical purposes, it is important to use such a broadened definition of toxemia to capture patients for appropriate monitoring and therapy. The most common neurologic manifestations of cerebral edema are headache, mental status changes consistent with diffuse encephalopathy, seizures, and visual phenomena localizing to the occipital and posterior parietal lobes. Although the headache is nonspecific, and it may be difficult to distinguish it from migraine or other benign headache syndromes, the occurrence of a new and

Chapter 189

TME 189-1. Standard Criteria for the Diagnosis of Preeclampsia and Eclampsia Preeclampsia Hypertension: diastolic BP 290 mm Hg or systolic BP 2140 mm Hg or rise of diastolic BP by 15 mm Hg or systolic BP by 30 mm Hg on at least two readings 6 hr apart and Proteinuria: 2300 mg protein/24 hr or 21 g/L protein in at least two random specimens 26 hr apart or Edema: >1+ pitting edema after 12 hr bed rest or weight gain of 25 Ib in 1 week Eclampsia Seizures: convulsions not caused by any coincidental neurologic disease, such as epilepsv, in a woman who meets the criteria for preeclammia From Kaplan Pw, Repke IT: Eclampsia. Neurol Clin 12:566, 1994, with permission.

persistent headache in late pregnancy or during the postpartum period and headache with features suggestive of increased intracranial pressure, such as nausea and vomiting or increased intensity in the lying position, should raise suspicion. Diffuse encephalopathy may be accompanied by somnolence, inattention, and disorientation or by agitation in some cases. When severe, somnolence may progress to stupor and coma, especially in the setting of brainstem or thalamic edema. Other manifestations of focal dysfunction, such as aphasia or apraxia, may be signs of encephalopathy. Tremor, myoclonus, and asterixis may also occur. Seizures may be partial or generalized, although generalized

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seizures probably are secondarily generalized after a subtle focal onset. Because of the posterior predominance of the cerebral edema, cortical visual phenomena are common complaints and findings. Women may complain of blurring of vision, positive visual phenomena, or blindness with findings consistent with a cortical localization. DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC TESTING HTN, proteinuria, and edema have many potential causes that must be considered in pregnant patients as they would in any patient. Headaches must be distinguished by diagnostic testing from common benign headache syndromes. Late pregnancy and the puerperium must raise the possibility of cerebral venous sinus thrombosis and intracranial hemorrhage from an unidentified arteriovenous malformation or other cause. Encephalopathy and focal neurologic deficits and seizures may all be caused by venous or arterial infarction, hemorrhage, or less commonly encephalitis, abscess, or other brain lesions. To look for evidence of venous sinus thrombosis or other alternative diagnoses and for positive features suggestive of eclampsia, MRI is the best test (Figure 189-1). Diffusion-weighted MFU (DWI) can distinguish acute ischemic stroke (high-intensity DWI, decreased apparent diffusion coefficient) from reversible vasogenic edema secondary to increased blood flow (normal or low-intensity DWI, increased apparent diffusion coefficient). Perfusion-weighted imaging can

B

A

FIG. 189-1. Eclampsia. A 21-year-old woman presented 1 week after normal delivery with a severe headache and a generalized tonic-clonic seizure. Blood pressure on admission was 180/108. A, Axial fluid-attenuated inversion recovery (FLAIR) image shows hyperintense signal in the right cerebellar white matter (arrow). 6, Axial FLAIR image shows hyperintense signal bilaterally in the medial occipital and parietal cortex and white matter (arrows).

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show evidence of increased cerebral blood flow, as can SPECT, although these are rarely needed to establish a diagnosis. Electroencephalogram may show slowing, often with posterior predominance, characteristic of encephalopathy, or it may show ictal discharges. Lumbar puncture usually is not necessary but should be done when central nervous system infection is a serious consideration. Lumbar puncture does not reliably differentiate eclampsia with HTE from venous sinus thrombosis. Transcranial Doppler ultrasound may show increased flow velocities caused by vasoconstriction and possibly by increased blood flow. Angiogram is rarely needed, but it may show multifocal, segmental arterial narrowings. Many reported cases of supposed postpartum angiitis with the diagnosis based on angiography probably are misdiagnoses and represent eclampsia rather than a vascular inflammatory disorder. Cases of severe eclampsia with hemolysis and thrombocytopenia (HELLP syndrome) may resemble other hematologic syndromes, such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, sepsis, systemic vasculitis, systemic lupus erythematosus,or antiphospholipid antibody syndrome. Appropriate laboratory studies must be done to differentiate these disorders. Although the five major features of TTP may all occur in the HELLP syndrome, several features of HELLP syndrome usually can distinguish these two diagnoses: encephalopathydespite a high platelet count in HELLP syndrome (encephalopathy usually only occurs with platelet counts less than 20,000 in TTP), HTN, lack of fever, lack of renal failure, characteristic neuroimaging, and response to therapy for eclampsia (antihypertensive agents, magnesium sulfate, and delivery). Table 189-2 compares clinical and laboratory features of HELLP with disseminated intravascular coagulation and TTP or hemolytic uremic syndrome.

TREATMENT PreventiveTherapies Although the many hypotheses to explain the underlying mechanisms of preeclampsia suggest many possible preventive strategies, few have been tested. Aspirin and the antioxidant vitamins C and E have been systematically studied. Several studies in the 1980s suggested that by inhibiting the formation of thromboxane A,, low-dose aspirin (60 to 100 mg/day) and other platelet inhibitors

W TAW 189-2.

might prevent preeclampsia in patients at increased risk. Two large studies in the 1990s failed to find such a benefit of low-dose aspirin. However, one of them, the Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP), did demonstrate a decrease in the rate of preterm delivery in treated women and a trend in favor of therapy to prevent preeclampsia (CLASP Collaborative Group, 1994). Although the benefit has not been established with certainty, some practitioners use low-dose aspirin for women at high risk. There is evidence that oxidative stress contributes to the pathogenesis of preeclampsia. This has prompted a trial in high-risk women of vitamin C (1000 mg/day) and vitamin E (400 IU/day) beginning at 16 to 22 weeks’ gestation (Chappell et al, 1999). In this trial preeclampsia occurred in 17% of patients receiving placebo and 8% of those receiving vitamin therapy ( P = .02). The authors concluded that vitamin C and E supplements may benefit women at high risk. These potential preventive therapies warrant further study. Acute Therapies

When control of pregnancy-induced HTN is poor despite outpatient therapy, patients are admitted for bed rest and obstetric monitoring. This should include observation for symptoms of increased intracranial pressure and focal neurologic disease. Prompt control of blood pressure is crucial to prevent progression of encephalopathywhen it occurs. It must be remembered that in eclampsia, HTE may occur at blood pressure levels that usually are well tolerated. Antihypertensive therapy usually has been started earlier as part of high-risk obstetric care. To achieve rapid blood pressure control, labetalol and hydralazine are useful agents. Other P-blockers and calcium channel blockers may also be used. Nitroprusside and nitroglycerin introduce the risk of possible fetal cyanide toxicity and are best avoided during pregnancy. They may be good choices when preeclampsia-eclampsia occurs after delivery. Angiotensin-converting enzyme inhibitors are contraindicated during pregnancy because they have been associated with fetal morbidity and mortality. Mean arterial blood pressure should be lowered by approximately 15% to 20%. Excessive blood pressure lowering may compromise placental perfusion. Therefore, it is important that the obstetrician monitor the fetus for signs of distress during aggressive antihypertensive therapy. Most patients

Differentiation of HELLP Syndrome from DIC and l T P or HUS

Parameter

HELLP

DIC

l l P or HUS

Blood pressure Edema Proteinuria Liver function tests Lactate dehydrogenase Blood urea nitrogen and creatinine Computed tomography and magnetic resonance imaging Anemia Platelets Coagulation tests Antinuclear antibodies Biopsy vWF-CPb Antithrombin 111

Elevated Variable Usually present Elevated Elevated Variable HTE changes MAHA Low Normal Normal Not done Normal Low

Any Vanable Variable Often elevated Elevated Variable Normal or variable MAHA Low

Any Variable Variable Often elevated Elevated Highest in HUS Normal or variable MAHA Very low if neurologic symptoms Normal 20% positive Gingival biopsy positive” Antibodies or low-level activity Normal

DIC Normal None recommended Normal Normal

’Hyaline platelet clots in microvessels. bVonWillebrand factor-cleaving protein studies are not currently available for routine clinical use. Abbreviations: DIC, disseminated intravascular coagulation; HELLP, hemolytic anemia, elevated liver enzymes, and low platelets; HUS, hemolytic uremic syndrome; MAHA, microangiopathic hemolytic anemia; lTP, thrombotic thrombocytopenic purpura. From Feske SK:Toxemia of pregnancy. In NoseworthyJ (ed): Neurological Therapeutics: Principles and Practice. Martin Dunitz Publishers, London, in press, with permission.

Chapter 189 H Eclampsia and Hypertensive Encephalopathy

respond to medical therapy for HTN and careful fluid management. However, because the volume status and hemodynamic profiles of women with preeclampsia-eclampsia vary and may be difficult to define by clinical examination, invasive hemodynamic monitoring with a pulmonary artery catheter may be indicated in some patients with refractory HTN, oliguria, or pulmonary edema. With the information provided by a pulmonary artery catheter, use of fluids, diuretics, vasodilators, and P-blockers can be directed by knowledge of the cardiac output and systemic vascular resistance. Magnesium has been the major agent used by obstetricians to treat severe preeclampsia-eclampsia for many years. Although magnesium has been reported to have many beneficial effects in women with preedampsia-eclampsia (decreased systemic vascular resistance and blood pressure, increased cardiac output, increased uterine blood flow, and enhanced prostacyclin activity in endothelial cells), until there was evidence from well-designed trials, there was much controversy in the neurologic literature concerning the benefits of magnesium therapy for eclamptic seizures. Recent clinical trials support the use of magnesium sulfate both for treatment and prevention of eclamptic seizures. The Eclampsia Trial Collaborative Group compared magnesium sulfate with diazepam and with phenytoin in women who had had an eclamptic seizure (Eclampsia Trial Collaborative Group, 1995). In this study, intravenous magnesium sulfate 1 g/hour was superior to both diazepam and phenytoin when both seizure recurrence and maternal mortality were compared. In the comparison of magnesium sulfate and phenytoin, newborns also had better outcomes in the magnesium sulfate group. This is a conservative dosage of magnesium sulfate, and although phenytoin levels were not checked to ensure adequate dosing, commonly used dosages were given. In a second trial, magnesium sulfate was shown to prevent seizures in women with preeclampsia (Lucas, 1995). This study compared patients with pregnancy-induced HTN who received magnesium sulfate by intravenous loading and intramuscular maintenance dosing with patients treated with phenytoin (1000 mg loading dose and a second dose of 500 mg after 10 hours). Fewer patients in the magnesium sulfate group developed seizures. In 9 of 10 patients who developed seizures on phenytoin, serum levels at the time of the seizure were therapeutic (more than 10 pg/mL), and in 8 of 10 the levels exceeded 15 pg/mL. A protocol for administering intravenous magnesium sulfate for severe preeclampsia-eclampsia is given in Table 189-3. Such high intravenous dosages of magnesium sulfate should always be given with an infusion pump to avoid overdosing. Although the expected response to different serum levels of magnesium has been defined, it is not clear that monitoring of serum levels reliably guides therapy. Serum magnesium levels of 4 to 7 mEqlL are considered desirable. At 8 to 10 mEq/L, reflex depression typically is apparent, and above 10 mEq/L, respiratory depression is likely. Respiratory depression should be treated with discontinuation of magnesium sulfate and intravenous administration of calcium gluconate. In patients with renal insufficiency, a lower loading dosage (4 g) should be used, and the maintenance dosage should be halved (to 1 g/hour), and serum levels should be monitored closely. When patients with severe preeclampsia progress to convulsions, the term eclampsia is applied. Sometimes this term is also applied to women with severe preeclampsia and other evidence of severe encephalopathy, such as coma without seizures. These distinctionsare largely arbitrary classifications. Like seizures, coma and convulsions occur as manifestations of cerebral edema on the

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TABLE 189-3. Protocol for Magnesium Sulfate Therapy for

Preeclampsia-Eclampsia 1. MgSO, 4-6 g in 5 0 mL normal saline, infused over 20-30 min” 2. MgSO, 20 g/500 mL H,O, begin at 2 g/hr by infusion pump 3. May give additional MgSO, 2 g IV over 3-5 min if further seizures occur

4. Discontinue MgSO, if a. The patellar reflexes are lost (test in upper extremities if epidural anesthesia is used) b. Respirations are depressed, or c. Urine output 400 cc in prior 4 hr 5. If serious toxicity occurs, give calcium gluconate 1 g slow IV push and repeat until signs begin to abate ’If more rapid effect is desired, give a MgSO, 4 g loading dose over 5 rnin and, if seizures persist an additional 2 g over 3-5 min. From the Center for Labor and Birth, Brigham and Women‘s Hospital, Boston, W with permission.

severe end of the spectrum of the preeclampsia-eclampsia syndrome. Seizures may occur in late pregnancy, during labor and delivery, or postpartum. Although most postpartum seizures occur within 48 hours of delivery, they may occur much later, and standard definitions probably understate the interval after delivery within which it is reasonable to attribute seizures to eclampsia. Still, when seizures occur beyond 48 hours after delivery, careful consideration should be given to other possible causes. Traditionally defined preeclampsia usually precedes seizures, but cases have been reported of presumed eclamptic seizures when typical preceding symptoms and signs were lacking. It remains unclear what the proper role is for traditional anticonvulsant agents in the context of eclamptic seizures. Recent trials have compared magnesium sulfate with anticonvulsants, but they have not evaluated their combined use. The Eclampsia Trial Collaborative Group study suggests that magnesium sulfate is the drug of choice for eclamptic seizures, and in most cases no additional anticonvulsant is needed. However, when it is given properly and carefully monitored, it is unlikely that phenytoin will cause serious side effects to mother or child. When seizures recur despite appropriate therapy with magnesium sulfate, and when lesions are identified by computed tomography or MRI that suggests a need for anticonvulsant therapy beyond 48 hours, then traditional anticonvulsants should be given. Refractory seizures should be treated aggressively based on standard protocols for the treatment of status epilepticus.

SUGGESTED READINGS Chappell LC, Seed PT, Briley AL et al: Effect of antioxidants on the occurrence of pre-eclampsiain women at increased risk a randomized trial. Lancet 35481c816, 1999 CLASP: A randomized trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet 343:619-629, 1994 Eclampsia Trial Collaborative Group: Which anticonvulsant for women with eclampsia? Evidence from the collaborative trial. Lancet 345: 1455-1463, 1995

Lucas MJ, Levano KJ, Cunningham FG et ak A comparison of magnesium sulfate and phenytoin for the prevention of eclampsia. N Engl J Med 333~201-205, 1995

Mantello MT, Schwartz RB, Jones KM et ak Imaging of neurologic complications associated with pregnancy. AJR 160843-847, 1993 Naidu S, Payne AJ, Moodley J et al: Randomized study assessing the effect of phenytoin and magnesium sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound. Br J Obstet Gynaecol 103:lll-116, 1996

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Qureshi AI, Frankel MR, Ottenlips JR, Stern B7: Cerebral hemodynamics in preeclampsia and eclampsia. Arch Neurol 53:1226-1231, 1996 Schwartz RB, Feske SK, Polak JF et al: Clinical and neuroradiographic correlates in preeclampsia-eclampsia: insights into the pathogenesis of hypertensive encephalopathy. Radiology 217:37 1-376, 2000

Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Gynecol 142:159-167, 1982 Williams KP, Wilson S: Persistence of cerebral hemodynamic changes in patients with eclampsia: a report of three cases. Am J Obstet Gynecol 181~1162-1165, 1999

190 Aortic Dissection Cormac A. O‘Donovan and John P. Conomy

Although aortic dissection is uncommon, it is being recognized more as a result of an increased awareness of its existence and the availability of new radiologic diagnostic methods. Clinical diagnosis remains difficult and often occurs only when the physician has a high index of suspicion of the condition. The difficulty arises because many of the symptoms usually are associated with more common diseases. Sir William Osler said, “There is no disease more conducive to clinical humility than aneurysm of the aorta.” The term aortic dissection is used interchangeably with dissecting aortic aneurysm, but the presence of an aneurysm is not a prerequisite for the occurrence of dissection of the aorta. At the beginning of the twentieth century, aortic dissection was diagnosed mainly at autopsy, after the patient had presented in an obtunded state and had deteriorated rapidly to death. Although aortic dissection remains uncommon and diagnosis can be difficult, early recognition is important because delays in instituting treatment have a significant impact on survival. At the other end of the spectrum, small aortic dissections often are discovered at autopsy, and only careful retrospective analysis of the medical record points to undiagnosed aortic dissection as the likely cause of symptoms that persisted for many years before the death of the patient. The marked improvement in outcome after treatment in recent years is related to early diagnosis in cases of atypical chest pain and other unexplained symptoms. Recognition of the differences between proximal and distal dissections in terms of symptoms, the temporal course of the disease progression, and outcomes from different treatment modalities is necessary for understanding this important condition. The first case of dissecting aortic aneurysm described in the literature was that of George I1 of England, who died of it in 1761. The condition was not named until about 50 years later, when two more cases were described. Until the early 1930s, the diagnosis was rarely made before death. Catastrophic rupture of the aorta was the most commonly reported presentation. In those cases, profound shock from hemodynamic instability dominates the clinical picture, and death from shock rapidly supervenes. A small, contained rupture of a dissecting aortic aneurysm mimics the signs and symptoms of lesions more often associated with other structures in the vicinity of the aorta, so aortic dissection often is undiagnosed as the cause. This difficulty in diagnosis is reflected in an 1843 statement by Peacock, who said, “Nor are the symptoms which attend its formation and progress such as can be regarded as characteristic of its affection.”

INCIDENCE The incidence of aortic dissection is difficult to establish from the reported series and probably is underestimated because of the occurrence of sudden death with this condition. Population-based studies using data from angiography, surgical cases, and autopsy reports estimate 40 cased1 ,000,000/year, which would mean an incidence rate of 10,000 cases annually in the United States. Historically, when aortic dissection was usually diagnosed postmortem, autopsy series showed an overall incidence of 4%. The enhanced awareness of the condition and the availability of newer radiologic methods for detection, not an increased incidence, are responsible for the extensive literature available today on the subject. Dissecting aortic aneurysm is said to be the second most common form of aneurysm affecting the aorta, after the dilated fusiform atherosclerotic form. However, it may prove to be the most common as our diagnostic ability improves. Antemortem diagnosis is made more readily when the tear is more severe and symptoms are more florid. Small dissections of the aorta in patients with less profound clinical symptoms are detected today primarily as a result of radiologic techniques. Aortic dissection is thought to occur most commonly in middle-aged hypertensive patients. Cases involving children are rare. The incidence of dissecting aneurysm at autopsy in patients younger than 20 years is low, approximately 1 in 2500. Younger patients with dissection of the aorta show a higher incidence of the conditions that predispose the medial layer of blood vessels to weakness. CAUSES The association of different diseases with aortic dissection is difficult to assess for a number of reasons. Because the overall incidence is low, the possibility that aortic dissection is associated by chance with a given disease rather than being one of the cardinal features of it often exists. However, conditions featuring inherited defects in connective tissue formation, such as EhlersDanlos syndrome, are common causes of aortic dissection. Marfan’s syndrome has the most well-known association with aortic dissection, which is the most common cause of death in this syndrome. Other congenital conditions in which aortic dissection is sometimes seen include Turner’s syndrome, congenital bicuspid or tricuspid aortic valve, and Noonan’s syndrome. Systemic conditions giving rise to dedifferentiation of elastic tissue can

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Qureshi AI, Frankel MR, Ottenlips JR, Stern B7: Cerebral hemodynamics in preeclampsia and eclampsia. Arch Neurol 53:1226-1231, 1996 Schwartz RB, Feske SK, Polak JF et al: Clinical and neuroradiographic correlates in preeclampsia-eclampsia: insights into the pathogenesis of hypertensive encephalopathy. Radiology 217:37 1-376, 2000

Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Gynecol 142:159-167, 1982 Williams KP, Wilson S: Persistence of cerebral hemodynamic changes in patients with eclampsia: a report of three cases. Am J Obstet Gynecol 181~1162-1165, 1999

190 Aortic Dissection Cormac A. O‘Donovan and John P. Conomy

Although aortic dissection is uncommon, it is being recognized more as a result of an increased awareness of its existence and the availability of new radiologic diagnostic methods. Clinical diagnosis remains difficult and often occurs only when the physician has a high index of suspicion of the condition. The difficulty arises because many of the symptoms usually are associated with more common diseases. Sir William Osler said, “There is no disease more conducive to clinical humility than aneurysm of the aorta.” The term aortic dissection is used interchangeably with dissecting aortic aneurysm, but the presence of an aneurysm is not a prerequisite for the occurrence of dissection of the aorta. At the beginning of the twentieth century, aortic dissection was diagnosed mainly at autopsy, after the patient had presented in an obtunded state and had deteriorated rapidly to death. Although aortic dissection remains uncommon and diagnosis can be difficult, early recognition is important because delays in instituting treatment have a significant impact on survival. At the other end of the spectrum, small aortic dissections often are discovered at autopsy, and only careful retrospective analysis of the medical record points to undiagnosed aortic dissection as the likely cause of symptoms that persisted for many years before the death of the patient. The marked improvement in outcome after treatment in recent years is related to early diagnosis in cases of atypical chest pain and other unexplained symptoms. Recognition of the differences between proximal and distal dissections in terms of symptoms, the temporal course of the disease progression, and outcomes from different treatment modalities is necessary for understanding this important condition. The first case of dissecting aortic aneurysm described in the literature was that of George I1 of England, who died of it in 1761. The condition was not named until about 50 years later, when two more cases were described. Until the early 1930s, the diagnosis was rarely made before death. Catastrophic rupture of the aorta was the most commonly reported presentation. In those cases, profound shock from hemodynamic instability dominates the clinical picture, and death from shock rapidly supervenes. A small, contained rupture of a dissecting aortic aneurysm mimics the signs and symptoms of lesions more often associated with other structures in the vicinity of the aorta, so aortic dissection often is undiagnosed as the cause. This difficulty in diagnosis is reflected in an 1843 statement by Peacock, who said, “Nor are the symptoms which attend its formation and progress such as can be regarded as characteristic of its affection.”

INCIDENCE The incidence of aortic dissection is difficult to establish from the reported series and probably is underestimated because of the occurrence of sudden death with this condition. Population-based studies using data from angiography, surgical cases, and autopsy reports estimate 40 cased1 ,000,000/year, which would mean an incidence rate of 10,000 cases annually in the United States. Historically, when aortic dissection was usually diagnosed postmortem, autopsy series showed an overall incidence of 4%. The enhanced awareness of the condition and the availability of newer radiologic methods for detection, not an increased incidence, are responsible for the extensive literature available today on the subject. Dissecting aortic aneurysm is said to be the second most common form of aneurysm affecting the aorta, after the dilated fusiform atherosclerotic form. However, it may prove to be the most common as our diagnostic ability improves. Antemortem diagnosis is made more readily when the tear is more severe and symptoms are more florid. Small dissections of the aorta in patients with less profound clinical symptoms are detected today primarily as a result of radiologic techniques. Aortic dissection is thought to occur most commonly in middle-aged hypertensive patients. Cases involving children are rare. The incidence of dissecting aneurysm at autopsy in patients younger than 20 years is low, approximately 1 in 2500. Younger patients with dissection of the aorta show a higher incidence of the conditions that predispose the medial layer of blood vessels to weakness. CAUSES The association of different diseases with aortic dissection is difficult to assess for a number of reasons. Because the overall incidence is low, the possibility that aortic dissection is associated by chance with a given disease rather than being one of the cardinal features of it often exists. However, conditions featuring inherited defects in connective tissue formation, such as EhlersDanlos syndrome, are common causes of aortic dissection. Marfan’s syndrome has the most well-known association with aortic dissection, which is the most common cause of death in this syndrome. Other congenital conditions in which aortic dissection is sometimes seen include Turner’s syndrome, congenital bicuspid or tricuspid aortic valve, and Noonan’s syndrome. Systemic conditions giving rise to dedifferentiation of elastic tissue can

Chapter I90

cause overproduction of a mucoid substance, which subsequently accumulates in the medial layer of the aorta. Aortic dissection commonly occurs in conditions in which the aorta has been previously dilated by any of several different pathologic processes. In many of these cases, the dissection is overshadowed by the distention of the aorta, especially when the dissection is small and clinically silent. The classification of idiopathic cases under the category of medial degeneration occurs commonly and is most often seen in patients over 40 years of age. This term is applied when intimal tears are not evident and the only detectable lesion is the hematoma within the medial layer. Focal ischemic necrosis of muscle may be followed by degeneration of elastic tissue and collagen to produce clefts in the medial layer. In younger patients, abnormal accumulation of mucoid substance in the media caused by excessive production may degrade the elastic tissue. Intimal tears, which are seen in almost 95% of cases, may occur as a result of weakening of the aortic wall through a defect in the media rather than as a rupture of the intimal lining as the primary process. Older adults with aortic dissection have a history of hypertension, and they predominantly have distal lesions. However, the exact association between aortic dissection and hypertension is tenuous, given its low incidence in hypertensive patients in whom dilated, fusiform atherosclerotic aneurysms are the most common aortic lesion. Of women younger than 40 with aortic dissection, up to half are pregnant; despite the

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high frequency of this occurrence, the mechanism remains obscure. A number of vasculitides are associated with aortic dissection, including giant cell arteritis, relapsing polychondritis, systemic lupus erythematosus, Takayasu’s arteritis, and rheumatic fever, but these associations usually are based on single case reports. If it affects the aorta, trauma to the chest wall usually causes transection but can occasionally cause aortic dissection. Aortic surgery involving either the aorta or the aortic valve can result in dissection postoperatively.

CLASSIFICATION SYSTEM The systems used to classify aortic dissections are based on the location of the dissection. Determining the extent of the hematoma is of value for comparing results of various treatments so as to guide management of these patients. However, categorizing the different types based solely on location of the dissection leaves out other important factors, such as location of the associated intimal tears and the extent of retrograde as well as anterograde progression of the dissecting process. The most widely used classification system probably is that of DeBakey, who has extensive surgical experience with this disease (Fig. 190-1). This system is based on findings from the series of patients with aortic dissection on whom he operated. The system consists of three types; type 1 lesions occur in the ascending aorta

FIG. 190-1. DeBakey‘s surgical management of dissecting aneurysms of the aorta. (From DeBakey ME, Henly WS, Cooley DA 1 Thorac Cardiovasc Surg 49:130, January 1965, with permission.)

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to beyond the aortic arch (60%to 70%), type.2 lesions involve the ascending aorta only, and type 3 lesions arise beyond the subclavian artery (20% to 30%). The Stanford system, developed by Dailey and colleagues, classifies lesions on whether the ascending aorta is involved (type A) or not (type B). Further subdivision using this system is made according to the location of the associated intimal tear (site 1, ascending; site 2, arch; site 3, descending). ANATOMIC CONSIDERATIONS The human spinal cord is supplied with blood via a single anterior and two posterior spinal arteries (Fig. 190-2). The spinal arteries are terminal branches of the radiculomedullary arteries, which follow the anterior nerve roots through the intervertebral foramina. The radiculomedullary arteries are derived from the segmental arteries, which arise along the length of the aorta. The anterior spinal artery is formed at its rostra1 end by the union of two branches of the vertebral arteries. In the cervical region, the anterior spinal artery receives contributions from the costocervical and thyrocervical trunks, branches of the extracranial portion of the vertebral artery, the occipital branch of the external carotid artery, the deep cervical artery, and the ascending cervical artery, all of which have multiple anastomoses with each other (Fig. 190-3). As the anterior spinal artery descends caudally, it receives a variable number of feeders from the radiculomedullarybranches of the segmental arteries. These segmental feeders are least developed in the upper to midthoracic region, where the anterior spinal artery may be discontinuous, retelike, and narrow. In the midthoracic to upper lumbar region, the large artery of Adamkiewicz reinforces the blood supply of the anterior spinal artery and continues as the anterior median sulcal artery, which extends to the caudal region. There it joins an anastomotic ring at the conus medullaris, which receives segmental branches from the lumbar and iliolumbar arteries and has a collateral circulation with the

posterior spinal arteries in this region (Fig. 190-4). This circulation provides a rich blood supply to the lumbosacral enlargement and the cauda equina. The posterior spinal artery, in contrast to the anterior spinal artery, has an abundant supply of feeding radiculomedullary branches. This dual supply of the posterior third of the spinal cord segment is in stark contrast to the anterior aspect, where the sulcal branches of the single anterior spinal artery supply alternate halves of the spinal cord. Therefore, the anterior spinal cord is more vulnerable to vascular insults because the anterior spinal artery is an end artery with little anastomotic flow from the posterior artery. Clinical features of vascular lesions involving the anterior spinal cord therefore are consistent. PATHOPHYSIOLOGY Whereas aortic dissection has been used synonymously with dissecting aortic aneurysm, dissecting aortic hematoma is also appropriate to describe this condition. Pathologic examination of dissecting aortic hematomas after surgery or at autopsy may be unable to distinguish whether the abnormalities in the media and intima are primary or secondary. Hematomas within the aortic wall are thought to arise from tears in the intima or disruption of the vasa vasorum within the media. Connective tissue disorders affect the integrity of the media of blood vessels and therefore predispose them to rupture of the vasa vasorum. However, they can also weaken vessel walls, which subsequently stretch, tearing the intimal lining. Atherosclerosis and systemic hypertension are thought to be the most common causes of aortic dissection initiated by intimal tears. The gap between the intima and media in aortic dissection causes symptoms through different mechanisms. The effects of the dissecting process depend not only on the extent of the dissection but also on the proximity to critical vessels supplying regions of the spinal cord that have poor collateral circulation. When aortic dissection causes symptoms of focal ischemia, blockage of the

Posterior Posterior spinal a.

.I.

radiculomedullary a.

FIG. 190-2. Segmental arteries of the aorta giving rise to radiculomedullary and spinal arteries. (From ODonovan CA, Conomy J P Neurological complications of diseases of the aorta. p. 63. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 19. ElsevierNorth Holland Publishing, Amsterdam, 1993, with permission.)

Chapter 190 W Aortic Dissection

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External carotid a.

FIG. 190-3. Rostra1 end of the anterior spinal artely formed by two branches of the vertebral arteries with multiple feeding vessels. (From O’Donovan CA, Conomy JP: Neurological complications of diseases of the aorta. p. 63. In Vinken PJ, Bruyn CW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 19. Elsevier-North Holland Publishing, Amsterdam, 1993, with permission.)

Common carotid a.

ostia of the aortic branches is the presumed mechanism. Ischemia of the spinal cord causes predominantly lower motor neuron signs because the gray matter needs more oxygen than the white matter does. Animal experiments have shown that the overall oxygen needs of the spinal cord are about two fifths that of cerebral tissue. Indeed, during aortic surgery, the spinal cord blood supply can be occluded for up to 30 minutes without causing postoperative neurologic deficits. This phenomenon may partly explain how extensive aortic dissections can cause either no symptoms or only transient ones. Collateral circulation also determines whether ischemic symptoms result from occlusion of the ostia of the radicular branches. However, collateral circulation does not account for the low incidence of clinical ischemic syndromes of the spinal cord compared with the cerebral circulation. The blood supply of the spinal cord was described in some classic works a few decades ago. Little is known about the frequency of anatomic variations between individuals because these studies have not been repeated recently because of the tedious work involved in dissecting and identifymg the various branches. The small size and number of vessels in the midthoracic region often are invoked to explain the

high incidence of ischemia in this region of the spinal cord compared with others. When symptoms resolve rapidly without persistent neurologic deficits because the dissecting process is self-contained, the diagnosis can be extremely difficult. Nonvascular lesions close to the aortic dissection may be misdiagnosed as the cause of the symptoms. This misdiagnosis has sometimes resulted in inappropriate operations on these “incidental” lesions in an attempt to alleviate symptoms.

CLINICAL FEATURES The difficulty in diagnosing aortic dissection clinically arises not from the unusual nature of the symptoms but from the close resemblance to those occurring in more common conditions. Acute dissection is easily confused with myocardial infarction; chronic aortic dissection tends to be more associated with distal lesions, for which the differential diagnosis is much more extensive. Few large series of well-studied cases report on the clinical signs because shock supervenes in many cases and obscures the details of the patient’s history and physical examination. The most common symptom is pain, and most of the

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Posterior spinal a.

Common iliac a. lntemal iliac a.

-4u

-

FIG. 190-4. Caudal end of the aorta demonstrating an anastomoses at the conus rnedullaris formed by the lumbar and iliolumbar arteries. (From O’Donovan CA, Conomy JP: Neurological complications of diseases of the aorta. p. 63.In Vinken PJ, Bruyn CW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 19. Elsevier-North Holland Publishing, Amsterdam, 1993, with permission.)

literature on the clinical features contains lengthy descriptions of the characteristics of the pain in an attempt to highlight the features peculiar to aortic dissection. Neurologic symptoms occur frequently and when present result in a much higher rate of antemortern diagnosis. Discussion of the clinical features of this condition may be easier to understand when seen in relation to different organ systems. Cardiovascular Features Pain. Chest pain is the most common symptom in aortic dissection, occurring in up to 90% of patients. Despite its frequent occurrence, the precise mechanism is unknown. Animal experiments suggest that the pain is caused by the diffusion of blood into surrounding tissues, not by distention of the aortic wall. This mechanism explains the pain that occurs when blood leaks from the dissection but not that associated with small, contained ruptures that do not extend to the external layers of the aortic wall. The three most common characteristics of the pain in these descriptions are its severity, mode of onset, and radiation. The pain usually is described by patients as the most severe pain they have ever experienced, abrupt in onset, and of maximum intensity from the start, in contrast to that of myocardial infarction, which is often gradual in onset. The pain is described in many different terms, such as ripping, tearing, choking, sharp, constricting, stabbing, knifelike, or burning, as “something broken loose in the chest,” and (rarely) as throbbing, pulsating, or colicky.

Location of the pain is also highly variable and has been described in the substernal area, precordium, and back of the chest, but it can occur in many other regions of the chest. The region of the chest to which the pain is referred does not appear to be consistently related to the area of dissection. Anterior thoracic pain is more often related to proximal dissection and posterior interscapular pain to distal dissections. Pain commonly radiates from anterior to posterior; however, it can also have a wandering character. The patient tends to shift positions without relief, and the pain may be aggravated by respiration. Painless aortic dissection is unusual, occurring in only one tenth of patients. Underecognition of pain may result from altered mental status, particularly in those who subsequently experience cardiovascular collapse as a result of hypovolemic shock. Murmur. A murmur in a patient with chest pain may provide a valuable clue for diagnosing aortic dissection. Diastolic murmurs in the region of the aortic valve are of greatest significance. Murmurs can be produced either by the dilation of the aortic ring or by alterations in the alignment of the aortic valve leaflets. Dilation of the aortic ring can result from loss of tone secondary to hematoma formation in the medial layer or disruption of the nerve endings in the outer adventitial layer. Alteration of alignment of the aortic valves can result from currents occurring in the region of intimal tears, and aortic insufficiency can result from blood flowing into the aneurysmal sac and returning to the lumen in diastole. Pulsations and thrills may also be detected in the thoracic and abdominal area and may provide other evidence of aortic dissection when chest pain is the only symptom. Shock and Syncope. Shock may occur in up to 25% of patients with aortic dissection and varies in degree according to the rate and amount of blood loss. Half of these patients have severe shock, and the other half maintain a systolic blood pressure greater than 100 mm Hg. Syncope at the onset of chest pain is thought to distinguish aortic dissection from myocardial infarction. Although the cause of syncope in aortic dissection may overlap with that of shock caused by cerebral ischemia from blood loss, syncope can occur through other mechanisms, such as reflex neurogenic stimulation of the aortic depressor nerve by the pooling of blood in the false lumen after dissection occurs along the innominate or carotid arteries. Paradoxically, hypertension may occur as a result of ischemia of the kidney or the medullary region of the brainstem, destruction of the aortic depressor nerve, or aortic obstruction. Congestive heart failure is not uncommon. Pericardial tamponade, which is the most common cause of death in aortic dissection, can be seen in some survivors. Pericardial friction rubs, venous distention (including the superior vena cava syndrome), and inequality of the pulses in the upper and lower extremities have also been reported. Neurologic Features

The most comprehensive description of the neurologic aspects of aortic dissection was compiled by Weissmann and Adams (1944) who examined 38 cases of aortic dissection in detail and confirmed the diagnosis postmortem. Neurologic symptoms and signs are present in 15% to 20% of patients with aortic dissection. The actual incidence probably is much higher because neurologic findings often are overlooked in the presence of other clinical features. In some cases, the only clinical manifestations described are neurologic. When symptoms and signs of aortic dissection

Chapter 190

include neurologic abnormalities, the antemortem diagnosis rate of aortic dissection increases. Cerebrum. Transient disturbances of cerebral function caused by aortic dissection can result in focal symptoms similar to those of a transient ischemic attack or of a more global cerebral hypoperfusion causing dizziness without prolonged loss of consciousness. These transient symptoms may resolve spontaneously because of a reentrant tear. When symptoms progress to include coma, a focal neurologic deficit in the obtunded patient may reflect the effects of the initial phase of the dissecting process in a branch of the aorta. Dissection of the carotid arteries can result in unequal carotid pulses, increased amplitude of the carotid pulsations as a result of periarterial sympathectomy,or asynchrony of the pulses in the carotids as a result of velocity differences. Less common cerebral manifestations include transient global amnesia, headaches caused by the superior vena cava syndrome, and hemorrhagic cerebral infarcts, which are thought to be caused by reperfusion after occlusion of vessels. Impingement of the aneurysmal sac on nerves in the neck may cause speech or voice changes from inferior or recurrent laryngeal nerve involvement. Horner’s syndrome secondary to sympathetic nerve dysfunction is occasionally caused by aortic dissection. Spinal Cord. The occurrence of paraplegia after aortic surgery is well known, but it also occurs in aortic dissection. The same factors that cause paraparesis postoperatively also apply to aortic dissection. Infrared dissection of the aorta is less likely to cause paraparesis than a dissection located above the renal arteries, probably because of the location of the artery of Adamkiewicz. In fact, a number of intercostal arteries may dissect without clinical evidence of spinal cord damage. When paraplegia occurs as a result of aortic dissection, the role of ischemia of the peripheral nerves versus spinal cord is difficult to determine. As with all other vascular insults to the spinal cord, the findings in paraplegia usually are limited to those of anterior spinal artery occlusion. Aortic dissection may be difficult to distinguish from other causes of paraplegia associated with pain, such as spinal epidural abscess and spontaneous hematomyelia, in which widening of the aorta on a chest x-ray may be the only clue for differentiating between these conditions. Peripheral Nerves. Ischemic necrosis of nerves in aortic dissection is said to be the most common neurologic complication of aortic dissection, occurring about three times as often as spinal cord or brain involvement. The clinical presentation usually is that of a cold, pulseless extremity with weakness, anesthesia, and loss of tendon reflexes. However, an aneurysmal dilation of the aorta, extending to involve a small nutrient branch artery and causing a mononeuropathy from compression or regional ischemia limited to one or two nerves, offers a greater diagnostic challenge. Proximal occlusion of vessels close to their origin at the aorta can result in ischemia of nerves distally with axonal loss in a condition known as ischemic monomelic neuropathy. Acute rupture of the aorta with hemorrhage and chronic contained rupture with hematoma formation are other mechanisms by which a compressive neuropathy may occur. Femoral, sciatic, and obturator nerves are the most commonly affected. Involvement of these nerves can occur in unusual combinations, which is sometimes explained by the occurrence in combination of a compartment syndrome from compression by extravasated blood, in addition to aneurysmal compression of a nerve at another site where the initial rupture occurred. Iliopsoas hematoma can cause the iliacus syndrome and compress the femoral nerve, whereas the psoas syndrome involves

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the obturator and lateral femoral cutaneous nerves, in addition to the femoral nerve. Pain radiating into the lower abdomen and inguinal regions may be caused by iliohypogastric nerve irritation, and when this pain is localized to the testes, the anterior scrota1 branches of the inguinal nerve and the genital branch of the genitofemoral nerve probably are involved. Other unusual presentations of mononeuropathies can result from lateral popliteal nerve compression and from impingement on the lateral femoral cutaneous nerve of the thigh, causing buttock pain with numbness on the outer aspect of the thigh. Historically, radicular pain was a common occurrence in aortic dissection as a result of syphilitic aneurysms affecting the proximal aspect of aortic branches. Miscellaneous Symptoms

Arrhythmias, fever, and cyanosis have all been reported in a minority of patients. Symptoms referable to the respiratory system are many and include cough, hemoptysis, altered breathing caused by tracheal tug, and pleural effusions. Gastrointestinal symptoms are also common, and almost half of these patients experience abdominal pain. Dysphagia caused by esophageal displacement can be the presenting symptom of aortic dissection in some cases. Gastrointestinal bleeding may occur with hematemesis as a result of rupture into the esophagus, and melena may be caused by bowel infarction from mesenteric artery occlusion. Nausea and vomiting may result from stimulation of the mesenteric autonomic ganglia during acute rupture. Examination of the abdomen in these cases may reveal tenderness, rigidity, abdominal discoloration, or a mass. Chronic dissection may be associated with uremia and acidosis as a result of a contained dissection occluding the renal arteries. Clinical diagnosis of renal artery involvement by the dissecting process is difficult because the pain described in these situations is rarely typical of renal pain. Ocular complications include blindness from carotid artery dissection or hypertensive retinopathy.

DIAGNOSTIC TESTING Abnormal laboratory test results are common in cases of aortic dissection; however, their clinical importance is overshadowed by the many different radiologic tests that have greater sensitivity and specificity. The laboratory test findings in aortic dissection are reported in more detail in earlier series of cases of aortic dissection at a time when chest x-ray was the only radiographic technique available. The abnormal laboratory test results reported usually were seen in a minority of patients and consisted of modest deviations from normal values. Results are nonspecific for aortic dissection and include findings such as leucocytosis, increased serum amylase and blood urea nitrogen concentrations, progressive elevation of the sedimentation rate over days, and hematuria. The development over several days of anemia and increased serum bilirubin as a result of progressive loss of blood into the aneurysmal sac and subsequent hemolysis may be useful as a diagnostic aid. Normal cardiac enzymes in a patient with sudden onset of severe chest pain should also alert the clinician to the diagnosis of aortic dissection. The choice of radiologic test is determined both by the degree of suspicion of the diagnosis and the clinical condition of the patient. Although angiography may be the radiologic gold standard for diagnosing aortic dissection, the risk of complications, which is greatest with emergent angiography, still exists in

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elective procedures. Chest x-rays were used almost exclusively as a screening test for aortic dissection many decades ago, but newer radiographic techniques are more specific and delineate more accurately the extent of the dissection. Chest x-ray has a sensitivity of up to 90%. Although none of the chest x-ray findings are specific enough to allow a precise radiographic diagnosis of aortic dissection, they prove extremely useful in the acute setting in differentiating from conditions such as myocardial infarction, spinal cord lesions, or abdominal emergencies. The most pathogonomic finding is deformity of the supracardiac shadow, which is produced by extension of the dissection along the aortic arch branches (Fig. 190-5). Fluid often is seen in the left pleural cavity from rupture into this cavity. Other findings may include enlargement of the heart and displacement of the trachea and esophagus. Computed tomography (CT) often is used because of its widespread availability and ability to visualize the site and extent of aortic dissection (Fig. 190-6). The intimal tear may be more readily identified with CT than with angiography because the scanning plane is perpendicular to the long axis of the vessel and because calcifications can be seen in displaced intima. Aortic wall thickening is a feature of many processes, and aortic dissection can be differentiated from these conditions based on its appearance on CT. Fluid in the pleural, pericardial, and mediastinal spaces commonly accompanies aortic dissection and is readily recognizable by CT. One limitation of CT is its inability to determine which channels fill major vessels. Transesophageal echocardiography is in many ways the diagnostic procedure of choice, particularly in emergencies, in which its sensitivity and specificity are almost 100%. Lesions of the arch of the aorta and to a slightly lesser extent the proximal ascending aorta are particularly well visualized.

FIG. 190-5. Chest radiograph showing tortuosity and prominence of the aorta and widening of the superior mediastinum in aortic dissection. (Courtesy of R. White, MD, Cleveland Clinic Foundation, Cleveland, OH.) .

Distal lesions are not well seen, however, and other lesions such as thrombi may be interpreted incorrectly as aortic dissections. Experience with magnetic resonance imaging (MRI) is less than with other procedures but is increasing rapidly. One of the main limitations of MRI in urgent situations is the greater length of time needed to carry out the scan compared with other radiologic tests. However, imaging can be carried out in many different planes without loss of spatial resolution. Furthermore, the different MRI signal characteristics of other vascular lesions, such as plaques, and the signals from various flow patterns and velocities are particularly useful in assessing aortic dissection for conditions such as a false lumen (Fig. 190-7). Angiography remains the standard by which other diagnostic methods are assessed (Fig. 190-8). It continues to be widely used, especially where it is readily available and can be performed safely, even in acutely ill patients, by experienced radiologists. One of its advantages is in determining the relationship of the major aortic branch vessels to the dissection. Thrombosis of the false lumen is a possible source of false-negative angiographic studies, but other angiographic features usually can alert one to this misdiagnosis. In practice, transesophageal echocardiography probably is the most frequently used emergency radiologic test. Echocardiography also allows aortic valve and cardiac function to be assessed. Surgeons tend to use angiography for preoperative planning, particularly if coronary artery disease coexists, but these strategies may change as experience with other procedures accumulates. CT is used when transesophageal echocardiography and angiography are unavailable. CT and MRI are best for distal dissections because they are useful in long-term follow-up of the progression of aortic dissection.

Varying approaches to the management of aortic dissection are increasingly reported in the literature, paralleling the increased availabilityof diagnostic methods for early detection and increased experience with different surgical approaches. There is consensus on the general principles for treatment, based mostly on the location of the lesion. However, dissections warranting surgery in an otherwise healthy younger patient may be treated more conservatively by medical methods in an older adult. Proximal lesions generally are treated by surgery because the shearing forces of cardiac outflow speed the progression of the lesion, and medical management is insufficient in these patients, who deteriorate rapidly without urgent surgical intervention. Medical treatment should begin even before a definitive diagnosis of aortic dissection is made. Patients with aortic dissection are best treated in an intensive care unit with the cooperation of both medical and surgical services. The immediate goals of treatment are to lower the absolute blood pressure and reduce the rate of increase of the blood pressure. The drugs used must not only modulate these factors but also show high potency in this regard and have a short half-life for easy titration of dosages. Sodium nitroprusside, the most widely used hypotensive agent, is used in dosages ranging from 25 to 300 pgminute. Diuretics increase the effectiveness of these hypotensive agents by decreasing fluid retention. However, agents with pure hypotensive effects increase heart rate and probably are best avoided. Therefore, simultaneous use of a P-adrenergic blocking drug is almost always necessary. Propranolo1 is the P-blocking agent most often used, but other agents, such as esmolol, which is cardioselective and ultra-short-acting, are

Chapter 190 H Aortic Dissection

FIG. 190-6. CT scan of the chest showing thrombus in the false channel of the posterior aspect of the descending aorta. (Courtesy of R. White, MD, Cleveland Clinic Foundation, Cleveland, OH.)

FIG. 190-7. MRI scan of DeBakey type 2 dissection in the ascending aorta showing signal changes consistent with slow flow in the false channel. (Courtesy of R. White, MD, Cleveland Clinic Foundation, Cleveland, OH.)

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exists of leaking, rupture, or rapid aortic enlargement. Acute distal dissections that may also necessitate surgical therapy are those in which medical therapy fails and blood pressure elevation persists, there is retrograde extension into the ascending aorta, or ischemia of an organ or limb develops. Less definitive indications include distal dissections in patients with conditions such as connective disorders that predispose them to aneurysm formation. Chronic dissections that result in aortic insufficiency or that show evidence of recurring invariably necessitate surgical correction. Operating on chronic dissections may prove easier than during the acute stage because the tissues have more tensile strength after partial regeneration. PROGNOSIS

FIG. 190-8. Angiogram of DeBakey type 3 dissection showing mild early enhancement of false channel, which extends to base of subclavian artery. (Courtesy of R. White, MD, Cleveland Clinic Foundation, Cleveland, OH.)

also useful. P-Blocking agents may be used alone in normotensive patients. Trimethaphan camyslate, which reduces the rate of rise and absolute level of blood pressure, may be useful when P-blockers are contraindicated, but its side effects and tolerance building allow it to be used only for less than 48 hours. Calcium antagonists have also been used with some success when P-blockers are contraindicated. Reserpine was given intramuscularly many decades ago, but it has now been superseded by other agents. A detailed discussion of surgical techniques and the rationale for choosing between them is beyond the scope of this text. The published indications for surgical treatment show a fair consensus. However, centers with a low surgical mortality rate advocate operative treatment for all types of aortic dissection and do not acknowledge the role of medical treatment early in acute proximal aortic dissection. Surgical therapy is warranted for all acute proximal dissections and also for arch dissections, which are complicated by rupture or localized aneurysm formation. Distal dissections generally are treated medically except when evidence

The survival of patients with aortic dissection depends on many factors, including where the dissection is located, how rapidly treatment is instituted, how well hypertension is controlled, and whether reentry tears develop. The increased survival rate in modern times is related not only to more aggressive management but also to earlier diagnosis. Rupture into the pleural, pericardial, and peritoneal cavities occurs in up to 80% of patients. The most common mechanism of death is pericardial tamponade. Longterm survival usually is associated with distal aneurysms, for which carefully monitored medical management has increased the favorable outcome rates considerably in recent years. Whereas 40 years ago antemortern diagnosis was rare and the survival rate low, aggressive treatment of this condition has improved survival rates to between 60% and 90%. SELECTED READINGS Anagnostopoulos C E Acute Aortic Dissections. University Park Press, Baltimore, 1975 Cooke JP, Safford RE: Progress in the diagnosis and management of aortic dissection. Mayo Clin Proc 61:147, 1986 DeBakey ME, McCollum CH, Crawford ES et al: Dissection and dissecting aneurysms of the aorta: twenty year follow-up of five hundred twenty-seven patients treated surgically. Surgery 92:1118, 1982 Hirst AE Jr, Johns VJ Jr, Kime SW Jr: Dissecting aneurysm of the aorta: a review of 505 cases. Medicine 37:217, 1958 Moersch FP, Sayre G P Neurologic manifestations associated with dissecting aneurysm of the aorta. JAMA 144:1141, 1950 O’Donovan CA, Conomy J P Neurological complications of diseases of the aorta. p. 63. In Goetz CG, Tanner CM, Aminoff MJ (eds): Systemic Diseases, Part 1. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 19. Elsevier-North Holland Publishing, Amsterdam, 1993 O’Gara PT, DeSanctis RW: Aortic dissection. p. 931. In Loscalzo J, Creager MA, Dzau VJ (eds): Vascular Medicine: A Textbook of Vascular Biology and Diseases. Little, Brown, Boston, 1992 Slater EE, DeSanctis RW: The clinical recognition of dissecting aortic aneurysm. Am J Med 60625, 1976 Weismann AD, Adams RD: The neurological complications of dissecting aortic aneurysm. Brain 67:69, 1944 Wolfe WG: Dissecting aneurysms of the aorta, p. 1548. In Sabiston DC Jr (ed): Textbook of Surgery. 14th Ed. WB Saunders, Philadelphia, 1991

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PULMONARY DISORDERS

191 Neurosarcoidosis Barney J. Stern Sarcoidosis affects the nervous system in 5% of patients with the disease. Patients typically present in their third or fourth decade, although they can be affected at any age. Neurologic symptoms are the presenting feature of sarcoidosis in one half of patients with neurosarcoidosis. Some three quarters of patients destined to develop neurologic disease do so within 2 years of becoming afflicted with sarcoidosis. One third to one half of patients with neurosarcoidosis have more than one neurologic manifestation. PATHOPHYSIOLOGY

The cause of sarcoidosis remains unknown. Inflammatory cells, particularly CD4 lymphocytes, are activated; these cells congregate at sites of disease activity and secrete various cytokines, including interleukin-2, interleukin- 1, interferon-y, and tumor necrosis factor-a. Monocytes and macrophages form granulomas, and ultimately irreversible fibrosis can develop. Small foci of ischemic necrosis can be found, presumably a result of vascular compromise from perivascular inflammation. Meningeal inflammation is the most characteristic pathologic feature of central nervous system (CNS) sarcoidosis. Inflammation can extend to the cranial nerves, compromising these structures, and to the cerebrospinal fluid (CSF) pathways, leading to hydrocephalus. Brain or spinal cord disease can result from spread of inflammatory cells along the Virchow-Robin spaces, leading to the appearance of discrete granulomatous mass lesions or a diffuse encephalopathy or vasculopathy. Hypothalamic inflammation is the most common site for parenchymal disease. Finally, peripheral nerves and muscle can be involved in the inflammatory state. CLINICAL MANIFESTATIONS AND DIAGNOSIS

The neurologic manifestations of sarcoidosis, together with their approximate frequencies, are outlined in Table 191-1. Many of the diverse presentations of neurosarcoidosis can be best approached if they are thought of as fitting within one of these broad categories. Patients with known systemic sarcoidosis who develop neurologic disease consistent with sarcoidosis should be evaluated for the reasonable exclusion of other disease entities, particularly infection and neoplasia. The patient can then be treated for neurosarcoidosis. If the patient does not respond as expected, the diagnosis should be questioned and a more extensive evaluation pursued to consider other diagnoses.

If a patient without known sarcoidosis develops a clinical syndrome consistent with neurosarcoidosis, the diagnostic challenge can be great. Because corticosteroid therapy can mask signs of systemic disease, treatment should be postponed, if possible, while a search for systemic disease is initiated. An examination of the skin and lymph nodes may reveal abnormalities that can be biopsied. Sarcoidosis most often affects intrathoracic structures (87% of patients), followed by lymph node, skin, and ocular disease (15% to 28% of patients). Systemic disease often can be demonstrated if a comprehensive approach is followed, using the following tests: Serum angiotensin-converting enzyme Serum calcium Chest x-ray Thoracic computed tomography scan Pulmonary function tests including diffusing capacity Ophthalmologic examination Endoscopic nasal examination Whole-body gallium scan 24-hour urinary calcium excretion Anergy screen Muscle magnetic resonance imaging (MRI) Whole body fluorodeoxyglucose positron emission tomography imaging If the patient has impaired smell or taste, nasal or olfactory nerve disease might be present. If dry eyes or mouth are noted, lacrimal, parotid, or salivary gland inflammation is possible. Patients with possible CNS disease should be questioned about symptoms relating to neuroendocrinologic or hypothalamic dysfunction because problems in these areas are the most common parenchymal disorders found in CNS sarcoidosis. Inquiry about alterations in menses, libido, and potency should be made as well as the presence of galactorrhea. Excessive thirst can be caused by resetting of the hypothalamic osmostat, diabetes insipidus, hypercalcemia, hypercalciuria, and corticosteroid-induced diabetes mellitus. Alterations in body temperature, sleep, and appetite can develop. Patients with CNS symptoms other than transient cranial nerve palsies or aseptic meningitis should undergo neuroendocrinologic evaluation including tests for thyroid function (for consideration of hypothalamic hypothyroidism), prolactin, testosterone or estradiol, follicle-stimulating hormone, luteinizing hormone, and cortisol. 1221

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TABLE191-1. Neurologic Manifestations of Sarcoidosis Clinical Manifestation

Cranial neuropathy Facial palsy Meningeal disease. . Aseptic meningitis Mass Hydrocephalus Parenchymal disease Brain Endocrinopathy Mass lesion Encephalopathy or vasculopathy Seizures Vegetative dysfunction Spinal canal Extramedullary or intramedullary disease Cauda equina syndrome Neuropathy Axonal neuropathy Mononeuropathy Mononeuropathy multiplex Sensorimotor Sensory Motor Demyelinating neuropathy Guillain-Barre syndrome Myopathy Nodule Polymyositis Atrophy

Approximate Frequency (46)

50-75 25-50 10-20 10 50 10-1 5

5-1 0 5-10 5-10

15

15

Adapted from Stern BJ: Neurosatcoidosis. Neurol Chronicle 2:1992 and Stern BJ, Schoufeld SH: Neurosarcoidosis. p. 289. In Arieff Al, Grim RC (eds): Metabolic Brain Dysfunction in Systemic Disorders. Little, Brown, Boston, 1992, with permission.

Although computed tomography scans can demonstrate abnormalities in CNS sarcoidosis, the preferred imaging technique is MRI with contrast enhancement. Rarely do brain T1-weighted images provide much information, although hydrocephalus and optic nerve and chiasm enlargement can be seen. With T2weighted imaging, areas of increased signal intensity can be appreciated, especially in a periventricular distribution. Contrast administration can demonstrate leptomeningeal enhancement and parenchymal abnormalities. Spine MRI can visualize intramedullary disease, which appears as an enhancing fusiform enlargement, focal or diffuse enhancement, or atrophy. Enhancing nodules or thickened or matted nerve roots can be appreciated with images of the cauda equina. CSF analysis can reveal an elevated pressure, increased total protein, hypoglycorrhachia, and a predominantly mononuclear pleocytosis. The immunoglobulin G index can be elevated, and oligoclonal bands may be detected. CSF angiotensin-converting enzyme can also be elevated in patients with CNS sarcoidosis, although abnormalities are also seen in the presence of infection and malignancy. A normal CSF angiotensin-converting enzyme assay does not exclude the diagnosis of neurosarcoidosis. Visual, auditory, or somatosensory evoked potentials can be abnormal in patients with optic nerve, eighth nerve, or spinal cord disease, respectively. Occasional patients with CNS sarcoidosis have evoked potential abnormalities without overt clinical disease in the area being studied. Furthermore, rare patients with sarcoidosis but no clinically evident CNS disease can have evoked potential abnormalities. CNS tissue is rarely obtained for pathologic examination. Therefore, the clinician should always keep an open mind as to the diagnosis. Patients can be classified as having possible, probable,

and definite CNS sarcoidosis based on the certainty of the diagnosis of multisystem sarcoidosis, the characteristics of the CNS disease, and the patient’s response to therapy. If the patient is not responding to therapy, consideration should be given to biopsy so as to exclude other diagnoses and confirm the clinical suspicion of sarcoidosis. Some other diagnostic considerations are listed here: Multiple sclerosis Sjogren’s syndrome Systemic lupus erythematosus Neurosyphilis Neuroborreliosis Human immunodeficiency virus infection Behget’s disease Vogt-Koyanagi-Harada disease Toxoplasmosis Brucellosis Whipple’s disease Lymphoma Germ cell tumors Craniopharyngioma Isolated angiitis of the CNS Lymphocytic hypophysitis Pachymeningitis Low CSF pressure/volume meningeal enhancement Patients without known systemic sarcoidosis who develop a brain or spinal cord mass usually undergo biopsy. If pathologic examination suggests noncaseating granulomas, appropriate cultures should be obtained. Surgical excision should be avoided because surgery is rarely curative and patients can deteriorate from surgical excision of a granulomatous mass. As mentioned, corticosteroid therapy can mask systemic disease. If a patient with known sarcoidosis develops a CNS mass, an empiric trial of corticosteroid therapy is appropriate, especially if infection and malignancy can be reasonably excluded by CSF examination. If the patient does not respond to corticosteroid therapy, a biopsy should be pursued. In either of these scenarios, if a mass progressively enlarges despite corticosteroid therapy, surgical exploration should be strongly considered to evaluate the possibility of a malignancy. Nerve conduction studies can characterize peripheral nerve disease as primarily axonal or demyelinating. Entrapment neuropathies can be demonstrated, especially at the carpal tunnel. Electromyography can help define the presence of a myopathy or further characterize the pattern of peripheral nerve compromise. Muscle or nerve biopsy is informative if the diagnosis of neuromuscular disease is in doubt. If the patient is functional, much of the diagnostic evaluation can be done on an outpatient basis. Patients need to be counseled as to the complexity of the evaluation and understand that a comprehensive and deliberate evaluation is time-consuming; therefore answers may not be immediately available.

TREATMENT No rigorous studies have defined the optimal treatment for neurosarcoidosis. Most authorities recommend corticosteroid therapy for patients without contraindications. Therapeutic decisions should be guided by the patient’s clinical course, the

Chapter 191

expected natural history of the patient’s clinical manifestations, and adverse treatment effects. Some two thirds of patients have a monophasic neurologic illness; the remainder have a chronically progressive or remittingrelapsing course. The former patients typically have an isolated cranial neuropathy, most often involvingthe facial nerve, or a bout of aseptic meningitis. Those with a chronic course usually have CNS parenchymal disease, hydrocephalus, multiple cranial neuropathies (especially involving cranial nerves I1 and VIII), peripheral neuropathy, and myopathy. It is not at all certain that treatment changes the natural history of the disease, although in the short term symptoms often can be alleviated with therapy. A goal of treatment is to diminish the irreversible fibrosis that can develop and minimize tissue ischemia that might result from perivascular inflammation. With time, the inflammatory process can “burn out,” allowing immunosuppressive therapy to be withdrawn. A peripheral facial nerve palsy usually responds to 2 weeks of prednisone therapy. The first week‘s prednisone dosage usually is 0.5 to 1.0 mg/day (or 40 to 60 mg/day), followed by a taper over the second week. This approach can also be used as initial therapy for other cranial neuropathies and aseptic meningitis. However, even prolonged, aggressive therapy can fail to prevent irreversible optic and eighth nerve dysfunction. Patients with a peripheral neuropathy or myopathy can respond to a short course of corticosteroid therapy. However, prolonged treatment often is necessary. Corticosteroids should be tapered slowly. Asymptomatic ventricular enlargement probably does not warrant treatment. Mild, symptomatic hydrocephalus can respond to corticosteroid therapy, although prolonged treatment often is needed. Life-threatening hydrocephalus or corticosteroid-resistant hydrocephalus necessitates ventricular shunting. Unfortunately, patients can evolve from mild hydrocephalus to severe disease quite rapidly. Patients and caregivers must be educated as to when to seek emergent care. Shunt placement is not without risk in this patient population, which is why prophylactic shunting is not usually performed. Shunt obstruction from the inflamed CSF and ependyma is common, and placement of a foreign object in the CNS of an immunosuppressed host predisposes to infection. Corticosteroid therapy can improve the status of patients with a diffuse encephalopathy or vasculopathy or a CNS mass lesion. Only rarely does immunosuppressive treatment improve neuroendocrine dysfunction or vegetative symptoms. Seizures occur most commonly in patients with parenchymal disease or hydrocephalus. Control of seizures usually is not difficult if the underlying inflammatory process can be controlled. Corticosteroid treatment for CNS parenchymal disease and other severe neurologic manifestations of sarcoidosis usually starts with prednisone 1.0 to 1.5 mg/kg/day. The higher dosages are used in patients with particularly severe disease. These patients often need prolonged therapy, and prednisone should be tapered very slowly. The patient might be observed on high corticosteroid dosages for 2 to 4 weeks to ascertain the clinical response. The prednisone dosage can then be tapered by 5-mg decrements every 2 weeks as the clinical course is monitored. The disease tends to exacerbate at a prednisone dosage of approximately 10 mg daily. Patients often exhibit an individual dosage floor below which worsening can be expected. If a prednisone dosage of 10 mg daily can be achieved, the patient should be evaluated for evidence of subclinicalworsening of disease. For patients with CNS disease, an enhanced MRI scan is useful. Intense enhancement suggests that

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disease is active, and further decreases in corticosteroid dosage may lead to a clinical exacerbation. On the other hand, persistent CSF abnormalities usually are not an indication for continuing high-dose corticosteroid therapy because patients can remain quite functional despite an abnormal CSF. Efforts to “normalize” the CSF often entail intense immunosuppression, with its attendant adverse effects. If the disease appears quiescent, the daily prednisone dosage can be tapered by 1 mg every 2 to 4 weeks. If a patient has a clinical relapse, the prednisone dosage can be doubled (unless the dosage is very modest, in which case prednisone 10 to 20 mg daily can be prescribed). The patient should be observed for approximately 4 weeks before another taper is begun. Patients may need multiple cycles of higher and lower corticosteroid dosages. This effort usually is warranted because the disease can become quiescent, and without attempts at withdrawing medication, patients may be needlessly exposed to the harmful side effects of corticosteroids. A short course of methylprednisolone 20 mg/kg/day intravenously for 3 days, followed by high-dose prednisone for 2 to 4 weeks, is occasionally warranted. Patients with severe acute neurologic compromise can improve on this regimen. Another potential agent to treat severe, progressive disease is infliximab, a monoclonal antibody directed at tumor necrosis factor. If it is unclear whether a patient might benefit from more intense immunosuppression, intravenous methylprednisolone can be used to judge a response over a short time. One or two target signs or symptoms can be used to judge the clinical response, such as the results of psychometric tests or a timed walk. One caveat should be noted If the patient has a CNS mass lesion unresponsive to high-dose intravenous corticosteroids, surgical resection probably is appropriate in life-threatening situations. Daily dosing of corticosteroids usually is superior to alternateday therapy in patients with neurosarcoidosis. However, if a patient is doing very well on a modest dosage of daily prednisone, an attempt can be made to wean the patient slowly onto alternate-day therapy. Alternative Treatments

Alternative therapies occasionally are considered for neurosarcoidosis. Experience in this area is limited, and firm recommendations are not available. Indications for the use of alternative treatments include the need to avoid corticosteroids as initial therapy, serious adverse chronic corticosteroid effects, and disease activity despite aggressive corticosteroid therapy. Immunosuppressive medications used to treat sarcoidosis include azathioprine, methotrexate, cyclophosphamide,cyclosporine, and chlorambucil. None of these agents have been studied in a placebo-controlled manner, and none has been rigorously compared with others. Rarely is it possible to withdraw corticosteroid treatment completely; patients do best on a modest dosage of corticosteroid combined with an alternate agent. Azathioprine is a reasonable first-line agent that can be added to the patient’s existing corticosteroid dosage. After the dosage of the alternative agent has been brought to the desired level, the corticosteroid dosage can be slowly lowered as the clinical status is monitored. The patient must be monitored closely for adverse effects of the alternative agent. One way of choosing between the various alternative agents is to note the organ systems compromised by sarcoidosis and avoid drugs that have notable adverse effects directed at the already compromised organ. For instance, azathioprine, methotrexate, and chlorambucil are associated with

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TABLE191-2. Selected Long-Term Complications of Neurosarcoidosis Infection Cryptococcal meningitis Tuberculous meningitis Toxoplasmosis Progressive multifocal leukoencephalopathy Listeria monocytogenes Spinal epidural lipomatosis Corticosteroid myopathy Lymphoma Inclusion bodv mvositis Adapted from Stern BJ: Neurosarcoidosis.Neurol Chronicle 2:1, 1992. ~

~~

liver toxicity, cyclosporine can cause renal impairment, and methotrexate, cyclophosphamide, and chlorambucil can cause pulmonary fibrosis. All these agents except cyclosporine are implicated in causing malignancies. Immunomodulatory agents can also be used to treat sarcoidosis and neurosarcoidosis. Experience with these drugs is limited, but these agents can be used in conjunction with corticosteroids or corticosteroids and immunosuppressive agents. Hydroxychloroquine, pentoxifylline, thalidomide, and infliximab have been reported in case reports and small case series to be beneficial. The latter three drugs have activity against tumor necrosis factor, and thalidomide antagonizes a variety of cytokines and other inflammatory modulators. If a patient with CNS disease fails or cannot tolerate alternate agents, consideration should be given to radiotherapy. Patients may stabilize, at least in the short term. Ultimately, corticosteroids and alternative agents often must be continued, at least in modest dosages. General Supportive Care

Patients need close attention to their general medical condition. Potential adverse effects of treatment should be sought. Exercise and dietary programs often are highly beneficial. Rehabilitation services should be used as appropriate. Depression is not uncommon, and treatment can be helpful. Treating endocrinologic disturbances is important. In particular, hypothyroidism and hypogonadism should be treated. Because patients often are on protracted, low-dose corticosteroid regimens, a supplement of corticosteroid is appropriate during periods of intercurrent illness. Patients are at risk for osteoporosis. Screening should be done on a regular basis. Treatment of osteoporosis often is a challenge because sarcoidosis itself can cause hypercalcemia and hypercalciuria. Because the management of osteoporosis is an evolving science, it is best to work closely with an expert in this area.

LONG-TERM COMPLICATIONS Patients with refractory neurosarcoidosis not only are prone to the primary effects of the inflammatory process but also are at risk for the long-term complications of treatment. If a patient is not doing well, the diagnosis of sarcoidosis should be questioned, and a search for intercurrent complications should ensue. Some potential complications are noted in Table 191-2.

SUGGESTED READINGS Agbogu BN, Stern BJ, Sewell C, Yang G: Therapeutic considerations in patients with refractory neurosarcoidosis. Arch Neurol 52:875, 1995 Baughman RP, Lower EE Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 18:70, 2001 Cheng TM, O’Neill BP, Scheithauer BW, Piepgras D G Chronic meningitis: the role of meningeal or cortical biopsy. Neurosurgery 34:590, 1994 Edmonds LC, Stubbs SE, Ryu JH: Syphilis: a disease to exclude in diagnosing sarcoidosis. Mayo Clin Proc 67:37, 1992 Ferriby D, de Seze J, Stojkovic T et al: Long-term follow-up of neurosarcoidosis. Neurology 57927, 2001 Junger SS, Stern BJ, Levine SR et ak Intramedullary spinal sarcoidosis: clinical and magnetic resonance imaging characteristics. Neurology 43:333, 1993 Krumholz A, Stern BJ: Neurosarcoidosis. In Vinkin PJ, Bruyn GW (eds.). Handbook of Clinical Neurology. Systemic Diseases (Part 111). Elsevier, Amsterdam, 1998 Krumholz A, Stern BJ, Stern EG: Clinical implications of seizures in neurosarcoidosis. Arch Neurol 48:842, 1991 Meierhofer C, Dunzendorfer S, Wiedermann CJ: Theoretical basis for the activity of thalidomide. Biodrugs 15:681, 2001 Nowak DA, Widenka DC: Neurosarcoidosis: a review of its intracranial manifestations. J Neurol 248:363, 2001 Peeples DM, Stern BJ, Jiji V, Sahni K S Germ cell tumors masquerading as central nervous system sarcoidosis. Arch Neurol 48:554, 1991 Sherman JL, Stern BJ: Sarcoidosis of the CNS: comparison of unenhanced and enhanced MR images. AJNR 11:915, 1990 Soucek D, Prior C, Luef G et al: Successful treatment of spinal sarcoidosis by high-dose intravenous methylprednisolone. Clin Neuropharmacol 16464, 1993 Stern BJ: Neurosarcoidosis. p. 535. In Evans RW, Baskin DS, Yatsu FM (eds): Prognosis of Neurological Disorders. Oxford University Press, New York, 1992 Stern BJ, Krumholz A, Johns C et ak Sarcoidosis and its neurological manifestations. Arch Neurol 42:909, 1985 Stern BJ, Schonfeld SA, Sewell C et al: The treatment of neurosarcoidosis with cyclosporine. Arch Neurol 491065, 1992 Yee AMF, Pochapin M B Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 135:27, 2001 Zajicek JP, Scolding NJ, Foster 0 et al: Central nervous system sarcoidosis: diagnosis and management. Q J Med 92:103, 1999

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3 NEPHROLOGY AND UROLOGY

192 Neurologic Manifestations of Renal Failure and

Dialysis Charles f . Bolton and G. Bryan Young In the United States, more than 100,000 people receive treatment for end-stage renal disease, 80% by various types of dialysis, a few with continued conservative treatment, and the rest by transplantation. Nervous system complications are common in all groups. This chapter concentrates on the principal neurologic complications of renal failure and its treatment as they would present in office neurologic practice, usually where the consultant is in proximity to a major hemodialysis center. Comments concerning the general principles of the clinical and laboratory approach are followed by a review of the main disorders of the central and peripheral nervous systems.

GENERAL PRINCIPLES The Central Nervous System Clinical Evaluation. Mental status changes generally are the earliest and most common central nervous system effects of renal failure or its treatment. The practitioner should ask the patient's companion about changes in behavior, speech, memory, and intellectual capabilities. The time course of such changes should be established. For example, progressive dialysis encephalopathy tends to fluctuate at first, then steadily progresses, and slowly resolves with effective treatment. Stroke, transient ischemic attacks, and seizures are of sudden onset and resolve quickly. A simple mental status examination, such as the Mini-Mental State Examination (Table 192-l), documents specific deficits and quantifies the dysfunction for follow-up purposes. Investigative Tests. Investigative tests depend on the history and physical examination. The indications and limitations of tests of function and structure should be clearly understood. Electrophysiologic tests of brain function include electroencephalography (EEG) and evoked responses. EEG is useful for assessing uremic encephalopathy, the adequacy of dialysis, and seizure disorders and in making the specific diagnosis of progressive dialysis encephalopathy. Quantitative tests, including frequency analysis and middle latency auditory evoked responses, are useful in assessing the adequacy of dialysis. Tests of brain structure include computed tomography (CT) and magnetic resonance imaging (MRI) scans. These can detect specific structural lesions such as subdural hematomas, abscesses, or neoplasms. Because of the presence of bony artifact in posterior fossa structures and the temporal lobes on CT, MRI is a more sensitive examination.

Peripheral Nervous System Clinical Evaluation. Neuromuscular conditions associated with acute renal failure are uncommon and are usually limited to muscle weakness induced by disturbances of water and electrolyte metabolism. On the other hand, such conditions are common in chronic renal failure. The nature of these neuromuscular disorders varies according to the stage of renal failure (during conservative treatment, during hemodialysis, or after successful renal transplantation; Table 192-2). These facts should be kept in mind because they wdl help to focus questioning during history taking and in the selection of the most appropriate tests on physical examination. In taking a history, one should ask about muscle weakness or fatigue, cramps, the presence or absence of sweating in the hands and feet, disorders of bowel and bladder function, and problems in

8 T ~ l l191-1. i~ Mm~Mental State Examination Maximum Score 5 5

3

5

3

9

Test

Orientation What is the (year) (season) (day) (month)? Where are we (state/province) (country) (city) (building) (floor)? Registration Name three objects (lsecond to say each), then ask the patient to repeat all three. Give 1 point for each correct answer. Repeat until the patient learns all three. Count trials and record. Attention and Concentration Serial 7 (counting backward by 7 from 100); stop after five answers. Alternatively, spell "world backward. Recall Ask for the three objects repeated above. Give 1 point for each answer. Language Name a pencil and a watch (2 points). Repeat the following: "No ifs, ands, or buts" (1 point). Follow a three-stage command: "Take a paper in your right hand, fold it in half, and put it on the floor" (3 points). Read and obey: "Close your eyes" (1 point). Write (not copy) a sentence (1 point). Cow a desinn (1 Doint).

From Folstein MF, Folstein SE, McHugh PR: Mini-Mental State: a practical guide, for grading the cognitive state of patients for the clinician. 1 Psychiab Res 12:189-98, 1975, with permission.

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rn TABIS192-2. The Main Disorders of the Peripheral Nervous System in the Management Stages of Uremia Conservative Management

Dialysis

Developing uremic polyneuropathy

Stabilizing uremic polyneuropathy

Diabetic rnononeuropathy and polyneuropathy Pressure palsies

Persisting diabetic neuropathy

Cachetic myopathy

Renal Transplantation

Recovery from uremic polyneuropathy Persisting diabetic neuropathy

Carpal tunnel syndrome and amyloidosis Ischemic neuropathy and shunts or fistulas Primary myopathy and bone disease

standing or walking. Impotence in the male can be clarified from the observation that it is probably psychogenic if early morning penile erections regularly occur but is probably organic in their absence. The patient’s own words in describing symptoms should be noted and are important diagnostically. Thus, the sensory symptoms of neuropathy are characteristically not only numbness and tingling but a tight or bandlike feeling about the ankles, a sensation on the soles of the feet as if the patient is wearing tight socks, and (rarely) pain or burning. The restless leg syndrome, which may or may not be associated with peripheral neuropathy, often is an indescribably unpleasant sensation that is relieved only by movement of the legs. On physical examination, observe the location and type of surgical scars, particularly those related to the creation of arteriovenous fistulas in the upper limbs for access during chronic hemodialysis, because they may play a role in the development of upper limb mononeuropathies. The type and severity of muscle wasting is important diagnostically. Diffuse muscle wasting may be caused by disuse, secondary either to the cachexia associated with chronic renal failure or to diffuse pain from underlying bone or joint disease. In the bone disease induced by hyperparathyroidism or the toxic effects of aluminum, muscle pain and wasting are characteristically more severe in the proximal lower limbs but occasionally involve the proximal upper limbs as well. Focal wasting may occur in the distribution of the nerves that are subject to compression or entrapment, particularly in carpal tunnel syndrome, in the proximal thenar, in wasting of the median nerve in the hand (Fig. 192-l), in the ulnar-innervated hand muscles in case of compressive neuropathy of the ulnar nerve at the elbow, and in anterior compartment wasting in compression of the common peroneal nerve at the fibular head. In my experience, fasciculations are not a manifestation of neuromuscular disease in renal failure. Many patients in chronic renal failure are frail, and excessive force should be avoided when testing muscle strength. The deep tendon reflexes usually are preserved in primary myopathies and defects in neuromuscular transmission and are characteristically decreased in neuropathy. Reduced or absent ankle jerks are one of the early signs of uremic polyneuropathy. In eliciting deep tendon reflexes, it is important to use a hammer that is of sufficient length and heavy enough to move the tendon effectively with soft enough rubber not to cause undue discomfort.

In testing sensation, one should first ask the patient to outline carefully (with a finger) the areas of impaired sensation they have experienced. This is often more reliable than formal sensory testing in delineating areas of sensory loss. Light touch should be tested with a tissue and pain with a sharp splinter from a tongue depressor. The splinter should be disposed of to avoid transmitting an infectious agent. Vibratory sensation is tested with a 128-Hz tuning fork. Position sense first becomes abnormal at a distal digital joint in the hands or feet and normally is sensitive enough that the patient can detect even the smallest movement. Two-point discrimination can be measured with an instrument that has two well-defined but not excessively sharp points. Values greater than 3 mm in the fingertips of patients of all ages (and in the feet greater than 1 cm in the young and greater than 3 cm in older adults) should be considered abnormal. I have found formal testing of temperature sensation of little practical value in this group of patients. In testing stance and gait, look for a steppage gait caused by predominant weakness of the feet and ankles. In proprioceptive loss involving the lower limbs, the gait is ataxic and this phenomenon is worse with the eyes closed. Early distal weakness in the lower limbs can be determined by asking the patient to walk on either the toes or heels; proximal weakness is detected by having the patient attempt to rise from the squatting position. Postural hypotension is common in patients on chronic hemodialysis because of fluctuations in fluid volume. However, postural hypotension is rarely caused by an autonomic neuropathy alone. Autonomic insufficiency can be tested clinically by observing blood pressure and pulse in the recumbent position and then on standing. A significant postural hypotension is present if the systolic pressure drops 30 mm or more; the heart rate normally should increase by a factor of at least 1.04. Sweating can be crudely assessed by palpating the skin surfaces. Sweating in the axilla is mediated by apocrine glands that are stimulated by circulating catecholamines and therefore are not affected by neuropathy. Neurophysiologic Studies. After the history and physical examination are complete, the nature of the underlying neuromuscular disorder often is still in doubt, and electrophysiologic studies are of great value. They will clearly identify the presence and severity of uremic polyneuropathy and are valuable in following the course of this neuropathy during the various stages of chronic renal failure (Table 192-2). They are also valuable in detecting the presence and severity of mononeuropathies, such as carpal tunnel syndrome and compressive neuropathy of the ulnar nerve at the elbow and of the common peroneal nerve at the fibular head. For example, in carpal tunnel syndrome, symptoms may be strongly suggestive of the disorder, but the physical examination is negative, with no evidence of muscle weakness or sensory loss. In my experience, Phalen’s and Tinel’s signs are unreliable. In cases of primary myopathy, if the cause is simply disuse atrophy, electrophysiologic studies are entirely normal. Repetitive nerve stimulation studies rule out neuromuscular transmission defects induced by antibiotic drugs. Patients on chronic hemodialysis are understandably reluctant to undergo unnecessary painful procedures. However, standard motor and sensory nerve conduction studies cause little discomfort, particularly when performed by a sensitive and experienced electromyography technician. On the other hand, needle electromyography of muscle clearly is more uncomfortable, so this type of testing should be reserved for patients who have moderate or severe polyneuropathies and are likely to have evidence of

Chapter 192

denervation. Moreover, abnormal spontaneous activity, a sign of denervation, may be peculiarly absent in uremic neuropathy. Nerve and Muscle Biopsy. Nerve and muscle biopsy may be necessary in only a few instances, when history, physical examination, and electrophysiologic studies are still inconclusive. This is most likely to occur in cases of primary myopathies, in which electrophysiologic studies may be normal in cases of metabolic disturbances of muscle or equivocal in other types of primary myopathies. In patients in end-stage renal failure, the usual indications for nerve biopsy are suspicion of underlying vasculitis or amyloidosis. If nerve biopsy is decided on, it is usually best to take a longitudinal section of the entire cross-section of a sural nerve. The biopsy should include adjacent muscle, subcutaneous tissue, and skin, particularly when a vasculitis is in question. Special stains must be performed in suspected amyloidosis. In cases of muscle biopsy, the muscle should be chosen from a muscle that is moderately weak and has not been needled by a previous electromyographic examination. These biopsies should be performed only by an experienced and skilled surgeon. The neuropathologist should also be competent and will want to be informed, in advance, about the nature of the suspected disorder, so that the tissue can be received in optimal condition and the appropriate testing and analysis carried out.

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PRINCIPAL DISORDERS OF THE NERVOUS SYSTEM

Central Nervous System Uremic Encephalopathy. The first symptoms of uremia include lethargy, slowness in thinking, general malaise, sleep disturbance, headache, and decreased libido. Personality changes include apathy, flatness of affect, depression, or irritability. Restlessness and impaired concentration, attention, and memory are common. Occasionally patients become frankly delirious. Symptoms are variably improved by hemodialysis or peritoneal dialysis, depending on their adequacy and frequency, but are completely reversed by successful renal transplantation. Convulsive seizures still are occasionally encountered in chronic renal failure. If they are not caused by acute, severe metabolic derangement, the possibility of a complication such as a stroke, cerebral neoplasm or abscess, progressive dialysis encephalopathy, or drug-related cause should be considered. Persistent focal signs are rare in uremic encephalopathy and should prompt the search for a structural lesion. Diffuse motor phenomena such as postural tremor, asterixis, and multifocal myoclonus are not uncommon in uremia. Tremor is found in mild renal failure, even when treated by dialysis; asterixis and multifocal myoclonus reflect a more severe or advanced metabolic disturbance.

FIG. 192-1. The upper limbs of a patient who had P,-rnicroglobulin amyloidosis that caused bilateral carpal tunnel syndrome (note proximal thenar wasting) and a right ulnar neuropathy (note wasting of interosseus muscles). Tissue biopsy performed at the time of carpal tunnel surgery revealed infiltration of blood vessels by amyloid. The pain may have been caused by an arthropathy (note thickening and flexion contraction of interphalangeal joints) and periodic nerve ischemia. Repeated surgery for carpal tunnel syndrome provided only transient relief. (The Brescia-Cimino forearm fistula caused the dilated veins of the right forearm). (From Bolton CF, Young CB: Neurological Complications of Renal Disease. Butterworth, Boston, 1990, with permission.)

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PROJECTED DELTA AND ATTENUATION

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FIG. 192-2. EECs from patients with mild uremic encephalopathy. (A) The 63-year-old man was less affected; his recording shows bursts of 4- to 5-Hz low-voltage waves in the anterior head. (B) The 54-year-old man's EEG contains a burst of less than 3 Hz medium voltage, frontally predominant rhythmic &waves, which is coincident with a reduction in normal, faster rhythms. Following this burst is a 2-second period of generalized flattening or attenuation. (From Bolton CF, Young CB: Neurological Complications of Renal Disease. Butterworth, Boston, 1990, with permission.)

Routine EEGs show mild, intermittent slowing in the 8 frequency range (more than 4-Hz but less than 8-Hz waves), more prominent in the anterior head (Fig. 192-2). Arousal from sleep often is abnormal, showing rhythmic &waves in adults. Spontaneous epileptiform activity is uncommon but may appear in a generalized fashion during photic stimulation. Triphasic waves or intermittent rhythmic 6 patterns usually are features of more advanced uremia, sufficient to necessitate hospitalization. Improvement in the EEG, quantitative EEG, and middle latency evoked responses parallel clinical improvement with adequate dialysis therapy or after renal transplantation. The differential diagnosis of uremic encephalopathy includes drug intoxication (especially when renal excretion is a major determinant of the drug or its active metabolites, e.g., amantadine, opiates, and P-blockers), degenerative conditions such as Alzheimer's disease (usually associated with gradual decline in memory and then other intellectual functions in a steadily progressive manner; confusion and fluctuation in mental status are not early features, as they often are in metabolic encephalopathies such as uremia), complications of dialysis including subdural hematomas and progressive dialysis encephalopathy, depressive illness, and conditions that may affect both the kidneys and the brain such as lead intoxication and certain collagen-vascular diseases. Management includes adequate clearance of uremic neurotoxins (e.g., by increasing the frequency of dialysis treatments from twice to three times weekly). Neurologic Complications of Dialysis PROGRESSIVE DIALYSIS ENCEPHALOPATHY. It has been shown that

progressive dialysis encephalopathy, which is found in patients on chronic dialysis, relates to aluminum intoxication of the brain. The encephalopathy may be associated with symptomatic aluminum

poisoning of other organ systems (e.g., vitamin D-resistant osteomalacia with a tendency toward fractures), proximal myopathy in the lower limbs, and a severe, refractory, non-iron deficiency hypochromic microcytic anemia. The main manifestations include a prominent speech disturbance usually consisting of a nonfluent aphasia and dysarthria, involuntary motor phenomena (myoclonus, tremor, asterixis, and seizures), gait disturbance (ataxia or apraxia, or both, wide based or small stepped), and general mental decline or dementia. The symptoms and signs fluctuate widely early in the course of the illness and are more progressive later in the course. The tempo varies markedly among patients. The differential diagnosis includes chronic uremic encephalopathy, drug intoxication, subdural hematoma, degenerative conditions, and Creutzfeldt-Jakob d'isease. The EEG can help to establish the diagnosis. Characteristically, generalized bursts of slow-frequency waves, triphasic waves, or irregular spike-and-wave patterns are seen. This occurs out of proportion to the uremia and, unlike uremic encephalopathy, is not helped by increasing the frequency of dialysis treatments. Serum or bone aluminum concentrations and the desferoxamine infusion tests give estimates of the body burden of aluminum and offer indirect support of the diagnosis. Patients with progressive dialysis encephalopathy, at least in the early stages, often respond to benzodiazepines, with prompt but temporary resolution of signs for several hours. Treatment depends first on prevention. Epidemics related to high aluminum content in the tap water or dialysate have largely been eliminated, but it pays to remain vigilant. Aluminumcontaining antacids, used to bind phosphate in the gut, are a source of aluminum exposure for some. Citrate increases aluminum absorption from the gastrointestinal tract. It is best to

Chapter 192 W

substitute calcium carbonate. Secondary treatment in the early phases includes eliminating aluminum exposure and the use of desferoxamine. Benzodiazepines have only a transient beneficial effect. SUBDURAL HEMATOMA. Chronic subdural hematomas, probably related to the intrinsic coagulopathy of uremia and the iatrogenic anticoagulation, occur in 3% of patients on hemodialysis. A history of trauma may or may not be reported. Any adult age group is affected. Patients often complain of headache, and when they are brought to medical attention, the level of consciousness often is diminished. Focal signs such as lateralized motor weakness often are present but may be hard to detect if the patient is obtunded or poorly cooperative or if bilateral subdural collections are present. Gait disturbance is especially common (eg., features of apraxia, ataxia, or hemiparesis may be found). Patients’ signs and symptoms may fluctuate widely. Subdural hematomas are best confirmed by neuroimaging using CT or MRI scans. The treatment is almost always surgical, with drainage or evacuation of the clot. DIALYSISDYSEQUILIIIRIUM. Full-blown dialysis dysequilibrium rarely presents in office practice, but some patients exhibit transient symptoms of a less severe nature. This condition occurs mainly in patients with chronic renal failure who have just started on hemodialysis. It relates to osmotic shifts of water causing edema of the brain, especially of the cerebral cortex. It is associated with metabolic acidosis of the brain and cerebrospinal fluid. Symptoms and signs include headache, anorexia, nausea, vomiting, dizziness, blurring of vision, and muscle cramps in milder cases; more severely affected patients may experience myoclonus, tremors, seizures, and coma. The EEG may show generalized, excessive rhythmic slowing. The incidence is higher in children, hypertensives, and those with preexisting brain disease (e.g., trauma or recent stroke). The syndrome should be recognized and differentiated from progressive dialysis encephalopathy, dementing illness, and threatened stroke. Dialysis dysequilibrium can be prevented by using hemofiltration (no osmotic gradients) rather than dialysis. Slower hemodialysis or substitution of hemodialysis for chronic ambulatory peritoneal dialysis will also prevent the syndrome. Alternatively, increase in osmolality of the dialysate by the addition of mannitol, glycerol, or glucose is effective. The substitution of bicarbonate for acetate in the dialysate has also been recommended. Hemodialysis headache, which affects HEMODIALYSIS HEADACHE. about 60% of patients on hemodialysis, begins within a few hours of dialysis, usually as a throbbing bifrontal or generalized headache, often with nausea or vomiting. Antimigraine treatment often is effective. OTHERCoNDrnoNs. Vitamin deficiencies are now uncommon because supplements of water-soluble vitamins are provided to replace those lost from the body in dialysis. However, it is wise to be on guard for the possibility of thiamine deficiency (which may cause a Wernicke’s encephalopathy or a polyneuropathy) and biotin deficiency (which may also produce a neuropathy with or without an encephalopathy characterized by myoclonic jerks, asterixis, and amnesia). Neurologic Complicationsof Renal Transplantation CommxnoNs OF IMMUNOSUPPRESSWE DRUGS.Primary central ner-

vous system lymphoma and opportunistic infections of the brain or meninges are now much less common than before the advent of

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cyclosporin A. This drug is the main immunosuppressant used in transplants. It has better success and fewer severe adverse effects than earlier immunosuppressive agents, although a number of neurologic side effects are seen. These include postural tremors (22% of cases), seizures (up to 5% often associated with hypomagnesemia), less commonly cerebellar intention tremors or ataxia, burning feet, myoclonus, hallucinations, encephalopathy, polyneuropathy, or spinal cord dysfunction (rare). The syndrome of posterior reversible leukoencephalopathy is associated with cyclosporin A. Stroke. Cerebrovascular complications are increased in patients with chronic renal failure, whereas patients on dialysis are more prone to intracranial hemorrhage. After transplantation, patients are more prone to ischemic stroke. The main risk factor is hypertension. Lipid abnormalities, diabetes mellitus, and secondary polycythemia may play a contributory role. Attending physicians should be aware of these complications, should reduce risk factors as much as possible, and should investigate promptly if patients have features of threatened stroke, such as transient ischemic attacks. Peripheral Nervous System Uremic Polyneuropathy. In the early stages of chronic renal failure, during conservative management, uremic polyneuropathy usually is not clinically evident, although mild abnormalities may be detected with electrophysiologic studies or very mild clinical signs may be evident. Only when end-stage renal failure has been reached, when the creatine clearance is less than 5 mL/minute, does significant polyneuropathy occur. At that point 60% of patients have some evidence of uremic polyneuropathy. The most common early symptoms are restless leg syndrome, cramps, numbness, tingling, and uncomfortable sensations, but these may be nonspecific and may occasionally occur in the absence of clinical or electrophysiologic evidence of uremic neuropathy. They may be related to transient neural membrane dysfunction brought about by changes in water and electrolytes. The earliest clear-cut clinical signs are impaired vibratory perception in the toes and reduced ankle jerks. Rarely, the neuropathy is severe, with distal wasting and weakness, absent deep tendon reflexes, severe distal sensory loss to all modalities, and an inability to walk. On occasion, uremic polyneuropathy seems to advance rapidly over a matter of weeks and may be predominantly of a motor variety. It is likely that this type of neuropathy is associated with underlying sepsis, possibly at the site of shunts or fistulas, or following intercurrent operation. The neuropathy is more properly called critical illness polyneuropathy. It reverses satisfactorily once the sepsis is brought fully under control. The autonomic nervous system is commonly involved in a mild form, detected only by testing of the cardiac R-R interval, in which the normal variation in this interval is lost or diminished. However, overt clinical evidence of autonomic nervous system dysfunction is uncommon. Any manifestations of autonomic neuropathy stabilize during chronic hemodialysis and improve after successful renal transplantation. In uremic polyneuropathy, electrophysiologic studies show a primary axonal degeneration of motor and sensory fibers. Secondary segmental demyelination may be present, and thus conduction velocities may be moderately reduced and distal latencies prolonged. Compound muscle action potential amplitudes and sensory action potential amplitudes are the earliest to be involved, along with prolongation of H- or F-wave latencies. These

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electrophysiologic abnormalities may be present in up to 80% of patients on chronic hemodialysis, whether children or adults. Because of the discomfort, needle electromyography need not be performed, except in polyneuropathies that are moderate or severe. We have recently observed that abnormal spontaneous activity, positive sharp waves, and fibrillation potentials may be strangely absent when clinical and histologic evidence of denervation of muscle is present. We have speculated that uremic toxins may inhibit the production of this abnormal spontaneous activity. Clinical and electrophysiologic assessment of the peripheral nervous system in patients on chronic hemodialysis is a valuable method of assessing how well controlled the uremic syndrome is by the particular dialysis techniques. Thus, if the polyneuropathy appears to be worsening (because it should normally stabilize during chronic hemodialysis), efforts should be made to optimize the hemodialysis. The nephrologist may do this in a variety of ways: increase the weekly frequency, change the type of dialyzer, and so forth. However, improvement in the neuropathy may not occur for a number of months or may not occur at all. Therefore, if the uremic neuropathy continues to worsen, the patient should be strongly considered for successful renal transplantation. When this is done, one can expect prompt and progressive improvement in the uremic polyneuropathy, even in severe cases. Peritoneal dialysis does not appear to be any more effective than chronic hemodialysis in controlling uremic polyneuropathy. Uremic Mononeuropathy. A variety of mononeuropathies may occur during chronic hemodialysis because uremic toxins render nerves susceptible to damage from focal compression or ischemia. CARPAL TUNNEL SYNDROME. Carpal tunnel syndrome may occur in 31% of patients on chronic hemodialysis. It causes symptoms remarkably similar to those experienced by patients who are not in chronic renal failure. Therefore, periodic numbness and tingling throughout the median nerve distribution and aching pain radiating proximally occur commonly and are characteristically worsened by acts such as reading a newspaper and repeatedly grasping objects. These symptoms may seriously disturb the patient’s sleep. However, a distinctive feature is that in patients in chronic hemodialysis with this syndrome, the symptoms are worse during each hemodialysis procedure. Moreover, the carpal tunnel syndrome is more likely to occur in the arm that contains the Cimino-Brescia fistula (Fig. 192-1). Physical signs of median nerve compression, such as wasting of the thenar eminence, are late signs, so electrophysiologic studies usually are necessary to establish the diagnosis. Abnormalities in sensory conduction are the first to appear. In most cases, the carpal tunnel syndrome is of uncertain cause or is clearly secondary to the forearm Cimino-Brescia fistula. However, less commonly, patients develop amyloidosis (Fig. 192-1) if they have been on chronic hemodialysis for longer than 10 years. This produces generalized arthropathy, in addition to carpal tunnel syndrome. This type of amyloidosis is seen only in chronic renal failure and is caused by the accumulation of P-microglobulin, a substance normally present in the body in very small amounts but that accumulates in end-stage renal failure. At the time of carpal tunnel syndrome, appropriate stains for this type of amyloid must be performed to establish the diagnosis. Avoidance of cuprophan membranes for chronic hemodialysis may eliminate this serious complication. Conservative management, such as splinting the wrists, usually is not effective in treating carpal tunnel syndrome, but sectioning of the flexor retinaculum usually is effective. If it appears that the

Cimino-Brescia fistula is a significant contributing factor, it may ultimately be necessary to band or ligate the fistula. MONONEUROPATHIES ASSOCIATED WITH ARTERIOVENOUS FISTULA OR SHUNTS.

The Cimino-Brescia fistula commonly used for access during chronic hemodialysis occasionally produces periodic aching and burning in the hand; this is really a steal syndrome, causing periodic ischemia to the tissues. It can be successfully treated with either banding or ligation of the fistula. However, in other instances, true carpal tunnel syndrome is caused by vascular congestion and ischemia in the region of the carpal tunnel. The diabetic patient is particularly prone to this disorder. Again, surgical decompression of the carpal tunnel area may be beneficial. In rare circumstances, an arteriovenous fistula or shunt placed more proximally in the upper arm may induce a sudden, severe, ischemic neuropathy affecting the median, ulnar, and radial nerves. This is an emergency that necessitates immediate surgical takedown of the fistula or shunt. Even then, severe and permanent neurologic dysfunction may result. Chronic renal failure, through the EIGHTH NERVE DYSFUNCTION. toxicity of uremic toxins or the use of antibiotics or diuretics, may affect both cochlear and vestibular divisions. Improvement may occur, either through hemodialysis or by successful renal transplantation. COMPARTMENT SYNDROMES. Because of the tendency toward excessive bleeding in chronic renal failure, and particularly if anticoagulant drugs are being used, compartment syndrome may develop suddenly. A typical site is the psoas muscle. There may be sudden, severe pain and motor and sensory loss within the distribution of the femoral nerve. CT scan may demonstrate the acute hemorrhage, and surgical decompression may be beneficial. COMBINED Duemc AND UREMIC POLYNEUROPATHY. In recent years, more diabetic patients have been accepted into dialysis and transplant programs, so the problem of combined diabetic and uremic polyneuropathy is being seen with increasing frequency. In both types of polyneuropathy, a symmetrical motor and sensory involvement is present, with reduced deep tendon reflexes, ataxia, and distal loss of sensation. However, diabetic polyneuropathy is more likely to induce compressive palsies, such as tardy ulnar palsy or carpal tunnel syndrome, and autonomic disturbances and multifocal denervation of muscle are more common. Also, in diabetic polyneuropathy, conduction velocities tend to be lower, and attempts at collateral reinnervation usually are more successful than in uremia. Each polyneuropathy also acts differently in response to organ transplantation. As already noted, uremic polyneuropathy improves promptly with successful kidney transplantation. On the other hand, pancreatic transplantation causes minimal improvement in diabetic polyneuropathy. Disturbances of Muscle in Uremia. Defects in neuromuscular transmission are quite uncommon and, when present, are caused by certain antibiotic drugs or high levels of magnesium. Such defects can readily be demonstrated in the electromyographic laboratory by repetitive nerve stimulation techniques. Severe disturbances of water or electrolytes may induce significant muscle weakness. Attacks of hyperkalemic periodic paralysis may occur in uremic patients, and, in contrast to familial varieties, the serum potassium remains abnormal between attacks. Tetany is a rare manifestation of chronic uremia and is caused by lowered serum levels of calcium or magnesium or is a result of respiratory alkalosis. Hypocalcemia occurs in renal failure as a result of the kidney’s inability to synthesize 1,25-dihydroxyvitamin D,. It may also be caused by poor mobilization of calcium salts

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are also present in patients who have muscle wasting caused by the cachexia of renal failure. Myoglobinuria may be a cause of acute and severe renal failure necessitating hemodialysis. The muscles may be weak, swollen, and painful; occasionally they are surprisingly normal on examination. The creatinine phosphokinase is invariably elevated. With successful treatment, muscle strength usually promptly returns to normal.

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FIG. 192-3. Severe muscle wasting in a 67-year-old man who had received chronic hemodialysis for 7 years. It was associated with underlying pain secondary to progressive bone disease. He also had a progressive dementia, but aluminum intoxication was never proved. Although he had a mild uremic polyneuropathy, needle electromyography of shoulder girdle muscles revealed only an increased proportion of polyphasic units, consistent with a primary myopathy. (From Bolton CF, Young CB: Neurological Complications of Renal Disease. Butterworth, Boston, 1990, with permission.)

from bone. The rarity of tetany in renal failure probably is caused by the corrective action of the associated acidosis. Therefore, it becomes manifest only if patients are treated with large amounts of alkali. Tetany presents as numbness and tingling in the extremities, lightheadedness, and carpopedal or laryngospasm. Percussion of a peripheral nerve may induce contraction of the muscle it supplies (Chvostek's sign). During electrophysiologic studies, needle electromyogram may reveal spontaneous repetitive discharges appearing as double, triple, or multiple discharges with the typical appearance of motor unit potentials. Tetany can be treated successfully by correction of hypocalcemia and alkalosis. In rare circumstances when high-dose steroids are used to treat certain forms of primary renal disease, a steroid myopathy may be induced. This is usually mild and is characterized by normal levels of creatine phosphokinase and normal electrophysiologic studies, including needle electromyography of muscle. Muscle biopsy may be normal or may reveal a type 2 fiber atrophy. When bone is significantly affected by hyperparathyroidism or aluminum accumulation, it may induce painful and sometimes severe wasting of muscle, particularly in proximal muscles (Fig. 192-3). However. as in steroid myopathy, electrophysiologic and morphologic studies of muscle often are normal, or biopsy may reveal type 2 fiber atrophy, a nonspecific finding. These features

Alfrey AC, LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294184188, 1976 Asbury AK, Victor M, Adam RD: Uremic polyneuropathy. Arch Neurol 8:413428. 1963 Baker LRI, Brown AL, Byrne J et ak Head scan appearances and cognitive function in renal failure. Clin Nephrol 32:242-248, 1989 Bolton CF, Young G B Neurological Complications of Renal Disease. Butterworth, Boston, 1990 Bosch BA, Schlebush L Neurophysiological deficits associated with uraemic encephalopathy. SAMJ 79:560-562, 1991 Folstein MF, Folstein SE, McHugh PR Mini-Mental State: a practical guide for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198, 1975 Jablecki C K Myopathies. p. 385. In Brown WF, Bolton CF (eds): Clinical Electromyopathy. Butterworth, Boston, 1987 Nielsen VK: Pathophysiological aspects of uraemic neuropathy. p. 197. In Canal N, Pozza G (eds): Peripheral Neuropathies. ElseviedNorthHolland, New York, 1978 O'Hare JA, Callaghan NM, Murnaghan DJ: Dialysis encephalopathy: clinical, electroencephalographic and interventional aspects. Medicine 62:129-141, 1983 Okada J, Yoshikawa K, Matsuo H et ak Reversible MRl and CT findings in uremic encephalopathy. Neuroradiology 333526526, 1961 Penn AS: Myoglobinuria. In Engel AG, Banker BQ (eds): Myology. McGraw-Hill, New York, 1986 Shields RW, Root KE, Wilbourn AJ: Compartment syndromes and compression neuropathies in coma. Neurology 36:1370-1374, 1986 Swift T R Disorders of neuromuscular transmission other than myasthenia gravis. Muscle Nerve 4334-353, 1984 Tegner R, Lindholm B Vibratory perception threshold compared with nerve conduction velocity in the evaluation of uraemic neuropathy. Acta Neurol Scand 71:284-289, 1985 Tyler H R Neurologic disorders in renal failure. Am J Med 44734-748, 1968 Vallance P, Leone A, Calver A et al: Accumulation of an endogenous inhibitor of nitric acid synthetase in chronic renal failure. Lancet 339572-575, 1992 Wyrtzes L, Markley HG, Fisher M, Alfred AJ: Brachial neuropathy after brachial artery-antecubital vein shunts for chronic hemodialysis. Neurology 37:1398-1400, 1987 Zochodne DW, Bolton CF, Wells GA et al: Polyneuropathy associated with critical illness: a complication of sepsis and multiple organ failure. Brain 110:819-842, 1987

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193 Neurologic Manifestations of Electrolyte

Disorders rn

Robert Lauren0

Electrolyte disorders may manifest as neurologic problems ranging from coma to muscle cramps. In ambulatory medicine the neurologist typically encounters the less severe neurologic manifestations, and vigilance is necessary to diagnose such cases. When encountering patients with headache, depression weakness, and many other symptoms, the neurologist should consider electrolyte disorders in the differential diagnosis.

HYPONATREMIA In normal volunteers, experimental hyponatremia causes cramps, weakness, decreased taste sensation, fatigue, and mental dullness. Hyponatremia may also cause tremor, dizziness, nausea, vomiting, headache, and altered mentation. Any one or combination of these problems may bring the patient to the doctor. Although delirium, coma, and convulsions typically are treated in the acute care environment, less severe cerebral manifestations such as confusion and lethargy may be encountered in the ambulatory setting. The physician’s level of suspicion for hyponatremia should be heightened when the patient is taking diuretics, carbamazepine, or oxcarbazepine. Duration and rapidity of onset of hyponatremia are important determinants of the clinical manifestations. More than one third of Daggett’s patients with serum sodium below 120 mEq/L were without neurologic symptoms, perhaps because the hyponatremia had evolved slowly. The implication of this data for outpatient practice is that a complaint of malaise, cramps, headache, or vomiting occasionally has as its basis severe hyponatremia (“a+] less than 110 mEq/L). Sterns (1987) has shown that severe hyponatremia has a mortality rate of only 8%, primarily because of the underlying disease rather than the hyponatremia itself. The poor prognosis of severe hyponatremia reported in some other series may result, in part, from myelinolysis, a disease caused by the correction of hyponatremia. Myelinolysis After Correction of Hyponatremia When a physician discovers a severely hyponatremic patient in the office setting, the first inclination may be to admit the patient to a hospital for prompt correction of the extreme metabolic derangement. This impulse must be checked because correction of hyponatremia can cause central pontine and extrapontine myelinolysis. The outpatient clinician’s awareness of this iatrogenic disorder can ensure that appropriate precautions are taken when the patient is transferred to a hospital ward. Myelinolysis is a dissolution of myelin disproportionate to any associated damage of neurons and axons. The lesions occur symmetrically in the center of the pons, the thalamocapsular regions, subcortical white matter, and elsewhere. This disease characteristically causes spastic tetraplegia and muteness in the acute phase. Cognitive, emotional, and movement disorders as well as other features may occur. Sometimes the lesions of

myelinolysis can be seen on computed tomography scans, but they are more reliably seen on T2-weighted magnetic resonance imaging scans done 1 week or more after symptom onset. Treatment of Hyponatremia When admitting a hyponatremic patient to the hospital, the outpatient physician should remind the inpatient team to proceed with caution. Whenever possible the serum sodium should be elevated less than 10 mEq/L over any 24-hour period to minimize the risk of myelinolysis. Such control of the rate of rise of serum sodium may not always be achievable because of the variables of a given case. Often simply eliminating diuretics, alcohol, or some other cause of hyponatremia suffices to correct the serum sodium. Coma, status epilepticus, or agitated confusion cannot be taken lightly. When these extreme neurologic manifestations suggest that life is in danger, hypertonic (3%) saline can be given in 100-mL boluses. However, corrective saline infusion should be moderated as soon as the patient is clinically improving, even though the serum sodium may still be at a severely low level. The serum sodium should be checked at least every 2 or 3 hours to monitor the rate of correction.

HYPERNATREMIA In the outpatient clinic the encephalopathy of hypernatremia may be encountered as lethargy, mild confusion, or generalized weakness. More severe manifestations (rhabdomyolysis, seizures, or coma) are unlikely to be encountered outside the hospital. Although only 11% of patients remain fully alert when serum sodium exceeds 160 mEq/L, symptoms may be absent in chronic hypernatremia even when serum sodium exceeds 175 mEq/L. This adaptation to hypernatremia is caused by a compensatory increase in brain osmolality caused by an accumulation of potassium, amino acids such as taurine, and polyols. This beneficial increase in intracellular osmolality can be problematic when treatment is administered. Should there be a rapid therapeutic decline of extracellular osmolality, the brain’s increased osmoles cannot diminish as quickly. In other words, the extracellular fluid becomes hypotonic to the brain, which, as a result, can swell. Aware of this danger of cerebral edema, the outpatient physician should remind the inpatient team to avoid rapid correction of hypernatremia. Certainly in children, and probably in adults as well, it is best to limit the decline in serum sodium to 0.5 mEq/L/hour.

HYPOKALEMIA Generalized weakness, the primary neurologic manifestation of hypokalemia, may be episodic or acute. However, the weakness usually is subacute or chronic. When serum potassium is greater than 2.5 mEq/L, prominent weakness is rarely seen. However,

Chapter I93

some patients with minimal depression of potassium (3.0 to 3.5 mEq/L) have malaise, fatigue, cramps, or restless legs. When potassium drops below 2.0 mEq/L, some weakness almost always exists. Although quadriparesis may occur with potassium less than 2.0 mEq/L, some patients are ambulatory with potassium at that level. The weakness initially is worse in proximal muscles. Tendon reflexes often are retained, but areflexia can occur when weakness is profound. Hypokalemic weakness usually is caused by changes in muscle membrane polarization, but rhabdomyolysis may be a contributing or predominant cause of weakness in some cases. Hypokalemia can cause tetany, usually but not always in the setting of alkalosis. Paradoxically, hypokalemia protects against tetany in the setting of hypocalcemia. The physician’s index of suspicion for hypokalemia must be high when the outpatient is taking diuretics or is in some other way at risk for hypokalemia.

HYPERKALEMIA As opposed to the muscle disorder seen in hypokalemia, the

generalized weakness of nonhereditary hyperkalemia appears to be caused by peripheral nerve dysfunction. Depression of tendon reflexes, numbness, paresthesias, slow nerve conduction velocities, and retained mechanical irritability of muscle all indicate neuropathy. Guillain-Barre syndrome has been incorrectly diagnosed in some cases. Usually no weakness occurs until the serum potassium exceeds 7 mEq/L. Weakness almost always occurs when potassium exceeds 9 mEq/L. Weakness may be gradually progressive or episodic; it may be mild or so severe as to cause quadriplegia.

HYPOCALCEMIA Tetany, the characteristic neurologic manifestation of hypocalcemia, is caused by peripheral nerve hyperirritability. Spontaneous discharge of motor and sensory axons causes a syndrome of sensory symptoms and muscle contractions that develop and abate in a characteristic sequence. Muscle contractions begin distally with carpopedal spasm. Eventually wrist flexion, elbow bending, arm adduction, and supination of the forearms are seen. Although tetany can culminate in opisthotonos, it is not always so severe. For years some patients have only occasional,brief attacks of stridor or carpopedal spasm. In such patients, latent tetany may be detected by eliciting Chvostek sign, which is said to be present when percussion of the facial nerve anterior to the external auditory meatus results in contraction of ipsilateral facial muscles. Unless the orbicularis oculi contracts, Chvostek sign is not present. Whereas Chvostek sign is present in 8% of normal people, Trousseau sign, more specific for latent tetany, occurs in only 1% of normal individuals and is said to be present when a pneumatic cuff, inflated on the upper arm to 20 torr above systolic blood pressure, produces paresthesias and carpal spasm in that limb. Central nervous system manifestations of hypocalcemia such as a coma and convulsions are not encountered in a physician’s office, but confusion, dementia, and personality change are. Headache, presumably caused by increased intracranial pressure, can also be the primary manifestation of hypocalcemia in the outpatient. Hypocalcemia sometimes causes cramps and uncommonly causes parkinsonism. Evidence shows that hypocalcemic patients are more vulnerable than normal individuals to phenothiazineinduced dystonia. Occasionally, hypocalcemia may present as syncope with a prolonged QT interval.

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HYPERCALCEMIA Hypercalcemia can cause a wide range of mental disorders. Confusion, drowsiness, depression, anxiety, paranoia, and mania have all been observed in the ambulatory patient. Generalized weakness, usually chronic but occasionally acute, can also occur. In these cases there may be brisk tendon reflexes, Babinski signs, and muscle atrophy. With or without these objective findings, hypercalcemia can cause cramps. Occasionally these features have suggested the misdiagnosis of amyotrophic lateral sclerosis. Rarely hypercalcemia causes parkinsonism.

HYPOMAGNLSEMIA Tetany has been reported inconsistently in hypomagnesemia. Although it has been suggested that hypomagnesemia induces tetany by decreasing the ionized calcium levels, the tetany is successfully treated with magnesium. As a rule, major manifestations such as delirium and convulsions are not seen in office practice, but cramps, confusion, other mental disorders, Chvostek sign, tremor, myoclonus, and dysphagia are encountered. Although hypomagnesemia should be corrected in the setting of alcohol withdrawal, it is an epiphenomenon to, rather than the cause of, withdrawal symptoms.

HYPERMAGNESEMIA Typically weakness emerges when serum magnesium reaches 7 to 9 mEq/L; areflexia develops at 9 to 10 mEq/L. No sensory symptoms or mental features are present. Edrophonium injection transiently improves strength because magnesium causes its paralyzing effect at the neuromuscular junction. The electrical manifestations resemble those of the Lambert-Eaton syndrome, namely, low-amplitude compound muscle action potentials, a progressive decline in amplitude at 2/second repetitive nerve stimulation, and an increase in amplitude after isometric exercise or with 50/second repetitive nerve stimulation. A slight increase in serum magnesium can aggravate underlying myasthenia gravis or Lambert-Eaton syndrome.

HYPOPHOSPHATEMIA Hypophosphatemia usually is an inpatient problem that can cause apathy, confusion, and seizures. It may also cause neuromuscular disorders, myopathy, rhabdomyolysis, or acute aretlexic paralysis (which resembles Guillain-BarrC syndrome). In the latter disorder the paresthesias, slow nerve conduction velocities, prolonged distal latencies, and slow F responses indicate neuropathy. Alcoholic patients often develop hypophosphatemia 2 to 4 days after hospitalization. When the outpatient clinician admits an alcoholic patient to the hospital, the inpatient team should be reminded to monitor for hypophosphatemia and to treat it promptly to avoid these neurologic problems.

CONCEPTS Electrolyte disorders manifest by effects at all levels of the nervous system. The central nervous system is affected by hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypophosphatemia. Peripheral nerve is affected by hypocalcemia, hypomagnesemia, hyperkalemia, and hypophosphatemia.

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The neuromuscular junction is affected by hypermagnesemia. Hypokalemia, hypophosphatemia, and sometimes sodium derangements affect muscle. The major neurologic presentations of electrolyte disorders are generalized weakness, tetany, and encephalopathy. Generalized weakness occurs in hypokalemia, hyperkalemia, hypercalcemia, hypermagnesemia, hypophosphatemia, and, to a lesser extent, hyponatremia and hypernatremia. Ambulatory patients may complain of weakness when no conspicuous abnormality is seen on examination. Tetany occurs in hypocalcemia, hypomagnesemia, and hypokalemia. Because the tetany can be mild and episodic for years, patients may mention these spasms only in passing. Encephalopathy occurs in hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypophosphatemia. In the outpatient setting, lethargy, confusion, dementia, depression, anxiety, paranoia, and mania all necessitate that the physician measure electrolytes. Other manifestations of electrolyte disorders include parkinsonism (hypocalcemia, hypercalcemia), cramps (hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, and hypomagnesemia), and headache (hypocalcemia, hyponatremia). When patients are taking particular medications, the neurologist should be alert to the possibility of certain electrolyte disorders. For example, antacids can cause hypercalcemia, phosphate-containing cathartics can cause hypocalcemia, and diuretics can cause hypokalemia or hyponatremia. Carbamazepine- or oxcarbazepine-induced hyponatremia, which can manifest as breakthrough seizures in a previously wellcontrolled epileptic, is of particular importance to the neurologist. Although most patients with metabolic encephalopathy have symmetrical neurologic manifestations, focal neurologic features are possible in any electrolyte-related encephalopathy. Such focal signs usually are seen in the acute care rather than the ambulatory setting. Severe neurologic signs can emerge when an electrolyte disorder accentuates a mild, underlying neurologic disease. For example, modest hypermagnesemia may greatly accentuate preexisting Lambert-Eaton syndrome or myasthenia gravis. For several reasons the severity of an electrolyte derangement does not correlate simply with the severity of the neurologic manifestation. First, some people are more sensitive than others to a given metabolic insult. Second, the electrolyte level measured sometimes is not the critical physiologic parameter. Whereas ionized calcium is a stronger correlate of neurologic dysfunction, total serum calcium often is routinely measured. Third, the duration and rapidity of onset of an electrolyte derangement are major factors determining severity of symptoms. An extreme

electrolyte derangement may be largely asymptomatic when the problem develops over weeks or months. On the other hand, a moderate electrolyte derangement may cause severe symptoms when the problem develops acutely. Finally, other variables may interact with the electrolyte in question. For example, when hypocalcemia and hypokalemia coexist, the latter disorder prevents the former from causing tetany. Correction of electrolyte derangements can cause or precipitate neurologic disorders. Correction of hypokalemia may unmask tetany in a hypocalcemic patient. The rapid correction of sodium derangements can be even more perilous. Rapid correction of hypernatremia can cause brain swelling. Rapid correction of hyponatremia can cause central pontine and extrapontine myelinolysis. When admitting a vulnerable patient to the hospital, the neurologist should remind the inpatient team that caution in therapy lessens the incidence of these complications.

SUGGESTED READINGS Comi G, Testa D, Cornelio F et al: Potassium depletion myopathy: a clinical and morphological study of six cases. Muscle Nerve 8:17, 1985 Daggett P, Deanfielf J, Moss F: Neurological aspects of hyponatremia. Postgrad Med J 58:737-740, 1982 Evers S, Engelien A, Karsch V et al: Secondary hyperkalaemic paralysis. Neurol Neurosurg Psychiatry 64:249-252, 1998 Fishman, RA: Neurological aspects of magnesium metabolism: Arch Neurol 12:562, 1965 Henson Rik The neurological aspects of hypercalcaemia: with special reference to primary hyperparathyroidism. J R Coll Physicians Lond 1:41, 1966

Karp B, Laureno R: Central pontine and extrapontine myelinolysis following correction of hyponatremia. Neurologist 6255-266, 2000 Karp B, Laureno R Central pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 72:359, 1993 Krendel DA Hypermagnesemia and neuromuscular transmission. Semin Neurol 1042, 1990 Laureno R Neurologic syndromes accompanying electrolyte disorders. p. 545. In Goetz CG, Tanner CM, Aminoff MJ (eds): Handbook of Clinical Neurology. Vol. 1 9 Systemic Diseases. Elsevier Science Publishers, Amsterdam, 1993 Layzer R B Neuromuscular Manifestations of Systemic Disease. FA Davis, Philadelphia, 1985 Siddiqui M, Bertorini T Hypophosphatemia-induced neuropathy: clinical and electrophysiologic findings. Muscle Nerve 2 k650-652, 1998 Sowden JM, Borsey DQ: Hyperkalemic periodic paralysis: a rare presence of Addison’s disease. Postgrad Med J 65:238, 1989 Sterns RH: Severe symptomatic hyponatremia: treatment and outcome study of 64 cases. Ann Intern Med 107:656, 1987

SECTION

4

GASTROENTEROLOGY AND HEPATOLOGY

194 Neurologic Effects of Malabsorption and Vitamin

Deficiency rn

Martin A. Samuels

Intestinal malabsorption is an impairment of one or more of the steps involved in normal digestion and absorption of nutrients. The neurologic manifestations of malabsorption are mostly related to the vitamin deficiency that may result, regardless of the underlying disease causing the malabsorption. Vitamins are biologically active organic compounds that are essential for normal growth, development, and health and that cannot be synthesized by the body. The four fat-soluble vitamins are A, D, E, and K, and the nine water-soluble vitamins are B, (thiamine), B, (riboflavin), niacin, B, (pyridoxine), folic acid, B,, (cyanocobalamin), C (ascorbic acid), pantothenic acid, and biotin.

FAT-SOLUBLE VITAMIN DEFICIENCY Fat-soluble vitamin deficiency usually is caused by disorders that lead to fat malabsorption and steatorrhea. The main neurologic complication of vitamin A deficiency is night blindness, usually associated with xerophthalmia (dryness of the conjunctivae). Vitamin D deficiency may result in diffuse bone pain or tetany related to the associated hypocalcemia. Vitamin K deficiency causes decreased prothrombin activity in the blood not associated with liver disease or the use of warfarin. Intracerebral, intraventricular, subarachnoid, subdural, and epidural hemorrhages may occur in patients with vitamin K deficiency. Vitamin E deficiency consists of ophthalmoplegia, retinal pigmentary degeneration, spinocerebellar ataxia, myopathy, and an axonal polyneuropathy.

WATER-SOLUBLE VITAMIN DEFICIENCY The water-soluble vitamin deficiencies occur in a variety of circumstances.

Thiamine, Riboflavin, Niacin, and Pyridoxine Deficiency Thiamine (vitamin B,) deficiency usually is caused by severe malnutrition, sometimes coupled with increased requirements (e.g., pregnancy, hyperthyroidism). In North America it is usually associated with alcoholism. Because it tends to be associated with generalized malnutrition, thiamine deficiency often is part of a multiple deficiency state, particularly including riboflavin and niacin. For this reason, some of the early, nonspecific effects of

thiamine deficiency such as an axonal polyneuropathy cannot be strictly proved to be caused by thiamine deficiency itself. However, acute Wernicke’s encephalopathy has been clearly shown to be caused by thiamine deficiency. It consists of an array of symptoms and signs usually including a mental abnormality (confusion, delirium, or amnesia), ataxia, and ocular abnormalities (e.g., nystagmus, cranial nerve palsies, ptosis). However, it is quite clear from pathologic studies that most patients suffering from thiamine deficiency do not show the entire classic triad (i.e., amnesia, ataxia, and ophthalmoplegia). For this reason, it is prudent to have a low threshold for treating patients with thiamine if the suspicion of malnutrition is raised. Failure to treat can lead to permanent deficits, the most disabling of which is chronic amnestic dementia (Korsakoffs psychosis). Red blood cell transketolase levels and careful magnetic resonance imaging focusing on the mammillary bodies may help in making the diagnosis, but any serious suspicion of malnutrition, particularly in alcoholic patients, should lead the clinician to replace thiamine, parenterally at first, followed by long-term oral supplementation. Riboflavin (vitamin B,) deficiency results from inadequate dietary intake of milk, liver, meat, eggs, and some green leafy vegetables. The major neurologic manifestation is photophobia, usually associated with excessive lacrimation and itching of the eyes. Niacin deficiency (i.e., deficiency of either nicotinic acid or nicotinamide, or both) usually is related to malnutrition and alcoholism. The deficiency state, known as pellagra, causes the triad of dermatitis, diarrhea, and dementia. The dementia is characterized by memory loss and slowness of thought without the aphasic or apraxic phenomena commonly seen in Alzheimer’s d’isease. Pyridoxine (vitamin B6) deficiency is caused by malnutrition or by the intake of a pyridoxine antagonist such as isoniazid. The major neurologic manifestation is a severe polyneuropathy.

Folic Acid and Vitamin B,, Deficiency Folic acid and cobalamin (vitamin B,J deficiencies result in megaloblastic anemias. The term megaloblastic anemia refers to a characteristic pattern of morphologic abnormality in the blood and bone marrow that probably arises from impaired DNA 1235

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synthesis. Clinically, this is usually the result of a deficiency of one of two factors, vitamin B,, or folic acid, both of which are essential to the formation of the deoxyribosyl precursors of DNA. This deficiency results in abnormal development of erythroblasts in the marrow such that intramedullary hemolysis occurs, resulting in anemia. The peripheral blood contains macrocytic erythrocytes. The disordered DNA metabolism also affects the maturation of granulocytes and megakaryocytes, resulting in hypersegmented polymorphonuclear leukocytes in the peripheral blood. This disordered DNA metabolism clearly is not confined to the blood cells because giant epithelial cells are found in many other organs, including the mouth, stomach, and skin. The neurologic effects of the megaloblastic anemias probably are caused by a primary metabolic derangement in neural tissue and are clearly not directly related to the anemia per se. Because the blood-forming organs are particularly sensitive to the effects of B,, or folate deficiency, it is unusual to find the neurologic effects in patients in whom no blood disorders are found. However, anemia is only one and probably a late sign of B,, or folate deficiency, so it is possible to find a clear example of the neurologic effects of B,, or folate deficiency without anemia. However, it is distinctly rare to find no hematologic signs of B,, or folate deficiency in a patient with proved neurologic effects of these vitamin deficiencies. Vitamin B,, Vitamin B,, deficiency may result from a number of causes which are summarized in Table 194-1. The most prevalent form, at least in North America, is pernicious anemia (or Addison’s anemia, Biermer’s anemia, or primary anemia). It arises from failure of the gastric fundus to secrete adequate amounts of intrinsic factor to ensure intestinal absorption of cobalamin, a process that usually is immune mediated but may be familial or result from gastric neoplasia. Histamine-fast achlorhydria usually is present in pernicious anemia, but this method of diagnosis will not be useful in other forms of vitamin B,, deficiency. In disorders

TABLE194-1. Causes of Vitamin B,, Deficiency Defective diet (low in animal or bacterial products) Defective absorption Deficiency of intrinsic factor Pernicious anemia Castrectomy Intestinal disease Malabsorption (sprue, resection, bypass, or disease of terminal ileum) ”Blind loop” syndrome Fish tapeworm infestation Deranged metabolism or increased requirement (thyrotoxicosis, pregnancy, neoplasia)

(2) dUMP

- dTMP

DNA

other than pernicious anemia, serum B,, levels are needed for diagnosis. Because vitamin B,, is stored in various tissues in large amounts, the appearance of pernicious anemia after the cessation of B,, absorption or intake is delayed by at least 3 years. Even though pernicious anemia is the most common cause of B,, deficiency, it seems clear that vitamin B,, deficiency from any of the causes listed in Table 194-1 may result in the identical clinical picture. The three neurologic manifestations of vitamin B,, deficiency are subacute combined degeneration of the spinal cord, mental changes, and optic neuropathy. PATHOGENESIS OF THE NEUROLOGIC COMwianoNs. The pathogenesis of the neurologic complications of vitamin B,, deficiency is not entirely clear, but several facts are known. Cobalamin, a pyrrol, is synthesized by microorganisms and ingested in meat, liver, fish, eggs, and milk. In a normal North American diet, 5 to 30 pg is ingested a day, of which 1 to 5 pg is absorbed. Two to 5 mg is stored in the body, of which about 1 mg is stored in the liver. It is therefore very difficult to become vitamin B,, deficient based on dietary deficiency. Only a pure vegetarian could perform such a feat, and even then, the huge stores would forestall symptoms for 3 to 5 years. Four forms of cobalamin exist in animals: hydroxocobalamin, its analogue cyanocobalamin, and its two coenzymes adenosylcobalamin and methylcobalamin. Cobalamin is bound to intrinsic factor, a 44,000-Da mucoprotein secreted by the parietal cells of the stomach. This intrinsic factor-cobalamin complex is absorbed via specific receptors in the terminal ileum and carried to the portal blood by transcobalamin molecules. COBALAMINENZYMESYSTEMS.Two major cobalamin-dependent enzyme systems exist, each using a different one of the two coenzymes, methylcobalamin and adenosylcobalamin. The purpose of the methylcobalamin-dependent system is to generate tetrahydrofolate, which in turn is needed to convert uridylmonophosphate to thymidylyl monophosphate, to be incorporated into DNA. In the system shown in Figure 194-1, methylcobalamin acts as a coenzyme for methyltransferase, otherwise known as methionine synthetase. Methylcobalamin acts as a methyl donor for the generation of methionine from homocysteine and then acts as a methyl group acceptor for the conversion of N5methyltetrahydrofolate (serum folate) to tetrahydrofolate. Deficiency of methylcobalamin results in a low serum methionine and elevated homocysteine (i.e., greater than 16.2 ymol/L), which in turn is oxidized to homocystine. Thus, one form of homocystinuria is caused by methylcobalamin deficiency. The inherited form of homocystinuria is caused by deficiency in cystathione syntheHornocysteine O2

4

,Homocysteine + Serine

Tetrahydrofolate

Cystathione synthetase

-.r

Cystathione

Pyridoxine ( B6)

N5-Methyltetrahydrofolate

Methionine

(serurnfolate)

FIG. 194-1. The methylcobalamin-dependent methyl transferase system.

Chapter 194

H

(1 ) propionic acid

FIG. 194-2. The adenosylcobalamin-dependent methylmalonyl coenzyme A (CoA) mutase system.

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Neurologic Effects of Malabsorptionand Vitamin Deficiency

-

proprionyl CoA

-

+

valine

methylmalonylCoA

methylmalonyl CoA mutase adenosylcobalamin

I

succinyl CoA

tase, the enzyme that combines serine with homocysteine to form cystathione. In vitamin B,, deficiency, inadequate methyltransferase activity results in the so-called folate trap, meaning that serum folate cannot be converted to tetrahydrofolate. This results in a high serum folate level and the incorporation of uridyl residues into DNA. This abnormal DNA is fragile, leading to all the manifestations of vitamin B,, deficiency seen in rapidly dividing cells, such as those in the bone marrow, skin, and intestinal tract. For these reasons, patients with vitamin B,, deficiency have hypersegmented polymorphonuclear leukocytes in the peripheral blood, macrocytosis, megaloblasts in the bone marrow, intramedullary hemolysis, and gastrointestinal symptoms. Because central nervous system neurons do not multiply, it has been traditionally considered unlikely that the methyltransferase system had anything to do with the neurologic manifestations of the disease. However, oligodendrocytes do multiply, so it is conceivable that failure of this system could lead to a disorder of myelin metabolism. One supporting bit of evidence for this hypothesis is the fact that nitrous oxide toxicity is known to produce all the manifestations of subacute combined degeneration of the nervous system and is known to be an inhibitor of methyltransferase activity. It is a clinical fact that patients with borderline low levels of cobalamin may develop acute neurologic symptoms caused by vitamin B,, deficiency after exposure to nitrous oxide, as may occur when this gas is used as an induction agent for general anesthesia (anesthesia paresthetica). The second vitamin B,,-dependent enzyme system uses the adenosylcobalamincoenzyme to help methylmalonyl coenzyme A (CoA) mutase catalyze the conversion of methylmalonyl CoA to succinyl CoA, as shown in Figure 194-2. Deficiency of adenosylcobalamin therefore results in elevated methylmalonic acid (i.e., greater than 271 mmol/L). Evidence shows that methylmalonic acid is toxic to myelin because it substitutes for malonic acid, leading to long chain fatty acids with odd (rather than the normal even) numbers of carbon atoms. The abnormal myelin composed of fatty acids with odd numbers of carbon atoms is fragile, leading to demyelination. Evidence from animal experiments supports this concept in that the addition of valine to the diet exacerbates latent vitamin B,, deficiency. As can be seen from Figure 194-2, valine is a precursor of the presumptive toxin, methylmalonic acid. Clinical Neurologic Syndromes. The clinical neurologic syndromes of vitamin B,, deficiency are subacute combined degeneration of the spinal cord, mental abnormalities, and optic neuropathy. They have in common an identical pathology consisting of a myelinopathy followed by axonal disease, which is probably secondary. Subacute Combined Degeneration of the Spinal Cord. Subacute combined degeneration of the spinal cord (or subacute combined sclerosis, posterohteral sclerosis) is the term used to designate the spinal cord disease caused by pernicious anemia. Patients tend to

complain of generalized weakness and paresthesias that begin distally and progress proximally. As these symptoms progress, stiffness and weakness in the limbs develop. Loss of vibration sense is the most profound sign, often joined later in the course of disease by joint position sense loss as well. The Romberg sign is positive, and the gait is unsteady and awkward. Weakness and spasticity usually are worse in the legs than the arms and may progress to a spastic paraplegia if untreated. Babinski signs are present, but the deep tendon reflexes are variable. They may be grossly increased with clonus or absent or may show any intermediate degree of activity. Occasionally, a sensory level may be found on the trunk, implicating the spinothalamic tracts. This finding should always be viewed with the greatest skepticism and lead one to exhaustively exclude other causes of spinal cord disease. All the findings of pure vitamin B,, deficiency may be attributable to myelopathy alone, and no convincing evidence shows that B,, deficiency itself causes a neuropathy. However, in practice, the frequent concomitant existence of folate and other vitamin deficiencies makes it difficult to be sure of this point. Many patients with vitamin B,, deficiency have distal symmetrical impairment of cutaneous sensation, absent deep tendon reflexes, and even slowed nerve conduction velocities, suggesting a neuropathic component. This is probably caused by concomitant folate deficiency, but the outside chance that vitamin B,, deficiency itself may cause a peripheral neuropathy cannot be rigorously excluded. Pathologically the lesion in the nervous system is a degeneration of white matter in the spinal cord and occasionally the brain. The myelin sheaths and axons are both involved, the former more profoundly than the latter. These changes begin in the posterior columns of the lower cervical and upper thoracic segments and spread from there up and down and also laterally in the cord to involve the lateral columns. On microscopic study, early changes consist of swelling and destruction of the myelin sheath with subsequent axonal destruction. Later, a cribriform appearance develops. Eventually, white matter is lost and is replaced by gliosis. The focal lesions have a rough but not absolute symmetry, and they extend caudally and rostrally so that ultimately the entire area of the dorsal columns is involved. In the meantime, the lesions have begun in the lateral columns and extend into the other long tracts. The gray matter is spared. Similar changes can be seen in the cerebral hemispheres and optic nerves. The myelin of peripheral nerves may also be involved, but axons have not been shown to be unequivocally affected. MentalChanges. Mental changes are common in patients with vitamin B,, deficiency. In most cases these changes reflect abnormalities in level of consciousness, with inattention, conhsion, somnolence, apathy, and delirium being the cardinal features. True dementia, defined as intellectual impairment in the absence of a disorder of level of consciousness, is certainly a rare manifestation of pure vitamin B,, deficiency. Pure mental change as the only manifestation of vitamin B,, deficiency is rare. Case

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reports of true dementia and pure mental change as manifestations of vitamin B,, deficiency are contaminated with concomitant causes of dementia and disordered mental status. optic Neuropathy. Optic neuropathy (papillopathy and retrobulbar neuropathy) is the third and last major neurologic complication of vitamin B,, deficiency. It is characterized by bilateral involvement of the optic nerves, resulting in loss of central visual acuity and depressed sensitivity greater for color than for white in the centrocecal area of the field of vision. This is the rarest of the three neurologic manifestations of vitamin B,, deficiency but may be the only or presenting manifestation of the syndrome. It may be subclinically present in many more cases than previously believed if a very sensitive measurement of optic nerve function, such as visual evoked responses, is used. This syndrome is clinically similar to a number of other bilateral optic neuropathy syndromes including the so-called tobacco/alcohol amblyopia, diabetic optic neuritis, Leber’s hereditary optic neuropathy, and tropical ataxic neuropathy. Some neurologists feel that the cause of all of these syndromes, including vitamin B,, deficiency-induced optic neuropathy, is linked to an abnormality in metabolism caused by a shortage of sulfur-donating amino acids. Recent evidence from an epidemic of optic neuropathy and myelopathy in Cuba has raised the question of whether a mitochondrial disorder, such as that known to cause Leber’s hereditary optic neuropathy, may be present in patients whose metabolism is then stressed by vitamin B,, deficiency and perhaps cyanide toxicity (as might be acquired by eating large amounts of casava or smoking cigarettes or cigars, as is done in Cuba), leading to the expression of an optic neuropathy and myelopathy in people who otherwise would not have become ill were it not for the mitochondrial defect. DIAGNOSIS.The diagnosis of vitamin B,, deficiency rests on various laboratory tests. The microbiologic assay with Euglena grucilis remains the gold standard against which other tests are measured, but the study is done in only a few laboratories and is not practical for routine use. The radioimmunoassay for vitamin B,, is now quite accurate. Formerly this test often yielded falsely high values compared with the microbiologic assay, but now all commercial kits use intrinsic factor itself, yielding an accurate result. In general, levels under 100 pg/mL are associated with neurologic disease. The Schilling test is now used only in patients who have received vitamin BIZ. The best assays for intracellular cobalamin deficiency are the serum methylmalonic acid (normal, 73 to 271 nmol/L), which tests adenosylcobalamin coenzyme activity, and the serum homocysteine (normal, 5.4 to 16.2 pmol/L), which tests methylcobalamin coenzyme activity. Elevated levels indicate vitamin B,, deficiency. TREATMENT.Treatment consists of parented vitamin B,, injections. Shortly after vitamin B,, is begun, the folate trap is released, causing a sudden drop in serum folate level. That must be replaced, or a secondary folate deficiency will result. If one inadvertently treats a vitamin B,,-deficient patient with folate alone, this may partially correct the hematologic manifestations of the illness while masking the progression of the neurologic problems. Therefore, one should treat the patient with vitamin B,, initially and follow the serum folate. When it falls, folate may be safely replaced. Folic Acid Deficiency. Folk acid (folate) deficiency accounts for nearly all the cases of megaloblastic anemia not caused by vitamin B,, deficiency. The causes of folate deficiency are summarized in Table 194-2. Unlike vitamin B,,, the bodily stores of folic acid are limited. A folate deficiency syndrome may commence within several months

TABLE 194-2. Causes of Folate Deficiency Defective diet (low in vegetables and liver) Defective absorption Intestinal malabsorption (sprue, steatorrhea, massive diverticulosis, short circuits of gastrointestinal tract) ”Blind-loop” syndrome Deranged metabolism Increased requirement (hernolytic anemia, pregnancy, neoplasia) Impaired utilization (liver disease, administration of folk acid antagonists or anticonvulsants)

of dietary deprivation, making it a much more common problem among the malnourished than is vitamin B,, deficiency. Folate, once absorbed through the entire small intestine, is reduced by specific liver enzymes to tetrahydrofolic acid, a compound that plays a major role in the metabolism of one carbon fragment by its synthesis and transfer of methyl groups. Via this mechanism folate is vital for the conversion of deoxyuridate to thymidylate, a precursor needed for DNA synthesis. Therefore, tetrahydrofolate derivations are closely linked to vitamin B,,-dependent reactions, and the hematologic alterations in vitamin B, and folate deficiency are indistinguishable. Deficiencies of the two vitamins have very similar effects, and a deficiency of one may lead to faulty use of the other. For example, patients with vitamin B,, deficiency may have an initially elevated serum folate, which plummets rapidly when vitamin B,, is administered, thus necessitating concomitant treatment with folate lest a folate deficiency state, previously masked by the vitamin B,, deficiency, should become clinically significant. Many patients with vitamin B,, deficiency have concomitant folate deficiency, but most of those with the overwhelmingly more common folate deficiency state have no vitamin B,, deficiency. Folic acid deficiency is almost never pure. Because it accompanies malnutrition, it is nearly always associated with multiple vitamin deficiencies. The most common neurologic manifestation of this state is a polyneuropathy. POLYNEUROPATHY. The symptoms of nutritional polyneuropathy include distal paresthesias, burning, and weakness. On examination, a distal loss of reflexes and sensation is found. The essential pathologic change is an axonal degeneration with dying back of the axons according to length. Some minor degrees of segmental demyelination may also occur, usually caused by entrapment of metabolically weakened nerves. The common entrapment neuropathies (e.g., carpal tunnel syndrome, meralgia paresthetica, peroneal palsy, and ulnar palsy) are all more common in patients with an underlying metabolic axonopathy such as that caused by vitamin deficiency. In circumstances in which the major vitamin deficiency is likely to be folic acid (i.e., when folate antagonists have been given), a mild polyneuropathy of the type described earlier occurs. No evidence shows that pure folate deficiency has any other neurologic manifestations.

,

Vitamin C and Biotin Deficiency

Ascorbic acid (vitamin C) deficiency is rarely seen in North America today. The resultant syndrome of scurvy may cause lassitude and irritability, but a specific neurologic syndrome is not known. Biotin deficiency cannot result from inadequate intake alone because it is produced by the intestinal bacteria. Raw eggs contain avidin, which binds biotin, and large consumption can result in biotin deficiency. The neurologic syndrome is nonspecific and consists of lassitude, somnolence, depression, and hyperesthesia.

Chapter 194

Disorders with Malabsorption and Neurologic Features Whipple’s disease is a multisystem illness caused by the grampositive actinomycete bacillus Tropheryma whippelii. The major features of the illness are malabsorption with chronic diarrhea, polyarthritis, lymphadenopathy, and fever, but the disease may also affect the nervous system either directly by infection of the central nervous system or indirectly via the effects of malabsorption. The neurologic manifestations of malabsorption are enumerated earlier in this chapter. The direct effects are caused by a chronic mesencephalic and diencephalic encephalitis because ‘I: whippelii has a predilection for infecting the midbrain and hypothalamus. The reason for this predilection is unknown. As a result of this focal encephalitis, the major clinical syndromes of neuro-Whipple disease are oculomasticatory myorhythmia, supranuclear vertical gaze paresis, amnestic syndrome, anal hypothalamic dysfunction. Oculomasticatory myorhythmia is almost pathognomonic of neuro-Whipple disease. It consists of a rhythmic movement disorder involving ocular vergence, tongue and jaw movements, and, less commonly, similar rhythmic jerking of the limbs, which may or may not persist in sleep, making it similar phenomenologically to palatal myoclonus. Supranuclear vertical gaze palsy is nearly always present when oculomasticatory myorhythmia is seen. A reverse light near dissociation (i.e., pupils that react to near but not to light) may also be present. An amnestic dementia with personality changes and some psychotic features (e.g., delusions, hallucinations) may slowly worsen over years. Hypothalamic dysfunction including temperature dysregulation, sleep disturbances, and abnormalities in sexual function, appetite, and thirst are also common, as are disorders of the menstrual cycle and salt and water metabolism. The magnetic resonance image may suggest the diagnosis if hyperintensity is seen on T,-weighted and fluid-attenuated inversion recovery images in characteristic regions in the midbrain, hypothalamus, medial temporal lobes, basal ganglia, and pons. The diagnosis may be confirmed using polymerase chain reaction (PCR) for T whippelii. Cerebrospinal fluid analysis using PCR may be adequate, but sometimes brain biopsy material is needed. Treatment of neuro-Whipple disease entails the use of antibiotics that are effective against the organism and cross the blood-brain barrier. Third-generation cephalosporins and an aminoglycoside are the drugs of choice (e.g., ceftriaxone 2 g every 12 hours IV and streptomycin 1 g IM daily for 2 weeks, followed by ce!Xme 400 mg PO once or twice a day for at least a

Neurologic Effects of Malabsorption and Vitamin Deficiency

1239

year). Alternatives include high-dose penicillin, trimethoprimsulfamethoxazole, rifampin, or doxycycline. Cerebrospinal fluid PCR may be followed to monitor effective treatment. Celiac disease is an immune-mediated enteropathy, the major symptoms of which are triggered by gluten ingestion. The major manifestation of the disease is intestinal malabsorption with consequent weight loss, abdominal distention, diarrhea, and steatorrhea. Most of the manifestations of the disease are caused by malabsorption and include metabolic bone disease, iron deficiency anemia, and a number of neurologic problems related to malabsorption including myelopathy (cobalamin deficiency), Ekbom’s syndrome (iron deficiency), peripheral neuropathy (multiple B vitamin deficiencies), and Wernicke-Korsakoff syndrome (thiamine deficiency). In addition to these indirect neurologic manifestations, some patients with celiac disease develop a progressive myoclonic ataxia, sometimes with seizures (Ramsay Hunt syndrome) that appears to be independent of gluten intake and is unresponsive to dietary gluten restriction. The mechanism of this illness is not fully understood, but it probably represents an immune-mediated attack on cerebellar antigens that shave epitopes with the gastrointestinal targets in patients with celiac disease. This would be an analogue of the several cerebellar paraneoplastic diseases. Despite this theory, treatment aimed at this mechanism (e.g., plasmapheresis, intravenous immunoglobulin, and immunosuppressive drugs) has not shown convincing beneficial effects. Antigliatin antibodies, which correlate with intestinal celiac disease, may be present in patients with the myoclonic ataxic syndrome of celiac disease, but their role in the pathogenesis of the neurologic disease has not been convincingly demonstrated.

SUGGESTED READINGS Beck WS Neuropsychiatric consequences of cobalamin deficiency. Adv Intern Med 36:33-56, 1991 Bhatia KP, Brown P, Gregory R et al: Progressive myoclonic ataxia associated with celiac disease. Brain 118:1087-1093, 1995 Gobbi G (ed): Epilepsy and Other Neurological Disorders in Coeliac Disease. John Libbey & Co., London, 1997 Harding AE, Mder DPR, Thomas PK et al: Spinocerebellardegeneration secondary to chronic intestinal malabsorption: a vitamin E deficiency syndrome. Ann Neurol 12:419-424, 1982 Healton EB, Savage DG, Brust JCM et ak Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 70221-245, 1991 Schmahmann J: Whipple disease of the nervous system. In Noseworthy JH (ed): Neurologic Therapeutics, Principles and Practice. Martin Donitz,

London, 2003

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Neurology in General Medicine H Gastroenterology and Hepatology

195 Hepatic Encephalopathy and Portosystemic

Encephalopathy Edward 1. Levine, Jeffrey D. Rothstein, and Martin A. Samuels Hepatic and portosystemic encephalopathy are common medical conditions that face the primary care physician and specialist alike. They are closely related neuropsychiatric syndromes characterized by abnormal mental status occurring in patients with hepatic insufficiency or portosystemic shunts. They may complicate both acute and chronic liver disease. Several important closely related and often interlocking terms should be defined Portal-systemic encephalopathy (PSE) Late-onset hepatic failure Fulminant hepatic failure Hepatocerebral degeneration Spastic paraparesis PSE generally results from cirrhosis but may occur in the absence of liver disease if portosystemic shunting of blood occurs, as happens with an Eck fistula. It can run an acute, subacute, or chronic course. Fulminant hepatic failure is defined as the onset of hepatic encephalopathy within 8 weeks of the beginning of the illness in the absence of prior liver disease. Late-onset hepatic failure is similar to fulminant hepatic failure with the exception that encephalopathy occurs from 8 to 24 weeks after the onset of illness. Hepatocerebral degeneration and spastic paraparesis are irreversible conditions that may rarely occur in patients with chronic liver disease.

Diagnosis The diagnosis of PSE is based on both clinical and laboratory findings. It is easy to recognize encephalopathy in a patient with fulminant hepatic failure. When hepatic disease is not clinically obvious, the nonspecific nature of early PSE may make the diagnosis more difficult. Abnormal laboratory tests of hepatic function may establish the presence of liver disease. An elevated plasma ammonia level may be useful in confirming the diagnosis, but a normal plasma ammonia concentration does not exclude this diagnosis. An elevation in cerebrospinal fluid glutamine concentration is the most specific and sensitive laboratory test for PSE and correlates best with the degree of hepatic encephalopathy. Unfortunately, glutamine assays are not performed in some clinical laboratories. The coagulopathy and thrombocytopenia that may accompany hepatic disease may make lumbar puncture unsafe. If a lumbar puncture is warranted in this situation, correction of the bleeding parameters with fresh frozen plasma or platelets may be necessary. The electroencephalogram is abnormal in patients with PSE, but the abnormalities are nonspecific. Triphasic slow waves, commonly attributed to PSE, may occur in patients with head injury, subdural hematomas, uremia, cerebral anoxia, and electrolyte abnormalities. Psychometric testing, although not particularly helpful in diagnosing PSE, provides a semiquantitative means of following response to therapy. Easy bedside evaluations include

PORTAL-SYSTEMIC ENCEPHALOPATHY Clinical Features PSE is characterized by alterations in behavior ranging from diminished attention span to coma. Alterations in motor tone and posture, slowing of the electroencephalogram with characteristic triphasic slow waves, and characteristic elevations in fasting plasma ammonia and cerebrospinal fluid glutamine concentrations are also present. The four clinical stages of hepatic encephalopathy, based on severity, are shown in Table 195-1. Stage 1 encephalopathy consists of very mild changes and may be quite subtle. Findings range from mild confusion to reversal of sleep patterns and personality changes. In stage 2 hepatic encephalopathy the mental status worsens, and asterixis is seen. Asterixis is a transient loss of postural tone of the antigravity muscles. It is not specific for hepatic encephalopathy and may be seen with uremia, pulmonary disease, and in some focal lesions, particularly in the midbrain, thalamus, and sensory cortex. Stage 3 encephalopathy signifies more profound and serious neurologic abnormalities. Focal or generalized seizures may develop. The patient may become somnolent or incontinent. Physical examination may reveal rapid, deep respirations accompanied by hyperreflexia, with Babinski signs present. In stage 4 coma, diminished responsiveness to pain occurs. Also, decerebrate and decorticate posturing is seen.

TABU 195-1. Signs and Symptoms of Hepatic

Encephalopathy Stage'

Mental Status or Behavior

1

Mild confusion Anxiety irritability Agitation Diminished attention Impaired serial 7s Altered sleep patterns Depression Drowsiness Lethargy Gross personality changes

Motor Signs or Reflexes

~

2

3

4

Disorientation (time) Poor recall Inappropriate behavior Delirium or profound confusion Paranoia Disorientation (time and place) Incomprehensible speech Somnolent but arousable Coma

'Signs and symptoms may vary within each stage.

Fine postural tremor Slowed coordination

Asterixis Dysarthria Primitive reflexes (suck, grasp) Paratonia Ataxia Hyperreflexia Seizures Babinski sign Hyperventilation Incontinence Hypothe rmia Myoclonus Decerebrate posturing Brisk oculocephalic reflexes

Chapter 195

trail making (Reitan number connection) and tests using block designs or star constructions. Differential Diagnosis

Because the neuropsychiatric manifestations of PSE are nonspecific, it is important to exclude other causes of encephalopathy in patients with liver disease. Toxins, metabolic abnormalities, and structural lesions can cause similar clinical features. Focal neurologic signs are unusual in PSE and should provoke a search for structural abnormalities, although patients with a stable, subclinical lesion (head trauma, chronic subdural hematoma, stroke) may develop focal neurologic signs or symptoms when PSE develops. If concern exists for structural disease, a PSE image scan of the brain is indicated. Meningitis, subarachnoid hemorrhage, and intracerebral hemorrhage all must be considered because they are not rare conditions in patients with alcoholic cirrhosis. Pathogenesis

Over the years multiple theories have attempted to explain the biochemical pathophysiology of PSE.In general these theories are based on serum, cerebrospinal fluid, or brain tissue abnormalities measured in patients or animal models. No single theory can account for all the behavioral, electrophysiologic,and biochemical changes found in patients or animal models. PSE probably is a multifactorial disorder, with several substances contributing to the altered mental status. Too often, theories have been based on measurements in humans, without sufficient animal modeling to prove causation. Nevertheless, two major theories have the most experimental support: the ammonia hypothesis and the endogenous benzodiazepine hypothesis. Ammonia Hypothesis. It has long been known that arterial blood ammonia concentrations often are elevated in patients with PSE,although the actual value may not always correlate with the severity of the attack. In experimental animal models of PSE, blood ammonia levels often are elevated. The mechanisms by which ammonia leads to disturbances of neural transmission have been studied extensively, and it has been found that ammonia can inhibit both excitatory synaptic transmission and inhibitory postsynaptic potentials. In addition, it can alter the metabolism of brain glutamate and as a result could be responsible for the brain edema associated with fulminant hepatic failure. It is likely that glial cells contain the glutamate/glutamine ammonia detoxification system. Elevations of serum ammonia lead to upregulation of this system with consequent enlargement of the protoplasmic astrocytes (Alzheimertype 11glia). It is likely that saturation of this system leads to ammonia toxicity, with consequent loss of normal glial cell functions, such as acting like potassium sponges and producing certain neurotransmitters (e.g., glutamate and gammaaminobutyric acid). Endogenous Benzodiazepine Hypothesis. In the 1980s specific benzodiazepine receptor antagonists, such as flumazenil, were found to ameliorate PSE in animal models, in anecdotal reports, and in uncontrolled clinical trials of human subjects. Because of the specificity of the benzodiazepine receptor antagonists, those observations suggested that the drug might be blocking the encephalopathic actions of a benzodiazepine-like substance. Subsequently,double-blinded,placebo-controlled trials confirmed the anecdotal clinical observations, although only a small subset of patients improved with flumazenil treatment. The nature of the benzodiazepine-likesubstance present in PSE is not entirely clear.

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TABU195-2. Precipitants of Hepatic Encephalopathy Drugs Sedatives Tranquilizers Narcotics Diuretics Electrolyte imbalance Hyponatremia Hypokalemicalkalosis Hypovolemia Excessive nitrogen load Gastrointestinal hemorrhage Excess dietary protein Azotemia Constipation Infection

At least two substances (together or separately) may be the causal agents. Small amounts of halogenated benzodiazepines, such as diazepam, have been found in excess in some patients, and even larger amounts of biologically active nonbenzodiazepine substances are present in the serum of patients with PSE. One such endogenous substance with benzodiazepine-like properties, endozepine-4, has been identified. It appears to be elevated in plasma and cerebrospinal fluid from patients or animals with PSE. The causal relationship of excess endozepine-4 with PSE is not yet certain, but interestingly, very large increases of endozepine-4 (more than 1000 times normal) have been found in a rare neurologic disorder of relapsing unconsciousness (idiopathic recurring stupor). This finding suggests that endozepine-4 could be responsible for or contribute to the encephalopathy in both diseases.

Treatment Recognition of Precipitating Causes. Perhaps the most important aspect of treating PSE is to treat the precipitating cause (Table 195-2). Agitated patients often are misdiagnosed and treated with sedatives, which obviously may worsen the situation. Use of sedatives (especially benzodiazepines) and narcotics should be avoided in stable cirrhotics to prevent encephalopathy. Excessive diuretic therapy may cause a hypokalemic alkalosis. Hypokalemia is a stimulus for the kidney to produce ammonia, and alkalosis favors the diffusion of ammonia in the central nervous system. Intravascular volume depletion from diuretic therapy reduces renal blood flow and increases the blood urea nitrogen concentration. Excess urea can then diffuse into the gut, leading to increased ammonia production by bacterial ureases. Bacterial infections can precipitate encephalopathy and often are unsuspected because patients with chronic liver diseases often are hypothermic. Cultures of blood, urine, ascites (if present), and cerebrospinal fluid should be obtained for all cases of unexplained encephalopathy. Specific Therapies. The therapy for PSE is based on the premise that substances in the gastrointestinaltract are acted on by intestinal bacteria and converted into toxins that are absorbed into the blood. These toxins bypass the liver via collateral circulation, enter the brain, and presumably induce encephalopathy. Based on these principles, therapy is directed at decreasing the colonic substrate for these putative comagenic toxins, reducing the bacteria capable of producing these toxins, diminishing the influx of these compounds into the central nervous system, and

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decreasing the effect of these compounds on neurotransmitter activity and metabolism. Reduction of Gastrointestinal Protein and Toxins. Reduction of dietary protein is a simple method of reducing gastrointestinal protein and should be the first step in therapy. Protein intake can be withheld for the first 1 to 2 days and is gradually increased in increments of 10 g/day. Dietary intake should not be less than 40 mg/day chronically because negative nitrogen balance ensues, with the subsequent risk of infection and with diminished hepatic regeneration. Optimally, the daily protein intake should be 1.5 g/kg/day to maintain positive nitrogen balance. Vegetable protein has been proved to produce less encephalopathy than animal protein diets. Patients with hepatic encephalopathy secondary to gastrointestinal hemorrhage, constipation, or large protein loads should be treated with tap water enemas and lactulose to evacuate nitrogenous substrates. Lactulose is the mainstay of therapy to prevent or diminish encephalopathy (a synthetic disaccharide). Its cathartic action increases ammonia elimination, and because there are no enzymes to metabolize lactulose in the upper gastrointestinal tract, it reaches the colon, where bacterial metabolism of lactulose acidifies the colonic contents and converts ammonia to its ionized and less absorbable form. Lactulose may be administered orally (30 mL per nasogastric tube hourly until a loose bowel movement occurs) or as a retention enema (300 mL in 700 mL water) in obtunded patients. For patients with recurrent PSE, lactulose can be used chronically ( 15 to 45 mL orally two to four times a day), aiming for two to three soft bowel movements a day. In patients refractory to dietary protein restriction and lactulose therapy, the oral antibiotics neomycin and metronidazole have been used to promote colonic bacteriostasis. Reduction of Gastrointestinal Bacteria. In patients who cannot be treated with dietary protein restriction and lactulose therapy, the elimination of gastrointestinal bacteria may prove useful. The premise of this therapy is that diminution of gastrointestinal flora diminishes the production of ammonia and other possible toxins. Neomycin can be taken orally in a dosage of 1 to 2 g every 6 hours. Only small amounts of this drug can be absorbed, however, and because it is excreted primarily in urine, its use should be avoided in patients with renal insufficiency. Even in patients with normal renal function, prolonged therapy can produce ototoxicity and nephrotoxicity. An alternative to neomycin is metronidazole. It is given 250 orally three times a day. Side effects include leukopenia, peripheral neuropathy, metallic taste, and disulfiram-like reaction. Other Therapies. Because patients with PSE have abnormal plasma and cerebrospinal fluid amino acid concentrations, it has been suggested that the increased plasma aromatic amino acids produced in these patients may interfere with normal neurotransmitter syntheses. Therefore, trials with solutions enriched with branched-chain amino acids for transport into the central nervous system have been tried. The results of these studies are mixed and controversial. Because of the high cost of these solutions, the high osmolality and fluid load, and the marginal benefit, this therapy is not routinely recommended. An important, rare subset of patients with PSE includes those suffering from inherited urea cycle defects (e.g., ornithine transcarbamylase deficiency). In these patients, primarily children, ammonia accumulation is believed to be responsible for the encephalopathy, and attempts to lower serum ammonia have proved useful. Infusions of sodium phenylacetate may be used to control potentially fatal hyperammonemia successfully. Alterna-

tive therapies include the use of arginine or citrulline, depending on the specific enzyme deficiency. Flumazenil (Romazicon, RO 15-1788) is a benzodiazepine receptor antagonist widely used in Europe. It is reported to reverse hepatic encephalopathy in some patients, eliminate relapsing encephalopathy, and allow the resumption of normal protein intake in patients with chronic hepatic failure. This drug is available in the United States but is used primarily for reversal of benzodiazepine overdose. At this time it is not approved for use in PSE. FULMINANT HEPATIC FAILURE Unlike chronic disease, fulminant hepatic failure is associated with a high mortality rate (more than 50%). It is usually secondary to viral hepatitis or drug- induced liver disease, usually acetaminophen overdose. The now rare Reye’s syndrome was another cause of acute hepatic failure before the recognition that avoidance of aspirin use in children could greatly diminish the incidence of this disorder. Patients have multiple metabolic abnormalities that can contribute to the encephalopathy. Of particular concern is hypoglycemia, which can be treated with infusions of 10% dextrose in water. Intensive care monitoring and particularly liver transplantation have been of benefit in decreasing overall mortality. In particular, attention must be paid to electrolyte disorders, acid-base balance, glucose, and coagulation defects, as well as pulmonary, cardiac, and renal status. Constant vigilance for infections must be maintained. Cerebral Edema Although this encephalopathy appears similar to that associated with chronic liver disease, the underlying mechanisms and the treatment may be quite different. Most importantly, fulminant hepatic failure is associated with lethal cerebral edema, which is the major extrahepatic lesion found at autopsy. Because papilledema may not be seen, no good clinical indices for cerebral edema exist. Sudden deterioration of consciousness and hyperactive reflexes, along with extensor plantar reflexes and decerebrate/ decorticate posturing may suggest elevated intracranial pressure (ICP), but these can also be seen in patients with metabolic encephalopathy. Abnormal pupillary light responses and vestibulo-ocular reflexes may be reversible, but abnormal cold water-induced vestibulo-ocular reflexes carry a poor prognosis. Brain imaging may reveal slitlike ventricles or other signs of an elevated ICP. ICP transducers have been used by some to help monitor ICP, but their use may cause significant intracranial bleeding. Therapies aimed at controlling ICP, such as hyperventilation and furosemide therapy, can be used. Mannitol has been used to reduce elevated pressure, but in patients with an ICP greater than 60 mm Hg, it may be deleterious. Mannitol should be used only when ICP transducers are in place. The value of steroids has not been proved. Treatment Given the large number of metabolic problems, the approach to fulminant hepatic failure is not as effective as that used for chronic hepatic disease. Most patients are obtunded or comatose, so little dietary protein is ingested. Lactulose can be used to remove nitrogen waste from the gut initially but can produce complicating electrolyte disturbances secondary to excessive diarrhea.

Chapter 196

Orthotopic liver transplantation is the treatment of choice for stage 3 and 4 encephalopathy, assuming the patient is a candidate. SUGGESTED READINGS Bade AS, Jones EA, Skolnick P The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 43:27, 1991 Butterworth RF: Pathophysiology of hepatic encephalopathy:the ammonia hypothesis revisited. p. 9. In Bengtsson F, Jeppsson B, Almdal T, Vilstrup H (eds): Progress in Hepatic Encephalopathy and Metabolic Nitrogen Exchange. CRC Press, Boca Raton, FL, 1991 Cole M, Mullen KD: Hepatic coma and portal-systemic encephalopathy. p. 326. In Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Disease. 4th Ed. BC Decker, St Louis, 1993

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Conn HO: Hepatic encephalopathy. p. 69. In Schiff L, Schiff ER (eds): Diseases of the Liver. Vol. 2. JB Lippincott, Philadelphia, 1993 Rothstein JD,Garland W, Puia G et al: Purification and characterization of naturally occurring benzodiazepine receptor ligands. J Neurochem 58:2102, 1992 Rothstein JD, Guidotti A Endozepines: non-benzodiazepine endogenous allosteric modulators of GABA, receptors. p. 115. In Izquierdo I, Medina J (eds): Naturally Occurring Benzodiazepines: Structure, Distribution and Function. Ellis Horword, London, 1993 Victor M, Rothstein JD: Neurologic manifestations of hepatic disease. p. 1442. In Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System. WB Saunders, Philadelphia, 1992

5

196 Neurologic Complications of Sickle Cell Disease Robert J. Adams Sickle cell diseases and thalassemias are common medical conditions that predispose to a small but important list of neurologic problems. This chapter focuses on the neurologic complications most commonly encountered in these diseases, with emphasis on diagnosis and treatment. These hemoglobinopathies are genetic abnormalities involving the production of hemoglobin. Sickle cell disease (SCD) is any condition in which the production of an abnormal hemoglobin (Hb) causes in vivo distortion of the erythrocyte (sickling), which in turn causes hemolysis and intermittent vascular obstruction. Thalassemias are diseases in which one or both of the a- or P-chains are underproduced, leading to imbalanced globin chain synthesis, abnormal hemoglobin, and subsequent damage to the red blood cell or its precursor. Thalassemias are further characterized as to the degree of underproduction, with a “0”superscript indicating no production and one or two “+” symbols denoting partial production. In SCD the chains are abnormal; in thalassemia they are normal but the hemoglobin tetramer is abnormal. The genes predisposing to these conditions are found primarily but not exclusively among certain ethnic populations. People of African, Saudi Arabian, or Asian descent have a likelihood of carrying genes for SCD and a-thalassemia, and people with lineage from countries bordering the Mediterranean Sea and all parts of Asia have a predisposition to P-thalassemia. However, any of these conditions may be seen in people from any racial background. Patients with SCD or thalassemia usually are

diagnosed through newborn screening or because all the clinically significant hemoglobinopathies produce some degree of anemia that comes to attention before any neurologic symptoms develop. It is rare for a neurologic complication to lead to the diagnosis of hemoglobinopathy. Clinically the most important of these diseases are homozygous SCD (Hb SS or sickle cell anemia), sickle C (Hb SC) disease, and P-thalassemia (also called Cooley’s anemia or thalassemia major), but many abnormal hemoglobin variants have been reported. More than one genetic abnormality may coexist in the same patient (e.g., sickle-thalassemia). Patients with sickle Pothalassemia have a malignant course similar to Hb SS, but sickle P+-thalassemia shows a much milder course and is less likely to have neurologic complications. The bewildering array of molecular aberrations and abnormal hemoglobins, the complex and varying terminologies, and the coexistence of conditions make it difficult for the neurologist to be confident that some of the less common hematologic abnormalities are related to the neurologic illness at hand. The ameliorating effect of fetal hemoglobin, which may be upregulated to levels much higher than normal in the presence of SCD, may partially negate the negative effect of Hb S. It is important to emphasize that whereas many case reports and small series exist in the literature, only a few neurologic syndromes have been firmly associated with the hemoglobinopathies, most of these with homozygous Hb SS. The clinician is cautioned against assuming a causal relationship in such patients without first

Chapter 196

Orthotopic liver transplantation is the treatment of choice for stage 3 and 4 encephalopathy, assuming the patient is a candidate. SUGGESTED READINGS Bade AS, Jones EA, Skolnick P The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 43:27, 1991 Butterworth RF: Pathophysiology of hepatic encephalopathy:the ammonia hypothesis revisited. p. 9. In Bengtsson F, Jeppsson B, Almdal T, Vilstrup H (eds): Progress in Hepatic Encephalopathy and Metabolic Nitrogen Exchange. CRC Press, Boca Raton, FL, 1991 Cole M, Mullen KD: Hepatic coma and portal-systemic encephalopathy. p. 326. In Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Disease. 4th Ed. BC Decker, St Louis, 1993

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Conn HO: Hepatic encephalopathy. p. 69. In Schiff L, Schiff ER (eds): Diseases of the Liver. Vol. 2. JB Lippincott, Philadelphia, 1993 Rothstein JD,Garland W, Puia G et al: Purification and characterization of naturally occurring benzodiazepine receptor ligands. J Neurochem 58:2102, 1992 Rothstein JD, Guidotti A Endozepines: non-benzodiazepine endogenous allosteric modulators of GABA, receptors. p. 115. In Izquierdo I, Medina J (eds): Naturally Occurring Benzodiazepines: Structure, Distribution and Function. Ellis Horword, London, 1993 Victor M, Rothstein JD: Neurologic manifestations of hepatic disease. p. 1442. In Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System. WB Saunders, Philadelphia, 1992

5

196 Neurologic Complications of Sickle Cell Disease Robert J. Adams Sickle cell diseases and thalassemias are common medical conditions that predispose to a small but important list of neurologic problems. This chapter focuses on the neurologic complications most commonly encountered in these diseases, with emphasis on diagnosis and treatment. These hemoglobinopathies are genetic abnormalities involving the production of hemoglobin. Sickle cell disease (SCD) is any condition in which the production of an abnormal hemoglobin (Hb) causes in vivo distortion of the erythrocyte (sickling), which in turn causes hemolysis and intermittent vascular obstruction. Thalassemias are diseases in which one or both of the a- or P-chains are underproduced, leading to imbalanced globin chain synthesis, abnormal hemoglobin, and subsequent damage to the red blood cell or its precursor. Thalassemias are further characterized as to the degree of underproduction, with a “0”superscript indicating no production and one or two “+” symbols denoting partial production. In SCD the chains are abnormal; in thalassemia they are normal but the hemoglobin tetramer is abnormal. The genes predisposing to these conditions are found primarily but not exclusively among certain ethnic populations. People of African, Saudi Arabian, or Asian descent have a likelihood of carrying genes for SCD and a-thalassemia, and people with lineage from countries bordering the Mediterranean Sea and all parts of Asia have a predisposition to P-thalassemia. However, any of these conditions may be seen in people from any racial background. Patients with SCD or thalassemia usually are

diagnosed through newborn screening or because all the clinically significant hemoglobinopathies produce some degree of anemia that comes to attention before any neurologic symptoms develop. It is rare for a neurologic complication to lead to the diagnosis of hemoglobinopathy. Clinically the most important of these diseases are homozygous SCD (Hb SS or sickle cell anemia), sickle C (Hb SC) disease, and P-thalassemia (also called Cooley’s anemia or thalassemia major), but many abnormal hemoglobin variants have been reported. More than one genetic abnormality may coexist in the same patient (e.g., sickle-thalassemia). Patients with sickle Pothalassemia have a malignant course similar to Hb SS, but sickle P+-thalassemia shows a much milder course and is less likely to have neurologic complications. The bewildering array of molecular aberrations and abnormal hemoglobins, the complex and varying terminologies, and the coexistence of conditions make it difficult for the neurologist to be confident that some of the less common hematologic abnormalities are related to the neurologic illness at hand. The ameliorating effect of fetal hemoglobin, which may be upregulated to levels much higher than normal in the presence of SCD, may partially negate the negative effect of Hb S. It is important to emphasize that whereas many case reports and small series exist in the literature, only a few neurologic syndromes have been firmly associated with the hemoglobinopathies, most of these with homozygous Hb SS. The clinician is cautioned against assuming a causal relationship in such patients without first

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Hematology

considering alternative and more common explanations for neurologic disease. There has been recent evidence that both environmental and genetic or epigenetic factors in addition to the basic gene defect play a role in the causation of stroke in this disorder, but at present this research has not led to new therapies. ACUTE MANIFESTATIONS Bacterial meningitis and stroke are the most important acute central nervous system emergencies to consider in the Hb SS patient with acute brain dysfunction. Meningitis

It is crucial to consider meningitis, for two reasons: The association of meningitis with Hb SS is less well known than that of stroke, often leading to the erroneous assumption that all brain problems in Hb SS are caused by stroke; and treatment is effective if started early. Most cases are caused by pneumococcus, and diagnosis and treatment with antibiotics and steroids should be undertaken as in any case with suspected or proven bacterial meningitis. This is primarily a problem in young children, many of whom now receive vaccine and prophylactic daily antibiotics. Chronic treatment with 250 mg of penicillin twice per day is common practice for children with Hb SS, which may complicate the interpretation of cerebrospinal fluid findings in cases of suspected meningitis. Hb SS patients are at risk of Salmonella osteomyelitis, and this agent may cause meningitis. Increased risk of Haemophilus influenme and Escherichia coli infections has also been suggested. Bacterial meningitis is associated with at least a 15% incidence of long-term neurologic sequelae including seizures, sensorineural hearing loss, focal neurologic deficits, and hydrocephalus. Release of cytokines, believed to play a causative role in inflammatory injury to brain during the infection, can be

reduced experimentally with steroids. Dexamethasone has been shown to improve outcome in childhood meningitis and should be used at a dosage of 0.15 mg/kg intravenously every 6 hours for 4 days beginning at the start of antibiotic treatment. Cerebral ischemia and hearing loss resulting from bacterial meningitis do not seem to be more common in SCD even though these patients are already at higher risk for such problems because of their hemoglobinopathy. Susceptibility to infection is caused by loss of splenic function and other abnormalities of the immune system. Adults with a history of frequent transfusions before 1985 must be considered at risk for human immunodeficiency virus infection. The initial manifestations, diagnostic tests, and management of the most important acute neurologic complications of Hb SS are shown in Table 196-1. Stroke

Stroke is the most common neurologic complication of Hb SS. The prevalence of symptomatic cerebrovascular disease may reach 10% in the United States, and as many as 15% to 20% of patients may have abnormal neuroimaging suggesting cerebrovascular disease. Unless otherwise specified, this discussion pertains only to symptomatic disease. In general, cerebral infarction tends to occur in children and intracranial hemorrhage in adults, but many exceptions are seen, and all manifestations have been reported in all age groups. Stroke may follow pain crisis, infection, and other systemic illness, but it is unclear whether such prodromes are characteristic or coincidental. Elevated blood levels of cytoadherence molecules may promote vaso-occlusion. Acute worsening of anemia was noted before 5 of 17 first-time strokes in one study, suggesting that sudden lowering of the oxygen-carrying capacity may cause ischemia in the presence of arterial stenosis. Other factors suggested to trigger symptoms include obstructive sleep apnea and

W TABLE196-1. Neurologic Complications of Homozygous Sickle Cell Disease

Syndrome

Symptoms

Neurologic Examination Findings

Diagnosis

Initial Treatment

Meningitis

Headache, lethargy, seizure, coma

Meningismus, stupor, coma

CSF abnormal; CT may

Transient weakness numbness; alteration of behavior

Normal or focal, transient deficits

CT, EEG, and CSF exam

Antibiotics; dexamethasone 0.15 mg/kg every hour for 4 days Transfusion; evaluate large vessels by angiography, TCD

Hemiparesis, hemisensory loss, abnormal speech or vision Headache, hemiparesis

Hemiparesis, aphasia, or other cortical abnormalities Hemiparesis, may have lethargy or coma

Transient ischemia

Cerebral infarction

show cerebral edema normal; MRI or MRA with contrast may show abnormality CT shows decreased attenuation; MRI shows decreased signal CT shows intraparenchyma1 blood

Transfusion; hydration; repeat CT 3-4 days

Check for coagulopathy; treat cerebral edema as needed; angiography when stable CT shows location of Stupor, coma, neck stiffSubarachnoid or Sudden severe headache, Transfuse; close observaness; may have normal blood; MR may show intraventricular vomiting, depression of tion, nimodipine, 60 aneurysm or consciousness exam mg every 4 hours PO; hemorrhage moyamoya intraventricular shunt for acute hydrocephalus; angiography when stable Seizure Tonic-clonic movements, Postictal or normal; may History, EEG, MRI with Treat focal seizures as contrast may show ceimpairment of conhave transient focal TIAs; generalized seirebral infarct zure treatment desciousness weakness Dends on etiolonv Abbreviations: CSF, cerebrospinal fluid; CT,computed tomography; EEC, electroencephalogram;MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; TCD, transcranial Doppler; TI& transient ischemic attack. lntraparenchymal hemorrhage

~

~

Chapter 196 H Neurologic Complications of Sickle Cell Disease

transfusion after prolonged priapism. However, most strokes occur without a recognized prodrome. Cerebral Infarction Cerebral infarction typically presents with the sudden onset of symptoms of acute hemispheric dysfunction, including hemiparesis, altered speech or aphasia, and hemisensory and visual deficits without alteration of consciousness. Seizures, often partial in onset, accompany about 20% of cases. Few are preceded by recognized transient ischemic attacks, although reporting of symptoms may be incomplete because infarction is especially common in young children with SCD. The initial cranial computed tomography (CT) often shows evidence of prior undetected brain lesions. Examination usually shows some degree of hemiparesis, which typically undergoes significant improvement in days to weeks after the ictus. Although motor symptoms improve, patients may show cognitive deficits. Posterior circulation syndromes and isolated cranial palsies caused by central nervous system disease are rare and probably represent neuropathy rather than stroke. Most patients with brain infarction who are studied with cerebral angiography show typical findings: dilated vessels generally, focal areas of stenosis or occlusion in the distal internal carotid artery and proximal middle and anterior cerebral arteries, variable irregularities of more distal vessels, and recruitment of willisian, leptomeningeal, and extracranial-intracranial collateral pathways. Although sickled cells do not pass well through the microcirculation, the simplistic notion that plugging is the cause of stroke is inadequate because both the large arteries and microcirculation are involved. The most important lesions are those at the level of the circle of Willis. Although the cause is not known, the initiating event could be injury to endothelium followed by loss of the thromboresistant properties of the endothelium and either gradual formation of clot or acute blockage of vessels by thrombus. The anemia itself, which is associated with high blood flow rates, may also predispose to vessel wall damage. Once initiated, the lesions are extended over time by endothelial hyperplasia, fibroblasts, fibrin thrombi, and even thrombus, with sickle red cells incorporated into the lesion. Acute thrombus formation causing total occlusion and hemodynamic failure may be the precipitating event, or stroke may be caused by artery-artery embolus. Hemodynamic failure is suggested by pathologic studies and neuroradiologic series showing a high incidence of so-called border zone infarctions between major arterial territories and in subcortical areas. Moyamoya is present in up to 30% of patients who have been studied by angiography. The cervical carotid artery and the vertebrobasilar system show only dilation or narrowing believed to be secondary to intracranial disease. The case shown in Figure 196-1 illustrates many of the typical features. This series is from a young girl who presented with left hemiparesis. Her initial scans showed old unrecognized infarcts, both deep and cortical lesions, and bilateral border zone infarctions. Angiography showed severe bilateral distal internal carotid artery disease with moyamoya formation and evidence of circle of Willis, leptomeningeal, and extracranial-intracranial vessels providing collateral circulation. Other potential causes of cerebral infarction in Hb SS are seldom noted in the literature, but these should be considered, especially in older patients and children without typical CT or angiographic findings. Patients with SCD often have cardiomyop-

1245

athy, and cardiogenic embolus may be underdiagnosed. The danger is to assume that the stroke is caused by HB SS and fail to consider entities such as endocarditis, drug abuse coagulopathy, antiphospholipid antibodies, arterial dissection, paradoxical embolus, or venous disease. Diagnosis is made from the clinical picture and either CT or magnetic resonance imaging (MRI) evidence of infarction. These techniques allow the acute distinction between hemorrhage and infarction and provide evidence as to the vascular territories involved. Diagnostic testing addresses three questions: What is the cause of the patient’s symptoms? If a stroke is the cause, are the symptoms caused by cerebral infarction or hemorrhage? What is the likelihood of recurrence? Management depends on prompt recognition of the cause of symptoms. The presenting symptoms and signs of four manifestations of cerebrovascular disease are described in Table 196-1, along with the results of diagnostic tests and initial management strategies. A patient presenting with a history of a transient focal neurologic deficit, especially hemiparesis, should be assumed to have had a transient ischemic attack or (less likely) a seizure with postictal weakness. Although cerebral ischemia (transient loss of brain blood flow) is the most likely, initial consideration should also be given to diseases other than stroke. If meningitis is suspected, treatment should be initiated with antibiotics at once and a CT scan performed, followed by a lumbar puncture. The CT scan in the acute evaluation of a patient with neurologic symptoms is the best initial diagnostic test because it can be performed rapidly and requires little cooperation. It is not necessary to use intravenous contrast to rule out most emergency conditions, but diagnostic sensitivity is enhanced by its use for other conditions. Brain tumors may present with transient symptoms but more typically are associated with subacute or chronic symptoms. The CT also helps to distinguish these conditions. Focal seizures should prompt evaluation for stroke risk. The electroencephalogram may help to localize the brain lesion, but imaging of the brain and assessment of the large vessels are necessary to evaluate cerebrovascular risk fully The cause of generalid seizures, especially in adults, may be obvious from the history, and an extensive workup may not be appropriate. Cranial CT or MRI should be done in all patients with suspected stroke to eliminate other lesions and to identify hemorrhages. Cerebral angiography is clearly useful when the diagnosis of cerebrovascular disease is doubtful and chronic transfusion is being considered. This situation arises in young children with extremity symptoms that might represent stroke or painful crisis. In such cases the angiogram is used to decide on transfusion. Angiography is safe in Hb SS if the patient is prepared with hydration and reduction of Hb S to a low level, arbitrarily 30% or less. Transfusion is initiated if the angiogram shows extensive large vessel disease and is withheld in the absence of impressive disease. Whether magnetic resonance angiography or transcranial Doppler can substitute for angiography depends on local experience with these noninvasive techniques. Transcranial Doppler can identify children at risk for stroke before symptoms develop, and a randomized controlled clinical trial showed 90% risk reduction with prophylactic transfusion. If the CT is normal or shows new or old cerebral infarction, the standard treatment of children is hydration with transfusion. Acute treatment of a proven or suspected cerebral infarction consists of immediate partial or complete exchange transfusion and intravenous hydration with isotonic fluids. Although

Neurology in General Medicine W

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Hematology

B

A

C

D

FIG. 196-1. Series from a 12-year-old girl with sickle cell disease who presented with left hemiparesis. She had been under observation because a transcranial Doppler performed 9 months earlier had shown high velocities in the right internal carotid artery consistent with narrowing and an abnormally low left middle cerebral artery velocity, suggesting severe stenosis or occlusion. (A) Axial T2-weighted magnetic resonance imaging (MRI) showing deep and cortical high signal lesions consistent with infarction. The deep border zone lesions (arrows) are particularly characteristic of sickle cell disease. Also typical is the presence of old hyposymptomatic lesions on MRI performed when these patients develop symptoms. (B) Axial proton density MRI showing decreased signal in the right middle cerebral artery distribution and bilateral high-signal areas in the centrum semiovale. (C) Lateral projection of a conventional angiogram during a left common carotid injection. A distal internal carotid artery occlusion and moyamoya (open arrow) are seen. The most distal patent segment of the internal carotid artery (single black arrow) is narrowed in the typical location just beyond the ophthalmic artery. This angiogram also demonstrates enlargement of the posterior communicator on the right with anterograde flow posteriorly. Typically the posterior cerebral artery, which is rarely involved in the sickle cell vasculopathy, will supply collateral flow to the anterior circulation through pericallosal collaterals or leptomeningeal collaterals (not shown) to the middle cerebral artery territory. Also depicted in this case are transdural collaterals from the external carotid circulation (double mows). (0) Anteroposterior projection of the right common carotid artery injection showing distal internal carotid narrowing and apparent occlusion of the anterior cerebral artery (open arrow). Note that the middle cerebral branches are enlarged, another typical feature of sickle cell disease apparent on both angiography and MRl/magnetic resonance angiography, and there is evidence of leptomeningeal collateral flow from the middle to the anterior circulation on this side (solid arrow).

Chapter 196

randomized study of the effects of this therapy on outcome have not been performed, the therapy seems reasonable on theoretical grounds and has become common practice. The optimal transfusion method and target parameters have not been established. In theory, reduction of the Hb S level would be expected to improve blood viscosity and might improve cerebral blood flow in the region of an acute infarct. On this basis rapid rather than slow reduction is preferable because the therapeutic window for the brain is limited to a few hours after the onset of ischemia. Simple transfusions are slower than exchange methods and risk increasing the hernatocrit to levels that markedly increase blood viscosity, further impairing flow. On the other hand, the rate of exchange should not be so rapid as to risk cardiovascular instability, which could decrease brain perfusion. Given these considerations, partial exchange is recommended with the goal of reducing the Hb S to less than 30% as rapidly as can be safely accomplished. Therapeutic limits are 10 to 11 g/dL Hb and 30% to 33% hematocrit, being careful not to raise the hematocrit higher than 33% to 35% because doing so could impair cerebral blood flow via elevated viscosity. Cautious hydration with colloid or normal saline and vigilance for seizures and increased intracranial pressure from cerebral edema are appropriate measures and may best be accomplished acutely in an intensive care setting. The efficacy of transfusion has not been tested in the acute setting, but it seems to be a reasonable approach that might improve outcome by reducing blood viscosity. There is more support, although no randomized data, for the use of chronic transfusion on a long-term basis to prevent recurrent stroke, which occurs in most cases not treated with transfusion. For children with ischemic stroke the recommendation is for indefinite regular transfusions at least up to 18 or 20 years of age, frequent enough to maintain the level of Hb S to less than 30% of total hemoglobin. While on chronic transfusion patients may report transient episodes of worsening numbness or weakness, but recurrent infarction is rare. The risk of stroke recurrence is not uniform and probably depends on the condition of the arterial system when symptoms first appear. A recent multicenter retrospective study of 137 children with stroke and SCD suggested that patients who have an initial stroke associated or just after a significant medical event such as acute chest syndrome may have a lower long-term risk of recurrence. The rationale is that the risk of stroke in these cases is temporarily elevated because of some medical factor. However, the study did not correlate recurrence risk with arterial status by imaging or ultrasound. Another report suggests that children with stroke and moyamoya on imaging are at high risk of recurrence despite what is considered adequate chronic transfusion. Most patients who develop cerebrovascular symptoms and have been studied have abnormal large arteries when studied with arteriography. It is reasonable to assume that risk is in part dependent on the degree of arterial stenosis, adequacy of collaterals, and number of vessels occluded. Other factors such as platelet or leukocyte count or viscosity probably modify risk. In patients with transient symptoms and no clear CT or MRI evidence of infarction, arteriography can identify patients with significant arterial stenoses. It is invasive and expensive but clearly demonstrates the status of the large arteries. Stroke has been reported as a complication of cerebral arteriography, but hydration and reduction of Hb to less than 30% have reduced the risk significantly. The risks of transfusion probably outweigh the benefits in patients with normal large arteries and should not be used indefinitely in such cases.

Neurologic Complications of Sickle Cell Disease

1247

Prolonged transfusion is associated with cumulative hazards from iron overload, chelation therapy, and antibody formation. Iron accumulation can be attenuated by using chronic partial exchange rather than direct transfusion and treatment with chelation. Various surgical procedures to bypass the stenosis or occlusion associated with moyamoya disease have been tried and may be suitable for patients with SCD who have significant iron overload or problems with alloimmunization that make prolonged transfusion difficult or hazardous. Enthusiasm is much lower for sustained transfusion in adults, and no consensus exists on the best means of secondary prevention in such patients. There is little experience with antiplatelet agents, but I recommend their use in adults who are not treated with transfusion. In theory, anticoagulants might be useful but could make the recognized problem of intracranial hemorrhage more ldcely in patients with extensive vascular disease and fragile moyamoya vessels. Silent or hyposymptomatic brain infarction has been detected in 10% to 20% of patients with SCD studied with MRI. These lesions may cause cognitive impairment, and recent evidence suggests that their presence indicates increased risk for clinical stroke (about 1%per year or about twice baseline) but more likely new or extensive silent infarcts (7%/year). Without other evidence of significant risk, their presence on imaging alone is not considered an indication of chronic transfusion by most workers in this area, although a clinical trial is being planned to address this issue.

lntracranlalHemorrhage Intracranial hemorrhage usually presents with ominous symptoms and signs such as sudden, severe headache, vomiting, and alteration of consciousness with or without focal findings. The cranial CT is important not only in the diagnosis of intracranial bleeding but in the determination of blood location: subarachnoid, intraparenchymal, or intraventricular. Convulsions and coma suggest massive subarachnoid or intraventricular bleeding. Parenchymal bleeding usually is subcortical and presents with depressed alertness or stupor and focal findings. Arteriographic and pathologic investigation of patients with SCD and intracranial hemorrhage identify several potential mechanisms including rupture of berry aneurysms or (less commonly) arteriovenous malformations, rupture of intraparenchymal or periventricular moyamoya-like small arteries, and no evident large artery disease (except for dilation), suggesting small vessel rupture as the presumed source. Aneurysms appear to be more common in Hb SS than in the general population, become manifest at a younger age, and may more often be multiple. Why aneurysms form is unclear, but hemodynamic stress caused by elevated flow rates has been suggested. Deleterious effects on small vessels similar to what is seen in moyamoya disease probably account for intraparenchyma1 bleeding. Bleeding risk appears to be higher in patients who have experienced previous cerebral infarction, and it may not be reduced by the use of chronic transfusion. If the CT scan shows hemorrhage, the patient should be transfused and hydrated in preparation for cerebral angiography. The clinical condition may necessitate urgent and intensive care to treat elevated intracranial pressure or acute hydrocephalus, to manage seizures, or to treat vasospasm. Patients with subarachnoid and intraventricular hemorrhage should receive nimodipine. Primarily intraventricular hemorrhage, often with third ventricular clot, is not uncommon in HB SS and is caused by parenchymal

1248

Neurology in General Medicine H Hematology

Seizures are more common in Hb SS because they occur in 15% to 30% of Hb SS patients with stroke, and stroke is prevalent in Hb SS. Two important points concerning seizures and Hb SS should be considered Focal seizures in children may be the only symptom of unrecognized vascular disease; a workup for large vessel disease should be considered with an eye toward transfusion to prevent stroke if significant disease and cerebral infarction is present; and in some settings patients with Hb SS receive demerol for pain management; generalized seizures may be provoked by its metabolite normeperidine and by toxic dosages of other narcotic analgesics. Apart from these considerations the diagnostic and treatment approach to seizures is the same as in any other patient. Comparative Risks

FIG. 196-2. Noncontrast cranial CT taken shortly after this 7-year-old boy with sickle cell disease presented with severe headache, vomiting, and coma. Note the blood in the third (arrow) and lateral ventricles and early increase in ventricular size. The patient expired before reaching a neurosurgical center, where emergency ventriculostomy may have been life saving. Because his scan showed little parenchymal hemorrhage, he is presumed to have died from acute ventricular obstruction. This patient had transcranial Doppler evidence of vasculopathy 2 years before his death. The presumed source of bleeding is rupture of moyamoya vessels.

hemorrhage in the deep subcortical areas with extension into the ventricular system. Such patients can undergo rapid deterioration after admission to hospital because of sudden blockage of the ventricular system (Fig. 196-2). Emergency ventriculostomy may be life saving and is associated with a good outcome if there has been little parenchymal involvement in the hemorrhage. Epidural hematoma may also be seen in the absence of major head trauma, presumably related to skull infarction and secondary bleeding. The angiogram is important to determine the cause of the bleeding. Aneurysms should be repaired after preparation of the patient with reduction of Hb S. An intracranial bleed associated with extensive large vessel intracranial occlusive disease should be followed by chronic transfusion, at least in younger patients. No data exist on the efficacy of chronic transfusion after aneurysm surgery, but continued transfusion indefinitely seems reasonable given the theories of aneurysm development in these patients. Important alternative diagnoses to consider in cases of atypical hemorrhage, infarct, or brain injury are drug abuse-related strokes and child abuse. Drug intoxication may mimic stroke symptoms in young children.

Despite an anemia that is more severe than that of Hb SS, little evidence shows that patients with P-thalassemia develop vascular disease or have higher risk of stroke. Intracranial hemorrhage with multiple blood transfusions has been reported, but this may have been caused by coagulopathy. A syndrome of hypertension, convulsions, and cerebral hemorrhage was reported in patients with thalassemia receiving blood transfusions but may have been a simple manifestation of malignant hypertension. Patients with Hb SC have a less severe anemia than those with Hb SS and a less severe clinical course generally, including little if any increased risk of neurologic disease. They do get more retinopathy, however, presumably through a higher blood viscosity because they are less anemic. Other Acute Manifestations

Other acute neurologic manifestations include sudden sensorineural hearing loss and vestibular dysfunction. These are usually caused by peripheral disease, but brainstem involvement is possible, and MRI should be considered. Only a few cases of myelopathy from spinal cord infarction or compression from extramedullary hematopoiesis have been reported. The differential diagnosis should first entertain more common causes such as transverse myelitis, demyelinating disease, or mass lesions (before Hb SS) when the spinal cord is involved. Central retinal artery occlusions have been reported. Visual disturbances may be part of a cerebrovascular syndrome or primarily retinal vascular, retinal (proliferative sickle retinopathy), or ocular from other sicklerelated cases. Despite case reports, few data suggest that patients with sickle cell trait (Hb SA) are at higher risk for neurologic disease. Consequences of Transfusion

It is important to mention that patients with hemoglobinopathy treated with chronic transfusion are at higher risk of both acute and chronic consequences of this treatment. A partial list includes immediate transfusion reactions, delayed hemolytic transfusion reactions, hypertension and seizures after transfusion, iron overload with hepatic and cardiac hemosiderosis, chelation side effects including vision and hearing problems, and infection with hepatitis B and C, human immunodeficiency virus, and possibly other agents.

Chapter 196 W

Alternatives to Transfusion

Hydroxyurea is effective in reducing pain crises, and one uncontrolled small study suggests that it may be an alternative to chronic transfusion for secondary stroke prevention after transfusion has been used for several years. It has not been tested in primary stroke prevention. Bone marrow transplantation has been used in a small number of cases and appears to arrest cerebrovascular disease, but there is no evidence that it reverses established arterial lesions. Primary Stroke Prevention

Since 1997 a strategy for primary stroke prevention has been advocated by National Heart Lung and Blood Institute based on the Stroke Prevention in Sickle Cell Anemia Trial (STOP study). In this trial 130 children with high-risk transcranial Doppler studies but no history of stroke were randomized to either standard care (episodic transfusion if elected by clinician for acute illness) or regular transfusion intended to lower Hb S to less than 30% of total hemoglobin. At the point where the standard care arm had experienced 11 strokes compared with 1 in the transfused group, the trial was halted. The untreated risk was 10% per year, compared with less than 1% per year on transfusion. The trial confirmed in a separate prospective population the ability of transcranial Doppler to detect high risk (using 200 cmhecond time-averaged maximal mean in the middle cerebral or internal carotid arteries or higher as the treatment threshold) and established a major reduction in stroke events with transfusion. However, it is not clear how long transfusion must be maintained, and a new study is being performed examining the outcome with randomized withdrawal and transcranial Doppler surveillance after 30 or more months of transfusion. There are almost no data on use of other modalities for primary or, except as noted earlier, secondary prevention. The role of antiplatelet agents and anticoagulation has not been established in this disorder.

CHRONIC MANIFESTATIONS Frequent and bothersome headaches are reported in more than 30% of patients. The headache pattern may suggest migraine but more commonly resembles tension-type headache. Unless it is part of a well-established migraine pattern, severe headache with vomiting should prompt an urgent CT scan because of the increased risk of intracranial hemorrhage. No evidence shows that chronic headache is more common in patients destined to have stroke. Treatment is approached as with any similar-aged patient using episodic and prophylactic therapy as appropriate. Children with Hb SS appear to have a small but significant baseline cognitive deficit when compared with sibling controls without the disease. This deficit becomes evident by early childhood and occurs outside the recognized cerebrovascular syndromes. The cause is unclear, but recent evidence indicates that this problem begins early in life and probably is underappreciated. A child with severe learning problems should be worked up for stroke with a CT or MRI. In the presence of extensive vessel and

Neurologic Complications of Sickle Cell Disease

1249

parenchymal disease and clear focal deficits, transfusion should be considered. In most cases cerebral infarction is not found, however. Clinicians should be alert to the likelihood that children and adults with HB SS and perhaps other hemoglobinopathies may have special educational or training needs and should ensure that neuropsychological testing is conducted to assist in educational and vocational planning, even in the absence of major clinical manifestations of brain disease. A few cases of peripheral neuropathy with Hb SS have been reported including mental neuropathy related to mandible infarctions.

SUGGESTED READINGS Adams RJ: Neurological complications. p. 599. In Embury SH, Hebbel RP, Narla M, Steinberg MH (eds):Sickle Cell Disease: Scientific Principles and Clinical Practice. Raven Press, New York, 1994 Adams RJ, Brambilla DJ, McKie VC et ak Transfusion prevents first stroke in children with sickle cell disease: the “STOP” study. N Engl J Med 3395-11, 1998 Adams RJ, McKie V, Nichols FT et ak The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 326:605, 1992 Adams RJ, Nichols FT Sickle cell anemia, sickle cell trail and thalassemia. p. 503. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vascular Diseases 111.Vol. 11. Elsevier, Amsterdam, 1989 Frempong K O Stroke in sickle cell disease: demographic, clinical and therapeutic considerations. Semin Hematol 28:213, 1991 Hess DC, Adams RJ, Nichols: Sickle cell anemia and other hemoglobinopathies. Semin Neurol 11:314, 1991 Miller ST, Wright E, Abboud M et ak Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 139:785-789, 2001 Nichols FT, Jones AM, Adams RJ: Stroke Prevention in Sickle Cell Disease

(STOP) study guidelines for transcranial Doppler testing. J Neuroimaging 113354362, 2001 Olopoinia L, Frederick W, Greaves W et a 1 Pneumococcal sepsis and meningitis in adults with sickle cell disease. South Med J 83:1002, 1990

Pavlakis S G Neurologic complications of sickle cell disease. Adv Pediatr 36247, 1989

Pegelow CH, Macklin EA, Moser FG et al: Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood 993014-3018, 2002 Powars ER, Wilson B, Imbus C et al: The natural history of stroke in sickle cell disease. Am J Med 65461, 1978 Prengler M, Pavlakis SG, Prohovnik I, Adams R Sickle cell disease: the neurological complications. Ann Neurol 5 1:543-552, 2002 Rothman SM, Fulling KH, Nelson JS et al: Sickle cell anemia and central nervous system infarction: a neuropathological study. Ann Neurol 20684, 1986

Scothorn DJ, Price C, Schwartz D et ak Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after initial stroke. J Pediatr 140348-354, 2002 Serjeant G R The nervous system. p. 292. In Sickle Cell Disease. 2nd Ed. Oxford University Press, New York, 1992

6

SECTION

ENDOCRINOLOGY AND METABOLISM

197 Neurologic Manifestations of the Porphyrias Melvin Greer The porphyrias are diseases caused by inherited or acquired deficiencies of enzymes in the heme biosynthetic pathway (Table 197-1). They manifest mainly as skin photosensitivity or neurologic abnormalities. The enzyme deficiencies that underlie the eight porphyrias are each expressed predominantly in one of the two major sites of heme synthesis in the body: the liver and the erythropoietic system. This chapter presents four of the five hepatic porphyrias (which are associated with prominent neurologic effects): acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 6-aminolevulinic acid (ALA) dehydratase deficiency porphyria (Doss porphyria). The erythropoietic porphyrias, by contrast, mainly cause skin photosensitivity, which may lead to mutilating skin lesions and hypertrichosis and also may cause anemia and splenomegaly. The rate-limiting step of the heme biosynthetic pathway is the first reaction, which is the synthesis of ALA from succinyl coenzyme A and glycine catalyzed by the enzyme ALA synthase. Induction of this enzyme activates the pathway. Heme production is thought to exert feedback repression on the production of the enzyme, and various drugs and hormones can induce it. If a

porphyria is present, the intermediates downstream from the deficient enzyme tend to accumulate when the pathway is running at high volume, and derivatives of these intermediates are then excreted in the urine or stool. Diagnosis of the porphyrias therefore depends on inducing the pathway and examining the urine and stool for enhanced excretion of one or more of the relevant metabolites. The diagnosis can be confirmed by measuring the specific enzyme deficiency in erythrocytes, fibroblasts, or mitogen-stimulated lymphocytes. Currently the most reliable method is DNA analysis. Patients with these enzyme deficiencies are clinically asymptomatic except when the pathway is strongly induced. The most common cause of disease attacks is administration of barbiturate drugs, although the hormone changes that occur during the menses may also precipitate an acute attack. The pathophysiology of the porphyrias represents not a deficiency in the manufacture of heme but rather the accumulation of heme synthesis intermediates. A mouse porphyria model has been created by gene targeting techniques. A partial disruption of porphobilinogen deaminase,

TABLE197-1. Heme Biosynthetic Pathway and Porphyria Classification CLINICAL

B i o m m c PATHWAY

ENZYME

PORMIA AND INHE~ANCE

INCREASED EXCRETION

PRESEhTAllON

Urine

Stool

Clycine + succinyl-CoA

I I PBC I

ALA synthase

ALA

PBC synthase

Doss porphyria, AR

N

ALA

PBC deaminase

Acute intermittent porphyria, AD

N

AM, PBC

Uroporphyrinogen 111 synthase

Cong. erythropoietic porphyria, AR

S

Uroporphyrinogen decarboxylase

Porphyria cutanea tarda, AD, ACQ

s

Coproporphyrinogen oxidase

Hereditary coproporphyria, AD

N,S

AM, PBG Coproporphyrin

Coproporphyrin

Protoporphyrinogen oxidase

Variegate porphyria, AD

NS

ALA, PBC Coproporphyrin

Coproporphyrin Protoporphyrin

Ferrochelatase

Erythropoietic protoporphyria, AD

S

Uroporphyrin Coproporphyrin

Coproporphyrin

Hydroxymethylbilane

1 Uroporphyrinogen

1

Uroporphyria

Coproporphyrinogen

I Protoporphyrinogen

I Protoporphyrin

.1 Heme

Abbreviations: ACQ acquired; AD autosomal dominant; ALA, Gaminolevulinic acid; AR, autosomal recessive; N, neurologic; PBG, porphobilinogen; S, skin.

1250

Chapter 197

with drug induction, can recapitulate the biochemical changes identified in human disease. Moreover, the neuropathologic features are similar to those noted in patients with porphyria.

ACUTE INTERMllTENT PORPHYRIA Acute intermittent porphyria (AIP), also called Swedish porphyria and intermittent acute porphyria, is the most common of the hepatic porphyrias in the United States. It is caused by a defect in the gene for porphobilinogen deaminase (PGB deaminase), which is located on chromosome region 11 q 24. In classic AIP more than 100 mutations have been described. The incidence of the defective gene is estimated to be about 5 to 10 in 100,000, but in the United States about 90% of the people who carry the genetic defect remain clinically unaffected. The incidence of clinical disease is much higher in Sweden (estimated at 1.5 in 100,000). Women are three times as likely as men to experience clinical disease. PGB deaminase activity is about 50% of normal in people with the genetic defect. Clinical features emerge when such a person is exposed to drugs that strongly induce ALA synthase, resulting in an overproduction of A M and PBG. These drugs include steroids, barbiturates, and some other common lipid-soluble compounds. Chemicals that can induce p-450 hemoproteins may also pose a risk. Severe dieting, infection, alcohol excess, surgery (including dental extraction), and severe stress have also been reported to cause clinical manifestations, and some women experience repeated attacks in relation to menstrual cycles. However, because these factors may not cause a clinical problem in a patient every time they occur, other, unknown circumstances evidently modify the response. In one study of 48 attacks in a series of patients, a specific inciting cause was found for 75% of the attacks, including barbiturate usage in 16 cases and the approach of menstruation in 6 patients. In essence, the signs and symptoms reflect an acute problem of varying severity, with abdominal pain usually the earliest manifestation (Table 197-2). This pain may be severe and colicky, localized or generalized, and may radiate to the back. In one series, abdominal pain occurred in 95% of patients and was the most common component of the acute attack; constipation, nausea, and vomiting were also described about half the time. Accompanying fever and leucocytosis often lead to laparotomy. Stasis and intestinal dilation are observed by radiographic studies. These features are consistent with an abrupt change in splanchnic autonomic nervous system function. Other features of the acute attack that imply a change in autonomic nervous system function include tachycardia (more than 100/bpm) (noted in go%), hypertension (36%), postural hypotension (21 percent), bladder retention (12%), hyperhidrosis (12%), fever (9%), and fecal impaction (6%). In general, the presence and persistence of tachycardia is a useful indicator of the active process. Extremity pain and paresthesias occurred in about 50% of patients. In the more severely impaired patients, involvement of peripheral and cranial nerves was noted that in one series progressed to flaccid quadriparesis in 11 of 35 patients. Weakness reflecting motor nerve dysfunction was proximal or distal, symmetrical or asymmetrical, and even focal. Patchy sensory impairment and dysesthesias were evident when motor deficits were pronounced. Selective truncal sensory deficits have been described. Tendon reflexes were depressed or absent, although they may be normal in the early phase of the neuropathy.

Neurologic Manifestations of the Porphyrias

1251

rn TAM 197-2. Signs and Symptoms of Acute Intermittent Porphyric Attack Sian or Svmptom Abdominal pain Vomiting Constipation Diarrhea Myalgia Weakness Sensory loss Respiratory paralysis Transient blindness Mental changes Convulsions Hypertension Tachycardia Fever

46 of Patients

85-95 43-88 48-84 5-1 2 50-52 42-68 9-38 9-14 4-6 40-58 10-20 36-54 28-80 9-37

From a total of 417 patients described in Waldenstrom J: The porphyrias as inborn errors of metabolism. Am J Med 22:758,1957;Goldberg A: Acute intermittent porphyria: a study of 50 cases. Q J Med 28:183, 1959;and Stein JA, Tschudy DP Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine 49:l. 1970.

During the acute event, the emergence of hyponatremia secondary to gastrointestinal sodium loss, sodium-losing nephropathy, sodium-poor fluid administration, or the syndrome of inappropriate antidiuretic hormone excretion (SIADH) was noted in 40% of patients. Behavioral changes that also may be witnessed in the acute attack include hallucinations, delirium, and altered consciousness. These changes in mentation, as well as seizures, are likely to be related to changes in fluid and electrolyte balance or to profound hypertension reflecting autonomic dysfunction. On the other hand, in one series, hyponatremia was considered the cause of hallucinations and mental confusion in only 3 of 16 patients. Other behavioral changes noted in the acute attack include such features as agitation, restlessness, anxiety, and depression. The relationship of these psychological responses to the accumulation of intermediates of porphyrin metabolism is uncertain. If they are not caused by hypertension or fluid and electrolyte imbalance, they may represent a reactive state based on premorbid psychological factors. It is likewise uncertain whether the emergence of seizures can be accepted as a separate manifestation reflecting a toxic effect of the intermediates of porphyrin metabolism that accumulate in the body. In reports suggesting this phenomenon, the accompanying hypertension and hyponatremia are more likely to be causal. The neurologic features reflect an acute progressive motor neuropathy that may mimic the Guillain-Barre syndrome, ascending from lower to upper extremities and leading to motor cranial nerve impairment. In certain circumstances a selective nerve impairment, usually the radial nerve, may be involved, leading to wrist drop, a feature similar to lead poisoning (in which a disturbance in porphyrin metabolism also occurs). In lead poisoning, increased urinary ALA excretion but normal PBG excretion are noted. Visual disturbances including transient blindness and subsequent optic atrophy have been noted, but here again the relationship to associated hypertension implies an effect on the basis of ischemic vasculopathy rather than a direct toxic process caused by a metabolic change. The duration of the neuropathy is variable. The patient’s weakness may continue to progress even after the abdominal pain improves. The acute attack may last days, or it may progress over a period of weeks to months. In women, an acute attack may occur

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with menses or during pregnancy. In this circumstance, the clinical features may be so severe that pregnancy may have to be terminated. On the other hand, most women with AIP tolerate gestation well. As a rule, the features of a porphyric attack are not seen before puberty or after menopause. Variability in recurrent attacks often is seen in the same patient. Most patients experience an event that is time circumscribed, followed by an asymptomatic state. Infrequently, however, the patient may exhibit a course of smoldering clinical abnormalities with episodes of exacerbation. The patient with severe motor neuropathy usually improves with supportive therapy; however, the duration of the deficit may be years, and incomplete recovery may be noted. In one series of 3867 subjects with chronic psychiatric disorders, 8 were found to have AIP by measurement of appropriate urine and blood tests. These patients, who had chronic problems such as schizoaffective disorders, agitated psychosis, and depression, did not exhibit other features of AIP such as episodic abdominal pain, autonomic dysfunction, or neuropathy. Diagnostic Studies

The diagnosis is made on the basis of increased urinary excretion of ALA and PBG. The appearance of a port wine color of the urine on exposure to sunlight is caused by porphobilin, an oxidation product of PBG, and by other degraded porphyrin compounds. The qualitative Watson-Schwartz or Hoesch tests are the most commonly performed screening diagnostic assays. A positive reaction occurs only when the PBG concentration is three to five times the upper limit of normal. This is indicative of the acute attack. In the latent state the test results often are negative, although variably increased amounts may be excreted by carriers and by patients between attacks. Because of the incidence of false-positive reactions, certain quantitative confirmatory tests performed by column chromatography should be used to measure PBG and ALA. Periodic measurement of these excreted compounds provides a useful determinant of the activity of the porphyric attack; however, no strict correlation exists between the levels of urinary PBG and ALA and the severity of the attack. Porphyrinuria characterized by the detection of coproporphyrinuria and uroporphyrinuria may be present as a result of many disorders. In essence, porphyrinuria does not mean porphyria. Measurement of elevated plasma levels of ALA and PBG occurs only in the acute attack. Increased urinary excretion of porphyrins is noted in lead poisoning and in hereditary tyrosinemia, as well as in other nonspecific infectious, toxic, and metabolic disorders. The selective increase of urinary ALA and PBG establishes the diagnosis of AIP. Confirmation of the diagnosis is based on the detection of a depressed level (about 50%) of reduced PBG deaminase in erythrocytes, fibroblasts, or mitogen-stimulated lymphocytes. This identifies the latent patient as well as the porphyric patient in the acute attack. Erythrocyte PBG deaminase is also decreased in uremia. Stool porphyrin excretion usually is normal in AIP. Other biochemical changes that may be detected include hypercholesterolemia and hyper-P-lipoproteinemia. Abnormalities reflecting a disturbance of the pituitary-hypophyseal axis in the acute attack include SIADH, paradoxical glucose-stimulated growth hormone release, impaired corticotropin release, and increased prolactin release. No cerebrospinal fluid abnormalities exist in the patient with porphyric polyneuropathy. Early in the course, the motor nerve conduction velocity tests and the F-wave responses are normal.

Increase in the minimal-to-maximal latency difference of the nerve impulse is the earliest abnormality detected in the patient with porphyric neuropathy. Normal latency duration and amplitude of orthodromic sensory nerve action potentials are noted. Electromyography (EMG) is also normal early in the course; however, with maximal effort only a few motor unit potentials are recruited. With progressive weakness over time, nerve stimulation induces motor nerve conduction potentials with reduced amplitude. Orthodromic sensory nerve stimulation is likewise reduced in amplitude, but sensory conduction velocities and minimal latency are unchanged. Fibrillations and positive sharp waves are then noted by EMG. These findings are consistent with an axonal neuropathy: decreased amplitude of compound nerve and muscle action potentials and normal conduction velocity, fibrillation, and sharp waves. Brain magnetic resonance imaging changes and electromyographic abnormalities have been described in patients having acute attacks in which changes in mentation and seizures exist. Concomitant hypertension and fluid and electrolyte abnormalities are likely interpretations for these changes. These abnormalities revert to normal after the attack subsides unless complications ensue such as central pontine myelinolysis attributed to rapid correction of hyponatremia. Pathology and Pathogenesis

Axonal changes are observed in the biopsied peripheral nerve as the primary area of change. Secondary features of peripheral nerve demyelination have also been described in patients whose neuropathic course was prolonged. In addition, at autopsy, anterior horn cell chromatolysis and vacuolation have been described. Splanchnic motor cells of the lateral horns, medullary nuclei, and dorsal vagal nuclei have also shown chromatolytic change. In the central nervous system, nonspecific neuronal changes, focal reactive glial changes, and perivascular demyelination have been described. With respect to the hormonal changes noted such as SIADH, the selective neuronal involvement of the supraoptic and paraventricular nuclei in the hypothalamus is of specific interest. Although certain of the central nervous system changes may be attributable to the effects of acute hypertension and the often dramatic alteration in fluid balance, the selective hypothalamic change and the more common neuropathy imply a metabolic or toxic process. Nevertheless, no convincing evidence has indicated a causal relationship between a deficiency of heme or heme products an excess of porphyrin intermediates, which may induce a toxic effect or inhibition of neurotransmitter function. Treatment

Preventive treatment for the porphyric patient is to emphasize the avoidance of inducing factors, including drug ingestion and dietary indiscretion. The patient should be made aware of drugs considered safe (Table 197-3). Prompt treatment of infections and elimination of alcohol are also urged. In women who experience an acute attack perimenstrually, ovulatory suppressant hormones may reduce the frequency and severity of the episodes. On the other hand, caution is needed with respect to the use of the steroid hormones, which may themselves induce an attack. Daily intranasal or subcutaneous luteinizing hormone treatment has been used with some success. During the early phase of the attack, increased carbohydrate consumption may abort the event. If the signs and symptoms increase, intravenous 10% dextrose in water or other sugars that can be metabolized to glucose are indicated. A level as high as

Chapter 197 rn Neurologic Manifestations of the Porphyrias

TAW 197-3. Drugs Probably Safe for Patients with Porphyria Antibiotics Penicillin Streptomycin Tetracycline Nitrofurantoin (?) Mandelamine Chloramphenicol (?) Analgesics and narcotics Acetaminophen Aspirin Codeine Morphine Anticonvulsants Paraldehyde Magnesium sulfate Bromides Diazepam (?) Cabapentin Autonomic nervous system Atropine Propranolol Cuanethidine (?) Labetalol (?) Lactulose Neostigmine Psychotropic drugs Chloral hydrate Phenothiazines Amitriptyline Droperidol Others Insulin Adrenocorticosteroids Succinylcholine Ether

500 g/day is recommended. Precautions are necessary in giving large fluid volumes intravenously: The risk of SIADH and hypertension may be enhanced. Symptomatic treatment for pain with narcotics such as codeine and meperidine and the use of phenothiazines for agitation, hallucination, nausea, and vomiting are appropriate as well. Other drugs including chloral hydrate and diazepam may be offered for insomnia. Both the tachycardia and hypertension may be effectively treated with P-adrenergic blocking agents such as propranolol. The abdominal distress may also be benefited by this approach. If seizures occur, gabapentin, magnesium sulfate, paraldehyde, and diazepam are recommended. Hematin drugs such as heme arginase given intravenously at the dosage level of 3 to 4 mg/kg/24 hours for 4 days appear to be effective in reducing the duration of the acute attack. The drug's beneficial effect is presumably related to a repression of ALA synthase activity. Its use is accompanied by a more rapid fall of urinary PBG. It must be given slowly over at least a 15-minute period, but a heightened risk of thrombophlebitis still exists. Other risks include coagulopathy and hemolysis. Treatment for SIADH with fluid restriction is of primary concern for patients with progressive evidence of encephalopathy and seizures. This need for fluid and electrolyte control should supersede treatment with other intravenous therapies in which large fluid volumes are necessary.

VARIEGATE PORPHYRIA (SOUTH AFRICAN PORPHYRIA, PROTOCOPROPORPHYRIA) Both photosensitivity and features of neurologic involvement characterize variegate porphyria, heterozygous autosomal dominant hepatic porphyria. As in AIP, an overproduction of porphyrin

I253

metabolites exists after induction of ALA synthase. The enzyme deficiency is protoporphyrinogen oxidase. In the disease state there is excess urinary excretion of ALA, PBG, and coproporphyrin and protoporphyrin in the stool. This condition is most commonly observed in South Africa, where the incidence is 3 in 1000.Elsewhere, it is less common than AIP. Moreover, the features of photosensitivity, not evident in AIP, often exist in the absence of neurovisceral symptoms. Skin lesions on exposed surfaces manifest as bullous eruptions and skin fragility. In time, hyperpigmented areas and hypertrichosis are observed as permanent residua. Inducing factors including drugs, alcohol, and diets deficient in carbohydrates are known to cause the neurovisceral symptoms in a manner similar to AIP; however, the clinical features usually are not as severe. Rarely seen are patients in whom more than one enzyme deficiency exists. In other words, clusters of families exist in which variegate porphyria and AIP enzyme deficiency have been described in the same person. Also, a homozygous form of variegate porphyria with onset in childhood has been identified. This is characterized by severe photosensitivity, growth restriction, and profound psychomotor retardation. As with AIP, elevated urine porphyrin excretion may be measured; during an acute attack, however, in contrast to AIP, in which fecal excretion is not increased, in variegate porphyria marked fecal porphyrin excretion is noted. The treatment approach, both prophylactically and for the acute attack, is similar to that recommended for AIP.

HEREDITARY COPROPORPHYRIA Clinical features associated with hereditary coproporphyria are secondary to a heterozygous deficiency of coproporphyrinogen oxidase. This rare disorder is inherited in an autosomal dominant manner. The neurologic signs and symptoms usually are milder than those seen in AIP. Photosensitivity may be noted. In the very rare homozygous enzyme-deficient states, the clinical features are more severe. Abdominal pain, vomiting, and constipation are the hallmarks of the acute attack, which is induced particularly by drugs, as in other hepatic porphyrias; as in the other forms, recurrent attacks may also occur in menstruation. Neuropathy and psychiatric features may also be evident, although in such patients with hereditary coproporphyria neuropathy the signs and symptoms usually are not as severe as in AIP. In about 30% of patients skin photosensitivity exists, and in some patients evidence of recurrent liver impairment has been noted with the attacks. This resolves after the attack subsides. In the rarer homozygous form that may be seen in childhood, hepatosplenomegaly, hemolytic anemia, and evidence of liver dysfunction are noted. Urine hyperexcretion of ALA, PBG, and coproporphyrin and increased fecal excretion of coproporphyrin are noted in the acute attack. The diagnosis is confirmed by measurement of the enzyme deficiency. Treatment of the acute attack and prophylactic management are identical to that of patients with AIP.

ALA DEHYDRATASE DEFICIENCY PORPHYRIA (DOSS) ALA dehydratase deficiency porphyria, a very rare autosomal recessive disorder, is caused by a homozygous deficiency in ALA dehydratase. In an acute attack, neurologic signs and symptoms are similar to those described in the patient with AIP, in whom abdominal pain, extremity pain, and a mixed motor and sensory polyneuropathy occur. Inducing factors such as drugs, alcohol ingestion, and decreased food intake are causal.

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Increased urinary excretion of ALA but not PBG as well (as in AIP) in noted. The treatment approach for the acute attacks and prophylaxis are similar to those used in AIP. Liver transplantation was performed in a child who had significant neurologic deficits from recurrent attacks of neuropathy. This did not affect the excess urinary excretion of porphyrin intermediates; however, fewer attacks occurred after the transplant.

SUGGESTED READINGS Black KS, Mirsky P, Kalina P et al: Angiographic demonstration of reversible cerebral vasospasm in porphyric encephalopathy. AJNR 161650, 1995

Bourgeois F, Gu XF, Deybach JC et al: Denaturing gradient gel electrophoresis for rapid detection of latent carriers of a subtype of acute intermittent porphyria with normal erythrocyte porphobilinogen deaminase activity. Clin Chem 38:93, 1992 Bylesjo I, Forsgren L, Lithner F et al: Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria. Epilepsia 37:230, 1996 Crimlisk HL The little imitator-porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry 62:319, 1997 Goldberg A Acute intermittent porphyria: a study of 50 cases. Q J Med 28:183, 1959

Greer M: Neurologic manifestations of the porphyrias. p. 1029. In Samuels MA, Feske S (eds): Office Practice of Neurology. Churchill Livingstone, New York, 1996 Greer M Neuropathy of porphyria. p. 117. In de Jong JMBV (ed): Handbook of Clinical Neurology. Vol. 60. American Elsevier, New York, 1991

Greer M: Porphyria. p. 429. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol. 27. American Elsevier, New York, 1976 Gross U, Hoffmann GF, Doss MO: Erythropoietic and hepatic porphyrias. J Inherit Metab Dis 23:641, 2000 Herrick AL, Moore, MR, McColl KEL et al: Controlled trial of haem arginate in acute hepatic porphyria. Lancet 1:1295, 1989 Kappas A, Sassa S, Galbraith RA et al: The porphyrias. p. 1305. In Scriver CR, Beaudet AL, Sly WS et a1 (eds): The Metabolic Basis of Inherited Disease. Vol. 1. McGraw-Hill, New York, 1989 King PH, Bragdon AC MRI reveals multiple reversible cerebral lesions in an attack of acute intermittent porphyria. Neurology 41:1300, 1991 Lindberg RLP, Martini R, Baumgartner M et ak Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria. J Clin Invest 103:1127, 1999 Meyer UA, Schuurmans M, Lindberg RL et ak Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 18:43, 1998 Muley SA, Midani HA, Rank JM et ak Neuropathy in erythropoietic protoporphyrias. Neurology 51:262, 1998 Stein JA, Tschudy DP: Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine 49:1, 1970 Suarez JI, Cohen ML, Larkin, J et al: Acute intermittent porphyria: clinicopathologic correlation. Neurology 48:1678, 1997 Thunell S, Henrichson A, Floderus YI: Liver transplantation in a boy with acute porphyria. Eur J Clin Chem Clin Biochem 30599, 1992 Tishler PV, Woodward B, OConnor J et ak High prevalence of intermittent acute porphyria in a psychiatric patient population. Am J Psychiatry 142:1430, 1985 Waldenstrom J: The porphyrias as inborn errors of metabolism. Am J Med 22:758, 1957

198 Lysosomal Storage Diseases Edwin H. Kolodny The lysosomal storage diseases are a clinically heterogenous group of inherited diseases, at least 50 in all, with a combined incidence of approximately one in 7000 births (Table 198-1). They present with protean manifestations, including significant involvement of the central and peripheral nervous systems. They are a challenge to the physician because signs and symptoms of these disorders may lack specificity, and their clinical appearance may occur at almost any age. Prompt diagnosis greatly facilitates proper management, including, in certain instances, the initiation of treatments that may halt disease progression. In the case of a young patient, early diagnosis also gives the child’s family the option of prenatal diagnosis of future pregnancies.

LYSOSOMAL METABOLISM Lysosomes are sedimentable organelles present in the cytoplasm of all cells. They contain more than 50 hydrolytic enzymes capable of degrading both natural products of cellular metabolism and foreign materials ingested by the cell. They are vacuolar in appearance, with a single limiting membrane that protects the cell from the potentially harmful effects of the degradative enzymes within it. In 1955, C. DeDuve coined the term Zysosorne and first proposed its role in intracellular digestion. An endocytic vacuole containing either intracellular debris or foreign material of

extracellular origin coalesces with a primary lysosome to form a secondary lysosome. The acidified environment of the secondary lysosome provides a n optimal milieu for the degradative action of its hydrolytic enzymes. Any remaining undigested material is secreted from the cell in the form of a residual body to enter the urine, bile, or other excretory pathway. Lysosomal enzymes are capable of catalyzing irreversibly the hydrolysis of lipids, carbohydrates, proteins, and nucleotides to their basic structural units. They are glycoproteins, which are first synthesized as preproproteins on membrane-bound ribosomes attached to the rough endoplasmic reticulum. To reach their destination in lysosomes, they must undergo a series of posttranslational modifications that involve protein and carbohydrate recognition signals. First, an amino terminal signal peptide is attached to the nascent protein, directing it into the lumen of the rough endoplasmic reticulum. A large preformed oligosaccharide is then transferred to the enzyme polypeptide by attachment to selected asparagine residues. The signal peptide is then cleaved and the asparagine-linked oligosaccharide partially degraded. The maturing lysosomal protein then enters the Golgi apparatus, where it is acted o n by a phosphotransferase that transfers N-acetylglucosamine- 1-phosphate from uridine diphosphate-Nacetylglucosamine to mannose residues on the lysosomal enzyme. Subsequently, the N-acetylglucosamine residue is removed with the formation of mannose-6-phosphate (Man-6-P). This phos-

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Increased urinary excretion of ALA but not PBG as well (as in AIP) in noted. The treatment approach for the acute attacks and prophylaxis are similar to those used in AIP. Liver transplantation was performed in a child who had significant neurologic deficits from recurrent attacks of neuropathy. This did not affect the excess urinary excretion of porphyrin intermediates; however, fewer attacks occurred after the transplant.

SUGGESTED READINGS Black KS, Mirsky P, Kalina P et al: Angiographic demonstration of reversible cerebral vasospasm in porphyric encephalopathy. AJNR 161650, 1995

Bourgeois F, Gu XF, Deybach JC et al: Denaturing gradient gel electrophoresis for rapid detection of latent carriers of a subtype of acute intermittent porphyria with normal erythrocyte porphobilinogen deaminase activity. Clin Chem 38:93, 1992 Bylesjo I, Forsgren L, Lithner F et al: Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria. Epilepsia 37:230, 1996 Crimlisk HL The little imitator-porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry 62:319, 1997 Goldberg A Acute intermittent porphyria: a study of 50 cases. Q J Med 28:183, 1959

Greer M: Neurologic manifestations of the porphyrias. p. 1029. In Samuels MA, Feske S (eds): Office Practice of Neurology. Churchill Livingstone, New York, 1996 Greer M Neuropathy of porphyria. p. 117. In de Jong JMBV (ed): Handbook of Clinical Neurology. Vol. 60. American Elsevier, New York, 1991

Greer M: Porphyria. p. 429. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol. 27. American Elsevier, New York, 1976 Gross U, Hoffmann GF, Doss MO: Erythropoietic and hepatic porphyrias. J Inherit Metab Dis 23:641, 2000 Herrick AL, Moore, MR, McColl KEL et al: Controlled trial of haem arginate in acute hepatic porphyria. Lancet 1:1295, 1989 Kappas A, Sassa S, Galbraith RA et al: The porphyrias. p. 1305. In Scriver CR, Beaudet AL, Sly WS et a1 (eds): The Metabolic Basis of Inherited Disease. Vol. 1. McGraw-Hill, New York, 1989 King PH, Bragdon AC MRI reveals multiple reversible cerebral lesions in an attack of acute intermittent porphyria. Neurology 41:1300, 1991 Lindberg RLP, Martini R, Baumgartner M et ak Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria. J Clin Invest 103:1127, 1999 Meyer UA, Schuurmans M, Lindberg RL et ak Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 18:43, 1998 Muley SA, Midani HA, Rank JM et ak Neuropathy in erythropoietic protoporphyrias. Neurology 51:262, 1998 Stein JA, Tschudy DP: Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine 49:1, 1970 Suarez JI, Cohen ML, Larkin, J et al: Acute intermittent porphyria: clinicopathologic correlation. Neurology 48:1678, 1997 Thunell S, Henrichson A, Floderus YI: Liver transplantation in a boy with acute porphyria. Eur J Clin Chem Clin Biochem 30599, 1992 Tishler PV, Woodward B, OConnor J et ak High prevalence of intermittent acute porphyria in a psychiatric patient population. Am J Psychiatry 142:1430, 1985 Waldenstrom J: The porphyrias as inborn errors of metabolism. Am J Med 22:758, 1957

198 Lysosomal Storage Diseases Edwin H. Kolodny The lysosomal storage diseases are a clinically heterogenous group of inherited diseases, at least 50 in all, with a combined incidence of approximately one in 7000 births (Table 198-1). They present with protean manifestations, including significant involvement of the central and peripheral nervous systems. They are a challenge to the physician because signs and symptoms of these disorders may lack specificity, and their clinical appearance may occur at almost any age. Prompt diagnosis greatly facilitates proper management, including, in certain instances, the initiation of treatments that may halt disease progression. In the case of a young patient, early diagnosis also gives the child’s family the option of prenatal diagnosis of future pregnancies.

LYSOSOMAL METABOLISM Lysosomes are sedimentable organelles present in the cytoplasm of all cells. They contain more than 50 hydrolytic enzymes capable of degrading both natural products of cellular metabolism and foreign materials ingested by the cell. They are vacuolar in appearance, with a single limiting membrane that protects the cell from the potentially harmful effects of the degradative enzymes within it. In 1955, C. DeDuve coined the term Zysosorne and first proposed its role in intracellular digestion. An endocytic vacuole containing either intracellular debris or foreign material of

extracellular origin coalesces with a primary lysosome to form a secondary lysosome. The acidified environment of the secondary lysosome provides a n optimal milieu for the degradative action of its hydrolytic enzymes. Any remaining undigested material is secreted from the cell in the form of a residual body to enter the urine, bile, or other excretory pathway. Lysosomal enzymes are capable of catalyzing irreversibly the hydrolysis of lipids, carbohydrates, proteins, and nucleotides to their basic structural units. They are glycoproteins, which are first synthesized as preproproteins on membrane-bound ribosomes attached to the rough endoplasmic reticulum. To reach their destination in lysosomes, they must undergo a series of posttranslational modifications that involve protein and carbohydrate recognition signals. First, an amino terminal signal peptide is attached to the nascent protein, directing it into the lumen of the rough endoplasmic reticulum. A large preformed oligosaccharide is then transferred to the enzyme polypeptide by attachment to selected asparagine residues. The signal peptide is then cleaved and the asparagine-linked oligosaccharide partially degraded. The maturing lysosomal protein then enters the Golgi apparatus, where it is acted o n by a phosphotransferase that transfers N-acetylglucosamine- 1-phosphate from uridine diphosphate-Nacetylglucosamine to mannose residues on the lysosomal enzyme. Subsequently, the N-acetylglucosamine residue is removed with the formation of mannose-6-phosphate (Man-6-P). This phos-

Chapter 198

Lysosornal Storage Diseases

1255

TABLE198-1. Lysosomal Storage Diseases Disorder

Stored Substance

Primary Defiaency

Enzyme Substrate

Gene location

Fabty's disease

Ceramide trihexoside

a-Galactosidase A

xq22

Farber's disease

Ceramide

Cerarnidase

Gaucher's disease

Glucosylceramide, glycopeptides G,, -ganglioside, galactosyl oligosaccharides, keratan sulfate

Glucocerebrosidase

4-MU-a-galactopyranoside + N-acetylgalactosarnine N-[1-l4C]lauroylsphingosine ["c] cerebroside sulfate 4-MU-P-glucopyranoside

P-Galactosidase

4-MU-P-galactopyranoside

3~21.33

C,,-ganglioside

P-N-Acetylhexosaminidase a-subunit

4-MU-P-N-acetylglucosaminide 4-MU-P-Nacetylglucosaminide sulfate 4-MU-P-N-acetylglucosaminide

15q23-24 5q13

G,,-ganglioside Galactosylceramide

5q32-33 14q31

Sphingolipidoses

G, -Gangliosidosis G,,-Gangliosidosis Tay-Sachs disease Sandhoffs disease Activator deficiency Krabbe's disease (globoid cell leukodystrophy) Metachrornatic leukodystrophy Niernann-Pick disease Types A and B Type c Schindler's disease

8p22-21.2 lq21

G,,-ganglioside, oligosaccharides, glycosaminoglycans G,,-ganglioside Galactosylcerarnide Galactosylsphingosine Galactosylsulfatide Lactosylsulfatide

P-NAcetylhexosaminidase P-subunit ,C , activator Calactocerebrosidase Arylsulfatase A (sulfatidase), sulfatide activator (saposin 6)

p-Nitrocatecholsulfate, sulfatide

22q 13.3 1-qter 1Oq21 (activator)

Sphingornyelin, cholesterol Unesterified cholesterol, bisrnonoacylglycerophosphate a-N-Acetylgalactosaminyl oligosaccharides and glycopeptides

Sphingomyelinase Cholesterol esterification

Sphingornyelin Filipin staining LDL-cholesterol

1 1~15.1-15.4 1Bqll-12; 14q24.3

a-N-Acetylgalactosaminidase (a-galactosidase 6)

pNP-a-Gal NAC 4-MU-a-Gal NAC

22q13.1-13.2

Palmitoyl protein thioesterase 1

Electron microscopy

1q32

Tripeptidyl peptidase 1

Electron microscopy

llp15

CLN3 protein

Electron microscopy

16~12.1

CLNS protein CLN6 protein CLN8 protein Unknown

Electron microscopy Electron microscopy Electron microscopy Electron microscopy

13q22 15q21-23 8p23

Neuronal Ceroid-lipofuscinoses

CLNl (infantile form) CLN2 (late infantile form) CLN3 (juvenile form)

CLNS CLN6 CLN8 Adult form (Kufs's disease)

Granular osrniophilic deposits Curvilinear bodies, subunit C of mitochondria1ATP sy nthase Curvilinear and laminated (fingerprint) bodies, subunit C of mitochondria1 ATP synthase

Mixed type, osrniophilic deposits and lamellar inclusions

Mucopolysaccharidoses

Derrnatan

+ heparan sulfate

a-lduronidase

4-MU-a-L-lduronide

4pl6.3

Derrnatan

+ heparan sulfate

lduronate sulfatase

4-MU-a-lduronide 2 sulphate

Xq27.3-28

Heparan sulfate

Heparan N-sulfamidase

17q25.3

Type B

Heparan sulfate

a-N-Acetylglucosaminidase

17q21.1

Type c

Heparan sulfate

Type D

Heparan sulfate

Acetyl CoA: a-glucosarninide acetykranserase N-Acetyl-a-glucosarnine-6sulfatase

4-MU-a-D-Nsulphoglucosarninide 4-MU-a-M-acetyl-a-Dglucosarninide 4-MU-P-D-glucosaminide 4-MU-a-N-acetylglucosamine6-sulphate

12q14

Hurler's, Hurler-Scheie, Scheie's diseases (MPS-I) Hunter's disease (MPS-II) Sanfilippo's disease (MPS-Ill) Type A

Morquio syndrome (MPS IV) Type A Type B Maroteaux-Lamy syndrome (MPS Vl) Sly disease (MPS VII) Multiple sulfatase deficiency Hyaluronidase deficiency (MPS IX)

Keratan sulfate Chondroitin-6-sulfate Keratin sulfate Dermatan sulfate Derrnatan and heparan sulfate, chondroitin-4-6sulfates Sulfated lipids, rnucopolysaccharides Hyaluronan

Galactosamine-6-sulfatase

P-Calactosidase N-Acetylgalactosamine 4-sulfatase (arylsulfatase 6) P-Clucuronidase Arylsulfatases A, B, C, fatases Hyaluronidase

+ other sul-

16q24.3

4-MU-P-galactopyranoside p-Nitrocatecholsulfate

3p2 1.33 5q13-14

4-MU-~-glucuronide

7q21.11

p-Nitrocatecholsulfate 3p21.3 Table continued on followng page

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TABLE198-1. Lysosomal Storage Diseases Continued Disorder

Stored Substance

Primaw Deficiency

Enzyme Substrate

Gene location

Glycoproteinoses Aspartylglucosaminuria

Aspartylglucosarnine

Aspartylglucosaminidase

4q34-35

Fucosidosis Galactosialidosis

Fucosyloligosaccharides Sialyloligosaccharides Calactosyloligosaccharides

a-Mannosidosis P-Mannosidase

a-Mannosyl-oligosaccharides P-Mannosyl-oligosaccharides

a-L-Fucosidase Protective protein (pgalactosidsase and a-neuraminidase) a-Mannosidase B-Mannosidase

1-Aspartarnido-P-Nacetylglucosamine 4-MU-a-L-fucopyranoside 4-MU-P-galactopyranoside 4-MU-a-D-Nacetylneuraminic acid 4-MU-a-mannopyranoside 4-MU-P-D-rnannopyranoside

Mucolipidoses Sialidosis (mucolipidosis 1) Mucolipidosis II (I-cell disease)

Sialyloligosaccharides Sialylglycopeptides Clycolipids, glycoproteins, sialyloligo-saccharides

4-MU-a-D-N-acetylneuraminic acid UDP-N-acetylglucosamine a-methyl-mannose

6p21.3

Same as above

4q21-23

Mucolipidosis 111 (pseudoHurler polydystrophy) Mucolipidosis IV Other Lysosomal Diseases Acid lipase deficiency Wolman’s disease Cholesterol ester storage disease Cystinosis Danon’s disease Glycogenosis type II (Pompe’s disease) Pycnodysostosis Sialic acid storage disease Infantile form Salla disease

Sialyloligosaccharides,glycoproteins, glycolipids Gangliosides, phospholipids, rnucopolysaccharides

a-Neuraminidase UDP-N-Acetylglucosamine: lysosoma1 enzyme N-acetylglucosarnine-lphosphotransferase Same phosphotransferaseas above Mucolipin 1

+

G,,-ganglioside

turnover

1p34.1-36.1 20q 12- 13.1

19p13.2-12 4q22-25

4q2 1-23

19~13.2-13.3

Cholesterol esters, triglycerides Cholesterol esters, triglycerides Free qstine Glycogen and cytoplasmic debris Glycogen

Acid lipase

4-MU-oleate; cholesteryl oleate

1Oq23.2-23.3

Acid lipase

4-MU-oleate; cholesterol oleate

1Oq23.2-23.3

a-Glucosidase (acid maltase)

4-MU-a-D-glucopyranoside

17q23

Collagen, osteonectin

Cathepsin K

Specific dipeptides

lq2l

Free sialic acid Free sialic acid

Sialin Sialin

Cystosin LAMP-2

phomonoester serves as a recognition marker, directing the nascent enzyme to a prelysosomal endocytic compartment. Two recently described proteins, AP-1 and GGA, facilitate this process in the trans-Golgi network. AP-1 is involved in assembling clathrin-coated vesicles. Delivery of the enzyme-receptor complex into these newly formed endosomes is assisted by GGA connector proteins. The low pH in the endosome facilitates uncoupling of the Man-6-P receptor from its ligand and the receptor recycles back to the trans-Golgi apparatus. Further proteolytic modification and partial dephosphorylation of the enzyme proform occur before the mature acid hydrolase enters the lysosome. Not all the acid hydrolase proforms pass directly to lysosomes. Some are glycosylated with high-mannose-type oligosaccharide, are further processed to complex type units containing galactose and sialic acid residues, and leave the trans-Golgi apparatus as secretory glycoproteins. Also, a fraction of the enzyme containing the Man-6-P recognition marker may leave the cell. These molecules are capable of subsequent recapture by binding to Man-6-P receptors on the cell surface. As a practical matter, the Man-6-P recognition system is of immense importance to the clinician, providing a rational basis for enzyme replacement therapy in the lysosomal storage diseases. There is evidence also of other mechanisms not involving Man-6-P receptors for delivery of acid hydrolases to the lysosome. Some of this comes from the study of mucolipidosis I1 (I-cell disease) fibroblasts, which lack the ability to form the Man-6-P recognition marker. One class of lysosomal membrane proteins contributes to the special properties of the lysosomal membrane, that is, maintenance of an acidic pH environment, sequestration of acid hydrolases, resistance to degradation by lysosomal enzymes, and the ability to fuse with other membrane organelles. Transport of

17~13 Xq24-25

6q14-15 6a 14-1 5

these glycoproteins to the lysosome depends not on the attached N-glycans but on the character of the cytoplasmic tail in which a tyrosine residue is essential. Lysosomal acid phosphatase is one example of such Man-6-P-independent targeting. PATHOPHYSIOLOGY The concept of an inborn disease of lysosomal enzyme metabolism was first proposed by Hers in 1965 based on his studies of type I1 glycogen storage disease (Pompe’s disease). In this disorder, the deficiency of a specific lysosomal enzyme (acid a-glucosidase) results in the accumulation of its particular substrate (glycogen)in membrane-bound vesicles of lysosomal origin. As increasing amounts of the nonmetabolizable substrate accumulate in lysosomes, they hypertrophy, producing mechanical crowding in the cell, which in turn interferes with its normal functions and may eventually cause cell death. The signs and symptoms of each inborn error of lysosomal metabolism vary according to the pattern of distribution of the nondegradable natural products and their usual rate of metabolic turnover in each tissue. In the classic infantile form of glycogenosis type 11, glycogen is concentrated in heart and skeletal muscle, in the liver, and in cortical and spinal cord neurons. Consequently, the affected child has extreme cardiomegaly, moderate hepatomegaly, and generalized hypotonia. Light microscopy of fresh frozen or ethanol-fixed paraffin-embedded sections of muscle demonstrate periodic acid-Schiff-positive cytoplasmic granules, which disappear when the tissue is preincubated with diastase, an enzyme that digests glycogen. The concentration of certain types of macromolecules such as GMl- and G,,-gangliosides and the galactolipids, galactocerebroside and sulfatide, normally is much higher in the

Chapter 198

central nervous system than in other tissues. Therefore, in diseases in which the hydrolysis of these compounds is defective, the signs and symptoms are almost exclusively confined to the nervous system, whereas in enzyme deficiencies affecting more widely distributed natural products such as glycoproteins and mucopolysaccharides, a variety of different organ systems, both neural and non-neural, are affected. However, in nearly all lysosomal storage diseases there is a tendency for the nervous system to be preferentially affected. This is because the cells of visceral organ systems besieged by lysosomal hypertrophy are capable of replacing themselves, but neurons destroyed by lysosomal overcrowding are not renewable. Therefore, one might encounter a patient with marked hepatosplenomegaly with only minimal disturbance of hematologic parameters or of liver enzymes, yet even mild neuronal storage produces marked psychomotor delay and mental retardation. Morphologic and histochemical studies alert the diagnostician not only to the presence of a lysosomal storage disease but often to one particular class or form of lysosomal disease. Electron microscopic analysis of readily available tissues such as white blood cells or skin may disclose the presence of increased numbers and size of intracytoplasmic vacuoles, alerting the clinician to the possibility of a lysosomal storage disease. The character of the inclusions may then permit further refinements in diagnosis. For example, alternating dark and light lines arranged in a circular lamellated pattern are a distinctive feature of the membranous cytoplasmic body characteristic of the neuronal inclusions in Tay-Sachs disease (late-infantile G,,-gangliosidosis). Such bodies also are present in axons of dermal nerves in later-onset forms of GM2-gangliosidosisas well. The presence of this same type of inclusion in cell types other than neurons or their axons is highly suggestive of mucolipidosis IV. Parallel lamellar arrays in the form of zebra bodies are a distinguishing feature of the mucopolysaccharidoses.This type of inclusion may be found in several cell types, including muscle and connective tissues. Homogeneous dense bodies and membranovesicular and fingerprint-like inclusions are highly suggestive of the neuronal ceroid lipofuscinoses. Large empty vacuoles or vacuoles with a finely granular appearance suggest a glycoprotein storage disorder such as fucosidosis, mannosidosis, or sialic acid storage disease. These may occasionally occur alongside other vacuoles containing laminated membrane structures and electron-dense bodies, suggesting the presence of different types of nondegradable compounds. In certain forms of lysosomal storage disease with prominent involvement of the reticuloendothelial system, the bone marrow can be a source of distinctive cell types. Foam cells, enlarged histiocytes containing lipid droplets that impart a mulberry- or honeycomb-like appearance to the cell, are found in NiemannPick disease, G,,-gangliosidosis, the Sandhoff variant of GMzgangliosidosis, sialidosis, mucolipidoses I1 and 111, fucosidosis, a-mannosidosis, and Wolman’s disease. Sea-blue histiocytes, revealing a blue or blue-green color with Giemsa and Wright stains, often indicate Niemann-Pick disease type C. Another distinctive cell, the Gaucher cell, is similar in size to the foam cell but contains rod-shaped inclusions, imparting a wrinkled tissue paper or crumpled silk appearance to the cell. Bone marrow smears may also reveal Alder-Reilly bodies, characteristic of Hurler’s disease and multiple sulfatase deficiency. GENETICS

Elucidation of the biochemical defect in many of the lysosomal storage diseases has followed a similar sequence. First, the nature

Lysosomal Storage Diseases

1257

of the accumulating material was discovered. Because lysosomal enzymes are exohydrolases, that is, they cleave the terminally linked moiety from the nonreducing end of a complex lipid or carbohydrate, the chemical composition and structure of the stored substance provided a clue as to the nature of the defective enzyme. The enzyme was purified from normal tissues and subsequently shown to be deficient in activity in the tissues of the affected patient. The third step has been cloning of the gene coding for the enzyme or relevant enzyme subunit. In most cases, this was simplified by the availability of amino acid sequence for the protein product of the gene. In a few instances, however, such as Niemann-Pick disease type C and mucolipidosis W,the search for the defective protein began with mapping of the gene, then analysis of candidate genes for mutations and finally translation of the gene product to characterize its function. With certain exceptions, the inheritance of each lysosomal disease follows an autosomal recessive pattern. Equal numbers of males and females are affected, parental consanguinity often is present, and the recurrence risk in a family is 25% for each subsequent pregnancy. Vertical transmission is rare except in the case of a gene occurring with high frequency in a population subgroup, as found in the case of the Gaucher’s disease trait among Ashkenazi Jews. Therefore, it is unlikely for a lysosomal disease to occur in a family with a history of the disease in another branch of the family. Exceptions include Hunter’s and Fabry’s diseases, which are X-linked. Hunter’s disease presents as the full-blown disease in males only, whereas in the female with Fabry’s disease symptoms occur but are milder and develop later in life than in hemizygous males. Inheritance of these disorders would be through the carrier female, that is, the mother, so an affected maternal uncle might be expected. The genes involved in the pathogenesis of most lysosomal diseases have been mapped and cloned and mutations in their genomic DNA structure identified. The chromosomal map positions of these genes are shown in Table 198-1. The table also lists the substrates in common use for in vitro determination of the lysosomal enzyme activity known to be deficient in each disease. Many biochemists prefer the fluorigenic 4-methylumbelliferyl derivatives. These artificial substrates contain the specific linkage targeted by the enzyme, although the lysosomal enzymes appear not to discriminate very critically with respect to the aglycan portion of the molecule. Before cleavage, the molecule is nonfluorigenic, but after its hydrolysis, free 4-methylumbelliferyl appears. This highly fluorigenic substance provides a high degree of sensitivity to the analysis of specific enzymes without the need to use radiolabeled natural products as substrates. However, for certain enzyme determinations, the natural product is still needed, so such determinations can be done only in the few laboratories that have access to these compounds. Enzyme analyses using plasma or leukocytes are the most common method for arriving at a specific diagnosis, but several important exceptions must be noted. When the deficiency is of a protein activator, artificial substrate assays may not show any abnormality. Rare cases of G,,-gangliosidosis and metachromatic leukodystrophy are in this category. Also, certain lysosomal diseases do not have a known enzyme deficiency. If the sequence of the defective gene has been described, then DNA mutation analysis is undertaken. This is best done using cDNA, but occasionally the gene defect is within intronic material, necessitating the use of genomic DNA. An international directory of genetic testing laboratories is available through the Geneclinics Web site (www. genec1inics.org). Its database can be searched by individual disease. Carriers of the trait for a particular lysosomal disease demonstrate low levels of activity of the relevant enzyme, but overlap

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with normal noncarrier values sometimes occurs so that enzyme determination is not an entirely dependable method for heterozygote identification. This problem can be circumvented when DNA from the affected family member is analyzed for the mutations on both alleles. If these are known, then they can be sought in close relatives using DNA probes specific for the family mutations. In the search for carriers, a few healthy individuals may be found who have very low enzyme values, suggesting that they are affected. These people may be presymptomatic, or they may be carrying a pseudodeficiency allele, which is not disease-associated. This occurs commonly in tests of arylsulfatase A for metachromatic leukodystrophy. ONSET AND PROGRESSION The lysosomal storage diseases are inborn errors of metabolism, so that the person affected with one of these diseases carries evidence of the disorder from the time of conception. Histologic signs of lipid accumulation have been found in spinal cord neurons of fetuses with the GMl- and G,,-gangliosidoses as early as 20 weeks of gestation. Similarly, Gaucher’s disease has been detected in a fetus with hydrops in whom lipid-filled histiocytes were present in the lungs, liver, and other organs. Although histologic, biochemical, and molecular DNA evidence of a lysosomal storage disease can be found at birth or before, it is unusual for the disease to be manifest in the neonate. Dramatic exceptions are Pompe’s disease, I-cell disease, GMlgangliosidosis, and infantile sialic acid storage disease. The infant with Pompe’s glycogenosis presents as an alert youngster who is markedly hypotonic, with flabby muscles and an enlarged heart and liver. Facial dysmorphism, hyperplastic gums, and limited joint movements are characteristic of the neonate with I-cell disease. Some infants with G,,-gangliosidosis can be spotted as neonates with frontal bossing, midfacial hypoplasia, macroglossia, broad hands, short stubby fingers, stiff joints, and edema of the extremities. The clinical appearance in the neonatal form of sialic acid storage disease is also very distinctive. Coarse facial features, ascites, hepatosplenomegaly, hypopigmented skin and hair, anemia, and renal failure are typical presenting features. In the early neonatal period, Niemann-Pick disease type C, Gaucher’s disease type 2, Farber’s disease, and Wolman’s disease may be suspected. Neonatal jaundice and the appearance of a giant cell hepatitis on liver biopsy are early signs of type C NiemannPick disease. The infant with Farber’s disease develops painful, swollen joints, hoarseness, and feeding and respiratory difficulties. In the child with Wolman’s disease, within the first few weeks of life abdominal distention, forceful vomiting, diarrhea, hepatosplenomegaly, and anemia occur. The distinctive features of the neonate with type 2 Gaucher’s disease are a bilateral fixed strabismus, opisthotonic posturing, bulbar signs, limb rigidity, seizures, and severe hepatosplenomegaly. Other lysosomal storage diseases appear later in the first year after a variable period of apparently normal development. These include Krabbe’s disease, Niemann-Pick disease type A, the GMland G,,-gangliosidoses, the mucopolysaccharidoses, and the glycoproteinoses. Marked irritability and variability in muscle tone are characteristic of infants with Krabbe’s disease. The child with Niemann-Pick type A disease is beset with feeding problems, failure to thrive, and marked hepatosplenomegaly. Psychomotor retardation and cherry-red maculae are characteristic of the classic Tay-Sachs and Sandhoff‘s variants of G,,-gangliosidosis. An important feature distinguishing Krabbe’s disease, Niemann-Pick disease type A, and the G,,-gangliosidoses is that in these diseases

the facial appearance remains normal, but in the mucopolysaccharidoses and glycoproteinoses there is a slowly progressive infiltration of connective tissue with coarsening of the facial features, thickening of hair, skin, and ear cartilage, and skeletal dysmorphism. This may be plainly evident before the child is 1 year old, as in the severe form of Hurler’s disease, or may be more subtle and progress much more slowly, as in Sanfilippo’s disease or fucosidosis. In the second year, developmental delay or loss of motor milestones usually is the presenting feature. Multiple sulfatase deficiency, metachromatic leukodystrophy, and mucolipidosis IV may first become obvious during this period. However, it must be recognized that because of the slowly progressive nature of the lysosomal diseases, the child’s developmental progress may continue, albeit more slowly than normal, for many months before a problem is recognized. This occurs less often in a family with older normal children, who serve as a comparison, than in the family with an only child. The tendency for delay in diagnosing a progressive degenerative disease may also exist when an acute illness or surgery intervenes. A febrile illness in a child with metachromatic leukodystrophy may cause prolonged weakness and apathy from which the child recovers only to become afflicted, several months later, with gait difficulty, loss of speech, and incoordination. Repeated ear infections in the youngster with a mucopolysaccharidosis may cause partial deafness and delay speech development. Inserting tubes into the tympanic membranes improves hearing, speech begins to develop, and the child’s progress may obscure the underlying illness until further clinical signs appear. In general, the earlier the onset, the more rapid the disease progression. Disorders with neuronal storage as the prime pathologic focus progress more rapidly than disorders affecting primarily white matter. Cognition is most severely compromised in the gangliosidoses and in the mucopolysaccharidosesin which heparan sulfate is the principal accumulating substance, namely, the severe form of Hurler’s disease and the various forms of Sanfilippo’s disease. In the glycoproteinoses, that is, aspartylglucosaminuria, fucosidosis, mannosidosis, and juvenile-onset sialic acid storage disease, the impact of the biochemical lesion is most evident during the developmental period, so that in these patients there is little noticeable further cognitive decline after childhood. LATER-ONSET FORMS The family members of patients who appear well for several years or even a decade or more before developing symptoms of a lysosomal storage disease often ask how a metabolic disease could be present for so many years without becoming manifest. If an infantile form of the disease is also known, then the question also arises as to what factors exist in the later-onset form to delay its appearance. Phenotype-genotype comparisons reveal that slightly more residual enzyme activity may be associated with the later-onset forms and that the error in genomic DNA is also less severe. In a classic infantile form, the mutation may affect transcription, so that no enzyme protein is produced, whereas the mutation in the late-onset variant might result only in a single base substitution with the production of an enzyme protein differing in only one amino acid from the normal situation. Both residual enzyme analyses and molecular DNA studies are now undertaken by laboratories with a special interest in one of the lysosomal diseases, but it is not yet possible in all cases to explain phenotypic differences within an inborn lysosomal disease. This presents a problem in genetic counseling, for one may encounter siblings with different degrees of expression of the same disease at the same age. I have noted this in families with later-onset

Chapter 198

Krabbe’s disease, adult-onset glycogenosis type 11, and chronic G,,-gangliosidosis. The onset of seizures, macular degeneration, and intellectual loss should alert the clinician to the possibility of a neuronal ceroid lipofuscinosis. In the late infantile Jansky-Bielschowsky form (CLN2), hyperactivity, ataxia, and seizures, typically between ages 2 and 4, precede the onset of visual failure and loss of intellect. The juvenile Spielmeyer-Sjogren (CLN3) form usually starts with retinitis pigmentosa and blindness at age 5 to 10. Seizures, an extrapyramidal movement disorder, cerebellar signs, and cognitive decline follow. Another cause of new-onset seizures in the adolescent is the cherry-red spot myoclonus epilepsy syndrome (sialidosis type 11). Grand mal attacks, especially on awakening in the morning, and intention myoclonus become very debilitating. Blindness eventually develops, but cognition may be retained for many years. Niemann-Pick disease type C and Gaucher’s disease type 3 have a wide range in age of onset. Vertical gaze paresis in the former and gaze initiation failure in the latter are common eye signs. I have known of children age 3 to 5 years with Niemann-Pick disease type C who have massive hepatosplenomegaly and severe intellectual impairment progressing to death in the juvenile period, and others with the same disease but only mild hepatosplenomegaly and adequate intellectual functioning into the third decade. Many patients with the type 3 subacute neuronopathic form of Gaucher’s disease are homozygous for a base change at nucleotide 1448 of the gene for glucocerebrosidase. Unlike those with classic Tay-Sachs disease, adolescents and young adults with late-onset G,,-gangliosidosis are intellectually intact and seizure-free. However, proximal muscle weakness, first in the lower extremities and later in the shoulders, together with tremor, dysarthria, and gait difficulties suggest a picture of Kugelberg-Welander disease or slowly progressive amyotrophic lateral sclerosis. Many patients also develop intermittent psychosis resembling the manic phase of bipolar disease or catatonia. Treatment of the psychiatric symptoms with major neuroleptics may cause worsening of the neurologic signs through the lysosomotropic effect of these drugs. Carbamazepine, valproic acid, fluoxetine, and electrocortical shock therapy have been most helpful in managing the psychotic symptoms in this disease. Fabry’s disease, an X-linked disorder, presents in the preadolescent or adolescent male with bouts of a peculiar burning dysesthetic pain in the extremities. The pain is triggered by exercise, hot weather, or fever and may last minutes to hours. Abdominal complaints, including postprandial pain and diarrhea, are also common. Widespread vascular occlusive disease develops, leading to myocardial infarction, multiple small strokes, especially involving the brainstem, and kidney failure, usually necessitating chronic renal dialysis. An early sign is the presence of purple angiokeratoma in the skin, especially at points of friction such as the umbilicus, over the elbows and knees, in the creases of the axillae and buttocks, and over the skin of the penis and scrotum. Affected patients and at least 90% of female carriers have feathery corneal opacities that are best seen in a slit lamp examination. Therapy for this progressive disabling neurovascular disease is directed at pain relief using phenytoin, carbamazepine, acetaminophen, and increased use of fluids in hot weather and prevention of occlusive vascular disease with antiplatelet agents. Recent trials of enzyme replacement therapy for this disease have shown promise in stabilizing kidney function, reducing myocardial thickness, and improving general well-being. Glycogenosis type I1 can also present in the adult with proximal muscle weakness, especially of truncal musculature, leading to

Lysosornal Storage Diseases

1259

sudden respiratory failure. There is no cardiac involvement, and liver enlargement may be minimal. Assisted respiration at night during sleep may be needed. Variants of both metachromatic leukodystrophy and Krabbe’s disease may also manifest in adults. Failing memory, behavioral changes, incontinence, and ataxia suggest late-onset metachromatic leukodystrophy. The patient may preserve social chatter and some comprehension of his local environment, but, over many years, quadriparesis and dementia develop. For years, club feet may be the only sign of incipient Krabbe’s disease in the child or young adult. Patients with slow progression may have school difficulties, a suggestion of cortical blindness, or a monoparesis. After months or years, weakness and spasticity spread to involve the other limb on the same side of the body and then the limbs on the opposite side. Intellect in some cases has been remarkably preserved. The oldest recorded patient developed limb weakness in her 40s and survived with intact sensorium into her 70s. Comparing the brain magnetic resonance imaging findings of adult-onset metachromatic leukodystrophy with those of late-onset Krabbe’s disease, one notices in the former a predilection for the loss of frontal white matter, including that of the genu of the corpus callosum, whereas in Krabbe’s disease the white matter loss is primarily parieto-occipital, with preferential involvement of the splenium of the corpus callosum. Maroteam-Lamy disease in the adult may not be recognized until signs of spinal cord compression supervene. Affected patients are of normal intelligence, with short stature and mildly dysmorphic facial features. Childbirth in affected women necessitates cesarean section because of cephalopelvic disproportion. Vertebral and lumbosacral radiculopathy develop as mucopolysaccharide infiltrates the dura and compresses the spinal cord and adjacent nerve roots. This complication necessitates neurosurgical intervention with laminectomy and opening of the dural sheath to prevent further cord compression. DIAGNOSIS History Suspicion of the possibility of a lysosomal storage disease should be raised on review of the history. Developmental delay alerts the pediatrician to scrutinize closely the prenatal history and birth history for any complication leading to a fixed encephalopathy, including cerebral dysgenesis from a chromosomal disorder, perinatal infection, and germinal matrix hemorrhage associated with prematurity. Because the repertoire of a young infant is quite limited with respect to gross and fine motor control, language, and socialization, signs of early delays in development may not be appreciated, and consequently parents may insist that their child’s early development was entirely normal until some event supervened such as a febrile illness, immunization, or injury necessitating hospitalization. Therefore, it is important to try to document milestones in growth and neurologic development sequentially from birth and make comparisons with standard growth charts. This rigorous approach will help all concerned to appreciate the degree of developmental delay, to time its onset, and to follow its trajectory. As a neurologist, 1pay particular attention to the parents’ assessment of their child’s degree of alertness and responsiveness to stimuli, his ability to learn new skills and words and to understand what is being said to him, his motor milestones, and his play activity. Feeding behavior and sleep habits are also considered. A family history is also taken to check on consanguinity and the occurrence in the family of a similar disorder, as well as other genetic diseases in the family. At this time, a pedigree is drawn up,

1260 W TABU 198-2.

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Common Clinical Signs of Lysosomal Storage Diseases

Cardiomegaly Danon's disease, Fabty's disease, Pompe's disease Coarse facies Clycoproteinoses, C,,-gangliosidosis, mucolipidoses II and 111, mucopolysaccharidoses, multiple sulfatase deficiency, sialic acid storage disease Eye Corneal clouding: cystinosis, Hurler's disease, Hurler-Scheie disease, Morquio's disease, Maroteaux-Lamy disease, mucolipidosis 11, mucolipidosis IV, Sly's disease Lens opacities: Fabty's disease Macular degeneration: CMl- and G,,-gangliosidoses, neuronal ceroid lipofuscinoses Optic atrophy: Krabbe's disease, metachromatic leukodystrophy Ophthalmoparesis: Caucher's disease types 2 and 3, Niemann-Pick disease type 3 Pigmentary retinopathy: neuronal ceroid lipofuscinoses, cystinosis Hepatosplenomegaly Cholesterol ester storage disease, Danon's disease, Farber's disease, Caucher's disease, glycoproteinoses, C,,-gangliosidosis, mucopolysaccharidoses, Niemann-Pick disease, Wolman's disease Nephropathy Cystinosis, Fabty's disease Skeletal abnormalities Caucheh disease, C,, -gangliosidosis, glycoproteinoses, rnucolipidoses 1-111, multiple sulfatase deficiency, pyknodysostosis Skin Angiokeratoma: Fabty's disease, fucosidosis type 2, R-mannosidosis, Schindler's disease type I1 Fair complexion: infantile sialic acid storage disease Neonatal ascites: Cauchefs disease, G,,-gangliosidosis, infantile sialic acid storage disease, Sly's disease Neonatal jaundice: Niemann-Pick disease type C Peau d'orange: rnucopolysaccharidoses White papules: Hunter's disease

which can be used for carrier testing and genetic counseling of other family members. Physical Examination

Common physical signs associated with the lysosomal storage diseases are shown in Table 198-2. On inspection of the skin, only a diligent search may reveal angiokeratoma of Fabry's disease, whitish papules on the upper back of the 4-year-old with Hunter's disease, or thickening of the skin over the finger joints of the child with a mucopolysaccharidosis. Similarly, dysmorphism of facial features may be missed unless the child's appearance is compared with that of his siblings and parents. A broad forehead, flattening of the nasal bridge, fullness of the cheeks, and a short, underslung jaw may easily be missed on the first examination. Therefore, I take full frontal and side view photographs of the face of each child I examine so that I can study their features and make comparisons with their appearance on subsequent visits. I also measure the distance between the inner and outer canthi to determine whether hypotelorism or hypertelorism is present. Other helpful measurements are head circumference, recumbent height, weight, length of the ears, distance between the root of the nose and upper lip, length of the hands and feet, and ratio of upper body to lower body. Club feet may indicate long-standing hypertonicity in the legs, as in late-onset Krabbe's disease. Contractures are appreciated if there is a systemic survey of all joints by passive range of motion testing. Claw hand is found in Scheie's disease, Maroteaux-Lamy disease, and I-cell disease. A gibbus deformity suggests an underlying deformity of the vertebral spine in I-cell disease and the mucopolysaccharidoses.

Abdominal swelling on the general physical examination leads to the suspicion of hepatosplenomegaly. The examiner should attempt to quantitate the size of the liver and spleen on repeated visits to gain a better idea as to the pace of the storage process. Marked hepatosplenomegaly, as occurs in Gaucher's and Niemann-Pick diseases, is associated with physical discomfort in the abdomen, digestive difficulties, stunting of growth, and emotional embarrassment to the child on account of his appearance. Although the eye examination, especially in a child, may take patience and may need to be delayed until the end of the visit, it is often very revealing. Extraocular movements are abnormal in Gaucher's disease types 2 and 3, in Niemann-Pick disease type C, and after blindness supervenes in the gangliosidoses, sialidosis, and leukodystrophies. Corneal clouding may be difficult to appreciate unless a penlight is directed obliquely at the cornea. The pupil should be dilated with a mydriatic to carefully assess the retina for optic atrophy characteristic of the late-infantile leukodystrophies and the later stages of the gangliosidoses, for retinal pigmentation characteristic of the juvenile form of neuronal ceroid lipofuscinosis, and for macular degeneration as seen in the gangliosidoses, sialidosis type 11, and the neuronal ceroid lipofuscinoses. As part of the neurologic examination, I look for macrocephaly indicative of communicating hydrocephalus in a child with a mucopolysaccharidosis or glycoproteinoses or of megacephaly as in Tay-Sachs disease. Microcephaly or failure of the head to grow may suggest a leukodystrophy. Muscle tone is another important indicator. Tone is decreased in the early stages of many of the lysosomal diseases with central nervous system involvement, whereas in the late stages muscle hypertonicity is more common. In infantile Krabbe's disease, muscle tone is not consistent, varying from examination to examination. The presence of spinal cord compression, as in Hurler's or Maroteaux-Lamy disease, leads to spasticity in the extremities. Loss of knee and ankle deep tendon stretch reflexes and sensory functions distally in the legs is consistent with the peripheral neuropathies of classic Krabbe's disease and late infantile and juvenile metachromatic leukodystrophy. Laboratory Workup

With a heightened awareness that a patient may have a lysosomal storage disease, how best should one proceed without doing a large battery of expensive tests? I favor a stepwise approach that targets one (presumably the correct) diagnosis as swiftly as possible. Common laboratory tests are listed in Table 198-3. A skin biopsy is the

TABLE 198-3. Diagnostic Workup for Lysosomal Diseases Radiology Skeletal radiographs Brain computed tomography, magnetic resonance imaging Neurophysiology Electroencephalogram Evoked potentials Electromyogram, nerve conduction Urine Mucopolysaccharide spot test, thin-layer chromatography Thin-layer chromatography for oligosaccharides Quantitation of cystine, sialic acid Blood Peripheral blood smear Serum, plasma, and leukocyte enzyme assays Molecular DNA analyses Skin Electron microscopy Cell culture for enzyme and DNA analvses

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endings, thus offering the opportunity to examine Schwann cells and nerve axons as well as sweat glands, vascular endothelia, and other cell types. The skin site is prepared with 70% alcohol. Skin preparations containing iodine should be avoided because iodine may inhibit the growth of cells in tissue culture. A 1% to 2%

FIG. 198-1. Electron micrograph of a skin biopsy from a 5-year-old boy with mucopolysaccharidosis II illustrating Schwann cell (S) and two endoneural fibroblasts (6.The fibroblasts are packed with secondary lysosomes filled with fine fibrillar material (1 4,200). (Joseph Alroy, DVM, kindly provided the electron micrographs.) FIG. 198-3. Electron micrograph of a skin biopsy from a 22-monthold boy of Ashkenazi Jewish ancestry who presented at age 8 months with generalized hypotonia, microcephaly, and mild delays in motor and speech development. Visible are three Schwann cells (S) and unmyelinated axons. The Schwann cell contains numerous secondary lysosomes filled with fine lamellated membrane structures, which is consistent with mucolipidosis IV (1 3,500). (Joseph Alroy, DVM, kindly provided the electron micrographs.)

FIG. 198-2. Electron micrograph of a skin biopsy from a 9-year-old girl with hepatomegaly, retarded growth, and retarded mental development caused by deficient a a i v i i of lysosomal a-fucosidase. The figure shows an endothelial cell (€1, two pericytes (P) and a fibroblast (6 containing numerous secondary lysosomes filled with fine fibrillar material and a few membrane fragments (13,500). (Joseph Alroy, DVM, kindly provided the electron micrographs.)

most direct way to screen for a lysosomal storage disease. Two microscopy (Figs* 198-1 to 'pecimens are taken*One for 198-6) and the second for culture and subsequent biochemical studies, as needed. A disposable 3-mm skin punch is used. The skin on the inner aspect of the upper arm adjacent to the d a is preferred. This is an area with a high density of dermal nerve

FIG. 198-4. Electron micrograph of a skin biopsy from a 20-year-old man who presented at age 5 with retinitis pigmentosa, intellectual decline, and progressively developing grand ma1 myoclonus and drop attacks. Demonstrated are vascular endothelium (€) and pericyte (PI. The endothelial cell has three secondary lysosomes filled with curvilinear bodies (arrowheads) (21,700). (Joseph Alroy, DVM, kindly provided the electron micrographs.)

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FIG. 198-5. Electron micrograph of a skin biopsy from a 34-year-old man who presented at age 28 with ruptured enlarged spleen that contained foamy macrophages. The figure shows a macrophage containing coarse lamellating membrane structures suggestive of Niemann-Pick type C. Cholesterol esterification assay that was performed after the biopsy confirmed the diagnosis (1 3,500). (Joseph Alroy, DVM, kindly provided the electron micrographs.)

solution of lidocaine is infiltrated in the skin surrounding the site to be biopsied. The specimen is placed in glutaraldehyde for electron microscopy and the other in tissue culture media such as minimal essential media or Eagle’s media. Both specimens should be delivered promptly to the respective laboratories with refrigeration overnight of the tissue culture specimen if there is to be a delay in delivery to the laboratory. They may also be sent by Express Mail without refrigeration. Nonspecific Slowly Progressive Mental Retardation. Skin biopsy as a screening tool has allowed us to diagnose fucosidosis and juvenile sialic acid storage disease when there are few clues other than a clumsy child with little or no speech. If the child is dysmorphic or the skeletal survey suggests a storage disease, then before proceeding to a skin biopsy, we will analyze urine for its content of mucopolysaccharides, oligosaccharides, sialyloligosaccharides, and free sialic acid. This covers a large number of conditions, including the mucopolysaccharidoses, glycoproteinoses, sialidoses, Sandhoffs disease, GMlgangliosidosis, and sialic acid storage disease. Cystinosis may also be detected in a urine test. The first morning void is preferred because it is likely to be the most concentrated specimen of the day. A 24-hour collection generally is not needed because most laboratories standardize their findings by comparing with the creatinine content of the specimen. For an infant or young child, the collection may be performed by affixing a specially designed plastic container such as a Hollister U-bag adjacent to the perineum with the opening facing the urethra or penis. An adhesive edge around the opening maintains a closed system, with the child’s diaper placed over the bag to hold it in place. In the morning, the child is supported vertically while the bag and its contents are removed. The specimen should be kept frozen in a plastic container until it is delivered to the testing laboratory. A spot test will reveal the presence of an excess of mucopolysaccharides, but quantitative tests for uronic acid and thin-layer chromatography to separate the individual species (i.e., dermatan sulfate, heparan sulfate, and chondroitin sulfate) and other tests will help in further characterizing- the type . _ of mucopolysacchari- . dosis present. Similarly, thin-layer chromatography is performed

to separate the individual oligosaccharides and sialyloligosaccharides. The relative mobility of the individual compounds on the thin-layer plate and their pattern may point to one particular form of glycoprotein storage disease. Facial and Skeletal Dysmorphism. In addition to a urine exam, the diagnostic workup for developmental delay associated with facial and skeletal dysmorphism should also include a radiograph of the skull looking for thickening of the inner table and J-shaped sella, radiographs of the long bones and hands to check on cortical thickness and other evidence of dysplasia, and a lateral view of the spine for anterior beaking of the vertebrae and rounding of the edges of the vertebral bodies. Radiographic studies may also disclose pelvic bone dysplasia. Pathologic fractures could indicate Gaucher’s disease or pyknodysostosis. If the urine or radiographic studies are suggestive, then blood or a skin biopsy is taken for lysosomal enzyme determinations. Hepatosplenomegaly. Enlargement of the liver or spleen often signifies a storage disease of the reticuloendothelial system. Examination of the peripheral blood smear can confirm the presence of storage vacuoles in lymphocytes and monocytes and Reilly-Alder bodies in granulocytes. Further investigations may include a bone marrow smear and biopsy for foam cells and Gaucher’s cells, but eventually lysosomal enzyme studies on blood or cultured cells are needed to make a definitive diagnosis. Seizures. Seizures are a feature of the neuronal ceroid lipofuscinoses, the gangliosidoses, sialidosis type 2, and Krabbe’s disease. An electroencephalogram is desirable to document epileptiform discharges because stimulus-provoked spasms often can be misinterpreted as seizures. A careful examination of the retina will also help to discern the presence of a cherry-red macula or other form of macular degeneration. Further evaluation includes a skin biopsy for ultrastructural analysis and enzyme analyses of cultured fibroblasts. In exceptional circumstances, one might elect to do a rectal biopsy or remove the appendix to search for neuronal storage in the cells of the myenteric plexuses.

FIG. 198-6. Electron micrograph of a skin biopsy from a 50-year-old woman of Ashkenazi Jewish ancestry with adult form of GM2gangliosidosis. At age 28 she developed progressive neurologic signs, including oral dyskinesia, muscle weakness, and intermittent numbness. The figure shows a Schwann cell (S) and an axon (A). The axon is enlarged and contains secondary lysosomes filled with lamellated membrane structures (1 9,300). (Joseph Alroy, DVM, kindly provided the electron microaraphs.) - . ,

Chapter 198 W

leukodystrophy. Brain white matter degeneration occurs primarily in Krabbe’s disease, metachromatic leukodystrophy, and multiple sulfatase deficiency but also develops secondarily in the neuronal storage diseases as a consequence of nerve cell and axonal degeneration. A brain magnetic resonance imaging examination, evoked potentials, and nerve conduction studies help characterize the leukodystrophies. If metachromatic leukodystrophy or multiple sulfatase deficiency is being considered, collection of 100 mL of urine to quantitate sulfatide excretion greatly aids in differentiating pseudodeficiency of arylsulfatase A from true arylsulfatase A deficiency and also allows detection of the activator deficiency form of metachromatic leukodystrophy in the presence of normal levels of arylsulfatase A activity. If clinical signs point to a leukodystrophy and tests for the lysosomal diseases are negative, other nonlysosomal leukodystrophies should be considered, including adrenoleukodystrophy, Alexander’s disease, Canavan’s disease, and Pelizaeus-Merzbacher disease. Biochemical and molecular tests for each of these diseases are available.

TREATMENT The first obligation of the clinician when faced with the prospect of a lysosomal storage disease is to reach a definitive diagnosis as quickly as possible. This saves the family money and time that would otherwise be devoted to numerous fruitless diagnostic excursions. It provides information that can be used immediately for the prenatal diagnosis of subsequent pregnancies and can give therapists in early intervention programs a more realistic idea of what types of progress they can expect for the child in the future. In certain of the mucopolysaccharidoses and leukodystrophies, if the diagnosis is made early enough, the child might be a candidate for bone marrow transplantation (BMT). This is one of several therapeutic options now available to patients with lysosomal storage diseases; others are enzyme replacement therapy and substrate synthesis inhibition. Several inherited leukodystrophies, including metachromatic leukodystrophy and globoid cell leukodystrophy, have responded to BMT with stabilization and in some cases reversal of certain aspects of their disease. Patients with mucopolysaccharidosis I and I1 have also benefited from BMT, primarily with arrest in the progression of their disease. BMT is most effective when performed early in the clinical course, before significant clinical deterioration is evident. The circulating donor macrophages make their way across the blood-brain barrier, reinventing themselves as brain microglial cells capable of producing and secreting into the surrounding neuropil lysosomal proteins including the deficient enzyme. Both in the central nervous system and in the visceral organs, lysosomal enzyme secreted by the donor cells is recaptured via the mannose-6-phosphate receptor recognition system and transported into lysosomes of host cells, where they are capable of degrading the storage material. For mucopolysaccharidosis I and 11, the correction is more effective in the organs of the reticuloendothelial system than in skeletal or connective tissue. In the future, addition of mesenchymal cells to the transplanted cells may overcome the difficulty of repairing the enzyme defect in these tissues. Morbidity and mortality are still associated with BMT. The conditioning regime of chemotherapeutic agents increases susceptibility to overwhelming infection, graft-versus-host disease can occur, and there is a high likelihood of a graft failure even with a suitable human leukocyte antigen match. The recent introduction of umbilical cord cells, an immunologically privileged source containing stem cells, should in the future reduce the incidence of graft-versus-host disease.

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Enzyme replacement therapy is now firmly established for type 1 Gaucher’s disease and has also shown promise in patients with the chronic neuronopathic type 3 form of the disease. It has not halted the progression of myoclonic seizures in type 2 Gaucher’s disease, but its ability to clear accumulated glucocerebrosidase from extraneural sites improves quality of life for these patients. In most Gaucher’s disease centers, an intravenous infusion of the enzyme preparation is given every 2 weeks. Allergic reactions have been few and mild. Many patients are able to receive their infusions at home, with periodic checkups to monitor their progress and adjust the enzyme dosage. Consequently, only rarely is splenectomy now done for this disease. Clinical trials of enzyme replacement therapy in patients with Fabry’s disease, mucopolysaccharidosis I, and Pompe’s disease have also shown promise, with amelioration of symptoms and improvements in quality of life. European patients with Fabry’s disease are able to access enzyme preparations manufactured by two different companies. One is a recombinant protein produced in CHO cells; the other is produced by activation of the a-galactosidase gene in human cells. Approval of these drugs by U.S. authorities is under consideration. Another therapeutic approach, substrate synthesis inhibition, uses small molecules that block endogenous production of the offending compound. Because they can cross the blood-brain barrier, they can potentially inhibit synthesis of stored lipid in the central nervous system. An example of this type of compound is N-butyldeoxynojirimycin, which has been shown to reduce G,,-ganglioside accumulation in mouse models of Tay-Sachs and Sandhoffs diseases. It is being used to treat patients with Gaucher’s disease, and clinical trials are under way with this compound in patients with late-onset G,,-gangliosidosis and Niemann-Pick disease type C. Depletion of cystine in cystinosis has been achieved by complexing cystine with cysteamine. The cystine-cysteamine mixed disulfide resembles lysine structurally. It is therefore recognized by the lysosomal transport system for lysine and in a carrier-mediated fashion is transported across the cystinotic lysosomal membrane. The drug is delivered orally and is most effective when given in the first 2 years of life. Cysteamine eyedrops have also shown efficacy in removing the accumulated corneal crystals, but this form of therapy has not yet been approved by the U.S. Food and Drug Administration. When kidney failure occurs, as in Fabry’s disease and cystinosis, hemodialysis and peritoneal dialysis act as temporizing measures until a suitable donor can be found for renal transplantation. However, the donor kidney does not prevent the progression of these diseases in other organs and may in time reaccumulate ceramide trihexoside or cystine, respectively. Gene therapy is also under consideration for treatment of the lysosomal storage diseases. Although this approach has been applied successfully to cells in tissue culture and in animal models, many obstacles remain to its successful implementation in patients. The use of totipotent hematopoietic stem cells transfected with the missing gene would be desirable, but problems have been encountered in achieving sustained gene expression and avoiding host reactions to the vector. For most lysosomal diseases, supportive care is all that can be offered, with the expectation that the disease may continue to progress. Seizures can be treated with anticonvulsants, muscle spasms with diazepam and baclofen, and ankle contractures by orthoses placed in the shoe. A child who is not eating and is losing weight may need a permanent gastrostomy. Heel cord lengthening and other types of tendon

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surgery may be needed for severe contractures and club foot deformities. The neurologist should remain available to the patient with a lysosomal disease, offering to see the patient and his or her family frequently. In this way, new complications can be recognized, its pathogenesis explained to the family, and strategies developed to minimize its effects. Also, frequent visits allow the physician to update the patient and family concerning new findings regarding the biochemistry and molecular genetics of the disease and what is happening locally, nationally, and internationally in research on the condition. Support groups now exist for many of the lysosomal storage diseases. They provide patients and families with the opportunity to share their knowledge of the disease, available treatments, and medical specialists with a special interest in their condition. They are also involved in the support of medical research and legislative action. Nearly all have Web sites. The National Organization for Rare Diseases (NORD) is also an excellent resource for patients and physicians alike.

ACKNOWLEDGMENT

SUGGESTED READINGS Haltia M: The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 62:1, 2003 Kolodny EH, Charria-Ortiz G Storage diseases of the reticuloendothelial system. In Nathan DG, Orkin SH, Look AT, Ginsburg D (eds):Nathan and Oski’s Hematology of Infancy and Childhood. 6th Ed. WB Saunders, Philadelphia, 2003 Krivit W, Auborg P, Shapiro E, Peters: Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy and Hurler syndrome. Curr Opin Hematol6377,1999 Lyon G, Adam RD, Kolodny EH: Neurology of Hereditary Metabolic Diseases of Children. 2nd Ed. McGraw-Hill, New York, 1996 Mancini GMS, Haveleer AC, Verheijen Fw:Lysosomal transport disorders. J Inherit Metab Dis 23:278, 2000 Schiffman R, Brady RO: New prospects for the treatment of lysosomal storage diseases. Drugs 62:733, 2002 Scriver CR, Beaudet AL, Sly WS, Valle D: Lysosomal disorders. pp. 33713896. In The Metabolic and Molecular Bases of Inherited Diseases. 8th Ed. McGraw-Hill, New York, 2001 Tifft, CJ, Proia RL: Stemming the tide: glycolipid synthesis inhibitors as therapy for storage diseases. Glycobiology 10:1249, 2000 Wenger DA, Coppola S, Liu SL: Lysosomal storage disorders: diagnostic dilemmas and prospects for therapy. Genet Med 4:412, 2002

JosephAlroy, DVM, kindly provided the electron micrographs for Figures 198-1 to 198-6.

199 Diagnosis and Management of Mitochondrial Diseases Donald R. Johns The mitochondrial encephalomyopathies are a diverse group of disorders that have in common functional, structural, or genetic abnormalities of mitochondria. A wide variety of neurologic symptoms occur in association with these disorders affecting almost the entire neuraxis. Cardinal neurologic manifestations include the following: Chronic progressive external ophthalmoplegia (CPEO): ptosis and ophthalmoplegia Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: strokelike episodes Myoclonic epilepsy with ragged red fibers (MERRF): myoclonus and seizures Leber’s hereditary optic neuropathy (LHON): optic neuropathy Overlap neurologic manifestations include the following: Myopathy Fatigability and exercise intolerance Sensorineural hearing loss Ataxia Vascular headache Dementia Peripheral neuropathy

Seizures Dystonia In addition to these neurologic manifestations, a number of somatic organ systems may be prominently affected, so the internist may be in a pivotal position to recognize these patients and initiate a diagnostic evaluation. The main systemic manifestations are as follows: Cardiac conduction defects Cardiomyopathy Diabetes mellitus Short stature Renal tubular dysfunction Hepatopathy Pigmentary retinopathy, cataracts Sensorineural hearing loss Episodic nausea and vomiting Intestinal pseudo-obstruction Hypoparathyroidism “Horse-collar” lipomas Recent advances in the molecular genetic analysis of these diseases have had a major impact on their diagnosis and management.

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surgery may be needed for severe contractures and club foot deformities. The neurologist should remain available to the patient with a lysosomal disease, offering to see the patient and his or her family frequently. In this way, new complications can be recognized, its pathogenesis explained to the family, and strategies developed to minimize its effects. Also, frequent visits allow the physician to update the patient and family concerning new findings regarding the biochemistry and molecular genetics of the disease and what is happening locally, nationally, and internationally in research on the condition. Support groups now exist for many of the lysosomal storage diseases. They provide patients and families with the opportunity to share their knowledge of the disease, available treatments, and medical specialists with a special interest in their condition. They are also involved in the support of medical research and legislative action. Nearly all have Web sites. The National Organization for Rare Diseases (NORD) is also an excellent resource for patients and physicians alike.

ACKNOWLEDGMENT

SUGGESTED READINGS Haltia M: The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 62:1, 2003 Kolodny EH, Charria-Ortiz G Storage diseases of the reticuloendothelial system. In Nathan DG, Orkin SH, Look AT, Ginsburg D (eds):Nathan and Oski’s Hematology of Infancy and Childhood. 6th Ed. WB Saunders, Philadelphia, 2003 Krivit W, Auborg P, Shapiro E, Peters: Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy and Hurler syndrome. Curr Opin Hematol6377,1999 Lyon G, Adam RD, Kolodny EH: Neurology of Hereditary Metabolic Diseases of Children. 2nd Ed. McGraw-Hill, New York, 1996 Mancini GMS, Haveleer AC, Verheijen Fw:Lysosomal transport disorders. J Inherit Metab Dis 23:278, 2000 Schiffman R, Brady RO: New prospects for the treatment of lysosomal storage diseases. Drugs 62:733, 2002 Scriver CR, Beaudet AL, Sly WS, Valle D: Lysosomal disorders. pp. 33713896. In The Metabolic and Molecular Bases of Inherited Diseases. 8th Ed. McGraw-Hill, New York, 2001 Tifft, CJ, Proia RL: Stemming the tide: glycolipid synthesis inhibitors as therapy for storage diseases. Glycobiology 10:1249, 2000 Wenger DA, Coppola S, Liu SL: Lysosomal storage disorders: diagnostic dilemmas and prospects for therapy. Genet Med 4:412, 2002

JosephAlroy, DVM, kindly provided the electron micrographs for Figures 198-1 to 198-6.

199 Diagnosis and Management of Mitochondrial Diseases Donald R. Johns The mitochondrial encephalomyopathies are a diverse group of disorders that have in common functional, structural, or genetic abnormalities of mitochondria. A wide variety of neurologic symptoms occur in association with these disorders affecting almost the entire neuraxis. Cardinal neurologic manifestations include the following: Chronic progressive external ophthalmoplegia (CPEO): ptosis and ophthalmoplegia Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: strokelike episodes Myoclonic epilepsy with ragged red fibers (MERRF): myoclonus and seizures Leber’s hereditary optic neuropathy (LHON): optic neuropathy Overlap neurologic manifestations include the following: Myopathy Fatigability and exercise intolerance Sensorineural hearing loss Ataxia Vascular headache Dementia Peripheral neuropathy

Seizures Dystonia In addition to these neurologic manifestations, a number of somatic organ systems may be prominently affected, so the internist may be in a pivotal position to recognize these patients and initiate a diagnostic evaluation. The main systemic manifestations are as follows: Cardiac conduction defects Cardiomyopathy Diabetes mellitus Short stature Renal tubular dysfunction Hepatopathy Pigmentary retinopathy, cataracts Sensorineural hearing loss Episodic nausea and vomiting Intestinal pseudo-obstruction Hypoparathyroidism “Horse-collar” lipomas Recent advances in the molecular genetic analysis of these diseases have had a major impact on their diagnosis and management.

Chapter 199

Each of the mitochondrial diseases is a rare entity, but the availability of specific molecular genetic assays for many of these diseases indicates that they have a higher prevalence than previously suspected on clinical grounds alone. Moreover, they represent some of the first molecularly proven examples of many cardinal types of neurologic disease: myopathy (CPEO), stroke (MELAS), seizures (MERRF), and optic neuropathy (LHON). Therefore, information gleaned from the detailed study of the pathophysiologic basis of these diseases may further our understanding of much more prevalent diseases such as stroke and epilepsy. Mitochondria function to produce sufficient adenosine triphosphate to fuel the myriad energy-requiring cellular processes. Mitochondria contain their own mitochondrial DNA (mtDNA), which encodes essential components of oxidative phosphorylation. mtDNA has a number of properties that make it a unique genetic element, including exclusive maternal inheritance and a high mutation rate. The human mitochondrial diseases have been associated with a variety of pathogenetic mutations involving mtDNA-encoded genes. Single deletions of mtDNA, as opposed to point mutations, are not transmitted from one generation to the next. For this reason diseases caused by mtDNA deletions such as CPEO usually are sporadic, whereas diseases that result from point mutations of mtDNA such as MELAS, MERRF, and LHON may demonstrate a maternal pattern of inheritance. Unusual autosomal dominant families occur who have CPEO-plus on the basis of multiple mtDNA deletions. Not all people who harbor a pathogenetic mtDNA point mutation express the disease. Therefore, these mitochondrial diseases often appear to occur sporadically despite the existence of the mutation in previous generations. The mitochondrial diseases exhibit variable penetrance and expressivity and marked intrafamilial and interfamilial variation. Consideration of the possibility of a mitochondrial disease depends on the recognition of characteristic clinical features or laboratory findings or a maternal pattern of inheritance. Many of the mitochondrial diseases have prominent neuroophthalmologic manifestations, and referral to an experienced neuro-ophthalmologist may be invaluable. The simplest tests for mitochondrial dysfunction are serum or cerebrospinal fluid lactate concentrations, which are often increased in patients with mitochondrial disease. Unfortunately, this increased concentration is insensitive and may be mild and present intermittently. Skeletal muscle, an accessible tissue, is clinically involved in many of these disorders and is the focus of most diagnostic procedures. Electromyography can document the presence of a myopathy even in the absence of clinically overt symptoms. In vivo phosphorus magnetic resonance spectroscopy of muscle and brain is a powerful tool that may detect associated metabolic abnormalities, but it is not 100% specific and is not widely available. Skeletal muscle biopsy, with appropriate histochemical stains, has remained the gold standard in the diagnosis of most mitochondrial diseases. Light microscopy may reveal ragged red fibers on Gomori trichrome stain or focal cytochrome oxidasenegative fibers. Ultrastructural analysis may reveal more direct evidence of abnormal, proliferating mitochondria. Skeletal muscle is suitable for biochemical analysis and provides appropriate material for the molecular genetic assays that have revolutionized the diagnostic workup of these diseases. MAJOR CATEGORIES OF MlTOCHONDRlAL DISEASE

The basic clinical features of each of the major mitochondrial encephalomyopathies are outlined here, with an emphasis on the

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molecular genetic testing now available for each of them and the evolving clinical conceptualizations of these diseases. CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA

One of the cardinal manifestations of human mtDNA disorders is CPEO, which manifests as a slowly progressive disorder of extraocular muscle that is typically symmetrical and unaccompanied by diplopia. The initial manifestation of this disorder usually is ptosis, but the ophthalmoparesis is progressive and eventually results in total ophthalmoplegia. CPEO may occur in isolation or may be accompanied by a number of other ophthalmologic, neurologic, and systemic features (called ophthalmoplegia-plus). One subset of the ophthalmoplegia-plus disorders is the KearnsSayre syndrome, which is characterized by ophthalmoplegia, onset before 20 years of age, and pigmentary retinopathy plus at least one of the following: cardiac conduction defects, elevated cerebrospinal fluid protein concentration (more than 100 mg/dL), or cerebellar ataxia. Many of the neurologic and somatic findings in CPEO, other than ophthalmoplegia and ptosis, are also seen in other mtDNA diseases. Molecular genetic analysis of mtDNA from skeletal muscle demonstrates large deletions in most patients with CPEO. The frequency of demonstrable mtDNA deletions depends on the presence of other features: 50% of patients with isolated CPEO harbor a deletion, whereas 80% of patients with CPEO and pigmentary retinopathy and 90% of patients with the KearnsSayre syndrome have deletions. At least some of the deletionnegative patients have pathogenetic mtDNA point mutations in transfer RNA (tRNA), including the 3,243-mtDNA point mutation seen in most patients with MELAS syndrome. These deletions, which were the first proven examples of mtDNA abnormalities causing human disease, can be detected by several different molecular genetic methods. Size, location, and proportion of deleted mtDNA are poorly correlated with the phenotypic expression or associated biochemical abnormalities. MEWS Syndrome

The MELAS syndrome is a significant cause of stroke in the young. The strokelike episodes tend to occur in the setting of prolonged focal seizures or prolonged vascular headache. A number of molecularly confirmed MELAS patients were initially misdiagnosed as having herpes simplex encephalitis. Episodic nausea and vomiting are noted intercurrently and are particularly severe at the time of the strokelike events. The strokes do not follow vascular territories but have a definite posterior preponderance, so many patients develop cortical visual field defects. The strokes appear to be caused by an overwhelming defect in substrate utilization rather than the usual defect in substrate availability operative in occlusive vascular disease. The neurologic deficits may be reversible despite demonstrable signal abnormalities on magnetic resonance imaging (MRI) studies. The availability of molecular genetic testing has broadened the clinical parameters of MELAS syndrome. The age of onset ranges from infancy to 45 years. Developmental delay and short stature may be noted in the early-onset cases, whereas dementia may predominate in older patients. Seizures are almost always present, and vascular headache is common. A host of other neurologic accompaniments common to many mitochondrial diseases are also found, and these may precede the development of strokelike episodes. Computed tomography may demonstrate basal ganglia

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calcification or evidence of tissue loss. MRI may reveal the signal abnormalities of new and old “infarcts” with a posterior predominance. The laboratory abnormalities found in all mitochondrial encephalopathies are as follows: Myopathic potentials on electromyography Ragged red fibers in skeletal muscle biopsy Sensorineural hearing loss on audiogram Cardiac conduction defects Elevated serum and cerebrospinal fluid lactate concentration Basal ganglia calcification or focal signal abnormalities on MRI Axonal and demyelinating peripheral neuropathy on nerve conduction studies Oxidative phosphorylation defects on biochemical studies Molecular genetic demonstration of mtDNA mutation MELAS syndrome has been linked to two-point mutations in the tRNA-leucineUURmtDNA gene. The mutation at position 3,243 accounts for 80% to 90% of patients with the MELAS phenotype and can be detected by molecular genetic analysis of polymerase chain reaction-amplified mtDNA, The mutation was originally described in DNA extracted from muscle, but DNA derived from noninvasive tissues such as blood and urine also contains a detectable proportion of the mutation. Recognition of the MELAS syndrome in a young stroke patient may dramatically alter the extent and nature of the diagnostic workup and management. Because many strokelike episodes occur in the setting of prolonged seizures, we recommend aggressive treatment of the seizure disorder with vigilant attention to anticonvulsant levels. Genetic counseling must be individualized in each family and can be supplemented with molecular genetic testing of noninvasive tissues from maternal relatives. Most cases are sporadic, but mild oligosymptomatic manifestations may be seen in maternal relatives. One important goal of genetic counseling is to ensure an affected male proband that because of the strict maternal transmission of mtDNA he will not pass the disorder to his offspring. His maternal relatives are at risk for the disorder, and the women may also act as carriers, Myoclonic Epilepsy and Ragged Red Fibers

MERRF is the third major mitochondrial encephalomyopathy to have its molecular basis identified in recent years. The dominant clinical symptoms are myoclonus, seizures, and ataxia. A peculiar form of respiratory insufficiency is seen in the most severe cases. Some of the associated neurologic and somatic manifestations of mitochondrial encephalomyopathies are also seen. Most patients with MERRF have a point mutation in the tRNA-lysine gene at position 8,344 that can be detected by molecular genetic methods in skeletal muscle and blood. Characteristic “horse-collar’’lipomas also occur in association with this mutation. Lebel‘s Hereditary Optic Neuropathy

LHON was the first human disease shown to be caused by a heritable defect in mtDNA. The core clinical phenotype is that of a painless optic neuropathy occurring in an otherwise healthy young person. Loss of central vision may occur rapidly or may progress slowly for several months. Visual symptoms often affect only one eye initially but almost always involve both eyes within 1 year. Most patients become symptomatic in the third or fourth decade

of life, with a mean age at onset of 28 years (range, 6 to 80 years). Men are affected much more frequently than women (male/female ratio, 2 to 3 :1). Because most patients with molecularly proven LHON have no documented family history of visual loss, the neurologist should not be dissuaded from the diagnosis of LHON in the absence of a suggestive family history. The visual loss is severe, with a nadir of visual acuity ranging from 20/200 to hand motions and is accompanied by central or cecocentral scotomas. The funduscopic findings at the onset of visual loss are variable and may be entirely normal. Optic atrophy eventually supervenes in the chronic phase. Significant recovery of visual acuity is noted in some patients and is more commonly associated with certain LHON genotypes. Other neurologic accompaniments are infrequent and include peripheral neuropathy and demyelinating disease. The pathogenesis of acute visual loss in LHON appears to involve a complex interplay of genetic and epigenetic factors. Environmental factors that have been implicated include the use of tobacco and alcohol, diabetes mellitus, vitamin deficiency, head trauma, and occupational exposures. Major diagnostic errors occur in a number of different situations of acute visual loss in patients who are eventually proven to have LHON on a molecular basis. LHON should be considered in any patient with an atypical optic neuritis (painless, bilateral, no recovery), a presumed toxic or nutritional optic neuropathy (especially alcohol-tobacco amblyopia), or anterior ischemic optic neuropathy. The most important dictum for the workup of suspected LHON is to have a high index of suspicion and to order appropriate molecular genetic testing. The availability of reliable molecular genetic testing has revolutionized the diagnosis of LHON. Four primary pathogenetic mtDNA mutations have been described to date in LHON, and each can be readily detected with molecular genetic techniques. The first mutation at nucleotide position 11,778 in the ND-4 gene accounts for 50% to 55% of cases and can be detected with 100% sensitivity and specificity by molecular genetic analysis of polymerase chain reaction-amplified mtDNA extracted from a routine blood sample. The 11,778 mutation is a poor prognostic sign for significant recovery of visual acuity and in 5% of families is associated with demyelinating disease in maternal relatives. Three other LHON-associated mtDNA mutations account for about 30% of cases and occur at nucleotide positions 3,460 (ND-1 gene), 15,257 (cytochrome b gene), and 14,484 (ND-6 gene) of mtDNA. The core clinical phenotype of painless visual loss is the same, but each mutation has some specific clinical features that distinguish it. The most notable distinctive feature is the prognosis for visual recovery, which varies nearly 10-fold among the various mutations: 4% ( 1 1,778 mutation), 22% (3,460 mutation), 28% 15,257 mutation), and 37% (14,484 mutation). The 15,257 mutation is associated with a higher prevalence of neurologic accompaniments, particularly spinal cord and peripheral nerve involvement, and with a pigmentary retinopathy. Molecular genetic testing for each of the three primary mtDNA mutations is 100% specific but is only approximately 80% to 85% sensitive at present. This testing has proved useful in a number of different settings, including confirmation of the diagnosis in probable cases and establishment of the diagnosis in atypical or obscure cases of optic neuropathy. In addition to expediting the diagnostic workup of LHON, molecular genetic testing has implications for family counseling, risk factor intervention, prognosis for visual recovery, and therapy. Coexistent systemic abnormalities that are occasionally associated with LHON such as cardiac conduction defects, migraine,

Chapter 199

and peripheral neuropathy should be recognized and treated appropriately. Referral for genetic counseling and low vision assessment are also important in treating patients with LHON.

Mitochondrial Myopathy and Peripheral Neuropathy Mitochondrial disorders have prominent manifestations in the peripheral system. Mitochondrial myopathy may occur in association with one of the known mitochondrial phenotypes or may occur as the sole or predominant manifestation. Exerciseinduced weakness and fatigability are prominent features, but fixed weakness is also often present. Rarely myoglobinuria can occur in mitochondrial myopathy, but generally the creatine kinase level is normal or mildly elevated. Less well appreciated are a variety of peripheral neuropathic manifestations of mitochondrial disease, including both axonal and demyelinating forms. Coexistent muscle and nerve involvement (“myoneuropathy”) occurs in only a small number of diseases, including mitochondrial disease.

Novel Mitochondria1 Disease Phenotypes The disorders discussed earlier in this chapter were for many years thought to have a mitochondrial origin based on clinical, laboratory, or maternal inheritance characteristics. Recent advances in molecular genetics have established their precise etiologic basis. A number of novel mitochondrial disease phenotypes have been identified on the basis of mtDNA defects. These include a family from England with a syndrome of peripheral neuropathy, ataxia, retinitis pigmentosa, seizures, developmental delay, and dementia (NARP) caused by an mtDNA mutation at nucleotide 8,993 in the ATPase 6 gene. This mutation was subsequently found in a subset of Leigh’s disease patients who demonstrated maternal inheritance. We have identified a family with a syndrome of subacute optic neuropathy and myelopathy (Devic’s syndrome) that harbored mtDNA mutations in the cytochrome oxidase I1 gene and in the tRNA-aspartate gene. We predict that a wide array of neurologic and non-neurologic manifestations will be demonstrable in future novel mitochondrial disease phenotypes. Movement disorders have only rarely been associated with mitochondrial diseases, but recently dystonia has emerged as a prominent manifestation in patients with several different mtDNA mutations. We have seen dystonia as the dominant clinical feature in patients with the 3,243 mtDNA mutation and with multiple mtDNA deletions who also had CPEO. Dystonia has also been prominent in exceptional maternal families with LHON-like visual loss and infantile bilateral striatal necrosis. Mitochondrial dysfunction may also play a somewhat different role in some of the more prevalent neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. It is unclear at present whether these mitochondrial abnormalities reflect a primary or secondary alteration in these diseases, and a great deal of investigative interest is now focused on these issues. Perhaps most intriguing of all is the potential role of mtDNA mutations in aging (arguably the most prevalent condition in humans). Molecular genetic analysis of mtDNA in human disease has had a rapid and profound impact on a number of different diseases that are of primary interest to the internist and neurologist. Although the diseases covered in this chapter are discussed as separate entities, many of the patients have clinical and laboratory features that overlap. Internists and neurologists are in a pivotal position to recognize these patients and to guide their diagnosis

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and management. Many patients with mitochondrial diseases present with partial or novel phenotypes and necessitate a high index of suspicion from an astute clinician. We anticipate that molecular genetic advances in the near future will allow us to diagnose more of these challenging patients definitively and will eventually guide their effective treatment.

TREATMENT The treatment of mitochondrial diseases is similar to that of most other neurologic disorders in that no “magic bullet” is available and we must instead focus on broader therapeutic goals.

Detection and Correction of Comorbid Features A number of signs and symptoms occur in the mitochondrial encephalomyopathies that contribute significantly to their morbidity, and these could be rigorously pursued and corrected. Seizures should be treated with carbamazepine or phenytoin if parented therapy is needed; phenobarbital is avoided. Myoclonus may respond to clonazepam. Vascular headache in the proband or oligosymptomaticrelatives should be treated with calcium channel blockers (e.g., verapamil, sustained release 120 to 480 mg/day). Ptosis surgery should be performed only by an experienced oculoplastic surgeon who is aware of the need for undercorrection to avoid disabling exposure keratitis caused by concomitant facial weakness in patients with CPEO. Sensorineural hearing loss is a correctable condition that contributes significantly to the disability caused by a number of different mitochondrial diseases and should be vigorously diagnosed and treated. Almost every organ system can be affected in mitochondrial encephalomyopathy, and referral to the appropriate specialist is warranted. Cardiologic consultation can be particularly important because the cardiac manifestations may be life-threatening. Diabetes mellitus is very prevalent in the mitochondrial diseases and can be the dominant clinical feature in some families.

Avoidance of Inappropriate Therapy In addition to having direct therapeutic implications, establishment of the correct diagnosis as a mitochondrial encephalomyopathy avoids inappropriate therapy for the wrong condition (e.g., treatment for myasthenia gravis in CPEO, anticoagulation in the MELAS syndrome, or high-dose steroids in LHON). Molecular genetic techniques may expedite the diagnostic workup and thereby avoid risks and complications of unnecessary procedures, such as angiography in the MELAS syndrome.

General Recommendations Energy metabolism is compromised in patients with mitochondrial encephalomyopathies, so overexertion to the point of fatigue and exhaustion should be avoided. Aerobic conditioning has been shown to improve exercise capacity in patients with mitochondrial myopathies. No specific dietary regimen is recommended, but patients are advised to avoid prolonged fasting and to eat frequent light meals. Exposure to potential environmental cofactors, such as alcohol and tobacco use in LHON, should be eliminated. Fever is treated aggressively with acetaminophen, and aspirin should be avoided. When antibiotic treatment is needed, chloramphenicol and tetracycline should be avoided because of the toxicity to mitochondria.

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Endocrinology and Metabolism

Phannacologic Therapy

Genetic Counseling and Therapy

Our knowledge of specific pharmacotherapy of the mitochondrial encephalomyopathies is limited by several factors, including their variable natural history (especiallythe MELAS syndrome) and their low prevalence. A cohort of molecular genetically defined cases may provide an appropriate study population for future clinical trials. Our current knowledge is dominated by anecdotal experience and clinical trials with limited numbers of patients. Nevertheless, rational treatments have been formulated based on our knowledge of oxidative phosphorylation and intermediary metabolism. Pharmacologic therapy is aimed at circumventing the biochemical deficit and preventing the secondary deleterious effects (e.g., the accumulation of reactive oxygen free radicals). One underlying principle is to avoid toxicity, so many agents are naturally occurring substances. Therapeutic monitoring can be accomplished by observation of the clinical response, changes in the levels of lactate and pyruvate at rest and with standardized exercise, and phosphorous nuclear magnetic resonance spectroscopy. Carnitine may become depleted from the muscle of patients with mitochondrial encephalopathy, especially those with a significant lactic aciduria. Repletion with L-carnitine, 2 to 3 g/day is advocated in patients with documented low levels in plasma or muscle. Coenzyme Qlo (ubiquinone) has been used in a number of patients with mitochondrial encephalomyopathy at dosages ranging from 60 to 300 mg/day (average dosage, 90 to 120 mg/day). The beneficial effects of coenzyme Qlo have been more prominent on skeletal muscle and cardiac muscle than on extraocular muscles or the central nervous system. Coenzyme Qlo has been remarkably free of side effects, although some of our patients have complained of malodorous body secretions. Cofactors of oxidative phosphorylation have been given in pharmacologic dosages, including riboflavine (vitamin B,, 100 mg/day) and thiamine (vitamin B,, 100 to 1000 mg/day). Free radical scavengers are used to allay the deleterious effects (e.g., lipid peroxidation) of excess free radicals that accumulate proximal to blocks in the electron transport chain. These include vitamin C (ascorbate, 2 to 4 g/day), vitamin E (tocopherol, 400 IU/day), and coenzyme Qlo (ubiquinone, 60 to 300 mg/day). Dichloroacetate, which stimulates pyruvate dehydrogenase, has been used to treat lactic acidosis of diverse origins, including mitochondrial encephalomyopathy. It is not available in the United States for routine use, however. Corticosteroids are used in every neurologic condition for which definitive therapy is not available, and the mitochondrial encephalomyopathies are no exception. Steroids have had anecdotal success in the treatment of patients with MELAS syndrome, but they must be used with great caution in patients with mitochondrial diseases because of the frequent coexistence of impaired glucose tolerance.

The genetics of the mitochondrial encephalomyopathies are complicated because of the genetic composition of oxidative phosphorylation complexes by nuclear DNA and mtDNA-encoded proteins that must interact in a very precise manner. Most cases of CPEO-plus are sporadic, so relatives are not at increased risk. Exceptional autosomal dominant CPEO cases have been noted that were caused by a defect in a nuclear-encoded factor involved in the maintenance of mtDNA fidelity. MERRF is maternally inherited, but a wide spectrum of clinical manifestations is found among maternal relatives. The MELAS syndrome is also maternally inherited, but only one or a few individuals tend to be overtly affected, and most relatives have a partial, oligosymptomatic presentation. LHON is strictly maternally inherited, but our extensive studies of molecularly confirmed cases reveal that only one or a few people are affected in most families. One powerful genetic counseling principle for the maternally inherited disorders is the lack of paternal transmission, such that an affected male can be confidently assured he will not pass his condition to his offspring. Our knowledge of the precise molecular basis of the mitochondrial encephalomyopathies is advancing rapidly, and ultimately this information may guide effective therapy.

SUGGESTED READINGS Ciafaloni E, Ricci E, Shanske S et al: MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 31:391-398, 1992 DiMauro S, Hirano M, Schon EA Mitochondrial encephalomyopathies: therapeutic approaches. Neurol Sci 21:5901-5908,2000 Holt IJ, Harding AE, Cooper JM, Morgan-Hughes JA Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of mitochondrial DNA. Ann Neurol26699-708, 1989 Johns DR Diseases caused by genetic defects of mitochondria. pp. 404-407.In: Braunwald E, Fauci AS, Kasper DL, et a1 (eds): Harrison’s Principles oflnternal Medicine. McGraw-Hill, New York, 2001 Johns DR, Colby KA: Treatment of Leber’s hereditary optic neuropathy: theory to practice. Semin Ophthalmol 2002 Johns DR, Stein AG, Wityk RJ: MELAS syndrome masquerading as herpes simplex encephalitis. Neurology 43:2471-2473, 1993 Nardin RA, Johns D R Mitochondrial dysfunction and neuromuscular disease. Muscle Nerve 24170-191, 2001 Newman NJ: Leber’s hereditary optic neuropathy: new genetic considerations. Arch Neurol 50540-548, 1993 Simon D, Johns DR Mitochondrial disorders: clinical and genetic features. Ann Rev Med 5O;lll-127, 1999 Sims K, Holtzman D: Diseases of adenosine triphosphate synthesis in children. Curr Opin Neurol 15:145-150, 2002

SECTION

7 TOXINS AND DRUG EFFECTS

200 Neurologic Complications of Alcoholism Michael E. Charness

Alcohol ingestion and alcoholism are associated with protean changes in the nervous system. This chapter reviews the diagnosis and management of alcohol intoxication, alcohol withdrawal, and the nervous system complications of alcoholism. The biochemical and physiologic effects of alcohol on the nervous system are reviewed elsewhere. INTOXICATION, PHYSICAL DEPENDENCE, AND ALCOHOL WITHDRAWAL Intoxication

Incoordination can be measured at blood ethanol concentrations of approximately 35 mg/dL. A blood ethanol concentration of 80 mg/dL is defined as the legal definition of intoxication in most states. At these and higher concentrations, ethanol causes dysarthria, ataxia, encephalopathy, and sedation. In nonalcoholic people, blood ethanol concentrations greater than 450 mg/dL often are lethal, with death resulting from inhibition of medullary control of respiration. Tolerance

Chronic ethanol consumption produces significant tolerance to its intoxicating effects. In emergency rooms, hundreds of sober alcoholics are found to have blood ethanol concentrations well above 100 mg/dL. The highest blood ethanol concentration ever reported, 1510 mg/dl, was measured in an alcoholic described as ‘‘agitated and slightly confused but alert, responsive to questioning, and oriented to person and place (though unclear as to time).’’ The fact that some alcoholics show few signs of intoxication at blood ethanol concentrations that would prove lethal in nonalcoholic people attests to the remarkable capacity of the nervous system to adapt to ethanol. This adaptation begins during the first hours of drinking. During a single bout of drinking, naive subjects became sober at blood ethanol concentrations higher than those associated with initial intoxication. Animal studies confirm that tolerance to ethanol may occur after as little as 30 minutes of ethanol administration. Physical Dependence and the Withdrawal Syndrome

Physical dependence is a state in which ethanol is needed to maintain normal central nervous system (CNS) function. Chronic ethanol ingestion provokes biochemical and physiologic adapta1268

tions that render CNS function normal in the presence of ethanol. These plastic CNS responses become maladaptive when ethanol intake is abruptly discontinued. There ensues a state of tremulousness, agitation, and autonomic hyperactivity that is in many ways opposite to the clinical syndrome of acute intoxication. The alcohol withdrawal syndrome evolves gradually over hours to days after the cessation of drinking. Tremulousness appears after 8 to 12 hours, followed in some instances by generalized tonic-clonic seizures. Delirium tremens, a state of autonomic hyperactivity, agitation, and hallucinations, typically begins 1 to 2 days after alcohol withdrawal and lasts for several days to a week or more. Delirium tremens may directly follow a series of alcohol withdrawal seizures, leading to a prolonged postictal alteration of sensorium. Alcohol Withdrawal Seizures

Most alcohol withdrawal seizures occur between 12 and 48 hours after a sharp decline in blood alcohol concentrations. Some alcoholics drink to control the tremulousness that sometimes precedes seizures; therefore, the smell of alcohol on the breath does not rule out the diagnosis of alcohol withdrawal seizures. Typically, alcohol withdrawal seizures are brief, recur within a period of 6 to 12 hours, and are self-limited. If the patient has recovered completely within this period of time and has a clear history of recent alcohol withdrawal and a normal neurological examination then neuroimaging studies are unlikely to disclose a cerebral lesion. In contrast, prolonged or widely separated seizures, focal seizures, prolonged postictal state, or a focally abnormal neurologic examination should prompt a search for correctable structural lesions, metabolic abnormalities, or infection (Table 200-1). Nearly half of seizure admissions to a city hospital were attributable to alcohol withdrawal. Whereas only a small percentage of patients withdrawing from alcohol develop status epilepticus, alcohol withdrawal may be a complicating factor in approximately one fifth of all patients with status epilepticus. Likewise, alcohol withdrawal may precipitate seizures in patients with idiopathic or symptomatic epilepsy. The observation that some patients have ingested alcohol within an hour of a first seizure has led some investigators to postulate that ethanol intoxication can lower seizure threshold. Treatment of alcohol withdrawal seizures is largely symptomatic. Benzodiazepines are effective in the primary prevention of ethanol-withdrawal seizures during alcohol detoxification. The

Chapter 200

TABLE 200-1. Causes of Prolonged Postictal State after Alcohol Withdrawal Seizures Trauma Subdural hematoma Traumatic subarachnoid hemorrhage Intracerebral hemorrhage Infection Meningitis Seizure Nonconvulsive status epilepticus Previous brain injury Metabolic encephalopathy Hypoglycemia Wernicke’s encephalopathy Hyponatremia Hepatic encephalopathy Drug or toxin ingestion Sepsis Hypoxia

intravenous administration of 2 mg of lorazepam after a single ethanol withdrawal seizure significantly reduced the incidence of multiple ethanol withdrawal seizures within a 6-hour time period and decreased the likelihood that patients with withdrawal seizures would need hospital admission. In contrast, intravenous phenytoin was not effective in preventing a second ethanol withdrawal seizure. Status epilepticus in the setting of ethanol withdrawal should be treated according to standard protocols, including the use of phenytoin. The long-term administration of anticonvulsants for uncomplicated ethanol withdrawal seizures is unnecessary and possibly dangerous. Some alcoholics abruptly withdraw from both alcohol and anticonvulsants, thereby increasing the risk of status epilepticus.

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blockers may be useful in suppressing tremulousness and autonomic hyperactivity. Dehydration may develop rapidly during alcohol withdrawal because of agitation and diaphoresis. Vigorous intravenous hydration and sedation may be needed to prevent hypotension. Venous access provides an opportunity to rapidly correct potential deficiencies of multiple vitamins and electrolytes. Symptomatic hyponatremia should be corrected slowly to prevent the occurrence of central pontine myelinolysis, which occurs more frequently in alcoholics than in nondrinkers. It is important to administer multivitamins as well as additional supplements of thiamine (100 mg per day) because of the high incidence of unrecognized Wernicke’s encephalopathy in alcoholics. Magnesium deficiency is particularly common in alcoholics and may contribute to the alcohol withdrawal syndrome. Hypomagnesemia is associated with cardiac arrhythmias and complicates the correction of coexisting hypokalemia and hypocalcemia. Magnesium is also a cofactor for transketolase, one of the thiaminedependent enzymes implicated in the pathogenesis of Wernicke’s encephalopathy. Serum magnesium in alcoholics often is in the low-normal to low range, despite the presence of significant magnesium deficiency. Metabolic studies have established magnesium deficits of approximately 2 mEq/kg in alcoholic patients; therefore, seemingly enormous quantities of magnesium must be administered to replete total body stores. One suggested regimen is to administer 6 g of magnesium (1 ampoule of magnesium sulfate contains 1 g or 8.13 mEq of magnesium) over 3 hours in intravenous fluids followed by another 10 g of magnesium by continuous intravenous infusion over the next 24 hours and 6 g daily for an additional 3 days. CENTRAL NERVOUS SYSTEM COMPLICATIONS OF ALCOHOLISM

Management of the Alcohol Withdrawal Syndrome

Brain Lesions in Alcoholics

Mild alcohol withdrawal syndromes can be managed effectively with oral benzodiazepines, which may be titrated against agitation and tremulousness. Symptom-triggered administration of benzodiazepines results in shorter durations of treatment and lower total dosages than fixed-schedule regimens. Replacement of most vitamins and minerals can also be accomplished orally, although it is preferable to administer thiamine parenterally because oral absorption of thiamine is unreliable in alcoholic and malnourished patients. Intravenous benzodiazepines, hydration, and replacement of magnesium and vitamins are the mainstays of therapy for severe alcohol withdrawal syndromes. The neuropharmacologic actions and therapeutic efficacies of most commonly used benzodiazepines are similar; therefore, the selection of a particular benzodiazepine often is based on pharmacokinetic considerations. Chlordiazepoxide, diazepam, and lorazepam are effective benzodiazepines that may be administered orally or parenterally. Oxazepam may be preferable in patients with liver disease because oxazepam clearance is less dependent on hepatic metabolism than that of other benzodiazepines. Strikingly high dosages of benzodiazepines may be needed to control agitation caused by alcohol withdrawal. Benzodiazepines produce sedation by potentiating the actions of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS, and studies in animals and humans suggest that chronic ethanol administration decreases the number and function of selective GABA receptor subunits. Clonidine has been reported to decrease the autonomic hyperactivity of alcohol withdrawal, and β-adrenergic receptor

Alcoholism is complicated by a variety of neurologic disorders, most of which produce characteristic brain lesions (Table 200-2). Malnutrition is common in alcoholics, who may derive the majority of their calories from nonnutritive ethanol (7 kcal/g). Thiamine deficiency is particularly common and leads to Wernicke’s encephalopathy. Thiamine deficiency may also contribute to alcoholic cerebellar degeneration and alcoholic peripheral neuropathy. Pellagra is a disorder of dementia, dermatitis, and diarrhea resulting from a deficiency of nicotinic acid, which is now rare in the Western world. Alcoholics are subject to repeated episodes of head trauma. Alcoholic liver disease may cause hepatocerebral degeneration. Prenatal exposure to alcohol causes a variety of brain lesions associated with cognitive dysfunction. Finally, alcohol may directly damage the nervous system, although specific lesions of alcoholic neurotoxicity have not yet been described.

TABLE 200-2. Causes of Brain Lesions in Alcoholics Wernicke’s encephalopathy Alcoholic cerebellar degeneration Hepatocerebral degeneration Trauma Central pontine myelinolysis Fetal alcohol syndrome Marchiafava-Bignami syndrome Alcohol neurotoxicity Pellagra

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Cognitive Disorders in Alcoholics

Mild cognitive impairment can be demonstrated by neuropsychological testing in 50% to 70% of detoxified alcoholics, and several groups have reported that abstinence leads to an improvement in cognitive function, particularly in the first weeks after the cessation of drinking. Approximately 10% of alcoholics exhibit stable and severe cognitive dysfunction ranging from Korsakoff ’s amnestic syndrome, a selective anterograde and retrograde amnesia, to dementia. Both patterns of cognitive dysfunction have been documented in patients whose brains reveal only the lesions of nutritional deficiency. Wernicke’s Encephalopathy

Wernicke’s encephalopathy is the neurologic manifestation of thiamine deficiency. The characteristic lesions occur symmetrically in structures surrounding the third ventricle, aqueduct, and fourth ventricle. The mamillary bodies are involved in almost all cases, and the dorsomedial thalamus, locus ceruleus, periaqueductal gray, ocular motor nuclei, and vestibular nuclei are commonly affected. Acute Wernicke’s lesions can be identified by endothelial prominence, microglial proliferation, and occasional petechial hemorrhages. In chronic lesions, there is demyelination, gliosis, and loss of neuropil with relative preservation of neurons. Atrophy of the mamillary bodies develops in up to 80% of cases after acute Wernicke’s encephalopathy and occurs rarely in other disorders. In the Western world, Wernicke’s lesions are found most commonly in alcoholics. In clinically based series, most patients with Wernicke’s encephalopathy present with a classic triad of encephalopathy, oculomotor dysfunction, and gait ataxia. The encephalopathy is characterized by profound disorientation, indifference, and inattentiveness. Some patients exhibit an agitated delirium related to ethanol withdrawal. Ocular motor abnormalities include nystagmus, lateral rectus palsy, and conjugate gaze palsy. Gait ataxia is common and is probably caused by a combination of polyneuropathy, midline cerebellar involvement, and vestibular paresis. In contrast, ataxia of the arms and dysarthria or scanning speech are infrequent. Computed tomography (CT) scanning may show symmetrical, low-density abnormalities in the diencephalon and periventricular regions, which enhance after contrast injection. Gross hemorrhages are uncommon in acute Wernicke’s encephalopathy but have also been detected by CT. Symmetrical areas of increased or decreased signal in the diencephalon, midbrain, and periventricular regions are uncommon in other disorders, and when present in alcoholics they should strongly suggest the diagnosis of acute Wernicke’s encephalopathy. However, the paucity of reports of such findings suggests that CT is an insensitive method for their detection. Magnetic resonance imaging (MRI) is more sensitive than CT in detecting acute diencephalic and periventricular lesions. Patients with acute Wernicke’s encephalopathy show increased T2 signal surrounding the aqueduct and third ventricle and within the medial thalamus and mamillary bodies, consistent with the localization of the pathologic lesions (Fig. 200-1). Corresponding areas of decreased T1 signal have also been detected. The alterations in T2 signal resolve over as little as 48 hours, leaving an enlarged aqueduct and third ventricle. The presence or absence of T2 signal abnormalities may be a function of the duration of time between thiamine treatment and imaging. Reversible increases in

signal intensity in characteristic brain regions are seen on diffusion-weighted images of patients with Wernicke’s encephalopathy treated with thiamine, suggesting a reversible component of extracellular edema. Clinical recognition of Wernicke’s encephalopathy is straightforward when alcoholics present with the classic triad of ataxia, oculomotor disorders, and encephalopathy. However, autopsybased series suggest that many patients lack one or more elements of this triad, and in some, lethargy or coma is the predominant clinical feature. In these patients, the diagnosis of Wernicke’s encephalopathy often is overlooked. Caine et al (1997) have proposed criteria for diagnosing Wernicke’s encephalopathy and Korsakoff ’s amnestic syndrome in chronic alcoholics. Wernicke’s encephalopathy is diagnosed in patients with two of the following four criteria: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, and either altered mental status or mild memory impairment. These criteria are clearly more sensitive than the classic triad; however, they are not specific enough, nor were they intended, to apply to a general population. Therefore, it is important to administer large dosages of parenteral thiamine (100 mg per day for 5 days) to all patients with undiagnosed altered mental status, oculomotor disorders, or ataxia. Gastrointestinal absorption of thiamine is erratic in alcoholic and malnourished patients, making oral administration of thiamine an unreliable treatment for Wernicke’s encephalopathy. With prompt administration of thiamine, ocular signs improve within hours to days and ataxia and confusion within days to weeks. However, a majority of patients are left with horizontal nystagmus, ataxia, and Korsakoff ’s amnestic syndrome. Korsakoff’s Amnestic Syndrome

Many alcoholic patients recovering from classic Wernicke’s encephalopathy exhibit the selective memory disturbance of Korsakoff ’s amnestic syndrome. This striking neurologic disorder is characterized by marked deficits in anterograde and retrograde memory, apathy, an intact sensorium, and relative preservation of long-term memory and other cognitive skills. Confabulation is a feature of some cases. One alcoholic poet passed an hour with me reciting flawlessly the works of Wordsworth but had no recollection of our meeting 1 minute after I stepped out of the room. Korsakoff ’s amnestic syndrome may develop without an antecedent episode of Wernicke’s encephalopathy. Some alcoholics with Wernicke’s lesions exhibit global abnormalities of higher cognitive function, leading to the mistaken diagnosis of Alzheimer’s disease. Indeed, alcohol-related dementia was diagnosed in 24% cognitively impaired residents of a long-term care facility, second only to Alzheimer’s disease. Mamillary body atrophy is a specific abnormality in patients with chronic lesions of Wernicke’s encephalopathy. A decrease in the volume of the mamillary bodies can be identified by MRI in approximately 80% of alcoholics with a history of classic Wernicke’s encephalopathy and is not found in control subjects, patients with Alzheimer’s disease, or alcoholics without a history of Wernicke’s encephalopathy, including those with liver disease (Fig. 200-2). Mamillary body atrophy can be imaged within 1 week of the onset of Wernicke’s encephalopathy. The finding of small mamillary bodies in a demented patient should raise the possibility that alcoholism and malnutrition have contributed to the dementia. Enlargement of the third ventricle and, by inference, shrinkage of the diencephalon have been reported in patients with chronic Wernicke’s encephalopathy. This finding clearly is less

Chapter 200

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FIG. 200-1. Resolution of areas of increased T2 signal in acute Wernicke’s encephalopathy. Increased T2 signal is seen surrounding the aqueduct (arrows, top left) and third ventricle (arrows, top right). A later study shows resolution of these abnormalities and enlargement of the aqueduct (lower left) and third ventricle (white arrows, lower right). (From Gallucci M, Bozzao A, Splendiani A et al: Wernicke encephalopathy: MR findings in five patients. AJNR 11:887–892, 1990, with permission.)

specific than mamillary body atrophy in diagnosing chronic Wernicke’s encephalopathy. Ventricular Enlargement and Cognitive Dysfunction in Alcoholics

Imaging studies, neuropathologic observations, and animal experimentation suggest that ethanol neurotoxicity may contribute to chronic cognitive dysfunction in alcoholics. However, there is as yet no unequivocal evidence for a brain lesion in humans that is caused solely by chronic ethanol ingestion and is unrelated to coexisting nutritional deficiency, liver disease, or trauma. Reductions in brain weight in alcoholics are small and inconsistently reported. Brain volume, estimated by the volume of the pericerebral space—the cerebrospinal fluid–filled region between the brain and skull—is lower in alcoholics than in controls, but this indirect measure of cerebral atrophy is most abnormal in alcoholics with liver disease or Wernicke’s encephalopathy. Quantitative morphometry suggests that alcoholics, including those with liver disease and Wernicke’s encephalopathy, lose a disproportionate amount of subcortical white matter as compared with cortical gray matter. This loss of cerebral white matter is also apparent when brains of nondemented alcoholics with liver disease are compared with those from patients with nonalcoholic liver disease; therefore, liver disease cannot be the sole cause of this selective loss of brain tissue. The loss of cerebral white matter is evident across a wide range of ages, is not accentuated in the frontal lobes, and is of sufficient magnitude (6% to 17%) to account for the associated

ventricular enlargement. Gene microarray analysis of alcoholic and normal brain revealed a selective downregulation of myelinrelated genes in the alcoholic brains. Effects of ethanol on myelin-related gene expression or on the integrity of oligodendroglia could therefore contribute to the predilection of alcoholics to develop loss of cerebral white matter, central pontine myelinolysis, and Marchiafava-Bignami disease. CT and MRI show enlargement of the cerebral ventricles and sulci in a majority of alcoholics (Fig. 200-2), but when corrected for the effects of aging, the radiographic indices do not correlate consistently with either the duration of drinking or the severity of cognitive impairment. The ventricles and sulci become significantly smaller within about 1 month of abstinence, whereas brain water, estimated by MRI or chemical analysis, does not change consistently. Based on these findings, it has been hypothesized that changes in brain parenchyma, but not brain water, may account for the reversible radiographic and cognitive abnormalities of alcoholics. Reversible brain shrinkage, as determined by neuroimaging, is a nonspecific abnormality that has also been documented after treatment of anorexia nervosa and Cushing’s syndrome. Alcoholic Cerebellar Degeneration

Some alcoholic patients develop a chronic cerebellar syndrome related to the degeneration of Purkinje cells in the cerebellar cortex. Midline cerebellar structures, especially the anterior and superior vermis, are predominantly affected, a pattern identical to that in Wernicke’s encephalopathy. Alcoholic cerebellar degenera-

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A

B

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D

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FIG. 200-2. MRI of chronic Wernicke’s encephalopathy. (A) Normal control. (B) Alzheimer’s disease. (C) Chronic Wernicke’s encephalopathy. T1-weighted sagittal (left) and coronal (right) images in the plane of the mamillary bodies (arrows). The patient with Wernicke’s encephalopathy shows atrophy of the mamillary bodies (arrows) and anterior superior cerebellar vermis (arrowheads) and enlargement of the third ventricle (black arrowheads), lateral ventricles, interhemispheric fissure (white arrowheads), and cerebral sulci (white arrowhead). The patient with Alzheimer’s disease exhibits greater cerebral atrophy and ventricular enlargement than the patient with Wernicke’s encephalopathy yet shows larger mamillary bodies. Images were acquired using TR 600, TE 25. (From Charness ME, DeLaPaz RL: Mamillary body atrophy in Wernicke’s encephalopathy: antemortem identification using magnetic resonance imaging. Ann Neurol 22:595–600, 1987, with permission.)

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FIG. 200-3. MRI of Marchiafava-Bignami syndrome. T1-weighted image shows a cystic region of decreased signal throughout the corpus callosum (arrows). There is also atrophy of the mamillary bodies and anterior superior cerebellar vermis. (Courtesy of Professor Jacques Thie´bot, Centre Hospitalier University de Rouen.)

tion typically occurs only after 10 or more years of excessive ethanol use. It is usually a gradually progressive disorder that develops over weeks to months but may also evolve over years or commence abruptly. Mild and apparently stable cases may become suddenly worse. As in Wernicke’s encephalopathy, ataxia affects the gait most severely. Limb ataxia and dysarthria occur more often than in Wernicke’s encephalopathy, whereas nystagmus is rare. The diagnosis of alcoholic cerebellar degeneration is based on the clinical history and neurologic examination. CT or MRI scans may show cerebellar vermian atrophy (Figs. 200-2 and 200-3), but one half of alcoholic patients with this finding are not ataxic on examination. It is unclear whether these represent subclinical cases in which symptoms will develop subsequently. Marchiafava-Bignami Disease

Marchiafava-Bignami disease is a rare disorder of demyelination or necrosis of the corpus callosum and adjacent subcortical white matter, which occurs predominantly in malnourished alcoholics. In some cases there are associated lesions of Wernicke’s encephalopathy or selective neuronal loss and gliosis in the third cortical layer. A few cases have been described in nonalcoholics, demonstrating that ethanol alone is not responsible for the lesion. The course may be acute, subacute, or chronic and is marked by dementia, spasticity, dysarthria, and inability to walk. Patients may lapse into coma and die, survive for many years in a demented condition, or occasionally recover. An interhemispheric disconnection syndrome has been reported in survivors. The disorder was formerly diagnosed only at autopsy, but lesions can now be imaged using CT or MRI. CT may demonstrate hypodense areas in portions of the corpus callosum. MRI typically shows cystic areas of decreased T1 signal (Fig. 200-3) or increased T2 signal (Fig. 200-4). The abnormalities may be limited to one region of the

FIG. 200-4. MRI of Marchiafava-Bignami syndrome. The splenium of the corpus callosum shows an area of increased T2 signal (arrow). (TR 2000, TE 40). (From Charness ME: Brain lesions in alcoholics. Alcohol Clin Exp Res 17:2–11, 1993, with permission.)

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corpus callosum or may be present diffusely throughout the corpus callosum. The CT and MRI findings may persist after the resolution of clinical signs, but resolution of imaging abnormalities has also been reported. Alcoholics without liver disease, amnesia, or cognitive dysfunction show thinning, particularly in the genu and body of the corpus callosum on MRI, suggesting that some involvement of the corpus callosum occurs in the absence of the necrotic lesions of Marchiafava-Bignami disease. Central Pontine Myelinolysis

Central pontine myelinolysis is a disorder of cerebral white matter that usually affects alcoholics but also occurs in nonalcoholics with liver disease, including Wilson’s disease, malnutrition, anorexia, burns, cancer, Addison’s disease, and severe electrolyte disorders, such as thiazide-induced hyponatremia. Central pontine myelinolysis often is associated with a rapid correction of hyponatremia; however, the majority of cases occur in alcoholics, suggesting that alcoholism may contribute to the genesis of central pontine myelinolysis, perhaps through effects on oligodendroglial function or myelin-related gene expression. The most common macroscopic lesion is a triangular region of pallor in the base of the pons. Approximately 10% of cases also show symmetrical extrapontine lesions, most often in the striatum, thalamus, cerebellum, and cerebral white matter. Microscopic examination reveals demyelinated axons with preserved cell bodies except in the center of lesions, which may reveal cavitation. Symptoms and signs of central pontine myelinolysis may be absent or obscured by associated conditions such as ethanol withdrawal, Wernicke’s encephalopathy, or hepatic encephalopathy. Treatment of these disorders may lead to an initial improvement in mental status, followed within days by confusion, lethargy, and coma caused by central pontine myelinolysis. Involvement of the corticospinal tracts causes paraparesis or quadriparesis, and demyelination of the corticobulbar tracts leads to dysarthria,

dysphagia, and inability to protrude the tongue. The tendon reflexes may be increased, decreased, or normal, and Babinski signs may be present. Disorders of conjugate eye movement occur occasionally and may reflect extension of the lesion in the pons or associated Wernicke lesions. Disproportionate involvement of motor function may produce the ‘‘locked-in’’ syndrome, with only limited ability to move the limbs or face despite a normal level of consciousness. The lesions of central pontine myelinolysis can be visualized using CT scanning or MRI. MRI is more sensitive than CT in imaging the pontine lesions; however, even MRI may be unremarkable early in the course of central pontine myelinolysis. The most common MRI finding is an area of decreased T1 signal or increased T2 signal within the basis pontis (Fig. 200-5). CT and MRI have also detected symmetrical extrapontine abnormalities in patients suspected of having central pontine myelinolysis. Other disorders, such as multiple sclerosis, multi-infarct dementia, and encephalitis, may produce areas of increased T2 signal in the pons that resemble those of central pontine myelinolysis, but these conditions also cause significant periventricular abnormalities and a distinctive clinical picture. Serial CT or MRI studies indicate that the radiographic lesions of central pontine myelinolysis may resolve in parallel with patient recovery; therefore, the absence of lesions on MRI does not exclude a past episode of central pontine myelinolysis. Because small lesions of central pontine myelinolysis may be asymptomatic, typical MRI abnormalities can be an incidental finding in seriously ill patients. Ethanol Neurotoxicity in the Developing Nervous System

Brain lesions in alcoholics may antedate birth. Alcoholism runs in families, and many alcoholics have been exposed to high concentrations of alcohol during critical stages of brain development. Fetal alcohol syndrome is characterized by prenatal and postnatal growth retardation, microcephaly, neurologic abnormalities, facial dysmorphology, and other congenital anomalies. Ophthalmic

A

B

FIG. 200-5. MRI of central pontine myelinolysis in an alcoholic man. (A) T1-weighted sagittal image (TR 600, TE 25) reveals a sharply delineated zone of decreased signal in the midpons. (B) An axial image through the same region shows a triangular area of increased T2 signal (TR 2000, TE 70). (From Charness ME: Brain lesions in alcoholics. Alcohol Clin Exp Res 17:2–11, 1993, with permission.)

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FIG. 200-6. MRI showing agenesis of the corpus callosum after gestational exposure to alcohol. (A) Normal 13-year-old girl. (B) 13-year-old boy with fetal alcohol syndrome and focal thinning (arrow) of the corpus callosum. (C) 14-year-old boy with fetal alcohol syndrome and agenesis of the corpus callosum. (Courtesy of Dr. Edward P. Riley, San Diego State University.)

abnormalities are common, including optic nerve hypoplasia, retinal vessel tortuosity, and impaired vision. More often, heavy intrauterine exposure to ethanol is associated with a constellation of less severe fetal alcohol effects, including mental retardation, behavioral abnormalities, attention deficit hyperactivity disorder, intrauterine growth retardation, and minor, ungrouped congenital anomalies involving the cutaneous, genitourinary, musculoskeletal, and cardiac systems. The behavioral and neurologic abnormalities are called alcohol-related neurodevelopmental disorder. Neuropathologic examination in fetal alcohol syndrome reveals microcephaly, cerebellar dysplasia, agenesis of the corpus callosum, and neuronal-glial heterotopias, lesions consistent with the decreased proliferation and disordered migration of neurons. Overlapping neuropathologic abnormalities are observed in children with mutations in the gene for the L1 cell adhesion molecule, and cellular studies suggest that ethanol decreases L1-mediated cell adhesion. MRI in children with fetal alcohol syndrome has identified microcephaly, agenesis, or hypoplasia of the corpus callosum (Fig. 200-6) and selective reductions in the volume of the cerebrum, cerebellum, and basal ganglia. The severity of these macroscopic lesions is proportional to the degree of cognitive impairment. Agenesis of the corpus callosum occurs infrequently in the general population, and its presence on MRI in the retarded offspring of an alcoholic mother should suggest the possibility of a neurodevelopmental abnormality related to gestational alcohol exposure. PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF ALCOHOLISM Neuropathy

Alcoholic patients have a high incidence of peripheral nerve disorders, including symmetrical polyneuropathy and compression mononeuropathies. Alcoholic polyneuropathy is believed to result from inadequate nutrition, particularly from deficiencies of thiamine and other B vitamins. A direct, neurotoxic effect of ethanol may also contribute to this disorder because ethanol induces a disturbance of fast axonal transport that could promote alcoholic polyneuropathy. Alcoholic polyneuropathy is a gradually progressive disorder of sensory, motor, and autonomic nerves. The clinical abnormalities usually are symmetrical and predominantly distal. Symptoms include numbness, paresthesia, burning dysesthesia, pain, weakness, muscle cramps, and gait ataxia. The most common neurologic signs are loss of tendon reflexes, beginning with the ankle jerks, defective perception of touch and vibration sensation,

and weakness. Cardiac autonomic abnormalities are present in about one quarter of alcoholics with peripheral neuropathy. Autonomic nervous dysfunction is associated with increased mortality in alcoholics. ‘‘Saturday night palsies’’ occur when intoxicated patients fall asleep with their arms leaning against a firm surface, thereby compressing the radial nerve against the spiral groove of the humerus. Alcoholic polyneuropathy also renders patients susceptible to compression of peripheral nerves at common sites of entrapment, including the median nerve at the carpal tunnel, the ulnar nerve at the elbow, and the peroneal nerve at the fibular head. Because malnutrition may contribute to the development of alcoholic polyneuropathy, patients with this disorder should receive parenteral thiamine supplementation. Improved nutrition with cessation of drinking appears to be associated with a good prognosis for improvement. Low dosages of tricyclic antidepressants or gabapentin are sometimes effective in controlling the burning dysesthesias of alcoholic peripheral neuropathy. Myopathy

Skeletal myopathy is an underrecognized complication of alcohol abuse. Almost half of alcoholic patients visiting an ambulatory clinic and 60% of hospitalized alcoholics had biopsy evidence of myopathy. Skeletal muscle can be damaged by the administration of ethanol to well-nourished volunteers, and most patients with alcoholic myopathy are not demonstrably malnourished. Electrolyte abnormalities such as hypokalemia, which are often present in alcoholic patients, can also impair skeletal muscle function. However, studies of alcoholic patients and of ethanol-induced myopathy in rats show no correlation between hypokalemia and muscle damage. The biochemical basis for ethanol-induced muscle damage is unknown, although disturbances of sodium and potassium transport, mitochondrial function, calcium sequestration, and actin-myosin interaction have been proposed. Alcoholic myopathy may present as either an acute, necrotizing disorder or a more indolent process. The acute form develops over hours to days, often in relation to an alcoholic binge, and is characterized by weakness, pain, tenderness, and swelling of affected muscles. Animal studies suggest that fasting during a binge may precipitate muscle injury. Most affected patients are men. Proximal muscles are often most severely involved, but the distribution of involvement may be asymmetrical or focal. Dysphagia and congestive heart failure may occur. Laboratory findings include moderate to severe elevation of serum creatine

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kinase, myoglobinuria, fibrillations, and myopathic changes in the electromyogram and muscle fiber necrosis on biopsy; type I muscle fibers defined by their low myosin adenosine triphosphatase activity may be selectively vulnerable. Initial treatment is directed at correcting cardiac arrhythmias, renal failure caused by rhabdomyolysis, and electrolyte disturbances such as hypophosphatemia or hypokalemia. Abstinence from ethanol usually is associated with gradual recovery. Chronic alcoholic myopathy, which evolves over weeks to months, is a more common disorder. Pain is less prominent than in acute alcoholic myopathy, but muscle cramps may occur. On examination, the major findings are muscle weakness and atrophy, which affect predominantly the hip and shoulder girdles. Although a polyneuropathy coexists in many cases, the clinical and laboratory features of this disorder indicate a primary disturbance of muscle. Muscle biopsies show preferential atrophy of type II fibers defined by their high myosin adenosine triphosphatase activity. Serum creatine kinase is less elevated than in acute alcoholic myopathy, and myoglobinuria does not occur. Cessation of drinking leads to improvement in most cases, whereas continued heavy ethanol abuse results in clinical deterioration. SUGGESTED READINGS Adams RD, Victor M, Mancall EL: Central pontine myelinolysis. A hitherto undescribed disease occurring in alcoholic and malnourished patients. Arch Neurol 81:154–172, 1959 Aminoff MJ, Simon RP: Status epilepticus. Causes, clinical features and consequences in 98 patients. Am J Med 69:657–666, 1980 Bergui M, Bradac GB, Zhong JJ et al: Diffusion-weighted MR in reversible Wernicke encephalopathy. Neuroradiology 43:969–972, 2001 Brion S: Marchiafava-Bignami syndrome. pp. 317–329. In Vinken PJ, Bruyn GW (eds): Metabolic and Deficiency Diseases of the Nervous System, Part 2. North-Holland Publishing Company, Amsterdam, 1976 Caine D, Halliday GM, Kril JJ, Harper CG: Operational criteria for the classification of chronic alcoholics: identification of Wernicke’s encephalopathy. J Neurol Neurosurg Psychiatry 62:51–60, 1997 Cardellach F, Taraschi TF, Ellingson JS et al: Maintenance of structural and functional characteristics of skeletal-muscle mitochondria and sarcoplasmic-reticular membranes after chronic ethanol treatment. Biochem J 274:565–573, 1991 Carlen PL, McAndrews MP, Weiss RT et al: Alcohol-related dementia in the institutionalized elderly. Alcohol Clin Exp Res 18:1330–1334, 1994 Carlen PL, Wortzman G, Holgate RC et al: Reversible cerebral atrophy in recently abstinent chronic alcoholics measured by computed tomography scans. Science 200:1076–1078, 1978 Charness ME: Brain lesions in alcoholics. Alcohol Clin Exp Res 17:2–11, 1993 Charness ME: Intracranial voyeurism: revealing the mammillary bodies in alcoholism. Alcohol Clin Exp Res 23:1941–1944, 1999 Charness ME: Molecular mechanisms of ethanol intoxication, tolerance, and physical dependence. pp. 155–199. In Mendelson JH, Mello NK (eds): Diagnosis and Treatment of Alcoholism. McGraw-Hill, New York, 1992 Charness ME, DeLaPaz RL: Mamillary body atrophy in Wernicke’s encephalopathy: antemortem identification using magnetic resonance imaging. Ann Neurol 22:595–600, 1987 Charness ME, Simon RP, Greenberg DA: Ethanol and the nervous system. N Engl J Med 321:442–454, 1989 Clark CM, Li D, Conry J et al: Structural and functional brain integrity of fetal alcohol syndrome in nonretarded cases. Pediatrics 105:1096–1099, 2000 Daeppen JB, Gache P, Landry U et al: Symptom-triggered vs fixedschedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med 162:1117–1121, 2002

de la Monte SM: Disproportionate atrophy of cerebral white matter in chronic alcoholics. Arch Neurol 45:990–992, 1988 Diamond I, Gordon AS: Cellular and molecular neuroscience of alcoholism. Physiol Rev 77:1–20, 1997 D’Onofrio G, Rathlev NK, Ulrich AS et al: Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 340:915–919, 1999 Earnest MP, Feldman H, Marx JA et al: Intracranial lesions shown by CT scans in 259 cases of first alcohol-related seizures. Neurology 38:1561– 1565, 1988 Earnest M, Yarnell PR: Seizure admissions to a city hospital: the role of alcohol. Epilepsia 17:387–393, 1976 Feussner JR, Linfors EW, Blessing CL, Starmer CF: Computed tomography brain scanning in alcohol withdrawal seizures: value of the neurologic examination. Ann Intern Med 94:519–522, 1981 Flink EB: Therapy of magnesium deficiency. Ann N Y Acad Sci 162:901–905, 1969 Gallucci M, Bozzao A, Splendiani A et al: Wernicke encephalopathy: MR findings in five patients. AJNR 11:887–892, 1990 Harper CG, Giles M, Finlay-Jones R: Clinical signs in the WernickeKorsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 49:341–345, 1986 Harper CG, Kril JJ: Brain atrophy in chronic alcoholic patients: a quantitative pathological study. J Neurol Neurosurg Psychiatry 48:211– 217, 1985 Harper CG, Kril JJ, Holloway RL: Brain shrinkage in chronic alcoholics: a pathological study. BMJ 290:501–504, 1985 Hillbom M, Muuronen A, Holm L, Hindmarsh T: The clinical versus radiological diagnosis of alcoholic cerebellar degeneration. J Neurol Sci 73:45–53, 1986 Johnson RA, Noll EC, Rodney WM: Survival after a serum ethanol concentration of 1 1/2% [letter]. Lancet 2:1394, 1982 Lewohl JM, Wang L, Miles MF et al: Gene expression in human alcoholism: microarray analysis of frontal cortex. Alcohol Clin Exp Res 24:1873–1882, 2000 Martin F, Ward K, Slavin G et al: Alcoholic skeletal myopathy, a clinical and pathologic study. QJM 55:233–251, 1985 Mayo-Smith MF: Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA 278:144–151, 1997 McLean RM: Magnesium and its therapeutic uses: a review [review]. Am J Med 96:63–76, 1994 Mirsky IR, Piker P, Rosenbaum M, Lederer H: ‘‘Adaptation’’ of the central nervous system to varying concentrations of alcohol in the blood. Q J Stud Alcohol 2:35–45, 1941 Monforte R, Estruch R, Valls-Sole J et al: Autonomic and peripheral neuropathies in patients with chronic alcoholism. A dose-related toxic effect of alcohol. Arch Neurol 52:45–51, 1995 Ng SKC, Hauser WA, Brust JCM, Susser M: Alcohol consumption and withdrawal in new-onset seizures. N Engl J Med 319:666–673, 1988 Park SH, Kim M, Na DL, Jeon BS: Magnetic resonance reflects the pathological evolution of Wernicke encephalopathy. J Neuroimaging 11:406–411, 2001 Pfefferbaum A, Lim KO, Desmond JE, Sullivan EV: Thinning of the corpus callosum in older alcoholic men: a magnetic resonance imaging study. Alcohol Clin Exp Res 20:752–757, 1996 Ramanathan R, Wilkemeyer MF, Mittal B et al: Ethanol inhibits cell-cell adhesion mediated by human L1. J Cell Biol 133:381–390, 1996 Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW: Teratogenic effects of alcohol in humans and laboratory animals. Science 209:353– 361, 1980 Stromland K, Pinazo-Duran MD: Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies. Alcohol Alcoholism 37:2–8, 2002 Torvik A, Lindboe CF, Rodge S: Brain lesions in alcoholics. A neuropathological study with clinical correlation. J Neurol Sci 56:233–248, 1982

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Urbano-Marquez A, Estruch R, Navarro-Lopez F et al: The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 320:409–415, 1989 Urso T, Gavaler JS, Van Thiel DH: Blood ethanol levels in sober alcohol users seen in an emergency room. Life Sci 28:1053–1056, 1981 Victor M, Adams RD: The effect of alcohol on the nervous system. Res Public Assoc Nerv Ment Dis 32:526–573, 1953

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Victor M, Adams RA, Collins GH: The Wernicke-Korsakoff Syndrome and Related Disorders due to Alcoholism and Malnutrition. FA Davis, Philadelphia, 1989 Victor M, Brausch C: The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 8:1–20, 1967

201 Drug Dependence John C. M. Brust This chapter addresses drugs of dependence other than ethanol and tobacco, with an emphasis on phenomena likely to be encountered in ambulatory patients. It is worth remembering that the symptoms and signs associated with drug intoxication, overdose, or withdrawal are often predominantly neurologic. Space limitations here dictate cursory attention to diverse agents and syndromes. Further information on any of the topics discussed can be found in Brust (1993). DEFINITIONS Psychic dependence is a psychic drive (a craving) to administer a drug periodically or continuously to achieve pleasure or to avoid discomfort. Physical dependence is an adaptive state such that cessation of drug administration produces discomfort and objective physical signs. Depending on the drug and the setting, psychic and physical dependence can occur independently or together. Addiction is psychic dependence. Tolerance is the need for increasing dosages of a substance to achieve the same desired effect or to avoid withdrawal symptoms. It may be the result of enhanced metabolism of the drug or of poorly understood adaptive responses in the brain. Abuse is a social judgment that may be based on a drug’s perceived harmfulness or its legal status. In the United States the harm a drug does (as in the case of ethanol and tobacco, for example) has little to do with its legality. TYPES OF DRUGS: INTOXICATION AND WITHDRAWAL Opioids

Opioids include natural and synthetic agonists, antagonists, and mixed agonist-antagonists (Table 201-1). Acute effects of opioid agonists include euphoria or dysphoria, drowsiness, analgesia, nausea, vomiting, miosis, pruritus, dry mouth, sweating, suppression of the cough reflex, hypothermia, postural hypotension, respiratory depression, and constipation. Parenteral injection produces a ‘‘rush,’’ a brief ecstatic feeling, followed by more lasting euphoria and either drowsy ‘‘nodding’’ or garrulous hyperactivity. Heroin, which is metabolized to morphine, must be taken more than once daily to avoid withdrawal symptoms, and the mental clouding it produces prevents normal social or occupational functioning. It is usually injected intravenously (‘‘mainlining’’) or subcutaneously (‘‘skinpopping’’); fear of acquired immunodeficiency syndrome (AIDS) has made heroin sniffing and smoking increasingly popular. Methadone produces similar effects when

taken parenterally; maintenance methadone therapy for heroin addiction is oral once daily and in most patients produces little or no cognitive disturbance. Overdose from heroin or other antagonists produces the triad of coma, pinpoint (but reactive) pupils, and apnea. It is treated with respiratory support and titrated dosages of the antagonist naloxone. Because the effects of naloxone are short-lived, hospitalization and close observation are necessary. Withdrawal symptoms begin 4 to 6 hours after the last heroin dose and include irritability, lacrimation, rhinorrhea, sweating, yawning, myalgia, mydriasis, piloerection, nausea, vomiting, diarrhea, hot flashes, fever, tachypnea, tachycardia, muscle spasms, abdominal cramps, and orgasm. Craving is intense, but seizures, hallucinations, and delirium are not part of the syndrome, which in adults is rarely life-threatening. In neonates myoclonus and probably seizures do occur (they can be difficult to distinguish from jitteriness), and mortality is as high as 90% in untreated patients. Treatment of withdrawal in adults is with methadone and in infants with paregoric.

TABLE 201-1. Major Opioids Agonist Powdered opium Tincture of opium Camphorated tincture of opium (paregoric) Purified opium alkaloids Morphine Heroin Methadone Fentanyl Hydromorphone Codeine Oxycodone Meperidine Levorphanol Propoxyphene Antagonist Naloxone Naltrexone Mixed agonist-antagonist Pentazocine Butorphanol Nalbuphine Partial agonist Buprenorphine

Chapter 201 rn Drug Dependence

Torvik A, Lindboe CF, Rodge S: Brain lesions in alcoholics. A neuropathological study with clinical correlation. J Neurol Sci 56233-248, 1982 Urbano-Marquez A, Estruch R, Navarro-Lopez F et al: The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 320409-415, 1989 Urso T, Gavaler JS, Van Thiel DH: Blood ethanol levels in sober alcohol users seen in an emergency room. Life Sci 28:1053-1056, 1981

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Victor M, Adams RD: The effect of alcohol on the nervous system. Res Public Assoc Nerv Ment Dis 32526-573, 1953 Victor M, Adams RA, Collins GH: The Wernicke-KorsakoffSyndrome and Related Disorders due to Alcoholism and Malnutrition. FA Davis, Philadelphia, 1989 Victor M, Brausch C The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 8: 1-20, 1967

201 Drug Dependence John C. M. Brust This chapter addresses drugs of dependence other than ethanol and tobacco, with an emphasis on phenomena likely to be encountered in ambulatory patients. It is worth remembering that the symptoms and signs associated with drug intoxication, overdose, or withdrawal are often predominantly neurologic. Space limitations here dictate cursory attention to diverse agents and syndromes. Further information on any of the topics discussed can be found in Brust (1993). DEFINITIONS Psychic dependence is a psychic drive (a craving) to administer a drug periodically or continuously to achieve pleasure or to avoid discomfort. Physical dependence is an adaptive state such that cessation of drug administration produces discomfort and objective physical signs. Depending on the drug and the setting, psychic and physical dependence can occur independently or together. Addiction is psychic dependence. Tolerance is the need for increasing dosages of a substance to achieve the same desired effect or to avoid withdrawal symptoms. It may be the result of enhanced metabolism of the drug or of poorly understood adaptive responses in the brain. Abuse is a social judgment that may be based on a drug’s perceived harmfulness or its legal status. In the United States the harm a drug does (as in the case of ethanol and tobacco, for example) has little to do with its legality. TYPES OF DRUGS: INTOXICATION AND WITHDRAWAL

Opioids Opioids include natural and synthetic agonists, antagonists, and mixed agonist-antagonists (Table 201-1). Acute effects of opioid agonists include euphoria or dysphoria, drowsiness, analgesia, nausea, vomiting, miosis, pruritus, dry mouth, sweating, suppression of the cough reflex, hypothermia, postural hypotension, respiratory depression, and constipation. Parenteral injection produces a “rush,” a brief ecstatic feeling, followed by more lasting euphoria and either drowsy “nodding” or garrulous hyperactivity. Heroin, which is metabolized to morphine, must be taken more than once daily to avoid withdrawal symptoms, and the mental clouding it produces prevents normal social or occupational functioning. It is usually injected intravenously (“mainlining”) or subcutaneously (“skinpopping”); fear of acquired immunodeficiency syndrome (AIDS) has made heroin sniffing and smoking increasingly popular. Methadone produces similar effects when

taken parenterally; maintenance methadone therapy for heroin addiction is oral once daily and in most patients produces little or no cognitive disturbance. Overdose from heroin or other antagonists produces the triad of coma, pinpoint (but reactive) pupils, and apnea. It is treated with respiratory support and titrated dosages of the antagonist naloxone. Because the effects of naloxone are short-lived, hospitalization and close observation are necessary. Withdrawal symptoms begin 4 to 6 hours after the last heroin dose and include irritability, lacrimation, rhinorrhea, sweating, yawning, myalgia, mydriasis, piloerection, nausea, vomiting, diarrhea, hot flashes, fever, tachypnea, tachycardia, muscle spasms, abdominal cramps, and orgasm. Craving is intense, but seizures, hallucinations, and delirium are not part of the syndrome, which in adults is rarely life-threatening. In neonates myoclonus and probably seizures do occur (they can be difficult to distinguish from jitteriness), and mortality is as high as 90% in untreated patients. Treatment of withdrawal in adults is with methadone and in infants with paregoric.

TABLE 201-1. Major Opioids Agonist Powdered opium Tincture of opium Camphorated tincture of opium (paregoric) Purified opium alkaloids Morphine Heroin Methadone Fentanyl Hydromorphone Codeine Oxycodone Meperidine Levorphanol Propoxyphene Antagonist Naloxone Naltrexone Mixed agonist-antagonist Pentazocine Butorphanol Nalbuphine Partial agonist Buprenorphine

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Psychostimulants Psychostimulants include amphetamine-like drugs and cocaine; the major drugs in this category are the following: Dextroamphetamine Methamphetamine Methylphenidate Phenmetrazine Diethylpropion Fenfluramine Phenylpropanolamine Ephedrine Pseudoephedrine Cocaine The major psychic effects probably are the result of dopamine agonism; in addition, cocaine has local anesthetic properties. Amphetamine-like drugs are taken orally or parenterally; methamphetamine can be smoked (“ice”). Cocaine hydrochloride is taken intranasally or parenterally; alkaloidal cocaine (“crack”) is smoked. Acutely, psychostimulants produce euphoria and increased motor activity. Taken parenterally or smoked, they produce a “rush” that is subjectively different from an opioid rush. With repeated psychostimulant use stereotypic movements progress to bruxism and other dyskinesias, paranoia progresses to frank hallucinatory psychosis, and, especially with cocaine, there may be seizures. Overdose causes excitement, delirium, headache, chest pain, fever (sometimes severe), hypertensive crisis, tachycardia and atrial or ventricular arrhythmias, myoglobinuria, seizures, metabolic acidosis, coma, and death. Treatment is complex and, depending on symptoms, includes benzodiazepines, oxygen, bicarbonate, anticonvulsants,antihypertensives, cardiorespiratory monitoring, and cooling. Psychostimulant withdrawal produces few objective signs. There is exhaustion, hunger, and depression, which may be severe and necessitate hospitalization. Craving can be intense.

Sedative Drugs Sedative drugs include barbiturates, benzodiazepines, and miscellaneous agents (Table 201-2). Some recently developed sedative drugs, such as buspirone and zolpidem, are believed to be free of dependence liability; sedative effects resemble ethanol intoxication; there is euphoria or dysphoria, impaired judgment, sleepiness, and ataxia. Overdose causes coma and respiratory depression (far less pronounced with benzodiazepines than with barbiturates or ethanol). Withdrawal causes tremor, seizures, and, with barbiturates, potentially fatal delirium tremens. Treatment of overdose or withdrawal often necessitates intensive care.

Cannabinoids Marijuana is made from the tops and leaves of the hemp plant, Cannabis sativa, which contains numerous cannabinoid compounds, of which 8-9-tetrahydrocannabinol (8-9-THC) is the principal psychoactive ingredient. Hashish, made from plant resin, has a high concentration of 6-9-THC. Acutely, marijuana causes relaxed dreamy euphoria (“stoned), often with jocularity or silliness; there may be drowsiness, depersonalization, subjective time-slowing, conjunctival injection, tachycardia, and hyperten-

TABU201-2. Major Sedatives and Hypnotics Barbiturates Amobarbital Butalbital Pentobarbital Phenobarbital Secobarbital Benzodiazepines Alprazolam Chlordiazepoxide Diazepam Lorazepam Oxazepam flurazepam Triazolam Nonbarbiturates and nonbenzodiazepines Bromides Chloral hydrate Ethchlorvynol Clutethimide Meprobamate Methaqualone Methyprylon Paraldehyde

sion or postural hypotension. Higher dosages impair judgment and coordination, and very high dosages cause illusions or hallucinations and excitement or depression. Regular doses sometimes cause paranoia or panic, but fatal overdose has never been documented, and intoxication usually does not necessitate treatment. Withdrawal can produce nervousness, headache, and craving, but objective signs are not evident.

Hallucinogens For thousands of years hallucinogenic plants have been used ritualistically and recreationally.Today both natural and synthetic products are available in the United States, and during the early 1990s their popularity increased among American adolescents. The three major categories of hallucinogens are as follows: Ergot-derived d-lysergic acid diethylamide (LSD) Indolalkylamines: psilocybin, psilocin Phenylalkylamines: mescaline, dimethoxymethylamphetamine, dimethoxyethylamphetamine, methylenedioxyamphetamine, methylenedioxymethamphetamine(“ecstasy”) Among these, methylenedioxymethamphetamine has both hallucinogenic and amphetamine-like effects. Drugs such as mescaline, psilocybin, and LSD produce illusions or hallucinations, often visual, formed, and elaborate, as well as depersonalization,elation, or paranoia and, variably, tremor, ataxia, tachycardia, hypertension, and fever. Adverse reactions can lead to panic, accidents, or suicide, and some users have flashbacks (the spontaneous reappearance of symptoms days or weeks after use). Treatment of overdose usually consists of calm reassurance. Benzodiazepines can be given for severe agitation. There are no withdrawal symptoms.

Household Products Used as Recreational Inhalants Among the products recreationally inhaled are aerosols (e.g., refrigerants, hair sprays, antiseptics), spot removers, glues, lighter fluid, fingernail polish remover, bottled fuel gas, paints, thinners, gasoline, anesthetics, and room odorizers (amyl or butyl nitrite).

Chapter 201 w

Users often are children. Although the compounds inhaled are quite different (e.g., halogenated hydrocarbons, n-hexane, toluene, butane, nitrous oxide), their acute effects are similar and resemble ethanol intoxication. The need to inhale provides a check against overdose, but fatalities have resulted from accidents, cardiac arrhythmia, suffocation, or aspiration of vomitus. Treatment of overdose is focused on cardiorespiratory monitoring. There does not appear to be a withdrawal syndrome, but psychic dependence is common. Phencyclidine Phencyclidine (“angel dust”) was introduced as an anesthetic but withdrawn because it caused psychosis. It can be eaten, snorted, or injected but is usually smoked, often with marijuana. Low dosages produce euphoria or dysphoria, emotional lability, a sense of time-slowing, and a feeling of numbness. Higher dosages cause sensory illusions, amnesia, agitation, burst nystagmus, sweating, hypersalivation, tachycardia, hypertension, and fever. With overdose there is psychosis with hallucinations or catatonia, dystonia, myoclonus, seizures, rhabdomyolysis, stupor (with a blank stare), and cardiorespiratory collapse. Treatment includes a quiet environment (trying to “talk down” agitation only increases it), continuous gastric suctioning, activated charcoal, forced diuresis, cardiorespiratory monitoring, and, as needed, antihypertensives, anticonvulsants,benzodiazepines, or neuroleptics. However, neuroleptics can aggravate seizures, hypotension, or myoglobinuria. Symptoms can last days or even weeks. Although abstinence can produce craving, evidence of physical dependence is difficult to discern. Antichollnergic Drugs Around the world a number of plants are ingested recreationally for their anticholinergic properties. In the United States the most popular is the jimson weed, Datura stramonium. Users often are children. Other abused anticholinergic agents include antiparkinsonian drugs, antihistamines, and tricyclic antidepressants, especially amitriptyline. The desired effect is euphoria, but higher dosages produce dry mouth, decreased sweating, tachycardia, mydriatic unreactive pupils, urinary retention, delirium, hallucinations, seizures, and coma. The diagnosis is confirmed with physostigmine, which can then be continued in titrated dosages as treatment. Other measures include gastric suctioning, activated charcoal, magnesium sulfate, cooling, bladder catheterization, fluids, cardiorespiratory monitoring, and anticonvulsants as needed. Phenothiazines are contraindicated. Symptoms can last days (especially mydriasis), but fatalities are unusual. Few anticholinergic abusers use the drug on a daily basis, but some do develop withdrawal craving, tremor, nausea, and vomiting. MEDICAL AND NEUROLOGIC COMPLICATIONS Trauma

Violence among drug abusers has different causes. It may be secondary to altered behavior induced by the drug, to predatory activities necessary to procure it, or to the lifestyles and business methods of drug traffickers. In contrast to alcohol, which causes violence largely of the first type, violence and trauma associated with illicit drugs are overwhelmingly the consequence of activities related to their illegality. In 1986, for example, one third of male

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homicides in Manhattan were drug-related,and in 1987 more than 40% of New York City felony indictments were for drug law violations. Before the AIDS epidemic, the case fatality rate for New York City heroin addicts was 1% to 2% yearly, and approximately 40% of deaths were from violence. Marijuana impairs judgment and coordination and contributes to automobile accidents. So do sedatives, including long-acting benzodiazepines taken the day before, which can interact synergistically with ethanol. Especially in older adults, sedatives can produce paradoxical hyperactivity or agitation. Paranoia induced by psychostimulantsand phencyclidine can make users a danger to others. Inhalant and hallucinogen users are prone to fatal accidents; some have committed self-mutilation and suicide. Infection Parenteral drug use of any kind causes infections that can affect the nervous system. Hepatitis predisposes to hepatic encephalopathy and hemorrhagic stroke. Endocarditis, bacterial or fungal, causes cerebral infarction or abscess, meningitis, and intracerebral or subarachnoid hemorrhage from ruptured septic (“mycotic”) aneurysm. Vertebral osteomyelitis can cause radiculopathy or myelopathy, and cellulitis or local abscesses can damage peripheral nerves. Tetanus, especially common in skin-poppers, tends to be severe in parented drug users, often necessitating weeks of intensive care with neuromuscular blockade. Botulism can result from local wound infection or, in intranasal cocaine users, from infected nasal sinuses. Malaria has occurred in epidemic form among needle sharers. As of 2001, nonhomosexual drug abusers made up 25% of AIDS cases reported to the U.S.Centers for Disease Control, and an additional 6% were male homosexual or bisexual drug users. In New York City roughly two thirds of subjects receiving methadone maintenance treatment are human immunodeficiency virus (HIV)-seropositive. Drug abusers with AIDS are subject to the same neurologic complications that affect other risk groups. Related to their often low socioeconomic status, they are at special risk of tuberculosis, including drug-resistant strains, and syphilis, which in such subjects, despite negative blood serology, can progress with unexpected rapidity to tertiary forms of neurosyphilis. Although parented drug abusers are continually bombarding their immune systems with foreign material and a number of drugs (including ethanol) are themselves immunosuppressant, drug abuse per se does not appear to accelerate the emergence of AIDS in HIV-seropositive subjects. Parenteral drug users often are seropositive for the retrovirus human T-cell lymphotropic virus type I (HTLV-I), and myelopathy has been reported in some. seizures

Seizures in drug abusers may be secondary to stroke, infection, recent or remote head injury, or concomitant use of ethanol. With some drugs, seizures are a feature of intoxication and, with others, of withdrawal. Although opioids lower seizure threshold, seizures are seldom encountered during heroin intoxication or overdose, and, except in neonates, they are not a feature of withdrawal. In either setting, therefore, additional disease (e.g., other drugs, meningitis, or head injury) must be sought. For reasons that remain unclear, heroin use is a risk factor for new-onset seizures not temporally related to

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use and independent of other risk factors, such as trauma or ethanol. Seizures have occurred during intoxication from parenterally administered pentazocine combined with the antihistamine tripelennamine (“T’s and blues”), popular in the Midwest in the 1980s. Seizures are common during psychostimulant intoxication. With amphetamine-like drugs overdose usually is obvious. Perhaps because of the drug’s local anesthetic properties, cocaine users appear to be more seizure-prone. Seizures often complicate overdose but can also occur without other signs of toxicity, sometimes emerging after extended use in a fashion suggestive of reverse tolerance or electrical kindling. Difficultto-control status epilepticus is not unusual. Seizures have also occurred in users of the over-the-counter diet remedy and decongestant phenylpropanolamine. Sedatives, including benzodiazepines, can cause seizures as a withdrawal phenomenon. Some sedatives, notably methaqualone (no longer available in the United States) and glutethimide, have reportedly caused seizures during intoxication. A case control study found marijuana to be protective against new-onset seizures. A possible explanation is the constituent cannabidiol, which is an anticonvulsant. Although in low dosages it is an anticonvulsant, phencyclidine overdose often is complicated by seizures or myoclonus. Seizures are also sometimes encountered during intoxication from hallucinogens, inhalants, or anticholinergics. Stroke

That tobacco and heavy ethanol use are risk factors for stroke was established by epidemiologic case control and cohort studies. By contrast, the relationship of illicit drug use to stroke is based on case reports and small series. Parented drug users are at risk for stroke secondary to endocarditis, hepatitis, meningitis, or AIDS. Heroin nephropathy can cause hemorrhagic stroke. Occlusive and, less often, hemorrhagic strokes have also occurred in young heroin users without systemic disease or other risk factors. Cerebral angiography in some has suggested vasculitis. Hypotension accompanying heroin overdose can result in infarction of cerebral border zones and end zones. Intracranial hemorrhage, probably related to acute hypertension, has complicated amphetamine intoxication. Hemorrhagic and occlusive strokes without other obvious signs of overdose also occur in chronic users of amphetamine-like psychostimulants. In some, autopsy reveals systemic and cerebral vasculitis of mediumsized arteries, suggestive of polyarteritis nodosa. In others, changes more resemble small vessel hypersensitivity angiitis. However, the diagnosis of vasculitis often has been based on nonspecific angiographic signs, such as beading. By 2001 more than 400 strokes, including stroke in neonates, had been reported in association with cocaine. Roughly half were occlusive and half hemorrhage, and of those with intracranial hemorrhage who received angiography (or autopsy), roughly half had a saccular aneurysm or a vascular malformation. Occlusive strokes have included transient ischemic attacks and infarction of cerebrum, thalamus, brainstem, spinal cord, and retina. Possible mechanisms for stroke include cardioembolism in association with cocaine-induced myocardial infarction or cocaine cardiomyopathy, hypertensive surges during intoxication, and cerebral vasospasm. Cerebral vasculitis has been infrequently observed, and some autopsy cases have excluded it. For unclear reasons, cocaine

hydrochloride is more often associated with hemorrhagic stroke, and alkaloidal cocaine is associated with occlusive and hemorrhagic stroke with roughly equal frequency. The rising prevalence of stroke since the “crack epidemic began in the 1980s probably is related to plentiful supplies of an inexpensive drug taken in high dosages rather than to specific pharmacologic risk. Cocaine also influences platelet function and clotting factors. LSD, a vasoconstrictor, has caused occlusive stroke in young users. Phencyclidine, also a vasoconstrictor, has caused both hemorrhagic stroke and hypertensive encephalopathy. Altered Mentation

Whether abuse of drugs other than ethanol directly leads to lasting changes in cognition or behavior is a chicken versus egg question. Predrug psychometric baselines are seldom available, and although there is no such thing as an addictive personality, many psychopathologic conditions are overrepresented among users of illicit agents. Additional confounders include concomitant ethanol use and many of the systemic and neurologic complications of drug use already discussed. Heroin and other opioids appear to have little direct long-term adverse effect on cognition. Tolerant addicts tend to be depressed, apathetic, irritable, and socially withdrawn, but most patients receiving methadone maintenance therapy have normal social and occupational function. Suggesting reverse tolerance, chronic amphetamine and cocaine users become progressively paranoid, sometimes to frank hallucinatory psychosis, but such symptoms clear with abstinence. Less certain is how long withdrawal depression can last. It has been speculated that chronic cocaine use causes lasting dopamine depletion in the limbic “reward circuit,” producing a chronic anhedonic state. On the other hand, many psychostimulant abusers are unwittingly treating preexisting depression (or, in some instances, attention deficit disorder). Computed tomography scans in chronic cocaine users has revealed cerebral atrophy, with ventricular and sulcal enlargement, and positron emission tomography and single photon emission computed tomography imaging have suggested patchy decreases in cerebral blood flow. An alleged “antimotivational syndrome” in marijuana users consists of diminished drive, apathy, inattentiveness, decreased recent memory, and impaired visuomotor performance. Studies of such a relationship, conducted in many countries, have been conflicting, and, as with other drugs, even when such symptoms are found, it is difficult to distinguish cause from effect. Although there is tolerance to the hypnotic effects of barbiturates, chronic users, with or without dosage escalation, often display lethargy, inattentiveness, and social deterioration. In small children barbiturates impair learning. Whether such effects are permanent is unclear. In older adults, barbiturates cause reversible dementia (as well as falls), and in both children and older adults they can cause paradoxical hyperactivity or agitation. In addition to drowsiness, benzodiazepines can cause amnesia lasting hours, including the day after their use as sleeping pills. Paradoxical agitation, confusion, and even hallucinations have been attributed to the benzodiazepine triazolam, although much of the “evidence” has been from the popular media rather than from the scientific literature. Long-term benzodiazepine use, with or without physical dependence, appears to be without lasting cognitive or behavioral consequence. Bromides, long associated with chronic cognitive impairment, are no longer present in over-the-counter sleeping pills.

Chapter 201

Toluene sniffers have developed dementia with cerebral white matter changes, and gasoline sniffers have had lead encephalopathy. The weight of evidence is against permanent mental change associated with hallucinogen use, but anxiety, depression, and insomnia have lasted weeks after use of “ecstasy,” and LSD flashbacks have precipitated suicide. Much attention has been paid to the psychopharmacology of phencyclidine, which, unlike amphetamine, reproduces both the “positive” (paranoia, delusions) and “negative” (loss of ego boundaries, apathy, loose associations) effects of schizophrenia. Psychotic symptoms can last days or weeks after single doses of phencyclidine, and chronic users often demonstrate persistent cognitive and behavioral abnormalities. As with other drugs, causality is difficult to establish. Anticholinergic abuse does not appear to cause lasting mental impairment. Fetal Effects

Similarly problematic are possible effects of illicit drugs on fetal development. Pregnant substance abusers often avoid prenatal care, abuse ethanol and tobacco, and after delivery are suboptimal mothers. In utero exposure to opioids (including methadone) can cause a severe withdrawal syndrome, and such children often are small for gestational age and at risk for respiratory distress and sudden infant death. Hyperactivity, sleep disturbances, and cognitive impairment have been reported in later life. Others claim that such abnormalities tend to be outgrown. In utero cocaine exposure has been associated with abruptio placentae, retarded fetal growth, microcephaly, and numerous congenital malformations, including those of the brain, spinal cord, and eye. However, meta-analysis of a number of such reports identified significant risk only for intrauterine death and genitourinary malformations. A prospective controlled study found a high incidence of hypertonus resembling cerebral palsy, which tended to clear within the first 2 years of life. Marijuana smoking during pregnancy is associated with decreased birth weight and length. Reports related to cognition and behavior have been inconsistent. Detrimental cognitive effects of barbiturates on small children raises the fear that in utero exposure would be even more harmful, but evidence of such an association with either barbiturates or benzodiazepines is lacking.

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dine. Symptoms responded dramatically to levodopa but recurred when it was stopped. Positron emission tomography has shown reduced numbers of dopaminergic neurons in asymptomatic subjects exposed to methylphenyltetrahydropyridine, raising the fear that parkinsonism will emerge as they grow older. A heroin user whose mixture contained large amounts of quinine became blind; vision improved when he switched to heroin lacking quinine. Chronic cocaine use induces dystonia and other dyskinesias in a pattern suggestive of reverse tolerance, and abnormal movements can persist for days or weeks despite abstinence. Cocaine has precipitated symptoms in otherwise well-controlled patients with Tourette’s syndrome. Marijuana inhibits luteinizing hormone and folliclestimulating hormone, causing impotence and sterility in men and menstrual irregularity in women. Symptoms are reversible with abstinence. Cerebellar ataxia, with white matter changes, occurs in toluene sniffers. European smokers of heroin pyrolysate (“chasing the dragon”) have developed acute dementia, ataxia, quadriparesis, chorea, blindness, and death. Autopsies reveal cerebral white matter spongiform change. The responsible toxin has not been identified.

CONCLUSION Regarding substance abuse, a physician should keep several general points in mind Drug abusers are in no way stereotypical. Higher education, occupational success, and elevated socioeconomic standing do not exclude abuse of any substance. Many drug abusers use more than one substance, including ethanol, leading to complex and confusing symptoms and signs. In fact, someone might be simultaneously intoxicated from one substance while withdrawing from another. In known substance abusers, medical and neurologic complications as described in this chapter should be suspected or anticipated. Conversely, in patients with trauma, seizures, infection, stroke, and cognitive or behavioral change, drug abuse should be considered.

SUGGESTED READINGS MSscellaneous Effects

Heroin has been associated with Guillain-Barri peripheral neuropathy and with brachial and lurnbosacral plexopathy, probably immune-mediated. Brachial neuropathy has also occurred secondary to compression by a subclavian artery septic aneurysm. Angiography should be considered in such patients. Severe sensorimotor peripheral neuropathy affects sniffers of glue containing n-hexane. Polyneuropathy has also affected gasoline sniffers. Rhabdomyolysis and renal failure can occur in users of heroin or cocaine with or without other signs of intoxication. Rhabdomyolysis in users of amphetamine or phencyclidine usually accompanies other obvious signs of overdose. Myopathy affects gasoline and toluene sniffers. Severe parkinsonism in California drug users was traced to a synthetic opioid contaminated with methylphenyltetrahydropyri-

Barnes PF, Bloch AB, Davidson PT, Snider D E Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324:1644, 1991

Britton CB: HIV infection. Neurol C h 11:605, 1993 Brust JCM Neurological Aspects of Substance Abuse. ButterworthHeinemann, Stoneham, MA, 1993 Brust JCM, Dickinson PCT, Hughes JEO, Holtzman RHH.The diagnosis and treatment of cerebral mycotic aneurysms. Ann Neurol 22238, 1990

Chiriboga CA Fetal effects. Neurol Clin 11:707, 1993 Chiriboga CA, Bateman DA, Brust JCM, Hauser WA Neurological outcome of neonates exposed in-utero to cocaine. Pediatr Neurol 9115, 1993

Earnest M P Seizures. Neurol Clin 11:563, 1993 Goldfrank LR, Bresnitz EA: Opioids. p. 433. In Goldfrank LR, Flomenbaum NE, Levin NA et al (eds): Toxicologic Emergencies. 4th Ed. Appleton & Lange, Norwalk, CT, 1990

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Goldfrank LR, Hoffman RS: The cardiovascular effects of cocaine. Ann Emerg Med 20165, 1991 Holman BL, Carvalho PA, Mendelson J et al: Brain perfusion is abnormal in cocaine-dependent polydrug users: a study using technetium-99MHMPAO and ASPECT. J Nucl Med 32:1206, 1991 Jannsen RS, Kaplan JE, Khabbaz RF et al: HTLV-1 associated myelopathy/ tropical spastic paraparesis in the United States. Neurology 41:1355, 1991

Kiokkinos J, Levine S R Stroke. Neurol Clin 11:577, 1993 Levine SR, Brust JCM, Futrell N et al: Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 323:699, 1990

Levine SR, Brust JCM, Futrell N et al: A comparative study of the cerebrovascularcomplications of cocaine: alkaloidal versus hydrochloride: a review. Neurology 41:1173, 1991 Lutiger B, Graham K, Einarson TR, Koren G: Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 44405, 1991 Musher DM, Hammill RJ, Baughn RE: The effect of human immunodeficiency virus infection on the course of syphilis and the response to treatment. Ann Intern Med 113:872, 1990

Ng SKC, Brust JCM, Hauser WA, Susser M Illicit drug use and the risk of new onset seizures: contrasting effects of heroin, marijuana, and cocaine. Am J Epidemiol 40:1017, 1990 Pascual-Leone A, Anderson DC: Cerebral atrophy in habitual cocaine abusers: a planimetric CT study. Neurology 41:34, 1991 Pascual-Leone A, Dhuna A Cocaine-associatedmultifocal tics. Neurology 40:999, 1990

Pascual-Leone A, Dhuna A, Altafallah I, Anderson D C Cocaine-induced seizures. Neurology 40404, 1990 Richter RW: Infections other than AIDS. Neurol Clin 11:591, 1993 Selwyn PA, Alcabes P, Hartel D et al: Clinical manifestations and predictors of disease progression in drug users with human immunodeficiency virus infection. N Engl J Med 327:1697, 1992 Shafer SQ: Disorders of spinal cord, nerve, and muscle. Neurol Clin 11:693, 1993

Weinrieb RM, O’Brien C P Persistent cognitive deficits attributed to substance abuse. Neurol Clin 11:663, 1993

202 Neurologic Complications of Commonly

Prescribed Drugs John C. M. Brust This chapter describes neurologic side effects of drugs taken by ambulatory patients for nonneurologic indications. Neurologic complications of agents used to treat nervous system disorders such as seizures, migraine, multiple sclerosis, myasthenia gravis, Parkinson’s disease, Alzheimer’s disease, and anxiety are addressed in other chapters. Drugs susceptible to abuse, such as opioid analgesics, psychostimulants, and sedatives, are discussed in Chapter 201.

DRUGS TO TREAT INFECTION Most drugs used to treat infection, whether bacterial, fungal, viral, o r parasitic, are capable of causing neurologic complications (Tables 202- 1 to 202-5). Nitrofurantoin polyneuropathy usually is seen with renal failure and with treatment of long duration. Penicillin G can cause altered mentation and seizures when the concentration in cerebrospinal fluid (CSF) exceeds 10 pg/mL, and procaine in the preparation can contribute to symptoms. Streptomycin and gentamicin cause mainly vestibular toxicity; amikacin, kanamycin, and neomycin cause deafness; tobramycin causes both. Aminoglycoside-induced neuromuscular blockade, often in patients also receiving anesthetics, can precipitate myasthenic crisis. Tetracycline-induced pseudotumor cerebri is most common in infants. Chloramphenicol-induced encephalopathy, seen in neonates and called the “gray syndrome,” includes vomiting, refusal to suck, irregular respiration, diarrhea, flaccidity, hypothermia, and metabolic acidosis. Isoniazid-induced peripheral neuropathy occurs in about 2% of patients receiving usual dosages of 5 mg/kg; polyneuropathy and central nervous system (CNS) toxicity are prevented by giving pyridoxine. Ethambutol-induced optic neuropathy causes reduced visual acuity as well as red-green color blindness.

TABLE 202-1. Drugs to Treat Bacterial Infection Anent

Neurolonic ComDlication

Sulfonamides

CNS-induced anorexia, nausea, vomiting Potentiate phenytoin Headache, depression, hallucinations Aseptic meningitis Vertigo, ataxia Seizures Peripheral neuropathy Headache, dizziness Potentiate rnethylxanthines (theophylline, caffeine) Headache, vertigo, drowsiness, rnyalgia, nystagrnus Peripheral neuropathy Sciatic nerve injury after local injection Arachnoiditis, encephalopathy after intrathecal injection Lethargy, confusion, rnyoclonus, seizures with high dose or renal insufficiency Dizziness, tinnitus, headache, hallucinations, seizures with procaine penicillin C Disulfirarn-like ethanol reaction Seizures with high dose or renal insufficiency Ototoxicity Neurornuscular blockade Optic neuropathy and peripheral neuropathy (streptomycin) Radiculopathy or myelopathy after intrathecal injection Increased intracranial pressure Optic neuropathy Encephalopathy Peripheral neuropathy Transient hearing loss Potentiate carbarnazepine Neurornuscular blockade Dizziness, nausea, insomnia Ototoxicity

Trirnethoprirnsulfarnethoxazole

Quinolones (e.g., nalidixic acid, ciprofloxacin) Nitrofurantoin Penicillins

Cephalosporins lrnipenem Arninoglycosides

Tetracyclines Chlorarnphenicol Erythromycin Clindarnycin Spectinornycin Vancornycin

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Goldfrank LR, Hoffman RS: The cardiovascular effects of cocaine. Ann Emerg Med 20165, 1991 Holman BL, Carvalho PA, Mendelson J et al: Brain perfusion is abnormal in cocaine-dependent polydrug users: a study using technetium-99MHMPAO and ASPECT. J Nucl Med 32:1206, 1991 Jannsen RS, Kaplan JE, Khabbaz RF et al: HTLV-1 associated myelopathy/ tropical spastic paraparesis in the United States. Neurology 41:1355, 1991

Kiokkinos J, Levine S R Stroke. Neurol Clin 11:577, 1993 Levine SR, Brust JCM, Futrell N et al: Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 323:699, 1990

Levine SR, Brust JCM, Futrell N et al: A comparative study of the cerebrovascularcomplications of cocaine: alkaloidal versus hydrochloride: a review. Neurology 41:1173, 1991 Lutiger B, Graham K, Einarson TR, Koren G: Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 44405, 1991 Musher DM, Hammill RJ, Baughn RE: The effect of human immunodeficiency virus infection on the course of syphilis and the response to treatment. Ann Intern Med 113:872, 1990

Ng SKC, Brust JCM, Hauser WA, Susser M Illicit drug use and the risk of new onset seizures: contrasting effects of heroin, marijuana, and cocaine. Am J Epidemiol 40:1017, 1990 Pascual-Leone A, Anderson DC: Cerebral atrophy in habitual cocaine abusers: a planimetric CT study. Neurology 41:34, 1991 Pascual-Leone A, Dhuna A Cocaine-associatedmultifocal tics. Neurology 40:999, 1990

Pascual-Leone A, Dhuna A, Altafallah I, Anderson D C Cocaine-induced seizures. Neurology 40404, 1990 Richter RW: Infections other than AIDS. Neurol Clin 11:591, 1993 Selwyn PA, Alcabes P, Hartel D et al: Clinical manifestations and predictors of disease progression in drug users with human immunodeficiency virus infection. N Engl J Med 327:1697, 1992 Shafer SQ: Disorders of spinal cord, nerve, and muscle. Neurol Clin 11:693, 1993

Weinrieb RM, O’Brien C P Persistent cognitive deficits attributed to substance abuse. Neurol Clin 11:663, 1993

202 Neurologic Complications of Commonly

Prescribed Drugs John C. M. Brust This chapter describes neurologic side effects of drugs taken by ambulatory patients for nonneurologic indications. Neurologic complications of agents used to treat nervous system disorders such as seizures, migraine, multiple sclerosis, myasthenia gravis, Parkinson’s disease, Alzheimer’s disease, and anxiety are addressed in other chapters. Drugs susceptible to abuse, such as opioid analgesics, psychostimulants, and sedatives, are discussed in Chapter 201.

DRUGS TO TREAT INFECTION Most drugs used to treat infection, whether bacterial, fungal, viral, o r parasitic, are capable of causing neurologic complications (Tables 202- 1 to 202-5). Nitrofurantoin polyneuropathy usually is seen with renal failure and with treatment of long duration. Penicillin G can cause altered mentation and seizures when the concentration in cerebrospinal fluid (CSF) exceeds 10 pg/mL, and procaine in the preparation can contribute to symptoms. Streptomycin and gentamicin cause mainly vestibular toxicity; amikacin, kanamycin, and neomycin cause deafness; tobramycin causes both. Aminoglycoside-induced neuromuscular blockade, often in patients also receiving anesthetics, can precipitate myasthenic crisis. Tetracycline-induced pseudotumor cerebri is most common in infants. Chloramphenicol-induced encephalopathy, seen in neonates and called the “gray syndrome,” includes vomiting, refusal to suck, irregular respiration, diarrhea, flaccidity, hypothermia, and metabolic acidosis. Isoniazid-induced peripheral neuropathy occurs in about 2% of patients receiving usual dosages of 5 mg/kg; polyneuropathy and central nervous system (CNS) toxicity are prevented by giving pyridoxine. Ethambutol-induced optic neuropathy causes reduced visual acuity as well as red-green color blindness.

TABLE 202-1. Drugs to Treat Bacterial Infection Anent

Neurolonic ComDlication

Sulfonamides

CNS-induced anorexia, nausea, vomiting Potentiate phenytoin Headache, depression, hallucinations Aseptic meningitis Vertigo, ataxia Seizures Peripheral neuropathy Headache, dizziness Potentiate rnethylxanthines (theophylline, caffeine) Headache, vertigo, drowsiness, rnyalgia, nystagrnus Peripheral neuropathy Sciatic nerve injury after local injection Arachnoiditis, encephalopathy after intrathecal injection Lethargy, confusion, rnyoclonus, seizures with high dose or renal insufficiency Dizziness, tinnitus, headache, hallucinations, seizures with procaine penicillin C Disulfirarn-like ethanol reaction Seizures with high dose or renal insufficiency Ototoxicity Neurornuscular blockade Optic neuropathy and peripheral neuropathy (streptomycin) Radiculopathy or myelopathy after intrathecal injection Increased intracranial pressure Optic neuropathy Encephalopathy Peripheral neuropathy Transient hearing loss Potentiate carbarnazepine Neurornuscular blockade Dizziness, nausea, insomnia Ototoxicity

Trirnethoprirnsulfarnethoxazole

Quinolones (e.g., nalidixic acid, ciprofloxacin) Nitrofurantoin Penicillins

Cephalosporins lrnipenem Arninoglycosides

Tetracyclines Chlorarnphenicol Erythromycin Clindarnycin Spectinornycin Vancornycin

Neurologic Complications of Commonly Prescribed Drugs

Chapter 202

TABU202-2. Drugs to Treat Tuberculosis and Leprosy

W

Anent

Neurologic Complication

lsoniazid

Peripheral neuropathy Seizures Optic neuropathy Dizziness, ataxia, tinnitus Euphoria, impaired memory, psychosis, coma Hepatic encephalopathy Potentiationof phenytoin Increased methadone metabolism, withdrawal symptoms Optic neuropathy Headache, dizziness, confusion, hallucinations Peripheral neuropathy Hepatic encephalopathy Postural hmotension. drowsiness, dizziness, trernor,'headache,. olfactory diAurbance, .diplopia, restlessness, depression, seizures, peripheral neuropathy Peripheral neuropathy Headache, insomnia, anxiety, psychosis

Rifampin Ethambutol Pyrazinamide Ethionamide

Sulfones (dapsone, etc)

W

Neurologic Complication

Amphotericin B

Headache Uremic encephalopathy Hypokalemic myopathy Hepatic encephalopathy Hepatic encephalopathy Potentiate phenytoin Headache Peripheral neuropathy Lethargy, confusion Macular edema Hepatic encephalopathy Disulfiram-like ethanol reaction

Flucytosine lmidazoles (e.g., ketoconazole, fluconazole) Griseofulvin

W

retinotoxic. Metronidazole-induced peripheral neuropathy can be irreversible. DRUGS TO TREAT PAIN, FEVER, INFLAMMATION, AND ARTHRITIS Salicylism consists of ototoxicity and CNS stimulation, including hyperventilation and seizures, followed by depression (Table 202-6). Because of epidemiologic evidence linking aspirin with Reye's syndrome, salicylates are contraindicated in children with varicella or influenza. Severe headache often develops in patients taking indomethacin for long periods. With the related drug sulindac, drowsiness is common. Among nonsteroidal antiinflammatory drugs, ibuprofen has caused toxic amblyopia.

W

TABU202-5. Antiparasitic Drugs

Agent

Neurologic Complication

Quinine

Tinnitus, deafness, vertigo Impaired color vision, constricted visual fields, blindness Headache, fever, vomiting, confusion, delirium, coma Tachypnea, respiratory depression Uremic encephalopathy Retinopathy Headache Myopathy Peripheral neuropathy Abnormal behavior Headache, dizziness, vertigo, ataxia, seizures Peripheral neuropathy Disulfiram-like ethanol reaction Headache, dizziness Hypoglycemia (tremor, altered behavior, seizures, coma) Headache, dizziness Headache, dizziness

TAW 202-3. Antifungal Drugs

Agent

TAW 202-4. Antiviral Drugs

Azent

Neuroldc Comdication

Acyclovir, gancyclovir

Headache Encephalopathy Tremor, dizziness, ataxia Psychosis, hallucinations, seizures, coma Insomnia, decreased concentration, confusion, hallucinations, seizures, coma Asthenia, seizures Headache, insomnia Seizures Wernicke's encephalopathy Myopathy Peripheral neuropathy Retinal depigmentation Peripheral neuropathy

Vidarabine Amantadine Ribavirin Zidovudine

Didanosine Dideoxycytidine

Antifungal agents indirectly cause encephalopathy by damaging the liver or the kidneys. The antiviral agent acyclovir is directly encephalopathic but usually in association with renal failure and high blood concentrations. Wernicke's encephalopathy and myopathy can emerge after months of treatment with zidovudine. Peripheral neuropathy is less often encountered with dideoxycytidine than with didanosine. Quinine retinopathy and ototoxicity are secondary to both ischemia and direct cellular injury. Chloroquine is directly

1283

Chloroquine

Metronidazole Pentamidine Pyrimethamine Praziquantel

W

TAW 202-6. Drugs to Treat Pain, Fever, Inflammation, and Arthritis

Anent

Neurologic Complication

Salicylates

Headache, dizziness, tinnitus, high-tone deafness, hyperventilation, sweating, thirst, nausea, vomiting, drowsiness, confusion, progressing to seizures, delirium, hypoventilation, coma, cardiovascular collapse. Reye syndrome Headache, lightheadedness, vertigo, drowsiness, confusion, psychosis, hallucinations Hepatic encephalopathy Headache, dizziness, tinnitus, anorexia, fatigue, confusion Amblyopia Aseptic meningitis Headache, dizziness, drowsiness Headache, dizziness Hepatic encephalopathy Uremic encephalopathy Hypoglycemia (tremor, altered behavior, seizures, coma) Vertigo, insomnia, nervousness, euphoria, blurred vision Encephalitis Peripheral neuropathy Hepatic encephalopathy Uremic encephalopathy Headache, drowsiness Headache]dizziness

Indomethacin, sulindac Propionic acid derivatives (ibuprofen, ketorolac, naproxen, etc.) Piroxicam Diclofenac Acetaminophen

Phenylbutazone Gold

Probenecid

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Neurology in General Medicine rn Toxins and Drug Effects

TABLE 202-7. Drugs to Treat Acute Muscle Spasm Anent

Neurolomc Comdication

Orphenadrine

Dizziness, syncope Drowsiness, temor Anticholinergic effects (dry mouth, tachycardia, urinary hesitancy, blurred vision, agitation, hallucinations) Drowsiness, nervousness, headache, dizziness, tremor, ataxia, syncope Withdrawal: headache, nervousness, insomnia, muscle cramps Headache, drowsiness, dizziness Drowsiness, dizziness, dry mouth Confusion, agitation Taken with monoamine oxidase inhibitor: febrile crisis. seizures

Carisoprodol

Methocarbamol Cyclobenzamine

meningitis with such opportunists as Cryptococcus and Listeria. Some, such as ifosfamide and methotrexate, are directly toxic to the brain. Acute cerebellar ataxia has followed fluorouracil administration, and myelopathy has affected patients receiving the drug intrathecally. Neurotoxicity, especially peripheral neuropathy, is more often associated with vincristine than vinblastine. Mental change in patients receiving L-asparaginase often is accompanied by elevated blood ammonia concentration. Ototoxicity, neurotoxicity, and nephrotoxicity are less often encountered with carboplatin than with cisplatin.

DRUGS FOR DIABETES MELLITUS The major complication of both insulin and oral sulfonylurea drugs is hypoglycemia, which causes symptoms either through

TABLE 202-8. Cardiovascular Drugs

DRUGS TO REDUCE MUSCLE SPASM Although their efficacy in reducing muscle spasm is questionable, a number of agents so promoted are widely prescribed (Table 202-7). Their use in older adults is especially inappropriate.

Agent

Neurologic Complication

Nitrates

Headache Postural syncope Headache, fatigue, drowsiness Neuralgia, paresthesias Confusion, aphasia, delirium, hallucinations Blurred vision, chromatopsia, retrobulbar neuritis Tinnitus, deafness, dizziness, headache, blurred vision, diplopia, altered color perception, confusion, delirium Dizziness, psychosis, hallucinations Dizziness, tremor Fatigue, tremor, abnormal movements, ataxia Peripheral neuropathy Hepatic encephalopathy Hypo- and hyperthyroidism Postural syncope Hyponatremic encephalopathy Hypokalemic myopathy Exacerbation of hepatic encephalopathy Postural syncope Hypokalemic myopathy Deafness Hyperkalemic myopathy

Digitalis

CARDIOVASCULAR DRUGS Vasodilation is responsible for nitrate-induced headache and dizziness (Table 202-8). In digitalis toxicity, neuropathic, visual, and encephalopathic symptoms can be prominent. Both quinidine and procainamide directly cause psychosis and delirium; in procainamide-induced systemic lupus erythematosus the brain is spared. Amiodarone can cause neurologically symptomatic hypothyroidism or hyperthyroidism. Ethacrynic acid is more likely than furosemide to cause lasting deafness.

Quinidine Procainamide Tocainide, mexiletine Amiodarone

Thiazide diuretics

DRUGS FOR GASTROINTESTINAL DISORDERS Among H, antihistamines (Table 202-9) cimetidine is most likely to cause mental change; unlike ranitidine and other agents, it also prolongs the half-life of phenytoin, barbiturates, benzodiazepines, and tricyclic antidepressants. In patients with renal failure, aluminum-containing antacids have been implicated in the development of osteodystrophy, myopathy, and the dialysis dementia syndrome, which can progress to seizures and death. Metoclopramide is more likely than trimethobenzamide to cause extrapyramidal symptoms. Trimethobenzamide has been implicated in some cases of Reye’s syndrome, but the evidence is inconclusive. ~~

DRUGS FOR NASAL CONGESTION AND ALLERGY With the exception of the piperidines terfenadine and astemizole, all H, antihistamines cause sedation, and overdose can cause seizures, delirium, and coma (Table 202-10). The serotonin antagonist cyproheptadine also has H, antihistamine effects. Structurally similar to caffeine, theophylline causes CNS stimulation and is more likely than caffeine to cause seizures, sometimes without other signs of toxicity.

ANTINEOPLASTIC AND IMMUNOSUPPRESSANT DRUGS Many antineoplastic drugs cause neurologic symptoms secondary to hepatic or renal injury (Table 202- 11). They also cause nausea and vomiting and increase the risk of infection, including

Ethacrynic acid, furosemide Spironolactone, trimaterene Acetazolamide Methyldopa, clonidine

Cuanethidine Reserpine P-Adrenergic antagonists (propranolol,etc.) aAdrenergic antagonists (prazosin, etc.) Hydralazine, minoxidil

Angiotensin-converting enzyme inhibitors (captopril, enalapril, etc.) Calcium channel blockers (verapamil, diltiazem, nifedipine, etc.)

Somnolence, paresthesias Exacerbation of hepatic encephalopathy Postural syncope Somnolence, forgetfulness, dry mouth, headache, impotence, blurred vision, parkinsonism Withdrawal headache, anxiety, tremor, sweating,tachycardia, abdominal pain Postural syncope Delayed or retrograde ejaculation Somnolence, decreased concentration, psychotic depression, parkinsonism Somnolence, insomnia, nightmares, depression, seizures Paresthesias of hands Postural syncope Headache, dizziness, drowsiness, nausea Postural syncope Headache, dizziness, nausea Anxiety, depression Peripheral neuropathy Postural syncope Loss of sense of taste Postural syncope Headache, nausea, dizziness, paresthesias of hands, somnolence

Chapter 202

TABU202-9. Drugs for Gastrointestinal Disorders Agent

Neurologic Complication

H, antihistamines (cimetidine, ranitidine, etc.) Orneprazole

Sedation Headache, dizziness Confusion, agitation, psychosis, hallucinations Sedation Headache, dizziness Myopathy Dialysis dementia, seizures

Aluminumcontaining antacids (e.g., Maalox, Mylanta, Gelusil, sucralfate) Bismuth compounds (e.g., Peptobismol) Metoclopramide, trimethobenzamide

Laxatives

Neurologic Complications of Commonly Prescribed Drugs

ANTICOAGULANT AND ANTIPLATELET DRUGS The major neurologic complication of anticoagulant and antiplatelet drugs is hemorrhage, centrally or into peripheral nerves or roots (Table 202- 14). Intraspinal hemorrhage can follow lumbar puncture in patients receiving warfarin.

TABU202-1 1. Antineoplastic and Immunosuppressant Drugs Encephalopathy Extrapyramidal symptoms (acute dystonia, parkinsonism, akathisia, perioral tremor, tardive dyskinesia) Anxiety, depression Drowsiness Reye syndrome? Electrolyte imbalance, especially hypokalemic myopathy

Agent

Neurologic Complication

Cyclophosphamide

Inappropriate secretion of antidiuretic hormone Somnolence, dizziness, confusion, psychotic depression, hallucinations, cranial neuropathy, seizures Tremor, agitation, ataxia, hallucinations, seizures Retinopathy Lethargy, confusion, ataxia, dysarthria Headache, sedation, blurred vision, seizures, coma Headache Cerebellar ataxia Myelopathy Headache, dizziness, myalgia, sedation Altered behavior Peripheral neuropathy Neuritic pain, peripheral neuropathy Constipation Seizures Optic neuropathy Inappropriate secretion of antidiuretic hormone Peripheral neuropathy Seizures (rare) Peripheral neuropathy Lethargy, myalgia Lethargy Lethargy, depression, agitation, hallucinations, coma Parkinsonism Nonketotic hyperosmolar hyperglycemia Tinnitus, deafness Peripheral neuropathy Tetany Myelopathy Loss of taste Seizures Headache, dizziness Confusion, hallucinations, seizures Sedation, nystagmus, ataxia Altered behavior, seizures, coma Peripheral neuropathy Disulfiram-like ethanol reaction Headache, dizziness, depression Retinopathy Tremor Seizures

lfosfamide Chlorambucil Carmustine, lomustine Methotrexate fluorouracil, floxuridine

TABU202-10. Drugs for Nasal Congestion, Skin Allergy, or Asthma Agent

Neurologic Complication

H, antihistamines (diphenhydramine, tripelennamine, hydroxyzine, meclizine, etc) Cyproheptadine

Sedation Dizziness, tinnitus, blurred vision, tremor, nervousness, insomnia, euphoria Ataxia, athetosis, delirium, seizures, coma, rnydriasis, apnea

Theophylline P,-Adrenergic agonists (rnetaproterenol, terbutaline, albuterol, etc.) Mixed a-and P-adrenergic agonists (pseudoephedrine, phenylpropanolamine, etc.) Cromolyn

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Sedation and other side effects of H, antihistamines Nervousness, insomnia, tremor, delirium Seizures Nausea, vomiting Tremor Restlessness, anxiety, insomnia

Cytarabine Vincristine, vinblastine

Taxol Etoposide Dactinornycin Mithramycin L-Asparaginase

Cisplatin, carboplatin

Tremor Restlessness, anxiety, insomnia Psychosis, hallucinations Seizures Hypertensive crisis, intracerebral hemorrhage

Hydroxyurea

Headache (rare)

Procarbazine

Tamoxifen

epinephrine release (masked by P-adrenergic blockers) or by direct CNS effects (Table 202-12). Focal signs can be present upon emerging from coma or a seizure; they can also occur in the absence of either, mimicking a stroke.

Cyclosporine

TABLE 202-12. Drugs for Diabetes Mellitus

HORMONES AND ANTIHORMONES

Agent

Neurologic Complication

Neurologic complications of adrenocortical steroids can be direct (altered mentation, myopathy), indirect (CNS infection, traumatic myelopathy, electrolyte abnormality), or the result of withdrawal (Table 202-13). Evidence for the association of occlusive and hemorrhagic stroke with oral contraceptive drugs, especially in smokers, is epidemiologic; the mechanism, poorly understood, probably is related to both the estrogen and progestin content of the preparations.

Insulin

Hypoglycemia (tremor, sweating, hunger, blurred vision, weakness, altered behavior, confusion, seizures, coma, strokelike symptoms) Hypoglycemia Hyponatremic encephalopathy Disulfirarnlike ethanol reaction Inappropriate secretion (or potentiation) of antidiuretic hormone Exacerbation of hepatic porphvria

Sulfonylureas (tolbutamide, chlorpropamide, glyburide, glipizide)

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rn TABLE202-13. Hormones and Antihormones Agent

Neurolonic Complication

Adrenocortical steroids

Altered behavior, psychotic depression Myopathy Vertebral compression fracture, myeloradiculopathy CNS infection Hypokalemia, weakness Withdrawal: addisonian crisis, pseudotumor cerebri Nausea, anorexia Headache, fatigue Thromboembolic disease, occlusive and hemorrhagic stroke Increased muscle growth Virilization, feminization Headache, nausea, paresthesias, myalgia, loss of taste, drowsiness Hypoglycemia

Estrogen Progestins and oral contraceptives Androgens Antithyroid thioureylenes (propylthiouracil, methimazole, etc.)

rn TABLE202-14. Anticoagulant and Antiviscosity Drugs

elevated creatine kinase, and myoglobinuria. Among tricyclic antidepressants, anticholinergic side effects are especially prominent with amitriptyline and much less with desipramine. Priapism associated with trazodone is a medical emergency. Hemorrhagic stroke has occurred in patients taking monoamine oxidase inhibitors who ingested beer, wine, yeast, liver, pickled herring, chocolate, or other tyramine-containing foods. Neurologic side effects of lithium usually are associated with blood levels above 1.25 mEq/L. VITAMINS Hypervitaminosis A, including pseudotumor cerebri and visual loss, is most often seen in adolescents taking vitamin A in large dosages for weeks or months (Table 202-17). Repeated ingestion of large dosages of vitamin D causes hypercalcemia with a wide array of mental symptoms as well as life-threatening kidney damage.

TABU 202-16. Antipsychotic and Antidepressant Drugs

Agent

Neurologic Complication

Agent

Neurolonic Complication

Warfarin

lntracranial and intraspinal hemorrhage Nausea, anorexia See Table 196-6

Pheniothiazines, haloperidol

Sedation Extrapyramidal symptoms (acute dystonia, parkinsonism, akathisia, perioral tremor, tardive dyskinesia) Neuroleptic malignant syndrome Seizures Postural syncope Hyperprolactinemia, galactorrhea Anticholinergic effects (blurred vision, decreased sweating, dry mouth, constipation, urinary retention) Sedation, dizziness, headache Restlessness, insomnia, confusion Tremor, akathisia, bradykinesia Seizures Blurred vision, increased sweating and salivation, dry mouth Neuroleptic malignant syndrome Postural syncope Postural dizziness or syncope Anticholinergic effects Increased sweating Sedation, fatigue, weakness, tremor Manic excitement, delirium Seizures Inappropriatesecretion of antidiuretic hormone Postural dizziness or syncope Anticholinergic effects (very weak) Priapism Sedation, fatigue Nervousness, insomnia, abnormal dreams, agitation Sedation, fatigue, dizziness Tremor Increased sweating Seizures Anxiety, agitation, tremor, increased sweating Seizures Tremor, nervousness, insomnia, agitation, confusion, hallucinations Increased sweating Seizures Hypertensive crisis, intracranial hemorrhage (when taken with sympathomimetic agents or tyraminecontainingfoods) Hyperthermic crisis (when taken with meperidine) Peripheral neuropathy (phenylzine and isocarboxazid) Sedation, tremor, dysarthria, ataxia, confusion, seizures, coma Polydipsia, polyuria Exacerbation of rnvasthenia nravis

Aspirin and other nonsteroidal anti-inflammatory drugs Dipyridamole Ticlopidine, clopidogrel Pentoxifvlline

Headache, dizziness Dizziness, anorexia, thrombotic thrombocytopenic purpura Dizziness, nelvousness

rn TABLE202-1 5. Drugs to Lower Blood Lipoprotein

Clozapine

Concentrations Agent

Neurologic Complication

Clofibrate

Headache, sedation, dizziness, blurred vision Elevated serum creatine kinase, polymyositis, rhabdomyolysis Potentiation of warfarin anticoagulation Headache, dizziness, anxiety, sedation, myalgia Headache, dizziness Elevated serum creatinine kinase, polymyositis, rhabdomyolysis Altered taste

Cholestyramine Lovastatin, pravastatin, etc.

Tricyclic antidepressants (imipramine, nortriptyline, amitriptyline, etc.) Trazodone

LIPID-LOWERING DRUGS Both clofibrate and hydroxymethylglutaryl (HMG)-CoA reductase inhibitors cause myopathy, which can range from asymptomatic creatine kinase elevation to acute rhabdomyolysis and renal shutdown (Table 202-15).

ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUGS Among neuroleptic agents, extrapyramidal side effects are especially common with fluphenazine, trifluoperazine, pimozide, and haloperidol, which in turn are less likely to cause sedation (Table 202- 16). With chlorpromazine, mesoridazine, thioridazine, and chlorprothixene the opposite is true. Clozapine is far less likely to cause extrapyramidal signs but more likely to cause seizures. The potentially fatal neuroleptic malignant syndrome consists of severe akinetic parkinsonism, labile pulse and blood pressure, fever,

Fluoxetine

Bupropion Monoamine oxidase inhibitors (phenylzine, tranylcypromine, isocarboxazid)

Lithium salts

Chapter 203 H TABLE 202-17.

Vitamins

Agent

Neurologic Complication

Vitamin A (retinol,

Sedation, dizziness Increased intracranial pressure (headache, papilledema, diplopia) Weakness, fatigue, lassitude, disturbed sleep (“neurasthenia”) Impaired memory, dementia, altered behavior, depression, paranoia, hallucinations,delirium, obtundation, coma Polydipsia, polyuria Peripheral neuropathy Correction of cobalamin deficiency anemia with progression of myeloneuropathy Retinopathy Lactic acidosis, delirium

etc.)

Vitamin D (calciferol,

cholecalciferol)

Pyridoxine Folk acid Niacin

Neurotoxic Manifestations of Exposure to Metals

1287

Although pyridoxine-induced sensory neuropathy usually is associated with “megadoses” (2 to 6 g daily for months), it has resulted from as little as 200 mg daily. Niacin overdose has caused retinal maculopathy, and lactic acidosis with delirium has followed combined ingestion of niacin and ethanol.

SUGGESTED READINGS Albin RL, Albers Tw: Long-term follow-up of pyridoxine-induced acute sensory neuropathy-neuronopathy.Neurology 4013 19, 1990 Cedarbaum JM, Schleifer LS: Drugs for Parkinson’s disease, spasticity, and acute muscle spasms. p. 463. In Gilman AG, R d TW, Nies AS, Taylor P (eds): The Pharmacological Basis of Therapeutics. 8th Ed. Pergamon Press, New York, 1990 Schwab RA, Bachhuber BH Delirium and lactic acidosis caused by ethanol and niacin ingestion. Am J Emerg Med 9363, 1991 Willcox M, Himmelstein DU, Woolhandler S: Inappropriate drug prescribing for the community dwelling elderly. JAMA 272:292, 1994

203 Neurotoxic Manifestations of Emosure to Metals Robert C. Feldman Metals are ubiquitous and important to our daily lives. Certain metals such as manganese and iron are essential for the activity of enzymes involved in metabolic processes. However, if the concentration of these metals in living tissues exceeds critical threshold levels, normal cellular functioning can be disrupted, producing serious and often fatal consequences. The mechanism of neurotoxicity of a metal may include interference with the actions of enzymes, alterations of the integrity of cell membranes by lipid peroxidation, and disruption of cellular respiration and oxidative phosphorylation processes, which impedes adenosine triphosphate (ATP)-dependentprocesses in affected cells. Early detection of the neurotoxicity of metals is important in clinical practice so that the exposed patient can immediately be removed from further exposure to prevent additional intake, permit recovery of reversible effects, and minimize the risks of permanent damage. This chapter describes the neurologic manifestations of exposure to toxic levels of lead, arsenic, and mercury, the three neurotoxic metals most common in environmental and occupational settings that must be considered in the differential diagnosis of neurologic disease in clinical practice. The material presented here will allow the clinician to readily recognize and treat patients with clinical manifestations associated with exposure to three commonly encountered metals. The reader is referred to additional references for information about other metals with neurotoxic capability, including thallium, manganese, aluminum, organotin, iron, and copper.

DETECTING NEUROTOXIC DISEASE The differential diagnosis of neurologic dysfunction depends on a thorough examination of the patient and a complete medical history. Because the effects of neurotoxic substances can mimic those of neurodegenerative and metabolic disease processes, the

patient should be questioned carefully about possible exposures while on the job and about his or her use of hazardous substances in recreational activities or hobbies. The proximity of the patient’s household to sources of exposure such as mines or smelters is important because the water supply or soil where the patient gardens or plays may be contaminated with neurotoxic metals. A reasonable degree of suspicion and a systematicline of questioning will lead the examiner to an association between the presenting symptoms and a possible neurotoxic cause, if one exists. A medical history will provide information about present and past discomforts and impairments of functions experienced by the patient. It should also reveal details about the patient’s work history. Knowledge of the chemical substances used in various industrial processes and workplaces will alert the examiner to a potential risk for exposure to probable neurotoxic substances associated with the clinical manifestations (Table 203-1). Neurologic signs and symptoms arise from disruptions of the normal functioning of the neurons and supportive cellular structures of the central and peripheral nervous systems. Therefore, common symptoms such as headache, personality changes, mood disturbances, cognitive dysfunction (including memory and problem-solving deficits), muscle weakness, tremor, ataxia, numbness, and tingling are found in cases of neurotoxic disease as well as idiopathic neurologic disorders. An appreciation for the clinical manifestation of the particular neurotoxic substance facilitates the diagnosis. A detailed neurologic examination may reveal the physical signs of a lateralized intracranial lesion caused by a stroke or the more diffuse and bilateral effects commonly associated with exposure to a neurotoxic substance. Symptoms and signs of encephalopathy or polyneuropathy may be noted. The focal peripheral nerve damage of an entrapment syndrome is in contrast with the bilateral deficits and reflex changes usually associated with mixed sensorimotor polyneuropathy caused by toxic sub-

Chapter 203 H TABLE 202-17.

Vitamins

Agent

Neurologic Complication

Vitamin A (retinol,

Sedation, dizziness Increased intracranial pressure (headache, papilledema, diplopia) Weakness, fatigue, lassitude, disturbed sleep (“neurasthenia”) Impaired memory, dementia, altered behavior, depression, paranoia, hallucinations,delirium, obtundation, coma Polydipsia, polyuria Peripheral neuropathy Correction of cobalamin deficiency anemia with progression of myeloneuropathy Retinopathy Lactic acidosis, delirium

etc.)

Vitamin D (calciferol,

cholecalciferol)

Pyridoxine Folk acid Niacin

Neurotoxic Manifestations of Exposure to Metals

1287

Although pyridoxine-induced sensory neuropathy usually is associated with “megadoses” (2 to 6 g daily for months), it has resulted from as little as 200 mg daily. Niacin overdose has caused retinal maculopathy, and lactic acidosis with delirium has followed combined ingestion of niacin and ethanol.

SUGGESTED READINGS Albin RL, Albers Tw: Long-term follow-up of pyridoxine-induced acute sensory neuropathy-neuronopathy.Neurology 4013 19, 1990 Cedarbaum JM, Schleifer LS: Drugs for Parkinson’s disease, spasticity, and acute muscle spasms. p. 463. In Gilman AG, R d TW, Nies AS, Taylor P (eds): The Pharmacological Basis of Therapeutics. 8th Ed. Pergamon Press, New York, 1990 Schwab RA, Bachhuber BH Delirium and lactic acidosis caused by ethanol and niacin ingestion. Am J Emerg Med 9363, 1991 Willcox M, Himmelstein DU, Woolhandler S: Inappropriate drug prescribing for the community dwelling elderly. JAMA 272:292, 1994

203 Neurotoxic Manifestations of Emosure to Metals Robert C. Feldman Metals are ubiquitous and important to our daily lives. Certain metals such as manganese and iron are essential for the activity of enzymes involved in metabolic processes. However, if the concentration of these metals in living tissues exceeds critical threshold levels, normal cellular functioning can be disrupted, producing serious and often fatal consequences. The mechanism of neurotoxicity of a metal may include interference with the actions of enzymes, alterations of the integrity of cell membranes by lipid peroxidation, and disruption of cellular respiration and oxidative phosphorylation processes, which impedes adenosine triphosphate (ATP)-dependentprocesses in affected cells. Early detection of the neurotoxicity of metals is important in clinical practice so that the exposed patient can immediately be removed from further exposure to prevent additional intake, permit recovery of reversible effects, and minimize the risks of permanent damage. This chapter describes the neurologic manifestations of exposure to toxic levels of lead, arsenic, and mercury, the three neurotoxic metals most common in environmental and occupational settings that must be considered in the differential diagnosis of neurologic disease in clinical practice. The material presented here will allow the clinician to readily recognize and treat patients with clinical manifestations associated with exposure to three commonly encountered metals. The reader is referred to additional references for information about other metals with neurotoxic capability, including thallium, manganese, aluminum, organotin, iron, and copper.

DETECTING NEUROTOXIC DISEASE The differential diagnosis of neurologic dysfunction depends on a thorough examination of the patient and a complete medical history. Because the effects of neurotoxic substances can mimic those of neurodegenerative and metabolic disease processes, the

patient should be questioned carefully about possible exposures while on the job and about his or her use of hazardous substances in recreational activities or hobbies. The proximity of the patient’s household to sources of exposure such as mines or smelters is important because the water supply or soil where the patient gardens or plays may be contaminated with neurotoxic metals. A reasonable degree of suspicion and a systematicline of questioning will lead the examiner to an association between the presenting symptoms and a possible neurotoxic cause, if one exists. A medical history will provide information about present and past discomforts and impairments of functions experienced by the patient. It should also reveal details about the patient’s work history. Knowledge of the chemical substances used in various industrial processes and workplaces will alert the examiner to a potential risk for exposure to probable neurotoxic substances associated with the clinical manifestations (Table 203-1). Neurologic signs and symptoms arise from disruptions of the normal functioning of the neurons and supportive cellular structures of the central and peripheral nervous systems. Therefore, common symptoms such as headache, personality changes, mood disturbances, cognitive dysfunction (including memory and problem-solving deficits), muscle weakness, tremor, ataxia, numbness, and tingling are found in cases of neurotoxic disease as well as idiopathic neurologic disorders. An appreciation for the clinical manifestation of the particular neurotoxic substance facilitates the diagnosis. A detailed neurologic examination may reveal the physical signs of a lateralized intracranial lesion caused by a stroke or the more diffuse and bilateral effects commonly associated with exposure to a neurotoxic substance. Symptoms and signs of encephalopathy or polyneuropathy may be noted. The focal peripheral nerve damage of an entrapment syndrome is in contrast with the bilateral deficits and reflex changes usually associated with mixed sensorimotor polyneuropathy caused by toxic sub-

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TABLE 205-1. Recognition and Diagnosis of Metal Neurotoxicity Metal

Sources of EXpOSUre

Clinical Manifestations

Biolonical Exposure Indices

Lead

Lead-based paint Lead pipes Foundries and smelters Stained glass Solders Lead shot Automobile body repair Lead acid storage battery manufacturing and reclamation Illicit whiskey Antifouling paints Pesticides Smelters Pigmen ts Electroplating industry Semiconductors Seafood (organic arsenic) Chlorine synthesis Scientific instruments Electroplating industry Felt making Seafood (methyl mercury) Dry battery manufacturing Photography Electrical equipment Amalgams

Acute: Encephalopathy Chronic: Encephalopathy and peripheral neuropathy

Blood: 30 pg/lOO mL (any time) Urine: N/A

Acute: Encephalopathy Chronic: Encephalopathy and peripheral neuropathy

Blood: N/A Urine: 35 pg/L (end of workweek)

Acute: Headache, nausea, onset of tremor Chronic: Encephalopathy, ataxia, tremor and peripheral neuropathy

Blood: 15 pg/L (end of workweek) Urine: 35 pg/g creatinine (preshift)

Arsenic

Mercury

stances. An insidious, slowly progressive course primarily affecting the most distal portion of the lower extremities and subsequently involving the upper extremities is often reported and is in contrast to the more rapid onset associated with a demyelinating polyneuropathies such as Guillian-Bard syndrome. Laboratory studies to rule out metabolic conditions such as diabetes and hypothyroidism that may cause neuropathies should be performed if necessary to confirm and support the diagnosis. Documenting the presence of a suspected toxic substance in the patient’s environment is very important to the diagnosis of neurotoxic disease. Air and water levels of the suspected toxic substance should be determined and the source identified. However, the mere presence of a substance known to be capable of producing neurotoxic effects does not mean that each exposed person will be affected to the same extent. Patients with underlying systemic diseases (e.g., diabetes) or a history of previous chemical exposures may be more sensitive to the effects of exposure. Individual susceptibility and the duration and intensity of exposure are the major factors that determine the severity of neurotoxic effects. Neurologic effects of exposure to toxic substances may be reversible or irreversible, depending on the specific substance, the nature and duration of exposure, and the selective vulnerability of particular target elements of the peripheral and central nervous systems. The clinical diagnosis of neurotoxicity is made based on the history, subjective complaints, and objective findings on neurologic examination. Neurophysiologic, neuropsychological, neuroimaging, neuropathologic, and biochemical findings (biological markers) support the clinical diagnosis. Biological markers of exposure such as determination of concentrations of the parent molecule or its metabolites in samples of blood, urine, hair, or nails are used to confirm the cause of such clinical discriminations. Proof of exposure can be obtained by sampling the air, water, and soil sources to which the patient has been exposed. The contaminant usually is still present after the patient has left the site, but the blood and or urine levels may have

diminished or returned to normal because of excretion and no further exposure. Hair or nails may contain stored traces of suspected neurotoxic metal long after exposure has ended and urine and blood levels have returned to normal.

LEAD Sources of Exposure

Lead ore is mined as a compound with other metals such as zinc, cadmium, and silver. Lead has found many commercial uses throughout history and throughout the world, so recognition of its toxic effects dates back hundreds of years. The ubiquitous nature of lead and lead products makes the risks of exposure a serious public health problem in modern societies. The smelting process used to obtain pure lead releases particulate lead products into the atmosphere, exposing nearby populations. Undue lead absorption should be suspected to occur more in certain industries: ore mining, crushing, and smelting; lead acid battery manufacturing and recycling; radiator repair; paint and pigment manufacturing; and soldering, welding, and cutting operations. Artists and craftspersons may use lead pigments in paint and pottery glazes and in making lead glass objects. Government-mandated reductions in the use of organic lead compounds as antiknock agents in gasoline have significantly reduced the risk of nonoccupational exposures. Recent ordinances have likewise required the removal of lead from soil, housing, and other structures. The laborers responsible for its removal are susceptible to exposure if they do not use proper protective measures and practices. Metabolism Particulate lead is inhaled and absorbed through the lungs. Larger size particles (greater than 1 pm) do not reach the alveoli for absorption but are brought to the oral pharynx by the mucociliary escalator and expectorated or swallowed. Ingested lead particles or lead compounds in food and other sources (e.g., calcium

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supplements) are absorbed through the gastrointestinal tract. Organic lead compounds are absorbed through the skin, although inorganic lead is not. Once in the bloodstream, lead bound to red blood cells is carried throughout the body, where it is deposited in bone, teeth, liver, lung, kidney, brain, and spleen. Bone serves as a long-term storage site from which lead can subsequently be released. Lead readily crosses the blood-brain barrier and concentrates in neurons. Lead mimics calcium in its tissue distribution. As lead is distributed and stored in tissues, the blood level rapidly drops. This occurrence can be diagnostically misleading because the actual tissue content of lead is still significant. For this reason, heme synthesis disruption and blood and urine lead concentrations are used as biological markers of effect and exposure when the blood level is no longer significantly elevated. When the urine level of 8-aminolevulinic acid and blood levels of free erythrocyte protoporphyrin (FPP) and zinc protoporphyrin (ZPP) are elevated, heme synthesis has been disrupted. ZPP is the preferred marker of lead exposure. This biological marker of effect reflects the presence of low levels of lead released from tissue storage compartments such as bone and can be very helpful in early diagnosis of lead poisoning. Lead levels in dentin, hair, nails, and bone can also be used to document exposures. Radiologic studies reveal metaphyseal bands in long bones of patients exposed that can be used to document current and past exposures. X-ray fluorescence has become a useful way to quantify levels of lead stored in bone. Lead is excreted primarily by the kidneys, but unabsorbed ingested lead may also be found in feces. Urinary lead excretion is increased by chelation therapy. Clinical Diagnosis

The American Conference of Governmental Industrial Hygienists (ACGIH) recommends that blood lead levels of occupationally exposed adults not exceed 30 pg/dL. The first symptoms of lead poisoning begin to emerge at blood levels greater than 30 yg/dL and may include nonspecific complaints of constipation, bloating, and fatigue associated with lead-induced porphyria and anemia. Headache, dizziness, and mood changes may occur at blood lead concentrations greater than 35 pg/dL. Attention and memory problems characterized by confusion typically occur at levels greater than 70 pg/dL, but behavioral and cognitive impairments have been seen in adults at low levels of lead (less than 70 pg/dL) as well. Higher blood lead levels (greater than 100 pg/dL) are associated with overt symptoms of encephalopathy including seizures and coma. Death occurs after severe renal damage or when there has been extreme cerebral edema associated with the encephalopathy, causing brainstem herniation and cardiorespiratory arrest. Developmental deficits in cognitive abilities and intellectual capacity have been reported in children exposed to very low levels of lead, with blood lead concentrations as low as 10 pg/dL. For this reason the blood lead levels of women of childbearing age should not exceed 10 pg/dL. Symptoms of lead poisoning may spontaneously resolve and recur with intermittent exposures. Chronic exposure to lead results in symptoms and signs that become more and irreversible as the lead stores accumulate. Cognitive problems and a mixed sensorimotor peripheral neuropathy develop insidiously after several months of exposure to lead. Distal weakness and mild sensory changes are found on clinical neurologic examination. Electrophysiologictests of nerve conduc-

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tion demonstrate conduction velocity slowing in the myelinated motor fibers compared with relative preservation of this parameter in the unmyelinated sensory fibers. Carefully controlled studies of peripheral nerve conduction in exposed workers showed a correlation between reduced amplitudes and conduction velocity at blood lead levels above 70 pg/dL, suggesting that demylination and axonal loss are associated with lead exposure. Patients with complaints of cognitive deficits should be referred for formal neuropsychological assessment. Laboratory tests of renal function including blood urea nitrogen should be ordered to determine kidney involvement in any symptomatic patient with documented lead exposure. The porphyrias must be considered in the differential diagnosis of all cases of lead poisoning. Patients with hypothyroidism may present with progressive distal extremity weakness and paresthesias or symptoms and signs of median nerve involvement and therefore must also be differentiated from patients with lead poisoning.

Treatment Early diagnosis allows removal of the patient from the suspected source of lead exposure. Symptoms typically spontaneously resolve after cessation of exposure but may persist indefinitely in some patients because of differences in susceptibility. Leadexposed children should also be tested for iron deficiency and treated accordingly. Gastric lavage and whole-bowel irrigation can be used to reduce absorption of ingested lead compounds and lead-containing compounds such as ceramic glazes. Chelation therapy is recommended to prevent ongoing cellular damage if blood lead levels remain elevated because of release of lead stored in soft tissues after cessation of exposure. Chelating agents are sulfur-containing compounds that combine with the metal ions in tissues to facilitate their excretion in the urine. A baseline measure of the urine lead concentration in a 24-hour sample should be obtained before initiation of chelation therapy. These results can be compared with the output obtained after chelation. Total urinary output and urinary lead content are determined. Lead excretion is increased by the administration of several chelating agents including dimercaprol (British antiLewisite, BAL), edetate calcium disodium (Ca-EDTA), succimer (2,3-meso-dimercaptosuccinic acid, DMSA), and D-penicillamine. BAL is a dithiol compound that forms a stable product with lead. D-Penicillamine has been used for a long time with success, despite the risks of dose-related side effects, which include hypertension, rash, nausea, vomiting, headache, and numbness and tingling of extremities. Renal tubular necrosis and cardiac dysrhythmias are the most serious adverse effects, but they are reversible upon cessation of therapy. BAL can be used in patients with known renal damage because it is excreted in the bile. However, BAL may produce side effects in as many as 50% of patients. In the presence of severe encephalopathy and when blood lead levels exceed 100 pg/dL, treatment should include combined therapy with BAL and Ca-EDTA. Administer the first dose of BAL alone (3 to 5 mg/kg IM every 4 hours for the first 2 to 3 days, then twice daily for the next 4 to 5 days). The first dose of Ca-EDTA (25 mg/kg IM with 0.5% procaine every 4 hours for 5 to 7 days) should be administered at the same time as the second dose of BAL. Ca-EDTA can alternatively be administered intravenously (infuse entire dose of 150 mg/kg over 24 hours). Ca-EDTA is less effective given intramuscularly and not effective orally. Cardiac and renal

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function should be monitored closely throughout therapy. Intravenous fluids should be administered for the first several days to maintain hydration, optimize renal clearance, and prevent tubular necrosis. Hemodialysis is recommended for patients with impaired renal functioning. BAL can be discontinued when the blood lead level falls below 50 pg/dL. If the blood lead level is lower than 100 pg/dL, therapy can start with Ca-EDTA alone (25 mg/kg IM every 12 hours for 5 to 7 days), omitting the BAL. Continuous intravenous infusion of Ca-EDTA can also be used while the electrocardiograph is monitored for dysrhythmias. Therapy is given for 5 days, and urinary levels are again tested after a rest period of several weeks. Another course of 5 days of chelation should be given if the blood or urine lead levels are still elevated. Succimer is an oral preparation related to dimercaprol. This water-soluble analogue of BAL has proven helpful and less noxious for treating lead poisoning in children with blood lead levels greater than 45 pg/dL and adults. It should be administered in a dosage of 10 mg/kg every 8 hours for 5 days and then every 12 hours for next 14 days; this course can be repeated after a 2-week rest. D-Penicillamine is a monothiol oral investigational chelating agent that can be given for mild cases (250 mg four times a day for 5 days) and over a prolonged period of time (20 to 30 mg/kg/day, administered in single dose on empty stomach). D-Penicillamine inhibits the activity of pyridoxal-dependent enzymes, so pyridoxine should be administered with it. D-Penicillamine is contraindicated in patients who are allergic to penicillin. ARSENIC

Sources of Exposure Arsenic is found naturally in soil and water, especially in areas with high geothermal (i.e., volcanic) activity. Arsenic is mined from the earth as an ore usually mixed with other metals, such as copper, lead, and gold. Exposure to arsenic dust occurs among the workers who crush and process the ore to separate out the metals. Arsenic trioxide is released during smelting and can pollute the environment around smelting plants. Occupational and paraoccupational exposures to arsenic occur among people involved in construction projects where chromium-copper-arsenate-treated lumber is cut in poorly ventilated areas. Some of the many uses for arsenic are listed in Table 203-1. Contaminated ground water in areas where arsenic-containing insecticides and wood preservatives are manufactured and used can be a source for human consumption of arsenic. The most common source of arsenic intake by the general population is the ingestion of food and water containing the metal. Seafoods contain high concentrations of organic arsenic (e.g., arsenocholine and arsenobetaine). These “fish arsenic” compounds are low in toxicity compared with the inorganic arsenic compounds. Accidental intake of inorganic arsenic occurs when wood treated with chromium-copper-arsenate is unwittingly burned and the fumes inhaled. Intentional ingestion of inorganic arsenic during suicide attempts and malicious poisonings have also been reported.

Metabolism Inorganic arsenic enters the body by inhalation and ingestion. Dermal absorption is minimal. Airborne arsenic generally takes the form of arsenic trioxide. Arsine gas, the most toxic form of

arsenic, also enters by the pulmonary route. Inorganic arsenic compounds are absorbed through the gastrointestinal tract most easily when they are in the pentavalent water-soluble form. Trivalent forms are more lipid soluble and are less readily absorbed by the gastrointestinal tract. Elemental arsenic has very low solubility and is not absorbed. Once in the bloodstream arsenic is localized in erythrocytes combining with the globin portion of hemoglobin. It also is found in leukocytes and bound to plasma proteins. Arsenic clears from the bloodstream within 24 hours and becomes widely distributed in body tissues. Arsenic in the trivalent form binds to sulfhydrylgroups in keratin-rich tissues such as hair, skin, and nails, and pentavalent arsenic displaces phosphates in bone and teeth. Arsenic also accumulates in lipid-rich tissues such a myelin of the brain and peripheral nerves. Arsenic is detoxified in the liver by methylation. There is some interconversion between the more toxic pentavalent and the less toxic trivalent forms, but both forms are biomethylated. The methylation of pentavalent arsenic compounds is facilitated by glutathione-mediated reduction to the trivalent state. After lowlevel exposure to inorganic arsenic, most of the urinary arsenic is present as methylated metabolites (monomethylarsinic acid, dimethylarsinic acid, and trimethylarsinic acid). Methylation efficiency increases with increasing arsenic dosage. However, polymorphism in the enzymes that facilitate detoxification, including glutathione peroxidase, may influence individual susceptibility to the effects of inorganic arsenic. Subjects with poor nutrition also have a lower capacity to methylate and therefore to detoxify inorganic arsenic. If the methylation capacity is exceeded, arsenic retention in soft tissues increases. Although the organic arsenic compounds occur also in trivalent or pentavalent states, they do not undergo extensive metabolism. Most arsenic is excreted in the urine. Other routes of elimination include desquamation of arsenic-containing skin and excretion through sweat, milk, and bile. Arsenic has a half-life of about 10 hours, and 50% to 80% is excreted after 3 days. If there is no further accumulation by continued exposure, then tissue clearance is completed within 2 to 4 weeks. The organic arsenic compounds found in seafoods are rapidly excreted. After a single meal of seafood known to contain large amounts of organic arsenic, a human subject eliminated 50% of the dose within 20 hours.

Clinical Diagnosis The clinical manifestations of arsenic intoxication depend on the route, dosage, and duration of exposure, the individual susceptibility of the exposed person, and the physiochemical characteristics of the arsenic compound including its valence, whether it is an inorganic or organic compound, and whether it is a gas, solution, or powder. Urine concentrations of arsenic above 35 kg/dL are associated with toxicity. The mechanism of toxic effects of arsenic compounds, especially the trivalent forms, is related to the inhibition of sulfhydryl-containingenzymes in the body. Another possible mechanism, more likely to occur with pentavalent arsenic compounds, is disruption of oxidative phosphorylation by replacement of the stable phosphoryl with less stable arsenyl compounds, leading to rapid hydrolysis of the high-energy bonds in ATP and disturbances of cellular processes dependent on ATP such as ion pumping and axonal transport. Acute arsenic poisoning by ingestion is associated with nausea, vomiting, abdominal pain, and watery or bloody diarrhea. Serious

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fluid and electrolyte problems develop in extreme cases, often leading to cardiopulmonary arrest and death, The clinical picture of chronic exposure to arsenic includes anxiety, mood changes, headaches, sleep disturbances, and the insidious emergence of cognitive impairments and then the emergence of neuropathy. The typical symptoms of arsenical neuropathy are primarily sensory, but motor findings are seen as well. Numbness and tingling in the feet progressing to affect the hands with continued exposure has been reported. Painful paresthesias are common. Vibration sense is affected early in the clinical course, so this finding can be considered as a marker to recommend removal of a worker from exposure. Perception of pain and temperature is reduced as the neuropathy progresses. The lower extremities are more vulnerable than are the upper ones. Electrical evidence of impaired conduction is seen in the sensory fibers more than in the motor fibers. Although sensory symptoms predominate, the changes in myelin and axonal degeneration also lead to motor signs, so that patients with both sensory and motor neuropathies are seen in clinical practice. Both short- and long-term exposures to arsenic have been associated with encephalopathy. Chronic encephalopathy is associated with exposure to inorganic arsenic. Careful neuropsychological tests reveal subtle cognitive and affective disturbances in mild cases. Severe encephalopathy may be associated with memory disorders, seizures, and psychotic symptoms of hallucinations, delusions, paranoia, and delirium. Diagnosis of arsenic poisoning is made by the usual careful and detailed history, ruling out other medical conditions such as alcoholism, diabetes, and nutritional problems. Guillian-Barrk syndrome should be included in the differential diagnosis of acute arsenic poisoning that may be associated with segmental demyelination. The cause can be confirmed by analysis of the urine for arsenic content. Baseline urine levels of arsenic in unexposed people range from 0 to 130 pg/L, and for those with known occupational exposure to arsenic the level can be as much as 4 mg/L. Blood levels are useful only when there is ongoing exposure. After careful control to avoid measuring external contamination, analysis of nails and hair shaft arsenic content may reveal previous exposures at times when the blood and urine levels are no longer elevated. Treatment

Patients with suspected arsenic poisoning must immediately be removed from any source of continuing exposure and the body burden of arsenic reduced to safer levels. In cases of severe acute intoxication, stabilization of electrolytes and cardiopulmonary function in an intensive care unit may be needed. Gastric lavage and whole-bowel irrigation can be used to remove any remaining ingested arsenic. Several other remedies for reducing absorption and increasing excretion include administration of a mixture of 300 mL tincture of ferric chloride and 30 mg calcium carbonate in 120 mL of water. Hemodialysis and plasma exchange can be used to help clear the body of any still-circulating arsenic. Dimercaprol (BAL) is recommended for use as a chelating agent in cases of arsenic poisoning. The earlier it is given, the better the prognosis. BAL should be administered IM at an initial dosage of 3 to 5 mg/kg body weight every 4 to 5 hours for first day, 2 mglkg every 4 hours the second day, 3 mglkg every 6 hours on the third day, and 3 mglkg every 12 hours for the next 10 days.

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Urine output and kidney function should be monitored during chelation. The degree of recovery depends on the extent of axonal damage. MERCURY sources of Exposure Mercury is extracted from cinnabar ore, consisting of mercury sulfide. It is found in the environment in three forms: elemental, inorganic, and organic. Elemental mercury often is called quicksilver because of its shiny metallic appearance and liquid consistency. Inorganic mercury salts include mercuric chloride (HgC1,) and calomel (HgC1). Elemental mercury and inorganic mercury are used in the manufacture of scientific instruments, in amalgams with copper, silver, or gold, in solder with lead, and in plating processes. It is found in industries that use photographic materials, paints and pigments, and dyes. Thermometers, batteries, vapor lamps, and taxidermy solutions contain elemental or inorganic mercury. Organic mercury compounds include long-chain alkyl and aryl compounds and short-chain alkyl mercurial compounds. Organic mercury compounds are used in certain embalming solutions, fungicides, insecticides, wood preservatives, and germicides.

Metabolism The vaporization of elemental mercury at room temperature allows inhalation of the metal fumes, Inorganic and organic mercury compounds can be inhaled or ingested. Elemental mercury vapor is rapidly diffused through the alveolar membrane and is taken up to the brain by the red blood cells. Elemental mercury is highly lipophilic and can easily cross the blood-brain barrier. The concentration of mercury in the brain may remain elevated as long as 10 years after exposure. Inorganic mercurial compounds are highly corrosive and produce serious tissue necrosis of the mucosa of the mouth and the gastrointestinal tract. This usually prevents ingestion and thus absorption of large amounts of inorganic mercury compounds. Organic mercurial compounds are taken in mainly by ingestion of foods such as cereals that have been treated with mercury-containing fungicides or accidental spills of mercury compounds in water, where they are methylated by microorganisms and ingested by fish, which in turn are eaten by humans. Organic mercurial compounds are very lipid-soluble, with up to 90% absorbed through the gastrointestinal tract after ingestion. Dermal absorption of organic mercury compounds is also considerable. Tissue distribution of mercurial compounds is widespread, so concentrations are increased in the liver, kidney, blood, brain, hair, and epidermis after exposure. The amount of elemental and organic mercury found in brain tissue, although less than in the liver and kidney, is greater than that found after inorganic mercury poisoning. Autopsy material from victims of a large outbreak of methyl mercury poisoning in Japan showed severe cerebellar cellular atrophy of neurons in the calcarine cortex and precentral and postcentral gyri. Neurotoxic effects of methyl mercury are related to its ability to disrupt intracellular calcium concentrations and thus neurotransmitter release. Methyl mercury also disrupts cellular respiration processes and reduces ATP production. The effect of inorganic mercury on chloride currents has also been proposed as a mechanism of neurotoxicity.

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There is a correlation between the exposure and the amount of mercury excreted in the urine and increased risk of neurotoxic effects. Deficits in finger-tapping and eye-hand coordination have been reported in mercury-exposed workers whose urine mercury levels were above 50 pg/L. Clinical Diagnosis

Clinical neurologic manifestations of mercury intoxication depend on the type of compound involved (elemental, inorganic, or organic) and the concentrations, durations, and routes of exposure. Acute inhalation of elemental mercury is associated with respiratory symptoms including pulmonary edema that in severe cases may necessitate mechanical ventilation. Ingestion of inorganic mercurial salts is followed immediately by gastrointestinal symptoms including gastrointestinal bleeding. Patients exposed to elemental and inorganic mercury may also experience renal failure. Neurologic manifestations emerge 24 hours after exposure and may include cognitive problems and changes in mood and affect. Behavioral and cognitive problems are also the earliest neurologic manifestations associated with chronic exposure to elemental and inorganic mercury compounds. These early manifestations are followed by the emergence of movement disorders including ataxia, tremor, chorea, and peripheral neuropathy. A syndrome similar to lower motor neuron disease has been associated with exposure to mercury. The tremor of mercurialism is similar to that seen in hyperthyroidism. It is a fine and rapid tremor in contrast to the slower pill-rolling tremor of Parkinson’s disease. The tremor may be worse during activity, much like an essential tremor. It begins in the fingers and hands but may progress to affect the eyelids, face, and eventually the head, neck, and torso. An electromyographic recording of the tremor and tests of eye-hand coordination, finger-tapping, and cerebellar functions can be used to more objectively document the motor findings of mercury poisoning. Formal neuropsychological testing is helpful in documenting the cognitive impairment of mercurial encephalopathy. Nerve conduction velocity studies demonstrate the slowing in the peripheral nerves if neuropathy has developed. Laboratory diagnosis entails a 24-hour urine collection and analysis of the whole blood. Hair analysis is not recommended because of the possibility of external contamination. Inorganic and elemental mercury are looked for in blood and urine samples. Organic mercury is concentrated in the red blood cells, so a blood sample is the best biological marker of exposure. Blood levels normally are less than 5 p,g/L and should not exceed 15 pg/L. Urine mercury levels normally are less than 15 pg/g creatinine, but exposed workers often have urine levels over 500 pglg creatinine. The ACGIH recommends that preshift urine inorganic mercury levels not exceed 35 pg/g creatinine. End-of-shift blood levels of inorganic mercury should not exceed 15 pg/L. Paresthesias are experienced by people with urine mercury levels above 35 pglg creatinine, and tremor is clinically noticeable when urine contains over 50 p,g/g creatinine. Treatment

People at risk for increased intake of mercury should be monitored. A fourfold increase in urine mercury over baseline indicates a significant body burden, and action must be taken. Immediate removal from the source of exposure and serial urinalysis to ascertain that excretion is occurring satisfactorily

must be accomplished because mercury is also toxic to the kidneys, and renal dysfunction may occur in some exposed people. Syrup of ipecac should be administered to or gastric lavage performed on patients who have ingested elemental or inorganic mercury. If symptoms of neurologic dysfunction have been noted and renal function is normal, then chelation therapy is recommended to reduce the body burden and minimize‘ ;he clinical effects of intoxication. Dimercaprol (BAL) is the agent of choice for chelating patients exposed to inorganic or elemental mercury compounds but is contraindicated for use in patients exposed to organic mercury compounds because it has been shown to rapidly mobilize the body burden and may increase brain mercury levels. Chelation with BAL is recommended for adults with overt manifestations of acute inorganic mercury poisoning. BAL is administered for 5 days beginning with IM dosages of 3 to 4 mg/kg every 4 hours for the first 24 hours, 3 mg/kg every 4 hours for the second 24 hours, and then 3 mg/kg per day for the next 3 days. This regime can be repeated as necessary after a 2-day rest period until the urine mercury level has been reduced to 50 pg/L or less. Renal and cardiac function should be monitored throughout therapy. Children can be given IM BAL at a dosage of 3 to 4 mg/kg four times a day for 3 days; intensive care monitoring is recommended during chelation of children exposed to mercury. Less severely affected adults exposed to inorganic mercury and those exposed to organic mercury compounds can be chelated with succimer (10 mglkg PO three times a day for 5 days, then twice daily until urine mercury levels are satisfactorily reduced) or D-penicillamine (adults should receive 250 to 350 mg PO four times a day until the urine mercury levels are satisfactorily reduced). Because D-penicillamine inhibits the activity of pyridoxal-dependent enzymes, pyridoxine should be administered during its use. D-Penicillamine is contraindicated for patients with renal failure or histories of penicillin hypersensitivity reactions. N-Acetyl-d,l-penicillamine (NAP), an analogue of D-penicillamine, and 2,3-dimercapto-l-propanesulfonate (DMPS), a water-soluble form of BAL, have been used to chelate adults and children exposed to organic and inorganic and forms of mercury. An oral nonabsorbable polythiol resin can be used to facilitate elimination of organic mercury compounds and may be particularly useful in patients exposed to elemental mercury. Hemodialysis with L-cysteine or succimer infused into the dialyzer may be necessary to reduce the body burden of patients with renal dysfunction.

SUGGESTED READINGS Baker EL, Feldman RG, White RF et al: Occupational lead neurotoxicity: a behavioral and electrophysiological evaluation. Study design and year one results. Br J Ind Med 41:352-361, 1984 Berlin M: Mercury. pp. 3877445. In Friberg L, Nordberg GF, Vouk VB (eds): Handbook on the Toxicology of Metals. Vol. 11. Elsevier, New York, 1986 Feldman RG: Neurological manifestations of mercury intoxication. Acta Neurol Scand Suppl. 66:201-209, 1982 Feldman RG Occupational and Environmental Neurotoxicity. LippincottRaven, Philadelphia, 1999 Feldman RG, Niles CA, Kelly-Hayes M et al: Peripheral neuropathy in arsenic smelter workers. Neurology 29:939-944, 1979 Goldfrank LR, Flomenbaum NE, Lewin NA et al: Goldfrank’s Toxicologic Emergencies. 6th Ed. Appleton & Lange, Stamford, CT, 1998 Ishinishi N, Tsuchiya K, Vahter M, Fowler BA Arsenic. pp. 43-83. In Friberg L, Nordberg GF, Vouk VB (eds): Handbook on the Toxicology of Metals. Vol. 11. Elsevier, New York, 1986

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Klaasen C D Heavy metals and heavy-metal antagonists. In GoodmanGilman A, Rall TW, Nies AS, Taylor P (eds): Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th Ed. Pergamon Press, New York, 1990 Threshold Limit Values and Biological Exposure Indices for Chemical Substances and Physical Agents. American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 2000

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Tsai SW, Schwartz J, Lee MLT et al: The independent contribution of bone and erythrocyte lead to urinary lead among middle-aged and elderly men: the normative aging study. Environ Health Perspect 107391-396, 1999 Tsuchiya K Lead. pp. 298-353. In Friberg L, Nordberg GF, Vouk VB (eds): Handbook on the Toxicology of Metals. Vol. 11. Elsevier, New York, 1986

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204 Neurologic Complications of Organ

Transplantation Roy A. Patchell Martin A. Samuels Organ transplantation, begun in the mid-twentieth century with renal transplantation, has burgeoned into one of the greatest advances in twentieth-century medicine. Advances in immunology have allowed longer survival for transplant recipients, but this has resulted in the emergence of a number of neurologic problems in these patients, most of which are presented to the primary care physician. Three types of transplants exist: syngenic (identical twins), allogenic (different genetic origins), and autologous (patient’s own tissue). When a new organ is implanted in place of an old one (e.g., liver transplantation), the transplant is said to be orthotopic. In most cases the transplants are allogenic, so the recipients need some form of lifelong immunosuppression to prevent rejection. Therefore, the neurologic complications of organ transplantation may be divided into two major categories: those common to all allogenic transplants, caused primarily by the effect of long-term immunosuppression, and those specific to particular transplants, caused by either the underlying disease, which lead to the need for a transplant, or some phenomenon that is peculiar to the transplantation technique. NEUROLOGIC COMPLICATIONS CAUSED BY THE LONG-TERM EFFECTS OF IMMUNOSUPPRESSIVEDRUGS Cyclosporine Cyclosporine, the most commonly used drug to prevent rejection, works by inhibiting lymphokine release. This effect is exerted through inhibition of the calcium calmodulin-dependent protein phosphate calcineurin and binding to proteins known as immunophilins. Its major toxicity is renal. The hypertension that nearly always complicates cyclosporine use results in part from renal

toxicity but to a larger extent from the tendency of cyclosporine to stimulate the sympathetic nervous system by an unknown mechanism. Most, if not all, of its neurologic toxicity results from its tendency to produce hypertension combined with its tendency to disrupt cerebral autoregulation. The encephalopathy of cyclosporine toxicity is roughly correlated with blood levels (therapeutic level is 250 to 500 ng/mL of whole blood or 500 to 300 ng/mL of plasma) but is better correlated with the rate of change in blood pressure from the patient’s baseline level. Cyclosporine neurotoxicity could be thought of as a forme fruste of hypertensive encephalopathy. It is characterized by tremor; abnormalities in mental states, ranging from mild inattention to coma; seizures; and various visual syndromes characteristic of dysautoregulation in distal arterial territories of the posterior circulation. These include visual hallucinations, visual field deficits, visual agnosias, Balint’s syndrome (i.e., the triad of simultanagnosia, abnormalities in visually directed reaching, and difficulties with voluntary eye movements), and cortical blindness with denial of deficit (i.e., Anton’s syndrome). Magnetic resonance imaging shows increased signal on T2weighted images in the parietal-occipital white matter, a finding that may be evanescent and does not represent stroke. Flow studies such as single photon emission computed tomography demonstrate that this is caused by increased flow with extravasation of water. These findings are identical to those found in patients with hypertensive encephalopathy, including the syndrome of toxemia of pregnancy, and have sometimes been called posterior reversible leukoencephalopathy. A similar pathogenesis underlies the hypertension syndrome seen after carotid endarterectomy. It should be emphasized that the patient’s blood pressure need not be very high (i.e., in the range of malignant hypertension) for this syndrome to

Chapter 204

Klaasen C D Heavy metals and heavy-metal antagonists. In GoodmanGilman A, Rall TW, Nies AS, Taylor P (eds): Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th Ed. Pergamon Press, New York, 1990 Threshold Limit Values and Biological Exposure Indices for Chemical Substances and Physical Agents. American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 2000

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Tsai SW, Schwartz J, Lee MLT et al: The independent contribution of bone and erythrocyte lead to urinary lead among middle-aged and elderly men: the normative aging study. Environ Health Perspect 107391-396, 1999 Tsuchiya K Lead. pp. 298-353. In Friberg L, Nordberg GF, Vouk VB (eds): Handbook on the Toxicology of Metals. Vol. 11. Elsevier, New York, 1986

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204 Neurologic Complications of Organ

Transplantation Roy A. Patchell Martin A. Samuels Organ transplantation, begun in the mid-twentieth century with renal transplantation, has burgeoned into one of the greatest advances in twentieth-century medicine. Advances in immunology have allowed longer survival for transplant recipients, but this has resulted in the emergence of a number of neurologic problems in these patients, most of which are presented to the primary care physician. Three types of transplants exist: syngenic (identical twins), allogenic (different genetic origins), and autologous (patient’s own tissue). When a new organ is implanted in place of an old one (e.g., liver transplantation), the transplant is said to be orthotopic. In most cases the transplants are allogenic, so the recipients need some form of lifelong immunosuppression to prevent rejection. Therefore, the neurologic complications of organ transplantation may be divided into two major categories: those common to all allogenic transplants, caused primarily by the effect of long-term immunosuppression, and those specific to particular transplants, caused by either the underlying disease, which lead to the need for a transplant, or some phenomenon that is peculiar to the transplantation technique. NEUROLOGIC COMPLICATIONS CAUSED BY THE LONG-TERM EFFECTS OF IMMUNOSUPPRESSIVEDRUGS Cyclosporine Cyclosporine, the most commonly used drug to prevent rejection, works by inhibiting lymphokine release. This effect is exerted through inhibition of the calcium calmodulin-dependent protein phosphate calcineurin and binding to proteins known as immunophilins. Its major toxicity is renal. The hypertension that nearly always complicates cyclosporine use results in part from renal

toxicity but to a larger extent from the tendency of cyclosporine to stimulate the sympathetic nervous system by an unknown mechanism. Most, if not all, of its neurologic toxicity results from its tendency to produce hypertension combined with its tendency to disrupt cerebral autoregulation. The encephalopathy of cyclosporine toxicity is roughly correlated with blood levels (therapeutic level is 250 to 500 ng/mL of whole blood or 500 to 300 ng/mL of plasma) but is better correlated with the rate of change in blood pressure from the patient’s baseline level. Cyclosporine neurotoxicity could be thought of as a forme fruste of hypertensive encephalopathy. It is characterized by tremor; abnormalities in mental states, ranging from mild inattention to coma; seizures; and various visual syndromes characteristic of dysautoregulation in distal arterial territories of the posterior circulation. These include visual hallucinations, visual field deficits, visual agnosias, Balint’s syndrome (i.e., the triad of simultanagnosia, abnormalities in visually directed reaching, and difficulties with voluntary eye movements), and cortical blindness with denial of deficit (i.e., Anton’s syndrome). Magnetic resonance imaging shows increased signal on T2weighted images in the parietal-occipital white matter, a finding that may be evanescent and does not represent stroke. Flow studies such as single photon emission computed tomography demonstrate that this is caused by increased flow with extravasation of water. These findings are identical to those found in patients with hypertensive encephalopathy, including the syndrome of toxemia of pregnancy, and have sometimes been called posterior reversible leukoencephalopathy. A similar pathogenesis underlies the hypertension syndrome seen after carotid endarterectomy. It should be emphasized that the patient’s blood pressure need not be very high (i.e., in the range of malignant hypertension) for this syndrome to

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occur. The pathogenesis appears to be related to the rate of change of blood pressure combined with loss of cerebral autoregulation rather than the absolute level of blood pressure. Lowering of blood pressure by any means, including lowering the blood level of cyclosporine, results in resolution of the clinical syndrome and the imaging abnormalities. Cyclosporine nephrotoxicity may result in hypomagnesemia, which may in turn result in cerebral dysautoregulation. It is important to recognize that serum magnesium is a poor reflection of whole body magnesium, so that magnesium supplementation should be carried out in all patients with the magnetic resonance imaging or clinical findings of posterior reversible leukoencephalopathy, regardless of its cause. FK 506 (Tacrollmus)

FK 506 (tacrolimus) is an antirejection drug that works by a mechanism similar to that of cyclosporine. It also inhibits calcineurin and binds to immunophilins known as FK binding proteins. Although there is less experience with this drug, the range of side effects seems identical to those of cyclosporine, probably because it has the same effects on blood pressure and cerebral autoregulation. The newer drug sirolimus has similar effects. OK 13

OK T3 is a monoclonal antibody directed against T cells. Its major neurologic side effect is aseptic meningitis, which occurs in about 5% of patients during the first 3 days of exposure to the drug. Cerebrospinal fluid analysis shows a lymphocytic pleocytosis with normal glucose and normal or slightly elevated protein. The syndrome is self-limited and benign, but one should be certain to perform a lumbar puncture and culture the spinal fluid to exclude a bacterial or fungal meningitis before settling on the more benign diagnosis of OK T3-induced aseptic meningitis. The mechanism of the meningeal inflammation probably is allergic, similar to that seen in some patients placed on nonsteroidal anti-inflammatory drugs such as ibuprofen or in some patients treated with intravenous immunoglobulin (IV Ig). The ibuprofen syndrome appears to be more common in patients with rheumatic diseases such as lupus erythematosus. Whether this is also true for the IV Ig and OK T3-induced meningitis is unknown. A more severe syndrome with variable degrees of mental status derangement, including seizures, may occur even more rarely. It is associated with neuroimaging evidence of cerebral edema but is also self-limited and benign, even if the OK T3 is continued. The long-term serious side effect of OK T3 use is the development of lymphoma, which appears to be dose-related.

Antithymocyte and Antilymphoblast Globulins

Antithymocyte globulin and antilymphoblast globulin are antisera directed against thymocytes or lymphocytes. Rarely, patients develop an aseptic meningitis picture, similar to that seen with OK T3, which is also self-limited and benign in nature.

Corticosteroids are the oldest immunosuppressive drugs and are less specific in their actions than the newer agents discussed earlier. Neurologic complications include psychosis and mania, a proximal myopathy, and, rarely, spinal cord compression caused by

epidural lipomatosis. Long-term use of steroids also predisposes to glucose intolerance, gastrointestinal bleeding, and osteoporosis, all of which have their own secondary neurologic effects. These are well known to most generalists and are covered in other chapters of this text. Other immunosuppressive drugs used in transplant recipients, such as mycophenolate mofetil, azathioprine, leflunomide, daclizumab, and rituximab, have few or no serious neurologic side effects. Neurologic Infections

Neurologic infections occur in about 10% of all transplant recipients but are more important clinically than that number implies because about half of the central nervous system (CNS) infections that occur in immunocompromised patients result in death. Nearly every conceivable organism has been reported to infect transplant recipients, but about 80% of the cases are caused by infection with Listeria monocytogenes, Cryptococcus neoformans, and Aspergillus firmigatus. CNS infections in immunocompromised hosts may be difficult to recognize because the usual signs of infection, such as fever and meningismus, may be minimally present or absent in such patients because these signs depend on a vigorous immune response to the infection. Because the usual signs of CNS infection may be absent and because nearly any organism (bacterium, fungus, parasite, or virus) may be responsible, the clinician should have a high suspicion index for infectious causes of neurologic deterioration in any transplant recipient. A few clues may be of help in determining the likely predominant organism. An infection outside the nervous system should alert the clinician of a possible neurologic infection. Skin lesions may be found to harbor Cryptococcus, and lung infection suggests Aspergillus, Nocardia, or Cryptococcus. Acute meningitis often is caused by Listeria monocytogenes, whereas chronic meningitis, often with cranial nerve palsies, suggests tuberculosis or fungal organisms. A progressive multifocal syndrome with hemiparesis, visual symptoms, ataxia, dysarthria, and dementia should raise the specter of progressive multifocal leukoencephalopathy caused by the JC polyoma virus. A localized mass lesion (e.g., a brain abscess) often is caused by multiple organisms, including anaerobes, but the predominant organism in the immunocompromised patient usually is Aspergillus, Nocardia, or Toxoplasma. Another clue to the causative organism is the time period after transplantation. In the early period (up to 1 month after transplantation), infections are caused by organisms common in the nonimmunocompromised patient. In the intermediate period (1 to 6 months after transplantation), the risk of neurologic infection peaks, usually because of either virus (e.g., cytomegalovirus, Epstein-Barr virus) or opportunistic bacteria and fungi (e.g., Listeria, Aspergillus, and Nocardia). Late infections (more than 6 months after transplantation) are related to the chronic use of potent antirejection medications such as steroids, monoclonal antibodies, and cyclosporine; the most common organisms at this time are Cryptococcus, Listeria, and Nocardia. Lymphoproliferative syndromes occur after prolonged immunosuppression, ranging from apparently benign polyclonal lymphoid hyperplasia to monoclonal lymphoma. The nervous system is involved in about 20% of such patients. When the CNS is involved, it is the only apparent site of involvement 85% of the time. Post-transplant lymphoproliferative syndromes are strongly

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associated with Epstein-Barr virus infection, but primary CNS lymphomas in immunocompetent people are not associated with this virus. These B-cell lymphomas arise deep in the brain, with a propensity for the perivascular spaces. CNS lymphoma is distinguished from progressive multifocal leukoencephalopathy by the fact that the former produces mass effect and demonstrates contrast enhancement with gadolinium. NEUROLOGIC COMPLICATIONS ASSOCIATED WITH SPECIFIC TRANSPLANT TYPES Renal Transplantation

Renal transplantation is most often performed in patients with glomerulonephritis (membranous or membranoproliferative)diabetes mellitus and hypertensive renal disease. Other underlying diseases include polycystic kidney disease, lupus erythematosus, amyloidosis, analgesic nephropathy, and obstructive nephropathy. Most of the neurologic complications of renal transplantation are caused by the underlying disease for which the transplant was performed. For example, polycystic kidney disease may be associated with multiple cerebral berry aneurysms, hypertension with ischemic and hemorrhagic stroke, lupus erythematosus with antineuronal antibodies, and mental state changes and uremic encephalopathy with hepatorenal syndrome. Rapid correction of hyponatremia may lead to central pontine myelinolysis, a syndrome that can range in severity from mild tetraparesis to deep coma or even death and can now be easily demonstrated in the pons or in extrapontine sites by magnetic resonance imaging. The renal transplantation procedure itself is the oldest of all the organ transplants and now rarely causes any neurologic problems. Occasionally, peripheral nerve injuries (e.g., the lateral femoral cutaneous nerve of the thigh) may be caused by retractors or patient positioning during the surgical procedure, but these are usually reversible without specific treatment. The most common postrenal transplantation neurologic complication is stroke related to underlying cerebrovascular or cardiac disease, caused by the risk factors of hypertension and diabetes, which are so often present in renal transplant recipients. Bone M a m w Transplantation

Bone marrow transplants are performed for two major indications: abnormal or absent marrow (e.g., aplastic anemia; genetic diseases such as lysosomal storage diseases or thalassemia major; acute leukemia, such as acute myelocytic, acute lymphoblastic, or chronic lymphocytic; or combined immunodeficiency disease) and hazard to the marrow as the limiting factor in aggressive treatment of a disease (e.g., lymphoma, solid tumor autologous marrow programs, glioblastoma multiforme, breast cancer, or neuroblastoma). Neurologic complications occur in about 70% of bone marrow transplant recipients and are the cause of death in 6%. The most common problem is metabolic encephalopathy caused by respiratory failure, hepatic failure, electrolyte disorders, or renal failure. The drugs used to prepare patients for the transplantation, including intrathecal methotrexate, busulfan, cyclophosphamide, and adriamycin, may also contribute to metabolic encephalopathy. Total body irradiation often is used (2000 cGy or less), which can lead to long-term cognitive dysfunction, particularly in children. Graft-versus-host disease (GVHD) occurs in about one third of human leukocyte antigen (HLA)-matched and two thirds of HLA-mismatched transplants. Acute GVHD, which occurs within

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3 months of transplantation, consists of rash, diarrhea, and hepatic dysfunction, but no neurologic complications have been reported. Chronic GVHD occurs in about a third of patients who survive more than 3 months after transplantation. It may have an autoimmune pathogenesis and has been associated with polymyositis, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy. A leukoencephalopathy occurs in bone marrow transplant recipients who have been treated with methotrexate and wholebody irradiation. It appears that high-dose intravenous or intrathecal methotrexate must be combined with radiation therapy to produce the leukoencephalopathy.Hemorrhages usually are related to severe thrombocytopenia (i.e., platelets fewer than 20,000/mm3). Cerebral infarcts are largely caused by emboli from endocarditis, either infective or nonbacterial thrombotic endocarditis, which can occur as part of a generalized hypercoagulable state in bone marrow transplant recipients.

Cardiac Transplantation

Cardiac transplantation is used to treat medically intractable dilated, hypertrophic, restrictive, and ischemic cardiomyopathies and some patients with rheumatic heart disease. Neurologic complications are very common, occurring in 50% to 60% of the patients. The cardiac transplantation procedure is associated with variable periods on extracorporealcirculation, which may result in diffuse hypoxic-ischemicinjury or focal cerebral infarction related to thromboembolism or air embolism. Damage to the brachial plexus is also commonly seen because of retraction of the chest wall, and the phrenic nerve may be damaged when the heart is packed in ice during the procedure. Liver Transplantation

Liver transplantation is used to treat chronic advanced liver disease (e.g., cholestatic diseases, such as primary biliary cirrhosis and sclerosing cholangitis; hepatocellular diseases, such as alcohol or viral hepatitis; vascular diseases, such as the Budd-Chiari syndrome), hepatic malignancies (e.g., hepatoma, cholangiocarcinoma, and isolated hepatic metastasis, as may be seen in carcinoid), fulminant hepatic failure (e.g., caused by viral hepatitis or drug-induced liver damage with acetaminophen, halothane, or gold), and metabolic liver diseases (e.g., a,-antitrypsin deficiency, Wilson’s disease, glycogen storage diseases I and 11, and protoporphyria). Many neurologic complications are related to the underlying liver disease. Most patients have some degree of portosystemic encephalopathy. In patients with Wilson’s disease or acquired hepatocerebral degeneration, the neurologic syndrome usually is dramatic, consisting of dysarthria, movement disorder, dementia, and spasticity. The transplantation procedure is particularly traumatic, often associated with a great deal of blood loss, necessitating aggressive blood product and fluid replacement. Hypotension is common, often resulting in some degree of hypoxic-ischemic cerebral damage. Coagulation often is defective, leading to cerebral hemorrhages, and intraoperative cerebral infarctions may result from air or arterial embolism. Central pontine myelinolysis is particularly common in liver transplant recipients, occurring in about 10% of autopsied cases. This is probably related to the fact that fluid and blood replacement often results in rapid rises in

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serum sodium concentrations, the presumed cause of central pontine myelinolysis.

though the usual neurologic effects of metabolic encephalopathy are particularly common in patients undergoing these complex procedures.

Pancreas Transplantation Pancreas transplantation is used to treat patients with type I diabetes who have severe end organ damage. Many times, it is done in conjunction with renal transplants, with the aim being to make the patient insulin-independent and reverse some of the end organ damage. Neurologic complications are very common, occurring in perhaps as many as two thirds of the patients. Much of the neurologic difficulty is related to the fact that almost all pancreas transplant recipients have retinopathy and neuropathy at the time of the transplant. In addition, nearly all patients have cerebrovascular disease related to the premature atherosclerosis associated with type I diabetes. The procedure involves either transplanting the whole pancreas into the abdomen or transplanting free islet cells. The former is by far the most successful in correcting the diabetes and reversing or retarding damage to end organs. There are no unique neurologic complications caused by the procedure itself. Lung Transplantation Single and double lung transplantation and combined heart-lung transplantation are now being performed in specialized centers. No specific neurologic complications have been identified, al-

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IntestinalTransplantation A few specialized centers are now performing intestinal transplantation for patients with intestinal failure. Because prolonged total parented nutrition may lead to liver failure, many such patients receive combined liver and intestinal transplants. Experience with these rare patients is limited, but it appears that the neurologic complication spectrum is similar to that seen with other solid organ transplants but perhaps more common because of the higher dosages of immunosuppressive drugs needed to prevent rejection in these patients.

SUGGESTED READINGS Estol CJ, Pessin MS, Martinez AJ: Cerebrovascular complications after orthotopic liver transplantation. Neurology 41:815-819, 1991 Patchell RA: Neurological complications of organ transplantation. Ann

Neurol 36688-703, 1994 Patchell RA, White CL, Clark AW et al: Neurologic complications of bone marrow transplantation. Neurology 35:300-306, 1985 Pless M, Zivkovic S A Neurologic complications of transplantation. Neurologist 8: 107-120, 2002. Textor SC, Canzanello VJ, Taler SJ et ak Cyclosporine-induced hypertension after transplantation. Mayo C h Proc 6 9 1 182-1 193, 1994

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205 Neurologic - Manifestations of Rheumatic Diseases Patricia M. Moore

The rheumatic diseases comprise numerous conditions centering around inflammation of the joints, muscles, blood vessels, or connective tissue. The two largest categories, the connective tissue diseases and the vasculitides, typically manifest systemic inflammation and multiorgan injury. Diagnosis of these immunologically mediated diseases depends on clinical and histologic features. The pattern and extent of disease and specific serologic, histologic, and, occasionally, radiographic features render the individual diseases distinctive. Neurologic abnormalities, prominent in some disorders, occasionally herald disease. However, these diseases may be difficult to diagnose in their early stages.

The connective tissue diseases are multisystem diseases characterized by inflammation of joint, muscle, and skin, and the vasculitides are multiorgan or organ-specific diseases characterized by inflammation of blood vessels (Table 205-1). Ischemia is the common denominator of tissue injury caused by the vasculitides. IMMUNOPATHOGENIC MECHANISMS Lymphocytes and their products can mediate tissue damage. The complex interplay of lymphocyte subsets often makes it difficult to

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serum sodium concentrations, the presumed cause of central pontine myelinolysis.

though the usual neurologic effects of metabolic encephalopathy are particularly common in patients undergoing these complex procedures.

Pancreas Transplantation Pancreas transplantation is used to treat patients with type I diabetes who have severe end organ damage. Many times, it is done in conjunction with renal transplants, with the aim being to make the patient insulin-independent and reverse some of the end organ damage. Neurologic complications are very common, occurring in perhaps as many as two thirds of the patients. Much of the neurologic difficulty is related to the fact that almost all pancreas transplant recipients have retinopathy and neuropathy at the time of the transplant. In addition, nearly all patients have cerebrovascular disease related to the premature atherosclerosis associated with type I diabetes. The procedure involves either transplanting the whole pancreas into the abdomen or transplanting free islet cells. The former is by far the most successful in correcting the diabetes and reversing or retarding damage to end organs. There are no unique neurologic complications caused by the procedure itself. Lung Transplantation Single and double lung transplantation and combined heart-lung transplantation are now being performed in specialized centers. No specific neurologic complications have been identified, al-

SECTION

IntestinalTransplantation A few specialized centers are now performing intestinal transplantation for patients with intestinal failure. Because prolonged total parented nutrition may lead to liver failure, many such patients receive combined liver and intestinal transplants. Experience with these rare patients is limited, but it appears that the neurologic complication spectrum is similar to that seen with other solid organ transplants but perhaps more common because of the higher dosages of immunosuppressive drugs needed to prevent rejection in these patients.

SUGGESTED READINGS Estol CJ, Pessin MS, Martinez AJ: Cerebrovascular complications after orthotopic liver transplantation. Neurology 41:815-819, 1991 Patchell RA: Neurological complications of organ transplantation. Ann

Neurol 36688-703, 1994 Patchell RA, White CL, Clark AW et al: Neurologic complications of bone marrow transplantation. Neurology 35:300-306, 1985 Pless M, Zivkovic S A Neurologic complications of transplantation. Neurologist 8: 107-120, 2002. Textor SC, Canzanello VJ, Taler SJ et ak Cyclosporine-induced hypertension after transplantation. Mayo C h Proc 6 9 1 182-1 193, 1994

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205 Neurologic - Manifestations of Rheumatic Diseases Patricia M. Moore

The rheumatic diseases comprise numerous conditions centering around inflammation of the joints, muscles, blood vessels, or connective tissue. The two largest categories, the connective tissue diseases and the vasculitides, typically manifest systemic inflammation and multiorgan injury. Diagnosis of these immunologically mediated diseases depends on clinical and histologic features. The pattern and extent of disease and specific serologic, histologic, and, occasionally, radiographic features render the individual diseases distinctive. Neurologic abnormalities, prominent in some disorders, occasionally herald disease. However, these diseases may be difficult to diagnose in their early stages.

The connective tissue diseases are multisystem diseases characterized by inflammation of joint, muscle, and skin, and the vasculitides are multiorgan or organ-specific diseases characterized by inflammation of blood vessels (Table 205-1). Ischemia is the common denominator of tissue injury caused by the vasculitides. IMMUNOPATHOGENIC MECHANISMS Lymphocytes and their products can mediate tissue damage. The complex interplay of lymphocyte subsets often makes it difficult to

Chapter 205 w

TABLE205-1. The Connective Tissue Diseases and Vasculitides Connective tissue diseases Systemic lupus erythematosus Primary Sjogren’s syndrome Mixed connective tissue disease Rheumatoid arthritis Systemic sclerosis Polymyositis and dermatositis Vasculitides Polyarteritis nodosa Churg-Strauss angiitis Hypersensitivityvasculitis Wegenet‘s granulornatosis Lymphomatoid granulomatosis Isolated angiitis of the central nervous system Temporal arteritis Takayasu’s arteritis BehCet‘s disease Secondary vasculitis (caused by infections, neoplasia, toxins)

dissect components of an immune cascade. Genetic factors influence aspects of the immune system, particularly immunoregulatory mechanisms. The role of genetic factors explains the overlap in autoimmune diseases in patients and their relatives. Understanding mechanisms of immune-mediated diseases provides clues to appropriate diagnostic tests and will guide choices between the newer immunotherapies. Autoantibodies and immune complexes predominate in some of these disorders. Transient autoantibody formation is a normal phenomenon in both humans and animals that probably performs a physiologic “housecleaning” function. Persistent autoantibodies occur and may be nonspecific manifestations of inflammation, as with antinuclear antibodies; markers for a specific disease, as with anti-Sm in systemic lupus erythematosus (SLE); or pathogenic. Autoantibody-mediated disease develops through several mechanisms. Antibodies binding to the cell surface may alter cell function or cause cell death. The antibodies to the acetylcholine receptor in myasthenia gravis and to a skin antigen in pemphigus are examples. Antibodies to intracellular autoantigens such as DNA and Sm produce renal and cutaneous damage largely by immune complex-recruited inflammation. Deposition of circulating immune complexes or in situ immune complex formation (with filtered or planted antigen) both occur. The immune complexes trapped along the basement membrane activate complement components. Complement-derived chemotactic factors (C3a, C5a, C567) cause accumulation of polymorphonuclear leukocytes. The pathogenicity of other antibodies is uncertain. Antiphospholipid antibodies including anticardiolipin antibodies and lupus anticoagulant are strongly associated with recurrent fetal loss, venous thromboses, and some cases of stroke. Another potentially pathogenic antibody is antineutrophilic cytoplasmic antibody (ANCA). Although the antigen is intracellular, there is a surface molecule on the neutrophils to which the antibodies bind. Binding of antibody to this surface molecule may induce a respiratory burst in neutrophils, leading to degradation with subsequent vessel wall injury. Of the antigenic targets of ANCA, proteinase 3 defines a population of antibodies closely associated with Wegener’s granulomatosis and microscopic PAN. Cell-mediated tissue damage is, increasingly, the focus of study in autoimmunity. These interactions occur over short distances (millimeters), and histology is central to understanding of cyto-

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toxic mechanisms and diagnosis. Many of the vasculitic syndromes illustrate this. Endothelial cells are in an immunologically unique position: They direct traffic of lymphocytes by expression of cell surface adhesion molecules. They function as antigen-presenting cells, and they secrete cytokines. Cytokines, small proteins produced by lymphocytes, macrophages, and fibroblasts, affect gene expression in cells with cytokine receptors. Among other effects, cytokines amplify and perpetuate inflammation. Uncontrolled production of interleukin-1 and tumor necrosis factor may result in tissue injury. The mechanisms appear to be intravascular coagulation, thrombosis, vasculitis, and tissue trauma. Interleukin-1 and other cytokines also induce thromboplastin, prostacyclin, and platelet activating factors from endothelial cells, which result in altered vascular permeability and thrombosis. Other mediators released by the endothelium govern chemotaxis and adherence of leukocytes, changes in permeability of the vessel wall, and molecular and cellular transport across the endothelial barrier.

CONNECTWE TISSUE DISEASES Systemic Lupus Erythematosus SLE is a multisystem inflammatory disease that affects the skin, kidneys, blood, joints, muscles, heart, lungs, gastrointestinal tract, and nervous system. The course ranges from indolent to fulminant. Autoantibodies are a hallmark of SLE; patients and animals with this disease produce exaggerated responses to exogenous antigens and spontaneous production of autoantibodies, some to unique antigens. Autoantibodies to nuclear components, including nucleic acids, proteins, and nucleoprotein complexes, are prominent. The particular pattern of autoantibody formation may be an important diagnostic feature. For example, anti-Sm antibodies rarely occur in any disease except SLE. Immune complex deposition with subsequent inflammation is the principal pathogenesis of the renal and cutaneous injury. Anemia, leukopenia, thrombocytopenia, and some coagulopathiesprobably result from direct antibody-mediated effects. Neurologic abnormalities (neuropsychiatric SLE) result from multiple pathogenic mechanisms (Table 205-2). Some clinical events develop from acute immunologic mechanisms and are treatable. Others are the results of chronic injury, and therapy may produce more complications than benefit. Primary manifestations (both acute and delayed) of the chronic hypergammaglobulinemia in SLE may result in neurologic abnormalities. Immune complex deposition occurs readily in the choroid plexus and perhaps some small cerebral vessels. Although these may provide the setting for later clinical effects or may alter the blood-brain barrier, there is no direct correlation between the presence of immune complexes and clinical neurologic dysfuncT l w 205-2. Pathogenic Mechanisms in Neuropsychiatric Systemic Lupus Erythematosus Primary-Immune-mediated Direct effects Immune complex Autoantibodies Indirect effech Vasculopathy Coagulopathy Cardiac emboli Secondary Infectious Metabolic Toxic (includinn effects of medications)

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tion as there is for renal disease. Direct antibody (antineurona1)mediated effects are potentially important in many transient, diffuse neurologic abnormalities where alterations in cellular function occur without cytopathic effect. There is a correlation between certain neuron-reactive antibodies in the sera and cerebrospinal fluid (CSF) of patients with encephalopathies and psychiatric abnormalities, but a specific pathogenic effect has not been established. Vasculitis occurs in visceral organs in SLE, but involvement of the neuraxis by frank arteritis is rare even in patients with recurrent vascular disease. Stroke in SLE is more likely to result from cardiac emboli, coagulopathies, and degenerative vasculopathies. The latter is histologically demonstrable, particularly in the small vessels. It is difficult to ascertain the pathogenesis because it develops slowly. Chronically low levels of circulating immune complexes or cytokines may well be causative. The absence of inflammation is clinically important because there is minimal benefit to glucocorticoid or immunosuppressant therapy. Secondary causes of neurologic abnormalities are common, demand a high index of suspicion, and necessitate different therapies from the primary manifestations. The most prominent of these are infections that remain a major cause of death in patients with SLE. Bacterial infections usually are readily diagnosed. Fungal infections may remain undetected antemortem. Toxic (usually from medications, notably corticosteroids and antihypertensive agents) and metabolic (typically uremia) effects are consequential and treatable causes of encephalopathy. Hypertension is common in patients with SLE primarily because of their renal disease. AU of the usual complications of hypertension are more common in patients with SLE. These include ischemic and hemorrhagic stroke, both of which are substantially more common in patients with SLE than in patients of comparable age.

Mixed Connective Tissue Disease Mixed connective tissue disease was initially described on the basis of high titers of antibodies to ribonuclear protein. Clinically, it appears to be a mild variant of SLE. The clinical features of generalized systemic inflammation, scleroderma, and polymyositis associated with Raynaud’s phenomenon suggest the disease. Titers of greater than 1:4000 anti-U1 ribonuclear proteins are typical. Neurologic manifestations occur in more than half the patients and include aseptic meningitis, psychosis, febrile headaches, peripheral neuropathies, trigeminal neuropathy, and seizures.

Sjtigren’s Syndrome Sjogren’s syndrome is a chronic autoimmune inflammatory disease characterized by diminished lacrimal and salivary secretion resulting in keratoconjunctivitis sicca and xerostomia. It is usually a benign disease manifest primarily by exocrine gland impairment as a result of destructive mononuclear infiltrates. In a number of patients, however, visceral involvement occurs. A wide spectrum of extraglandular manifestations develops from lymphoid infiltration of lung, kidney, skin, thyroid gland, stomach, liver, and muscle. There is a strong association between Sjogren’s and anti-Ro antibodies, although anti-La antibodies also occur. The importance of these autoantibodies in the pathogenesis of the disease is not established. Diagnosis of Sjogren’s syndrome rests on clinical features, salivary or lacrimal gland biopsy showing lymphocyte infiltration, and, usually, circulating autoantibodies. Attention to strict histologic criteria on the labial biopsy is helpful in forming a more precise diagnosis.

Neurologic manifestations are more common in the peripheral than the central nervous system (CNS). The most distinctive neurologic abnormalities are the sensory and autonomic neuropathies. Cranial neuropathies, particularly trigeminal neuropathy, are also common and may occur in up to 40% of patients. In some patients the trigeminal neuropathy is so profound that they lose the sensation of food in their mouth. CNS abnormalities appear less often, although the exact incidence is not yet established. The two most likely pathogenic mechanisms for the neurologic abnormalities are direct mononuclear cell infiltration and vasculitis. Histologic studies are needed to better understand immunopathogenic mechanisms. Nerve biopsy often shows an immunemediated inflammatory neuropathy.

Rheumatoid Arthritis Rheumatoid arthritis consists of progressive erosive inflammation of the joints. Activation of a cellular immune response in the genetically susceptible host generates the early stages; ensuing proliferation of polyclonal B cells results in proliferative synovitis; cytokines drive the proliferation of synovial cells, which invade and destroy articular cartilage. Because the damage to the joints is widespread, secondary injury to the nervous system occurs. Cervical spine abnormalities occur in up to 25% of patients. Potentially devastating is the dissolution of the transverse ligament, allowing forward displacement of the skull and atlas. Physicians must be vigilant to prevent a high cervical myelopathy in these patients. Particularly in unconscious patients, neck manipulations should be performed carefully. Peripheral neuropathies develop from several mechanisms. Compression from swollen tissue and subcutaneous nodules typically results in the chronic, progressive neuropathies. Other pathogenic mechanisms of neuropathy include ischemia. Vascular occlusion from vasculitis and obliterative vasculopathy causes neuropathies usually more acute in onset than the compressive neuropathies. Distal sensory neuropathies often occur. CNS abnormalities are less common and result from subcutaneous nodules or the systemic vasculitis that complicates a small percentage of cases of rheumatoid arthritis.

Progressive Systemic Sclerosis Progressive systemic sclerosis (or scleroderma) involves the cardinal features of proliferative intimal arterial lesions, obliterative microvascular defects, and atrophy and fibrosis of the involved organs. It is largely a cell-mediated (T lymphocytes and mast cells) immune process, and some distinctive autoantibodies may be markers of the disease. Neurologic abnormalities are unusual. In one large series they occurred in less than 1% of patients. When clinical neurologic disease does occur it is usually a consequence of accelerated hypertension, uremia, or pulmonary insufficiency. Rarely, a vasculitis complicates scleroderma, and this may involve the CNS. Because an inflammatory myopathy occurs occasionally, differentiation from mixed connective tissue disease may be needed in the early stages of disease.

Other Connective Tissue Disorders Patients may present with neurologic signs and serologic evidence of inflammation, including autoantibodies, yet defy clinical classification. Sometimes, this is an early manifestation of a specific syndrome. In other cases, the disease may remain undefined. After infections, toxins, and neoplasia are excluded as a cause of the abnormalities, undifierentiated connective tissue disease

Chapter 205 H Neurologic Manifestationsof Rheumatic Diseases

may be the only term that applies. Such patients may exhibit a polyneuropathy that, on biopsy, shows features of an immunemediated inflammatory process.

VASCULITIS Idiopathic Vasculitides The vasculitides are a group of disorders characterized by inflammation and, usually, necrosis of the blood vessel wall. Ischemia is the common denominator of tissue injury. Classification of the vasculitic syndromes incorporates clinical, radiologic, and pathologic features. Sometimes the pattern of disease changes over time, and the diagnosis becomes clearer in retrospect. Identification of any underlying causes of vasculitis is central to the management because it guides treatment. Therefore, clinically, primary vasculitides must be distinguished from the secondary vasculitides in patient evaluation.

Polyarteritis Nodosa A systemic necrotizing vasculitis, polyarteritis nodosa (PAN), targets small and medium-sized muscular arteries with a predilection for bifurcations and branchings. Clinically, the disease affects the kidneys, musculoskeletal system, nervous system, gastrointestinal tract, skin, heart, and genitourinary system. Hypertension is common. Laboratory features may reflect systemic inflammation but are not diagnostic. Although its role in the pathogenesis is not clear, about 20% to 30% of patients with PAN have a hepatitis B antigenemia. Diagnosis of PAN depends on angiography and biopsy. Peripheral neuropathies, which may be the presenting manifestation of PAN, occur in 60% of patients. The six major patterns of neuropathy are mononeuropathy multiplex, extensive mononeuropathy multiplex, polyneuropathy, cutaneous neuropathy, brachial plexopathy, and radiculopathy. CNS abnormalities develop in 40% of patients, including encephalopathies, subarachnoid hemorrhage, seizures, strokes, and cranial neuropathies. These usually occur later in the course of the disease than the peripheral neuropathies and are not typically a presenting manifestation of PAN.

Churg-Strauss AndMs Churg-Strauss angiitis affects small and medium-sized vessels with prominent involvement of pulmonary vessels, eosinophilic infiltrates, and granulomas. Neurologic abnormalities are similar to those of PAN, but encephalopathiesoccurring early in the course of the disease are more common. Peripheral neuropathies are common. Adult-onset asthma, particularly in association with eosinophilia, should suggest the diagnosis.

HypersensitivityVasculitis Hypersensitivity vasculitis, the most common of all the vasculitides, is a heterogeneous group of clinical syndromes characterized by inflammation of small vessels, mainly the venules. The skin is the predominantly affected organ. In many instances, the vessel inflammation can be identified as a response to a precipitating antigen such as a drug, foreign protein, or microbe. Several groups of hypersensitivity vasculitis including serum sickness, HenochSchbnlein purpura, and vasculitis with mixed cryoglobulinemia have distinctive clinicopathologic characteristics. Involvement of the nervous system is variable. Neurologic abnormalities are common in serum sickness and include encephalopathy, seizures,

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stroke, brachial plexopathy, and peripheral neuropathies. In other subgroups of hypersensitivity vasculitis, neurologic involvement is unusual, although reports of subarachnoid hemorrhage and peripheral neuropathies exist.

Wegenets Granulomatosis Wegener’s granulomatosis is a systemic necrotizing vasculitis with a characteristic organ specificity. The involvement of the upper and lower respiratory tracts with granulomatous vasculitis together with a necrotizing glomerulonephritis is quite distinctive. Histologically, granulomata are prominent in the vasculitic lesions. The diagnosis often is suggested by cough, hemoptysis, or recurrent sinus abnormalities in a patient with evidence of systemic inflammation. Neurologic abnormalities, particularly cranial neuropathies, may be among the presenting manifestations of disease. Two processes produce most of the neurologic abnormalities: contiguous extension of granulomas from primary sites in the nasopharynx (cranial neuropathies, cavernous sinus compression, diabetes insipidus), and vasculitis (peripheral neuropathies, encephalopathies, stroke). Ocular abnormalities, including proptosis and inflammation of the anterior structures of the eye, occur in just under half the patients. Wegener’s granulomatosis is unusual among the vasculitides in the strong association between the disease and an autoantibody, antineutrophilic cytoplasmic antibody. These autoantibodies are reactive with myeloperoxidase and proteinase 3. Controversy exists over whether these antibodies are serologic markers for disease activity, pathogenic, or neither.

Lymphomatold Granulomatosis Lymphomatoid granulomatosis, a rare disease affecting the lungs, skin, and nervous system, is now classified with lymphoma rather than vasculitis. Lung involvement is central and usually manifests as multiple nodular infiltrates, which tend to cavitate. Histologic lesions are characterized by infiltration of vessels with atypical lymphocytes, plasmacytes, and histiocytes in an angiocentric angiodestructive pattern. Granulomas are plentiful. Both central and peripheral nervous systems may be affected. CNS dysfunction is reported in 20% of patients and peripheral nervous system dysfunction in 15%. The spectrum of neurologic abnormalities is wide and includes visual loss, nystagmus, cranial neuropathies, ataxia, aphasia, encephalopathies, and upper motor neuron signs such as weakness, spasticity, hyperreflexia and Babinski signs.

Giant Cell Arteritis Two histologically similar but clinically distinct diseases are included under the term giant cell arteritis: temporal arteritis and Takayasu’s arteritis. Temporal Artentis. Temporal arteritis is a systemic panarteritis affecting mainly older adults. Despite the widespread nature of the vasculitis, symptoms below the neck are unusual. Neurologically, visual impairment and cranial neuropathies predominate. Because blindness is an often devastating complication of temporal arteritis, it is important for physicians to remain vigilant for the disease. The disease should be considered in any patient over age 40 with new onset of headaches or visual changes. Jaw claudication, lingual ischemia, and occipital headache are alternative presenting manifestations. Immediate erythrocyte sedimentation rate measurement and temporal artery biopsy guide diagnosis. The alkaline phosphatase often is elevated.

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Takayasu’s Artefltis. Takayasu’s arteritis is a large-vessel arteritis affecting the aortic arch and its branches in young women. It is often called the pulseless disease, because absence of at least one arterial pulse is identified in 98% of patients. Bruits are often heard. The disease may be divided into an acute stage characterized by signs and symptoms of systemic inflammation, followed by a chronic phase marked by signs and symptoms of vascular occlusion. Typically the disease is recognized by ischemia secondary to the reduced blood flow to the extremities and other organs. Most of the neurologic abnormalities occur in the later vasoocclusive stage of the illness. Syncope is reported by more than half of patients. Hypertension exacerbates the vascular disease. Strokes, transient, ischemic attacks, and syncope are prominent.

Behqet‘s Disease Behget’s disease, characterized by relapsing ocular lesions and recurrent oral and genital ulcers, is histologically a small-vessel vasculitis that mainly affects venules. A genetic role is suggested by the apparent increased incidence of the disease in patients from eastern Mediterranean countries. The disease is often benign, although the recurrent ulcers are symptomatically distressing. In some patients neurologic abnormalities are associated with a more serious course; 10% to 50% of patients have neurologic abnormalities including meningoencephalitis, brainstem abnormalities, and focal CNS changes. Neuro-Behget’s disease has two major syndromes. About two thirds of patients with neurologic symptoms have a hypercoagulable state with cerebral venous occlusive disease. Any of the dural sinuses may be affected. About one third of patients with neurologic symptoms have an inflammatory, perivenous inflammatory disease and CSF pleocytosis with lesions seen on T2weighted magnetic resonance imaging reminiscent of multiple sclerosis (Behcet’s sclerosis).

Isolated Angiltis of the CNS Isolated angiitis of the CNS is a recurrent, inflammatory disease of the small and medium-sized blood vessels of the brain and spinal cord. It was initially included under the term granulomatous angiitis ofthe CNS, but the name was changed because granulomas are a variable and often absent feature. The disease has been recognized with increasing frequency in the past decade, possibly because current treatment methods are so effective. The precise diagnosis may be difficult. Appropriate clinical features, absence of evidence of systemic inflammation, and angiographic and histologic data are necessary. In addition, because an occasional self-limited vasculopathy occurs, evidence of recurrent or persistent disease is necessary. Symptoms and signs are limited to the nervous system and typically include headaches, encephalopathies, strokes, cranial neuropathies, and myelopathies. Notably, symptoms and laboratory evidence of systemic inflammation are absent. Neurodiagnostic studies including computed tomography and magnetic resonance imaging often are nonspecifically abnormal. Angiography is the most sensitive (though nonspecific) diagnostic study, although an occasional patient with only small vessel disease may have a normal angiogram. Of greater concern is the fact that the angiographic features are not specific for vasculitis. Similar abnormalities may occur in noninflammatory vasculopathies as well as vasculitis secondary to infections, drugs, and neoplasia. Treatment is not recommended on the basis of angiogram alone. Biopsy of brain and meninges is recommended

to confirm the diagnosis. Steroid treatment usually is ineffective, making more potent immunosuppression with cyclophosphamide necessary. Clinical features that should suggest the diagnosis are headaches and encephalopathy, particularly in association with multifocal signs. Angiography often shows single or multiple areas of beading along the course of a vessel, abrupt vessel terminations, hazy vessel margins, and neovascularization. The pathogenesis of the CNS vascular inflammation is not known. A cell-mediated process appears most likely.

Other Vasculitides There are several reports and series of patients with neurologic abnormalities not readily classifiable in the aforementioned disease groups. Among these are a vasculitis limited to the peripheral nervous system (although many of these patients later develop systemic vasculitis) and a small vessel vasculitis limited to the CNS, skin, and muscle. Another disorder of small vessel is more likely to be a microvasculopathy than a vasculitis. This retinocochlear encephalopathy (Susac syndrome), appears to be more prevalent in Europe. The syndrome consists of a subacute encephalopathy (often with early psychiatric features) sensorineural hearing loss, and retinal arteriolar occlusions. This hearing loss in association with vascular disease must be distinguished from Cogan’s syndrome (nonsyphilitic interstitial keratitis and vestibuloauditory symptoms). Some patients with Cogan’s syndrome have a vasculitic component that is predominantly an aortitis.

Secondary Vasculitides CNS infections reveal the clearest association between a specific cause and vasculitis. A wide range of infectious agents cause a vasculitis, including bacteria, fungi, viruses, treponemes, mycobacteria, Rickettsia, and parasites. The infection may range in tempo and severity. At times, an infection is so indolent (such as aspergillosis) that only a rigorous search for the cause of a vasculitis reveals the pathogen. Multiple mechanisms can lead to vascular inflammation: direct infection of the vessel wall, immune complexes, or toxic products of the bacteria. Fungal infections may result in a vasculitis clinically indistinguishable from an idiopathic vasculitis. Herpes zoster ophthalmicus associated with contralateral hemiplegia is well described. Identifylng an underlying infection in a patient is crucial. Corticosteroid or immunosuppressive therapy without appropriate antimicrobial agents could result in dissemination of disease. The earliest reports of toxin-associated vasculitis probably were sulfonamide-induced hypersensitivity vasculitides. Amphetamine abuse is associated with both a systemic necrotizing vasculitis and a vasculitis limited to the CNS. More recently, cocaine has become a common cause of stroke. The underlying mechanism usually is a hemorrhagic vasculopathy, but occasionally a vasculitis occurs. Because drug use is prevalent in all socioeconomic sectors of society, a careful drug history is important in all patients. Neoplasia may cause a vasculitis by several mechanisms. Typically immune complex formation associated with a large tumor load causes nonspecific systemic inflammation. Hodgkin’s disease, by an unknown mechanism, is associated with a vasculitis limited to the CNS. It is important to distinguish lymphomainduced cerebral vasculitis from diffuse involvement of the cerebral vessels by lymphoma. This so-called angiocentric lymphoma may be limited to the CNS. Involvement of the eye by slit lamp examination and adrenal enlargement seen by computed

Chapter 205

tomography may be clues, but cerebral biopsy usually is needed. An unusual paraneoplastic complication of oat cell and ovarian carcinoma is a peripheral nerve vasculitis. Accurate diagnosis is important because the vasculitis may resolve with treatment of the underlying disease.

DIAGNOSIS The physician will encounter the rheumatic diseases primarily in two settings: when a neurologic abnormality is the presenting complaint, and the physician must determine whether there is an underlying connective tissue disease or vasculitis; and when a patient with an established diagnosis presents with a new neurologic event that may indicate either an undertreated disease, a complication of treatment, or a diagnosis that is inaccurate and must be revised. Tables 205-3 and 205-4 summarize some general points. Features that warrant a search for an underlying connective tissue disease or vasculitis include a young or female patient, evidence of multisystem disease, the presence of systemic inflammation, and previous unexplained neurologic or systemic abnormalities. The clinician relies on serologic and histologic studies for diagnosis while realizing that in several of these diseases there may be no serologic markers of a progressive disease. Histology is central to the diagnosis in most of the vasculitides and is important in SLE and Sjogren’s disease. Specific serologic studies (autoantibodies) may be diagnostic or at least narrow the diagnostic possibilities in cases with high titers of anti-DNA, anti-Sm, anti-Ro, anti-La, ANA (antinuclear antibodies), and ANCA. Angiography is useful in the medium and large vessel vasculitides. Among the valuable information provided by angiography is the distribution of the disease and serial evaluations to show healing or progression. The physician is also asked to evaluate patients with an identified connective tissue disease or vasculitis and new neurologic symptoms. In this situation the new features usually results from either inexorable disease progression, inadequate therapy, or a complication of the treatment regimen. Occasionally the initial diagnosis was incorrect, and the clinician must reevaluate the data for diagnosis. Among the most important clinical concerns in this group are complications of therapy, largely avoidable or treatable. Because many of these patients are immunosuppressed, infections occur and contribute prominently to the morbidity and mortality.

rn TAW 205-3. General Points to Remember Regarding Rheumatic Diseases with Neurologic Manifestations Antinuclear antibodies, immune complexes, rheumatoid factor, and sedimentation rate are not tests for vasculitis; they neither confirm nor exclude a diagnosis. Vasculitis has no pathognomonic radiographic features. The erosive and destabilizingchanges in the cervical spine in rheumatoid arthritis render the cord susceptible to compression and trauma. The diagnosis of temporal arteritis rests on a high index of suspicion in any patient over 45 with new-onset headaches or visual changes. Extended treatment with corticosteroids (usually 1 year) is important to reduce the incidence of relapses. Antiphospholipid antibodies occur in a variety of autoimmune diseases and are associated with strokes, but the pathogenesis of the antibodies is not yet established. Treatment directed at the antiphospholipid antibodies usually is resewed for patients who fulfill the criteria for the syndromes of recurrent fetal loss, recurrent thrombophlebitis, or stroke.

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rn TABU205-4. Outline for the Evaluation and Treatment of Rheumatic Diseases with Neurologic Manifestations Evaluation Delineate neurologic abnormalities (central or peripheral nervous system, white or gray matter, mixed). Determine distribution of systemic disease (renal, cutaneous, cardiac, hepatic, ocular). Determine immunologic abnormalities (autoantibodies, immune complexes, cellular infiltrates). Discover any underlying conditions. Treatment Evaluate immunopathogenic mechanisms. Remove any underlying causes. Determine extent of tissue damage. Determine the least toxic and most effective treatment. Plan dosage, duration, and goals of therapy.

Diagnosis of infection may be overlooked because symptoms (malaise, fever, headache) and signs are attributed to the underlying disease. Specifically, the usually indolent CNS fungal infections are underdiagnosed. A high clinical index of suspicion, repeated CSF analyses, and occasionally brain biopsy are important. Other complications of therapy include the side effects of medications. Corticosteroids are common causes of psychopathy, visual changes, and myopathy. Antihypertensive medications may cause headaches and cognitive changes.

TREATMENT The results of treatment vary from excellent to frustrating. Some regimens in individual diseases dramaticallyreduce morbidity and mortality, whereas in other disorders the optimal treatment remains empirical. The general guidelines to therapy are as follows: Treat any precipitating causes such as infections or toxins in the secondary vasculitides. Use the current, standard treatment in the primary vasculitides with known responsiveness to specific therapies (prednisone in temporal arteritis and prednisone and cyclophosphamide in Wegener’s granulomatosis, PAN, and isolated angiitis of the CNS) (Table 205-5). In the primary vasculitideswith less well-defined treatments, such as lymphomatoid granulomatosus and Behget’s disease, compare the benefit-risk ratio for treatment in each patient and begin with the least toxic treatment. Remember that in the later stages of vasculitic disease, ischemia may result from chronic scarring rather than acute inflammation. Scarring is not responsive to immunosuppressive therapy, and the patient should be spared the side effects of ineffective medication. Experience in the use of immunosuppressant medications is also important because of the wide range of potential and actual side effects. Side effects occur with any of these agents, and the physician should be thoroughly acquainted with all potential side effects before initiating treatment (Table 205-4).

Anti-platelet Agents, Aspirin Given the prominent scarring and early atherosclerosisreported in patients with long-term survival from systemic vasculitis, maintenance with anti-platelet agents would appear to be useful. We

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recommend daily aspirin to patients after therapy for isolated angiitis and for a variety of disorders involving vasculitis of the peripheral nervous system.

Selective COX-2 Inhibitors Selective COX-2 inhibitors are newer medications that reduce the inducible form of cyclooxygenase (COX-2), which is the major source of prostaglandin in the inflammatory response. Two agents marketed as Vioxx and Celebrex are selective COX-2 inhibitors effective in both inflammatory and pain disorders. Of note, the COX-2 inhibitors do not affect platelet function. This is an advantage if bleeding is a potential complication. However, many physicians accustomed to using a nonsteroidal for its antiinflammatory and anti-platelet actions need to remember to add a specific anti-platelet agent if needed.

Corticosteroids Corticosteroids (CS) are small lipophilic molecules that circulate in the blood, mostly bound to CS binding globulin and albumin. The immunomodifying and anti-inflammatory actions of CS result from several actions including changing in the traffic patterns of leukocytes and reduced expression of proinflammatory cytokines (IL-1,IL-2, IL-6, IFNy, and TNF) thus inhibiting T-cell proliferation and T-cell dependent immunity. The anti-inflammatory effects of corticosteroids are probably the greatest, or at least most discernible, on macrophages where they inhibit cytokine gene transcription, PGH synthase 2 (COX-2) mediated production of prostanoids, and nitric oxide synthetase, thus reducing vasodilation. Occupancy of glucocorticoid and mineralocorticoidreceptors throughout the body (including in the hippocampus and hypothalamus) determines the net activity of many pathways. Both inadequate and excessive (endogenous or pharmacological) levels of cortisol damage the host. The immunological effects of CS in man are considered high above the equivalent of 30 mg prednisone/day, medium with 10 to 30 mg/day, and low
metabolite, it causes interstrand and intrastrand DNA cross-links that result in dysfunction of the DNA template. These intracellular biochemical reactions lead to cell death, largely through apoptotic mechanisms. Cyclophosphamide’s effect on clonal expansion of lymphocytes underlies its use in immune mediated disorders. It is currently most effectively used in autoimmune disease in combination with a glucocorticoid both in steroid-sensitiveand steroidresistant diseases. In steroid-sensitive diseases, the addition of cyclophosphamide permits a lower and less toxic dosage of prednisone to be effective. In steroid-resistant diseases it provides an additional and possibly synergistic immunomodulatory effect. Combination cyclophosphamide/prednisoneis effective and firstline agent in Wegener’s granulomatosis, polyarteritis nodosa, isolated angiitis of the CNS, and in autoimmune processes without a central vasculitis such as neuropsychiatric-SLE.There are several dosage regimens by both intravenous and oral routes that are reported successful. Patients usually tolerate cyclophosphamide well, although it must be used with care and scrupulous attention to hydration (>2 liters per day) to avoid hemorrhagic cystitis and potential bladder malignancies. Some patients develop prominent nausea requiring antiemetic therapy. Infrequently, allergic reactions, teratogenicity, and carcinogenicity (0.1% to 1% with long-term use) occur. Rarely, we encounter cardiac, pulmonary, or hepatic disorders or SIADH. In the dosages used for treatment of vasculitis (smaller than those used to treat cancers), the major side effects include infection, nausea, gonadal failure, and hemorrhagic cystitis.

Methotrexate Methotrexate is a potent folate antagonist that has been successfully utilized in rheumatoid arthritis and psoriasis.

Mycophenolate MofetFl Mycophenolate mofetil (MFF) is the morpholinoethyl ester prodrug of mycophenolic acid (MPA). MPA is an immunosuppressant drug that acts by impairment of de novo purine synthesis. This drug is relatively selective for lymphocytes and inhibits antibody production by B cells more than other immunosuppressants. MFF has recently been approved by the FDA for the prevention of rejection in renal transplantation. There has been reported success with this medication in the maintenance phase of systemic vasculitis after traditional induction with cyclophosphamide/prednisone as well as in Takayasu’s syndrome. If the low side effect profile continues, this medication may decrease the long-term morbidity of traditional vasculitis therapies.

Thalidomide Thalidomide appears to have a specific inhibitory activity on tumor necrosis alpha production. It is undergoing a reevaluation of its utility based upon recent studies indicating efficacy in erythema nodosa leprosum, acquired immunodeficiency syndrome (AIDS), graft-versus-host disease (GVHD), and BehGet’s disease. Side effects include peripheral neuropathy, drowsiness/ somnolence, orthostatic hypotension, and teratogenicity.

Interferon (Y Cyclophosphamide is a cytotoxic alkylating agent introduced for the treatment of malignancies nearly 40 years ago. An anti-

Interferons as a class possess antitumor, antiviral, and immunomodulating activity. They are species restricted and receptor

Chapter 205

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TABLE 205-5. Treatments in Specific Vasculitides Disease/Natural History

Recommended Therapy

Small Series

Wegener‘s

Cyclophosphamide/prednisone Trimethoprim-sulfamethoxazole Cyclophosphamide/prednisone Cyclophosphamide/prednisone

Etaneracept

PAN

Churg-Strauss Temporal arteritis isolated angiitis of the CNS Ta kayasu’s

Prednisone Cyclophosphamide/prednisone ??? Anti-platelet Corticosteroid/cyclophosphamide

Behcet‘s

Azathioprine Chlorambucil

Interferon a Prednisone/methotrexate MMF

Surgery Interferon a Thalidomide Methotrexate

Secondary vasculiiider

Viral Other infectious Kawasaki

interferon a, vidarabine, plasmapheresis Appropriate agent to treat underlying infection Intravenous immunoglobulin, aspirin

dependent, and binding to specific cell-surface receptors is required for activity. Interferon 01 is a primary therapeutic agent in the treatment of viral vasculitis, most specifically that associated with hepatitis B viremia. There is some reported success with Churg-Strauss angiitis as well as Behget’s disease. Of note, interferon a is suspected of either inducing or exacerbating a vasculitis as well as an SLE-like syndrome. Characteristic side effects of alpha interferons are flu-like symptoms and gastrointestinal disturbances; however, alopecia, neutropenia, thrombocytopenia, and liver enzyme elevations also occur. In addition, the neurological, psychiatric, as well as autoimmune side effects of interferon a therapy may be considerable. Agents That InterfereWith Activity of TNFa

Tumor necrosis factor (TNF) promotes inflammation by binding to receptors on a variety of cells, stimulating them to release a host of other inflammatory mediators. Soluble TNF receptors are cleaved from the membrane portions of the cell complex and appear to function as a natural counterbalance to TNF. Etanercept is an expressed protein which contains two chains of a soluble TNF receptor linked by the Fc portion of an immunoglobulin molecule (TNFRFc = soluble TNF receptor (p75):Fc fusion protein). The molecule functions by absorbing excess circulating TNF and keeping it from binding to its natural receptor. Several studies have indicated efficacy and safety in patients with rheumatoid arthritis and Wegener’s granulomatosis. Infliximab is a chimeric (part-mouse, part-human) monoclonal antibody to TNF. This also reduces inflammation and is currently indicated for Crohn’s disease. IntewentSonal Procedures/Maneuvers

Plasmapheresis may be effective therapy in vasculitis when circulating autoantibodies or immune complexes contribute to the pathogenesis of the vasculitis. It is most effective in essential mixed cryoglobulinemiabut also may be useful in Kawasaki’s syndrome. A controlled study of glucocorticoids alone compared with glucocorticoids and plasmapheresis did not demonstrate improved short-term or long-term outcome in patients with polyarteritis arteritis or Churg-Strauss. Except for patients with refractory systemic vasculitis, it is not recommended for routine or initial treatment. Both the complications of central venous access and the high cost limit its utility. The main side effects are hypotension and occasional clotting abnormalities.

Intravenous immunoglobulin is proven effective in Kawasaki’s disease, where it is the treatment of choice. It is variably effective in systemic vasculitis, although no controlled studies have been performed. Side effects include fever, chills, hypotension, nausea, abdominal pain, headache, dizziness and, rarely, anaphylaxis.

SUGGESTED READINGS Abu-Shakra M, Smythe H, Lewtas J, Badley E, Weber D, Keystone E Outcome of polyarteritis nodosa and Churg-Strauss syndrome. An analysis of twenty-five patients. Arthritis Rheum 37:1798-1803, 1994 Alhalabi M, Moore P M Serial angiography in isolated angiitis of the central nervous system. Neurology 441221-1226, 1994 Calabrese LH, Gragg LA, Furlan AJ: Benign angiopathy: a distinct subset of angiographically defined primary angiitis of the central nervous system. J Rheumatol 202046-2050, 1993 Guillevin L, Lhote F, Gherardi R The spectrum and treatment of virus-associated vasculitides. Curr Opin Rheumatol 9:31-36, 1997 Jennette JC, Falk RJ, Andrassy K et ak Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 37:187-192, 1994 Langford CA, Sneller M C New developments in the treatment of Wegener’s granulomatosis, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Curr Opin Rheumatol926-30, 1997 Mader R, Keystone EC: Infections that cause vasculitis. Curr Opin Rheumatol43538, 1992 Moore PM: Diagnosis and management of isolated angiitis of the central nervous system. Neurology 39167-173, 1989 Moore PM: Neuropsychiatricsystemiclupus erythematosus: stress, stroke, and seizures, Ann N Y Acad Sci 823:l-17, 1997 Moore PM, Richardson B Neurology of the vasculitides and connective tissue diseases. J Neurol Neurosurg Psychiatry 65: 10-22, 1998 Nishino H, Rubino FA, DeRemee RA et ak Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 33:49, 1993 Parisi JE: Neurological Nishino H, Rubino FA, DeRemee RA, Swanson JW, involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 33:4-9, 1993 Recommendations for the prevention and treatment of glucocorticoidinduced osteoporosis: American College of Rheumatology Task Force on Osteoporosis Guidelines. Arthritis Rheum 39:1791-1801, 1996 Sneller M C Evaluation, treatment, and prophylaxis of infections complicating systemic vasculitis. Curr Opin Rheumatol 1038-44, 1998

SECTION

1

GENERAL ASPECTS OF HEADACHE

206 Anatomy and Physiology of Headache Egilius L. H. Spierings The head hurts more often without harm having been done to it than any other part of the body. Pain in the head, or headache, affects 70% to 80% of the population, men and women alike. Fifty percent of the population has headache at least once per month, 15% at least once per week, and 5%, that is 1 of 20 people, suffers from headache daily. Headaches generally are classified as mild, moderate, or severe. Mild headaches do not interfere with the ability to function, whereas moderate headaches do, and severe headaches disable the person. Moderate and severe headaches affect women twice as often as men; moderate headaches occur in 23% of women and 13% of men, and severe headaches occur in 12% of women and 6% of men. The prevalence of migraine is 16% for women and 9% for men. Headaches are not only gender-dependent but also agedependent. The prevalence of headache sharply increases during the first and second decades of life, then levels off until age 40. Thereafter the prevalence gradually decreases. In a recent epidemiologic study in Denmark, the lifetime prevalence of headache was 96% (93% for men and 99% for women) for a group ranging in age from 25 to 64 years. The headaches were diagnosed according to the classification criteria of the International Headache Society. The lifetime prevalence of migraine was found to be 16% (8% for men and 25% for women). The lifetime prevalence of tension-type headache was 78% (69% for men and 88% for women). Of those who ever had migraine, 87% also had tension-type headache at some time. Three percent of the population had chronic tension-type headache, with more than 180 days with headache per year.

EPIDEMIOLOGY OF MIGRAINE IN THE UNITED STATES The prevalence of migraine was also studied in the United States. AU regions of the United States were included, and the segment of the population studied were those between 12 and 80 years of age. A self-administered questionnaire was sent to a stratified random sample of 15,000 households. A designated member of each household responded to the questionnaire by reporting the number of members in the household and the number who suffer from severe headaches. In addition, each household member with severe headaches was asked to complete the questionnaire. Of the 15,000 households, 9507 (63%) responded to the questionnaire for a total base population of 23,611 household members. The response rate was higher among whites (64%) than blacks (49%) and other racial groups (38%). By age, it was highest among older adults (76%) and lowest among adults between 18 and 29 years of age (52%). The response rate was also lower in the 1306

South Central United States (59%) than in other regions of the country. It did not differ by gender, urban versus rural residence, or household income. Migraine was defined as at least one severe headache during the preceding 12 months, which had one of the following features: unilateral or pulsatile pain with nausea, vomiting, or photophobia and phonophobia; or visual or sensory aura preceding the headache. These criteria were derived from the definition of migraine as proposed by the International Headache Society. A total of 6% of the men and 18% of the women in the base population of 23,611 household members was found to have migraine according to the definition. The prevalence of severe headache per se was 14% in men and 27% in women, figures similar to those reported earlier for the prevalence of moderate headache. It is important to remember that “severe” in the study was self-defined and therefore not necessarily related to the impact of the headaches on the ability to function. Of the respondents diagnosed with migraine, 82% of the men and 86% of the women reported at least mild interference with the ability to function. No information is provided in the study with regard to the prevalence of disability, that is, headaches necessitating bed rest, in those with severe headache or migraine. No differences in migraine prevalence were found for men or women between urban and rural residence or between the six regions studied. However, white men had a prevalence of migraine twice that of black men (6% versus 3%). Also, for both men and women, the prevalence of migraine was the highest in the group with the lowest household income, less than $10,000 per year. There was also a clear age dependence in both men and women, with the highest prevalence between ages 25 and 45. Of those identified, a physician had diagnosed 29% of the men and 40% of the women with migraine. Of these people, 23% of the men and 15% of the women were not confirmed by the study as having migraine. When both genders are taken together, this means that physician and study diagnoses disagreed in 17% and agreed in 83% of cases. The International Headache Society criteria were published in 1988, and the study was conducted in 1989, which means that the physician diagnosis was made mostly independent of the criteria but nevertheless agreed in the majority of cases. The proportion of respondents with a physician diagnosis increased in the men from one fifth to one third and in the women from one third to one half with a rise in household income from less than $10,000 to more than $45,000 per year. There were no significant differences in physician diagnosis of migraine between the races, between urban and rural residence, and between the different regions of the United States, except in the North and

Chapter 206 rn Anatomy and Physiology of Headache

South Central regions, where it was lower in women. The headache features that in both men and women were most strongly associated with a physician diagnosis were vomiting, blurred vision, visual aura, and sensory aura. A physician diagnosis was also found to be two times as frequently associated with severe disability, that is, headaches necessitating bed rest (50% versus 25%). With regard to medication use, 28% of the men and 40% of the women with migraine in the study population used prescription medications. This was almost twice as common as those in the study who reported severe headaches but were not diagnosed with migraine. The use of prescription medications was more common among whites than blacks and was the highest between ages 50 and 59. It did not depend to any great extent on household income or on rural versus urban residence. With regard to the different regions of the United States, it was the highest in New England and in the Mountain region. Higher use of prescription medications was associated with sensory aura (43%) and vomiting (38%) in men and sensory aura (54%), vomiting (52%), and visual aura (48%) in women. The use of prescription medications was also higher in both men and women with a migraine frequency of two to six attacks per week (40% and 48%, respectively). It was also higher in both men and women with a duration of migraine of 3 days or longer (56% and 49%, respectively). Thirteen percent of the men and 20% of the women with migraine used emergencyroom services for headache. It was about three times higher in those who used prescription medications than in those who used nonprescription medications. Sixty-seven percent of the men and 57% of the women with migraine used nonprescription medications. Only 5% of the men and 3% of the women did not use any medications. However, their use of emergency room services was two or three times higher than that of those who used nonprescription medications. ANATOMY

OF HEADACHE

Headaches often involve not only the head proper but also the face and neck. Therefore, a description of the pain-sensitive structures of the face and neck is included in this section on the anatomy of headache. The basic structures of the head, face, and neck-the bones-are insensitive to pain. However, they are enveloped in membranes, the periost, that are sensitive to pain. Most of what makes up the head-the brain-is also insensitive to pain. In this way the brain does not differ from other internal organs, all of which derive their protection against nociceptive stimuli from the encapsulating membranes. The encapsulating membrane of the brain is the arachnoid, which is very sensitive to pain. It is innervated by nerve fibers that travel along the blood vessels, both arteries and veins. As a result, the arachnoid is most sensitive to pain in areas adjacent to the blood vessels. Like everywhere else in the body, the blood vessels of the brain, both arteries and veins, are sensitive to pain. However, in their course through the arachnoid, they give off their nerve fibers to innervate the arachnoid. As a result, the blood vessels gradually become less pain-sensitive as they travel toward the brain, to become insensitive to pain by the time they enter the brain proper. The pain fibers that travel along the (intracranial) carotid artery to the cerebral arteries come from the ophthalmic branch of the trigeminal nerve. This so-called ophthalmic nerve gives off pain fibers to the carotid artery when it passes alongside it in the cavernous sinus. This is before it enters, along with the ophthalmic artery, the orbit through the superior orbital fissure to innervate

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the contents of the orbit as well as the forehead and anterior vertex. The arteries innervated in this way by the ophthalmic nerve are the anterior, middle, and posterior cerebral arteries because they are all branches of the carotid artery. Through nerve fibers that run along these arteries, the ophthalmic nerve provides pain innervation of the arteries and the arachnoid in the anterior and middle cranial fossae. In the central nervous system there is convergence of somatic and visceral pain information, resulting in referral of pain from stimulation of carotid and cerebral arteries and adjacent arachnoid to the ipsilateral eye and forehead. The cerebral veins drain into the venous sinuses and derive their pain innervation from these structures. The venous sinuses lie embedded in the dura mater, which is essentially thickened periost of the inside of the skull. A branch of the ophthalmic nerve, called the tentorium nerve, innervates them. This nerve originates from the ophthalmic nerve close to the ganglion and travels along the tentorium to the sagittal sinus in the falx, in which the cerebral veins drain. Therefore, painful stimulation of the cerebral veins and sinuses refers pain to the area of somatic innervation of the ophthalmic nerve, the ipsilateral forehead and anterior vertex. The dura mater is also innervated by nerve fibers that travel along the meningeal arteries. The main meningeal artery, the middle, is a branch of the maxillary artery. The middle meningeal artery divides into frontal and parietal branches, which vascularize most of the dura mater above the tentorium. Along with the meningeal arteries run branches of the mandibular nerve, which innervate the arteries and adjacent dura mater. The mandibular nerve also innervates the temple and anterior ear through the auriculotemporal nerve and the anterior jaw through the mental nerve. As a result, painful stimulation of the dura mater in the anterior or middle cranial fossa results in pain referred to the temple. The recurrent meningeal nerves, originating from the first three cervical spinal nerves, innervate the pain-sensitive structures of the posterior fossa. These nerves originate from the anterior branches of the spinal nerves just distal to the ganglia and run back into the spinal canal through the intervertebral foramina. They innervate the dura mater and, through nerve fibers that run along the vertebral arteries, the basilar artery, its cerebellar branches, and the adjacent arachnoid. The first three cervical spinal nerves also innervate the back of the head and upper neck through their posterior branches. The major occipital nerve (C2) innervates the medial side of the back of the head, and the minor occipital nerve (C3) innervates the lateral side. Therefore, painful stimulation of structures in the posterior fossa causes pain referred to the back of the head and upper neck. Apart from innervating the back of the head and neck, the posterior branches of the cervical spinal nerves also innervate the posterior neck muscles, zygapophyseal joints, and interspinous ligaments. The anterior neck muscles and intervertebral discs are innervated by the anterior branches of the cervical spinal nerves, which, as mentioned earlier, also innervate the spinal dura mater and vertebral arteries through the recurrent meningeal nerves. The innervation of the face is through the three branches of the trigeminal nerve. The first branch, the ophthalmic nerve, innervates the forehead and anterior vertex through the supraorbital nerve. The second branch, the maxillary nerve, innervates the cheek through the infraorbital nerve. The third branch, the mandibular nerve, innervates the anterior ear and temple through the auriculotemporal nerve and the anterior jaw through the mental nerve. The auricular nerve, a branch of the C3 spinal nerve,

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which also innervates the inferior ear, innervates the posterior jaw. The posterior ear is innervated by the minor occipital nerve, also a branch of the C3 spinal nerve, which innervates the lateral side of the back of the head as well. The border between the innervation of the scalp by the trigeminal and cervical nerves is formed by an imaginary line that runs from ear to ear over the vertex. Of the deeper structures of the face, in particular the nasal cavity and paranasal sinuses are important in relation to headache. As mentioned earlier, the bones making up these structures are insensitive to pain, but their linings (the periost) and the linings of the cavities (the mucosal membranes) are sensitive to pain. The mucosal membranes are very sensitive to pain where they cover the approaches to the paranasal sinuses. The nasal branches of the maxillary nerve innervate the turbinates in the lateral side of the nasal cavity. The maxillary nerve also innervates the maxillary sinus through the infraorbital nerve, and, as mentioned earlier, the infraorbital nerve also innervates the cheek. As a result, painful stimulation of the nasal turbinates or maxillary sinus causes pain referred to the cheek. The upper part of the nasal septum and the ethmoid sinuses are innervated through the ethmoidal branches by the ophthalmic nerve. The ophthalmic nerve also innervates the frontal sinus, giving rise to pain referred to the forehead. The sphenoid sinus, although innervated by the maxillary nerve, causes pain referred to the vertex. In summary, the structures of the head, face, and neck that are sensitive to pain are the following: Cerebral arteries, particularly those at the base of the brain Dural venous sinuses and cerebral veins on the surface of the brain Arachnoid adjacent to the pain-sensitive cerebral arteries and veins Meningeal arteries Dura mater adjacent to the meningeal arteries and dural venous sinuses Mucosal membranes of the nasal cavity and paranasal sinuses, especially those covering the approaches to the sinuses Temporomandibular and zygapophyseal joints Vertebral arteries, interspinous ligaments, and intervertebral disks Extracranial arteries, veins, muscles, and skin These structures are innervated predominantly by the trigeminal and cervical nerves, with the border between the two innervation systems formed intracranially by the tentorium, separating the anterior and middle from the posterior cranial fossa, and extracranially by an imaginary line that runs from ear to ear over the vertex. The nociceptive information from the trigeminal and cervical innervation systems of the head, face, and neck converges in the dorsal horn of the upper part of the cervical spinal cord, also known as cervicotrigeminal relay. The information from the trigeminal system reaches the cervicotrigeminal relay through the descending limb of the tract of the trigeminal nucleus, which runs from the port of entry of the trigeminal nerve-the pons-to the upper part of the cervical spinal cord. It is through the cervicotrigeminal relay that painful stimulation of the face or head causes pain in the neck and painful stimulation of the neck causes pain in the head or face. As mentioned earlier, in the central nervous system there is also convergence of somatic and visceral pain information, resulting in referral of pain from stimulation of visceral structures to the corresponding somatic areas. In this way, painful stimulation of structures within the anterior and middle cranial fossae causes

pain referred mostly to the somatic areas innervated by the ophthalmic nerve, that is, the forehead and anterior vertex. Painful stimulation of structures in the posterior fossa causes pain referred mostly to the somatic areas innervated by the upper three cervical nerves, that is, the back of the head and upper neck.

PHYSIOLOGY OF HEADACHE The bones of the head, face, and neck are insensitive to pain. Nevertheless, afflictions of the bones, such as inflammation (osteomyelitis) or neoplasm (metastasis), cause pain but they do so through chemical (inflammation) or mechanical stimulation (stretching) of the periost. The brain is also insensitive to pain, but afflictions of the brain do cause pain. However, to cause pain they have to involve pain-sensitive intracranial structures, either directly or indirectly. For example, a neoplasm of the brain, either primary or secondary, that is, metastatic, causes pain only when it causes a mass effect, either through its own size or through the induction of edema, to cause displacement and thereby stretching of major arteries or veins. It also causes pain, regardless of its mass effect, when it is in a strategic location, for example, to cause obstruction of cerebrospinal fluid flow or cause compression of a cranial nerve carrying sensory information, particularly the trigeminal nerve. Obstruction of cerebrospinal fluid flow by a neoplasm is most likely to occur in the third ventricle (colloid cyst obstructing the interventricular foramina), the cerebral aqueduct in the mesencephalon (pinealoma), and the fourth ventricle (ependymoma). The obstruction of cerebrospinal fluid flow under these circumstances causes biventricular or triventricular hydrocephalus with expansion of the ventricles, causing stretching of the major arteries and veins on the surface of the brain. Of course, triventricular hydrocephalus can also be caused by a neoplasm or other lesion, such as an infarct or hematoma, in the cerebellum with enough mass effect to cause obstruction of the foramina in the roof of the fourth ventricle. Similar to a neoplasm, an infarct, hematoma, or abscess of the brain causes pain when it has enough mass effect to cause displacement, thereby stretching the major arteries and veins on the surface of the brain. A cerebral hematoma usually is caused by rupture of an intracerebral artery, which by itself is a painless event because the intracerebral arteries are insensitive to pain, and the same is true for a cerebellar hematoma. This is also the case with a cerebral infarct when it is caused by obstruction of an intracerebral artery but not when it is caused by obstruction of a major artery by thrombosis or embolism. In the latter case, the obstruction of the major cerebral artery causes inflammation and distention of the blood vessel wall and, as a result, pain, and the same is true for a cerebellar infarct caused by obstruction of a major cerebellar artery. Stretching of the major cerebral arteries and veins on the surface of the brain can also be caused by swelling of the brain. The swelling can either be locally as in encephalitis, such as herpes encephalitis with swelling of a temporal lobe, or generally as in pseudotumor cerebri or benign intracranial hypertension. Encephalitis can be associated with inflammation of the membrane encapsulating the brain, the arachnoid, and in meningoencephalitis with severe pain caused by the inflammation of the pain-sensitive meningeal membrane. Of course, the meningeal membrane can also be inflamed by itself, which is usually the case as in bacterial, viral, or fungal meningitis, subarachnoid hemorrhage, or carcinomatous meningitis, and conditions associated with severe generalized headache.

Chapter 206

Subarachnoid hemorrhage usually is caused by rupture of an aneurysm and sometimes by rupture of an arteriovenous malformation or by a bleeding disorder. A cerebral aneurysm generally originates from a major artery at the base of the brain and would therefore be sensitive to pain. However, the pain caused by rupture of an aneurysm does not stand in comparison to that caused by the resulting subarachnoid hemorrhage. Pain from the aneurysm may be appreciated when the lesioning affecting it is not severe enough to result in subarachnoid hemorrhage, such as in expansion of the aneurysm or bleeding in its wall. A cerebral arteriovenous malformation is a congenital abnormality that often also involves major, pain-sensitive arteries and veins. It causes pain when subjected to inflammation. A cerebral arteriovenous malformation can also affect the metabolism of the brain tissue with which it is in contact, resulting in seizures or migraine attacks. Seizures are associated with increased metabolism of the brain, which, in turn, is associated with increased blood flow and dilation of the pain-sensitive major cerebral arteries causing generalized headache. Generalized dilation of the major cerebral arteries also occurs when cerebral metabolism is increased by fever or when oxygen saturation is decreased by high altitude, sleep apnea, carbon monoxide poisoning, or pulmonary insufficiency, for example. Generalized cerebral vasodilation also occurs with hypercapnia, hypoglycemia (diabetes mellitus), and nitroglycerine, as well as when cerebral autoregulation is impaired, as after a concussion or carotid endarterectomy. The major cerebral arteries are distended in a generalized way when blood pressure rises abruptly, as in malignant hypertension, pheochromocytoma, toxemia of pregnancy, dysreflexia of the bladder or bowel in quadriplegics, and ingestion of a sympathomimetic agent in a patient treated with a monoamine oxidase inhibitor. Finally, apart from dilation and distention, inflammation can also affect the major cerebral arteries in a generalized way, such as in the arteritis seen in lupus erythematosus. Inflammation of venous structures, such as major cerebral veins and dural venous sinuses, is generally associated with thrombosis and distention of the structures. The inflammation and distention affecting the venous structures cause pain. The pain can also be caused by swelling of the brain tissue drained by the affected structures, through edema, infarction, or bleeding, with displacement and stretching of major arteries and veins on the surface of the brain. With regard to the venous structures, the inflammation can be primary (e.g., of the sagittal sinus due to scalp cellulitis, the sigmoid sinus due to otitis media, or the cavernous sinus due to a nasal carbuncle). The thrombosis can also be primary, such as during pregnancy or disseminated intravascular coagulation. Displacement and concomitant stretching of the major veins on the surface of the brain also occurs with space-occupying lesions in the subdural space, the space between the arachnoid and dura mater. Lesions that can occupy the subdural space are hematoma, acute or chronic, resulting from rupture of a cerebral vein by trauma, or abscess. Stretching of the major cerebral veins can also result from traction by a downward displaced brain, as is seen with low cerebrospinal fluid pressure, caused by lumbar puncture or a (traumatic) fistula of the dural sac. Downward displacement of the brain can sometimes be associated with herniation of the cerebellar tonsils into the cervical spinal canal, which causes pain by stretching of the arachnoid. Stretching of the pain-sensitive meningeal arteries occurs with space-occupying lesions in the dura mater, such as a meningioma, hematoma, or abscess. A hematoma in the dura mater is called an epidural hematoma and is caused by rupture of a middle

w Anatomy and Physiology of Headache

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meningeal artery due to trauma of the head; in people over the age of 25 this trauma is always associated with a fracture of the skull crossing the artery. The cranial nerves that carry sensory information, particularly the trigeminal nerve, cause pain when compressed by a neoplasm, such as a neuroma or meningioma. They also cause pain when compressed chronically by a blood vessel, either artery or vein, as is thought to be the case in trigeminal neuralgia or tic doulourew. Other processes that affect the sensory cranial nerves and cause pain are inflammation, such as herpes zoster (ophthalmic zoster), or demyelination, such as multiple sclerosis (trigeminal neuropathy). Extracranially in the head as well as in the face and neck, skeletal muscle is the largest component that causes pain by prolonged contraction, leading to accumulation of waste products and irritation of nerve fibers in the muscles. Prolonged contraction of the muscles can be caused by the following: Increased arousal caused by psychosocial stress or excessive caffeine intake Muscle strain originating from the neck, eyes, or jaws Macrotrauma consisting of a stretch injury (whiplash) Microtrauma resulting from a systemic viral infection Impaired relaxation caused by fatigue, lack of sleep, exposure to cold (draft), or low thyroid function Reflex contraction of the muscles caused by an irritative focus in the face (chronic sinusitis) or neck (arthrosis) Second in line to the muscles in terms of causing headache are the extracranial arteries, which generally cause pain by a combination of dilation and inflammation. The dilation and inflammation create a vicious cycle in which the dilation causes stretching of the perivascular nerve fibers. As a result, the nerve fibers secrete inflammatory chemicals, such as substance P and calcitonin gene-related peptide, which further dilate the blood vessel, leading to further stretching of the nerve fibers, and so on. In giant cell or temporal arteritis, the initiating event is inflammation caused by the presence of antibodies against the elastin in the wall of the arteries, but otherwise the initiating event tends to be dilation of the arteries, followed by inflammation, and so on. A great number of factors can cause dilation of the extracranial arteries, including the following: Prolonged contraction of the craniocervical muscles Overrelaxation of the arteries (as in poststress, oversleeping, or taking a nap) Cardiovascular activation (e.g., caused by physical exertion, emotional excitement, or intercourse) Estrogen induction (postmenstruation) or estrogen withdrawal (premenstruation, ovulation) Ingestion of a vasodilator agent, such as alcohol, nitrites (cured meats), or histamine (red wine) Withdrawal from a vasoconstrictor agent, such as caffeine, tyramine (red wine), or phenylethylamine (dark chocolate) A decrease in blood pressure, as occurs nocturnally in hypertension or during renal dialysis The joints in the head and neck-the temporomandibular and zygapophyseal joints-cause pain through arthrosis. The skin and the mucosal membranes of the nasal cavity and paranasal sinuses cause pain by inflammation, known as cellulitis and rhinosinusitis, respectively. Whereas cellulitis is bacterial, fungal, or parasitic in origin, rhinosinusitis can be viral or bacterial but can also be

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caused by allergy irritant, or mucosal contact, such as a septa1spur making contact with a turbinate, or can be caused by vasomotor rhinitis. In summary, the pain-sensitive structures of the head, face, and neck can be affected by a number of mechanisms, which in turn can be activated by a great variety of conditions. The resulting pain, that is, the headache, is in its location determined by the pain-sensitive structures involved, the innervation of the structures, the extent of activation within the cervicotrigeminal relay, and the somatic projections of the neurons activated. Unilateral involvement of pain-sensitive structures causes pain limited to the ipsilateral side of the head, face, or neck with extension to the other side only when secondarily contralateral pain-sensitive structures get involved, most commonly consisting of contraction of craniocervical muscles secondary to the pain.

SUGGESTED READINGS Celentano DD, Stewart WF, Lipton RB, Reed ML Medication use and disability among migraineurs: a national probability sample survey. Headache 32:223-228, 1992 Goldstein M, Chen T C The epidemiology of disabling headache. Adv Neurol33:377-390, 1982

Lipton RE$ Stewart WF, Celentano DD, Reed ML Undiagnosed migraine headaches. Arch Intern Med 152:1273-1278, 1992 Rasmussen BK, Jensen R, Schroll M, Olesen J: Epidemiologyof headache in a general population: a prevalence study. J Clin Epidemiol 441 147-1 157, 1991

Ray BS, Wolff HG Pain-sensitive structures of the head and their significance in headache. Arch Surg 41:813-856, 1940 Stewart WF, Lipton RI3, Celentano DD, Reed ML Prevalence of migraine headache in the United States. JAMA 26736449, 1992

207 Approach to the Patient with Headache Fred D. Shefiell

Pain is ultimately a personal and subjective experience, and the patient is the expert in the report of his or her pain. First and foremost, patients are to be believed, and proper treatment must focus on the pain in the context of the entire patient. The Oslerian principle that it is more helpful to approach the person who has the disease than the disease the person has is well taken in regard to headache. One can take a logical approach to the diagnosis and treatment of headache and still miss the boat. Both take place in the atmosphere of a relationship between the physician and the patient. It is the quality of that particular atmosphere that often makes the difference between treatment success and treatment failure. A nonbiased and nonjudgmental approach should be the template on which diagnosis and treatment are built. John R. Graham (1987) wrote, “Any style will be effective providing it clearly demonstrates to the patient that the physician is interested in him and his life as a person, as well as in the details of the medical complaint.” This quote catches the essence of the approach to the patient with headache. Patients who come to our center often have seen a variety of medical professionals, saying, “The ear, nose, and throat doctor I saw told me my head pain was from sinus infections,” “The allergist told me it was clearly allergic,” “The nutritionist said it was hypoglycemia,” “The dentist said I had problems with my temporomandibular joint,” or “The psychiatrist said I was over-controlling, perfectionistic, and tense.” Who is right: one of them, none of them, or all of them? To make this determination, openness on the part of the physician during the history and examination is essential. You might ask yourself some of the following questions as you begin to explore the formal history: Who is this person? Why is he or she coming now? What are the patient’s expectations, concerns, and fears? Is the fear of a tumor lurking somewhere in the patient’s mind? What has his or her experience with previous physicians been like? What does the patient do for a living? What hobbies or interests does he or she have? How are things with family and friends? I find it useful to ask a patient to describe

a typical day. It is not unusual to see a patient whose lifestyle is filled with demands and yet has no insight as to the extent of these demands and the effects on him or her. It is crucial to understand the impact of the patient’s headaches on his or her life at work, home, and play. Two user-friendly instruments are available for evaluating impact, disability, and quality of life: the Migraine Disability Assessment Scale and the Headache Impact Test. The Migraine Disability Assessment Scale is a highly intuitive office-based paper tool that addresses and scores impact at work, home, and social activities as well as frequency and intensity of headache. Scores are helpful in stratifymg levels of disability and suggesting intensity of therapeutic approaches from specific abortive treatment to the need for headache prevention. The Migraine Disability Assessment Scale is also useful in following patients’ progress and assessing the need to change therapy. It is available on the Internet at http://www.midas-migraine.netor on the American Council for Headache Education’s site at http://www.achenet.org. The Headache Impact Test is available as a computerized questionnaire using the Item Response Theory models to score widely used measures of headache impact. Several measures are incorporated into the questions, with a larger pool of questions than the Migraine Disability Assessment Scale, and the patient has to answer only a few to derive a score and suggestions for consultation. The computerized version is available on the Internet at http://www.iamhealthy.com. The Headache Impact Test is also available as an office-based paper tool. The Headache Impact Test, like the Migraine Disability Assessment Scale, is also useful as a means of tracking patient progress over time. Both of these instruments are useful in helping patients to communicate with their doctors and helping doctors to appreciate the level of impact and associated disability. By the time you have completed the initial consultation, you should have not only an idea in regard to diagnosis and initial treatment plan but also a good sense of who the patient is. Finally,

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caused by allergy irritant, or mucosal contact, such as a septa1spur making contact with a turbinate, or can be caused by vasomotor rhinitis. In summary, the pain-sensitive structures of the head, face, and neck can be affected by a number of mechanisms, which in turn can be activated by a great variety of conditions. The resulting pain, that is, the headache, is in its location determined by the pain-sensitive structures involved, the innervation of the structures, the extent of activation within the cervicotrigeminal relay, and the somatic projections of the neurons activated. Unilateral involvement of pain-sensitive structures causes pain limited to the ipsilateral side of the head, face, or neck with extension to the other side only when secondarily contralateral pain-sensitive structures get involved, most commonly consisting of contraction of craniocervical muscles secondary to the pain.

SUGGESTED READINGS Celentano DD, Stewart WF, Lipton RB, Reed ML Medication use and disability among migraineurs: a national probability sample survey. Headache 32:223-228, 1992 Goldstein M, Chen T C The epidemiology of disabling headache. Adv Neurol33:377-390, 1982

Lipton RE$ Stewart WF, Celentano DD, Reed ML Undiagnosed migraine headaches. Arch Intern Med 152:1273-1278, 1992 Rasmussen BK, Jensen R, Schroll M, Olesen J: Epidemiologyof headache in a general population: a prevalence study. J Clin Epidemiol 441 147-1 157, 1991

Ray BS, Wolff HG Pain-sensitive structures of the head and their significance in headache. Arch Surg 41:813-856, 1940 Stewart WF, Lipton RI3, Celentano DD, Reed ML Prevalence of migraine headache in the United States. JAMA 26736449, 1992

207 Approach to the Patient with Headache Fred D. Shefiell

Pain is ultimately a personal and subjective experience, and the patient is the expert in the report of his or her pain. First and foremost, patients are to be believed, and proper treatment must focus on the pain in the context of the entire patient. The Oslerian principle that it is more helpful to approach the person who has the disease than the disease the person has is well taken in regard to headache. One can take a logical approach to the diagnosis and treatment of headache and still miss the boat. Both take place in the atmosphere of a relationship between the physician and the patient. It is the quality of that particular atmosphere that often makes the difference between treatment success and treatment failure. A nonbiased and nonjudgmental approach should be the template on which diagnosis and treatment are built. John R. Graham (1987) wrote, “Any style will be effective providing it clearly demonstrates to the patient that the physician is interested in him and his life as a person, as well as in the details of the medical complaint.” This quote catches the essence of the approach to the patient with headache. Patients who come to our center often have seen a variety of medical professionals, saying, “The ear, nose, and throat doctor I saw told me my head pain was from sinus infections,” “The allergist told me it was clearly allergic,” “The nutritionist said it was hypoglycemia,” “The dentist said I had problems with my temporomandibular joint,” or “The psychiatrist said I was over-controlling, perfectionistic, and tense.” Who is right: one of them, none of them, or all of them? To make this determination, openness on the part of the physician during the history and examination is essential. You might ask yourself some of the following questions as you begin to explore the formal history: Who is this person? Why is he or she coming now? What are the patient’s expectations, concerns, and fears? Is the fear of a tumor lurking somewhere in the patient’s mind? What has his or her experience with previous physicians been like? What does the patient do for a living? What hobbies or interests does he or she have? How are things with family and friends? I find it useful to ask a patient to describe

a typical day. It is not unusual to see a patient whose lifestyle is filled with demands and yet has no insight as to the extent of these demands and the effects on him or her. It is crucial to understand the impact of the patient’s headaches on his or her life at work, home, and play. Two user-friendly instruments are available for evaluating impact, disability, and quality of life: the Migraine Disability Assessment Scale and the Headache Impact Test. The Migraine Disability Assessment Scale is a highly intuitive office-based paper tool that addresses and scores impact at work, home, and social activities as well as frequency and intensity of headache. Scores are helpful in stratifymg levels of disability and suggesting intensity of therapeutic approaches from specific abortive treatment to the need for headache prevention. The Migraine Disability Assessment Scale is also useful in following patients’ progress and assessing the need to change therapy. It is available on the Internet at http://www.midas-migraine.netor on the American Council for Headache Education’s site at http://www.achenet.org. The Headache Impact Test is available as a computerized questionnaire using the Item Response Theory models to score widely used measures of headache impact. Several measures are incorporated into the questions, with a larger pool of questions than the Migraine Disability Assessment Scale, and the patient has to answer only a few to derive a score and suggestions for consultation. The computerized version is available on the Internet at http://www.iamhealthy.com. The Headache Impact Test is also available as an office-based paper tool. The Headache Impact Test, like the Migraine Disability Assessment Scale, is also useful as a means of tracking patient progress over time. Both of these instruments are useful in helping patients to communicate with their doctors and helping doctors to appreciate the level of impact and associated disability. By the time you have completed the initial consultation, you should have not only an idea in regard to diagnosis and initial treatment plan but also a good sense of who the patient is. Finally,

Chapter 207

it is important to examine your own attitudes about headache complaints. Do you lean toward believing that these patients are neurotics, or do you prefer an exclusively neurobiological and molecular explanation? Although we have learned a great deal about the neurobiological basis of headache, it is important to understand that whatever the pathophysiological mechanisms, they are occurring in the context of a human being. Pain is a multidimensional phenomenon, influenced by neurologic, physiologic, psychological, social, ethnocultural, and cognitive factors. To tell a patient, “The pain is all in your mind” is to invite treatment disaster and a major breach in the relationship with the patient. The patient should not be challenged about the reality, intensity, or debilitating quality of the pain. STYLES OF PHYSICIAN-PATIENT INTERACTION Roter and Hall’s book Doctors Talking with Patients/Putients Talking with Doctors (1992) explores the dynamics of the doctor-patient relationship and should be required reading for all medical students and residents as well as physicians in practice. The authors defined four typical types of doctor relationships: paternalism, consumerism, default, and mutuality. These relationships are based on relative degrees of physician and patient control. Where physician control is high and patient control is low, the relationship is paternalistic. The physician takes charge of the decision making, which is ultimately “in the best interest” of the patient; the patient’s role is to cooperate and obey. High patient control and low physician control characterize consumerism, where the physician accommodates the demands of the patient. Where both physician and patient control is low, the relationship is one of default, with neither the doctor nor the patient taking responsibility for decisions and stagnation resulting. Finally, mutuality exists when patient and physician control is high and both take an active role in decision making. Another way of looking at this situation involves an internal versus external locus of control. Patients who have an external locus of control have a passive attitude and rely on the physician to make them better. They take no responsibility for their illness or its remediation and fit nicely with physicians who tend to be paternalistic. Studies have shown that patients who demonstrate an external locus of control have a poorer prognosis than patients with an internal locus of control. The latter take a more active attitude of “What can I do to help?” These patients take more responsibility for their illness, are motivated to make changes in their lifestyles, and comply better with treatment regimens. The terms of alliance or partnership can be used to describe what I believe is the best type of doctor-patient relationship. INITIAL CONSULTATION The initial consultation can be divided into three phases: history, examination, and closing.

History At our center, the initial consultation involves 3 to 5 hours of history taking, examinations, patient education, and treatment planning, which is done in the context of a multidisciplinary staff. Our center is a tertiary care center and, although one may not need to spend this amount of time, I believe that exploration of the chief complaint of headache on the first visit should take at least 1

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hour. It would not be unusual to spend 3 or 4 hours during this initial assessment. We find it useful to have patients complete a questionnaire before their first visit. The questionnaire includes all previous pharmacologic (including nonprescription medications) and nonpharmacologic therapies, dosages, routes of administration, frequency of use, efficacy, and side effects. We often see patients who have taken numerous headache medications without success because of inappropriate dosing, timing of dosing, or failure to use antiemetic therapy before using an ergot medication. Most importantly, however, many patients with chronic daily headache may have taken every known headache medication in the Physician’s Desk Reference but had never been taken off their daily use of prescription or nonprescription analgesics or ergotamine, which decreases the effectiveness of all preventive pharmacologic and nonpharmacologic maneuvers. All previous examinations and tests for headaches are recorded, and all potential triggers for headache are listed and explored. Medical and surgical history and pertinent family history are recorded. Nutritional status with attention to caffeine intake is important. These forms are used as a guideline for in-depth review at the time of the initial consultation. We use a modified version of the format developed by Lee Kudrow, MD, for the headache history (Rapoport and Sheftell, 1996). Because most patients present with more than one type of headache, we take the history by dividing headache intensity on a three-point scale. This information is recorded on the cover sheet shown in Figure 207-1. Severe or level 3 intensity includes only headaches that render the patient totally incapacitated. The moderate or level 2, though annoying and clearly present, does not render the patient incapacitated, although it interferes with his or her ability to function. Finally, the dull or level 1 headache is mild, does not interfere with the patient’s functioning, and may not be noticed when the patient’s attention is diverted. For each level of intensity we explore the following parameters: Age of onset Frequency (a) previous (b) current Location: frontal, orbital, vertex, parietal, occipital, temporal, or other Laterality: Is the pain on the right or left side? Is the pain bilateral? Does it alternate sides?In the patients who have both right- and left-sided headache we determine whether one side predominates Description: Is the pain throbbing, pounding, pulsating, squeezing, pressing, or aching? Most patients can accurately describe the quality of their pain, but for those who cannot we give them a list of pain descriptors Duration: We note the minimum and maximum duration of the headaches and the average duration when not treated Prodrome: This may be divided into nondescript prodrome before the onset of headache, such as changes in appetite, energy, mood, or sleep patterns, and more well-defined symptoms of aura, such as scintillating scotomas, field defects, and sensorimotor disturbances Associated symptoms: These include anorexia, nausea, vomiting, diarrhea, dizziness, sensitivity to light or sound, stuffed or running nostrils, red or tearing eyes, ptosis, and miosis Behavior: We explore the patient’s behavior during the headaches. The patient with migraine is more likely to retreat to a dark and

Headache and Pain rn General Aspects of Headache

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Name:

Date:

Age:

Sex:

Ref.:

Marital Status: S

M

W

D

D

D

SEP

Occupation: Intensity Onset

Severe

Moderate

Dull

Menstrual & Hormonal

- Previous _--------

Frequency

Habits (alcohol, tobacco, caffeine, sleep, drugs)

- Current Location RLBA

Medical

Description

Trauma

Duration

Surgical LOC

S.D.

Min. Av. Max.

Prodrome NVAD Association Stuffed/Running dizzy sono Rednearing photo Ptosis/Miosis Behavior Diagnosis

Current Medication

Previous

Tests:

FIG. 207-1. Cover sheet of the headache history form used at the New England Center for Headache, Stamford, Connecticut.

Chapter 207 W

quiet room, whereas the patient with cluster headache is restless, cannot sit or lie still, and will pace or rock Postdrome: Identify symptoms that follow the main headache, such as exhaustion, exhilaration, residual symptoms Diagnosis: We place the tentative diagnosis based on the aforementioned characteristics and incorporate other historical data related to family history and trigger factors Although this format was developed before the International Headache Society (IHS) classification, we have found that it works very nicely. As a rule we find that migraine and cluster headache tend to fall primarily into the more severe categories, with the dull category demonstrating tension-type headache. The moderate category may demonstrate any of the three primary headache disorders. As you will note in other chapters outlining the IHS criteria for the primary headache disorders, one can clearly find these characteristics using this format of history taking. Although we certainly allow and encourage patients to describe their headaches in any manner that they see fit, many patients with chronic daily headache state that they have headaches all the time, which get worse from time to time. Using this intensity model, one can tease out and separate the primary headache disorders and see how they relate to each other. We find that this model works well even for patients who have had both migraine and cluster headache in that the headaches are described differently, although both may fall into the severe category. One can also see how the headaches relate to each other. For example, patients may tell us that their moderate headaches may escalate in intensity and move into the severe category, with the characteristic associated symptoms of migraine or cluster headache, which may not be seen at the mild or moderate intensity level. You can see that the cover sheet in Figure 207-1 summarizes pertinent identifying information. We then collate and review the overall history; all previous medications are listed and summarized as well as those currently taken. Again, be sure to include in your history nonprescription medications, such as analgesics, sinus and allergy medications, and nasal sprays. Under habits we summarize alcohol intake, tobacco history, caffeine intake, sleep patterns, and recreational drugs. Under the menstrual and hormonal section, we record the age of menarche and any possible association with the onset of headache. We record current or past use of oral contraceptives and possible association with headache. We record regularities or irregularities in the menstrual cycle, all pregnancies, and live births. Where appropriate, we record age of menopause and details of hormonal replacement therapy. We summarize the medical and surgical histories with special attention to head trauma, loss of consciousness, and seizure disorder. We record all previous tests, examinations, and results, along with their dates. Notice the genogram in the lower right-hand corner, which we find very useful for outlining the family history of headache, family medical history, age of siblings and parents, marital relationships, and offspring. A consideration of the major types of headache will show how their diagnostic criteria fit into this format. For example, age of onset is an important part of the history and may suggest a particular diagnosis. Cluster headache generally tends to start in later life, whereas migraine often is present by late adolescence or the early 20s.It is important to note how the frequency and intensity have changed over the years. Most patients with chronic daily headache start off with intermittent migraine headaches, which over a period of years transform into chronic daily headache, often complicated by the overuse of analgesics or ergotamine. Cluster headache is almost always

Approach to the Patient with Headache

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unilateral, migraine often is unilateral, and tension-type headaches often are bilateral. The pain of migraine often is throbbing, that of cluster often boring, and that of tension-type headache often dull, squeezing, or aching. The duration of cluster headache usually averages 45 minutes, whereas migraine headaches may go on for many hours and tension-type headaches may last hours to days. Migraine with aura is well defined, whereas no such aura or prodrome exists with tension-type headache. Migraine may be associated with nausea, vomiting, and sensitivity to light or sound, whereas cluster and tension-type headaches are not. However, cluster headache usually is associated with ipsilateral stuffed and running nostril, conjunctival injection, and lacrimation, as well as with ptosis and miosis. Patients who have clear-cut attacks of migraine with aura have a less busy-looking cover sheet, whereas patients with more complex disorders and numerous symptoms and levels of intensity provide more information. Danger signals in the history include the following: Watch for sudden onset of new, severe headache or the first and worst headache. Watch for headaches that are worsening over time. Watch for headache onset associated with exertion, coughing, bending, sneezing, straining, or sexual activity; activity will always make migraine worse, but the concern here is that the headache comes on as a result of the activity. Changes in mentation and level of consciousness, such as drowsiness, confusion, or loss of memory, may signal a structural lesion, such as a tumor or subarachnoid hemorrhage. Chronic malaise, myalgias, and arthralgias in the older age group should alert you to the possibility of temporal arteritis. The presence of fever should alert you to an infectious process, such as meningitis or brain abscess; meningitis should be suspected if neck pain or rigidity is present as well. The presence of any neurologic symptom associated with headache should alert you to an organic basis for disease. The first headache occurring after the age of 50 (migraine and tension-type headache generally start earlier in life) should alert you to the possibility of organic disease. It is important not to neglect the psychosocial history and to be alert for psychological contributors and trigger factors. A variety of psychometric tests are extremely helpful in indicating the presence of disorders such as depression or anxiety, which tend to be comorbid with chronic daily headache. The Minnesota Multiphasic Personality Inventory, Hamilton Depression Scale, and Beck Inventory are examples of these tools. At the end of your history taking, ask whether there is anything you have left out that the patient feels is important.

A complete neurologic and physical examination should be done at the time of the initial consultation. I find that patients are impressed when we examine and palpate their heads. They often say, “You know, you’re the first doctor who ever looked at my head!” I will not dwell on all the details of a thorough neurologic examination but will focus on the head, neck, and mental status. Head and Neck One should observe the size and shape of the head. Look for signs of obvious deformity and unusual bumps. The size of the head should be measured, which is especially important in children who may have headaches caused by

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hydrocephalus. Note any obvious abnormalities related to the eyes, such as ptosis, exophthalmus, asymmetrical pupils, conjunctival injection, and strabismus. Palpate the entire head and neck looking for signs of pericranial tenderness and excessive muscle contraction about the head and neck. Many patients with headaches may also complain of tightness of the neck, and some have exquisitely tight neck muscles and not be aware of this. Palpate the trapezius and paracervical muscles and the cervical spine. Check the range of motion of the neck in flexion, extension, and rotation and ask whether there is any pain on these movements. Some patients may demonstrate areas of explicit tenderness in the muscles that may or may not radiate. Pay attention to the occiput, looking for tenderness of the greater and lesser occipital nerves and looking for referral of pain to other parts of the head. Many patients are unaware of how tight they keep themselves. Hold the patient’s arm extended by the wrist, then tell the patient to make his or her muscles as loose as possible. Let go at the count of three, dropping the patient’s arm into your other hand. It is not unusual to have a patient say that his or her muscles are relaxed and then to let go and find that there is no drop of the arm or that it is done voluntarily. The patient’s perception of muscle tension may be such that the patient is not aware of how tight his or her muscles are. Rigidity of the neck is a common symptom of meningitis and should be evaluated. Gentle pressure may be applied to the orbits to check for increased pressure related to glaucoma or orbital tenderness related to meningitis. The temporomandibular joints should be checked by palpation and should be observed in regard to any pain when the jaw is opened and closed. Check for signs of deviation of the jaw on opening and check for any limitation of range of motion. The patient should be asked about any pain in these joints when he or she is chewing. Auscultation may reveal evidence of clicks, pops, or crepitation. The internal pterygoid muscles also may be palpated for presumptive evidence of temporomandibular dysfunction. Observe the temporal arteries for prominence and palpate them to determine the presence or absence of induration or tenderness. The frontal and maxillary sinuses may be palpated for tenderness and swelling. One may also transilluminate the sinuses with the light from the otoscope to determine translucence, opacity, or the presence of an air fluid level. Auscultation of the carotid arteries should be performed to rule out the presence of bruits. One may also auscultate the orbits with the bell of the stethoscope, which may reveal bruits secondary to arteriovenous malformation. The thyroid gland should be palpated. Look for adenopathy, which may reveal the presence of an infection such as sinusitis or an abscess. The rest of the neurologic examination should include a review of the cranial nerves and sensory, motor, cerebellar, and reflexive (including pathological) functions. Mental Status. Look for signs of depression and anxiety. These may include a blunted, restricted, sad, or labile affect. Look for signs of cognitive disturbance, including intrusive, obsessional thoughts and an inability to concentrate; check the patient’s memory for both recent and remote events. Simple tests such as subtraction of serial sevens, spelling five-letter words forward and backward, and remembering phone numbers are all useful. In particular, patients with post-traumatic headache may show deficits in concentration, memory, and ability to perform complex tasks.

Further evaluations that are part of the general physical examination should be performed as well. The heart and lungs should be auscultated. There is a higher incidence of mitral valve prolapse in patients who have migraine, and if this is suspected, an echocardiogram may be ordered to confirm the diagnosis. Comorbid medical disorders such as asthma, hypertension, coronary artery disease, and peptic ulcer all must be evaluated in terms of pharmacotherapy and potential side effects that may be detrimental to one or another of the comorbid conditions. For example, you would not want to prescribe nonsteroidal antiinflammatory analgesics to a patient with active peptic ulcer disease. You would not want to prescribe a P-blocker to a patient with asthma. You would not want to prescribe vasoconstrictor medications, such as ergotamine, dihydroergotamine, or sumatriptan, to a patient with active coronary artery disease or stroke. The physical and neurologic examinations also provide an opportunity to evaluate the side effects of any medications that the patient may be on. These may include bradycardia or wheezing with patients on P-blockers, symptoms of ergot overuse such as decreased or absent pulsations, myalgias, and nausea, and signs of ataxia, impaired concentration, and the like secondary to the overuse of butalbital, benzodiazepines, or opioids. The latter may also produce symptoms of depression, impaired cognition, and impaired concentration. For patients who have been overusing opioids, barbiturates, or benzodiazepines, one should be alert to the possible symptoms and signs of withdrawal if they have recently stopped these medications. This would be of most concern with withdrawal from barbiturates or benzodiazepines. Here one can look for symptoms and signs of irritability, tremors, hyperreflexia, dilated pupils, and piloerection. Closing

The final consultation before completing the initial evaluation is as essential as the initial history and the physical and neurologic examinations. All findings pertinent to the history and examinations should be reviewed thoroughly with the patient in terms that are easily understandable. Your conclusions related to these findings and recommendations for further tests and treatment plan should be explained thoroughly. Let the patient ask questions and voice his or her concerns and feelings about your findings and suggestions. Here, the role of patient education is of paramount importance and will go a long way toward maximizing compliance. One can follow precisely all the details of the history, and examinations and still wind up with an unhappy and dissatisfied patient if education is not included. A study by Packard (1979) demonstrated that patients with headache come looking for an explanation of their disorder as well as relief of the pain. With primary headache disorders in the absence of positive findings on the physical and neurologic examination, negative results from testing such as magnetic resonance imaging, computed tomography, or electroencephalography, the patient is understandably concerned about the cause. There are a variety of materials that one can use to aid patient education. We have used a modification of the model suggested by John R. Graham, MD, demonstrated in Figure 207-2 (Rapoport and Shefiell, 2002). Primary headache disorders may be described using this “stick of dynamite” model. Once it has been established that you are dealing with one of the primary headache disorders, this model is useful. If you believe that there may be an organic basis to the disorder, express your concerns based on your findings in the history and examinations

Chapter 207 W

Approach to the Patient with Headache

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FIG. 207-2. Diagrammatic representation of potential migraine triggers: a modified version of a model suggested by John R. Graham, MD.

and be as reassuring as possible. If further testing is necessary, explain the reason for the tests and describe the procedure, such as magnetic resonance imaging or electroencephalography. Many patients are claustrophobic and cannot tolerate the closed environment of the magnetic resonance machine. These patients are best referred to an open magnet, and when their anxiety level is high, it would be appropriate to prescribe a small dose of a benzodiazepine 1 hour before the test, especially if a study in a closed scanner is warranted. Again, once the headache is determined to be one of the primary headache disorders, we explain that these headaches are definitely a valid biological disorder. They are as valid as coronary artery disease, hypertension, ulcer, and the like. We explain that there are no biological markers, such as blood tests, that can determine or demonstrate the existence of the disorder. For example, our current thinking has demonstrated that migraine is a disorder of the brain, involving changes in biochemistry or chemical messengers known as neurotransmitters. We explain that to the best of our knowledge, migraine represents a cascade of complicated events beginning in the brain and leading ultimately to changes in blood vessel activity. Once the biology or vulnerability is present, there are a variety of factors that may trigger (not cause) the explosion (e.g., involving hormones). We explain that the reason that migraine is more common in women is related to the cyclical nature of estrogens. Before puberty, migraine is more common in boys than in girls, but once menstruation occurs, the male-female ratio goes up to almost 3:l. Many women have their headaches around the time of menstruation or ovulation, many get worse on oral contraceptives, many get better during the second and third trimester of pregnancy, many worsen around the time of menopause, and some improve after menopause. We explain that it is not an abnormality of the hormones themselves but rather the way changes in estrogen levels affect the underlying biology of migraine. We review the various dietary factors that may trigger migraine and cite alcohol as the most commonly identified food trigger. Providing a list of these foods is helpful, and an overview of triggers is provided in Figure 207-3. These are used in conjunction with headache calendars. We suggest that these foods be eliminated for a period of 1 month, and we also give patients a list of

permissible foods. A number of lay books can be helpful in as well (see the list of Suggested Readings at the end of this chapter). We explain that patients with migraine are very susceptible to changes in their environment, both internal and external. Internal changes may be related to factors such as menstruation and sleep. External factors may be related to change of season, weather or schedule changes, traveling, time zone changes, skipping meals, and the like. We make suggestions as to how patients may better regulate and respond to these environmental changes. Migraine may be triggered by a variety of sensory stimuli including odors and strong or flickering lights. Last, but not least, we explain the role of stress. We state that if the biological vulnerability were not present, then no matter what kind of stressors the patient is exposed to, no matter what kind of personality he or she has, and no matter what his or her ability is to deal with stress, he or she will not get migraine. However, if the biology is present then a variety of factors, including stress, may provoke attacks. Behavioral patterns or maladaptive reactions to stress may indeed trigger migraine. We let patients know that migraine is more likely to occur during letdown periods than during times of active stress. Because of the nature of this biology, patients who tend to be intense and competitive, have high expectations of themselves and others, and be rigid and perfectionistic will find it useful to explore issues related to stress management and personality and may be candidates for stress management and behavioral techniques, such as biofeedback. If we find comorbid evidenceof depression or anxiety, we review this thoroughly with the patient and suggest an appropriate psychiatric or psychological referral. We do not communicate that we believe the patient’s pain is all in his or her head or suggest that we are abandoning treatment. Rather, we let the patient know that psychotherapy is an important adjunct to the treatment if applicable. We reassure the patient that we will continue to treat the headaches and are not abandoning him or her. We take time to explore the patient’s reaction to these kinds of suggestions. We let the patient know that although there are times that he or she can clearly identify a trigger, there are often times when he will not because migraine attacks may occur spontaneously as a result of some innate periodicity. We do not want the patient to feel that he or she has somehow caused the attack.

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General Aspects of Headache

Hormones

3. Hormone replacement (progesterone)

6. Aged cheeses 7. Monosodium glutamate (MSG) 8. Aspartame (Nutrasweet) 9. Caffeine 10. Nuts 11. Nitrites, nitrates 12. Other

Changes 14. Seasons

Biology

15. Travel (crossing time zones) 16. Altitude

FIG. 207-3. Overview of possible headache triggers.

17. Schedule changes 18. Sleeping patterns 19. Diet 20. Skipping meals

21. Strong light 22. Flickering lights

23. Odors

L

“Stress“ 24. Let-down periods 25. Times of intense activity 26. Loss (death, separation, divorce) 27. Moving 28. Job loss change 29. Crisis 30. Other

We can also use the stick of dynamite model to review our treatment planning. Nonpharmacologic approaches include evaluating these trigger factors, nutritional changes, exercise, stress management techniques, and adequate sleep. The calendars provide very useful information about these factors. We next look at the frequency of attacks, and where preventive medication is indicated, we let the patient know that the purpose of this medication is to reduce the frequency, intensity, and duration of the headaches. We review potential benefits and side effects and respond to patient’s questions. We let the patient know that when the attack frequency is reduced sufficiently for a period of several

months, we can then begin to slowly titrate the preventive medication downward. Lastly, we explain that abortive medication will be used to treat the “explosion” when it occurs. Once again, we review a variety of options, benefits, and side effects. It is imperative that in prescribing abortive medications, strict limits be set on the frequency of use, and calendars are helpful in maintaining these limits. Limit setting on the use of abortive medication is key in preventing rebound phenomenon. For patients who are overusing medication, such as analgesics or ergots, we provide them with a structure and clear guidelines as to how to eliminate these medications and provide them with

Chapter 207

appropriate pharmacologic and nonpharmacologic tools. As a general guideline we educate patients thoroughly as to the mechanism of rebound headache. They are told that as long these analgesics are maintained on a daily basis, their headaches are likely to remain chronic and unresponsive to a wide variety of pharmacologic and nonpharmacologic interventions. Initially, the patients usually are noted to be apprehensive about discontinuing the medications because they are afraid of not being able to function. A variety of suggestions to treat analgesic or ergotamine rebound are found in the Suggested Readings and other chapters. For patients who need hospitalization, the reasons and indications for hospitalization are explained, as is length of stay, description of hospital treatment, and goals of hospitalization. Here again, it is wise to stop and ask for questions and concerns. USE OF HEADACHE CALENDARS The use of a logging system or headache diary is essential to successful treatment and compliance. As stated earlier, calendars and other behavioral tools are helpful in bringing patients around to an internal locus of control and having them take responsibility and be active participants in their treatment. From the physician’s point of view, the calendars provide detailed information as to the

Approach to the Patient with Headache

frequency, intensity, and duration of the headaches. A calendar is shown in Figure 207-4. Again, we use a three-point intensity scale, as explained earlier. The patients note the levels of intensity, frequency, and duration using this numerical system on a daily basis, with the day being divided up into three parts. Underneath these data we place the medications that the patient is taking. The name of the medication and the dosages are clearly written, along with specific guidelines for the use of both preventive and abortive medications. The times of menstruation and relationship of preventive medication to morning or evening or to mealtimes is clearly stated. Patients are given information about potential side effects. In regard to abortive medications, instructions for exact use and timing and routes of administration are given, as well as the limits on the frequency of administration. In regard to prescribing practices, we recommend that until you get to know the patient, small amounts of as-needed medications should be prescribed that are nonrefillable. It is not useful to prescribe butalbital compounds in quantities of 100 tablets with five refills, as has been seen in clinical practice. When treating analgesic and ergotamine overuse, tapering schedules and alternatives are given. We suggest that patients not medicate with as-needed medications for mild and, if possible, moderate headaches. We make sure that they are given adequate abortive medication for their most severe

Headache Calendar Name

Month

1317

Year

#1 Mild headache #2 Moderate headache #3 Incapacitating

01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Morning Afternoon Evening Sleeptime Medication

11111111111llll1ll1111111111111 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I H I 1 1 1 1 1 1 1 1 1 1 1 1 1 l l l l l l I I I I I I I I I I I I 111111111111111111111ll111111I I J 111111111111111111111lll111111 I I 111111ll111111111ll111lll111111 111111111111111lllll1111111ll~1 1 1Relief10-11-2-3 1 1 1 (0)1- None 1 1 1 (1)1- Slight 1 relief 1 1 1 1(2) -1Moderate 1 1relief1 l l 1(3) 1- Complete 1 1relief1 l ~ ~ 1 1Triggers: 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 IPeriods: I I I I I I I I I I I I I I I I I I I l l l r l l l l l l l l

FIG. 207-4. Headache calendar given to patients at the New England Center for Headache, Stamford, Connecticut.

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Headache and Pain rn General Aspects of Headache

headaches. Again, limits are set on the use of these abortive medications, and patients are instructed to call us if they are not able to stay within these limits. We use a four point relief scale in which 0 means no relief and 3 is complete relief. We also ask patients to include the names of other medications other physicians are giving them, so that any interactions may be noted. Our patients find it useful to show these calendars to other physicians so that all prescribing physicians are aware of the entire picture. Patients also indicate their use of oral contraceptives or estrogen replacement to determine possible trigger factors. Finally, on the front of the calendar female patients are asked to report the days of their periods by marking each appropriate box with an X. The triggers listed in Figure 207-3 are listed on the back of the calendar, and patients are asked to record them by number, as appropriate. Some patients are good historians, but even the best of them, when asked to review their progress over several months, are not able to include the kind of information necessary to make assessments. After the initial history is taken, we record baseline frequencies and intensities as a denominator. Consider a patient with chronic daily headache. When these headaches are occurring daily, we may have the denominator 30 under the intensities 1 or 2. The incapacitating or level 3 intensity is recorded separately and may show that a patient is having four attacks of incapacitating headache, lasting an average of 36 hours. When the patient returns for follow-up visits, we review the data on the calendar on a monthly basis and record current frequency, intensity, and duration as a denominator. This enables us to clearly evaluate the patient’s progress and response to the preventive and abortive medications. One patient returned for a follow-up visit and on initial questioning said that her headaches had remained unchanged. This was a patient with chronic daily headache who reported mild to moderate waxing and waning pain on a daily basis, with three clearly migrainous headaches lasting for 24 hours. The patient had been placed on a P-blocker at the time of her initial evaluation. If we had gone on the verbal data alone, we probably would have increased the dosage of the medication if side effects were not a problem or changed to another medication. When her calendars were reviewed, although indeed she continued to have mild to moderate pain on a daily basis, she had experienced no incapacitating headaches, had not missed work, and had not been confined to bed during that initial time period. It was clear that the P-blocker had been successful in reducing the frequency and intensity of the migrainous headaches, but her daily background pain remained intact. The Migraine Disability Assessment Scale or Headache Impact Test would have also demonstrated these issues, and this is but one example of the usefulness of headache calendars and disability instruments. GUIDE TO SELF-ASSESSMENT Roter and Hall (1992) reviewed a number of questions and criteria for the patient to assess at the conclusion of the initial consultation. I will paraphrase this from the physician’s point of view so that you may incorporate them into your thinking and assessment: Have you informed the patient of your formulation of his or her problem and diagnosis? Have you explained your concept of the cause of the problem in clearly understandable terms?

Have you discussed the prognosis, its potential seriousness, and how long you believe the problem will continue? Have you explained thoroughly your treatment plan, why you believe this is the best, and any alternatives that exist? If you have prescribed medication, does the patient know the name of the medication, how the medication works, when to take it, and its side effects, including drowsiness or nausea? Are there any interactions with other medications, including nonprescription medications or alcohol? If you have ordered tests, have you explained the purpose and nature of the tests and how the results will be used? Have you reviewed suggestions relative to lifestyle, such as nutrition, smoking, alcohol intake, exercise, or weight? If you have, have you explored with the patient any compliance issues? Did you tell the patient how long it might take to notice a difference?Did you give the patient some directions as to how to go about making these changes? Have you reviewed the patient’s expectations of treatment? For example, I believe that it is important when talking about primary headache disorders to talk in terms of control and not cure. If the patient’s expectations are total cure, this is obviously unrealistic, and the concept of decreased frequency, duration, and intensity of headaches must be explained. Although headache disorders may remit on their own, they cannot be cured. Again, the more education and the more materials you give the patient, the better the compliance and the greater the likelihood of a spirit of partnership. It is important to communicate your expectations of the patient and listen to the patient’s expectations of you.

FOLLOW-UP VISITS The ongoing follow-up visits are key, particularly in understanding that most headache patients present with a chronic disorder. The frequency of follow-up visits obviously depends on the progress of the patient and the intensity of the pharmacotherapy. We generally schedule a follow-up visit after the initial consultation within 2 to 4 weeks. The purpose of the follow-up visits is obviously to review progress via the patient’s verbal reports and a careful monitoring of the headache calendars. Treatment plans may be modified based on the patient’s response to medication. Vital signs should be taken at each follow-up visit, and brief examinations as necessary may be performed. Review of efficacy and side effects will determine dosing regimens. Because many patients may experience tachyphylaxis, changes of preventive regimens are necessary. Review of nonpharmacologic maneuvers related to diet, exercise, stress management, and lifestyle should also be reviewed. I find it useful to make small notes related to any upcoming important events in the patient’s life or even a vacation that he or she is looking forward to. I inquire about this in follow-up visits, demonstrating interest and concern. Phone calls between visits are important to note and record. Although emergencies must be responded to, major changes in preventive medications should not be made over the phone and should be reserved for discussion at follow-up visits. Ongoing follow-up via formal revisits and phone calls will begin to elucidate compliance issues, such as failure to adhere to medical regimens, loss of prescriptions, receiving as-needed medications

Chapter 208 rn Classification and Differential Diagnosis of Headache

from other physicians, and missed visits. It is important to confront these issues directly and to review problems that the patient may have in adhering to these regimens. Pharmacists often are very helpful in alerting the physician to multiple prescribing physicians. If we learn of these activities, we will let the patient know clearly that we can no longer go on prescribing or treating if they are getting medications from other sources without our knowledge. Patients with borderline personalities present some of the most difficult problems to the treating physician, and clear limits, boundaries, and structure must be maintained. If the patient cannot or will not adhere to them, then psychiatric referral must be considered. Only a very small percentage of headache patients make up this population but can present with the highest frequency of phone contacts, missed visits, and misplaced or lost prescriptions. Finally, be aware of the changing headache. Primary headache disorders do not preclude a patient from developing organic disease, such as tumor or aneurysm. It is important not to become complacent, even after years of treating a chronic sufferer with primary headache. Be alert to changes in the characteristics and presentation of the patient’s headache. When these are noted, proceed as if you are evaluating the patient for the first time and do what is necessary in regard to examination and tests.

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SUGGESTED READINGS Graham J R The headache patient and the doctor. In Adler CS, Adler SM, Packard RC (eds): Psychiatric Aspects of Headache. Williams & Wilkins, Baltimore, 1987 American Council for Headache: http:/fwww.achenet.org. American Council for Headache Education: Migraine: The Complete Guide. Dell Trade Paperbacks, New York, 2000 Angell M: The quality of mercy. N Engl J Med 30698, 1982 Headache Impact Test (HIT): http//www.iamhealthy.com Kosinski M, Bjorner J, Bayliss M, Ware J E Measuring the impact of migraine and severe headache with the headache impact test: using item response theory (IRT) models to score widely-used measures of headache impact and assess disability due to migraine or other severe headaches. Neurology 53(Suppl3):A453,2000 Lipton RE%, Goadsby PJ, Sawyer JPC et al: Migraine: diagnosis and assessment of disability. Rev Contemp Pharmacother 11:63-73, 2000 Migraine Disability Assessment Scale (MIDAS): http//www.midasmigraine.net or http://www.achenet.org Packard RC What does the headache patient want? Headache 19370-374, 1979

Rapoport AM, Sheftell FD. Conquering Headache. Empowering Press, Hamilton, Ontario, 2002 Rapoport AM, Sheftell FD: Headache associated with medication and substance withdrawal. p. 227 In Tollison CD, Kunkel RS (eds): Headache: Diagnosis and Treatment. Williams & Wilkins, Baltimore, 1993

CONCLUSION Although patients with recurrent and chronic headache can present a challenge to the treating physician, they can also give the physician a great deal of satisfaction and gratification. To quote Angell(l982) “Few things a doctor does are more important than relieving pain. . . . Pain is soul destroying. . . . No patient should have to endure intense pain unnecessarily. The quality of mercy is essential to the practice of medicine.”

Rapoport AM, Sheftell F D Headache Disorders: A Management Guide for Practitioners. WB Saunders. Philadelphia, 1996 Rapoport AM, Sheftell, Purdy A (eds):Advanced Headache Therapy: Case Based Learning. Decker, Hamilton, Ontario, 1999 Roter DL, Hall J A Doctors Talking with PatientslPatients Talking with Doctors. Auburn Health, Westport, CT, 1992 Sheftell F D Chronic daily headache. Neurology (Suppl 2):32-36, 1992 South V, Sheftell F Communicating with the patient. In Silberstein S, Lipton R, Dalessio DJ (eds): Wolff’s Headache and Other Head Pain. Oxford University Press, New York, 2001

208 Classification and Differential Diagnosis of

Headache Robert S. Kunkel The diagnosis of headache is based on the history presented by the patient. The history usually suggests whether the headache is caused by some neurologic, pericranial, or systemic condition. Currently, the classification of headache is based on the symptoms and signs presented by the patient or elicited by the neurologic and physical examination. Historically, headaches have been classified according to their presumed cause. Terms such as constipation headache, congestive

headache, neuralgic headache, stress headache, allergy headache, emotional headache, and headache of monotony have been used in books written about headaches. Migraine has been called sick

headache for years, and this term is still used by many today. Horton, who wrote the first detailed description of what is now known as cluster headache, called it histamine headache because he assumed that the pain was caused by the response of the patients to histamine. Because the diagnosis of one of the three primary headache syndromes (migraine, tension-type, and cluster) is based on the history obtained from the patient, an accurate history is essential to making the correct diagnosis. Few headaches are secondary to some underlying disease process or other condition: More than 90% of patients complaining of head pain have either migraine,

Chapter 208 rn Classification and Differential Diagnosis of Headache

from other physicians, and missed visits. It is important to confront these issues directly and to review problems that the patient may have in adhering to these regimens. Pharmacists often are very helpful in alerting the physician to multiple prescribing physicians. If we learn of these activities, we will let the patient know clearly that we can no longer go on prescribing or treating if they are getting medications from other sources without our knowledge. Patients with borderline personalities present some of the most difficult problems to the treating physician, and clear limits, boundaries, and structure must be maintained. If the patient cannot or will not adhere to them, then psychiatric referral must be considered. Only a very small percentage of headache patients make up this population but can present with the highest frequency of phone contacts, missed visits, and misplaced or lost prescriptions. Finally, be aware of the changing headache. Primary headache disorders do not preclude a patient from developing organic disease, such as tumor or aneurysm. It is important not to become complacent, even after years of treating a chronic sufferer with primary headache. Be alert to changes in the characteristics and presentation of the patient’s headache. When these are noted, proceed as if you are evaluating the patient for the first time and do what is necessary in regard to examination and tests.

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SUGGESTED READINGS Graham J R The headache patient and the doctor. In Adler CS, Adler SM, Packard RC (eds): Psychiatric Aspects of Headache. Williams & Wilkins, Baltimore, 1987 American Council for Headache: http:/fwww.achenet.org. American Council for Headache Education: Migraine: The Complete Guide. Dell Trade Paperbacks, New York, 2000 Angell M: The quality of mercy. N Engl J Med 30698, 1982 Headache Impact Test (HIT): http//www.iamhealthy.com Kosinski M, Bjorner J, Bayliss M, Ware J E Measuring the impact of migraine and severe headache with the headache impact test: using item response theory (IRT) models to score widely-used measures of headache impact and assess disability due to migraine or other severe headaches. Neurology 53(Suppl3):A453,2000 Lipton RE%, Goadsby PJ, Sawyer JPC et al: Migraine: diagnosis and assessment of disability. Rev Contemp Pharmacother 11:63-73, 2000 Migraine Disability Assessment Scale (MIDAS): http//www.midasmigraine.net or http://www.achenet.org Packard RC What does the headache patient want? Headache 19370-374, 1979

Rapoport AM, Sheftell FD. Conquering Headache. Empowering Press, Hamilton, Ontario, 2002 Rapoport AM, Sheftell FD: Headache associated with medication and substance withdrawal. p. 227 In Tollison CD, Kunkel RS (eds): Headache: Diagnosis and Treatment. Williams & Wilkins, Baltimore, 1993

CONCLUSION Although patients with recurrent and chronic headache can present a challenge to the treating physician, they can also give the physician a great deal of satisfaction and gratification. To quote Angell(l982) “Few things a doctor does are more important than relieving pain. . . . Pain is soul destroying. . . . No patient should have to endure intense pain unnecessarily. The quality of mercy is essential to the practice of medicine.”

Rapoport AM, Sheftell F D Headache Disorders: A Management Guide for Practitioners. WB Saunders. Philadelphia, 1996 Rapoport AM, Sheftell, Purdy A (eds):Advanced Headache Therapy: Case Based Learning. Decker, Hamilton, Ontario, 1999 Roter DL, Hall J A Doctors Talking with PatientslPatients Talking with Doctors. Auburn Health, Westport, CT, 1992 Sheftell F D Chronic daily headache. Neurology (Suppl 2):32-36, 1992 South V, Sheftell F Communicating with the patient. In Silberstein S, Lipton R, Dalessio DJ (eds): Wolff’s Headache and Other Head Pain. Oxford University Press, New York, 2001

208 Classification and Differential Diagnosis of

Headache Robert S. Kunkel The diagnosis of headache is based on the history presented by the patient. The history usually suggests whether the headache is caused by some neurologic, pericranial, or systemic condition. Currently, the classification of headache is based on the symptoms and signs presented by the patient or elicited by the neurologic and physical examination. Historically, headaches have been classified according to their presumed cause. Terms such as constipation headache, congestive

headache, neuralgic headache, stress headache, allergy headache, emotional headache, and headache of monotony have been used in books written about headaches. Migraine has been called sick

headache for years, and this term is still used by many today. Horton, who wrote the first detailed description of what is now known as cluster headache, called it histamine headache because he assumed that the pain was caused by the response of the patients to histamine. Because the diagnosis of one of the three primary headache syndromes (migraine, tension-type, and cluster) is based on the history obtained from the patient, an accurate history is essential to making the correct diagnosis. Few headaches are secondary to some underlying disease process or other condition: More than 90% of patients complaining of head pain have either migraine,

1320

Headache and Pain w General Aspects of Headache

tension-type, or cluster headache. However, it is essential to recognize headaches caused by organic or structural conditions because treatment of the underlying abnormality usually lessens or brings an end to the headache. Specific symptoms and causes of specific types of headache are discussed in detail in other chapters of this book. Many classifications have been used over the years. In 1962, an ad hoc committee of the National Institutes of Health developed the first attempt at a comprehensive classification of headache (Table 208-1). This classification was used as a reference by nearly every author who wrote about headache in the subsequent years. Diamond and Dalessio (1993) proposed one of the most useful classifications of headache. Their classification is very helpful in clinical practice. Headaches are separated into those with vascular components (migraine and cluster), tension-type headache, or traction and inflammatory headaches. All headaches that are secondary to some underlying disease, such as intracranial masses, hemorrhage, infection, or inflammation of the pericranial structures, or caused by some structural abnormality such as an Arnold-Chiari malformation or hydrocephalus, are in this category, This simple scheme is both practical and adequate for most practitioners treating headache patients. In 1988, after 3 years of deliberations, the International Headache Society (IHS) published a very detailed and complete headache classification, which was modeled after the Diagnostic and Statistical Manual of Mental Disorders, third edition (Table 208-2). This classification is now accepted throughout the world; the intention is that it will be revised after it has been used and tested in clinical practice. Diagnostic criteria are listed for the three primary headache syndromes and for nine categories of secondary headaches. This very detailed classification is not used extensively in the office practice of headache medicine. For reliable and comparable research, however, it is essential that its diagnostic criteria be used. The classification of the primary headache syndromes is based on symptoms, not on the pathophysiology or causes of the headaches. Therefore, it is essential to get as much information from the patient as possible to diagnose properly the type of headache present. As medication and possibly other treatments become more specific for alleviating various types of head pain, it is essential that an accurate diagnosis of headache be made. In addition to the fact that the history may not be very accurate, many patients have more than one lund of headache. Perhaps the most significant ongoing controversy in the field of headache

TABLE208-1. Headache Classification, 1962 1. Migrainous vascular

Classic Common Cluster Hemiplegic and ophthalmoplegic Lower-half 2. Muscle contraction 3. Combined: vascular and muscle contraction 4. Nasal vasomotor reaction 5. Delusional, conversion, or hypochondriacal 6. Nonmigrainous vascular 7. Traction 8. Overt cranial inflammation 9-1 3. Ocular, aural, nasal, sinus, dental, or other cranial or neck structure disorders 14. Cranial neuritides 15. Cranial neuralgias

classification is related to this situation. The IHS classification does not contain the category of mixed headache or chronic daily headache, which are mentioned repeatedly in the literature. Most headache clinics see many patients who have daily headache that at times fits the migraine criteria and at other times fits the chronic tension-type headache criteria. These headaches often blend together, and it is impossible for the patient to separate them. The IHS classification states that each headache type should be diagnosed and listed separately. It is essential to remember that the IHS classification is a classification of headaches, not of patients. Some new terms were introduced in the 1988 classification. Classic migraine is now known as migraine with aura and common migraine as migraine without aura. Migraine aura without headache is the new term for what has been known as migraine equivalents or acephalgic migraine. Tension-type headache is the term for what has been previously known as tension headache, psychogenic headache, muscle contraction headache, ordinary headache, and many other terms. The term tension-type headache was a compromise term. Most recognize this headache as being a pressure type of discomfort, which is nonlocalized and usually not very intense. Most recently it had been known as muscle contraction headache. Because studies have shown that the scalp muscles are not always in a state of increased contraction during the time of this headache, it was felt that muscle contraction was not an accurate term. One of the new categories in the IHS classification is headache caused by substances or their withdrawal. There is increasing evidence that one of the most common causes of daily or near-daily headache is the persistent use or overuse of combination analgesics, opioids, tranquilizers, caffeine, and ergotamine. Frequent use of these agents can cause a dependency, with subsequent withdrawal or rebound headache when the use is not continued. Usually effective preventive medications and other treatment modalities are not beneficial as long as the other agents are used so frequently. Therefore, it is important to get a very accurate history of all medication use, including all nonprescription medications consumed; many of these contain caffeine along with analgesic compounds. Patients who are difficult to classify include those with a new onset of headache and those with many years of headache. The IHS classification requires that patients with tension-type, cluster, or migraine headache have several typical attacks before the diagnosis is made and the type of headache classified. Frequent medication intake may be an important factor in those with chronic headache. Patients who have had headache for many years may not remember some of the specific details about the symptoms that occurred when their headaches were beginning years previously. Therefore, symptoms that were suggestive, or even diagnostic, of migraine when the headaches started years previously may have been forgotten. The patient may well have had migraine but now has a daily headache with very few migraine features. The primary headache may be migraine, with the current headache being caused by overuse of medications. DIFFERENTIAL DIAGNOSIS OF HEADACHE A reliable history from an observant patient should allow the clinician to come up with a reasonable differential diagnosis of the headache present. The physical and neurologic examinations usually confirm the suspicion that the headache is caused by an underlying disease. The overwhelming majority of patients have one of the three primary headache syndromes. If it seems unlikely

Chapter 208

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Classification and Differential Diagnosis of Headache

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rn TAME 208-2. International Headache Society Classification, 1988 1. Migraine 1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Migraine with typical aura 1.2.2 Migraine with prolonged aura 1.2.3 Familial hemiplegic migraine 1.2.4 Basilar migraine 1.2.5 Migraine aura without headache 1.2.6 Migraine with acute onset aura 1.3 Ophthalmoplegic migraine 1.4 Retinal migraine 1.5 Childhood periodic syndromes that may be precursors to or associ-

ated with migraine 1.5.1 Benign paroxysmal vertigo of childhood 1.5.2 Alternating hemiplegia of childhood 1.6 Complications of migraine 1.6.1 Status migrainous 1.6.2 Migrainous infarction 1.7 Migrainous disorder not fulfilling above criteria 2. Tension-type headache 2.1 Episodic tension-type headache 2.1.1 Episodic tension-type headache associated with disorder of pericranial muscles 2.1.2 Episodic tension-type headache unassociated with disorder of pericranial muscles 2.2 Chronic tension-type headache 2.2.1 Chronic tension-type headache associated with disorder of pericranial muscles 2.2.2 Chronic tension-type headache unassociated with disorder of pericranial muscles 2.3 Headache of the tension type not fulfilling above criteria 3. Cluster headache and chronic paroxysmal hemicrania 3.1 Cluster headache 3.1.1 Cluster headache periodicity undetermined 3.1.2 Episodic cluster headache 3.1.3 Chronic cluster headache 3.1.3.1 Unremittingfrom onset 3.1.3.2 Evolved from episodic 3.2 Chronic paroxysmal hemicrania 3.3 Cluster headache-like disorder not fulfilling above criteria 4. Miscellaneous headaches unassociated with structural lesion 4.1 Idiopathic stabbing headache 4.2 External compression headache 4.3 Cold stimulus headache 4.3.1 External application of a cold stimulus 4.3.2 Ingestion of a cold stimulus 4.4 Benign cough headache 4.5 Benign exertional headache 4.6 Headache associated with sexual activity 4.6.1 Dull type 4.6.2 Explosive type 4.6.3 Postural type 5. Headache associated with head trauma 5.1 Acute post-traumatic headache 5.1.1 With significant head trauma and/or confirmatory signs 5.1.2 With minor head trauma and no confirmatory signs 5.2 Chronic post-traumatic headache 5.2.1 With significant head trauma and/or confirmatory signs 5.2.2 With minor head trauma and no confirmatory signs 6. Headache associated with vascular disorders 6.1 Acute ischemic cerebrovascular disease 6.1.1 Transient ischemic attack (TIA) 6.1.2 Thromboembolic stroke 6.2 lntracranial hematoma 6.2.1 lntracerebral hematoma 6.2.2 Subdural hematoma 6.2.3 Epidural hematoma 6.3 Subarachnoid hemorrhage 6.4 Non-ruptured vascular malformation 6.4.1 Arteriovenous malformation 6.4.2 Saccular aneurysm 6.5 Arteritis 6.5.1 Giant cell arteritis 6.5.2 Other systemic arteriiides 6.5.3 Primary intracranial arteritis

6.6 Carotid or vertebral artery pain 6.6.1 Carotid or vertebral dissection 6.6.2 Carotidynia (idiopathic) 6.6.3 Postendarterectomy headache 6.7 Venous thrombosis 6.8 Arterial hypertension 6.8.1 Acute pressor response to exogenous agent 6.8.2 Pheochromocytoma 6.8.3 Malignant (accelerated) hypertension 6.8.4 Pre-eclampsia and eclampsia 6.9 Headache associated with other vascular disorder 7. Headache associated with nonvascular intracranial disorder 7.1 High cerebrospinal fluid pressure 7.1.1 Benign intracranial hypertension 7.1.2 High pressure hydrocephalus 7.2 Low cerebrospinal fluid pressure 7.2.1 Post-lumbar puncture headache 7.2.2 Cerebrospinal fluid fistula headache 7.3 lntracranial infection 7.4 lntracranial sarcoidosis and other noninfectious inflammatory dis-

eases 7.5 Headache related to intrathecal injections 7.5.1 Direct effect 7.5.2 Due to chemical meningitis 7.6 lntracranial neoplasm 7.7 Headache associated with other intracranial disorder 8. Headache associated with substances or their withdrawal 8.1 Headache induced by acute substance use or exposure 8.1.1 Nitrate/nitriie-induced headache 8.1.2 Monosodium glutamate-induced headache 8.1.3 Carbon monoxide-induced headache 8.1.4 Alcohol-induced headache 8.1.5 Other substances 8.2 Headache induced by chronic substance use or exposure 8.2.1 Ergotamine-induced headache 8.2.2 Analgesic-abuse headache 8.2.3 Other substances 8.3 Headache from substance withdrawal (acute use) 8.3.1 Alcohol withdrawal headache (hangover) 8.3.2 Other substances 8.4 Headachefrom substance withdrawal (chronic use) 8.4.1 Ergotamhe withdrawal headache 8.4.2 Caffeine withdrawal headache 8.4.3 Narcotics abstinence headache 8.4.4 Other substances 8.5 Headache associated with substances but with uncertain mecha-

nism 8.5.1 Birth control pills or estrogens 8.5.2 Other substances 9. Headache associated with noncephalic infection 9.1 Viral infection 9.1.1 Focal noncephalic 9.1.2 Systemic 9.2 Bacterial infedon 9.2.1 Focal noncephalic 9.2.2 Systemic (septicemia) 9.3 Headache related to other infection 10. Headache associated with metabolic disorder 10.1 Hypoxia 10.1.1 High-altitudeheadache 10.1.2 Hypoxic headache 10.1.3 Sleep apnea headache 10.2 Hypercapnia 10.3 Mixed hypoxia and hypercapnia 10.4 Hypoglycemia 10.5 Dialysis 10.6 Headache related to other metabolic abnormality 1 1. Headache or facial pain associated with disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial struc-

tures 11.1 Cranial bone 1 1.2 Neck 11.2.1 Cervical spine 11.2.2 Retropharyngeal tendinitis 1 1.3 Eyes 11.3.1 Acute glaucoma 11.3.2 Refractive errors 1 1.3.3 Heterophoria or heterotropia Table continued on follooWing page

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Headache and Pain W General Aspects of Headache

T u u 208-2. Continued 1 1.4 Ears 1 1.5 Nose and sinuses 1 1.5.1 Acute sinus headache 1 1.5.2 Other diseases of nose and sinuses 1 1.6 Teeth, jaws, and related structures 1 1.7 Temporomandibular joint disease 12. Cranial neuralgias, nerve trunk pain, and deafferentation pain 12.1 Persistent (in contrast to ticlike) pain of cranial nerve origin 12.1.1 Compression or distortion of cranial nerves and second or third cervical roots 12.1.2 Demyelination of cranial nerves 12.1 2 . 1 Optic neuritis (retrobulbar neuritis) 12.1.3 Infarction of cranial nerves 12.1.3.1 Diabetic neuritis 12.1.4 Inflammation of cranial nerves 12.1.4.1 Herpes zoster 12.1.4.2 Chronic postherpetic neuralgia 12.1.5 Tolosa-Hunt syndrome 12.1.6 Neck-tongue syndrome 12.1.7 Other causes of persistent Dain of cranial nerve orinin

that the headache is one of these, then a search for neurologic, cranial, cervical, or systemic causes is indicated. There are systemic factors, such as hypertension, anemia, medication, and fever, which may affect the frequency and intensity of migraine headaches. If the pattern or frequency has changed, the reason for this should be pursued. Typical attacks of migraine with aura and cluster headache rarely warrant further investigation. Rarely, a lesion of the occipital lobe may cause visual symptoms that mimic the aura of migraine. It is often more difficult to be certain of the diagnosis of migraine without aura and tension-type headache. CRANIAL AND CERVICAL CAUSES OF HEADACHE

Disease involving the head and upper neck can cause tension-type headache and, at times, headache indistinguishablefrom migraine without aura. However, examination usually reveals disease or infection of the head or neck. Sinus and dental disease are the most common cephalalgic problems causing headache. Sinus disease usually causes frontal or facial pains, but sphenoid sinusitis may cause pain in the vertex of the skull. Dental infection and periodontal disease may cause headaches; dental abscesses or the cracked tooth syndrome are less common causes. Computed tomography of the sinuses with coronal cuts is very helpful in evaluating the extent of sinus disease. Diseases of the eyes or ears usually are evident on examination. Refractive errors rarely cause headache, and if they do, it occurs during reading or close work with the eyes and is not present on awakening. Other diseases of the eye, such as glaucoma or inflammatory conditions, should be evident on examination and usually are of recent onset. Tension-type headache that is secondary to some other problem usually is caused by spasm of the muscles around the temporomandibular joint or the cervical spine. Most pains that are related to the temporomandibular joint are secondary to clenching or grinding of the teeth. Rarely is there any significant disease in the joint or a symptomatic malalignment of the bite. Examination of the joint and inspection of the bite of the patient when opening and closing the mouth usually demonstrate abnormalities. Radiographs and magnetic resonance imaging of the temporomandibular joint show disease of the joint, if present. Degenerative changes in the cervical spine can be associated with neck and head pain, which is more often a muscular rather than a radicular or

12.2 Trigeminal neuralgia 12.2.1 Idiopathic trigeminal neuralgia 12.2.2 Symptomatic trigeminal neuralgia 12.2.2.1 Compression of trigeminal root or ganglion 12.2.2.2 Central lesions 12.3 Clossopharyngeal neuralgia 12.3.1 Idiopathic glossopharyngeal neuralgia 12.3.2 Symptomatic glossopharyngeal neuralgia 12.4 Nervus intermedius neuralgia 12.5 Superior laryngeal neuralgia 12.6 Occipital neuralgia 12.7 Central causes of head and facial pain other than tic douloureux 12.7.1 Anesthesia dolorosa 12.7.2 Thalamic pain 12.8 Facial pain not fulfilling criteria in groups 1 1 or 12 13. Headache not classifiable

neuralgic type of pain. Associated spasm in the cervical and trapezius muscles with tender points often palpable on examination and decreased neck motion, as well as sloping shoulders and forward-positioned head, are often seen. INTRACRANIAL CAUSES OF HEADACHE

Intracranial disease, if the cause of headache, usually is associated with neurologic symptoms and signs. It is most unusual to have headache as the only symptom of a central nervous system lesion or infection. A patient with a recent onset of headache should be investigated, as should one who has had a chronic headache but develops new neurologic symptoms or has a change in symptoms. The headache caused by a brain tumor is of progressing intensity and almost always is accompanied by neurologic symptoms and signs. Aneurysms in the brain do not cause chronic headache unless they compress a cranial nerve, and neurologic signs should be evident. Of course, ruptured aneurysms cause an acute severe headache and often are rapidly fatal. Subdural hematoma, Amold-Chiari malformation, and hydrocephalus may cause headache of a subacute nature, but the headaches occurring with these conditions usually are not severe. Again, neurologic signs should be evident, and the headache usually is worsened by a change of position or Valsalva maneuver. Intracranial infections may be the cause of acute headache and usually are accompanied by fever and neurologic abnormalities that are evident on examination. An abscess may not be associated with fever but usually causes progressive symptoms as it expands. Meningitis and encephalitis, both of which are accompanied by headache, usually are also associated with alterations in mentation. SYSTEMIC CAUSES OF HEADACHE

Fever, hypertension, anemia, or hypoxemia may cause a vascular type of headache that is not episodic but persistent. This type of headache could be chronic or of recent onset, depending on the underlying cause. Viral illnesses may cause a diffuse throbbing headache that is aggravated by Valsalva maneuvers, such as bending, straining, coughing, and sneezing. This type of headache is not at all uncommon and tends to improve spontaneously, although it may take weeks or even months to subside. Often patients can remember that the headache started with an acute

Chapter 209

flulike illness; other systemic infections can cause headache, which may be caused by a toxic effect of the infection itself or secondary to fever. Paroxysmal or episodic throbbing headaches, diffuse and nonlocalized, are a common symptom of acute hypertensive attacks of pheochromocytoma. Acute onset of exertional or orgasmic headache must be evaluated to exclude intracranial hemorrhage, intracranial obstruction, or conditions aggravated by exertion, such as the Arnold-Chiari malformation. Studies that have been done in patients suffering from acute orgasmic headache have demonstrated a vascular lesion on only very rare occasions. Benign orgasmic headache, although very frightening, is rarely caused by underlying disease. Various endocrinopathies, such as thyroid dysfunction or hyperparathyroidism, can cause headache of a nonspecific type. Electrolyte abnormalities, hypoglycemia, and hypoxemia also are possible causes of headache, although they are quite rare. Awakening with headache in the morning should raise suspicion of sleep apnea with subsequent hypoxemia. This usually is diagnosed by history from the spouse and confirmed by sleep studies. Neuralgic pains involving the head usually occur in older adults. Tic douloureux or trigeminal neuralgia typically involves the second and third divisions of the fifth nerve. The characteristic of this headache is the triggering of sharp stabbing pains by touching the trigger zones about the face. Patients with tic douloureux never rub or touch their face or head, but patients with almost all other types of headaches press, push, and rub their scalp in an effort to obtain relief. Occipital neuralgia is a headache involving the posterior part of the skull and can be associated with trauma or degenerative changes in the upper cervical spine. The location and type of pain is quite typical, and the diagnosis can be confirmed by local injections around the nerve, which cause an alleviation of the pain.

SECTION

Migraine with and without Aura

1323

SUMMARY The differential diagnosis of headache is extensive. The three primary headache syndromes-migraine, tension-type, and cluster headacheusually are diagnosed by the history and lack demonstrable abnormalities on the physical and neurologic examinations. Headaches that by description do not fit one of the primary headache syndromes or are occurring with neurologic symptoms must be investigated for some specific underlying cause. The headache may be neurologic, caused by conditions of the central nervous system. or may be caused by problems in the cervical spine or systemic conditions. Any headache associated with signs on examination must be vigorously investigated in the hope that an underlying cause may be found and treated. However, it must be remembered that some neurologic or systemic conditions cause headache that may be indistinguishable, on history, from migraine or tension-type headache. It is unusual for the symptoms of cluster headache to be confused with any other condition.

SUGGESTED READINGS Ad Hoc Committee on Classification of Headache, National Institute of Neurological Disease and Blindness: Classificationof headache. JAMA 1797 17-7 18, 1962 Diamond S, Dalessio DJ: The Practicing Physician’s Approach to Headache. 5th Ed. Williams & Wilkins, Baltimore, 1993 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):l-96, 1988

2

HEADACHE SYMPTOMS AND THEIR TREATMENT

209 Migraine with and without Aura 0

Richard B. Lipton Alan M. Rapoport Migraine is a common neurologic disorder characterized by head pain and various combinations of neurologic, gastrointestinal, and autonomic features. In a given year, 15% to 18% of women and about 6% of men have at least one migraine attack. Prevalence is highest from ages 25 to 55, so migraine affects people during their peak productive years. According to recent estimates, 28 million Americans currently suffer from migraine headaches, and more

rn than 13 million experience significant levels of headache-related disability. The cost of migraine in the United States almost certainly exceeds $13 billion per year. Yet the majority of migraine cases are not diagnosed as such and are not treated with prescription medications. Undiagnosed and untreated migraine is an important public health problem. Most migraine sufferers who seek care for their headaches do so in the primary care setting.

Chapter 209

flulike illness; other systemic infections can cause headache, which may be caused by a toxic effect of the infection itself or secondary to fever. Paroxysmal or episodic throbbing headaches, diffuse and nonlocalized, are a common symptom of acute hypertensive attacks of pheochromocytoma. Acute onset of exertional or orgasmic headache must be evaluated to exclude intracranial hemorrhage, intracranial obstruction, or conditions aggravated by exertion, such as the Arnold-Chiari malformation. Studies that have been done in patients suffering from acute orgasmic headache have demonstrated a vascular lesion on only very rare occasions. Benign orgasmic headache, although very frightening, is rarely caused by underlying disease. Various endocrinopathies, such as thyroid dysfunction or hyperparathyroidism, can cause headache of a nonspecific type. Electrolyte abnormalities, hypoglycemia, and hypoxemia also are possible causes of headache, although they are quite rare. Awakening with headache in the morning should raise suspicion of sleep apnea with subsequent hypoxemia. This usually is diagnosed by history from the spouse and confirmed by sleep studies. Neuralgic pains involving the head usually occur in older adults. Tic douloureux or trigeminal neuralgia typically involves the second and third divisions of the fifth nerve. The characteristic of this headache is the triggering of sharp stabbing pains by touching the trigger zones about the face. Patients with tic douloureux never rub or touch their face or head, but patients with almost all other types of headaches press, push, and rub their scalp in an effort to obtain relief. Occipital neuralgia is a headache involving the posterior part of the skull and can be associated with trauma or degenerative changes in the upper cervical spine. The location and type of pain is quite typical, and the diagnosis can be confirmed by local injections around the nerve, which cause an alleviation of the pain.

SECTION

Migraine with and without Aura

1323

SUMMARY The differential diagnosis of headache is extensive. The three primary headache syndromes-migraine, tension-type, and cluster headacheusually are diagnosed by the history and lack demonstrable abnormalities on the physical and neurologic examinations. Headaches that by description do not fit one of the primary headache syndromes or are occurring with neurologic symptoms must be investigated for some specific underlying cause. The headache may be neurologic, caused by conditions of the central nervous system. or may be caused by problems in the cervical spine or systemic conditions. Any headache associated with signs on examination must be vigorously investigated in the hope that an underlying cause may be found and treated. However, it must be remembered that some neurologic or systemic conditions cause headache that may be indistinguishable, on history, from migraine or tension-type headache. It is unusual for the symptoms of cluster headache to be confused with any other condition.

SUGGESTED READINGS Ad Hoc Committee on Classification of Headache, National Institute of Neurological Disease and Blindness: Classificationof headache. JAMA 1797 17-7 18, 1962 Diamond S, Dalessio DJ: The Practicing Physician’s Approach to Headache. 5th Ed. Williams & Wilkins, Baltimore, 1993 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):l-96, 1988

2

HEADACHE SYMPTOMS AND THEIR TREATMENT

209 Migraine with and without Aura 0

Richard B. Lipton Alan M. Rapoport Migraine is a common neurologic disorder characterized by head pain and various combinations of neurologic, gastrointestinal, and autonomic features. In a given year, 15% to 18% of women and about 6% of men have at least one migraine attack. Prevalence is highest from ages 25 to 55, so migraine affects people during their peak productive years. According to recent estimates, 28 million Americans currently suffer from migraine headaches, and more

rn than 13 million experience significant levels of headache-related disability. The cost of migraine in the United States almost certainly exceeds $13 billion per year. Yet the majority of migraine cases are not diagnosed as such and are not treated with prescription medications. Undiagnosed and untreated migraine is an important public health problem. Most migraine sufferers who seek care for their headaches do so in the primary care setting.

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Headache Symptoms and Their Treatment

Therefore, primary care physicians have the best opportunity to improve the diagnosis of migraine and ultimately to improve the outcome of this potentially devastating disorder through effective treatment. The diagnosis of migraine and other types of headache has been facilitated by the criteria published in Cephalalgia in 1988 by the International Headache Society (IHS). This classification system divides all headache disorders into two major groups: primary and secondary. In secondary disorders, the headache is symptomatic of some underlying condition, such as a brain tumor, temporal arteritis, or medication rebound. In primary disorders, the headache is caused by underlying biochemical, physiologic, and electrical dysfunction of the brain. The major categories of primary headaches are migraine, tension-type headache, and cluster headache. Based on international consensus, the criteria determine which headache features are required to establish or exclude the diagnosis of migraine. The diagnosis of migraine is based largely on patient reports of headache characteristics and associated symptoms. No biological markers or laboratory tests are used to confirm the clinical diagnosis. The general medical and neurologic examinations and laboratory studies usually are normal and exclude secondary causes of headache. Therefore, the headache history is the key to accurate diagnosis. In this chapter, we present an overview of the clinical characteristics of migraine, beginning with a description of the phases of the migraine attack. We then review the IHS diagnostic criteria for migraine and discuss their role in primary care. We close with an approach to the differential diagnosis of migraine. MIGRAINE AllACK

Blau (1986) has divided the migraine attack into five phases: 1. The premonitory phase (or prodrome) is characterized by changes in mood or behavior that occur hours or days before the headache. 2. The aura phase is characterized by focal neurologic deficits often preceding the migraine headache. 3. The headache phase consists of pain and associated features. 4. In the termination phase, pain gradually subsides. 5. In the postdrome, residual symptoms persist after pain has remitted. Although most people with migraine experience more than one of these five phases, no single phase is obligatory for diagnosis. A description of the phases of the migraine attack provides a structured way to review the protean manifestation of migraine. Premonitory Phase

Premonitory features, or prodromes, occur in about 60% of migraine sufferers and often begin hours to 1 or 2 days before headache onset. Although features vary from person to person, for an individual sufferer they may be quite stereotypical. Information about prodromal features is elicited by asking, “Before the pain begins, do you know that a headache is coming? How do you know?” Premonitory features include changes in mood (depression, euphoria, irritability, restlessness), mental slowing, hyperactivity, sluggishness, fatigue, and drowsiness. Increased sensory sensitivity (photophobia and phonophobia), alterations in fluid balance (increased thirst, fluid retention, increased urination), changes in appetite (anorexia, food cravings), and alterations in

gastrointestinal function (nausea, constipation, or diarrhea) may occur. Some people simply report a poorly characterized feeling that a migraine attack is coming. Premonitory features are believed to result from cerebral and brainstem dysfunction before pain onset, supporting the idea that migraine is primarily a disease of the brain, not of the blood vessels. Aura

The migraine aura consists of focal neurologic symptoms that typically precede but may also accompany the headache. About 20% of migraine sufferers experience an aura, which mostly develop slowly, over 5 to 20 minutes, and usually last from 10 to 60 minutes. The aura is characterized by visual, sensory, or motor features and may also involve language or brainstem disturbances. Headache usually occurs within 60 minutes of the end of the aura. Descriptions of aura can be improved through the use of diaries or by having patients draw pictures of their experience. Our knowledge of the phenomenology of aura is derived primarily from patient accounts and drawings. The most common type of migraine aura is the visual aura. The visual aura includes a range of positive visual phenomena, such as scintillations (flickering lights), photopsias (flashes of light), and fortification spectra (jagged, luminous zigzag lines, often in an overall crescent shape). Scintillations may be so subtle that they are barely noticed; at other times they may be almost blinding in intensity. The visual aura often includes negative visual phenomena as well, in the form of a scotoma. Scotomas are areas of visual loss, which may take the form of a graying- or blacking-out of vision. In the absence of positive visual features, small scotomas may sometimes go unnoticed. The visual aura classically includes a mix of positive and negative visual features, taking the form of a scintillating scotoma with flickering around the edges of a region of visual loss. It characteristically begins in the central vision and expands laterally to encompass an enlarging segment of a homonymous visual field. Scintillations less often begin laterally and travel medially across a visual field, and only the upper or lower half of a visual field may be involved. Occasionally, objects may change in size (micropsia or macropsia) or shape (metamorphopsia). The sensory aura is the second most common type, occurring in about one third of people who have migraine with aura. Like the visual aura, a mix of positive (tingling) and negative (numbness) features also characterizes the sensory aura. Sensory aura often evolves in a cheiro-oral (hand-mouth) pattern, beginning in an isolated part of the hand (e.g., the thumb), expanding to involve the whole hand and then the perioral region. Involvement of half the tongue is common. Most people with sensory aura also have visual aura. Motor aura occurs as a variable feature in up to 15% of patients who have migraine with aura. Although not well studied, it consists of paresis, usually developing in a focal region and gradually spreading to involve a larger area. Most patients with weakness also experience sensory and visual symptoms. Motor phenomena usually are limited to the hand and arm, although the face, arm, and leg may be involved in various combinations. Unilateral involvement is the rule; bilateral paresis is very rare, although a complaint of generalized weakness is common. A subgroup of patients with motor aura have an autosomal dominant disorder called familial hemiplegic migraine. These patients usually have episodes of hemiparesis and headache lasting from several hours to several days. Genetic linkage to chromosome

Chapter 209

19 has been demonstrated in about 50% of affected families; the pathogenic gene on chromosome 19 codes for a PQ-type calcium channel. Linkage in other families has been demonstrated to chromosome 1. There are a number of less common aura manifestations. Various combinations of typical visual aura symptoms, vertigo, tinnitus, diplopia, ataxia, and a depressed level of awareness characterize basilar migraine. Some object to this term on the grounds that the basilar artery is not involved. This rare condition typically begins in childhood and adolescence. Speech disturbances may occur, usually with other symptoms indicating dominant hemisphere dysfunction, including right-sided motor or sensory disturbances. Hemispatial neglect and spatial disorientation have been described. A variety of deficits in higher integrative functions, including alexia (difficulty reading), acalculia (difficulty calculating), and palinopsia (visual preservation), have been reported. The various types of migraine aura should not be regarded as discrete, mutually exclusive syndromes. More than one kind of aura may occur within a single attack; visual aura may be followed by sensory aura, for example. In addition, the type of aura may shift over time within individual sufferers. Someone with basilar migraine in childhood may develop typical visual aura in adolescence and migraine without aura in adult life. In families with several affected members, different patterns of aura may occur in different patients, suggesting that aura characteristics are controlled by some nongenetic factors. Although aura was once regarded as highly specific for migraine, several groups have reported that aura may occur in association with cluster headache, the paroxysmal hemicranias, and hemicrania continua. In addition, there are a few organic mimics of aura including occipital lobe seizures, transient ischemic attacks, and carotid dissection.

Headache Phase Table 209-1 summarizes the frequency of the various migraine symptoms. The typical headache is unilateral, throbbing, moderate or severe in intensity, and aggravated by physical activity. Not all of these features are necessary for diagnosis. Pain may be bilateral at onset (in 40% of cases) or on one side and then become generalized. The headache of migraine can occur at any time of day or night but occurs most often on arising in the morning. The onset usually is gradual; the pain typically increases over minutes to hours, reaches a sustained plateau, and then subsides slowly, lasting an average of 1 day with a range of 4 to 72 hours in adults and 2 to 48 hours in children. Some people awaken from sleep with moderate or severe pain. Pain begins quite suddenly in a rare disorder sometimes called “crash migraine.” The head pain varies greatly in intensity, although most people with migraine report severe or very severe pain. The pain is

TABLE209-1. Proportion of Migraine Sufferers with Selected

Symptoms symptom

Throbbing pain Unilateral pain Nausea Photophobia Phonophobia Vomiting

Symptom Frequency (%) 85 60

72 80 76 29

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described as throbbing or pulsatile in about 80% of cases. Throbbing pain is also often described in other types of headache. Pain is commonly aggravated by physical activity, such as climbing stairs, bending over, simple head movement, coughing, or head rotation. The pain is hemicranial in 50% to 60% and tends to have a frontotemporal or retro-orbital location. Migraine sufferers often experience momentary stabs and jabs of sharp, shooting pains at a variety of cephalic locations. These benign, idiopathic, stabbing pains tend to occur on the same side as migraine attacks and may frighten patients. The pain of migraine is invariably accompanied by other associated symptoms (Table 209-1). Anorexia is common, although food craving can occur. Nausea occurs in 60% to 75% of patients, and vomiting occurs in about one quarter of migraineurs. Nausea that begins only after the administration of medications (e.g., ergots) should not be used to support the diagnosis. Many patients experience sensory hyperexcitability, as manifested by photophobia, phonophobia, and osmophobia. Because many people are sensitive to light or sound at baseline, we ask about unusual or heightened sensory sensitivity. These reports are more convincing if they have a behavioral consequence, such as going to a dark, quiet room to avoid light or sound. Some patients report lowering the windowshades, turning off lights, or wearing sunglasses to limit light exposure. Patients may turn down the stereo, ask people to talk quietly, or wear earplugs to avoid sound. During an attack, exposure to light or sound often exacerbates the pain; exposure to strong or noxious odors may exacerbate nausea. Other associated symptoms include blurred vision, nasal stuffiness, hunger, diarrhea, abdominal cramps, polyuria (sometimes followed by decreased urinary output after the attack), pallor (or, less commonly, redness) of the face, sensations of heat or cold, and sweating. There may be localized edema of the scalp, the face, or under the eyes, tenderness of the scalp, unusual prominence of a vein or artery in the temple, stiffness of the neck, and tenderness of the cervical musculature. Difficulty with concentration is common; less often there is memory impairment. Depression, fatigue, anxiety, nervousness, and irritability may occur. There may be lightheadedness and feeling of faintness. The distal extremities may be cold and moist. As discussed later in this chapter, the IHS criteria have selected particular associated symptoms as cardinal manifestations for diagnosis.

Termination and Postdrome In the termination phase, the pain gradually decreases in intensity, usually over several hours. Migraine sufferers often find that sleep or vomiting helps end an attack. After the headache, the patient often feels tired, washed out, irritable, and listless. Some report impaired concentration, scalp tenderness, or mood changes. Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise.

Exacerbatingor Ameliorating Factors Identifymg factors that precipitate or aggravate migraine can help support the diagnosis. In addition, recognizing and avoiding these factors provides an opportunity to improve headache control. Frequently reported trigger factors include menstruation (especially within a day of the onset of flow), stress or relaxation after stress, fatigue, changes in the sleep-wake cycle (excessive or insufficient sleep), and changes in weather conditions. Exposure to

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bright lights, loud noises, chemical fumes, and perfume may all trigger attacks. Many patients with migraine report dietary triggers. The most commonly reported precipitants include alcohol (especially red wine), followed by chocolate, aged cheese, aspartame, caffeine consumption or withdrawal, and fermented foods. Patients with diet-provoked migraine may have defects in the metabolism of particular dietary chemicals, such as tyramine and phenolic compounds, increasing their vulnerability to these agents. Most dietary triggers probably do not operate through allergic mechanisms mediated through immunoglobulin E. Ameliorating factors vary from patient to patient, sometimes with the symptom profile of the migraine attack. For patients with photophobia and phonophobia, lying in a dark, quiet room can bring some relief. For people with movement sensitivity, lying motionless may decrease pain. Pressure on the extracranial arteries with hot or cold compresses often brings transient relief. Vomiting or sleep may terminate an attack. Effective medication is the major ameliorating factor for most patients. Migraine also often improves in the second two trimesters of pregnancy and after menopause, especially when replacement estrogens are avoided or used daily in low dosages. DIAGNOSTIC CRITERIA OF THE IHS To improve the classification of headache disorders both in clinical practice and in research, the IHS published diagnostic criteria for a broad range of headache disorders in 1988. These criteria, based on expert consensus, have had a major impact on clinical trials and on epidemiologic research, although they have not been widely used in clinical practice, perhaps because of their complexity. The IHS system defines many subtypes of migraine. For use in the primary care setting, we discuss two major types of migraine. Although the IHS criteria are being revised based on empirical evidence and clinical experience, they are the best currently available diagnostic tool for the clinician and investigator. Migraine without Aura (Common MPgraPne)

To establish a diagnosis of IHS migraine without aura ( l . l ) , at least five attacks are required (Table 209-2). Each attack must last 4 to 72 hours and must have two of the following four pain characteristics: unilateral location, pulsating quality, moderate to severe intensity, and aggravation by routine physical activity. In addition, the attacks must have at least one of the following: nausea, vomiting, or photophobia and phonophobia. Using these criteria, no single characteristic is mandatory for diagnosing migraine. A patient who has moderate, nonthrobbing, bilateral pain aggravated by routine activity, with photophobia and phonophobia, meets criteria, just like the more typical patient with unilateral, throbbing pain and nausea. When a migraine attack lasts longer than 72 hours (3 days), the term status migrainosus is sometimes applied. The frequency of attacks is extremely variable, from a few per lifetime to several per week, but the average migraineur experiences one to three headaches per month. By definition, migraine is a recurrent phenomenon. The requirement for at least five attacks is imposed because headaches simulating migraine may be caused by organic disease, ranging from brain tumor to sinusitis to glaucoma. As the number of lifetime attacks increases, the probability of an ominous cause declines.

TMU 209-2. Migraine without Aura: International Headache Society Criteria Previously used terms: common migraine, hemicraniasimplex Diagnostic criteria: A. At least five attacks fulfilling items 6 to D. B. Headache lasting 4 to 72 hours (untreated or unsuccessfullytreated). C. Headache with at least two of the following characteristics: I . Unilateral location. 2. Pulsating quality. 3. Moderate or severe intensity (inhibits or prohibits daily activities). 4. Aggravation by walking stairs or similar routine physical activity. D. During headache at least one of the following: 1. Nausea or vomiting. 2. Photophobia and phonophobia. E. At least one of the following: 1. History and physical and neurologic examinations do not suggest one of the disorders listed in groups 5-1 1 (organic disorders). 2. History or physical or neurologic examinations suggest such disorder, but it is ruled out by appropriate investigations. 3. Such disorder is present, but migraine attacks do not occur for the first time in close temooral relation to the disorder.

The IHS criteria also require the exclusion of secondary headache disorders (Section E, Table 209-2) in one of several ways. Therefore, migraine is both a diagnosis of inclusion, as specific combinations of symptoms are required, and a diagnosis of exclusion, as alternative causes of headache must be systematically eliminated. Migraine With Aura (Classic Migraine)

The diagnosis of migraine with aura (1.2) requires at least two attacks with any three of the following four features: one or more fully reversible aura symptoms indicating brain dysfunction, aura developing over more than 4 minutes, aura lasting less than 60 minutes, and headache following aura with a free interval of less than 60 minutes (Table 209-3). If the first three criteria are met, migraine with aura can be diagnosed even in the absence of headache. Fewer attacks are required than for migraine without aura, based on the assumption that typical aura is highly specific for migraine. Other causes of this symptom complex must once again be excluded. To use these criteria effectively, the clinician must make judgments about what features meet the criterion “one or more fully reversible aura symptoms indicating brain dysfunction.” For example, if a patient sees spots of light for 10 seconds while climbing stairs during a headache, this “neurological” event arguably meets criteria B1, B3, and B4 (Table 209-3). Recurrence

TAW 209-3. Migraine with Aura: International Headache Society Criteria Diagnostic criteria: A. At least 2 attacks fulfilling item 6. 6. At least 3 of the following 4 characteristics: 1. One or more fully reversible aura symptoms indicate brain dysfunction. 2. At least one aura symptom develops gradually over more than 4 minutes or 2 or more symptoms occur in succession. 3. No single aura symptom lasts more than 60 minutes. 4. Headache follows aura with a free interval of less than 60 minutes (it may also begin before or simultaneously with the aura). C. History, physical examination and, where appropriate, diagnostic tests exclude a secondarv cause.

Chapter 209

on two occasions might qualify the patient for a diagnosis of migraine with aura. Similarly, 30 seconds of isolated tinnitus during a headache on two occasions may be judged to be migraine with aura. Most experienced clinicians would agree that these symptoms do not warrant a diagnosis of migraine with aura. More specific diagnostic criteria therefore are needed. Migraine with aura is subdivided into migraine with typical aura (1.2.1;homonymous visual disturbance, unilateral numbness or weakness, or aphasia), migraine with prolonged aura (1.2.2; aura lasting more than 60 minutes), familial hemiplegic migraine (1.2.3), basilar migraine (1.2.4), migraine aura without headache (1.2.5), and migraine with acute-onset aura (1.2.6). Other varieties of migraine include ophthalmoplegic (1.3), retinal (1.4), and childhood periodic syndromes (1.5). The descriptive features of most of these syndromes are reviewed in the previous section. Focal symptoms and signs of the aura may persist beyond the headache phase. The IHS classification has introduced two more specific diagnostic categories, formerly called complicated migraine. If the aura lasts for more than 1 hour but less than 1 week, the term migraine with prolonged aura is applied. If the signs persist for more than 1 week or neuroimaging demonstrates a stroke, a diagnosis of migrainous infarction is assigned. Particularly in middle or late life, the aura may occur without headache; it is then considered a migraine equivalent (migraine aura without headache [ 1.2.51).

Migrainous Headache The IHS defines a group of people who fulfill all criteria for migraine but one (IHS 1.7). This group is sometimes described as having migrainous headache. Patients in this group may have many different patterns. For example, a patient with otherwise typical migraine without aura with fewer than five lifetime attacks or with headache duration of less than 4 hours is classified here. A patient with typical pain features associated with photophobia or phonophobia (but not both) in the absence of nausea or vomiting also belongs in this category. Features that are not part of the IHS criteria may help support the diagnosis. These features include the presence of a typical premonitory phase, osmophobia, and an accurate family history of migraine in one or more first-degree relatives. Relief with sleep, exacerbation during menses, and the presence of dietary triggers (alcohol, tyramine-containing foods, chocolate) may also add diagnostic confidence in these atypical cases.

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TAW 209-4. Alarms in the Diagnosis of Headache Disorders Headache Alarm

Headache beginning after age 50 Sudden-onset headache

Accelerating pattern of headaches New-onset headache in a patient with cancer or human immunodeficiency virus Headache with systemic illness (fever, stiff neck, rash) Focal neurologic symptoms or signs of disease (other than typical aura)

Selected Diagnostic Considerations

Temporal arteritis, mass lesion Subarachnoid hemorrhage, pituitary apoplexy, bleed into a mass or arteriovenous malformation, mass lesion (especially posterior fossa) Mass lesion, subdural hematoma, medication overuse Meningitis (chronic or carcinomatous), brain abscess (including toxoplasmosis, metastasis)

Possible Workup

Erythrocyte sedimentation rate, neuroimaging Neuroimaging, lumbar puncture

Neuroimaging, drug screen Neuroimaging, lumbar puncture

Meningitis, encephalitis, Neuroimaging, lumbar puncLyme disease, systure, blood tests temic infection, collagen, vascular disease Mass lesion, arterioveNeuroimaging,collagen vascular nous malfunction, stroke, collagen vasevaluation cular disease (including antiphospholipid antibodies) Neuroimaging, Papilledema Mass lesion, pseudotulumbar puncture mor, meningitis Based on Silberstein SD, Lipton RB, Coadsby PJ: Headache in Clinical Practice. lsis Medical Media, London, 1998.

evaluation is negative, the clinician then attempts to diagnose a specific primary headache disorder. If the patient has no alarms and meets criteria for a primary headache disorder, treatment often is initiated without additional diagnostic tests other than those dictated by the choice of treatment. Several recent studies suggest that in headache patients without alarms by history or examination, routine computed tomography and magnetic resonance imaging have extraordinarily low yields. If headache alarms are present, if patients do not fit neatly into established diagnostic categories, or if response to treatment is atypical, then the diagnosis should be revisited and neuroimaging should be considered. Some important causes of secondary headaches that simulate migraine are listed in Table 209-5.

DIFFERENTIAL DIAGNOSIS For patients presenting with a history of recurrent, temporarily disabling headaches, migraine is the most likely diagnosis. Nonetheless, the primary care physician must consider the myriad conditions that can cause secondary headache and then diagnose a specific primary headache disorder. In approaching this problem, the clinician looks for diagnostic alarms, and a directed workup is undertaken to determine whether an underlying condition is present. The patient’s medical history provides a context for evaluating new headaches. The likely diagnoses in a previously well 30-year-old with new-onset headache are quite different from those in a 30-year-old with acquired immunodeficiency syndrome or cancer. Table 209-4 summarizes some important alarms, the diagnostic concerns they raise, and the initial diagnostic evaluations that should be considered. If alarms are absent or the diagnostic

Secondary Headaches Headache is a common feature in transient ischemic attacks, thromboembolic stroke, and intracerebral hemorrhage. Like migraine with aura, these syndromes may be characterizedby focal neurologic symptoms associated with headache. In general, migraine begins in adolescence or early adult life, whereas stroke tends to occur with advancing years, simplifying the diagnostic problem. Most patients with stroke are not difficult to diagnose. For example, an older hypertensive man with a single episode of headache associated with the onset of a persistent neurologic symptoms and an appropriate abnormality on neuroimaging has stroke and not migraine. On rare occasions, stroke may develop as a sequel of prolonged but otherwise typical migraine aura (migrainous infarction). In addition, the antiphospholipid antibody syndromes (anticardiolipin antibody syndrome or lupus

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TABLE209-5. Selected Secondary Headaches in the Differential Diagnosis of Migraine Cerebrovascular disease Thrombotic or embolic stroke lntracerebral hemorrhage Transient ischemic attack Subarachnoid hemorrhage Subdural hematoma Arteriovenous malformation Carotid or vertebral dissection Venous thrombosis Cranial vasculitis (i.e., giant cell arteritis, systemic lupus erythematosus) Other neurologic disorders Primary or metastatic tumor Other mass lesions (i.e., brain abscess, granulomatous disease) Pseudotumor cerebri Epilepsy Chronic meningitis (i.e., Lyme) Parkinson’s disease Post-traumatic headache Toxic or metabolic systemic disorders Vasodilators (e.g., nitrates, nitrites, calcium channel blockers) Respiratory disturbance (hypoxia or hypercarbia) Hypoglycemia Fever and other systemic disease Other medications (tetracycline, caffeine, fluoxetine, trazodone, vitamin A, indomethacin) Disease of the cranium, neck, eyes, and skull Posterior fossa and cervical spine malformations Acute sinusitis Glaucoma Temporomandibular joint syndrome

anticoagulant) with or without systemic lupus erythematosus may predispose to both migraine-like headaches and cerebrovascular disease. Patients with atypical or prolonged aura should be evaluated for antiphospholipid antibody syndromes with a partial thromboplastin time and anticardiolipin antibody titers. Mitral valve prolapse and oral contraceptives may account for some strokes that occur in patients with migraine. Transient ischemic attacks, if accompanied by headache, and migraine with aura can be difficult to distinguish. Several features can facilitate differential diagnosis. Transient ischemic attacks are characterized primarily by negative features, such as weakness, numbness, or visual loss. A mix of positive and negative features often characterizes migraine with aura. In transient ischemic attacks the symptoms evolve quickly. In migraine, symptoms often spread slowly over a number of minutes before reaching their maximum distribution. In addition, the classic aura syndromes of migraine (e.g., the scintillating scotoma) are rarely caused by transient ischemic attacks, and classic features of transient ischemic attacks (e.g., amaurosis fugax) are rarely caused by migraine. Nonetheless, diagnostic evaluations to exclude cerebrovascular disease often are necessary. Subarachnoid hemorrhage enters the differential diagnosis of new or recent-onset migraine. Severe headache, neck stiffness, nausea, and vomiting are features of both conditions. The typical patient with a subarachnoid hemorrhage, exhibiting the paroxysmal onset of a devastating headache and nuchal rigidity, usually receives the necessary diagnostic evaluation with computed tomography and lumbar puncture. This is particularly true for patients with persistent neurologic symptoms. However, patients with diagnosed subarachnoid hemorrhage often report one or two headaches of sudden onset before diagnosis. These sentinel headaches probably represent warning bleeds, which precede the major bleed. Often, patients with sentinel headache are sent out of

emergency rooms and physicians’ offices with the diagnosis of migraine. Because early diagnosis and surgical clipping of an underlying aneurysm can save lives, these missed diagnostic opportunities are important. Several features facilitate the differential diagnosis of subarachnoid hemorrhage and migraine. Whereas migraine pain typically intensifies over 30 minutes to 2 hours, the headache of subarachnoid hemorrhage begins suddenly and is often maximal at onset. If patients are able to report exactly what they were doing at the precise moment the headache began, suspect subarachnoid hemorrhage. In migraine, neck stiffness is common but meningismus is rare. In subarachnoid hemorrhage, there is often true meningismus, but it can take several hours to develop. Syncope or near syncope at onset, the worst headache ever, and persistent neurologic symptoms (i.e., third nerve palsy) all suggest subarachnoid hemorrhage. If the patient has had many similar attacks, subarachnoid hemorrhage becomes much less likely. The patient with a long history of migraine who develops the worst headache ever poses a serious diagnostic challenge. All migraineurs, sooner or later, have their worst headache. If that headache is of gradual onset and perfectly typical of their migraine, extensive diagnostic evaluation may be avoided. However, workup for subarachnoid hemorrhage is advisable if the headache is of sudden onset or atypical in its location and associated features. A number of vascular abnormalities can produce headaches that resemble migraine. Arteriovenous malformations may mimic migraine. The headache tends to occur on the side of vascular malformation. Dural arteriovenous malformations may also produce migraine-like headaches. These conditions can sometimes be detected by auscultation of the skull, listening for a cranial bruit. Carotid dissection causes pain that radiates to the eye or temple, often associated with an ipsilateral Horner’s syndrome and visual symptoms. A history of neck trauma is sometimes present. Workup of the suspected vessels by magnetic resonance angiography usually can spare the patient an assessment with cerebral angiography. Arteritis produces headache with neurologic symptoms. The vasculitis that most seriously enters into the differential diagnosis of migraine is systemic lupus erythematosus, with the overlapping antiphospholipid antibody syndromes discussed earlier. The rare disorder, primary vasculitis of the nervous system, produces multifocal neurologic defects and headache, often in young adults. Diagnosis entails cerebral angiography and, at times, meningeal or cortical biopsy. Systemic tests for vasculitis are negative in this condition. Giant cell arteritis rarely begins before age 55. The diagnosis usually is not difficult when systemic features are present, such as polymyalgia rheumatica, jaw claudication, tender temporal arteries with decreased pulses, anemia, and weight loss. The headache in giant cell arteritis has no characteristic pattern and can resemble migraine. It tends to be in one or both temples and associated with a tender temporal artery. When giant cell arteritis is suspected, a high erythrocyte sedimentation rate warrants high-dose prednisone (60 mg daily) pending temporal artery biopsy. Headaches associated with mass lesions of all kinds may be unilateral (often on the side of the mass), with episodic exacerbations as well as nausea and vomiting. In this setting, headaches more often resemble tension-type headache than migraine. Episodic exacerbations of headache may be associated with transient elevations of intracranial pressure caused by plateau waves or transient obstruction of the cerebrospinal fluid pathways.

Chapter 209

In pseudotumor cerebri, there is an idiopathic elevation of intracranial pressure, often associated with papilledema. The differential diagnosis of migraine and epilepsy can be challenging. Both conditions may produce episodic neurologic symptoms as well as headache. Migraine-like headaches and epilepsy occur together in the same person with a frequency much greater than chance. Migraine aura can trigger seizures under certain circumstances. Seizures can activate the trigeminovascular system to produce ictal and postictal headache. Several features are helpful in differential diagnosis. Seizures typically produce positive symptoms such as tonic-clonic movements or tinghg; migraine aura often produces a mix of positive and negative symptoms. In addition, the interictal electroencephalogram is more likely to show spikes in patients with epilepsy than migraine. The ictal electroencephalogram shows characteristic sequences of spikes or sharp waves, which change in frequency and amplitude (electroencephalographic seizure pattern) during seizures. These changes generally do not occur with migraine. Finally, both conditions can and do occur in the same patient. A number of medications and recreational drugs can trigger headaches. The key to diagnosis is to discover the association between their use and the onset of the headache disorder. Nitrites, nitrates, certain calcium channel blockers, caffeine, tetracycline, monosodium glutamate, certain antihypertensives,and indomethacin can all cause headaches de novo. Many of these agents may also exacerbate an underlying headache disorder such as migraine. The same agents used to treat headache may exacerbate headache through the mechanisms of medication rebound. Cocaine intoxication and cocaine withdrawal can precipitate headache. A number of metabolic derangements may also cause headache. Hypoxia, hypercapnia, hypoglycemia, fever, and a number of systemic diseases, such as viremia, may produce throbbing headache. Acute sinusitis, glaucoma, and post-traumatic headache all enter into the differential diagnosis of migraine. Primary Headaches A number of primary headache disorders should be considered in the differential diagnosis of migraine. For the major categories of

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primary headache, the keys to differential diagnosis are summarized in Table 209-6. The headaches of cluster headache are of shorter duration and have a radically different temporal profile than migraine, with distinct associated autonomic features such as ipsilateral lacrimation, rhinorrhea, and ptosis. Features that distinguish it from migraine define tension-type headache. In pure cases with bilateral nonpulsatile pain and no associated features, diagnosis is not difficult. Differential diagnosis can be challenging in patients with both migraine and tension-type headache and in patients who have headaches with intermediate characteristics. In transformed migraine, patients initially experience typical episodic migraine. Over a period of months to years, headaches gradually increase in frequency but decrease in intensity, leaving the patient with near-daily headaches of mild or moderate intensity, occasionally punctuated by attacks of more severe headache. The daily headaches often resemble tension-type headache. The more severe attacks often meet criteria for migraine. The term transformed migraine is used for this clinical syndrome and encompasses both types of headache. In subspecialty clinics, in 80% of cases the process of transformation is associated with medication overuse and the development of rebound headaches. In population studies, 30% of transformed migraine sufferers overuse medication. Because this syndrome occurs in the absence of medication overuse, it may represent the natural history of a particularly pernicious part of the migraine spectrum. In patients taking analgesics or ergots daily, successful treatment entails breaking the pattern of daily medication use. If the patient emphasizes the daily headache disorder and the physician fails to inquire about the pattern of evolution, transformed migraine often is missed. Occasionally, rare primary headache disorders are mistaken for migraine. In hemicrania continua, there is a constant unilateral pain that waxes and wanes in intensity. During exacerbations, pain usually is associated with autonomic features resembling those of cluster headache (Horner’s syndrome, lacrimation, rhinorrhea), but nausea and photophobia may occur. Patients may describe their exacerbations but not their background pain, giving the impression of an episodic disorder rather than a waxing and waning continuous disorder. The pain goes away completely in

TAW 209-6. Primary Headache in the Differential Diagnosis of Migraine Headache Type

Typical Age of Onset (Years)

Migraine

5-40

Cluster

Tension-type

10-40

5-50

Frequency andnming

Severity

Quali

Associated Features

Variable

Moderatesevere

Throbbing > steady ache

30-1 20 min

1-8 times

Excruciating

Boring, piercing

30 min to 7+

per day, nocturnal attacks Variable

Dull ache,

Viselike, bandlike pressure Variable

Nausea, vomiting, photophobia, phonophobia, osmophobia, aura ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, miosis Generally none

location

Duration

Hemicranial

Several hours to 3 days

Unilateral, periorbital, or retroorbitaI Bilateral

days Transformed migraine

10-50

Variable

Usually >4 hr

Hemicrania continua

10-50

Hemicranial

Constant

Progressive frequency to 15+ days per month Constant

may wax and wane Variable

Waxes and wanes

Variable

Less severe attacks lack associated features Medication overuse common During exacerbations, ipsilateral autonomic features resembling cluster

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migraine but not in hemicrania continua or transformed migraine. The syndromes of benign cough headache or benign exertional headache are occasionally confused with migraine. The headaches are of paroxysmal onset and short duration (often minutes) brought on by coughing, sneezing, lifting, straining, or Valsalva maneuvers of other kinds. Similar paroxysmal onset headaches are triggered by sexual activity. Although these headaches are usually benign, subarachnoid hemorrhage, mass lesions, and other disorders, especially of the posterior fossa, must be considered in the differential diagnosis. A clear history of the temporal relationship to the provoking stimulus is the key to distinguishing these headaches from migraine.

Campbell JK, Saki F Migraine: diagnosis and differential diagnosis. pp. 359-363. In Olesen J, Tfelt-Hansen P, Welch KMA (eds): The Headaches. 2nd Ed. Raven Press, New York, 2000 Goadsby PJ, Lipton RB, Ferrari MD: Migraine: Current understanding and treatment. N Engl J Med 364:257-270, 2002 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):l-96, 1988 Rasmussen BK, Olesen J: Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 12221-228, 1992 Silberstein SD, Lipton RB, Goadsby PJ: Headache in Clinical Practice. Martin Dunitz, London, 2002 Silberstein SD, Saper JR, Freitag F G Migraine: diagnosis and treatment. pp. 121-238. In Silberstein SD, Lipton RB, Dalessio DJ (eds):Wolff‘s Headache. 7th Ed. Oxford University Press, New York, 2001

SUGGESTED READINGS Blau J N Headache: history, examination, differential diagnosis and special investigations. pp. 43-58. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 48. Elsevier, New York, 1986

210 Neurologic Symptoms of Migraine Egilius L. H. Spierings The neurologic symptoms of migraine are transient in nature, which means that they are fully reversible. If they are not fully reversible, they are either not migraine related or they represent a complication of migraine. As complications of migraine, the International Headache Society lists in its classification: 1.6.1 Status migrainosus, that is, a migraine headache lasting longer than 72 hours despite treatment 1.6.2 Migrainous infarction, that is, an attack of migraine with aura in which the neurologic symptoms are not fully reversible within 7 days or neuroimaging demonstrates ischemic infarction of a relevant brain area.

MIGRAINE AURA STATUS Status migrainosus is not a true complication of migraine but rather a migraine headache that is beyond spontaneous resolution. The suggested time span of 72 hours is both arbitrary and too short; menstrual migraine headaches often last longer than that and still reverse spontaneously. Migrainous infarction can also occur as a complication of migraine without aura. In fact, a prospective stroke registry study of 3502 patients with ischemic stroke identified 27 cases of stroke that occurred during a migraine attack. Of the migraine attacks involved, 59% were without aura and 41% with aura. The neurologic symptoms of migraine can last beyond 7 days without being associated with cerebral infarction. This is the case with migraine aura status, characterized by the continuation of aura symptoms beyond their usual duration. Aura symptoms of migraine usually last less than 1 hour and often approximately 20 minutes. The International Headache Society speaks of prolonged aura when the symptoms last longer than 1 hour. However, they could be called migraine aura status when they last longer than 24 hours. This time boundary, although

equally arbitrary, at least parallels that used to distinguish transient ischemic attack from stroke. The following case study illustrates migraine aura status: A 41 -year-old man had experienced headaches since childhood. The headaches occurred 12 to 15 times per year, often in flurries. They were always preceded by a visual disturbance, which lasted for 20 or 40 minutes. The visual disturbance consisted of bright white, flickering zigzag lines (“white snakes”) in the periphery of both visual fields. It developed over 5 to 10 minutes and was immediately followed by headache. The headache built to its maximum intensity as the visual disturbance faded away and lasted for one half to 1 hour, treated with a nonprescription analgesic. The headache was severe, located in the anterior vertex as a throbbing pain, and was associated with photophobia. In October 1996, the patient was watching President Clinton’s reelection on TV, which upset him greatly. He subsequently developed the visual disturbance as just described but much more intense. It came along with tingling of the left arm and hand, which developed without a march and lasted for 15 to 30 minutes. It was associated with severe headache, photophobia, and a general sense of weakness. In addition, he was confused and kept repeating the same sentence. The visual disturbance has been present since and makes him see everything as if through a veil. The “white snakes” in the periphery of both visual fields come and go. Cranial magnetic resonance imaging was normal, particularly without evidence of cerebral infarction.

STROKE IN MIGRAINE Migraine is an uncommon cause of stroke; it is not considered a major stroke risk factor, which, in order of decreasing importance, are: hypertension, cardiac disease, atrial fibrillation, diabetes mellitus, cigarette smoking, and heavy alcohol use. The stroke risk

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migraine but not in hemicrania continua or transformed migraine. The syndromes of benign cough headache or benign exertional headache are occasionally confused with migraine. The headaches are of paroxysmal onset and short duration (often minutes) brought on by coughing, sneezing, lifting, straining, or Valsalva maneuvers of other kinds. Similar paroxysmal onset headaches are triggered by sexual activity. Although these headaches are usually benign, subarachnoid hemorrhage, mass lesions, and other disorders, especially of the posterior fossa, must be considered in the differential diagnosis. A clear history of the temporal relationship to the provoking stimulus is the key to distinguishing these headaches from migraine.

Campbell JK, Saki F Migraine: diagnosis and differential diagnosis. pp. 359-363. In Olesen J, Tfelt-Hansen P, Welch KMA (eds): The Headaches. 2nd Ed. Raven Press, New York, 2000 Goadsby PJ, Lipton RB, Ferrari MD: Migraine: Current understanding and treatment. N Engl J Med 364:257-270, 2002 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):l-96, 1988 Rasmussen BK, Olesen J: Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 12221-228, 1992 Silberstein SD, Lipton RB, Goadsby PJ: Headache in Clinical Practice. Martin Dunitz, London, 2002 Silberstein SD, Saper JR, Freitag F G Migraine: diagnosis and treatment. pp. 121-238. In Silberstein SD, Lipton RB, Dalessio DJ (eds):Wolff‘s Headache. 7th Ed. Oxford University Press, New York, 2001

SUGGESTED READINGS Blau J N Headache: history, examination, differential diagnosis and special investigations. pp. 43-58. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol. 48. Elsevier, New York, 1986

210 Neurologic Symptoms of Migraine Egilius L. H. Spierings The neurologic symptoms of migraine are transient in nature, which means that they are fully reversible. If they are not fully reversible, they are either not migraine related or they represent a complication of migraine. As complications of migraine, the International Headache Society lists in its classification: 1.6.1 Status migrainosus, that is, a migraine headache lasting longer than 72 hours despite treatment 1.6.2 Migrainous infarction, that is, an attack of migraine with aura in which the neurologic symptoms are not fully reversible within 7 days or neuroimaging demonstrates ischemic infarction of a relevant brain area.

MIGRAINE AURA STATUS Status migrainosus is not a true complication of migraine but rather a migraine headache that is beyond spontaneous resolution. The suggested time span of 72 hours is both arbitrary and too short; menstrual migraine headaches often last longer than that and still reverse spontaneously. Migrainous infarction can also occur as a complication of migraine without aura. In fact, a prospective stroke registry study of 3502 patients with ischemic stroke identified 27 cases of stroke that occurred during a migraine attack. Of the migraine attacks involved, 59% were without aura and 41% with aura. The neurologic symptoms of migraine can last beyond 7 days without being associated with cerebral infarction. This is the case with migraine aura status, characterized by the continuation of aura symptoms beyond their usual duration. Aura symptoms of migraine usually last less than 1 hour and often approximately 20 minutes. The International Headache Society speaks of prolonged aura when the symptoms last longer than 1 hour. However, they could be called migraine aura status when they last longer than 24 hours. This time boundary, although

equally arbitrary, at least parallels that used to distinguish transient ischemic attack from stroke. The following case study illustrates migraine aura status: A 41 -year-old man had experienced headaches since childhood. The headaches occurred 12 to 15 times per year, often in flurries. They were always preceded by a visual disturbance, which lasted for 20 or 40 minutes. The visual disturbance consisted of bright white, flickering zigzag lines (“white snakes”) in the periphery of both visual fields. It developed over 5 to 10 minutes and was immediately followed by headache. The headache built to its maximum intensity as the visual disturbance faded away and lasted for one half to 1 hour, treated with a nonprescription analgesic. The headache was severe, located in the anterior vertex as a throbbing pain, and was associated with photophobia. In October 1996, the patient was watching President Clinton’s reelection on TV, which upset him greatly. He subsequently developed the visual disturbance as just described but much more intense. It came along with tingling of the left arm and hand, which developed without a march and lasted for 15 to 30 minutes. It was associated with severe headache, photophobia, and a general sense of weakness. In addition, he was confused and kept repeating the same sentence. The visual disturbance has been present since and makes him see everything as if through a veil. The “white snakes” in the periphery of both visual fields come and go. Cranial magnetic resonance imaging was normal, particularly without evidence of cerebral infarction.

STROKE IN MIGRAINE Migraine is an uncommon cause of stroke; it is not considered a major stroke risk factor, which, in order of decreasing importance, are: hypertension, cardiac disease, atrial fibrillation, diabetes mellitus, cigarette smoking, and heavy alcohol use. The stroke risk

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factor involved in heavy alcohol use is dehydration, a factor that may also play a role in migraine as a cause of stroke. I define “complicated migraine” as an attack of migraine with or without aura complicated by ischemic stroke, as shown on neuroimaging. The following case study illustrates complicated migraine defined as such: A 30-year-old woman had experienced headaches since age 16, when she hit a tree riding a motorbike. The headaches occurred seven or eight times per year and usually came on in the late afternoon. They gradually built in intensity to reach their maximum in the early evening, forcing her to retire early. The headaches were located in the right temple and were throbbing. They were not associated with nausea, vomiting, photophobia, or phonophobia. One early evening, she retired with a headache but then became nauseated and vomited throughout the night. She also noticed tingling in the left side of her body. The next morning she had difficulty seeing off to the left with either eye. The headache and tingling persisted for the entire day. On examination, she had a left homonymous hemianopia with sparing of central vision. Cranial computed tomography without contrast revealed an infarct in the territory of the right calcarine artery. Angiography showed irregular narrowing of the right posterior cerebral artery, suggestive of vasospasm (Fig. 210- 1). Complicated migraine is not a stroke occurring in a patient with a history of migraine, as is illustrated by the following case study: A 30-year-old woman with an 8-year history of migraine without aura was admitted because of cough, fever, blood-stained

FIG. 210-2. Cranial computed tomogram showing a deep infarct in the left hemisphere, involving the internal capsule and lentiform nucleus (arrows), in a migraine patient with Mycoplasma pneumoniae infection complicated by intravascular coagulation.

sputum, shortness of breath, and chest pain. The examination was normal except for a slightly elevated temperature of 37.9OC and tachycardia, with a pulse rate of 120/minute. The sedimentation rate was significantly elevated at 96 mm/hour, with a normal leukocyte count of 7.4 x 109/L.Chest radiographs showed diffuse infiltrates in both lungs. She was treated with amoxicillin,trimethoprim, and sulfamethoxazole,on which she improved clinically. A week later, while still admitted, she suddenly developed a rightsided hemiparesis and motor aphasia with preserved comprehension. Cranial computed tomography showed a deep infarct in the left hemisphere involving the internal capsule and lentiform nucleus (Fig. 210-2). Angiography revealed total occlusion of the left middle cerebral artery near the bifurcation, without irregularities of the vessel wall. On the day of the stroke, the antibody titer for Mycophma pneumoniae was significantly higher than on the day of admission, implying a recent infection. There was also a sharp rise in the plasma level of fibrin-fibrinogen degradation products, indicating intravascular coagulation as the cause of the stroke. Intravascular coagulation is a rare but documented complication of infection with Mycophma pneumoniae.

STROKE MECHANISMS IN MIGRAINE FIG. 210-1. Vertebral angiogram, showing vasospasm (arrows) of the right posterior cerebral artery in a patient with migraine (without aura) complicated by stroke. (Reproduced from Spierings, 1999.)

Cerebral vasospasm is the mechanism traditionally related to the aura symptoms of migraine. However, in 1958 Milner WXested that the aura symptoms are caused by a neurophysiologic phenomenon called spreading cortical depression. Although called

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“depression,” it is actually spreading cortical excitation, followed by prolonged depression of neuronal activity. Cerebral blood flow studies conducted since the 1980s have provided support for this view. Recent functional magnetic resonance imaging performed at Harvard Medical School further confirmed it. However, cerebral vasospasm may still be the mechanism involved in complicated migraine, as is also suggested by the preceding case study. Other mechanisms that probably play a role as well are dehydration from lack of fluid intake, vomiting, or diarrhea and platelet activation caused by increased levels of circulating catecholamines. The stroke in migraine typically occurs in the occipital lobe, and an explanation of its causation should account for this preferential location. It may relate to the decreased autoregulation present in this part of the brain, also making it the preferential site of hypertensive encephalopathy. The decreased autoregulation may be compensated for by increased sympathetic innervation of the posterior cerebral arteries. This could make the arteries particularly vulnerable to vasospasm resulting from excessive sympathetic activation. There is ample biochemical evidence pointing to activation of the sympathetic nervous system during migraine headache. In my experience, complicated migraine occurs particularly during severe and prolonged migraine headaches.

MIGRAINE AURA SYMPTOMS In the International Headache Society classification, migraine is subdivided into: Migraine without aura Migraine with aura Ophthalmoplegic migraine Retinal migraine Periodic syndromes of childhood Complications of migraine The two most common migraine presentations are migraine without and with aura. The only difference between the two is that in migraine with aura, the attacks are preceded by transient focal neurologic symptoms. These symptoms are almost always sensory in nature: They are visual in most cases and somatosensory in the minority. In addition, it is rare for the somatosensory symptoms to occur by themselves; they usually follow an occurrence of the visual symptoms. The typical visual aura of migraine is the scintillating scotoma, also called teichopsia or fortification spectra (Fig. 210-3). It usually begins near the center of vision as a twinkling star, which develops into a circle of bright and sometimes colorful flickering zigzag lines. Subsequently, the circle opens up on the inside to form a semicircle or horseshoe, which further expands into the periphery of one or the other visual field. On the inside of the visual disturbance, a band of dimness follows in the wake of the crescent of flickering zigzag lines. The visual disturbance ultimately disappears as it fades away in or moves out of the visual field in which it developed. The typical presentation of the somatosensory disturbance of migraine consists of digitolingual or cheiro-oral paresthesias (Fig. 210-3). It concerns a sensation of numbness or tingling that typically starts in the fingers of one hand, extends upward into the arm and, at a certain point, also involves the nose-mouth area on the same side. The progression of the somatosensory disturbance, like that of the scintillating scotoma, is slow and usually takes 10 to 30 minutes. A similarly progressing somatosensory disturbance

FIG. 210-3. Scintillating scotoma (top) and digitolingual paresthesias (bottom), shown from left to right in their successive stages of

development.

can also occur with stroke, although this is rare. What differentiates one from the other is the resolution of the disturbed sensation, to which the first-last rule applies: In migraine, what is involved first resolves first, whereas in stroke, what is involved first resolves last. This particular difference relates to the different mechanisms involved, which is spreading cortical excitation and depression in migraine and ischemic corticoneuronal dysfunction in stroke. The digitolingual paresthesias in migraine are always unilateral and should be differentiated from the bilateral tingling in the hands and around the mouth typical for hyperventilation syndrome. The tingling sometimes is so intense that the involved extremity is perceived as weak, but examination disproves this. If real muscle weakness exists, the condition is that of either hemiplegic migraine or migrainous infarction.

MIGRAINE AURA WITHOUT HEADACHE The International Headache Society classification recognizes several subdivisions of migraine with aura: 1.2.1 Migraine with typical aura 1.2.2 Migraine with prolonged aura 1.2.3 Familial hemiplegic migraine 1.2.4 Basilar migraine 1.2.5 Migraine aura without headache 1.2.6 Migraine with acute onset aura As mentioned, the typical aura lasts less than 1 hour, often approximately 20 minutes, and the prolonged aura 1 to 24 hours. The International Headache Society classification does not recognize migraine aura status as a form of migraine with aura. Acute-onset aura probably is more a reflection of a hurried physician taking the history than a hurried onset of the aura symptoms. In clinical practice, probably the most important subtype of migraine with aura is that of migraine aura without headache, also called isolated migraine aura. In particular in the

Chapter 210 rn Neurologic Symptoms of Migraine

older “stroke-age”patient, it is an important differential diagnosis of transient ischemic attack. The following case studies illustrate migraine aura without headache: A 32-year-oldwoman in the final months of pregnancy experiences a visual disturbance. The disturbance consists of a shiny light close to the center of vision, which develops into a twinkling star. The star opens on the inside to give rise to a semicircle of scintillating, gold and silver zigzag lines. The semicircle gradually expands as it moves into one of the visual fields and subsequently fades away. The visual disturbance lasts for 10 to 15 minutes. It is not associated with or followed by headache or any other symptom. A 39-year-old woman has experienced a visual disturbance for 2 years. The disturbance starts with a cloud appearing in front of the left eye. After 5 minutes, a bowed line of bright and flickering zigzag lines appears in the upper quadrant of the left visual field. The bowed line, which gives the impression of being electrified, disappears after 30 minutes as abruptly as it starts. She has the visual disturbance once per month and feels completely exhausted afterward, but headache is absent. As mentioned, migraine aura without headache is an important differential diagnosis of transient ischemic attack. The following case study illustrates the features of this condition: A 47-year-old man experiences two types of attacks. The first type consists of loss of feeling in the right hand and forearm, which comes on within 10 seconds. The loss of feeling is associated with weakness and clumsiness. The attacks occur two or three times per week and last for 2 to 5 minutes. He has experienced them for 4 or 5 months. The second type of attack consists of loss of peripheral vision in the left eye. The loss of vision is concentric and gray rather than black. It develops in 5 to 10 minutes and lasts for 15 to 30 minutes. This type of attack he has experienced for 3 weeks. On examination, he has a high-pitched bruit in the neck over the left carotid artery. Angiography reveals a stenosis of more than 90% at the origin of the internal carotid artery (Fig. 210-4). A rare condition with a somewhat similar presentation to migraine aura without headache is focal, temporal or occipital lobe epilepsy. The following case study illustrates the features of this condition: A 23-year-old woman experiences fear of entering supermarkets because she fainted twice while shopping in one. Before the fainting, she experienced tingling, which lasted for seconds and moved very rapidly from the right hand to the lower arm and from there to the shoulder. She subsequently lost consciousnessand woke up, lying on the floor. She did not bite her tongue or lose urine. Electroencephalography and cranial computed tomography with contrast were normal.

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steady. The headaches can be located on one side or the other, with a preference for the right side of the head. They often begin in the side of the nose and extend from there to behind the eye. Sometimes the headaches begin in the back of the neck. They are associated with photophobia and phonophobia and with throbbing in the temple on the side of the pain. When the headaches start during the day, a feeling of weakness in the ipsilateral arm and hand precedes them. The weakness is not associated with loss of feeling, numbness, or tingling. It begins 1 hour before the onset of headache and lasts for its full duration. Basilar (artery) migraine, similar to hemiplegic migraine, is a rare condition that affects mostly young adults. In basilar migraine, the aura symptoms originate from the brainstem and often are alarming, such as double vision, bilateral numbness or tinghng, or drowsiness. The condition must be differentiated from migraine associated with hyperventilation or vasovagal lability. Symptoms of hyperventilation are lightheadedness and a feeling of numbness or tingling in both hands and around the mouth; those of vasovagal lability are lightheadedness and seeing black before the eyes. The following case study illustrates basilar (artery) migraine: A 22-year-old man has experienced headaches since age 9. The headaches occur once per month and last for 24 to 72 hours. They come on during the day and build to their maximum intensity in 1 or 2 hours. The headaches are located bilaterally in the temples and the sides of the head, usually worse on the right. They are severe, sharp, and pounding in the temples. The headaches are associated with nausea, photophobia, phonophobia, blurred vision, and vomiting to the point of dehydration. They are

HEMlPLEGlC AND BASllAR MIGRAINE Familial hemiplegic migraine is a rare (childhood) condition of recurrent headaches associated with hemiparesis. An additional prerequisite for the diagnosis is that at least one first-degree relative is affected by it as well. It also occurs in a nonfamilial form, which the International Headache Society does not recognize in its classification. It is important that the hemiparesis is not associated with paresthesias. Otherwise, the weakness can be caused solely by the somatosensory disturbance and does not necessarily imply motor involvement. The following case study illustrates nonfamilial hemiplegic migraine: A 37-year-old woman has experienced headaches since age 10. The headaches occur two or three times per month and last for 2 or 3 days. They are present on awakening in the morning or come on during the day. The headaches build to their maximum intensity in 1 hour. They are severe, sharp, and

FIG. 210-4. Carotid angiogram of a patient with transient ischemic attacks, showing a more than 90% stenosis at the origin of the internal carotid artery (arrow).

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headaches had occurred once per month and after that, two or three times per year. However, over the last 10 days he has experienced the headaches five times. The headaches come on during the day, usually in the afternoon. They build to their maximum intensity in 5 to 10 minutes and last for 6 to 12 hours. The headaches are located on the left, in the forehead and behind the eye. They feel like an intense pressure, and in half of them the pain is severe. The headaches are associated with photophobia and

FIG. 210-5. Cranial magnetic resonance scan, TI -weighted sagittal image, showing thickening and gadolinium enhancement of the oculomotor nerve (arrows). (From Mark AS, Casselman J, Brown D et al: Ophthalmoplegic migraine: reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-enhanced MR images. Am J Neuroradiol 19:1887-1891, 1998, with permission.)

also associated with lightheadedness, confusion, irritability, slurred speech, double vision, and impaired coordination. The latter symptoms begin 2 to 4 hours before the onset of headache and remain present for its full duration.

FIG. 210-6. Cranial magnetic resonance scan, TI -weighted coronal image, showing enlargement and gadolinium enhancement of the cavernous sinus (arrows). (From Alvarez de Arcaya A, Cerezal L, Canga A et al: Neuroimagingdiagnosis of Tolosa-Hunt syndrome: MRI contribution. Headache 39:321-325, 1999, with permission.)

OPHTHALMOPLEGIC MIGRAINE In this subtype of migraine, the headache overlaps with paresis of one or more of the cranial nerves 111, IV,and VI, with a parasellar lesion excluded by appropriate investigations. Ophthalmoplegic migraine is one of the so-called painful extraocular ophthalmoplegias. Other conditions that are grouped in this category are oculomotor neuropathy and Tolosa-Hunt syndrome. Oculomotor neuropathy is characterized by thickening and contrast enhancement of the oculomotor nerve on magnetic resonance imaging (Fig. 2 10-5). Tolosa-Hunt syndrome is a granulomatous inflammation of the cavernous sinus (Fig. 210-6), associated with elevated sedimentation rate and treated with corticosteroids. Painful intraocular ophthalmoplegias tend to be of a more ominous origin. Painful mydriasis typically is caused by an (expanding) aneurysm of the posterior communicating artery, compressing the oculomotor nerve. Painful miosis and ptosis are caused by lesioning of the pericarotid plexus, typically by dissection of the carotid artery in the neck. Retinal migraine is migraine with aura, with the aura being visual and monocular rather than homonymous. It is probably a very rare condition because I don’t remember having encountered it in two decades of dedicated headache practice.

SYMPTOMATIC MIGRAINE Symptomatic migraine is migraine (with or without aura) caused by structural neurologic illness. A typical cause of symptomatic migraine with aura is an occipital arteriovenous malformation, illustrated by the following case study: A 37-year-old man has experienced headaches since college. Until 5 years ago, the

FIG. 210-7. Cranial magnetic resonance scan, T1 -weighted transverse image, showing a large arteriovenous malformation of the left occipital lobe in a patient with symptomatic migraine with aura.

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followed up with neuroimaging, either computed tomography with contrast or magnetic resonance imaging. Important in symptomatic migraine without aura are fixed lateralization of the headache and progression over time. Fixed lateralization is a hallmark of headache conditions such as cluster headache, paroxysmal hemicrania, and hemicrania continua. With the exclusion of these conditions, a total lack of alternation should always be looked upon with suspicion of structural illness, although not necessarily neurologic. Nonneurologic causes of fixed lateralization include unilateral musculoskeletal abnormalities or rhinosinusitis.

CONCLUSION In summary, the neurologic symptoms of migraine are transient, that is, fully reversible, unless we are dealing with migraine aura status or migrainous infarction (complicated migraine). The neurologic symptoms exhibit positive features, that is, scintillations when visual and paresthesias when somatosensory. One should always look for side alternation of the neurologic symptoms, preferably independent of the headache, creating the “neurologic non-sense” of lateralized neurologic symptoms with ipsilateral headache.

SUGGESTED READINGS FIG. 210-8. Cranial computed tomogram with contrast, axial image, showing a meningioma on the right (arrows) in a patient with symptomatic migraine without aura. (From Spierings ELH: Differentiating headache from organic disease. Intern Med 9(10):106-131, 1988, with permission.)

occasionally also with nausea and vomiting. For 10 to 20 minutes, they are preceded by a visual disturbance, consisting of blue spots in the right visual field. The visual disturbance lasts for the duration of the headache. Bright light, overexertion, red wine, monosodium glutamate, and more than two cups of coffee bring on headache. Cranial magnetic resonance imaging reveals a large arteriovenous malformation of the left occipital lobe (Fig. 210-7). The significant feature in this case is the fixed and crossed lateralization of the aura symptoms and headache. This means that the aura symptoms always occur on one fixed side and the headache always on the opposite side. This clearly indicates the existence of structural neurologic illness and should always be

Alvarez de Arcaya A, Cerezal L, Canga A et al: Neuroimaging diagnosis of Tolosa-Hunt syndrome: MRI contribution. Headache 39:32 1-325, 1999

Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia S(supp1 7):l-96, 1988 Mark AS, Casselman J, Brown D et al: Ophthalmoplegic migraine: reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-enhanced MR images. Am J Neuroradiol 19:1887-1891, 1998 Milhaud D,-BogousslavskyJ, Van Melle G, Liot P Ischemic stroke and active migraine. Neurology 57:1805-1811, 2001 Milner P M Note on a possible correspondence between the scotomas of migraine and spreading depression of Lelo. Electroencephalogr Clin Neurophysiol 10705, 1958 Mulder LJMM, Spierings ELH Stroke due to intravascular coagulation in Mpneumoniae infection. Lancet 2:1152-1153, 1987 Spierings ELH:Acute and chronic hypertensive headache and hypertensive encephalopathy. Cephalalgia 22:3 13-3 16, 2002 Spierings ELH: Angiographic changes suggestive of vasospasm in migraine complicated by stroke. Headache 30:727-728, 1990

2 1 1 Pathogenesis of the Migraine Attack Egilius L. H. Spierings Migraine is a chronic condition of recurring attacks of transient focal neurologic symptoms, headache, or both. The headache is so intense that it interferes with the physical ability to function, sometimes necessitating bed rest, and it interferes with the functioning of other systems in the body, resulting in a plethora of associated symptoms. This interference occurs through activation of the sympathetic nervous system, and there is ample biochemical

evidence of heightened sympathetic activity during migraine headache (Fig. 211-1). The often most prominently affected system is the gastrointestinal tract, resulting in inhibition of its proximal and acceleration of its distal part. The ensuing nausea, vomiting, and diarrhea are common associated symptoms of the migraine headache. Another system that is affected by the increased sympathetic nervous system activity is the peripheral

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followed up with neuroimaging, either computed tomography with contrast or magnetic resonance imaging. Important in symptomatic migraine without aura are fixed lateralization of the headache and progression over time. Fixed lateralization is a hallmark of headache conditions such as cluster headache, paroxysmal hemicrania, and hemicrania continua. With the exclusion of these conditions, a total lack of alternation should always be looked upon with suspicion of structural illness, although not necessarily neurologic. Nonneurologic causes of fixed lateralization include unilateral musculoskeletal abnormalities or rhinosinusitis.

CONCLUSION In summary, the neurologic symptoms of migraine are transient, that is, fully reversible, unless we are dealing with migraine aura status or migrainous infarction (complicated migraine). The neurologic symptoms exhibit positive features, that is, scintillations when visual and paresthesias when somatosensory. One should always look for side alternation of the neurologic symptoms, preferably independent of the headache, creating the “neurologic non-sense” of lateralized neurologic symptoms with ipsilateral headache.

SUGGESTED READINGS FIG. 210-8. Cranial computed tomogram with contrast, axial image, showing a meningioma on the right (arrows) in a patient with symptomatic migraine without aura. (From Spierings ELH: Differentiating headache from organic disease. Intern Med 9(10):106-131, 1988, with permission.)

occasionally also with nausea and vomiting. For 10 to 20 minutes, they are preceded by a visual disturbance, consisting of blue spots in the right visual field. The visual disturbance lasts for the duration of the headache. Bright light, overexertion, red wine, monosodium glutamate, and more than two cups of coffee bring on headache. Cranial magnetic resonance imaging reveals a large arteriovenous malformation of the left occipital lobe (Fig. 210-7). The significant feature in this case is the fixed and crossed lateralization of the aura symptoms and headache. This means that the aura symptoms always occur on one fixed side and the headache always on the opposite side. This clearly indicates the existence of structural neurologic illness and should always be

Alvarez de Arcaya A, Cerezal L, Canga A et al: Neuroimaging diagnosis of Tolosa-Hunt syndrome: MRI contribution. Headache 39:32 1-325, 1999

Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia S(supp1 7):l-96, 1988 Mark AS, Casselman J, Brown D et al: Ophthalmoplegic migraine: reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-enhanced MR images. Am J Neuroradiol 19:1887-1891, 1998 Milhaud D,-BogousslavskyJ, Van Melle G, Liot P Ischemic stroke and active migraine. Neurology 57:1805-1811, 2001 Milner P M Note on a possible correspondence between the scotomas of migraine and spreading depression of Lelo. Electroencephalogr Clin Neurophysiol 10705, 1958 Mulder LJMM, Spierings ELH Stroke due to intravascular coagulation in Mpneumoniae infection. Lancet 2:1152-1153, 1987 Spierings ELH:Acute and chronic hypertensive headache and hypertensive encephalopathy. Cephalalgia 22:3 13-3 16, 2002 Spierings ELH: Angiographic changes suggestive of vasospasm in migraine complicated by stroke. Headache 30:727-728, 1990

2 1 1 Pathogenesis of the Migraine Attack Egilius L. H. Spierings Migraine is a chronic condition of recurring attacks of transient focal neurologic symptoms, headache, or both. The headache is so intense that it interferes with the physical ability to function, sometimes necessitating bed rest, and it interferes with the functioning of other systems in the body, resulting in a plethora of associated symptoms. This interference occurs through activation of the sympathetic nervous system, and there is ample biochemical

evidence of heightened sympathetic activity during migraine headache (Fig. 211-1). The often most prominently affected system is the gastrointestinal tract, resulting in inhibition of its proximal and acceleration of its distal part. The ensuing nausea, vomiting, and diarrhea are common associated symptoms of the migraine headache. Another system that is affected by the increased sympathetic nervous system activity is the peripheral

Headache and Pain rn Headache Syndromes and Their Treatment

1336

BIOCHEMICAL CHANGES DURING THE MIGRAINE HEADACHE /urinary 5-HIAA

I freeltotal plasma tryptophan 4 platelet 5 - H T ,

plasma dopamine- 6- hydroxylase (DBH 1

activation

/urinary VMA

U f adrcno-sympal he tic ac t i vit y

FIG. 211-1. A summary of the biochemical changes as observed during the migraine headache. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; 5-HIAA. 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine, or serotonin; VMA, 3-methoxy-4-hydroxymandelic acid. (Adapted from Spierings ELH: The pathophysiology of the migraine attack. Doctoral thesis, Erasmus University, Rotterdam, The Netherlands, 1980.)

circulation. The resulting vasoconstriction causes the characteristic facial pallor and coldness of the hands and feet. Increased arousal from the sympathetic nervous system activation is what results in the heightened sensitivity to sensory stimuli. With increasing headache intensity, heightened sensitivity to light, noise, smell, and touch develops. Relaxation of the muscle of accommodation contributes to the increased sensitivity to light. This muscle has a rudimentary sympathetic innervation, activation of which results in its relaxation. The ensuing symptoms are increased sensitivity to light, constriction of peripheral vision, and blurring of vision, particularly near vision. The transient focal neurologic symptoms of migraine are always sensory: They are visual in 95% and somatosensory in the remaining 5%. When occurring with headache, they generally precede the onset of the headache and therefore are also called aura symptoms. The typical presentation of the visual aura of migraine is the scintillating scotoma, also called teichopsia or fortification spectra (Fig. 21 1-2). The typical somatosensory aura of migraine consists of digitolingual or cheiro-oral paresthesias, a feeling of pins-and-needles experienced in a hand and arm and in the ipsilateral nose-mouth area (Fig. 21 1-2). The paresthesias sometimes are so intense that they suggest weakness; however, examination disproves this and normal strength is found with symmetrical tendon reflexes and absent pathologic reflexes. Rarely, an inability to speak of a dysphasic-dysarthric nature occurs. Motor symptoms should be viewed with great suspicion and necessitate further neurologic evaluation or imaging. When appearing with recurring headaches, they are often caused by cerebrovascular illness.

FIG. 2 1 1-2. Scintillating scotoma (fop)and digitolingual paresthesias (bottom), shown from left to right in their successive stages of development.

PATHOGENESIS OF THE MIGRAINE HEADACHE Traditional thinking attributes the migraine headache to vasodilation in the cerebral circulation. However, in the first half of the 20th century, evidence emerged discrediting this view. In addition,

Chapter 21 1

evidence was provided that the vasodilation of the migraine headache occurs in the extracranial circulation, in particular affecting the frontal branch of the superficial temporal artery (Fig. 211-3). Additional evidence for this view emerged in 1990, when it was published that there is relative dilation of the ipsilateral temporal artery during the migraine headache (Fig. 211-4). The dilation is relative because of the generalized vasoconstriction that occurs, caused by the increased activity of the sympatheticnervous system. Recently, it was also confirmed that migraineurs have dilated temporal arteries between attacks, making them vulnerable to headache (Fig. 21 1-5). The present focus on dural or meningeal vasodilation is based on animal experimental research only. The research relates to the plasma extravasation aspect of neurogenic inflammation, studied in the rat and guinea pig. When the plasma extravasation is induced by trigeminal stimulation, the ergot antimigraine mediations and sumatriptan block it in the dura but not in the extracranial tissues. The migraine headache was never considered to be the result Of extracranial vasodilation alone, as it is often contended; an inflammatory mechanism was implicated as Well, called

FIG. 211-5. Systolic pulse wave amplitude ofthe frontal branch ofthe superficial temporal artery, in during and between migraine headaches and in nonheadache controls. (Data from Tunis MM, Wolff HG: Long-term observations of the reactivity of the Cranial arteries in subjects with vascular headache of the migraine type. Arch Neurol Psychiatry 70:551-557, 1953.) mmp

21 1-4. Luminal diameterof the superficial temporal artery, in mm, during and between migraine, ipsilateral and contralateral to the headache (n = 25). (Data from lversen HK, Nielsen TH, olesenJ, Tfelt-Hansen P: Arterial responses during migraine headache. Lancet 336:837-839, 1990.)

rn Pathogenesisof the MigraineAttack

1337

FIG. 211-5. Luminal diameter of the superficial temporal artery, in mm, in migraineurs between headaches (n = 50), in comparison to = 50). (Data from De Hoon JNJM: Migraine nonheadache and anti-migraine drugs. Focus on aspects. Doctoral thesis, Maastricht University, Maastricht, The Netherlands, 2000.)

FIG. 211-6. Inflammatory aakity of subcutaneous perfusates of sites of migraine headache, in bradykinin units, in relation to the intensity of A the pain. (Data from Chapman LF, Ramos AO, Coodell H et humoral agent implicated invascular headache of the migraine type. Arch Neural 3:223-229, 1960.)

genic inflammation (Fig. 211-6). The inflammation is caused by the release of chemicals, neuropeptides, from the peripheral nociceptive nerve fibers. The neuropeptides are substance P and calcitonin gene-related peptide in particular, released from the Cand AG-fibers, respectively. In migraine, the neuropeptides are released from the nerve fibers that coil around the arteries affected by the vasodilation. The dilation causes stretching of the perivascular nerve fibers, which, in turn, results in their depolarization. On one hand, the depolarization generates the action potentials that are relayed to the central nervous system; on the other, it releases the chemicals from the nerve fibers, which further dilate the arteries (calcitonin gene-related peptide) (Fig. 2 11-7) and make the dilation painful (substance P). There is probably also a central mechanism involved in causing the pain of the migraine headache. This is suggested by measurements, in migraineurs, of the level of enkephalin in the cerebraSpinal fluid. Enkephalin is an endogenous opioid that inhibits the transmission of pain signals in the central nervous system. I t s level is lower during the migraine headache than between headaches and in nonheadache controls (Fig. 211-8).

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FIG. 211-7. Level of calcitonin gene-related peptide in blood drawn from the external jugular vein, in pmol/L, during migraine headache in comparison to blood drawn from the antecubital vein. (Data from Goadsby PJ, Edvinsson,.I Ekman R: Vasoactive peptide release in the extracerebral circulation of human during migraine headache. Ann Neurol 28:183-187, 1990.)

other within a tight time frame. This sequential occurrence has been considered indicative of their causal relationship, but there is no evidence that the two are indeed causally related and that the aura is the cause of the headache. The traditional view contends that the cerebral vasoconstriction causing the migraine aura is followed by reactive vasodilation (Fig. 21 1-9). The cerebral vasodilation is supposedly accompanied by extracranial vasodilation, which in turn initiates the mechanism of neurogenic inflammation through stretching of the perivascular nerve fibers. The migraine headache is caused by the resulting vicious cycle, in which vasodilation triggers neurogenic inflammation, which in turn enhances the vasodilation and renders it painful. We now include “sick headache” in the migraine paradigm, initially under the name common migraine and now as migraine without aura. To include this “new” migraine condition within a unifymg theory, it was proposed that when no aura occurs, the transient, localized cerebral vasoconstriction takes place in a clinically silent area of the cerebral cortex, not giving rise to symptoms. This is clearly a forced concept, and it does not explain the occurrence of aura without headache, as in isolated migraine aura or migraine aura without headache. Also, there is no evidence that reactive cerebral vasodilation is accompanied by extracranial vasodilation. In addition, spreading excitation and depression is associated with a short-lasting increase in cerebral blood flow,

PATHOGENESIS OF THE MIGRAINE AURA Traditional thinking attributes the migraine aura to transient, localized cerebral vasoconstriction. This notion is based on the observation that inhalation of a cerebral vasodilator, such as amyl nitrite or carbon dioxide, causes a transient regression of the symptoms. However, the specific clinical presentation of the migraine aura suggests a neurophysiologic phenomenon, called spreading depression, as the underlying mechanism. Spreading depression is a wave of neuronal excitation that travels over the cerebral cortex at a slow rate and is followed by prolonged depression of cortical neuronal activity. Cerebral blood flow studies performed since the 1980s and the more recently conducted functional magnetic resonance imaging studies support this view (Plate 211-1).

PATHOGENESIS OF THE MIGRAINE AllACK It is not known what triggers the spreading excitation and depression and how it causes the headache after the aura, assuming that the aura and headache are causally related. The aura and headache typically occur sequentially, with one following the

cerebral vrroconatrlction

-+

hypoxla

1

L)

Between During Controls migraine migraine (n = 4) (n = 10) (n = 8) FIG. 211-8. Enkephalin level of the cerebrospinal fluid, in pmol equivalents of met-enkephalin/mL, during and between migraine headaches and in nonheadache controls. (Data from Anselmi 6,Baldi E, Casacci F, Salmon S: Endogenous opioids in cerebrospinal fluid and blood in idiopathic headache sufferers. Headache 20:294-299, 1980.)

-

cerebral circulation

reactive varodilatlon

L

G

extracranial circulation

HEADACH E

neurogenic inflammation

FIG. 211-9. Traditional view on the pathogenesis of the migraine attack, in which the aura and headache are considered sequential and causally related.

PLATE 111-1. Above, high-field magnetic resonance images of an "inflated" right cerebral hemisphere taken over a time course of 20 minutes, including 12 minutes after the onset of exercise-induced migraine aura paracentrally in the left visual field (arrow). The circle projected on some of the images indicatesthe primary visual cortex or striate area. The activity shown in color is the so-called blood oxygenation-level dependent signal, elicited by visual stimulation through a flickering checkerboard and reflects the balance between oxygen delively and oxygen consumption. At the onset of the migraine aura, the signal is suppressed starting in the striate area and gradually extending anteriorly at a rate of 3.5 mm/min. Below, a graphic display over the same time period of the amplitude of the blood oxygenation-level dependent signal. At the onset of the aura, the mean level of the amplitude increases markedly, which suggests heightened cortical neuronal activity. The increase in mean level is rapidly followed by almost complete abolition of the signal, indicating suppression of cortical neuronal activity despite continuing checkerboard stimulation. (Courtesy of Margarita Sanchez del Rio, M.D., Madrid, Spain; recorded at the Massachusetts General Hospital, Hatvard Medical School, Boston, Massachusetts.)

Chapter 21 1

w Pathogenesisof the Migraine Attack

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+AURA

apraadlng daprraalon YlQRAlNE PROCESS

SENSORY +SYYCTOYI varodllatlon

+HEADACHE+

aympathatlc rctlvatlon

1 Lparlpkarat

nauroganlc Inflammatlon

+AUTONOYIC SYYPTOYS

FIG. 211-10. Alternative view on the pathogenesis of the migraine attack, in which the aura and headache are considered parallel phenomena and the associated symptoms seen as secondary to the headache. (Adapted from Spierings ELH: Recent advances in the understanding of migraine. Headache 28:655-658, 1988.)

confirmed, and it is not known how from there cortical neurons are activated and extracranial arteries dilated. ABORTIVE TREATMENT OF MIGRAINE

FIG. 211-11. Increased blood flow in an area of mesencephalon contralateral to the pain in patients with unilateral migraine headache (n = 9), as obsenred with positron emission tomography. Also shown is the increased blood flow in the ipsilateral cingulate cortex. (From Weiller C, May A, Limmroth V et al: Brain stem activation in spontaneous human migraine attacks. Nature Med 1 :658-660, 1995, with permission.)

followed by a prolonged decrease of oligemic magnitude (spreading oligemia). To accommodate these considerations, I created, out of the traditional sequential theory, the parallel theory of the pathogenesis of the migraine attack (Fig. 211-10). The parallel theory not only includes spreading excitation and depression as the mechanism underlying the migraine aura; it also includes an explanation of the associated symptoms of the migraine headache as a result of sympathetic nervous system activation caused by the pain. It better explains the occurrence of the migraine aura during the headache, as is sometimes seen, as well as the isolated occurrence of the aura or headache, when the migraine process activates one of the two tracks only. The migraine process is now thought to be located in the dorsal mesencephalon (Fig. 2 11- 11) which remains to be

Most specific and therefore most effective for the abortive treatment of the migraine headache are the ergots and triptans (Table 211-1). The ergots have been available since the first half of the 20th century and the triptans since the early 1990s. Contrary to general belief, the first triptan, sumatriptan, was not developed as an abortive antimigraine medication. It was developed as a pharmacologic tool, that is, a selective agonist of the serotonin 1-like receptor on the dog saphenous vein. Stimulation of this receptor causes contraction of the vein, in contrast to the receptor on the cat saphenous vein, which causes relaxation. The serotonin 1-like receptor on the dog saphenous vein is now known as the serotonin 1B receptor and that on the cat saphenous vein as the serotonin 7 receptor. Stimulation of the serotonin 1-like receptor in the cranial circulation of the pig had been shown to redistribute carotid blood flow. This particular redistribution of cranial blood flow suggested constriction of arteriovenous anastomoses; the serotonin 1-like receptor most likely to be involved was that of the dog saphenous vein. In the 1950s, Heyck suggested opening of arteriovenous anastomoses to be the vascular mechanism underlying the migraine headache. This led to the introduction of sumatriptan and thus of the triptans in the abortive treatment of migraine. It was not the link between migraine and serotonin that was established by Sicuteri in the 1960s, as it is often suggested, despite the fact that the triptans are structural analogues of this biogenic amine. Cranial vasoconstriction probably is the most important mode of action of the ergots and triptans in the abortive treatment of migraine (Figs. 211-12 and 211-13). It is mediated through stimulation of the serotonin 1B receptor, which is a postjunctional receptor located on the vascular smooth muscle. As mentioned

TABU211-1. Abortive Antimigraine Medications Ergots Di hydroergotarnine Ergotarnine Triptans Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan

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The ergots also stimulate the serotonin 1A and dopaminergic receptors, which cause nausea and vomiting and make them less well tolerated than the triptans. They also stimulate the serotonin 2A and a-adrenergic receptors, causing coronary and peripheral arterial vasoconstriction, respectively. This makes them less safe from a cardiovascular perspective and contraindicated, more so than the triptans, in coronary artery disease and uncontrolled hypertension. The ergots also have a much longer duration of action because of very slow receptor dissociation, further decreasing their cardiovascular safety. PREVENTWE TREATMENT OF MIGRAINE

FIG. 211-12. Percentage decrease in pulsation amplitude of the extracranial (temporal and occipital) arteries during migraine headache (n = 20) and in nonheadache controls (n = 34) after intravenous administration of 0.37 to 0.5 mg ergotamine. (Data from Graham JR, Wolff HG: Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 39:737-763, 1938.)

FIG. 211-13. Effect of oral triptans, 1.5 to 2.5 hours after administration, in comparison to placebo, on the luminal diameter of the superficial temporal artery, in mm, between migraine headaches (n = 16). (Data from De Hoon JNJM: Migraine and anti-migraine drugs. Focus on cardiovascular aspects. Doctoral thesis, Maastricht University, Maastricht, The Netherlands, 2000.)

earlier, the vasoconstriction that led to the introduction of the triptans in migraine treatment was that of arteriovenous anastomoses. However, these vascular structures, which establish direct communications between arteries and veins, have never been considered very important in the pathogenesis of the migraine headache. The medications also inhibit neurogenic inflammation by stimulating the prejunctional, neuronal serotonin 1D and 1F receptors. However, medications that inhibit neurogenic inflammation but do not cause cranial vasoconstriction are ineffective in the abortive treatment of migraine. This suggests that the additional effect of the ergots and triptans on these receptors probably is not important for their antimigraine efficacy.

The only preventive antimigraine medication that was specifically developed for that purpose is methysergide. It was developed as a potent serotonin antagonist, derived from lysergic acid diethylamide, when it was believed that the migraine attack was caused by a “serotonin storm.” It has since been shown in animal experiments to cause cranial vasoconstriction and inhibit neurogenic inflammation. Its clinical usefulness is limited because of restricted concomitant use of triptans and potentially serious fibrotic side effects. The remaining preventive antimigraine medications can be divided into five groups, as is shown in Table 21 1-2. The P-blockers that are effective in migraine prevention are those that lack partial agonist or intrinsic sympathomimetic activity. This feature is associated with increased peripheral vascular resistance caused by an increase in arterial tone. It is plausible that this increase in arterial tone hampers the mechanism of migrainous vasodilation, thereby decreasing the frequency of migraine headaches and mitigating the ones that do occur. The tricyclics and anticonvulsants may prevent migraine headaches by inhibiting central pain transmission. They do so by potentiating the serotoninergic and GABA-ergic systems, respectively, which are potent inhibitory systems within the central nervous system. The calcium entry blockers and anti-inflammatory medications may prevent migraine headaches by impairing the activation of the mechanism of neurogenic inflammation. Neurogenic inflammation, like neurotransmitter release, is a calcium-dependent process that could be affected by the calcium entry blockers. It is possible that other modes of action of the preventive antimigraine medications are important as well. This may include the reduction in sympathetic tone by the P-blockers and increase in pain threshold by the calcium entry blockers.

D TABLE 211-2. PreventiveAntimigraine Medications

&Blockers Atenolol Bisoprolol Metoprolol NadoIoI Propranolol Timolol Tricyclics Amitriptyline Calcium entry blockers Verapamil Anticonvukants Divalproex sodium Gabapentin Anti-inflammatory medications Aspirin Naproxen sodium

Chapter 212

SUGGESTED READINGS Anselmi B, Baldi E, Casacci F, Salmon S Endogenous opioids in cerebrospinal fluid and blood in idiopathic headache sufferers. Headache 20294-299, 1980 Chapman LF, Ramos AO, Goodell H et al: A humoral agent implicated in vascular headache of the migraine type. Arch Neurol 3:223-229, 1960

De Hoon JNJM: Migraine and anti-migraine drugs. Focus on cardiovascular aspects. Doctoral thesis, Maastricht University, Maastricht, The Netherlands, 2000 Goadsby PJ, Edvinsson L, Ekman R Vasoactive peptide release in the extracerebral circulation of human during migraine headache. Ann Neurol 28:183-187, 1990 Graham JR, Wolff HG Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 39737-763, 1938 Hadjikhani N, Sanchez del Rio M, Wu 0 et al: Mechanisms of migraine aura revealed by fMRI in human visual cortex. Proc Natl Acad Sci U S A 98:4687-4692, 2001 Heyck H: Pathogenesis of migraine. Res Clin Stud Headache 2:l-28, 1969

Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P Arterial responses during migraine headache. Lancet 336:837-839, 1990

Pharmacologic Treatment of Migraine

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Marcussen RM, Wolff H G 1. Effects of carbon dioxide-oxygen mixtures given during preheadache phase of the migraine attack. 2. Further analysis of the pain mechanisms in headache. Arch Neurol Psychiatry 63~42-51, 1950

Olesen J, Friberg L, Olsen TS et al: Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 28~791-798, 1990

Schumacher GA, Wolff H G A. Contrast of histamine headache with the headache of migraine and that associated with hypertension. B. Contrast of vascular mechanisms in preheadache and in headache phenomena of migraine. Arch Neurol Psychiatry 45199-214, 1941 Spierings ELH The pathophysiology of the migraine attack. Doctoral thesis, Erasmus University, Rotterdam, The Netherlands, 1980 Spierings ELH: Recent advances in the understanding of migraine. Headache 28:655-658, 1988 Tunis MM, Wolff H G Long-term observations of the reactivity of the cranial arteries in subjectswith vascular headache of the migraine type. Arch Neurol Psychiatry 70551-557, 1953 Weiller C, May A, Limmroth V et al: Brain stem activation in spontaneous human migraine attacks. Nature Med 1:658-660, 1995 Wolff HG, Tunis MM, Goodell H: Evidence of tissue damage and changes in pain sensitivity in subjects with vascular headache of the migraine type. Arch Intern Med 92478-484, 1953

2 12 Pharmacologic Treatment of Migraine Alan M. Rapoport Marcel0 E. Bigal The pharmacologic treatment of migraine is only part of the entire regimen of good management principles for migraine. Specifically, it is important to establish a good patient-physician relationship, arrive at an accurate set of diagnoses of the patient’s headache disorders, review the various treatment options with the patient (including the nonpharmacologic ones), and reassure the patient that on the basis of the history, examination, and available testing, no other significant problems exist. Helping patients learn how to identify and avoid headache triggers and to understand how medications work (including avoiding medications that cause adverse reactions or drug-drug interactions) are essential parts of successful management. In this chapter we focus on the pharmacotherapy of migraine but continue to stress that other nonpharmacologic practices are an essential part of treating patients with primary headache disorders. Pharmacotherapy is traditionally divided into acute and preventive medications. Acute care treatment (also called abortive treatment) is intended to reverse attacks once they begin and to reduce or stop the pain and associated symptoms. Some patients use only acute care treatments and get fairly rapid and complete relief when needed. We have learned from observation and are attempting to teach our patients that when the migraine attack is treated shortly after the pain has begun and the pain is only of mild intensity, the medications are more effective, often leading to a pain-free state. This treatment approach also is more likely to cause fewer adverse reactions and fewer recurrent headaches. Preventive (also called prophylactic) treatment is used in patients who have 3 or more days of headache-related disability per month and in patients who are not rapidly responsive to acute

care treatment. Today, it may not even be necessary to use preventive medication for patients who have up to eight migraine attacks per month if their treatment with acute care medications is rapidly and completely effective, without significant side effects or recurrence. Prevention is also appropriate for patients who have very frequent headaches of any intensity or to treat or avoid medication overuse with resultant rebound headache. Patients who have two or more severe migraine attacks per month and a poor response or contraindications to acute treatment also may benefit from preventive medication. Importantly, even with effective preventive treatment, most patients need acute care medications for breakthrough headaches. Once a clinical diagnosis of migraine is made, the next task is to develop a successful treatment plan. The goals in designing and initiating a treatment plan are to: Reduce attack frequency, intensity, and duration Reduce disability Improve quality of life Prevent headaches completely Avoid headache escalation Avoid medication misuse Return to normal functioning Educate about managing illness (e.g., trigger avoidance and lifestyle changes) Choosing from the myriad pharmacotherapies currently available for migraine can be difficult. Selecting a first-line treatment

Chapter 212

SUGGESTED READINGS Anselmi B, Baldi E, Casacci F, Salmon S Endogenous opioids in cerebrospinal fluid and blood in idiopathic headache sufferers. Headache 20294-299, 1980 Chapman LF, Ramos AO, Goodell H et al: A humoral agent implicated in vascular headache of the migraine type. Arch Neurol 3:223-229, 1960

De Hoon JNJM: Migraine and anti-migraine drugs. Focus on cardiovascular aspects. Doctoral thesis, Maastricht University, Maastricht, The Netherlands, 2000 Goadsby PJ, Edvinsson L, Ekman R Vasoactive peptide release in the extracerebral circulation of human during migraine headache. Ann Neurol 28:183-187, 1990 Graham JR, Wolff HG Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 39737-763, 1938 Hadjikhani N, Sanchez del Rio M, Wu 0 et al: Mechanisms of migraine aura revealed by fMRI in human visual cortex. Proc Natl Acad Sci U S A 98:4687-4692, 2001 Heyck H: Pathogenesis of migraine. Res Clin Stud Headache 2:l-28, 1969

Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P Arterial responses during migraine headache. Lancet 336:837-839, 1990

Pharmacologic Treatment of Migraine

1341

Marcussen RM, Wolff H G 1. Effects of carbon dioxide-oxygen mixtures given during preheadache phase of the migraine attack. 2. Further analysis of the pain mechanisms in headache. Arch Neurol Psychiatry 63~42-51, 1950

Olesen J, Friberg L, Olsen TS et al: Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 28~791-798, 1990

Schumacher GA, Wolff H G A. Contrast of histamine headache with the headache of migraine and that associated with hypertension. B. Contrast of vascular mechanisms in preheadache and in headache phenomena of migraine. Arch Neurol Psychiatry 45199-214, 1941 Spierings ELH The pathophysiology of the migraine attack. Doctoral thesis, Erasmus University, Rotterdam, The Netherlands, 1980 Spierings ELH: Recent advances in the understanding of migraine. Headache 28:655-658, 1988 Tunis MM, Wolff H G Long-term observations of the reactivity of the cranial arteries in subjectswith vascular headache of the migraine type. Arch Neurol Psychiatry 70551-557, 1953 Weiller C, May A, Limmroth V et al: Brain stem activation in spontaneous human migraine attacks. Nature Med 1:658-660, 1995 Wolff HG, Tunis MM, Goodell H: Evidence of tissue damage and changes in pain sensitivity in subjects with vascular headache of the migraine type. Arch Intern Med 92478-484, 1953

2 12 Pharmacologic Treatment of Migraine Alan M. Rapoport Marcel0 E. Bigal The pharmacologic treatment of migraine is only part of the entire regimen of good management principles for migraine. Specifically, it is important to establish a good patient-physician relationship, arrive at an accurate set of diagnoses of the patient’s headache disorders, review the various treatment options with the patient (including the nonpharmacologic ones), and reassure the patient that on the basis of the history, examination, and available testing, no other significant problems exist. Helping patients learn how to identify and avoid headache triggers and to understand how medications work (including avoiding medications that cause adverse reactions or drug-drug interactions) are essential parts of successful management. In this chapter we focus on the pharmacotherapy of migraine but continue to stress that other nonpharmacologic practices are an essential part of treating patients with primary headache disorders. Pharmacotherapy is traditionally divided into acute and preventive medications. Acute care treatment (also called abortive treatment) is intended to reverse attacks once they begin and to reduce or stop the pain and associated symptoms. Some patients use only acute care treatments and get fairly rapid and complete relief when needed. We have learned from observation and are attempting to teach our patients that when the migraine attack is treated shortly after the pain has begun and the pain is only of mild intensity, the medications are more effective, often leading to a pain-free state. This treatment approach also is more likely to cause fewer adverse reactions and fewer recurrent headaches. Preventive (also called prophylactic) treatment is used in patients who have 3 or more days of headache-related disability per month and in patients who are not rapidly responsive to acute

care treatment. Today, it may not even be necessary to use preventive medication for patients who have up to eight migraine attacks per month if their treatment with acute care medications is rapidly and completely effective, without significant side effects or recurrence. Prevention is also appropriate for patients who have very frequent headaches of any intensity or to treat or avoid medication overuse with resultant rebound headache. Patients who have two or more severe migraine attacks per month and a poor response or contraindications to acute treatment also may benefit from preventive medication. Importantly, even with effective preventive treatment, most patients need acute care medications for breakthrough headaches. Once a clinical diagnosis of migraine is made, the next task is to develop a successful treatment plan. The goals in designing and initiating a treatment plan are to: Reduce attack frequency, intensity, and duration Reduce disability Improve quality of life Prevent headaches completely Avoid headache escalation Avoid medication misuse Return to normal functioning Educate about managing illness (e.g., trigger avoidance and lifestyle changes) Choosing from the myriad pharmacotherapies currently available for migraine can be difficult. Selecting a first-line treatment

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depends on a comprehensive evaluation of several clinical factors, including assessment of the severity of illness (e.g., measuring disability or impact of illness), frequency and intensity of attacks, pattern of associated symptoms (nausea, vomiting, photophobia, phonophobia, osmophobia, and worsening of pain with movement), presence of coexisting conditions (e.g., asthma, allergy, hypertension, depression, anxiety, pregnancy), efficacy, side effect profiles, and contraindications of the medications being considered. Determining the treatment goals with the patient will help the physician to design a plan that the patient is willing to follow. To achieve this, it is especially important to understand which features of the attack are most disturbing to the patient (e.g., pain or certain associated symptoms). In designing the most appropriate treatment plan for each patient, discussion about potential adverse events, frequency of dosing preferences, lifestyle considerations (e.g., alcohol consumption, use of over-the-counter products, use of herbal or vitamin supplements) will help ensure that the patient receives a medication he or she will take as prescribed. Women of childbearing age should be asked whether there is any chance they are pregnant or whether they are planning to become pregnant in the near future because this significantly affects medication choices.

ACUTE CARE MlGRAlNE THERAPY Treating patients with migraine requires individualized acute care that follows several basic principles: Engage the patient in the treatment plan to create a true patient-physician partnership Tailor treatment to meet the individual headache needs, based on severity of illness (disability), prior response to specific medications (including presence of side effects), and presence of coexisting conditions Educate the patient about their medical condition and current theories of pathophysiology Use migraine-specific agents when possible Select a route of administration appropriate for the attack characteristics and patient preferences Follow the patient closely and frequently and help him or her manage medication side effects and avoid overuse syndromes Give the patient a headache calendar and review it at each office visit. Many different medications are available worldwide for acute treatment of migraine (of which only 25% have approved indications for use in migraine). Some are scientifically proven to be clinically useful for migraine, and others are known to be empirically useful but lack good evidence of efficacy. Consequently, choosing a medication for acute therapy is a complex, multistep process that necessitates a good understanding of the patient’s overall health, the range of appropriate treatment options, patient-specific migraine characteristics, and patient preferences. For example, some patients prefer taking oral medications (tablets or orally disintegrating tablets), but many of these medications are also available in different formulations (nasal spray, injection, liquid, and rectal suppository) or as combination therapies (e.g., with caffeine or acetaminophen). It is the task of the physician to take all these factors into consideration when designing an optimal treatment plan for the patient.

Simple Analgesics

Some patients can successfully treat migraine by taking simple analgesics, especially if treatment is taken early in the course of the attack, when the pain is of mild intensity. Studies suggest that aspirin monotherapy in selected patients at a dosage of 650 mg may be helpful in alleviating headache. Conflicting evidence in the literature suggests that acetaminophen as monotherapy may not be an ideal first-line treatment choice; however, for selected patients with contraindications to other therapies (e.g., pregnancy, easy bruisability, or aspirin hypersensitivity), a trial of acetaminophen 1000 mg with a repeat in 2 hours may be justified. The efficacy of simple analgesics may be improved by the coadministration of metoclopramide (5 or 10 mg given before or concomitant with oral analgesics); this addition may improve absorption of the analgesic, decrease nausea, and improve the therapeutic response. Combination Analgesics

Caffeine acts as an analgesic adjuvant in treating headache and other pain disorders. Many patients treat themselves with simple analgesics and a cup of coffee (or soda containing caffeine). Others use off-the-shelf combination medications that contain caffeine. These medications are helpful, but there is a greater risk of overuse in patients who have frequent headaches. At dosages of 300 to 500 mg/day (the equivalent of 3 to 5 cups of coffee), several days per week, caffeine can exacerbate the headache syndrome, causing caffeine rebound and withdrawal headaches. It is important that patients understand what drugs are in the combination analgesics and how to take these medications properly so they can avoid the risks associated with excessive caffeine and analgesic use. Other combination medications include the use of analgesics with opiates such as codeine; often these combinations are tried if migraine-specific medications are ineffective or contraindicated. An alternative combination analgesic contains isometheptene 65 mg, acetaminophen 325 mg, and dichloralphenazone 100 mg (Midrin). Isometheptene is a sympathomimetic amine, which constricts blood vessels; dichloralphenazone is a muscle relaxant. It is most helpful in treating episodic tension-type headache and could help in mild migraine when taken early in the attack. The dosage is two capsules immediately at onset and another one or two capsules every 1 hour if the headache is not substantially improved (totaling five capsules per 24 hours). The combination generally is well tolerated; it cannot be used in a patient on a monoamine oxidase inhibitor. Nonsteroldal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proven clinically effective for acute treatment of migraine. Lack of response to one agent does not preclude response to another. Clinical evidence has shown that diclofenac (50 to 100 mg), flurbiprofen (100 to 300 mg), ibuprofen (200 to 800 mg), naproxen sodium (550 to 1100 mg), piroxicam (40 mg), and tolfenamic acid (200 to 400 mg) are effective in migraine. Indomethacin can be compounded into a 50-mg rectal suppository, which can be very helpful in acute care of migraine. Celecoxib, rofecoxib, and valdecoxib are three new NSAIDs that selectively inhibit the enzyme cyclooxygenase-2 (COX-2). As a result, they may be associated with a decreased risk of certain

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adverse effects (e.g., on gastric mucosa or blood platelets). Rofecoxib 25 mg has been shown to be less effective than a triptan, but a combination of both sometimes is used to enhance effectiveness and reduce recurrence, achieving a better sustained response. Butalbital-Containing Medications Butalbital is a short-acting barbiturate that has been used for many years in North America to treat headache. Although it has not been specifically tested in double-blind, placebo-controlled studies in migraine patients, clinical experience clearly supports the clinical efficacy of butalbital-containing compounds for the early treatment of mild migraine and episodic tension-type headache. Although the combination of butalbital, caffeine, simple analgesics, and even opiates (codeine) may confer additional clinical benefits compared with using the components separately, these combination products may lead to increased risks of sedation and dependency. Many clinicians reserve the use of butalbitalcontaining combinations for patients who do not respond to most off-the-shelf medications and are not at risk of dependency (e.g., patients with infrequent attacks). These medications are often over used by patients with frequent headache. Codcostemids The mechanism of action of steroids in migraine is not clearly understood but probably relates to their effect on neurogenic inflammation, one of the mechanisms causing the pain of migraine. The clinical evidence supporting the use of corticosteroids for migraine is limited, but they may be used as an oral rescue medication when a triptan is not effective in controlling a migraine attack. They gradually decrease both the headache and the associated symptoms and may decrease the chance of recurrence. The most common adverse reactions associated with short courses of corticosteroid therapy are face reddening, mild blood pressure elevation, blood sugar elevation, psychosis, and insomnia. The administration of steroids at higher dosages over a longer period of time has been rarely associated with aseptic necrosis of the femoral head and other large joints. Long-term frequent use should be avoided because it can produce osteoporosis, diabetes, hypertension, cataracts, and other unwanted effects. Although there is no consensus, it appears that 2 days per month of steroids or a 1-week burst every 2 to 3 months is safe. EWts

Ergotamine was discovered more than 50 years ago and has been used clinically in oral, sublingual, injectable, inhaled, nasal, and rectal preparations. Before the triptans became available in the early 1990s, it was the only vasoactive medication in widespread use for migraine and cluster headache. Oral ergotarnine is erratically and poorly absorbed, and its bioavailability is less than 5% of the ingested dose. Rectal administration of ergotamine leads to better absorption and better treatment efficacy. Currently the most commonly used ergotamine preparations are tablets and suppositories. Selected combination tablets contain 1 mg ergotamine and 100 mg caffeine. The rectal suppositories contain 2 mg ergotamine and 100 mg caffeine. Because ergotamine is better absorbed rectally, a smaller dosage should be given. It is

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not uncommon to start with only one quarter of a suppository, which can be repeated in 1 hour if needed. The maximum dosage of ergotamine is 4 mg per day, and it should be used only 1 or 2 days per week to prevent ergotamine-induced rebound headache. The side effect profile of ergotamine limits its use as a regular acute migraine treatment. The adverse events include exacerbation of nausea or vomiting associated with a migraine attack, abdominal pain, distal paresthesias, and muscle cramps. If it is used more than two times per week, even in low dosages, ergotamine dependency and rebound headaches may develop. Ergotamine is contraindicated in pregnancy, uncontrolled hypertension, coronary artery disease, peripheral vascular disease, sepsis, and liver and kidney disease. It should not be given to a patient on erythromycin or other macrolide antibiotics (which decrease its metabolism and raise blood levels). Today in the United States few patients are started on ergotamine tartrate preparations for migraine treatment unless they have failed triptans. The triptans work more quickly and completely and also can reduce nausea instead of exacerbating it. Dihydroergotamine is a hydrogenated ergot that has been available since the early 1940s. Although it is considered a weaker arterial constrictor and a stronger venoconstrictor than ergotamine, it carries the same contraindications Dihydroergotamine has been tested clinically and proven useful when administered by injection or intranasally for acute migraine treatment. Pretreatment with an antinausea medication such as metoclopramide, promethazine prochlorperazine, or ondansetron usually is not needed unless it is given intravenously. Because dihydroergotamine is most effective by parented administration, it is less convenient than an oral triptan but is often quite effective. Its half-life is 10 hours, so it has a long-lasting effect and lower recurrence rate. Clinical use of dihydroergotamine for acute treatment of migraine outside the clinic setting is limited to the nasal spray formulation, which is administered as a 0.5 mg dose in each nostril, repeated 15 minutes later for a total of four sprays (2 mg total dosage). The nasal spray is well tolerated, compared with injectable delivery, but it is not always effective, and patients occasionally develop nasal stuffiness. Dihydroergotamine given by injection in an emergent care or clinic setting is very effective in reducing headache associated with migraine. The starting dosage is often 0.25 to 0.5 mg given by slow intravenous push over 5 minutes through a heparin lock after administration of an antiemetic. Another 0.5 mg can be given in 60 minutes if there are no significant side effects. If the patient is hospitalized for repetitive intravenous administration, the usual dosage is 0.5 to 1 mg given slowly through a heparin lock every 8 hours, over a period of 3 to 5 days. An effective way to use the medication is 1 mg intramuscularly, with or without an antiemetic such as promethazine or prochlorperazine. A 4-mg dose of dexamethasone also can be given orally or parenterally. Opioids Opioids have been used for centuries to control pain. Efficacy studies in migraine are limited but do support a therapeutic role. One of the more commonly used agents is butorphanol, which is available in an injectable form but is most commonly used as a nasal spray in a 1-mg dose. However, given the risk of dependency with frequent use, butorphanol should be reserved for occasional rescue therapy when first-line migraine medications fail. It should

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not be used more than 2 days per week except in special circumstances; care must be taken when prescribing butorphanol because it comes in a multidose vial with up to 14 doses. Prescriptions should be limited to no more than one vial per month except in unusual circumstances. Patients have to be warned to use the medication only when in bed because it can cause dizziness, sleepiness, and dysphoria. Its benefits include rapid onset of action (15 to 20 minutes), sleep induction, and pain relief. Similarly, codeine-containing medications and all other opioids may be used to reduce the pain of migraine. These drugs also should be used sparingly to avoid overuse and dependency. Although opioids are good pain relievers with rapid onset of action, for many patients they may cause sedation, dizziness, and functional impairment. Patients should be warned of these adverse events and instructed to rest after taking them. Opioids usually do not reduce the disability from migraine as well as triptans do, and they often cause drowsiness and decreased cognition. However, opioids are useful as rescue medications when used on an occasional basis. If a patient comes to an emergent care setting and a vasoactive medication has failed or is contraindicated, then an opioid may be used either alone or in combination with promethazine or other antiemetic. Although meperidine is commonly used, it should be avoided because it may cause a paradoxical reaction, and beneficial effect often is inadequate and short in duration. Opioids should not be given to patients who must drive home. Patients also should be advised of the risk of sedation associated with opioid analgesics when working or operating heavy equipment because they may be impaired while under the influence of these medications, thereby putting the patient, family, colleagues, and the public at risk. Triptans

Triptans are the most selective, migraine-specific acute care treatment currently used in the outpatient setting. S i x triptans are available and listed in their order of clinical development: sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan and frovatriptan. The triptans are available in different strengths and formulations including oral tablet, orally disintegratingtablet, nasal spray, and subcutaneous injection (Table 21 1-1); in Europe, one is also available as a suppository. Specific differences between the triptans appear to exist as evidenced by differences in time to maximum plasma concentration (Tma), maximum plasma concentration (Cma), plasma elimination half-life (TI,*),area under the curve (AUC), metabolism, and drug interactions, among others. How these differences translate into clinical efficacy and tolerability differences is not well understood. Consequently, clinical distinctions between these medications are subtle and necessitate attention to the specific characteristics of the patient and individual features of the medication and its tolerability profile. Delivery systems may play an important role in the onset of action of triptans. Subcutaneous delivery of sumatriptan offers the most rapid and complete pain relief beginning as early as 10 to 15 minutes, yet it also is associated with a higher occurrence of adverse events. The second most rapid onset of action is achieved through nasal spray delivery of sumatriptan (and zolmitriptan nasal spray in selected European countries), but the headache relief at 2 hours is not as good as with the subcutaneous delivery. The onset of headache relief from the sumatriptan nasal spray begins in 15 to 20 minutes, which is faster than with the oral

formulations. All of the triptans are available as conventional tablets, and two (rizatriptan and zolmitriptan) are also available in an orally disintegrating formulation. These formulations are more convenient to use and can be taken when the patient is nauseated, but they do not work any faster than the regular tablets. Beside delivery options, other clinical distinctions to consider are the duration of action, percentage of patients attaining either headache relief or pain-free state at 2 hours, and frequency of recurrence or headache persistence (Table 21 1-2). Sumatriptan has been available for the longest time and has been given successfully to the largest number of patients; zolmitriptan is the only triptan proven effective when repeated for a persistent headache; naratriptan has a slower onset of action but a longer half-life and possibly a longer duration of action, which may help address the clinical challenges of treating migraine associated with menses or migraine in patients who have a history of long attacks; rizatriptan has the highest 2-hour pain-free rates and the fastest response rate for an oral tablet; almotriptan has a slightlybetter side effect profile, with less chest pain; and frovatriptan is a slower-actingtriptan with the longest half life (26 hours) in the class. Despite these differences, the triptans are more similar than different, and one cannot predict which triptan will work best for any given patient. If the first triptan tried is not ideal in all clinical respects, a second or third should be tried; the patient should be questioned carefully to determine whether the triptan they are taking is ideal in terms of rapid onset of action, complete response, lack of recurrence, and minimal side effects. If it is not, another triptan should be tried. Adverse event profiles also may be helpful in determining which triptan is the best match for a particular patient. Rizatriptan dosage must be reduced to 5 mg in patients taking propranolol; naratriptan clearance is reduced with concomitant administration of oral contraceptives, and the zolmitriptan dosage may need to be reduced in patients taking cimetidine. As a class, triptans are vasoconstrictive agents with coronary vasoconstriction that is minimal with therapeutic dosages. However, as a safety precaution, patients with specific cardiovascular risk factors or those on other vasoconstrictive medications should not take triptans. Triptan contraindications include coronary artery disease, risk factors for coronary artery disease (such as smoking, obesity, family history of early or severe coronary artery disease, diabetes, high cholesterol, peripheral vascular or cerebrovascular disease. Additionally, triptans should not be used in patients with unusual or prolonged auras, basilar or hemiplegic migraine, or uncontrolled hypertension. PREVENTIVE THERAPY Principles

The decision to initiate preventive migraine therapy should be based on individual clinical judgment combined with the patient’s willingness take daily medication and comply with the treatment regimen. Patients with frequent, prolonged, or debilitating headaches often benefit from preventive therapies. However, defining these parameters for a typical patient is not an easy task. Some patients have very infrequent yet severely debilitating and prolonged migraine attacks and are better treated with preventive therapies. In contrast, others have more frequent headaches that respond well to acute care medications, and they may prefer to avoid daily medication regimens. As a result of these patient preferences and attack differences, clinical decision making regarding the use of preventive therapies often is complex and must be based on individualized consultation with the patient and

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an in-depth understanding of the impact of illness on the patient’s life. In addition to frequency and disability associated with attacks, patients with contraindications to triptans and other vasoactive medications or patients with significant triptan side effects may do better on preventive medication. Sometimes coexisting medical conditions, such as depression, hypertension, or asthma, may benefit from a daily therapy that is also effective in treating migraine and the coexisting condition. Therefore, giving a P-blocker or calcium antagonist to a severe migraineur with hypertension, a leukotriene antagonist to an asthmatic migraineur, or a tricyclic antidepressant to a migraineur who is depressed or has early morning awakening will help both medical conditions. This is why a complete health screening, history, and physical examination are needed before a preventive regimen is initiated. Some migraine medications are contraindicated in certain medical conditions; for example, some patients may have uncommon migraine features or medical conditions that prevent them from using certain therapies (e.g., prolonged or frequent aura, migrainous infarction or transient ischemic attacks, hypotension, or Raynaud’s phenomenon). Once one decides to initiate preventive pharmacotherapy, several general principles of management may prove helpful. Begin treating with preventive medications at a low dosage and gradually increase over an extended period of time. For example, if no side effects emerge and if the desired clinical response is not yet achieved, the dosage can be escalated. Manage the patient’s expectationsregarding when he or she can anticipate clinical benefit. Most patients must be taught how to monitor improvement and deterioration in their headache patterns. Many preventive medications take 3 or 4 weeks for a therapeutic response; patients need to be patient and compliant with the agreed-upon treatment plan. Establish a comprehensive migraine management plan that includes long-term goals, tips on when the medication must be changed, a regular office visit schedule, and specific information on adverse reactions that may warrant discontinuing the medication, returning to the clinic, calling the office, or even going to the hospital on an emergent basis.

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Gabapentin is an anticonvulsant agent structurally related to the inhibitory neurotransmitter y-aminobutyric acid (GABA). However, the medication has no direct GABA-mimetic action, and its precise mechanism of action has not been elucidated. Gabapentin seems to be particularly effective in treating chronic pain syndromes. A recent double-blind trial that used gabapentin 1800 to 2400 mg per day showed it to be superior to placebo in reducing frequency and intensity of pain. Gabapentin was effective as a migraine preventive in 46% of patients (compared with 14% of controls) in whom other therapies had failed. Topiramate is a structurally unique anticonvulsant that is rapidly and almost completely absorbed. A less common side effect that the patient must be warned about is cognitive dysfunction that is fully reversible with therapy discontinuation. There is a possible interaction between topiramate and birth control pills resulting in breakthrough bleeding or cramps, and a few cases have been reported of reversible acute angle-closure glaucoma associated with topiramate use. A double-blind study showed that topiramate produced more than a 50% decrease in pain in 46.7% of patients. Topiramate must be gradually increased from 25 mg per day, no faster than 25 mg per week, to avoid side effects. Patients who reach 100 mg without effect but who have no side effects can be raised slowly to 250 mg per day, usually without significant side effects. Side effects associated with anticonvulsants include weight gain, hair loss, tremor, gastrointestinal upset, sedation, asthenia, dizziness, and cognitive changes. Topiramate is unique in that it has been associated with weight loss. If side effects occur, dosage reduction or even drug discontinuation is recommended. Most anticonvulsants are contraindicated in pregnancy. Specifically, sodium valproate has been associated with neural tube defects and should be used very cautiously in women of childbearing potential. The risk of neural tube defects is decreased with administration of supplemental folic acid. The use of sodium valproate in patients with hepatic disease is not recommended. Sodium valproate interacts with barbiturates and benzodiazepines, so caution is necessary if these medications are combined because patients may become drowsy. The commonly used butalbitalcontaining analgesics must be given cautiously if administered with anticonvulsants. Valproate has been associated with pancreatitis and possibly polycystic ovary syndrome.

Antlconvulsants Anticonvulsants clinically tested and proven effective for migraine prevention include divalproex sodium (500 to 1500 mg per day; serum level 70 to 120 mg/L), sodium vdproate (800 to 1500 mg per day; serum level above 50 mg/L), topiramate (50 to 200 mg per day), and gabapentin (900 to 2400 mg per day). Dosing regimens for the anticonvulsants such as the shortacting form of divalproex sodium include starting at a low dosage, 125 mg or 250 mg once daily, and increasing slowly up to 250 mg in the morning and 500 mg in the evening. If the patient continues to have breakthrough migraine attacks during a 3-week period and there are no significant side effects, the dosage can be gradually raised up to 2000 mg, but most patients do not have added improvement over 1000 mg per day. The new long-acting form of divalproex sodium can be given once per day in the evening. The starting dosage is 500 mg, which can be raised to 1000 mg or higher at intervals if there is no improvement. The once-daily dose improves compliance and stabilizes drug blood levels, which can minimize side effects. Divalproex sodium is the only antiepileptic approved by the FDA for migraine prevention.

Three major types of antidepressants are available-monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants-and have been used extensively for migraine prevention. Several of these agents have been specifically tested and proven effective; others are used empirically. One important clinical benefit of these agents is their usefulness in patients with migraine and coexisting depression, a condition previously reported with a higher prevalence in migraine than,the general population. Antidepressants for migraine prevention can also be helpful in patients with coexisting sleep disorders and anxiety. Monoamine oxidase inhibitors appear to work well for frequent or daily headache and depression and for transformed migraine with daily milder headache and intermittent migraine. More than 80% of migraine sufferers report an improvement of at least 50%. However, despite their efficacy, monoamine oxidase inhibitors are not widely used for migraine prevention because they necessitate significant dietary limitations and extreme caution regarding drug

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interactions. There are strict rules about giving them with other types of antidepressants, and they can never be given with vasoactive amines, such as isometheptene (contained in Midrin), pseudoephedrine, and other vasoconstrictors often found in off-the-shelf cold preparations. The consequence of such simultaneous drug use may be severe, including intracerebral hemorrhage and, at the very least, hypertension and severe headache. Other possible side effects include orthostatic hypotension, weight gain, insomnia, constipation, increased perspiration, peripheral edema, and, less commonly, inhibition of ejaculation or reduced libido. One commonly used monoamine oxidase inhibitor is phenelzine, a monoamine oxidase A inhibitor. The dosages range from 30 to 90 mg per day, in divided doses. Because there are many other effective preventive medications for migraine, monoamine oxidase inhibitors often are saved for last or ruled out as a treatment. Three tricyclic antidepressants have been tested in controlled clinical studies: amitriptyline, clomipramine, and opipramol (not currently available in the United States). Amitriptyline is the most commonly studied and used tricyclic antidepressant treatment for migraine prevention and has been shown to reduce headache intensity and frequency when given at 30 to 150 mg per day. Most of the tricyclic antidepressants, including nortriptyline, doxepin, desipramine, imipramine, and protriptyline have been successfully used clinically, but there are no good studies showing evidence of therapeutic benefit in migraine prevention. Most tricyclic antidepressants are available in a 10-mg dose, and a typical regimen for amitriptyline (or nortriptyline or similar medication) begins with 10 mg given at least 60 minutes before bedtime. The dosage may be escalated in 10-mg increments every 3 to 7 nights as tolerated. The average dosage is 50 to 75 mg, and some patients may need up to 150 mg if they have coexisting conditions, including sleep disorder or depression. Nortriptyline has a narrow therapeutic window and should not be given in too low or too high a dosage. Blood levels can be monitored if the patient is not responding to treatment, but clinical response usually is adequate in finding the therapeutic dosage. Most tricyclic antidepressants entail a 3- to 4-week treatment period before clinical benefits are observed. Side effects associated with tricyclic antidepressants include weight gain, drowsiness in the morning, dry mouth, constipation, blurred vision, reduced libido, other sexual disturbances, and urinary retention. These medications are contraindicated in the presence of cardiac arrhythmia, glaucoma, and urinary retention. Special caution must be taken when these medications are used in older adults. Doxepin is helpful in patients with sleep problems. Desipramine, imipramine, and protriptyline in similar dosages are somewhat activating and can be given in the morning. Nortriptyline may be better tolerated in some patients. Selective serotonin reuptake inhibitors tested for migraine prevention include fluoxetine and fluvoxamine, with only fluoxetine (20 mg every other day escalated to 40 mg/day) providing some therapeutic benefit (therapeutic benefits of fluoxetine have not been reported for all clinical studies). Paroxetine, sertraline, and citalopram have been shown in some smaller open studies to be helpful but have not been shown to work conclusively in well-designed, multicenter studies. Some reports suggest that the selective serotonin reuptake inhibitors help in tension-type but not migraine headache but can be tried in migraineurs who have a significant coexisting problem with sleep, depression, or anxiety. Adverse events often associated with selective serotonin reuptake inhibitors are fewer in number but different in nature from those reported with the tricyclic antidepressants. Adverse reactions

include nausea, agitation (which often improves within 1 to 2 weeks), insomnia, tremor, anorgasmia, and other sexual dysfunction. A small percentage of patients have an increase in headaches, so patients must be warned about the risk of this adverse event. Although the selective serotonin reuptake inhibitors usually are weight neutral, a few patients may gain weight. Patients should be warned to discontinue the therapy if they have mood alterations, strange feelings, or increase in headache. p-Blockers

P-Blockers are among the most commonly used medications for migraine prevention. Propranolol, the first P-blocker approved for migraine treatment, was accidentally found to prevent migraine. The lipophilic P-blockers, which readily pass into the central nervous system, such as propranolol and metoprolol, and the hydrophilic P-blockers, atenolol and nadolol, which do not, are effective in migraine prevention. Cardioselectivity also appears to have no bearing on efficacy, but the presence of intrinsic sympathomimetic activity may be related to effectiveness. Propranolol is the most extensively studied P-blocker for migraine prevention, with additional reports for metoprolol, acebutolol, atenolol, bisoprolol, nadolol, pindolol, and timolol. Meta-analyses of these studies report that propranolol provides a moderate reduction in headache frequency. Comparative studies of the different P-blockers report few differences in efficacy between propranolol, metoprolol, timolol, atenolol, and nadolol. Long-acting medications or extended-release formulations also do not appear to confer additional clinical benefits for migraine prevention but do improve patient compliance. For all these agents, lower dosages are started during initial treatment, and the dosage is gradually increased over time. Clinically effective dosages for use in migraine prevention are atenolol25 to 100 mg per day, metoprolol 50 to 200 mg per day, nadolol40 to 240 mg per day, propranolol 60 to 240 mg per day, and timolol20 to 30 mg per day, but all are often effective at low dosages. P-blockers as a class may be associated with several adverse events including depression, fatigue, reduced tolerance for physical activity, nausea, dizziness, and insomnia. Some patients have reported increased coldness in the extremities, dizziness on standing, and abnormal dreaming. These medications are contraindicated in certain disorders such as asthma, chronic lung disease, diabetes, hypoglycemia, bradycardia, hypotension, Raynaud’s disease, peripheral vascular disease, and severe depression. Additionally, b-blockers probably should not be used in hemiplegic migraine and cautiously, if at all, in frequent attacks of migraine with aura. When deciding to discontinue therapy, it is essential that the dosage be tapered gradually over a period of more than a week because abrupt cessation may produce rebound tachycardia, angina, or anxiety. Note that if a patient is taking propranolol and is given rizatriptan for acute treatment of attacks, the rizatriptan dosage should be lowered from 10 to 5 mg. Calcium Antagonists

Calcium antagonists have been used for several years for migraine prevention, including verapamil, flunarizine (not available in the United States), nimodipine, nifedipine, cyclandelate, and nicardipine. Flunarizine (10 mg per day) has been the most extensively studied and has been proven clinically effective in multiple controlled trials. Clinical studies of verapamil (240 mg per day)

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and nimodipine (120 mg per day) report modest clinical benefits in preventing headache. Other agents that are used clinically but have not been tested in clinical trials include diltiazem, nisoldipine, and amlodipine. Newer calcium antagonists also may offer therapeutic benefits for migraine prevention, including isradipine and nicardipine. Nifedipine is occasionally helpful but at times actually worsens headache because it is a strong vasodilator. Dosing regimens with calcium antagonists should start at a low dosage and escalate therapy every 2 weeks. For verapamil, the dosage may be increased to 240 mg daily, and the maximum recommended dosage is 480 mg daily. In healthy patients, higher dosages can be used. The recommended dosage for flunarizine is 10 mg at bedtime. The calcium channel blockers work better in cluster headache prevention than in migraine prevention, and the effective dosage is usually higher; however, they can be extremely effective for individual patients with migraine. The most common side effects reported with calcium antagonists are constipation and fluid retention in the ankles. Less common but more significant side effects are cardiac dysfunction, hypotension, drowsiness, and dizziness. Calcium antagonists are contraindicated in congestive heart failure, heart block, bradycardia, sick sinus syndrome, and other cardiac problems. If they are used concomitantly with a P-blocker, caution is needed and blood pressure should be checked frequently. Flunarizine can be associated with depression and Parkinson’s syndrome and therefore should be used with caution in older adults. Unlike the other calcium antagonists, flunarizine produces a synergism when used with propranolol. NonsteroidalAd-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs, often used as acute treatment, also can prevent migraine. A meta-analysis of seven placebo-controlled studies of naproxen (500 mg per day) or naproxen sodium (1100 mg per day) suggest a modest but clinically significant reduction in headache frequency. Few studies are available for other nonsteroidal anti-inflammatory drugs, but similar efficacy has been reported for ketoprofen (150 mg per day), mefenamic acid ( 1500 mg per day), and flurbiprofen (200 mg per day). Clinical studies of aspirin (1300 mg per day), aspirin plus dipyridamole (975 + 75 mg per day), fenoprofen (1800 mg per day), indomethacin, and nabumetone were either inconclusive or negative. Patients on long-term treatment with nonsteroidal antiinflammatory drugs should be monitored carefully for gastrointestinal upset and complications. The medications should always be taken with food, and consideration should be given to adding a concomitant proton pump inhibitor to prevent gastrointestinal problems. Side effects may be gastric ulceration, dyspepsia, gastritis, diarrhea, and bleeding tendency. A recent study suggests that nonsteroidal anti-inflammatory drugs may decrease the effectiveness of aspirin being given for cardiac protection. Contraindications include gastric ulcers, liver disease, kidney disease, and bleeding disorder. Serotonherglc Antagonist Agents

Methysergide is one of the original medications used for migraine prevention, but its use is limited because of the risk of retroperitoneal, pleuropulmonary, and endocardial fibrosis associated with extended use. Several studies report that methysergide is effective

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as a preventive treatment for migraine, and comparative studies suggest that its effectiveness in reducing headache frequency is similar to that of propranolol. An initial methysergide dosage is 2 mg daily and can be gradually increased to 6 mg per day. Side effects include nausea, dizziness, muscle cramps, weight gain, abdominal pain, diarrhea, and paresthesias. The medication is contraindicated in coronary artery and peripheral vascular disease, hypertension, pregnancy, phlebitis, lung, liver, and kidney disease. It should be discontinued for a 3- or 4-week washout period after every 6 months of therapy. The risk of developing a fibrotic complication appears to be approximately 1 in 1500. Because it is an ergot, methysergide should not be given concomitantly with a triptan. Cyproheptadine’s efficacy has not been proven in double-blind, placebo-controlled studies, but clinical experience suggests that it may confer some benefit in migraine prevention, especially in children. It is rapidly absorbed and produces few side effects other than dizziness, dry mouth, weight gain, and sedation, which can be beneficial in insomnia. The initial dosage is 2 mg (half a tablet) 1 to 2 hours before bedtime, which can be gradually increased over a 1-month period to 8 to 12 mg daily, in divided doses. Cyproheptadine is contraindicated in closed-angle glaucoma and prostatic hypertrophy. Pizotifen is structurally related to cyproheptadine and is not available in the United States. Studies show the medication to be of benefit in 40% to 80% of patients when given in dosages ranging from 1.5 to 3.0 mg at bedtime. The main side effects are drowsiness and weight gain, similar to those of cyproheptadine. Miscellaneous Medications

Montelukast, a specific leukotriene receptor antagonist, was first studied in migraine prevention after the clinical observation of a decrease in migraine frequency in patients with comorbid asthma. In an open label study of montelukast 10 or 20 mg per day, 53% of patients showed a reduction of more than 50% in the frequency of severe attacks, with 41% showing a reduction greater than 60%. Montelukast similarly was reported as being effective and well tolerated as a preventive therapy in children and adolescents with migraine. Lisinopril was studied in a double-blind, placebo-controlled crossover trial for migraine prevention, showing moderate efficacy. The main side effects are cough, hypotension, and fatigue. The oral dosages of lisinopril for use in hypertension range from 5 to 40 mg daily (in single or divided doses), with 10 mg daily as appropriate for the initiation of therapy. Botulinum toxin in migraine prevention was evaluated in a double-blind study of 25-unit and 75-unit doses, which showed that, compared with vehicle treatment, subjects in the 25-unit treatment group had significantly fewer migraine attacks per month. The toxin is symmetrically injected into glabellar, procerus, frontalis, and temporalis muscles and into more posterior pericranial regions. The major side effect, avoidable with proper placement of the toxin, is mild ptosis that usually lasts less than 1 week. Injections can be repeated every 3 months if patients have a beneficial effect, which wears off 3 months after treatment. Feverfew (Tanacerumparthenium) is an herb that is available as an off-the-shelf remedy for treatment of mild depression. A few small clinical studies reported feverfew (50 to 82 mg per day) to decrease the frequency of migraine attacks when used on a daily basis. Additionally, one study reported increased headache frequency with discontinuation of feverfew. Studies show that it has

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an aspirin-like effect on platelets, but the exact mechanism of action is uncertain. Side effects seem to be limited to local effects on oral mucosa. Magnesium has been studied in five clinical trials for migraine prevention with conflicting but promising results. The dosages tested included 400 to 600 mg per day and suggest possible therapeutic benefits in some patients. A study on menstrual migraine was positive. Adverse events include diarrhea and gastric irritation. Only one placebo-controlled study of riboflavin (vitamin B2) has been done to date, testing its clinical efficacy in migraine prevention, with positive outcomes reported for a treatment regimen of 400 mg per day over a 4-month period.

Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and

SELECTED READINGS

Saper JR, Silberstein SD, Gordon CD, Hamel RL: Handbook of Headache Management. Williams & Willcins, Baltimore, 1993 Spierings ELH: Management of Migraine. Butterworth-Heinemann, Boston, MA, 1996

treatment. N Engl J Med 346:257-270, 2002

Humphrey P, Ferrari M, Olesen J (eds): Frontiers in Headache Research Volume 1 0 The Triptans: Novel Drugs for Migraine. Oxford University Press, New York, 2001 Lob0 BL, Cooke SC, Landy SH: Symptomatic pharmacotherapy of migraine. Clin Ther 21:1118-1130, 1999 Mathew N, Saper J, Silberstein S et al: Migraine prophylaxis with divalproex. Arch Neurol 52:28 1-296, 1995 Rapoport AM, Sheftell FD (eds): Headache: A Clinician’s Guide to Diagnosis, Pathophysiology and Treatment Strategies. PMA Publishing, Costa Mesa, 1993 Rapoport AM, Sheftell FD, Purdy RA (eds): Advanced Therapy of Headache. Decker, Hamilton, Canada, 1999 Rapoport AM, Tepper SJ: Triptans are all different. Arch Neurol 58: 1479-1480, 2001

Blumenthal HJ, Rapoport AM: The clinical spectrum of migraine. Med Clin North Am 85:897-909, 2001 Cady R K Treatment strategies for migraine headache. JAMA 285:10141015, 2001

2 13 Chronic Daily Headache Egilius L. H. Spierings Chronic daily headache is the daily or almost daily occurrence of headache. However, not all daily or almost daily headaches fall in this category, as is the case with the daily or almost daily headaches of (chronic) cluster headache and paroxysmal hemicrania and those of hypnic headache or nocturnal migraine. These conditions can be called paroxysmal daily headaches, in which the headaches occur in well-defined attack patterns. In cluster headache, the attack pattern is that of headaches occurring once or twice per day, lasting for 30 minutes to 2 hours, whereas in paroxysmal hemicrania, it is that of headaches occurring 5 to 15 times per day, lasting for 10 to 30 minutes. In hypnic headache or nocturnal migraine, the headaches occur once per day, waking the patient up out of sleep at night, usually between 4 and 6 AM, and lasting for a variable amount of time, also depending on the efficacy of the treatment. Of the nonparoxysmal daily headaches, hemicrania continua does not fall in the category of chronic daily headache either. However, it is discussed in this chapter because it is very difficult, if not impossible, to distinguish from chronic daily headache on the basis of its presentation alone. It differs from chronic daily headache in a somewhat more consistent and less variable intensity of the pain and in an absolute response to preventive treatment with indomethacin. Chronic daily headache is not the same as chronic tension-type headache as defined by the International Headache Society (IHS). The IHS defines chronic tension-type headache as headaches with an average frequency of 15 days per month (180 days per year) or more for at least 6 months. In addition, the headaches have to have at least two of the following features: pressing quality, mild or moderate intensity, bilateral location, and no aggravation by routine physical activity. In addition, there must be no vomiting and no more than one of the following symptoms: nausea, photophobia, or phonophobia. Also, the history and the physical

and neurologic examinations do not suggest the presence of another cause of headache. If the presence of such a cause is suggested, it is ruled out by appropriate investigations, or if such a cause is present, the headaches did not occur for the first time in close temporal relation to occurrence of the disorder. The IHS classification states that sometimes migraine gradually transforms into chronic tension-type headache. However, in my opinion that is not correct, although migraine may transform into chronic daily headache, as will be discussed later. The confusion results from the fact that the IHS sees chronic daily headache as a previously used term for chronic tension-type headache, which is not correct either. Chronic daily headache is a replacement of the old term mixed or combined headache. This is also the largest group of patients classified under the diagnosis of chronic daily headache. In the general population, this may comprise only half of the sufferers, with the other half being made up of chronic tension-type headache. PREVALENCE With regard to the prevalence of daily headache in the general population, the best information available comes from a study conducted in the Netherlands in 1975-1976. The study was conducted in two districts of Zoetermeer, a middle-size town near Leiden, and involved a random sample of 15,563 subjects. The sample size was 4522, that is, 29% of the population, and the response rate was 77%, generating 2198 subjects who were 20 years of age or older. The respondents were asked to fill out a questionnaire that asked, “How often do you have headache?” and one of the answer options was “daily.” In the study, 6% of the respondents aged 20 years or older-4% of the men and 8% of the women-acknowledged the daily occurrence of headache. The highest prevalence was found in the age groups 20 to 24 (8%) and

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Headache and Pain H Headache Syndromes and Their Treatment

an aspirin-like effect on platelets, but the exact mechanism of action is uncertain. Side effects seem to be limited to local effects on oral mucosa. Magnesium has been studied in five clinical trials for migraine prevention with conflicting but promising results. The dosages tested included 400 to 600 mg per day and suggest possible therapeutic benefits in some patients. A study on menstrual migraine was positive. Adverse events include diarrhea and gastric irritation. Only one placebo-controlled study of riboflavin (vitamin B2) has been done to date, testing its clinical efficacy in migraine prevention, with positive outcomes reported for a treatment regimen of 400 mg per day over a 4-month period.

Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and

SELECTED READINGS

Saper JR, Silberstein SD, Gordon CD, Hamel RL: Handbook of Headache Management. Williams & Willcins, Baltimore, 1993 Spierings ELH: Management of Migraine. Butterworth-Heinemann, Boston, MA, 1996

treatment. N Engl J Med 346:257-270, 2002

Humphrey P, Ferrari M, Olesen J (eds): Frontiers in Headache Research Volume 1 0 The Triptans: Novel Drugs for Migraine. Oxford University Press, New York, 2001 Lob0 BL, Cooke SC, Landy SH: Symptomatic pharmacotherapy of migraine. Clin Ther 21:1118-1130, 1999 Mathew N, Saper J, Silberstein S et al: Migraine prophylaxis with divalproex. Arch Neurol 52:28 1-296, 1995 Rapoport AM, Sheftell FD (eds): Headache: A Clinician’s Guide to Diagnosis, Pathophysiology and Treatment Strategies. PMA Publishing, Costa Mesa, 1993 Rapoport AM, Sheftell FD, Purdy RA (eds): Advanced Therapy of Headache. Decker, Hamilton, Canada, 1999 Rapoport AM, Tepper SJ: Triptans are all different. Arch Neurol 58: 1479-1480, 2001

Blumenthal HJ, Rapoport AM: The clinical spectrum of migraine. Med Clin North Am 85:897-909, 2001 Cady R K Treatment strategies for migraine headache. JAMA 285:10141015, 2001

2 13 Chronic Daily Headache Egilius L. H. Spierings Chronic daily headache is the daily or almost daily occurrence of headache. However, not all daily or almost daily headaches fall in this category, as is the case with the daily or almost daily headaches of (chronic) cluster headache and paroxysmal hemicrania and those of hypnic headache or nocturnal migraine. These conditions can be called paroxysmal daily headaches, in which the headaches occur in well-defined attack patterns. In cluster headache, the attack pattern is that of headaches occurring once or twice per day, lasting for 30 minutes to 2 hours, whereas in paroxysmal hemicrania, it is that of headaches occurring 5 to 15 times per day, lasting for 10 to 30 minutes. In hypnic headache or nocturnal migraine, the headaches occur once per day, waking the patient up out of sleep at night, usually between 4 and 6 AM, and lasting for a variable amount of time, also depending on the efficacy of the treatment. Of the nonparoxysmal daily headaches, hemicrania continua does not fall in the category of chronic daily headache either. However, it is discussed in this chapter because it is very difficult, if not impossible, to distinguish from chronic daily headache on the basis of its presentation alone. It differs from chronic daily headache in a somewhat more consistent and less variable intensity of the pain and in an absolute response to preventive treatment with indomethacin. Chronic daily headache is not the same as chronic tension-type headache as defined by the International Headache Society (IHS). The IHS defines chronic tension-type headache as headaches with an average frequency of 15 days per month (180 days per year) or more for at least 6 months. In addition, the headaches have to have at least two of the following features: pressing quality, mild or moderate intensity, bilateral location, and no aggravation by routine physical activity. In addition, there must be no vomiting and no more than one of the following symptoms: nausea, photophobia, or phonophobia. Also, the history and the physical

and neurologic examinations do not suggest the presence of another cause of headache. If the presence of such a cause is suggested, it is ruled out by appropriate investigations, or if such a cause is present, the headaches did not occur for the first time in close temporal relation to occurrence of the disorder. The IHS classification states that sometimes migraine gradually transforms into chronic tension-type headache. However, in my opinion that is not correct, although migraine may transform into chronic daily headache, as will be discussed later. The confusion results from the fact that the IHS sees chronic daily headache as a previously used term for chronic tension-type headache, which is not correct either. Chronic daily headache is a replacement of the old term mixed or combined headache. This is also the largest group of patients classified under the diagnosis of chronic daily headache. In the general population, this may comprise only half of the sufferers, with the other half being made up of chronic tension-type headache. PREVALENCE With regard to the prevalence of daily headache in the general population, the best information available comes from a study conducted in the Netherlands in 1975-1976. The study was conducted in two districts of Zoetermeer, a middle-size town near Leiden, and involved a random sample of 15,563 subjects. The sample size was 4522, that is, 29% of the population, and the response rate was 77%, generating 2198 subjects who were 20 years of age or older. The respondents were asked to fill out a questionnaire that asked, “How often do you have headache?” and one of the answer options was “daily.” In the study, 6% of the respondents aged 20 years or older-4% of the men and 8% of the women-acknowledged the daily occurrence of headache. The highest prevalence was found in the age groups 20 to 24 (8%) and

Chapter 213

Chronic Daily Headache

1349

FIG. 213-1. Distribution of patients according to the number of headache days per month. (From Langemark M, Olesen J, Loldrup D, Bech P: Clinical characterization of patients with chronic tension

headache. Headache 28:590-596, 1988, with permission.)

older than 64 (8%) and the lowest prevalence in the age group 35 to 54 (5Vo). The prevalence of frequent headache, that is, headaches occurring at least 180 days per year, in the general population we know from two recent studies. One of the studies was conducted in Baltimore County, Maryland. It involved 13,343 randomly selected subjects 18 to 65 years of age, which was 77% of the total of 17,237 eligible subjects. Of the respondents 40% were men and 60% women, and their median age was 38 years. The 1-year prevalence of frequent headache was 4% (3% in men and 5% in women). Using the IHS criteria, they found a prevalence of 2.2% for chronic tension-type headache, 1.3% for frequent headache with migrainous features, and 0.6% for other frequent headaches. They found the prevalence of frequent headache to be the highest in the age group 41 to 55 and the lowest in the age group 56 to 65. The other study was conducted in Camargo, Spain. The study involved 1883 subjects more than 14 years of age, which was 84% of the randomly selected sample of 2252. Of the respondents, 47% were men and 53% women. Those who indicated having headaches 10 days per month or more were asked to keep a headache diary for a month. On the basis of the diary, the prevalence of frequent headache, that is, headaches occurring 15 days per month or more, was determined to be 4.7% (1.0% in men and 8.7% in women). The mean age of the subjects with frequent headache was 50; the mean age at onset of the frequent headaches was 38 years. The prevalence of chronic tension-type headache was determined to be 2.2% and that of transformed migraine 2.4%. Overuse of abortive medications was found to be the case in 19% of the patients with chronic tension-type headache and in 31% of those with transformed migraine. With regard to frequent headache, Langemark et al. (1988) studied the clinical features of 148 patients with chronic tension headache. The patients had to have at least 10 days with headache per month and no more than one migraine attack. Ninety-three percent of them turned out to have at least 28 days with headache per month, that is, daily headaches (Fig. 213-1). With regard to headache dynamics, this suggests that once headaches have increased to a frequency of 2 or 3 days per week, they rapidly progress to daily or almost daily occurrence. The implication of this observation for the diagnostic criteria of chronic daily headache is that there is no need for an arbitrary number of headaches. The diagnostic criterion for the condition with regard to frequency of headache could simply be “daily or almost daily,” and the same simplification can be made for chronic tension-type headache. Everything that falls short of this frequency criterion would be episodic, that is, episodic tension-type headache or (episodic) migraine. It also means that the prevalence of frequent headache can be equated with that of daily headache. On the basis of the above studies and taking the study by Langemark et al. (1988) into account, it can be safely stated that

the prevalence of daily headache in the general population is approximately 5%. About half of it is accounted for by chronic tension-type headache as defined by the IHS. With regard to the age and gender characteristics of chronic daily headache, women are affected two times more often than men are, but age does not seem to have much of an effect on the prevalence of the condition. The prevalence of chronic tension-type headache in the general population, as defined by the IHS, was also separately determined in Denmark. The study included 740 (76%) of 975 randomly selected subjects out of a total population of 325,621. The subjects were clinically interviewed, generating a prevalence number for chronic tension-type headache of 3% (2% in men and 5% in women). It can therefore be safely stated that the prevalence of IHS-defined chronic tension-type headache in the general population is 2% to 3%, which accounts for about half of daily headache. PRESENTATION In a study of chronic daily headache that my colleagues and I conducted, we defined the condition as headaches occurring at least 5 days per week for a period of 1 year or longer. We excluded only the patients with paroxysmal daily headaches, that is, cluster headache and paroxysmal hemicrania, to capture as much of the presentation, development, and outcome of chronic daily headache as possible. The study was conducted in 258 patients from my private headache practice, 19% men and 81% women; their average age at consultation was 42 years. The age distribution of any headache onset for the men and women separately is shown in Figure 213-2. Seventy-seven percent of the patients (69% of the men and 79% of the women) experienced the onset of headache before age 30. The onset of headache occurred in the second decade of life in 36% of the women, as opposed to 24% of the men. The peak of headache onset in the second decade in women is consistent with the importance of the menstrual cycle in headache occurrence. With regard to diurnal pattern, the daily headaches were present on awakening or came on in the morning in 79% of the patients, came on in the afternoon or evening in 6%, and had a variable time of onset in 15% (Fig. 213-3). In 25% the headaches were worst on awakening or in the morning; in 53% they were worst in the afternoon or evening, and in 22% they were worst at a variable time of the day. The results agree with my clinical observation that daily headaches come in two distinct diurnal patterns. The most common pattern is that in which the headaches gradually increase in intensity as the day progresses, to be worst in the afternoon or evening. According to the results of the study, this is the pattern in more than half of the patients with chronic daily headache. The less common pattern, which I have called reversed diurnal pattern, is that in which the headaches are worst on

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Headache Syndromes and Their Treatment

awakening in the morning and gradually improve as the day progresses. This was the case in a quarter of the patients, and in the remaining quarter the diurnal course of the headaches was variable. In my experience, the reversed diurnal pattern is particularly associated with the overuse of analgesics and vasoconstrictors for headache. Overuse in this context is defined as medication intake that is detrimental rather than beneficial to headache. In the reversed diurnal pattern, the severe headaches on awakening in the morning are caused by the withdrawal of medication overnight, and the gradual improvement during the day results from the resumption of medication intake. This scenario is also associated with the most frequent nighttime awakenings with headache. In our study, nocturnal awakening by headache occurred at least once per week in 36% of the patients. Of the patients who were woken up by headache at least once per week, 48% experienced the worst headache on awakening or during the morning, as opposed to 22% of the patients who were woken up by headache less than once per week. Ninety-four percent of the patients experienced severe headaches in addition to the daily headaches. The distribution of the frequency of the severe headaches in days per month is shown in Figure 2 13-4. Twenty-six percent of the patients experienced severe headaches more than 15 days per month. Sixty-three percent experienced severe headaches 10 days per month or less.

The results suggest that the majority of patients with chronic daily headache who seek specialty care for their headaches do not have chronic tension-type headache. They have chronic tension-type headache combined with migraine, or tension-type vascular headache. In the development of chronic daily headache, medication use is considered to play an important role, particularly the intake of analgesics and vasoconstrictors. A widely used vasoconstrictor for the abortive treatment of headache is caffeine in beverages, especially coffee, but also in prescription and nonprescription medications. We established the caffeine intake in our patients with chronic daily headache by looking at their coffee and medication intake. A cup of coffee was considered to contain 100 mg of caffeine. We found that 43% of the patients used less than 100 mg of caffeine per day, 35% between 100 and 300 mg, and 22% more than 300 mg. The average caffeine intake was 170 mg per day, which is approximately the equivalent of two cups of coffee. With regard to analgesic use, we considered only the nonopioid medications because the patients rarely used opioids to treat their headaches. Of the barbiturate-containing medications, we did not take into account the barbiturate component because it is not strictly an analgesic. With these limitations, we found that 26% of the patients used less than 500 mg of aspirin equivalents per day and 48% less than 1500 mg. The average analgesic intake was 1860 mg of aspirin equivalents per day.

FIG. 113-2. Distribution of the age of headache onset by gender (n = 251). (From Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38:191-196, 1998, with permission.)

FIG. 213-3. Diurnal pattern of daily headaches (n = 214). (From Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38:191-196, 1998, with permission.)

Chapter 213

Chronic Daily Headache

1351

FIG. 213-4. Frequency of the severe headaches in days per month (n = 197). (From Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38991196, 1998, with permission.)

FIG. 213-5. Distribution of the age of daily headache onset in the patients with primary chronic daily headache (n = 50). (From Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38: 191-1 96, 1998, with permission.)

TMU 213-1. Circumstances of Abrupt Onset of Daily Headaches

DEVELOPMENT Of the 230 patients in the study with known onset of the daily headaches, 22% experienced daily headaches from the onset. This could be called primary chronic daily headache, in the same way as we speak of primary and secondary chronic cluster headache. The remaining 78% initially experienced intermittent headaches, that is, had secondary chronic daily headache. The distribution of the age of onset of (daily) headaches in the patients with daily headaches from the onset, or primary chronic daily headache, is shown in Figure 213-5. Sixty-six percent of the patients experienced the onset of the daily headaches between ages 10 and 39. Of the patients with daily headaches who initially had intermittent headaches, that is, of those with secondary chronic daily headache, 19% experienced an abrupt onset of the daily headaches and 81% a gradual one. The distribution of the age of onset of the daily headaches in the patients with abrupt-onset secondary chronic daily headache is similar to that of the patients with primary chronic daily headache shown in Figure 213-5. The circumstances related to the onset of the daily headaches in the patients with primary chronic daily headache and in those with abrupt-onset secondary chronic daily headache are shown in Table 213-1. The table also shows the circumstances of daily headache onset for the two groups combined because there was no

Abrupt-onset Secondary Chronic Daily Headache In = 34)

Combined Croup In = 85)

25%

29%

27%

12%

18%

14%

14%

15%

14%

18% 31%

12%

15%

26%

30%

Primary Chronic Daily Headache In = 511 ~~

Head, neck, or back iniuy Flulike illness or sinusitis Medical illness or surgical procedure Miscellaneous No apparent reason

~

~

difference in distribution of the circumstances between the two groups. The most common circumstance of daily headache onset in the two groups combined was head, neck, or back injury, caused by a motor vehicle accident in 61%. It is followed by flulike illness or sinusitis and medical illness or surgical procedure as causes of daily headache onset. Examples of medical illness associated with

1352 40 1

Headache and Pain H Headache Syndromes and Their Treatment

V

-- -0

the abrupt onset of chronic daily headache are colitis, fibromyalgia, vertigo, encephalitis, and meningitis. There were also no differences between the patients with primary chronic daily headache and those with abrupt-onset secondary chronic daily headache with regard to the following features: gender distribution, time of daily headache occurrence, worst headache time daily, nocturnal headache awakening, laterality of the daily headaches, Occurrence and frequency of severe headaches, laterality of the severe headaches, and parental occurrence of headache. The only difference between the two groups was the association of the daily and severe headaches with nausea. Nausea was more common in the patients with abruptonset secondary chronic daily headache than in those with primary chronic daily headache. The difference probably results from the fact that 57% of the patients in the abrupt-onset group had a history of severe headaches, which tend to be associated with gastrointestinal symptoms. The distribution of the age of onset of the daily headaches in the patients with gradual-onset secondary chronic daily headache is shown in Figure 213-6. Seventy-eight percent of the patients experienced the onset of the daily headaches between ages 20 and 49. The distribution of the age of onset of the initial, intermittent headaches in these patients is also shown in Figure 213-6. The average duration of the transition of the headaches from intermittent to daily was 11 years, which is reflected in the figure by the separation of the two distributions by approximately a decade. With regard to parental occurrence, headache in the father or mother was more common in the patients with gradual-onset secondary chronic daily headache than in the combined group of those with primary chronic daily headache and abrupt-onset secondary chronic daily headache (69% versus 45%). This is interesting because conditions that develop abruptly generally have less of a genetic involvement than those that develop gradually. On the basis of the information gathered on parental headache occurrence, this also seems to be the case in chronic daily headache. With regard to the intensity of the initial headaches, in the 145 patients with gradual-onset secondary chronic daily headache, the headaches were mild in 33% and severe in 67% (Table 213-2). The mild headaches were associated with nausea in 25% and vomiting in O%, as opposed to the severe headaches, which were associated with nausea in 84% and vomiting in 72%. With regard to the frequency of the initial headaches, there was no difference between the mild and severe headaches. The mild headaches occurred less than twice per week in 88% and the severe headaches in 91%.

Age of daily headache onset Age of initial headache onset

FIG. 213-6. Distribution of the age of initial and daily headache onset in the patients with gradual-onset secondary chronic daily headache (n = 106 and 145, respectively). (From Spierings ELH, Schroeven M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38: 191-1 96, 1998, with permission.)

TABU213-2. Features of Initial Headaches in Patients with Gradual-Onset Secondary Chronic Daily Headache Mild

Headache intensity (n = 1 12) Associated symptoms Nausea Vomiting Headache frequency 34 per month 5-9 per month 10-1 9 per month 220 per month

Severe

33qo (n = 12)

67%

25%

84% 72%

0% (n = 25)

(n = 61) (n = 60)

60%

73%

28% 8%

18% 7%

4%

2%

The features of the daily headaches that these patients ultimately developed were the same, whether the initial headaches were mild or severe in intensity. They were the same with regard to age of onset of the initial headaches, gender distribution, diurnal headache pattern, nocturnal headache awakening, associated symptoms and laterality of the daily headaches, occurrence of severe headaches, and the frequency, associated symptoms, and laterality of the severe headaches. From a classification perspective, does it make sense to distinguish between primary and secondary chronic daily headache as we did and, within the latter group, between abrupt and gradual onset? Judging from the age of onset of the daily headaches, gender distribution, headache presentation, circumstances of headache onset, and parental headache occurrence, there does not seem to be a reason for the distinction between primary chronic daily headache and secondary chronic daily headache with abrupt onset. The two groups probably should be considered to have the same chronic daily headache condition, which could be called abrupt-onset chronic daily headache, representing 37% of our study group. However, this group probably should be distinguished from the one with chronic daily headache with gradual onset because of the very different development of the headaches and the difference in parental headache occurrence. The latter condition could be called gradual-onset chronic daily headache, and future studies will determine whether this distinction is meaningful in terms of predicting treatment or outcome. HEADACHE CONTINUUM

The aforementioned findings with regard to the development of chronic daily headache support the headache continuum as

Chapter 213 rn Chronic Daily Headache

proposed by the author and shown schematicallyin Figure 213-7. The headache continuum includes episodic and chronic tensiontype headache, migraine, and tension-type vascular headache. Tension-type headache and migraine are the two most common headache conditions. Episodic tension-type headache is almost universally experienced, whereas migraine affects 10% to 15% of the population. The major distinction between the two, in my opinion, is the intensity of the headaches. Headache intensity is traditionally divided into three categories (mild, moderate, and severe) depending on the extent to which the headache affects the ability to function. A mild headache does not affect the ability to function, a moderate headache affects the ability to function but does not necessitate bed rest, and a severe headache is incapacitating and necessitates bed rest. Tension-type headaches are mild or moderate in intensity, whereas migraine headaches are moderate or severe. Related to the (peripheral) mechanisms involved in causing the pain, the migraine headache is localized, whereas the tension-type headache is more diffuse. The migraine headache is localized not only to one side of the head but within the side of the head, to areas such as the temple or eye. The pain tends to be throbbing or sharp and steady, whereas the pain of tension-type headache is more dull and steady. Also related to the mechanisms involved in causing the pain, the migraine headache is affected by movement and activity, which is not the case with tension-type headache. The migraine headache often develops during the night and is present on awakening in the morning or wakes the patient up out of sleep at night, usually between 4 and 6 AM. Episodic tension-type headache generally comes on during the day, often in the late afternoon, that is, between 4 and 6 PM. The episodic tension-type headache lasts a couple of hours, whereas the migraine headache lasts from part of a day to several days. Related to the low intensity of the pain, tension-type headache has few, if any, symptoms associated with it, and when symptoms are present they are mild. The migraine headache has intense associated symptoms related to the high intensity of the pain. Almost universally present in migraine are photophobia and phonophobia; however, nausea also is common, and with the most intense migraine headaches vomiting occurs as well.

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There is ongoing debate with regard to the mechanisms involved in causing the pain of tension-type headache and migraine. It is my belief that peripheral mechanisms are important in both headache conditions, although the present thinking is more oriented toward central mechanisms. In tension-type headache, the peripheral mechanism is that of sustained contraction of the craniocervical muscles and in migraine that of extracranial arterial vasodilation. The arterial vasodilation in migraine activates a secondary mechanism, which is known as neurogenic inflammation. Stretching of the nerve fibers involved in pain transmission (A6 and C) surrounding the blood vessels causes the neurogenic inflammation. The stretching causes the nerve fibers to depolarize, which generates the action potentials that are transmitted to the central nervous system. It also causes the release of inflammatory chemicals into the peripheral tissues, such as substance P and calcitonin gene-related peptide. The inflammatory chemicals act to further dilate the arteries and also lower the pain threshold locally in the peripheral tissues. Thus, a vicious cycle is created in which vasodilation causes inflammation, which in turn accentuates the vasodilation and renders it extremely painful. When headaches occur regularly, they lead through an involuntary reflex mechanism to progressive tightening of the craniocervical muscles. The greater intensity of the pain makes this effect more pronounced in migraine than in tension-type headache. Therefore muscular symptoms are more prominent in patients with migraine than in those with tension-type headache. Contributing factors to the process of tightening of the craniocervical muscles are treatment of tension-type headaches with analgesics (as opposed to efforts to relax the muscles) and lack of effective abortive treatment in migraine. In tension-type headache, the progressive increase in tightness of the craniocervical muscles leads over time to an increase in frequency of the headaches. It also leads to a progressive earlier occurrence of the headaches during the day. Ultimately, a daily or almost daily headache condition develops in which the headaches are present on awakening or come on shortly after the patient gets up. As long as the headaches remain mild or moderate in intensity, the condition can be called chronic tension-type headache. How-

vascular headache

FIG. 213-7. The continuum of headache syndromes, which includes episodic and chronic tension-type headache, migraine, and tension-type vascular headache.

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Headache and Pain H Headache Syndromes and Their Treatment

ever, once the headaches have taken up all available time, they tend to increase in intensity to create migraine headaches. The condition is then called migraine with chronic tension-type headache. However, a better term would be tension-type vascular headache, emphasizingthe existence of one single headache condition rather than suggesting the presence of two separate ones. When the regular occurrence of migraine headaches leads to a progressive increase in tightness of the craniocervical muscles, a gradual increase in frequency of the headaches occurs as well as a progressive interposition of the migraine headaches with tensiontype headaches. The increase in frequency of the migraine headaches results from the fact that the muscle tightness in itself becomes a trigger of migraine headaches. As the muscles become tighter, they begin to interfere mechanically with their own circulation, creating a stimulus for dilation of the feeding arteries. One such feeding artery is the frontal branch of the superficial temporal artery, which overlies the powerful temporalis muscle. This is also the artery that is involved preferentially in migrainous vasodilation, causing the throbbing or sharp, steady pain in the temple so characteristic of migraine. Ultimately, the migraine and tension-type headaches merge into a condition of daily or almost daily headaches with frequent migraine headaches. A condition is thus created that is identical to what has been described earlier as migraine with chronic tension-type headache or tension-type vascular headache. However, the difference is that here the condition developed out of migraine, whereas the one described earlier developed out of episodic tension-type headache. OUTCOME Of the 145 patients in our study with gradual-onset (secondary) chronic daily headache, we were able to contact 91 (63%). Seven patients refused to participate in the follow-up telephone interview, and 11 no longer remembered the nature of their initial headaches. One patient was excluded from the analysis because of the absence of headaches at the time of contact and three patients because of missing data. The remaining 69 patients (76%) were able to provide adequate information to classify their initial and present headaches as tension-type headache or migraine according to IHS criteria. Twenty-three of the 69 patients (33%) still had daily headaches, and the remaining 46 (67%) again experienced intermittent headaches. Of the latter 46 patients, the initial headaches were classified as migraine in 39 (85%) and as tension-type headache in 7 (15%). Their present headaches were classified as migraine in 34 (74%) and as tension-type in 12 (26%). Thus, over time a shift had occurred from migraine to tension-type headache, accomplishing an improvement of the intermittent headaches for the group as a whole. However, the question that we wanted to address was not whether the patients with intermittent headaches had improved in comparison to their initial headaches, but whether patients with gradual-onset chronic daily headache revert to their initial headache condition once the headaches become intermittent again. Of the 39 patients whose initial headaches were classified as migraine, 30 (77%) also had migraine at follow-up, and 9 (23%) had tension-type headache. Of the 7 patients whose initial headaches were classified as tension-type headache, 3 (43%) had tension-type headache at follow-up and 4 (57%) migraine. Therefore, it seems that after going through daily headaches, patients with migraine as a rule revert back to migraine, although some find their headaches improved to the extent that they are

classified as episodic tension-type headache. The numbness for the patients who initially had episodic tension-type headache are too small to allow a meaningful interpretation. TREATMENT The first step in treating chronic daily headache is to accurately establish the use of analgesics and vasoconstrictors, prescription and nonprescription. It is important to establish their use in terms of the number of tablets or capsules taken per day and the number of days of use per week or month. Patients are notoriously vague about their intake of medications that they take as needed only. They also often have to be reminded specifically with regard to the use of nonprescription medications. Once the exact intake of analgesics and vasoconstrictors has been established, it must be determined whether there is overuse. As mentioned earlier, overuse is defined as medication intake that is detrimental rather than beneficial to headache. It is use that promotes the long-term occurrence of headache rather than providing headache relief. Analgesics and vasoconstrictors promote headache if they are taken for headache at time intervals shorter than their duration of action. Therefore, when these medications are allowed to accumulate in the system and bring on headache when their effect wears off, a phenomenon occurs that has become known as rebound. Rebound headache generally occurs when analgesics or vasoconstrictors are taken more often than 2 days per week on the average. This is particularly true for caffeine-containing medications because of the prolonged vasoconstrictor effect of caffeine, which can last for up to 60 hours. A higher-frequency of intake of analgesics or vasoconstrictors can be allowed for simple analgesics and the shorter-acting triptans, such as sumatriptan. A lower frequency of intake must be considered with the longer-acting ergots, ergotamine and dihydroergotamine. However, it has to be kept in mind that the rebound threshold has not been determined for any medication or group of medications. Also, the diagnosis of rebound headache can be made only retrospectively, after withdrawal from analgesics or vasoconstrictors has been accomplished and improvement of headaches has occurred. A suspicion of rebound headache can be based not only on the frequency of medication intake but also on increased medication use over time with decreasing efficacy(Fig. 213-8). The decreasing efficacy often is attributed to the development of tolerance, but in my opinion it is more a manifestation of worsening of the headaches and an indication that use has become overuse. If it is suspected that medication overuse and rebound headache are present, this must be addressed next. However, it can be addressed only after the patient has been given insight into the situation. With regard to vasoconstrictors, reference can be made to the vascular mechanism of headache. The vascular mechanism is antagonized by the vasoconstrictors, resulting in rebound vasodilation and headache recurrence when the vasoconstrictor effect wears off. Analgesics address only the pain of the headache and not the underlying mechanisms. Consequently, and as with symptomatic treatment in general, the underlying mechanisms deteriorate, resulting in worsening of the headaches. The withdrawal of analgesics or vasoconstrictors is generally best accomplished abruptly. However, whether that is possible also depends on the kind and quantity of the medications taken. When specific quantities of barbiturate-containing or opioid medications are involved, withdrawal may necessitate hospitalization for close monitoring of withdrawal symptoms and intravenous administration of medications. The withdrawal of a significant

Chapter 213 W

1355

Chronic Daily Headache

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amount of barbiturate-containing medications also must be tapered to prevent seizure. Withdrawing a significant amount of opioid medications takes expertise in addiction medicine and may have to be done in a detoxification center. Otherwise, it can be accomplished on an outpatient basis, and several protocols have been developed to assist the patient with the withdrawal. A recent protocol uses sumatriptan for withdrawal headache after abrupt discontinuation of the rebound-causing medications. The sumatriptan is given in a dose of 25 mg orally three times per day for 10 days or until the patient is headache-free for 24 hours. After that it is used only as needed for the abortive treatment of moderate or severe headache. Of the 35 sequentially selected patients enrolled in a study using this particular protocol, 9 left the clinic and 26 were treated. They had suffered from daily headaches for an average of 8.2 years. Of the 26 patients treated, 58% no longer experienced daily headaches after 1 month, and 69% had reverted to intermittent headaches after 6 months. An outpatient protocol that I have used successfully for the last 15 years to withdraw patients with daily headaches from daily or almost-daily use of abortive medications is a short course of prednisone. Depending on the kind and quantity of the medications that the patient has to be withdrawn from, I give the prednisone for 3 or 6 days. The 3-day schedule consists of 15 mg prednisone four times per day for 1 day, 10 mg four times per day for 1 day, and 5 mg four times per day for 1 day; the days are doubled in the 6-day schedule. If the patient exhibits prominent muscular symptoms, that is, complains of tight or sore neck and shoulder muscles, I add diazepam to the schedule in a dose of 1 to 5 mg four times per day to help to relax the muscles.

I have used a similar schedule for patients admitted to the hospital when outpatient withdrawal was unsuccessful because of inability of the patient to tolerate the withdrawal headache or its association with severe nausea or vomiting. Under these circumstances, I add metoclopramide as an antinausea medication, which I give intravenously in a dose of 10 mg four times per day. It is important to start the metoclopramide immediately, that is, before the patient becomes sick, because once vomiting has developed, it is difficult to control even with intravenous administration of the medication. Instead of prednisone orally, dexamethasone can be given intravenously, in a dose of 4 mg four times per day, for a number of consecutive days. The diazepam can then be given every 6 hours, but only as needed for severe headache, and can also be given intravenously. An alternative to diazepam intravenouslyis lorazepam intramuscularly in a dose of 1 or 2 mg as needed every 6 hours. An alternative to these protocols is that with metoclopramide and dihydroergotamine. In this protocol, both medications are given intravenously on a regular, generally 8-hour schedule, with the metoclopramide administered before the dihydroergotamine. The latter is done this way to prevent the occurrence of nausea or vomiting as a result of the intravenous administration of dihydroergotamine. The metoclopramide dose usually is 10 mg, whereas that of dihydroergotamine is gradually increased from 0.25 to 1 mg, depending on the patient's ability to tolerate the medication, especially in terms of its gastrointestinal side effects. A long-term follow-up study of 50 consecutivepatients with chronic daily headache treated with an intravenous dihydroergotamine protocol showed 44% to have good or excellent results after 3 months and 59% after 2 years.

~

1356

Headache and Pain

Headache Syndromes and Their Treatment

After withdrawal from analgesics or vasoconstrictors, headaches may improve for up to 3 months. Often preventive pharmacologic treatment is initiated immediately after the withdrawal, but I generally do not do that. An exception is when the patient has problems sleeping at night, for which I prescribe amitriptyline, doxepin, or trazodone. These are sedating tricyclics and tetracyclics of which the first two have also been shown to be effective in the preventive treatment of chronic tension headache. However, I recommend that patients immediately use nonpharmacologic treatments, such as using a heating pad daily on the neck and shoulders to help decrease the muscle tightness that many of these patients have developed over time. At a later stage, I may prescribe more formal physical therapy consisting of massage, ultrasound, and stretching exercises or do trigger point injections to further help to relax the muscles. For the daily headaches, I allow patients to use muscle relaxants such as metaxalone or carisoprodol. For severe headaches, promethazine 50-mg suppositories can be helpful as long as it is judged better for the patient not to use analgesics or vasoconstrictors. Once the headaches have become intermittent, I focus with the abortive treatment on the severe headaches, for which I try to find effective treatment, relying as much as possible on specific antimigraine medications. I define effective treatment as treatment that provides full relief of headache and associated symptoms within 2 hours of initiation. It is important for this treatment to be consistently effective as well, which would allow the patient to wait until the headache is severe before initiating it. This is the only way in which patients can be prevented from falling back over time into the pattern of frequent analgesic or vasoconstrictor use. With regard to preventive pharmacologic treatment, a particularly useful combination in patients with frequent and severe headaches is that of a tricyclic and a P-blocker. The tricyclics I prefer are amitriptyline, doxepin, and imipramine. The first two I prescribe when sedation is needed to help the patient fall asleep or sleep through the night. If sleep is not an issue, I prefer imipramine because it has fewer side effects, particularly increased appetite and weight gain. With regard to the P-blockers, six have been shown in randomized, double-blind, placebo-controlled studies to be effective in migraine prevention. These P-blockers are atenolol, bisoprolol, metoprolol, nadolol, propranolol, and timolol. In the patients with chronic daily headache, they are often effective in decreasing the intensity of the headaches, whereas the tricyclics tend to have more of an effect on headache frequency. The calcium entry blockers, particularly verapamil, are helpful if the headaches continue to wake the patient up out of sleep after analgesic or vasoconstrictor withdrawal. Kudrow (1982) determined the effect of analgesic withdrawal and preventive treatment with amitriptyline in 200 patients with chronic muscle-contraction headache who used analgesics daily, as documented by 1-month pretrial records. He randomly divided the patients into two groups and four subgroups. Half of the patients were prescribed amitriptyline (25 mg per day for 1 week and 50 mg per day thereafter). In each group, half of the patients were allowed to continue taking analgesics without restriction, and the other half was instructed to discontinue these medications. The percentage headache improvement he observed in the four groups is shown in Table 213-3. Analgesic withdrawal alone resulted in a 43% improvement 1 month after initiation of treatment. The addition of amitriptyline to the analgesic withdrawal increased the headache improvement to 72%.

TMU 213-3. Headache Improvement 1 Month after Initiation of Treatment in 200 Patients with

Chronic Muscle-Contraction Headache Who Used Analgesics Daily ImDrovement

Treated with arnitriptyline Analgesics continued (n = 50) Analgesics withdrawn (n = 50) Not treated with arnitriptyline Analgesics continued (n = 50) Analgesics withdrawn (n = 50)

30% 72% 18% 43%

Our study suggests that with the treatment approach described in this chapter, two third of patients who have daily headaches can be improved to intermittent headaches. Preventive treatment in these patients may make the intermittent headaches somewhat better than what they were initially, as is suggested by the shift from migraine to tension-type headache observed in our study, when the present headaches were compared with those that occurred initially. However, for patients who continue to have frequent and severe headaches, despite being off analgesics and vasoconstrictors and despite efforts at preventive treatment, there may be an indication for the use of long-acting opioids to relieve the pain and allow these patients to function. The long-acting opioids I have used in these patients are fentanyl patch, oxycodone, and morphine sulfate. I have found these medications to work shorter than the manufacturers indicate, so I use the fentanyl patch every 2 rather than 3 days and long-acting oxycodone every 6 or 8 rather than 12 hours, for example. I gradually increase the dose of the medication until satisfactory pain control is achieved and the patient is back to a normal level of functioning. I prefer the use of long-acting to short-acting opioids because of less development of tolerance and addiction. For some reason, rebound headache does not seem to develop with the long-acting opioids, whereas it typically occurs with short-acting analgesics, including opioids. The development of tolerance and rebound headache both increase the use of opioid analgesics over time and make it very difficult, if not impossible, to accomplish adequate pain control. HEMICRANIA CONTINUA As far as its presentation is concerned, hemicrania continua can be seen as a form of chronic daily headache. It is a nonparoxysmal daily headache, present continuously throughout the day, limited to one side of the head. However, it is different from chronic daily headache in its treatment. Hemicrania continua is treated with indomethacin, to which it has an absolute response similar to paroxysmal hemicrania. The different treatment suggests a different cause, which would preclude the condition from being grouped together with chronic daily headache. It has been suggested that there is a form of hemicrania continua resistant to preventive treatment with indomethacin. However, resistance to indomethacin treatment by definition means that it is not hemicrania continua. This does not mean that there are not numerous patients who have continuous unilateral headaches with fixed lateralization that do not respond preventively to indomethacin. These patients have chronic daily headache and should be treated accordingly. The key to look for in the history is a response to aspirin, which seems to predict the

Chapter 214

responsiveness of the headaches to indomethacin. This is also the feature that ultimately led to the identification of both paroxysmal hemicrania and hemicrania continua as indomethacin-responsive headache syndromes. SUGGESTED READINGS Castillo J, MuNoz P, Guitera V, Pascual J: Epidemiology of chronic daily headache in the general population. Headache 39:190-196, 1999 Drucker P, Tepper S: Daily sumatriptan for detoxification from rebound. Headache 38:687490, 1998 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):1-96, 1988 Instituut Epidemiologie: Epidemiologisch Preventief Onderzoek Zoetermeer (EPOZ): Tweede en Derde Voortgangsverslag. Erasmus University, Rotterdam, The Netherlands, 1976 Kudrow L: Paradoxical effects of frequent analgesic use. Adv Neurol 33:335-341, 1982

Cluster Headache and Paroxysmal Hemicrania

1557

Langemark M, Olesen J, Loldrup D, Bech P Clinical characterization of patients with chronic tension headache. Headache 28:590-596, 1988 Rasmussen BK, Jensen R, Schroll M, Olesen J: Epidemiology of headache in a general population: a prevalence study. J Clin Epidemiol44:11471157, 1991 Scher AI, Stewart WF, Liberman J, Lipton RE%:Prevalence of frequent headache in a population sample. Headache 38497-506, 1998 Silberstein SD, Silberstein J R Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE. Headache 32:439445, 1992 Sjaastad 0, Spierings ELH: “Hemicrania continua”: another headache absolutely responsive to indomethacin. Cephalalgia 465-70, 1984 Spierings ELH: Headache continuum: concept and supporting evidence from recent study of chronic daily headache. Clin J Pain 17:337-340, 2001 Spierings ELH, Ranke AH, Schroevers M, Honkoop P C Chronic daily headache: a time perspective. Headache 40:306-3 10,2000 Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38:191-196, 1998 Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Development of chronic daily headache: a clinical study. Headache 38:529-533, 1998

2 14 Cluster Headache and Paroxvsmal Hemicrania David Kudrow Of all primary headache disorders, cluster headache and paroxysmal hemicrania are most stereotypic in presentation and, in general, most amenable to medical management. Differences between the two disorders are so subtle as to present difficulties in their classification. For example, both conditions share the same site of painful attacks, associated autonomic symptoms, and episodic and chronic states. Although the frequency and duration of cluster headache attacks generally differ from those of paroxysmal hemicrania, these features may overlap to make diagnosis difficult and to call into question the distinctiveness of these disorders. Yet there is one characteristic that distinguishes one disorder from the other: response to preventive medications. The diagnosis of paroxysmal hemicrania is ensured when a complete response to indomethacin has occurred; with few exceptions, cluster headache does not respond to indomethacin prevention. Conversely, cluster headache is quite responsive to preemptive treatment with verapamil, lithium, or ergotamine, but paroxysmal hemicrania is completely refractory to these medications. The currently accepted classification system holds that paroxysmal hemicrania is a subcategory of cluster headache, as are other variants. Classification of these disorders, as recently established by the International Headache Society, is presented in Table 2 14- 1.

It should be noted that the current classification of headache disorders reflects only our current knowledge of this topic and is subject to change with improved understanding. Therefore, classification is a dynamic process. CLUSTER HEADACHE Prevalence, Age, Sex, and Habits

Cluster headache is believed to occur in approximately 0.4% of men and in one fifth of that number in women. The mean age of onset of cluster headache is 30; the mean age of onset for women and chronic patients is older. Onset in early childhood has been reported. Curiously, nearly 80% of patients with cluster headache smoke or have smoked tobacco, and approximately 50% give a history of at least moderate alcohol intake. Patients with cluster headache are also more likely to have sustained head injury with loss of consciousness than control populations. The significance of these factors in cluster headache is unclear, but many have suggested that they are components of a “cluster personality.” Family History

TABLE21 4-1. Classification of Cluster Headache Cluster headache Periodicity undetermined Episodic Chronic Primary chronic Secondary chronic Chronic paroxysmal hemicrania Cluster headache-like syndrome

3.1 3.1.1 3.1.2 3.1.3 3.1.3.1 3.1.3.2 3.2 3.3

Seven to ten percent of patients with cluster headache give a positive family history of cluster headache in at least one relative, which is a much greater occurrence than would be expected in the general population. Inheritance analyses suggest a possible autosomal dominant pattern of transmission. Also, the family history of migraine among relatives of patients with cluster headache is similar to that for relatives of patients with migraine, suggesting that inheritance of cluster headache may depend on a linkage to migraine genetics.

Chapter 214

responsiveness of the headaches to indomethacin. This is also the feature that ultimately led to the identification of both paroxysmal hemicrania and hemicrania continua as indomethacin-responsive headache syndromes. SUGGESTED READINGS Castillo J, MuNoz P, Guitera V, Pascual J: Epidemiology of chronic daily headache in the general population. Headache 39:190-196, 1999 Drucker P, Tepper S: Daily sumatriptan for detoxification from rebound. Headache 38:687490, 1998 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):1-96, 1988 Instituut Epidemiologie: Epidemiologisch Preventief Onderzoek Zoetermeer (EPOZ): Tweede en Derde Voortgangsverslag. Erasmus University, Rotterdam, The Netherlands, 1976 Kudrow L: Paradoxical effects of frequent analgesic use. Adv Neurol 33:335-341, 1982

Cluster Headache and Paroxysmal Hemicrania

1557

Langemark M, Olesen J, Loldrup D, Bech P Clinical characterization of patients with chronic tension headache. Headache 28:590-596, 1988 Rasmussen BK, Jensen R, Schroll M, Olesen J: Epidemiology of headache in a general population: a prevalence study. J Clin Epidemiol44:11471157, 1991 Scher AI, Stewart WF, Liberman J, Lipton RE%:Prevalence of frequent headache in a population sample. Headache 38497-506, 1998 Silberstein SD, Silberstein J R Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE. Headache 32:439445, 1992 Sjaastad 0, Spierings ELH: “Hemicrania continua”: another headache absolutely responsive to indomethacin. Cephalalgia 465-70, 1984 Spierings ELH: Headache continuum: concept and supporting evidence from recent study of chronic daily headache. Clin J Pain 17:337-340, 2001 Spierings ELH, Ranke AH, Schroevers M, Honkoop P C Chronic daily headache: a time perspective. Headache 40:306-3 10,2000 Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Presentation of chronic daily headache: a clinical study. Headache 38:191-196, 1998 Spierings ELH, Schroevers M, Honkoop PC, Sorbi M: Development of chronic daily headache: a clinical study. Headache 38:529-533, 1998

2 14 Cluster Headache and Paroxvsmal Hemicrania David Kudrow Of all primary headache disorders, cluster headache and paroxysmal hemicrania are most stereotypic in presentation and, in general, most amenable to medical management. Differences between the two disorders are so subtle as to present difficulties in their classification. For example, both conditions share the same site of painful attacks, associated autonomic symptoms, and episodic and chronic states. Although the frequency and duration of cluster headache attacks generally differ from those of paroxysmal hemicrania, these features may overlap to make diagnosis difficult and to call into question the distinctiveness of these disorders. Yet there is one characteristic that distinguishes one disorder from the other: response to preventive medications. The diagnosis of paroxysmal hemicrania is ensured when a complete response to indomethacin has occurred; with few exceptions, cluster headache does not respond to indomethacin prevention. Conversely, cluster headache is quite responsive to preemptive treatment with verapamil, lithium, or ergotamine, but paroxysmal hemicrania is completely refractory to these medications. The currently accepted classification system holds that paroxysmal hemicrania is a subcategory of cluster headache, as are other variants. Classification of these disorders, as recently established by the International Headache Society, is presented in Table 2 14- 1.

It should be noted that the current classification of headache disorders reflects only our current knowledge of this topic and is subject to change with improved understanding. Therefore, classification is a dynamic process. CLUSTER HEADACHE Prevalence, Age, Sex, and Habits

Cluster headache is believed to occur in approximately 0.4% of men and in one fifth of that number in women. The mean age of onset of cluster headache is 30; the mean age of onset for women and chronic patients is older. Onset in early childhood has been reported. Curiously, nearly 80% of patients with cluster headache smoke or have smoked tobacco, and approximately 50% give a history of at least moderate alcohol intake. Patients with cluster headache are also more likely to have sustained head injury with loss of consciousness than control populations. The significance of these factors in cluster headache is unclear, but many have suggested that they are components of a “cluster personality.” Family History

TABLE21 4-1. Classification of Cluster Headache Cluster headache Periodicity undetermined Episodic Chronic Primary chronic Secondary chronic Chronic paroxysmal hemicrania Cluster headache-like syndrome

3.1 3.1.1 3.1.2 3.1.3 3.1.3.1 3.1.3.2 3.2 3.3

Seven to ten percent of patients with cluster headache give a positive family history of cluster headache in at least one relative, which is a much greater occurrence than would be expected in the general population. Inheritance analyses suggest a possible autosomal dominant pattern of transmission. Also, the family history of migraine among relatives of patients with cluster headache is similar to that for relatives of patients with migraine, suggesting that inheritance of cluster headache may depend on a linkage to migraine genetics.

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Headache and Pain W

Headache Syndromes and Their Treatment

Cllnlcal Presentation

Few disorders in medicine are as identifiable and as stereotypical from patient to patient as cluster headache because of the characteristic periodicity of the syndrome and the attack features (Table 214-2). There are essentially two varieties of cluster headache: episodic (about 80% of cluster sufferers) and chronic (20%). In episodic cluster headache, the patients experience periods of headache susceptibility lasting from 2 weeks to 3 months, with a mean duration of 2 months. They may experience one or two cluster periods per year, but this is variable, and some patients may have remissions of 9 years or longer. During remission, cluster attacks do not occur, nor can they be precipitated. The absence of a remission for at least 1 year defines chronic cluster headache. In primary chronic cluster headache, patients are chronic from the outset, whereas in secondary chronic cluster the chronic phase follows an initial episodic pattern. The pain of a cluster headache is excruciating and one of the most dreaded described in the headache literature. Its character usually is constant and boring rather than throbbing. Many patients describe a sensation of the eye being forced out from the inside. The mean frequency of cluster attacks in episodic cluster headache is one to three per day and in chronic cluster two to four per day. Attack frequencies may range from one to eight attacks per 24 hours. While in a cluster period, patients can experience almost precise periodicity to attack occurrence. The most common time for an attack is in the late afternoon, typically after work, while the patient is relaxing. Attacks also typically occur 90 minutes to 2 hours after the patient falls asleep at night, and some patients have only nocturnal attacks. Cluster headache is characterized by a short-lasting, discrete headache attack, which ranges from 15 minutes to 3 hours but is usually between 45 and 90 minutes. The location of pain in cluster headache is always unilateral and usually retro-orbital, frontotemporal, and less often suboccipital or maxillary. Although laterality may sometimes change from cluster period to cluster period, the headache always remains on the same side during a cluster period. The cluster attack typically is accompanied by autonomic phenomena, specifically lacrimation and rhinorrhea on the

TABLE 214-2. Diagnostic Criteria for Cluster Headache A. At least 5 attacks fulfilling B-D 8. Severe unilateral orbital, supraorbital, or temporal pain lasting 15 to 180 min untreated C. Headache associated with at least one of the following signs, which must be present on the pain side: 1. lacrimation 2. Conjunctival injection 3. Nasal congestion 4. Rhinorrhea 5. Forehead and facial sweating 6. Miosis 7. Ptosis 8. Eyelid edema D. Frequency of attacks: from 1 every other day to 8 per day E. At least one of the following: 1. History and physical and neurologic examination do not suggest one of the disorders listed in groups 5-1 1 2. History or physical or neurologic examination suggests such disorder, but it is ruled out by appropriate investigations 3. Such disorder is present, but cluster headache does not occur for the first time in close ternDora1 relation to the disorder

ipsilateral side. Also, during the cluster attack, patients may demonstrate a partial Horner’s syndrome (miosis and ptosis) and conjunctival injection. Nausea, vomiting, photophobia, and phonophobia are not characteristic features of cluster headache. In the midst of an attack, the cluster headache sufferer usually isolates himself or herself and paces around, rocks to and fro in a chair, or goes outdoors to get some air. The patient cannot lay flat or remain still. This motor agitation and movement is a pathognomonic feature of the cluster headache syndrome. When the acute attack is over, many patients describe a sense of euphoria or being drained of energy. Despite frequent, severe, and incapacitating headaches, loss of sleep, the need for frequent medication, and the stress of anticipating the next headache, very few cluster sufferers yield to their disorder, and most continue to work and lead productive lives. Lay resources, such as Internet support groups and newsgroups, often refer to cluster headache as “suicide headache,” without justification. We have followed more than 1300 patients with cluster headache since 1970 at the California Medical Clinic for Headache. Only one suicide was reported in this population, and that was in a patient who was not in his cluster period at the time of suicide. Differential Diagnosis As mentioned earlier, paroxysmal hemicrania most resembles

cluster headache and is discussed in greater detail later in this chapter. Other disorders to be differentiated from cluster headache include Raeder’s syndrome, pheochromocytoma, temporal arteritis, trigeminal neuralgia, and migraine (Table 214-3). Raedefs Syndrome. Raeder’s syndrome is similar to cluster headache in terms of pain intensity (early in its course), unilaterality, supraorbital distribution, and an associated partial Horner’s syndrome. Distinct from cluster headache is the persistence of the pain in Raeder’s syndrome. In the latter, there are no distinct attacks; pain is constant throughout. Pheochromocytoma. Headache attacks of another rare disorder, pheochromocytoma, are similar to those of cluster headache in that they may recur daily, last less than an hour, and have associated symptoms of tachycardia, sweating, and blood pressure changes. Additionally, pain may be exacerbated in the supine position. However, the headache of pheochromocytoma probably is bilateral and occipital in location. It should be noted that in the rare case of cluster headache, bioccipital attacks have been documented. Temporal Arteiltis. The headache of temporal arteritis generally is unitemporal in laterality and generally of mild to moderate intensity, but it may be severe. It is constant or waxing and waning, which distinguishes it from cluster headache. Other differentiating features include chewing claudication, a tender and pulseless temporal artery, and an elevated sedimentation rate. During some cluster attacks, however, the ipsilateral temporal artery may become distended, torturous, and tender and, as in temporal arteritis, have a burning quality. The finding of giant cells on temporal artery biopsy is diagnostic of temporal arteritis. Trigeminal Neuralgia. Trigeminal neuralgia is characterized by electric, lancinating paroxysms of only seconds in duration, often triggered solely by a tactile stimulus on the face. None of these features resemble cluster headache. Also, trigeminal neuralgia is apt to occur initially at an older age. However, there is a condition in which trigeminal neuralgia seems to be part of cluster

Chapter 214

Cluster Headache and Paroxysmal Hemicrania

1359

T a u 214-3. Differential Diagnosis of Cluster Headache Disorders

Frequency

Duration

Intensity

Location

Quality

Other

Raeder's syndrome Pheochromocytoma

Constant

Persistent

Severe

1 hour

Severe in supine

Burning, throbbing to nonthrobbing Throbbing

Partial Hornets syndrome

Daily to monthly

Temporal arteritis

Constant

Persistent

Moderate

Unilateral, supraocular Bilateral, occipital position Unilateral, temporal

Trigeminal neuralgia

Several per day

Seconds to minutes

Severe

Electric, lancinating

Migraine

1-3/month

6-36 hr

Severe

Unilateral, 5th nerve distribution Hemicranial 60%

Paroxysmal hemicrania (chronic and episodic) Cluster headache

4-30/day

3-45 min

Severe

Unilateral, periorbital

Boring

1-3/day

15-1 20 min

Severe

Unilateral, periorbital

Boring

headache; symptoms and signs of both disorders may be present at the same time or at different times. This is called cluster-tic syndrome. Migraine. Finally, migraine should be differentiated from cluster headache. For a majority of cases this presents little problem. Spontaneous migraine attacks are generally infrequent, occurring one to three times a month on average. Its duration is usually half a day to 3 or 4 days. Migraine headaches are bilateral in as many as 40% of cases, often associated with nausea and less often vomiting and temporally related to hormonal-menstrual changes in as many as 80% of attacks in women. Except in rare cases, migraine attacks are not associated with autonomic signs and symptoms, as characteristically found in cluster headache. Migraineurs tend to lay still in a dark, quiet room, fearful of any movement or exertion, which will increase the intensity of their pain and nausea. By contrast, patients with cluster headache cannot lie still and are constantly moving. It would seem from the foregoing that cluster headache could hardly be confused with migraine. This is true until one sees a patient with a variant called cluster-migraine. Patients with this disorder may present in two ways: with migraine attacks having cluster headache periodicity or with typical cluster attacks occurring monthly and having associated symptoms of both disorders.

Pathophysiology The cause of cluster headache is unknown. However, the possible pathogenesis of this disorder has been the subject of numerous reports. It is clear that its pathogenesis involves numerous systems, including central and peripheral neuronal and vascular systems, involving cranial nerves, neuropeptides, and hormones. It is the ordering of these systems into sequential events that has presented the greatest challenge to researchers. One hypothesis holds that there are three clinicopathologic phases of cluster headache: the cluster period, attack onset or provocation, and attack signs and symptoms. Cluster Period. The cluster period appears to be the result of two major pathophysiologic changes. Evidence suggests that cyclic

Burning, throbbing to nonthrobbing

Throbbing, 80%

Sweating, pallor, tachycardia, blood pressure elevation Chewing claudication; tender, torturous, and pulseless temporal artery; elevated erythrocyte sedimentation rate; polymyalgia Facial trigger zones Nausea, vomiting, photophobia, sonophobia 1) See cluster headache 2) Response to indomethacin pathognomonic Unilateral lacrimation, rhinorrhea, injection, partial Hornets syndrome

hypothalamic dysfunction may be associated with certain chronobiological events, which cause an impaired sympathetic neuronal activity. For example, the frequency of cluster periods was found to be related to seasonal photoperiod changes (ambient light exposure), increasing with shortening or lengthening photoperiods. Thus, onset of cluster periods tends to increase 2 weeks after the longest and shortest days of the year and decrease within 2 weeks of daylight savings and standard time changes. These changes may be responsible for the altered physiologic state and attack susceptibility that characterize the cluster period. Hypothalamic-pituitary axis neuroendocrine disturbances have also been observed during the cluster period, including lowered testosterone levels, altered circadian secretion of luteinizing hormone, growth hormone and cortisol, and suppressed nocturnal melatonin levels. These findings lend further support for evidence of central, hypothalamic dysfunction in this disorder. Attack Onset Although there is some disagreement, one hypothesis holds that hypoxemic events may induce cluster attacks. Studies have demonstrated that nitroglycerin-induced and spontaneous cluster attacks are preceded by mild but sustained oxygen desaturation. It was suggested that during the cluster period, chemoreceptor activity may become blunted as a result of impaired sympathetic function. A significant hypoxemic event may then hyperactivate chemoreceptors (denervationhypersensitivity response). This model may also explain why oxygen inhalation rapidly aborts cluster attacks (blocks chemoreceptor activity). However, others believe that the beneficial effect of oxygen is mediated via its vasoconstrictive activity. Attack Signs and Symptoms. The third phase of cluster headache is the attack itself. In considering the pathophysiology of the acute cluster attack, one must explain the unilateral pain and autonomic features, which are so integral to cluster headache. In the few instances that have been reported of secondary cluster headache, the site of pathology has most often been in or around the area of the cavernous sinus. Primary intraictal inflammation in this area, causing dysfunction of the pericarotid sympathetic nerves and parasympathetic fibers resulting in the autonomic features of the attack, has been suggested with no real supporting

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evidence. More recently, studies with positron emission tomography in the acute cluster attack have demonstrated activation in the ipsilateral hypothalamic gray matter. A similar pattern of activation is not seen in acute migraine subjects nor in subjects given intradermal capsaicin injections in the first division trigeminal sensory distribution. From these results, the investigators surmise that such activation implies a permissive or triggering role of the hypothalamus. A sophisticated neuroimaging measurement, voxel-based morphometric analysis, also shows significantly increased neuronal density in the area coinciding with the inferior posterior hypothalamus in a cohort of active and inactive cluster patients, adding further evidence of structural and functional hypothalamic abnormalities in cluster headache.

Management Successful treatment of cluster headache includes patient education about the condition, an appropriate prophylactic medication regimen, and effective symptomatic treatment. Patient Education. During active cluster periods, patients should be advised to avoid alcohol or vasodilating medications, exposure to oil-based solvents, high altitude, or strenuous exercise because such stimulants may induce cluster attacks. Patients should be encouraged by the recent advances in the treatment of this disorder and should be told of these advances. Patients with episodic cluster headaches must understand that a preventive regimen is used only on an as-needed preventive basis during the active cluster period. Therefore, most patients are heartened by not having to take a daily medication regimen for the rest of their lives. An appropriate prophylactic regimen should prevent 90% of attacks, and breakthrough headaches may be rapidly aborted in most cases. Such encouraging news helps to diminish the anticipatory anxiety that accompanies this disorder.

Phannacotherapy Preventive Treatment. The treatment of episodic cluster headache is rewarding because treatment regimens are effective. Patients are initiated on prophylactic therapy as soon as a new cluster period begins, with the goal of tapering and discontinuing therapy when the period ends. Dosing adjustment may be needed during the treatment interval because headache frequency may change within the cluster period. The treatment of first choice is verapamil, 80 to 120 mg three to five times per day spread evenly over waking hours. Dosages of up to 720 mg per day are rarely needed. Verapamil is generally well tolerated but may cause constipation, fatigue, leg cramps, extremity edema, and dizziness. Ergotamine 1 or 2 mg an hour before bedtime may be added to prevent nocturnal attacks. Patients tend to tolerate daily ergotamine, and they do not develop rebound headaches as migraineurs do. Ergotamine is contraindicated in patients with uncontrolled hypertension, peripheral vascular disease, and coronary artery disease. Lithium carbonate in dosages of 300 mg twice or three times daily is also effective in preventing cluster headache. This medication is particularly useful in treating patients with chronic cluster headache but may be added to verapamil and ergotamine in cases of resistant episodic cluster headache. Because lithium carbonate dosages used in cluster headache are generally lower than those used in mania, side effects usually are minimal but may include tremor and diarrhea. Serum levels may need to be followed to avoid the unlikely possibility of toxicity. Triple therapy

with verapamil, lithium, and ergotamine often is needed in chronic cluster headache. Methysergide 2 to 8 mg per day in divided doses has long been used to prevent cluster headache. Although methysergide is effective, potentially devastating side effects limit its usefulness, particularly with the availability and efficacy of safer medications such as verapamil, lithium, and ergotamine. Retroperitoneal, endocardial, and pulmonary fibrosis may occur idiosyncratically. Patients should not be maintained on methysergide for longer than 6 months without at least a 1-month medication holiday. Valproic acid has also been shown to be effective in cluster headache prophylaxis in dosages of 600 to 2000 mg per day. Small studies have demonstrated efficacy with topiramate, indomethacin, and baclofen as well. Corticosteroids may be used in particularly refractory cases. Prednisone beginning at dosages of 60 mg tapering over 2 or 3 weeks may be used for rapid effect. Adverse events even with short courses of steroids have been reported in cluster headache populations and include ruptured diverticula and aseptic necrosis of the hip. Symptomatic Treatment. The most effective symptomatic treatment of cluster headache is oxygen inhalation. Properly administered, oxygen inhalation should abort more than 90% of attacks in more than 90% of patients. This compares with success rates of approximately 50% with 4.0% intranasal lidocaine solution and 75% to 80% for sublingual or inhaled ergotamine or injected dihydroergotamine. However, oxygen inhalation is the most inconvenient. Achieving maximal success rates with oxygen requires the proper equipment and technique. A portable or “E” tank, flow rate regulator, and face mask without rebreathing apparatus may be rented from a medical supply store. Tanks may be refilled when needed. At the onset of an attack, the patient should be seated, bent forward with elbows on the knees and face mask held loosely against the face. This positioning is crucial for oxygen therapy to work effectively. The flow rate should be preset at 7 L/minute. The patient should breathe normally until the attack is aborted but for no longer than 20 minutes. If unsuccessful, oxygen inhalation may be repeated after a 5-minute break. Back-to-back attacks, which may be experienced on occasion, may be similarly treated. Subcutaneous sumatriptan is the most reliable, convenient, and rapid abortive treatment for the cluster headache attack. An autoinjection device makes administration easy, and 76% to 100% of patients experience complete relief within 15 minutes, a majority within 5 to 7 minutes. Long-term, repetitive daily use has been shown to be effective without the development of tachyphylaxis. The most prohibitive factor in regular use of sumatriptan for abortive treatment is its expensive cost. It should also be remembered that most patients with cluster headache are smokers, and sumatriptan is contraindicated in patients at high risk for coronary artery disease, overt symptoms or signs of coronary artery disease, uncontrolled hypertension, cerebrovascular disease, and peripheral vascular disease. Also, if patients are using ergotamine as a preventive medication, sumatriptan should not be used within 24 hours of using ergotamine. Sumatriptan 20-mg nasal spray is less effective than the subcutaneous form. Injectable dihydroergotamine is also effective in aborting the cluster attack. Oral triptan preparations are less practical because their latency of effect is too great for most cluster sufferers. Surgical Treatment. Surgical treatment may be considered in patients who are resistant to pharmacologic therapy. Various surgical therapies have been reported with varying degrees of

Chapter 214 W Cluster Headache and Paroxysmal Hemicrania

success and complications, making the choice of operative treatment difficult. Sphenopalatine gangliectomy showed little benefit in long-term follow-up. Results with radiofrequency thermocoagulation of the trigeminal ganglion were more impressive, with about 75% of patients achieving freedom from cluster headache, but complications include anesthesia dolorosa and ocular problems. More recently, a small study reported significant benefit using gamma knife radiosurgery of the trigeminal root entry zone, in which four of six patients achieved excellent results. PAROXYSMAL HEMICRANIA Of all primary headache disorders, paroxysmal hemicrania is the most clinically similar to cluster headache. There are two types: chronic paroxysmal hemicrania and the more recently described episodic paroxysmal hemicrania. These differ from cluster headache in sex distribution, ratio of episodic to chronic, attack frequency and duration, and response to medication. Chronic and episodic paroxysmal hemicrania are indistinguishable from cluster headache in pain intensity, quality, and location. They also share associated signs and symptoms (Table 214-4). The sex distribution of paroxysmal hemicrania favors women by a ratio of approximately 2:l to 3:l. Although the mean age of onset is in the early thirties, patients presenting in early childhood and into the ninth decade have also been reported. There appears to be a greater occurrence of chronic over episodic types, but this may result from earlier reports, which suggested that paroxysmal hemicrania existed solely in a chronic state; many episodic paroxysmal hemicrania cases were dismissed as prechronic states. However, it is true that as with secondary chronic cluster headache, episodic paroxysmal hemicrania may convert to chronic paroxysmal hemicrania. Pain intensity is described as moderately severe or excruciating, and as in cluster headache, the pain usually is boring or constant rather than throbbing. Most patients with paroxysmal hemicrania prefer to sit still and quietly or lay in bed rather than pace, rock, or move about as in cluster headache. As in cluster headache, pain location tends to be ocular, temporal, frontal, and maxillary.

TAW 2164. Diagnostic Criteria for Chronic Paroxysmal

Hemicrania A. At least 50 attacks fulfilling B-E B. Attacks of severe unilateral, orbital, supraorbital, or temporal pain, always on the same side, lasting 2 to 45 min C. Attack frequency >5 per day for more than half of the time (periods with lower frequency may occur) D. Pain is associated with at least one of the following signs or symptoms on the pain side: 1. Conjunctival injection 2. Lacrimation 3. Nasal congestion 4. Rhinorrhea 5. Ptosis 6. Eyelid edema E. Absolute effectiveness of indomethacin (1 50 mg per day or less) F. At least one of the following: 1. History and physical and neurologicexaminations do not suggest one of the disorders listed in groups 5 to 1 1 (eg., organic headaches, headaches associated with drug withdrawal, metabolic disorder) 2. History or physical or neurologic examination suggests such disorder, but it is ruled out by appropriate investigations 3. Such disorder is present, but chronic paroxysmal hemicrania does not occur for the first time in close temporal relation to the disorder

I361

The frequency of attacks of chronic paroxysmal hemicrania has been reported to range from 4 to 38 per day, with a mean frequency of 14 attacks; that of cluster headache is 1 to 15 per day, with a mean of 1 to 2 per day. The difficulty of distinguishing cluster headache from paroxysmal hemicrania occurs when attack frequencies are at the high end in the former or at the low end in the latter. This difficulty is also encountered when considering the duration of attacks. In paroxysmal hemicrania, attack duration usually is quite short; the duration in chronic paroxysmal hemicrania has been reported to range from 3 to 46 minutes, with a mean of 13 minutes. The duration of attacks of cluster headache may range from 15 minutes to 3 hours, with a mean of 45 minutes. The major distinguishing feature of paroxysmal hemicrania from cluster headache is the response to indomethacin. Whereas the occasional cluster patient is found to be responsive to indomethacin, all patients with paroxysmal hemicrania respond to it dramatically. Therefore, the sole efficacious prophylactic medication for chronic or episodic paroxysmal hemicrania is indomethacin, 75 to 150 mg per day, in divided doses. Attacks generally are arrested within 24 hours of treatment onset. The dosage may be subsequently reduced to a maintenance level of 25 to 50 mg per day. SUMMARY Cluster headache and paroxysmal hemicrania are primary headache disorders that are characterized by their stereotypic presentations and consistent responses to specific treatment modalities. These features allow the clinician to recognize and effectively treat such cases. Our knowledge of the pathophysiology of cluster headache has provided insight into the more recently described paroxysmal hemicranias. However, in neither case has the cause of these conditions been elucidated. In this chapter cluster headache has been classified, described clinically, and its pathogenesis briefly reviewed. Differential diagnosis of this condition, with particular attention to paroxysmal hemicrania, was discussed. Finally, the most efficacious prophylactic and symptomatic treatment modalities were described. SUGGESTED READINGS Ekbom K A clinical comparison of cluster headache and migraine. Acta Neurol Scand 46(Supp141):1-48, 1970 Gabel IJ, Spierings ELH: Prophylactic treatment of cluster headache with verapamil. Headache 29:167-168, 1989 Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):9-96, 1988 Kudrow L Cluster Headache: Mechanisms and Management. Oxford University Press, London, 1980 Kudrow L The pathogenesis of cluster headache. Curr Opin Neurol 727~82,1994 Kudrow L, Kudrow DB: Association of sustained oxyhemoglobin desaturation and onset of cluster headache attacks. Headache 30474-480, 1990 May A, Bahra A, Buchel C et al: Hypothalamic activation in cluster headache attacks. Lancet 352:275-278, 1998 Moskowitz MA: The neurobiology of vascular head pain. Ann Neurol 16~157-168, 1984 Sjaastad 0: Chronic paroxysmal hemicrania: clinical aspects and controversies. pp. 135-152. In Blau JN (ed): Migraine: Clinical, Therapeutic, Conceptual and Research Aspects. Chapman & Hall, London, 1987

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2 15 Psychological Evaluation and Treatment of the

Patient with Headache Randall E. Weeks and Steven M. Baskin

Clinicians agree that psychological factors may be important variables in the evaluation and treatment of patients with headache. There is a lack of agreement as to exactly how psychological variables interact with underlying biochemical, biological, and physiologic factors in the headache process, however. Although psychological issues are primary causes of headache in a small number of patients, it is widely accepted that they more often coexist or are secondary to the pain process itself. Still, clinicians tend to attribute psychological causation to patients with refractory headache more quickly than to patients with other medical diagnoses. The purpose of this chapter is to provide a practical psychological assessment of patients with headache as well as a treatment paradigm that targets underlying physiologic, cognitive, behavioral, and psychological factors that are part of the headache process. The assessment strategy uses a multimodal scheme that includes detailed discussion of the clinical interview, behavioral assessment, self-report data, interview with significant others, and psychometric data. Such an assessment enables the clinician to make the proper headache diagnosis and highlights psychological factors that may be important treatment considerations. Treatment targets the interactive psychobiological processes in which biology affects behavior, physiologic, and neurochemical mechanisms, which are routinely modified by environmental influences, learning, and comorbid psychological predispositions.

ASSESSMENT Clinical Interview The clinical interview includes a basic headache history and attention to psychological issues that may either contribute to head pain or be a result of head pain. It is important to assess whether the patient is having more than one type of headache because patients often refer only to “the headache” with no differentiation between qualitatively different types of headache attacks. Care is taken to note the manner in which symptoms are described (e.g., dramatic, indifferent, obsessive) and whether the pain and associated symptoms are consistent with supposed underlying headache pathophysiology. The extent of disability (both direct and indirect costs), including the impact of pain on usual activities and absences from work or school, is also noted. Finally, the clinician needs to examine the role that medical factors, pharmacologic agents, and pain may play in the patient’s psychological status. Intensity. Headaches are graded by intensity as severe or incapacitating, moderate, or mild. Operationally, severe or incapacitating pain levels occur when a patient is no longer able to perform (e.g., has to leave work or hibernates in a dark, quiet room) or attempts to continue functioning but with a greater than 50% reduction in performance. Moderate pain levels exist when

pain is significant and it inhibits a patient’s performance but does not reach the disability criteria noted earlier. Mild pain is described as slight pain that may not be apparent if the patient is distracted by work or other activities. It may be noticeable only when there is a break in the patient’s activity and is usually described as a pressure or fullness in the head or not feeling totally clearheaded. Care is taken to assess how many days out of the month the patient is dysfunctional and the impact of severe pain on current functioning (e.g., missing time from school or work, decreasing pleasurable events, causing greater social isolation, or having increased feelings of guilt). It is noted whether there is a distinct pattern to changing levels of pain (e.g., in patients with chronic headache, those who are depressed may feel consistently worse in the morning but better as the day goes on). Similarly, some patients with migraine may report that their headaches increase during a poststress letdown, such as on weekends or vacations. Finally, in young patients who attend school, it is important to assess whether their headaches are less intense during the summer, on weekends, or during school vacations. Age of Onset. The age of headache onset is noted as well as any particular life circumstances or stressors that may have served as triggers. In women, the association between menarche and headache onset may be important. Attention is paid to periods of time when the frequency of head pain has increased and any contributing factors that the patient feels may be relevant. The length of time that the frequency has been at its present rate is also noted. Frequency. Each grade of headache intensity is reviewed with respect to how many days of the month a patient may have pain of that magnitude (e.g., 30 days would indicate daily headache). It is also important to note patterns of increased pain with respect to greater levels of stress and letdown periods from stress, weather changes, dietary triggers, and weekends versus regular routines. Changes in a patient’s headache pattern are noted if the patient starts taking birth control pills or hormone replacement, as are changes in frequency that occur during and after pregnancy. An assessment is made of how menstrual patterns may relate to headache pain. Location. The location for each kind of headache is described, with close attention paid to the unilateral versus bilateral experience of pain. Changes in location (e.g., alternating sides with respect to pain) are also assessed. Description of Pain. The patient is asked to describe the sensations of pain (e.g., throbbing, stabbing, pressure). Attention is paid to whether bending or physical exertion increases the pain or introduces a throbbing component. It is also important to note at what point in the pain process the patient uses abortive medications in an attempt to relieve pain. It is not unusual for some patients to medicate more to control their fear of getting a bad headache rather than responding to the intensity of the pain.

Chapter 215 W Psychological Evaluation and Treatment of the Patient with Headache

Such data are important treatment considerations when rebound headaches may be part of the clinical picture. Duration. The physician records duration for each headache and, if the patient has chronic daily headache, whether the pain waxes and wanes throughout the day. Patients using frequent abortive medications are asked the degree of relief and the “window” of reduced headache before the return of the headache (headache recurrence). The impact of the pain on the patient’s ability to perform work (and other regular activities) and enjoy leisure activities is noted. Prodrome. Prodromal activity is noted with respect to changes in mood, “funny feelings,” or formal aura before headaches. It is also important to make certain that the prodromal activity exists before the onset of pain and is not described as part of the pain process. How the patient handles the prodrome emotionally is also noted (e.g., feelings of helplessness and anxiety versus developing an effective action plan for treatment). Clinically, close observation of migraine prodrome and the initiation of appropriate treatment improves outcome for both pharmacologic and nonpharmacologic therapies. Associated Symptoms. Symptoms of cluster headache (e.g., stuffed and running nostrils, red and tearing eyes, ptosis, miosis) are noted, as well as usual associated symptoms of migraine (nausea, vomiting, anorexia, diarrhea, dizziness, phonophobia, and photophobia). Care is taken to assess whether these symptoms are more pronounced when the pain is intense than during less severe headaches or headache-free times and whether they may be a result of abortive medication. Behavior During Headache. How patients react to pain during the headache may provide important information that contributes to a valid diagnosis. Patients with cluster headache tend to have difficulty remaining still and often pace the floor or rock back and forth holding their head. Patients with migraine prefer to hibernate in a dark, quiet room. Patients with tensiontype headache may report a decrease in their pain with physical activity. The patient’s thoughts and feelings during the headache are assessed for issues of helplessness and desperation (e.g., “I just wanted to die,” “I’m afraid the pain will never go away,” “It’s getting harder to hide the pain from other people,” or ‘‘I feel guilty I can’t be with my family”). Assessment of such variables allows development of therapeutic action plans to address these cognitive, behavioral, and physiologic factors. Medications. A complete history is recorded with respect to the various medications, dosages, and the length of time the patient has taken a given dosage. This includes nonheadache medications and vitamins. Side effects are noted. Past medications are also listed, including the length of time they were taken and the efficacy of treatment. Side effects from those medications are also noted. Issues of analgesic, ergotamine, triptan, or benzodiazepine rebound are assessed, with respect to whether those medications may have compromised the effects of usually effective prophylactic medications. Allergic reactions and any medication contraindications are noted. Finally, there is a need to assess whether patients may be getting prescriptions for headache medications from more than one physician (corroboration by a close relative or friend of the patient is helpful in this). It is also important to assess whether patients have been compliant in taking medications as prescribed. Medication compliance should never be taken for granted. Studies have shown that more than 50% of patients with headache do not properly adhere to drug treatment regimens. Consequences of nonadherence

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include progressive disability and dysfunction, development of secondary complications including overuse of analgesics or anxiolytics, increased acute care and emergency room visits, unnecessary prescriptions of “more potent” medications, treatment failures, and problematic interactions with other medications. There are numerous reasons for nonadherence to treatment regimens. These include receiving poor instruction regarding the treatment, misconceptions about headache and the treatment strategy, inappropriate expectations, sociocultural taboos, strong belief systems (e.g., “I don’t need medicine”), pessimism regarding efficacy, anger and dissatisfaction with previous health care providers, financial issues, complexity of the therapy regimen, poor management of medication side effects, lack of insight, feelings of helplessness, and psychiatric problems. In addition, many patients become confused by poor continuity of care when numerous medication changes take place with a long waiting time between appointments with the physician. From a psychological perspective, the chronic use and overuse of pain medication may lead to a depressed mood and mental dullness. Similarly, medications that contain caffeine may cause an alternation between excitation and depression. Finally, a frequent side effect of the use of P-blockers is depression. In the psychological assessment of a patient with headache, it is important to assess what role, if any, adverse events from medications may be playing with respect to mood. As mentioned previously, it is essential to note at what point patients medicate. Some patients medicate to reduce their fear of the headaches getting worse rather than basing medication use on pain levels. Others may take abortive medications based on time factors and not pain (e.g., “I take two aspirin before I get out of bed each morning”). Patients also tend to use (and overuse) medications in which they have little confidence with respect to pain relief. It is important to assess expectancy of efficacy because “nonspecific effects” have been shown to be powerful contributors to medication effectiveness or failure. Medical History. A complete history is taken with respect to head or neck trauma, loss of consciousness, seizure disorder, or other neurologic events. Other systems are also reviewed (e.g., cardiac, gastrointestinal, pulmonary, endocrine). Gynecologic and hormonal history (e.g., presence or absence of headaches during pregnancy, headache changes secondary to birth control pills, hormone replacement therapy) is important information in women. Patients are asked whether they have other types of pain (e.g., joint pain, back pain, neck and shoulder pain). Psychiatric history is reviewed with respect to any previous hospitalizations, psychotherapy experiences, or detoxification programs. Surgical history is also obtained. Previous Testing. Patients are asked whether they have had a neurologic workup and formal neurologic testing (e.g., electroencephalogram, magnetic resonance imaging, computed tomography). In addition, they are asked about the results of any blood studies they may have had previously (regarding Lyme disease, Epstein-Barr virus, or thyroid function). There is an assessment of any previous psychological or neuropsychological testing. Habit History. History of cigarette consumption, alcohol use or abuse, recreational drug use or abuse, and caffeine intake is noted. Many patients believe that because several abortive antimigraine medications contain caffeine, increased consumption will have an antimigraine effect. Significant daily caffeine consumption may increase the frequency of headaches through the effects of caffeine withdrawal and could create an anxiety-like state.

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Issues of sleep difficulty and consistency of sleep are assessed. Other behavioral factors such as inconsistency in eating habits and exercise history are important. Physiologic markers such as bruxism, neck and shoulder tightness, temporomandibular joint issues, cold extremities, and history of motion sickness are also noted. Family History. A genogram is used to assess information about the family. This reviews the patient's position within the family unit, areas of family conflict, and a description of the family's reaction to the patient's pain. Family history of headache, alcohol or substance use or abuse, psychiatric disturbance, and neurologic difficulties is also assessed. If family history of headache is positive, diagnostic and treatment information about other family members is gathered. Similarly, if family history is positive for psychiatric disturbance, information about diagnosis and treatment is also obtained. Academic and Vocational History. The impact of headache on employment or schooling is assessed. Absences from work or school caused by headaches are noted, as is any pattern of increased headache during conflicting or demanding times. Evidence of secondary gain from head pain (e.g., school avoidance) is also assessed. Personal History. Assessment is made of the patient's pleasurable pursuits, amount of exercise and physical activity, and any history of biofeedback or relaxation training. In addition, other treatment modalities are noted (e.g., acupuncture, physical therapy, or self-hypnosis). Summary. The clinical interview provides data from which to make a headache diagnosis and evaluate current psychological functioning. It explores the impact of head pain on the patient's life and how it affects the other systems. It generates questions that can be explored more fully in the rest of the assessment and helps the clinician develop initial behavioral treatment goals. Practitioners must be mindful that effective treatment involves treating patients, not merely head pain (especially, in the treatment of patients with frequent headache). BEHAVIORAL CHECKLISTS The second part of the assessment gathers information about symptomatic factors that may be markers of underlying affective disturbance. Three considerations should be kept in mind in the evaluation of these data. First, many of these symptoms can be side effects of medication. Second, patients may develop psychological difficulties as a result of pain, and affective symptoms markedly diminish as the patient's pain is ameliorated. Finally, affective disturbance secondary to other medical conditions (e.g., thyroid dysfunction, Lyme disease) must be ruled out. The patient (with corroboration by a significant other) is asked to identify which of the behavioral correlates in Table 215-1 currently exists, their intensity, and whether they are becoming increasingly disabling. Whether these symptoms existed before headaches became a serious problem is also assessed. As can be seen in Table 215-1, the clinician needs to carefully consider whether the behavioral correlates are independent of any underlying medical condition or medication side effect. It is usual for patients with migraine to have coldness in the extremities and other autonomic signs that are also markers for anxiety. In addition, patients with frequent pain may develop muscular tension as part of a bracing response, which is a reaction to pain and not an indication of affective disturbance. In sum, the purpose of the checklist is to provide an additional piece to the diagnostic

W

TABLE 215-1. Behavioral Markers of Depression

The DSM-IV lists the following behavioral correlates of depression: Poor appetite, significant weight loss (when not dieting) Increased appetite or significant weight gain Insomnia (initial, middle, or terminal) Hypersomnia Psychomotor agitation Psychomotor retardation (but not merely subjective feelings of restlessness or being slowed down) Loss of interest or pleasure in usual activities Decrease in sex drive Loss of energy or fatigue Feelings of worthlessness, self-reproach, or excessive or inappropriate guilt Difficultieswith concentration, memory, or ability to think Recurrent thoughts of death, suicidal ideation, wishes to be dead, or suicide attempt Depressed mood perceived as distinctly different from the kind of feeling experienced after the death of a loved one Depression is regularly worse in the morning Excessive or inappropriate guilt Feelings of inadequacy Decreased effectiveness at work, school, or home Social withdrawal Less talkative than usual Pessimistic attitude toward the future or brooding about past events Tearfulness or crying The following are behavioral correlates defined by the DSM-///Rfor symptoms of anxiety and panic disorders: Shortness of breath or smotheringsensations Dizziness, unsteady feelings, or faintness Palpitations or accelerated heart rate Trembling or shaking Sweating Choking Nausea or abdominal distress Depersonalization or derealization Numbness or tingling sensations (paresthesias) Flushes (hot flashes or chills) Chest pain or discomfort Fear of dying Fear of going crazy or doing something uncontrolled Muscle tension, aches, or soreness Restlessness Sweaty or cold clammy hands Dry mouth Frequent urination Trouble swallowing or "lump in throat" Feeling keyed-up or on edge Exaggerated startle response Difficulty concentrating or "mind going blank" because of anxiety Irritability

puzzle with respect to entertaining hypotheses of affective disturbance in headache patients. SELF-REPORT An important part of the evaluation is to ask patients with

headache their impressions with respect to the following: Why do they get headaches? What factors contribute to their headaches (e.g., triggers, stressrelated events)? What impact do the headaches have on their life (e.g., low family tolerance for their having pain, guilt they feel when they have to miss important events)? Do they feel depressed? Do they feel anxious? Do they think they are imagining or causing their headaches?

Chapter 21 5

Psychological Evaluation and Treatment of the Patient with Headache

What do they think would help relieve or eliminate their headaches (pharmacologic and nonpharmacologic treatments)? What treatments have been most effective in the past? Do they think they will ever feel better? Often, feelings of helplessness and frustration must be managed through support and education. This information allows the clinician to better understand the patient’s attitude about headache and treatment to more effectively engage the patient as an active participant in his or her care. INTERVIEW WITH SIGNIFICANT OTHERS Often, it is useful to include significant others in the assessment to describe their perceptions of the patient’s medical and psychological status. They provide additional data regarding the impact of the patient’s pain on vocational, family, or academic functioning. Issues of the family’s reactions to the patient with headache are important with respect to whether they are supportive or punitive. Patients with headache often attempt to hide their pain because they believe other people do not understand it. In contrast, what patients have witnessed historically with respect to how other family members have coped with pain (or other medical issues) may be important. Significant others may also provide additional information with respect to the behavioral correlates of underlying affective factors and impressions of the psychological and cognitive functioning of the patient. Other dynamic factors may emerge because the patient may be receiving more empathy and nurturance from people around them because of their pain. For children who have headaches, it is important to explore family dynamics, peer relations, and reactions to the academic environment. Issues of school anxiety or school phobia must be ruled out. In addition, there is often a great deal of family upheaval as a result of the family struggling to deal with a child’s headache problem.

PSYCHOMETRICTESTING A limitation in using traditional psychological tests with patients with headache is that their performance on these tests may reflect headache symptoms rather than psychopathology. Our group has raised this issue with respect to the Minnesota Multiphasic Personality Inventory (MMPI and MMPI-2), and this concern has been extended to a variety of other instruments by other clinicians. Psychological tests provide important information with respect to the patient’s present functioning but must be interpreted by a person who is skilled in working with such patients as to not overestimate psychological issues. The following section offers a brief sample of traditional psychological test instruments used to assess patients with headache.

Personality Assessment Objective Tests. The MMPI and MMPI-2 are the most commonly used personality inventory in the assessment of patients with headache. They include a series of true-or-false questions yielding a personality profile across validity scales and clinical scales. There are a number of experimental and “special population” scales as well. Other personality inventories include the Spielberger State/Trait Personality Inventory and the Eysenck Personality Inventory.

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Projective Tests. Projective tests are used less often because they are more complicated to administer and score, and their results are viewed as less objective. The Thematic Apperception Test (adult and children’s versions) includes a series of scenes from which the patient is to make up a story about what is taking place. The pictures elicit information about interpersonal dynamics and reactions to classic human situations. This test can be useful in discovering more about family issues and attachment, relationship issues, mood variables, and body image. It can be especially useful in evaluating children. The Rorschach is another well-known projective test used in psychological assessment but is rarely used in evaluating patients with headache.

Affective Inventories

The Beck scales measuring subjective feelings of depression, anxiety, and helplessness are efficient inventories to be used for patients with headache. Other inventories include the Zung Depression Inventory and the Spielberger State/Trait Anxiety Inventory. Locus of Control Scales

The Health Attribution Inventory was designed to assess issues pertaining to perceived causes of health and disease. It was based on theoretical premises, including locus of control and health attribution. The inventory is a 22-item questionnaire that measures beliefs about causes and cures of illness. It yields scores on three scales regarding locus of control. These scores have been shown to predict behavioral reactions to illness and response to medical treatment. Other scales include Penzien’s Headache Locus of Control Scales, Holroyd’s Health Self-Efficacy Scale, and Rotter’s Internal/External Locus of Control Scales. Disability Scales The Migraine Disability Assessment Test (MIDAS, available at www.midas-migraine.net.edu) and the Headache Impact Test (HIT, available at www.amihealthy.com/headachetest) are new assessment instruments that have been developed to measure the impact of headache on a patient’s life. They have been designed to be taken online, and patients can print out results to share with their doctor to monitor treatment efficacy regarding headache management. Other Scales

A variety of other instruments are used to provide additional personality data. The Life Change Index Scale by Thomas Holmes Stress can assess issues regarding life changes, the Lazarus Hassles Scale can assess daily hassles, the Rathus Assertiveness Inventory can measure issues of assertion, and the McGill Pain Questionnaire can measure psychological factors and pain. Summary

The aforementioned psychological tests are only a brief sample of traditional psychological instruments reported in the literature. Unfortunately, most of these tests were not standardized on headache populations (or, for that matter, medical patients in general). Therefore, they tend to overestimate psychopathology

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because scores may reflect headache symptoms and not purely psychological issues.

TREATMENT Intervention follows the detailed initial assessment. The program is built on a coping skills model in which undifferentiated head pain is reduced to smaller and more manageable components that are amenable to psychological intervention. This type of model helps self-regulation and increases a patient’s sense of mastery and control. Even in strictly pharmacologic interventions, these coping skills can be important to maximize a patient’s internal locus of control. Psychological and pharmacologic treatments often are combined to provide a comprehensive, multifaceted treatment program. The program is composed of education about the causes, triggers, and treatment of headache to help the patient become an active participant in their treatment and coping skills that foster self-regulation attending to sensory and reactive components. The coping skills model assumes that therapeutic gains are partially the result of changes in sensations, feelings, perceptions, and thought processes that accompany acute or chronic headache. The sensory component involves the patient learning to control various physiologic responses. The reactive component is a combination of cognitive and behavioral interventions that examine and help change certain actions, thoughts, attitudes, expectations, and emotional states that may lead to problematic behavior, a lowered pain threshold, and heightened levels of sympathetic arousal. Participation is encouraged, which allows the patient to assume partial responsibility for his or her treatment in an individually tailored treatment strategy. This program exists as a series of appointments after the initial evaluation. The absolute number of sessions is determined by clinical considerations and is typically fewer than 15 appointments.

Education A detailed educational program is undertaken because headache often is a result of a complicated interplay of biological and psychological factors. These explanations may include headache predisposition (including genetic and familial aspects), biochemical factors, the physiology and psychology of the stress response, dietary factors, biological rhythm factors, and relevant cognitive, emotional, and behavioral mechanisms. It is emphasized that the conditions that control chronic headache are multidimensional, and a rationale is given for psychological and pharmacologic management. Patients are taught that the conditions that triggered the onset of headache often are not the same as the conditions that maintain the disorder. Sensory and physiologic responses, biochemical events, and cognitive and emotional elements may be part of the maintenance process of chronic head pain. Traditionally accepted myths regarding “perfectionistic” personality traits or “repressed hostility” as singular causes of headache are examined and exposed as untrue. It is important to educate the patient about the process of time-limited, goaloriented psychological interventions. These treatments are very different from many patients’ beliefs that psychological treatment involves long-term “reconstructive” psychotherapy. Patients are taught to keep a headache calendar that is brought to each treatment session. The patient is taught how to selfmonitor the frequency, intensity, and duration of each headache. They also monitor the type and amount of medications taken

(both prescription and over-the-counter) and extent of relief, environmental triggers (if known), and menstrual days. These calendars generate important data about treatment efficacy or failure, provide data for outcome research, and are easy and efficient to use. There is a low correlation between self-report and objective calendar data. When pharmacologic treatment is based only on self-report, a practitioner can sometimes change medication orders without adequate clinical indication.

Skill Acquisition A variety of elements may act as triggers for headache. These vary from person to person. Among the many factors that have been shown to affect headaches are diet, sleep rhythm changes, acute stress, chronic stress, exertional factors, hormonal factors, or fasting and skipping meals. When appropriate, patients are put on an elimination diet to limit foods that have been shown to trigger headaches (Table 215-2). Patients are encouraged to empirically validate this list for themselves, however, because dietary modification may be of limited benefit for many patients. Patients are taught to modify the factors that may act as headache triggers and are given some general guidelines to assist with headache control. They are encouraged to maintain consistent biological rhythms (keeping to normal, consistent sleep-wake patterns) even on weekends. Patients are advised to eat nutritious meals at regular intervals without fasting for long periods and to reduce their intake of caffeine and alcoholic beverages. Behavioral goals are set that include increasing pleasurable activities, decreasing downtime, increasing aerobic exercise, and using time management. Aspects of the “type A” behavioral pattern are assessed (including both of the time urgency and hostility

TABLE 215-2. Elimination Diet: Foods to Be Avoided Chocolate Canned figs Nuts Peanut butter Onions Pizza . Sour cream Yogurt Herring Chicken livers Avocado Aspartame Ripened cheeses (e.g., cheddar, Gruyere, Brie, Camembert); cheeses that are permissible include American, cottage, cream, and Velveeta Vinegar (however, white vinegar is permissible) Anything that is fermented, pickled, or marinated Hot, fresh breads, raised coffee cakes, doughnuts (with activated yeast) Pods of broad beans (lima, navy, and pea pods) Monosodium glutamate (any foods containing large amounts, e.g., Chinese foods) Citrus fruits (e.g., no more than 1 orange per day) Bananas (no more than one half banana per day) Pork (limit intake) Tea, coffee, cola beverages (excessive amounts) Fermented sausage (bologna, salami, pepperoni, summer sausage, and hot dogs) Alcoholic beverages (to be avoided if possible; of all possible food triggers for migraine, alcohol is most frequently cited) It is recommended that the patient begin with a total elimination of the above for 1 month. If there occurs a decrease in frequency or intensity of headache, foods may be slowly reintroduced one at a time and the effect observed. If headache increases, that food should be eliminated, and the patient should continue to reintroduce other foods one at a time.

Chapter 215 H PsychologicalEvaluation and Treatment of the Patient with Headache

components), which often place excessive demands on the patient and those around them. Brief educational interventions help improve medication adherence and compliance. As stated previously, studies suggest that more than 50% of chronic headache sufferers do not adhere properly to medication regimens. Abortive antiheadache medications often are not optimally used, and noncompliance sometimes creates rebound phenomena, which limit the effectiveness of preventive interventions. Educational interventions (using a selfinstruction model) increase adherence to abortive medication regimens. These brief, time-limited meetings with health care professionals other than the prescribing physician are helpful in teaching the complex self-management skills needed to maximize therapeutic gains. Patients are taught how to accurately identify migraine onset, to keep medication readily available, and to have clear written instructions as to dosage, repeating dosage, pretreatment with an antiemetic (if needed, to limit nausea), and other necessary behaviors for adherence. Medication limits are set, and patients are instructed to self-monitor with a headache calendar. Patients need to be instructed about the time lag between beginning a medication and expected onset of therapeutic benefit. It is important to contact a patient if an appointment has been missed and to increase visits with the patient when headache control is tenuous. The involvement of spouses or significant others may increase compliance with complex medication regimens. In summary, brief self-instruction training with the patient, which includes complete written instructions for abortive antiheadache medications regimens, specific drug titration schedules for prophylactic medications, and strategies for side effect management increase medication therapy effectiveness.

Coping Skills and Biofeedback In a coping skills model to foster self-regulation of headache, patients learn to intervene on two components: sensory and reactive. The sensory component consists of the physical precursors to the headache and changes secondary to the sensation of pain. Effective coping teaches the patient to control various physiologic responses determined by both central and peripheral mechanisms. The reactive component is cognitive and affective and consists of thoughts and feelings that often precede or accompany headache attacks. Strategies that treat the reactive component of the pain experience help enhance pain tolerance and alter pain perception. In many patients with chronic head pain, the disorder has acquired a life of its own. Environmental triggers become less important as the frequency of headache increases from intermittent to continuous. The initial sessions of treatment are directed toward the sensory component, using relaxation exercises and biofeedback training to learn physiologic self-regulation. Later sessions focus on the thoughts and feelings that accompany headache and contribute to increased headache susceptibility (one’s internal dialogue). Biofeedback is the use of instrumentation to monitor and display physiologic responses so that the patient may become more aware of such responses and ultimately change them to allow more healthy functioning. The feedback provides objective data, ensuring that the patient is emitting more adaptive responses. Biofeedback facilitates self-regulation as the patient gains information about biological processes that are normally out of his or her

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rn TABU215-3. Relaxation and Biofeedback Program Step 1 : Step 2: Step 3: Step 4: Step 5: Step 6: Step 7:

Body awareness and diaphragmatic breathing Progressive muscle relaxation exercises and home practice with audiotapes; electromyograms are monitored, as are respiration and finger temperature Passive relaxation using imagery and breathing as relaxation cues, with electromyography, respiration, and finger temperature monitor Scalp and facial relaxation and neck and shoulder relaxation, using electromyographic monitor Dynamic movement exercises of neck and shoulder with electromyographic monitor Smooth muscle relaxation, using autogenic phrases with thermal (hand-warming) biofeedback Generalization exercises

awareness and learns to bring them more under voluntary control. The feedback may be visual or auditory, and, via training, physiologic responses are shaped in the most adaptive directions (e.g., decreased muscle tension and increased finger temperature). Biofeedback also helps the patient to feel more in control of his or her internal environment. Such training is a learning-based therapy and therefore cannot be applied when that process is disrupted. Significant psychiatric problems (e.g., those in which concentration and cognition are impaired) or in people with severe depression or helplessness are relative contraindications until the disorders are adequately treated. The biofeedback program is a step-by-step skill-building approach over a series of sessions (Table 215-3). Each step must be mastered before moving to the next one. Electromyographic (EMG) feedback is the most commonly used type of biofeedback in tension-type headache. It is accomplished through the application of surface electrodes across various skeletal muscle groups. Thermal biofeedback (or hand temperature training) that targets increased peripheral blood flow is the most common type of biofeedback in migraine. EMG biofeedback therapy programs tend to move from general relaxation to more specific musculoskeletal training. For example, some programs teach EMG functional training of various muscle groups. For the upper trapezius muscle, they tend to teach various dynamic movements, including shoulder shrug and relaxation, shoulder abduction and relaxation, shoulder rotations and relaxation, and numerous postural changes (all guided by EMG instrumentation). EMG functional training of facial and scalp muscles attempts to enhance the recovery of relaxation after a 10-second muscle contraction. Also, discrimination training can be helpful when patients are taught to attempt to discriminate differences between high, medium, and low levels of muscle contraction across different skeletal muscles. These programs tend to merge physical medicine approaches with general relaxation therapies as they incorporate shoulder girdle and neck-stretching exercises with general muscle relaxation (all guided by EMG biofeedback instrumentation). Patients use generalization or “mini-exercises”throughout the day to heighten body awareness and increase muscle relaxation. Goals over time include a reduction of pain symptoms and the eventual elimination of the need for biofeedback instruments. Internal feedback mechanisms are developed, as is the ability to generalize the responses to the natural environment. Patients are taught to look for signs of tension throughout the day and to recognize when they are contracting muscles. Practicing these mini-exercises increases body awareness and leads to more automatic muscle relaxation.

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In thermal biofeedback, a superficial thermistor is attached to a patient’s index finger. Superficial skin temperature is determined largely by volume of blood flow to the area because both blood flow and skin temperature usually change together. Some researchers believe that the mode of action of thermal biofeedback (hand warming) is a general decrease in sympathetic tone secondary to a retraining of the autonomic nervous system. Since the mid-l980s, there have been several reviews of the biofeedback literature for both migraine and tension-type headache. Although many different biofeedback techniques are used, no single intervention has emerged as clearly more efficacious than any other. In biofeedback therapy, research has failed to show a high correlation between the target physiologic response and headache outcome (especially in the EMG data). Outcome data are good and, according to some studies, similar to that for single-drug interventions. The effects appear to be maintained over long-term follow-up, and positive changes in psychological state may also occur. Combined psychophysiologic and pharmacologic therapy has been reportedly underused in primary and secondary care settings. Cognitive Therapy

In the reactive component of treatment, patients learn to identify and modify maladaptive styles of thinking via cognitive therapy. Cognitive therapies emphasize the role of thoughts, belief systems, evaluations, and appraisals in influencing emotional states and behavior. Cognitive techniques are aimed at providing patients with a set of problem-solving and coping skills that can be used in a wide range of situations that trigger and maintain headache. Distress-related cognitions and negative self-talk (“Why me?”; “I can’t believe I’m getting another migraine”; “It’s no use”) mediate poor outcome via a variety of mechanisms. These include decreased mood, increased anxiety, and poor compliance (as in overuse of pain medications and tranquilizers). Patients are taught that this reactive component can be treated with coping strategies to help them actively challenge counterproductive automatic thinking processes. The clinician attempts to get the patient to develop an enhanced internal locus of control and to view pain as a challenge to be met rather than an event that elicits helplessness. Patients with low pain tolerance make more negative comments about themselves and their ability to deal with pain. They tend to magnify the negative aspects of the entire situation, often becoming fatalistic and appearing helpless. Such patients focus on suffering and tend to look for the “magic pill” to take their pain away. These patients are taught self-statements to help develop alternative, more positive cognitive responses to the experience of recurrent severe pain or chronic, unremitting pain. A form of cognitive therapy called self-instructional training involves approaching headache as a problem that can be solved and reducing global aspects to smaller, more manageable components. These self-instructions help the patient rehearse adaptive cognitive and behavioral responses to, for example, the development of a migraine. This involves a cognitive process in which the patient learns to appraise the nature of the problem and to develop task-relevant skills to manage it. Such an action plan reduces anxiety feelings that can lead to symptom magnification. Selfinstructions are broken down into preparation for an attack, initial symptom management, handling of critical moments, and postheadache behavior. Migraine and tension-type headache can be significantly influenced by the patient’s cognitive actions and reactions in dealing with the symptoms themselves. It is helpful to train

patients to become keen observers and to be prepared to cope adaptively with the headache without being hypervigilant to pain sensations. Through classic conditioning, patients associate a variety of prodromal sensations with migraine. In doing so, many patients exhibit irrational ideation about loss of control or perceived threat of a future feared event, which causes patients to underestimate their coping skills. They often misinterpret bodily sensations and “catastrophize.” One important aspect in cognitive treatment of these anxietyrelated features is to help the patient accurately interpret and react to perceived “danger signals” with rational self-statements. Patients are taught the following self-talk sequence: What do I have to do?What does the situation require?What strategies can I use? I will follow my plan, one step at a time. I can handle the attack, use many strategies, and take appropriate medicines at the appropriate amount and time. Just focus on what the situation requires, without worrying. I can use my relaxation skills and keep things under control without creating a catastrophe. Remember, I have many strategies to use if I stay focused. The last time, I did well, used my skills, and had only a small amount of time that I could not function. I am getting better at managing these attacks. There are also cognitive coping skills that increase pain tolerance through attention diversion. These are attention-based distraction exercises that are often used in chronic pain programs but have been adapted for headache treatment. It is helpful to encourage patients to focus attention outside themselves (away from the thought of pain) to music, photos, children, and so forth. Distraction can be helpful when patients focus on future plans (e.g., going on vacation) or recall past enjoyable events from their personal history. Patients may also learn to make a mental movie of relaxing images incompatible with pain. Attention strategies can also help a patient visualize success, despite the pain, as they overcome obstacles. Patients with high pain tolerance view increased headache as a challenge to be met and believe that they will eventually exercise some degree of control. They believe that they can alter the pain experiences by actively engaging in some type of coping strategy (including attention diversion). Data suggest that many of these coping strategies are more effective with episodic headache (even when frequent) than with continuous pain. Recent research has shown a high comorbidity between migraine and depression. Some patients with headache need cognitive therapy for depression. This involves modifying a patient’s internal dialogue that predisposes him or her to helplessness, self-blame, and an expectation of uncontrollability of future events. It is a time-limited psychotherapeutic approach with proven efficacy. The approach integrates well with pharmacologic therapies for depression. These cognitive and behavioral therapies help the headache patient incorporate a variety of problem-solving skills to become an active collaborator with the health care professional. These techniques are invaluable for patients with complex headache problems. Primary Psychiatric Disorders

In the previous edition of this text, primary psychiatric disorders were described that would necessitate direct psychological or psychiatric intervention. Although most patients who present in a primary or secondary care setting do not fall into these psychiatric categories, the experienced clinician must be attentive to evaluate and refer patients who might need mental health services. Patients with headache (and other “medical patients”) often resist a

Chapter 216

psychological interpretation of their pain experience. Biofeedback referral and behavioral treatment may offer the treating physician an option that will allow the patient to establish a relationship with a mental health professional to begin to address some of the deeper psychological issues. Knowledge of comorbidity issues between headache and affective disorders and the ability to recognize problematic dual-diagnosis patients are critical skills for practitioners who treat patients with complicated or frequent headaches.

SUMMARY This chapter presented a model for evaluating and treating psychological factors in patients with headache. Patients with frequent and severe head pain appear to have coexisting psychological issues that may be related to the biochemical aspects of the headache process itself (e.g., serotonin changes), a reaction to the experience of frequent or chronic pain, a reaction to pharmacologic treatment, or comorbid psychiatric issues. Psychological symptoms and affective disturbance appear to be less evident in patients with intermittent, less severe pain patterns. Clinicians need be mindful of psychological symptoms that are present but not view their existence in a vacuum. The skilled practitioner will appreciate the emotional impact of frequent or severe pain on a patient’s life. Identifymg such psychological issues assists the clinician in effective patient care and appropriate referral.

SUGGESTED READINGS Andrasik F: Psychological and behavioral aspects of chronic headache. pp. 961-976. In Mathew NT (ed): Neurologic Clinics. WB Saunders, Philadelphia, 1990

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Baskin SM, Weeks RE: The nonpharmacological treatment of migraine. pp. 107-113. In Tollison CD, Kunkel RS (eds): Headache. Williams & Wilkins, Baltimore, 1993 Cram J R EMG muscle scanning and diagnostic manual for surface recordings. pp. 1-141. In Cram JR (ed): Clinical EMG for Surface Recordings. Vol. 2. Clinical Resources, Seattle, 1990 Diamond S, London L Psychological management of headaches. Headache Q 11:263-267,2000 French DJ, Holroyd KA, Pinell C et ak Perceived self-efficacy and headache-related disability. Headache 40:647-656, 2000 Holroyd KA, Martin PR Psychological treatments of tension-type headache. In Olesen J, Tfelt-Hansen P, Welch Kh4A (eds): The Headaches. 2nd Ed. Lippincott Williams & Wilkins, Philadelphia, 2000

Holroyd KA, Stensland M, Lipchik GL et ak Psychosocial correlates and impact of chronic tension-type headaches. Headache 403-16, 2000 McGrady AV, Andrasik F, Davies T et ak Psychophysiologic therapy for chronic headache in primary care. J Clin Psychiatry 1:96-102, 1999

McGrath PJ, Holroyd KA, Sorbi MJ: Psychological and behavioral treatments of migraine. In Olesen J, Tfelt-Hansen P, Welch KMA (eds): The Headaches. 2nd Ed. Lippincott Williams & Wilkins, Philadelphia, 2000

Packard RC, O’Connel R Medication compliance among headache patients. Headache 26:41&419, 1986 Taylor W. Dynamic EMG biofeedback in assessment and treatment using a neuromuscular re-education model. pp. 175-196. In Cram JR (ed): Clinical EMG for Surface Recordings. Vol. 2. Clinical Resources, Seattle, 1990 Weeks R, Baskin S, Rapoport A et ak A comparison of MMPI personality data and frontalis electromyographic readings in migraine with combination headache patients. Headache 23:75-82, 1983

3 SPECIAL HEADACHE PROBLEMS

2 16 Pediatric and Geriatric Headache Egilius L. H. Spierings Migraine is most common between the ages of 15 and 55 (Fig. 216-1) but also occurs in the young and old. At the two ends of the age spectrum, it can have specific features that affect diagnosis and treatment. With regard to pediatric migraine, the prevalence, prognosis, presentation, triggers, differential diagnosis, and abortive and preventive treatment are discussed in this chapter. With regard to geriatric migraine, the condition of nocturnal migraine is discussed in terms of presentation, treatment, and differential diagnosis, the latter including migraine in general, cluster headache, and hypnic headache.

PEDIATRIC MIGRAINE

Prevalence Migraine is far less common in children than in adults. A review of population studies revealed a prevalence of migraine of 3.4% in boys and 4.0% in girls. The prevalence increases sharply as the children enter their teens, and the gender gap widens. In a cohort study of children in Finland, the prevalence of migraine was 2.7% at age 7 and 10.6% at age 14. At age 7,2.9% of the boys and 2.5% of the girls were affected, but the numbers increased to 6.4% and

Chapter 216

psychological interpretation of their pain experience. Biofeedback referral and behavioral treatment may offer the treating physician an option that will allow the patient to establish a relationship with a mental health professional to begin to address some of the deeper psychological issues. Knowledge of comorbidity issues between headache and affective disorders and the ability to recognize problematic dual-diagnosis patients are critical skills for practitioners who treat patients with complicated or frequent headaches.

SUMMARY This chapter presented a model for evaluating and treating psychological factors in patients with headache. Patients with frequent and severe head pain appear to have coexisting psychological issues that may be related to the biochemical aspects of the headache process itself (e.g., serotonin changes), a reaction to the experience of frequent or chronic pain, a reaction to pharmacologic treatment, or comorbid psychiatric issues. Psychological symptoms and affective disturbance appear to be less evident in patients with intermittent, less severe pain patterns. Clinicians need be mindful of psychological symptoms that are present but not view their existence in a vacuum. The skilled practitioner will appreciate the emotional impact of frequent or severe pain on a patient’s life. Identifymg such psychological issues assists the clinician in effective patient care and appropriate referral.

SUGGESTED READINGS Andrasik F: Psychological and behavioral aspects of chronic headache. pp. 961-976. In Mathew NT (ed): Neurologic Clinics. WB Saunders, Philadelphia, 1990

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1369

Baskin SM, Weeks RE: The nonpharmacological treatment of migraine. pp. 107-113. In Tollison CD, Kunkel RS (eds): Headache. Williams & Wilkins, Baltimore, 1993 Cram J R EMG muscle scanning and diagnostic manual for surface recordings. pp. 1-141. In Cram JR (ed): Clinical EMG for Surface Recordings. Vol. 2. Clinical Resources, Seattle, 1990 Diamond S, London L Psychological management of headaches. Headache Q 11:263-267,2000 French DJ, Holroyd KA, Pinell C et ak Perceived self-efficacy and headache-related disability. Headache 40:647-656, 2000 Holroyd KA, Martin PR Psychological treatments of tension-type headache. In Olesen J, Tfelt-Hansen P, Welch Kh4A (eds): The Headaches. 2nd Ed. Lippincott Williams & Wilkins, Philadelphia, 2000

Holroyd KA, Stensland M, Lipchik GL et ak Psychosocial correlates and impact of chronic tension-type headaches. Headache 403-16, 2000 McGrady AV, Andrasik F, Davies T et ak Psychophysiologic therapy for chronic headache in primary care. J Clin Psychiatry 1:96-102, 1999

McGrath PJ, Holroyd KA, Sorbi MJ: Psychological and behavioral treatments of migraine. In Olesen J, Tfelt-Hansen P, Welch KMA (eds): The Headaches. 2nd Ed. Lippincott Williams & Wilkins, Philadelphia, 2000

Packard RC, O’Connel R Medication compliance among headache patients. Headache 26:41&419, 1986 Taylor W. Dynamic EMG biofeedback in assessment and treatment using a neuromuscular re-education model. pp. 175-196. In Cram JR (ed): Clinical EMG for Surface Recordings. Vol. 2. Clinical Resources, Seattle, 1990 Weeks R, Baskin S, Rapoport A et ak A comparison of MMPI personality data and frontalis electromyographic readings in migraine with combination headache patients. Headache 23:75-82, 1983

3 SPECIAL HEADACHE PROBLEMS

2 16 Pediatric and Geriatric Headache Egilius L. H. Spierings Migraine is most common between the ages of 15 and 55 (Fig. 216-1) but also occurs in the young and old. At the two ends of the age spectrum, it can have specific features that affect diagnosis and treatment. With regard to pediatric migraine, the prevalence, prognosis, presentation, triggers, differential diagnosis, and abortive and preventive treatment are discussed in this chapter. With regard to geriatric migraine, the condition of nocturnal migraine is discussed in terms of presentation, treatment, and differential diagnosis, the latter including migraine in general, cluster headache, and hypnic headache.

PEDIATRIC MIGRAINE

Prevalence Migraine is far less common in children than in adults. A review of population studies revealed a prevalence of migraine of 3.4% in boys and 4.0% in girls. The prevalence increases sharply as the children enter their teens, and the gender gap widens. In a cohort study of children in Finland, the prevalence of migraine was 2.7% at age 7 and 10.6% at age 14. At age 7,2.9% of the boys and 2.5% of the girls were affected, but the numbers increased to 6.4% and

-

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Special Headache Problems

(9.1)

ADULTS

FEMALE

(16.1)

I CHILDREN

(3.41

MALE

FEMALE

14.0)

I

0

I

5

I 10

1

I

I

I

15

20

25

30

PREVALENCE (percent)

FIG. 216-1. Prevalence profile of migraine in relation to age and gender. (From Goldstein M, Chen TC: The epidemiology of disabling headache. Adv Neurol 33:377-390, 1982, with permission.)

headaches lasted less than 10 hours, and only 4% experienced headaches longer than 24 hours. With regard to the frequency of the headaches, in 57% they occurred once or twice per month, and in 39% once per week or more. The onset of the headaches generally was during the day, and they rarely woke the child up out of sleep at night. In the study, 17% of the children experienced headaches on awakening in the morning and only 4% during the night. The headaches are also more often bilateral in location. Of the children in the study, 65% experienced headaches located across the forehead, 31% in one or the other temple, and 4% in both temples. The headaches generally were associated with nausea or vomiting, which was the case in 100% of the children in the study. Thirteen percent of the children experienced a visual aura of stars, flashes, spots, circles, or loss of vision. Eleven percent experienced blurred vision, 5% double vision, and 2% micropsia. Triggers

TABLE216-1. Features of Migraine Attacks at Ages 7 and 14

Visual aura Unilateral headache Nausea or vomiting

Age 7 (n = 79)

Age 14 (n = 309)

1 go/, 44%

380h 7 1 010 40%

8lV0

14.8%, respectively, at age 14.As the children grew older, changes occurred in their attacks as well. In particular, the headaches became more unilateral, less associated with nausea or vomiting, and more often preceded by visual aura (Table 216-1). The family history remained about the same and was positive in 81% at age 7 and in 73% at age 14 (average, 75%).

Prognosis

Of the children who had migraine at age 7, 22% no longer had attacks at age 14. In 37%, the headaches had become milder at age 14, and in 41%, they were unchanged or more intense. The boys did somewhat better than the girls did, and 63% of them had improved, as opposed to 53% of the girls. With regard to age of onset, of the children who had migraine at age 14,35% of the boys and 22% of the girls experienced their first headache before school age. Migraine in childhood was followed into adulthood in a cohort study of 73 children in Sweden. It showed the prevalence of migraine to increase from 2.5% to 5.3% between age 7 and 15. Of the children with migraine, those with more pronounced migraine were followed until age 30 (Fig. 216-2). These children had experienced their first headache, on average, at age 6. As teenagers or young adults, 38% of them still experienced headaches, and 62% had been headache-free for at least 2 years. At age 30 or older, 60% still experienced headaches and only 40% had been headache-free for at least 2 years. Of the adults who had children, 32% had one child with migraine, representing 17% of the children born to them. Presentation

The headaches in children generally are shorter but rn01-efrequent. In a study of 300 children with migraine, 61% experienced headaches shorter than 5 hours. In 80% of the children, the

Traveling brought on headache in 9%, cold weather in 8%, excessive exercise in 4%, watching television in 3%, bright sunlight in 2%, and certain foods in 2%. With regard to traveling, 45% of children with migraine are susceptible to motion sickness, which was observed in a study of 60 children aged 5 to 20 years. The prevalence of motion sickness in a comparable group of children with epilepsy was 7%. The same study found children with migraine to walk in their sleep more often, which was the case in 30%, as opposed to 7% of the children with epilepsy. Stress, as a trigger, was studied in 37 children with migraine who were mostly 8 to 14 years of age. Of these children, 86% indicated stress to be a trigger of their headaches. Light was indicated as a trigger by 56%, hunger by 35%, lack of sleep by 35%, foods by 24%, cold environment by l8%, and fatigue by 11%. On psychological examination, 17% of the children were found to suffer from anxiety and 11% from depression. The comparable numbers were 2% and 7%, respectively, for a group of control children.

FIG. 216-2. Follow-up from school age through puberty into adulthood of 73 children with more pronounced migraine. (From Bile B: Migraine in childhood and its prognosis. Cephalalgia 1:71-75, 1981, with permission.)

Chapter 216 H Pediatric and Geriatric Headache

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Differential Diagnosis An important differential diagnosis of migraine in childhood is headache caused by brain tumor. Brain tumor is the second most common cancer in childhood (leukemia is the first) and is generally highly invasive and rapidly progressive. A retrospective study of 60 children with brain tumor revealed that 69% of them experienced headache. The children were 1 to 16 years old, but 64% of them were younger than 11. The headaches were generalized in location in 50%, occipital in 28%, and unilateral in 22%. They were associated with vomiting in 78%, which was daily in 11% and intractable in 3%. The headaches were particularly severe or prolonged in 13% and changed over time in frequency, intensity, or time of occurrence in 31%. They were present on awakening in the morning or woke the child up out of sleep at night in 67%. Of the children with headache caused by brain tumor, 55% had an abnormal physical examination within 2 weeks after headache onset, 85% within 2 months, and 100% within 6 months. The examination included a neurologic and ophthalmologic evaluation, the latter consisting of an examination of the pupils, fundi, visual fields, extraocular movements, and visual acuity. Abortive Treatment

For the abortive treatment of migraine in childhood, nonprescription analgesics generally are adequate. However, aspirin is better avoided in children under 12 because of the risk of Reye’s syndrome. Before treatment with an analgesic, an antinausea medication should always be given, for two reasons: Migraine headaches in children are almost always associated with gastrointestinal symptoms. Children with migraine often respond with relief of their headache to treatment with an antinausea medication only. The antinausea medications that can be used in children are the gastrokinetics and antihistamines. The gastrokinetics are metoclopramide and domperidone (not available in the United States). For use in children, they are available in suspensions containing 5 mg of the medication per 5 mL. The antihistamines are diphenhydramine and promethazine. For use in children, they are also available as suspensions, in concentrations of 5 to 15 mg per 5 mL. The medications do not have contraindications. Domperidone generally does not cause side effects, whereas metoclopramide can cause restlessness and, occasionally, dystonia. Diphenhydramine and promethazine generally cause drowsiness, which is helpful because it allows the child to sleep, thereby facilitating the recovery from the headache. The efficacy and tolerability of acetaminophen and ibuprofen in the abortive treatment of childhood migraine were determined in a randomized, double-blind, placebo-controlled study. The dose of acetaminophen was 15 mg per kg and ibuprofen 10 mg per kg; the children were 4 to 15.8 years old, with a mean age of 10.7 years. They were instructed to take one dose of the medication or placebo at the onset of headache, and a five-point scale was used to record headache intensity. The primary endpoint was a reduction in pain intensity by at least two points 2 hours after treatment. The results presented in Figure 216-3 show that the children improved one-and-a-half times as often with acetaminophen or ibuprofen than with placebo. There was no statistically significant difference in the occurrence of side effects: 4.8% with acetaminophen, 9.8% with ibuprofen, and 11.1% with

FIG. 216-3. Effect of acetaminophen (15 mg per kg) and ibuprofen (1 0 mg per kg) on migraine headache in children 4 to 15.8 years old, 1 and 2 hours after treatment, in comparison to placebo. (Data from Hamalainen ML, Hoppu K, Valeila E et al: ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study. Neurology 48:1 03107, 1997.)

placebo. After taking acetaminophen, two children reported nausea and two vomited; after taking ibuprofen, three children reported nausea, four vomited, and one complained of stomach pain. After taking placebo, three children reported nausea and six vomited. Preventive Treatment

The medications that have been shown in randomized, doubleblind, placebo-controlled studies to be effective in preventing childhood migraine are propranolol and flunarizine (not available in the United States). The study with propranolol included 28 children aged 7 to 16, treated for 3 months with the medication or placebo in a crossover fashion. The dose of the medication was 60 mg per day for children weighing less than 35 kg and 120 mg per day for those weighing 35 kg or more. The average frequency of migraine headaches was 3.1 during the 3 months on propran0101 and 9.3 during the 3 months on placebo (p < .001). The study with flunarizine included 63 children aged 5 to 11, treated for 3 months with the medication (5 mg per day), or placebo, also in a crossover fashion. Flunarizine significantly reduced the frequency and duration of the headaches; its main side effects were drowsiness and weight gain. Propranolol is contraindicated in children with sinus bradycardia or obstructive pulmonary disease, including asthma. In addition, it should be used with care in children with diabetes mellitus or depression. Flunarizine is long acting and should be given at bedtime; there are no contraindications to its use. GERIATRIC MIGRAINE

Although migraine tends to abate with age, often this does not occur until age 50 to 60 years and in women generally not until menopause. The menopausal improvement takes place particularly when there is a history of perimenstrual migraine and may be negated by estrogen replacement therapy. With the advancement of age, migraine headaches tend to become less intense. However, before this occurs they seem to change in two ways: They become more frequent and start to develop nocturnally. The nocturnal development in particular makes the headaches more difficult to treat, abortively as well as preventively.

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With regard to abortive treatment of nocturnal migraine, nonoral administration of medication by suppository (ergotamine) or injection (sumatriptan) may be needed to secure absorption. The generally high frequency of the headaches, amounting to several times per week, precludes the use of ergotamine because of ergotamine's long duration of action, possibly leading to rebound. Sumatriptan has a much shorter duration of action because of its shorter plasma elimination half-life and weaker receptor binding. The nocturnal headaches in the older patient with migraine tend to be short lasting. However, they are longer lasting than the headaches of the cluster or hypnic type, which last for 1 to 3 hours and also tend to occur at night. The headaches of the cluster type are unilateral in location and those of the hypnic type bilateral. Whereas nocturnal migraine headaches wake the patient in the early morning (4 to 6 AM), cluster headaches do so in the early night (midnight to 2 AM). Preventively, similar to cluster headache, the headaches of nocturnal migraine seem to respond preventively particularly well to calcium entry blockers. They do not tend to respond to the preventive medications that are generally most effective in migraine, that is, the P-blockers and tricyclics. Nocturnal Migraine

The condition of nocturnal migraine, as it is seen in particular in the older patient, is illustrated here with two case studies. The patients in the case studies suffered from episodic and chronic nocturnal migraine, respectively. Episodic Nocturnal Migraine. A 56-year-old woman related the onset of headaches at age 52 years, 1 or 2 months after she discontinued estrogen replacement therapy. Since their onset, the headaches had occurred 3 or 4 times per year in episodes lasting 2 months each, with headaches every other day. In 50% they woke her at night, usually between 3 and 4 AM, and in 50% they came on during the day. The headaches lasted for most of the day and were usually gone by the next morning. The nocturnal headaches were 9 over 10 in intensity and the diurnal headaches 6 over 10. The diurnal headaches built to their maximum intensity in 1 hour. The headaches were located behind the eyes, in the bridge of the nose, and in the cheeks. Sometimes they also involved the back of the neck or the upper teeth. The headaches were associated with slight photophobia and phonophobia and with tenderness of the temples, which became sore to touch. Lying down made the headaches worse, and getting out of bed, applying heat to the neck and shoulders, massaging the neck and temples and sometimes, deep breathing made them somewhat better.

On treatment with verapamil, 120 mg sustained-release twice daily, the nocturnal headaches improved rapidly. They no longer woke the patient at night and when present on awakening were mild in intensity. The diurnal headaches improved in frequency and intensity on treatment with imipramine, 25 mg at dinnertime. Chronic Nocturnal Migraine. A 69-year-old woman related the onset of headaches at age 14 years, when she started menstruating. Since their onset, the headaches had been severe in intensity but not associated with nausea or vomiting. When she was in her mid-twenties, they occurred 3 or 4 times per week, but for the last 25 to 30 years the headaches had been daily. In 85% they came on during the night and woke her between 2 and 4 AM. This occurred 6 or 7 nights per week, with the intensity of the headaches being 8-10 over 10. In 15% they came on during the day but not at any regularly defined time. The diurnal headaches were 7-8 over 10 in intensity and built to their maximum intensity in one half to 1 hour. The headaches were reduced to 1 to 3 hours with treatment consisting of 2 tablets of a combination of aspirin, acetaminophen, and caffeine but occasionally lasted as long as a day. In 55% the headaches were located in the left temple, in 40% across the forehead, and in 5% in the right temple. When located in the temple, they sometimes extended over the ear into the back of the head. The headaches were sharp, steady, and, when severe, associated with photophobia and phonophobia; in 20% to 30% they were also associated with nausea. Stress and sometimes bending over made the headaches worse, whereas lying down and applying ice to the head and back of the neck made them somewhat better. On treatment with verapamil, 120 mg sustained-release twice daily, the headaches gradually improved over the course of 2 weeks. However, they still occurred frequently, were present on

TMLE 216-2. Clinical Presentation of Nocturnal Migraine and Hypnic Headache

Frequency Duration Location Predominant time of occurrence

Nocturnal Migraine

Hvunic Headache

Once per week to once per 2 4 hr ?3 to 2 4 hP Unilateral or bilateral Nocturnal

Once or twice per 24 hr 112 to 1 hr Bilateral Nocturnal

'Duration of migraine headaches in general. Data from Lipton RB, Stewart WF, Diamond S et al: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41 :646-657, 2001.

TABLE216-3. DifferentiatingNocturnal Migraine from Migraine and Cluster Headache Nocturnal Minraine

Migraine Headache

Cluster Headache ~~~

Frequency

Duration Location Predominant time of occurrence

Once per week to once per 24 hr ?3 to 24 hr Unilateral or bilateral Nocturnal

Less than once per wk"

3 to 24 hrb Unilateral or bilateral Diurnal or on awakening

Once or twice per 2 4 hr 112 to 2 hr Unilateral Nocturnal

'Range covers 74% of migraine headaches in the general population. bRange covers 73% of migraine headaches in the general population. Data from Lipton RB, Stewart WF, Diamond S et al: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41 646-657, 2001.

Chapter 217

awakening in the morning, although they were mild in intensity. The headaches fully disappeared when the dose of verapamil was increased to 240 mg sustained-release twice daily. Differential Diagnosis

Nocturnal migraine is distinguished from hypnic headache by the longer duration of the headaches and the (generally) lower frequency of occurrence of the headaches (Table 216-2).Also, in contrast to hypnic headache, nocturnal migraine headaches can be, like migraine headaches in general, unilateral or bilateral. Hypnic headaches cannot be unilateral, although it has been claimed otherwise, because then they should be diagnosed as cluster headache. Despite claims to the contrary, attacks of cluster headache do not have to be associated with local autonomic symptoms, in the same way as systemic autonomic symptoms are not mandatory for migraine, nor do attacks of cluster headache have to be associated with a behavior, characterized by agitation or pacing. The features differentiating nocturnal migraine from migraine in general and from cluster headache are shown in Table 216-3. The differentiation from migraine may be particularly important with regard to its preventive treatment. Preliminary clinical observation suggests nocturnal migraine to preferentially respond to preventive treatment with a calcium entry blocker, with a similarly high efficacy as has been described for cluster headache.

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SELECTED READINGS Barabas G, Ferrari M, Matthews WS: Childhood migraine and somnambulism. Neurology 33:948-949, 1983 Barabas G, Matthews WS, Ferrari M: Childhood migraine and motion sickness. Pediatrics 72:188-190, 1983 Bille B: Migraine in childhood and its prognosis. Cephalalgia 1:71-75, 1981 Congdon PJ,Forsythe WI:Migraine in childhood a study of 300 children. Dev Med Child Neurol 21:209-216, 1979 Goldstein M, Chen TC: The epidemiology of disabling headache. Adv Neurol 33:377-390, 1982 Hamdainen ML, Hoppu K, Valeila E et al: Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study. Neurology 48:103107, 1997 Honig PJ, Charney E B Children with brain tumor headaches. Am J Dis Child 136 121-124, 1982 Ludvigsson J: Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 50109-115, 1974 Maratos J, Wilkinson M: Migraine in children: a medical and psychiatric study. Cephalalgia 2: 179-187, 1982 Sillanpaa M Changes in the prevalence of migraine and other headaches during the first seven school years. Headache 23:15-19, 1983 Sorge F, De Simone R, Marano E et ak Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalalgia 8:1-6, 1988

2 17 Menstruation, Pregnancy, and Menopause Elizabeth W. Loder The two most common primary headache disorders of migraine and tension-type headache occur more frequently in women than men. Because migraine is the most common headache disorder for which patients consult a physician, this chapter focuses on that condition. Tension-type headache, although more common than migraine, is rarely disabling, whereas cluster headache is rare and predominantly affects men. Four percent of prepubertal girls and boys are affected by migraine, but after menarche more girls than boys have migraine, and at all ages after puberty, women with migraine outnumber men with the disorder. The prevalence ratio for migraine in women compared with men fluctuates, with peak ratios from 2.5:l to 3.8:l between 25 and 55 years of age. In that age group, migraine prevalence ranges from 12.9% to 17.6% in women and from 3.4% to 6.1% in men. Presumably, this sex-based discrepancy in the prevalence of migraine reflects the influence of the estrogen cycle on the central nervous system. It has long been noted that in women with migraine, the hormonal milestones of menarche, menopause, and pregnancy can produce significant changes in activity of the disorder. For example, many women report an increased tendency toward migraine attacks associated with the menstrual period. Migraine often is said to improve during pregnancy, especially in women whose headaches were previously correlated with menstrual periods. And finally, many women look forward to menopause as a time when headaches lessen or disappear, although in fact headaches worsen in a significant minority of women after menopause. That the prevalence in women remains

higher than that in men even after menopause suggests that early exposure of a migraine-prone central nervous system to estrogen cycling creates lasting changes that predispose to migraine even after the inciting event is no longer present. MENSTRUAL PHYSIOLOGY

A review of menstrual physiology is helpful in understanding the role estrogen and other sex steroids may play in headache. Estrogen is a basic steroid hormone produced by the ovaries and extraglandular tissue, primarily adipose cells. Estradiol is the most potent naturally occurring estrogen and makes up the majority of estrogen produced by the ovaries. The menstrual cycle is divided into the follicular phase, during which follicles mature and develop, and the luteal phase, when the corpus luteum dominates. In the follicular phase, gonadotropin-releasing hormone (GNRH) is released in a pulsatile fashion by the hypothalamus. The release of GNRH stimulates the pituitary to release both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH stimulates ovarian follicles to mature and produce estradiol; estradiol exerts negative feedback on the hypothalamus and on FSH. Low levels of estradiol have a negative feedback effect on LH, whereas high levels of circulating estradiol have a positive feedback effect on pituitary LH release. Estradiol levels peak before ovulation and then fall abruptly; as a result, a surge of LH occurs and ovulation follows within 24 hours. The luteal phase is highlighted by increases in both estrogen and progesterone, which

Chapter 217

awakening in the morning, although they were mild in intensity. The headaches fully disappeared when the dose of verapamil was increased to 240 mg sustained-release twice daily. Differential Diagnosis

Nocturnal migraine is distinguished from hypnic headache by the longer duration of the headaches and the (generally) lower frequency of occurrence of the headaches (Table 216-2).Also, in contrast to hypnic headache, nocturnal migraine headaches can be, like migraine headaches in general, unilateral or bilateral. Hypnic headaches cannot be unilateral, although it has been claimed otherwise, because then they should be diagnosed as cluster headache. Despite claims to the contrary, attacks of cluster headache do not have to be associated with local autonomic symptoms, in the same way as systemic autonomic symptoms are not mandatory for migraine, nor do attacks of cluster headache have to be associated with a behavior, characterized by agitation or pacing. The features differentiating nocturnal migraine from migraine in general and from cluster headache are shown in Table 216-3. The differentiation from migraine may be particularly important with regard to its preventive treatment. Preliminary clinical observation suggests nocturnal migraine to preferentially respond to preventive treatment with a calcium entry blocker, with a similarly high efficacy as has been described for cluster headache.

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SELECTED READINGS Barabas G, Ferrari M, Matthews WS: Childhood migraine and somnambulism. Neurology 33:948-949, 1983 Barabas G, Matthews WS, Ferrari M: Childhood migraine and motion sickness. Pediatrics 72:188-190, 1983 Bille B: Migraine in childhood and its prognosis. Cephalalgia 1:71-75, 1981 Congdon PJ,Forsythe WI:Migraine in childhood a study of 300 children. Dev Med Child Neurol 21:209-216, 1979 Goldstein M, Chen TC: The epidemiology of disabling headache. Adv Neurol 33:377-390, 1982 Hamdainen ML, Hoppu K, Valeila E et al: Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study. Neurology 48:103107, 1997 Honig PJ, Charney E B Children with brain tumor headaches. Am J Dis Child 136 121-124, 1982 Ludvigsson J: Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 50109-115, 1974 Maratos J, Wilkinson M: Migraine in children: a medical and psychiatric study. Cephalalgia 2: 179-187, 1982 Sillanpaa M Changes in the prevalence of migraine and other headaches during the first seven school years. Headache 23:15-19, 1983 Sorge F, De Simone R, Marano E et ak Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalalgia 8:1-6, 1988

2 17 Menstruation, Pregnancy, and Menopause Elizabeth W. Loder The two most common primary headache disorders of migraine and tension-type headache occur more frequently in women than men. Because migraine is the most common headache disorder for which patients consult a physician, this chapter focuses on that condition. Tension-type headache, although more common than migraine, is rarely disabling, whereas cluster headache is rare and predominantly affects men. Four percent of prepubertal girls and boys are affected by migraine, but after menarche more girls than boys have migraine, and at all ages after puberty, women with migraine outnumber men with the disorder. The prevalence ratio for migraine in women compared with men fluctuates, with peak ratios from 2.5:l to 3.8:l between 25 and 55 years of age. In that age group, migraine prevalence ranges from 12.9% to 17.6% in women and from 3.4% to 6.1% in men. Presumably, this sex-based discrepancy in the prevalence of migraine reflects the influence of the estrogen cycle on the central nervous system. It has long been noted that in women with migraine, the hormonal milestones of menarche, menopause, and pregnancy can produce significant changes in activity of the disorder. For example, many women report an increased tendency toward migraine attacks associated with the menstrual period. Migraine often is said to improve during pregnancy, especially in women whose headaches were previously correlated with menstrual periods. And finally, many women look forward to menopause as a time when headaches lessen or disappear, although in fact headaches worsen in a significant minority of women after menopause. That the prevalence in women remains

higher than that in men even after menopause suggests that early exposure of a migraine-prone central nervous system to estrogen cycling creates lasting changes that predispose to migraine even after the inciting event is no longer present. MENSTRUAL PHYSIOLOGY

A review of menstrual physiology is helpful in understanding the role estrogen and other sex steroids may play in headache. Estrogen is a basic steroid hormone produced by the ovaries and extraglandular tissue, primarily adipose cells. Estradiol is the most potent naturally occurring estrogen and makes up the majority of estrogen produced by the ovaries. The menstrual cycle is divided into the follicular phase, during which follicles mature and develop, and the luteal phase, when the corpus luteum dominates. In the follicular phase, gonadotropin-releasing hormone (GNRH) is released in a pulsatile fashion by the hypothalamus. The release of GNRH stimulates the pituitary to release both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH stimulates ovarian follicles to mature and produce estradiol; estradiol exerts negative feedback on the hypothalamus and on FSH. Low levels of estradiol have a negative feedback effect on LH, whereas high levels of circulating estradiol have a positive feedback effect on pituitary LH release. Estradiol levels peak before ovulation and then fall abruptly; as a result, a surge of LH occurs and ovulation follows within 24 hours. The luteal phase is highlighted by increases in both estrogen and progesterone, which

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prime the uterine lining for implantation of a fertilized egg. This hormonal peak has a negative feedback effect on gonadotropin release. If fertilization does not occur, the corpus luteum begins to resolve and circulating estrogen and progesterone levels decline. The endometrial lining eventually sloughs as a result of intense vasospasm caused by locally produced prostaglandins (PGs).

ESTROGENS Around 60% of migrainous women report a link between at least some of their headaches and their menstrual periods. In the early 1970s, Somerville investigated the link between hormones and migraine. He studied a small group of women with known premenstrual or menstrual headache. The premenstrual administration of progesterone was observed to delay the menstrual period but had no effect on occurrence of the menstrually associated headache. In contrast, when 10 mg of estradiol was injected premenstrually, menstrual migraine was delayed 3 to 9 days in all six patients, consistent with the period of time that the additional estrogen would be expected to exert its effects. Based on these results, Somerville hypothesized that estradiol withdrawal occurring in the normal menstrual cycle triggered a sequence of events leading to a migraine attack in susceptible women. In later work, he determined that several days of exposure to high levels of estradiol was needed to provoke a withdrawal headache. A study attempting to prevent menstrual migraine with estradiol implants was unsuccessful, however. Somerville theorized that the implant devices were faulty, producing erratic estradiol levels and unpredictable headaches. Somerville’s data were the first to suggest that declining estrogen levels play a role in the genesis of migraine associated with menstruation and have been influential in subsequent thinking about the disorder. The way in which falling levels of estradiol might enhance vulnerability to a migraine attack may have to do with the multiple effects of estrogen on the central nervous system. The brain has receptors for all five classes of steroid hormones: estrogens, progestins, androgens, glucocorticoids, and mineralocorticoids. Receptor sites are not distributed randomly; for example, estrogen receptors are concentrated in the hypothalamus, limbic system, and spinal and trigeminal dorsal horn. At least some of these areas have enkephalin-producing neurons that contain estradiol receptors. Estrogen supplementation increases enkephalin production, with subsequent effects on pain modulation. Simulated pregnancy in rodents, with stable high levels of estrogen, has been shown to decrease sensitivity to painful stimuli. Estrogen also increases levels of inhibitory neurotransmitters such as serotonin and +-aminobutyric acid, which can decrease susceptibility to headache. It is known that estrogen influences the sensitivity of central opiate receptors, which are diffusely distributed throughout the central nervous system. p-Opioid receptors are located primarily in the arcuate nucleus of the hypothalamus, where opioids exert tonic inhibition of luteinizing hormone-releasing hormone. In contrast, naloxone is a p-receptor antagonist that stimulates luteinizing hormone-releasing hormone pulsatility. Genazzani compared both physiological and surgical menopausal migraine sufferers with controls. Menopausal women with migraine showed a lack of LH response to naloxone administration, which returned to normal when they were treated with estrogen and progesterone replacement. Progestins given alone were not effective in restoring normal LH response to naloxone. Young women who underwent bilateral oophorectomy demonstrated the same lack of LH

response to naloxone administration, suggesting that central opioid tone is modulated by estrogen. Estrogen has also been shown to modulate serotonin receptors found on blood vessels. In animal models, estrogen blocks smooth muscle reuptake of norepinephrine at the neurovascular junction and upregulates postsynaptic a,-adrenergic receptor populations on vascular smooth muscle. In the vascular endothelium, estrogens also inhibit the enzymes catechol-0-methyltransferase and monoamine oxidase, responsible for the breakdown of norepinephrine, leading to increased local levels of that substance. Welch (1988) has hypothesized that physiologic levels of estrogen may influence central aminergic and cerebrovascular function. In this model, when estrogen-enhanced receptors are sympathetically stimulated, they produce intense vasoconstriction. The resulting oligemia is believed to correlate with the initial aural migraine phase, with ultimate vasodilation occurring as a result of local acidosis, leading to headache. Estrogens both directly and indirectly stimulate PG biosynthesis via stimulation of prolactin secretion. PGs play an important role in pain genesis: Both intramuscular and subcutaneous injections of PGE, or PGF,, cause intense local pain. PGE, when injected into humans, has been shown to trigger migraine-like headaches. PGs also sensitize pain receptors to chemical and mechanical stimulation. This PG-produced hyperalgesia probably results from a decrease in the activation threshold of polymodal nociceptor C fibers. PGI, appears to protect against ischemia. Levels of 6-ketoPGF,,, a stable metabolite of PGI,, were measured at different phases of the menstrual cycle and during migraine attacks in patients who are known to have true menstrual migraine and in controls. 6-Keto-PGF1, levels were significantly lower in the patients with migraine throughout the cycle than in controls. Baseline PGE, levels were slightly lower in the patients with migraine than in the control patients but increased significantly during a migraine attack. Other work suggests that the baseline deficit of PGI, in women prone to menstrual migraine may result in vascular hypersensitivity. In support of this hypothesis is the finding that PGI, levels are elevated during pregnancy, when migraine is less common, and that P-blockers, which increase 6-keto-PGF1, levels, are effective in preventing migraine. Prostacyclin, a potent vasodilating PG with hyperalgesic and inflammatory properties, did not trigger migraine headaches when injected and is not felt to be a primary trigger in migraine pathogenesis. Prolactin has been associated with migraine pathogenesis and the theory of central dysmodulation. The pituitary releases prolactin in response to vasoactive intestinal peptide, angiotensin, and thyrotropin-releasing hormone (TRH). Dopamine tonically inhibits prolactin release, and serotonin inhibits thyroidstimulating hormone (TSH) indirectly via TRH and directly at the pituitary level. In a study of 11 women with migraine and 9 control subjects, exogenous injection of TRH, luteinizing hormone-releasing hormone, and insulin resulted in significantly higher prolactin levels in patients with migraine than in controls. TSH levels were higher in controls than in patients with migraine, but the difference was not statistically significant. In another study, the dopamine antagonists sulpiride and domperidone, injected during the follicular phase, resulted in a significantly higher LH release in both menstrual and nonmenstrual patients with migraine than in controls. If dopamine were the only focus of dysmodulation, marked elevation in TSH levels would have been expected as well. However, serotonin triggers an increase in prolactin without TSH

Chapter 21 7

elevation, suggesting that serotonin hyperfunction in combination with dopaminergic hypofunction may exist in patients with menstrual migraine. Serotonin receptors in turn are modulated by estrogen. Another finding consistent with this theory is the increase in prolactin response to TRH demonstrated during acute migraine attacks as compared with attack-free periods.

MENSTRUALLY ASSOCIATED MIGRAINE Treatment of most menstrually associated migraine attacks is identical to that for other migraine attacks. Despite many assertions to the contrary, there is no credible evidence that the majority of menstrually associated migraine attacks are longer, more intense, or more likely to recur than nonmenstrual attacks. As a result of the many large-scale clinical trials necessary to gain approval for the marketing many of the new triptan medications and some over-the-counter combination medications, ample evidence clearly shows no difference in the likelihood of response to acute treatment for menstrual and nonmenstrual attacks. Therefore, for most patients with menstrually associated migraine attacks, traditional treatment will prove satisfactory. However, the predictable nature of the trigger in menstrually associated migraine makes preemptive treatment of an anticipated attack a possibility. For women with regular menstrual cycles and a headache that can be demonstrated to occur in predictable fashion associated with the cycle, such treatment may be practical. In general, a preventive medication is started 1 or 2 days before the expected onset of the headache (which may or may not coincide with the onset of menstrual flow) and continued for the expected duration of the headache. Such a strategy often is called mini-prophylaxis. Because timing is so important in this treatment regimen, it is advisable to monitor the menstrual cycle and headaches for 3 months before embarking on such treatment. The best evidence regarding this type of treatment is for the use of naproxen sodium 550 mg twice daily for 5 days perimenstrually. An open label trial suggested benefit for sumatriptan 25 mg three times daily used in this fashion, and a recent double-blind, placebo-controlled trial found a modest beneficial effect for naratriptan 1.0 mg twice daily but none for 2.5 mg twice daily. Until further studies clarify this lack of a dose-response relationship and confirm the findings, the usefulness of triptans for perimenstrual migraine prophylaxis remains unclear. However, compared with other suggested alternatives, this would be a second-line strategy for patients desiring prophylaxis who have not benefited from or cannot take nonsteroidal anti-inflammatory drugs. Women who have migraine headaches throughout the month and are already on prophylactic medicine yet continue to have persistent breakthrough menstrual migraine may benefit from a perimenstrual increase in the prophylactic agent. As with other headaches, when a severe attack of menstrual migraine is refractory to standard therapy, short-term high-dose corticosteroids, major tranquilizers, or intravenous dihydroergotamine can be used to break the cycle. If these treatments are relied on too heavily or fail to benefit, some would recommend proceeding to a trial of estrogen supplementation. In 20 women with menstrual migraine and regular menstrual cycles, the prophylactic effect of 1.5 mg percutaneous estradiol was studied in a double-blind placebo-controlled crossover trial. Treatment was begun 2 days before expected migraine and was continued for 7 days each month. Migraine attacks occurred in 31% of the estradiol cycles and 96% of the placebo cycles. Migraine attacks in the estradiol-

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treated group were milder and than those occurring in patients receiving placebo treatment. In another study, 24 patients with refractory menstrual migraine were treated with subcutaneous estradiol implants for up to 5 years. Headaches in 23 patients improved with treatment. Twenty patients (83%) became almost headache-free. All these patients were able to stop previous therapies and believed that the implants had been the most effective migraine therapy. However, a follow-up placebo-controlled study on premenstrual syndrome did not demonstrate this degree of benefit, underscoring the importance of interpreting open label studies with caution. There may be a threshold dosage of estrogen necessary to produce a beneficial effect, as suggested by a study that showed that supplementation with the 25-pg estrogen patch was not effective in preventing menstrually associated migraine, but the 100-pg patch was effective. Therefore, if a patch formulation of estrogen is desired, the evidence suggests that the 100-pg patch should be used. Danazol, an ethinyl-testosterone derivative, has also been used in refractory menstrually associated migraine. Danazol prevents the rise in estrogen and progesterone levels in the luteal phase of the menstrual cycle, maintaining a constant estrogen state. In the initial study phase, 63% of patients reported relief of their hormonal migraine. Eighty-one women continued the medication for a 6-month period, and 82% showed continued migraine prevention. Prophylaxis was maintained with 400 mg danazol taken 25 days each month in combination with a diuretic. The open label nature of this study, along with the notable side effects and unclear long-term risks associated with such treatment, should temper enthusiasm for this unproven treatment strategy. Tamoxifen, an antiestrogen, binds to estrogen receptors and inhibits messenger RNA transcription. The medication has been given for 7 to 14 days during the luteal cycle, with dosages ranging from 5 to 15 mg per day. Bromocriptine, in dosages of 2.5 to 5.0 mg per day given during the luteal phase, has also used to prevent premenstrual symptoms and headache. As with danazol, the risk-benefit ratios of these medications have yet to be established; the lack of placebo-controlled trials means their use cannot be advocated for any but the most refractory cases of menstrually associated migraine.

ORAL CONTRACEPTIVES Can women with migraine safely use oral contraceptives? Headache specialists differ in their opinions: Some recommend avoiding them, and others suggest they may be used safely in the majority of women with migraine. Controversy about their use stems from two concerns: Do oral contraceptives increase the risk of ischemic stroke in women with migraine above the risk to women without migraine? Do oral contraceptives increase the risk that migraine will begin for the first time or worsen in patients who already have it? The use of oral contraceptives is known to impart a small but statistically significant increased risk of ischemic stroke. Patients with undetected coagulation abnormalities may be at higher risk for this complication. That migraine, particularly migraine with aura, may be an independent risk factor for stroke is suggested by many studies. Several authors have attempted to assess the interaction between the risk factors of migraine and oral

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contraceptives. When their results are summarized, the suggestion is of a small increase in the absolute risk of stroke for most patients with migraine. This has led many experts to suggest that in women who have uncomplicated migraine without aura, the use of oral contraceptives often is justified, particularly if the woman wants to avoid conception. Most would argue for caution in the use of oral contraceptives in women who have migraine with aura. They would discontinue use immediately in women who develop worsening or prolonged aura or other focal neurologic symptoms. Only one rather old study has assessed the impact of oral contraceptive use on migraine frequency and intensity in patients with preexisting headache. That study suggested that in one third of migrainous women using oral contraceptives, migraine worsened, in one third it improved, and in the other third it remained unchanged. The impact of a gradual shift toward the use of lower-dose estrogen pills on these percentages has never been assessed; it is reasonable to suppose these lower-dose regimens are less likely to aggravate migraine because the magnitude of the fall in estrogen is less. It is important to note that the controversy regarding oral contraceptive use is limited to patients with migraine; there is no reason to believe that oral contraceptives cannot be used safely in women with tension-type or cluster headache. PREGNANCY The primary headache disorders of migraine and tension-type headache disproportionately affect women of childbearing age; consequently, the occurrence of headache in some form during pregnancy or the puerperium is common. Studies of the natural history and prevalence of headache during pregnancy and the puerperium show certain trends. In women with preexisting tension-type headache, retrospective studies indicate that around 25% of women find that headaches improve during pregnancy, but the majority experience headaches of similar intensity and duration during and after pregnancy as before. The pathogenesis of tension-type headache is poorly understood, but hormonal factors are not generally thought to play a role in causing or aggravating these headaches. For that reason, the hormonal events of pregnancy presumably have little effect on the preexisting headache pattern. Retrospective studies suggest that about 50% of women whose headaches meet the criteria for the diagnosis of migraine without aura before pregnancy will experience significant improvement in their headaches during the second and third trimesters; however, headache can be a serious problem during the first trimester. In addition, prospective studies suggest that the percentage of patients with headache improvement may be less than the estimates generated by retrospective studies: In one study by Marcus et al., (1999) the improvement rate was only 29%, well below estimates produced by retrospective studies. This study also demonstrated that if improvement in headache has not occurred by the end of the first trimester, headaches are likely to continue to be troublesome throughout pregnancy and warrant treatment at that point. Headache in pregnancy can be aggravated by concomitant pregnancy-related nausea. Medication use is of concern throughout pregnancy but particularly during the first trimester, when organogenesis is occurring, and this presents a clinical challenge. Improvement of headache with pregnancy may be more likely to occur if headaches have previously been correlated with hormonal changes, for example, in women whose headaches

began with menarche or were worse with the menstrual periods or during use of oral contraceptives. If headaches improve with pregnancy, they may resume or worsen when the menstrual cycles resume after delivery or cessation of lactation. Women who suffer from migraine with aura before pregnancy may be more likely to note no improvement in headache frequency or intensity or even worsening during pregnancy. Cluster headache and related conditions, such as paroxysmal hemicrania, are much less common in women than men and therefore rarely complicate pregnancy. When they do, they may be more resistant to treatment than those occurring in nonpregnant women. Women with preexisting headache disorders may be more prone than other women to develop headache in response to epidural anesthesia during delivery. In addition to changes in preexisting headache conditions that can be provoked by pregnancy, headaches, particularly migraine with aura, can occur for the first time during pregnancy or after delivery. Thorough investigation or passage of time generally reveals such headaches to be of benign origin. However, pregnancy and lactation do not confer immunity to such serious causes of headache as brain tumor, meningitis, or vasculitis. Therefore, evaluation of new or worsening headaches in the pregnant patient should be as thorough as that undertaken in nonpregnant patients. This may include imaging studies if clinically indicated. When a choice is possible between magnetic resonance imaging and computed tomography, the theoretical but undemonstrated risks of fetal exposure to the electromagnetic fields generated in magnetic resonance imaging are preferable to the known risks of exposure to ionizing radiation in computed tomography. In situations such as suspected intracranial hemorrhage, where computed tomography is clinically indicated and superior to magnetic resonance imaging, pregnancy should not deter its use. The occurrence of some serious causes of headache, such as subarachnoid hemorrhage or cerebral venous thrombosis, increases in pregnancy and the puerperium. It should also be borne in mind that new onset or worsening of headache during pregnancy can be caused by pregnancy-specific conditions. Most notable among these is preeclampsia, in which headache or other nonspecific neurologic complaints may precede objective signs of the disorder, such as hypertension or proteinuria. It has been theorized that pregnancy-induced hypertension is more common in migraine sufferers, but studies have produced conflicting data. Finally, a history of recurrent spontaneous abortions or thromboembolic disease in combination with migraine-like headaches should prompt a search for anticardiolipin antibodies. Mild to moderate primary headache disorders occurring during pregnancy do not correlate with poor reproductive outcomes, and there is no evidence of a higher risk of birth defects in the offspring of headache patients. Common sense and case reports in the medical literature suggest that pregnant patients whose headaches are severe enough to lead to intractable vomiting and poor weight gain or who take frequent doses of headache medications, particularly those containing ergotamine, are at risk of pregnancy complications, including fetal malformation, intrauterine growth retardation, stillbirth, spontaneous abortion, and abruptio placentae. Women of childbearing age form the majority of patients seeking headache evaluation and treatment, and it is not uncommon for a headache patient who has been in treatment for some time to unexpectedly become pregnant. Inadvertent fetal exposure to headache medications can generate a great deal of anxiety. Patients seeking information on possible fetal harm from exposure

Chapter 21 7

to medications taken for headache can be referred to one of several national teratogen information services that provide available information about the reproductive effects of many substances. However, it is obviously desirable to minimize the frequency with which this situation occurs. This can be accomplishedby including in the initial headache evaluation of any fertile woman a reminder to avoid any unnecessary medication if she plans to attempt pregnancy or has reason to think she might be pregnant. Consideration should always be given to the fact that any woman of childbearing age may already be pregnant, and a pregnancy test should be done if indicated. Finally, it is well to remember that approximately 50% of pregnancies in the United States are unplanned and to emphasize to the patient the need to plan for pregnancy and discuss with her physician the advisability of medication use for headache during pregnancy. Whereas evaluating headache in pregnancy is straightforward, managing the disorder is not. Treating headache disorders in the pregnant patient or the patient attempting pregnancy is controversial and largely empirical. Because of concern about legal liability arising from potential harm to a fetus, women of childbearing potential have traditionally been excluded from medication studies or required to take strict precautions against pregnancies. Despite these efforts, some unintended pregnancies have occurred during trials of headache medications; their outcomes are carefully tracked but do not provide adequate information about the reproductive effects of the medication during pregnancy. Many pharmaceutical companies maintain pregnancy registries in which the outcome of pregnancies that have been exposed to the medication is followed. However, because of the large number of pregnancies needed to make definitive statements about safety in pregnancy, these registries are useful primarily for ruling out large increases in teratogenicity as a result of medication exposure; they are less useful for proving that a medication has no known teratogenic effect. For all these reasons, there is a serious lack of information about the effects of many medications in pregnant women. Pregnant women with chronic illnesses of many kinds, including headache disorders, may be undertreated because of concern about adverse effects of medication on the fetus. In some instances, untreated headache or the complications of unprescribed or unsupervised medication use by a desperate patient with headache may be far more dangerous to the mother or fetus than carefully prescribed and supervised medication regimens. Little is known about the extent of medication use among pregnant women with headache; clinical experience indicates that many pregnant patients with headache continue to use medications that are contraindicated during all or part of pregnancy, such as ergots, barbiturate-containing medications, and platelet-active agents such as aspirin or ibuprofen. Ideally, patients with headache who want to become pregnant or who become pregnant while in treatment should be encouraged to discontinue all medications whenever possible. In most cases, both the pregnant patient and the physician will be eager to avoid the use of medication if at all possible. This resolve is generally aided by the previously mentioned improvement in headache that many patients experience. Most patients, with regular office visits to monitor their condition and offer psychosocial support, are successful in tolerating headaches without the use of medication or with use of a medication such as acetaminophen that is generally accepted as safe for use in pregnancy. Nonpharmacologic treatments, such as biofeedback and relaxation, have been demonstrated to be useful adjuncts to medication

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therapy for both migraine and tension-type headaches. Both biofeedback-assisted relaxation and other relaxation techniques have proven as useful as prophylactic and analgesic medications in nonpregnant patients and, by extension, should be useful in pregnant patients as well. In one study, pregnant patients treated with physical therapy, relaxation, and biofeedback had an 81% reduction in headache compared with a 33% reduction in a control population. Identifylng headache trigger factors, although an important adjunct to treatment in any patient, is particularly important in the pregnant patient or the patient attempting pregnancy. Too often, such nonpharmacologic “avoidance therapy” is overlooked or underemphasized by physicians, who may have more experience with pharmacologic approaches to headache. However, scrupulous avoidance of headache triggers can greatly reduce the need for medication in pregnant patients. Toward this end, dietary regimens should be carefully reviewed with patients who have migraine and the avoidance of alcohol emphasized. Skipping meals should be discouraged. Caffeine intake should be avoided or minimized. Caffeine use in acute headache (e.g., having a strong cup of coffee early in a headache episode) is very helpful for many patients and may preclude the use of stronger medications later. Patients to whom this approach is suggested should be informed that there is weak evidence that caffeine may slightly increase the risk of early spontaneous abortion; it may be wise to save this approach for the second and third trimesters, when the risk of spontaneous abortion is lower. The importance of obtaining adequate rest cannot be overemphasized. The pregnant patient with job and family responsibilities may have great difficulty obtaining needed sleep. If headaches are intense enough that pharmacologic treatment is a possibility, serious consideration should be given to a reduction in work hours or a medical leave of absence from work. If effective, a temporary reduction in work responsibilities is clearly preferable to pharmacologic treatment of headache during pregnancy. Psychosocial stressors during or after pregnancy may contribute to the burden of headache or render it intolerable; those patients may benefit from such interventions as counseling or relaxation training. Serious mood disturbances or emotional distress should prompt psychiatric referral. The occurrence of postpartum depression in patients with migraine has not been studied separately, but evidence that depression and anxiety are more common in patients with migraine in general prompt concern that patients with migraine may also be more vulnerable to postpartum depression as well; a high index of suspicion for the disorder should be maintained. Biofeedback has been shown to reduce the frequency and intensity of migraine during pregnancy and should always be considered in place of or as an adjunct to medication in pregnant patients. Physical therapy interventions, such as massage, postural training, and exercise, can be helpful in nearly all patients with headache and should also be considered before a trial of medication. If clinically indicated, local anesthetic infiltration of trigger points in the head or neck region can be performed safely during pregnancy. With any nonpharmacologictreatment (as with any pharmacologic treatment), placebo response and patient expectation of benefit greatly influence the outcome of treatment and should be exploited whenever possible. The decision to use pharmacologic approaches to headache management in the pregnant patient should represent a consensus of the patient, her partner, and her physicians. Common sense dictates that the potential benefits of medication treatment should

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clearly outweigh the potential risks to the mother and fetus. The clinical situation varies from patient to patient, and treatment must be individualized. Nonetheless, certain principles apply in most cases: Nonpharmacologic methods should be tried before medication is used, and even if they are suboptimally effective alone, they should be continued with medication in most cases because they may have a medication-sparing effect. Whenever possible, pharmacologic treatment of headache should be delayed until the second and third trimester, when organogenesis is complete. The lowest effective dosage of medication should be used for the shortest time possible. Medications selected for use should be those that, on the basis of current knowledge, are least likely to pose a danger to mother or fetus. Patients should be discouraged from using herbal or “natural” headache remedies about which little or no information is available. A number of easily obtainable herbal preparations can be harmful to the pregnant women or fetus. For acute treatment of mild or moderate headache in pregnancy, acetaminophen is the medication of choice. If nausea or vomiting precludes oral use, it is available as a rectal suppository. Combined with rest, relaxation techniques, and perhaps caffeine, this reasonably safe approach often is effective in the pregnant patient with headache. Aspirin and nonsteroidal anti-inflammatory medications should be avoided late in pregnancy because they may produce early closure of the ductus arteriosus. Barbituratecontaining medications, though frequently used by nonpregnant patients for mild or moderate headache, should probably be avoided in pregnancy because of concern over their association with possible later neurobehavioral abnormalities. Isometheptenecontaining medications should be avoided because of their vasoconstrictive properties and potential effects on uterine circulation. Ergots (methylergonovine, ergotamine, dihydroergotamine) are absolutely contraindicated during pregnancy because of concern over their stimulatory effects on uterine muscle. However, these medications can be used for headache after delivery, when they may be doubly useful in reducing the frequency of uterine atony. For more severe headaches, opioid medications may be appropriate, in combination with acetaminophen. Clear limits must be placed on frequency of use to avoid habituation or dependence, and the drawback of sedation must be clearly explained. Nonetheless, opioid medications have been extensively used in pregnancy with no indication of major teratogenic effects. Acetaminophen may be used in combination with narcotic medications to obtain synergistic pain relief. Phenothiazines sometimes are used in severe headache to provide sedation and control of vomiting. Trimethobenzamide is believed to be a safe treatment for nausea and vomiting during pregnancy and may therefore be preferable if antiemetics are necessary. The use of sumatriptan or other triptans during pregnancy is not recommended. A prospective sumatriptan pregnancy registry is maintained by the manufacturer, with more than 289 exposed pregnancies at the time of this writing. To date, there is no evidence of an increase in the rate of malformations or other abnormalities above those expected in the general population, but the number of pregnancies is too small for definitive statements of safety in pregnancy to be made. Nonetheless, the

evidence is reassuring for patients in whom inadvertent exposure during pregnancy has occurred. Among the commonly used prophylactic agents for headache, the anticonvulsants sodium valproate and Tegretol as well as lithium carbonate and methysergide should not be used during pregnancy because safer alternatives exist. Sodium valproate, in particular, is a known teratogen, causing neural tube defects in 1% to 2% of exposed pregnancies. Because formation of the neural tube occurs at a very early stage of pregnancy (day 28), the use of this medication should be avoided not only in pregnancy but also in any woman who might become pregnant unless she is carefully informed of the risks and any alternative treatments. If prophylaxis for headache is thought to be necessary, it is probably wise to choose a P-blocker or a tricyclic for migraine, a tricyclic for tension-type headache, and steroids for cluster headache. There is accumulated and reassuring experience with the use of these medications in pregnant women with other chronic conditions. Calcium channel blockers have been less extensively studied in pregnancy but may ultimately prove to be appropriate for prophylaxis in certain situations. It is possible that they can delay or lengthen labor through their tocolytic action on the uterine muscle. Fluoxetine, a serotonin reuptake inhibitor, has limited usefulness in preventing headache disorders, but a recent retrospective study found no increase in birth defects in infants born to women who had used the medication in pregnancy. The medical, legal, and ethical risks of pharmacologic management of headache disorders in pregnancy can be minimized by careful attention to all aspects of the patient-physician relationship. Referral to a genetic pharmacologist may be helpful to discuss the implications of specific medications that a patient may want to use during pregnancy. It is important to review with the patient that the background risk of fetal malformation is 2% to 4% and to inform her of the known risks and benefits of any suggested approach to her headaches. Careful documentation of advice about avoiding medications should be entered in the chart; it is common for pregnant patients to say that they were never told not to use certain medications. If pharmacologic treatment is recommended, it may be wise to have the patient initial or sign a statement indicating that she has been informed of the potential risks and benefits of such treatment and of alternatives to treatment and that she consents to the proposed treatment. Headache may return abruptly after delivery, when estrogen levels fall quickly. Lactation seems to have little effect on headache activity, despite the fact that it stimulates increases in both oxytocin and vasopressin, substances that generally increase pain thresholds. If headaches do occur in a breastfeeding woman, both acute and prophylactic medication use may be necessary. With acute medications, depending on the half-life of the medication used, many physicians advise pumping and discarding the milk until the medication is likely to have been excreted. Discontinuation of breastfeeding is not necessary. If prophylaxis is felt to be necessary, consultation with the pediatrician is advisable to determine which of the available prophylactic agents can be used safely. Many headache physicians have experience using P-blockers and tricyclics in this situation and feel comfortable recommending their use. It is remarkable how little formal attention has been paid to the problem of headache in pregnancy, given the frequency with which the two conditions occur together. Increased emphasis on research into disorders that primarily affect women and greater participation of women of childbearing age in clinical trials will

Chapter 218 W

eventually improve the treatment of pregnant women with headache disorders.

CLIMACTERIC The climacteric is defined as the transitional period from the reproductive to the nonreproductive years. Menopause, on the other hand, begins with the last menstrual period and generally occurs around age 5 1. Women who are 50 years old today can be expected to live into their late 80s, so that most women will be living one third of their lives postmenopausally. Although the overall trend is for headaches to improve with age, it is not uncommon for headaches to worsen significantly during the perimenopausal period, perhaps as a result of erratic estrogen levels. As the ovarian synthesis of estradiol comes to a halt, adipose tissue becomes the primary site of estrogen aromatization into estrone, a biologically weaker hormone. Thirty to 80% of postmenopausal women experience vasomotor instability as a result of estrogen deprivation. Although the pathogenesis of hot flashes is not certain, they have been correlated with the rapid decline of estrogen E, and E, levels and surges of LH. The hypothalamic-pituitary axis remains intact into old age. It is believed that the estrogen influence on neurohormones has a parasympathomimetic effect on the hypothalamus. Alterations of various neurohormones, catecholamines, PGs, endorphins, and low estrogen levels may be responsible for the hypersympathetic state associated with the vasomotor and mood changes seen with hot flashes. The instability of these factors may also be responsible for the erratic nature of migraine often seen during this time. Exogenous estrogens are commonly used in postmenopausal women to treat a variety of symptoms, ranging from osteoporosis to vasomotor instability. The effect of hormone replacement therapy on preexisting migraine is unclear. Anecdotally, both worsening and improvement have been reported. Complicating interpretation of these reports is a change over the last decade from the use of interrupted hormone replacement therapy regimens to continuous replacement with low daily dosages of estrogen and progesterone. (Estrogen-only regimens are used in women without a uterus.) Continuous regimens may be less likely to trigger migraine attacks because they do not include an estrogen-free period of treatment. For these reasons, the decision about whether to use hormone replacement therapy in a patient with migraine is best made on an individual basis after the potential advantages and disadvantages are weighed. Limited study has been made of the effects of various

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regimens on migraine; it has been shown that in patients on intermittent therapy whose headaches worsen, decreasing estrogen dosage and converting to continuous therapy produces a 60% improvement in headache control. Several reports suggest that transdermal estrogen preparations are less likely to worsen migraine than oral estrogens. Transdermal estradiol increases circulating estradiol and estrone and bypasses hepatic metabolism, whereas oral conjugated estrogens primarily raise estrone. Fifty micrograms of transdermal estradiol is roughly equivalent to 0.625 mg of oral estrogen.

SUGGESTED READINGS Edelson R Menstrual migraine and other hormonal aspects of migraine. Headache 25376-379, 1985 Epstein MT, Hockaday TD: Migraine and reproductive hormones throughout the menstrual cycle. Lancet 1:543-548, 1975 Kudrow L The relationship of headache frequency to hormone use in migraine. Headache 15:36-49, 1975 Lignieres B, Vincens M, Mauvais-Jarvis P Prevention of menstrual migraine by percutaneous oestradiol. BMJ 293: 1540, 1986. Loder EW Migraine and menstruation. J SOC Obstet Gynaecol Can 22:512-517, 2000

Loder E The woman with monthly headache. In Rapoport A, Sheftell F, Purdy A (eds): Advanced Therapy of Headache. Decker, Hamilton, Canada, 1999. Marcus DA, Scharff L, Turk D Longitudinal prospectivestudy of headache during pregnancy and postpartum. Headache 39:625-632, 1999 Rothrock J, North J, Madden K et al: Migraine and migrainous stroke: risk factors and prognosis. Neurology 43:2473-2476, 1993 Ryan R A controlled study of the effect of oral contraceptiveson migraine. Headache 17:250-252, 1978 Scharff HL, Marcus DA, Turk D: Maintenance of effects in the nonmedical treatment of headaches during pregnancy. Headache 36:285-290, 1996 Shuhaiber S, Pastuszak A, Schick B et ak Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 51:58 1-583, 1998 Silberstein S, Merriam G Estrogens, progestins, and headache. Neurology 41:786-793, 1991

Somerville B Estrogen-withdrawal migraine I: duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology 253239-244, 1975 Somerville B: Estrogen-withdrawal migraine 11: attempted prophylaxis by continuous estradiol administration. Neurology 25:245-250, 1975 SomervilleB The role of estradiolwithdrawal in the etiologyof menstrual migraine. Neurology 22:355-364, 1972 Welch K, Darnley D, Simkins R The role of estrogen in migraine: a review and hypothesis. Cephalalgia 4:227-316, 1988 Wood A Drugs in pregnancy. N Engl J Med 338:1130-1137, 2000

2 18 Post-Traumatic Headache Russell C. Packard Post-traumatic headache is the most common symptom of mild or minor injury to the head. These headaches often are very difficult to manage because of the problems in evaluating and treating a subjective symptom, the unclear clinical picture, and minimal evidence of organic abnormality. Many clinicians tend to avoid

patients with post-traumatic headache because of the litigation that is often associated with their cases. Symptoms of mild head injury have been recognized for more than a hundred years, although the reasons hypothesized for the symptoms have shifted dramatically. In the mid-19th century, the

Chapter 218 W

eventually improve the treatment of pregnant women with headache disorders.

CLIMACTERIC The climacteric is defined as the transitional period from the reproductive to the nonreproductive years. Menopause, on the other hand, begins with the last menstrual period and generally occurs around age 5 1. Women who are 50 years old today can be expected to live into their late 80s, so that most women will be living one third of their lives postmenopausally. Although the overall trend is for headaches to improve with age, it is not uncommon for headaches to worsen significantly during the perimenopausal period, perhaps as a result of erratic estrogen levels. As the ovarian synthesis of estradiol comes to a halt, adipose tissue becomes the primary site of estrogen aromatization into estrone, a biologically weaker hormone. Thirty to 80% of postmenopausal women experience vasomotor instability as a result of estrogen deprivation. Although the pathogenesis of hot flashes is not certain, they have been correlated with the rapid decline of estrogen E, and E, levels and surges of LH. The hypothalamic-pituitary axis remains intact into old age. It is believed that the estrogen influence on neurohormones has a parasympathomimetic effect on the hypothalamus. Alterations of various neurohormones, catecholamines, PGs, endorphins, and low estrogen levels may be responsible for the hypersympathetic state associated with the vasomotor and mood changes seen with hot flashes. The instability of these factors may also be responsible for the erratic nature of migraine often seen during this time. Exogenous estrogens are commonly used in postmenopausal women to treat a variety of symptoms, ranging from osteoporosis to vasomotor instability. The effect of hormone replacement therapy on preexisting migraine is unclear. Anecdotally, both worsening and improvement have been reported. Complicating interpretation of these reports is a change over the last decade from the use of interrupted hormone replacement therapy regimens to continuous replacement with low daily dosages of estrogen and progesterone. (Estrogen-only regimens are used in women without a uterus.) Continuous regimens may be less likely to trigger migraine attacks because they do not include an estrogen-free period of treatment. For these reasons, the decision about whether to use hormone replacement therapy in a patient with migraine is best made on an individual basis after the potential advantages and disadvantages are weighed. Limited study has been made of the effects of various

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regimens on migraine; it has been shown that in patients on intermittent therapy whose headaches worsen, decreasing estrogen dosage and converting to continuous therapy produces a 60% improvement in headache control. Several reports suggest that transdermal estrogen preparations are less likely to worsen migraine than oral estrogens. Transdermal estradiol increases circulating estradiol and estrone and bypasses hepatic metabolism, whereas oral conjugated estrogens primarily raise estrone. Fifty micrograms of transdermal estradiol is roughly equivalent to 0.625 mg of oral estrogen.

SUGGESTED READINGS Edelson R Menstrual migraine and other hormonal aspects of migraine. Headache 25376-379, 1985 Epstein MT, Hockaday TD: Migraine and reproductive hormones throughout the menstrual cycle. Lancet 1:543-548, 1975 Kudrow L The relationship of headache frequency to hormone use in migraine. Headache 15:36-49, 1975 Lignieres B, Vincens M, Mauvais-Jarvis P Prevention of menstrual migraine by percutaneous oestradiol. BMJ 293: 1540, 1986. Loder EW Migraine and menstruation. J SOC Obstet Gynaecol Can 22:512-517, 2000

Loder E The woman with monthly headache. In Rapoport A, Sheftell F, Purdy A (eds): Advanced Therapy of Headache. Decker, Hamilton, Canada, 1999. Marcus DA, Scharff L, Turk D Longitudinal prospectivestudy of headache during pregnancy and postpartum. Headache 39:625-632, 1999 Rothrock J, North J, Madden K et al: Migraine and migrainous stroke: risk factors and prognosis. Neurology 43:2473-2476, 1993 Ryan R A controlled study of the effect of oral contraceptiveson migraine. Headache 17:250-252, 1978 Scharff HL, Marcus DA, Turk D: Maintenance of effects in the nonmedical treatment of headaches during pregnancy. Headache 36:285-290, 1996 Shuhaiber S, Pastuszak A, Schick B et ak Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 51:58 1-583, 1998 Silberstein S, Merriam G Estrogens, progestins, and headache. Neurology 41:786-793, 1991

Somerville B Estrogen-withdrawal migraine I: duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology 253239-244, 1975 Somerville B: Estrogen-withdrawal migraine 11: attempted prophylaxis by continuous estradiol administration. Neurology 25:245-250, 1975 SomervilleB The role of estradiolwithdrawal in the etiologyof menstrual migraine. Neurology 22:355-364, 1972 Welch K, Darnley D, Simkins R The role of estrogen in migraine: a review and hypothesis. Cephalalgia 4:227-316, 1988 Wood A Drugs in pregnancy. N Engl J Med 338:1130-1137, 2000

2 18 Post-Traumatic Headache Russell C. Packard Post-traumatic headache is the most common symptom of mild or minor injury to the head. These headaches often are very difficult to manage because of the problems in evaluating and treating a subjective symptom, the unclear clinical picture, and minimal evidence of organic abnormality. Many clinicians tend to avoid

patients with post-traumatic headache because of the litigation that is often associated with their cases. Symptoms of mild head injury have been recognized for more than a hundred years, although the reasons hypothesized for the symptoms have shifted dramatically. In the mid-19th century, the

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prevailing opinion was that a brain injury did not occur in the absence of obvious external injury or damage to the head. Many symptoms of mild head injury were considered to be malingering or “psychogenic.” With a dramatic increase in the number of head injuries caused by accidents in the late 20th century, more credence was given to organic causes of post-traumatic headache. Controversy continues to exist about the legitimacy of posttraumatic headache, often because evidence of anatomic abnormality is minimal. Only recently has technology provided means of assessing mild head or brain injury (such as positron emission tomography, single photon emission computed tomography, and evoked potential studies) that may indicate abnormalities in neurophysiology. EPIDEMIOLOGY

It is estimated that 2 million people in the United States sustain closed head injuries each year. Surveys of the number of people who develop post-traumatic headache as a result of mild head injury usually range from 30% to 50%. Paradoxically, the milder the head injury, the more frequently severe post-traumatic headache is noted. Motor vehicle accidents are the most common cause of head injuries and males between 15 and 24 years old are the group at highest risk. Other causes of head injury include falls, assaults, and sports injuries. DEFINITIONS

Mild head injury and mild traumatic brain injury are difficult to define compared with moderate or severe injuries in which structural damage is evident. Most recent definitions have used the Glasgow Coma Scale score to determine the degree of severity of a traumatic brain injury. In short, the Glasgow Coma Scale is a 15-point clinical rating with three independent measures of wakefulness: eye opening, verbal response, and motor response. The lowest score (3) indicates unresponsiveness, and the highest score (15) indicates normal alertness. The most widely used definition of mild head injury included a period of unconsciousness less than 20 minutes, a Glasgow Coma Scale of 13 or greater without subsequent deterioration, and a duration of posttraumatic amnesia less than 48 hours. Recently, the American Congress of Rehabilitation Medicine defined mild traumatic brain injury as “a traumatically induced physiological disruption of brain function” with at least one of the following: any period of loss of consciousness, any memory loss for events just before or after the accident, any alteration in mental state at the time of accident, or focal neurologic deficits that may or may not be transient. In addition, the injury could not result in a loss of consciousness greater than 30 minutes, an initial Glasgow Coma Scale of less than 13 (after 30 minutes), or post-traumatic amnesia exceeding 24 hours. It is noteworthy that post-traumatic headache and other symptoms may occur when there is no actual head trauma or loss of consciousness, such as accelerationdeceleration movements (whiplash). Concussion has also been variously defined. For many years a concussion was considered to be a brief, reversible brain injury with transient loss of consciousness. We now recognize that loss of consciousness is not necessary for a concussion to have occurred or for development of the postconcussion syndrome. For the purpose of classifying head trauma in sports, concussion has been divided into three grades. In grade 1 concussion, there is no loss of consciousness, and post-traumatic amnesia lasts less than 30

minutes. Grade 2 injuries involve loss of consciousness of less than 5 minutes or post-traumatic amnesia greater than 30 minutes but less than 24 hours. Headaches are common after grade 1 and 2 injuries. Grade 3 injuries involve prolonged loss of consciousness and prolonged post-traumatic amnesia. These definitions allow a range of severity and treatment protocols to be considered for athletes or patients with head trauma. DIAGNOSTIC CRITERIA

Diagnostic criteria from the International Headache Society for acute post-traumatic headache with significant head trauma or confirmatory signs include the following: A. Significance of head trauma documented by at least one of the following: 1. Loss of consciousness 2. Post-traumatic amnesia lasting more than 10 minutes 3. At least two of the following showing relevant abnormality: clinical neurologic examination, radiograph of skull, neuroimaging, evoked potentials, cerebrospinal fluid examination, vestibular function test, neuropsychological testing B. Headache occurs less than 14 days after regaining consciousness (or after trauma if there has been no loss of consciousness). C. Headache disappears within 8 weeks after regaining consciousness (or after trauma if there has been no loss of consciousness). International Headache Society diagnostic criteria for acute post-traumatic headache with minor head trauma and no confirmatory signs include the following: A. Head trauma that does not satisfy criterion A for “significant” head trauma noted earlier B. Headache occurring less than 14 days after injury C. Headache disappearing within 8 weeks after injury MECHANISMS OF HEAD INJURY

Mechanisms of head injury and subsequent post-traumatic headache include direct contact injury, indirect or nonimpact injury (whiplash), soft tissue injury, and a cascade of metabolic changes that occur in both brain injury and headache. Most injuries probably are mixed and may give a mixed clinical picture of post-traumatic headache (i.e., an acceleration-deceleration head movement, forehead collision on steering wheel, cervical strain, and brain metabolic changes). There is increasing evidence of an organic basis in the pathophysiology of mild head injury. Organic changes may also play a role in the pathogenesis of post-traumatic headache, although the specifics are still uncertain. After both mild and severe head injuries, damage to nerve fibers and nerve fiber degeneration are evident. Cerebral circulation often is slowed after head injuries. Recently, evidence has accumulated to support a neurochemical basis for migraine headache. Neuropeptides have been found in perivascular nerve fibers and are thought to maintain homeostasis in the cerebral circulation. Possible mediators of migraine attacks at the biochemical level may include neuronal depolarization, excessive release of excitatory amino acids and nitric oxide, abnormal serotonergic neurotransmission, magnesium deficiency, and loss of calcium homeostasis. Many similar biochemical alterations

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occur after traumatic brain injury and may, at least partially, explain neurochemical changes in post-traumatic headache.

HEADACHE TYPES Patients suffering from post-traumatic headache may develop one or several types of headache. Tension-type, migraine-like, clusterlike, and mixed post-traumatic headache are similar to their nontraumatic counterparts. Post-traumatic headache may also occur when the soft tissues of the head or neck are injured, or with scar formation. The site of injury often is extremely sensitive to finger pressure. Patients may have one type of headache or more often a variety of symptoms together that are characteristic of more than one type.

Tension-Type Post-Traumatic Headache This is probably the most frequent and may occur daily, usually consisting of a dull, aching sensation with varying degrees of intensity. Emotionally tense or stressful situations often aggravate headaches. Mixed post-traumatic headache is also quite common, usually consisting of a combination of tension-type and vascular headaches.

Post-Traumatic Migraine This condition may occur more often than originally suspected. It has been suggested that trauma to the head or neck triggers the migraine process in a susceptible person who previously did not have migraine headaches. In addition, head or neck injuries often increase the intensity of headaches in preexisting migraine conditions. Cluster-likeheadache has also been reported after head trauma and may be without the periods of remission that are expected in the episodic variety. Our experience has shown this to be a very unusual headache symptom of head injury.

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severe headache associated with an unprepared occupant, a rear-end collision, or rotated head position at the time of impact. The use of seat belts, the speed of the vehicles, and the amount of damage to the vehicles had no influence on symptoms or signs.

Occipital Neuralgia This term implies pain in the distribution of the greater occipital nerves, although it has also been loosely applied to any radiating pain triggered by palpation of occipital structures. Compression or irritation of the occipital nerve may cause a continuous aching or throbbing pain in the suboccipital region, with radiation over the posterior and lateral scalp. Retro-orbital pain is common in severe attacks. Trigger zones generally are not present, although pressure on the occipital nerve can aggravate the pain. Pain of intermittent stabbing quality in the distribution of the greater or lesser occipital nerves can also occur. There is usually tenderness to palpation of the occipital nerves and temporary easing of the pain by local anesthetic nerve blocks.

Tdgeminal Nodcepthe System This system may also play a role in cervicogenic headaches. The terminations of trigeminal afferents within the spinal descending nucleus lie near the terminations of cervical afferents at the levels of C2, C3, and C4. The collection of cells in the upper cervical segments that receive nociceptive input from both the trigeminal and cervical nerves is called the trigeminocervical nucleus. Any irritation to structures innervated by the cervical sensory nerves can activate the trigeminal nucleus and result in referred pain to the head. This may explain how cervical muscle tenderness or myofascial trigger points might act as generators for primary headaches. Patients with migraine may also report neck pain and stiffness at some point during an attack. Injection of the tender muscles may relieve the migraine. Such injections may act at the level of the peripheral nerve or its more central connections.

Temporomandibular Joint Headaches related to temporomandibular joint, a subtype of tension-type headache, are less frequent and usually result from stretching and tearing of the ligamentous structures of the jaw joint. The mastoid muscles usually are tender, with pain, clicking, or popping in the involved joint and limited jaw opening. This is an uncommon headache problem to occur in isolation after head or neck injuries, but it may contribute to overall headache discomfort.

Whiplash Injuries These occur with neck hyperextension followed by flexion, which usually occurs to an occupant of a motor vehicle that is hit from behind by another vehicle. Headaches have been reported in approximately 80% of patients immediately after whiplash injuries. Most neck injuries are myofascial injuries to muscles and ligaments. This may evolve into a myofascial pain syndrome in which trigger point areas, on palpation, may radiate pain into the head or down the arm. Most headaches after whiplash injury are tension-type headaches, often associated with cervical muscle injury or greater occipital neuralgia. Despite its common occurrence, this is one of the most controversial types of post-traumatic headache. Recent studies of presenting symptoms after whiplash have noted a higher frequency of multiple symptoms and more

PSYCHOLOGICALFACTORS Other factors may contribute to headaches caused by trauma, including injury-related or psychosocial stress, anxiety, depression, and analgesic overuse. Also, a variety of post-traumatic symptoms may follow mild head injury in addition to headache. Although these symptoms may differ somewhat in degree, they are surprisingly consistent from patient to patient. The classic post-traumatic syndrome consists of a mixture of psychophysiologic, cognitive, and psychosocial symptoms. Patients with posttraumatic headache usually do not present with all the features of post-traumatic headache but generally experience at least a few additional symptoms, such as dizziness, fatigue, depression, insomnia, attention and concentration disturbances, loss of memory, and irritability. Psychological factors are also important to consider in posttraumatic headache cases. Personality and behavioral changes often lead to significant social, marital, family, and occupational difficulties. Over time, as patients become more aware of their difficulty adjusting to the injury, they typically become more distressed. For the most part, patients with post-traumatic headache are a heterogenous group, with some functioning more effectively than others. Although injuries may be similar, each injured patient is an individual. Some patients have minimal psychological disturbances, others will have more psychological

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difficulties as a result of pain or limitations, and a few, particularly those with pronounced psychopathology before the accident, exhibit significant psychological difficulties. Psychological evaluation is indicated for patients with chronic post-traumatic headache and significant impairment of occupational and psychological functioning. Neuropsychological testing can be useful for evaluating cognitive deficits. MANAGEMENT Patients with post-traumatic headache need individualized assessment and management. A variety of methods have been useful. Although most physicians recognize the importance of medication, nonpharmacologic therapies (biofeedback, physical therapy, massage, and psychotherapy) can also be helpful for many patients. Patients with chronic post-traumatic headache may need to be placed on some type of preventive medication such as tricyclics or some of the newer anticonvulsants that have been used for pain and headache (e.g., gabapentin, valproate sodium). Not only do preventive medications decrease the use of opioids and analgesics, they also may allow other treatments (such as biofeedback or physical therapy) to be used more effectively. Anti-inflammatory medications and muscle relaxants may be useful for some patients. Unfortunately, there is a tendency for patients to continue analgesic medications in the long term if symptoms persist. Ergotamine, dihydroergotamine, and sumatriptan can also be used to treat individual attacks of post-traumatic migraine. Headaches associated with myofascial trigger points in the neck or upper back often respond to a local anesthetic injected into the tender areas. These are helpful but typically last only 2 to 4 weeks. Traditional psychotherapy or behavior modifications may be necessary for some patients with post-traumatic headache. Many patients simply need support and education. Others need limited dynamic psychotherapy, and a few may need long-term psychotherapy. Some of the issues involved in therapy for post-traumatic headache include depression, anxiety, frustration, excessive expectations, anger, and unresolved grief or loss. Depression with associated loss of energy and sleep disturbance must be treated vigorously.

OUTLOOK AND LEGAL ISSUES Despite various efforts at treatment, some patients have persisting symptoms and develop chronic or permanent post-traumatic headache. Two months has traditionally been used as the time indicator for determining chronicity. Our experience, and that of some other investigators, is that most improvement in posttraumatic symptoms occurs during the first 6 months, with a greater tendency to become chronic or persistent after that time. Some risk factors associated with longer periods of incapacity include advanced age, a history of previous head injury, high levels of achievement or demanding occupations, and family or social stressors. The natural course of most post-traumatic headache is one of improvement during the first year. Approximately four of five patients recover without significant sequelae. Some cases of chronic post-traumatic headache do not improve and become permanent conditions.

Post-traumatic headache typically is the result of a multiparty accident, which stirs a mixture of litigation, attorneys, insurance companies, physicians, and the patient. This is particularly true when post-traumatic headache is permanent, a condition often needed for legal action in some states. Despite increasing evidence that mild head injury may involve actual brain injury from acceleration-deceleration and rotational forces, the attitude that post-traumatic headache is simply a manifestation of accident neurosis or malingering continues to persist among some physicians, attorneys, and insurance companies. Deliberate exaggeration of symptoms in patients involved in litigation usually is overestimated. Several studies have shown that legal settlement does not necessarily bring an end to symptoms or return to work. Although most research supports the legitimacy of posttraumatic symptoms after mild head injury, one must be alert for malingering or exaggeration in a small number of cases. Medicolegal context of the presentation, marked discrepancy between claimed disability and objective findings, lack of cooperation during diagnostic evaluation, and presence of antisocial personality disorder may suggest exaggeration or malingering. In mild head injury, these guidelines may be less useful because many patients are involved in litigation, and there are often discrepancies between objective findings and subjective symptoms. Limited cooperation may result from difficulty with attention, concentration, or memory. The physician may be called into court as the treating physician or to give expert testimony. Whether a physician qualifies as an expert witness is determined by the trial judge. The expert witness is not expected to prove or disprove a case. The physician or expert is expected to define the physical and psychological condition of the client and to address the question of whether there has indeed been an injury. Expert opinion may also be provided about the severity of injury, prognosis, and probability of permanent injury. The expert often is called upon to determine whether injuries seem “within a reasonable degree of medical probability” to be related to the trauma. “Medical probability” is considered to be more than a 50% chance. SUGGESTED READINGS Barcellos S, Rizzo M Posttraumatic headaches. In Rizzo M, Tranel D (eds): Head Injury and Post-Concussive Syndrome. Churchill Livingstone, New York, 1996 Foreman SM, Croft AC: Whiplash Injuries: The Cervical Acceleration/ Deceleration Syndrome. 3rd Ed. Williams & Wilkins, Baltimore, 2002 Kelly JP, Rosenberg R Concussion in sports: practice parameter of the American Academy of Neurology. Neurology 48:576, 1997 Packard R C Epidemiology and pathogenesis of posttraumatic headache. J Head Trauma Rehabil 149, 1999 Packard R C Treatment of chronic daily posttraumatic headache with divalproex sodium. Headache 40736, 2001 Packard RC, Ham L P Pathogenesis of posttraumatic headaches and migraine: a common headache pathway? Headache 37142, 1997 Sturzenegger M, DiStefano MA: Presenting symptoms and signs after whiplash injury: the influence of accident mechanisms. Neurology 44688, 1994 Young WB, Packard RC, Ramadan N Headaches associated with head trauma. In Silberstein SD, Lipton RB, Dalessio DJ (eds): Wolff‘s Headache. 7th Ed. Oxford University Press, New York, 2001

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GENERAL ASPECTS OF PAIN

2 19 Anatomy and Physiology of Pain Zahid H. Bajwa, Barth L. Wilsey, and Scott M. Fishman

Pain is the most common symptom reported to physicians. It has been a prominent concern of mankind since the beginning of recorded history. The word pain is derived from the Latin poena, meaning punishment. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience arising from the actual or potential tissue damage or described in terms of such damage.” Over the past several years, the field of pain management has undergone a revolution marked by great advances in knowledge and therapeutic options. To better understand the anatomy and physiology of pain, this chapter subdivides pain into three major categories: neuropathic, nociceptive, and idiopathic pain. Before discussing specific neural pathways, it is useful to discuss some basic concepts and definitions.

BASIC CONCEPTS Neuropathic pain is defined as pain caused by dysfunction of the nervous system in the absence of ongoing tissue damage. Patients describe the pain as sharp, shooting, or burning, usually felt in the area of sensory deficit and worsened by mild stimuli that normally do not produce pain, such as light touch or cool air (allodynia). Many other labels have been given to neuropathic pain, including nerve pain, neurogenic pain, and deafferentation pain. Examples of neuropathic pain include trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, postherpetic neuralgia, thalamic pain, and pain from spinal cord injury. Nociceptive pain results from direct tissue damage and may occur with or without damage to the nervous system. Nociceptive pain results from the activation of nociceptors (i.e., intact peripheral afferent pain receptors). Arthritic, acute postoperative, and post-traumatic pain belong in this category. Nociceptive pain is further subdivided into somatic and visceral pain, which can be distinguished by the quality of the pain and associated clinical features. Somatic pain usually is well localized and described as stabbing, aching, or throbbing. Visceral pain arises from the viscera and is characteristically dull, cramping, and poorly localized. The term idiopathic pain has been used interchangeably with the term psychogenic pain. In our opinion, idiopathic pain is the more appropriate term because it implies a wider spectrum of poorly understood pain states. Fibromyalgia, regional myofascial pain, and somatoform pain are examples of idiopathic pain. In

addition to the lack of organic origin, the pain and associated symptoms often are thought to be grossly out of proportion to any identifiable disorder. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) refers to “pain disorder associated with psychological factors (acute and chronic)” and “pain disorder associated with both psychological factors and a general medical condition (acute and chronic).” These terms have begun to replace the older terminology of idiopathic pain in instances in which no identifiable organic origin could be found. The newer terminology reflects the understanding that emotions and mood alter pain (and vice versa) without there being any need to categorize pain as organic or nonorganic. The latter tended to imply that the pain was not real, introducing biases that were counterproductive to the physician-patient relationship. It is worth emphasizing that all pain has a psychological component. Psychological factors, which often are not obvious, and cultural and environmental factors must be considered to fully evaluate pain. For example, emotional arousal can enhance nociception at the periphery. Heightened sympathetic activity with the release of norepinephrine at sympathetic terminals can sensitize or directly activate nociceptors. Similarly, reflex skeletal muscle spasm caused by anxiety can contribute to a positive feedback loop, in which nociception fosters increased tone in muscle near the site of injury, eventually activating muscle nociceptors. However, pain may also induce negative emotions. The unpleasantness or disagreeable nature of pain inherently motivates the organism to escape from the noxious input. Investigation into the role of emotion has been helpful separating pain unpleasantness from the intensity of pain. The latter, commonly known as the sensory-discriminative aspect, refers to somatotopic localization (body map) and intensity of the painful stimuli. The former, known as the affective-motivationalcomponent, refers to the emotional characteristic that induces mood changes and drives one to avoid painful stimuli. The quantity of affective-motivationalpain often differs from the level of sensorydiscriminative pain in the same person when analyzed with visual analogue scales. For example, consider the patient with cancer pain. The pain associated with neoplasm has been characterized as having a higher visual analogue scale pain unpleasantness than visual analogue scale pain intensity. It may be that associating the pain with one’s mortality leads to a higher degree of emotional distress and consequently, unpleasantness. Conversely, the pain associated with labor tends to have a higher visual analogue scale 1383

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pain intensity than visual analogue scale unpleasantness. Presumably, the parturient is subconsciously aware of the temporary nature of the pain and the expected outcome (i.e., childbirth). We will return to a discussion of these two categories of pain when we discuss forebrain mechanisms of pain later in this chapter. Finally, it should be mentioned that patients in clinical practice often tend to exhibit more than one type of pain. For instance, a patient with cancer may have somatic pain from invasion of a lumbar vertebra (nociceptive pain). Often, the tumor is locally invasive and involves the exiting nerve root (neuropathic pain). Incursion of tumor into the nerve root may induce muscle spasm in the lower back and leg, resulting in a regional myofascial pain syndrome (idiopathic pain). There are many other commonly encountered pain syndromes that involve nociceptive, neuropathic, and idiopathic pain. For instance, surgical patients may continue to have pain after an otherwise successful operation (e.g., phantom pain after limb amputation, post-thoracotomy and postmastectomy pain). The type of pain often is differentiated by use of descriptors, such as burning and lunn’nuting, suggesting neuropathic pain. Such clues provide valuable insight into the types of therapies to be offered. PERIPHERAL PAIN PATHWAYS Nociception involves perception of pain and its subsequent response. The perception of pain can be modified at any level from the periphery to the central nervous system. The peripheral sensory system becomes activated when nociceptors, which are free nerve endings of primary afferent neurons, are stimulated by mechanical, thermal, or chemical stimuli. With the exception of the central nervous system, all other tissues contain nociceptors, especially the skin, which is richly innervated. There are three major types of nociceptors: A-6 high threshold mechanoreceptors, which respond to noxious pressure; A-6 mechanothermal receptors, which respond to both noxious mechanical and thermal stimuli; and C-fiber polymodal nociceptors, which respond to noxious mechanical, thermal, and chemical stimuli. In addition, some A-6 fibers respond specifically to cold stimuli. Nociceptive impulses are transmitted from the periphery to the spinal cord via the dorsal roots (Fig. 219-1). The intensity of a painful experience tends to correlate with the degree of noxious stimulation in normal pain states. However, sometimes nerve fibers depolarize independently of noxious stimulation. This tends to happen in response to nerve injury whereby sensitization of the primary afferents or the second-order neurons in the spinal cord result in spontaneous depolarization or a decrease in pain threshold. Clinical manifestations of this include pain independent of noxious stimulation (spontaneous pain), enhanced pain to noxious stimuli (primary hyperalgesia), the ability of nonnoxious stimuli to produce pain (allodynia), and an exaggerated response to noxious stimuli (hyperpathia). Primary afferent nociceptors transform chemical, thermal, and mechanical stimuli into electrical energy (e.g., action potentials), transmitting the impulses to the central nervous system. This process is called transduction and is the initial event in pain transmission. DORSAL HORN As mentioned earlier, the perception of pain is not a simple phenomenon mirroring the signal from the peripheral neuron. Rather, the noxious input may be modified at every level of the neural axis. The dorsal horn is the first site in the central nervous

system where incoming nociceptive information is processed and modulated. Modulation involves inhibition or augmentation of impulses along ascending and descending pathways via biochemical mediators. We will discuss modulation shortly, but first we will review the anatomy of the dorsal horn. As was first described by Rexed in 1952, the gray matter of the spinal cord is organized into laminae. There are 10 such laminae, with laminae I through VI making up the dorsal horn, a very important structure in pain transmission and modulation. Laminae VII through X make up the intermediate and ventral horns of the spinal cord, and their role in pain transmission is less well defined. There are two types of neurons in the dorsal horn that respond to incoming nociceptive stimuli: nociceptive-specific neurons, which respond to a specific type of stimulus (i.e., only those that are noxious), and wide-dynamic range neurons, which respond to a wide variety of stimuli (i.e., both noxious and those that are painful). Nociceptive-specific neurons have small receptive fields, are somatotopically organized, and are most abundant in lamina I. Widedynamic range neurons have larger receptive fields and are the most prevalent cells in the dorsal horn. Lissauer’s tract is a superficial bundle made up of primary afferent fibers consisting of A-6 fibers, C-fibers, and propriospinal axons that run longitudinally between the surface of the spinal cord and the dorsal horn. Dorsal roots enter the spinal cord, with fibers traversing through Lissauer’s tract to enter the dorsal horn. A-6 fibers, upon entering Lissauer’s tract, terminate in laminae I, 11, V, and X. C-fibers terminate in laminae I, 11, and V. Lamina I is also called the marginal layer and represents the most superficial lamina. In addition to the nociceptive-specific and wide-dynamic range neurons, the most abundant cell type in lamina I are projection cells. Some of them make up projection pathways, whereas others synapse with interneurons. Lamina I1 is called the substantia gelatinosa because of its gelatinous appearance. It also contains nociceptive-specific and widedynamic range neurons. Lamina I11 through V are known as the nucleus proprius. Lamina I11 contains myelinated axons and dendrites from deeper laminae. The most common cell type in lamina IV are low-threshold mechanoreceptors, responding to tactile and thermal stimuli from the skin. Lamina V consists mainly of wide-dynamic range neurons and axons that give rise to ascending systems. Lamina VI contains cells that provide information on movement. The gate control theory of pain, as proposed by Wall and Melzack in 1965, states that the dorsal horn in the spinal cord acts as a gate on which all nociceptive stimuli converge. Although this model does not explain all pain phenomena, the dorsal horn certainly is a pivotal player in pain processing where excitation, inhibition, modulation, and integration of nociceptive impulses affect the expression of pain. More specifically, the substantia gelatinosa of the dorsal horn is one of the principal areas where pain processing can be modified. Specific target cells located in the dorsal horn are stimulated by both large mechanofibers and smaller pain-conducting fibers. These cells relay information to higher brain centers. The substantia gelatinosa acts primarily as an inhibitory structure. Small pain fibers inhibit the substantia gelatinosa, reducing its inhibitory effect on fibers that stimulate target cells; thus, pain persists. The large fibers stimulate the substantia gelatinosa, enhancing its inhibitory effect; this tends to be self-limiting and would reduce painful stimuli from the same area. This pathway may explain the “counterirritation theory,” which asserts that applying pressure or rubbing an area at the site of injury reduces pain perception by stimulation of large mechanofibers. Electrical

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FIG. 219-1. A model of the ascending and descending systems that transmit and modulate pain. (A) The ascending transmission system starts with sensory afferents that synapse in the dorsal horn of the spinal cord and decussate to form the spinothalamic tract At brainstem levels, some fibers leave the spinothalamic tract and ascend in the reticulothalamic tract In the thalamus, spinothalamic projections terminate in both lateral and medial thalamic structures. The message is then relayed to the frontal and somatosensory cortex. (ff) The descending modulation system involves direct projections to the dorsal horn of the spinal cord from cells in the pontine reticular formation, locus ceruleus, and nucleus raphe magnus. In addition, input from the somatosensoryand frontal cortex as well as hypothalamus activates cells in the midbrain, which control spinal pain transmission cells via cells in the rostroventral medulla.

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stimulation of large afferent fibers has been shown to inhibit small primary afferents. This has been used to explain the therapeutic effectiveness of nervous system stimulation in reducing pain and may at least partially explain the mechanism of action of spinal cord and transcutaneous electrical nerve stimulators.

The spinohypothalamic tract is a recently identified direct ascending pathway that has been and is currently the focus of intense research. Anatomically, it is as abundant as the spinothalamic tract and is hypothesized to play an important role in the motivational-affective aspect of pain.

ASCENDING PATHWAYS

SUPRASPINAL STRUCTURES

The ascending nociceptive pain pathways arise mainly from laminae I, 11, and V. These include the spinothalamic tract, spinoreticular tract, dorsal columns, propriospinal system, and spinomesencephalic tract. The spinothalamic tract is located in the anterolateral quadrant of the spinal cord and is involved with sensing mechanical or tactile stimuli and transmitting nociceptive stimuli. Most of these axons cross in the ventral white commissure to ascend in the opposite anterolateral quadrant, whereas a smaller number of axons ascend ipsilaterally. The spinothalamic tract neurons separate into medial and lateral divisions as they approach the thalamus. Neurons projecting to the lateral thalamus arise from laminae I, 11, and V and synapse with fibers that project to the somatosensory cortex. These neurons are thought to be involved with the sensory-discriminative aspect of pain. Neurons projecting to the medial thalamus originate from the deeper laminae VI through IX, ultimately projecting to the reticular formation of the brainstem, periaqueductal gray, and hypothalamus. These fibers then synapse with neurons that project to the limbic system, somatosensory cortex, and other cortical centers. These fibers are thought to be involved in the motivational-affective aspect of pain. Along with the spinothalamic tract, the spinoreticular tract and spinomesencephalic tract are also located in the anterolateral quadrant. These tracts are similar in that both are involved in autonomic reflex responses and, putatively, in the behavioral and motivational aspects of pain. Unlike that of the spinothalamic tract, the origin of spinoreticular tract neurons is not clear. They may arise predominantly from laminae VII and VIII and possibly also from laminae I and V. Many of these cells are wide-dynamic range neurons that transmit nociceptive stimuli, both ipsilaterally and contralaterally, to the reticular formation. The spinoreticular tract probably is involved in the behavioral, autonomic, and motivational components of pain. The spinomesencephalic tract contains mostly nociceptive neurons that arise from laminae I and V. These neurons ascend contralaterally and terminate in a number of structures, including the periaqueductal gray matter, reticular formation, and limbic system. The dorsal column system is thought to play an important role in proprioception and possibly inhibition of nociceptive transmission. In addition, it may provide information on the localization of pain. The cells in the dorsal column system are mainly largediameter myelinated primary afferents found in laminae 111 through IV. These fibers travel ipsilaterally in the nucleus gracilis and nucleus cuneatus, decussate in the brainstem, and terminate in the posterolateral thalamus. The propriospinal system is composed of multisynaptic interneurons located in the spinal cord. This system may contribute to the transmission of nociception, possibly in a role of maintaining chronic pain states. The propriospinal system cell bodies are located in the deeper laminae, receiving input from visceral and deep structures; they then ascend within various laminae of the spinal cord, projecting to the medial thalamus and reticular formation.

The supraspinal system comprises the reticular formation, thalamus, hypothalamus, limbic system, and cerebral cortex. Within this system are extensive communicating projections for ascending algesic and descending analgesic pathways. The reticular formation extends through the entire length of the brainstem. The reticular formation receives input mainly from the spinoreticular tract but also from other structures in the supraspinal system. At the reticular formation level, receptive fields usually are extremely large, arising from both ipsilateral and contralateral parts of the body. The reticular formation controls the state of arousal and is important in autonomic reflex responses (fast defense reactions), inducing powerful analgesia in crisis situations. The thalamus consists of multiple nuclei and acts as the major relay station for incoming nociceptive stimuli. The thalamus is subdivided phylogenetically into paleothalamus and neothalamus or by nuclei location. The paleothalamus or medial thalamus has input mainly from the spinothalamic tract and the reticular formation. Its receptive fields are large, and it is involved primarily with the motivational-affective aspect of pain. The paleothalamus has extensive connections with the cerebral cortex. The neothalamus or lateral thalamus rests at the ventrobasal portion of the thalamus. The neothalamus, unlike the paleothalamus, is organized somatotopically and subdivided into the ventral posterolateral nucleus and the ventral posteromedial nucleus. The ventral posterolateral nucleus receives input mainly from the spinothalamic tract but also from the dorsal column system and the somatosensory cortex. The ventral posteromedial nucleus receives input mainly from the trigeminothalamic tract, which carries sensory input from the head and face and projects to the somatosensory cortex, involved with craniofacial pain. Although most of the neothalamic neurons respond to mechanoreceptive input, some are nociceptive-specific and are wide-dynamic range neurons. The neothalamus appears to be involved with the sensory-discriminative aspect of pain and, because of its somatotopic organization, the localization of pain. The thalamus thus provides parallel processing systems. The medial projections, involved with the motivational-affective aspect of pain, have slower conduction and poor spatial information. In contrast, the lateral thalamus, involved with the sensory-discriminative component, conveys information quickly in a somatotopic format. In 1911, Head reported 22 cases of patients with damage to the lateral thalamus with hyperalgesic response to painful stimuli contralaterally. He postulated that the medial thalamus, once released from the influence of the lateral thalamus, produced exaggerated response to somatosensory input. This disinhibition is believed to explain some cases of thalamic pain syndrome. The hypothalamus handles both noxious and nonnoxious stimuli from the entire body, including deep tissues and the viscera. The neurons are not somatotopically organized and therefore do not provide information about the discriminatory aspects or location of pain. Hypothalamic nuclei send projections to the pituitary gland via the hypophyseal stalk. These nuclei

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regulate the autonomic and neuroendocrine responses to stress and pain. The role of the hypothalamus in pain perception and pain modulation is a fascinating and rapidly evolving area. The limbic system receives input from the thalamus, reticular formation, and perhaps many other areas of the central nervous system. It involves the frontal and temporal cortex and is important in the motivational and emotional aspects of pain, including mood and affect. CEREBRAL CORTEX In the brain, blood flow apparently is related to neural activity, so functional magnetic resonance imaging and positron emission tomography can be used to observe the brain functioning when subjects perform specific tasks or are exposed to specific stimuli. Functional neuroimaging and neurologic lesioning studies (i.e., cerebrovascular events, tumors, war injuries) have implicated multiple cortical regions in the perception of pain. These regions include the somatosensory cortices, the anterior cingulate cortex, the insular cortex, and regions of the frontal cortex. The primary somatosensory cortex has long been known to play a major role in localizing nonnoxious stimulation (i.e., touch), as indicated by the depiction of somatotopic localization on the homunculus, a distorted human figure drawn to replicate the space that our body parts occupy on the sensory and motor cortices. Located posterior to the central sulcus of the brain, the primary somatosensory cortex receives input from various nuclei of the thalamus, including the ventral posterolateral nucleus, the ventral posteromedial nucleus, and the posterior thalamus. Interestingly, until recently the cerebral cortex has not been thought to play a major role in the perception of pain. In 1939, Penfield stimulated the cortex during craniotomies performed under local anesthesia. Only 1 of 426 stimulation sites in the postcentral gyrus elicited a painful reaction, and it was concluded that appreciation of pain was not cortical. In 1968, White and Sweet reported their 40-year experience of unilateral surgical excision of the postcentral gyrus. This operation failed to relieve contralateral pain sensation, thus corroborating Penfield’s findings. Recent studies using functional magnetic resonance imaging and positron emission tomography have provided contradictory evidence supporting the role of the cortex in pain perception. These newer techniques have shown that the primary sensory cortex is quixotic; sometimes it is activated during the presentation of noxious stimuli, and sometimes it is not. Several factors have been thought to contribute to this mystery. Most significantly, the activation of the primary sensory cortex is highly influenced by cognitive factors (attention) altering pain perception. Thus, whether the primary sensory cortex is activated depends on whether the subject’s attention is being diverted at the time of noxious stimulation. In addition, it is believed that the precise somatotopic organization of the primary sensory cortex may lead to small focal activations not readily recognized when averaged across subjects. However, the bulk of the evidence now strongly supports an influential role of the somatosensory cortex in the sensory-discriminative aspects of pain. Brain lesion studies indicate that the anterior cingulate cortex is implicated in processing pain unpleasantness. It has been known for many years that patients with destruction of this cortical area do not find painful stimuli to be unpleasant. Known as asymbolia, damage to this area produces individuals who have a disconnection between their ability to detect pain intensity and pain

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unpleasantness. These patients do not experience noxious stimuli as unbearable; they do not withdraw from painful provocations or threatening gestures. Yet they retain the capacity to detect the sensory features (location and intensity) of nociceptive stimulation. Suggesting that cognitive mechanisms in the anterior cingulate cortex may modulate the motivational-affectivedimension of pain, investigators have turned their attention to this area using functional magnetic resonance imaging. Hypnotic suggestion was provided to subjects to modulate their perception of the degree of unpleasantness during immersion of a finger in a hot water bath. Subjects who received the suggestion that the experimental noxious stimulation was going to be disagreeable rated the actual stimulation as highly unpleasant. This group of subjects had a concomitant increase in the activity of the anterior cingulate cortex. Their cortical activity in this area was significantly greater than when the control subjects underwent the same experiment without the benefit of hypnotic suggestion. Demonstrating that motivational-affectivepain correlates with activity in the anterior cingulate cortex, functional brain imaging has corroborated the clinical syndrome of asymbolia. In addition to the somatosensory cortices and the anterior cingulate cortex, several other brain regions are activated during painful stimulation. Specifically, the insula, lentiform nucleus, prefrontal cortex, and brainstem are activated during perception of pain on imaging studies. Interestingly, even areas thought to be involved primarily with locomotion, the primary and secondary motor cortex and the cerebellum, have increased activity during pain processing. This dispersion of pain processing might have had phylogenetic survival value whereby an organism would not lose the ability to recognize pain, as might have occurred with the loss of a discrete pain center from trauma or a cerebrovascular accident. Because organisms with a deficit in pain detection are at a disadvantage vis-A-vis escape from tissue trauma, the decentralization of pain intensity and localization might have been a favorable adaptation in the evolutionary process. DESCENDING MODULATING SYSTEM In 1965, Melzack and Wall first proposed a clear description of a descending pain modulation system in their gate control theory of pain. This theory discarded the existing model of pain as a specialized sensation with its own receptors and nervous system pathways to the brain. It hypothesized that the experience of pain involved numerous areas of the central nervous system and that pain could be modulated at the level of the first synapse in the spinal cord and at supraspinal levels. This theory paved the way for transcutaneous electrical nerve stimulation, spinal cord dorsal column stimulation, and spinal medication administration, whereby neuromodulation of the first synapse in the spinal cord is pharmacologically manipulated. In the intervening decades, efforts have been made to define the anatomy and physiology of this system. Despite recent advances, our knowledge of the descending modulatory system remains less than complete. This system modulates incoming information and is generally inhibitory in nature. The descending system can influence the transmission of nociceptive stimuli anywhere along its path from the brain to the periphery. Structures in the descending system include the cortex, subcortical centers, and basal ganglia; the thalamus-hypothalamus system; the midbrain, pons, and medulla; and the dorsal horn (Fig. 219-1).

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Cortex, Subcortex, and Basal Ganglia

Several functional imaging studies have indicated that pain processing may be modulated by cognitive mechanisms. Psychologists have shown that pain perception can decrease and even disappear when distraction is used. Experiments have shown that when subjects are actively involved in a highly attentiondemanding task, noxious stimulation is perceived as less painful when compared with normal conditions. On the corresponding imaging studies, activity is lower in cortical and subcortical areas (somatosensory regions, periaquaductal gray, anterior cingulate gyrus, insula, and thalamus). Besides the modulation of pain processes in the forebrain, cortical areas are also involved in pain inhibition at the spinal cord level via descending pathways. Stimulation of the somatosensory cortex seems to have an inhibitory effect on wide-dynamic range neurons of the spinothalamic tract and possibly other tracts involved in pain transmission. This inhibition may also be mediated by the corticospinal tract, which is primarily a motor system pathway that descends ipsilaterally, branching to the trigeminal system before crossing to the opposite side in the medulla and partially terminating in the dorsal horn. Extrapyramidal pathways may also play a role in cortical inhibition of afferent transmission. Cortical structures in the limbic system, particularly the insular cortex and amygdala, seem to exert modulatory effects via their input to the periaqueductal gray.

Thalamus-Hypothalamus System The thalamus-hypothalamus system seems to play an important role in pain transmission and pain modulation but is not completely understood. Its descending analgesic properties are suggested by findings that electrical stimulation of specific hypothalamic regions in experimental animals produce analgesia. The paraventricular nucleus of the hypothalamus is thought to be involved in pain modulation, probably via its effects on the periaqueductal gray.

Midbrain, Pons, and Medulla The midbrain, pons, and medulla contain not only the reticular formation but also the periaqueductal gray, nucleus raphe magnus, locus ceruleus, dorsolateral pontomesencephalic tegmentum, and rostra1 ventromedial medulla, all participating in the descending analgesic system. These brainstem centers send projections via the dorsolateral funiculus to the dorsal horn of the spinal cord. Likewise, descending modulatory influences from the cortex, limbic system, hypothalamus, and brainstem are also carried to the dorsal horn via the dorsolateral funiculus, which is located primarily in the spinal cord and represents the primary descending modulatory pathway. Thus, lesions of the dorsolateral funiculus block the inhibition by brainstem neurons of behavioral responses to noxious stimuli. BIOCHEMICAL MEDIATORS

Neurotransmitters link one neuron to the next via chemical and receptor activity within the synaptic cleft between neurons. The classic neurotransmitters, such as epinephrine, acetylcholine, and serotonin, are small molecules. However, peptides are also recognized constituents of nerve cells and often coexist with classic neurotransmitters in the same nerve cell. That a single neuron may produce, store, and release more than one messenger molecule

significantly expands the complexity of possible interactions of pain signals. Through varied mechanisms at the site of tissue damage, pain signals initiate and sustain an elaborate alarm of impending or ongoing damage. Nociception may be the first signal to activate local tissue reactions that promote defense, stimulate tissue repair, and enhance sensitivity to further physical or chemical insults. In response to noxious stimuli, nociceptors may release their algesic substances for purposes of afferent neurotransmission and modulation of local reactions such as inflammation and possibly tissue repair. Algesic substances trigger the release of inflammatory mediators from mast cells, endothelial cells, and other surrounding neural and nonneural cells. Sensitization of nociceptors results in a reduced response threshold to noxious stimuli and enhanced activity once activated. Within the spinal cord, sensitization also takes place as the threshold for excitation of pain transmission decreases. The spontaneous firing rate and duration of nerve action (“windup”) increases during repeated or ongoing nociceptive input. Sensitization underlies the experience of injured patients with hyperalgesia or hyperesthesia (exaggeratedpain in response to noxious stimuli). Recent studies indicate that there are significant long-term consequences of sensitization. Pain is intensified because of a reorganization of spinal cord circuitry, whereby nociceptors discharge spontaneously and produce ongoing pain. Prolonged firing of C-fiber nociceptors causes release of glutamate, which acts on N-methyl D-aspartate (NMDA) receptors in the dorsal horn. NMDA receptors become sensitized, and second-order neurons become more responsive, resulting in central sensitization. NMDA receptor antagonists, such as ketamine and dextromethorphan, can suppress central sensitization in experimental animals. NMDA receptor activation not only increases the response of spinal cord neurons to painful stimuli but also decreases neuronal sensitivity to opioid receptor agonists. Thus, nerve injury induces opioid tolerance, which reduces the effectiveness of our most potent class of analgesics. Many investigationsare under way in an attempt to find solutions to this problem, so that neuropathic pain caused by nerve injury can be more effectively treated. A large variety of mediators are involved at the synaptic level, allowing a multiplicity of pain-modulating signals. The list of possible algesic and analgesic substances and neurotransmitters is rapidly expanding and includes substance P, calcitonin generelated peptide, somatostatin, bradykinin, serotonin, histamine, acetylcholine, y-amino-butyric acid, Leu- and Met-enkephalin, pancreatic polypeptide, neurotensin, vasoactive intestinal peptide, cholecystokinin, gastrin-releasing peptide, bombesin, angiotensin, adenosine, prostaglandins, leukotrienes, adenosine triphosphate, and the amino acids L-glutamate and L-aspartate (Table 219-1). In addition to neurotransmitters, numerous second messengers and ion channels are involved in nociception. Protein kinase C and nitric oxide are intermediaries that are believed to play pivotal roles in the persistence of some neuropathic pain states. Sodium and calcium ion channel blockers that are specific for the neuraxis are being sought to find the ideal modulator of pain at the level of the dorsal horn. Preliminary investigations in animals and a small number of human trials are investigating pain modulation by a small number of these chemicals. Scientific inquiry into the mechanisms of pain transmission is expected to pay large dividends, providing new therapeutic options for the millions of patients who have neuropathic pain. Endogenous opioids play a key role in pain modulation. Opiate receptors are found throughout many structures involved with

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rn TABU 219-1. Key Neurotransmitters and Their Interaction with Common Analgesics Excitatory Mediator

Medications Affecting Excitatory Mediators

Glutamate and aspartate

N-methyl D-aspartate antagonists (e.g., memantine) Capsaicin cream Nonsteroidal anti-inflammatory analgesics (e.g., aspirin) Antihistamine drugs Nonsteroidal anti-inflammatory analgesics

Substance P Bradykinin Histamine Prostaglandins

pain, especially the dorsal horn. There are several types of opiate receptors: the p receptor, found in the dorsal horn, limbic system, and brainstem; the K-reCeptOr, distributed in the dorsal horn, limbic system, brainstem, and cerebral cortex; and the h-receptor, distributed throughout the spinal cord. The three classes of endogenous opioids each arise from specific precursors or prohormones: enkephalin, which is derived from pro-enkephalin, P-endorphin, derived from proopiomelanocortin; and dynorphin, derived from prodynorphin. These precursors are found in the highest concentrations in the structures thought to be involved with analgesia, including the dorsal horn, nucleus raphe magnus, periaqueductal gray, hypothalamus, and cingulate gyrus. Noradrenergic receptors are found in the pons and dorsal horn. Activation of these receptors produces an inhibitory effect on nociception. Applying norepinephrine to the spinal cord has been shown to inhibit the transmission of nociceptive impulses. Tricyclic antidepressantsprovide analgesia in part by inhibiting the norepinephrine reuptake and thus increasing its blood level. Clonidine, an a,-agonist, can be given centrally or systematically to produce analgesia by inhibiting nociceptive impulses. Clonidine acts synergistically with opioids and can decrease the amount of opioids needed for analgesia. Serotonin is found, among other areas, in the medulla and spinal cord, especially laminae I and 11. Like norepinephrine, stimulation of serotonin-containing neurons also inhibits nociceptive stimuli. Central application of serotonin induces analgesia. Tricyclic antidepressants can also inhibit serotonin reuptake, producing an increase in its blood level. y-Aminobutyric acid is an inhibitory amino acid found in high concentrations in laminae I and I1 that acts principally on large primary afferents. The proposed mechanism of action of benzodiazepines is through allosteric binding and modulation of the y-aminobutyric acid receptor, with resulting change of its chloride channels.

SUMMARY Although pain has no molecular weight or DNA sequence, no other physiologic process has been more scrutinized. However, the central and peripheral mechanisms of pain remain incompletely

Inhibitory Mediator

Medications Affecting Inhibitory Mediators

Serotonin Norepinephrine

Antidepressants Antidepressants

y-Aminobutyricacid Endogenous opioids (enkephalin, endorphin, dynorphin)

Baclofen and benzodiazepines Opioids

understood. Although it may maintain needed vigilance to protect tissues already damaged, the role of pain goes beyond a warning system and has significant impact on normal physiology. Therefore, there may be significant medical consequencesto inadequate recognition or treatment of pain. Pain transmission is well integrated with other major physiologic processes, such as immune, endocrine, cardiac, hemodynamic, gastrointestinal, and mental functions. A system of such complexity is a marvel of nature that may have devastating effects when malfunctioning. Continued advances in the understanding of the anatomy and physiology of pain will enhance health care for those in pain and offers hope for greater relief from suffering.

SUGGESTED READINGS Bonica JJ: Anatomic and physiologic basis of nociception and pain. pp. 28-94. In The Management of Pain. 2nd Ed. Lea & Febiger, Philadelphia, 1990 Bonica JJ: Biochemist and modulation of nociception and pain. pp. 95121. In The Management of Pain. 2nd Ed. Lea & Febiger, Philadelphia, 1990 Fields HL, Basbaum AJ: Central nervous system mechanisms of pain modulation. pp. 243-256. In Wall PD, Melzack R (eds): Textbook of Pain. Churchill Livingstone, Edinburgh, 1994 Guilbaud G, Bernard JF, Besson JM: Brain areas involved in nociception and pain. pp. 113-128. In Wall PD, Melzack R (eds): Textbook of Pain. Churchill Livingstone, Edinburgh, 1994 Head H, Holmes G Sensory disturbance from cerebral lesions. Brain 34102-154, 1911 Penfield W, Boldrey E Somatic motor and sensory representation in the cerebral cortex of man. Brain 60116-126, 1937 Rainville P, Duncan GH, Price DD et ak Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277:96&971, 1997 White JC, Sweet WH: Pain and the Neurosurgeon: A Forty Year Experience. Springfield, I L Thomas Publishers, 1968 Wilson PR, Lamer TJ: Pain mechanisms: anatomy and physiology. pp. 65-80. In Raj PP (ed): Practical Management of Pain. 2nd Ed. Mosby, St Louis, 1992 Woolf E J The dorsal horn: state-dependent sensory processing and the generation of pain. pp. 101-112. In Wall PD, Melzack R (eds): Textbook of Pain. ahurchill Livingstone, Edinburgh, 1994

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220 Approach to the Patient with Chronic Pain Gerald M. Aronoff

Chronic pain is a major public health problem, inflicting not only tremendous personal suffering but also huge economic loss on individuals and society. If the pain remains intractable, physicians and patients become increasingly uncertain as to the most appropriate course of treatment, and both develop a sense of helplessness. As each becomes frustrated and disappointed in the other, their interaction becomes more strained and less direct. Much more is known of the mechanisms and pathophysiology of acute pain and cancer pain than of chronic nonmalignant pain. Attempts to generalize from one to the other have resulted in dismal failures to control the pain, frequent iatrogenic complications, and inappropriate and excessive use of medications. Current treatment approaches for chronic pain offer strategies for peripheral management of pain but increasingly emphasize central factors. Pain is a subjective, unpleasant sensory and perceptual experience that may or may not be related to tissue damage. Try as we may to quantify, measure, and objectify it, we ultimately fall short. We attempt to incorporate the patient’s subjective symptoms, objective signs, and the results of diagnostic testing with our own clinical interpretations (which include subjective biases). Yet finally, our response to a patient’s complaint of pain depends heavily on the credibility of the patient. Most physicians specializing in pain medicine believe that all pain is real, with the rare exception of malingering. Yet in my experience it is still true, as it was decades ago, that we give more credence to the patient for whom there are well-documented, objective findings that support the complaint of pain than to the depressed, somatically preoccupied patient who has a chronic pain syndrome not supported by objective findings. This is unfortunate and is often a disservice to the latter patient. The United States has the most technologically advanced medical system in the world. However, in recent years physicianpatient relationships have deteriorated significantly. This has resulted from both the medical bureaucracy and the trend toward increased specialization and compartmentalization of patients’ medical disorders. In the current traditional medical model and especially that practiced in most urban regions, it is uncommon for one physician to be the primary caretaker for a patient and his or her family. Even within medical and surgical specialties, there are increasing subspecialties. The jogger who develops knee or ankle pain no longer contacts a general orthopedist for care but instead goes to a sports medicine clinic. The obese patient with chest pain is seen by an internist, often referred to a cardiologist, and then treated at a weight loss clinic. Do health care providers truly get to know the patients and their psychosocial problems that, as studies indicate, often contribute to or cause the medical complaints? Or is this lack of rapport an unavoidable consequence of the increasing depersonalization in the medical system? The all-too-common scenario of the patient who takes a tranquilizer before going to the physician’s office has replaced the antiquated model of the physician-healer who visited the patient’s home. Recognizing the impact of medical specialization has become

crucial in chronic pain management. Studies indicate that a large percentage of patients presenting to primary care outpatient clinics with complaints of headaches, backaches, general myalgias, and other physical symptoms have no objective findings, or the findings are inconsistent with the subjective complaints. Many receive treatment for their primary physical symptoms while the underlying problems continue. This is especially true in such problems as chronic daily headaches, myofascial pain syndromes, fibromyalgia, and nonspecific low back pain to give just a few examples. It is essential to search for predisposing and activating factors for the pain, but equally important are perpetuating factors that often maintain these pains, delay recovery, and contribute to disability. These factors can be mechanical (leg length discrepancy, severe degenerative changes), systemic (poor healing in diabetics), or more related to emotional conflicts or life stressors. It is not uncommon to find that perpetuating factors have predated the activating factors or the onset of the pain syndrome but did not cause the patient significant symptoms until after the activating factor, after which these perpetuating factors developed major clinical significance. For example, musculoskeletal pain has become a major public health problem with medical, occupational, and socioeconomic implications. Aronoff and Dupuy (1997) reviewed the problem of musculoskeletal pain and impairment and the implications for disability, with specific reference to recent meta-analyses such as those performed by the Agency for Health Care Policy and Research (1994) and the Task Force on Pain in the Workplace of the International Association for the Study of Pain (1995). Data from these and other studies are consistent with our clinical findings suggesting that most cases of low back pain are idiopathic with an obscure origin. Therefore, they should be classified as nonspecific low back pain or back pain of undetermined origin. We suggest that despite a paucity of objective findings, many patients receive diagnoses difficult to justify and extensive diagnostic evaluation, some of which may be inappropriate and contribute to iatrogenic disability. The concept of pain proneness is important to recognize; Engle, Blumer, and Heilbrunn, and this author have written extensively about the process. Certain people have a characteristic developmental history notable for unmet dependency needs, emotional neglect, physical or sexual abuse, and hyperresponsibility at an early age, often to take care of ill family members or to raise younger siblings. Their psychosocial history reveals that patterns of maladaptive behavior continue into adult life. They become injured (at times insignificantly) or develop an illness (with symptoms far in excess of objective findings) from which they never recover or have significantly prolonged recovery. This author believes it is their way of saying, “Now it is my turn to be taken care of.” The clinician who does not recognize this process is likely to use excessive diagnostic techniques, medications, and interventional approaches and runs the risk of promoting iatrogenic complications and becoming an enabler in the disability process.

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Patients with pain syndrome, in their desperate search for the elusive cure, often chase will-o’-the-wisps, convincing their physicians to perform myriad invasive tests and procedures. As a result of their pain behaviors, many experience iatrogenic complications, suffering, and disability. Those involved in their treatment must find better ways to detect this highly susceptible population, establish a therapeutic alliance, and short-circuit their pain careers. Our health care system cannot rely solely on the traditional methods of medical and surgical approaches so often used with this population. Despite technological advances in medicine, chronic pain syndromes remain among the most difficult problems to treat. Many believe that the high-technology, interventional procedures developed in the recent years have benefited a small group of patients with chronic pain. However, they have not made a significant impact on the disability epidemic from back pain, soft tissue problems, and other disorders. This is because the basic problem leading to the associated disability is not primarily structural but rather has its roots in the reasons that many seek out disability (e.g., job dissatisfaction, poor work ethic, difficulty coping with life stressors). Most treatment approaches have been based on a dichotomy between physiologic and psychological causes. This dualism greatly reduces the treatment available to the patient. It reinforces the tendency to isolate the symptoms from the person experiencing the pain and to focus treatment on target organs. Although this dichotomy has not been universally rejected, medical science has made significant contributions to the theory of pain as a multidimensional phenomenon.

MEDICAL EVALUATION

Certainly, we should not ask people to live with pain if there is an acceptable way to alleviate it and if the potential benefits outweigh the potential risks and side effects. Therefore, I believe that all those involved in pain evaluations should begin with a comprehensive review of the patient’s medical status and a detailed review of past medical evaluations and interventions. This should be performed by those experienced in evaluating chronic pain. Through the years, I have been distressed at the many clinical recommendations offered by inexperienced consultants. When seeing a patient with chronic pain syndrome, they often order extensive diagnostic studies and invasive therapies, whereas more experienced consultants tend toward a more conservative course. As pain clinicians, we should strive to develop and provide the most effective therapies for the various pains we treat. It is hoped that clinical research on the spectrum of pain disorders will help us delineate not only the treatments of choice but also the methods involved in their implementation. One way to improve the cost-effectiveness of our system would involve the use of experienced consultants before surgery in populations thought to be at high risk for treatment failure. I suggest obtaining second opinions for all nonemergency surgeries for patients with chronic pain in the following situations: Those in which a patient has already undergone two or more pain-related surgeries without documented beneficial results Those in which a patient has undergone one or more pain-related surgeries with negative findings Those in which a patient is referred by attorneys and is actively involved in accident-related litigation

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Those involving a patient with known or highly suspected major psychopathology Those involving a patient with a history indicative of excessive use of the health care system without adequate justification In terms of treatment choice, I believe that the same general rule that applies throughout all medical practice also holds true for chronic pain syndromes. That is, the least invasive treatment capable of bringing about the desired effect is not only the treatment of choice for the patient but it is also the most cost-effective for society. All other factors being equal, a noninvasive therapy should be preferred over an invasive one. The term chronic pain syndrome is meant to describe subjective pain complaints, resultant suffering, and pain behaviors that are excessive and disproportionate to the actual pathophysiology. There is accompanying life disruption, self-limitation in activities, maladaptive behavior, and excessive health care use. In an effort to expand the patient’s choice of treatment modalities, the multidisciplinary pain center has emerged. In this setting the medical, psychological, and social contributions to chronic pain problems are addressed by staff from various disciplines. Physicians (most often anesthesiologists, neurologists, psychiatrists, internists, physiatrists, orthopedists, and neurosurgeons) participate in a coordinated treatment approach with nurses, psychologists, social workers, physical and occupational therapists, vocational counselors, and other health care personnel. The multidisciplinary pain center team offers evaluation and treatment directed toward modifying pain and drug-seeking behavior and interrupting the disability process. However, the survival of multidisciplinary pain center is in doubt. With blatant disregard for extensive research supporting clinical and cost efficacy of the multidisciplinary pain center in the management of chronic pain, associated suffering, and disability, access to care and adequate pain treatment is extremely limited (by payers) for most chronic pain sufferers. Administrative barriers not only limit patients’ access to care but also beleaguer physicians who try to care for them. Yet ample research indicates that early referral to a recognized pain specialist may prevent the vortex of events that often leads to permanent disability. Traditionally, individual physicians have been primarily responsible for pain management. Treatment options generally included bed rest, physical therapy, analgesic medications, surgery, and nerve blocks. Unfortunately, these approaches often reinforce passive-dependent traits, which are common to many patients with chronic pain syndrome. Bed rest is contraindicated for most chronic nonmalignant pain syndromes. The indications for appropriate use of nonsteroidal anti-inflammatory analgesics, opioids, adjuvant analgesics and nerve blocks, surgery and other interventional approaches (e.g., morphine pumps, spinal cord stimulators) are being better defined. Since the 1970s, research has demonstrated the importance of the multidisciplinary pain center team approach to chronic pain, particularly when the pain problem has eluded diagnosis or adequate treatment via conventional techniques. An assumption of almost all multidisciplinary pain centers is that chronic pain syndromes always involve psychological, social, biologic, and medical factors. This assumption has been widely accepted throughout the community of pain clinicians. I have always emphasized that any treatment program designed for patients with chronic pain syndrome must be holistic in its orientation if it is to be effective. This assumption does not imply that psychosocial factors are merely sequelae to a more fundamentally medical

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disorder or that patients treated in a multidisciplinary pain center have primarily psychogenic pain. However, it does suggest that regardless of medical subspecialty, our treatment approach should be psychotherapeutic, assisting patients with the suffering component of the pain and encouraging them to discuss their fears, apprehensions, depressive feelings, and so on. If we do not feel equipped (or do not have the time) to personally treat the emotional components, these patients should be referred to an appropriate colleague. Emotional disorders associated with chronic pain syndromes include the following: Somatoform disorders Somatization disorder Conversion disorder Pain disorder (formerly somatoform pain disorder) Hypochondriasis Atypical somatoform disorder Psychological factors affecting physical conditions Affective disorders Personality disorders Malingering Schizophrenia Substance use disorders Referral to a pain center sometimes is regarded as the treatment of last resort. Unfortunately, by the time most patients are referred for a pain management approach, their lives have become significantly disrupted by depression, disability, vocational difficulties, financial strain, difficulty in interpersonal relationships, and a general loss of productivity. It must be emphasized that early patient referrals may help eliminate needless or multiple surgeries, reduce health care costs, and promote patients’ return to productivity. It is my belief that most patients with chronic pain syndrome (more than 85%) can be treated effectively in an outpatient setting. This avoids costly hospitalization and more realistically simulates typical activities of daily living. Unfortunately, this has been one of the major problems with the hospital model since its inception. Many patients find that after being confined in a sheltered and artificial environment, they have a difficult transition back to the workplace or normal daily activities. Criteria for inpatient treatment include the following: Unstable medical illness necessitating around-the-clock medical or nursing supervision Major substance dependence Active suicidal ideation Patients who are not ambulatory Failure of prior outpatient pain treatment I have also found that having inpatients participate with outpatients is effective in shortening the in-hospital portion of the treatment program. Treatment is based on a wellness model, recognizing that these patients’ pain generally does not make them “sick” in the acute medical sense of the word but that it interferes with optimal functioning in various areas of their lives. The main goal of treatment should be overcoming the disabling effects of chronic pain and returning patients to productivity rather than continued dependency on the health care system. Therefore, the preferred treatment approach is one geared to functional restoration coupled with cognitive-behavioral psychosocial interventions.

Staffs in multidisciplinary pain centers generally view the chronic pain syndrome itself as the focal point of treatment, not merely as a symptom of an underlying pathophysiologic process. Therefore, legitimate directions of treatment are to reduce pain behaviors, life disruption, medication dependence, and secondary gain; to increase activity levels despite pain (teaching patients that hurt does not necessarily mean harm) and physical functioning; and to help patients return to a more functional and productive lifestyle. As other medical and surgical specialists are selective in choosing patients likely to benefit from a given treatment (e.g., blocks or surgery), so too must pain centers be selective. As part of the pain center program, behavior modification to reinforce adaptive coping skills and extinguish self-defeating, maladaptive behaviors entails use of the patient’s capacity for insight and self-change. Some patients are incapable of this process, and if this is detected initially, they are recognized as being inappropriate candidates for inclusion in a pain center treatment program. Patients with major cognitive deficits from cerebrovascular accidents or dementia generally do not do well in this type of program. Patients with limited comprehension in the primary language used at the pain center also have difficulty grasping the concepts of the program and interacting in a meaningful way with other patients or staff. Pain center personnel must be aware of the limitations that may place the treatment of many patients with pain beyond their grasp. PHARMACOLOGIC MANAGEMENT

It is beyond the scope of this chapter to discuss all aspects of pharmacologic management of chronic pain. However, several important areas are discussed because their uses may not be well known to some primary care physicians or other nonpain physicians. These include the use of nonsteroidal antiinflammatory analgesics, opioids, adjuvant analgesics, antidepressants, and benzodiazepines. NONS‘EROIDAL ANTI-INFLAMMATORY ANALGESICS

Nonsteroidal anti-inflammatory analgesics provide analgesia primarily through actions outside the central nervous system by inhibiting prostaglandin formation through mechanisms via the arachidonic acid cascade. Unfortunately, it is this mechanism that also contributes to the gastropathy caused by these medications. Nonsteroidal anti-inflammatory analgesics are perhaps the most widely prescribed analgesics to the point of being used excessively and at times indiscriminately. The most common adverse side effects from these medications are gastrointestinal. A recent article in the American Journal of Medicine emphasizes the importance of using this medication class selectively (Singh, 1998). For example, it was noted that 170,000 patients are hospitalized annually for gastropathy caused by nonsteroidal anti-inflammatory analgesics. More than 16,500 deaths related to nonsteroidal antiinflammatory analgesics occur each year among patients with arthritis alone. Patients with osteoarthritis and rheumatoid arthritis are 2.5 to 5.5 times more likely than the general population to be hospitalized for gastrointestinal events related to nonsteroidal anti-inflammatory analgesics. The absolute risk for serious gastrointestinal toxicity related to these medications remains constant, and the cumulative risk increases over time. There are no reliable warning signals, and more than 80% of patients with serious gastrointestinal complications had no prior gastrointestinal symptoms. Independent risk factors for serious

Chapter 220 W Approach to the Patient with Chronic Pain

gastrointestinal events were age (over 60), prednisone use, dosage of the nonsteroidal anti-inflammatory analgesics, disability level, and previous gastrointestinal symptoms caused by these medications. (Other studies also note alcohol use as an additional risk factor.) Antacids and histamine-2 receptor antagonists often do not prevent gastric ulcers induced by nonsteroidal antiinflammatory analgesics. High-risk users of these medications who take gastroprotective medications are more likely to have serious gastrointestinal complicationsthan do patients who do not take such medications. The authors concluded that limiting use of nonsteroidal anti-inflammatory analgesics is the only way to decrease the risk of gastrointestinal events related to these medications. The newer cyclo-oxygenase-2 inhibitors are said to be as effective as traditional nonsteroidal anti-inflammatory analgesics at suppressing inflammation and providing analgesia, with a much lower incidence of analgesic gastropathy. The decrease in upper gastrointestinal toxicity is strongest among patients not taking aspirin concomitantly. Increasing evidence suggests that this class of medication should be used preferentially in high-risk patients for whom an anti-inflammatory analgesic is indicated. Further studies are warranted to assess whether the additional expense is also justified in other patients without significant risk factors. 0p5o5ds

In the last decade there has been significant controversy about the appropriateness, efficacy, safety, and wisdom of treating patients with chronic pain with opioids. Arguments against their use have included concerns about tolerance, dependence, addiction, persistent side effects, and interference with physical or psychological functioning. However, extensive experience and research with long-term cancer pain treatment suggests that in appropriately selected patients, opioids have a low morbidity and a low addiction potential. In addition to the primary analgesic action, they can reduce suffering, enhance functional activity level, and improve the quality of life without significant risk of addiction. It is generally accepted that nociceptive pain is most opioid responsive, neuropathic and central pain is less predictably but variably responsive, and psychogenic pain is generally unresponsive and inappropriate for chronic opioid treatment. Guidelines for maintenance opioid use are as follows: A medical condition has been documented as the cause of pain. Prior systemic therapeutic trials of alternative pain control regimens (analgesics, adjuvants, psychosocial interventions, appropriate medical treatments, and behavioral approaches) have been unsuccessful. Nonopioid treatments have resulted in inadequate analgesia, continued suffering, and impaired functional activities of daily living. Before initiating opioid maintenance, non-pain medicine physicians should consult with a pain specialist or with a specialist in management of the specific problem being treated. The consultation report should document concurrence with opioid treatment. Detailed discussion of short and long-term effects and risks of opioid maintenance should be documented. Signed informed consent is recommended. One physician should be responsible for writing prescriptions (which should be on a time-contingent rather than paincontingent basis) and monitoring clinical progress. The

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recommended initial frequency of appointments is at least monthly. Patients must be seen, and records must show reason for continuing opioids. When possible, the patient should be encouraged to use one pharmacy for his or her opioid prescriptions. The physician should document that maintenance opioids improve analgesia and function in activities of daily living and diminish suffering without being limited by adverse side effects (therapeutic efficacy). The lowest clinically effective opioid dosage should be used. Peripherally acting nonopioids and adjuvants used concurrently may allow lower opioid usage. A history of substance dependence or abuse is a relative contraindication. Any evidence of drug-seeking behavior, obtaining opioids from multiple sources, or frequent requests for dosage escalation, without documentation of significant worsening of the clinical condition, should be a cause for careful review and reconsideration of maintenance opioid use. It should be documented that patients on maintenance opioid treatment remain functional while receiving opioid analgesics and that periodic attempts to taper these result in diminished control of pain and suffering and impairment in overall function. Patients with a history of substance abuse or dependence, significant psychopathology, or excessive environmental stressors contributing to their pain and suffering in general should not be maintained on opioids for nonmalignant pain. It must be emphasized that the majority of patients with chronic pain syndrome can be treated effectively without the use of opioids. There is a subgroup of patients with chronic pain for whom long-term use of opioids is appropriate and represents good medical judgment. Patients who would otherwise be disabled can be kept functional and productive. Pain and suffering levels and functional abilities all can be demonstrated to improve. Other patients with chronic pain do less well with opioid treatment. Their pain complaints, dysfunctional pain behaviors, and selflimitations in activities remain (or increase). Appropriate opioid treatment does not cause drug addiction. Inadequate analgesic treatment in patients whose clinical conditions warrant more effective analgesia are at risk for pseudoaddiction, an iatrogenic process resolved by giving the patient adequate analgesia. Indiscriminate opioid treatment with patients at high risk for substance problems may cause drug addiction, however.

Antidepressants There is a complex relationship between pain and depression. Studies have found that a high percentage of psychiatric inpatients who presented with depression also experienced some form of pain, many psychiatric outpatients somatize, and the majority of patients referred to pain centers have some degree of depression spectrum disorder, with most showing improvement in pain when treated with antidepressants. This depression often is masked by somatic symptoms rather than presenting as a mood disturbance. There is growing evidence that depression lowers pain tolerance, increases analgesic needs, and adds to the debilitating effects of pain. Patients in chronic pain often suffer from insomnia, with early-onset latency, frequent awakenings, and early morning awakenings. These are also extremely common vegetative signs of depression. Although patients usually attribute insomnia to pain rather than depression, this may be because pain is the more

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General Aspects of Pain

socially acceptable malady. It is difficult to distinguish cause and effect with the pain-depression-insomnia, cycle but once established, the cycle becomes self-perpetuating and necessitates active intervention. Sedating tricyclic antidepressants may be useful in breaking this cycle. Although it has been suggested that the apparent analgesic effects of tricyclic antidepressants may be the result of changes in sleep, other studies suggest that these compounds are adjuvant analgesics, independent of their action on sleep or depression. Many studies of clinical pain syndromes suggest the efficacy of tricyclic antidepressants in migraine headaches, tension headaches, diabetic neuropathy, postherpetic neuralgia, low back pain, mixed arthritic and fibromyalgic disorders, atypical facial neuralgia, and others. The serotonergicenhancing medications have been the most studied, including amitriptyline, doxepin, imipramine, and desipramine. Patient compliance often is a problem because of the high occurrence of anticholinergic and antihistaminic side effects, with frequent complaints of weight gain, constipation, daytime somnolence, and dry mouth. Compliance is significantly higher with the selective serotonin reuptake inhibitors (citalopram, fluoxetine, sertraline, and paroxetine) because the occurrence of adverse side effects is much lower. Although further studies are needed to assess their efficacy as adjuvant analgesics, anecdotal reports and my initial trials for chronic headaches and other pain disorders suggest that they are efficacious for depression and variably but less so as adjuvant analgesics, when compared with tricyclics. Serotonin reuptake inhibitors often are used alone, or they may be used in combination with sedating tricyclics given in reduced dosages in the evening in the patients with insomnia. One must be aware that some serotonin reuptake inhibitors can increase serum tricyclic levels, and in patients already taking high dosages of these agents, the serum tricyclic level should be monitored if these agents are used in combination. This effect on serum tricyclic level is more pronounced with coadministration of fluoxetine than it is with sertraline or citalopram. It should also be mentioned that pharmacologic agents do not treat underlying emotional conflicts, solve family problems, or resolve motivational issues. Therefore, in most cases, chronic pain coexisting with depression must be treated multidimensionally with agents such as antidepressants and a variety of other medical, psychotherapeutic, and social interventions. Combinations of tricyclic antidepressants and phenothiazines have been used to treat a variety of pain syndromes. The only phenothiazine noted to have analgesic action is methotrimeprazine, but its clinical usefulness is limited by a high occurrence of side effects. Because certain antihistamines, such as hydroxyzine, often seem to be as effective as phenothiazines when used for patients with chronic pain, the long-term use of phenothiazines must be weighed against the potential risk of tardive dyskinesia. Monoamine oxidase inhibitors and lithium have also been found to have adjuvant analgesic properties in some pain states.

gabapentin has gained increasing popularity as a first-line medication because of its wide margin of safety and tolerability.

Anticonvulsanb

Research for this chapter was supported by an unrestricted educational grant from Purdue Pharma.

Anticonvulsants, widely accepted in management of chronic neuropathic pain, particularly lancinating, burning, and dysesthetic pain, are postulated to cause their analgesic effects primarily by suppressing ectopic neuronal discharges. Increasingly, this class of medications, as well as other membrane stabilizers, is used either alone or in combination with other adjuvant analgesics and primary analgesics to manage neuropathic pain. In recent years,

Benzodiazepines

Many clinicians treating chronic pain syndromes are dismayed by the frequency with which the benzodiazepines are prescribed for patients with chronic pain and concurrent depression. Lipman (1981) has noted that benzodiazepines cause an increase in anger and hostility when given over a 9-week period. This can be an adverse response for this already difficult population of chronic pain sufferers. It has been suggested that one of the mechanisms by which benzodiazepines and barbiturates reduce pain is by actions on the neurotransmitters (depletion of y-aminobutyric acid). It is suggested that benzodiazepines deplete serotonin, often adding to depression, paradoxical rage, habituation, disrupted sleep, and hangovers caused by alterations of stage 3 and 4 sleep and rapid eye movement sleep. It has also been suggested that the benzodiazepines inhibit serotonin release and may increase pain perception. These views, coupled with my 18-year experience at the Boston Pain Center, suggest that this class of medication should not be used for long-term treatment of chronic pain. DISABILITY

Patients with pain rarely are totally and permanently disabled. If patients must live with pain, we do them a far greater service by helping them not be disabled and by teaching them how to cope with pain and resume a productive lifestyle than by promoting the sick role. Lack of productivity in our society almost always leads to lower self-esteem, passive dependency, and depression. The importance of our authoritarian guidance as physicians should not be underestimated; it can take the form of supportive paternalism or maternalism. I believe that patients will either live up to our expectations that they need not be disabled or, conversely, become invalids unnecessarily through learned helplessness. It remains my conviction that the patient who must endure chronic pain suffers less when his or her life has purpose and meaning. Gainful employment often can serve as a distraction from pain. People with legitimate painful injuries should be appropriately compensated for pain and suffering. However, we need an alternative to the current reimbursement system that often rewards people more for malingering. As physicians, we must rate impairment by objective criteria and not confuse our goal of being the patient’s advocate with assigning him or her an unwarranted disability status. As clinicians, working together, we can continue to make the types of breakthroughs that will benefit our patients and contribute to a more productive society. In doing so, we are living up to the meaning of the word physician, one skilled not only in the art of healing but also in helping to decrease suffering. ACKNOWLEDGMENT

SUGGESTED READINGS Aronoff GM: Pain Centers: A Revolution in Health Care. Raven Press, New York, 1988 Aronoff GM: Chronic pain and the disability epidemic. Clin J Pain 7:330-338, 1991

Chapter 221 W Addiction and Detoxification in Chronic Pain

Aronoff GM: Evaluation and Treatment of Chronic Pain. 3rd Ed. Lippincott Williams & Wilkins, Baltimore, 1999 Aronoff GM: Psychiatric aspects of nonmalignant chronic pain: a new nosology. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. 3rd Ed. Lippincott Williams & W i h s , Baltimore, 1999 Aronoff GM: Opioids in chronic pain management: is there a significant risk of addiction? Curr Rev Pain 4112-121,2000 Aronoff GM: The role of pain centers. In Warfield CA (ed): Principles and Practice of Pain Management. 2nd Ed. McGraw-Hill, New York, 2001 Aronoff GM, Dupuy D N Evaluation and management of back pain: preventing disability. J Back Musculoskeletal Rehabil9109-124, 1997 Aronoff GM, Evans WO: Evaluation and treatment of chronic pain at the Boston Pain Center. J Clin Psychiatry 43:4-8, 1982 Aronoff GM, Feldman JB: Preventing disability from chronic pain: a review and reappraisal. Int Rev Psychiatry 12:157-169,2000

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Aronoff GM, Gallagher RM: Pharmacological management of chronic pain: a review. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. 3rd Ed. Lippincott Williams & Wilkins, Baltimore, 1999 Aronoff GM, McAlary PW Multidisciplinary treatment of intractable pain syndromes. Adv Pain Ther 13:270, 1990 Lipman RS Pharmacotherapy of anxiety and depression. PsychopharmaC O ~B d 17:91-103, 1981 Raj PP (ed): Practical Management of Pain. 3rd Ed. Mosby, St Louis, 2000 Silverstein FE, Faich G, Goldstein JL et ak Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study, a randomized controlled trial. JAh4A 2841247-1255, 2000 Singh G Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 105:31S-38S, 1998

221 Addiction and Detoxification in Chronic Pain John R. Peteet Suspected, past or active addiction often complicates the treatment of chronic pain. This chapter outlines an approach to diagnosing addiction, assessing and treating pain, and managing addiction in these cases. It focuses primarily on the use of opioids to manage chronic nonmalignant pain. DIAGNOSING ADDICTION A lack of standard terminology has traditionally hampered the

diagnosis of addiction in patients with pain. The Diagnostic and Statistical Manual of Mental Disorders, Revised Fourth Edition, specifies criteria for substance dependence and abuse but omits consideration of the issues that arise in the setting of pain. Portenoy (1990) has attempted to fill this gap by suggesting an operational definition that includes An intense desire for the medication or an overwhelming concern about its continued availability (psychological dependence) Evidence of compulsive medication use, characterized by unsanctioned dosage escalation, continued dosing despite significant side effects, use of medication to treat symptoms not targeted by the therapy, or unapproved use during periods of no symptoms Evidence of one or more of a group of associated behaviors, including manipulation of the treating physician or medical system for the purpose of obtaining additional supplies of the medication (e.g., altering prescriptions), acquisition from other medical sources or from a nonmedical source, hoarding or sales, or unapproved use of other medications (particularly other sedative hypnotics) or alcohol during opioid therapy

Weissman and Haddox (1989) use the contrasting term pseudoaddim'on to refer to the patient who is both physically dependent on

opioids and preoccupied with receiving them (for relief of pain) but not addicted in any other sense. A recent review found that only 7 of 24 papers addressing the treatment of these patients used acceptable diagnostic criteria or definitions for medication misuse. In these 7 papers, percentages for the prevalence of medication misuse, dependence, and addiction in patients with chronic pain ranged between 3.2% and 18.9%. Accurately identifjmg an addiction problem in the presence of chronic pain obviously entails knowledge of the patient's pain syndrome, use of other means to relieve it, relationships to pain and pain care providers, opioid use patterns, and past and family history. Careful assessment and the use of more precise definitions of addiction in the patient with pain generally allow clinicians to distinguish three populations: long-time polysubstance users, those who abuse their prescribed medications, and patients who tend to misuse medication under stress to deal with anxiety or depression. Polysubstance users have a history of illicit use of multiple drugs, often dating from their teens and often including a history of intravenous drug abuse. Urine toxicology often identifies the presence of other illicit drugs. Prescription medication abusers typically have initially obtained an opioid from a physician for a legitimate medical reason but have gradually increased the dosage and frequency on their own. They may show pain complaints and disability out of proportion to structural disease and resist trying nonopioid medications (e.g., tricyclic antidepressants or nonsteroidal anti-inflammatory analgesics) for pain management, fearing the loss of their mood-altering effects. Without careful assessment, these patients may be difficult to distinguish from a third category of patients, who tend to misuse medication under stress to deal with anxiety or depression but can also use opioids appropriately for long periods of time. Making distinctions between these categories of addicted or misusing patients often is

Chapter 221 W Addiction and Detoxification in Chronic Pain

Aronoff GM: Evaluation and Treatment of Chronic Pain. 3rd Ed. Lippincott Williams & Wilkins, Baltimore, 1999 Aronoff GM: Psychiatric aspects of nonmalignant chronic pain: a new nosology. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. 3rd Ed. Lippincott Williams & W i h s , Baltimore, 1999 Aronoff GM: Opioids in chronic pain management: is there a significant risk of addiction? Curr Rev Pain 4112-121,2000 Aronoff GM: The role of pain centers. In Warfield CA (ed): Principles and Practice of Pain Management. 2nd Ed. McGraw-Hill, New York, 2001 Aronoff GM, Dupuy D N Evaluation and management of back pain: preventing disability. J Back Musculoskeletal Rehabil9109-124, 1997 Aronoff GM, Evans WO: Evaluation and treatment of chronic pain at the Boston Pain Center. J Clin Psychiatry 43:4-8, 1982 Aronoff GM, Feldman JB: Preventing disability from chronic pain: a review and reappraisal. Int Rev Psychiatry 12:157-169,2000

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Aronoff GM, Gallagher RM: Pharmacological management of chronic pain: a review. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. 3rd Ed. Lippincott Williams & Wilkins, Baltimore, 1999 Aronoff GM, McAlary PW Multidisciplinary treatment of intractable pain syndromes. Adv Pain Ther 13:270, 1990 Lipman RS Pharmacotherapy of anxiety and depression. PsychopharmaC O ~B d 17:91-103, 1981 Raj PP (ed): Practical Management of Pain. 3rd Ed. Mosby, St Louis, 2000 Silverstein FE, Faich G, Goldstein JL et ak Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study, a randomized controlled trial. JAh4A 2841247-1255, 2000 Singh G Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 105:31S-38S, 1998

221 Addiction and Detoxification in Chronic Pain John R. Peteet Suspected, past or active addiction often complicates the treatment of chronic pain. This chapter outlines an approach to diagnosing addiction, assessing and treating pain, and managing addiction in these cases. It focuses primarily on the use of opioids to manage chronic nonmalignant pain. DIAGNOSING ADDICTION A lack of standard terminology has traditionally hampered the

diagnosis of addiction in patients with pain. The Diagnostic and Statistical Manual of Mental Disorders, Revised Fourth Edition, specifies criteria for substance dependence and abuse but omits consideration of the issues that arise in the setting of pain. Portenoy (1990) has attempted to fill this gap by suggesting an operational definition that includes An intense desire for the medication or an overwhelming concern about its continued availability (psychological dependence) Evidence of compulsive medication use, characterized by unsanctioned dosage escalation, continued dosing despite significant side effects, use of medication to treat symptoms not targeted by the therapy, or unapproved use during periods of no symptoms Evidence of one or more of a group of associated behaviors, including manipulation of the treating physician or medical system for the purpose of obtaining additional supplies of the medication (e.g., altering prescriptions), acquisition from other medical sources or from a nonmedical source, hoarding or sales, or unapproved use of other medications (particularly other sedative hypnotics) or alcohol during opioid therapy

Weissman and Haddox (1989) use the contrasting term pseudoaddim'on to refer to the patient who is both physically dependent on

opioids and preoccupied with receiving them (for relief of pain) but not addicted in any other sense. A recent review found that only 7 of 24 papers addressing the treatment of these patients used acceptable diagnostic criteria or definitions for medication misuse. In these 7 papers, percentages for the prevalence of medication misuse, dependence, and addiction in patients with chronic pain ranged between 3.2% and 18.9%. Accurately identifjmg an addiction problem in the presence of chronic pain obviously entails knowledge of the patient's pain syndrome, use of other means to relieve it, relationships to pain and pain care providers, opioid use patterns, and past and family history. Careful assessment and the use of more precise definitions of addiction in the patient with pain generally allow clinicians to distinguish three populations: long-time polysubstance users, those who abuse their prescribed medications, and patients who tend to misuse medication under stress to deal with anxiety or depression. Polysubstance users have a history of illicit use of multiple drugs, often dating from their teens and often including a history of intravenous drug abuse. Urine toxicology often identifies the presence of other illicit drugs. Prescription medication abusers typically have initially obtained an opioid from a physician for a legitimate medical reason but have gradually increased the dosage and frequency on their own. They may show pain complaints and disability out of proportion to structural disease and resist trying nonopioid medications (e.g., tricyclic antidepressants or nonsteroidal anti-inflammatory analgesics) for pain management, fearing the loss of their mood-altering effects. Without careful assessment, these patients may be difficult to distinguish from a third category of patients, who tend to misuse medication under stress to deal with anxiety or depression but can also use opioids appropriately for long periods of time. Making distinctions between these categories of addicted or misusing patients often is

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Headache and Pain w Generalized and Regional Pain Syndromes

difficult because a history of illicit polysubstance use is common in the general population, and anxiety is common in patients with pain. Several patient characteristics predict the development of addiction or misuse of opioids treated for chronic pain. They include selling or stealing prescription medications, active concurrent use of alcohol or illicit drugs, multiple dosage escalations or other noncompliance despite warnings, and multiple episodes of prescription “loss.” By contrast, aggressive complaining, requesting specific medications, hoarding, and unapproved use of medications to treat other symptoms are less predictive. In general, patients who complain of mild to moderate pain appropriate to structural disease, with mild disability and mild psychological difficulties, seem to respond better to long-term opioid treatment, particularly if they show evidence of adaptive coping. ASSESSING PAIN Addiction is not only difficult to recognize in patients with chronic pain but pain is notoriously difficult to assess in patients with addictive disorders. Actively addicted patients may report pain to procure their medication of choice, anxiety can enhance their experience of pain, and personality styles (e.g., entitled or manipulative) can influence their credibility. Furthermore, cultural differences between addicts and clinicians may compound misunderstanding. A careful history, including data obtained from independent sources, is essential in disentangling the contributions of each of these factors. TREATING PAIN Three general principles guide the treatment of pain in patients with addictive disorders. Reduce Anxiety Most addicted patients have become extremely attuned to the management of their physical or emotional distress through the use of medication and therefore fear losing control of their ability to self-medicate. The prospect of relying on a physician to relieve their distress often increases rather than diminishes their anxiety. Hospitalized addicts also fear, at times with justification, that they may be forced to experience withdrawal or untreated pain because their opioid medications are withheld or inadequately dosed. Many medical practitioners still do not appreciate that a patient stabilized or maintained on a stable dosage of methadone (which may average 60 to 120 mg/day for patients in methadone treatment programs) needs additional analgesics, as would any other patient. Physicians may also use agonist and antagonist medications (e.g., pentazocine) in these patients, which can precipitate withdrawal. Finally, some physicians remain reluctant to use methadone for pain treatment of pain (although the U.S. Food and Drug Administration approved this use in 1947) because its use in treating opioid addiction has been so heavily regulated since 1973. Many addicted patients also fear that they will be reported to legal authorities, either because of the illegal nature of their procurement activities or because their substance use jeopardizes the health or welfare of others, such as their living or unborn children. Anxiety about discovery and efforts to hide addiction can contribute to underreporting of their substance use, misdiagnosis, and in-hospital drug abuse.

Whereas active opioid addicts and those in methadone maintenance treatment typically fear that their pain will not be adequately relieved, recovering addicts in 12-step programs may be reluctant to take opioids out of fear that doing so will reactivate their addiction. They may benefit from reassurance that the prescription of an opioid will be short-lived, closely monitored, and different from the ones previously abused. Similarly, the supervision of pain control for anxious outpatients often can be improved by recruiting a spouse, recovering friend, or sponsor to hold or administer the medication. The concerns and emotional responses of clinicians can also have important effects on the assessment and treatment of pain in active or recovering addicts. These include fears of reactivating addiction by administering opioids, anger at being manipulated, and a desire to rescue patients from overly punitive or rejecting behavior by other clinicians. Many patient and clinician concerns can be substantially relieved by anticipation and shared planning. For example, hospitalized patients who recognize difficulty distinguishing cravings from a need for pain relief may welcome the use of a specific medication schedule (e.g., every 4 to 6 hours) rather than an as-needed schedule. Identify Realistic Treatment Goals Preventing or minimizing withdrawal symptoms is an important initial goal. Respecting the patient’s report of pain by seriously attempting to relieve it is also important, although it may not be feasible to relieve all of the patient’s distress. Recognizing and remaining within acceptable parameters of risk is a third important goal. Risks of treating addicted patients with opioids include Worsening of active addiction and psychosocial functioning, which can be difficult to evaluate in patients who deny their abuse or who are not engaged in addiction treatment Possible overdosage in the presence of unaccustomed medication use, as in the case of a patient who requests and is given a higher methadone dosage than he or she can tolerate Precipitation of withdrawal through the use of medications, such as pentazocine, which have opioid antagonist activity Consider Multiple Modalities Behavioral approaches (e.g., guided imagery, relaxation, and pain support groups) and the use of nonopioid pain medications (e.g., nonsteroidal anti-inflammatory analgesics or tricyclic antidepressants) are particularly important to consider. Some patients respond to complementary treatments, such as acupuncture. MANAGING ADDICTION Reducing anxiety is also important in managing addiction. Early, frank discussion of clinicians’ concerns and policies about substance abuse generally helps to prevent a destructive cycle of anxiety, substance misuse, and mutual mistrust. At a minimum, patients can be expected to accept evaluation and recommended treatment by addiction consultants and to refrain from illicit substance use. In some cases, written contracts are useful in describing what constitutes medication misuse and what procedures, such as urine screens, will be used to document compliance.

Chapter 221

In more complex or difficult cases, a meeting of all involved providers can help to refine a consensus on limits and expectations that the team can then apply. Medically supervised withdrawal, or detoxification, is indicated if opioids have failed to achieve treatment goals or if a patient cannot adhere to the therapeutic contract. Such patients may need treatment in inpatient pain treatment programs. These programs can address complicating psychosocial factors, such as somatization, depression, and disability, using a multidisciplinary approach that combines detoxification, physical and occupational therapy, behavioral modalities such as relaxation and guided imagery, family interventions, and group support. The ultimate goal of such programs is freedom from medication dependence and improved overall functioning. The goal of detoxification itself is to steadily reduce the dosage at a rate that results in a tolerable level of discomfort and a continued ability to function, without the use of additional opioids or other medications. The most appropriate setting for detoxification depends on whether the patient is a polysubstance abuser, a prescription medication abuser, or a patient in methadone maintenance treatment and the patient’s remaining level of pain. Polysubstance abusers are best referred to substance abuse treatment programs because outpatient detoxification often is too difficult for them to complete, and relapse is predictable without rehabilitation. Even though patients often initially refuse addiction treatment, ongoing collaboration between medical, pain, and addiction specialists may be effective over time in engaging such patients in treatment. Prescription medication abusers and misusers with pain can be detoxified more easily by medical clinicians, using a taper that minimizes withdrawal symptoms (e.g., over 7 to 10 days for inpatients and somewhat longer for outpatients), according to the duration and size of the patient’s opioid needs. More rapid detoxification may be possible, but slower tapering may be indicated if the patient has been dependent on large dosages for extended periods of time or if he or she is anxious about experiencing increased pain. Converting the patient’s medication to an equianalgesic dosage of a longer-acting opioid, such as methadone, can prevent peaks of euphoria and valleys of dysphoria. Patients who find such a detoxification regimen difficult may benefit from the adjunctive use of clonidine (e.g., 0.1 mg three times a day) and from consultation with addiction specialists.

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Patients in methadone maintenance programs are best detoxified slowly in conjunction with their methadone treatment providers because various psychotherapeutic considerations influence the optimal timing of dosage reductions. Opportunity for ongoing collaboration between pain and addiction specialists is basic to the successful treatment of chronic pain. Both Portenoy (1990, 1994) and the California Medical Association ( 1985) have proposed guidelines for prescribing controlled substances to treat chronic pain, which emphasize the need for adequate evaluation, diagnosis, documentation, informed consent, objectives, periodic review, and modification. Kennedy and Crowley (1990) have similarly described a program of methadone for pain, which includes weekly routine urinalysis, weekly psychotherapy sessions, and the use of quarterly self-report tests of mood, pain, and function to evaluate change.

SELECTED READINGS American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 4th Ed. Washington, DC: APA Press, 1994 California Medical Association Board of Medical Quality Assurance (CMA-BMQA): Guidelines for Prescribing Controlled Substances for Chronic Conditions: A Joint Statement by the BMQA and the CMA. Action Report BMQA. San Francisco, 1985 Fishbein DA, Rosomoff HL, Rosomoff RS: Drug abuse, dependence and addiction in chronic pain patients. Clin J Pain 8:77-85, 1992 Kennedy JA, Crowley TJ: Chronic pain and substance abuse: a pilot study of opioid maintenance. J Subst Abuse Treat 7:223-238, 1990 Miotto K, Compton P, Ling W, Connolly M: Diagnosing addictive disease in chronic pain patients. Psychosomatics 3T223-233, 1996 Portenoy RK: Chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage 5:546-562, 1990 Portenoy RK: Opioid therapy for chronic nonmalignant pain: current status. pp. 247-287. In Fields HL, Liebeskind JC (eds):Progress in Pain Research and Management. Vol 1. Seattle: IASP Press, 1994 Savage S R Addiction in the treatment of pain: significance, recognition, and management. J Pain Symptom Manage 8:265-278, 1993 Schofferman I: Long-term use of opioid analgesics for the treatment of chronic pain of non-malignant origin. J Pain Symptom Manage 8~279-288, 1993

Sees KL, Clark Hw: Opioid use in the treatment of chronic pain: assessment of addiction. J Pain Symptom Manage 8:265-278, 1993 Washton AK, Resnick RB: Clonidine for opiate detoxification: outpatient clinical trials. Am J Psychiatry 137:1121-1122, 1980 Weissman DE, Haddox J D Opioid pseudoaddiction: an iatrogenic syndrome. Pain 5363-366, 1989

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GENERALIZED AND REGIONAL PAIN SYNDROMES

222 Mvofascial Pain Svndrome 4

4

Zahid H. Bajwa, Scott M. Fishman, and Carol A. Wadield

Chronic and disabling pains are commonly of musculoskeletal origin. These may arise from a pathologic process involving the joints, muscles, or their associated connective tissues. When pain arises from one or more joints and can be confirmed by objective signs of localized inflammation and appropriate imaging studies, the diagnosis of arthritis can be established easily. Another form of musculoskeletal pain is persistent, deep-aching pain that is not localized to the joints, commonly called myofascial pain syndrome. As the name implies, this is a syndrome that encompasses a spectrum of symptoms, primarily involving muscles and their ligamentous attachments. It can be persistent, severe, and disabling and afflicts women about five times more commonly than men. Often it arises from mild trauma or muscular overuse and can persist for prolonged periods of time. This syndrome is known by other names, including fibromyalgia, fibrositis, muscular rheumatism, nonarticular rheumatism, and idiopathic myalgia. Traditionally, it is subdivided into localized and diffuse myofascial pain syndromes. The International Association for the Study of Pain defines it as “diffuse, aching musculoskeletal pain associated with discrete predictable tender points and stiffness.” The tender points, commonly called trigger points, are considered of vital importance in maintaining the pain syndrome and, by analogy, in treating it. Simple techniques directed at disarming tender or trigger points are the mainstay of therapy. They are easy to perform in the office setting once the diagnosis of myofascial pain syndrome has been established. CLINICAL FEATURES A thorough history and physical examination are absolutely essential in diagnosing myofascial pain syndrome. Patients often describe diffuse muscular pain, often deep, continuous, dull, and aching in character and rarely throbbing or burning. Often, the patient remembers no inciting event, but sometimes the pain begins abruptly and an inciting event is precisely remembered. Mild trauma such as a whiplash injury from a motor vehicle accident may be noted. Simple increased physical activity, often found in weekend athletes, can be the inciting event. Even increased office hours with resultant strain on back musculature from prolonged desk and computer work under the stress of approaching tests or deadlines can incite myofascial pain. Muscle spasm and radiation of pain can be prominent. Although it is most often located in the trunk and neck muscles, any muscle or group 1398

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of muscles can be involved. The pain often is increased by stress, inadequate sleep, fatigue, and cold, humid weather. Continued use of the involved muscle group tends to aggravate the pain. Stiffness is an important feature, which is worse in the morning. Chronic fatigue often is a prominent symptom and may be associated with restless and nonrefreshing sleep. On physical examination, diffuse tenderness may be noted. Discrete areas of point tenderness overlying muscles and their ligaments usually are found. Although the patient usually is unaware of the presence and location of tender points, such discrete sites are exquisitely tender to palpation. Often they are approximately the size of the examiner’s finger pad. True trigger points have features in addition to tenderness and may present as a small palpable collection of contracted muscle. These trigger points usually are located within taut bands of muscle, which can be rolled between the examiner’s fingers. A “jump sign” may be elicited as the trigger point is palpated, and the patient may cry out and move away upon palpation. A local muscle twitch may be felt and occasionally seen during palpation of a trigger point. Reactive hyperemia to palpation may be seen, most commonly on the trunk. These trigger points usually are within the region of the patient’s reported pain but sometimes are not. However, palpation of true trigger points should reproduce the patient’s typical pain. Radiation patterns have been well described. For example, trigger points over the neck and scapula tend to cause pain in the ipsilateral shoulder and arm. Those of the flank tend to cause pain in the ipsilateral buttock and those of the buttock into the posterior thigh and calf. The radiation of pain should be regional and nondermatomal in nature. If the radiation pattern of peripheral nerve or nerve root is observed, other causes such as radiculopathy or other nerve lesions should be sought out. It should be noted that, although the presence of trigger points is an essential feature of this syndrome, in itself it is not sufficient for the diagnosis of myofascial pain syndrome. Based on studies involving healthy and asymptomatic volunteers, up to 50% of the general population has been estimated to harbor latent trigger points, which are difficult to distinguish from true myofascial trigger points in patients suffering from myofascial pain. It is conceivable that a significant portion of the general population that harbors latent trigger points may be at higher risk for developing myofascial pain syndrome. These latent trigger points do not cause spontaneous pain at rest or with movement, as opposed to active trigger points. However, they are painful to

Chapter 222

palpation and produce radiation to typical reference areas. Latent trigger points may be activated by rapid movements or muscle overuse. After resolution of an episode of transient myofascial pain, trigger points may persist for years, leaving patients susceptible to relapse. The appearance of the affected region tends to be normal but can occasionally show mild swelling and other signs of muscle spasm, particularly in the neck and shoulder region. There usually is no evidence of muscle wasting, although long-standing disuse of an extremity secondary to pain can lead to biomechanical alterations, including weakness, decreased range of motion, and atrophy. Heat and cold intolerance is not prominent. There should not be evidence of true allodynia (pain caused by a stimulus that normally does not produce pain, e.g., light touch). If trophic changes and allodynia are present, a component of neuropathic or sympathetically maintained pain may be present, which may warrant further evaluation. Myofascial pain syndrome is common in pain clinic populations and usually is a straightforward diagnosis, but many practicing physicians are not familiar with it. This results at least partly from the absence of objective signs, normal imaging studies, and lack of any diagnostic laboratory tests. Myofascial pain syndrome is further complicated by the fact that it occurs in varying intensity, duration, and location and cannot be accurately diagnosed unless the affected muscles are examined properly. The following case studies from our own clinical experience illustrate some key points about myofascial pain syndrome. Readers are encouraged to consult references at the end of this chapter for a detailed review of the topic.

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FIG. 222-1. The pattern of the myofascial pain syndrome in patient 1. The oval represents the trigger point in the temporalis muscle, and the zones of stippling mark the areas of referred pain.

bulges at L4/L5 and L5/S1. The patient received two epidural steroid injections and bed rest over a 6-week period with partial and transient relief. His symptoms worsened, and he could not continue to work. Physical examination showed a well-appearing and muscular man who walked with a slight limp. Neurologic examination was normal, but he had two tender spots in the quadratus lumborum muscle and one tender spot over the piriformis muscle (Fig. 222-2). Palpation of the trigger points reproduced his symptoms, and they were infiltrated with a 20-mL mixture of 1% lidocaine, 0.25% bupivacaine, and 40 mg of

CASE STUDIES Case Study 1 A 27-year-old woman had a 6-month history of severe, daily headaches involving the right side of her head after striking her head against a window while at work. She had no immediate symptoms, and it was not considered a serious incident. Gradually, over the next few days, she developed worsening headaches, which did not respond satisfactorily to butalbital. After a neurologic evaluation and normal computed tomography of her brain, a diagnosis of post-traumatic headache was established. Amitriptyline in increasing dosages was prescribed, and she was instructed to use acetaminophen or ibuprofen on an as-needed basis. At the time of her evaluation, she reported improved sleep with a single nighttime dose of 125 mg of amitriptyline but continued to complain of daily headaches. She also reported worsening of pain on chewing and combing her hair. Physical and neurologic examinations were normal, but she had an exquisitely tender point in her right temporalis muscle (Fig. 222-1). Palpation of that trigger point reproduced her headache. She initially declined to have an injection, but after being unable to tolerate occupational therapy manipulation she allowed the trigger points to be infiltrated with a 6-mL mixture of 1% lidocaine and 0.25% bupivacaine, which gave her lasting relief from headaches.

Case Study 2 A manual laborer, aged 36, had suffered for 8 months from low back pain radiating to his right hip and posterior thigh area. He could not recall a single precipitating event but described gradual worsening of his pain. He was diagnosed with lumbosacral radiculopathy after magnetic resonance imaging revealed disc

FIG. 222-2. The pattern of the myofascial pain syndrome in patient 2. The ovals represent the trigger points in the quadratus lumborum and piriformis muscles, and the zones of stippling mark the areas of referred pain.

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triamcinolone. He was also referred for physical therapy and was able to return to work after 2 months. Case Study 3

A 29-year-old painter complained of progressively worsening shoulder and neck pain, radiating into his right arm over a 3-month period. The pain was described as continuous, deep, and aching and was aggravated by any use of the right arm. He also complained of neck stiffness and had exacerbations of pain on any movement of his neck. He had well-defined trigger points in his right neck and scapular regions (Fig. 222-3). Palpation of the points produced referred pain in his neck, shoulder, and right arm. Over a 3-week period, he received multiple trigger point injections with local anesthetic and physical therapy three times per week. He reported pain relief for up to 4 hours after each session of trigger point injections followed by physical therapy. He continued to hold his head flexed to the right, and all neck movements were greatly limited by pain. He also complained of numbness and the tingling sensation in his hand and forearm on sudden movement of the neck. Palpation of the trigger points reproduced his typical pain pattern but not the numbness and the tingling sensation in his hand and forearm. His neurologic examination was otherwise normal. We subsequently performed the trigger point injections using a long-acting local anesthetic and steroids in an attempt to provide long-lasting relief. He also underwent magnetic resonance imaging of his cervical spine, which revealed a C61C7 disc herniation impinging on the right neural foramen, without other significant abnormalities. His pain finally responded to a combination of cervical traction, cervical epidural steroid injections, and physical therapy.

PATHOPHYSIOLOGY The underlying mechanism of myofascial pain syndrome remains uncertain. Kellgren (1938), who is credited for pioneering work in this syndrome, demonstrated that injecting a particular muscle with an irritating solution consistently produces pain, which is felt over a much larger region than the muscle injected. He described classic cases of myofascial pain with trigger points that referred pain in the same pattern as in his earlier experiments. However, how the contracted, hyperirritable trigger point is formed and maintained remains unclear. Overuse of deconditioned muscle and acute trauma may contribute to formation and activation of trigger points. Trauma or muscle overload can lead to microscopic tissue injury resulting in release of tissue humoral factors, which cause inflammation and pain. Local instability of calcium channels may occur. Increased levels of extracellular calcium may play a part in initiating and maintaining local muscle spasm, producing a region of local vasoconstriction, ischemia, and uncontrolled metabolism within the muscles. Central and sympathetic nervous system reflexes may also be involved, leading to persistent inflammation, spasm, and pain. This process results in shortened muscle fibers in an area of increased metabolism and decreased circulation, which manifest as palpable taut bands in muscle associated with palpation of trigger points. Once muscle becomes injured, afferent impulses from damaged tissue bombard the central nervous system. Stress responses intercede, leading to increased sympathetic activity in the affected muscle. Generalized fatigue and anxiety feed into this cycle. Local vasomotor changes occur as metabolic demand increases secondary to continued spasm coupled with decreased blood supply caused by heightened sympathetic tone. Local ischemia results in further release of humoral factors such as histamine, serotonin, kinins, and prostaglandins. A vicious cycle of local trigger point muscle spasm ensues, leading to vasomotor constriction and continued pain and inflammation. This cycle can perpetuate itself long after the inciting event. DIAGNOSIS

FIG. 222-3. The pattern of the myofascial pain syndrome in patient 3. The ovals represent the trigger points in the levator scapulae and infraspinatus muscles, and the zones of stippling mark the areas of referred pain.

The diagnosis of myofascial pain syndrome is based on an extensive history and physical examination. Often, a recent or remote episode of tissue trauma is elicited. A contralateral injury may be found to cause asymmetrical body mechanics with resultant muscular stress of the painful muscle groups. Chronic muscle overload may be found. If a history of trauma is lacking and the pain has been gradual in onset, a thorough exploration into significant emotional stressors should be elicited. Sleep patterns are important because insomnia and fatigue are thought to be a potential cause of myofascial pain syndrome in susceptible people. Depression is common in these patients, but whether it is a cause or consequence is controversial. Certainly, any emotional derangement can augment the pain cycle. The pain may have been present for months to years and is often debilitating. Many patients are unable to work secondary to pain. A complete list of previous medication trials and therapies should be sought. Radiation of pain is typical but should be regional and nondermatomal in character. History of paresthesias and numbness should be absent. Trigger points are pathognomonic for myofascial pain syndrome. Their inactivation with resultant long-lasting relief of pain

Chapter 222

therefore should be considered diagnostic. Palpation for typical trigger points should be performed, and they may be outside the patient’s described area of pain. Upon palpation, however, the typical referred pain is elicited. Local tenderness is not considered a trigger point. Often a jump response is obtained. A taut band of muscle with a discrete trigger point within it may be discerned as the muscle is rolled between the examiner’s fingers. Reactive hyperemia may be found after trigger point palpation. Each trigger point should be labeled with a skin marker for later treatment. Deep tendon reflexes and sensory examination should be normal. Motor function may be diminished in patients with long-standing myofascial pain syndrome. Thermography of the skin overlying trigger points may show increased temperature secondary to the increased metabolism of a muscle in spasm, a nonspecific finding of uncertain relevance in the diagnosis of myofascial pain. In fact, there are no radiographic or laboratory test abnormalities considered diagnostic of myofascial pain syndrome. Some cases of polymyalgia rheumatica, other inflammatory muscle diseases, and rheumatologic disorders may mimic myofascial pain syndrome. In these patients, laboratory markers such as erythrocyte sedimentation rate, muscle enzyme levels, antinuclear antibody, and rheumatoid factor become valuable screening tools, with further management dependent on the results of these tests. However, the typical case of myofascial pain syndrome is idiopathic and often a diagnosis of exclusion. TREATMENT

The treatment of myofascial pain syndrome generally involves a multimodality approach. Inactivation of trigger points with local anesthetic injections, dry needling, and stretch-and-spray techniques are the mainstay of interventional therapy. Physical therapy, transcutaneous electrical nerve stimulation, and conditioning exercise programs have also been used. Trials of antiinflammatory medications, antidepressants, and other pharmacologic agents have been reported to help some patients in combination with other modalities. Biofeedback and relaxation therapy have also been used. Trigger point injections often are used for myofascial pain. The optimal injectate for a trigger point injection is not clear, and many believe that it is the needling rather than the injecting that has therapeutic value. Dry needling without injection may be of value. Injections often contain local anesthetics with or without corticosteroids. Corticosteroids are thought to be most useful when hyperemia is present or there is history of prolonged pain after injection and should not be used frequently. Trigger points are located by palpation and marked during the physical examination. The skin overlying the trigger points is prepared with alcohol or povidone-iodine. If corticosteroid is to be included in the injectate, a mixture may be prepared containing 20 to 40 mg of triamcinolone in 10 mL of 0.25% bupivacaine. The total volume of the solution depends on the size of the muscles involved and the number of trigger points to be injected. If a shorter duration of action is desired, 1% to 1.5% lidocaine can be substituted for bupivacaine. A 1.5-inch 25-gauge needle on a 10-mL syringe is typically used. The trigger point can be isolated between the physician’s first and second fingers. Often, it is possible to isolate the trigger and insert the needle between the fingers. Anesthetizing the skin overlying the trigger point is controversial because some patients prefer only a single injection rather than the sting and burn of the

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initial skin wheel. Upon placing the needle tip into the trigger point, a local muscle twitch may be felt and occasionally seen. At that point, the patient may experience pain in his or her typical referral pattern. A total volume of 1 to 5 mL of local anesthetic typically is placed in the trigger point. Then the needle is withdrawn almost to the surface and redirected to the same depth, injecting other areas of the muscle surrounding the original injection site, thereby ensuring complete inactivation of the trigger point. Shortly after each trigger point is injected, the patient’s pain should resolve or become markedly diminished and muscle spasm should abate. Dry needling can be performed in a similar manner without injectate, with the needle repeatedly passed in and out of the trigger point. However, dry needling can be painful and does not necessarily offer a benefit over local anesthetic injection. Stretch and spray can be performed when injection therapy is undesirable or contraindicated. The patient is placed in a comfortable position, and the muscle to be treated is sprayed with a vapocoolant such as ethyl chloride or chlorofluoromethane. The coolant is applied to the skin overlying the trigger point and continuing in the direction of the referred pain. The muscle is then carefully stretched through its normal range of motion. This sequence of spray and stretch can be repeated a few times before rewarming. The involved muscle should reach its full stretch length to inactivate trigger points. This technique is particularly useful and preferred over trigger point injections in patients with diffuse myofascial pain. One advantage of the spray and stretch is that it can be performed at home by the patient or a by a friend or family member. Regardless of the technique chosen for trigger point inactivation, the patient should note prolonged pain relief, which should far outlast the duration of local anesthetic action. Often, patients may note prolonged pain relief after only one set of injections. Sometimes, however, a series of injections are needed as the effects of the last injections start to wane. Usually the interval between symptomatic recurrences increases until the patient’s myofascial pain syndrome resolves. A series of three to six sets of trigger point injections over a few weeks to months may be necessary for some cases of myofascial pain. It is often useful to have patients treated with physical therapy after and between trigger point injections. Passive stretching and massage treatments can be instituted. Gradual increase in activity and gentle graduated exercise programs complement trigger point inactivation. Care must be taken to avoid straining already compromised muscle groups. Overly vigorous physical therapy regimens can aggravate the syndrome and may alienate patients who either give up or go elsewhere for treatment. As patients improve, general exercise and body conditioning programs should be instituted. Transcutaneous electrical nerve stimulation may also be used during physical therapy. If patients respond, a portable unit may be taken home on a trial basis and later purchased or rented if effective. Nonsteroidal anti-inflammatory analgesics are sometimes useful adjuncts in treating myofascial pain syndrome. They have intrinsic analgesic properties and help reduce inflammation. They may be particularly useful in treating the inherent soreness patients exhibit after the local anesthetic effect of trigger point therapy abates. Nonsteroidal anti-inflammatory analgesics generally are considered safe and offer the advantage of being nonaddicting. Although it has a favorable side effect profile over standard nonsteroidal anti-inflammatory analgesics, it is not certain whether COX-2 selective inhibitors have an analgesic

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advantage in myofascial pain. Other useful medications include tricyclic antidepressant medications. At low dosages, they may help with sleep and, with time, may help diminish pain. Amitriptyline is a common choice, but nortriptyline often is substituted if anticholinergic side effects are prominent. A 10- to 25-mg starting dosage of either medication is generally well tolerated. The dosage can then be titrated by the patient under strict guidelines every 4 to 7 days by the same starting increment. It must be remembered that nortriptyline is approximately twice as potent as amitriptyline and other tricyclic antidepressants commonly prescribed for chronic pain. Pain tends to improve within several days after an adequate dosage of the medication is reached, with the maximum benefit found over weeks. Most patients respond to dosages between 25 and 100 mg, although some may need much higher dosages for effect. An adequate trial of these medications would take at least a few weeks of therapy at the highest dosage tolerated. Biofeedback and relaxation techniques also afford significant pain relief in selected patients and should be considered as adjunct therapies. PROGNOSIS As with most pain syndromes, the prognosis depends on the

chronicity of the pain. Patients with myofascial pain syndrome of short duration often respond to just a few trigger point injections. These patients tend to be active and leading functional, albeit dramatically modified lives. As the chronicity of the pain syndrome increases, the period of time needed to treat it and the modalities incorporated in its treatment may also increase. Too often, such patients have had to cease work or other significant

activities and fall into depression. A vicious cycle of pain, diminished function, deconditioning, and more pain sets in. Therefore, it is usually as important to treat the primary pain as the collateral problems such as depression, anxiety, insomnia, and deconditioning. In such cases, physical therapy, psychopharmacology, and psychological counseling can be invaluable. With weeks to months of interdisciplinary therapy, chronic pain sufferers with myofascial pain syndrome can attain significant relief. SUGGESTED READINGS Buskila D: Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 11:119-126, 1999 Cummings TM, White AR: Needling therapies in the management of myofascial trigger point pain: a systematic review. Arch Phys Med

Rehabil 82986-992,2001 Frost FA, Jesson B, Siggaard-Anderson J: A controlled, double-blind comparison of mepivacaine injection versus saline injection for myofasckd pain. Lancet 1:499, 1980 Gunn C C Dry needling of muscle motor points for chronic low-back pain. Spine 5:279, 1980 Kellgren JH: A preliminary account of referred pains arising from muscle. BMJ 1:325-327, 1938 Simons DG, Travell J G Myofascial origins of low back pain. Postgrad Med 73:66-108, 1983 Sola AE: Treatment of myofascial pain syndromes. pp. 467-485. In Benedetti C et a1 (eds): Recent Advances in Pain Research and Therapy. Vol. 7. Raven Press, New York, 1984 Travell JG, Simons D G Myofascial Pain and Dysfunction: The Trigger Point Manual. Vol. 1. Williams & Wilkins, Baltimore, 1983 Travell JG, Simons DG: Myofascial Pain and Dysfunction: The Trigger Point Manual. Vol. 2. Williams & Wilkins, Baltimore, 1991

223 Neuropathic Pain David Borsook

Neuropathic pain may be defined as a symptom resulting from neural injury to peripheral or central components of the pain transmission system. Such pain may be severe, delayed in onset after injury, burning or electrical in quality, and present in the absence of an ongoing source for the pain. As a result of scientific and clinical endeavors in molecular biology, pain genetics, and functional neuroimaging and pain epidemiology, the past 5 years have witnessed a revolution in our understanding of neuropathic pain. As a result, we have a better understanding of the mechanisms of neuropathic pain disorder and specific targets for therapies. Physiologic pain such as a pinprick is clearly understood and does not produce any significant long-term sequelae. Inflammatory pain such as that following mechanical, thermal, or chemical injury usually is reversible. However, damage to a nerve, particularly partial injury, may result in a permanent change in neuroanatomic, neurochemical, and functional systems. Thus, this is a specific pathological entity. Damage to the very system that normally conveys pain sensation under physiologic conditions, when damaged, may produce a neuropathic pain syndrome.

NEUROANATOMY Neuroanatomy, neurophysiology, clinical science (particularly neurosurgery), and functional neuroimaging have provided a great deal of insight into pain pathways. Aside from classic pain pathways such as the spinothalamic tract, new pathways such as the spinohypothalamic tract, dorsal column system, and the spino-parabrachial-forebrain system have provided insight into how we evaluate the sensory stimulus of pain and the perception of the stimulus as a threat and interpret the stimulus in terms of a negative emotion. Under physiologic conditions, a painful stimulus is conveyed to the central nervous system via primary afferent fibers that have processes in the tissue. The afferent pain fibers comprise slowconducting unmyelinated C and faster-conducting, thinly myelinated A6 fibers; these fibers normally send projections into the epidermis. AP fibers, normally conducting light touch, are involved in conducting pain information under conditions of allodynia. Mechanical, chemical, or thermal stimuli are transduced

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advantage in myofascial pain. Other useful medications include tricyclic antidepressant medications. At low dosages, they may help with sleep and, with time, may help diminish pain. Amitriptyline is a common choice, but nortriptyline often is substituted if anticholinergic side effects are prominent. A 10- to 25-mg starting dosage of either medication is generally well tolerated. The dosage can then be titrated by the patient under strict guidelines every 4 to 7 days by the same starting increment. It must be remembered that nortriptyline is approximately twice as potent as amitriptyline and other tricyclic antidepressants commonly prescribed for chronic pain. Pain tends to improve within several days after an adequate dosage of the medication is reached, with the maximum benefit found over weeks. Most patients respond to dosages between 25 and 100 mg, although some may need much higher dosages for effect. An adequate trial of these medications would take at least a few weeks of therapy at the highest dosage tolerated. Biofeedback and relaxation techniques also afford significant pain relief in selected patients and should be considered as adjunct therapies. PROGNOSIS As with most pain syndromes, the prognosis depends on the

chronicity of the pain. Patients with myofascial pain syndrome of short duration often respond to just a few trigger point injections. These patients tend to be active and leading functional, albeit dramatically modified lives. As the chronicity of the pain syndrome increases, the period of time needed to treat it and the modalities incorporated in its treatment may also increase. Too often, such patients have had to cease work or other significant

activities and fall into depression. A vicious cycle of pain, diminished function, deconditioning, and more pain sets in. Therefore, it is usually as important to treat the primary pain as the collateral problems such as depression, anxiety, insomnia, and deconditioning. In such cases, physical therapy, psychopharmacology, and psychological counseling can be invaluable. With weeks to months of interdisciplinary therapy, chronic pain sufferers with myofascial pain syndrome can attain significant relief. SUGGESTED READINGS Buskila D: Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 11:119-126, 1999 Cummings TM, White AR: Needling therapies in the management of myofascial trigger point pain: a systematic review. Arch Phys Med

Rehabil 82986-992,2001 Frost FA, Jesson B, Siggaard-Anderson J: A controlled, double-blind comparison of mepivacaine injection versus saline injection for myofasckd pain. Lancet 1:499, 1980 Gunn C C Dry needling of muscle motor points for chronic low-back pain. Spine 5:279, 1980 Kellgren JH: A preliminary account of referred pains arising from muscle. BMJ 1:325-327, 1938 Simons DG, Travell J G Myofascial origins of low back pain. Postgrad Med 73:66-108, 1983 Sola AE: Treatment of myofascial pain syndromes. pp. 467-485. In Benedetti C et a1 (eds): Recent Advances in Pain Research and Therapy. Vol. 7. Raven Press, New York, 1984 Travell JG, Simons D G Myofascial Pain and Dysfunction: The Trigger Point Manual. Vol. 1. Williams & Wilkins, Baltimore, 1983 Travell JG, Simons DG: Myofascial Pain and Dysfunction: The Trigger Point Manual. Vol. 2. Williams & Wilkins, Baltimore, 1991

223 Neuropathic Pain David Borsook

Neuropathic pain may be defined as a symptom resulting from neural injury to peripheral or central components of the pain transmission system. Such pain may be severe, delayed in onset after injury, burning or electrical in quality, and present in the absence of an ongoing source for the pain. As a result of scientific and clinical endeavors in molecular biology, pain genetics, and functional neuroimaging and pain epidemiology, the past 5 years have witnessed a revolution in our understanding of neuropathic pain. As a result, we have a better understanding of the mechanisms of neuropathic pain disorder and specific targets for therapies. Physiologic pain such as a pinprick is clearly understood and does not produce any significant long-term sequelae. Inflammatory pain such as that following mechanical, thermal, or chemical injury usually is reversible. However, damage to a nerve, particularly partial injury, may result in a permanent change in neuroanatomic, neurochemical, and functional systems. Thus, this is a specific pathological entity. Damage to the very system that normally conveys pain sensation under physiologic conditions, when damaged, may produce a neuropathic pain syndrome.

NEUROANATOMY Neuroanatomy, neurophysiology, clinical science (particularly neurosurgery), and functional neuroimaging have provided a great deal of insight into pain pathways. Aside from classic pain pathways such as the spinothalamic tract, new pathways such as the spinohypothalamic tract, dorsal column system, and the spino-parabrachial-forebrain system have provided insight into how we evaluate the sensory stimulus of pain and the perception of the stimulus as a threat and interpret the stimulus in terms of a negative emotion. Under physiologic conditions, a painful stimulus is conveyed to the central nervous system via primary afferent fibers that have processes in the tissue. The afferent pain fibers comprise slowconducting unmyelinated C and faster-conducting, thinly myelinated A6 fibers; these fibers normally send projections into the epidermis. AP fibers, normally conducting light touch, are involved in conducting pain information under conditions of allodynia. Mechanical, chemical, or thermal stimuli are transduced

Chapter 223

by the free nerve endings of pain fibers via activation of a number of receptors, such as vallinoid (capsaicin), prostaglandin, and adenosine. The C- and AG-fibers terminate predominantly in laminae I, 11, and V of the dorsal horn. Second-orderneurons then cross (spinothalamic or spinohypothalamic) the dorsal horn and ascend to brainstem, thalamic, limbic (including the hypothalamus and amygdala), and paralimbic structures. Third-order neurons project to cortical regions, including the somatosensory cortex and anterior cingulate cortex. At this time, functional neuroimaging studies have identified a number of regions in humans that are activated by noxious stimuli, including those involved in somatosensoryinterpretation of location and intensity (thalamus, insula, and somatosensory cortex), in autonomic function (hypothalamus), in emotion (e.g., cingulate cortex, orbital cortex, and amygdala), and in descending analgesia (e.g., periaqueductal gray). Although descending analgesic systems exist (e.g., periaqueductal gray-raphe magnus with descending pathways to the dorsal horn via the dorsolateral funiculus), it is unknown whether damage to these systems may result in neuropathic pain. ETIOLOGY The underlying clinical etiology of painful neuropathies is quite varied. In many cases it is not possible to determine the cause of the painful symptom. Damage to peripheral nerve may result from infectious (e.g., acquired immunodeficiency syndrome, GuillainBarre syndrome, or herpes zoster), endocrine (e.g., diabetes), toxic (e.g., alcohol, arsenic), inherited (e.g., Fabrys disease or hereditary sensory neuropathy), entrapment (e.g., carpel tunnel, herniated disc, cancer invasion of a plexus), traumatic (e.g., surgery), or metabolic (e.g., B,, deficiency) causes. Damage to the central nervous system may affect the dorsal horn (e.g., avulsion injuries), the spinal cord (e.g., trauma, tumors, syringomyelia, and demyelination), and the thalamus or cortex (stroke, demyelination, tumor). Pain assessment and physical examination are critical in diagnosing these pain disorders because they still are diagnosed on clinical grounds.

FUNCTIONAL FEATURES The symptoms and signs of neuropathic pain vary as a result of a number of different mechanisms. The sensory symptoms include loss of or altered sensation in the area affected, shooting pain, burning pain, increased pain to a normally nonnoxious stimulus (e.g., mechanical or thermal [cold] allodynia), shooting pain or dysesthesia, altered sensation outside the area affected, and elevated pain to a painful stimulus (hyperpathia). Emotional sequelae of pain, including depression, anxiety, and inability to concentrate, are clearly evident in many patients with chronic (more than 6 months) neuropathic pain. These sequelae are not discussed in this chapter. The symptoms of neuropathic pain have their origins in known alterations in peripheral or central neural systems, and the pain may be continuous or episodic or have a background component with exacerbations.

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(e.g., PG-9, substance P). Sensory loss to heat is considered to be mediated by loss of C-fibers and loss to cold to AP-fibers. Concomitant with these alterations is a change in receptors. For example, after nerve damage, there is a loss of 1 receptors on C-fibers, which may be one reason that morphine may not act via peripheral (fiber of dorsal horn) mechanisms in patients with C-fiber loss.

Allodynia is pain caused by normally nonnoxious stimuli. Stimuli that produce mechanical allodynia (e.g., brush or light touch) normally activate AP systems to produce the sensation of touch. However, in neuropathic pain, activation of these pathways produces pain. Such activity is transmitted via dorsal column pathways, and these systems may activate facilitatory descending systems that act on dorsal horn projection neurons in laminae I and V. Cold allodynia, on the other hand, may be produced by activation of AG-fibers. Allodynia is associated with phenotypic changes in dorsal root ganglion cells (e.g., AP-fibers may produce substance P). Importantly, patients with allodynia complain that this sensation is more unpleasant than it is painful. One mechanism for allodynia is a result of central sensitization. Central sensitization reflects an increase in the excitability of neurons in the central nervous system (e.g., spinal cord and thalamus). These changes are seen as a decrease in threshold for activation, an increased activation and change in the distribution and spatial extent, and the recruitment of new inputs. Central sensitization therefore can account for the increase in sensitivity in the injured area and increased sensitivity in the uninjured area. Central sensitization is thought to result from damage to central neurons after excessive C-fiber inputs (e.g., at the time of nerve damage). Central sensitization may also explain the clinical observation of hyperpathia, an elevated pain response to a normally painful stimulus. Recent evidence suggests that tactile allodynia arising from peripheral nerve injury is integrated predominantly at supraspinal rather than spinal sites (e.g., sprouting). Tonic descending facihtation from sites such as the periaqueductal gray acts on sensitized spinal projecting neurons, which may thus explain the circuit of AP-facilitated drive-producing pain. Spontaneous ActMty or Shooting Pain

Under basal conditions there is no electrical activity in pain fibers. After nerve damage, abnormal spontaneous activity may be present. These spontaneous action potentials are thought to result from accumulation of sodium channels along damaged nerves, resulting in a lowering of the membrane potential and the increased potential for the occurrence of spontaneous activity. This process, which may take place in the central or peripheral nervous system, probably is the reason for the clinical phenomena of shooting or dysesthetic pains (e.g., trigeminal neuralgia).

Burning Pain

Sensory or Fiber Loss Loss of pain fibers has been shown in animal and human studies using punch biopsies. In particular, there is a decrease in small fibers penetrating into the epidermis. This may be evaluated using skin punch biopsies and special staining procedures on the tissue

Burning pain, usually spontaneous or unprovoked, has its origin in ongoing C-fiber activity and may relate to central changes in the dorsal horn or thalamus (in the case of strokelike pain). Although they are minor levels of input, these action potentials act on an abnormal spinal cord.

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Headache and Pain rn Generalized and Regional Pain Syndromes

DIAGNOSTIC APPROACH Most of the pain mechanisms described earlier can be evaluated at the bedside, although to perform all of these evaluations may take more time than is available in a busy clinic. Quick tests should include alteration of pinprick, touch, and temperature sensation (fiber loss); evaluation of static and dynamic light touch (allodynia); cold (e.g., acetone) induced changes (AG-fiber dysfunction); repetitive stimuli to pin (recruitment or hyperpathia); and mild pressure or stretching over the damaged nerve (ectopic firing). There is often a measurable change in the contralateral (undamaged) side to the affected area. Pain may be further defined in terms of whether it is spontaneous pain (unprovoked or stimulus-independent) versus stimulated (provoked or stimulusdependent). Specific History and Physical Examination

A neuropathic pain syndrome can be diagnosed based on history of nerve trauma and evidence of a sensory deficit in the painful area. Sometimes there is pain in a region of the body that has been removed, or phantom pain. Examples of other phantom pains include phantom anal pain or phantom breast pain. Often, the pain is a result of an otherwise minor stretch injury or repetitive motion (e.g., idiopathic brachial plexopathy). Special attention should be paid to factors that exacerbate or relieve the pain. Many patients with chronic pain do not sleep well, and this may contribute to the pain state. Although a careful history and examination may be performed, it is often difficult to define the type of neuropathic pain. Some forms of neuropathic pain (formerly called sympathetically maintained pain or causalgia) have been classed as chronic regional pain type I and type 11. These definitions reflect a lack of understanding of some of the mechanisms underlying neuropathic pain syndromes. For example, in chronic regional pain type I, there are reports that the pain can spread, including mirror image spread, from the initial site of presentation. Similar changes may be observed in other neuropathies including sural neuropathy and postherpetic neuralgia. Diagnostic Tests

Specific blood tests for diabetes, hypothyroidism, or B,, deficiency should be routine when the clinical evidence indicates the underlying cause. Such tests are used more in the diagnosis of generalized painful neuropathies. Unusual tests would be needed when an unusual painful neuropathy, such as Fabry’s disease, porphyria, amyloidosis, or mitochondria1 disease is suspected. Diagnostic Drug Tests. Some advocate the systemic administration of medications as useful diagnostic tools in patients with neuropathic pain. To determine whether the pain arises from abnormal neural (ectopic) activity, one approach has been to administer intravenous lidocaine (1 mglkg), either as a slow bolus or as a constant infusion where the pharmacokinetics are easy to model. Particularly when there is ongoing (e.g., diabetic neuropathy) or recent nerve damage (e.g., brachial plexus avulsion), intravenous lidocaine in most cases decreases the patient’s pain by more than 50%. In these cases, patients are candidates for neuropathic pain medications (most of which stabilize membrane potentials). Therefore, agents such as mexiletine, phenytoin, carbamazepine, clonazepam, gabapentin, and topiramate are the medications of choice. Another diagnostic test is the use of

intravenous ketamine (a clinical available N-methyl D-aspartate [NMDA] receptor antagonist) to establish the benefit of future NMDA blockade. Currently, the two most common approaches to sympathetic blockade are the phentolamine test, in which 0.5 to 1 mg/kg of the medication is given intravenously slowly, and local anesthetic blockade of the sympathetic ganglia (e.g., stellate or lumbar ganglia). A phentolamine dosage of 1 mglkg over 10 minutes will effectively block a-adrenoceptor function. If the pain is not affected by sympathetic blockade, is it inhibited by the infusion of intravenous lidocaine? Finally, a subgroup of patients do not respond to either of these tests, and an opioid infusion may be a good approach to determine whether the neuropathic pain syndrome is responsive to opioids. Evaluation of Neural Function. A number of tests have been used to measure alterations in neural function, including electromyography, imaging studies, thermography and quantitative sensory testing, and skin punch biopsies. In general, electromyography is not particularly useful in diagnosing most pain syndromes because the clinical examination, if performed properly, defines the location, severity, and origin of the neuropathic pain states. Furthermore, electromyography does not determine alterations in C-fiber function. In some cases, particularly entrapment neuropathies, it is very helpful. Electromyography may also be helpful in defining the progression of recovery, for example, in a patient with a traumatic peripheral nerve injury. The use of imaging studies is useful in diagnosing central lesions and cord or nerve root involvement. Other imaging tests that may be of use include the recently introduced method of magnetic resonance neurography for defining damaged nerves or invasion by tumor. Thermography probably does not have a useful role in routine neurologic practice of the diagnosis and treatment of neuropathic pain. Quantitative sensory testing has been used in recent years, providing some objective data on alterations of sensory levels to heat thresholds, cold thresholds, heat pain, cold pain, and sensation to vibration thresholds. Currently, there is no objective test for pain. Skin punch biopsies have been helpful in determining anatomic changes that may correlate with the patient’s clinical condition. Intraepidermal nerve fiber density can be quantified in skin obtained by punch skin biopsy. It is usually significantly lower in patients with painful sensory neuropathies than in age-matched control subjects. Loss of penetrating fibers in the epidermis generally has been found to correlate with pain. Future developments such as functional neuroimaging of pain provide one avenue for objective evaluation of a patient’s pain state and, perhaps more importantly, the efficacy of therapy. WHAT TO TELL THE PATIENT It is rational to inform the patient that he or she has pain as a result of nerve damage. It is unclear why some patients develop neuropathic pain. Animal studies point to a significant genetic component that is important in the development of neuropathic pain. Dealing with chronic neuropathic pain from the perspective of the patient or physician is difficult, and one of the most frequently asked questions by patients is, “How long will the pain last?” Unfortunately there are no good data to answer this question. The presence, onset, intensity, and duration of neuropathic pain in patients are highly variable. In some patients the pain gets better spontaneously, whereas in others it lasts for less than a year. In some patients, the pain persists for years without

Chapter 223 w

any improvement. A number of conditions may affect the onset and duration of neuropathic pain including sex, mechanism of nerve damage (stretch, cut, or infection), level of the nervous system damaged (e.g., for central lesions, the spinal cord, thalamus, and cortex; for peripheral nerve lesions, the face, hand, foot, thorax, and abdomen); time of treatment (e.g., preemptive analgesia and aggressive early treatment), type of treatment (e.g., invasive therapies may exacerbate the pain), and genetic background. Many of these are still being evaluated in clinical studies. In general, many neuropathic pain conditions (e.g., phantom pain or postherpetic neuralgia) dramatically decrease in their intensity within a year, no matter what the treatment. On the other hand, neuropathic conditions exacerbated by incident pain (motion, compression [e.g., sciatica]) are much more difficult to treat. CURRENT TREATMENT APPROACHES At this time there are no effective medications for neuropathic pain. Large discrepancies in side-effect profile make the use of some agents more efficacious in particular patients. In treating patients with neuropathic pain it is useful to consider pharmacologic agents that target these specific mechanisms. Clearly, the discovery of new mechanisms and new targets will contribute to a larger analgesic armamentarium. Because many patients with neuropathic pain have multiple mechanisms for their pain, combination therapy is often considered.

Pharmacologic Approaches Medications That Decrease Spontaneous Activity (Shooting Pains). Local anesthetic derivatives, such as mexiletine to treat

patients with neuropathic pain, inhibit sodium channel activity. In patients without QT or QRS prolongation times, mexiletine is started at 150 mg per day for 1 to 3 days and then increased to three times per day. Dosages may be increased to 300 to 600 mg three times per day. The medication has some side effects, including those on the gastrointestinal tract and central nervous system. Lamotrigine is another medication in the same class that has been used for the same indications but with less success. It takes a long time to build up to therapeutic levels. The usual starting dosage is 25 mg per day for 1 week and then building up in 25-mg increments to a maximal dosage of 200 mg per day. A recent addition to the clinical armamentarium has been the introduction of a 5% lidocaine patch. More than one patch may be used to cover an area. Minimal systemic absorption has been reported. The patch has been shown to be effective in neuropathic pain in controlled randomized trials. Some antidepressants, such as amitriptyline, are also thought to exert their effect by inhibiting sodium channels. Antidepressants, including amitriptyline, desipramine, or nortriptyline, have been used for neuropathic pain. Although the exact mechanism of antidepressants on pain systems is unclear, it is thought that some exert their action via inhibition of sodium channels. For a younger population, amitriptyline is well tolerated. Dosing is usually 25 to 150 mg per day. Side effects are predominantly anticholinergic. Other antidepressants, including desipramine and nortriptyline, can also be used. Gabapentin may be the most prescribed medication for neuropathic pain. Its mechanism of action is unknown but may act on calcium channels. It is very well tolerated in the majority of patients, usually starting at 300 mg three times per day and

Neuropathic Pain

1405

building up to 3600 mg per day, if tolerated. A minimum of 900 mg three times per day seems to be necessary for the agent to be effective. Side effects include somnolence, dizziness, ataxia, and peripheral edema. A more potent derivative of gabapentin (pregabalin) may soon become available for clinical use. Medications That Inhibit or Block Central Sensitization. As described earlier, central sensitization is a critical component of the pathology of neuropathic pain. The NMDA receptor system plays a role in continuous and particularly in stimulus-evoked pain after nerve injury. If central sensitization can be inhibited before its development (e.g., by preemptive analgesia) or decreased once it has taken place, a significant clinical therapeutic option becomes available. This group of agents may inhibit excitatory neurotransmitter (glutaminergic) systems or activate inhibitory (GABA-ergic) systems. Recent clinical data suggest that chronic pain caused by injury may result in the sensitization of the central nervous system, mediated in part by excitatory amino acids. NMDA antagonists, including dextromethorphan and the antiparkinson medications, memantine and amantadine, ketamine, and the opioid methadone, may be helpful. Unfortunately, many of these medications have dose-limiting side effects. Ketamine, a general anesthetic medication, may reduce allodynia and increase pressure-pain thresholds. It may be taken orally in low dosages (10 to 50 mg four times per day), but oral dosing is limited by poor uptake, and subcutaneous ketamine has been used. This should be done with patients who have experience using the medication. Limited clinical data suggest that this may be done safely (i.e., without addiction or tolerance), but wellcontrolled trials are still necessary. Dextromethorphan may be partially effective in neuropathic pain. Dosages of 350 to 425 mg per day may be necessary. Starting dosages should be 60 mg per day in three divided doses, building up slowly as tolerated. Side effects at the higher dosages are common. Memantine, an NMDA receptor antagonist, was initially used in patients with Parkinson’s disease. In some trials it has been shown to be useful, but some controlled studies fail to demonstrate a benefit that is greater than that of placebo. Dosing is increased slowly from 5 to 20 mg per day. Inhibitors of GABA-ergic systems, including baclofen and benzodiazepines (e.g., clonazepam), have been used in trigeminal neuralgia and other peripheral neuropathies with some benefit. The starting dosage is 10 mg three times daily, building up to 100 to 160 mg per day as tolerated. In central pain syndromes these medications should be tried, but in our experience they are of minimal use. Medications That Augment Central Descending Pathways.

Morphine is still the gold standard for pain. Opioids have been shown to be effective in neuropathic pain in some controlled studies, and given the limited therapeutic armamentarium, if other medications fail, we then consider using this group of pharmacologic agents. Aside from regulatory issues, which vary from state to state (e.g., need to see patients when prescribing the medication, reassessment of need for medication every 6 month to 1 year), there are a few principles for opioid use. Short-acting opioids should be avoided in patients with chronic pain. Longacting agents should be used (e.g., slow-release oxycodone, slow-release morphine, or a methadone or fentanyl patch). In patients with cancer pain, rapid titration of dosing is necessary. We recommend slow-release oxycodone or methadone because of its presumed NMDA antagonist effects as the opioids of choice. Some

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Generalized and Regional Pain Syndromes

have advocated the use of intraspinal opioids, necessitating minor surgery. There are no good data to support their use in patients with chronic pain. A new class of opioids with only peripheral effects will soon become available for clinical use. Anti-Inflammatory Medications. The role of inflammation and inflammatory cytokines in neuropathic pain is receiving more attention. In patients with an exacerbation of their pain, a steroid taper can be extremely beneficial. A single Medrol dose pack (7-day course) is prescribed at this time. Anti-inflammatories may induce inhibition of both peripheral and central systems involved in the response to neuropathic pain. The more recently introduced Cox-2 inhibitors may have some benefit relating to their lack of gastrointestinal side effects. Biosystems Approaches Physical Therapy. Recent data suggest that motor cortex stimulation or the effects of stimulation of nerves in upper limb amputees produce significant benefit. Physical therapy may produce similar effects through motor activity. It is strongly recommended that referrals for physical therapy are done carefully. It is preferred that such referrals are to specialists with training in neurophysiology, not physical therapists involved in orthopedics. Stretching nerves with exuberant therapy only worsens the patient’s condition. Electrical Stimulation. In general, the efficacy of electrical stimulation including transcutaneous electrical nerve stimulation, spinal cord electrodes, or centrally placed electrodes is at best not well defined. Recent work with patients with phantom pain has shown that peripheral stimulation in the area of the stump can enhance recovery. Careful use of stimulation may be considered, and there is no evidence that this may be harmful. Compassionate Care. Although it is the medical creed to do one’s best to provide compassionate care to all patients, patients with chronic pain are a special group. This is because the treatment options are not great and the frustrations for the patient are significant. In addition, we are further confronted with varied clinical and social settings. Multiple variables including race, creed, age, and sex of the patient have a significant impact on patient care. Believe the patient. Patients with chronic pain have lives that we can hardly imagine, including difficulty sleeping, extreme suffering, difficulty with marriage, and other social and psychological problems. Often overlooked is the level of compassion provided by the caregiver. Many patients know that little can be done but are optimistic that the physician will learn about new developments in improved therapies. In addition, regular clinic visits provide an incentive to maintain therapy and an opportunity to try additional therapies, such as physical therapy or psychological therapy. The placebo effect in pain is very powerful, ranging from 30% to 80%. Interestingly, it has a well-described neurobiology, and it should not be underestimated or misunderstood. Many patients request alternative therapies such as acupuncture. Although there is no evidence that such therapies have any benefit in controlled trials, many patients find them very helpful. The mechanism underlying acupuncture is not known, although activation of endogenous opioid systems has been postulated.

InterventionalApproaches A number of interventional approaches are used for neuropathic pain, including spinal cord stimulators and intrathecal opioids or

other medications, such as a,-receptor blockers (clonidine). These are usually lucrative procedures, but they have not been tested in controlled trials and do not provide long-term relief. The cost of such interventions that do not have proper outcomes should be considered before a patient is referred for such a treatment. Interventional therapies for patients with shortened life expectancies (i.e., patients with neuropathic pain resulting from cancer pain) makes more sense than for patients with chronic conditions. Patients with chronic pain should not be referred for ablative procedures. AU scientific evidence supports the notion that ablations, including thermocoagulation and cryotherapy, produce nerve damage and therefore a neuropathic pain condition. lntrathecal Agents. A number of agents are undergoing evaluation for intrathecal use in chronic neuropathic pain, including opioids, clonidine, and conotoxin. The a,adrenoreceptor agonist is approved for neuropathic pain in patients with cancer and seems to be quite useful. Sympathetic Blocks. Sympathetic blockade, by ganglionic blockade or intravenous infusion with phentolamine, may provide two useful pieces of information: a mechanistic basis for neuropathic pain (i.e., involvement of the sympathetic system in the maintenance of neuropathic pain) and pain relief for a period of time that allows the patient to undergo physical therapy if the block is effective. Patients should be referred to appropriate facilities for these procedures (i.e., to pain clinics or radiology services). Epidural Steroids. The use of epidural steroids may have a role in neuropathic pain of vertebral or spinal origin. Intrathecal administration may be useful in patients with acute or chronic herpes zoster. Currently there are no data to indicate whether epidural steroids are effective in common low back pain or sciatica. Nonetheless, these are safe to perform, and patients should be referred to clinics that perform these procedures under fluoroscopy. Surgical Treatment. For nonmalignant pain there is a very small role for surgical treatment of pain. Removal of neuromas, sectioning or lesioning of somatic or sympathetic nerves, and surgery on the spinal cord or thalamus all have proved to be limited in the ability to provide long-term pain relief. Current understanding of the pain system and clinical experience has shown that in most cases pain returns in the original distribution and in the same intensity as that before the surgery. After sympathectomy, for example, patients may experience new pain in regions different from their original pain at the level above or below the sympathectomy. One surgical procedure that may be useful in patients with brachial plexus avulsions is dorsal root entry zone surgery, in which the afferent fibers together with laminae I-V are lesioned (recall that most nociceptive fibers terminatejn laminae I, 11, and V). Some institutions provide more aggressive surgical interventions, such as thalamic surgery or implantation of spinal cord stimulators or epidural or intrathecal subcutaneous pumps for administering morphine. In selected patients these may have a role, but large prospective clinical studies are needed.

Treating Secondary Effects of Pain Chronic neuropathic pain reduces quality of life, including mood, physical, and social functioning. Depression and pain coping strategies may predict pain intensity. For many patients neuropathic pain syndromes may be very debilitating: They cannot sleep or cannot participate at work, leisure, or at home because the pain

Chapter 224

is so severe and incapacitating. It is helpful to the patient for the physician to develop a treatment plan. The plan should address specific issues related to the pharmacologic treatment of neuropathic pain syndrome and more global issues, such as the potential need for medications to sleep or the potential to increase activity at home and at work. With respect to these latter issues, referrals for physical or psychological therapy may be necessary. Depression often is associated with chronic pain. There is evidence that treating the pain often alleviates depressive symptoms. Some antidepressants used for neuropathic pain provide dual therapy. Often, pain limits range of movement and ambulation. This should be addressed with physical and occupational therapists. Such referrals can be extremely helpful. Everything that can be done should be to encourage patients to get back to work or some useful activity. Learned pain behavior including seeking treatment, seeking medications, or an inability to perform menial tasks at home or in the office is a major problem. In certain cases a referral to a pain rehabilitation program may be useful. When using opioids, benzodiazepines, or ketamine, patients may be abusing their prescriptions. A simple method that can be helpful is to have the patient agree to and sign a contract. This increases the patient’s accountability and explains his or her responsibility regarding receiving scheduled medications, including getting medications from only one physician and not using more than the prescribed amount. In addition, patients should be told that they may need to undergo a random drug screen to ascertain that they are taking these agents. With regard to the latter, be sure to have a proper understanding of what metabolites should be present. For example, metabolites of oxycodone may not be there even if the patient has taken the medication 4 hours earlier. Behavioral and Physical Treatment

Some patients with neuropathic pain syndromes may respond to physical therapy, behavioral therapy such as biofeedback, or psychiatric therapy. How these modalities work is not clear. The

Orofacial Pain

use of TENS units is also controversial, although some patients seem to benefit from them. Many patients with chronic pain are very difficult to treat, and psychological or psychiatric input often is necessary. Because some pain syndromes have no cure, other psychosocial factors may contribute to the patient’s pain. In these instances, appropriate referrals to centers that have multidisciplinary pain management teams may be helpful. CONCLUSIONS The treatment of neuropathic pain syndromes in benign and malignant pain can be difficult. Recent progress in the neurobiology of alterations in the nervous system that take place after peripheral or central damage to pain pathways has provided new insights to the mechanism of neuropathic pain. These developments will no doubt produce new pharmacologic agents that will help in pain treatment. SUGGESTED READINGS Backonja M M Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain 16(Suppl2):S67-72, 2000 Besson JM: The neurobiology of pain. Lancet 353:1610-1615, 1999 Fishman SM, Bandman TB, Edwards A, Borsook D: The opioid contract in the management of chronic pain. J Pain Symptom Manage 18~27-37,1999 Gybels JM, Sweet WH: Neurosurgical Treatment of Persistent Pain. Physiological and Pathological Mechanism of Human Pain. Karger, Basel, 1989 Leijon G, Bovie J, Johansson I: Central post stroke pain: neurological symptoms and characteristics. Pain 3613-25, 1989 Max M B Treatment of post-herpetic neuralgia: antidepressants. Ann Neuro135:S50-53, 1994 Ossipov MH, Lai J, Malan TP Jr, Porreca F Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci 909:12-24, 2000

Woolf CJ, Mannion RJ: Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959-1964, 1999

224 Orofacial Pain Sheldon G. Cross The differential diagnosis of orofacial pain is based on a thorough history and examination and the findings from laboratory testing and imaging. Often, during the history the clinician must redirect the interview based on the patient’s response. Having an appreciation of the clinical characteristics of orofacial pain, as shown in Table 224-1, may help establish the proper focus for the clinical interview. PAIN CATEGORIES Somatic pain is the result of noxious stimulation and can be divided into superficial, involving the skin or mucosa, and deep, involving the muscles, bones, glands, or organs. Superficial pain is

1407

rn TABU224-1. Categories of Orofacial Pain Somatic Superficial Deep Musculoskeletal visceral Neurogenic Paroxysmal Pretrigeminal Clossopharyngeal N e w s intermedius Continuous Deafferentation Psychogenic

Chapter 224

is so severe and incapacitating. It is helpful to the patient for the physician to develop a treatment plan. The plan should address specific issues related to the pharmacologic treatment of neuropathic pain syndrome and more global issues, such as the potential need for medications to sleep or the potential to increase activity at home and at work. With respect to these latter issues, referrals for physical or psychological therapy may be necessary. Depression often is associated with chronic pain. There is evidence that treating the pain often alleviates depressive symptoms. Some antidepressants used for neuropathic pain provide dual therapy. Often, pain limits range of movement and ambulation. This should be addressed with physical and occupational therapists. Such referrals can be extremely helpful. Everything that can be done should be to encourage patients to get back to work or some useful activity. Learned pain behavior including seeking treatment, seeking medications, or an inability to perform menial tasks at home or in the office is a major problem. In certain cases a referral to a pain rehabilitation program may be useful. When using opioids, benzodiazepines, or ketamine, patients may be abusing their prescriptions. A simple method that can be helpful is to have the patient agree to and sign a contract. This increases the patient’s accountability and explains his or her responsibility regarding receiving scheduled medications, including getting medications from only one physician and not using more than the prescribed amount. In addition, patients should be told that they may need to undergo a random drug screen to ascertain that they are taking these agents. With regard to the latter, be sure to have a proper understanding of what metabolites should be present. For example, metabolites of oxycodone may not be there even if the patient has taken the medication 4 hours earlier. Behavioral and Physical Treatment

Some patients with neuropathic pain syndromes may respond to physical therapy, behavioral therapy such as biofeedback, or psychiatric therapy. How these modalities work is not clear. The

Orofacial Pain

use of TENS units is also controversial, although some patients seem to benefit from them. Many patients with chronic pain are very difficult to treat, and psychological or psychiatric input often is necessary. Because some pain syndromes have no cure, other psychosocial factors may contribute to the patient’s pain. In these instances, appropriate referrals to centers that have multidisciplinary pain management teams may be helpful. CONCLUSIONS The treatment of neuropathic pain syndromes in benign and malignant pain can be difficult. Recent progress in the neurobiology of alterations in the nervous system that take place after peripheral or central damage to pain pathways has provided new insights to the mechanism of neuropathic pain. These developments will no doubt produce new pharmacologic agents that will help in pain treatment. SUGGESTED READINGS Backonja M M Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain 16(Suppl2):S67-72, 2000 Besson JM: The neurobiology of pain. Lancet 353:1610-1615, 1999 Fishman SM, Bandman TB, Edwards A, Borsook D: The opioid contract in the management of chronic pain. J Pain Symptom Manage 18~27-37,1999 Gybels JM, Sweet WH: Neurosurgical Treatment of Persistent Pain. Physiological and Pathological Mechanism of Human Pain. Karger, Basel, 1989 Leijon G, Bovie J, Johansson I: Central post stroke pain: neurological symptoms and characteristics. Pain 3613-25, 1989 Max M B Treatment of post-herpetic neuralgia: antidepressants. Ann Neuro135:S50-53, 1994 Ossipov MH, Lai J, Malan TP Jr, Porreca F Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci 909:12-24, 2000

Woolf CJ, Mannion RJ: Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959-1964, 1999

224 Orofacial Pain Sheldon G. Cross The differential diagnosis of orofacial pain is based on a thorough history and examination and the findings from laboratory testing and imaging. Often, during the history the clinician must redirect the interview based on the patient’s response. Having an appreciation of the clinical characteristics of orofacial pain, as shown in Table 224-1, may help establish the proper focus for the clinical interview. PAIN CATEGORIES Somatic pain is the result of noxious stimulation and can be divided into superficial, involving the skin or mucosa, and deep, involving the muscles, bones, glands, or organs. Superficial pain is

1407

rn TABU224-1. Categories of Orofacial Pain Somatic Superficial Deep Musculoskeletal visceral Neurogenic Paroxysmal Pretrigeminal Clossopharyngeal N e w s intermedius Continuous Deafferentation Psychogenic

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Headache and Pain H Generalized and Regional Pain Syndromes

sharp and well localized and generally has a known cause, such as a scrape, pinch, or burn. The source and site of the pain are the same, and the pain alerts us to a threat in the environment. Deep pain behaves in an entirely different manner and generally presents as a dull, poorly localized pain, often exhibiting central excitatory effects that may mislead the practitioner. These central excitatory effects are believed to be related to convergence and may occur via motor, autonomic, or sensory routes. Motor excitatory effects often present as tightness of muscles adjacent to the painful area but may also present as myofascial pain if the pain is intense or of sufficient duration. Autonomic excitatory effects in the head and neck may be seen as lacrimation, nasal congestion, local edema, or flushing. Common examples of referred pain, an excitatory effect via the sensory route in the head and neck, are a lower molar tooth pain presenting as ear pain or a posterior cervical muscle pain presenting as retro-orbital or temporal pain. A different and confusing sensory excitation may be seen as secondary hyperalgesia, with increased sensitivity in an area adjacent to the pain. In this way, a patient with masticatory muscle pain may also present with skin tenderness over the ipsilateral temporomandibular joint, although no joint disorder is present. The two major sources of deep somatic pain are musculoskeletal and visceral. Musculoskeletal pain differs from visceral pain in that it is generally related to function. It appears to be in proportion to the intensity of the injury and to activity or movement. In visceral pain often a threshold must be reached before symptoms are experienced. For example, a salivary gland with an obstruction may be asymptomatic until increased demand for saliva occurs. Neurogenic pain often has the same sharp quality, as seen with superficial somatic pain. The primary difference is that no local cause for the pain is present. The patient usually can localize the site accurately, but all findings are negative. In addition, neurogenic pain often is characterized as burning and shocking. It is caused by a dysfunction of the central or peripheral nervous system, so that the patient often experiences pain in completely healthy tissue. Central excitatory effects, such as referred pain, are not typical for neurogenic pain. Psychogenic pain is not a diagnosis of exclusion but one of inclusion. A physiologic basis for the pain may not be present, and very often multiple medical problems are present, with the intensity and location of the pain being out of proportion to the degree of injury or illness. Examples of psychogenic pain include somatization, conversion, hypochondriasis, and body dysmorphic disorders. Psychogenic pains are not reviewed in this chapter, and a more complete description can be obtained in the Diagnostic and Statistical Manual of Mental Disorders. EXTRACRANIAL DISORDERS

Table 224-2 shows the classification of orofacial pain as established by the American Academy of Orofacial Pain. The intracranial pain disorders are not discussed in this chapter. A complete review of extracranial disorders is very extensive, and emphasis therefore is placed on the more common extracranial pains caused by tooth, nose or sinus, throat, mouth, tongue, and salivary gland disorders. Tooth Disorders

Tooth pain originates either from the pulp or the periodontal ligament. It is the most common cause of pain in the mouth and

TMU 224-2. Classification of Orofacial Pain lntracranial disorders Extracranialdisorders Musculoskeletal disorders Primary headache disorders Neurologic disorders Paroxysmal neuralgias Continuous neuralgias Psvcholonical disorders

is a form of deep somatic pain. Pulpal pain, occurring from within the tooth, behaves very much like visceral pain. Usually, it does not occur until a certain threshold has been reached. Most people are familiar with pulpal pain from experience with a cold substance or during a dental procedure. As soon as the threshold is reached, intense pain is experienced, which subsides rapidly after the stimulus is removed. Visceral pain is poorly localized and is capable of causing central excitatory effects. Therefore, the patient with pulpal pain usually cannot localize the source, or tooth, and may have other symptoms of central excitatory effects. If an infection is present, heat produces expansion within the pulp, resulting in worse pain, but often the patient is still unable to localize the tooth. Because hard tissues of tooth or bone confine the pulp, no allowance for swelling is present. Although it may cause pain from minor pulp inflammation, cold often relieves the more intense pain from pulp infection. Pulpal pain continues to behave as a visceral pain until the infection extends through the apex of the tooth into the periodontal ligament. As soon as the ligament becomes involved, tooth movement causes increased pain, so that the pain behavior changes to that more characteristic of musculoskeletal pain. Periodontal pain usually is well localized because chewing or tapping the tooth causes pain. For most purposes, pulpal pain therefore is the difficult diagnostic problem. If intraoral temperatures of extreme hot or cold influence the orofacial pain, it is appropriate to refer the patient for dental evaluation. The finding of pain in a tooth or tooth site is not sufficient to make a diagnosis. As will be discussed later in this chapter, some patients experience neuropathic pain that presents as a localized tooth pain, and even cardiac pain may present as lower tooth pain. Often analgesic blocks help refine the diagnoses of these odontogenic pains. Nose and Sinus Disorders

Stimulating the mucosa of the nasal turbinates or sinus ostia causes referred pain to the ipsilateral upper teeth, cheek, eye, or temple. The main causes for most benign painful disorders of the nose and sinuses involve inflammation, traction, or distention. Because mucous membranes behave as visceral tissue, it is likely that the pain will be referred to adjacent structures. Sinus infections involving just one of sinuses are uncommon and usually occur as pansinusitis. Accompanying symptoms of acute sinusitis generally include periorbital pressure, nasal congestion, pain in the upper teeth, or ear pain. Chronic sinusitis may be more difficult to diagnose, and the cause, such as obstructed sinus ostium or chronic dental infection, may be more difficult to localize. The clinician cannot overlook the possibility of malignancy, ranging from squamous cell carcinoma, melanoma, and Kaposi's sarcoma to metastatic disease, as a cause of nose or sinus pain.

Chapter 224 H Orofacial Pain

Throat Disorders The throat is divided into three sections: the nasopharynx, oropharynx, and laryngopharynx. Although injury to the mucous membrane of the pharynx produces superficialsomatic pain, some areas of the throat respond as visceral tissue, making the diagnosis more difficult. The innervation of the throat is by the glossopharyngeal and vagal nerves, and both have somatosensory branches that supply the middle and external ear. Therefore, it is not uncommon for patients with inflammatory or neoplastic disease of the throat to have referred pain to the ear. Intense or continuous throat pain, which is a form of deep somatic pain, often is accompanied by ipsilateral facial muscle tightness or pain. It is important to remember that a patient may not discuss pain on swallowing but rather pain with eating.

Tongue Disorders Most tongue disorders can be easily located or seen and need not be reviewed. Two conditions, carcinoma of the base of the tongue and burning tongue, warrant special mention. Carcinoma of the base of the tongue often is difficult to see or palpate. Even a small lesion may present as intermittent or continuous ear or throat pain, aggravated by eating. Although rare, this very serious condition must not be overlooked when all other findings are negative. Burning tongue may result from local causes, such as irritation or Candida infection, systemic causes, such as vitamin B deficiencies, and possibly neuralgic causes. Neuralgic causes may present as a paroxysmal or continuous neuralgia not responding to topical anesthesia and actually intensifylng for its duration.

Mouth Disorders Burning mouth (stomatodynia) is now believed to be another form of pain secondary to central pain disinhibition. It refers to various pains experienced in the oral mucosa or tongue, with no identifiable organic cause. The typical complaint usually is bilateral and often described as burning, annoying, dry, granular, or swollen. The location, in order of frequency, is the tongue, palate, gingiva, oropharynx, and lips. Although remissions occur, the symptoms usually are daily and continuous. Patients often complain of spontaneous and phantom tastes aggravated by spicy or acidic foods. Stomatodynia is found predominantly in women and occurs more often after menopause. Studies have shown taste to have an inhibiting effect on the trigeminal and glossopharyngeal nerves. They have also shown that patients with a burning mouth have a greater number of taste buds. Damage to the chorda tympani, possibly secondary to inner ear infection, is believed to result in loss of inhibition of the trigeminal fibers that surround the fungiform (taste) papillae on the tongue, therefore resulting in a central cause for the burning. When a topical anesthetic is applied, the remaining taste fibers are anesthetized, thereby eliminatingany inhibition still present. Because the burning is central, the pain intensifies for the duration of the topical anesthetic. These same patients also suffer from phantom tastes, usually described as metallic or bitter.

Salivary Gland Disorders The salivary glands can be divided into major and minor, and only problems with the major glands are reviewed here. Salivary gland

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responds as visceral tissue, which means that a threshold must be reached to become symptomatic. Visceral pain may be accompanied by secondary symptoms involving muscles, referred pain, or concomitant autonomic complaints, such as nasal congestion or tearing. The most common site for pain referred from the parotid gland is the region of the temporomandibular joint and ear, whereas the sublingual and submandibular glands refer to the lower jaw. Because the major function of the glands is to produce and regulate the flow of saliva, alterations in this function may be a cause of symptoms. Factors that have a significant influence on salivary gland function include medications, especially those with anticholinergic activity, systemic disease, such as alcoholism and hypertension, and endocrine disorders, such as diabetes mellitus, Cushing’s disease, Addison’s disease, and menopause. Inflammatory and duct obstruction are the two more common major salivary gland problems. Gland inflammation presents as a localized, painful enlargement and is generally not difficult to diagnose. When the enlargement and accompanying symptoms are related to meals, a duct obstruction should be considered. The more unusual causes of salivary gland problems involve catscratch disease and Sjogren’s syndrome. Dry mouth (xerostomia) may be a major problem with gland disease, resulting in a decrease in taste, a burning sensation in the mouth, and difficulties with speaking and swallowing. A common sequela of xerostomia is candidiasis. Sjogren’s disease is the major differential diagnosis for chronic xerostomia. It is a chronic, slowly progressive autoimmune exocrinopathy, often associated with keratoconjunctivitis caused by diminished tear secretion.

MUSCULOSKELETAL DISORDERS Temporomandibular Joint Disorders Affected tissues may include the temporomandibular joint, muscles of mastication, and adjacent structures. The characteristic signs and symptoms often include pain and tenderness in the face, head, neck, and shoulders. The intensity may range from barely noticeable to debilitating. The estimated prevalence in the general population is 6%, with a ratio of 3 to 1 of women seeking treatment over men. The temporomandibular joint consists of two separate joints: a lower, hinge joint between the head of the condyle and the inferior surface of the articular disk and a sliding, upper joint between the superior surface of the articular disk and the articular eminence. It functions as a hinge joint within a sliding socket. In addition to general joint conditions, such as osteoarthritis, articular disk derangements are a major reason for pain and dysfunction. The articular disk, which forms the complete articular surface for the two separate joints, is different from the meniscus in the knee, which aids its functions but is not the primary articular surface. Disk displacement is the slipping of the articular disk partially or totally off the head of the condyle, resulting in clicking noises and pain from disk ligament strain. Continuous noises imply that irreversible changes have occurred in the ligaments attaching the disk to the condyle, allowing the disk to be displaced usually anteriorly or anteromedially to the condyle (Fig. 224-1). Patients usually present with noise on mouth opening because the forward positioned disk reduces to a more proper position when the condyle moves forward. A second, often very quiet closing noise occurs when the teeth are near contact and the disk again dislocates. Because this problem is the result of irreversible alteration in the ligaments and possibly the disk shape, the noises

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I

FIG. 224-1. Disk displacement with reduction, showing late reduction of the disk. (A) Closed joint position. (6) Early in the translatory cycle, the condyle is unable to pass under the posterior border of the disk. (C) Reduction of the disk usually is accompanied by an opening click. (Modified with permission from Quintessence Publishing Company.) continue to occur throughout the day and may be influenced by forces within the joint, as during chewing. Although most patients adapt to a displacement, in some patients the disk displacement progresses, allowing the disk to gradually assume a position further off the condyle, interfering with joint function. Pain usually results from strained, collateral disk ligaments and tears within the highly vascular and extensively innervated, posterior disk attachment. Limitation in mouth opening is the result of the dislocated disk mechanically interfering with the forward movement of the condyle (Fig. 224-2). Often this condition is self-limiting, and the disk eventually becomes totally dislocated and nonfunctional. Patients may experience episodes of jaw catching or a louder than usual popping noise. Sometimes the posterior attachment tissues become altered to form a pseudodisk. A form of articular disk derangement necessitating additional clarification is disk sticking. This problem occurs on awakening as a subtle joint clicking or catching noise that disappears after one or two mouth openings. The description of the noise implies that the articular disk adheres slightly to the articular eminence, often explained as a suction cup effect. It is believed to result from alterations in synovial fluid or pressure as a result of sustained

nocturnal clenching. On mouth opening the disk is dislodged, allowing joint lubrication to occur. For this reason joint function remains symptom-free throughout the day. However, the wear and tear of persistent disk sticking slowly results in the development of minor surface irregularities within the joint. Treatment for articular disk sticking depends on the cause, frequency, and intensity of the condition. Although infrequent morning catching may warrant only monitoring, if it results in disk ligament pain or increased dysfunction, treatment becomes necessary. It may include medications to decrease nocturnal bruxing and clenching, behavioral modification, or the wearing of a nocturnal appliance. The finding of a displaced disk is not sufficient to necessitate treatment. Studies with magnetic resonance imaging have shown as many as 34% of asymptomatic patients to have disk displacement, with an increase to 86% in symptomatic patients. When the cushioning effect of the fibrous articular disk is lost, imaging shows degenerative joint changes, believed to be caused partially by the change in joint mechanics. If the changes have accompanying inflammation that causes pain, treatment is indicated. Such patients present with point tenderness over the joint, pain with function, or limited range of motion. When patients present with symptoms of temporomandibular joint inflammation, the sys-

I

FIG. 224-2. Disk displacement without reduction. (A) Closed joint position. (6)Failure to reduce the displaced disk early

in the translatory cycle. (C) Later in the translatoty cycle, the disk is still displaced, preventing normal condylar movement. (Reproduced with permission from Quintessence Publishing Company.)

Chapter 224

temic arthritides and other causes for joint inflammation, including Lyme disease, must be considered and ruled out. Nondental approaches involve a soft diet and limited function within a pain-free range of motion. Nonsteroidal antiinflammatory analgesics may help the inflammation, and, as with other joints, when refractory a steroid injection into the joint may be beneficial.

Mastlatoy Muscle Disorders Whereas tooth pain is the most common cause of pain in the mouth, muscle pain is considered the most common cause of pain in the head and neck. Muscle pain usually is described as a diffuse, continuous, deep, dull ache, tightness, or pressure. Because muscle pain is a form of deep somatic pain, the pain may be poorly localized, and the site of pain may not identify the true source. Most muscle pains are influenced by functional demands, and pain from masticatory muscle often worsens with chewing. Acute masticatory muscle pain can be divided into four categories: muscle splinting, muscle spasm, muscle inflammation, and myofascial pain. Muscle splinting is a reflex protective response mediated through the central nervous system, resulting in muscle tightening and pain to protect an injured part. Usually splinting is minimal if the injured part is not under threat. When the part is provoked, muscle splinting and pain occur in proportion to the threat. Splinting may result from various causes, such as muscle or ligament strain, minimizing movement of a painful joint. Muscle splinting presents as local muscle soreness, limited range of motion, increased pain with movement, and a subjective feeling of weakness. Management of muscle splinting is directed toward the injured part, and no treatment of the muscle should occur because it is not the primary problem. Muscle spasm is an involuntary, sudden contraction of a muscle or group of muscles, causing pain and limited range of movement. Muscle spasm may result from strain or from aggravating a previously weakened muscle involved in muscle splinting. The spasm may last from minutes to days and may by itself become a source of deep somatic pain. Certain medications, such as prochlorperazine, may produce a central cause for muscle spasm. Spasm is accompanied by limitation and distortion in movement and by increased pain with stretching of the involved muscle. Usually muscle spasms subside without treatment or with gentle stretching. The muscle usually is limited to the pain-free limit, and simple therapy, such as heat and massage, often is beneficial; in the acute stage ice may be helpful. If the symptoms do not improve in a matter of days, anesthetic blocks often relieve the pain and allow the muscle length to be restored. Prolonged spasm may lead to contracture and become irreversible. Muscle inflammation, when localized, often results from a local cause. Usually the diagnosis is not a problem, and in most instances the patient can define the onset. Myositis results from such simple causes as mild strain or prolonged muscle splinting or spasm. Common forms are seen as limited mouth opening accompanying dental infection or following a needle injection. Characteristics of myositis include continuous muscle pain, tenderness, and often swelling. The dysfunction is caused by muscle pain and inflammation. Therefore, injection of the muscle is contraindicated because injecting an inflamed muscle often produces greater protective splinting and increased pain. If other causes, such as infection, are present, the patient will also have the symptoms of that related problem. It is very important to look

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for aggravating or perpetuating factors, such as nocturnal bruxing. Myofascial pain is a regional muscle disorder that is one of the most common causes of persistent pain in the head, neck, or face. Myofascial pain is characterized by pain referred from a localized area within a muscle to another region, not necessarily in the same dermatome. The myofascial trigger point is defined as a localized deep tenderness in a taut band of skeletal muscle, tendon, or ligament that has the potential of referred pain in a reproducible manner. Myofascial pain usually begins with a defined onset and often a recognizable cause. The clinical signs include muscle fatigue and stiffness, mild limited range of motion, muscle pain when stretched, and the presence of myofascial trigger points. Treatment involves restoring muscle length and reducing or eliminating the myofascial trigger point. Establishing and eliminating perpetuating factors, such as nocturnal bruxing or work habits, is very important if recurrence is to be avoided. When conservative measures are not effective, injection of the trigger point may prove beneficial. CERVICAL DISORDERS Symptoms originating from the upper cervical spine cannot always be separated from those resulting from an orofacial cause. Cervical structures refer pain to the face, and the actual innervation by upper cervical nerve roots includes parts of the face, ear, and lower jaw. Figure 224-3 demonstrates a few of the variations in innervation by the C2 and C3 nerve roots, making it easy to recognize that nociception originating in the upper neck may extend into the lower jaw, cheekbone, and ear. In addition to the direct cervical innervation of the face, all trigeminal afferent signals synapse in the cervicotrigeminal relay, which runs from the pons to the level of C3. Because this complex also receives input from the upper cervical nerve roots, deep cervical pain has been experimentally shown to cause muscle splinting in the muscles of mastication. It has also been shown that electromyographic

FIG. 224-3. Composite C2 and C3 algesic dermatomes established from actual case studies. Note that either C2 or C3 may innervate the ear and periauricular tissues. (Courtesy of Charles E. Poletti, MD.)

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activity in the ipsilateral masseter muscle dramatically subsides when a myofascial trigger point in the trapezius muscle is anesthetized.

PRIMARY HEADACHE DISORDERS The primary headache disorders are covered in other chapters of this book. However, it is important to understand that conditions such as migraine or cluster headache may present primarily as tooth, gum, ear, sinus, or jaw pain. Pain in these areas may also serve as a generator, increasing the frequency of headaches in a predisposed patient. A second concern is that many patients with primary headaches experience secondary muscle tightness, which may occur in the head, jaw, face, or neck. These muscular symptoms may be part of the patient’s chief complaint, leading to a misdiagnosis of temporomandibular or cervical disorder. When a patient does not respond in a predictable manner to treatment, a reevaluation with an understanding of this complex relationship must be taken into consideration.

NEURALGIC DISORDERS Neuralgic disorders include both the paroxysmal and continuous neuralgias. Patients often experience pain on light touch of a specific area, as if they were experiencing superficial somatic pain. In neuralgic pain, although the patient can identify the site, no disorder is present on clinical examination. In addition, patients

may experience a temporal delay or exaggerated atypical response to mild stimulation. In superficial somatic pain, the site and source are the same and are easily identified. The differential diagnosis of neuralgic pain should always include traction and inflammation, caused by lesions such as a tumor or aneurysm, multiple sclerosis, or Lyme disease.

Paroxysmal Neuralgia Neuralgia is severe pain experienced in the innervation of a sensory nerve. The paroxysmal neuralgias include trigeminal, glossopharyngeal, nervous intermedius, recurrent laryngeal, and occipital neuralgia. Trigeminal neuralgia is a unilateral affliction, involving one or more branches of the trigeminal nerve. The facial pain is characterized by spontaneous brief episodes of shocklike pains, limited to the distribution of the involved branches of the nerve. Pain may be triggered by light touch in a trigger zone, usually in the same area as the pain, and can be prevented by topical or local anesthesia of the involved nerve branch. It is considered symptomatic when a demonstrable structural lesion, such as a tumor (Figs. 224-4 and 224-5), vascular malformation (Figs. 224-6 and 224-7), or demyelinating disease (Fig. 224-8), can be identified. When the cause is unknown, it is classified as idiopathic. Although statistics vary, 95% of the cases of trigeminal neuralgia are unilateral, with V2 and V3 together more commonly involved than V2 or V3 alone; V1 is least affected. Often the pain

FIG. 2264. Cranial magnetic resonance scan, T1 -weighted transverse image, showing a petroclival meningioma displacing the trigeminal newe. (Courtesy of Sherry L Gross, MD.)

Chapter 224

Orofacial Pain

FIG. 224-5. Gadolinium-enhancedcranial magnetic resonance scan, T I -weighted transverse image, showing the petroclival meningioma overlaying the trigeminal root entry zone. (Courtesy of Sherry L. Gross, MD.)

FIG. 224-6. Cranial magnetic resonance scan, T I -weighted transverse image, showing a persistent trigeminal artery (congenital anomaly). The asterisk shows the point of contact with the trigeminal nerve. (Courtesy of Sherry L Gross, MD.)

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FIG. 224-7. Gadolinium-enhanced cranial magnetic resonance scan, TI -weighted transverse image, showing a prominent blood vessel adjacent to the trigeminal nerve. (Courtesy of Sherry L. Gross, MD.)

FIG. 224-8. Cranial magnetic resonance scan, T2-weighted transverse image, showing multiple plaques of multiple sclerosis in the pons in a patient with symptoms of trigeminal neuralgia. (Courtesy of Sherry L Gross, MD.)

Chapter 224

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FIG. 224-9. Gadolinium-enhanced cranial magnetic resonance scan, T I -weighted coronal image, showing a meningioma in the area of the cavernous sinus causing symptoms of trigeminal neuralgia. (Courtesy of Sherry L Gross, MD.)

goes into remission but usually returns at a greater intensity afterward. The female-to-male ratio is approximately 1.61, with the onset usually after age 50. When the symptoms occur at a younger age, suspect multiple sclerosis, Lyme disease, or other intracranial disorder (Fig. 224-9). Pretrigeminal neuralgia was first described by Symmonds in 1949 and refers to an early manifestation of trigeminal neuralgia. It presents in the cheek or jaw as a dull, continuous, aching pain, which may be present for months or years before the characteristic shocklike pain of trigeminal neuralgia emerges. Imaging of the brain is negative, and anesthesia of the nerve totally eliminates the pain. The author has seen many patients in their 20s and 30s presenting with symptoms consistent with this disorder and completely subsiding with carbamazepine. The pain can go into remission for several months or years only to return later. Glossopharyngeal neuralgia is a rare neurogenic pain in the distribution of the ninth cranial nerve. Patients may experience up to 30 or 40 attacks per day, and the pain may also occur at night. Sometimes stimulation of the external auditory canal may precipitate an attack. The symptoms may also be present in the distribution of the auricular and pharyngeal branches of the vagal nerve. A small percentage of patients may experience episodes of bilateral ear pain. Because of the relationship with the vagal nerve, bradycardia, syncope, and very rarely seizures may accompany an attack. The condition may go into remission. Although glossopharyngeal neuralgia often presents with complaints of stabbing pain on swallowing, ipsilateral sharp burning ear pain or stabbing by the angle of the mandible in the distribution of C2 may occur. Nervus intermedius (geniculate) neuralgia is a very rare condition, characterized by paroxysms of pain felt very deep in the

ear, lasting for seconds or minutes. A trigger zone may be present in the posterior wall of the ear canal, and the onset may be associated with a diagnosis of herpes zoster. Autonomic symptoms of increased salivation, lacrimation, or altered taste may be present as well. Recurrent laryngeal neuralgia is an extremely rare type of neuralgia that may be felt in the throat, in the submandibular region, or under the ear. Its presentation may be very similar to that of glossopharyngeal neuralgia. The paroxysms of pain may last for minutes or hours and are precipitated by activities such as swallowing or head turning. The condition is believed to be caused by injury of the recurrent laryngeal nerve, a branch of the vagal nerve, caused by trauma or surgery. Occipital neuralgia is characterized by paroxysmal pain in the distribution of the greater and sometimes the lesser occipital nerve, often accompanied by dull pain in the back of the head. The symptoms may also be accompanied by altered sensation or dysesthesia, with tenderness over the greater occipital nerve. More than one cause has been attributed to this condition, but the pathogenesis seems to be related to trauma to the nerve. ContPnuous Neuralgias

Emphasis here is placed on the continuous neuralgias because these neuralgic pains are poorly understood and may play a major role in orofacial pain. Although the focus is on the intraoral continuous neuralgias, viral neuritis and postherpetic neuralgia warrant a separate comment. Neuritis can be seen on contrast magnetic resonance imaging as enhancement of the nerve (or ganglion) (Fig. 224-10). When a sensory nerve is involved, the

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FIG. 224-1 0. Gadolinium-enhanced cranial magnetic resonance scan, T1 -weighted transverse image, showing enhancement of the geniculate ganglion in a patient with Bell's palsy. (Courtesy of Sherry L. Gross, MD.)

patient of continuous burning or shooting pains and altered or unpleasant sensations or periods of numbness. Continuous neuralgias include complaints of intraoral pain, burning, dysesthesias, and altered taste. Often the patient complains of tooth pain or describes the onset after a dental procedure. Continuous neuralgias are thought to be a form of deafferentation pain, resulting from peripheral or central sensitization or disinhibition. They originate from multiple causes and develop for different reasons with similar but confusing presentations. The following three examples represent different manifestations of continuous orofacial neuralgias: A 32-year-old women developed a mild pain between the upper right central and lateral incisors after dental prophylaxis. Gradually, the pain intensified and became constant. The teeth were extracted, but the pain worsened. All dental and medical evaluations were normal. A 46-year-old man developed a periapical abscess. While undergoing a root canal procedure, he experienced sharp pain. Since that time, although the root canal was finished and an apicoectomy performed, he has had ongoing intense, constant, throbbing, and burning pains, extending into the upper lip and now involving several adjacent teeth. All evaluations were normal. A 56-year-old woman complained of a severe burning tongue and bitter taste. All medical and dental evaluations were normal. A topical anesthetic made the pain worse, so a psychological cause was pursued. All three of these patients suffer pain caused by centrally influenced mechanisms. Instead of tissue injury causing nociception along a healthy nerve, in these cases the disorder is within the nervous system, signaling that healthy tissue hurts. Viral neuritis may be the cause of some of the more perplexing and difficult to treat orofacial pains. In the orofacial region,

adenovirus should be suspected in patients suffering intense burning and sharp pains in the ear or in a trigeminal dermatome after upper respiratory infection. Because the principal determinant of recovery is the extent of axonal degeneration, some patients continue to suffer from persistent pain refractory to most medications. The more difficult cases may warrant polypharmacy, including opioid medications. Postherpetic neuralgia is pain that starts with an acute episode of herpes zoster but persists longer than 6 months after the lesions have healed. Recent studies have implied that more than one mechanism may be responsible for the pain. For example, some patients have minimal sensory loss but present with an abnormal sensitization of unmyelinated cutaneous nociceptors, called irritable nociceptors. The pain from this condition temporarily responds to infiltration anesthesia. Other patients may present with scarring and profound sensory loss to both pain and temperature. These patients suffer severe allodynia, believed to be caused by small fiber deafferentation. In contrast to the irritable nociceptors, this presentation does not respond to infiltration anesthesia. A third manifestation is spontaneous pain without hyperalgesia or allodynia, believed to result from loss of both large- and small-diameter nerve fibers. Any or all three problems may occur in the same patient, and each condition may necessitate a different treatment. It is this complex presentation that has produced such varied treatments, ranging from amitriptyline or gabapentin to the topical use of capsaicin or lidocaine.

EPILOGUE Assessment is the process of making observations from all possible perspectives. It leads to a diagnosis only when the person making the assessments has the training and skill to evaluate the outcome of the assessment and determine that a condition or series of conditions is likely to be present. Most diagnoses have a pre-

Chapter 225 H Neck and Arm Pain

dictable response. When the response is inappropriate, a reassessment is necessary, but can only be done with a full appreciation of the various causes leading to the differential diagnoses. SUGGESTED READINGS Backonja MM: Neuropathic pain syndromes. Neurol Clin 16775-966, 1998 Dubner R Neural basis of persistent pain: sensory specialization, sensory modulation, and neuronal plasticity.pp. 243-257. In JensenTS, Turner JA, Wiesenfeld-Hallin Z (eds): Progress in Pain Research and Management. Vol 8. IASP Press, Seattle, 1997 Fields HL, Rowbotham M, Baron R Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5:209-227, 1998 Hu SW, Sessle BJ, Raboisson P et ak Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brain-stem neurons. Pain 48:53-60, 1992 Hu SW, Yu XM, Vernon H, Sessle BJ: Excitatory effects on neck and jaw muscle activity of inflammatory irritant applied to cervical paraspinal muscles. Pain 55:243-250, 1993

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Merrill R Orofacial pain mechanisms and their clinical application. Dent Clin North Am 41:167-188, 1997 Okeson J P Bell’s Orofacial Pain. 5th Ed. Quintessence Publishing Company, Chicago, 1995 Okeson JP (ed): Orofacial Pain: Guidelinesfor Assessment, Diagnosis, and Management. Quintessence, Chicago, 1996 Pertes RA, Gross SG (eds): Clinical Management of Temporomandibular Disorders and Orofacial Pain. Quintessence, Chicago, 1995 Sessle BE Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 11:57-91, 2000 Amano N, Zhong G Convergence of cutaneous, tooth Sessle BJ, Hu JW, pulp, visceral, neck and muscle afferents onto nociceptive and non-nociceptiveneurons in trigeminal subnucleus caudalis (medullary dorsal horn) and its implications for referred pain. Pain 22219-235, 1986 Truelove E Role of oral medicine in the teaching of temporomandibular disorders and orofacial pain. J Orofacial Pain 16:185-190, 2002 Woda A, Navez ML, Picard P et ak A possible therapeutic solution for stomatodynia (burning mouth syndrome). J Orofacial Pain 12:272278, 1998

225 Neck and Arm Pain Nathaniel P. Katz Pain in the neck and arm are among the most common complaints brought to the physician’s attention. The approach to these patients requires awareness of the general principles of managing acute and chronic pain and detailed knowledge of the neuroanatomy and cardinal features of the painful disorders of this region of the body. Basic skills are needed, including specific physical examination techniques, interviewing skills, and, for some patients, injection skills. In the case of the chronic pain patient, a biopsychosocial approach is most useful, and multidisciplinary pain management may be indicated. Failure to recognize psychosocial contributions to the patient’s distress may leave the physician perplexed at the failure of multiple treatment interventions. Even worse, such patients often report temporary success, inviting multiple repeated interventions with no long-term benefit and eventual complications. This chapter assumes basic expertise in the multidimensional approach to the patient with chronic pain and focuses on the medical diagnosis and treatment of conditions that present with neck and arm pain. The common disorders are presented with emphasis on the neurologic syndromes. For ease of discussion, disorders are presented sometimes by region (e.g., neck pain) and sometimes by system (e.g., neuropathies). NECK PAIN Cervical Anatomy The cervical spine consists of seven vertebrae, C1 through C7, bounded rostrally by the occiput and caudally by the first thoracic vertebra. The upper two vertebrae are unique in that the odontoid process projects rostrally from the body of C2, sitting within the

ringlike body of C1. Each vertebra articulates with the one above and the one below by two paired facet (zygapophyseal) joints posteriorly and, for vertebrae below C2, by discs anteriorly. The lateral aspects of the vertebral bodies are further interconnected by articulations, called uncovertebral joints. The spinal canal contains the spinal cord, surrounded by spinal fluid in the subarachnoid space, then the arachnoid, dura, epidural space, and finally the bony spinal canal. Eight cervical nerves (Cl-C8) exit the cervical spine. All of the nerves exit above their respective vertebral level except C8, which exits below the C7 vertebral body (there is no C8 vertebral body). Upon exiting the neural foramina, the spinal nerves divide into anterior and posterior rami. The anterior rami of Cl-C4 combine to form the cervical plexus, and the anterior rami of C P T l form the brachial plexus. The posterior ramus of C2 becomes the greater occipital nerve, of C3 the third occipital nerve, and of C P C 8 branches that innervate the facet joints, paraspinal muscles, and skin of the posterior midline. The anatomy of the cervical spine permits rotation mainly at C1-C2, flexion and extension mainly at the occiput-Cl and C2-C7, and lateral flexion at multiple levels. Approach to the Patient

The first priority in the approach to the patient with neck and arm pain is to exclude diagnostic imperatives, or illnesses that, if overlooked, will lead to dire consequences. Such diagnostic imperatives include the following: Tumor (primary, metastatic) Infection (osteomyelitis, epidural abscess, discitis, meningitis, retropharyngeal abscess)

Chapter 225 H Neck and Arm Pain

dictable response. When the response is inappropriate, a reassessment is necessary, but can only be done with a full appreciation of the various causes leading to the differential diagnoses. SUGGESTED READINGS Backonja MM: Neuropathic pain syndromes. Neurol Clin 16775-966, 1998 Dubner R Neural basis of persistent pain: sensory specialization, sensory modulation, and neuronal plasticity.pp. 243-257. In JensenTS, Turner JA, Wiesenfeld-Hallin Z (eds): Progress in Pain Research and Management. Vol 8. IASP Press, Seattle, 1997 Fields HL, Rowbotham M, Baron R Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 5:209-227, 1998 Hu SW, Sessle BJ, Raboisson P et ak Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brain-stem neurons. Pain 48:53-60, 1992 Hu SW, Yu XM, Vernon H, Sessle BJ: Excitatory effects on neck and jaw muscle activity of inflammatory irritant applied to cervical paraspinal muscles. Pain 55:243-250, 1993

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Merrill R Orofacial pain mechanisms and their clinical application. Dent Clin North Am 41:167-188, 1997 Okeson J P Bell’s Orofacial Pain. 5th Ed. Quintessence Publishing Company, Chicago, 1995 Okeson JP (ed): Orofacial Pain: Guidelinesfor Assessment, Diagnosis, and Management. Quintessence, Chicago, 1996 Pertes RA, Gross SG (eds): Clinical Management of Temporomandibular Disorders and Orofacial Pain. Quintessence, Chicago, 1995 Sessle BE Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 11:57-91, 2000 Amano N, Zhong G Convergence of cutaneous, tooth Sessle BJ, Hu JW, pulp, visceral, neck and muscle afferents onto nociceptive and non-nociceptiveneurons in trigeminal subnucleus caudalis (medullary dorsal horn) and its implications for referred pain. Pain 22219-235, 1986 Truelove E Role of oral medicine in the teaching of temporomandibular disorders and orofacial pain. J Orofacial Pain 16:185-190, 2002 Woda A, Navez ML, Picard P et ak A possible therapeutic solution for stomatodynia (burning mouth syndrome). J Orofacial Pain 12:272278, 1998

225 Neck and Arm Pain Nathaniel P. Katz Pain in the neck and arm are among the most common complaints brought to the physician’s attention. The approach to these patients requires awareness of the general principles of managing acute and chronic pain and detailed knowledge of the neuroanatomy and cardinal features of the painful disorders of this region of the body. Basic skills are needed, including specific physical examination techniques, interviewing skills, and, for some patients, injection skills. In the case of the chronic pain patient, a biopsychosocial approach is most useful, and multidisciplinary pain management may be indicated. Failure to recognize psychosocial contributions to the patient’s distress may leave the physician perplexed at the failure of multiple treatment interventions. Even worse, such patients often report temporary success, inviting multiple repeated interventions with no long-term benefit and eventual complications. This chapter assumes basic expertise in the multidimensional approach to the patient with chronic pain and focuses on the medical diagnosis and treatment of conditions that present with neck and arm pain. The common disorders are presented with emphasis on the neurologic syndromes. For ease of discussion, disorders are presented sometimes by region (e.g., neck pain) and sometimes by system (e.g., neuropathies). NECK PAIN Cervical Anatomy The cervical spine consists of seven vertebrae, C1 through C7, bounded rostrally by the occiput and caudally by the first thoracic vertebra. The upper two vertebrae are unique in that the odontoid process projects rostrally from the body of C2, sitting within the

ringlike body of C1. Each vertebra articulates with the one above and the one below by two paired facet (zygapophyseal) joints posteriorly and, for vertebrae below C2, by discs anteriorly. The lateral aspects of the vertebral bodies are further interconnected by articulations, called uncovertebral joints. The spinal canal contains the spinal cord, surrounded by spinal fluid in the subarachnoid space, then the arachnoid, dura, epidural space, and finally the bony spinal canal. Eight cervical nerves (Cl-C8) exit the cervical spine. All of the nerves exit above their respective vertebral level except C8, which exits below the C7 vertebral body (there is no C8 vertebral body). Upon exiting the neural foramina, the spinal nerves divide into anterior and posterior rami. The anterior rami of Cl-C4 combine to form the cervical plexus, and the anterior rami of C P T l form the brachial plexus. The posterior ramus of C2 becomes the greater occipital nerve, of C3 the third occipital nerve, and of C P C 8 branches that innervate the facet joints, paraspinal muscles, and skin of the posterior midline. The anatomy of the cervical spine permits rotation mainly at C1-C2, flexion and extension mainly at the occiput-Cl and C2-C7, and lateral flexion at multiple levels. Approach to the Patient

The first priority in the approach to the patient with neck and arm pain is to exclude diagnostic imperatives, or illnesses that, if overlooked, will lead to dire consequences. Such diagnostic imperatives include the following: Tumor (primary, metastatic) Infection (osteomyelitis, epidural abscess, discitis, meningitis, retropharyngeal abscess)

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Generalized and Regional Pain Syndromes

Spinal cord compression Fracture or dislocation Vertebral artery thrombosis or dissection These disorders generally can be ruled out by thorough history and physical examination and plain radiographs, supplemented, as needed, by more sophisticated imaging studies and blood tests. Such patients do not often present in medical practice and usually are the province of the emergency medicine physician, orthopedist, or neurosurgeon. A comprehensive diagnostic approach usually leads to a treatable disorder, sparing patients the tragedy of chronic pain. In patients already suffering from the complete chronic pain syndrome, comprehensive assessment most efficiently determines the most effective treatment approach, sparing partial approaches that do not address their multidisciplinary needs. For many patients, a precise diagnosis cannot be determined, and they fall into the vague category of soft tissue pain. Many of these patients are told there is nothing wrong and understandably seek out alternative therapy, which is often helpful or even curative. The arrogance of confusing inability to make a diagnosis with absence of pain discredits the medical profession and is best avoided, even in patients with prominent psychosocial factors contributing to the pain. Dismissing the patient’s concerns and problems benefits neither physician nor patient. The balance between legitimization and reassurance-that is, accepting the complaints as legitimate and real, conveying to the patient that the complaints are taken seriously, but also reassuring the patient of hope for improvement and lack of life-threatening or potentially crippling illness-is the crux of the art of managing the patient with pain. History and Physical Examination

The medical history begins with eliciting symptoms and signs of systemic illness, such as weight loss, fatigue, fevers, chills, and involvement of multiple joints; the history may suggest infection, malignancy, or an arthritic disorder. Involvement of the spinal cord or nerve roots is ascertained by inquiring about numbness, paresthesias, weakness of the arms and legs, and bowel, bladder, or sexual dysfunction. In acute post-traumatic pain, fracture or dislocation must be excluded, usually with radiographs. This approach rules out the diagnostic imperatives. Next, the distribution of the pain is ascertained and then the quality: somatic, neuralgic, or visceral. Learning about the provocative and palliative factors of the pain, such as which movements exacerbate the pain, gives insight into the tissue of origin. Many patients present in the setting of accidents, work-related injuries, or psychosocial disturbances. Information about ongoing legal action, disability hearings, employment issues, use of controlled substances, psychological symptoms, and a personal or family history of substance abuse or mental illness must be elicited. In the patients with nerve injury, the distribution of pain often does not correlate precisely with the sensory distribution of the injured nerve. The distribution of paresthesias and, better yet, of neurologic signs is more reliable. Once the localization of the nerve injury is ascertained, its cause can be more easily determined. The physical examination starts with the patient’s general habitus, posture, and appearance. The key to examining the patient is to reproduce the pain, thereby determining its tissue of

origin. Range of motion of the neck is checked and may be reviewed segmentally to determine the abnormalities of the spine. Palpation is performed for myofascial trigger points. The spinous processes and facet joints are palpated for tenderness. The thyroid, hyoid, and styloids may be palpated for reproduction of pain. The neurologic examination (Fig. 225- 1; Table 225-1) tests strength of the muscles of the shoulders and arms, reflexes, and sensation over the back of the head, neck, and arms. In suspected nerve entrapment syndromes, the entire course of the nerve must be palpated for masses or a Tine1 sign: elicitation of paresthesias in the distribution of the nerve when tapping the site of injury. The tone, strength, reflexes, and sensation of the legs may reveal signs of cord compression. The general physical examination may reveal important signs of systemic disease, related to the origin of the neck or arm pain. Diagnostic Studies

Diagnostic studies may be useful to confirm the clinical diagnosis or exclude serious disorders. In cases of acute post-traumatic neck pain, particularly with neurologic deficits, plain radiographs are useful to exclude fracture or dislocation. The neck cannot be cleared without visualization of the odontoid and the C7-T1 interspace. Plain radiographs are also useful in excluding malignancy or infection, although the sensitivity is not as great as with bone scanning, computed tomography, or magnetic resonance imaging. When suspicion of these disorders is high, one of the latter tests is generally necessary. Magnetic resonance imaging has become very useful in view of its high sensitivity to infection, neoplasm, and degenerative disease; its ability to visualize neural elements and demonstrate cord or root compression; and the ability to visualize the entire cervical spine in a single study. Its disadvantages are cost, lack of precise delineation of bony anatomy, and inability to perform dynamic studies. Electromyography and nerve conduction studies are useful in documenting the presence or absence of a nerve lesion and in delineating the anatomy of the lesion (e.g., distinguishing root from plexus lesion or localizing the site of a nerve entrapment). It cannot be overemphasized that objective findings, such as those obtained by imaging and electrodiagnostic studies, often bear no relationship to the patient’s symptoms. Imaging studies often disclose abnormalities that are common in the general population and of doubtful relevance in the individual patient. Electromyography and nerve conduction studies give no information about pain, and a nerve lesion can be painful with negative results. Documentation of a nerve lesion does not mean that it is the cause of the patient’s pain or that it is painful at all (most nerve lesions are not painful). The physician must keep the clinical syndrome foremost in mind, using studies to inform the clinical approach. The medicolegal system has encouraged the opposite approach, in which objective tests are given credence and the clinical impression is subject to debate.

Specific Disorders Neuralgias. Lancinating pain related to irritation of a nerve without evidence of damage to the nerve is called neuralgia, whereas pain in the presence of nerve damage is called neuropathy. The neuralgias are characterized by brief attacks of severe pain that last for seconds or less. Aside from possible trigger areas, physical examination is by definition negative. Strictly speaking, occipital neuralgia is pain in the occipital region produced by entrapment

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FIG. 225-1. Major neurologic findings in cervical radiculopathy. (Figs. 225-1 A-E from Hoppenfeld S: Physical Examination of the Spine and Extremities. Appleton-Century-Crofts, Norwalk, Cr, 1976; Fig. 225-lF from Bonica JJ (ed): The Management of Pain. 2nd Ed. JB Lippincott, Philadelphia, 1990, with permission.) Illustration continued on following page

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FIG. 225-1 Continued Major neurologic findings in cervical radiculopathy. (Figs. 225-1A-E from Hoppenfeld S: Physical Examination of the Spine and Extremities. Appleton-CenturyCrofts, Norwalk, Cr, 1976; Fig. 225-1 F from Bonica JJ (ed): The Management of Pain. 2nd

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Neck and Arm Pain

1421

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FIG. 225-1 Continued Major neurologic findings in cervical radiculopathy. (Figs. 225-1A-E from Hoppenfeld S: Physical Examination of the Spine and Extremities. Appleton-Century-Crofts, Norwalk, Cr, 1976; Fig. 225-1 F from Bonica JJ (ed): The Management of Pain. 2nd Ed. JB Lippincott, Philadelphia, 1990, with permission.)

TABLE 225-1. Examination of the Major Nerves of the Upper Extremity NeNe

Motor Test

Sensation Test

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Abduction of little finger Thumb pinch; thumb opposition Deltoid Biceps

Dorsal web space between thumb and index finger Distal ulnar aspect of little finger Distal radial aspect of index finger Lateral arm at deltoid insertion Lateral forearm

Median Axillary Musculocutaneous

of the occipital nerve. However, the term usually is used loosely to refer to any pain in the back of the head and carries its own differential diagnosis (Table 225-2). Many patients have undergone inappropriate section of the occipital nerve without adequate diagnostic approach. A history of neuralgic-type pain suggests true nerve entrapment, usually of the greater or lesser occipital nerves or of the C2 or C3 nerve roots. Pain that appears to arise from the neck or that is provoked by movement of the neck suggests cervical root pathology. A Tine1 sign should be sought over the suspected nerves. The sensory examination may reveal hypesthesia in the distribution of the affected nerve (Fig. 225-1F). Aching or other nonneuralgic pain, though possibly neuropathic in origin, often indicates myofascial or joint pain. Myofascial pain is associated with palpable trigger points. Neck extension or palpation of the joints provokes facet joint pain. These syndromes are discussed in more detail later in this chapter. Cervical Disc Disease. Precise estimates of the prevalence of pain caused by cervical disc disease vary because of the common occurrence of disc abnormalities in asymptomatic patients, contributing to overdiagnosis of disc disease, with medicolegal

implications. The normal disc consists of a small jelly-like central nucleus pulposus, surrounded by a fibrous capsule, the annulus fibrosus. Over the years, the nucleus dehydrates, resulting in loss of disc height, and tears form in the annulus. If subjected to excess pressure, the nucleus may herniate into the annulus, perhaps causing it to bulge or extrude completely through the annulus. Which of these pathological changes produces which symptoms, if any, is controversial. If the disc or annulus exerts pressure against nerve root or spinal cord, radiculopathy or myelopathy, respectively, results. Patients with disc disease present with acute or chronic neck pain, which may radiate into the periscapular region, occiput, thorax, or shoulder. Pain is worsened by maneuvers that increase pressure in the epidural space: coughing, sneezing, and Valsalva maneuver. The physical examination demonstrates decreased range of motion, particularly flexion, and muscle spasm. Pressing downward on the head or neck flexion may reproduce pain. Lateral neck flexion with pressure on the head reproduces neck or ipsilateral radicular pain (Spurling’s test). If radiculopathy is present, patients have pain and neurologic findings characteristic of the particular root. Pain may be decreased by manual distraction of the head. Cord compression manifests itself by

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DifferentialDiagnosis of Ocdp*MNeuralgia

Tumor, infection of the upper cervical spine Upper cervical facet syndrome Osteoarthritis Rheumatoid arthritis Idiopathic Myofascial pain C2 or C3 root entrapment True occipital nerve entrapment Lesser occiDital nerve entraoment

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weakness or sensory loss in the arms or legs, hyperreflexia and spasticity in the legs, Babinski and Hoffman signs, and bowel or bladder dysfunction. Patients with cervical cord compression may complain of aching in the thorax, low back, or legs. Computed tomography, magnetic resonance imaging, or myelography may confirm the diagnosis of cervical disc disease. These tests are confounded by a high false-positive rate and are appropriately used to confirm the clinical impression. The false-negative rate, that is, the percentage of patients with discogenic pain or radiculopathy with negative study results, is unknown, but false negatives certainly occur in practice. Electromyography or nerve conduction studies may be used to confirm the clinical impression of radiculopathy, but there are several limitations, as outlined earlier. These studies probably are not much more sensitive or specific than a thorough neurologic examination, have significant false positives and false negatives, and say nothing about pain. Discography involves dye injection into the disc and gives information on whether a disc is symptomatic by the radiographic appearance of its interior and by the reproduction of pain during the injection. Whether discography provides any useful information is controversial. The natural history of pain caused by disk herniation is favorable, with most patients improving over time, although complete resolution may take years and necessitates lifestyle modifications during the healing process. The goals of treatment are to hasten resolution of symptoms, minimize psychological or vocational impact, and prevent relapses and chronicity. Treatment consists of rest and immobilization, with a cervical collar in the acute or flare-up phases, physical therapy, home use of passive modalities (e.g., ice or heat and traction), and analgesics. For subacute or chronic symptoms, treatment focuses on maximizing activity, and reliance on the collar is kept to a minimum. Physical therapy may be used with the goal of patient education about relapse prevention and an independent exercise program. Care must be taken to avoid reliance on addicting medications; nonsteroidal anti-inflammatory analgesics and tricyclic antidepressants are appropriate. Muscle relaxants have not been shown to specifically relax muscles, and although they may be appropriate in the acute phase, their sedative properties and minimal efficacy make them undesirable for long-term use. For patients whose pain is not relieved by conservative therapy, cervical epidural steroid injections are a safe alternative, most effective for radicular pain. Contraindications include local infection or tumor, bleeding diathesis, and major psychiatric contribution to the pain syndrome. Early surgical discectomy is appropriate for patients with symptomatic cord compression or progressive neurologic deficits. Surgery for pain alone is fraught with difficulty: The best candidates are patients with demonstrable radiculopathy, minimal psychological issues, and duration of symptoms less than 6 months. Cervical Spondylosis. The joints of the cervical spine, like other joints, are vulnerable to osteoarthritic degeneration. Cervical osteoarthritis can be part of primary generalized osteoarthritis or can be a secondary, wear-and-tear arthritis related to traumatic, metabolic, or congenital factors. The pathophysiology of secondary degeneration is controversial, but degeneration of the disc is thought to play a primary role, with loss of disc height, followed by abnormal apposition of the facet joints, leading to progressive degeneration of the functional unit. The results are the same: loss of disc height, disc bulge or protrusions, arthritis and hypertrophy of the facet and uncovertebral joint, hypertrophy of the intraspinal ligaments, and inflammatory changes of the periarticular tissues.

Narrowing of the intervertebral foramina or spinal canal, with resultant radiculopathy or myelopathy, may result. Patients present with symptoms related to the joint disorder, radiculopathy if present, and myelopathy if present. In addition, osteophytic encroachment on the vertebral artery or the esophagus may produce symptoms related to these structures. Osteoarthritis can present as acute, severe ipsilateral pain in the neck, usually resolving in 7 to 10 days. Different joints have characteristic but overlapping referral patterns: the upper cervical spine to the occiput or frontal region, the midcervical spine to the shoulder, and the lower cervical spine to the interscapular region. Attacks may recur or may become longer, confluent, or constant, and stiffness and reduction of range of motion supervene. Physical examination reveals decreased range of motion, most notably extension, with fair preservation of flexion and rotation. In addition, the facet joints are tender. If nerve root compression or irritation occurs, patients complain of radiation of pain and paresthesias in characteristic distributions. Differences are that in osteoarthritis radiculopathy of the upper cervical nerve roots (C2-C4) may occur, neck extension rather than flexion brings on radicular symptoms, and the prognosis is less favorable. It is said that spondylitic radiculopathy is more likely to affect the sensory root, whereas discogenic radiculopathy is more likely to affect the motor root because of the posterior location of the motor root in the neural foramen. In patients with spondylitic myelopathy, Lhermitte sign, that is, an electric sensation radiating down the spine upon neck flexion, may be noted. Signs of cord compression may be elicited, which include Leg weakness Hyporeflexia (acute) or hyperreflexia (chronic) Sensory loss in the legs Sensory level Decreased sphincter tone Babinski sign These signs may accompany signs of radiculopathy in the arms. The combination of lower motor-neuron signs in the arms and upper motor neuron signs in the legs may suggest amyotrophic lateral sclerosis. Plain radiographs of the cervical spine are diagnostic of spondylosis, although the burden is on the physician to demonstrate the relevance of these findings in the individual patient. Radiologic findings include loss of disc height, sclerosis of bone and joints, osteophytes, irregular narrowing of joint spaces, and cyst formation. Oblique views demonstrate foraminal narrowing. Computed tomography shows details of bony anatomy best and, combined with myelography, is the definitive study for demonstrating bony impingement on neural structures. Many surgeons are becoming satisfied with magnetic resonance imaging for surgical purposes, although it does not demonstrate bony detail as well. The treatment of spondylitic pain consists of nonsteroidal anti-inflammatory analgesics, short-term opioids when needed, short-term use of the cervical collar, physical therapy, and exercise. Facet joint injections with a local anesthetic and corticosteroid are safe, easy to perform, and often helpful. For patients with chronic pain, radiofrequency denervation of the facet joints is safe in experienced hands; it provides 12 to 18 months of relief in 50% to 60% of patients. Cervical epidural steroid injections are helpful for radicular pain, although the long-term benefit is uncertain.

Chapter 225

For patients with myelopathy, treatment is similar except for greater reliance on the collar and less effort through exercise to improve range of motion. Surgical decompression is helpful for patients whose pain is clearly caused by compression of specific neural structures, nerve root, or spinal cord. Poor prognostic factors for patients with myelopathy include advanced age, sphincter involvement, leg weakness out of proportion to spasticity, long-standing severe neurologic deficits, muscle atrophy, and severe concurrent medical problems. Cervical Sprain. Probably the most common form of neck pain, sprain is acute injury without evidence of damage to neural or bony structures. The tissues affected are thought to include the ligaments, facet joint capsules, muscles, and tendons, which remain functional despite injury. The exact tissue traumatized in individual patients is difficult to ascertain. Symptoms include mild to moderate neck pain, headache, neck stiffness (which may develop days after the injury), dizziness, blurred vision, and gait imbalance. Physical examination reveals decreased range of motion, tenderness of the spinous processes, muscle spasm, and sometimes referred tenderness in the shoulder and arm. Neurologic findings are absent. Radiographs are most important for what they do not show: fracture, dislocation, or evidence of tumor or infection. Straightening of the cervical spine by muscle spasm is characteristic. Treatment consists of medication with nonsteroidal antiinflammatoryanalgesics, muscle relaxants, and short-term opioids if necessary. Rest, gentle progressive exercise, heat or ice, and judicious use of a soft collar are the mainstays of therapy. Local anesthesia injections into tender areas may be helpful. Early mobilization and attention to psychosocial and vocational issues are important to avoid long-term disability. Flexion-Extension (Whiplash) Injury. In our motor vehiclebased society, injuries to the cervical spine caused by acute hyperflexion followed by hyperextension, or vice versa, are common. When mild, the injury consists of stretching and microhemorrhage in the cervical muscles. When it is severe, the muscles suffer partial laceration, and stretching and tearing occur in the ligaments, annulus, and facet joint capsules. Severe extension may cause chip fractures of the vertebrae and impaction of the facets, with potential contusion of nerve roots or spinal cord. The temporomandibular joint may be injured as the head suddenly extends back from the jaw. Symptoms in mild cases are limited to neck pain, spasm, and reduced range of motion beginning 1 or 2 days after the injury. In severe cases, symptomsbegin right away. Headache, shoulder pain, and root or cord injury may be superimposed. Radiographs are used to exclude fracture or subluxation and reveal straightening of the cervical lordosis. The approach to the patient consists first of ensuring that bony injury necessitating surgical treatment has been ruled out with plain radiographs and, if necessary, special views or computed tomography. Injury to the brain, spinal cord, and nerve roots must then be addressed. From this point, treatment is conservative, as for cervical sprain, and with similar provisos to avoid chronicity. The term whiplash is best avoided because of the suggestive legal implications. In cases of chronic pain after flexion-extension injury, psychosocial and, when possible, legal issues must be dealt with. Tricyclic antidepressants replace muscle relaxants and analgesics. Recent evidence supports radiofrequency facet denervation for prolonged pain relief. Myofascial Pain. Myofascial pain is a regional disorder consisting of pain, muscle spasm, and decreased mobility related

Neck and Arm Pain

I423

to tender nodules or bands of muscle spasm, called trigger points. Patients complain of local and referred pain, subjective numbness, fatigability, and stiffness. Palpating the trigger points reproduces the symptoms. The syndrome may follow trauma to the muscle, such as a cervical sprain, chronic strain related to poor posture or overuse, or psychological stress. Reactive muscle spasm also occurs in response to primary local pathology, such as osteoarthritis. The muscles most commonly giving rise to neck pain are the trapezius, levator scapulae, multifidi, erector spinae, and suboccipital group. These syndromes commonly produce referred pain to the head, eye, or arm. Spasm of the scalenus or pectoralis minor muscles may constrict the brachial plexus, leading to a myogenic, thoracic outlet syndrome. The diagnosis depends on an accurate history and a thorough physical examination. Treatment consists of physical therapy and trigger point injections. Physical therapy focuses on stretching and strengthening of the involved muscles; strengtheningis critical but often overlooked. Patients are taught independent home programs. General conditioning, sleep, and proper dietary habits are encouraged. Trigger point injections are highly effective, and often only a few treatments are needed. Infectious, Inflammatoly, and Neoplastic Disorders. Infection is an uncommon cause of neck pain in clinical practice. A number of types of infections may occur, including osteomyelitis, epidural abscess, and discitis. Whereas infection is rare, diagnosis is imperative because of the devastating consequences of delayed treatment. Symptoms can be mild and nonspecific. Neck pain radiating to the occiput or shoulders, decreased range of motion, muscle spasm, and dysphagia occur. Findings on physical examination are nonspecific: They may disclose tenderness of the spinous processes, Spurling sign, and, perhaps, signs of radiculopathy or myelopathy. Diagnosis begins with plain radiographs, which may be negative, especially early in the disease. Bone scanning and magnetic resonance imaging are more sensitive and specific. An elevated white blood cell count, erythrocyte sedimentation rate, and anemia may occur, but their absence does not rule out infection. Biopsy may be needed for a definitive diagnosis. Treatment consists of nonspecific measures, including immobilization and analgesics, antibiotics, and, at times, surgical intervention. After osteoarthritis, the most common inflammatory disorders giving rise to neck pain are rheumatoid arthritis and ankylosing spondylitis. Rheumatoid arthritis is an inflammatory polyarthropathy that typically affects peripheral joints symmetrically. The cervical spine is commonly involved, particularly the upper portion. Symptoms include neck pain radiating to the occiput, temples, or retro-orbital regions. Upper cervical radiculopathy, with pain or numbness in the scalp, neck, or shoulder, may be present. Myelopathy or brainstem involvement may occur secondary to subluxation. Laboratory studies reveal anemia, elevated erythrocyte sedimentation rate, and positive rheumatoid factor in 80% of patients. Radiographs show osteopenia, periarticular soft tissue swelling, and joint space erosions. Treatment of rheumatoid arthritis of the cervical spine, beyond standard medical treatment, includes gentle physical therapy to maintain mobility, judicious use of cervical collars, and surgical intervention for neurologic involvement or instability. Ankylosing spondylitis is a polyarthropathy affecting mainly the joints of the axial skeleton, including the facet, costovertebral, and sacroiliac joints. Ossification of the longitudinal ligaments and disc spaces may occur. Symptoms typically begin in the second to third decade, with low back pain radiating to the buttocks or

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Headache and Pain rn Generalized and Regional Pain Syndromes

legs and morning stiffness. Decreased range of motion, especially flexion, occurs, with loss of the lumbar lordosis. Sacroiliac joint radiographs are a useful early study and show blurring of joint margins, then joint erosions, and finally joint fusion. Syndesmophytes and bone spurs are common. Ninety-five percent of patients have the HLA-B27 antigen. Treatment specific for cervical spine involvement includes physical therapy to maintain erect posture, sleeping prone or at least without a pillow when supine, and local corticosteroid injections. Tumors of the cervical spine are also an uncommon cause of neck pain. Most are metastatic, most commonly from carcinoma of the lung, breast, or prostate. Primary tumors may be benign (giant cell tumor, bone cyst) or malignant (chondrosarcoma, osteosarcoma, Ewing’s tumor). Symptoms often are nonspecific. Pain worse at rest or at night, torticollis, or constitutional symptoms arouse suspicion. Metastasis to the odontoid, complicated by fracture and subluxation, presents with severe neck pain, with or without myelopathy. Plain radiographs may need to be supplemented by computed tomography for diagnosis. Involvement of the C7 and T1 vertebral bodies by either direct spread or hematogenous metastases, with or without radiculopathy, is another well-known syndrome. Plain radiographs do not rule out tumor; computed tomography, magnetic resonance imaging, and bone scanning are more useful. Cervical Facet Syndrome. The term cervical facet syndrome refers to a acute, subacute, or chronic pain, with or without referral to the occiput, shoulder, arm, or periscapular region, accompanied by limitation of motion, particularly extension, and occasionally subjective neurologic symptoms in the arms but with a normal neurologic examination. Imaging studies correlate poorly with symptoms. Some patients have osteoarthritic changes of the facet joints, but most do not. The physical examination may show tenderness over the facet joints, decreased range of motion, and reproduction of pain by neck extension or ipsilateral flexion. The physical therapist may report hypomobility or locking of the facet joints at segmentally specific levels. The origin of the pain of this syndrome has been hypothesized to be the cervical facet joints; studies using local anesthetic blockades of the joints as a diagnostic tool have supported this claim. The syndrome is treated with physical therapy to restore mobility, analgesics, intra-articular corticosteroid injections, and radiofrequency denervation of the facet joints. Miscellaneous Disorders Disorders of the Thyroid Gland. Neoplastic or inflammatory disorders of the thyroid gland can produce anterior neck pain, often with radiation to the ear, jaw, or occiput. Thyroid malignancy may be accompanied by signs of systemic illness. Physical examination reveals enlargement, nodularity, and perhaps tenderness of the gland. Several types of thyroiditis can produce neck pain. Pyogenic thyroiditis is uncommon and usually results from hematogenous spread from a distant bacterial infection. Riedel’s thyroiditis consists of intense fibrosis of the thyroid gland, sometimes associated with retroperitoneal or mediastinal fibrosis. Subacute thyroiditis is a viral illness often occurring in the setting of an upper respiratory infection. Neck pain and tenderness, often severe, may be accompanied by hyperthyroidism. Diffuse Idiopathic Skeletal Hyperostosis. Diffuse idiopathic skeletal hyperostosis consists of idiopathic overproduction of bone, particularly of the spine, in men over age 50. Symptoms

include pain, stiffness, and tenderness to palpation. Cervical involvement often is accompanied by dysphagia. Plain radiographs are diagnostic and show dramatic osteophytosis and ossification of the anterior longitudinal ligament. Many cases are asymptomatic and are discovered during routine radiography. Treatment consists mainly of physical therapy and administration of nonsteroidal anti-inflammatory analgesics. Longus Colli Tendonitis. Tendonitis of the longus colli muscle can produce progressive anterior neck pain and dysphagia, worsened by head and neck movements. Physical examination is significant for palpation of the anterior cervical spine from C1 to C4 reproducing the pain. Styloid (Eagle) Syndrome. An elongated styloid process is said to be responsible for this syndrome, often following tonsillectomy. Pain in the anterior neck, radiating to the ear, and persistent sore throat are the dominant symptoms. Diagnosis is supported by radiographic evidence of an elongated styloid process. Treatment is with local measures, analgesics, and surgical excision of the styloid if necessary. Neuropathic A m Pain Spinal Cord Disorders. Disorders of the cervical spinal cord may mimic disorders that produce cervical radiculopathy or radiculomyelopathy, particularly advanced cervical spondylosis. Furthermore, the radiographic changes and even clinical signs of cervical spondylosis are so common in older adults that they often coexist with other disorders. Spinal cord tumors are rare and present with pain, sensory loss, reflex loss, and weakness in the arms. The presence of upper motor neuron signs in the legs, sphincter disturbance, involvement in the distribution of multiple cervical nerve roots, and dissociated sensory loss (loss of sensitivity to pinprick and temperature with preservation of sensitivity to position and vibration) suggest spinal cord involvement. Syringomyelia commonly affects the cervical cord and may occur in relation to spinal cord neoplasm or after trauma. Clinical findings are similar to those of tumor. Multiple sclerosis with spinal cord involvement may produce a pseudoradiculopathy affecting the arm. Magnetic resonance imaging of the cervical spine is the diagnostic study of choice for these disorders, and supplementation with other studies, such spinal fluid analysis or biopsy, may be needed. Cervical Radiculopathy. The major causes of cervical radiculopathy are cervical spondylosis and disc herniation. Other disorders discussed earlier, including the arthritides, trauma, tumor, and infection, may also produce cervical radiculopathy. Peripheral nerve tumors, including schwannomas and neurofibromas, present with a mass in the side of the neck and with the symptoms and signs of cervical radiculopathy. Herpes zoster may affect the cervical nerve roots, producing the characteristic vesicular rash, accompanied by severe pain, numbness, and weakness related to the affected roots. Treatment consists of antiviral therapy; topical applications to soothe, disinfect, and hasten healing of cutaneous lesions; and analgesics. Sympathetic blocks appear to decrease pain and decrease the occurrence of postherpetic neuralgia. The differential diagnosis of cervical radiculopathy begins with excluding nonneurologic disorders that produce referred pain in the neck and arm, such as tendinitis, bursitis, and arthritis of the shoulder, myocardial infarction, intrathoracic pathology, and cervical spine disorders. Central neurologic syndromes may cause confusion with cervical radiculopathy, such as thalamic infarction,

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Dorsal Scapular Nerve Suprascapular Nerve Lateral Pectoral New

Long Thoracic Nerve (nerve to Serratus Anterior)

Axillary Nerve RADIAL NERVE

Medial Pectoral Nerve Thoracodorsal Nerve

Musculocutaneous Nerve MEDIAN NERVE ULNARNERVE

\ p;/ I

.,g

Medial Cutaneous Nerve of Arm and Forearm

J

:I

FIG. 225-2. The brachial plexus. (From Stewart JD: Focal Peripheral Neuropathies. Elsevier, New York, 1987, with permission.)

which may present with surprisingly limited pain and numbness in the arm. Numbness in the ipsilateral face, trunk, or leg suggests a central disorder. Cervical Plexopathy and Accessory Nerve Damage. The ventral rami of C1 to C4 anastomose to form the cervical plexus proper, which innervates the skin of the posterolateral scalp, neck, and epaulet region. The dorsal rami innervate the midline skin over the neck and, as the occipital nerve, the posteromedial scalp. Muscular branches innervate the sternocleidomastoid, trapezius, and levator scapulae muscles, paraspinal muscles, and diaphragm. Damage to the superficial cervical plexus is rare and rarely symptomatic. Damage to the occipital nerve is discussed earlier in this chapter. Damage to the greater auricular nerve occurs after surgical procedures, mainly facelift and carotid endarterectomy, from trauma and leprosy. Symptoms are sensory loss in the distribution of the nerve and neuropathic pain. The accessory nerve arises from the cervical spinal cord, ascends within the spine through the foramen magnum into the skull, and exits the skull through the jugular foramen. It then descends deep to the sternocleidomastoid muscle, penetrates it to cross the posterior triangle of the neck, and ends in the trapezius muscle. Damage to the nerve can be caused by intracranial lesions, surgical procedures of the neck, or trauma, or it can be idiopathic. Symptoms include shoulder pain, paresthesias of the shoulder or arm, and weakness of shoulder elevation with winging of the scapula. Treatment may entail surgical repair of the nerve or functional orthopedic procedures. Brachial Plexopathy. The brachial plexus (Fig. 225-2) arises from the C P T l nerve roots after they exit the cervical spine. The nerve roots exit the spine into the paravertebral space by passing between the anterior and middle scalene muscles and then combine to form the trunks of the plexus. The plexus passes between the clavicle and first rib and under the attachment of the pectoralis minor muscle to the coracoid process, to finally lie free in the axilla.

Several branches important in pain evaluation arise from the plexus: the long thoracic, suprascapular, axillary, and medial cutaneous nerves of the arm and forearm. In the axilla, the plexus gives rise to its major terminal branches, the median, ulnar, and radial nerves. The brachial plexus can be damaged in a number of ways (Table 225-3). Traumatic brachial plexopathy occurs after motorcycle accidents, traction injuries, and penetrating wounds. Traumatic plexopathies often are combined with avulsion of roots from the spinal cord and injuries to individual nerve roots. Fracture or dislocation of the shoulder may cause acute injury to the brachial plexus; callus formation at the site of a clavicular fracture may cause chronic compression of the plexus. These lesions often are very painful. Management of the pain is similar to the management of neuropathic pain in general. Conservativemeasures often fail, but patients may derive tremendous benefit from spinal cord stimulation, spinal opioids, or neurosurgical procedures for pain control, particularly the dorsal root entry zone lesion.

TABLE 225-3. Differential Diagnosis of Brachial Plexopathy Trauma Shoulder fracture or dislocation Obstetric Stingers and burners Postoperative Acute brachial plexus neuropathy Hereditary Malignancy Radiation Thoracic outlet syndrome Neurologic Vascular Cervical rib Scalenus anticus Pectoralis minor Costoclavicular

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Intraoperative injuries to the brachial plexus are common. Most are minimally symptomatic and resolve in the early postoperative period, although some can be associated with terrible neurologic deficits and devastating pain. The syndrome can be confused with postoperative ulnar neuropathy. The most common associated procedures are median sternotomy and thoracotomy. Management is as for traumatic plexopathy. Acute brachial plexopathy, or Parsonage-Turner syndrome, presents with acute pain in the shoulder radiating down the arm or into the neck, followed by weakness and numbness of the arm, which may resolve after a few weeks or not for several years. The distribution of neurologic findings is variable. Worsening of pain by shoulder movements may lead to confusion with joint problems. A number of antecedent events have been described, including immunization, infection, trauma, and association with autoimmune illnesses. Acute brachial plexus neuropathy may also occur in hereditary forms, in association with involvement of other nerves. Treatment options include systemic or locally injected corticosteroids, physical therapy to prevent a frozen shoulder, and general treatment for neuropathic pain. Malignant infiltration of the plexus presents with pain, followed by neurologic deficits, including Horner’s syndrome. Most cases occur in patients with known metastatic disease, most commonly carcinoma of the breast; however, plexopathy can be the initial presentation of Pancoast’s tumor of the lung. Distinction from radiation plexopathy can be very difficult. The latter can begin months to years after radiotherapy and presents similarly. Several distinguishing features have been proposed Involvement of the lower trunk usually suggests tumor, whereas upper trunk involvement suggests radiation; tumor involvement presents with pain out of proportion to neurologic deficits, whereas radiation plexopathy presents with deficit greater than pain; and the electromyographic finding of myokymia suggests radiation plexopathy. Treatment for tumor plexopathy includes treatment of the primary tumor; radiation and corticosteroids are particularly useful for pain palliation. There is no specific treatment for radiation plexopathy, although revascularization procedures are gaining popularity. Aggressive pain control strategies, including neurolytic nerve blocks and neurosurgical procedures, often are necessary. Thoracic Outlet Syndrome. A variably accepted syndrome, thoracic outlet syndrome is compression of the brachial plexus or associated vasculature by a variety of structures, resulting in neck and arm symptoms. Patients present with pain in the neck, supraclavicular region, shoulder, or chest, radiating down the arm and often into the hand. Subjective paresthesias and weakness are common, but neurologic examination and neurophysiologic tests are negative. The physical examination may reveal tenderness, spasm, or reproduction of radiating pain by palpation of the scalene muscles or pectoralis minor. Various maneuvers have been suggested to be helpful in diagnosing thoracic outlet syndrome, but none have been demonstrated to be accurate. Psychological or work-related issues commonly appear. Imaging studies may reveal an elongated transverse process of C7 (“cervical rib”), but this is also seen in asymptomatic patients. Treatment focuses on improving strength, flexibility, and posture related to the neck and upper extremities and is best carried out by a physical therapist experienced with the syndrome. Attention should be paid to mental health and work-related issues. Diagnoses that are uncertain should be used sparingly in view of the legal implications. Surgery probably is overdone and should be left as a last resort in psychologically stable patients with a well-defined syndrome.

Surgical options include resection of a cervical rib and first rib resection. Injuries to individual branches of the brachial plexus may give rise to pain and neurologic dysfunction. Injury to the long thoracic nerve may result from trauma, surgery, general anesthesia, or an acute brachial plexus neuropathy. Patients present with difficulty using the shoulder and aching of the shoulder and chest wall; physical examination shows winging of the scapula and weakness of the serratus anterior muscle. The suprascapular nerve may be injured by trauma, especially scapular fracture, by ligamentous or bony compression in the suprascapular notch, or as part of an acute brachial plexus neuropathy. Patients present with shoulder pain and weakness of shoulder abduction. The main differential diagnosis is rotator cuff injury. The diagnosis can be confirmed by electrodiagnostic studies. Treatment consists of local injections; surgical decompression may be necessary. The axillary nerve can be damaged by trauma, usually shoulder dislocation or humerus fracture, compression, or injections. Deltoid weakness is the most prominent symptom, and sensory loss may be detectable over the area of the deltoid insertion. Pain is not a prominent feature. The musculocutaneous nerve may also be damaged by a variety of causes. Weakness of the biceps and sensory loss over the lateral forearm are the prominent features, with pain being less significant. Ulnar Neuropathy. The ulnar nerve (Fig. 225-3) derives, via the lower trunk and medial cord of the brachial plexus, from the C8 and T1 roots and passes down the medial aspect of the upper arm. It then passes through the ulnar groove of the elbow, under the aponeurosis of the flexor carpi ulnaris muscle to lie in the so-called cubital tunnel. At the wrist, the nerve passes through Guyon’s canal, finally splitting into superficial and deep terminal branches. The nerve may be injured at any of these sites. Deep sleep and coma, with prolonged pressure on the nerve, or misplaced crutches most commonly injure the nerve in the axilla. At the elbow, the most common site of damage, injury may result from old fractures or other bony deformities, trauma, scar tissue, tumors and masses, external pressure such as during anesthesia, supracondylar spurs, prolapse of the nerve, and leprosy. The nerve may also be damaged in the cubital tunnel by the aponeurosis of the flexor carpi ulnaris muscle, particularly after repetitive or prolonged flexion. Damage to the nerve at the wrist is uncommon and may occur in several locations, related to lacerations, fractures, ganglia, disorders of the ulnar artery, bony disorders, and abnormal muscle or connective tissue bands. The approach to the patient begins with careful elicitation of a medical history and a thorough physical examination. Neurophysiologic studies usually are necessary, and imaging studies of the potential sites of entrapments may reveal local injury. The exact site of injury can be quite difficult to determine, despite sophisticated neurophysiologic testing. Even with surgical exploration, findings indicative of nerve pathology are difficult to distinguish from findings in asymptomatic patients. The pain of ulnar neuropathy often is in the distribution of the sensory branches of the nerve and may concentrate around the elbow. However, the pain may also be distributed through the arm and provide no localizing value. Other clinical features include sensory loss, weakness, and muscle wasting, depending on the site of injury. Treatment depends on accurate diagnosis and treatment of the underlying disorder. For patients with focal nerve injury, local injections at the site of injury may relieve symptoms. In patients with neuropathy at the elbow, avoiding leaning on the

Chapter 225

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n -Brachial

\

FIG. 225-3. The course of the ulnar nerve. (From Stewart JD: Focal Peripheral Neuropathies. Elsevier, New York, 1987, with permission.)

Medial Cord Plexus

to Flexor Carpi Ulnaris

I

to Flexor Digitorum Profundus (digits 4, 5)

Palmar Cutaneous Branch Superficial Terminal Branch

-

Dorsal Ulnar Cutaneous Branch

Deep Motor Branch

nerve and use of elbow padding to prevent flexion may be very helpful. Surgical exploration with decompression or transposition of the nerve may afford relief. Median Neuropathy. The median nerve (Fig. 225-4) derives from contributions from the C5 through T1 cervical nerve roots, via union of parts of the lateral and medial cords of the brachial plexus. The nerve courses through the medial arm to cross the antecubital fossa in proximity to the brachial artery and biceps tendon. The nerve then passes beneath the bicipital aponeurosis and between the heads of the pronator teres muscle, after which it gives rise to the anterior interosseus nerve. The median nerve then passes under a tendinous structure, called the sublimis bridge, and courses down the forearm to enter the carpal tunnel. Beyond the carpal tunnel, the nerve divides into a number of branches that innervate the intrinsic hand muscles. The median nerve may be damaged in several locations. Compression in the axilla is unusual and may be caused by crutches, sharp trauma, sleep palsies, aneurysms from dialysis shunts, and axillary arteriography. Damage at the elbow is more common and may be caused by supracondylarspurs or anomalous ligaments, fractures or dislocations, injections, or compression by the bicipital aponeurosis or by bands within the pronator teres muscle. By far the most common cause of compression of the median nerve is carpal tunnel syndrome. Most cases are idiopathic and relate to excessive hand activity, as in manual laborers. Specific causes relate to anatomic compression in the carpal tunnel

caused by tendosynovitis, osteophytes, ganglia, or other lesions, increased susceptibility of nerves to compression, such as with diabetes, and miscellaneous conditions including pregnancy and hypothyroidism. Clinical features of median neuropathy include neuropathic pain, usually in the region of the compression and in the distribution of the nerve, but pain and paresthesias may be widespread. In addition to pain, weakness and sensory loss in the distribution of the nerve may be discernible. Diagnosis and treatment parallel those of the other focal peripheral neuropathies. The history and physical examination focus on identifying compressive lesions and predisposing factors. Electrodiagnostic studies and imaging of the putative region of compression may be diagnostic. Splinting to avoid nerve irritation, local injections, and, as a last resort, surgical decompression are effective. Radial Neuropathy. The radial nerve (Fig. 225-5) consists of contributions from the C5 through T1 cervical nerve roots and is the continuation of the posterior cord of the brachial plexus. The nerve winds around the humerus in the spiral groove, descends into the forearm between the biceps and brachioradialis muscles, and divides at the elbow into a motor (posterior interosseus) and sensory (superficial radial) branch. The radial nerve may be injured in the upper arm by external compression, fractures, blunt trauma, injections, and tourniquets. Posterior interosseus neuropathies may be painful and present similarly to tennis elbow, often accompanied by weakness of the wrist and finger extensors. Causes

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Pronator teres muscle uperficial and deep heads) Anterior interosseous nerve

Flexor digitorum superficialis FIG. 225-4. The median nerve. (From Stewart JD: Focal Peripheral Neuropathies. Elsevier, New York, 1987, with permission.)

FIG. 225-5. The radial nerve. (From Stewart JD: Focal Peripheral Neuropathies. Elsevier, New York, 1987, with permission.)

Axillary Nerve Posterior Cutaneous Nerve of Forearm to Triceps lntermuscular Septum to Extensor Carpi

Radialis Longus to Extensor Carpi Radialis Brevis' Posterior lnterosseous Nerve

Extensor Digiti Quinti to Extensor Carpi Ulnaris Extensor Pollicus Longus/Brevis Abductor Pollicis Longus Supinator Muscle Frohse

Chapter 225

include the types of trauma and injuries described for the other neuropathies, as well as compression by abnormal fibrous bands around the elbow. Injections, tight handcuffs or wristbands, and trauma may injure the superficial radial nerve. Patients present with a distinct syndrome of neuropathic pain in the distribution of the nerve. Reflex Sympathetic Dystrophy. This is a poorly understood disorder, consisting of the following triad spontaneous burning pain, allodynia (extreme pain during stimulation with a normally nonpainful stimulus), and autonomic or trophic changes in the limb (e.g., atrophy, pitting nails, hair loss, or changes in color, temperature, or sweating). Symptoms usually follow minor trauma, involve the distal aspect of the limb without respecting peripheral nerve boundaries, and occur in the absence of injury to a nerve. Similar symptoms following nerve injury are called causalgia. Many patients improve after blockade of the sympathetic nervous system. The syndrome is recognized to be nonspecific, and the pathophysiology is not understood. The basis of treatment consists of sympathetic blocks and active physical therapy. REGIONAL MUSCULOSKELETAL SYNDROMES A number of syndromes of musculoskeletal dysfunction may cause pain in the arm and shoulder. The pain of these syndromes typically is regional, concentrated in the area of the disorder, although referred pain may be prominent and may even overshadow the origin of the pain. The pain typically is described as sharp, aching, and constant, increased by physical activity of the affected parts. Although patients may complain of heaviness, weakness, or numbness of the limb, neurologic findings are absent. General principles apply to the diagnosis and treatment of these syndromes. Patients with acute injury must be evaluated for intactness of neurologic and vascular function. Even when symptoms arise acutely, underlying disease must be kept in mind, such as infection or neoplasm. Most acute injuries can be treated with ice, compression, immobilization, and analgesics titrated to effect, with appropriate follow-up as the most important next step. Follow-up care typically involves gradual remobilization, exercises to restore strength, flexibility, and function, tapering off analgesics as appropriate, and ensuring that psychosocial complications do not ensue, with particular emphasis on the injured worker. In the patient with chronic symptoms, accurate diagnosis is the first step in rational care. The first question is whether a specific syndrome can be diagnosed, and if so, specific treatment can be instituted. If not, general measures are indicated. Physical therapy with the goal of restoring function may be pivotal. Injections of a local anesthetic and corticosteroid into an area of localized pain and tenderness may be surprisingly effective, even in the absence of a definitive diagnosis. Nonspecific measures for treating chronic pain, analgesics, antidepressants, and psychological techniques may be the only indicated approaches and may make a tremendous difference in pain, function, and quality of life. The following discussion focuses on the most common regional musculoskeletal pain syndromes. Though not strictly neurologic, they often present in the context of the neurological evaluation of the patient with upper extremity pain.

Shoulder and Upper Ann Rotator Cuff Tendinitis and Subacromial Bursitis. The pain may be diffuse or located in the lateral aspect of the shoulder. Arm

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abduction is painful, and other movements may be as well. Flexion and elevation of the shoulder may be painful, the so-called impingement sign. Tenderness may be present in the subacromial region. If inflammation extends from the rotator cuff to the adjacent subacromial bursa, bursitis may result. The finding of true weakness on examination suggests rotator cuff tear; true limitation of range of motion suggests the development of adhesive capsulitis or a frozen shoulder. Acute symptoms are treated by the general measures described earlier. Subacute or chronic symptoms are treated with ice or heat, active exercises to restore mobility and prevent frozen shoulder, and local corticosteroid injections. Lack of response to conservative therapy or suggestion of a tear necessitates orthopedic referral. Biceps Tendinitis. Shoulder pain with tenderness over the biceps tendon suggests this diagnosis. The biceps tendon is palpated by externally rotating the shoulder and palpating anteriorly. Resisted forearm flexion or supination also is painful. Treatment is analogous to that for rotator cuff tendinitis. Acromioclavicular Joint Arthritis. Pain is diffuse, exacerbated by arm elevation, with associated tenderness of the acromioclavicular joint. Treatment is as described for rotator cuff tendinitis. Adhesive Capsulitis (Frozen Shoulder). This is a common end stage for any painful shoulder disorder and for neurologic conditions that diminish active shoulder movement. Patients present with progressive, diffuse shoulder pain and decreased active and passive range of motion. Physical examination reveals diffuse tenderness and painful limitation of range of motion; signs of the inciting injury may be evident. Treatment depends on mobility restoration with exercise; therefore, adequate analgesia with medications or injections is imperative. Osteoarthritis of the Glenohumeral Joint Patients present with chronic pain increased by activity in the setting of advanced age or trauma. Radiographs are confirmatory. Treatment consists of exercise, analgesia, injections, and, as a last resort, surgery for shoulder replacement. Elbow and Foreann Lateral Epicondylitis. Patients present with diffuse elbow pain concentrated around the lateral epicondyle, increased with resisted wrist or finger extension. Predisposing factors include repetitive wrist extension, hence the term tennis elbow. Treatment of persistent cases includes wrist splint or tennis elbow band, exercises, injections, and, as a last resort, one of several surgical options. Medial Epicondylitis. Otherwise known as golfer’s elbow, this condition occurs as a consequence of repetitive wrist flexion and pronation. Treatment is analogous to that of lateral epicondylitis. Arthritis of the Elbow. As in shoulder arthritis, patients present with diffuse pain increased by activity, generally in older patients or after trauma. Treatment is analogous to that of shoulder arthritis. Olecranon Bursitis. The olecranon bursa sits between the olecranon process and the triceps tendon and may become inflamed because of repetitive motion or leaning on the elbow. Differential diagnoses include joint infection and gout, or other arthritides, and tapping the joint may be necessary for diagnosis. In addition to the general measures described earlier, treatment includes aspiration of the bursa and instillation of corticosteroid. Surgical removal of the bursa is a last resort.

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De Quervain's Tendosynovitis. This fairly common syndrome consists of pain and tenderness over the radial aspect of the wrist. Physical examination shows a positive Finkelstein test, that is, increased pain on ulnar flexion of the wrist with the patient holding the thumb in the closed fist. Predisposing factors include repetitive wrist movements, including knitting or using a wrench. In addition to the general measures, treatment includes temporary casting, corticosteroid injection, and surgery. Wrist Tendonitis. Tendonitis can occur at any of the wrist tendons and presents with pain and tenderness that may be localized or diffuse, particularly in the setting of excessive use of the wrist, as in typists. As a component of the so-called repetitive strain or overuse syndrome, psychosocial or work-related issues are common. Signs of infection suggest infectious tendosynovitis, necessitating immediate orthopedic referral. Treatment is as for the other tendinitis syndromes. Arthritis of the First Carpornetacarpal Joint. This condition occurs in patients with chronic use of the joint, such as mail carriers. Diagnostic features include tenderness of the joint and positive radiologic findings. Treatment options include splinting and joint injection. Ganglia. Cystic masses overlying the wrist may arise from outpouchings of the synovium of the wrist joint or adjacent tendon sheaths. They may or may not be painful. If the mass is pulsatile or noncystic, further evaluation is necessary. Treatment options include splinting, aspiration, and surgical removal.

Miscellaneous Disorders Polymyalgia Rheumatica. This syndrome consists of severe aching pain and stiffness in the proximal arms and legs, occurring in older patients. Elevation of the erythrocyte sedimentation rate is characteristic. Constitutional symptoms may occur. Some cases are associated with temporal arteritis. Signs of muscle inflammation are absent. Response to corticosteroids is dramatic, with nearly complete elimination of symptoms with low dosages. Vascular Disease. A number of vascular diseases can present with upper extremity pain. The syndromes of acute and chronic arterial ischemia related to thrombotic or embolic disease are well

known. Patients present with pain, pallor, paresthesias, and, in the end, paralysis. Symptoms may be mild from small peripheral emboli or devastating from acute large vessel occlusion. Upper extremity compartment syndrome may result and cause further pain and neurologic injury. Thromboangiitis obliterans presents in young smokers, predominantly in the legs but often with pain or claudication in the arms as well. The vasospastic disorders include Raynaud's disease, acrocyanosis, and livedo reticularis. Raynaud's disease consists of idiopathic spasm of the microcirculation, resulting in blanching of the fingers, followed by cyanosis, then hyperemia, often in response to cold. Attacks may be severe enough to be disabling. Raynaud phenomenon is the syndrome in the setting of an underlying disease (e.g., rheumatoid arthritis). Therapy consists of systemic vasodilators and, in severe cases, sympathectomy. Acrocyanosis is a syndrome of unknown origin, consisting of constant coldness, cyanosis, and sometimes edema and hyperhidrosis. Trophic changes and gangrene, unlike in Raynaud's phenomenon, do not occur. Treatment is the same as for Raynaud's disease. Livedo reticularis is a bluish mottling of the skin of the extremities that may occur in the setting of underlying disease. The disorder is painful in some patients and may result in recurrent ulcerations. Treatment is again as for Raynaud's disease. The most important of the vasodilating disorders is erythromelalgia, a condition of hot, red, and painful extremities. Although usually idiopathic, it may occur in the setting of myeloproliferative and other disorders. The pathophysiology is uncertain but may relate to abnormal sensitization of receptors for warm and cold. Treatment consists of avoiding heat, application of cold, treatment of any underlying disorder, and administration of aspirin. SUGGESTED READINGS Birnbaum JS: The Musculoskeletal Manual. 2nd Ed. WB Saunders, Philadelphia, 1990 Bland JH: Disorders of the Cervical Spine: Diagnosis and Medical Management. WB Saunders, Philadelphia, 1987 Calliet R Neck and Arm Pain. FA Davis, Philadelphia, 1992 Staal A, Van Gijn J, Spaans F: Mononeuropathies. Examination, Diagnosis and Treatment. London: WB Saunders, 1999 Stewart JD: Focal Peripheral Neuropathies. Elsevier, New York, 1987

226 Low Back Pain Steven Feske

Fifty to 80% of adults have low back pain during their lifetimes. Although most of this represents benign, self-limiting pain, a significant percentage seek medical attention. Back pain is the single most common cause of lost workdays in the United States; about 2% of workers submit compensation claims for back pain annually. This chapter discusses the evaluation and treatment of acute and chronic low back pain.

ETIOLOGY A multitude of conditions can cause low back pain. The majority of patients who present with acute low back pain have minor musculoskeletal disorders, and the majority with chronic low back pain have degenerative disorders. Nevertheless, it is a major part of the initial task of assessment to properly diagnose those who do

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De Quervain's Tendosynovitis. This fairly common syndrome consists of pain and tenderness over the radial aspect of the wrist. Physical examination shows a positive Finkelstein test, that is, increased pain on ulnar flexion of the wrist with the patient holding the thumb in the closed fist. Predisposing factors include repetitive wrist movements, including knitting or using a wrench. In addition to the general measures, treatment includes temporary casting, corticosteroid injection, and surgery. Wrist Tendonitis. Tendonitis can occur at any of the wrist tendons and presents with pain and tenderness that may be localized or diffuse, particularly in the setting of excessive use of the wrist, as in typists. As a component of the so-called repetitive strain or overuse syndrome, psychosocial or work-related issues are common. Signs of infection suggest infectious tendosynovitis, necessitating immediate orthopedic referral. Treatment is as for the other tendinitis syndromes. Arthritis of the First Carpornetacarpal Joint. This condition occurs in patients with chronic use of the joint, such as mail carriers. Diagnostic features include tenderness of the joint and positive radiologic findings. Treatment options include splinting and joint injection. Ganglia. Cystic masses overlying the wrist may arise from outpouchings of the synovium of the wrist joint or adjacent tendon sheaths. They may or may not be painful. If the mass is pulsatile or noncystic, further evaluation is necessary. Treatment options include splinting, aspiration, and surgical removal.

Miscellaneous Disorders Polymyalgia Rheumatica. This syndrome consists of severe aching pain and stiffness in the proximal arms and legs, occurring in older patients. Elevation of the erythrocyte sedimentation rate is characteristic. Constitutional symptoms may occur. Some cases are associated with temporal arteritis. Signs of muscle inflammation are absent. Response to corticosteroids is dramatic, with nearly complete elimination of symptoms with low dosages. Vascular Disease. A number of vascular diseases can present with upper extremity pain. The syndromes of acute and chronic arterial ischemia related to thrombotic or embolic disease are well

known. Patients present with pain, pallor, paresthesias, and, in the end, paralysis. Symptoms may be mild from small peripheral emboli or devastating from acute large vessel occlusion. Upper extremity compartment syndrome may result and cause further pain and neurologic injury. Thromboangiitis obliterans presents in young smokers, predominantly in the legs but often with pain or claudication in the arms as well. The vasospastic disorders include Raynaud's disease, acrocyanosis, and livedo reticularis. Raynaud's disease consists of idiopathic spasm of the microcirculation, resulting in blanching of the fingers, followed by cyanosis, then hyperemia, often in response to cold. Attacks may be severe enough to be disabling. Raynaud phenomenon is the syndrome in the setting of an underlying disease (e.g., rheumatoid arthritis). Therapy consists of systemic vasodilators and, in severe cases, sympathectomy. Acrocyanosis is a syndrome of unknown origin, consisting of constant coldness, cyanosis, and sometimes edema and hyperhidrosis. Trophic changes and gangrene, unlike in Raynaud's phenomenon, do not occur. Treatment is the same as for Raynaud's disease. Livedo reticularis is a bluish mottling of the skin of the extremities that may occur in the setting of underlying disease. The disorder is painful in some patients and may result in recurrent ulcerations. Treatment is again as for Raynaud's disease. The most important of the vasodilating disorders is erythromelalgia, a condition of hot, red, and painful extremities. Although usually idiopathic, it may occur in the setting of myeloproliferative and other disorders. The pathophysiology is uncertain but may relate to abnormal sensitization of receptors for warm and cold. Treatment consists of avoiding heat, application of cold, treatment of any underlying disorder, and administration of aspirin. SUGGESTED READINGS Birnbaum JS: The Musculoskeletal Manual. 2nd Ed. WB Saunders, Philadelphia, 1990 Bland JH: Disorders of the Cervical Spine: Diagnosis and Medical Management. WB Saunders, Philadelphia, 1987 Calliet R Neck and Arm Pain. FA Davis, Philadelphia, 1992 Staal A, Van Gijn J, Spaans F: Mononeuropathies. Examination, Diagnosis and Treatment. London: WB Saunders, 1999 Stewart JD: Focal Peripheral Neuropathies. Elsevier, New York, 1987

226 Low Back Pain Steven Feske

Fifty to 80% of adults have low back pain during their lifetimes. Although most of this represents benign, self-limiting pain, a significant percentage seek medical attention. Back pain is the single most common cause of lost workdays in the United States; about 2% of workers submit compensation claims for back pain annually. This chapter discusses the evaluation and treatment of acute and chronic low back pain.

ETIOLOGY A multitude of conditions can cause low back pain. The majority of patients who present with acute low back pain have minor musculoskeletal disorders, and the majority with chronic low back pain have degenerative disorders. Nevertheless, it is a major part of the initial task of assessment to properly diagnose those who do

Chapter 226

have other diseases and, to do so efficiently, it is helpful to have access to a broad list of differential diagnoses (Table 226-1). It is also helpful to have access to a detailed description of the differential diagnosis of the various musculoskeletal disorders because their proper management depends on accurate diagnosis.

Common Skeletal and Muscular Causes Lumbosacral Strain and Sprain. This is the most common diagnosis made in cases of acute low back pain and implies stress to the musculoskeletal tissues without a precise anatomic localization or pathologic definition. The medical history usually is that of acute onset of low back pain after a minor injury, such as lifting or twisting. Sometimes, the onset is spontaneous, or the pain is present upon waking in the morning. The pain usually is in the lumbosacral area at the midline or slightly to one side. It often radiates into the buttocks and the posterolateral thighs, occasionally below the knee. Movement typically exacerbates the pain and rest partially relieves it, although significant resting pain often is present. Physical examination shows a decreased range of motion and marked sensitivity to movement in many cases. There is often mild to moderate tenderness in the lower back, along the spine, and in the paraspinal muscle mass. Palpable muscle spasm may be present but is difficult to distinguish from voluntary contraction or guarding. Pain in the back and tightness in the hamstrings may limit straight leg raising, but it does not cause shocklike radiation in a dermatomal distribution. If there are no features to suggest more serious disease, there is no serious trauma to the area, and the patient is less than 50 years old, no further testing is necessary in most cases. The mainstays of treatment have been rest, nonopioid analgesics, physical therapy, including exercises, and patient education to reduce the risk of future injury. Weisel and colleagues (1980) compared bed rest and ambulatory controls in military recruits and found that bed rest speeded recovery. Deyo and colleagues (1986) found 2 days of bed rest no different from 7 days of recovery but found that the 2-day regimen led to briefer periods of missed work. Malmivaara and colleagues (1995) compared 2 days of bed rest and light exercises with a control group undertaking normal activity limited by symptoms only. The control group recovered most quickly with the least pain; the patients restricted to bed rest fared the worst. If we equate ambulatory status in the military with a significant level of exercise, these data suggest that bed rest is not helpful and that ordinary light levels of activity promote the most rapid recovery from acute, nonspecific low back pain. If rest is recommended, it should be brief to avoid deconditioning and reinforcement of the sick role. Various physical therapy modalities have traditionally been recommended for acute low back pain: heat or cold application, exercises, traction, ultrasound, and diathermy. Data on the benefits of exercise are conflicting. Malmivaara and colleagues (1995) found ordinary activity better than extension and lateral bending exercises. Prior studies had also failed to show a benefit of exercise over usual care with information and analgesics. Other studies have found a benefit of back extension exercises compared with education only. Flexibility training and strengthening and conditioning exercises still have their advocates and probably do provide benefit to some patients, especially those with inactive lifestyles. Contrary to the conflicting data on acute low back pain, when pain of this type becomes chronic, there is much evidence in favor of exercise. The application of heat and cold may provide some symptom relief and is safe if done properly. There is little

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TABLE 226-1. Major Causes of Back Pain

Musculoskeletaldisorders Trauma Fracture Contusion Hematoma Degenerative disease Disc herniation Ligamentous Radicular Myelopathic Conus or cauda equina syndrome Postoperative "Failed back" Litigious or compensation-seeking Arthritis Facet arthritis Osteophyte impingement of neural foramina or central canal (spinal stenosis) with radicular syndrome Spondylolisthesis Spondylolysis Ankylosing spondylitis Ligamentous strain Muscle strain and spasm Congenital disorders Scoliosis and spinal anomalies Tethered cord Meningocele Spina bifida Lipoma, teratoma, and other congenitaltumors Infectious diseases Abscess Discitis Osteomyelitis Epidural abscess Meningitis Urologic infection Herpes zoster reactivation Parainfectious disorders and autoimmune disorders Transverse myelitis Cuillain-Barre syndrome Multiple sclerosis (Lhermitte sign) Inflammatory arthritides Ankylosing spondylitis Reiter's syndrome and other spondyloarthropathies Neoplasm Multiple myeloma Metastatic cancer Lung Breast Prostate Melanoma Renal cell carcinoma Others Lymphoma Primary tumors affecting the spinal cord or roots Astrocytoma Ependymoma Schwannoma Meningioma Others Tumors in the retroperitoneum Pancreatic carcinoma Retroperitoneal sarcoma Renal cell carcinoma Others Tumors infiltrating the pelvis and lumbosaual plexus Vascular disorders Epidural hematoma Spinal dural arteriovenous fistula (subacute necrosis of the spinal cord) Aortic dissection Aortic aneurysm Splenic and renal infarction and other renal causes Metabolic disorders Paget's disease Osteoporosis, compression fractures RetroDeritoneal fibrosis

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support in the literature for its use or for the use of other modalities, such as ultrasound, diathermy, or traction. Manipulation is a controversial topic: There may be some short-term benefit in the amelioration of pain and improvement of function, but there is no evidence of long-term benefit. Nonsteroidal analgesics and strictly time-limited dosages of muscle relaxants and, in case of severe pain, opioids may be used for acute pain. Nonsteroidal analgesics and tricyclic antidepressants may be used for chronic pain. Acute Disc Herniation. Acute lumbosacral disc herniation may cause isolated pain of a nonspecific sort, radicular pain caused by protrusion into the lateral recess and neural foramen, or cauda equina syndrome caused by massive central herniation. The onset of the pain often is sudden, with severe radicular symptoms, commonly precipitated by a lifting or twisting injury. Coughing and straining classically exacerbate the symptoms. The L5-S 1 disc is the most often involved with posterolateral herniation, causing entrapment of the S1 root as it descends to emerge below S1. Sciatica with S1 dermatomal (posterolateral leg, lateral heel and sole) pain, paresthesias, and sensory loss are most common (Table 226-2). The pain and paresthesias can be elicited by straight leg raising, often with radiation to the sole of the foot. The smaller the angle of elevation necessary to elicit the pain, the greater is the predictive value of the test for disc herniation. A positive test with elevation of the contralateral leg is even stronger evidence of root compression. The ankle jerk is diminished, and there may be weakness in the S1 myotome (gastrocnemius and hamstrings). A more lateral protrusion of the L5-S1 disc may entrap the L5 root exiting at that level, causing sciatica with L5 dermatomal (anterolateral lower leg and dorsum of foot) and myotomal (tibialis anterior group, extensor hallicus longus), peronei (foot eversion), and tibialis posterior (foot inversion) deficits. Again, straight leg raising is positive, eliciting dermatomal signs. In both cases, the sciatic nerve may be tender to palpation through the gluteus muscle mass at the sciatic notch in the buttocks and below.

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TABLE226-2. Some Causes of Sciatica”

Herniated nucleus pulposus Congenital abnormality of the spine (trefoil canal) Congenital spinal stenosis Anomalous roots (e.g., conjoined root) Degenerative disease of the lumbosacral spine Osteophyte impingement Spondylolisthesis or spondylolysis Spinal stenosis Synovial cysts Spinal osteochondrosis (Scheuermann’s disease) Neoplasms Schwannoma, meningioma, and other primary tumors Osseous tumors Metastatictumor Lymphoma Epidural hematoma Infections Epidural abscess Herpes zoster Retroperitonealand intrapelvictumors outside of the spine Local compression Wallets Toilet seats Piriformis syndrome ’See also Table 226-1. From Ftymoyer JW: Back pain and sciatica. N Engl J Med 315:1090, 1988, with permission.

Less commonly, L4 L5 disc herniation occurs. Herniations at other levels are much less common and may cause correspondingly higher radicular symptoms and signs. The massive central herniation of a lumbosacral disc may cause acute compression of multiple lower roots, leading to the cauda equina syndrome. In this syndrome, one finds radicular pain, paresthesias, and sensory loss at multiple and bilateral but often asymmetrical sites, bilateral leg weakness, and loss of lower extremity reflexes. There may be varying degrees of bowel and bladder dysfunction. When severe, there is perianal sensory loss, loss of anal tone and reflexes (reflex sphincter constriction to skin stimulation, bulbocavernosus reflex), and fecal and urinary retention and incontinence. When more subtle, there may be no bowel or bladder symptoms, but there may be a large, retained postvoid residual volume noted upon catheterization. Further evaluation depends on the level of suspicion for disease other than benign disc disease, such as cancer or abscess and on the intensity of the symptoms and neurologic deficit. When the bowel or bladder is acutely involved, patients should receive immediate intravenous dexamethasone and undergo imaging to define the lesion. In most cases magnetic resonance imaging is preferred, although computed tomography may better define bony disorders (Fig. 226-l), and computed tomography or myelography with computed tomography may substitute for or complement magnetic resonance imaging. This situation demands immediate neurosurgical consultation and surgery to optimize functional recovery. In patients in whom there are major radicular findings, early imaging is indicated. In those with significant motor deficits, early surgery for demonstrated disc herniation corresponding to the clinical deficit is indicated for patients who desire it. This may optimize early recovery; however, long-term functional recovery probably is not compromised by a delay of many weeks. Those with a significant motor deficit should go to surgery within 12 weeks to achieve the best long-term outcome. It is crucial to correlate symptoms and signs with the lesions found on imaging because the rates of abnormalities of computed tomography, myelograms, and magnetic resonance imaging are high in asymptomatic patients. For the more common patients in whom there are mild to moderate radicular findings or none at all, one half recover in 6 weeks. All patients with radicular findings probably should undergo at least plain radiographs to look for unexpected lesions. If the clinical diagnosis of disc herniation and mild radiculopathy is made and conservative treatment is planned, then no further immediate imaging is needed. When diagnosis is in doubt or when guidance is needed for later therapy (e.g., epidural steroid injection or surgery), imaging may be needed. Electromyography can help in questionable cases to define a radiculopathy. Initially, the electromyography typically is normal. If axonal loss develops, the amplitude of the compound muscle action potential is reduced and the electromyogram begins to show changes of acute denervation in the myotome in question after 1 to 2 weeks. In these milder cases, conservative treatment consists of rest and analgesics and sometimes short-term corticosteroids (e.g., prednisone 30 to 60 mg daily for 7 to 10 days) for antiinflammatory effect in acutely painful discs. During the recuperative phase, patients may benefit from physical therapy and education about preventing back injury. Manipulation should be avoided. Patients whose pain does not improve over 6 weeks of follow-up and who have neurologic deficits or intractable pain are candidates for surgical therapy for decompression. When pain is the indication for more aggressive therapy, epidural injection of

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FIG. 226-1. Axial computed tomography scan through the L4-L5 intervertebral disc level demonstrating a posterolateral left-sided disc herniation (arrow), resulting in impingement of the traversing left L5 nerve root. (From Cundry CR, Heithoff KB: Lumbar spine imaging. p. 176. In Kirkaldy-Willis WH, Burton W (eds): Managing Low Back Pain. 3rd Ed. Churchill Livingstone, New York, 1992, with permission.)

corticosteroids at the site of the herniation may promote symptomatic relief. Most patients with disc herniation can be treated successfully without surgery, although this approach probably results in more short-term disability in many patients. Spondylolisthesisand Spondylolysis. Spondylolisthesis is a slippage of one lumbar vertebra on another or of the L5 vertebra on the sacrum. In degenerative disease, this usually occurs at L P L 5 and does not include fracture of the vertebral arch (Fig. 226-2). Spondylolysis is a fracture of the pars interarticularis of the arch that often accompanies such slippage. A simple classification of spondylolisthesisbased on the degree of displacement facilitates communication and guides decision making: grade 1, less than 25%, grade 2, 25% to 50%, grade 3, 50% to 75%, and grade 4, greater than 75%. The abnormality is caused by abnormal development, trauma, or degenerative or other structural disease. An etiologic classification has also been proposed, as detailed in Table 226-3. Spondylolisthesis is common, occurring in about 5% of the general population. Isthmic spondylolysiswith spondylolisthesisis thought to be caused by a stress fracture of the pars interarticularis. Participation in demanding athletic pursuits, such as football and gymnastics, greatly increases the risk of developing this lesion. Although it may occur acutely after trauma, spondylolisthesis usually is asymptomatic or may present with persistent low back pain. The pain probably is caused by abnormalities of the pain-sensitive ligaments and joints, root compression, or lumbar spinal stenosis and, correspondingly, may be nonspecific in character or have radicular features or symptoms typical of spinal stenosis. It is usually aggravated by activity and relieved in part by rest. radiographs should be When low back Pain is Persistent, obtained to look for this lesion; oblique views may demonstrate the spondylolytic fracture. Sclerosis of the borders of such a fracture indicates a chronic lesion, and healing cannot be expected.

FIG. 226-2. Degenerative spondylolisthesis of the fourth to the fifth lumbar vertebra. (From Kirkaldy-Willis WH, Burton W,Cassidy JD: The site and nature of the lesion. p. 114. in Kirkaldy-Willis WH, Burton W (eds): Managing Low Back Pain. 3rd Ed. Churchill Livingstone, New York, 1992, with permission.)

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TABLE226-5. Etiologic Classification of Spondylolisthesis Dysplastic lsthmic Lytic fatigue fracture of the pars Elongated, intact pars Acute fracture of the pars Degenerative Traumatic (fracture elsewhere than the pars) Patholonic From Wiltse Ll., Newman PH, MacNab I: Classification of spondylolisthesis and spondylolysis. Clin Orthop 1 17:23, 1976, with permission.

When there is doubt, bone scanning may help to differentiate acute, active lesions with a potential to heal from chronic sclerotic ones. Flexion and extension radiographs allow quantitation of translational and angular movements large enough to correlate with instability of the spinal segment. Magnetic resonance imaging and computed tomography demonstrate associated root compression and spinal stenosis. In the more common degenerative and isthmic lytic varieties, treatment usually is conservative: rest for acute pain, nonopioid analgesics and external supportive devices. Surgery may be indicated in some cases for decompression of root entrapment and spinal stenosis. For acute lytic fractures with healing potential, external bracing may promote healing. Lumbar Spinal Stenosis. Spinal stenosis may result from degenerative changes of the bony spine and ligaments or from a congenital anomaly of the spine, usually a shortening of the pedicles. Degenerative disease leads to posterior bulging of the intervertebral discs, osteophyte formation, hypertrophy of the ligamentum flavum and other ligaments within the spinal canal, hypertrophy of the facet joints, spondylolisthesis without spondylolysis, and abnormal angulation of the spine. All of these features may compromise the space available to neural structures. The characteristic symptom is neural claudication: low back pain, often radiating to the buttocks and anterior thighs, brought on by extension and relieved by flexion of the spine. A typical history might be the onset of aching pain while walking, with relief by seated rest but not by rest while standing, in contradistinction to vascular claudication. Walking downhill exacerbates the pain by demanding spinal extension. When pain is severe, patients may have difficulty standing upright and therefore may bend forward when walking. Many patients have only mechanical symptoms and signs. Others also have radicular symptoms and signs from stenosis involving the lateral recess or degenerative compromise of the neural foramina. Evaluation includes imaging by computed tomography and magnetic resonance imaging. Magnetic resonance imaging simultaneously visualizes bony and neural tissues. This can demonstrate the stenotic bony canal and the effacement of the surrounding cerebrospinal fluid on T2-weighted images (Fig. 226-3). Computed tomography is good for evaluating lateral recess stenosis, whereas magnetic resonance imaging may underestimate the degree of bony overgrowth. A transverse interfacet dimension of less than 16 mm is low, and less than 10 mm represents severe stenosis. An anteroposterior dimension of less than 12 mm suggests stenosis but is insensitive. A lateral recess of 3 mm or less probably is stenotic. When lateral stenosis is significant, compression of the root can be seen within the recess. Although these dimensions are guidelines, again, clinical correlation of symptoms and anatomy is crucial to selection of patients for successful surgery. Symptomatic therapy is as for other causes of chronic low

back pain. Surgical therapy to decompress the stenotic canal is an option when disability and pain are significant. Facet Syndrome. It has been argued that radicular, chronic low back pain exacerbated by hyperextension and twisting, with tenderness over a facet joint in hyperextension, in the context of facet degenerative arthritis on imaging studies, suggests the diagnosis of facet syndrome. Some practitioners advocate direct or fluoroscopy- or computed tomography-guided injections of corticosteroid and local anesthetic into the presumed affected facet joint or around the joint capsule for more definitive diagnosis and specific control of symptoms. However, the joint injection is itself considered the best diagnostic test, and there is no reliable way to predict responders. Otherwise, treatment is as for other forms of chronic low back pain. Disc Disruption Syndrome. The annulus fibrosus can tear circumferentially between adjacent fibrous layers, without a complete disruption of the structure containing the nucleus pulposus, or it can rupture radially with a disruption of the disc but without prolapse of nuclear material. There may be a history of a twisting or lifting injury, often in a young patient, followed by severe and persistent back pain with radiation to the hip and leg. The examination is unremarkable or may show nonspecific, nonradicular signs. Imaging studies may show a small lesion indenting the dural sac but do not show prolapse or root compression. In the past, diagnosis was made by contrast discography, which can demonstrate the annulus tear and reproduce the characteristic pain. Magnetic resonance imaging may be as accurate but, clearly, it is difficult to correlate abnormalities on magnetic resonance imaging and the nonspecific symptoms of this syndrome. Conservative management is as for other types of chronic low back pain. Occasionally, such patients come to surgery for disc removal and interbody fusion. Piriformis Syndrome. There is controversy about the existence of this syndrome of sciatic entrapment by the tendinous origin of the piriformis muscle. Normally, the sciatic nerve passes just beneath the piriformis muscle as it exits the pelvis through the sciatic notch. In about 6% of cadavers, the sciatic nerve passes between the two parts of the tendinous origin of this muscle. Internal rotation of the thigh presses the sciatic nerve against the origin of the muscle. The nerves to the gluteus medius, gluteus minimus, and tensor fascia lata branch off of the sciatic trunk before this crossing. Nerves to all the other structures innervated by the sciatic nerve branch after it. Rare cases of symptomatic, proximal sciatic compression, presumably caused by compression by an inflamed or shortened muscle and tendon, have been reported (Table 226-2). The typical history is of a runner who develops local pain in the gluteus area, with radiation into the posterior thigh and lower leg. There might be mild weakness of knee flexion and movements below the knee. Images of the lumbosacral spine reveal no cause. Nerve conduction is normal; however, electromyography shows normal lumbar paraspinal, gluteus medius, gluteus minimus, and tensor fascia lata, with signs of denervation in the gluteus maximus and all muscles of the leg innervated by the sciatic nerve. This must be distinguished from other causes of proximal sciatic compression. Conservative treatment with anti-inflammatory analgesics should be tried. Operative decompression, removing one of the heads of the muscle, has reportedly been successful. Postoperative Low Back Pain. Low back pain after spinal surgery, sometimes called failed-back syndrome, can have many causes. Causes amenable to correction by a second operation include those causing root compression, those causing spinal

Chapter 226

instability, and those caused by any prior yet unrecognized surgically responsive lesion. Compression of a spinal root after surgery may be caused by retained disc material, especially a lateral disc herniation, recurrent disc herniation, or postoperative scar acting as a mass. Spinal instability may be caused by spondylolisthesis, surgical disruption of joints, or degenerative disease with incompetent ligaments. With careful selection, a small number of patients may benefit from reoperation to address such diagnoses. Nonsurgical causes of postoperative pain include adhesive epidural scar (probably), intraneural scar, arachnoiditis, and, on rare occasions, pseudomeningocele or disc space infection. Unfortunately, the majority of patients with chronic postoperative pain fall into the category of patients with degenerativedisease and chronic low back pain without a discrete medical explanation. Arachnoiditir. Arachnoiditis is adhesive fibrosis of the lumbosacral roots. This usually occurs after some inflammatory incitement. Causes include the following: Meningitis Trauma Chemical radiculitis (after subarachnoid injections of contrast, steroids, or other agents) Postoperative (after hemorrhage, trauma, infection, or the use of hemostatic agents, such as Gelfoam) Modern, water-solublecontrast agents are much less likely to cause arachnoiditis than the older, oil-based agents. Symptoms usually emerge long after the inciting event. They include low back pain radiating to the buttocks and legs and, later, weakness and wasting. Examination reveals positive findings from the straight leg raising test and weakness, atrophy, and diminished deep tendon reflexes in the legs, implicating multiple roots. Magnetic resonance imaging and computed tomography or myelogram can demonstrate thickening and clumping of the roots of the cauda equina and adherence to the dura. There is no effective treatment. Therefore,

FIG. 226-3. Sagittal magnetic resonance image of a patient with neurogenic claudication. The image shows central spinal stenosis caused by hypertrophy of the ligamentum flavum and posterior protrusion of the annulus fibrosus. (From Bernard TN, Kirkaldy-Willis WH: Making a specific diagnosis. p. 210. In Kirkaldy-Willis WH, Burton CV (eds): Managing Low Back Pain. 3rd Ed. Churchill Livingstone, New York, 1992, with permission.)

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efforts should be made to prevent it by using water-soluble contrast agents for myelogram and by careful neurosurgical technique.

APPROACH TO THE PATIENT History The history should include a description of the manner of onset of the pain, whether it can be associated with a particular event, such as an injury, or whether the onset was gradual and insidious. A description of the character and location of the pain will help to establish whether it is radicular or mechanical. Establishing its time course (i.e., acute, subacute, chronic, or recurrent) provides clues to its cause. Whether it is associated primarily with movement (mechanical), with axial loading and increased intraabdominal pressure (disc herniation), with extension and walking (spinal stenosis), or, perhaps, with quiet rest at night (malignancy or spinal infection) provides such information as well. A history of risk factors for low back pain may suggest both cause and treatment. Obtaining an occupational history is important to explore risk factors, especially those related to lifting. Others are exposure to vibrations caused by machinery or vehicles and cigarette smoking. A psychological profile may establish a context for the problem of chronic low back pain. Such patients often are depressed, anxious, or hypochondriacal. Other problems of living, such as alcoholism or divorce, and other medical problems, such as ulcer disease, may accompany chronic low back pain at a rate greater than otherwise expected. All patients should be questioned about bowel and bladder symptoms because the presence of retention or incontinence suggests possible disease of the spinal cord, conus, or cauda equina and, if acute, demands prompt evaluation. One of the major priorities in the initial evaluation of patients with low back and leg pain is to identify those with less common, especially treatable causes of pain. Much of this work can be done

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during history taking by use of a battery of screening questions, designed to elicit suspicion for the diseases and disorders listed in Table 226-1. Is there a history of cancer? Metastatic breast cancer, melanoma, and renal cell carcinoma may present years after the original tumor, in which case the patient may not volunteer the old diagnosis without a specific question. Back pain may be a major clue to the initial diagnosis of multiple myeloma. Constitutional symptoms, such as weight loss, fever, sweats, and local symptoms, such as cough or urinary or rectal bleeding, call for an aggressive search for the cause of the low back pain, particularly cancer. A history of fever, intravenous drug abuse, surgical procedures, and impaired immunity, including diabetes mellitus, should prompt a search for an abscess. Regional infections may also occasionally predispose to epidural abscess formation, as in the diabetic patient with urinary tract infection. Herpes zoster reactivation may cause persistent low back and leg pain before the telltale rash appears. Patients with inflammatory disorders usually carry the diagnosis of a rheumatic disease or have other characteristic features of the disease in question, such as conjunctivitis and urethritis in Reiter’s syndrome. Low back pain is rarely the only or primary complaint in those with multiple sclerosis, transverse myelitis, or Guillain-Barr.4syndrome. Patients should be questioned about any congenital or developmental spinal problems. Achondroplasia predisposes to shortened pedicles and congenital spinal stenosis. Scoliosis and other less common congenital spinal disorders may underlie the pain. Patients writhing in pain should raise the suspicion of an intra-abdominal disorder or vascular lesion. A patient with coagulopathy or on anticoagulant therapy should raise suspicion for a possible epidural hematoma. Although the differential diagnosis is long, the screening history can quickly eliminate most of the diagnoses in most cases and allow a selection of particular features to focus on during the physical examination.

The examiner’s goal is to find evidence of a localizing neurologic deficit and of features associated with particular diseases noted earlier and in Table 226-1. Inspection of the spine for deformities such as scoliosis, clues of congenital anomalies such as tufts of hair and dimples in the sacral region, or features of achondroplasia should take place early in the examination. It is informative to watch the patient walk into the room and to note how he or she stands. Patients with lumbar and sacral root compression may avoid full weight-bearing on the heel of the affected side. Posture should be noted; for example, flexed posture is seen in severe lumbar spinal stenosis. Observing the range of motion during extension, flexion, lateral flexion, and rotation tests spinal mobility. Direct palpation of the spine can identify local areas of concern. In cases of tumor or abscess, tapping each vertebral spine with a reflex hammer may localize the lesion at the tender site. Palpation of the sciatic nerve through the gluteus maximus at the sciatic notch and distally may demonstrate sensitivity in cases of compression. With the patient in the supine position, straight leg raising is performed with each leg, noting the angle of elevation at which pain and paresthesias arise and their character and location. Lowering the leg to an angle just less than that causing pain and then dorsiflexing the elevated foot may reproduce the pain and help to confirm that it is from sciatic stretch. In acute musculoskeletal pain, any movement may elicit low back pain. With root compression, consistent localizing radicular symptoms may

emerge with elevation of either leg. Pain on passive extension of the hip and leg with the patient prone is said to suggest benign disease of the posterior spinal elements, as opposed to tumorrelated pain, which almost always includes the vertebral bodies; however, this sign is not reliable for differentiation. The examiner should inspect muscles for signs of denervation (atrophy, fasciculations). Muscle power testing is done to identify weakness and localize it to a root or to multiple roots, as in cauda equina syndrome, to the conus or spinal cord, or to a peripheral nerve, as in femoral or peroneal palsies. With root lesions, the tone is normal or reduced. Spastic tone suggests a lesion at the level of the thoracic bony spine or above. Sensory testing is done to look for dermatomal patterns of loss or signs of isolated neuropathies. Patients with cauda equina syndrome and conus compression may have hypesthesia in the perianal area and perineum in addition to the legs. Especially in conus lesions, the saddle hypesthesia tends to occur early. A sensory level is sought on the torso by applying light touch, pinprick, and warm or cold stimuli. If reporting is a problem, an autonomic level can be demonstrated by scratching a line down the torso, looking for an abrupt termination of a normal flare response below the level of a deficit. The ankle reflex (S1) may be lost in L5-S 1 herniation. In some patients, a posterior tibial reflex (L5) can be elicited by tapping just posteroinferiorly to the medial malleolus. Asymmetries occasionally may help to localize an L5 lesion. Involvement of the L2 through L4 roots may dampen the knee jerk. Hyperreflexia and bilateral extensor plantar responses support a myelopathy. A screening general physical examination should be conducted to seek evidence of such associated disorders as those in Table 226- 1. Acute Low Back Pain without Neurologic Signs or Suspicion of Serious Disease

Most patients without neurologic signs or in whom there is no suspicion of serious disease have a minor, self-limiting disorder that improves without specific treatment. When these patients are young and healthy, no further tests may be necessary. If the patient is older or if there has been significant trauma, plain radiographs should screen for major abnormalities. Many patients are satisfied to receive confident reassurance that there is no major problem and that they should quickly return to full health. Short-term amelioration with nonopioid analgesics, light activity, and physical measures, such as heat or cold application, may be recommended. If rest is recommended, it should be brief, usually no more than 2 days. Acute Low Back Pain with Neurologic Signs and Suspicion of Serious Disease

Minor radicular signs in patients at low risk of other disease may be screened with plain radiographs and treated as described earlier (see “Acute Disc Herniation”). In those with major neurologic deficits, sufficient study should be done promptly to establish a diagnosis. This allows treatment to be directed to specific, remediable lesions. When the history or examination raises the possibility of associated illness, or in patients with cancer or symptoms raising the question of a new diagnosis of cancer, those with fever, and those with coagulation disorders or on anticoagulants, one should pursue an evaluation adequate to uncover potential serious causes of the pain. Tests must be individualized, but at times it is appropriate to pursue magnetic resonance

Chapter 226

imaging in the absence of neurologic deficits. When cancer is present or suspected, plain radiographs are not sensitive enough to eliminate the diagnosis of bony metastases. Bone scanning and magnetic resonance imaging with contrast are sensitive for such lesions. Chronic Low Back Pain The management of chronic low back pain is complex. All patients should undergo plain radiographs to look for major bony abnormalities. When instability is suspected, flexion and extension views should be included to look for displacement. If further study is needed, magnetic resonance imaging is preferred because it most easily visualizes both bony and soft tissue structures. This should include gadolinium contrast for those with a history of spinal surgery and those for whom there is a suspicion of tumor or infection and to better characterize certain lesions seen on prior noncontrast scans. Computed tomography substitutes for magnetic resonance imaging in those with contraindications or prohibitive claustrophobia, although most patients tolerate magnetic resonance imaging if they can be sedated safely. Computed tomography may surpass magnetic resonance imaging in visualizing bony lesions caused by trauma or other bony abnormalities. As noted earlier, asymptomatic patients have many abnormalities on imaging studies of all kinds; therefore, care must be taken to correlate images with symptoms and signs. Electromyography may help to clarify questionable findings on the neurologic examination. When surgically correctable causes are identified, treatment may be straightforward.Orthopedic or neurosurgical consultation should also be obtained when there is doubt about the need for surgery, further workup, or the indications for and proper use of further therapies, such as bracing. For most patients without surgical lesions, a constructive, multidisciplinaryapproach should emphasize functional recovery using nonopioid analgesics and pain-modulating medications (e.g., tricyclic antidepressants), exercise, nutrition, smoking cessation, education (“back school”), psychological support, and vocational rehabilitation. The services of physical therapists, psychologists, and physicians skilled in the management of chronic pain are invaluable. Several authors have reported significant rates of successful rehabilitation with aggressive programs of exercise and a multidisciplinary approach. When a patient is beginning pharmacologic treatment, it should be made clear that the goal of therapy is functional rehabilitation and that medications are only a limited part of the program. It should also be emphasized that the medications are not expected to rid the patient of all pain but to limit it and to aid physical therapy and functional recovery. Available medications include acetaminophen, aspirin, and other nonsteroidal antiinflammatory analgesics, several medications with unclear mechanisms but commonly called muscle relaxants, and tricyclic antidepressants. Although they may be effective for short-term use in acute low back pain and for occasional flares of chronic pain, most agree that opioids have little role in the treatment of chronic low back pain. Nonsteroidal analgesics may be given as needed or on a time schedule. In general, patients with persistent pain tend to take less medication when a time schedule is established. Acetaminophen use should be limited because of its renal and hepatic toxicity. Aspirin and other nonsteroidal analgesics are limited by their gastrointestinal side effects and, less commonly, by renal side

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effects. When one does not work, it is worthwhile to try another because patients may respond differently to particular members of this loose class of medications. The muscle relaxants include diazepam and other benzodiazepines.These do suppress the spinal reflex arc and may truly relieve spasm. However, high and sustained dosages may be needed to achieve this effect. Because their abuse potential is high, this use is problematic, and their use for low back pain and muscle spasm should be strictly short term. Other so-called muscle relaxants are methocarbamol, carisoprodol, and cyclobenzaprine. These all have no established effect on the spinal reflex arc and have central sedative effects. These effects may account for any positive responses and certainly cause most of the common side effects. Tricyclic antidepressants have painmodulating properties independent of their antidepressant effects. These medications may be helpful as long-term adjuvant therapy. Many patients challenge these simple recommendations, and ultimately the treatment of chronic low back pain requires the range of skills needed to treat chronic pain in general. SUGGESTED READINGS Dawson DM, Hallet M, Millender LH: Entrapment Neuropathies. 2nd Ed. Little Brown, Boston, 1990 Deyo RA, Diehl AK, Rosenthal M: How many days of bed rest for acute low back pain? A randomized clinical trial. N Engl J Med 315:10641070, 1986

Faas A, Chavannes AW, van Eijk JTM, Gubbels YW: A randomized, placebo-controlled trial of exercise therapy in patients with acute low back pain. Spine 18:1388-1395, 1993 Fredrickson BE, Baker D, McHolick WJ et ak The natural history of spondylolysis and spondylolisthesis. J Bone Joint Surg 66A699-707, 1984

Frymoyer YW: Back pain and sciatica. N Engl J Med 318291-300, 1988 Hadler M N Regional back pain. N Engl J Med 315:109&1092, 1986 Loeser JD, Volinn E Epidemiology of low back pain. Neurosurg Clin 2713-718, 1991

Long DM: Failed back Syndrome. Neurosurg Clin N Am 2899-919, 1991 Malmivaara A, H u e n U, Aro T et ak The treatment of acute low back pain: bed rest, exercises, or ordinary activity? N Engl J Med 332~351-355, 1995

Mayer TG, Gatchel RJ, Kishino N et ak Objective assessment of spine function following industrial injury: a prospective study with comparison group and one-year follow-up. Spine 10482-493, 1985 Mooney V, Robertson J: The facet syndrome. Clin Orthop 115:149-156, 1976

Nachemson AL: Instability of the lumbar spine: pathology, treatment, and clinical evaluation. Neurosurg Clin N Am 2:785-790, 1991 Nakano IUC Sciatic nerve entrapment: the piriformis syndrome. J Musculoskeletal Med 433, 1987 F‘yhtinen J, M d e S, Tanska EL, Laitinen J: Computed tomography after lumbar myelography in lower back and extremity syndromes. Diagn Imaging 52:19-22, 1983 Stankovic R, Johnell 0: Conservativetreatment of acute low-back pain. A prospective randomized trial: McKenzie method of treatment versus patient education in “mini back school.” Spine 15120-123, 1990 Thomas M, Grant N, Marshall J, Stevens J: Surgical treatment of low backache and sciatica. Lancet 2:1437-1439, 1983 Waddell G, McCulloch JA, Kummel E, Wenner RM: Nonorganic physical signs in low-back pain. Spine 5:117-125, 1980 Weber H: Lumbar disc herniation: a controlled prospective study with ten years of observation. Spine 8131-140, 1983 Wiesel SW, Cuckler JM, Deluca F et ak Acute low-back pain: an objective analysis of conservative therapy. Spine 5:324-330, 1980 Wdtse LL, Newman PH, Macnab I: Classificationof spondylolisthesisand spondylolysis.Clin Orthop 117:23-29, 1976

SECTION

6

TREATMENT OF PAIN

227

Pharmacologic (Analgesic) Treatment of Pain Gilbert 1. Fanciullo

Analgesic therapy may include opioids, nonsteroidal antiinflammatory drugs (NSAIDs), antidepressants, anticonvulsants, and other unique medications from a variety of classes. The use of all these drugs is more successful if the social, emotional, cognitive, behavioral, and even spiritual components of pain are addressed. The emphasis on pharmacologic therapy is based on the familiar model of diagnosis and treatment of acute disease and relies on medications as a major and often sole strategy. When treating painful conditions, drugs are important, but psychosociological factors are equally consequential. These factors can amplify pain, alter responses to nociceptive stimulation, and influence response to therapy. The Cartesian theory of pain, taught in the United States until about 1965, describes a one-nerve, one-function, simplistic approach to pain as exclusively a nociceptive experience. This was replaced by the gate control theory of Melzack and Wall, which added a modulating component and, ultimately, a degree of control from supraspinal brain sources. The present theory is the neuromatrix theory, which describes an individual basal state including contributions from genetics, illnesses, psychological and physical trauma, social circumstances, and lifetime experiences placing pain in a cognitive, emotional, and physical context. To this matrix is applied a nociceptive stimulus, and each person’s interpretation of that stimulus is unique. The neuromatrix should be considered in evaluating and treating patients. I will address only pharmacologic options in this chapter, but they should be applied along with procedural, psychological, behavioral, and physical medicine approaches to managing pain. OPlOlDS

Opioids are arguably the oldest known pharmacologic agents, predating alcohol, and remain the benchmark for effective analgesic therapy for moderate and severe pain. The word opium derives from the Greek word for “juice.” Opium, the juice of the poppy Papaverum somniferum, is seldom used today, but its alkaloid extracts and synthetic derivatives are commonly used and represent our modern-day opioids. Opiate is a term that describes medications directly derived from opium. The term narcotic derives from the Greek word for “stupor” and typically describes agents that are morphine-like and can produce physical or psychological dependence, or addiction. 1438

Societal and individual prejudices and fear of causing addiction in patients have greatly limited the use of these agents, except for acute pain and more recently pain from cancer. The use of opioids for chronic noncancer pain remains controversial; the efficacy of long-term opioid use has never been demonstrated. The risk of addiction in patients without a history of alcoholism or drug addiction has been demonstrated to be very slight, in the range of 1 in 3000 patients. This low number may reflect the definition of addiction used in the reports. If addiction is defined as using opioids for purposes other than pain relief, then the numbers are unknown. It is known that opioid abuse is common and can be difficult to identify and manage. Prescribing these agents can be problematic, and colleagues, pharmacists, nurses, family members, and patients themselves will question their use. Strict limit setting with patients can reduce the number of problems that can develop in patients receiving chronic opioid therapy. A controlled substance agreement (Fig. 227-1) can be useful in management and can help patients who are not benefitting from opioid therapy. Pain and activity levels should be well documented both before and during opioid use to determine efficacy. Urine toxicology can help to ameliorate concerns of physicians and patients if issues of compliance and veracity arise. Opioids act as agonists at stereospecific receptor sites in the brain, spinal cord, and other tissue sites. Opioids mimic the action of endogenous morphine-like substances (endorphins) activating pain-modulating pathways. Opioid side effects result from binding to receptors different from those that produce analgesia. It is likely that opioids will be developed that are specific for analgesia, and many of the side effects will become of historical interest only. Opioid agonists bind to p-receptors, resulting in supraspinal and intense analgesia. Agonist-antagonists are agonists at K-receptors, producing analgesia to a ceiling, at which point higher dosages do not produce greater analgesia. They are antagonists at p-receptors and can precipitate withdrawal in patients dependent on opioid agonists. K-Receptor activation results in little or no respiratory depression; &receptors modulate p-receptors. Naloxone is a pure opioid antagonist. It is most potent as a p-receptor antagonist but also has effects at K- and &sites. Its elimination half-life is 60 to 90 minutes, much shorter than that of morphine. If used to treat an opioid overdose, a naloxone drip often is necessary. It is usually possible to titrate the reversal of respiratory depression effect while still maintaining analgesia.

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Pain Management Center at Dartmouth-Hitchcock Medical Center Informed Consent and Controlled Substance Agreement for Treatment of Chronic Pain

,understand and agree to follow the DHMC Pain Management Center policies regarding the use of controlled 1, substances for management of chronic pain. I understand that my physician is under no obligation to prescribe these medications for me. I also understand that there are other treatment options available, and the risks and benefits of these alternatives have been discussed. RISKS OF OPIOID MEDICATION FOR CHRONIC PAIN I understand that these medications have potential risks, the most significant being: 1. Physical dependence which means that abrupt discontinuation of the opioid medication could lead to withdrawal symptoms such as abdominal cramping, diarrhea, anxiety, seizures, and death. 2. Psychological dependence or addiction, which means that my behavior becomes focused on obtaining additional opioid medication. 3. Overdose of the opioid medication leading to respiratory arrest and death. 4. Mental changes such as confusion, sedation, and changes in thinking ability. I agree to use caution and common sense before operating equipment or motor vehicles. Other side effects may include, but are not limited to, the following: nausea, constipation, unsteadiness, decreased appetite, problems urinating, sexual difficulties, and depression. CONDITIONS OF CONTRACT 1. I understand that opioid medication will be prescribed only if my physician determines that such treatment will improve my ability to participate in work and social activities. (initials) 2. I do not currently have problems with substance abuse (drugs and/or alcohol). (initials) 3. I am not involved in the use, sale, possession, diversion, or transport of illegally obtained controlled substances (narcoticsand/or illegal drugs). (initials) 4. I agree to use the opioid medication only as prescribed to me and will not take more medication than instructed. I agree to not allow other individuals to take my medication, nor will I take medication prescribed to another person. (initials) 5. I understand the potential harm of opioid medication to unborn children and agree to notify the Pain Management Center if I am or become pregnant in the future. (initials) 6. I will receive opioid medication only from the DHMC Pain Management Center and not from any other source. I agree to notify my Pain Management Center physician in advance of any anticipated acute needs (e.g., dental work or surgery) that may necessitate a change in my opioid dosage. (initials) 7. I agree to accept generic brands of my opioid medication. (initials) 8. If it appears to my physician that there are no demonstrable benefits in daily function from the opioid medication or that addiction, rapid loss of effect, or significant side effects are developing, I agree to gradually taper my medication as prescribed. If a substance abuse problem is suspected, I will be referred for evaluation and management of the problem. I will not hold any member of DHMC Pain Management Center liable for problems caused by discontinuance of opioid medication. (initials) 9. I agree to come to my scheduled appointments prepared to provide urine and blood samples to assess the effect of the opioid medication and compliance with my treatment plan. Any evidence to the contrary would necessitate termination of opioid treatment. (initials) 10. I understand that chronic pain is a complex problem that benefits from physical therapy, psychotherapy, and behavioral medicine strategies. I recognize that my active participation in the management of my pain is extremely important to improve my functioning and ability to cope. I agree to actively participate in all aspects of treatment. I agree to see other health care providers for evaluation and treatment of related and other medical conditions if determined necessary. (initials) 11. I understand that DHMC Pain Management Center is a specialty consulting practice and that my primary care physician or referring physician will be kept apprised of my treatment and progress. My Pain Management Center physician will collaborate with my primary care physician to determine the best course for continued care for chronic pain. (initials). I will be prescribed opioid medication only if I agree to follow these regulations:

i

State law allows no more than a 30-day supply or 100 tablets, whichever is less, of medication to be given in a single prescription. It is my responsibilityto stretch out my supply from months with 30 days or less to cover months having 31 days. I understand I will not receive additional medication before my next scheduled appointment. I understand that opioid prescriptions expire 5 days after the date on the prescription and agree to plan accordingly. State law also provides that it shall be unlawful for any person to knowingly acquire, obtain possession of, or attempt to acquire or obtain possession of a controlled drug by misrepresentation, fraud, forgery, deception, or subterfuge. This prohibition includes the situation in which a person independently consults two or more practitioners for treatment solely to obtain additional controlled drugs or prescriptions for controlled drugs. FIG. 227-1. Example of a controlled-substance agreement. Illustration continued on following page

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Treatment of Pain

Changes in my prescriptions, including dosage adjustments, refills, and new medication, will be made only during scheduled office visits and not over the phone or during unscheduled visits. Telephone calls regarding opioid medication should be limited to reports of significant side effects necessitating decreasing or stopping the medication. Lost or stolen medication will be replaced at the discretion of the physician. I understand any violation of this contract will result in a discontinuation of treatment with opioid medication. I also understand that, based on the clinical judgment of the Pain Management Center physician, treatment with opioid medication may be discontinued at any time. I have read this document, understand it, and have had all questions regarding risks and conditions of the contract answered satisfactorily,I agree to all conditions of this opioid contract and have been provided a copy.

Patient Signature

Date

I certify that I have reviewed this contract with the above-signed individual.

Physician Signature

Date

I certify that the above-signed individual has knowingly and willingly signed this contract.

Witness Signature

Date

FIG. 227-1. Continued Example of a controlled-substance agreement.

OPlOlD ACONISTS Opioid agonists include morphine, meperidine, hydromorphone, oxycodone, hydrocodone, methadone, fentanyl, codeine, and propoxyphene. Agonists that are not discussed in this chapter include alfentanil, sufentanil, and remifentanil, which are used almost exclusively in anesthesiology. Opioid agonists particularly suitable for chronic pain because of their longer duration of action include methadone, fentanyl transdermal, and continuous-release morphine and oxycodone preparations. More sustained serum levels around the clock make dosing schedules almost always more advantageous than pro re nata dosing.

Morphine was isolated from opium in 1803 and named after the god of dreams. It is the prototype opioid agonist against which all others are compared. Morphine produces analgesia, sedation, and euphoria. It can also produce nausea, vomiting, pruritus (often around the nose), constipation, lightheadedness, dysphoria, respiratory depression, and feelings of warmth in the body and heaviness of the extremities. Morphine is well absorbed after intramuscular injection, with onset of action in 15 minutes and peak effect in 45 to 90 minutes. Intravenous administration results in peak activity in approximately 20 minutes. The intravenous route is always preferred over the intramuscular route both for patient comfort and pharmacokinetic reasons. When it is administered intramuscularly, absorption can be erratic, and the peak effect of intramuscular morphine may occur long after the injection when no one is nearby to observe the patient. Morphine is metabolized in the liver and kidneys, and metabolites are eliminated in the urine. Principal metabolites include morphine-6-glucuronide (M-6-G) and morphine-3glucuronide (M-3-G). For clinical purposes, M-3-G is pharmaco-

logically inactive. M-6-G produces analgesia, respiratory depression, and sedation. In patients with normal renal function, the serum molar ratio of M-6-G to morphine may be as high as 1 0 1 within 90 minutes. In patients with impaired renal function, the molar ratio may rise to 45:l. Elimination of morphine glucuronides is delayed in patients with impaired renal function and unexpected sedation, and respiratory depression may result from low dosages. Unexplained sedation and respiratory depression in patients with deteriorating renal function on stable dosages of morphine may also be attributable to accumulation of morphine metabolites. Morphine is a poor choice for analgesia in patients with impaired renal function. Despite the complicated pharmacokinetics, morphine is well tolerated in patients with impaired hepatic function. The elimination half-life of morphine is 114 minutes. Older adults have higher plasma concentrations of morphine because of delayed metabolism and excretion. Older adults have also been shown to be more sensitive to morphine than younger patients. There is at least a fivefold variation in need for morphine in any age group, and this variation is not readily predictable based on weight or other factors. Dosages of morphine and other opioids should be individualized and reduced in older adults. Side effects described for morphine also apply to other opioid agonists, although there may be differences in incidence or magnitude. All opioid agonists produce dose-dependent depression of ventilation via depression of medullary and pontine centers that regulate responsiveness to carbon dioxide and centers that regulate rhythm of breathing. This can result in a shift of the carbon dioxide response curve to the right with an elevation in resting arterial carbon dioxide pressure and prolonged pauses between breaths or periodic breathing. It can also result in increased respiratory rate and decrease in tidal volume, with an overall decrease in minute ventilation. Patients may have opioidinduced respiratory depression even with a normal respiratory

Chapter 227

rate. The tidal volumes may be shallow, and reduced minute ventilation can still result in hypercapnia and hypoxemia. High dosages of opioids result in apnea. Patients may remain conscious and breathe if asked to do so. Pain stimulates patients to breathe, and patients who are complaining of pain are unlikely to have significant respiratory depression. Death may result from opioidinduced respiratory depression. Morphine can cause release of histamine and result in hypotension caused by histamine-induced vasodilation. Administration of 1 mg/kg of intravenous morphine over 10 minutes results in a significant decrease in systemic vascular resistance and blood pressure. Supine, euvolemic patients who receive analgesic dosages of morphine are at low risk for development of hypotension. Morphine does not increase the incidence of arrhythmias as long as normocarbia and oxygen saturation are maintained. Analgesic opioid dosages do not cause myocardial depression or bradycardia. Morphine should be used with caution in patients with head injury because of miosis and the decrease in wakefulness associated with its use, as well as the risk of respiratory depression with subsequent rise in carbon dioxide. Opioids increase intrabiliary pressure and can cause biliary colic. Pain from biliary colic can be confused with pain from coronary ischemia. The pain of opioid-induced biliary colic is reversible with naloxone, glucagon, or nitroglycerin. The pain of angina pectoris is reversible only with nitroglycerin. All opioid agonists increase intrabiliary pressure to the same degree, including meperidine. Opioids impair peristalsis and increase sphincter pressure in the gastrointestinal tract, causing constipation to which tolerance does not occur. Senna is a colon-specific agent that stimulates the Auerbach plexus, increasing peristalsis. It directly antagonizes the constipating effects of opioids and, used regularly, prevents opioid-induced constipation. It is important to predict opioidinduced constipation and treat it prophylactically; natural remedies that can be effective include all-bran cereal, laxative tea, and prune juice. Morphine can cause nausea and vomiting that is often dose related and eliminated by decreasing dosages. It seems to be idiosyncratic and can be eliminated by changing to another opioid agonist. Morphine can cause urinary retention by increasing the tone of the vesicle sphincter, particularly in older men or men with prostate hypertrophy. Opioids are not teratogenic, but hypercarbia is, and pregnant patients should be watched carefully when receiving opioids, particularly during organogenesis. The respiratory depressant effect of morphine and other opioids can be augmented by combination with benzodiazepines, phenothiazines, and antidepressants. Morphine is available for parenteral administration and as an elixir, suppository, immediate-release form, and sustainedrelease form.

Meperidine Meperidine is one tenth as potent as morphine. It was developed as an atropinic and has many properties more similar to atropine than to opioids. It is the only opioid to cause mydriasis. It increases heart rate at increased dosages rather than decrease it, as other opioids do. Meperidine can lower the seizure threshold. Accumulation of normeperidine in patients with impaired renal function has resulted in death in some cases. Meperidine interacts with monoamine oxidase inhibitors and can cause hyperpyrexia,

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hypertension, and death. Meperidine has an extensive first-pass hepatic effect and is a very poor medication for oral administration. Because of the myriad of side effects associated with its use, meperidine should be used only when other opioid agonists are unavailable or when there is a specific indication. For example, meperidine has smooth muscle relaxing properties and can be useful for ureteral colic and after surgery on the uterus. Meperidine is available for parenteral or oral administration.

Hydromorphone Hydromorphone is eight times as potent as morphine, but its duration of action is only 3 hours. Indications are the same as for morphine. It is available in parenteral form, liquid, and suppository.

Oxycodone Oxycodone is available alone or in many combination preparations with acetaminophen or aspirin. It is as potent as morphine and is available as a tablet, long-acting tablet, and solution.

Hydrocodone Hydrocodone is a semisynthetic analgesic and antitussive with efficacy similar to that of codeine. It is available in many combination tablet forms and as syrup.

Methadone Methadone has an elimination half-life of 35 hours but an analgesic duration of action of only 6 to 8 hours by oral route. This long analgesic duration of action, combined with its low cost and efficacy similar to that of morphine, make it an attractive medication for treating chronic pain. Methadone has N-methyl D-aspartate receptor antagonist properties, which may make it more useful than other opioids in treating neuropathic pain. Methadone is metabolized in the liver to inactive end products and excreted in the urine and bile. Methadone is available for parenteral administration and as tablets, in liquid form, and as diskettes, which are tablets with insoluble excipients to prevent intravenous use.

Fentanyl Fentanyl is approximately 100 times as potent as morphine and is available in an intravenous form, in a unique transbuccal, lollipop form, and as a transdermal system. Fentanyl has no metabolically active end products and is excreted in the urine only minimally unchanged. It produces no histamine release even at very high dosages. It has a duration of action when administered intravenously in usual dosages of only 30 minutes. The transdermal patches and transbuccal lollipops are useful in patients who are unable to take tablets. The patches must be changed every 48 to 72 hours.

Codeine Codeine is a commonly used analgesic and antitussive opioid agonist. There is a ceiling effect on its analgesic properties, thus limiting its usefulness to mild or moderate pain. Maximum

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analgesia is produced with a dosage of 60 mg and is equivalent to 650 mg of aspirin.

Propoxyphene Propoxyphene is another commonly used opioid with potency similar to that of aspirin. It is indicated only for mild or moderate pain.

OPlOlD AGONIST-ANTAGONISTS Commonly used opioid agonist-antagonists include pentazocine, butorphanol, nalbuphine, and buprenorphine. Their ceiling effect on analgesia and occurrence of psychotomimetic side effects mean that these medications are rarely indicated. They were initially popularized by the belief that they were not addictive, which has been disproven repeatedly. Intranasal butorphanol may be useful because of its unique route of administration.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs have been used for hundreds of years. The bark of the willow tree was described as a treatment for rheumatism as early as 1763 and is still available in health food stores. They produce analgesia, antipyrexia, and anti-inflammatory effects by inhibiting cyclo-oxygenase and a decrease in prostaglandin production. There is interpatient variability in efficacy, and failure with treatment with one agent does not eliminate the entire group of medications as potentially beneficial. Failure with a trial of three agents should eliminate NSAIDs as an efficacious class of drugs. Most patients who use opioids can benefit from concomitant use of an NSAID, as is recommended by many authorities. There are 27 available NSAIDs in the United States, and they should be selected based on their unique properties and side effect profiles. There are now two Cox-2-specific cyclo-oxygenase inhibitors, which have a much lower incidence of gastropathy associated with their use and may impair platelet aggregation to a lesser extent than nonspecific cyclo-oxygenase-inhibitingNSAIDs. NSAIDs are the most commonly prescribed medications in the United States and are the most common cause of gastric mucosal abnormalities. NSAIDs decrease the production of gastric mucous, which is prostaglandin dependent. Therefore, the mucosa is more sensitive to gastric acid, which can result in a characteristic pattern of gastric erosion. Histamine-2 blockers do not prevent gastric erosion because the problem is not with gastric acid but with loss of the protective mucosal layer. Misoprostol is a prostaglandin analogue that maintains the mucous layer and may provide prophylaxis against ulceration and erosion induced by NSAIDs. Nabumetone has been shown to have a lower occurrence of gastropathy than aspirin and naproxen. Choline magnesium trisalicylate may also be less likely to cause gastric erosion. Rofecoxib and celecoxib are Cox-2 selective and have been shown to have a much lower occurrence of gastropathy associated with their use. NSAIDs prolong bleeding time and should be used with caution in patients at high risk of bleeding. Aspirin irreversibly inhibits platelet aggregation and can prolong bleeding time for up to 11 days, the life of the platelet. Nonaspirin NSAIDs reversibly inhibit platelet aggregation, and ibuprofen, for example, prolongs bleeding time for approximately five half-lives, its half-life being approximately 5 hours. Choline magnesium trisalicylate may have

less of an effect on inhibition of platelet aggregation, as may rofecoxib and celecoxib, when compared with other NSAIDs, and may be a logical choice when bleeding is a risk but an NSAID is indicated. Choline magnesium trisalicylate is available as an oral suspension, as are ibuprofen, indomethacin, and naproxen. Only indomethacin and ketorolac are available in parented formulations. Intravenous indomethacin is associated with a high occurrence of gastropathy and nephropathy in infants and is not used often as an analgesic. Indomethacin is predominantly an antiinflammatory agent, with less activity as an analgesic. It may be useful to use a low dosage (25 mg) of indomethacin at bedtime to prevent early morning stiffness and pain. Ketorolac has a side effect profile similar to those of other NSAIDs. Parenteral ketorolac when used for more than 5 days is associated with a higher rate of gastropathy. Duration of therapy greater than 14 days with the oral form is also associated with a higher rate of gastropathy. As with all other NSAIDs, half the usual dosage of parented ketorolac should be used in patients more than 65 years old, less then 50 kg in weight, or with impaired renal function. NSAIDs cause elevation of hepatic transaminase levels in 15% of patients. The risk associated with this “idiopathic transaminasemia” is unknown, but when it is noted, the medication should be stopped and another agent can be instituted. Some authorities recommend routine testing of transaminases at 8 and 24 weeks after starting an NSAID; acute hepatic necrosis is rarely reported. NSAIDs can cause nephrotoxicity by a variety of mechanisms. Papillary necrosis, interstitial nephritis, and nephrotic syndrome have all been reported. Renal damage usually is reversible if it is detected in time and the medication is discontinued. A urinalysis to detect protein is the best single screening test for NSAIDinduced nephropathy. Sulindac may be associated with a lower risk of nephropathy, although this is controversial. Allergy to NSAIDs is rare, but manifestations can be severe. Patients with the triad of asthma, nasal polyposis, and aspirin hypersensitivity are at high risk of manifesting anaphylactoid reaction to other NSAIDs. Patients who are allergic to aspirin may cross-react to all other NSAIDs. Patients allergic to sulfa medications may cross-react to celecoxib. Phenylbutazone is a potent anti-inflammatory useful in treating acute gout and rheumatoid arthritis. Because of the frequent occurrence of anemia and granulocytosis, phenylbutazone use should be limited to 7 days. Piroxicam is a frequently used medication, largely because of its long duration of action, enabling once-a-day administration. Other once-a-day agents include nabumetone and oxaprozin. Diclofenac is unique in that it accumulates in bone and synovial fluid to an extent that may be greater than other NSAIDs. Diclofenac is also available in a fixed combination with misoprosto1 and is a potent analgesic with a lower occurrence of gastropathy. Phenacetin and its active metabolite, acetaminophen, may have some anti-inflammatory activity and may be classified as NSAIDs. They have antipyretic and analgesic properties. They do not produce gastric irritation, platelet inhibition, or bleeding abnormalities. Phenacetin may cause hemolytic anemia and methemoglobinemia in patients with glucose-6-phosphate deficiency. The clinician treating pain should become familiar with half a dozen or so of these agents, know them well, and be able to use them interchangeably.

Chapter 227

ANTIEPILEPTICS The antiepileptics are discussed only briefly here. The effective analgesic dosages are not known, so these medications should be dosed as if to treat epilepsy. They are most useful in treating neuropathic pain, particularly if there is a shooting, electrical, or lancinating component. They may also add efficacy when combined with antidepressants to treat the burning or dysesthetic components of neuropathic pain. Most studies have been with carbamazepine, but there have also been studies with phenytoin, valproic acid, and gabapentin. Clonazepam is becoming more widely used because of its advantageous side effect profile. The use of these agents to treat specific diseases, such as trigeminal neuralgia, is discussed elsewhere in this text. Gabapentin has become increasingly popular as an antiepileptic useful in treating neuropathic pain because of its high therapeutic index and its proven efficacy in treating postherpetic neuralgia and diabetic neuropathy. It is probably the medication of first choice for treating peripheral neuropathic pain and most other neuropathic pain syndromes. It is extremely well tolerated, even by older adults, with the most common side effect being sedation. It has no interactions with other medications, and the dosage can be escalated rapidly to approximately 3600 mg per day. Lamotrigine may have efficacy similar to that of gabapentin and can be used when gabapentin has not been tolerated. ~

TRICYCLIC ANTIDEPRESSANTS AND RELATED MEDICATIONS The efficacy of amitriptyline in treating neuropathic pain is well established. There are data to suggest analgesic onset within hours of administration in healthy volunteers in a model of acute pain, and data suggest a delay of analgesic efficacy for as long as 2 weeks in patients with diabetic neuropathy. Nortriptyline is the demethylated derivative of amitriptyline, and desipramine is the principal metabolite of imipramine. Trazodone, fluoxetine, sertraline, venlafaxine, and paroxetine are structurally unrelated to the tricyclics and tetracyclics. The analgesic mechanism of action of these agents is the same as for the tricyclics and is the potentiation of the biogenic amine serotonin and, to a lesser degree, that of norepinephrine. These amines are neurotransmitters in painmodulating pathways. Side effects from the use of tricyclic agents are common and are anticholinergic, cardiovascular, or sedating. Salutary effects of the medications include not only analgesia but also a restoration of disrupted sleeping patterns. Increase in appetite is usual with amitriptyline, nortriptyline, desipramine, and imipramine. Decrease in appetite is characteristic of fluoxetine, sertraline, venlafaxine, and paroxetine. Sexual dysfunction is common with all these agents but less common with venlafaxine. Bupropion is not considered an analgesic because of its nonserotonergic and nonadrenergic mechanism of action. Anticholinergic side effects are manifested as dry mouth, blurred vision, tachycardia, constipation, memory impairment, urinary retention, and delayed gastric emptying. Fluoxetine, sertraline, venlafaxine, and paroxetine have only very slight anticholinergic effects, if any, and are usually alerting rather than sedating. These agents have half-lives ranging from 21 to 72 hours and can be given once a day. Trazodone is extremely sedating but has a very low anticholinergic profile. Trazodone has no effect on norepinephrine, and there is some question of whether trazodone

Pharmacologic (Analgesic) Treatment of Pain

1445

has analgesic properties at all. Of amitriptyline, nortriptyline, desipramine, and imipramine, the agent with the strongest anticholinergic profile is amitriptyline and the weakest is desipramine. Amitriptyline is the most sedating of these medications, and imipramine and desipramine are less sedating. Tolerance to the anticholinergic and sedating side effects of these medications often occurs. Orthostatic hypotension and tachycardia are the most common cardiovascular side effects of these medications. Prolongation of the QT and PR intervals has unknown significance in the absence of overdose. Amitriptyline, nortriptyline, desipramine, and imipramine should be used with caution in patients with prolonged conduction times or heart block and with great caution in patients using type 1 antiarrhythmics, such as quinidine. Fluoxetine, sertraline, venlafaxine, and paroxetine are not associated with postural hypotension, conduction system abnormalities, or anticholinergic effects. There are no clinically significant changes in the electrocardiogram in patients treated with these agents. ADJUNCTIVE AND OTHER ANALGESICS Dextroamphetamine and methylphenidate are useful agents to decrease sedation associated with high dosages of opioids. They are structurally related stimulants of the central nervous system and may enhance analgesia produced by concomitantly administered opioids. Methylphenidate has been shown to eliminate the cognitive dysfunction associated with fluctuating dosages of opioids in patients with cancer pain. Dosing is typically at 7 AM and 2 PM, enabling the patient to sleep during the night. Mexiletine is a class 1B antidysrhythmic, which is a lidocaine analogue and had been thought to be useful in treating neuropathic pain. It is likely that there is no analgesic benefit associated with the use of mexiletine. Tramadol is an analgesic shown to be especially useful in treating neuropathic pain and has a dual mechanism of action. It is a partial p-agonist and inhibits the reuptake of serotonin and norepinephrine. It can be extremely useful as a rescue medication for patients with postherpetic neuralgia and other neuropathic pain syndromes. It is available as a scored 50-mg tablet that can be easily broken in half for older adults or sensitive patients. Capsaicin cream is an extract of the seeds and membranes of certain plant species of the nightshade family. Capsaicin stimulates and then blocks nociceptive sensory afferents from the skin and mucous membranes that contain substance P, somatostatin, and calcitonin gene-related peptide. These fibers have been implicated in mediating cutaneous pain and pathologic itch. The basis of capsaicin’s action is its ability to enhance the release of substance P and prevent its reaccumulation in these fibers. Several studies have demonstrated success in relieving postherpetic neuralgia and peripheral neuropathy pain. Lidocaine patches are now available and can be extremely useful in treating postherpetic neuralgia and other allodynic pain syndromes. The patches are placed on for 12 hours and off for 12 hours. EMLA cream (eutectic mixture of local anesthetics) is a mixture of lidocaine and prilocaine with a boiling point less than that of either medication individually. This accounts for its ability to be absorbed and to provide analgesia for peripheral neuropathic pain or postherpetic neuralgia. Successful treatment of both acute and chronic pain entails a commitment to understand the nature of the patient’s pain and his

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Headache and Pain W Treatment of Pain

or her psychosocial and environmental history. Trial-and-error approaches often are necessary. The patient should be warned that it may take months to develop an optimum regimen and that only rarely will pain be eradicated completely.

SUGGESTED READINGS Carr DB, Jacox AK: Acute Pain Management Clinical Practice Guidelines. Agency for Health Care Policy and Research, US Department of Health and Human Services, Pub. No. 92-0032, Rockville, MD, 1992 Casey K L Pain and Central Nervous System Disease. Raven Press, New York, 1991 Fields HL: Pain Syndromes in Neurology. Butterworths, London, 1990

Jacox AK, Carr DB: Management of Cancer Pain Clinical Practice Guidelines. Agency for Health Care Policy and Research, US Department of Health and Human Services, Pub. No. 94-0592, Rockville, 1994

Loeser JD: Bonica’s Management of Pain. 3rd Ed. Lippincott Williams & Wilkins, Philadelphia, 2001 Mann RD: The History of the Management of Pain. Parthenon Publishing, Carnforth, 1988 Patt RB: Cancer Pain. JB Lippincott, Philadelphia, 1993 Stein C: Opioids in Pain Control. Cambridge University Press, Cambridge, UK, 1999 Turk DC, Melzack R Handbook of Pain Assessment. Guilford, New York, 1992

Wall PD, Melzack R Textbook of Pain. 4th Ed. Churchill Livingstone, Edinburgh, 1999

228 Physical Therapy and Transcutaneous Nerve Stimulation Nathaniel P. Katz and Susan LaViolette Often, the most useful consultant in chronic pain management is the physical therapist, with the psychologist a close second. Once diagnostic imperatives have been excluded, most patients are diagnosed with musculoskeletal pain syndromes, the conservative treatment of which may be most effectively carried out by the physical therapist. The physical therapist provides an array of services: Diagnostic assessment of the patient’s condition and function Treatment of specific conditions Symptomatic reduction of pain Patient education Restoration of function Occupational therapists also carry out these functions, and distinguishing between the two services can be confusing. Generally, occupational therapists train patients to execute their activities of daily living, including their jobs, and therefore focus on the upper extremities. In practice, differences between physical therapists and occupational therapists depend to a great extent on individual interest, referral patterns, and the community setting. For the purpose of this chapter, the term physical therapy is understood to include the activities of the occupational therapist, recognizing the potential disservice of this oversimplification. For specific presenting complaints, the physical therapist can provide a diagnostic opinion and treat with the goal of cure. Treatments offered include passive modalities, performed by the therapist on a passive patient, and active treatments performed by the patient under the therapist’s guidance, such as exercise and relaxation techniques. For patients whose disease process may not be curable, such as patients with fibromyalgia, the therapist provides patient education in self-management techniques, including home pain control strategies, pacing, proper body mechanics and posture, general or regional conditioning, and the use of aids or special techniques to maximize function. Methods for symptomatic reduction of pain are offered. In patients with specific functional goals, such as achievements in work or athletics,

the physical therapist may perform a functional capacity assessment to provide rational recommendations for return to activity, for modifications of activity, or for a tailored functional restoration program designed to achieve specific realistic goals. The following sections elaborate on these points with the goal of helping the physician maximize the effectiveness of a relationship with the physical therapist.

DIAGNOSTIC ASSESSMENT The physical therapist is trained to perform in-depth musculoskeletal assessment. Sprains, myofascial pain, tendonitis, bursitis, facet joint syndromes, and other such entities can pose diagnostic dilemmas to the physician that the physical therapist can often clarify. These syndromes often have underlying causes, such as poor posture, a suboptimal workstation, repetitive strain, or inadequate strength of a group of muscles to meet their demand. The physician often overlooks these predisposing biomechanical factors, resulting in recurrence of symptoms after “successful” treatment. For example, trochanteric bursitis may result from tightness of the tensor fascia lata muscle; injection of the bursa temporarily corrects the problem, only to be followed inevitably by recurrence until the underlying muscle problem is addressed. A group of musculoskeletal disorders exists, recognized and treated by osteopaths, chiropractors, and manually trained physical therapists, for which there is scant language or acceptance in the orthodox medical community. Examples include misalignment of the joints of the spine, subluxations, and a variety of soft tissue syndromes. Such syndromes may be classified under the rubric of manual medicine. Whereas orthodox physicians may dispute the existence of these syndromes and the hypotheses offered to explain symptoms, the manually trained physical therapist can help recognize such syndromes and discuss them in a language acceptable to physicians. In addition to diagnosing the patient’s condition, the physical therapist is enormously useful in assessing the patient’s function. Though addressed in some way by all physical therapists,

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Headache and Pain W Treatment of Pain

or her psychosocial and environmental history. Trial-and-error approaches often are necessary. The patient should be warned that it may take months to develop an optimum regimen and that only rarely will pain be eradicated completely.

SUGGESTED READINGS Carr DB, Jacox AK: Acute Pain Management Clinical Practice Guidelines. Agency for Health Care Policy and Research, US Department of Health and Human Services, Pub. No. 92-0032, Rockville, MD, 1992 Casey K L Pain and Central Nervous System Disease. Raven Press, New York, 1991 Fields HL: Pain Syndromes in Neurology. Butterworths, London, 1990

Jacox AK, Carr DB: Management of Cancer Pain Clinical Practice Guidelines. Agency for Health Care Policy and Research, US Department of Health and Human Services, Pub. No. 94-0592, Rockville, 1994

Loeser JD: Bonica’s Management of Pain. 3rd Ed. Lippincott Williams & Wilkins, Philadelphia, 2001 Mann RD: The History of the Management of Pain. Parthenon Publishing, Carnforth, 1988 Patt RB: Cancer Pain. JB Lippincott, Philadelphia, 1993 Stein C: Opioids in Pain Control. Cambridge University Press, Cambridge, UK, 1999 Turk DC, Melzack R Handbook of Pain Assessment. Guilford, New York, 1992

Wall PD, Melzack R Textbook of Pain. 4th Ed. Churchill Livingstone, Edinburgh, 1999

228 Physical Therapy and Transcutaneous Nerve Stimulation Nathaniel P. Katz and Susan LaViolette Often, the most useful consultant in chronic pain management is the physical therapist, with the psychologist a close second. Once diagnostic imperatives have been excluded, most patients are diagnosed with musculoskeletal pain syndromes, the conservative treatment of which may be most effectively carried out by the physical therapist. The physical therapist provides an array of services: Diagnostic assessment of the patient’s condition and function Treatment of specific conditions Symptomatic reduction of pain Patient education Restoration of function Occupational therapists also carry out these functions, and distinguishing between the two services can be confusing. Generally, occupational therapists train patients to execute their activities of daily living, including their jobs, and therefore focus on the upper extremities. In practice, differences between physical therapists and occupational therapists depend to a great extent on individual interest, referral patterns, and the community setting. For the purpose of this chapter, the term physical therapy is understood to include the activities of the occupational therapist, recognizing the potential disservice of this oversimplification. For specific presenting complaints, the physical therapist can provide a diagnostic opinion and treat with the goal of cure. Treatments offered include passive modalities, performed by the therapist on a passive patient, and active treatments performed by the patient under the therapist’s guidance, such as exercise and relaxation techniques. For patients whose disease process may not be curable, such as patients with fibromyalgia, the therapist provides patient education in self-management techniques, including home pain control strategies, pacing, proper body mechanics and posture, general or regional conditioning, and the use of aids or special techniques to maximize function. Methods for symptomatic reduction of pain are offered. In patients with specific functional goals, such as achievements in work or athletics,

the physical therapist may perform a functional capacity assessment to provide rational recommendations for return to activity, for modifications of activity, or for a tailored functional restoration program designed to achieve specific realistic goals. The following sections elaborate on these points with the goal of helping the physician maximize the effectiveness of a relationship with the physical therapist.

DIAGNOSTIC ASSESSMENT The physical therapist is trained to perform in-depth musculoskeletal assessment. Sprains, myofascial pain, tendonitis, bursitis, facet joint syndromes, and other such entities can pose diagnostic dilemmas to the physician that the physical therapist can often clarify. These syndromes often have underlying causes, such as poor posture, a suboptimal workstation, repetitive strain, or inadequate strength of a group of muscles to meet their demand. The physician often overlooks these predisposing biomechanical factors, resulting in recurrence of symptoms after “successful” treatment. For example, trochanteric bursitis may result from tightness of the tensor fascia lata muscle; injection of the bursa temporarily corrects the problem, only to be followed inevitably by recurrence until the underlying muscle problem is addressed. A group of musculoskeletal disorders exists, recognized and treated by osteopaths, chiropractors, and manually trained physical therapists, for which there is scant language or acceptance in the orthodox medical community. Examples include misalignment of the joints of the spine, subluxations, and a variety of soft tissue syndromes. Such syndromes may be classified under the rubric of manual medicine. Whereas orthodox physicians may dispute the existence of these syndromes and the hypotheses offered to explain symptoms, the manually trained physical therapist can help recognize such syndromes and discuss them in a language acceptable to physicians. In addition to diagnosing the patient’s condition, the physical therapist is enormously useful in assessing the patient’s function. Though addressed in some way by all physical therapists,

Chapter 228

functional assessment has evolved into a full subspecialty. The physical therapist can compare the patient’s present functional abilities to those needed for his or her employment, sport, or demands at home, set reasonable goals, and guide the patient through a functional restoration program designed to achieve those goals. Such assessments and programs are particularly useful in the patient with a work-related injury or disability. Formal functional capacity assessment documents the patient’s abilities at the time of the assessment. The physician can use this information to make rational and consistent recommendations regarding return to work or other activities, which, among other advantages, reduces the liability of returning an injured worker to the job. In summary, referral to the physical therapist for diagnostic assessment is most useful when the patient suffers from a musculoskeletal disorder of which the exact nature is unclear, when underlying biomechanical predisposing factors may exist, and when functional assessment and goal setting are important, such as in the injured worker. PASSIVE TREATMENT MODALITIES Modalities are defined as passive treatments performed by the physical therapist on the patient. In general, the physical therapist applies treatment modalities to aid in the recovery from acute injury, to reduce pain during the initiation phase of an active exercise program, and to prevent or reduce exacerbations produced by individual exercise sessions. Modalities alone are frowned on in the chronic pain setting because they do not contribute to resolution of the painful disorder, do not resolve deconditioning, do not restore function, are not logically timelimited, and promote further dependence of the patient on the health care provider. We have been frustrated numerous times by the patient who has exhausted insurance physical therapy benefits on a useless course of passive modalities, only to be denied potentially effective therapy when properly evaluated. The common passive modalities are described in this section. ICe

Little scientific data exist to determine whether ice or heat is preferable. Ice is preferred in acute injuries because it decreases inflammation, swelling, and muscle spasm; heat worsens inflammatory injury. Ice is also helpful in chronic pain, especially after activity or during flare-ups. The analgesic effect of ice appears to last longer than that of heat. The benefits of ice are thought to derive from vasoconstriction, decreased nerve conduction velocity, a counterirritant effect, decreased vascular permeability and leukocyte activity, and decreased muscle spindle activity, leading to reduced muscle spasm. Ice may be applied using a variety of commercially available cold packs, immersion in ice water, or application of an ice stick. Perhaps the major advantage of ice is that patients can be taught to apply it at home with minimal expense or difficulty. Relative contraindications include vascular insufficiency, anesthetic skin, vasospastic disorders, and poorly healing wounds. Heat

Heat application is one of the oldest treatments for pain. Benefits include improved tissue circulation, relief of muscle spasm, analgesia, and increased flexibility of muscle and connective tissue. Heat generally is used before exercise to increase flexibility of tight

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muscles and stiff joints and for flare-ups of pain. Relative contraindications include acute injury (to avoid increased swelling), .cardiorespiratory failure (because of the increased cardiac output when much of the body is warmed), circulatory compromise, sensory impairment or obtundation, and multiple sclerosis. Numerous methods for applying heat have been developed. Hot packs are simple, effective, and least expensive. The heat remains superficial; therefore, the mechanism of relief of muscle spasm is not clear. Hydrocollator packs contain a silicone gel that retains heat for approximately 30 minutes, and they have similar effects to the heating pad. Electric heating pads are more expensive and must be used with caution, especially if they do not automatically shut off. An extremity can be dipped in a hot paraffin bath, which coats the limb with hot paraffin wax and heats the limb as the wax solidifies and cools. Whirlpools can be used to immerse a limb or the whole body, and exercise can be performed in a heated pool. These treatments are used for patients with widespread joint or muscular involvement, as in rheumatoid arthritis or fibromyalgia. Infrared radiation can be used to apply heat, but it heats superficially and probably has no advantage over a hot pack. Heating of deeper tissues requires one of the following methods. In short-wave diathermy, the patient is placed in an electromagnetic field. The impedance of the patient completes the circuit, causing tissue heating. Muscles may be heated directly using this method. Although it is in common use and theoreticallyattractive, the clinical advantages of this method are unclear. In microwave diathermy, the patient is placed in a microwave field, producing deep heating mainly of muscle and subcutaneous tissue. Ultrasound is a popular method that produces deep, localized heat, particularly at the soft tissue-bone interface. It has been found to be particularly useful in bursitis, periarthritic conditions, joint contractures, scar syndromes, and myofascial pain.

Electricity has been used since antiquity to treat a variety of ailments. Today electricity may be applied in several different forms. Direct current or galvanic stimulation is used to stimulate muscle contraction to prevent atrophy and speed muscular rehabilitation. Its use for pain is less well documented. Interferential therapy uses alternating current. Two pairs of electrodes are situated on the skin and aligned so that the two electric fields intersect at the site of pain. This allows the operator to selectively stimulate and heat deep tissue structures. Transcutaneous electrical nerve stimulation is described later in this chapter. Massage Massage has a long and venerable history in the treatment of pain and as a general health tonic. We have yet to meet anyone who would deny the beneficial and invigorating effects of a massage on mind and body. Massage enhances the flexibility of muscle and connective tissue, improves peripheral circulation, helps restore lymph flow, and can loosen scar or tight connective tissue. Massage can help prepare tissues for active exercise. Long-term regular massage therapy, though pleasurable and temporarily analgesic for many musculoskeletal conditions, like the other passive modalities, can lead to dependence on the part of the patient and in patients with chronic pain usually does not contribute to enduring symptom resolution. Therefore, massage as sole treatment generally is not appropriate in managing chronic pain.

Headache and Pain

Treatment of Pain

Traction

Traction is the application of a tonic force to a part of the body to distract soft tissues and joints. Benefits include pain relief, rest, immobilization, restoration of proper alignment, and preparation of tissues for active exercise or manipulation. Sufficient weight and proper angle of pull are important. For cervical traction, weight begins at about 25 pounds, applied at an angle of 20 degrees of flexion. Pelvic traction for lumbar pain begins at about 80 pounds at an angle of about 20 degrees of flexion. Studies have demonstrated minimal if any benefit of traction for lumbar pain but significant benefit for cervical disorders. Home traction units are available. Contraindications include tumor, cord compression, infection, and severe arthritis or osteoporosis.

Rest or splinting of an injured part probably is the oldest treatment for acute injuries, is the first step toward healing of an injured part, and remains a mainstay in treating acute pain. Even in chronic pain, rest and immobilization are useful for acute flare-ups or as part of a pacing regimen when activity increases pain. Immobilization can be achieved by simple rest or by use of supportive devices. For example, judicious use of a cervical collar in patients with chronic neck pain can allow patients to increase their function or to manage activity-induced flare-ups. In the patient with low back pain, rest after a period of activity constitutes healthy pacing. Supportive devices can be used to allow continued work that would otherwise be impossible, such as the wrist splint for the typist with carpal tunnel syndrome. However, long-term immobilization has caused much misery and disability. Consequences include weakness and atrophy of muscles, deconditioning, joint contractures, and osteoporosis. Prolonged immobilization probably causes a number of chronic pain syndromes, including reflex sympathetic dystrophy and some myofascial pain. For low back pain, about 2 days of bed rest probably is optimal; more does not help and probably hurts. Therefore, rest and immobilization must be prescribed judiciously, usually combined with an active exercise program. Supportive Devices

The physical therapist can be very helpful in prescribing supportive devices to reduce pain, improve function, or increase activities of daily living. Examples include canes to improve balance and increase ambulation, back braces to reduce back pain and allow increased activity, and gripping devices to aid in removing bottle tops or manipulating clothing. The cautions mentioned for immobilization apply.

pists may be trained in a variety of manipulative techniques. Debate on the relative merits of these techniques is imbued with heated argument over philosophical, historical, and economic issues, with little scientific evidence. Little can be stated regarding manipulation that would not be disputed by one or another camp. Most authorities and experienced clinicians agree on the following principles. If no improvement is noted after a few (3 to 10) manipulative treatments, treatment should be stopped and reassessed. High-velocity manipulation of the neck probably is dangerous and is best avoided (vertebral artery stroke has resulted). Manipulation without exercises to maintain proper alignment and function often is a sign of an inadequate practitioner. Manipulation is contraindicated in the presence of infection, tumor, fracture, severe osteoporosis, and neural compression. ACTIVE TREATMENT

Therapeutic exercise is one of the cornerstones of chronic pain management and is indispensable to the restoration of function after acute injuries. During the healing phase of an acute injury, passive range of motion often is prescribed to prevent stiffness and contractures that may impede rehabilitation. During therapy sessions exercise often is preceded and followed by the use of passive modalities. In patients with chronic pain, the goals of exercise are increased range of motion and flexibility, increased strength and endurance, decreased muscle spasm, and improved general conditioning and function. A balance must be maintained between giving in to the pain and not exercising sufficiently and overexercising to the point of relapse. Specific exercises to restore particular functions constitute the final phase of rehabilitation before return to previous activities. Educating patients to properly pace their exercise programs is one of the major contributions of the physical therapist to the management and rehabilitation of chronic pain. Aerobic fitness seems to decrease pain perception and is often taught because of its beneficial effects on the sense of well-being and psychological health. The specific exercise regimen prescribed depends on precise diagnosis and the therapist’s judgment. Whereas much energy has been expended debating the relative merits of different exercise regimens for various conditions, literature demonstrating important differences is scant. Several principles are accepted. Diagnosis must be accurate and should be reevaluated if the patient does not respond as expected to therapy. Passive modalities alone are not useful. Programs often begin with passive modalities, followed by gentle exercises to restore mobility. Such exercises include range of motion, stretching, and isometric strengthening, which are not very painful. However, these exercises do little to restore normal functioning and should be advanced to more natural activities, such as biking, swimming, and walking.

Manipulation

Manipulation is movement by the therapist of joints or periarticular tissues to restore normal alignment or range of motion. Though strictly a passive modality, manipulation is somewhat different in that resolution of the underlying disorder is the goal. Several types of manipulation are performed, classified according to whether the structure is moved within its normal range, to the endpoint of its range, or beyond the physiologic range and according to the velocity of motion. Different schools train practitioners in different techniques: Chiropractic incorporates high-velocity thrusts often accompanied by a snapping sound, osteopathy uses somewhat gentler techniques, and physical thera-

TREATMENT OF SPECIFIC CONDITIONS

Little systematic study has addressed whether the treatments are better than natural history, which treatments are best, what is the most effective or cost-effective manner of applying them, and how effectiveness compares with that of other forms of treatment (e.g., medications, injections, and operations). Designing the treatment program therefore is left to the judgment of the individual physical therapist, according to principles as outlined earlier. Treatment programs can be so variable that to state that a patient has already had “physical therapy” without specifymg exactly what therapy was performed is equivalent to stating that a patient has already

Chapter 228

had “medication” for an ailment without specifymg which medication. In general, physical therapy for pain is a short-term proposition. Acute injuries generally resolve rapidly, and the role of the physical therapist is to aid resolution, prevent complications, and educate the patient in a home exercise program, preventive measures, and the use of passive modalities to prevent or treat recurrence. For chronic pain, the goals are to train patients to treat themselves with home modalities, exercises to enhance general conditioning, and exercises to improve the underlying disorder or at least to improve function even if the pain cannot be reduced. In the patient with chronic pain, reducing fear of reinjury and enabling the patient to enjoy normal movement is another explicit goal. Many physical therapists experienced in treating chronic pain also teach relaxation techniques, biofeedback, and other specific treatments.

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exercises and aerobic conditioning. In certain patients, manual therapy to restore normal alignment and mobility of the spine at segmental levels may be needed; however, not all physical therapists are trained in these techniques. In patients with chronic pain, the general rules listed earlier apply. Functional restoration, reduction of fear of reinjury, muscle relaxation techniques, and general conditioning are the pillars of treatment. Manual therapy may be helpful. Return-to-work issues may dominate the picture, and the physical therapist may be helpful in assessing functional capacity, setting functional goals, and advising on the appropriateness of particular jobs. A work-conditioning program, designed to recondition the patient in a general way to meet the physical demands of the work environment, or a work-hardening program, designed to restore the function needed to perform a specific occupational task, may be needed. Usually a physical therapist or physiatrist directs these programs.

Arthritis

For acute flare-ups of arthritis pain, short-term immobilization and analgesics are indicated. For subacute or chronic symptoms, a number of modalities are used to provide symptomatic relief and to permit therapeutic exercise. Paraffin, whirlpool, short-wave diathermy, microwave, or ultrasound may be used to heat the tissues. For widespread arthritis, a heated pool is ideal. Exercises, including stretching, strengthening, and general mobilization and conditioning, may be performed during the period of relative comfort after the use of passive modalities. Myofasdal Pain

The principles of treating myofascial pain are restoring the strength and flexibility of the involved muscles, using passive modalities initially to facilitate exercise, and eliminating underlying factors such as emotional tension or poor posture. Whereas any of the passive modalities can be used initially, patients graduate to home use of ice or heat. Exercises begin with gentle stretching and general conditioning and progress to include strengthening and aerobic activities. Education to empower the patient to eliminate predisposing factors, including stress, completes the therapy. Bursitis and Tendonitis

The acute phase of bursitis or tendinitis is treated with ice, immobilization, and analgesics. Later, passive modalities, usually ice or heat, are applied, followed by passive and active rangeof-motion exercise. Strengthening exercises follow when tolerated, with instruction on proper body mechanics to avoid recurrence of pain. Back and Neck Pain

Aerobic conditioning, “back school,” and stretching and strengthening exercises are the only treatments, other than surgical discectomy, supported by controlled studies on the treatment of low back pain. Most cases of acute back or neck pain resolve without medical intervention. Bed rest is appropriate for a few days, followed by remobilization. Passive modalities are useful in this stage for pain relief and to allow mobilization. The patient can be quickly advanced to a supervised home program, consisting of ice or heat application, followed by strengthening and flexibility

Scar Pain Pain in the region of a surgical scar is a common chronic pain syndrome, worth recognizing in view of its good response to treatment. A variety of physical therapy techniques are used; two of the most useful are friction massage and cortisone phonophoresis.

TRANSCUTANEOUS ELECrCllCAL NERVE STlMULATlON Ancient Egyptians and Greeks were the first to use electricity to treat painful disorders by applying electric fish to the affected areas of desperate patients. Electrical therapy did not become practical until the 19th century, when devices to store and deliver electrical energy became readily available. These devices lost popularity in the early 20th century, but after publication of the gate control theory of pain in 1965, interest was renewed. The theory implied that stimulation of large, myelinated afferent fibers in the peripheral nerve would have an inhibitory effect on pain. Efforts began to implant electrostimulating devices to stimulate the peripheral nerves and spinal cord. Transcutaneous electrical nerve stimulation was developed as a method to screen patients who might benefit from spinal cord stimulation but became a therapy in its own right as its effectiveness became known. Technical Considerations

The transcutaneous electrical nerve stimulation unit consists of one or more pairs of electrodes attached by cables to a handheld electrical stimulator. Stimulation generally is delivered in either conventional mode, which elicits paresthesias, or acupuncture-like mode, which produces muscle contractions. The waveform refers to the contour of each electrical pulse and may be monophasic or biphasic. The frequency of stimulation determines whether paresthesias or muscle contractions are felt. Conventional transcutaneous electrical nerve stimulation uses 20 to 100 Hz; acupuncture-like transcutaneous electrical nerve stimulation uses 1 to 2 Hz. The pulse width and amplitude are adjusted to produce as strong a paresthesia in the painful area as is comfortable to the patient. Although many recommendations specifying the best electrical parameters and electrode placements have been given, there are no adequate scientific studies comparing the different parameters.

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Treatment of Pain

Technique Clinical experience suggests beginning with the conventional mode and placing electrodes to achieve paresthesias in the painful area. Placing electrodes over the area itself or over the nerve innervating the area can be effective. A second pair of electrodes can be placed paraspinally at the level of the pain. If conventional transcutaneous electrical nerve stimulation fails, acupuncture-like stimulation can be tried.

Indications Transcutaneous electrical nerve stimulation has been best studied in the relief of acute postoperative pain. Controlled studies have demonstrated benefit after thoracotomy, upper abdominal surgery, and knee surgery, with improvement in pain and function and decreased opioid needs. Controlled studies have also demonstrated good results in labor pain with no adverse effects on the fetus. In chronic pain, well-controlled studies are scant. Evidence suggests that pain related to peripheral nerve injury responds well. Musculoskeletal pain may respond as well, although one controlled study in patients with chronic low back pain showed no benefit. Visceral and psychogenic pains do not respond well.

Contraindications The major adverse effect of transcutaneous electrical nerve stimulation is skin irritation from the electrodes or tape. Placing

the stimulator on anesthetic areas of skin can result in burns. Patients with demand pacemakers should not use this technique.

Effectiveness Transcutaneous electrical nerve stimulation is a useful form of therapy, particularly in certain postoperative pain states, neuropathic pain, and regional musculoskeletal pains. Its lack of serious side effects makes it attractive. Effectiveness requires an experienced practitioner. The unit should be prescribed for long-term use only after a successful trial.

SUGGESTED READINGS Birnbaum JS: The Musculoskeletal Manual. 2nd Ed. W B Saunders, Philadelphia, 1986 Cotter DJ: Overview of transcutaneous electrical nerve stimulation for treatment of acute postoperative pain. Med Instrum 17:289, 1983 Kottke FJ, Stillwell GK, Lehmann JF et al: Krusen’s Handbook of Physical Medicine and Rehabilitation. 3rd Ed. WB Saunders, Philadelphia, 1982 Lee MHM, Itoh M, Yang GF, Eason A Physical therapy and rehabilitation medicine. pp. 1769-1788. In Bonica JJ (ed): The Management of Pain. 2nd Ed. Lea & Febiger, Philadelphia, 1990 Lehmann J F Therapeutic Heat and Cold. 3rd Ed. Williams & Wilkins, Baltimore, 1982 Melzack R, Wall P Pain mechanisms: a new theory. Science 150971, 1965

229 Psychological Evaluation and Treatment of

Chronic Pain Robert N. Jamison The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” This definition recognizes that pain is an emotional as well as a sensory phenomenon. Pain is the most common reason to see a physician; epidemiologic studies have independently documented that chronic noncancer pain is an international problem of immense proportions. Chronic pain influences every aspect of a person’s functioning, and profound changes in quality of life are associated with intractable chronic pain. Significant interference with sleep, employment, social function, and daily activities is common. Patients with chronic pain often report depression, anxiety, irritability, sexual dysfunction, and decreased energy. Family roles are altered, and worries about financial limitations and future consequences of a restricted lifestyle abound. Patients with chronic back pain generally present with a history of multiple medical procedures, yielding minimal physical findings.

PSYCHOLOGICALASSESSMENT OF CHRONIC PAIN Important components of chronic pain that must be evaluated as part of a psychological assessment include pain intensity, functional capacity, mood and personality, coping and pain beliefs, and medication usage. In addition, a behavioral analysis should be conducted and information on psychosocial history, adverse effects of treatment, and health care use should be obtained.

Semistructured Interview The most popular means of evaluating the psychological state of the patient is a semistructured interview. Pertinent information acquired during an interview often is given significant weight when a treatment decision is made. Before meeting with the patient, the interviewer should review all referral information, including discharge summaries, psychological testing results, previous physicians’ notes, and medical history reports. Each of

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Treatment of Pain

Technique Clinical experience suggests beginning with the conventional mode and placing electrodes to achieve paresthesias in the painful area. Placing electrodes over the area itself or over the nerve innervating the area can be effective. A second pair of electrodes can be placed paraspinally at the level of the pain. If conventional transcutaneous electrical nerve stimulation fails, acupuncture-like stimulation can be tried.

Indications Transcutaneous electrical nerve stimulation has been best studied in the relief of acute postoperative pain. Controlled studies have demonstrated benefit after thoracotomy, upper abdominal surgery, and knee surgery, with improvement in pain and function and decreased opioid needs. Controlled studies have also demonstrated good results in labor pain with no adverse effects on the fetus. In chronic pain, well-controlled studies are scant. Evidence suggests that pain related to peripheral nerve injury responds well. Musculoskeletal pain may respond as well, although one controlled study in patients with chronic low back pain showed no benefit. Visceral and psychogenic pains do not respond well.

Contraindications The major adverse effect of transcutaneous electrical nerve stimulation is skin irritation from the electrodes or tape. Placing

the stimulator on anesthetic areas of skin can result in burns. Patients with demand pacemakers should not use this technique.

Effectiveness Transcutaneous electrical nerve stimulation is a useful form of therapy, particularly in certain postoperative pain states, neuropathic pain, and regional musculoskeletal pains. Its lack of serious side effects makes it attractive. Effectiveness requires an experienced practitioner. The unit should be prescribed for long-term use only after a successful trial.

SUGGESTED READINGS Birnbaum JS: The Musculoskeletal Manual. 2nd Ed. W B Saunders, Philadelphia, 1986 Cotter DJ: Overview of transcutaneous electrical nerve stimulation for treatment of acute postoperative pain. Med Instrum 17:289, 1983 Kottke FJ, Stillwell GK, Lehmann JF et al: Krusen’s Handbook of Physical Medicine and Rehabilitation. 3rd Ed. WB Saunders, Philadelphia, 1982 Lee MHM, Itoh M, Yang GF, Eason A Physical therapy and rehabilitation medicine. pp. 1769-1788. In Bonica JJ (ed): The Management of Pain. 2nd Ed. Lea & Febiger, Philadelphia, 1990 Lehmann J F Therapeutic Heat and Cold. 3rd Ed. Williams & Wilkins, Baltimore, 1982 Melzack R, Wall P Pain mechanisms: a new theory. Science 150971, 1965

229 Psychological Evaluation and Treatment of

Chronic Pain Robert N. Jamison The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” This definition recognizes that pain is an emotional as well as a sensory phenomenon. Pain is the most common reason to see a physician; epidemiologic studies have independently documented that chronic noncancer pain is an international problem of immense proportions. Chronic pain influences every aspect of a person’s functioning, and profound changes in quality of life are associated with intractable chronic pain. Significant interference with sleep, employment, social function, and daily activities is common. Patients with chronic pain often report depression, anxiety, irritability, sexual dysfunction, and decreased energy. Family roles are altered, and worries about financial limitations and future consequences of a restricted lifestyle abound. Patients with chronic back pain generally present with a history of multiple medical procedures, yielding minimal physical findings.

PSYCHOLOGICALASSESSMENT OF CHRONIC PAIN Important components of chronic pain that must be evaluated as part of a psychological assessment include pain intensity, functional capacity, mood and personality, coping and pain beliefs, and medication usage. In addition, a behavioral analysis should be conducted and information on psychosocial history, adverse effects of treatment, and health care use should be obtained.

Semistructured Interview The most popular means of evaluating the psychological state of the patient is a semistructured interview. Pertinent information acquired during an interview often is given significant weight when a treatment decision is made. Before meeting with the patient, the interviewer should review all referral information, including discharge summaries, psychological testing results, previous physicians’ notes, and medical history reports. Each of

Chapter 229 W

the following categories should be assessed during the interview: pain description, aggravating factors, daily activity level, relevant medical history, past and current treatments, education and employment history, compensation status, history of drug or alcohol abuse, history of psychiatric disturbance, current emotional status and social support, and perceived directions for treatment. These areas have been identified as important in assessing candidacy for medical interventions for pain. Whenever possible the spouse, the significant other, or a close family member of each patient should be interviewed. Pain Intensity Measures

One of the primary goals of treatment for chronic pain is to decrease the intensity of the pain. As a result, it is important to monitor pain intensity both for a period before treatment and throughout the course of treatment. There are a number of ways to measure pain intensity, including numerical pain ratings, visual analogue scales, and verbal rating scales (Table 229-1). Numerical pain ratings often involve the patient’s rating of his or her pain on a scale of 0 to 10 or 0 to 100. Descriptive anchors that help the patient understand the meaning of each numerical value improve the measure. Another popular means of measuring pain intensity is the visual analogue scale, which uses a straight line (often 10 cm long) with extreme limits of pain at either end (e.g., “no pain” to “worst pain possible”). The patient is instructed to place a mark at the point on the line that best indicates present pain intensity. Scores are obtained by measuring the distance from the end labeled “no pain” to the mark provided by the patient. The disadvantages of this method are that it is time consuming to score and that its validity for older patients is questionable. Handheld computers enable visual analogue scale entry by screen touch with a stylus, and electronic diaries can aid in more complete and timely collection of patient diary data. There are a number of verbal rating scales, which consist of words (as few as 4 or as many as 15, often ranked in order of intensity from “no pain” to “excruciatingpain”), which are chosen

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by the patients to describe their pain. Verbal scales not only measure pain intensity but also assess sensory and reactive dimensions of the pain experience. Verbal scales can be used to measure the descriptive nature of pain; the patient chooses words from a list that best describe the pain experience (e.g., “piercing,” “stabbing,” “shooting,” “burning,” or “throbbing”). Of all of the self-report measures, numerical rating scales are most popular among professionals. However, there is no evidence to suggest that visual analogue scales or verbal rating scales are any less sensitive to treatment effects. All of these measures have been shown to be acceptable in quantifymg clinical pain. The McGill Pain Questionnaire is a frequently used comprehensive questionnaire that includes 20 subclasses of descriptors, a numerical pain intensity scale, and a dermatomal pain drawing. A short form of the McGill Pain Questionnaire is also popular. The questionnaire measures various aspects of the pain experience and is sensitive to treatment effects and differential diagnosis.

Mood and Personality Assessment Patients with pain often show signs of depression and anxiety. Psychopathology or extreme emotionality has been seen as a contraindication for certain therapies. There is ongoing debate among mental health professionals about the best way to measure psychopathology or emotional distress in patients with chronic pain. Most measures are helpful in ruling out severe psychiatric disturbance; unfortunately, none can boast validity in predicting treatment outcome. The measures most commonly used to evaluate personality and emotional distress include the Minnesota Multiphasic Personality Inventory, the Symptom Checklist 90, the Millon Behavior Health Inventory, the Illness Behavior Questionnaire, and the Beck Depression Inventory. Functional Capacity and Activity Interference Measures

Some clinicians consider pain reduction meaningless if there is no noticeable change in function. Therefore, some reliable measure-

rn Turc 229-1. Pain Rating Scales Examples of Verbal Rating Scales of Pain Intensity 1. No pain 2. Mild 3. Moderate 4. Severe

1. None 2. Mild 3. Moderate 4. Severe 5. Very severe

1. No pain 2. Mild 3. Discomforting 4. Distressing 5. Horrible 6. Excruciating

1. Not noticeable 2. Just noticeable 3. Very weak 4. Weak 5. Mild 6. Moderate 7. Strong 8. Intense 9. Very strong 10. Severe 1 1. Very intense 12. Excruciating

1. None 2. Extremely weak 3. Just noticeable 4. Very weak 5. Weak 6. Mild 7. Moderate 8. Uncomfortable 9. Strong 10. Intense 1 1. Very strong 12. Very intense 13.Extremely intense 14. Intolerable 15. Excruciating

Examole of Numerical Pain Ratinn Scale

0 No pain

1

2

3

4

5

6

7

8

10 Worst pain possible

9

Example of Visual Analogue Scale I

No Dain

I

Wont pain possible

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ment of functional capacity should be used before the onset of therapy. A noticeable increase in level of activity helps to justify continued therapy and supports treatment efficacy. A number of self-report measures can be used to assess activity level and function: the Sickness Impact Profile, the Short-Form Health Survey, the Multidimensional Pain Inventory, and the Pain Disability Index. Automated measurement devices, such as the portable up-time calculator and the pedometer, are useful in obtaining accurate measures of activity. These devices should be used in conjunction with self-monitoring assessment techniques. Performance measures of function include the Modified Symptom Limited Treadmill Test and the Fingertip to Floor Distance Test. The first test has much in common with the 6-minute treadmill walking test, where distance is measured by how fast a patient is able to walk on a treadmill in 6 minutes. In the latter test, patients are asked to bend forward as far as possible without bending the knees, and the distance from the tip of the middle finger to the floor is measured. These tests assess aerobic capacity and range of motion in the lumbar spine but are not always highly correlated with pain or disability. Pain Beliefs and Coping Measures Pain perception, beliefs about pain, and coping mechanisms are important in predicting the outcome of treatment. Unrealistic or negative thoughts about an ongoing pain problem may contribute to increased pain and emotional distress, decreased functioning, and greater reliance on medication. Certain patients with chronic pain are prone to maladaptive beliefs about their condition that may not be compatible with the physical nature of their pain. Patients with adequate psychological functioning exhibit a greater tendency to ignore their pain, use coping self-statements, and remain active to divert their attention from their pain. Because efficacy expectations have been shown to influence the efforts patients make to manage their pain, measures of selfefficacy or perceived control are useful in assessing a patient’s attitude. A number of self-report measures assess coping and pain attitudes. The most popular tests used to measure maladaptive beliefs include the Coping Strategies Questionnaire, the Pain Management Inventory, the Pain Self-Efficacy Questionnaire, the Survey of Pain Attitudes, and the Inventory of Negative Thoughts in Response to Pain. Newer instruments currently being tested include the Pain Beliefs and Perceptions Inventory and the Chronic Pain Self-Efficacy Scale. Patients who catastrophize, who are passive in coping with pain, who demonstrate low self-efficacy regarding their ability to manage their pain, who describe themselves as disabled by their pain, and who report frequent negative thoughts about their pain are at greatest risk for poor treatment outcome. It is suspected that patients who have unrealistic beliefs and expectations about their condition are also poor candidates for pain treatment. Monitoringof Medication and Adverse Effects Compliance is an important component in decisions about whether to continue, discontinue, or modify treatment for chronic pain. Clinicians ask patients to comply with their treatment protocol but rarely come up with a way to monitor compliance, particularly medication usage. A patient’s retrospective report of use of medication, although of value, is subject to inaccuracies. Recall can be enhanced if the patient continuously monitors usage. In addition, both compliance and accuracy in reporting are improved if a family member assists with the monitoring.

Medication records kept by patients should include the name of the medication, the date and time when it is taken, and the dosage. Adverse effects should be monitored regularly during treatment for chronic pain. Monitoring side effects related to medication use often is neglected in clinical practice but can be as important as monitoring pain intensity. Periodic monitoring of adverse effects by means of a checklist can provide objective criteria useful in assessing treatment. Such a checklist may include drowsiness, dizziness, coordination impairment, irritability, depression, headache, memory lapse, dry mouth, visual distortions, nausea or vomiting, sweating, constipation, heart palpitations, itching, breathing problems, nightmares, and difficulty urinating. Although patients often report adverse reactions to medication during the initial stage of treatment, many of these reactions diminish over time. Portable monitors using customized software have made the collection and storage of serial data about health behaviors both convenient and affordable. Electronic diaries allow two-way communication between patients and providers and may be an efficient means of evaluating and tracking medication use and associated symptoms. With the advent of handheld computers and the ability to capture time-stamped data and store it for uploading to a larger computer, more investigators are exploring options of capturing data throughout the day. Ecological momentary assessment consists of frequent data captured from patients in their natural environment. Studies have shown that “natural” data are less prone to fabrication and may be a truer indicator of patient responses in the environment. Patients are shown to demonstrate remarkably high compliance with electronic diary monitoring. Neuropsychological Testing As part of a comprehensive psychological assessment, a patient’s neuropsychological status must first be determined. In cases of physical trauma, such as head injury, or in cases of decreased cognitive functioning, neuropsychological assessment may be indicated. Such an assessment is important in evaluating potential organic pathology that may limit the usefulness of cognitive interventions. A number of neuropsychological assessment tools exist for such evaluations.

Substance Abuse Assessment Structured interview measures have been published for assessing alcoholism and drug abuse. Whenever possible, the patient’s family members or significant other should also be interviewed. The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), is a semistructured diagnostic interview that assigns current and lifetime diagnoses based on D S M - N criteria. For each positive identification of a symptom, it follows a question sequence to determine whether the symptom meets severity criteria for diagnosis. Other substance abuse measures include the CAGE Questionnaire, the Michigan Alcoholism Screening Test, and the Self-Administered Alcoholism Screening Test.

PSYCHOLOGICAL APPROACHES TO PAIN MANAGEMENT Goals of Psychological Interventions Patients with chronic pain who consult primary care physicians, pain specialists, pain services, or pain management programs usually are experiencing a significant degree of psychological

Chapter 229

distress that warrants intervention. Regardless of the setting, a number of treatment goals are relevant to the care of the patient with chronic pain: reduction of pain intensity, increased physical functioning, control of medication use, improvement in sleep, mood, and interaction with others, and eventual return to work or to normal daily activities.

Reduction of Pain Intensity A persistent pain problem is the reason most patients enter a pain management program. However, in such a program patients are taught not to set pain reduction as their primary treatment goal. Instead, they are encouraged to focus on other, more attainable goals. Although the elimination of pain is rarely reported, patients often describe a reduction in the intensity of their pain by the conclusion of a structured pain program.

Increased Physical Functioning Most interventions support regular exercise, including stretching, cardiovascular reconditioning, and weight training. Patients are encouraged to exercise regularly and to increase their activity at a progressive rate while under supervision. The goal is to gradually increase function without exceeding predetermined limits of pain and discomfort.

Control of Medication Use Through education and daily monitoring, most patients are able to use prescription pain medications responsibly. Patients often are requested to monitor and record their daily medication use as a way to become aware of patterns and any associated side effects.

Improvement in Sleep, Mood, and Interaction with Others Most patients report depression, problems relating to other people, and difficulties with memory and attention. Techniques aimed at decreasing emotional distress and increasing self-esteem should be considered in these instances.

Return to Work or to Normal Daily Acthries Patients who set as their goal an eventual return to work often are successful. Follow-up helpfulness ratings indicate that patients who have a positive experience in a pain management program tend to return to work or maintain an active, productive lifestyle. PSYCHOLOGICAL INTERVENTIONS AND PROGRAM COMPONENTS Education Most people with chronic pain have an inadequate understanding of the nature of their painful condition. It is important for them to be knowledgeable about their pain and the treatments designed for them. Information can be conveyed through patient manuals on chronic pain, video presentations, handouts, or individual sessions. An optimal way to educate patients is through didactic groups; however, individual psychoeducational training may be useful as well. Topics for these educational sessions may include physiology of pain, medication for chronic pain, exercise and pain, stress management, sleep disturbance, assertiveness training, posture and body mechanics, problem solving, weight management and nutrition, vocational rehabilitation, sexual issues,

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positive thinking, and relapse prevention. In general, patients who understand their condition and who have been exposed to relevant management techniques maintain a perception of control over their pain and show higher rates of success in meeting their goals. Active learning techniques, including the completion of homework such as periodic surveys, checklists, diaries, or questionnaires and brainstorming, should be emphasized. The ultimate goal of any intervention is to increase the patient’s perceived control over pain. Several themes critical to a pain management approach should be highlighted throughout a structured program: You will probably not be “cured,” you must expect ups and downs, rarely does pain intensity remain exactly the same over time, you need a fallback plan for times when you have a flare-up of pain, what you do about your pain may be as beneficial as anything that is done to you, and you need to work toward gaining control over your condition with the help of medical treatments and psychological pain management strategies. Repetition will ensure that patients leave with an understanding of these important principles.

Relaxation Training Patients with chronic pain tend to experience substantial residual muscle tension as a function of the bracing, posturing, and emotional arousal often associated with pain. Such responses, maintained over a long period, can exacerbate pain in injured areas of the body and can increase muscular discomfort. For example, it is common for patients with low back pain or limb injuries to develop neck stiffness and tension-type headaches. Relaxation training has been recommended as a way to reduce pain by relaxing tense muscle groups, reducing symptoms of anxiety, using distraction, and enhancing self-efficacy. In addition, this training can increase the patient’s sense of control over physiologic responses. In a pain management intervention, patients are taught and encouraged to practice a variety of relaxation strategies, including diaphragmatic breathing, progressive muscle relaxation, autogenic relaxation, self-hypnosis, and cue-controlled relaxation. Biofeedback training may also be used. Live demonstrations of these techniques are preferable to verbal explanations. All patients should be encouraged to practice each technique at home, and cassette tapes can be made or purchased for practice purposes.

Cognitive and Behavioral Therapy Patients with pain often show signs of emotional distress, with evidence of depression, anxiety, and irritability. Therapy with a cognitive and behavioral orientation is designed to help patients gain control of the emotional reactions associated with chronic pain. Specific problem-solving strategies can be offered during therapy sessions, including identifymg maladaptive and negative thoughts, disputing irrational thinking, constructing and repeating positive self-statements, learning distraction techniques, working to prevent future catastrophizing, and examining ways to increase social support. Personal relationship issues can also be explored. The patient’s strengths and positive coping mechanisms should be emphasized. Cognitive and behavioral therapy has a number of objectives. The first is to help patients change their view of their problem from overwhelming to manageable. Patients who are prone to catastrophize benefit from examining the way they view their situation. What might otherwise be perceived as a hopeless

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condition can be reframed as a difficult yet manageable condition over which the patient can exercise some control. The second objective is to help convince patients that treatment is relevant to their problem and that they need to be actively involved in their own treatment and rehabilitation. Patients need to understand how relaxation training, cognitive restructuring, adaptive coping skills, and pacing behaviors can help decrease their pain. They also need to reorient their view away from that of passive victim and toward that of proactive, competent problem solver. When patients are successful in managing difficult painful episodes, their views change. They eventually begin to believe themselves capable of overcoming any acute flare-up of pain. The third objective is to teach patients to monitor maladaptive thoughts and substitute positive thoughts. People with chronic pain are plagued, either consciously or unconsciously, by negative thoughts related to their condition. These negative thoughts have a way of perpetuating pain behaviors and feelings of hopelessness. Demonstrating how and when to attack these negative thoughts and when to substitute positive thoughts and adaptive management techniques for chronic pain is an important component of cognitive restructuring. Patients are encouraged to attribute success to their own efforts; they need to know that they are responsible for the gains they make. Finally, future problems and lapses need to be discussed so that the patient will have a plan to manage short-term setbacks.

Physical Activity and Exercise

Most patients are deconditioned because of their reluctance to exercise and because of a perceived need to protect themselves. Some patients have been medically advised to restrict activity when pain increases. Patients with chronic pain need to know that exercise is important. Some stretching, cardiovascular activity, and weight training should be encouraged. Each patient should be asked to keep track of his or her activity in an exercise record. It is important to set an exercise quota so that the patient will work to meet a weekly goal. The exercise plan should initially be determined by the patient and reviewed and supervised by a physical therapist or exercise physiologist. Patients should be instructed to stretch before and after each exercise session. Any attempt by patients with chronic pain to exercise is bound to entail some disappointment and perceived failure. Patients may make excellent gains, only to experience a flare-up of their condition. These setbacks should be anticipated so that the patient does not become excessively disappointed. Behavioral research suggests that compliance with exercise is best in a structured setting in which each person is monitored and given encouragement for his or her accomplishments. Unfortunately, many people with chronic pain tend to discontinue a regular exercise regimen within 6 months after a treatment program is concluded. Ways to encourage perseverance, such as organizing an exercise period with others, joining a health club, or combining exercise with another everyday activity, should be explored.

Croup Therapy

Vocational Counseling

Group therapy presents an opportunity to discuss concerns or problems that patients have in common. The specific problemsolving strategies used may be the same as in individual supportive therapy and cognitive and behavioral therapy. Unlike psychotherapists in traditional group sessions, group therapists in a pain management program are encouraged to be active facilitators. They may need to redirect the discussion so that every member has an opportunity to speak and no one person monopolizes the session. Participants should be offered individual therapy sessions in which to deal with personal issues. Certain group members may initially be reluctant to discuss personal problems related to their pain. The group therapist must prevent other group members from being overly judgmental and negative. Group members should be told that they are there to learn from one another and to support one another in gaining control over their pain.

The goal of vocational rehabilitation is a return to work. After an extended period out of work, patients become both physically and psychologically deconditioned to the demands and stresses of the workplace. Together, a vocational rehabilitation counselor and the patient can develop a plan that incorporates both long-range employment goals and short-term objectives based on medical, psychological, social, and vocational information. Vocational rehabilitation counselors are specialists in assessing aptitudes and interests, transferable skills, physical capacity, modifications in the workplace, skill training, and job readiness. Many patients with chronic pain receive workers’ compensation benefits or Social Security disability income. Patients may fear that their benefits will be jeopardized if they return to work. A vocational rehabilitation counselor can help a patient negotiate with an employer a return-to-work trial that will not jeopardize the patient’s income. Through counseling strategies and assessment tools, a patient’s suitability for returning to work or retraining can be determined. Patients should be familiar with the Americans with Disabilities Act in order to know their rights regarding discrimination due to a pain-related disability.

Family Therapy

Chronic pain significantly affects all members of a family. Family members need to be educated about the goals of therapy and should have an opportunity to share their concerns. Moreover, active involvement of family members helps ensure the patient’s long-term success. Therefore, both patients and members of their families should be invited to attend family therapy sessions in which the facilitator encourages them to ask questions about the pain management program, discuss their concerns and expectations, and express their feelings. Besides enhanced communication, important outcomes of these sessions are that family members learn how to help the person in pain to achieve and maintain goals and that they come to understand that they are not alone in dealing with the person in pain.

Relapse Prevention

Most patients with chronic pain need continued support if they are to maintain their gains. Patients should be encouraged to identify and anticipate situations that place them at risk for returning to previous maladaptive behavioral patterns. They should also be encouraged to rehearse problem-solving techniques and behavioral responses that will enable them to avoid a relapse. The goals of relapse prevention are to help the patient maintain a steady level of activity, emotional stability, and appropriate medication use; anticipate and deal with situations that cause

Chapter 230

setbacks, and acquire skills that will decrease reliance on the health care system. Follow-up has been shown to be a vital factor in the prevention of relapse. A specific written follow-up plan should be made for each patient before the end of treatment. The participant should be offered structured follow-up services such as participation in a monthly support group session or individual sessions. MultidisciplinaryTeam

Chronic pain involves a complex interaction of physiologic and psychosocial factors, and successful intervention entails the coordinated effort of a treatment team with expertise in a variety of therapeutic disciplines. Although some clinics offer a single treatment approach, most pain programs use a blend of medical, psychological, vocational, and educational techniques. Treatment modalities for chronic pain generally include medical assessment, medication management, pain reduction treatments, didactic instruction, relaxation training, biofeedback, physical therapy, psychotherapy, and vocational counseling. An interdisciplinary staff coordinates efforts to rehabilitate the patient and provides a comprehensive discharge and follow-up plan designed to meet the patient’s short- and long-term needs. The patient’s active participation in the treatment plan is strongly encouraged. Among the predictors of success in a multidisciplinary pain program are the patient’s motivation to cope with pain and his or her external support systems. Benefits of a Pain Management Program

Pain programs are cost-effective. Patients who complete a multidisciplinary pain program return to work or undergo vocational rehabilitation more often than patients who do not enter a pain program. Multidisciplinary pain programs also produce marked subjective and functional improvements in patients with chronic pain: Pain ratings decrease from admission to discharge, reliance on medication decreases, and physical functioning increases. These positive treatment outcomes often are maintained 2 to 3 years after discharge.

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Future Studies

There has been a rapid change in the way health care services are offered in the United States. Employers or insurance carriers make more and more decisions about treatment on the basis of financial resources rather than need. An increasing need for accountability and efficacy has encouraged the implementation of cost-saving measures and program evaluation. Preference is given to programs that are tailored to the individual rather than to programs in which all group participants receive every treatment. In light of the attention given to these changes, the economic efficiency of treatment for chronic nonmalignant pain is worthy of discussion. Although evidence supports the cost-effectiveness of therapy for chronic pain, such treatment may not meet the criterion of increased benefit with very little cost. Prior classification of patients may help in identifymg those who will most benefit from pain therapy. No reported studies have satisfactorily addressed this issue, and outcome data are needed. Documentation of increased function and decreased health care use among certain patients as a result of pain therapy would support the continuation of pain management programs. The field of remote data entry through personalized technology holds much promise for clinicians in the future. Currently available tracking methods can address the need for improved evaluation and treatment of patients with chronic pain.

SUGGESTED READINGS Fordyce WE (ed): Back Pain in the Workplace: Management of Disability in Nonspecific Conditions. IASP Press, Seattle, 1995 Gatchel RJ, Turk DC (eds): Psychological Approaches to Pain Management: A Practitioner’s Handbook. Guilford Press, New York, 1996 JamisonRN: Learning to Master Your Chronic Pain. Professional Resource Press, Sarasota, FL, 1996 JamisonRN: Mastering Chronic Pain: A Professional’s Guide to Behavioral Treatment. Professional Resource Press, Sarasota, FL, 1996 Karoly P, JensenMP MultimethodAssessment of Chronic Pain. Pergamon Press, New York, 1987 Turk DC, Melzack R (eds): Handbook of Pain Assessment. The Guilford Press, New York, 1992

230 Neurosurgical Treatment and ImDlantable Devices Thorkild Vad Norregaard Patients with chronic pain often seek a surgical solution to their problem. This is a logical approach, and significant time often is needed to explain physiologic and pharmacologic aspects of pain transmission so that the patient understands why this approach may or may not be a viable solution to the problem. Anatomic and physiologic studies have been very helpful in elucidating pathways transmitting acute pain. However, the exact mechanisms underlying chronic pain are much less well known. Because appropriate chronic animal pain models are scarce, neurosurgical intervention often is based on knowledge derived from acute pain. Neurosurgical interventions in chronic pain management are often, and appropriately, reserved for conditions intractable to

other, less invasive measures. A chronic pain condition can be initially largely insensitive to pharmacologic treatment or can develop tolerance to it. Interruption of peripheral and central pain pathways may initially be effective but subsequently lose its effectiveness after the emergence of a similar or slightly different pain. This might be thought of as a tolerance to destructive lesions in the nervous system; it serves as an example of pain being an essential protective mechanism and evolution having provided strong mechanisms for its upkeep. Neurosurgical pain management should be seen in a multidisciplinary setting. The overall treatment of a patient in chronic pain should follow an algorithm in which treatment attempts follow a

Chapter 230

setbacks, and acquire skills that will decrease reliance on the health care system. Follow-up has been shown to be a vital factor in the prevention of relapse. A specific written follow-up plan should be made for each patient before the end of treatment. The participant should be offered structured follow-up services such as participation in a monthly support group session or individual sessions. MultidisciplinaryTeam

Chronic pain involves a complex interaction of physiologic and psychosocial factors, and successful intervention entails the coordinated effort of a treatment team with expertise in a variety of therapeutic disciplines. Although some clinics offer a single treatment approach, most pain programs use a blend of medical, psychological, vocational, and educational techniques. Treatment modalities for chronic pain generally include medical assessment, medication management, pain reduction treatments, didactic instruction, relaxation training, biofeedback, physical therapy, psychotherapy, and vocational counseling. An interdisciplinary staff coordinates efforts to rehabilitate the patient and provides a comprehensive discharge and follow-up plan designed to meet the patient’s short- and long-term needs. The patient’s active participation in the treatment plan is strongly encouraged. Among the predictors of success in a multidisciplinary pain program are the patient’s motivation to cope with pain and his or her external support systems. Benefits of a Pain Management Program

Pain programs are cost-effective. Patients who complete a multidisciplinary pain program return to work or undergo vocational rehabilitation more often than patients who do not enter a pain program. Multidisciplinary pain programs also produce marked subjective and functional improvements in patients with chronic pain: Pain ratings decrease from admission to discharge, reliance on medication decreases, and physical functioning increases. These positive treatment outcomes often are maintained 2 to 3 years after discharge.

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Future Studies

There has been a rapid change in the way health care services are offered in the United States. Employers or insurance carriers make more and more decisions about treatment on the basis of financial resources rather than need. An increasing need for accountability and efficacy has encouraged the implementation of cost-saving measures and program evaluation. Preference is given to programs that are tailored to the individual rather than to programs in which all group participants receive every treatment. In light of the attention given to these changes, the economic efficiency of treatment for chronic nonmalignant pain is worthy of discussion. Although evidence supports the cost-effectiveness of therapy for chronic pain, such treatment may not meet the criterion of increased benefit with very little cost. Prior classification of patients may help in identifymg those who will most benefit from pain therapy. No reported studies have satisfactorily addressed this issue, and outcome data are needed. Documentation of increased function and decreased health care use among certain patients as a result of pain therapy would support the continuation of pain management programs. The field of remote data entry through personalized technology holds much promise for clinicians in the future. Currently available tracking methods can address the need for improved evaluation and treatment of patients with chronic pain.

SUGGESTED READINGS Fordyce WE (ed): Back Pain in the Workplace: Management of Disability in Nonspecific Conditions. IASP Press, Seattle, 1995 Gatchel RJ, Turk DC (eds): Psychological Approaches to Pain Management: A Practitioner’s Handbook. Guilford Press, New York, 1996 JamisonRN: Learning to Master Your Chronic Pain. Professional Resource Press, Sarasota, FL, 1996 JamisonRN: Mastering Chronic Pain: A Professional’s Guide to Behavioral Treatment. Professional Resource Press, Sarasota, FL, 1996 Karoly P, JensenMP MultimethodAssessment of Chronic Pain. Pergamon Press, New York, 1987 Turk DC, Melzack R (eds): Handbook of Pain Assessment. The Guilford Press, New York, 1992

230 Neurosurgical Treatment and ImDlantable Devices Thorkild Vad Norregaard Patients with chronic pain often seek a surgical solution to their problem. This is a logical approach, and significant time often is needed to explain physiologic and pharmacologic aspects of pain transmission so that the patient understands why this approach may or may not be a viable solution to the problem. Anatomic and physiologic studies have been very helpful in elucidating pathways transmitting acute pain. However, the exact mechanisms underlying chronic pain are much less well known. Because appropriate chronic animal pain models are scarce, neurosurgical intervention often is based on knowledge derived from acute pain. Neurosurgical interventions in chronic pain management are often, and appropriately, reserved for conditions intractable to

other, less invasive measures. A chronic pain condition can be initially largely insensitive to pharmacologic treatment or can develop tolerance to it. Interruption of peripheral and central pain pathways may initially be effective but subsequently lose its effectiveness after the emergence of a similar or slightly different pain. This might be thought of as a tolerance to destructive lesions in the nervous system; it serves as an example of pain being an essential protective mechanism and evolution having provided strong mechanisms for its upkeep. Neurosurgical pain management should be seen in a multidisciplinary setting. The overall treatment of a patient in chronic pain should follow an algorithm in which treatment attempts follow a

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Headache and Pain W Treatment of Pain

logical ladder from least invasive to more invasive and from few side effects to more potential side effects. The treating team must be sure that the pain is not amenable to direct attack. The team must generate a background of sympathetic understanding of the patient’s personality and general medical problems. Also, it must clearly understand the limitations inherent in the use of medications, nerve blocks, central administration of medications into the ventricular system or subarachnoid space, electrical stimulation of the central and peripheral nervous system, and classic ablative neurosurgery. INTRATHECAL AND EPIDURAL ADMINISTRATION OF PHARMACOLOGIC AGENTS Discovery of morphine receptors in the spinal cord and subsequent experimental studies showing the analgesic effect of intrathecal administration of opioids prompted extensive use of this modality for pain treatment in humans. Morphine sulfate is by far the most common agent used in this context: It is highly hydrophilic and diffuses throughout the intrathecal space. The exact position of the catheter tip in the intrathecal space therefore is less important. This is in contrast to lipophilic substances such as fentanyl, which binds rapidly and locally and therefore depends on the exact site of administration for its efficacy. When using a mixture of morphine sulfate and, for instance, bupivacaine, one is again faced with the importance of catheter tip location. Spinal administration of opioids is extremely potent. Ten percent and 1% of an intravenous dose administered in the epidural or subarachnoid space, respectively, produce an equianalgesic effect. It should be kept in mind that a patient whose pain does not respond well to opioids will not have a better response when the medication is given by intraspinal route. The best candidate for intraspinal opioid administration is the patient who has good analgesic effect from systemic opioids but intolerable side effects, such as constipation or sedation. Pain of a nociceptive nature, such as from cancer or from certain degenerative conditions, usually is a good candidate for this approach. The combination of opioids and local anesthetics offers certain clear-cut advantages. Local anesthetics, such as bupivacaine, can be given in a dosage up to 20 mg per 24 hours in the subarachnoid space, without causing motor disturbances. However, there can be slight tingling periodically in lower extremities. Clonidine and baclofen can also enhance the analgesic effect of intrathecal medication therapy. A candidate for spinal opioids first undergoes a test trial. During the test, a catheter is inserted percutaneously, and the patient receives daily injections. The test gives a unique opportunity to perform a placebo-controlled, patient-blinded study, which can give the best indication of the degree of pain relief after administration of intrathecal medications. In the event of a favorable response, a subcutaneous reservoir can be hooked up to an intrathecal catheter, and daily injections can be given through the reservoir in the event of short-term survival. When patients with longer survival times, and certainly those with benign pain conditions, are treated, a subcutaneous pump is implanted and attached to the intrathecal catheter. The pump can be programmed to give not just constant rate but also more complex infusion rates, including scheduled boluses at given time periods. Infection around the implanted system is one of the most serious complications, which would necessitate explantation of the system. Dose-related complications include respiratory depres-

sion, urinary retention, and nausea or vomiting. Long-term opioid infusions can also be associated with decreased hormone production, resulting in male impotence and absence of menstrual periods and ovulation in women. Fluid retention can be a significant side effect at times. Over time there can be a buildup of granulation tissue around the intrathecal catheter tip, causing reduced effect from the infusion and in some instances spinal cord compression. For certain pain syndromes related to the face and pain related to cancer of the head or neck, intraventricular morphine administration should be considered. ELECTRICAL STIMULATION OF PERIPHERAL NERVES AND CENTRAL NERVOUS SYSTEM Melzack and Wall’s gate control theory, presented in 1965, predicted a possible effect on pain transmission from stimulation of different parts of the nervous system. This has also turned out to be a powerful tool for pain control. The following years have seen a significant development and improvement of implantable stimulating devices. Completely implantable devices, including implantable stimulating units and complex electrode configurations, are now available for implantation. Patient selection is still difficult, thereby also necessitating a test trial. Pain of a neuropathic nature seems to respond better than pain of a nociceptive nature. Luckily, the latter is often more amenable to pharmacologic control than neuropathic pain. It is still not completely understood how electrical stimulation causes pain relief. The gate control theory, implying a modulatory effect from stimulation of large fibers, can explain certain aspects but, for instance, not why often after the stimulator is turned off, there is pain relief lasting minutes to hours. Measurement of transmitters in spinal fluid during stimulation has indicated an involvement of certain neurotransmitters, such as substance P. From a practical point of view, it is important to notice the need for stimulation-induced paresthesia, to cover the geographic area of pain to obtain pain relief. When dealing with causalgia or other pain syndromes clearly referable to a single peripheral nerve, it is natural to consider stimulation of the actual nerve in question. This involves the surgical implantation of test electrodes, allowing the patient to stimulate the nerve until a clear-cut answer can be given as to its effect. Pain covering more than a single peripheral nerve territory is common. Chronic sciatica and failed low back syndrome, including cases of multiple back surgeries or arachnoiditis, typically fall into this category. Phantom pain, postherpetic neuralgia, and sympathetically mediated pain, such as complex regional pain syndromes, also fall into this category. After careful medical trials and evaluation by a multidisciplinary pain group, including psychological assessment, it may be reasonable to proceed with a trial of spinal cord stimulation. Most spinal cord stimulators are inserted using a percutaneous technique, in which a Tuohy needle is positioned in the epidural space and a spinal cord test stimulator lead is inserted into the epidural space under fluoroscopic guidance. If large areas are to be covered, it is often beneficial to insert more than one electrode with multiple stimulation sites on each electrode. The leads are then exteriorized through a separate stab incision, and the patient typically is discharged wearing an external stimulator unit. The patient then goes through a careful trial period in which pain intensity during stimulation is charted and compared with pain

Chapter 230 W

during stimulation-free periods. The test stimulation typically lasts for 1 week. If the patient experiences at least 50% pain relief and considers this a valuable asset, then permanent implantation takes place. It is often beneficial to exchange the percutaneous electrodes with a slightly larger and sturdier paddle-shaped laminectomy electrode. This electrode is inserted through a laminotomy and has less of a tendency to move in the epidural space. The laminectomy electrode also provides better stimulation coverage of the painful area, uses less electrical energy, and moves less when the patient moves, thereby creating a more constant sensation of stimulation. Depending on the electrode system that is implanted, a stimulating unit is implanted subcutaneously or a subcutaneous receiver is implanted, and this receiver is then stimulated using an external stimulator electrode taped to the skin. When strict selection criteria are applied, success rates can be as high as 85%, with the long-term success rate being in the 60% to 65% range. Good results usually indicate more than 50% pain relief. Some patients have 100% pain relief; others fall short of this desirable level of relief. Deep brain stimulation focuses on two areas. As a rule, somatic nociceptive pain responds better to periventricular gray and periaqueductal gray stimulation; neurogenic pain seems to respond better to Stimulation of the ventral posteromedial and ventral posterolateral areas of the thalamus. The technique involves stereotactic electrode implantation, and the final electrode site is reached during test stimulation. Deep brain stimulation seems overall to have a 50% to 60% pain reduction in 50% to 60% of implants. Interestingly, stimulation of the motor cortex can be effective in treating central pain syndromes, for instance after strokes in the thalamus. Electrical stimulation of the peripheral and central nervous system is overall a safe modality. Infections can occur, which necessitate explantation of the system. Injury to peripheral nerves or the central nervous system rarely occurs. Why there is an overall reduction in efficacy over time is not entirely known. Local mechanical factors, such as electrode migration, can obviously play a role, but it seems apparent that neurophysiologic aspects also play a role. Together with intrathecal medication administration, the concept of stimulating the peripheral and central nervous system is minimally invasive and testable. Patients do not run the risk of worse outcome from trying these modalities, which otherwise can be the case in, for instance, repeated spinal surgery. NEUROABLATIVEPROCEDURES

All of the following procedures have in common an irreversible destruction of nociceptive pathways in the peripheral or central nervous system. They are associated with variable degrees of neurologic deficits, which usually are well tolerated. There is a risk from a few percent to 15% of anesthesia or analgesia dolorosa (i.e., a painful or unpleasant sensation in the anesthetic or analgesic area). Excellent pain relief over time can decrease, and the original pain can recur. Peripheral Neurectomles Morton's metatarsalgia and trigeminal neuralgia are well-known cases in which resection of a peripheral postganglionic nerve branch can result in pain relief. If it is possible clearly to locate the

Neurosurgical Treatment and Implantable Devices

1455

nerve with the tip of a needle, a percutaneous destructive lesion can also be performed, either using a neurolytic agent, such as alcohol or phenol, or by applying radiofrequency heat. The latter application has been well established for treating trigeminal neuralgia. Through this procedure, a needle with an uninsulated tip is inserted percutaneously, under fluoroscopic guidance, through the oval foramen into the trigeminal ganglion. Gentle stimulation in the awake patient verifies the position of the needle with reference to the three different divisions. The advantage of this technique is the possibility of applying gradually increasing heat and, at the same time, performing a sensory examination. The goal is a moderate hypalgesia with otherwise preserved sensation. This procedure is associated with 95% to 100% initial pain relief and a recurrence rate below 20%. The procedure can be repeated with an equally good up-front response. Other invasive procedures for trigeminal neuralgia include glycerol injection into Meckel's cave, percutaneous insertion of inflatable balloons to cause compression of the trigeminal ganglion, and posterior fossa microvascular decompression of the trigeminal root. The latter procedure is based on the remarkable observation that up to 90% of patients with trigeminal neuralgia have compression by a vessel loop against the trigeminal root. Pain relief is accomplished when this vessel is dissected and gently repositioned in a noncompressing manner or when a piece of Teflon, for instance, is positioned between the nerve root and the vessel loop. Successful microvascular decompression is associated with pain relief and no sensory deficits. In the absence of a major vascular compression, a partial rhizotomy can be performed. A percutaneous radiofrequency lesion of the trigeminal nerve usually is the treatment of choice, when medical treatment fails in older adults and is well tolerated by patients in their 70s and 80s. Careful blood pressure control during the procedure is necessary because hypertension often occurs during the lesion. Intravenous and intra-arterial access therefore is mandatory. A growing experience is gained from a single dose of focused radiation to the trigeminal root in the patients with trigeminal neuralgia. This is accomplished through the noninvasive application of stereotactically delivered focused radiation to the trigeminal root, typically using a gamma-knife device. This is a one-time treatment, but the effect does not set in until days to weeks after the treatment. When medical treatment fails, cluster headache or its more chronic variant, chronic migrainous neuralgia, can be treated along the guidelines of radiofrequency ablation of the gasserian ganglion. In general, diagnostic lidocaine block of the gasserian ganglion under induced attack should precede this. In the absence of effect of a radiofrequency lesion in this condition, lesions at the cervicomedullary junction should be entertained. The cephalic pain pathways loop down into the upper cervical cord with a fairly predictable relationship to surrounding structures before synapsing on second-order neurons in the nucleus caudalis. Fibers not only from cranial nerve V but also from VII, IX, and X are associated with this, the so-called descending nociceptive tract. A carefully placed lesion of the tract around the level of the obex can render the entire ipsilateral face, oral cavity, and pharynx analgesic, with preserved sensation to touch. This procedure has been used to treat chronic migrainous neuralgia with success. In a variant of the same procedure using a radiofrequency technique, the entire nucleus caudalis is destroyed, resulting in successful treatment of the pain of postherpetic neuralgia and anesthesia or analgesia dolorosa of the face.

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w

Treatment of Pain

The much less common vagoglossopharyngeal neuralgia can be treated according to similar guidelines, using percutaneous rhizotomy or open exploration with microvascular decompression or rhizotomy of ninth and parts of the tenth cranial nerve. These procedures are aimed primarily toward benign cephalic pain conditions. When used in a setting of head or neck cancer not responding to opioids, nucleus caudalis nucleotomy usually is indicated, including dorsal root entry zone lesions of the upper cervical dorsal root zones.

procedure takes into account the fact that pain fibers, after ascending one or two cord segments, cross to the contralateral hemicord. Because pain fibers are the only segmentally crossing fibers, it is feasible to eliminate pain, for instance, from pelvic structures by dividing the spinal cord over several segments in a vertical anteroposterior plane. A peculiar phenomenon of this procedure is that the resulting sensory deficits can be moderate despite the successful pain relief. Cerebral Lesions for Pain Control

Procedures Directed Toward Dorsal Roots and Dorsal Root Entry Zones

Dorsal rootlets can be sectioned through an open intradural procedure. The dorsal root ganglion can also be resected, and this procedure often has more merit because some sensory fibers travel through the ventral rootlets. Removing the entire ganglion therefore should also result in degeneration of fibers in the ventral root. These procedures have been used in chronic benign pain, such as chronic radiculopathies, and in cancer pain. Particularly patients with Pancoast’s tumors have benefited from these procedures. Because these two procedures result in complete analgesia and anesthesia of the involved areas, other, less invasive procedures should be tested first. There is also a significant risk of postlesion dysesthesia and recurrence of pain because of the plasticity of the central nervous system. These considerations spurred interest in the dorsal root entry zone, where open radiofrequency lesions in Rexed’s laminae have been proposed and successfully applied, particularly in brachial plexus avulsion injuries. These so-called dorsal root entry zone lesions can be associated with denervation paresthesias and, not infrequently, transient motor weakness. An open superficial surgical lesion of the dorsolateral aspect of the nerve root entry zone is an anatomically more pleasing procedure, aimed at interrupting the small-diameter pain fibers. Collectively, these procedures should be reserved for otherwise intractable cases in which spinal cord stimulation or intrathecal medication administration has failed. Lesions in the Spinal Cord

Interrupting the spinothalamic tract in the anterior cord can be an extremely successful procedure for pain in the extremities and trunk, when the pain is clearly off the midline. This procedure can be offered in malignant pain conditions and more benign pain conditions, particularly pain in an amputation stump. This so-called anterolateral cordotomy can be performed through an open procedure or through a percutaneous stereotactic computed tomography-guided radiofrequency technique. This latter technique often allows the differential cordotomy of the anteromedial or the posterolateral part or the anterior quadrant, thereby rendering either the forequarter or the hindquarter analgesic. The procedure can be performed in the high thoracic or high cervical region. When it is performed bilaterally, there may be an often transient bladder paralysis. Bilateral high cervical anterolateral cordotomy can be associated with respiratory failure caused by lesion of the descending respiratory pathways controlling involuntary breathing. Pain located in the midline of the body, such as pelvic pain, is more difficult to control surgically. These pain conditions can be associated with pelvic or rectal cancer. A procedure for this often-debilitating pain condition is commissural myelotomy. This

Lesions in the diencephalon are thalamotomy and hypothalamotomy; both, particularly the latter, should be reserved for otherwise completely intractable conditions. Like other procedures, thalamotomy can be associated with dysesthesia and only transient effect. Additional research based on lesioning and stimulation of these nuclei may result in a better understanding and possibly better results in the future. For reasons that are not completely known, pituitary ablation can be an effective procedure for controlling severe cancer pain refractory to other therapeutic attempts. Cingulotomy is a bilateral lesion in the cingulate gyrus and often the cingulate bundle, which can be quite helpful in chronic pain conditions. In addition, the cingulotomy is effective in treating associated depression. The procedure is well tolerated and is very effective for treating obsessive-compulsive disorders. Sympathectomy for Pain Control

The sympathetic nervous system clearly plays a role in a number of pain conditions. More modern nomenclature collectively refers to these pain conditions as sympathetically mediated pain. These conditions include causalgia and post-traumatic reflex sympathetic dystrophy. Any pain condition considered.to belong to this category should initially be treated with local anesthetic blocks of the relevant portions of the sympathetic nervous system. Because a number of neurolytic medications are available as well as stereotactic placement of needles, it is often possible to execute a chemical interruption of the relevant sympathetic pathways. Open surgical sympathectomy therefore is called on less and less frequently. Unfortunately, there is a tendency to significant recurrence of pain after an initial successful period lasting a few months. CONCLUSION

Neurosurgical intervention can be extremely helpful and effective in treating chronic pain. However, this modality clearly should be seen in the context of a multidisciplinary approach in which an appropriate algorithm is supplied, striving for optimal effect using the simplest means possible. This should also take into consideration a conscious effort to minimize potential side effects and long-term complications. SUGGESTED READINGS Burchiel KJ:Surgical Management of Pain. Thieme, Stuttgart, 2002 Burchiel KJ, Steege TD, Howe JF, Loeser JD: Comparison of a subcutaneous radiofrequency gangliolysis and microvascular decompression for the surgical management of tic douloureux. Neurosurgery 9:lll-119, 1981

Chapter 230

De La Port C, Siegfried J: Lumbosacral fibrosis (spinal arachnoiditis): its diagnosis and treatment by spinal cord stimulation. Spine 8:593-603, 1983 Gybelis JM, Sweet WH: Neurosurgical Treatment of Persistent Pain. Karger, Basel, 1989 North RB, Ewend MG, Lawton MT et ak Failed back surgery syndrome: 5-year follow-up after spinal cord stimulator implantation. Neurosurgery 28:692-699, 1991 North RB,Levy RM: Neurosurgical Management of Pain. Springer-Verlag, New York, 1997

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Onofrio BM, Yaksh T L Long term pain relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg 72:200-209, 1990 Sampson JH, Nashold BS Jr: Facial pain due to vascular lesions in the brain stem relieved by dorsal root entry zone lesions in the nucleus caudalis. J Neurosurg 77:473-475, 1992 Tasker RR, DeCarvalho GTC, Dolan EJ: Intractable pain of spinal cord origin: clinical features and implications for surgery. J Neurosurg 77:373-378, 1992

APPENDIX

A

The Expanded Disability Status Scale Score

Explanation

0 1.o

Normal neurologic exam (all grade 0 in FS; cerebral grade 1 acceptable). No disability, minimal signs in one R (i.e., grade 1 excluding cerebral grade 1). No disability, minimal signs in more than one FS (more than one grade 1 excluding cerebral grade 1). Minimal disability in one R (one FS grade 2, others 0 of 1). Minimal disabilii in two FS (two FS grade 2, others 0 or 1). Moderate disability in one R (one FS grade 3,others 0 or I), or mild disability in three or four R (three or four FS grade 2, others 0 or 1 ) though fully ambulatory. Fully ambulatory but with moderate disability in one R (one grade 3) and one or two R grade 2; or two R grade 3; of fnre R grade 2 (others

1.5 2.0 2.5

3.0 3.5

0 or 1).

4.0

Fully ambulatory without aid, self-sufficient, up and about some 12 hr a day despite relatively severe disability consisting of one R grade 4 (others 0 or 1) or combination of lesser grades exceeding limits of previous steps. Able to walk 500 m without aid or rest. 4.5 Fully ambulatory without aid, up and about much of the day, able to work a full day;may otherwise have some limitation of full activity or need minimal assistance; characterized by severe disability, usually consisting of one R grade 4 (others 0 of 1) of combinations of lesser grades exceeding limits of previous steps. Able to walk 300 m without aid or rest. Ambulatory without aid or rest for about 200 m; disability severe enough to impair full daily activities (e.g., to work full day without special 5.0 provisions). (Usual FS equivalents are one grade 5 alone, others 0 or 1 ;or combinations of lesser grades usually exceeding specifications for step 4.0.) 5.5 Ambulatory without aid or rest for about 100 m; disability severe enough to preclude full daily activities. (Usual R equivalents are one grade 5 alone, others 0 or 1;or combinations of lesser grades usually exceeding those for step 4.0.) 6.0 Intermittent or unilateral constant assistance (cane, crutch, or brace) needed to walk about 100 m with or without resting. (Usual FS equivalents are combinations with more than two R grade 3+.) 6.5 Constant bilateral assistance (canes, crutches, or braces) needed to walk about 20 m without resting. (Usual FS equivalents are combinations with more than two R grade 3+.) 7.0 Unable to walk beyond about 5 m even with aid, essentially needs wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair some 12 hours a day. (Usual R equivalents are combinationswith more than one R grade 4+; very rarely, pyramidal grade 5 alone.) Unable to take more than a few steps; needs wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full 7.5 day; may need motorized wheelchair. (Usual equivalents are combinationswith more than one R grade 4+.) 8.0 Essentially restricted to bed or chair or perambulated in wheelchair but may be out of bed much of the day; retains many self-care functions; generally has effective use of arms. (Usual R equivalents are combinations, generally grade 4+ in several systems.) 8.5 Essentially restricted to bed much of the day; has some effective use of arm(s); retains some self-care functions. (Usual R equivalents are combinations, generally 4+ in several systems.) 9.0 Helpless bed patient; unable to communicate effectively or eat. (Usual R equivalents are combinations, almost all grade 4+.) 9.5 Totally helpless bed patient; unable to communicate effectively or eat. (Usual R equivalents are combinations, almost all grade 4+.) 10 Death - -. due - - - to .- MS. .. Abbreviations: 6, functional system; MS, multiple sclerosis. Adapted from Kurtzke J F Rating neurologic impairmentin multiple sclerosis: an expanded disabilii status xale (EDSS) ~

Neurology 33:1444-1452, 1983, with permission.

1459

1460

Appendix A

Functional Systems Used in Expanded Disability Status Scale Pyramidal functions 0. Normal 1. Abnormal signs without disability 2.Minimal disability 3. Mild or moderate paraparesis or hemiparesis; severe monoparesis 4. Marked paraparesis or hemiparesis, quadriparesis, or monoplegia 5. Paraplegia, hemiplegia, or marked quadriparesis 6.Quadriplegia V. Unknown Cerebellar functions 0. Normal 1. Abnormal signs without disability 2.Mild ataxia 3. Moderate truncal or limb ataxia 4. Severe ataxia, all limbs 5. Unable to perform coordinated movements due to ataxia V. Unknown X. Is used throughout after each number when weakness (grade 3 or more on pyramidal) interferes with testing Brainstem functions 0. Normal 1. Signs only 2.Moderate nystagmus or other mild disability 3. Severe nystagmus, marked extraocular weakness, of moderate disability of other cranial nerves 4. Marked dysarthria or other marked disability 5. Inability to swallow or speak V. Unknown Sensory functions 0. Normal 1. Vibration or figure-writing decrease only, in one or two limbs 2. Mild decrease in touch or pain or position senseor moderate decrease in vibration in one or two limbs; or vibratory (with or without figure writing) decrease alone in three or four limbs 3. Moderate decrease in touch or pain or position senseor essentially lost vibration in one or two limbs; or mild decrease in touch or pain or moderate decrease in all proprioceptive tests in three or four limbs 4. Marked decrease in touch or pain or loss of proprioception, alone or combined, in one or two limbs; or moderate decrease in touch or pain or severe proprioceptive decrease in more than two limbs 5. Loss (essentially) of sensation in one or two limbs; or moderate decrease in touch or pain or loss of proprioceptionfor most of the body below the head 6.Sensation essentially lost below the head V. Unknown Bowel and bladder functions 0. Normal 1. Mild urinary hesitancy, urgency, or retention 2. Moderate hesitancy, urgency, retention of bowel or bladder, or rare urinary incontinence 3. Frequent urinary incontinence 4. In need of almost constant catheterization 5. Loss of bladder function 6.Loss of bowel and bladder function V. Unknown Visual (or optic) functions 0. Normal 1. Scotoma with visual acuity (corrected) better than 20/30 2.Worse eye with scotoma with maximal visual acuity (corrected) of 20/30-20/59 3. Worse eye with large scotoma, or moderate decrease in fields, but with maximal visual acuity (corrected) of 20/60-20/99 4. Worse eye with marked decrease of fields and maximal visual acuity (corrected) of 20/100-20/200;grade 3+ maximal acuity of better eye of 20/60 or less 5. Worse eye with maximal visual acuity (corrected less than 20/200;grade 4+ maximal acuity of better eye of 20/60 or less 6.Grade 5+ maximal visual acuity of better eye of 20/60 or less V. Unknown X. Is added to grades 0-6 for presence of temporal pallor Cerebral (or mental) functions 0. Normal 1. Mood alteration only (does not affect score) 2. Mild decrease in mentation 3. Moderate decrease in mentation 4. Marked decrease in mentation (chronic brain syndrome,moderate) 5. Dementia of chronic brain syndrome, severe or incompetent V. Unknown Other functions 1. None 2. Any other neurologic findings attributed to multiple sclerosis (specify) V. Unknown From KurIzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444-1452, 1983, with permission.

I. MEATATION, BEHAWORBAND MOOD 1. Intellectual impairment 0 = None 1 = Mild. Consistent forgetfulness with partial recollection of events and no other difficulties. 2 = Moderate memory loss, with disorientation and moderate difficulty handling complex problems. Mild but definite impairment of function at home with need of occasional prompting. 3 =Severe memory loss with disorientation for of time and often to of place. Severe impairment in handling problems. 4 = Severe loss with orientation preserved to person only. Unable to make judgments of or solve problems. Requires much help with personal care. Cannot be left alone at all. 2. Thought disorder (Due to dementia or drug intoxication) 0 = None. 1 = Vivid dreaming. 2 = “Benign” hallucinations with insight retained. 3 = Occasional to frequent hallucinations or delusions; without insight; could interfere with daily activities. 4 = Persistent hallucinations, delusions, or florid psychosis. Not able to care for self. 3. Depression 0 = Not present. 1 = Periods of sadness or guilt greater than normal, never sustained for days or weeks. 2 = Sustained depression (1 week or more). 3 = Sustained depression with vegetative symptoms (insomnia, anorexia, weight loss, loss of interest). 4 = Sustained depression with vegetative symptoms and suicidal thoughts or intent. 4. MotivatiodInitiative 0 = Normal. 1 = Less assertive than usual; more passive. 2 = Loss of initiative or disinterest in elective (nonroutine) activities. 3 = Loss of initiative or disinterest in day to day (routine) activities. 4 = Withdrawn, complete loss of motivation. 11. ACTMTIES OF DAZLY LIVING Cfor both “on” and “off”) 5. Speech 0 = Normal. 1 = Mildly affected. No difficulty being understood. 2 = Moderately affected. Sometimes asked to repeat statements. 3 = Severely affected. Frequently asked to repeat statements. 4 = Unintelligible most of the time.

6. Salivation 0 = Normal. 1 = Slight but definite excess of saliva in mouth; may have nighttime drooling. 2 = Moderately excessive saliva; may have minimal drooling. 3 = Marked excess of saliva with some drooling. 4 = Marked drooling, requires constant tissue or handkerchief. 7. swallowing 0 = Normal. 1 = Rare choking. 2 = Occasional choking. 3 = Requires soft food. 4 = Requires NG tube or gastrostomy feeding. 8. Handwriting 0 = Normal. 1 = Slightly slow or small. 2 =Moderately slow or smaU; all words are legible. 3 = Severely affected; not all words are legible. 4 = The majority of words are not legible. 9. Cutting food and handling utensils 0 = Normal. 1 = Somewhat slow and clumsy, but no help needed. 2 = Can cut most foods, although clumsy and slow; some help needed. 3 = Food must be cut by someone, but can still feed slowly. 4 = Needs to be fed. 10. Dressing 0 = Normal. 1 = Somewhat slow, but no help needed. 2 = Occasional assistancewith buttoning, getting arms in sleeves. 3 =Considerable help required, but can do some things alone. 4 = Helpless. 11. Hygiene 0 = Normal. 1 = Somewhat slow, but no help needed. 2 = Needs help to shower or bathe; or very slow in hygienic care. 3 = Requires assistance for washing, brushing teeth, combing hair, going to bathroom. 4 = Foley catheter or other mechanical aids. 12. lhming in bed and adjusting bed clothes 0 = Normal. 1 = Somewhat slow and clumsy, but no help needed. 2=Can turn alone or adjust sheets, but with great difficulty. 3 =Can initiate, but not turn or adjust sheets alone. 4 = Helpless. 1461

1462

Appendix 6

Unified Parkinson’s Disease Rating Scale

13. Falling (unrelatedto freezing) 0 = None. 1 = Rare falling. 2 = Occasional falls, less than once per day. 3 = Falls an average of once a day. 4 = Falls more than once a day. 14. Freezing when walking 0 = None. 1 =Rare freezing when walking; may have starthesitation. 2 = Occasional freezing when walking. 3 = Frequent freezing. Occasional falls from freezing. 4 = Frequent falls from freezing. 15. Walking 0 = Normal. 1 = Mild difficulty. May not swing arms or may tend to drag leg. 2 = Moderate difficulty, but requires little or no assistance. 3 = Severe disturbance of walking, requiring assistance. 4 = Cannot walk at all, even with assistance. 16. Tremor 0 = Absent. 1 = Slight and infrequently present. 2 = Moderate; bothersome to patient. 3 = Severe; interferes with many activities. 4 = Marked; interferes with most activities. 17. Sensory complaints related to parkinsonism 0 = None. 1 = Occasionally has numbness, tingling, or mild aching. 2 = Frequently has numbness, tingling, or aching; not distressing. 3 = Frequent painful sensations. 4 = Excruciating pain. 111. MOTOR EXAMZNATZON 18. Speech 0 = Normal. 1 = Slight loss of expression, diction, and volume. 2 = Monotone, slurred but understandable; moderately impaired. 3 = Marked impairment, difficult to understand. 4 = Unintelligible. 19. Facial expression 0 = Normal. 1 = Minimal hypomimia, could be normal “poker face.” 2 = Slight but definitely abnormal diminution of facial expression. 3 = Moderate hypomimia; lips parted some of the time. 4 = Masked or fixed facies with severe or complete loss of facial expression; lips parted 1/4 inch or more. 20. Tremor at rest 0 = Absent. 1 = Slight and infrequently present. 2 = Mild in amplitude and persistent; or moderate in amplitude but only intermittently present. 3 = Moderate in amplitude and present most of the time. 4=Marked in amplitude and present most of the time.

21. Action or postural tremor of hands 0 = Absent. 1 = Slight and; present with action. 2 = Moderate in amplitude, present with action. 3 = Moderate in amplitude, with posture holding as well as action. 4 = Marked in amplitude; interferes with feeding. 22. Rigidity (Judged on passive movement of major joints with patient relaxed in sitting position. Cogwheeling to be ignored.) 0 = Absent. 1 = Slight or detectable only when activated by mirror or other movements. 2 = Mild to moderate. 3 = Marked, but full range of motion easily achieved. 4 =Severe, range of motion achieved with difficulty. 23. Finger taps (Patient taps thumb with index finger in rapid succession with widest amplitude possible, each hand separately.) 0 = Normal. 1 = Mild slowing and/or reduction in amplitude (11-14/5 sec). 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement (710/5 sec). 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement (3-6/5 sec). 4 = Can barely perform the task (0-2/5 sec). 24. Hand movements (Patientopens and closes hands in rapid succession with widest amplitude possible, each hand separately.) 0 = Normal. 1 = Mild slowing and/or reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task. 25. Rapid alternating movements of hands (Pronationsupination movements of hands, vertically and horizontally, with as large an amplitude as possible, both hands simultaneously.) 0 = Normal. 1 = Mild slowing andlor reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task. 26. Foot agility (Patient taps heel on grouind in rapid succession picking up entire foot. Amplitude should be about 3 inches.) 0 = Normal. 1 = Mild slowing and/or reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task.

Appendix B H Unified Parkinson’s Disease Rating Scale

27. Arising from chair (Patient attempts to arise from a straightbackedchair with a r m s folded across chest.) 0 = Normal. 1 = Slow; or may need more than one attempt. 2 = Pushes self up from arms of seat. 3 = Tends to fall back and may have to try more than one time, but can get up without help. 4 = Unable to arise without help. 28. Posture 0 = Normal erect. 1 = Not quite erect, slightly stooped posture; could be normal for older person. 2 = Moderately stooped posture, definitely abnormal; can be slightly leaning to one side. 3 = Severely stooped posture with kyphosis; can be moderately leaning to one side. 4=Marked flexion with extreme abnormality of posture. 29. Gait 0 = Normal. 1 = Walks slowly, may shuffle with short steps, but no festination on propulsion. 2 =Walks with difficulty but requires little or no assistance; may have some festination, short steps, or propulsion. 3 = Severe disturbance of gait, requiring assistance. 4 = Cannot walk at all, even with assistance. 30. Postural stability (Response to sudden posterior displacement produced by pull on shoulders while patient erect with eyes open and feet slightly apart. Patient is prepared.) 0 = Normal. 1 = Retropulsion, but recovers unaided. 2 = Absence of postural response; would fall if not caught by examiner. 3 = Very unstable, tends to lose balance spontaneously. 4 = Unable to stand without assistance. 3 1. Body bradykinesia and hypokinesia (Combining slowness, hesitancy, decreased armswing, small amplitude, and poverty of movement in general.) 0 = None. 1 = Minimal slowness, giving movement a deliberate character; could be normal for some persons. Possibly reduced amplitude. 2 = Mild degree of slowness and poverty of movement which is definitely abnormal. Alternatively, some reduced amplitude. 3 = Moderate slowness, poverty or small amplitude of movement. 4 = Marked slowness, poverty or small amplitude of movement. IV. COMPLZCATZONS OF THERAPY (in the past week) A. Dyskinesias 32. Duration: What proportion of the waking day are dyskinesias present? (Historical information.) 0 = None. 1 = 1-25% of day 2 = 26-50% of day 3 = 51-75% of day 4 = 76-100% of day

1465

33. Disability: How disabling are the dyskinesias? (Historical information; may be modified by office examination.) 0 = Not disabling. 1 = Mildly disabling. 2 = Moderately disabling. 3 = Severely disabling. 4 = Completely disabling. 34. Painful dyskinesias: How painful are the dyskinesias? 0 = No painful dsykinesias. 1 = Slight. 2 = Moderate. 3 = Severe. 4 = Marked. 35. Presence of early morning dystonia (Historical information.) O=No 1 =Yes

B. Clinical fluctuations 36. Are any “off” periods predictable as to timing after a dose of medication? O=No 1 =Yes 37. Are any “off” periods unpredictable as to timing after a dose of medication? O=No 1 =Yes 38. Do any of the “off” periods come on suddenly, for example, over a few seconds? O=No 1 =Yes 39. What proportion of the waking day is patient “off” on average? 0 = None 1 = 1-25% of day 2 = 26-50-% of day 3 = 51-75% of day 4 = 76-100% of day C. Other complications 40. Does the patient have anorexia, nausea, or vomiting? O=No 1 =Yes 41. Does the patient have any sleep disturbances, for example, insomnia or hypersomnolence? O=No 1 =Yes 42. Does the patient have symptomatic orthostasis? O=No 1 =Yes V. MODZFZED HOEHNAND YAHR STAGING Stage 0 - No signs of disease. Stage 1 - Unilateral disease. Stage 1.5 - Unilateral plus axial involvement. Stage 2 - Bilateral disease, without impairment of balance. Stage 2.5 - Mild bilateral disease, with recovery on pull test. Stage 3 - Mild to moderate bilateral disease; some postural instability; physically independent. Stage 4 - Severe disability; still able to walk or stand unassisted. Stage 5 - Wheelchair bound or bedridden unless aided.

1464

Appendix B

Unified Parkinson's Disease Rating Scale

VI. SCHWAB AND ENGLAND ACTIVITIES OF DAILY LIVING

50% More dependent. Help with half of chores, slower, et

SCALE 100% Completely independent. Able to complete all chores without slowness, difficulty, or impairment. Essentially normal. Unaware of any difficulty. 90% Completely independent. Able to all complete chores with some degree of slowness, difficulty and impairment. Might take twice as long. Beginning to be aware of difficulty. 80% Completely independent in most chores. Takes twice as long. Conscious of difficulty and slowness. 70% Not completely independent. More difficulty with some chores. Three to four times as long in some. Must spend a large part of the day with chores. 60% Some dependency. Can do most chores, but exceedingly slowly and with much effort. Errors while performing chores; some impossible.

cetera. Difficulty with everything. 40% Very dependent. Can assist with all chores, but few alone. 30% With effort, now and then does a few chores alone or begins alone. Much help needed. 20% Nothing alone. Can be a slight help with some chores. Severe invalid. 10% Total dependent, helpless. Complete invalid. 0% Vegetative functions such as swallowing, bladder and bowel functions are not functioning. Bedridden.

From Gancher S T Quantitative Measures and Rating Scales, pp 118-123. In Factor SA, Weiner WJ (eds): Parkinson's Disease: Diagnosis and Management. Demos Medical Publishing, New York, 2002.

Index

A Ablation, Parkinson’s disease and, 758-759 Abnormal blinking, 68 Abnormal muscle activity, 734-737 complex repetitive discharges, 735-736 cramps, 736 hemifacial spasm, 736-737 myokymia, 734-735 myotonia, 737 neuromyotonia,735,736f Abscess brain. See Brain and spinal abscess. spinal epidural, 435-436, 1123 spinal See Brain and spinal abscess. Absence seizures, 925-926 Absence status epilepticus, 940,941f Academic history, headache and, 1364 ACE inhibitors, 264 Acetylcholine receptor antibodies, myasthenia gravis and, 177,659 Acetylcholinesterase inhibitors, 230-23 1,23It for Alzheimer’s disease, 233 myasthenia gravis and, 660 Acetylsalicylic acid, 225-226 ACGIH. See American Conferenceof Governmental Industrial Hygienists (ACGIH). Achromatopsia,899 Acid maltase deficiency, 143-144,717,717f Acoustic neuroma, 85, 1071-1076 in children, 1075 differential diagnosis of, 1074 history in assessment of, 1071 laboratory testing in assessment of, 1072f, 1073-1074 neurofibromatosis, 1075 physical examination in assessment of, 1072 presentation of, 1071-1072 treatment for, 1075 tumor growth in, 1074-1075 Acoustic trauma, chronic, tinnitus and, 100 Acquired adult rubella, 494-495 Acquired painless ptosis, 65-67.65t,66f, 67f of gradual onset, 66 of sudden onset, 66 Acromegaly, 594,1064-1065 Acromioclavicular joint arthritis, 1429 Acrylamide, toxic peripheral neuropathies and, 619-620 Action tremor, 799-801 Activated partial thromboplastin time (aPTT), 174 Activated protein C resistance, tests for, 175 Acute confusional state, differentiating dementia from, 860,860t Acute disc herniation, 1432-1433, 1432t, 1433f Acute disseminated encephalomyelitis(ADEM),423-425 Acute dystonic reactions, 813 Acute encephalopathy, 1140 Acute inflammatory demyelinating polyneuropathy (AIDP), 579-582 Acute inflammatorypolyneuritis, 579 Page numbers followed by f indicate figures; t, tables.

Acute intermittent porphyria (AIP), 1251-1253, 1251t Acute measles encephalitis of delayed type, 485-486 Acute memory loss, 906-907 Acute myonecrosis, myopathy and, 713 Acute necrotizing myopathy, 1154 Acute peripheral vestibulopathy, 82-84 Acute polyradiculoneuropathy,1152 Acute stroke, 382-383 Acute unilateral vestibulopathy, 82t Acyclovir, 76 AD. See Alzheimer’s disease (AD). Addiction in chronic pain, 1395-1397 diagnosis of, 1395-1396 management of, 1396-1397 ADEM. See Acute disseminated encephalomyelitis(ADEM). ADHD. See Attention deficit hyperactivity disorder (ADHD). Adhesive capsulitis, 1429 Adjunctive analgesics, 1443-1444 Adjustment sleep disorder, 971 Adjuvant chemotherapy,hypothalamic gliomas and, 1046 Adrenal dysfunction, 707-709 Adrenal insufficiency, 709 Adrenocorticotropichormone, 707-708 Adult hexosaminidaseA deficiency, 563-564 Adult infectious botulism, 672 Adult polyglucosan body disease, 564 Adults attention deficit hyperactivity disorder in. See Learning disabilities and attention deficit hyperactive disorder in adults. dyslexia in, 920-921 young, stroke in. See Stroke in young adults. Advanced sleep phase syndrome, 972 AFASAK. See Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation Study (AFASAK). Affective disorders epilepsy and, 958 nonverbal learning disability and, 919 Affective inventories, headache and, 1365 Afferent visual pathways, disorders of, 35-46 Age electromyographyand, 197-198 olfaction and, 106 stroke and, 252-253,254f Ageusia, 114-115 Aggressivity, epilepsy and, 959-960 Aging degenerative memory disorders of, 908,908f, 908t differentiating dementia from, 860,861t Agnosia object, 897-898,897t,898f olfaction and, 109 visual, 378 Agraphia, 378,893-894,894t AICA. See Anterior inferior cerebellar artery (AICA). AIDP. See Acute inflammatory demyelinatingpolyneuropathy (AIDP). AIDS, lumbar puncture in patients with, 500 1465

1466

Index

AIDS dementia complex, 496-498 AIP. See Acute intermittent porphyria (AIP). Akathisia, 812,813 Akinetic-rigid syndromes, 13-15, 13t ALA dehydratase deficiency porphyria (DOSS), 1253-1254 Alcohol, stroke and, 261-262,339,361-362 Alcohol withdrawal seizures, 1269-1270,1270t Alcohol-dependent sleep disorder, 971 Alcoholic cerebellar degeneration, 1273-1274, 1274f Alcoholic polyneuropathy, 1275 Alcoholism alcohol withdrawal and, 1269-1270 central nervous system complications of, 1270-1275 neurologic complications of. See Neurologic complications of alcoholism. peripheral nervous system complications of, 1275-1276 Alertness, fluctuation in, diffuse Lewy body disease and, 775 Mega, 893-894,894t aphasic, 894 pure, 896-897,896t without agraphia, 378 Alkaloids, vinca, neurotoxicity and, 1136 Allergic grandomatosis, 6 15 Allergy, drugs for, 1284,1285t Allodynia, neuropathic pain and, 1403 Allopurinol, 626 Ally1 chloride, 620-621 Almitrine bismesylate, 626 Alpha-interferon, 1139 ALS. See Amyotrophic lateral sclerosis (ALS). Altered fractionation schedules, malignant gliomas and, 1045 Altered mental status brain tumors and, 1014 drug dependence and, 1280-1281 Altered sexuality, epilepsy and, 959 Altitude insomnia, 971 Alveolar hyperventilation, 139 Alzheimer’s Association, 998 Alzheimer’s disease (AD), 868-873 acetylcholinesterase inhibitors for, 233 behavioral issues and, 872, 873t clinical profile of, 868-869 dementia and, 867 diagnosis, pathophysiology, and treatment of, 868-873 disorders of olfaction and, 112 newer diagnostic approaches to, 869-870 pathology of, 870 pathophysiology of, 870 treatment for, 870-872 Amantadine, 747 Ambulation, slowly progressive disorder of, 27 Ambulatory neurology, 1-250 American Academy of Neurology, Quality Standards Subcommittee of, 1021 American Conference of Governmental Industrial Hygienists (ACGIH), 1289 Amifostine, 1140 Aminoglutethimide, 1138 Amiodarone, 626-627,626t Ammonia hypothesis, portal-systemic encephalopathy and, 1241 Amnesia, transient global, 385,386 Amnestic dysnomia, 378 Amnestic syndromes, differentiating dementia from, 860 Amphetamines, 360-361 Amplification of illness, somatization and, 988-989 tinnitus and, 102

Amplitude electromyography and, 203 motor nerve conduction studies and, 199 Amyloid angiopathy, 136 Amyloid neuropathy, 32f, 147 Amyloidosis gelsolin, 641 multiple myeloma with, 1153 multiple myeloma without, 1152 primary systemic, 606-607,607t Amyotrophic lateral sclerosis (ALS), 548-553, 1151 clinical features of, 549-550 definition of, 548-549 dysarthria and dysphagia in, 124 electrophysiologic features of, 551-552 epidemiology of, 549 laboratory evaluation and differential diagnosis in, 550-551 treatment of, 552-553 Amyotrophy benign focal, 562-563 neuralgic, 577 Analgesic treatment of pain, 1438-1444 Analgesics, 1443-1444 adjunctive, 1443-1444 migraine and, 1342 nonsteroidal anti-inflammatory, for chronic pain, 1392-1394 Anaplastic astrocytoma, 1043f Anaplastic oligodendrogliomas, 1046 Anastrozole, 1138-1139 Anatomic substrate for upper motor neuron lesions, weakness and, 9-10 ANCA. See Antineutrophilic cytoplasmic antibody (ANCA). Ancillary visual testing, disorders of afferent visual pathways and, 37 Andersen’s syndrome, 718,728, 731,732 Anesthetics, inhaled, 945-946 Aneurysmal subarachnoid hemorrhage, 324,328 Aneurysms aortic, 1212-1220 atrial septal, 345-346 conventional angiography and, 292,292f dissecting aortic, 1212-1220 intracranial, subarachnoid hemorrhage and, 326 magnetic resonance angiography and, 290 mycotic, 324 unruptured intracranial. See Unruptured intracranial aneurysm (UIA). Angel dust, 361,1279 Angiitis Churg-Strauss, 1299 isolated, of central nervous system, 510, 1300 Angioendotheliomatosis, neoplastic, 1173 Angiogensin receptor antagonists, 264 Angiography brain tumors and, 1015-1016 cerebral, 213 conventional, 291-292 diagnostic coronary, 1195-1196, 1196f magnetic resonance. See Magnetic resonance angiography ( M U ) . negative, aneurysmal subarachnoid hemorrhage with, 328 spinal, 2 13 spinal cord tumors and, 1113, 1116f subarachnoid hemorrhage and, 327-328 Angiokeratoma corporis diffusum, 148 Angiomas, 336 Angiopathy, cerebral amyloid, 315 Angiotensin-converting enzyme inhibitors, 399-400 Anhidrosis, 148

Index

Anhidrotic sensory neuropathy, 148 Anicteric leptospirosis, 452 Anisocoria, 59-63,59f Anomic aphasia, 893 Anosmia, 106, 106t, 109, llOt Anterior cerebral artery, 369-370,369f Anterior choroidal artery, 370, 370f Anterior horn cell diseases, 10, 142-143,528 Anterior inferior cerebellar artery (AICA), 373-374 Anthracycline antibiotics, 1137 Antiangiogenesis,malignant gliomas and, 1047 Antibiotics, anthracycline, 1137 Antibodies acetylcholine receptor, 659 anti-CV2, 178 Anti-GM, ganglioside, 178-179 anti-Hu, 178 anti-MalTa, 178 antineutrophilic cytoplasmic, 177, 1297 antinuclear, 176-177 anti&, 178 anti-Yo, 177-178 aPL, 355-357,355t, 356f, 356t cancer-associated retinopathy, 178 to glutamic acid decarboxylase, 179 Lambert-Eaton myasthenic syndrome and, 667 monoclonal. See Monoclonal antibodies. to myelin-associatedglycoprotein, 178 neurosyphilis and, 446 paraneoplastic syndromes and, 177-178 to sulfated glucuronyl paragloboside, 178 Antibody assay, Lyme disease and, 450 Antibody-associated ataxia, 797 Anticardiolipin titers, 176, 176t Anticholinergics, 747, 1279 Anticoagulants, 226-227,1285,1286t brain metastases and, 1102-1103 infective endocarditis and, 1205, 1207 Anticoagulation chronic, in stroke patients, 398 endocarditis and, 1207 ischemic stroke and, 393-396 oral. See Oral anticoagulation. rheumatic disease and, 1303 in stroke patients, 398 Anticonvulsants brain metastases and, 1102 brain tumors and, 1020-1021 chronic pain and, 1394 migraine and, 1345 status epilepticus and, 943-945 Anti-CV2 antibodies, 178 Antidepressants,233,233t, 1286, 1286t anxiety and panic and, 979 chronic pain and, 1393-1394 migraine and, 1345-1346 tricyclic, 1443 Antiepilepticmedications, 233-237,234t, 1443 noncompliance with,933-934 withdrawing, in children, 927 Anti-Factor Xa, tests for, 174-175 Antifibrinolytic therapy, subarachnoid hemorrhage and, 330 Antifungal drugs, 1283t Antigen detection, 179 Antigen tests, central nervous system infection and, 427 Anti-GM, ganglioside antibodies, 178-179 Anti-HIV mehcations, drug-induced peripheral neuropathies and, 629

Antihormones, 1285,1286t Anti-Hu antibodies, 178 Antihypertensives, 264 ischemic stroke and, 399-400 recurrent stroke and, 264-265 Anti-inflammatory medications, 1406 Anti-invasive agents, 1047 Antilymphoblast globulin, 1294 Anti-MaITa antibodies, 178 Antineoplasticdrugs, 1162-1165,1284,1285t Antineutrophilic cytoplasmic antibody (ANCA), 177,1297 Antinuclear antibodies, 176-177 Antioxidant therapy, 744 Antiparasitic drugs, 1283t Antiparkinson agents, 231-233 Antiphospholipid antibody syndrome, 175-176, 176t Antiplatelet agents, 225-226, 1285, 1286t combination of, for stroke prevention, 392-393 ischemic stroke and, 391-393 rheumatic disease and, 1303 Antiprostaglandins, 1302-1303 Antipsychotic drugs, 1286, 1286t Anti-Ri antibodies, 178 Antisocial personality, 987,988 Antistriated muscle antibodies, 177 Antithrombin 111, tests for, 175 Antithymocyte globulin, 1294 Antivertiginous medications, 87t Antiviral drugs, 1283t Antiviscositydrugs, 1285, 1286t Anti-voltage-gated calcium channels, 178 Anti-Yo antibodies, 177-178 Anton’s syndrome, 379 Anxiety, 976-980 epilepsy and, 958 Parkinson’s disease and, 764 recognition and characterization of, 976 reduction of, 1396 Aortic aneurysm, 1212-1220 Aortic atheroma, ulcerated, 302,303f Aortic dissection, 1212-1220 anatomic considerations of, 1214,1215f, 1216f causes of, 1212-1213 classificationsystem for, 1213-1214 clinical features of, 1215-1217 diagnostic testing of, 1217-1218, 1219f, 1220f incidence of, 1212 management of, 1218-1220 pathophysiology of, 1214-1215 prognosis for, 1220 Aphasia, 891-894,891t anomic, 893 Broca’s, 892-893,892t conduction, 893 global, 893 loss of decision-makingability in, 1001-1002 primary progressive,882t, 884 subcortical, 893 transcortical, 893 transcortical motor, 893 Wernicke’s, 893 Aphasic alexia, 894 aPL antibodies, 355-357,355t, 3565 356t aPL syndrome, 355-357,355t, 356f, 356t Apnea central sleep, 696 sleep. See Sleep apnea. Apolipoprotein Al-related familial amyloid polyneuropathy,641

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1468

Index

Apoplexy, pituitary, 1064 Apraxia dressing, 901 gait, 26 of speech, 891 aPTT. See Activated partial thromboplastin time (aPTT). Ara-C. See Cytarabine (Ara-C). Arachnoid cysts, 1099-1100,1099f Arachnoiditis low back pain and, 1435 spinal, 511-512 Arboviruses, viruses causing, 468 Aredia. See Pamidronate. Argyll Robertson pupils, 60,62f Arimidex. See Anastrozole. Arm, upper, pain in, 1429 Arousal disorders, 972-973 Arousals, confusional, 972 Arsenic exposure to, 1290-1291 toxic peripheral neuropathies and, 623-624 Arterial dissection, 281,285f Arterial sources, cerebral embolism and, 302 Arteriovenous fistulas ischemic mononeuropathy associated with, 594 mononeuropathies associated with, 1230 pulmonary, stroke and, 344 Arteriovenous malformation (AVM), 332-336,333f conventional angiography and, 292,292f dural, 546-547 magnetic resonance angiography and, 290 Arteritis giant cell, 615, 1299-1300 Takayasu’s, 1300 temporal, 1300, 1358 Arthritis acromioclavicdar joint, 1429 of elbow, 1429 of first carpometacarpal joint, 1430 pharmacotherapy for, 1283,1283t physical therapy and, 1447 rheumatoid, 613, 1298 ASA. See Atrial septal aneurysm (ASA). Ascending pain pathways, 1386 Aseptic meningitis, drug-induced, 511,51It Asparaginase, 1137 Aspirin, 225-226 and clopidogrel for stroke prevention, 393 and dipyridamole for stroke prevention, 392-393 ischemic stroke and, 391 stroke and, 350 Associated physical signs in assessment of weakness, 9 Asthma, 1285t Astrocytic tumors, 1028-1029 Astrocytoma, 1107, 1110f anaplastic, 1043f desmoplastic infantile, 1030-1031 diffuse, 1028, 1028f pilocytic, 1028, 1028f subependymal giant cell, 1028 Asymptomatic Carotid Artery Study, 401 Asymptomatic carotid stenosis, 384-385 Asymptomatic coronary artery disease, 389-390 Asymptomatic stenosis, stroke and, 272 Ataxia antibody-associated, 797 autosomal dominant. See Autosomal dominant ataxias. autosomd recessive, 564

Ataxia-cont’d dominant, 79 1t episodic, 132 Friedreich‘s, 564,786-788 with isolated vitamin E deficiency, 788 maternally transmitted, 788,789t prion-associated, 797 progressive, 797-798 recessive, 784t-785t recessively inherited, 783-788,784t-785t sensory. See Sensory ataxia. spinocerebellar. See Spinocerebellar ataxia (SCA). sporadic, 796-797,796t with vitamin E deficiency (AVED), 788 X-linked, 783-788,784t-785t, 789t Ataxia telangiectasia, 783-786 Atherogenesis, 293-294 Atherogenic host factors, 255-258 Atheroma carotid artery, 302 symptoms of, 294-295,294f, 295f ulcerated aortic, 302,303f Atherosclerosis, symptomatic in tracranial, 397-398 Atherosclerotic cerebrovascular disease, 340 Atherothrombotic cerebral infarction, 293-299 atherogenesis, 293-294 atheroma distribution and mechanism of symptoms, 294-295 clinical presentation, 295-296 laboratory diagnosis, 296-297 treatment, 297-299 Atonic seizures, 1 3 1- 132 Atrial fibrillation cerebral embolism and, 300 nonvalvular, warfarin in treatment of, 265-266,265f stroke and, 258-259,266 Atrial Fibrillation Follow-up Investigation of Rhythm Management, 1200 Atrial myxoma cerebral embolism and, 302 stroke and, 345 Atrial septal aneurysm (ASA), 345-346 Atrophy, multiple-system, 766-769 Attention impaired visual, syndromes of, 899-901 mental state assessment and, 853-854, 854f Attention, shifting of in dealing with tinnitus, 101-102 Attention deficit hyperactivity disorder (ADHD) in adults. See Learning disabilities and attention deficit hyperactive disorder in adults. Attentional systems, psychology of, 887 Atypical amyotrophic lateral sclerosis, 575 Atypical motor neuron disease, 559-568 Atypical mycobacteria, tuberculosis and, 436-438 Audiogram, hearing loss and, 91 Audiometry, brain tumors and, 1016 Auditory agnosias, 96 Auditory anatomy, 87-91,88f, 89f, 90f Auditory evoked potentials, 91-92,195-197, 195f Auditory function, central, 95-96 Auditory nerve, 92-93 Auditory neuropathies, 94 Auditory system central, 90f peripheral, 88f Aura, migraine with or without. See Migraine with or without aura. Aurothioglucose, 627

Index

Autoantibodies, 178-179 inflammatory myopathy and, 700, 700t myasthenia gravis and, 177 paraneoplastic syndromes and, 177-178, 178t rheumatic disease and, 176-177, 177t systemic vasculitis and, 177 Autoimmune association, stiff-man syndrome and, 846 Autoimmune inner ear disease, 100 Autoimmune vasculitides, 5 10-511 Autonomic dysfunction, 145-153 autonomic failure and, 149-152 with central nervous system features, 146 diseases of autonomic nervous system and, 145-149 of gastrointestinaltract, 151-152 with peripheral nervous system features, 147-149 of urinary bladder, 150-151 Autonomic dysreflexia, 248-249 Autonomic failure, signs, symptoms, and treatment of, 149-152 Autonomic nervous system diseases of, 145-149, 145t medications working on, toxic myopathies and, 712 Autonomic nervous system dysfunction, isolated, 149 Autonomic neuropathies, 147,586-589,602,1153 acute and subacute, 147-148 hereditary, 148-149 immune-mediated, 148 Autonomic synkinesis, 78 Autophony, tinnitus and, 98 Autosomal dominant ataxias caused by noncoding nucleotide repeats, 794 caused by trinucleotide repeats and glutamine tracts, 790 cerebellar, 564 with defined genetic locus, 795 Autosomal dominant cerebellar ataxias, 564 Autosomal dominant SCA, 788-796,791t Autosomal recessive ataxia, 564 Autosomal recessive CMT 11,636 AVED. See Ataxia with vitamin E deficiency (AVED). Avocational exposure, central nervous system infection and, 426-427 Avoidant personality, 988,989 Avonex, 410 Awakenings, 741 Axonal degeneration, peripheral nerves and, 198 Axonal injury, diffuse, traumatic brain injury and, 169 Axonal neuropathies, 205 Azathioprine, 228-229, 1302

B Back pain low, 1430-1437 physical therapy and, 1447 Bacterial endocarditis, 300-301,301f Bacterial infection drugs to treat, 1282-1283,1282t,1283t facial palsy caused by, 72 Bacterial meningitis, 428-433 clinical manifestations of, 430 diagnosis of, 430-431 epidemiology of, 428 outcome of, 432-433 pathogens and, 429-430 pathophysiology of, 428-429 prophylaxis and, 433 treatment for, 431-432 vaccines and, 433 BAER. See Brainstem auditory evoked response (BAER).

Baht’s syndrome, 45,379,900-901 Ballismus, 19-20 Barbiturates, stroke and, 361 Basal cell news syndrome, 1011 Basal ganglia, pain and, 1388 Basal ganglia diseases, 836 dysarthria and dysphagia in, 124 ophthalmoparesis and, 54 Basilar artery, 375-377 Basilar artery penetrator territory, 377 Basilar artery territory stroke, 375-376,375f, 376f Basilar migraine, 1333-1334 Becker muscular dystrophy (BMD), 684-691 Bedside tests of vestibular function, 80 Bee stings, 675 Behavior epilepsy and, 849-1004,955-961,956t during headache, 1363,1364,1364t playful, unconscious, confusion and, 888 Behavioral neurology, 249,850-922 Alzheimer’s disease and, 872,872t, 873t and epilepsy, 849-1004 epilepsy and, 849-1004 medications and, 233 mental state assessment and, 850 minor traumatic brain injury and, 171-173 severe traumatic brain injury and, 168-171 Behavioral therapy chronic pain and, 1451-1452 disorders of memory and, 911 evaluation of central auditory function and, 95-96 neuropathic pain and, 1407 Behget’s disease, 507-508, 1300 Bell’s palsy, 601 Benign focal amyotrophy, 562-563 Benign intracranial hypertension, 163-164, 163t Benign paroxysmal positional vertigo (BPPV),82,82t, 83f Benign partial epilepsy with centrotemporal spikes, 924 Benign peripheral nerve tumors, 1118-1120 Benign positional vertigo, 83f Benign rolandic epilepsy (BRE),924 Benign variants of transient monocular blindness, 365 Benzodiazepines anxiety and panic and, 978-979,979f for chronic pain, 1394 Benztropine, 747 Beta-blockers, 1346 Beta-interferon, 1139 Beta-oxidation,defects in, disorders of fatty acid metabolism and, 7 16 Betaseron, 410 Bexxar. See Iodine- 131 tositumomab. Biceps tendinitis, 1429 Bilateral vestibulopathy, chronic, 82t, 84 Binaural sound lateralization test, 95 Binswanger’s disease, 312-313,312t Biochemicalmarkers, neoplastic meningitis and, 1130 Biochemicalmediators, pain and, 1388-1389, 1389t Biochemistry, dystonia and, 820 Biofeedback, headache and, 1367-1368,1367t Biologic agents, neurotoxicity and, 1139 Biology meningiomas and, 1054-1055, 1055f molecular, malignant gliomas and, l039,1039f, 1040f Bioprostheticheart valves, stroke and, 344 Biopsy of brain. See Brain, biopsy of. muscle. See Muscle biopsy.

1469

1470

Index

Biopsy-cont’d nerve, peripheral neuropathy and, 573-574 skin, 223-225 stereotactic, brain tumors and, 1027 Biosystems, neuropathic pain and, 1406 Biotin deficiency, 1238 Bipolar disorders, 981,984-985 Bites myopathy and, 7 13 snake, 674 spider, 674,674t Bithermal caloric test, nystagmus and, 81 Bizarre high-frequencydischarge, 736 Bladder, dysfunction of, 8 atypical motor neuron disease and, 560 autonomic, 150-151 multiple sclerosisand, 413-414 treatment of, 150-151, 151t Bladder hyperreflexia, 150-151, 151t Bladder hyporeflexia, 151 Blastomyces dermatitidis, 457 Blastomycosis, 457 Blepharospasm, essential, 68 Blind smell, 106 Blindness complete, 37 taste, 117 transient monocular, 365 Blinking, abnormal, 68 Blocks, sympathetic, neuropathic pain and, 1406 Blood lipids, stroke and, 256-257,257f Blood lipoprotein concentrations, drugs to lower, 1286,1286t Blood tests, central nervous system infection and, 427 Blood transfusion, sickle cell disease and, 1248,1249 Blowing tinnitus, 98 BMD. See Becker muscular dystrophy (BMD). B-mode ultrasound imaging, 269 BMT. See Bone marrow transplantation (BMT). Body sway, nystagmus and, 8 1-82 Bone marrow transplantation (BMT) hemorrhagic complications of, 1169 immune-mediated disorders of, 1169-1170 neurologic complications of. See Neurologic complications of bone marrow transplantation. secondary malignancy and disease recurrence and, 1170 thrombotic complications of, 1169 Bone metastases, 1157-1158 Bone scan, 1124 Borderline personalities, 987 Boston Area Anticoagulation Trial for Atrial Fibrillation, 396,397 Botulinum toxin, 82 1-826 Botulism, 143,669-672,669t, 682-683 adult infectious, 672 foodborne, 671-672,671t, 672t infant, 669-671,669t, 670t, 671t wound, 672 Bourneville’s disease, 349 Bowel dysfunction, 248 atypical motor neuron disease and, 560 multiple sclerosis and, 414 Bowel hypermotility, 152 Bowel hypomotility, 151-152, 151t BPPV. See Benign paroxysmal positional vertigo (BPPV). Brachial neuritis, 577, 1152 Brachial plexopathy breast cancer and, 1184-1185,1185t cancer and, 1161, 1161f neck and arm pain and, 1425-1426,1425f,1425t

Brachial plexus, 577-578,1425f Brachytherapy brain metastases and, 1105 malignant gliomas and, 1045 Brain biopsy of, 214-216 areas of difficulty in, 216 dementia and, 867 diagnostic issues and, 216, 216t intraoperative pathologic interpretations of, 2 14-215 sampling, 2 14 types of, 214 diseases of, HIV infection and. See Human immunodeficiency virus (HIV) and diseases of brain. and spinal abscess, 434-436 clinical features of, 434 diagnosis of, 434-435 epidemiologyof, 434 spinal epidural abscess, 435-436 treatment for, 435 Brain abscess, 1206 Brain and spinal abscess infective endocarditis and, 1206 Brain damage, markers of, cardiac surgery and, 1194 Brain disorders, 158 Brain injury post-traumatic, global incapacity and, 1002-1004, 1003f traumatic. See Traumatic brain injury (TBI). Brain lesions in alcoholics, 1270, 1270t structural, confusion and, 889 Brain mapping, olfaction and, 108 Brain metastases, 1101-1107 brain tumors and, 1012 breast cancer and, 1181-1182 clinical manifestations of, 1101 differential diagnosis of, 1101 evaluation of, 1101, 1102f lung cancer and, 1179-1180, 1179t management of, 1102-1106 pathophysiology of, 1101 prognosis of, 1106 Brain spells, 385-386 Brain tumors, 1006-1106 brain metastases and, 1012 classificationof, 1006-1007 clinical presentation of, 1013-1014 differential diagnosis of, 1014-1015 epidemiology of, 1007-1012 false localizing signs of, 1014 general principles of management of patients with, 1018-1024 intracerebral hemorrhage and, 317 intracranial cysts, 1098-1100 laboratory diagnosis of, 1016-1017 primary, 1006 radiologic diagnosis of, 1015-1016 skull base. See Skull base tumors. specific types of, 1025-1107 supportive therapy for, 1020-1024 treatment of, 1018- 1020 uncommon, 1092-1095 central neurocytoma, 1093-1094 choroid plexus tumors, 1092-1093 dysembryoplastic neuroepithelial tumors, 1094 dysplastic gangliocytoma of cerebellum, 1094 ganglion cell tumors, 1092, 1093f hemangioblastomas, 1094-1095 Lhermitte-Duclos disease, 1094

Index

Brainstem, nuclear and infranuclear disorders in, 49-5 1 Brainstem auditory evoked response (BAER), 91-92, 195, 195f Brainstem disease, dysarthria and dysphagia in, 124 Brainstem encephalitis,paraneoplastic,dysarthria and dysphagia in, 124 Brainstem gliomas, 1035-1038 classification of, 1035, 1036f diagnosis of, 1035 differential diagnosis of, 1036-1037 epidemiologyof, 1035 pathology of, 1035 prognosis for, 1037 treatment for, 1037 Brainstem lesions hearing impairment and, 96 localization of, 6t supranuclear disorders and, ophthalmoparesisand, 53,54f Brainstem syndromes, sensory loss and paresthesias and, 34 Brainstem tumors, 1014 Branch artery disease, 3 10 Brancher enzyme deficiency, 718 B E . See Benign rolandic epilepsy ( B E ) . Breast cancer cerebrovascularcomplications of, 1185-1186 cranial and peripheral neuropathy and, 1184-1185 leptomeningeal metastases and, 1183-1184 metabolic encephalopathy and, 1186 neurologic complications of, 1181-1186 paraneoplastic syndromes and, 1186 spinal cord compression and, 1182-1183 Breathing, sleep-disordered,696-697 Broca’s aphasia, 892-893,892t Bromocriptine, 232,745-746 Brown-Skquard syndrome, 33,33f, 525f, 526-527 Brucellosis, 440-441 Bruit, carotid, 384-385 Bruxism, sleep, 974 Burning pain, neuropathic pain and, 1403 Bursitis olecranon, 1429 physical therapy and, 1447 subacromial, 1429 Buspirone, 979 Busulfan, 1137 Butalbital-containing medications, 1343 C Cabergoline, 745-746 Cachectic myopathy, 1154 CAD. See Coronary artery disease (CAD). CADASIL. See Cerebral autosomal dominant arteriopathy subacute infarcts and leukoencephalopathy (CADASIL). Calcium antagonists, 1346-1347 Calendar, headache, 1317-1318,1317f Callosotomy, epilepsy and, 955 Caloric test, 80 Canadian Atrial Fibrillation Anticoagulation trial, 396, 397 Cancer breast. See Breast cancer. neurologic pain syndromes in. See Neurologic pain syndromes in cancer patients. polyneuropathy and, 609 systemic, neurologic complications of, 1121-1186 Cancer pain, 1156, 1157t Cancer-associatedretinopathy (CAR), 178, 1151 Candidosis, 457 Cannabinoids, 1278

1471

Capecitabine, 1138 CAPRIE. See Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE). Capsuhtis, adhesive, 1429 CAR. See Cancer-associatedretinopathy (CAR). Carbamazepine, 235,945 Carbidopa, 231 Carbohydrate metabolism, disorders of, 714-718 Carbon disulfide (CS,), 618-619 Carboplatin, 1136 Carcinoid myopathy, 1154 Carcinomatosis, meningeal, 5 11 Carcinomatous meningitis, 1180 Cardiac arrhythmias, myocardial damage and. See Myocardial damage and cardiac arrhythmias. Cardiac catheterization acute, after cardiac catheterization, 1196-1197, 1197f acute stroke after, 1196-1197,1197f central nervous system complicationsof, 1195-1I97 neurologic complicationsof, 1195-1198 peripheral nervous system complicationsof, 1197-1198 Cardiac complications of subarachnoid hemorrhage, 330 Cardiac disease, syncope and, 128 Cardiac embolism, 343-346,344t Cardiac function, impaired, stroke and, 258-259 Cardiac surgery cardiology and, 1188-1220 etiologic factors of, 1193-1194 hypotension and cerebral blood flow during cardiopulmonary bypass procedures, 1189-1190 infectiveendocarditis and, 1205 markers of brain damage and, 1194 microemboli and, 1190-1193 neurologic complications of, 1188-1195 peripheral nervous system complications of cardiopulmonary bypass procedures and, 1194 stroke and, 1188-1189 Cardiac system, inflammatory myopathy and, 699 Cardiac transplantation, neurologic complications associated with, 1295 Cardiac valvular heart disease, stroke and, 344 Cardioembolic stroke, oral anticoagulation to prevent, 396-397 Cardiology and cardiac surgery, 1188-1220 Cardiomyopathy, stroke and, 345 Cardiopulmonary bypass procedures hypotension and cerebral blood flow during, 1189-1190, 1190f, 1191f peripheral nervous system complications of, 1194 Cardiovascular drugs, 1284, 1284t CARE-HD study, Huntington’s disease and, 807-808,808f Carnitine deficiency syndrome, 718 Carnitine palmitoyl transferase I1 (CPTII) deficiency, 716 Carotid artery, internal. See Internal carotid artery. Carotid artery atheroma, 302 Carotid artery disease extracranial, 276 internal, prestroke manifestationsof, 364-366 Carotid artery evaluation, noninvasive, 268-272,268t Carotid Artery Stenosis with Asymptomatic Narrowing Operation Versus Aspirin, 400 Carotid bruit, 384-385 Carotid endarterectomy,seizures after, 388 Carotid stenosis, asymptomatic,384-385,390 Carotid territory, cerebral infarction in, 366-367 Carpal tunnel syndrome, 204,594,642-643,644f, 1230 Carpometacarpaljoint, first, arthritis of, 1430 CAST. See Chinese Acute Stroke Trial (CAST). Cataplexy, 966-967,968

1472

Index

Catechol-0-methyltransferase (COMT), 232-233 Catechol-0-methyltransferase inhibition, 232-233,752-753 Catheterization cardiac. See Cardiac catheterization. therapeutic coronary, 1196 Cauda equina syndrome, 528,600-601 Caudate hemorrhage, 318,318f Caudate thalamic infarcts, 387,387f Cavernomas, 336 Cavernous angiomas, 336 Cavernous sinus, 51,52f CBGD. See Corticobasal ganglionic degeneration (CBGD). Cell counts, cerebrospinal fluid analysis and, 181, 181t Centers for Disease Control and Prevention, 492 Central alveolar hypoventilation syndrome, 698 Central auditory function, behavioral methods for evaluating, 95-96 Central auditory system, 90f Central control of respiration, 138, 138f Central core disease, 721, 722t, 724f Central descending pathways, 1405-1406 Central nervous system (CNS) autonomic dysfunction with features of, 146 direct involvement of, by lymphoma, 1171-1173 electrical stimulation of, 1454-1455 hearing impairment as related to, 96 isolated angiitis of, 1300 Lyme disease and, 450,450t paraneoplastic syndromes of, 1147-1151 renal failure and dialysis and, 1225, 1225t, 1227-1228 tinnitus and, 100 tumors of, histologic classification of, 1008t, 1010t, 101It Central nervous system (CNS) angiitis, isolated, 510 Central nervous system (CNS) complications of alcoholism, 1270-1275 of cardiac catheterization, 1195-1197 Central nervous system (CNS) damage, focal, 836 Central nervous system (CNS) disorders, 243-245 hearing loss and tinnitus and, 95-96 tinnitus and, 101 Central nervous system (CNS) infection, 425-428 circumstances of, 426-427 delineating clinical syndrome and, 425-426 laboratory data in, 427-428 medical characteristics of patient with, 426 Central nervous system (CNS) lymphoma, primary. See Primary central nervous system lymphoma (PCNSL). Central neurocytoma, 1093-1094,1094f Central nystagmus, 80t, 81t Central pontine myelinolysis, 1274, 1274f Central sensitization, 1405 Central sleep apnea, 696,698 Central spinal cord syndrome, 525f, 528 Central taste disorder, 118-120 Centronuclear myopathy, 721-722, 722t, 725f, 726f Centrotemporal spikes, benign partial epilepsy with, 924 Cerebellar degeneration, paraneoplastic, 1147-1148 Cerebellar diseases, dysarthria and dysphagia in, 125 Cerebellar dysfunction, atypical motor neuron disease and, 560 Cerebellar gait, 26 Cerebellar hemorrhage, 320,320f Cerebellar infarction, 372-374,374t Cerebellar lesions, 6t Cerebellar tremors, 17, 801 Cerebellar tumors, 1014 Cerebellopontine angle tumors disorders of auditory nerve and, 93-94 tinnitus and, 100

Cerebral amyloid angiopathy, 3 15 Cerebral angiography, 213 Cerebral angiopathy, 346 Cerebral artery anterior, 369-370,369f middle, 367-369,368f, 368t, 369f posterior, 377-379,378f Cerebral autosomal dominant arteriopathy subacute infarcts and leukoencephalopathy (CADASIL),secondary dementias and, 879 Cerebral blood flow during cardiopulmonary bypass procedures, 1189-1190,1190f, 1191f Cerebral contusions, focal, traumatic brain injury and, 169-170 Cerebral cortex, pain and, 1387 Cerebral degenerative disorders, sleep disorders and, 974 Cerebral disorders, dysarthria and dysphagia in, 124-125 Cerebral dominance, aphasias and, 892 Cerebral edema, fulminant hepatic failure and, 1242 Cerebral embolism, 300-309 clinical features of, 303-306 consequences of embolization of intracranial arteries, 303,304f infective endocarditis and, 1204-1205 laboratory diagnosis of, 306-307 patterns of evolution of neurologic deficits caused by, 304-306, 306f sites of occlusion, 303, 305f, 305t sources of embolic material, 300-302,303f treatment and prevention of, 307-309 Cerebral infarction atherothrombotic. See Arteriovenous malformation (AVM). in carotid territory, 366-367 sickle cell disease and, 1245-1247 Cerebral injury, diffuse. See Diffuse cerebral injury. Cerebral lesions for pain control, 1456 Cerebral necrosis, focal, radiation therapy and, 1141-1142 Cerebrospinal fluid (CSF), 180-182 brain tumors and, 1017, 1017t central nervous system infection and, 427 dementia and, 867 disorders of, hydrocephalus and. See Hydrocephalus and disorders of cerebrospinal fluid flow. HTLV-I infection and, 504 neurosyphilis and, 446 pineal tumors and, 1089-1090 spinal cord tumors and, 1109 Cerebrospinal fluid (CSF) pleocytosis, confusion and, 888 Cerebrovascular disease, 25 1-405 asymptomatic coronary artery disease and, 389 atherosclerotic, 340 of breast cancer, 1185-1186 conventional angiography and, 291-292,291f epidemiology and stroke risk factors, 252-268 ischemic. See Ischemic cerebrovascular disease. neurodiagnostic testing and, 268-293 radiation therapy and, 1145 Cerebrum, aortic dissection and, 1218 Cervical causes of headache, 1322 Cervical disease, 541-543.542t, 542f, 543f neck and arm pain and, 1421- 1422 orofacialpainand, 1411-1412,1411f Cervical dystonia, 21,819, 823-825 Cervical facet syndrome, 1424 Cervical myotomes, lot Cervical plexopathy and accessory nerve damage, 1425 Cervical radiculopathy, 575-576, 1424-1425 Cervical spondylosis, 1422-1423 Cervical sprain, 1423 Cervicocephalic arterial dissection, 341-342,341f, 342f-343f, 342t

Index

CF. See Count fingers (CF). Chagas’ disease, 149 Channel-dependent domains, mental state assessment and, 854-857 Charcot, Jean, 830 CHD. See Coronary heart disease (CHD). Chemotherapy adjuvant, hypothalamic gliomas and, 1046 brain metastases and, 1105-1106, 1106f brain tumors and, 1019-1020,1027-1028 hypothalamic gliomas and, 1033-1034 malignant gliomas and, 1046-1047 metastatic epidural spinal cord compression and, 1128 neurologic complications of, 1134-1140 biologic agents, 1139 chemotherapeutic drugs, 1134-1138 hormonal therapy, 1138-1139 monoclonal antibodies, 1139 signal transduction inhibitors, 1140 pineal tumors and, 1091 recurrent gliomas and, 1046 spinal cord tumors and, 1115-1117 Chest imaging, myasthenia gravis and, 660 Chest radiographs, Lambert-Eaton myasthenic syndrome and, 667 Chiari malformation, vertigo and, 86 Chief complaint in neurologic history, 2-3 Children acoustic neuroma in, 1075 diffuse cerebral injury in, 1142-1143 epilepsy in. See Epilepsy in children. generalizedseizures in, 925-927 partial seizures in, 923-925 withdrawing antiepileptic drugs in, 927 Chinese Acute Stroke Trial (CAST), 391 Chlorambucil, 1138 Chloramphenicol,627 Chloroma, 1176 Chloroquine, 627 Chondrosarcoma, 1095-1097,1096f Chordoma, 1095,1096f Chorea, 18-19, 19t causes of, 19t Huntington’s, 803,809 Choreoathetoid tardive dyskinesia, 812 Choriomeningitis,lymphocytic. See Lymphocytic choriomeningitis (LCM). Choroid glioma of third ventricle, 1030 Choroid plexus tumors, 1092-1093, 1093f Choroidal artery, anterior, 370,370f Chronic acoustic trauma, tinnitus and, 100 Chronic and recurrent noninfectious meningitis, 507-512, 507t autoimmune vasculitides, 510-511 Behget’s disease, 507-508 causes of, 5 12 drug-induced aseptic meningitis, 5 11 isolated central nervous system angiitis, 510 lymphomatoid granulomatosis, 510 meningeal carcinomatosis,5 11 migraine, 512 Mollaret’s meningitis, 507 sarcoidosis,509 spinal arachnoiditis, 5 11-512 Vogt-Kayanagi-Harada syndrome, 508-509 Wegener’s granulomatosis, 509-510 Chronic bilateral vestibulopathy, 82t, 84 Chronic confusion, 890

1473

Chronic daily headache. See Headache, chronic daily. Chronic inflammatory demyelinatingpolyneuropathy, 582-585, 582t Chronic inflammatory demyelinatingpolyradiculopathy (CIDP), 239 Chronic low back pain, 1437 Chronic memory loss, 907-908 Chronic meningitis. See Chronic and recurrent noninfectious meningitis. Chronic nocturnal migraine, 1372-1373 Chronic pain. See Pain, chronic. Chronic Pain Self-Efficacy Scale, 1450 Chronic progressive external ophthalmoplegia, 1265-1267 Chronic progressive hearing loss, tinnitus and, 100 Chronic sensorimotor neuropathy, 1152 Churg-Strauss angiitis, 1299 Churg-Strauss syndrome, 615 CID, dementia and, 867 CIDP. See Chronic inflammatory demyelinatingpolyradiculopathy (CIDP). Cigarette smoking ischemic stroke and, 339 olfaction and, 106 stroke and, 260-261,261t, 266,362 Circadian rhythm sleep disorders, 971-972 Cisplatin drug-induced peripheral neuropathies and, 627 neurotoxicity and, 1134 CJD. See Creutzfeldt-Jakobdisease (CJD). Cladribine, 1138 Classic migraine, 1326-1327, 1326t Classic spinal muscular atrophy, 554,554 Clear focal onset, spells without, 129-133, 129t Clicking tinnitus, 97-98 Climacteric, 1379 Clinical diagnosis by lesion site, disorders of afferent visual pathways and, 38-46 Clinical problems, principles of ambulatory neurology and approach to, 1-250 Clivus syndrome, bone metastases and, 1158 Clonazepam, 236,945 Clopidogrel, 226,350-351 and aspirin for stroke prevention, 393 Versus Aspirin in Patients at Risk of Ischemic Events (CAPFUE), 226,350-351 ischemic stroke and, 391-392 in Unstable Angina to Prevent Recurrent Events (CURE) trial, 226 Cluster A diagnoses, 987 Cluster C diagnoses, 987 Cluster headache, 1357-1361 CMT I, 634-635,635f CMT IA,635 CMT IB, 635 CMT 11,636 CMT 111,636,636f CMT IV,636-637 CMT X, 637 CMV. See Cytomegalovirus (CMV). CNS. See Central nervous system (CNS). CNS blastomycosis,457 Coagulation disseminated intravascular, 176 tests of, 173-176, 174f Coagulation cascade, 174f Coagulation factors, stroke and, 258 Coagulation-relatedcauses of stroke. See Stroke, coagulation-related causes of.

1474

Index

Coagulopathies,353-355,353t Cobalamin deficiency, 592-593 Cobalamin enzyme systems, malabsorption and, 1236-1237,1236f, 1237f Cocaine, stroke and, 359,360f Coccidioidal meningitis, 456 Coccidioidomycosis,455-456 Cochlea, 89f Cochlear fluid homeostasis, disorders of, 93 Cochlear hearing loss, 92-93 Codeine, 1441-1442 Coenzyme Qlo (CoQ,, ubiquinone) deficiency, 716 Cognition, fluctuation in, diffuse Lewy body disease and, 775 Cognitive disorders, 249 in alcoholics, 1271-1273 atypical motor neuron disease and, 560 classificationof, 860,860t epilepsy and, 957 Huntington’s chorea and, 805 levodopa and, 755 multiple sclerosis and, 415 primary, 880-885 Cognitive impairment mild, 880-881,908,908f, 908t nonverbal learning disabilityand, 919 Cognitive therapy chronic pain and, 1451-1452 headache and, 1368 Coherence, 887 Colchicine, 627-628,628t Collier’s sign, eyelid retraction and, 67,68f Colloid cysts, 1098-1099,1099f Colony-stimulatingfactors, 1139 Color flow imaging, 270 Coma eye movements in, 56-57 pupils in, 64 Combination analgesics, 1342 Combined diabetic and uremic polyneuropathy, 1230 Commission on Classificationand Terminology of the International League Against Epilepsy, 930 Common migraine, 1326, 1326t Common presenting symptoms and signs, 8-173 Communicating hydrocephalus,26 Communication impairments, nonverbal, 919 Compartment syndromes, renal failure and dialysis and, 1230 Compassionatecare, neuropathic pain and, 1406 Competence in medical setting decision-makingcapacity in, 1000-1002 dementia with specific incapacity but not global incompetence, 999- 1000 evaluation of, 998- 1004 global incapacity in context of posttraumatic brain injury and, 1002-1004 informed consent and, 1001-1002 legal concept of, 999-1000 substitute decision maker in, 1002-1004 Competing stimuli, central auditory function and, 95-96 Complaint, chief, in neurologic history, 2-3 Complete blindness, 37 Complete spinal cord transaction syndrome, 524-526,525f Complex partial seizures, 923-925 Complex partial status epilepticus (CPSE),941-942 Complex repetitive discharges, 735-736,736f Complex visual stimuli, impaired identification of, syndromes of, 896-899 Complicated migraine, 1331 Comportment, mental state assessment and, 856-857

Comportmental learning disability, 921 Compression neuropathies. See Entrapment and compression neuropathies. Computed tomography (CT), 207-208,208f, 278-279 brain tumors and, 1015 Lambert-Eaton myasthenic syndrome and, 667 malignant gliomas and, 1040-1042, 1040f, 1041f metastatic epidural spinal cord compression and, 1124 nystagmus and, 82 perfusion, 279,279f single photon emission. See Single photon emission computed tomography (SPECT). spinal cord tumors and, 1109 subarachnoid hemorrhage and, 326-327,326f, 327t COMT. See Catechol-0-methyltransferase. Conduction aphasia, 893 Conduction velocity, motor nerve conduction studies and, 199 Conductive hearing loss, 92,93t, 94-95 causes of, 9% tinnitus and, 99 Confusion causes of, 888-889 chronic, 890 definition of, 886 pathophysiologyof, 887 physical signs of, 887-888 psychology of attentional systems and, 887 treatment for, 889-890 workup for, 889 Confusional arousals, 972 Confusional spells, 129-130 Confusional state, 889 acute, differentiating dementia from, 860,860t and metabolic encephalopathy, 886-890 Congenital fiber size disproportion, 722 Congenital heart disease, stroke and, 344 Congenital muscular dystrophy, 695-696 Congenital myopathies, 719-727 classic forms of, 721-723 classification and genetics in, 719, 719t, 720 clinical features of, 720 diagnosis of, 723-726 differential diagnosis of, 723 individual, 72 1-723 management of, 726-727 pathogenesis of, 720 Congenital rubella syndrome, 493-494,494f, 4 9 4 Congestive heart failure, stroke and, 258 Connective tissue disease, 1297-1299 associated with peripheral neuropathies, 613-615 association of inflammatory myopathy with, 699 mixed, 1298 neuropathies in, 610-615 Consent, informed, assessment of capacity for, 1001-1002 Constant positive airway pressure (CPAP), 970 Continuous wave Doppler, 269 Contraceptives,oral. See Oral contraceptives. Contracture idiopathic facial paralysis and, 78 joint, 246 Controlled-substanceagreement, 143951440f Conus medullaris, syndrome of, 528 Conventional angiography,291-292 Coordination in neurologic examination, 5 Copaxone, 410 Copenhagen Atrial Fibrillation,Aspirin, Anticoagulation Study (AFASAK),396

Index

Coping and headache, 1367-1368,1367t and stress, 985-986 Coping StrategiesQuestionnaire, 1450 Coproporphyria, hereditary, 1253 CoQ,, ubiquinone deficiency. See Coenzyme Q,, (CoQ,, ubiquinone) deficiency. Cord-Root syndrome, 527-528 Cori-Forbes disease, 717-718 Coronary angiography, 1195-1196, 1196f Coronary artery disease (CAD) asymptomatic, 389-390 underlying, in patients with stroke, 389-390 Coronary catheterization,therapeutic, 1196 Coronary heart disease (CHD), stroke and, 258 Cortex, pain and, 1388 Cortical atrophy, posterior, dementia and, 884 Cortical deafness, hearing impairment and, 96 Cortical depression, spreading, 1331-1332 Cortical lesions higher, disorders of afferent visual pathways and, 44-45 supranuclear disorders and, ophthalmoparesisand, 53 Cortical sensory loss, 34-35,34f Cortical tumors, 1014 Corticobasal degeneration, 777-778 Corticobasal ganglionic degeneration (CBGD), 885 Corticospinal tract, descending, weakness and, 9- 10 Corticosteroids, 227-228,228t brain metastases and, 1102 brain tumors and, 1021-1023, 1022t idiopathic facial paralysis and, 75-76 migraine and, 1343 neurotoxicityand, 1138-1139,1138t organ transplantation and, 1294 Cost-effectiveness, levodopa and, 755-756 Counseling genetic. See Genetic counseling. idiopathic facial paralysis and, 76 vocational, chronic pain and, 1452 Count fingers (CF), visual examination and, 37 Couple issues, epilepsy and, 997 Cover testing for ocular misalignment, 47f CPAP. See Constant positive airway pressure (CPAP). CPSE. See Complex partial status epilepticus (CPSE). CPTII deficiency. See Carnitine palmitoyl transferase I1 (CPTII) deficiency. Cramp(s), 736 dystonic, 827 occupational, 827-830 writer’s, 827 Cranial causes of headache, 1322 Cranial dystonia, 21,819,822-823 Cranial fossa syndrome, 1158 Cranial mononeuropathies, 590-59 1 Cranial nerves assessment of, in neurologic examination, 4 Lyme disease and, 448-449 Cranial neuropathies breast cancer and, 1184-1185 cisplatin and, 1134 dysarthria and dysphagia in, 124 radiation therapy and, 1144 Craniocervicaljunction, sensory loss and paresthesias and, 33-34 Craniopharpgioma, 43f, 1067-1071 diagnosis and preoperative evaluation of, 1068-1069 differential diagnosis of, 1069 treatment for, 1070-1071

1475

Creatine kinase, congenital myopathies and, 723 Creutzfeldt-Jakobdisease (CJD),512-514,879-880,880t Critical illness myopathy, 597 Critical illness polyneuropathy, 596-597 Critically ill patient, metabolic neuromuscular disease in, 596-597 Crocodile tears, idiopathic facial paralysis and, 78 Cryoglobulinemia, polyneuropathy and, 609 Cryptic vascular malformations, 336-337 Cryptococcosis,453-455,454f CS,. See Carbon disulfide (CS,). CSF. See Cerebrospinal fluid (CSF). CT. See Computed tomography (CT). CTA, 279,279f Culture, Lyme disease and, 449-450 CURE trial. See Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. Cushing’s disease, 1065-1066 Cutaneous neurofibroma, 1119 Cyclophosphamide,229,1302 Cyclosporin organ transplantation and, 1293-1294 rheumatic disease and, 1302 Cysticercosis, 458-46 1 clinical features of, 458-460 diagnosis of, 459f, 460 epidemiology of, 458 treatment of, 460-461 Cysts, intracranial, 1098-1100 Cytarabine (Ara-C), 628 Cytomegalovirus (CMV),477-480 Cytomegalovirus (CMV) polyradiculitis, 502 Cytopathology, cerebrospinal fluid analysis and, 181 Cytoplasmic antibodies, antineutrophilic, systemic vasculitis and, 177 Cytosine arabinoside, 1136-1137

D Daily headache, chronic. See Headache, chronic daily. Dapsone, 628 Daytime sleepiness, excessive, 964 DBS. See Deep brain stimulation (DBS). de la Tourette, George Gilles, 830 De Quervain’s tendosynovitis, 1430 Deafness, cortical, hearing impairment and, 96 Debrancher enzyme deficiency, 717-718 Decision maker, substitute, 1002-1004,1003f Decision-making capacity, assessment of, competence and, 1000-1002, lOOOt Declarative memory, 905 Decompression, idiopathic facial paralysis and, 77 Decreased perfusion, syncope and, 126-128 Deep brain stimulation (DBS),Parkinson’s disease and, 758-759 Deep sensory modalities, sensory loss and paresthesias and, 30 Deep vein thrombosis, prevention of, heparin and, 393-394 Degeneration, corticobasal, 777-778 Degenerativememory disorders of aging, 908,908f, 908t Dejerine-Sottas disease, 636,636f Delayed progressive myelopathy, radiation therapy and, 1144 Delayed sleep phase syndrome, 972 Delirium definition of, 886 differentiating dementia from, 860,860t Dementia, 836 associatedwith motor disorders, 884-885 definition of, 858-859,859t

1476

Index

Dementia-cont’d of depression, 875 diagnosis of, 861-867,868 differentiating, from other mental disorders, 860-861 epidemiology of, 859 evaluation of patients with, 858-868 examining for, in older adults, 857-858 frontal variant frontotemporal lobar, 881-883 frontal-variant frontotemporal lobar, 88 It language in, aphasia and, 894 with Lewy bodies, 883t, 884-885 motor neuron disease-related, 885 Parkinson’s disease and, 763 psychosis in, 993 psychosocial issues in, 994-995 recognition of, 861,861t secondary. See Secondary dementias. semantic, 882t, 883 sleep disorders and, 974 with specific incapacity but not global incompetence, 999-1000 subcortical, 875t Dementias infectious, 879-880 non-AD neurodegenerative, 881-885 non-Alzheimer. See Non-Alzheimer dementias. vascular, 878-879,878t Demyelinating neuropathies, 205 Demyelinating polyneuropathies, inflammatory. See Inflammatory demyelinating polyneuropathies. Demyehation, segmental, pathologic processes affecting peripheral nerves and, 198-199 Denervation, electromyography and, 203-204 Denial of illness, confusion and, 888 Denileukin difitox, neurotoxicity and, 1140 Deoxycoformycin, neurotoxicity and, 1138 Dependent personality, 988,989 Depression, 980,98Ot, 1332 dementia of, 875 and grief, 98 1 Huntington’s disease and, 808-809 major, 983-984 new diagnoses of, 982 Parkinson’s disease and, 763-764 recurrent, 982 secondary dementias and, 874-875,876t spreading cortical, 1331-1332 Depression-related cognitive impairment (DRCI), 875 Depressive symptoms in neurologic patients, 981 Dermatomyositis, 698-699,702f, 1154 Dermoid cysts, 1098, 1098f Dermoid tumors, 1108 Descending corticospinal tract, weakness and, 9- 10 Descending modulating system, pain and, 1387-1388 Descending pathways, central, medications augmenting, 1405-1406 Descending tracts, extrapyramidal, weakness and, 10 Desmoplastic infantile astrocytoma (DIA), 1030-1031 Desmoplastic infantile ganglioglioma (DIG), 1030-1031 Detoxification in chronic pain, 1395-1397 Developmental hearing loss, 94-95 DIA. See Desmoplastic infantile astrocytoma (DIA). Diabetes peripheral neuropathy and, 574-575 stroke and, 257,265 Diabetes mellitus (DM), 147,338,586, 1284-1285, 1285t Diabetic and uremic polyneuropathy, combined, 1230 Diabetic autonomic neuropathy, 147

Diabetic neuropathy, 586-59 1 autonomic neuropathy, 586-589 cranial mononeuropathies, 590-591 diabetic polyradiculopathy, 589-590 distal sensorimotor polyneuropathy, 586-589 peripheral mononeuropathies, 590 Diabetic polyradiculopathy, 589-590 Diagnosis clinical, by lesion site, disorders of afferent visual pathways and, 38-46 common presenting symptoms and signs in, 8-173 neurologic, general approach to, 2-8 special tests in, 173-225 topical, disorders of afferent visual pathways and, 37,38f Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), 830,913,1383,1450 Diagnostic coronary angiography, 1195-1196,1196f Dialysis neurologic complications of, 1228-1229 neurologic manifestations of. See Renal failure and dialysis, neurologic manifestations of. Dialysis disequilibrium, 1229 Diaphragm and vocal cord weakness, CMT I1 with, 636 Diary, headache, 1317-1318 Diastolic pressure, stroke and, 256 Diazepam, 87t, 944,944t DIC. See Disseminated intravascular coagulation (DIC). Diencephalic tumors, 1014 Diet, stroke and, 262 Difficulty in initiating and maintaining sleep, 964,966t Diffuse astrocytoma, 1028,1028f Diffuse axonal injury, traumatic brain injury and, 169 Diffuse cerebral injury in children, 1142-1143 radiation therapy and, 1142 Diffuse encephalopathy, 889 Diffuse idiopathic skeletal hyperostosis, neck and arm pain and, 1424 Diffuse infiltrative lymphocytosis syndrome (DILS), 602 Diffuse Lewy body disease (DLBD), 773-776 diagnosis of, 774-775 pathophysiology of, 774 prognosis for, 776 treatment for, 775-776 DILS. See Diffuse infiltrative lymphocytosis syndrome (DILS). Dimenhydramine, 87t Dimethylaminopropionitrile (DMAPN), 620-62 1 DIP. See Drug-induced parkinsonism (DIP). Diphenylhydantoin, 63 1 Dipyridamole, 226 and aspirin for stroke prevention, 392-393 stroke and, 351 Direct mutation analysis, 185-186 Directional preponderance formula, nystagmus and, 80 Disability chronic pain and, 1394 learning. See Learning disabilities and attention deficit hyperactivity disorder in adults. neurologic. See Neurologic deficits. Disability scales, headache and, 1365 Disability Status Scale, Expanded, 1459, 1460 Disc disease, spondylosis and, 537-543 Disc disruption syndrome, low back pain and, 1434 Disc herniation, acute, low back pain and, 1432-1433, 1432t, 1433f Disequilibrium, sensory, gait disorder and, 26-27 Disordered motor control, Huntington’s chorea and, 803-804

Index

Dissecting aortic aneurysm, 1212-1220 Dissection, aortic. See Aortic dissection. Disseminated encephalomyelitis, acute, 423-425 Disseminated intravascular coagulation (DIC), 176 Distal muscular dystrophy, 695,696t Distal sensorimotor polyneuropathy, 586-589 Distal sensory symmetrical polyneuropathy (DSP), 501-502 Distal symmetrical axonal polyneuropathy, 61 1-612 Distal symmetrical polyneuropathy, 600 Distorted stimuli, central auditory function and, 95 Distractibility, attentional systems and, 887 Disulfiram, 628 Diuretics, 1021 Division of Viral and Rickettsial Diseases, 492 Dizziness, 133 causes of, 7% hypoglycemic, 79 isolated, brain spells and, 385 multiple sclerosis and, 413 presyncopal, 79 and vertigo, 78-87 diagnosis and treatment of common neurotologic syndromes, 82-86 examination in assessment of, 79-81 laboratory evaluation in assessment of, 81-82 DLBD. See Diffuse Lewy body disease (DLBD). DM. See Diabetes mellitus (DM). DMAF”. See Dimethylaminopropionitrile (DMAPN). DMD. See Duchenne muscular dystrophy (DMD). Docetaxel, 1136 Doctors Talking with Patients/ Patients Talking with Doctors, 1311 Dominant ataxia, 791t Dominant hemisphere infarction, 386-387 Dopamine agonists, 232,745-747 Dopaminergic agonists, 754,754t Doppler continuous wave, 269 duplex, 269,270f transcranial, 272-277,273t, 2745 275f, 327 Dorsal columns, sensory loss and paresthesias and, 33 Dorsal horn, pain and, 1384-1386 Dorsal root entry zones, pain treatment and, 1456 DOSS. See ALA dehydratase deficiency porphyria (DOSS). Downbeat nystagmus, 56 Down’s syndrome (DS), 112-113, 113f Doxorubicin, 628-629 Drawing impairments, 90 1 DRCI. See Depression-related cognitive impairment (DRCI). Dreams, vivid, levodopa and, 755 Dressing apraxia, 901 Drop attacks, 131-132 Drug dependence, 1277-1282 definitions of, 1277 intoxication and, 1277-1279 medical and neurologic complications of, 1279-1281 types of drugs and, 1277-1279 withdrawal and, 1277-1279 Drug effects, toxins and, 1268-1293 Drug-induced aseptic meningitis, 51 1,511t Drug-induced movement disorders, 815-816 Drug-induced myopathies. See Endocrine, nutritional, and drug-induced myopathies. Drug-induced parkinsonism (DIP), 779,813-814,813t Drug-induced peripheral neuropathies, 626-633 allopurinol, 626 almitrine, 626

1477

Drug-induced peripheral neuropathies-cont’d amiodarone, 626-627 anti-HIV medications, 629 aurothioglucose, 627 chloramphenicol, 627 chloroquine, 627 cisplatin, 627 colchicine, 627-628 cytarabine, 628 dapsone, 628 disulfiram, 628 doxorubicin, 628-629 ethambutol, 629 gold, 627 HMG-CoA reductase inhibitors, 629 hydralazine, 629 isoniazid, 630 metronidazole, 630 misonidazole, 630 nitrofurantoin, 630 paclitaxel, 630-631 perhexiline, 631 phenelzine, 63 1 phenytoin, 631 platinum, 627 procarbazine, 63 1 pyridoxine, 631-632 sodium aurothiomalate, 627 suramin, 632 thalidomide, 632 vinca alkaloids, 632-633 zimeldine, 633 Drug-related mental effects, Parkinson’s disease and, 764-766 Drug-related movement disorders, tardive dyskinesia and. See Tardive dyskinesia (TD) and other drug-related movement disorders. Drugs. See also Medications. illicit. See Illicit drugs. prescription. See Prescription drugs. Dry ejaculation, 156, 157 DS. See Down’s syndrome (DS). DSM-IV See Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). DSP. See Distal sensory symmetrical polyneuropathy (DSP). Duchenne muscular dystrophy (DMD), 143-144, 185, 185f, 684-691, 685f, 686f Ductions, visual examination and, 46 Duplex Doppler, 269,270f Dural arteriovenous malformation, 335,546-547 Duration, electromyography and, 203 Dysarthria, 891 and dysphagia, 121-126 clinical approach to diagnosis of, 121-124 neurobiology of speech and swallowing and, 121 in selected diseases, 124-125 treatment of, 125 Dysautonomia, 148 Dyscontrol, emotional, Huntington’s disease and, 809 Dyscrasia, plasma cell, 604 Dysembryoplastic neuroepithelial tumors, 1094 Dysexecutive syndrome, 883 Dyskinesia peak effect, levodopa and, 755 tardive. See Tardive dyskinesia (TD). Dyskinetic syndromes, 13 Dyslexia in adulthood, 920-921 Dysnomia, amnestic, 378

1478

Index

Dysphagia, dysarthria and. See Dysarthria and dysphagia. Dysphonia, 891 cervical, 823-825 spasmodic, 823 Dysplastic gangliocytoma of cerebellum, 1094 Dysproteinemic polyneuropathy, 604-609 cancer, 609 cryoglobulinemia, 609 epidemiology of, 604,605t hematologic evaluation in, 604 leukemia, 609 lymphoma, 609 multiple myeloma neuropathy, 607 osteosderotic myeloma polyneuropathy, 607-608 polyneuropathy syndromes, 604-606 primary systemic amyloidosis, 606-607 Waldenstrijm’s macroglobulinemia, 608-609 Dyssomnias, 964-972 Dystonia, 20-22,20t acute, 813 cervical, 2 1 , 819 cranial, 21,819,822-823 etiologic classification of, 818t focal. See Focal dystonia. generalized, 20-2 1 laryngeal, 819 levodopa and, 755 limb, 21,819-820 nocturnal paroxysmal, 974 oromandibular, 8 19 paroxysmal, 21 primary, 20-21 primary and secondary generalized. See Primary and secondary generalized dystonias. secondary, 2 1 spasmodic, 819 tardive, 812 trunk, 820 Dystrophin gene genetics and, 687-688,687f mutations of, 687-688 Dystrophin immunostaining, muscular dystrophy and, 688-689,689f Dystrophinopathy, 684-691 Dystrophy, myotonic, 731-732,7301

E EAFT. See European Atrial Fibrillation Trial (EAFT). Eagle syndrome, neck and arm pain and, 1424 Ear external, hearing loss and, 92,93t middle, hearing loss and, 92,93t Early delayed encephalopathy, radiation therapy and, 1141 EBV. See Epstein-Barr virus (EBV). ECG. See Electrocardiogram (ECG). Echocardiogram stroke and, 259 transesophageal. See Transesophageal echocardiography. Echoing of voice, tinnitus and, 98 Eclampsia and hypertensive encephalopathy, 1207-1212 clinical features of, 1208-1209 differential diagnosis of, 1209-1210 epidemiology of, 1208 pathophysiology of, 1208 treatment of, 1210-1211 ECST. See European Carotid Surgery Trial (ECST). ED. See Erectile dysfunction (ED).

Edema cerebral, fulminant hepatic failure and, 1242 peritumoral, brain tumors and, 1021-1023 EDMD. See Emery-Dreifuss muscular dystrophy (EDMD). Edrophonium, 230-23 1 Education. See Patient education. EEG. See Electroencephalogram (EEG). Ehlers-Danlos syndrome, 348 Eight nerve dysfunction, renal failure and dialysis and, 1230 Ejaculatory disturbances, 156-157 Ejaculatory incompetence, 156, 157 Ekbom’s syndrome, 839-844 Elbow arthritis of, 1429 pain in, 1429 d n a r neuropathy at, 204-205,643-646,645f Electrical injury, MND and, 566 Electrical stimulation neuropathic pain and, 1406 of peripheral nerves and central nervous system, 1454-1455 tinnitus and, 102 Electrical studies, facial palsy and, 74-75 Electrocardiogram (ECG) abnormalities in, myocardial damage and, 1199-1200 left ventricular hypertrophy by, 259 Electrodiagnosis, 206 of common neuromuscular disorders, 204-206 congenital myopathies and, 723 femoral neuropathy in pelvis or at inguinal ligament, 654 muscle disorders and, 681-682 peroneal neuropathy at fibular head and, 649-650 sciatic neuropathy at hip or thigh and, 652 tarsal tunnel syndrome and, 656 utility and limitations of, 207 Electroencephalogram (EEG), 187-194, 188f, 189f, 190f, 191f, 191t, 192f brain tumors and, 1016 dementia and, 867 epilepsy and, 960-961 and evoked potentials, 187-197 HTLV-I infection and, 504-505 invasive, epilepsy and, 951-952 memory disorders and, 910-91 1 status epilepticus and, 946 Electrographic status epilepticus, 942 Electrolyte disorders, neurologic manifestations of, 1232-1234 hypercalcemia, 1233 hyperkalemia, 1233 hypermagnesemia, 1233 hypernatremia, 1232 hypocalcemia, 1233 hypokalemia, 1232-1233 hypomagnesemia, 1233 hyponatremia, 1232 hypophosphatemia, 1233 Electromyography (EMG), 202-204,205f abnormalities in, 203-204 amyotrophic lateral sclerosis and, 55 1 facial palsy and, 75 Lambert-Eaton myasthenic syndrome and, 666,666f muscular dystrophy and, 688 needle. See Needle EMG. and nerve conduction studies. See Nerve conduction and electromyography. single-fiber, 206,659 Electroneuronography (ENOG), facial palsy and, 75 Electronystagmography (ENG), dizziness and vertigo and, 81

Index

Electrophysiology acute inflammatory demyelinating polyneuropathy, 579-580,579t, SSOf, 580t amyotrophic lateral sclerosis and, 551-552 carpal tunnel syndrome and, 643 chronic inflammatory demyelinating polyneuropathy and, 583 disorders of afferent visual pathways and, 37 electroencephalographyand evoked potentials and, 187-197 nerve conduction studies and electromyographyand, 197-207 ulnar neuropathy at elbow and, 646 Electroretinogram (ERG),disorders of afferent visual pathways and, 37 Electrotherapy,physical therapy and, 1445 Embolism, 310 cardiac, 343-346,344t cerebral. See Cerebral embolism. pulmonary, prevention of, 393-394 Emboliiation from heart, 1200-1201 Embolus detection, 277,277f Emery-Dreifussmuscular dystrophy (EDMD),691 EMG. See Electromyography(EMG). Emissions, otoacoustic, tinnitus and, 99 Emotional dyscontrol, Huntington’s disease and, 809 Emotional processing deficits, nonverbal learning disability and, 9 19 Emotional support, brain tumors and, 1024 Encephaliticparkinsonism, 781 Encephalitides,viral, infectious dementias and, 879 Encephalitis acute measles, of delayed type, 485-486 herpes simplex. See Herpes simplex encephalitis (HSE). slow virus, infectious dementias and, 879-880 viral. See Viral meningitis and encephalitis. viruses causing, 468-469 Encephalomyelitis acute disseminated, 423-425 parainfectious, 485 paraneoplastic, 1148-1149, 1149t with rigidity, 847 Encephalopathies acute, radiation therapy and, 1140 differentiating dementia from, 860,860t diffuse, 889 early delayed, radiation therapy and, 1141 hepatic. See Hepatic encephalopathy. hypertensive,and eclampsia. See Eclampsia and hypertensive encephalopathy. metabolic. See Metabolic encephalopathies. portal-systemic, 1240-1242, 1240t portosystemic. See Hepatic encephalopathy and portosystemic encephalopathy. progressive dialysis, 1228-1229 toxic, 836 uremic, 1227-1228,1228f Wernicke’s, 1271, 1271f, 1272f Encoding, memory and, 905 Endocarditis bacterial, cerebral embolism and, 300-301,301f infective. See Infective endocarditis. Libman-Sachs, 345 prosthetic valve, infective endocarditis and, 1205 Endocrine, nutritional, and drug-induced myopathies, 707-713 adrenal dysfunction and iatrogenic steroid myopathy, 707-709 primary and secondary hyperparathyroidismand metabolic bone disease, 710-711 thyroid disease, 709-710 toxic myopathies, 711-713

Endocrine disease, 836 disorders of olfaction and, 110 disorders of taste and, 118 secondary dementias and, 877 Endocrine manifestations of brain tumors, 1017 of pituitary tumors, 1063-1064 Endocrine myopathies. See Endocrine, nutritional, and drug-induced myopathies. Endocrine neuropathies, 594 Endocrine ophthalmopathy, 709-710 Endocrinology anxiety and panic and, 977 and metabolism, 1250-1268 Endogenous benzodiazepine hypothesis, portal-systemic encephalopathy and, 1241 Endolymphatichydrops, cochlear hearing loss and, 93 Endovascularprocedures, 33 1,1196 Enhanced physiologic tremor, 800 ENOG. See Electroneuronography (ENOG). Enteral levodopa infusion, 754 Enteroviruses, viruses causing, 468 Entrapment and compression neuropathies, 204-205,613 of lower extremity, 647-657 femoral neuropathy in pelvis or at inguinal ligament, 652-654 peroneal neuropathy at fibular head, 647-650,651t sciatic neuropathy at hip or thigh, 650-652 tarsal tunnel syndrome, 654-657 of upper extremity, 642-647 carpal tunnel syndrome, 642-643,644f median nerve compression in forearm, 646-647 radial nerve entrapment, 646 thoracic outlet syndrome, 646 ulnar neuropathy at elbow, 643-646 Entrapment neuropathies, 613 Enuresis, sleep, 974 Environmentalfactors, stroke and, 260-262 Environmentalsleep disorder, 971 Environmentalstimuli, inattention to, confusion and, 888 Environmentalstressors, confusion and, 888 EPC. See Epilepsia partialis continua (EPC). Ependymomas, 1082-1084,1107-1108,l l l l f , 1112f myxopapillary, 1112f neuroimaging of, 1082,1083f pathology of, 1082-1084 prognosis for, 1084 signs and symptoms of, 1082 therapy for, 1084 Epicondylitis, 1429 Epidemic infection, central nervous system infection and, 426-427 Epidermoid cysts, 1098, 1098f Epidermoid tumors, 11C8 Epidural administration of pharmacologic agents, 1454 Epidural hematoma, 546 Epidural lymphoma, 1172-1173 Epidural spinal cord compression (ESCC) cancer and, 1160,1160f lung cancer and, 1180 metastatic. See Metastatic epidural spinal cord compression. Epidural steroids, neuropathic pain and, 1406 Epilepsia partialis continua (EPC), 941 Epilepsy, 923-96 1 affective disorders and, 958 aggressivity and, 959-960 altered sexuality and, 959

1479

1480

Index

Epilepsy-cont’d anxiety disorders and, 958 and behavior, 955-961,956t behavioral neurology and, 849- 1004 benign partial, with centrotemporal spikes, 924 benign rolandic. See Benign rolandic epilepsy (BRE). in children, 923-928 generalized seizures in, 925-927 partial seizures, 923-925 classification of behavioral changes and, 956 classification of epilepsy syndromes, 930-932 cognitive disorders and, 957 diagnosis and classification of, 928-932 disorders of olfaction and, 113, 113f evaluation of behavioral disorders in, 960-961 identification of population at risk for, 947-948 limbic, psychotic symptoms in, 993-994 personality disorders and, 958-959 progressive-myoclonus, 835-836 pseudoseizures and, 960 psychosis and, 957-958 psychosocial issues in, 996-998 seizures and seizure classification and, 928-930 sleep-related, 974 surgical treatment of, 947-955 use of seizure and syndrome classification in treatment decisions, 931-932 Epilepsy Foundation of America, 998 Epileptic myoclonus, 835-837 Episodic ataxia (EA), 132 Episodic dysarthria and dysphagia, 123, 123t Episodic memory, 905 Episodic nocturnal migraine, 1372 Epogen. See Erythropoietin. Epstein-Barr virus (EBV), 481 -482 Erb‘s palsy, 575-576 Erectile dysfunction (ED), 154-156 ERG. See Electroretinogram (ERG). Ergot agonists, 745-746 Ergots, 1343 Error, propagation of, confusion and, 887-888 Erythropoietin, 1139 ESCC. See Epidural spinal cord compression (ESCC). Essential blepharospasm, 68 Essential tremor, 16-17,800 Esthesioneuroblastoma, 1098 Estramustine, 1139 Estrogens, 1374-1375 Ethambutol, 629 Ethanol neurotoxicity in developing nervous system, 1274-1275, 1275f Ethanol-associated myopathies, 7 12-713 Ethical issues, genetic testing and, 186 Ethosuximide, 236 Ethylene oxide (EtO), 621-622 EtO. See Ethylene oxide (EtO). Etoposide, 1138 European Atrial Fibrillation Trial (EGFT), 396 European Carotid Surgery Trial (ECST), 352,400 Evaluation, laboratory. See Laboratory tests. Evoked potentials, 194-197 auditory, 91-92,195-197,195f brain tumors and, 1016-1017 and electroencephalography, 187-197 HTLV-I infection and, 504-505 somatosensory, 196f, 197 visual, 194-195, 195f Exaggerated startle syndrome, 837

Examination laboratory. See Laboratory tests. neurologic. See Neurologic history and examination. Excessive daytime sleepiness, 964 Executive functions, mental state assessment and, 856-857 Exercise, chronic pain and, 1452 Exercise intolerance defects of glycolysis associated with, 716 metabolic myopathies with, 714-716 Expanded Disability Status Scale, 1459, 1460 Expert Committee on Leprosy, WHO, 438 Expiratory pressure, pulmonary function tests and, 141 Explicit retentive memory, mental state assessment and, 855-856, 856f Exposure to metals, neurotoxic manifestations of. See Metals, neurotoxic manifestations of exposure to. External ear, hearing loss and, 92,93t Extracranial carotid artery disease, 276 Extracranial disorders, orofacial pain and, 1408-1409 Extraocular muscle weakness, atypical motor neuron disease and, 560 Extraocular muscles, innervation of, oculomotor nuclear complex and, 48,48f Extrapyramidal descending tracts, weakness and, 10 Extrapyramidal disorder, 17,26 Extrapyramidal dysfunction, atypical motor neuron disease and, 560 Extrinsic sleep disorders, 970-97 1 Extrinsic spinal cord compression, syndrome of, 527-528 Eye movement in coma, 56-57 control of, 54f-55f disorders of, 46-57 Eye protection, idiopathic facial paralysis and, 76 Eyelid retraction, 67-68,68f Eyelid-eye coordination, theoretical scheme of, 64f Eyelids disorders of, 64-68 disorders of. See Eyes and eyelids, disorders of. normal, 65f sympathetic innervation of, 58f Eyes disorders of afferent visual pathways and, 35-36,36f and eyelids, disorders of, 35-69 disorders of afferent visual pathways, 35-46 disorders of eye movements, 46-57 disorders of eyelids, 64-68 disorders of pupils, 57-64 normal, 65f

F F wave, late responses and, 200,202f Fabry’s disease, 148,347 Facet syndrome, low back pain and, 1434 Facial dysmorphism, lysosomal storage disease and, 1263 Facial motor function, physical examination of, in facial palsy, 73 Facial nerve, anatomy of, 70f Facial nerve palsy, 601 Facial palsy (FP), 69-78 anatomic considerations of, 70-71 associated with middle ear disease, 72 caused by neoplasm, 72 caused by systemic infection, 72 caused by trauma, 73 classification of, 71 clinical syndromes, 71-73 diagnostic evaluation of, 73-75

Index

Facial palsy (FP)-cont’d idiopathic, 71-72,75-77 in primary neurologic disorders, 73 prognosis for, 77 sequelae of, 77-78 staging of, 74 Facial paralysis, idiopathic, 75-77 Factor V Leiden, tests for, 175 Fall-related injury, intervention to reduce risk of, 28 Falls epidemiology of, 27-28 gait impairment and. See Gait impairment and falls. recurrent, neurologic perspective on, 28 False localizing signs of brain tumors, 1014 Familial amyloid polyneuropathy (FAP), 639-641 Familial ataxia syndromes, vertigo and, 86 Familial dysautonomia, 638 Familial insomnia, fatal, 514 Familial isolated vitamin E deficiency, 788 Family history headache and, 1364 in neurologic history, 3-4 peripheral neuropathy and, 572-573,574 of stroke, 257-258 Family therapy, chronic pain and, 1452 FAP. See Familial amyloid polyneuropathy (FAP). FAP IV, 641 Fareston. See Toremifene citrate. Fascioscapulohumeral (FSH) muscular dystrophy, 694-695, 694f, 695f Fatal familial insomnia, 514 Fatigue multiple sclerosisand, 413 Parkinson’s disease and, 764 Fat-soluble vitamin deficiency, 1235 Fatty acid metabolism, disorders of, 716 Fazio-Londe disease, 563 5-FC. See 5-Fluorouracil(5-FC). Febrile seizures, 927 Fecal incontinence, 152 Female sexual dysfunction, 157-159 Femara. See Letrozole. Femoral nerve injuries, cardiac catheterization and, 1197-1198 Femoral neuropathy in pelvis or at inguinal ligament, 652-654, 653f Fentanyl, 1441 Fetal effects, drug dependence and, 1281 Fetal transplantation, human, Parkinson’s disease and, 761-762 Fever pharmacotherapy for, 1283,1283t Q,515 Feverfew, migraine and, 1347-1348 Fibrinogen stroke and, 258 tests for, 175 Fibromuscular dysplasia (FMD), 341 Fibromyalgia, 1398 Fibrositis, 1398 Fibular head, peroneal neuropathy at, 647-650,648f-649f FICSIT trial, fall-related injury and, 28 Firing pattern, electromyographyand, 202-203,203f, 203t Fisher’s syndrome, 579 Fistulas arteriovenous. See Arteriovenous fistulas. perilymphatic.See Perilymphatic fistulas. Fixed progressive muscle weakness, myopathies associated with, 716-718 FK 506, organ transplantation and, 1294

1481

Flexion-extension injury, neck and arm pain and, 1423 Floating, dizziness and, 79 Floppy infant, 556 Flow-volume loops, pulmonary function tests and, 140, 140f Fluctuation in cognition and alertness, diffuse Lewy body disease and, 775 Fludarabine, 1138 5-Fluorouracil(5-FC), 1137 Fluttering, tinnitus and, 97 FMD. See Fibromuscular dysplasia (FMD). Focal brain spells, 385-386 Focal central nervous system damage, 836 Focal cerebral contusions, traumatic brain injury and, 169-170 Focal cerebral necrosis, radiation therapy and, 1141-1142 Focal dystonia, 821-826 cervical dystonia and, 823-825 cranial dystonia and, 822-823 spasmodic dysphonia and, 823 task-specific, 827-830 clinical features of, 827 diagnosis of, 827-828 epidemiology of, 827 pathophysiologyof, 828-829 treatment for, 829-830 treatment of, with botulinum toxin, 821-826 Focal excision of epileptic tissue, temporal lobe, 952-953 Focal neurologic symptoms and signs, brain tumors and, 1014 Focal seizures, 86,385-386 Focal symptoms, transient events and, 133-137,134t Foix-Alajouanine, 535 Folic acid deficiency, 1235-1238,1238t Foodborne botulism, 671-672,671t, 672t Forearm medial nerve compression in, 646-647 pain in, 1429 Forearm exercise test, exhaustive, myophosphorylase deficiency and, 714-715 Forebrain lesions, localization of, 6t Forgetfulness, levodopa and, 755 Fosphenytoin, status epilepticus and, 943,944t Fourth-nerve palsy, 49f, 50t FP. See Facial palsy (FP). Fractionation schedules, altered, malignant gliomas and, 1045 FRDA. See Friedreich’s ataxia (FRDA). Friedreich‘s ataxia (FRDA), 564, 786-788 Frontal gait disorder, 26 Frontal lobe personality, 988 Frontal removals, epilepsy and, 953 Frontal variant frontotemporal lobar dementia (fvFTLD), 881-883,881t Frontotemporal lobar dementia (FTLD),881-884,881t, 882t, 883t dementia and, 867 frontal-variant, 881t nonspecific, 884 with primarily language disturbance (FTLD-LD),883-884 temporal lobe, 883 Frozen shoulder, 1162,1429 FSH muscular dystrophy. See Fascioscapulohumeral (FSH) muscular dystrophy. FTLD. See Frontotemporal lobar dementia (FTLD). FTLD-LD. See Frontotemporal lobar dementia with primarily language disturbance (FTLD-LD). Fulminant hepatic failure, 1242-1243 Functional assessment in evaluation of chronic pain, 1449-1450 in neurologic examination, 7

1482

Index

Functional neuroimaging, dementia and, 866-867 Functional visual loss, disorders of afferent visual pathways and, 45-46 Fundus, 36f Fungal infections, 453-458 blastomycosis, 457 candidosis, 457 coccidioidomycosis, 455-456 cryptococcosis, 453-455 histoplasmosis, 456-457 and parasitic infections, 453-466 sporotrichosis, 457 Fusion tests, central auditory function and, 95 fvFTLD. See Frontal variant frontotemporal lobar dementia (fvFTLD).

G Gabapentin, 236 Gait cerebellar, 26 spastic, 25-26 and station in neurologic examination, 5 Gait apraxia, 26 Gait disorder classification of, by cause, 26 confusion and, 888 normal pressure hydrocephalus and, 160-161 principal patterns of, 25-27,26t psychogenic, 27 Gait impairment and falls, 25-29 approach to patient with slowly progressive disorder of ambulation, 27 epidemiology of falls, 27-28 intervention to reduce risk of fall-related injury and, 28 neurologic perspective on recurrent falls, 28 principal patterns of gait disorder and, 25-27 Gamma-interferon, 1139 Gammopathy IgM monoclonal, with antinerve activity, 604-605,606t monoclonal, 604 Ganglia, 1430 Gangliocytoma, dysplastic, of cerebellum, 1094 Ganglioglioma, 1030-1031, 1030f Ganglion cell tumors, 1092,1093f Ganglioneuritis, sensory ataxia caused by, 602 Gangliopathies, sensory, 32 Gastroenterology and hepatology, 1235-1243 Gastrointestinal bacteria, portal-systemic encephalopathy and, 1242 Gastrointestinal complications of corticosteroids, 1022 Gastrointestinal disorders drugs for, 1284,1285t metabolic neuropathy and, 591-593 Gastrointestinal protein, portal-systemic encephalopathy and, 1242 Gastrointestinal tract, autonomic dysfunction of, 151 Gaze, 56 GCSE. See Generalized convulsive status epilepticus (GCSE). G-CSF. See Granulocyte colony-stimulating factor (G-SCF). Gelsolin amyloidosis, 641 Gelsolin familial amyloid polyneuropathy, 64 1 Gemcitabine, 1138 Gemtuzumab ozogamicin, 1139 Gender olfaction and, 106 stroke and, 252-253,253f Gene therapy, malignant gliomas and, 1047

General medicine, neurology in, 1187-1303 Generalized convulsive status epilepticus (GCSE), 938-940,939t Generalized dystonia, 20-2 1. See also Primary and secondary generalized dystonias. Generalized pain syndromes, 1398-1437 Generalized seizures in children, 925-927 tonic-clonic, 925 Genetic counseling mitochondria1 encephalomyopathies and, 1268 neurofibromatosis and, 1079-1080 neurofibromatosis type 2 and, 1081 Genetic disorders, stroke and, 348-349 Genetic hearing loss, 94-95 Genetic locus, defined, autosomal dominant ataxias with, 795 Genetic markers, serum, dementia and, 867 Genetic testing approaches to, 184-186 and ethical issues, 186 Huntington’s disease and, 807 indications for, 183-184 linkage-based, 184-185,184f, 185f for neurologic disorders, 183-187 Genetics Alzheimer’s disease and, 870,870t attention deficit hyperactivity disorder in adulthood and, 9 14 CMT I and, 634-635,635f CMT I1 and, 636 dyslexia in adulthood and, 920 dystrophin gene and, 687-688,687f lysosomal storage disease and, 1256-1257,1258t-l259t molecular, Huntington’s chorea and, 806-807 myotonia and periodic paralysis and, 733 myotonic dystrophy, 692,693t nonverbal learning disability and, 919 spinal muscular atrophy and, 555 X-linked CMT neuropathy and, 637 Geniculate body, lateral, disorders of afferent visual pathways and, 42 Geniculate neuralgia, 1415 Geniculate segment, facial palsy and, 70 Geniculocalcarine pathway, disorders of afferent visual pathways and, 36-37 Geographic region, stroke and, 253,254f Geography, central nervous system infection and, 426 Geriatric headache, 1371-1373 Gerstmann-Straussler-Scheinker(GSS) syndrome, 514 Giant cell arteritis, 615, 1299-1300 Giant cell astrocytoma, subependymal, 1028 Giddy, dizziness and, 79 Gigantism, 1064-1065 Glasgow Coma Scale, 167, 168t Glatiramer acetate, 230 Gleevec. See Imatinib. Glenohumeral joint, osteoarthritis of, 1429 Glioma, 1006-1007,1009-1011 brainstem. See Brainstem gliomas. choroid, of third ventricle, 1030 diagnosis of, 1025-1027 hypothalamic, optic pathway and, 1031-1034, 03 f low-grade, 1025-1031 malignant. See Malignant gliomas. mixed, 1029-1030 recurrent, chemotherapy for, 1046 specific histologic subtypes of, 1028-1031 therapy for, 1027-1028 uncommon types of, 104 Global amnesia, transient, 385, 386

Index

Global aphasia, 893 Global incapacity, post-traumatic brain injury and, 1002-1004, 1003f Global incompetence,dementia and, 999- 1000 Glomus tumors, 1097-1098,1097f Glossopharyngealneuralgia, 1415 Glucocorticoid hormone, iatrogenic steroid myopathy and, 707-708 Glucocorticoid myopathy versus inflammatory myopathy, 708-709 Glucocorticoids, rheumatic disease and, 1302 Glucoprotein, myelin-associated, antibodies to, paraneoplastic syndromes and, 178 Glucose, cerebrospinal fluid analysis and, 181-182 Glutamic acid decarboxylase,antibodies to, 179 Glutamine tracts, autosomal dominant ataxias caused by, 790 Glycogenesis type V, 714-715 Glycogenosis, muscle, 714,715f, 716-717 Glycogenosis type 11,717,717f Glycogenosis type 111,717-718 Glycogenosis type IV,718 Glycogenosis type IX,715-716 Glycogenosis type VII, 715 Glycogenosis type VIII, 714 Glycolysis, defects of, associated with exercise intolerance, 716 GM-CSF. See Granulocyte-macrophagecolony-stimulatingfactor (GM-CSF). Gold, drug-induced peripheral neuropathies and, 627 Gorlin syndrome, 1011 Graft-versus-hostdisease (GVHD), 1169,1295 Graham, John R., 1310 Granulocytecolony-stimulating factor (G-SCF), 1139 Granulocyte-macrophagecolony-stimulatingfactor (GM-CSF), 1139 Granulomatosis allergic, 615 lymphomatoid, 510, 1299 Wegener’s, 509-510,615,1299 Granulomatous neuropathies, infectious neuropathies and. See Infectious and granulomatous neuropathies. Grave’s disease, 52f, 68f, 594 Grief depression and, 981 epilepsy and, 996-997,997t Group therapy, chronic pain and, 1452 Growth hormone, excess of, myopathy and, 710 GSS syndrome. See Gerstmann-Straussler-Scheinker(GSS) syndrome. Guillain-Barre syndrome, 143,579 dysarthria and dysphagia in, 124 facial palsy and, 73 sensory complaints in, 32 Gustatory problems, 120 GVHD. See Graft-versus-hostdisease (GVHD). H H reflex, late responses and, 200-202 Habit history, headache and, 1363-1364 Had it before, got it again (HIBGIA), 500 Hair cells, disorder of, cochlear hearing loss and, 93 Hallucinations, 133 levodopa and, 755 olfactory, 108-109 tinnitus and, 98 visual, diffuse Lewy body disease and, 775 Hallucinogens, 1278 Hallucinosis, visual, Parkinson’s disease and, 765

HAM. See HTLV-I-associated myelopathy (HAM). Hand injury, confusion and, 888-889 Hand motions (HM), visual examination and, 37 Handedness, aphasias and, 892 Hansen, G. Armour, 598 Hansen’s disease, 598 HD. See Huntington’s disease (HD). Head examination of, headache and, 1313-1314 and neck examination in facial palsy, 73 tinnitus and, 100-101,lOlt Head injury disorders of olfaction and, 109-110 hearing loss and, 94 post-traumatic headache and, 1380-1381 Head movements, coarse intermittent sounds coincident with, tinnitus and, 97 Headache alarms in diagnosis of, 1327, 1327t anatomy of, 1307-1308 approach to patient with, 1310-1319 behavior during, 1363,1364,1364t brain tumors and, 1013,1013t cancer and, 1158-1159,1159f cervical causes of, 1322 chronic daily, 1348-1357 development of, 1351-1352 headache continuum, 1352-1354 hemicrania continua, 1356-1357 outcome of, 1354 presentation of, 1349-1350, 1351f prevalence of, 1348-1349 treatment of, 1354-1356 classificationof, 1319-1323 cluster, 1357-1361 cranial causes of, 1322 differential diagnosis of, 1320-1322 follow-up visits for, 1318-1319 general aspects of, 1306-1323 geriatric, 1371-1373 guide to self-assessmentof, 1318 hemodialysis, 1229 initial consultation in assessment of, 1311-1317 intracranial causes of, 1322 migraine. See Migraine. migraine aura without, 1332-1333,1333f migrainous, 1327 orofacial pain and, 1412 and pain, 1305-1457 pediatric, 1369-1371 physiology of, 1308-1310 post-traumatic. See Post-traumatic headache. primary, 1329-1330,1329t psychologicalevaluation and treatment of patient with, 1362-1369 assessment in, 1362-1364 behavioral checklists, 1364 interviewwith significant others in, 1365 psychometric testing in, 1365-1366 self-report in, 1364-1365 treatment for, 1366-1369 secondary, 1327-1329 sick, 1338 sleep-related, 974-975 styles of physician-patient interaction and, 1311 symptoms of, and treatment for, 1323-1369 systemic causes of, 1322-1323 tension-type, 1320

1483

1484

Index

Headache-cont’d tension-type post-traumatic, 1381 use of headache calendars and, 1317-1318 Headache calendar, 1317-1318,1317f Headache continuum, 1352-1354,1353f Headache diary, 1317-1318 Headache history form, 1312f Headache Impact Test, 1310 Hearing impairment as related to level of CNS involvement,96 Hearing loss, 91-92 absence of, tinnitus and, 100-101, lOlt chronic progressive,tinnitus and, 100 cochlear, 92-93 conductive. See Conductive hearing loss. developmental, 94-95 diagnostic studies of, 91-92 external ear, 92,93t external or middle ear, 92,93t genetic, 94-95 hereditary, tinnitus and, 100 localization of, 9 1 meningeal, 94 middle ear, 92,93t neural, 94-95 noise-induced, cochlear hearing loss and, 93 peripheral sensorineural, 92-93 sensory, 94-95 sudden idiopathic, 94, 100 and tinnitus, 87-102 auditory anatomy and, 87-91 CNS disorders, 95-96 disorders of auditory nerve, 93-95 Hearing testing in facial palsy, 73 Heart, embolization from, 1200-1201.See also cardiac entries. Heart disease. See also cardiac entries. congenital, stroke and, 344 coronary, stroke and, 258 stroke and, 258-259 valvular, stroke and, 344 Heart failure, congestive,stroke and, 258. See also cardiac entries. Heart Outcomes Prevention Evaluation trial, 399-400 Heart valves, prosthetic, stroke and, 344 Heat, physical therapy and, 1445 Heel-to-toe walking, neurologic examination and, 5 Height, electromyography and, 197-198 HELPP syndrome, 1210 Hemangioblastoma, 1094-1095,1108, 1116f Hematology, 1243-1249 dysproteinemicpolyneuropathy and, 604 facial palsy and, 75 stroke and, 346,354-355 Hematoma epidural, 546 intradural, 546 subdural, 1229 Hematopoietic stem cell transplantation, 1166-1171 Hemianacusia,hearing impairment and, 96 Hemianopia homonymous, 45f visual pathways and, 38 Hemianopsia,43f Hemicrania, paroxysmal, 1361, 1361t Hemicrania continua, 1356-1357 Hemidystonia, 820 Hemifacial spasm, 68,736-737 Hemiplegic migraine, 1333-1334 Hemispherectomy, epilepsy and, 953-954

Hemisphericallesions, hearing impairment and, 96 Hemodialysis headache, 1229 Hemodilution, subarachnoid hemorrhage and, 330 Hemorrhage, 546-547 bone marrow transplantation and, 1169 caudate, 318, 318f cerebellar, 320, 320f intracerebral. See Intracerebral hemorrhage (ICH). leukemia and, 1176 lobar, 319, 319f medullary, 32 1 mesencephalic, 321 pontine, 320-321,321f putaminal, 317-318,318f stroke and, 383 subarachnoid. See Subarachnoid hemorrhage (SAH). thalamic, 318-319,319f in young patients, intracerebral hemorrhage and, 317 Hemorrhagic stroke, 279,281, 28lf, 282f Heparin, 226 intravenous low-molecular-weight, 394 intravenous unfractionated, 394 ischemic stroke and, 393-396 low-molecular-weight,226-227 stroke and, 351 subcutaneous low-molecular-weight 395-396 subcutaneous unfractionated, 394-395 Hepatic encephalopathyand portosystemic encephalopathy, 1240-1243,1240t hlminant hepatic failure, 1242-1243 portal-systemic encephalopathy, 1240-1242 Hepatic failure, fulminant, 1242-1243 Hepatology, gastroenterologyand, 1235-1243 Hepatosplenomegaly, lysosomal storage disease and, 1263 Herceptin. See Trastuzumab. Hereditary autonomic neuropathies, 148-149 Hereditary coproporphyria, 1253 Hereditary hearing loss, tinnitus and, 100 Hereditary motor neuropathy, 634-637 Hereditary neuropathy with liability to pressure palsies (HNPP), 578, 638-639,639f, 640f Hereditary sensory and autonomic neuropathies (HSAN), 637-638,637t Hereditary sensory neuropathy, 634-637 Hereditary spastic paraplegia, 563 Herniation, acute disc, low back pain and, 1432-1433, 1432t, 1433f Heroin, stroke and, 361 Herpes simplex encephalitis (HSE), 469-473 clinical features of, 470-471 diagnosis of, 470f, 470t, 471-473 epidemiologyof, 470 prognosis for, 473 treatment of, 473 Herpes simplex radiculitis, 602 Herpes simplex type 1,468 Herpes simplex type 2,468 Herpes zoster, 474 Herpes zoster oticus, 100 Herpes zoster radiculitis, 602-603 Herpes zoster virus infection, 1164-1165 Hexacarbons, 618 HIBGIA. See Had it before, got it again (HIBGIA). Higher cortical lesions, disorders of afferent visual pathways and, 44-45 Higher-order visual impairments, 895-902 achromatopsia, 899 related disorders of spatial-motor capacity and, 90 1

Index

Higher-order visual impairments-cont’d syndromes of impaired identification of complex visual stimuli, 896-899 syndromes of impaired visual attention, 899-901 “what” systems and, 896-899 High-pressurehydrocephalus, 160,160t Hindbrain malformation, syringomyelia associated with, 533-534,534f Hip, sciatic neuropathy at, 650-652 Histoplasma capsulatum, 456-457 Histoplasmosis, 456-457 History family. See Family history. headache and, 1364 neurologic. See Neurologic history and examination. past medical, in neurologic history, 3 of present illness in neurologic history, 3 sleep, 964,966t social, in neurologic history, 4 Histrionic personality, 987,988 Hitzig’s zones of tabes dorsalis, 31f HIV. See Human immunodeficiencyvirus (HIV). HIV meningoencephalitis,496 HIV-related mononeuritis multiplex, 601 HIV-related neuropathy, 599-602 HM. See Hand motions (HM). HMG-CoA reductase inhibitors, 266-267,629 HMSN, 637 HNPP. See Hereditary neuropathy with liability to pressure palsies (HNPP). Homocystinemia,357-358 Homonymous, visual pathways and, 38 Homonymous hemianopia, 45f HOPE trial, 264 Horizontal jerk nystagmus, 56 Hormone replacement therapy, stroke and, 261 Hormones, 1285,1286t brain metastases and, 1106 neurotoxicity and, 1138-1139 Horner’s syndrome, 60-63 House-Brackmannfacial paralysis rating scale, 73t Household products used as recreational inhalants, 1278-1279 HSAN. See Hereditary sensory and autonomic neuropathies (HSAN). HSE. See Herpes simplex encephalitis (HSE). HTE. See Hypertensive encephalopathy (HTE). HTLV-I. See Human T-cell lymphotrophic virus type I (HTLV-I). HTLV-I-associated myelopathy (HAM), 503-506 Human fetal transplantation, Parkinson’s disease and, 761-762 Human immunodeficiencyvirus (HIV), 495-500 and diseases of brain, 495-500 AIDS dementia complex, 496-498 HIV meningoencephalitis,496 HIV testing and, 495-496 meningitis in HIV-infected patients, 498-499 parenchymal brain diseases, 498 problems in diagnosis of, 499-500 and diseases of spinal cord, nerve roots, peripheral nerves, and muscle, 500-503 cytomegaloviruspolyradiculitis, 502 distal sensory, symmetrical polyneuropathy, 501-502 inflammatory demyelinatingpolyneuropathies, 502 mononeuritis multiplex, 502 myopathies, 502-503 vacuolar myelopathy, 500-501 meningitis in, 498-499 neurosyphilis and, 446

1485

Human T-cell lymphotrophic virus type I (HTLV-I), 503-506 clinical features of, 504 diagnosis of, 504-505 epidemiologyof, 503-504 pathogenesis of, 505 prevention and treatment of, 506 Humor, unconscious, confusion and, 888 Huntington’s disease (HD), 18-19,802-809 clinical manifestations of, 802-806 dementia and, 885 dysarthria and dysphagia in, 124 genetic testing in, 807 molecular genetics and, 806-807 neurobiology of Huntington’s disease protein in, 807 neuroimaging features of, 806 pathologic features of, 806 treatment for, 807-809 Huntington’s disease protein, neurobiology of, 807 Hydralazine, 629,629t Hydrocephalus, 160-163 communicating, 26 and disorders of cerebrospinalfluid flow, 159-167 benign intracranial hypertension, 163-164 intracranial hypotension, 164-166 pseudotumor cerebri, 163-164 high-pressure, 160, 160t normal pressure, 160-161,875-876 subarachnoid hemorrhage and, 328 Hydrocodone, 1441 Hydromorphone, 1441 Hydromyelia, 531 Hydrosyringomyelia,531 Hydroxyurea, 1138 Hygiene, inadequate sleep, 970 Hyperactivity, confusion and, 888 Hyperacute treatment of stroke, 401,401t Hypercalcemia, 1233 Hyperekplexia, 837 Hypergonadism, pituitary, 1066 Hypergraphia, 959 Hyperhomocystinemia,258 Hyperkalemia, 1233 Hyperkalemic periodic paralysis (HyperPP), 728,731,732 Hyperkinetic syndromes, 13 Hyperlipidemia,338-339 Hypermagnesemia,673, 1233 Hypermotility, bowel, 152 Hypernatremia, 1232 Hyperosmia, 108,114 Hyperparathyroidism, 565,594 primary, myopathy and, 710-711 secondary, myopathy and, 710-711 HyperPP. See Hyperkalemic periodic paralysis (HyperPP). Hyperprolactinemia, 1064, 1065t Hyperreflexia, 9, 150-151, 151t Hypersensitivity vasculitis, 1299 Hypersomnia, 968 Hypertension benign intracranial, 163-164,163t control of, and stroke prevention, 263-264,263f idiopathic intracranial, 39-40 induced, subarachnoid hemorrhage and, 330 intracerebral hemorrhage and, 3 15 isolated systolic, stroke and, 256 postural, levodopa and, 755 stroke and, 255-256,255f Hypertensive encephalopathy (HTE), eclampsia and. See Eclampsia and hypertensive encephalopathy.

1486

Index

Hyperthyroidism,68f, 594 myopathy and, 709 secondary, 1066 Hypertonia, weakness and, 9 Hyperventilation,increased intracranial pressure and, 1021 Hyperviscosity,stroke and, 354 Hypnotic-dependent sleep disorder, 971 Hypocalcemia, 1233 Hypocholesterolemicdrugs, 71 1 Hypocortisolism, secondary dementias and, 877 Hypoglycemic dizziness, 79 Hypokalemia, 1232-1233 Hypokalemic periodic paralysis (HypoPP), 728, 731,732 Hypomagnesemia, 1233 Hypomania and bipolar conditions, 982-983,984-985 Hypomotility, bowel, treatment of, 151-152, 151t Hyponatremia, 1232 myeholysis after, 1232 subarachnoid hemorrhage and, 328-330 treatment of, 1232 Hypoparathyroidism, myopathy and, 71 1 Hypophosphatemia, 593, 1233 HypoPP. See Hypokalemic periodic paralysis (HypoPP). Hyporeflexia,bladder, pharmacotherapy for, 151 Hyposmia, 110t Hypotension during cardiopulmonary bypass procedures, 1189-1190, 1190f, 1191f intracranial, 164-166 orthostatic, 149-150, 149t Hypothalamicgliomas, optic pathway and. See Optic pathway and hypothalamic gliomas. Hypothyroidism, 594 myopathy and, 710 secondary dementias and, 877 Hypoventilation,alveolar, 139 Hypoxic-ischemicinjury, traumatic brain injury and, 170 I Iatrogenic steroid myopathy, 707-709 Ice, physical therapy and, 1445 ICH. See Intracerebral hemorrhage (ICH). ICP. See Increased intracranial pressure (ICP). Idiopathic facial palsy, 71-72 Idiopathic facial paralysis (IFP), 75-77 Idiopathic hearing loss, sudden, 94, 100 Idiopathic hypersomnia, 968 Idiopathic intracranial hypertension, 39-40 Idiopathic myalgia, 1398 Idiopathic pain, 1383 Idiopathic Parkinson’s disease, 13, 110-112, 112f, 146 Idiopathic syringomyelia, 533 Idiopathic tinnitus, 101 Idiopathic vasculitides, 1299 IFN-P,,. See Interferon-PI, (IFN-PI,). IFN-Plb. See Interferon-P,, (IFN-Plb). Ifosfamide, 1137 IFP. See Idiopathic facial paralysis (IFP). IgA MGUS-associatedpolyneuropathies, 605-606 IgG MGUS-associatedpolyneuropathies, 605-606 IgM monoclonal gammopathy with antinerve activity, 604-605,606t IHS. See International Headache Society (IHS). ILAE. See International League Against Epilepsy (ILAE). Illicit drugs stroke and, 339,359-362 toxic myopathies and, 712

Illness present, history of, in neurologic history, 3 unconcern with or denial of, confusion and, 888 Imaging central nervous system infection and, 427-428 chest, myasthenia gravis and, 660 hearing loss and, 92 HTLV-I infection and, 504,505f low-grade gliomas and, 1025-1026, 1026f malignant gliomas and, 1040-1042 meningiomas and, 1057-1058, 1057f Parkinson’s disease and, 743 pituitary tumors and, 1062 stroke and, 382-384 Imatinib, 1140 Immobilization, physical therapy and, 1446 Immune and infectious disease, 407-518 central nervous system infection and, 426 medications and, 227-230 Immune-mediated autonomic neuropathies, 148 Immune-mediated disease, 408-425 bone marrow transplantation and, 1169-1170 sensory or neural hearing loss and, 94 Immunoglobulin, intravenous, 229-230,1302 Immunologic markers of disease, 176-179 Immunologicallymediated diseases, autoantibodies in, 177t Immunopathogenic mechanisms, rheumatid disease and, 1296-1297 Immunostaining, dystrophin, muscular dystrophy and, 688-689, 689f Immunosuppression, 1284, 1285t complications of, 1229 myasthenia gravis and, 660-661 organ transplantation and, 1293-1295 primary central nervous system lymphoma and, 1051-1052, 1052f, 1053 stiff-man syndrome and, 848 Immunotherapy malignant gliomas and, 1047 of multiple sclerosis,410-411 Impaired cardiac function, stroke and, 258-259 Impaired identification of complex visual stimuli, syndromes of, 896-899 Impaired visual attention, syndromes of, 899-901 Impairment cognitive, nonverbal learning disabilityand, 919 drawing, 901 gait, and falls. See Gait impairment and falls. nonverbal communication, nonverbal learning disability and, 919 Implantable devices, neurosurgical treatment and, 1453-1457 Inadequate sleep hygiene, 970 Inappropriate saccades, ophthalmoparesis and, 55-56 Inappropriate secretion of antidiuretic hormone, syndrome of, 437,1180 Inattention to environmental stimuli, confusion and, 888 Incapacity, global, post-traumatic brain injury and, 1002-1004,1003f Inclusion body myositis, 703f Incompetence ejaculatory, 156, 157 global, dementia and, 999-1000 Incontinence fecal, 152 normal pressure hydrocephalusand, 161 Incoordination, motor, nonverbal learning disability and, 919 Increased intracranial pressure, syncope and, 128 Increased intracranial pressure (ICP) brain tumors and, 1021 pineal tumors and, 1088

Index

Increased vagal tone, syncope and, 127 Induced hypertension, subarachnoid hemorrhage and, 330 Infant, floppy, 556 Infant botulism, 669-671,669t, 670t, 671t Infantile spasms, 926 Infarction leukemia and, 1176-1177 stroke and, 383 Infection(s), 507-518 bone marrow transplantation and, 1166-1168 central nervous system. See Central nervous system (CNS) infection. cytomegalovirus.See Cytomegalovirus(CMV). drug dependence and, 1279 drugs to treat, 1282-1283, 1282t, 1283t Epstein-Barr virus, 481-482 fungal. See Fungal infections. herpes zoster virus, 1164-1165 HIV. See Human immunodeficiency virus (HIV). mycoplasma. See Mycoplasma infections. neurologic, organ transplantation and, 1294-1295 parasitic, 453-466 rickettsial, of nervous system, 515-516 shunts and, intracranial hypotension and, 165 spirochetal, 445-453 systemic, facial palsy caused by, 72 tests of, 179-180 varicella-zoster virus. See Varicella-zoster virus (Vm). viral. See Viral infections. Infectious and granulomatous neuropathies, 597-603 herpes simplex radiculitis, 602 herpes zoster radiculitis, 602-603 HIV-related neuropathy, 599-602 leprosy, 597-598 Lyme disease, 598-599 sarcoidosis,603 Infectious dementias, 879-880 Infectious diseases, 425-455 atypical motor neuron disease and, 566-568 disorders of olfaction and, 109 and immune diseases, 407-518 neck and arm pain and, 1423-1424 peripheral nervous system and, 149 Infective endocarditis, 345 epidemiologyof, 1202-1204 management of, 1204-1207 neurologic complications of, 1201-1207 Inflammation pharmacotherapy for, 1283,1283t stroke and, 258 Inflammatory demyelinating polyneuropathies, 502, 579-585 acute, 579-582 chronic, 582-585 Inflammatorydemyelinating polyradiculoneuropathy, 60 1 Inflammatorydisease disorders of olfaction and, 113, 114f nasal, disorders of olfaction and, 110 neck and arm pain and, 1423-1424 secondary dementias and, 878 Inflammatory myopathy, 698-706 clinical features of, 698-700 diagnosis of, 703-704 versus glucocorticoid myopathy, 708-709 laboratory features of, 700-701 pathogenesis of, 701-703 pathology of, 701,702f, 703f treatment for, 704-705

1487

Information processing model, disorders of memory and, 903,903f Informed consent, assessment of capacity for, 1001-1002 Infranuclear disorders in brainstem, 49-51 cavernous sinus and, 51,52f neuromuscular junction and, 5 1 ocular myopathies and, 51-53,52f orbital apex and, 5 1,52f subarachnoid space and, 51,52f Infranuclear disorders in brainstem, 49-5 1 Inguinal ligament, femoral neuropathy at, 652-654,653f Inhalants, recreational, household products used as, 1278-1279 Inhaled anesthetics, 945-946 Inherited neuropathy, 633-641 associatedwith known metabolic defects, 640t, 641 familial amyloid polyneuropathy, 639-641 hereditary motor and sensory neuropathy, 634-637 hereditary neuropathy with liability to pressure palsies, 638-639,640f hereditary sensory and autonomic neuropathies,637-638 Initiating sleep, difficulty in, 964,966t Injury, traumatic brain. See Traumatic brain injury (TBI). Inner ear disease, autoimmune, tinnitus and, 100 Inner ear fluid system, 89f Innervation of extraocular muscles, 48,48f, 50f, 50t Inobvious stroke, 386-387 Insertional activity, electromyographyand, 202 Insomnia, 964,966t altitude, 971 fatal familial, 514 Inspiratory pressure, pulmonary function tests and, 141 Insufficient sleep syndrome, 97 1 Intensity modulated radiotherapy, 1045 Intention tremor, 16t, 17 Intentional transplantation, neurologic complications associated with, 1296 Interatrial septal aneurysm, cerebral embolism and, 302 Interferon-P,, (IFN-P,,), 230 Interferon-P,, (IFN-P,,), 230 Interleukin-2, 1139 Interleukin-4, 1139 Internal carotid artery cerebral infarction and, 366-367,367f disease of, prestroke manifestations of, 364-366 International Association for the Study of Pain, 1398 International Headache Society (IHS), 1313,1321f-l322f, 1332 International League Against Epilepsy (ILAE), 930 International Stroke Trial (IST), 351,391 Interview semistructured, chronic pain and, 1448-1449 with significant others, headache and, 1365 Intoxication confusion and, 888 drug, 1277-1279 Intra-arterial thrombolysis, ischemic stroke and, 402-403 Intracerebral hemorrhage (ICH), 3 15-323 clinical features of, 317-321 complicationsof, 322 diagnosis of, 321-322 infective endocarditis and, 1205-1206 management of, 322-323 pathogenesis of, 315-317 sickle cell disease and, 1247-1248,1248f Intracranial aneurysms, unruptured. See Unruptured intracranial aneurysm (UIA).

1488

Index

Intracranial arteries, embolization of, 303,304f Intracranial atherosclerosis, symptomatic, 397-398 Intracranial causes of headache, 1322 Intracranial cysts, 1098-1100 Intracranial hemorrhage infective endocarditis and, 1205-1206 sickle cell disease and, 1247-1248,1248f Intracranial hypertension benign, 163-164, 163t idiopathic, 39-40 Intracranial hypotension, 164-166 Intracranial pressure, increased brain tumors and, 1021 syncope and, 128 Intracranial stenosis, 274-276 Intracranial vertebral artery, 373,374f, 374t Intracutaneous sensory loss, 30-31,30f, 31f Intradural hematoma, 546 Intramedullary spinal cord metastases, 1123 Intramedullary spinal cord syndrome, 525f, 528 Intrathecal administration of pharmacologic agents, 1454 Intrathecal agents, 1406 Intrathecal methotrexate toxicity, 1134-1135 Intravascular lymphoma, 1173 Intravenous immunoglobulin, 229-230 myasthenia gravis and, 661 rheumatic disease and, 1302 Intravenous low-molecular-weight heparin, 394 Intravenous thrombolysis, 40 1-402 Intravenous unfractionated heparin, 394 Intrinsic sleep disorders, 964-970 Inventory(ies) affective, headache and, 1365 of Negative Thoughts in Response to Pain, 1450 Iodine-13 1 tositumomab, neurotoxicity and, 1139 Irregular sleep-wake pattern, 971-972 Ischemia leukemia and, 1176-1177 optic nerve, 389 retinal, 388-389 vertebrobasilar, stroke and, 272 Ischemic cerebrovascular disease anterior cerebral artery, 369-370 anterior choroidal artery, 370 basilar artery, 375-377 carotid territory, 363,364f, 366-367 cerebellar infarction, 372-374 cerebral infarction in carotid territory, 366-367 manifestations of internal carotid artery disease, 364-366 middle cerebra1 artery territory, 367-369 ocular stroke, 366 posterior cerebral artery, 377-379 prestroke, 364-366 in relation to vascular territories, 363-379 vertebral artery, 372,373f, 374f, 3 7 4 vertebrobasilar territory, 370-372 Ischemic mononeuropathy, arteriovenous fistulas and, 594 Ischemic stroke. See Stroke, ischemic. Isolated angiitis of central nervous system, 1300 Isolated autonomic nervous system dysfunction, 149 Isolated central nervous system angiitis, 5 10 Isolated disturbances of writing, confusion and, 888 Isolated dizziness, brain spells and, 385 Isolated dysphagia and dysarthria, 123, 123t Isolated systolic hypertension, stroke and, 256 Isolated vitamin E deficiency, ataxia with, 788 Isoniazid, 630 IST. See International Stroke Trial (IST).

J Jargon, occupational, confusion and, 888 Jaw movements, coarse intermittent sounds coincident with, 97 Jerk nystagmus, 56 Jet lag syndrome, 97 1 Joint contracture, 246 Jugular foramen syndrome, bone metastases and, 1158 Junctional plaque, 3 10 Juvenile pilocytic astrocytoma, 1028,1028f

K Kennedy syndrome, 554 Klumpke’s palsy, 576 Knee, peroneal neuropathy at, 205 Korsakoffs amnestic syndrome, 1271-1273, 1272f Korsakoffs psychosis, disorders of olfaction and, 110 Korsakoffs syndrome, secondary dementias and, 877-878 Kudrow, Lee, 1311 Kuru, 5 14

L Laboratory tests, 173-182 acoustic neuroma and, 1072f, 1073-1074,1073f, 1074f, 1074t atherothrombotic cerebral infarction and, 296-297 brain tumors and, 1016-1017 central nervous system infection and, 427-428 cerebral embolism and, 306-307 cerebrospinal fluid analysis and, 180-182 coagulation and, 173-176, 174f dementia and, 864,864t, 865t dizziness and vertigo and, 81-82 dysarthria and dysphagia and, 123 facial palsy and, 75 hearing loss and, 92 immunologic markers of disease and, 176-179 infection and, 179-180 inflammatory myopathy and, 700-701,701t memory disorders and, 91 1 primary central nervous system lymphoma and, 1050,1051f status epilepticus and, 942-943 stiff-man syndrome and, 846 stroke and, 382-384 Labyrinthine segment, facial palsy and, 70 Lacunar infarction, 309-3 14 clinical features of, 310-313 diagnosis of, 3 13,314f differential diagnosis of, 3 13 pathogenesis of, 310,31 If treatment for, 313-314 Lacunar syndromes, 310-312 Lambert-Eaton myasthenic syndrome (LEMS), 663-669,682,682f, 1153-1154 clinical diagnosis of, 664-665 diagnostic studies in, 665-667 differential diagnosis of, 665 electrodiagnosis and, 206 medications contraindicated in, 668 prognosis and follow-up in, 668 therapy for, 667-668 Lamotrigine, 236-237 Language in dementias, aphasia and, 894 mental state assessment and, 854-855 and right hemisphere, aphasia and, 894 and speech disorders. See Speech and language disorders.

Index

Language disorders, 891-894,891t Laryngeal dystonia, 819 Laryngeal neuralgia, recurrent, 1415 Laryngospasm, sleep-related, 975 Late responses, nerve conduction studies and, 200-202, 202f Latency, motor nerve conduction studies and, 199 Lateral epicondylitis, 1429 Lateral geniculate body, disorders of afferent visual pathways and, 42 LCM. See Lymphocytic choriomeningitis (LCM). LD. See Levodopa (LD). L-Deprenyl,231-232 Lead exposure to, 1288-1290 toxic peripheral neuropathies and, 622-623 Learning disabilities and attention deficit hyperactivity disorder in adults, 912-922 comportmental, 921 definitions of, 912-913 dyslexia in adulthood, 920-921 nonverbal, 918-920 Leber’s hereditary optic neuropathy (LHON), 1266-1267 Left fascicularthird-nerve palsy, 48,48f Left fourth-nerve palsy, 49f Left sixth-nerve palsy, 50f Left ventricular hypertrophy (LVH) by electrocardiogram,stroke and, 259 Legal issues competence and, 999-1000 post-traumatic headache and, 1382 Legioneflosis, 441-442 Legionnaire’s disease, 441 LEMS. See Lambert-Eaton myasthenic syndrome (LEMS). Lennox-Gastaut syndrome (LGS), 926 Lepromatous leprosy, 30f, 439 Leprosy, 438-440,597-598 clinical features of, 438-439 diagnosis of, 439 drugs to treat, 1283t epidemiology of, 438 lepromatous, 30f, 439 leprosy reactions, 439 treatment for, 439-440 tuberculoid, 439 WHO Expert Committee on, 438 Leprosy reactions, 439 Leptomeningeal metastasis (LM), 1160-1161 breast cancer and, 1183-1184 metastatic epidural spinal cord compression and, 1123 Leptomeninges, 1129f Leptospirosis,45 1-453 Lesionectomy, epilepsy and, 954-955 Letrozole, 1139 Leukemia direct nervous system involvement and, 1174-1176 meningeal, 1175-1176 neurologic complications of, 1174-1178 neurologic vascular complications of, 1176-1177 parenchymal, 1176 polyneuropathyand, 609 treatment-related neurologic complications of, 1177-1178 Leukodystrophy,lysosomal storage disease and, 1263 Leukoencephalopathy methotrexate and, 1135-1136 progressive multifocal, 488-490 reversible posterior, stroke and, 346 Leuprolideacetate, 1139

1489

Levetiracetam, 237 Levodopa (LD), 231 adverse effects and, 755 cost-effectivenessof, 755-756 improving responses to, 749-756 maximal use of alternativesto, 749-750 optimizing timing and amounts of therapy with, 750-752 Parkinson’s disease and, 747-748,748t patterns of drug response warranting change in treatment regimen, 754-755 responses to, suggesting alternative diagnosis, 755 strategies to extend effects of each dose of, 752-754 supportive services for patients and families, 756 Lewy bodies, 768 dementia with, 883t, 884-885 LGMD. See Limb-girdle muscular dystrophies (LGMD). LGS. See Lennox-Gastaut syndrome (LGS). Lhermitte-Duclos disease, 1094 Lhermitte’s sign cisplatin and, 1134 paresthesias and, 29 LHON. See Leber’s hereditary optic neuropathy (LHON). Libman-Sachs endocarditis, 345 Lid lag, 68f Lidocaine, 945 Life, quality of, behavioral disorders and, in epilepsy, 961 Lifestyle modifications, epilepsy and, 997 Li-Fraumeni syndrome, 1010 Light perception (LP), 37 Lightheaded,dizziness and, 79 Limb dystonia, 21,819-820 Limb praxis, 901 Limb-girdle muscular dystrophies (LGMD), 693-694,693t Limbic epilepsy, 993-994 Limit setting disorder, 971 Linkage-based genetic testing, 184-185, 184f, l85f Lipid metabolism, disorders of, 718 Lipid-lowering drugs, 1286, 1286t Lipids, blood, stroke and, 256-257,257f Lipohyalinosis,3 10,31If Liver transplantation, neurologic complications associated with, 1295-1296 LM. See Leptomeningeal metastasis (LM). LMN. See Lower motor neuron (LMN). Lobar hemorrhage, 319,319f Lobectomies, multiple, epilepsy and, 953-954 Local nasal disease, 109,109t Localized symptoms, transient events and, 133-137,134t Locus of control scales, headache and, 1365 Logging system, headache and, 1317-1318 Long-term anticoagulation for secondary stroke prevention, 398 for stroke prevention, 396-398 for symptomatic intracranial atherosclerosis, 397-398 Long-term memory, 904 Longus colli tendonitis, 1424 Lorazepam, 944,944t Loss, sensory, and paresthesias. See Sensory loss and paresthesias. Low back pain, 1430-1437 chronic, 1437 postoperative, 1434-1435 Lower extremity, entrapment and compression neuropathies of. See Entrapment and compression neuropathies of lower extremity. Lower motor neuron (LMN) diseases, 142-144, 142t Lower motor neuron (LMN) lesions localization of, 7t weakness and, 10

1490

Index

Lower motor neuron (LMN) patterns, weakness and, 10-12 Lower motor neuron (LMN) respiratory dysfunction, 142 Lower motor neuron (LMN) signs, concurrent, lack of, in same spinal segment, 560 Lower motor neuron (LMN) syndromes, non-immune-mediated, 562-563 Low-grade ghomas, 1025-1031 Low-molecular-weight heparin, 226-227 intravenous, 394 ’ subcutaneous, 395-396 LP. See Light perception (LP);Lumbar puncture (LP). LSD. See Lysergic acid diethylamide (LSD). Lumbar disease, 537-541,537t, 538f, 539f, 540f, 540t Lumbar plexopathy, cancer and, 1161-1162 Lumbar puncture (LP) cochlear hearing loss, 93 in patients with AIDS,500 subarachnoid hemorrhage and, 327 Lumbar spinal stenosis, 1434 Lumbosacral myotomes, lot Lumbosacral plexus, 578 Lumbosacral polyradiculopathy,600-601 Lumbosacral radiculopathy, 576 Lumbosacral strain and sprain, 1431-1432 Lung, peripheral nerve supply of, 137-138 Lung cancer brain metastases and, 1179-1180 carcinomatous meningitis and, 1180 epidural spinal cord compression and, 1180 local invasion by, 1178-1179 neurologic complicationsof, 1178-1181 nonmetastatic complications of, 1180-1181 paraneoplasticsyndromes and, 1181 spinal cord metastases and, 1180 Lung transplantation, neurologic complications associated with, 1296 Lupron. See Leuprolide acetate. LVH. See Left ventricular hypertrophy ( L W ) . Lyme disease, 447-451,598-599 clinical features of, 448 diagnosis of, 449-450 epidemiology of, 447-448 idiopathic facial paralysis and, 76 neurologic clinical syndromes and, 448-449 serologic tests for, 180, 180t treatment of, 450-451 Lymphocytic choriomeningitis (LCM), 492-493 clinical features of, 492 diagnosis of, 492-493 epidemiology of, 492 treatment for, 493 Lymphoma direct CNS involvement by, 1171-1173 epidural, 1172-1173 intravascular, 1173 neurologic compkations of, 1171-1174 paraneoplastic syndromes associated with, 1173-1174 polyneuropathy and, 609 primary central nervous system. See Primary central nervous system lymphoma (PCNSL). systemic, 1171 Lymphomatoid granulomatosis, 510, 1299 Lysergic acid diethylamide (LSD),361 Lysosomal metabolism, 1254-1256 Lysosomal storage diseases, 1254-1264 diagnosis of, 1260-1263 genetics and, 1256-1257, 1258t-1259t later-onset forms of, 1259-1260

Lysosomal storage diseases-cont’d lysosomal metabolism, 1254-1256 onset and progression of, 1257-1259 pathophysiologyof, 1256 treatment for, 1263-1264

M Machado-Joseph disease, 792-793 Macroglobulinemia,Waldenstrom’s, 608-609 Maddox rod testing for ocular misalignment, 47,47f Magnetic resonance angiography (M-M), 281-291,286f, 287f, 288f, 289f-290f infective endocarditis and, 1207 unruptured mycotic aneurysms and, 1207 vertebrobasilar insufficiencyand, 85 Magnetic resonance imaging (MRI), 207-213,210f, 211f, 212f, 280-281,327 brain tumors and, 1015 Lambert-Eaton myasthenic syndrome and, 667 metastatic epidural spinal cord compression and, 1124-1125, 1125f nystagmus and, 82 spinalcord tumorsand, 114f, llSf, 1109-1113, Illof, l l l l f , 1112f Magnetic resonance spectroscopy, 207-213,1042 Magnetic resonance venography, 290-291,291f Maintaining sleep, difficulty in, 964,966t Major depression, 983-984 Malabsorption and vitamin deficiency, neurologic effects of, 1235-1239 fat-soluble vitamin deficiency, 1235 water-soluble vitamin deficiency, 1235-1239 Male sexual dysfunction, 154-157 Malignancy association of inflammatory myopathy with, 699 secondary, bone marrow transplantation and, 1170 Malignant degeneration, nerve sheath tumors and, 1108 Malignant gliomas, 1038-1048 clinical features of, 1040 differential diagnosis of, 1042-1044 epidemiologyof, 1038 imaging of, 1040-1042 incidence of, 1038 molecular biology of, 1039,1040f prognostic factors for, 1044 treatment for, 1044-1048 uncommon types of, 1044 Malignant meningiomas, 1058 Malignant peripheral nerve sheath tumor (MPNST), 1120 Malignant peripheral nerve tumors, 1120 Malnutrition, peripheral neuropathy and, 573 Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, 226,298,395 Mania, 980-981,980t, 981t Manipulation, physical therapy and, 1446 Marchiafava-Bignamidisease, 1273,1273f Marcus Gun jaw-wink phenomenon, 66,66f Marfan syndrome, 348-349 Markers of brain damage, cardiac surgery and, 1194 Masking, tinnitus and, 102 Masking level difference, central auditory function and, 95 Massage, physical therapy and, 1445 Masticatory muscle disorders, orofacial pain and, 1411 Mastoid segment, facial palsy and, 71 MATCH trial. See Management of Atherothrombosiswith Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial.

Index

Maternally transmitted ataxias, 788,789t Maximal nerve stimulation, facial palsy and, 75 McArdleS disease, 714-715 McGill Pain Questionnaire, 1449 MCS. See Multiple chemical sensitivity (MCS). Measles and subacute sclerosing panencephalitis, 485-488 clinical features of, 485 diagnosis of, 486-487 epidemiology of, 485 neurologic complications of, 485-486 treatment of, 488 Measles encephalitis,acute, of delayed type, 485-486 Mechanical failure, shunts and, intracranial hypotension and, 165-166

Mechanical heart valves, stroke and, 344 Mechlorethamine, 1138 Meclizine, 87t Medial epicondylitis, 1429 Medial thalamic infarcts, 387,387f Median nerve, 1428f Median nerve compression in forearm, 646-647 Median nerve injuries, cardiac catheterization and, 1198 Median neuropathies neck and arm pain and, 1427,1428f at wrist, 204 Medical history, past, in neurologic history, 3 Medical Research Council (MRC), 680 Medical setting, competence in. See Competence in medical setting. Medical status in neurologic examination, 5 Medication-relatedtinnitus, 101 Medications anticholinesteraseinhibitor, 230-23 1 anticonvulsant, status epilepticus and, 943-945 antiepileptic. See Antiepilepticmedications. anti-inflammatory, neuropathic pain and, 1406 antiparkinson, 231-233 antivertiginous, 87t anxiety and panic and, 978-980 behavioral neurology and psychiatry and, 233 causing taste disturbances, 119 chronic pain and, 1450,1451 disorders of memory and, 911 immune function and, 227-230 mood disorders and, 983-985 olfaction and, 109,109t prescription. See Prescription drugs. thought disorders and, 99 1-993 thromboembolic disease and, 225-227 tinnitus and, 101 Medicine, general, neurology in, 1187- 1303 Medulla ophthalmoparesis and, 53 pain and, 1388 Medullary hemorrhage, 32 1 Medulloblastomas, 1007,1085-1087 clinical presentation of, 1085,1086f outcome of, 1087 pathology of, 1085 sequelae to, 1087 therapy for, 1085-1087 Meige’s syndrome, 21,822-823 Melanoma-associated retinopathy, 1151 MELAS syndrome. See Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome. Melkersson syndrome, 73

1491

Memory disorders of, 902-912 assessment of, 902-905 confusion and, 887 evaluation of, 908-911 mechanism of, 906-908 site of problem of, 905-906 explicit retentive, mental state assessment and, 855-856,856f types of, 904-905 Memory disorders, degenerative, of aging, 908,908f, 908t Memory loss acute, 906-907 chronic, 907-908 subacute, 907 transient, 130-131 Mhiere’s syndrome, 82t, 84 cochlear hearing loss, 93 tinnitus and, 99 Meningeal carcinomatosis,5 11 Meningeal hearing loss, 94 Meningeal involvement by lymphoma, 1171-1 172 Meningeal leukemia, 1175-1176 Meningioma, 1007,1011-1012,1054-1059,1108,1115f classification and pathology of, 1055-1056 clinical presentation of, 1056 etiology and biology of, 1054-1055 imaging of, 1057-1058 malignant, 1058 malignant meningiomas, 1059 treatment for, 1058-1059 Meningitis bacterial. See Bacterial meningitis. carcinomatous, lung cancer and, 1180 cerebrospinalfluid findings in, 181, 181t chronic. See Chronic and recurrent noninfectious meningitis. coccidioidal, 456 drug-induced aseptic, 5 11,511t in HIV-infected patients, 498-499 Mollaret’s, 507 neoplastic. See Neoplastic meningitis. sickle cell disease and, 1244, 1244t viral. See Viral meningitis and encephalitis. viruses causing, 468-469 Meningoencephalitis,HIV,496 Meningovascular syphilis, 445 Menopause, headache and, 1379 Menstrual-associatedsleep disorder, 975 Menstrually associated migraine, 1375 Menstruation headache and, 1373-1379 physiology of, 1373-1374 Mental changes in Parkinson’s disease. See Parkinson’s disease (PD), mental changes in. vitamin B,, deficiency and, 1237-1238 Mental disorders, sleep disorders associated with, 974 Mental effects, drug-related, Parkinson’s disease and, 764-766 Mental retardation, nonspecific slowly progressive, lysosomal storage disease and, 1262-1263 Mental status altered, brain tumors and, 1014 assessment of, 850-858 channel-dependentdomain assessment and, 854-857 dementia and, 863-864 dementia assessment in older adults and, 857-858 examination of, headache and, 1314 memory disorders and, 909 neurocognitiveand behavioral organization of, 850

1492

Index

Mental status-cont’d in neurologic examination, 4 principles of test selection and, 851,852t state-dependent domains assessment and, 853-854 structure and interpretation of examination of, 851 summarizing and interpreting assessment of, 857 Mentation altered, drug dependence and, 1280-1281 disturbance of, normal pressure hydrocephalus and, 161 Meperidine, 1441 Mercury exposure to, 1291-1292 toxic peripheral neuropathies and, 624-625 MERRF. See Myoclonic epilepsy and ragged red fibers (MERRF). Mesencephalic hemorrhage, 32 1 Mesencephalon, ophthalmoparesis and, 53 Metabolic bone disease, myopathy and, 710-71 1 Metabolic causes of secondary dementia, 876-877 of syncope, 128 Metabolic disease disorders of taste and, 118 gait disorder and, 27 Huntington’s chorea and, 805 inherited neuropathies associated with, 640t, 64 1 of neuromuscular junction. See Toxic and metabolic disorders of neuromuscular junction. with parkinsonian features, 781-782 stroke and, 346-348 Metabolic encephalopathies, 836 breast cancer and, 1186,1186t confusional states and, 886-890 Metabolic myopathies, 713-718 with exercise intolerance, 714-716 Metabolic neuromuscular disease in critically ill patient, 596-597 Metabolic neuropathy, 591-597 endocrine neuropathies, 594 metabolic neuromuscular disease in critically ill patient, 596-597 nutritional and gastrointestinal disorders, 591-593 porphyrias, 594-596 psychiatry and, 594-596 renal insufficiency, 593-594 Metabolism, endocrinology and, 1250-1268 Metals, neurotoxic manifestations of exposure to, 1287-1293 arsenic, 1290-1291 detecting neurotoxic disease, 1287-1288 lead, 1288-1290 mercury, 1291-1292 Metastases bone, 1157-1158 brain. See Brain metastases. leptomeningeal, 1160-1161 spinal cord, lung cancer and, 1180 without epidural extension, metastatic epidural spinal cord compression and, 1123 Metastatic epidural spinal cord compression, 1121-1128 clinical manifestations of, 1122-1123 diagnostic workup of, 1124-1125 differential diagnosis of, 1123-1124 epidemiology of, 1121 etiology of, 1121- 1122 management of, 1126-1128 pathophysiology of, 1122 prevention, risk factors, and associated conditions of, 1123 prognosis and complications of, 1125-1126 Methadone, 1441

Methotrexate neurotoxicity and, 1134-1136 rheumatic disease and, 1302 Methyl bromide, toxic peripheral neuropathies and, 621 Metoclopramide, 87t Metronidazole, 630 MG. See Myasthenia gravis (MG). MGUS-associated polyneuropathy syndromes, 604-606,605t Microatheroma, 310 Microbiologic tests, central nervous system infection and, 427 Microemboli, cardiac surgery and, 1190-1l93,1191f, 1192f, 1193f Midazolam, 944t, 945 Midbrain, pain and, 1388 Midbrain tegmentum, lesions of, 49-50 Middle cerebral artery, 367-369,368f, 368t, 369f Middle cranial fossa syndrome, 1158 Middle ear disease of, facial palsy associated with, 72 hearing loss and, 92,93t Migraine, 82t, 84-85, 135-136,385,512 abortive treatment of, 1339-1340,1339t, 1340f acute care therapy for, 1342-1344 aura in, 1330, 1332,1332f basilar, 1333-1334 classic, 1326-1327, 1326t cluster headache and, 1359 common, 1326, 1326t complicated, 1331 diagnostic criteria of, 1326-1327 differential diagnosis of, 1327-1330 disorders of olfaction and, 113 epidemiology of, in United States, 1306-1307 hemiplegic, 1333-1334 menstrually associated, 1375 migraine attack, 1324-1326 neurologic symptoms of, 1330-1335 nocturnal, 1372-1373 ophthalmoplegic, 1334, 1334f pharmacologic treatment of, 1341-1348 post-traumatic, 1381 preventive therapy for, 1340,1344-1348 stroke and, 259-260,1330-1332,1331f symptomatic, 1334-1335, 1334f, 1335f triggers for, 1315f, 1316f with or without aura, 1323-1330,1324-1325, 1326-1327,1326t, l330,1332,1332f, 1338 Migraine attack, 1324-1326 migraine aura and, 1138 migraine headache and, 1336-1137, 1338f pathogenesis of, 1335-1341,1338f, 1339f Migraine aura pathogenesis of, 1338 without headache, 1332-1333,1333f Migraine Disability Assessment Scale, 1310 Migrainous headache, 1327 Migrainous infarction, 342-343,344f Mild cognitive impairment, 861,861t, 880-881,908,908f, 908t Minor traumatic brain injury, 171-173 MisonidazoIe, 630 Mithramycin, 1138 Mitochondria1 disease chronic progressive external ophthalmoplegia, 1265-1267 diagnosis and management of, 1264-1268 dysarthria and dysphagia in, 124 major categories of, 1265 novel phenotypes of, 1267 treatment for, 1267-1268

Index

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, 39,347-348, 1265-1266

Mitochondrial myopathies, 716,1267 disorders of fatty acid metabolism and, 716 and peripheral neuropathy, 1267 Mitomycin-C, 1138 Mitotane, 1139 Mitral valve prolapse (MVP) cerebral embolism and, 301-302 stroke and, 344-345 Mixed connective tissue disease, 1298 Mixed gliomas, 1029-1030 Mixed nerves, pinprick, sensory loss and paresthesias and, 30-31, 30f, 3 If Mixed neuronal-glial tumors, 1030-1031 MM. See Multiple myeloma (MM). MND. See Motor neuron disease (MND). Mobius’s syndrome, 5 1 Molecular biology, malignant gliomas and, 1039, 1039f, 1040f

Molecular diagnosis, central nervous system infection and, 427 Molecular genetics, Huntington’s chorea and, 806-807 Molecular therapy, targeted, malignant gliomas and, 1047

Mollaret’s meningitis, 507 Mollaret’s triangle, 56 Monoamine oxidase inhibitors, 744 Monoamine oxidase-B inhibition, 753-754 Monoclonal antibodies neurotoxicity and, 1139 rheumatic disease and, 1302 Monoclonal gammopathy, 604-605,606t Monomelic amyotrophy, 562- 563 Mononeuritis multiplex, 502,578,601 Mononeuropathies associated with arteriovenous fistula or shunts, 1230 cranial, 590-591 ischemic, associated with arteriovenous fistulas, 594 peripheral, 590 uremic, 1230 Monosymptomatic disease, multiple sclerosisand, 4 1 1 Mood, assessment of chronic pain and, 1449,1451 mental state and, 853 Mood disorders, 415,980-985 Morphine, 1440-1441 Motivation, mental state assessment and, 853 Motor activity, partial status epilepticuswithout, 941 Motor control, 243-247 Huntington’s chorea and, 803-804 Huntington’s disease and, 809 Motor disorders, dementias associated with, 884-885 Motor function facial, physical examination of, in facial palsy, 73 in neurologic examination, 4-5 Motor incoordination, nonverbal learning disability and, 919 Motor innervation, principal, of peripheral nerves, 1 It Motor nerve conduction studies, 199-200,201f Motor neuron disease (MND), 548-568,559,566 atypical, 559-568 dysarthria and dysphagia in, 124 electromyography and, 206 paraneoplastic, 1151 radiation therapy and, 1145 Motor neuron disease-related dementias, 885

1493

Motor neuronopathy, subacute, 1151 Motor neuropathy, hereditary, 634-637 Motor speech disorders, 890-891 Motor synlunesis, idiopathic facial paralysis and, 77-78 Motor systems, spinal cord and, 521-523,523t Motor tics, 23 Motor unit action potentials (MUAF’s),205f Motor unit disorders, 245-246 Motor unit potentials, electromyographyand, 202-203, 203f, 203t

Motor units, abnormal, electromyography and, 203,205f MOTT. See Mycobacteria other than tuberculosis (MOTT). Mouth disorders, orofacial pain and, 1409 Movement, visually guided, syndromes of impaired visual attention and, 900 Movement disorders, 13-25,739-848 akinetic-rigid syndromes, 13-15 ballismus, 19-20 chorea, 18-19 drug-related, tardive dyskinesia and. See Tardive dyskinesia (TD) and other drug-related movement disorders. dystonia, 20-22 myoclonus, 22-23 non-parkinsonian, 783 psychogenic, 24-25 psychogenic movement disorders, 24-25 in sleep and restless legs syndrome, 839-844 causes of, 842-843 definitions and methods in, 839-842 epidemiology of, 842 treatment for, 843-844 tics, 23-24 tremor, 15-18 Moyamoya disease, 340-341 MPNST. See Malignant peripheral nerve sheath tumor (MPNST). M-protein, dysproteinemicpolyneuropathy and, 604 MR spectroscopy, 291 MRA. See Magnetic resonance angiography (MRA). MRC. See Medical Research Council (MRC). MRI. See Magnetic resonance imaging (MRI). MS. See Multiple sclerosis (MS). MSA. See Multiple-system atrophy (MSA). MSE. See Myoclonicstatus epilepticus (MSE). MSLT. See Multiple sleep latency test (MSLT). MUAF’s. See Motor unit action potentials (MUAPs). Mucormycosis,457-458 Multidisciplinaryteam chronic pain and, 1453 dysarthria and dysphagia and, 123-124 Multi-minicore disease, 722-723 Multineuritis, 1152 Multiple chemical sensitivity (MCS), 108 Multiple lobectomies, epilepsy and, 953-954 Multiple modalities, pain management and, 1396 Multiple myeloma (MM), osteolytic. See Osteolytic multiple myeloma. Multiple myeloma neuropathy, 607 Multiple sclerosis (MS), 158 acute therapy for, 410 bladder dysfunction and, 413-414 bowel dysfunction and, 414 chronic therapy for, 410-411 clinical features of, 408-409 cognitive deficits and, 415 diagnosis of, 409-410 disorders of olfaction and, 113 dizziness and, 4 13

1494

Index

Multiple sclerosis (MS)-cont’d epidemiology of, 408 fatigue and, 4 13 immunotherapy of, 410-41 1 management of disease complications of, 4 12-415 mood disorders and, 415 near fainting and, 413 pathophysiology of, 408 primary progressive,41 1 prognosis for, 409 relapsing-remitting,410-411 relationship of optic neuritis to, 419-420 secondary progressive,41 1 sensory symptoms of, 412-413 sexual dysfunction and, 414 spasticity and, 414 swallowing problems and, 415 tremor and, 414-415 vertigo and, 86,413 visual symptoms of, 412 weakness and, 414 Multiple sleep latency test (MSLT), 965 Multiple-systematrophy (MSA), 146, 766-769 clinical diagnosis of, 767,768t diagnostictests for, 767-768 neuropathologic features of, 768 therapeutic strategiesfor, 768-769 Multisystem disorders, dysarthria and dysphagia in, 125 Murmur, aortic dissection and, 1216 Muscle, 503-506 abnormal activity of. See Abnormal muscle activity. anatomy and physiology of, 198 biopsy of, 217-225 reactions to injury, 219-220,219f, 220f skeletal muscle biopsy, 217-218,218t diseases of, 676-737 approach to patients with, 676-684 laboratory evaluation in, 682-683 medical history in, 676-678,679t muscle biopsies in, 683-684 pharmacologic testing in, 683 physical examination in, 678-681,682f dysarthria and dysphagia in, 124 HIV infection and. See Human immunodeficiencyvirus (HIV) and diseases of spinal cord, nerve roots, peripheral nerves, and muscle. disturbancesof, in uremia, 1230-1231 Lyme disease and, 448 paraneoplastic syndromes of, 1154 pathologic processes affecting, 199,200f of respiration, 137-138 weakness and, 12 Muscle biopsy congenital myopathies and, 724-725,725f, 726f muscle disorders and, 683-684 muscular dystrophy and, 688 myotonia and periodic paralysis and, 730 renal failure and dialysis and, 1227 Muscle glycogenosis, 714,715f, 716-717 Muscle spasm, pharmacotherapy for, 1284, 1284t Muscle wasting, significant,absence of, in chronically weak limbs, atypical motor neuron disease and, 560 Muscle weakness, fixed progressive, myopathies associated with, 716-718 Muscular dystrophy, 684-697 Becker, 684-691 congenital, 695-696 distal, 695,696t

Muscular dystrophy-cont’d Duchenne, 143-144,185, I85f, 684-691,685f, 686f dystrophinopathies, 684-691 Emery-Dreifuss, 691 fascioscapulohumeral,694-695,694f, 695f limb-girdle, 693-694 myotonic dystrophy, 691-692,693t oculopharyngeal, 695 proximal myotonic myopathy, 692-693 Muscular rheumatism, 1398 Musculoskeletaldisease metastatic epidural spinal cord compression and, 1123-1124 orofacial pain and, 1409-1411 regional, neck and arm pain and, 1429-1430 Mutations direct, 185-186 myotonia and periodic paralysis and, 733 parkin gene, 740 Muteness, 892 MVP. See Mitral valve prolapse (MVP). Myalgia, idiopathic, 1398 Myasthenia, restricted ocular, myasthenia gravis and, 662 Myasthenia gravis (MG), 239,658-663,682 autoantibodies in, 177 clinical features of, 658-659 diagnosis of, 659-660 dysarthria and dysphagia in, 124 electrodiagnosisand, 206 etiology of, 660 ocular, 65f, 67f in pregnancy, 662 treatment of, 660-663 Myasthenic crisis, 662-663,662t Mycobacteria other than tuberculosis (MOTT), 436-438 Mycophenolate, 229 Mycoplasma infections, 516-518 clinical features of, 516-517 diagnosis of, 517 epidemiologyof, 516 treatment of, 518 ureaplasmas and, 518 Mycotic aneurysms, 324 Myelin-associatedglycoprotein, antibodies to, paraneoplastic syndromes and, 178 Myelinolysis after hyponatremia, 1232 central pontine, 1274,1274f Myelitis, transverse, 420-423 Myelography, 213 metastatic epidural spinal cord compression and, 1124-1125 spinal cord tumors and, 1113 Myeloma multiple. See Multiple myeloma (MM). osteosclerotic, 1153 Myelopathy atypical motor neuron disease and, 567f, 568 delayed progressive,radiation therapy and, 1144 paraneoplastic necrotizing, 1149 radiation, 1124, 1164 transient, radiation therapy and, 1144 vacuolar, 500-501 Mylotarg. See Gemtuzumab ozogamicin. Myoadenylatedeaminase deficiency,7 16 Myocardial damage and cardiac arrhythmias, 1199-1201 electrocardiographicabnormalities and, 1199-1200 embolization from heart and, 1200-1201 nervous system disease and, 1200

Index

Myocardial infarction cerebral embolism and, 300 stroke and, 345 Myoclonic epilepsy and ragged red fibers (MERRF), 1266 Myoclonic status epilepticus (MSE),940-941 Myoclonus, 22-23,22t, 834-838 classificationof, 834-835 common causes of, 22t differential diagnosis of, 834 epileptic, 835-837 nocturnal, 837,839 nonepileptic, 836-837 palatal, 837 postanoxic, 836 segmental, 837 special entities, 835-837 treatment for, 837-838 Myofascial pain neck and arm pain and, 1423 physical therapy and, 1447 Myofascial pain syndrome, 1398-1402 case studies in, 1399-1400 clinical features of, 1398-1399 diagnosis of, 1400-1401 pathophysiology of, 1400 prognosis for, 1402 treatment of, 1401-1402 Myofibrillar myopathy, 723 Myokymia, 734-735,735f Myonecrosis, acute, myopathy and, 713 Myopathic disorders, 143-144 electrornyographyand, 203,205f pathologic processes affecting muscle and, 199 Myopathies, 502-503,683 acute necrotizing, 1154 alcoholism and, 1275-1276 associated with fixed progressive muscle weakness, 716-718 cachectic, 1154 carcinoid, 1154 centronuclear, 721-722,722t, 725f, 726f congenital. See Congenital myopathies. critical illness, 597 electromyographyand, 205 endocrine, nutritional, and drug-induced. See Endocrine, nutritional, and drug-induced myopathies. ethanol-associated,7 12-713 with fixed progressive muscle weakness, 716-718 glucocorticoid, versus inflammatory myopathy, 708-709 iatrogenic steroid, adrenal dysfunction and, 707-709 inflammatory.See Inflammatory myopathy. metabolic, 7 13-718 myofibrillar, 723 nemaline rod, 721,722f 724f, 725f nutritional, 713 ocular, infranuclear disorders and, ophthalmoparesis and, 51-53,52f proximal myotonic, 692-693 steroid. See Steroid myopathy. toxic, myopathy and, 711-713 Myophosphorylase deficiency, 714-715 Myositis, inclusion body, 703f Myotomes, 10t Myotonia, 728,728f 729f 737 nondystrophic, 729t and periodic paralysis, 728-734 clinical disorders, 728-730 differential diagnosis and evaluation of, 732-733

1495

Myotonia-cont’d and periodic paralysis-cont’d genetic and mutation analysis, 732 muscle biopsy, 730 pathophysiologicstudies, 730-732 treatment for, 733 potassium-aggravated,730,731,732 Myotonia congenita, 730,731,732 Myotonic dystrophy, 124,691-692,692f, 730,731-732 Myxoma atrial cerebral embolism and, 302 stroke and, 345 nerve sheath, 1119 Myxopapillaryependymomas, 1112f N Narcissistic personality, 988 Narcolepsy, 966,967 NARP. See Neurogenic muscle weakness, ataxia, and retinitis pigmentosa with subacute optic atrophy (NARP). Nasal congestion, drugs for, 1284,1285t Nasal disease, local, disorders of olfaction and, 109, 109t Nasal inflammatory disease, disorders of olfaction and, 110 NASCET. See North American Symptomatic Carotid Endarterectomy Trial (NASCET). National Council on Aging, 998 National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (NHEFS), 252 National Joint Committee on Learning Disabilities (NJCLD),912 Near-syncope, 126-129,413 Neck examination in facial palsy, 73 headache and, 1313-1314 Neck pain, 1417-1429,1447 Necrotizing myopathy, acute, 1154 Needle electromyography (needle EMG) femoral neuropathy in pelvis or at inguinal ligament, 654 muscle disorders and, 682 peroneal neuropathy at fibular head and, 650 tarsal tunnel syndrome and, 656 Negative family history, neuropathy and, 574 Neglect, syndromes of impaired visual attention and, 899-900 Nemaline rod myopathy, 721,722t, 724f, 725f Neonate, ptosis in, 65-66 Neoplasms facial palsy caused by, 72 neck and arm pain and, 1423-1424 secondary dementias and, 876,879 Neoplastic angioendotheliomatosis, 1173 Neoplastic meningitis, 1128-1133 anatomy and physiology of, 1128-1129 biochemical markers in, 1130 clinical presentation and diagnosis of, 1130 incidence of, 1129 laboratory studies in assessment of, 1130 new therapeutic approaches to, 1132 pathogenesis of, 1129 radiologic studies in assessment of, 1130 therapeutic decisions in, 1132-1133 treatment for, 1130-1132 treatment-related toxicities of, 1132 Neostigmine, 23 1 Nephrology and urology, 1225-1234 Nerve biopsy peripheral neuropathy and, 573-574 renal failure and dialysis and, 1227

1496

Index

Nerve conduction, 199-202 and electromyography, 197-207 anatomy, physiology, and pathophysiologyin, 198-199, 200f electrodiagnosis of common neuromuscular disorders, 204-206 physiologic variables in, 197-198 tests of neuromuscular transmission, 206 facial palsy and, 75 motor, 201f sensory, 200,201f Nerve conduction studies amyotrophic lateral sclerosis and, 551 femoral neuropathy in pelvis or at inguinal ligament, 654 muscle disorders and, 681 peroneal neuropathy at fibular head and, 649-650,651f tarsal tunnel syndrome and, 656 Nerve plexus, weakness and, 11 Nerve roots diseases of, HIV infection and. See Human immunodeficiency virus (HIV) and diseases of spinal cord, nerve roots, peripheral nerves, and muscle. sensory loss and paresthesias and, 32 Nerve sheath myxoma, 1119 Nerve sheath tumors, 1108 Nerves, 503-506 anatomy and physiology of, 198 biopsy of, 217-225 reactions to injury, 222-223,223f, 224f structure of normal nerve, 221-222,222f normal, structure of, 221-222,222f peripheral. See Peripheral nerves. Nervous system central. See Central nervous system (CNS). developing, ethanol neurotoxicity in, 1274-1275,1275f direct involvement of, with leukemia, 1174-1176 peripheral. See Peripheral nervous system. principal disorders of, 1227-1231 rickettsial infections of. See Rickettsial infections of nervous system. Nervous system disease, cardiac arrhythmia as contributor to, 1200 Nervus intermedius neuralgia, 1415 Neumega. See Oprelvekin. Neural function, evaluation of, neuropathic pain and, 1404 Neural hearing loss, 94-95 Neuralgia continuous, orofacial pain and, 1415-1416, 1416f geniculate, 1415 glossopharyngeal,1415 neckand arm pain and, 1418-1421,1421t nervus intermedius, 1415 occipital, 1381, 1415,1421,1421t paroxysmal, orofacial pain and, 1412-1415,1412f, 1413f, 1414f, 1415f postherpetic,475 pretrigeminal, 1415 recurrent laryngeal, 1415 trigeminal, 1358-1359,1412-1415 Neuralgic amyotrophy, 577 Neuralgic disorders, orofacial pain and, 1412-1416 Neurectomies, peripheral, 1455-1456 Neuritis brachial, 577, 1152 optic. See Optic neuritis. paraneoplastic optic, 1151 Neuroablative procedures, 1455-1456

Neuroanatomy disorders of afferent visual pathways and, 35-37 disorders of eyelids and, 64,64f, 65f disorders of pupils and, 57-58,57f, 58f neuropathic pain and, 1402-1403 of respiration, 137-138 sexual dysfunction and, 154 Neuro-BehCet’s disease, 1300 Neurobiology of Huntington’s disease protein, 807 Neurobrucellosis, 440 Neurocognitive examination, dementia and, 863-864 Neurocognitive organization, mental state assessment and, 850 Neurocysticercosis,458 Neurocytoma, central, 1093-1094, 1094f Neurodegenerative dementias, non-AD, 881-885 Neurodegenerative disease corticobasal degeneration and, 778 disorders of olfaction and, 110-113, l l l f Neurodiagnostic testing cerebrovascular disease and, 268-293 computed tomography, 278-279 conventional angiography, 291-292 magnetic resonance angiography, 281-291 magnetic resonance imaging, 280-281,282f, 283f, 284f, 285f noninvasive carotid artery evaluation, 268-272 transcranial Doppler, 272-277 Neuroendocrine effects, radiation therapy and, 1143 Neuroepithelialtumors dysembryoplastic, 1094 of unknown origin, 1030 Neurofibroma, 1108,1119,1177-1179 cutaneous, 1119,1177-1178 nodular, 1078 pacinian, 1119 plexiform, 1078 Neurofibromatosis, 1075,1076-1082 classification of, 1076 type 1 (NF-l), 348-349,1010,1076-1080 type 2 (NF-2), 1010, 1080-1081 Neurogenic muscle weakness, ataxia, and retinitis pigmentosa with subacute optic atrophy (NARP), 788 Neurogenic processes,pathologic processes affecting muscle and, 199 Neurogenic respiratory dysfunction, 144-145, 144f localization and causes of, 141-142 management of, 144-145 symptoms and signs of, 138-139 Neurogenic versus myopathic lesions, electromyographyand, 203,205f Neuroimaging, 207-213 diffuse Lewy body disease and, 775 dizziness and vertigo and, 82 ependymomas and, 1082,1083f epilepsy and, 960-961 functional, dementia and, 866-867 Huntington’s chorea and, 806 memory disorders and, 910 pineal tumors and, 1088-1089 structural, dementia and, 865-866,865t toxoplasmosis and, 464,465f Neuroleptic malignant syndrome (NMS), 814 Neuroleptics anxiety and panic and, 979 thought disorders and, 991-992,991t Neurologic assessment, anxiety and panic and, 977 Neurologic clinical syndromes, Lyme disease and, 448-449

Index

Neurologic complications of alcoholism, 1269-1277 intoxication and, 1270-1271 physical dependence and, 1270-1271 of bone marrow transplantation, 1166- 1171,1295 infection as, 1166-1168 treatment-related toxicities as, 1168-1169 ofbreast cancer, 1181-1186 of cardiac catheterization, 1195-1198 of cardiac surgery, 1188-1195 of chemotherapy. See Chemotherapy, neurologic complications of. of commonly prescribed drugs, 1282-1287 of drug dependence, 1279-1281 of infective endocarditis, 1201-1207 of leukemia, 1174-1178 of lung cancer, 1178-1181 of lymphoma, 1171-1174 of measles, 485-486 of organ transplantation, 1293-1296 of radiation therapy. See Radiation therapy, neurologic complications of. of rubella, 493-495 of sickle cell disease, 1243-1249 of systemic cancer, 1121-1186 treatment-related,leukemia and, 1177-1178 Neurologic deficits aortic dissection and, 1216-1217 associated with dementia, 863,864t genetic testing for. See Genetic testing for neurologic disorders. patterns of, caused by cerebral embolism, 304-306,306f psychological adjustment after, 249-250 rehabilitation of. See Rehabilitation of neurologic disability. sleep disorders associated with, 974-975 spinal cord tumors and, 1109 Neurologic diagnosis, general approach to, 2-8 Neurologic effects of malabsorption and vitamin deficiency. See Malabsorption and vitamin deficiency, neurologic effects of. Neurologic history and examination, 2-8 approach to, 2 functional assessment, 7 neurologic localization, 5-7 purpose of, 2 Neurologic infections, organ transplantation and, 1294- 1295 Neurologic localization in neurologic examination, 5-7,6t, 7t Neurologic management of stroke, 349-350 Neurologic manifestations of brucellosis,440 of cytomegalovirus,478-480,478t, 479f of electrolyte disorders, 1232-1234 of legionellosis, 441 of pituitary tumors, 1063 of porphyrias. See Porphyria, neurologic manifestationsof. of renal failure and dialysis. See Renal failure and dialysis, neurologic manifestations of. of rheumatic diseases, 1296-1303 Neurologicpain syndromes in cancer patients, 1156-1165 cancer pain mechanisms in, 1156,1157t establishing pain diagnosis in, 1156 related to antineoplastictherapy, 1162- 1165 secondary to direct tumor invasion, 1157-1162 Neurologic perspective on recurrent falls, 28 Neurologic practice psychiatric and social issues in, 976 psychiatric issues in. See Psychiatricdisorders. Neurologic recovery, minor traumatic brain injury and, 171

I497

Neurologic symptoms focal, brain tumors and, 1014 transient. See Transient neurologic symptoms. Neurologic vascular complicationsof leukemia, 1176-1177 Neurology ambulatory, principles of, and approach to clinical problems, 1-250

behavioral. See Behavioral neurology. in general medicine, 1187-1303 Neurolymphomatosis, 1173 Neuroma, acoustic. See Acoustic neuroma. Neuromuscular blocking agents, 946 Neuromuscular disease common, electrodiagnosisof, 204-206 gait disorder and, 27 metabolic, in criticallyill patient, 596-597 peripheral, 519-737 pupils in, 64 Neuromuscular junction (NMJ) infranuclear disorders and, ophthalmoparesisand, 5 1 paraneoplastic syndromes of, 1153-1154 toxic and metabolic disorders of. See Toxic and metabolic disorders of neuromuscularjunction. weakness and, 11 Neuromuscularjunction blockade, 597 Neuromuscularjunction disorders, 124, 143 Neuromuscular transmission diseases of, 658-675 tests of, 206,206f Neuromyotonia, 735,736f, 1153 Neuronal form of CMT 11,636 Neuronopathies paraneoplastic sensory, 1151-1152 subacute motor, 1151 Neuro-oncology, 1005-1186 Neuropathic arm pain, 1424-1429 Neuropathic pain, 1402-1407 current treatment for, 1405-1407 diagnostic approach to, 1404 etiology of, 1403 functional features of, 1403 neuroanatomy and, 1402- 1403 patient education and, 1404-1405 secondary to tumor invasion, 1160-1162 Neuropathic pain syndromes secondary to tumor invasion, 1160-1162

Neuropathic tremor, 17,800-801 Neuropathies, 613 alcoholism and, 1275 amyloid, 32f, 147 auditory, 94 autonomic. See Autonomic neuropathies. axonal, electromyographyand, 205 cisplatin and, 1134 compression, 204-205,613 in connective tissue diseases, 610-615 cranial. See Cranial neuropathies. demyelinating,electromyographyand, 205 diabetic. See Diabetic neuropathy. disorders of taste and, 118 endocrine, 594 entrapment and compression. See Entrapment and compression neuropathies. femoral, in pelvis or at inguinal ligament, 652-654,653f HN-related, 599-602 infectious and granulomatous. See Infectious and granulomatous neuropathies. inherited. See Inherited neuropathy.

1498

Index

Neuropathies-cont’d median. See Median neuropathies. metabolic. See Metabolic neuropathy. multiple myeloma, 607 optic. See Optic neuropathies. peripheral. See Peripheral neuropathies. peroneal. See Peroneal neuropathies. predilection, proximal, sensory loss and paresthesias and, 32 presumed immune-mediated motor, 561-562,561f, 561t psychiatry and, 594-596,595f, 595t, 596f radial, neck and arm pain and, 1427-1429, 1428f sciatic, at hip or thigh, 650-652 sensory. See Sensory neuropathies. tomacdous, 578 trigeminal sensory, 612 ulnar. See Ulnar neuropathies. vascditic, 610-611 X-linked CMT, 637 Neuropathology, multiple-system atrophy and, 768 Neurophysiology, 1226-1227 Parkinson’s disease and, 742 sexual dysfunction and, 154 Neuroprotection ischemic stroke and, 403 theoretical basis of, Parkinson’s disease and, 743-744 Neuropsychiatric problems, Alzheimer’s disease and, 872,872t Neuropsychologicaltesting dementia and, 864-865 in evaluation of chronic pain, 1450 memory disorders and, 909-910,909f Neurosarcoidosis, 1221-1224 clinical manifestations and diagnosis of, 1221-1222 long-term complications of, 1224 pathophysiology of, 1221 treatment of, 1222-1224 Neurosurgical treatment and implantable devices, 1453-1457 Neurosyphilis, 445-447 clinical features of, 445 diagnosis of, 445-446 with HIV infection, 446 therapy for, 446-447 Neurothekeoma, 1119-1120 Neurotologic syndromes, 82-86,82t Neurotoxicity affecting peripheral nervous system, 616 chemotherapy and, 1134-1136 ethanol, in developing nervous system, 1274-1275,1275f exposure to metals and, 1287-1288, 1288t exposure to metals and. See Metals, neurotoxic manifestations of exposure to. medications for thought disorders and, 992-993 New England Center for Headache, 1312f NF-1. See Neurofibromatosis type 1 (NF-1). NF-2. See Neurofibromatosis type 2 (NF-2). NHEFS. See National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (NHEFS). Niacin deficiency, 1235 Nicotine, plants containing, 675 Nightmares, 973 Nitrofurantoin, 630 Nitrogen mustard, 1138 Nitrosoureas, 1137 NJCLD. See National Joint Committee on Learning Disabilities (NJCLD). NLD. See Nonverbal learning disability (NLD). NLP. See No light perception (NLP).

NMJ. See Neuromuscular junction (NMJ). NMS. See Neuroleptic malignant syndrome (NMS). No light perception (NLP), 37 Nociceptive system, trigeminal, post-traumatic headache and, 1381 Nocturnal drinking syndrome, 971 Nocturnal eating syndrome, 971 Nocturnal migraine, 1372-1373 Nocturnal myoclonus, 837,839 Nocturnal paroxysmal dystonia, 974 Nodular neurofibroma, 1078 Noise-induced hearing loss, cochlear hearing loss and, 93 Non-AD neurodegenerative dementias, 881-885 Non-Alzheimer dementias, 873-886 differential diagnosis of, 873, 874t, 875t primary cognitive disorders, 880-885 secondary dementias, 874-880 Nonaneurysmal subarachnoid hemorrhage, 324-325 Nonanticonvulsant therapy, status epilepticus and, 946 Nonarticular rheumatism, 1398 Nonatherosclerotic vasculopathy, 340-343,340t Noncardioembolic stroke oral anticoagulation for prevention of, 397 recurrent, warfarin in prevention of, 266 Noncoding nucleotide repeats, autosomal dominant ataxias caused by, 794 Noncommunicating syringomyelia, 533 Noncompliance with antiepileptic drug therapy, 933-934 Nonconvulsive status epilepticus, 942 Nondominant temporoparietal infarction, 386,386f Nondystrophic myotonias, 729t Nonepileptic myoclonus, 836-837 Nonergot dopamine agonists, 746-747,747t Nonfocal spells, 385 Non-24-hour sleep-wake syndrome, 972 Non-immune-mediated lower motor neuron syndromes, 562-563 Noninfectious meningitis, chronic and recurrent. See Chronic and recurrent noninfectious meningitis. Noninvasive carotid artery evaluation, 268-272,268t Noninvasive carotid studies, 270-272,271f Nonlateralized tinnitus, 97-98, 100-101 Nonmetastatic complications of lung cancer, 1180-1181 Nonmyotomal pattern of weakness, atypical motor neuron disease and, 560 Non-parkinsonian movement disorders, 783 Nonregional spread of weakness, atypical motor neuron disease and, 560 Non-REM (NREM) sleep, 962-963 Nonspecific frontotemporal lobar dementia (FTLD), 884 Nonspecific slowly progressive mental retardation, lysosomal storage disease and, 1262-1263 Nonspecific tinnitus, 99t Nonsteroidal anti-inflammatory analgesics, 1392-1394 Nonsteroidal anti-inflammatory drugs (NSAIDs), 1342-1343, 1347,1442 Nonvalvular atrial fibrillation, 265-266,265f Nonverbal communication impairments, 919 Nonverbal hallucinations, tinnitus and, 98 Nonverbal learning disability (NLD), 918-920 Normal pressure hydrocephalus (NPH), 160-161,875-876 North American Symptomatic Carotid Endarterectomy Trial (NASCET),352,400 Nose and sinus disorders, 1408 Novaldex. See Tamoxifen. Novantrone, 410 Novel mitochondria1 disease phenotypes, 1267 Novel therapies, brain tumors and, 1020

Index

NPH. See Normal pressure hydrocephalus (NPH). N-3-Pyridylmethyl-N-nitrophenylurea (PNU), 620 NSAIDs. See Nonsteroidal anti-inflammatory drugs (NSAIDs). Nuclear disorders in brainstem, 49-51 Nucleotide repeats, noncoding, autosomal dominant ataxia caused by, 794 Nutrition, stroke and, 262 Nutritional disorders Huntington’s chorea and, 805 metabolic neuropathy and, 591-593 secondary dementias and, 877-878 Nutritional myopathies. See Endocrine, nutritional, and drug-induced myopathies. Nystagmus central, 80t, 81t downbeat, 56 horizontal jerk, 56 jerk, 56 ophthalmoparesisand, 55-56 pathologic, tests for, dizziness and vertigo and, 80-81, 80t, 81t pendular, 55-56 peripheral, 80t spontaneous, of peripheral versus central origin, 80,80t 0 Obesity, stroke and, 257,339 Object agnosia, 897-898,897t, 898f Obsessive-compulsive disorder, 978 Obsessive-compulsive personality, 764,988,989 Obstruction, shunts and, intracranial hypotension and, 165 Obstructive sleep apnea syndrome, 968-969 Obstructive versus restrictive patterns and disorders, pulmonary function tests and, 140-141,141t Occipital condyle syndrome, 1158 Occipital infarction, 387 Occipital lobe, disorders of afferent visual pathways and, 43-44 Occipital neuralgia, 1381, 1415, 1421, 1421t Occult vascular malformations, 336-337 Occupational cramp, 827-830 Occupational jargon, confusion and, 888 Octreotide, 1139 Ocular misalignment, Maddox rod testing for, 47,47f Ocular myasthenia, restricted, myasthenia gravis and, 662 Ocular myasthenia gravis, 65f, 67f Ocular myopathies, infranuclear disorders and, ophthalmoparesis and, 51-53,52f Ocular stroke, 366,388-389 Oculomotor nuclear complex, innervation of extraocular muscles and, 48,48f, 50f, 5Ot Oculopharyngeal dystrophy, dysarthria and dysphagia in, 124 Oculopharyngeal muscular dystrophy (OPMD), 695 Oculosympathetic spasm, 63 OK T3,1294 Olecranon bursitis, 1429 Olfaction. See a h Smell. anatomy and physiology of, 102-106,104f-105f disease affecting, 109 disorders of, 108-110 central causes of, 110-113 disease categoriescausing, 109, 109t investigation,treatment, and general management of, 113-114 peripheral causes of, 109-110 influences on, 106 special tests of, 107-108

1499

Olfactory information, coding of, 104-106 Oligoastrocytoma, 1029-1030,1030f Oligodendroglial tumors, 1029,1029f Oligodendroglioma, 1029, l029f, 1046 Ontak. See Denileukin difitox. ONTT. See Optic Neuritis Treatment Trial (ONTT). OP compounds. See Organophosphorus (OP) compounds. 0P’-DDD. See Mitotane. Ophthalmoparesis in assessment of disorders of eye movements, 47-54,48f, 49f, 50f, 50t visual examination and, 46 Ophthalmopathy, 709-710 Ophthalmoplegia,chronic progressive external, 1265-1267 Ophthalmoplegicmigraine, 1334, 1334f Opiates, stroke and, 361 OPIDP. See Oragnophosphate-induceddelayed polyneuropathy (OPIDP). Opioid agonist-antagonists, 1442 Opioid agonists, 1440-1442 Opioids, l277,1277t, 1438, 1439f-1440f for chronic pain, 1393 migraine and, 1343-1344 OPMD. See Oculopharyngeal muscular dystrophy (OPMD). Oprelvekin, 1139 Opsodonus-myoclonus, paraneoplastic, 1150 Optic chiasm, 36,41-42,42f, 43f, 44t Optic nerve, disorders of afferent visual pathways and, 36,39-41, 40t-41t Optic nerve ischemia, 389 Optic neuritis, 39,416-420 clinical profile in, 416-417 diagnostic evaluation, 417-418 differential diagnosis of, 418-419 history in, 416-417 paraneoplastic, 1151 physical examination in, 416-417 prognosis for, 419 relationship of, to multiple sclerosis, 419-420 treatment of, 419 Optic Neuritis Treatment Trial (ONTT), 39,412 Optic neuropathies cause and frequency of, 40t-41t radiation therapy and, 1143-1144 vitamin B,, deficiency and, 1238 Optic pathway complications of, 1034 and hypothalamic gliomas, 1031-1034,1033f clinical presentation, staging, and workup of, 1032 radiologic evaluation of, 1032 therapy for, 1032-1034 Optic radiations, disorders of afferent visual pathways and, 42-43,45f Optic tract, disorders of afferent visual pathways and, 36,42 Oragnophosphate-induceddelayed polyneuropathy (OPIDP), 6 17 Oral anticoagulation intracerebral hemorrhage and, 316,316f-317f in prevention of cardioembolic stroke, 396-397 in prevention of noncardioembolic stroke, 397 Oral contraceptives headache and, 1375-1376 migraine and, 1375-1376 stroke and, 261,346 Orbital apex, infranuclear disorders and, ophthalmoparesis and, 51,52f Orbital syndrome, bone metastases and, 1158 Organ transplantation, 1293-1296 Organophosphate, toxic peripheral neuropathies and, 616-618

1500

Index

Organophosphate intoxication, 673-674,673t Organophosphorus (OP) compounds, 616-617 Orofacial pain, 1407-1417 categories of, 1407-1408 cervical disorders and, 1411-1412 extracranialdisorders and, 1408-1409 musculoskeletaldisorders and, 1409-1411 neuralgic disorders and, 1412-1416 primary headache disorders and, 1412 Oromandibular dystonia, 819 Orthostatic hypotension, 149-150, 149t Orthostatic tremor, 17,801 Osler, William, 1201 Osmotic agents increased intracranial pressure and, 1021 status epilepticus and, 946 Osteoarthritis of glenohumeraljoint, 1429 Osteolytic multiple myeloma with amyloidosis, 1153 without amyloidosis, 1152 Osteosclerotic myeloma, 1153 Osteoscleroticmyeloma polyneuropathy, 607-608, 609t Otoacoustic emissions hearing loss and, 92 tinnitus and, 99 Ototoxicity, cochlear hearing loss and, 93 Overdrainage, shunts and, intracranial hypotension and, 165 Overlap syndromes, 136 Oxaliplatin, 1136 Oxcarbazepine,235 Oxidative phosphorylation, defects in, 716 Oxycodone, 1441 P Pacinian neurofibroma, 1119 Paclitaxel drug-induced peripheral neuropathies and, 630-631 neurotoxicityand, 1136 PACNS. See Primary angiitis of CNS (PACNS). PAF. See Pure autonomic failure (PAF). Pain adjunctive analgesicsfor, 1443-1444 analgesics for, 1438-1444 anatomy and physiology of, 1383-1389 antiepileptics for, 1443 antineoplastic therapy and, 1162-1165 aortic dissection and, 1216 ascending pathways of, 1386 assessment of, 1396 back, physical therapy and, 1447 biochemical mediators and, 1388-1389 burning, neuropathic pain and, 1403 cancer, 1156,1157t cerebral cortex and, 1387 cerebral lesions for control of, 1456 chronic, 1390-1395 addiction and detoxificationin, 1395-1397 anticonvulsantsfor, 1394 antidepressants for, 1393-1394 assessment of, 1396 benzodiazepines for, 1394 medical evaluation of, 1391-1392 nonsteroidal anti-inflammatory analgesicsfor, 1392-1394 opioids for, 1393 pharmacologic management of, 1392 psychological approaches to management of, 1450-1453

Pain-cont’d chronic-cont’d psychological evaluation and treatment of, 1448-1453 treatment of, 1396 codeine for, 1441-1442 confusion and, 888 as depressivesymptom, 981 descending modulating system and, 1387-1388 distribution of, in Hitzig’s zones of tabes dorsalis, 31f dorsal horn and, 1384-1386 fentanyl for, 1441 general aspects of, 1383-1397 generalized syndromes of, 1398-1437 and headache, 1305-1457 hydrocodone for, 1441 hydromorphones for, 1441 idiopathic, 1383 low back, 1430-1437 meperidine for, 1441 methadone for, 1441 morphine for, 1440-1441 myofascial. See Myofascial pain; Myofascial pain syndrome. neck, 1417-1429,1447 neurologic, in cancer patients. See Neurologic pain syndromes in cancer patients. neuropathic. See Neuropathic pain. nonsteroidal anti-inflammatory drugs for, 1442 opioid agonist-antagonistsfor, 1442 opioid agonists for, 1440-1442 opioids for, 1438,1439f-1440f orofacial. See Orofacial pain. oxycodone for, 1441 peripheral pathways of, 1384, 1385f pharmacologic treatment of, 1438-1444 pharmacotherapy for, 1283, 1283t postamputation, 1162-1163 postchemotherapy, 1164 postmastectomy, 1162 postradiation, 1163-1164 post-radical neck dissection, 1163 postsurgical, 1162-1163 post-thoracotomy, 1162 propoxyphene for, 1442 reduction of intensity of, 1451 regional syndromes of, 1398-1437 scar, physical therapy and, 1447 secondary effects of, treatment for, 1406-1407 shooting, neuropathic pain and, 1403,1405 spinal cord tumors and, 1108-1109 supraspinal structures of, 1386-1387 sympathectomy for control of, 1456 temperature-linked loss of sense of, in lepromatous leprosy, 30f treatment of, 1438-1457 tricyclic antidepressants and related medications for, 1443 Pain beliefs, 1450 Pain Beliefs and Perceptions Inventory, 1450 Pain intensity measures in evaluation of chronic pain, 1449, 1449t Pain Management Inventory, 1450 Pain management program, 1453 Pain rating scales, 1449, 1449t Pain Self-Efficacy Questionnaire, 1450 Palatal myoclonus, 837 Palatal tremor, 837 Pallidal surgery, Parkinson’s disease and, 760-761 Palsy Bell’s, 601 Erb‘s, 575-576 facial. See Facial palsy (FP).

Index

Palsy-cont’d facial nerve, 601 fourth-nerve, 50t Klumpke’s, 576 left fascicular third-nerve, 48,48f left sixth-nerve, 50f progressive supranuclear. See Progressive supranuclear palsy (PSP). Saturday night, 1275 sixth-nerve, 50t third-nerve, 50t Pamidronate, 1140 Pancoast’s syndrome, 1178 Pancreas transplantation, 1296 Panencephalitis,subacute sclerosing. See Subacute sclerosing panencephalitis (SSPE). Panic, 976-980 Panic disorder, 978 Papilledema, 1013 Paragloboside,sulfated glucuronyl, antibodies to, 178 Parainfectiousencephalomyelitis,485 Paraldehyde, status epilepticus and, 945 Paralysis idiopathic facial, 75-77 periodic. See Periodic paralysis. sleep, 967,973 thyrotoxic periodic, 709 tick, 143,675 Paramyotonia congenita, 728-730,731,732 Paraneoplasticbrainstem encephalitis, 124 Paraneoplastic cerebellar degeneration, 1147-1148 Paraneoplastic disorders with motor system dysfunction, 565 Paraneoplastic encephalomyelitis(PEM), 1148-1149, 1149t Paraneoplasticmotor neuron syndromes, 1151 Paraneoplasticnecrotizing myelopathy (PNM), 1149 Paraneoplasticopsoclonus-myoclonus, 1150 Paraneoplasticoptic neuritis, 1151 Paraneoplasticsensory neuronopathy, 1151-1152 Paraneoplasticstiff-man syndrome, 847, 1150 Paraneoplastic syndromes, 1146-1156 associated with lymphoma, 1173-1174 autoantibodies in, 177-178, 178t breast cancer and, 1186 of central nervous system, 1147-1151 lung cancer and, 1181 of muscle, 1154 of neuromuscularjunction, 1153-1154 ofperipheral nerve, 1151-1153 visual, 1151 Paranoid personalities, 987-988 Paraplegia, hereditary spastic, 563 Parasellar cranial fossa syndrome, 1158 Parasitic infections and fungal infections, 453-466 Parasomnias, 972-974 Parasympathetic disruption, disorders of pupillary constriction and, 60,61f, 62f Parenchymal brain diseases, 498,498f Parenchymal leukemia, 1176 Parenchymalsyphilis, 445 Paresthesias, sensory loss and. See Sensory loss and paresthesias. Parkin gene mutations, 740 Parkinsonian syndromes metabolic diseases and, 781-782 Parkinson’s syndrome and, 740-782 Parkinsonism, 13 diffuse Lewy body disease and, 775,775t drug-induced, 779,813-814,813t encephalitic, 781

1501

Parkinsonism-cont’d post-traumatic, 781 secondary. See Secondary parkinsonism. sleep disorders and, 974 structural, 780 toxic, 780-781 vascular, 779-780 Parkinson’s disease (PD), 749 dementia and, 884 differential diagnosis of, 741-742 dysarthria and dysphagia in, 124 idiopathic, 13,110-112,112f, 146 initial therapy of, 743-748 measurement of, 742-743 mental changes in, 763-766 anxiety, 764 dementia, 763 depression, 763-764 drug-related, 764-766 fatigue, 764 obsessive-compulsive traits, 764 nonpharmacologictreatment for, 748 and parkinsonian syndromes, 740-782 proposed neuroprotectiveagents in, 744 psychosis in, 993 recognition of, 740-741 surgical treatment of, 757-762 ablation and deep brain stimulation in, 758-759 human fetal transplantation in, 761-762 novel, 762 pallidal and subthalamic,760-761 patient selection in, 758 thalamic, 759-760 symptomatic treatment for, 745-748 theoretic bases of neuroprotection in, 743-744 Parkinson’s disease rating scale, unified, 1461-1464 Paroxysmal dystonia, 21 Paroxysmal hemicrania, 1361, 1361t Paroxysmal neuralgia, 1412-1415,1412f,1413f, 1414f, 1415f Paroxysmal nocturnal dystonias, 136 Parsonage-Turner syndrome, 577 Partial seizures in children, 923-925 complex, 923-925 simple, 385-386,923-925 Partial status epilepticus without motor activity, 941 Past medical history, 3 Patent foramen ovale (PTO) cerebral embolism and, 302 long-term anticoagulation for secondary stroke prevention in patients with, 398 stroke and, 345 Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS),259 Pathologic nystagmus, 80-81,80t, 81t Patient education chronic pain and, 1451 cluster headache and, 1360 headache and, 1366 Patient history. See History. Patient-physician interaction, 1311 PCA. See Posterior cortical atrophy (PCA). PCBs. See Polychlorinated biphenyls (PCBs). PCNSL. See Primary central nervous system lymphoma (PCNSL). PCP. See Phencyclidine (PCP); Pneumocystis carinii pneumonitis (PCP). PD. See Parkinson’s disease (PD). Peak effect dyskinesias, 755 Pediatric headache, 1369-1371

1502

Index

Pelvis, femoral neuropathy in, 652-654,653f PEM. See Paraneoplasticencephalomyelitis (PEM). Pendular nystagmus, 55-56 Pentazocine, 361 Pentobarbital, 944t, 945 Pentostatin, 1138 Perception, visual, mental state assessment and, 855,855f Perceptual dysfunction, 249 Perfusion, decreased, syncope and, 126-128 Pergolide, 232,745-746 Perhexiline maleate, 631 Perilymphatic fistulas cochlear hearing loss, 93 tinnitus and, 100 Perimetry, brain tumors and, 1016 Perindopril Protection Against Recurrent Stroke Study (PROGRESS),299,399 Perineurioma, 1120 Periodic alternating gaze, 56 Periodic limb movements disorder, 970 of sleep (PLMD),839-840 Periodic paralysis, 729t hyperkalemic, 728,731,732 hypokalemic, 728,731,732 myotonia and. See Myotonia and periodic paralysis. thyrotoxic, 709 Peripartum cerebral angiopathy, stroke and, 346 Peripheral mononeuropathies, 590 Peripheral auditory system, 88f Peripheral nerve tumors, 1118-1121 benign typesof, 1118-1120 clinical diagnosis of, 1118 diagnostic testing in assessment of, 1118 malignant types of, 1120 Peripheral nerves aortic dissection and, 1218 diseases of, 569-657 HIV infection and. See Human immunodeficiencyvirus (HIV) and diseases of spinal cord, nerve roots, peripheral nerves, and muscle. electrical stimulation of, 1454-1455 injury to, radiation therapy and, 1145 leukemia and, 1176 Lyme disease and, 448 pathologic processes affecting, 198-199, 199f principal motor innervation of, 11t weaknessand, 11, l l t Peripheral nervous system neurotoxic illness affecting, 616 paraneoplastic syndromes of, 1151-1153 renal failure and dialysis and, 1225-1227, 1226t, 229- 231 Peripheral nervous system complications of alcoholism, 1275-1276 autonomic dysfunction with, 147-149 of cardiac catheterization, 1197-1198 of cardiopulmonary bypass procedures, 1194 Peripheral neurectomies, 1455-1456 Peripheral neuromuscular disease, 519-737 Peripheral neuropathies, 143 approach to and classificationof, 569-572,569-575 associated with connective tissue diseases, 610-613 breast cancer and, 1184-1185 cancer and, 1162 diagnostic classificationof, 574 drug-induced. See Drug-induced peripheral neuropathies. family history in assessment of, 572-573 malnutrition and, 573 mitochondria1myopathy and, 1267 Y

Peripheral neuropathies-cont'd nerve biopsy and, 573-574 physiology of, 573 problems in neuropathy diagnosis, 574-575 severity of, 574 spatial evolution and, 572 systemic disease and, 573 temporal evolution and, 572 toxic. See Toxic peripheral neuropathies (TxPNs). toxins and, 573 Peripheral nystagmus, 80t Peripheral pain pathways, 1384, 1385f Peripheral sensorineural hearing loss, 92-93 Peripheral taste disorder, 118 Peripheral vestibulopathy,acute, 82-84 Peritumoral edema, brain tumors and, 1021-1023 Peroneal neuropathies at fibular head, 647-650,648f-649f at knee, 205 Persistent postconcussive syndrome, 172-173 Personality assessment in evaluation of chronic pain, 1449 headache and, 1365 Personality syndromes, 987,988-989 Personality types and disorders, 986-987,986t epilepsy and, 958-959 and reaction to disease, 985-989 PET. See Positron emission tomography (PET). Petit ma1 status epilepticus, 940,941f Phantom breast phenomenon, mastectomy and, 1162 Phantom limb, uostamuutation uain and. 1162-1163 Pharmacologictreatment. See Medications. Pharmacotherapy. See Medications. Phases, electromyographyand, 203 Phencyclidine (PCP), 361, 1279 Phenelzine sulfate, 631 Phenobarbital, 234-235,943-944,944t Phenylpropanolamine (PPA), 36 1 Phenytoin, 233-234,234t drug-induced peripheral neuropathies and, 63 1 status epilepticus and, 943,944 Pheochromocytoma, 1358 Pheresis, rheumatic disease and, 1302 PHN. See Postherpetic neuralgia (PHN). Phobias, 978 Phosphofructokinase deficiency, 715 Phosphoglycerate kinase deficiency,7 15-716 Phosphorylase b kinase deficiency,714 Phosphorylation, oxidative, defects in, 716 Physical activity chronic pain and, 1452 stroke and, 262,262f, 266 Physical dependence, alcoholism and, 1270-1271 Physical therapy active treatment for, 1446 diagnostic assessment of, 1444-1445 idiopathic facial paralysis and, 76 neuropathic pain and, 1406,1407 passive treatment modalities for, 1445-1446 and transcutaneous nerve stimulation, 1444-1 4 treatment of specific conditions in, 1446-1447 Physician-patientinteraction, 1311 Physiologic tremor, 16,799-800 PICA. Sei Posterior inferior cerebellar artery (PICA). Pick's disease, 777 PICSS. See Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS). Pigments, cerebrospinal fluid analysis and, 180-181

Index

Pdocytic astrocytoma, 1028, 1028f Pineal region tumors, 1014 Pineal tumors, 1088-1092 diagnostic studies of, 1088-1090 pathology of, 1088,1089f presenting symptoms of, 1088 prognosis for, 1091 treatment for, 1090-1091 Ping-pong gaze, 56 Pinprick sensation, functional loss of, 30-31,30f, 31f Piriformis syndrome, 1434 Pituitary apoplexy, 1064 Pituitary dysfunction, 710 Pituitary hormone excess, syndromes of, 1064, 1065t Pituitary hypergonadism, 1066 Pituitary insufficiency, 710 Pituitary mass, 1062-1063, 1063f Pituitary tumors, 1060-1067 clinical presentation of, 1062-1066 diagnosis of, 1061-1062 pituitary anatomy and physiology, 1060-1061 treatment for, 1066-1067 Plants containing nicotine, 675 Plaque, junctional, 310 Plasma cell dyscrasias, 604, 1152-1153 Plasma exchange myasthenia gravis and, 66 1 therapeutic. See Therapeutic plasma exchange (TPE). Plasmin fibrinolytic system, tests for, 175 Platinum, drug-induced peripheral neuropathies and, 627 Playful behavior, unconscious, confusion and, 888 Pleocytosis, cerebrospinalfluid, confusion and, 888 Pleomorphic xanthoastrocytoma, 1029,1029f Plexiform neurofibroma, 1078 Plexopathies brachial. See Brachial plexopathy. cervical, and accessory nerve damage, 1425 lumbosacral, cancer and, 1161-1162 metastatic epidural spinal cord compression and, 1123-1124 radiation, 1163-1164, 1163t radiculopathies and, 575-578 Plexus lesions, 576-578 PLMD. See Periodic limb movements disorder of sleep (PLMD). PME. See Progressive-myoclonus epilepsy (PME). PML. See Progressive multifocal leukoencephalopathy(PML). Pneurnocystis curinii pneumonitis (PCP), 1023 PNM. See Paraneoplasticnecrotizing myelopathy (PNM). PNU. See N-3-Pyridylmethyl-N-nitrophenylurea (PNU). POEMS syndrome, 608,1153 Poliomyelitis, 143, 482-484 clinical features of, 483 diagnosis of, 483-484 epidemiology of, 482-483 treatment of, 484 Pollutants, disorders of taste and, 119 Polyarteritis nodosa, 614-615,1299 Polychlorinated biphenyls (PCBs),622 Polymerase chain reaction, 179 Polymyalgia rheumatica, 1430 Polymyositis, 1154 Polyneuritis acute inflammatory, 579 postinfectious, 579 Polyneuropathies,570f, 604-606 alcoholic, 1275 combined diabetic and uremic, 1230

Polyneuropathies-cont’d critical illness, 596-597 distal sensorimotor, 586-589 distal sensory symmetrical,501-502 distal symmetrical, 600 distal symmetrical axonal, 611-612 electromyography and, 205 familial amyloid, 639-641 inflammatorydemyelinating. See Inflammatory demyelinatingpolyneuropathies. MGUS-associated, 604-606,605t nutritional, 1238 osteoscleroticmyeloma, 607-608,609t sensory loss and paresthesias and, 31-32,32f uremic, 593-594,1229-1230 Polyradiculitis,cytomegalovirus, 502 Polyradiculoneuropathy acute, 1152 inflammatory demyelinating,601 Polyradiculopathy diabetic, 589-590 lumbosacral, 600-601 Pons ophthalmoparesis and, 53 pain and, 1388 Pontine hemorrhage, 320-321,321f Porphyria acute intermittent, 1251-1253 ALA dehydratase deficiency, 1253-1254 neurologic manifestations of, 1250-1254 hereditary coproporphyria, 1253 protocoproporphyria, 1253 South African, 1253 variegate, 1253 Portosystemic encephalopathy. See Hepatic encephalopathyand portosystemic encephalopathy. Positron emission tomography (PET), 207-2 13 brain tumors and, 1016 dementia and, 866-867 malignant ghomas and, 1042 Postamputation pain, 1162-1163 Postanoxic myoclonus, 836 Postchemotherapypain syndromes, 1164 Postconcussive syndrome, 249 injuries associated with, 172 natural history of, 172 persistent, 172-173 Posterior cerebral artery, 377-379,378f Posterior cortical atrophy (PCA),884 Posterior fossa tumors, 26 Posterior inferior cerebellar artery (PICA), 373 Posterior leukoencephalopathy,reversible, 346 Posterolateral sclerosis, 1238 Postherpetic neuralgia (PHN), 475,476-477,476t Postinfectiouspolyneuritis, 579 Postinfectioussyndromes, 566-568 Postinfectioustinnitus, 101 Postmastedomy pain, 1162 Postoperative low back pain, 1434-1435 Postpartum cerebral angiopathy, 346 Postpolio syndrome, 558-559 Postradiation MND, 566 Postradiation pain syndromes, 1163-1164 Post-radical neck dissection pain, 1163 Postsurgical pain syndrome, 1162-1163 Post-thoracotomy pain, 1162 Post-traumatic brain injury, 1002-1004, 1003f

1503

1504

Index

Post-traumatic headache, 1379-1382 definitions of, 1380 diagnostic criteria for, 1380 epidemiology of, 1380 legal issues and, 1382 management of, 1382 mechanisms of head injury and, 1380-1381 psychological factors and, 1381-1382 types of, 1381 Posttraumatic hypersomnia, 968 Post-traumatic migraine, 1381 Post-traumatic parkinsonism, 781 Post-traumatic stress disorder (PTSD), 978 Post-traumatic syringomyelia,535,535f Postural hypertension, 755 Posturd reflexes, loss of, 126-127 Postural-actiontremor, 16-17, 16t Posturography, 81-82 Potassium-aggravated myotonia, 730,73 1,732 Potentials, evoked. See Evoked potentials. PPA. See Phenylpropanolamine (PPA); Primary progressive aphasia (PPA). Pramipexole, 232,746-747,747t Praxis, limb, 901 Predilection neuropathy, proximal, 32 Predominant disturbances of writing, 888 Pregnancy arteriovenousmalformations and, 336 headache and, 1376-1379 myasthenia gravis in, 662 stroke and, 346,347f-348f subarachnoid hemorrhage and, 331 Premature ejaculation, 156-157 Premonitory phase of migraine attack, 1324 Presbycusis cochlear hearing loss and, 93 tinnitus and, 100 Prescription drugs for dergy, 1284,1285t anticoagulant, 1285, 1286t antidepressant, 1286 antihormones, 1285, 1286t antineoplastic, 1284, 1285t antiplatelet, 1285, 1286t antipsychotic, 1286 for arthritis, 1283 cardiovascular, 1284 for diabetes mellitus, 1284-1285 for fever, 1283 for gastrointestinaldisorders, 1284, 1285t hormones, 1285,1286t immunosuppressant, 1284, 1285t for infection, 1282-1283 for inflammation, 1283 lipid-lowering, 1286 for nasal congestion, 1284, 1285t neurologic complications of, 1282-1287 for pain, 1283 to reduce muscle spasm, 1284 toxic myopathies and, 711-712 vitamins, 1286-1287 Present illness, history of, in neurologic history, 3 Presenting symptoms and signs, common, 8-173 Presumed immune-mediated motor neuropathies, 561-562, 561f, 561t Presyncopal dizziness, 79 Pretrigemind neuralgia, 1415

Primary and secondary generalized dystonias, 8 16-821 anatomy of, 820 biochemistry of, 820 classification of, 817-820 pathophysiologyof, 820 treatment for, 820-821 Primary angiitis of CNS (PACNS), 510 Primary brain tumors, 1006 Primary central nervous system lymphoma (PCNSL), 1012, 1049-1054 c h i c d features of, 1049-1050 differential diagnosis of, 1050-1052 in immunosuppressed patients, 1053 laboratory evaluation of, 1050, 1051f pathology of, 1050 treatment for, 1052-1053 Primary cognitive disorders, 880-885 Primary deficits, primary domains, test procedures, and repercussions of, 851t Primary domains, primary deficits and, 851t Primary dystonia, 20-21 Primary headaches, 1329-1330,1329t, 1412 Primary hyperparathyroidism, 710-711 Primary memory, 904 Primary neurologic disorders, 73 Primary progressive aphasia (PPA), 882t, 884 Primary progressive multiple sclerosis, 41 1 Primary psychiatric disorders headache and, 1368-1369 secondary dementias and, 874-875 Primary systemic amyloidosis, 606-607,607t Primidone, 235 Principal motor innervation of peripheral nerves, 1It Pringle’s disease, 349 Prion diseases, 512-514 Creutzfeldt-Jakobdisease, 512-514 fatal familial insomnia, 514 Gerstmann-Straussler-Scheinkersyndrome, 5 14 kuru, 514 Prion-associatedataxia, 797 PROACT. See Prourokinase in Acute Cerebral Thromboembolism (PROACT)I1 trial. PROACT 11. See Prolyse in Acute Cerebral Thromboembolism Trial (PROACT 11). Procarbazine drug-induced peripheral neuropathies and, 63 1 neurotoxicity and, 1137 Procedural memory, 905 Processing model, disorders of memory and information, 903,903f psychological-anatomic, 903-904,904f Prochlorperazine, 87t Procrit. See Erythropoietin. Procyclidine, 747 Prodrome headache and, 1363 migraine and, 1324 PROGRESS. See Perindopril Protection Against Recurrent Stroke Study (PROGRESS). Progressive ataxia, 797-798 Progressive cognitive decline, diffuseLewy body disease and, 774-775 Progressive dialysis encephalopathy, 1228-1229 Progressive hearing loss, chronic, tinnitus and, 100 Progressive multifocal leukoencephalopathy(PML), 488-490 Progressive muscle weakness, fixed, 716-718 Progressive muscular atrophy, 563 Progressive myelopathy, delayed, 1144

Index

Progressive supranuclear palsy (PSP), 14,770-773,885 biologic basis of, 772 clinical features of, 770-771 corticobasal degeneration and, 778 course of, 773 dementia and, 885 diagnosis of, 771-772 differentialdiagnosis of, 771 dysarthria and dysphagia in, 124 treatment for, 772-773 unresolved issues in, 773 Progressive systemic sclerosis, 1298 Progressive-myoclonus epilepsy (PME), 835-836 Prolyse in Acute Cerebral Thromboembolism Trial (PROACT 11),394 Promethazine, 87t Propagation of error, confusion and, 887-888 Propofol, 944,945 Propoxyphene, 1442 Prosopagnosia,379,898-899,899t Prosthetic heart valves cerebral embolism and, 300 stroke and, 344 Prosthetic valve endocarditis, 1205 Prosthetics, idiopathic facial paralysis and, 76-77 Protein, cerebrospinal fluid analysis and, 182, 182t Protein C, tests for, 175 Protein S , tests for, 175 Prothrombin 20210A, tests for, 175 Prothrombin time, 174 Prothrombotic states, stroke and, 346 Protocoproporphyria, 1253 Prourokinase in Acute Cerebral Thromboembolism (PROACT) I1 trial, 352,403 Proximal myotonic myopathy, 692-693 Proximal predilection neuropathy, 32 Pseudoaddiction, 1395 Pseudohypoparathyroidism, 711 Pseudoneuropathy, 574 Pseudoradiculopathy, 574 Pseudoseizures, 960 Pseudostroke, 574 Pseudotumor cerebri, 39-40, 163-164 PSP. See Progressive supranuclear palsy (PSP). Psychiatric consultation, memory disorders and, 911 Psychiatric disorders, 133,976-994 anxiety and, 976-980 atypical motor neuron disease and, 560 Huntington’schorea and, 804-805 medications and, 233 mood disorders, 980-985 and neuropathy, 594-596,595f, 595t, 596f nonverbal learning disability and, 919 panic and, 976-980 personality disorders and reaction to disease, 985-989 primary, headache and, 1368-1369 primary, secondary dementias and, 874-875 sleep disorders, 974-975 thought disorders, 989-994 Psychogenic gait disorder, 27 Psychogenic movement disorders, 24-25 Psychological adjustment after neurologic disability, 249-250 Psychological disorders, post-traumatic headache and, 1381-1382 Psychological evaluation and treatment of chronic pain, 1448-1453 of patient with headache. See Headache, psychological evaluation and treatment of patient with.

Psychological support, brain tumors and, 1024 Psychological-anatomicprocessing model, disorders of memory and, 903-904,904f Psychology of attentional systems, 887 Psychometrics dementia and, 864-865 headache and, 1365-1366 Psychosis in dementia, 993 epilepsyand, 957-958 Parkinson’s disease and, 765-766,993 Psychosocial issues in dementia and epilepsy, 994-998 seizures and, 937 Psychostimulants,360-361, 1278 Psychotic symptoms in limbic epilepsy, 993-994 Psychotic thinking, 755 PTO. See Patent foramen ovale (PTO). Ptosis acquired painless. See Acquired painless ptosis. causes of, 65,65t in neonate, 65-66 non-neurologic causes of, 66-67 in ocular myasthenia gravis, 67f PTSD. See Post-traumatic stress disorder (PTSD). Pulmonary arteriovenous fistulas, 344 Pulmonary disorders, 1221-1224 Pulmonary embolism, 393-394 Pulmonary function tests, 139-141 Pulmonary system, inflammatory myopathy and, 699 Pulsatile tinnitus, 97, 98f Pupillary light reflex, 57,57f Pupils abnormalitiesof, caused by lesions of afferent visual pathways, 58-59 Argyll Robertson, 60,62f in coma, 64 disorders of, 57-64 disorders of constriction of, 60,61f, 62f disorders of dilation of, 60-63,63f in neuromuscular disease, 64 sympatheticinnervation of, 58f tonic, 60,61f Pure dexia, 896-897,896t Pure autonomic failure (PAF), 149 Putaminal hemorrhage, 317-318,318f Pyridostigmine, 231 Pyridoxine, 631-632 Pyridoxine deficiency, 593,1235

Q Q fever, 5 15 Quality of life, behavioral disorders and, in epilepsy, 96 1 Quality Standards Subcommitteeof American Academy of Neurology, 1021 Quantitative structural neuroimaging, dementia and, 866

R Rabies, 490-492 clinical features of, 490-491 diagnosis of, 491 epidemiology of, 490 treatment for, 491-492 Race, stroke and, 252-253,253f Radial nerve, 1428f Radial nerve entrapment, 646

1505

1506

Index

Radial neuropathy, neck and arm pain and, 1427-1429, 1428f Radiation optic, disorders of afferent visual pathways and, 42-43,45f secondary dementias and, 879 Radiation myelopathy, 1124, 1164 Radiation plexopathy, 1163-1164,1163t Radiation therapy. See also Radiotherapy. brain metastases and, 1104 brain tumors and, 1018-1019, 1027 malignant gliomas and, 1045-1046 neurologic complications of, 1140-1146 acute encephalopathy, 1140 cerebrovascular disease, 1145 cranial neuropathies, 1144 delayed progressive myelopathy, 1144 diffusecerebral injury in adults, 1142 diffuse cerebral injury in children, 1142-1143 early delayed encephalopathy, 1141 focal cerebral necrosis, 1141-1142 motor neuron syndrome, 1145 neuroendocrine effects, 1143 optic neuropathy, 1143-1144 peripheral nerve injury, 1145 radiation-induced tumors, 1145 transient myelopathy, 1144 pineal tumors and, 1090-1091 spinal cord tumors and, 1115 Radiation-induced tumors, 1145 Radiculitis herpes simplex, 602 herpes zoster, 602-603 Radiculopathies,575-576 atypical motor neuron disease and, 567f, 568 cervical, 575-576,1424-1425 electromyographyand, 205 lumbosacral, 576 Radiography chest, Lambert-Eaton myasthenic syndrome and, 667 metastatic epidural spinal cord compression and, 1124 skull, brain tumors and, 1015 spinal cord tumors and, 1109 Radiology, 207-2 13 brain tumors and, 1015-1016 facial palsy and, 75 hypothalamic gliomas and, 1032 neoplastic meningitis and, 1130 Radiosensitizers, 1045 Radiosurgery,stereotactic. See Stereotactic radiosurgery. Radiotherapy.See also Radiation therapy. hypothalamic gliomas and, 1032-1033 intensity modulated, malignant gliomas and, 1045 meningiomas and, 1058 metastatic epidural spinal cord compression and, 1126-1127 stereotactic. See Stereotactic radiotherapy. whole brain, brain metastases and, 1104, 1105 Raeder’s syndrome, 1358 Ramsay-Hunt syndrome, 100 Rapid eye movement (REM) sleep, 962-963,973-974 Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation, 1200 RBD. See REM sleep behavior disorder (RBD). Reaction to disease, personality disorder and, 985-989 Reasoning, mental state assessment and, 856-857 Reassurance, idiopathic facial paralysis and, 76 Rebif, 4 10

Rebleeding, subarachnoid hemorrhage and, 328 Recessive ataxia, 784t-785t Recessively inherited ataxias, 783-788, 784t-785t Recognition, memory and, 905 Recovery, aphasia and, 894 Recreational inhalants, household products used as, 1278-1279 Recurrent depression, 982 Recurrent falls, 28 Recurrent gliomas, 1046 Recurrent hypersomnia, 968 Recurrent laryngeal neuralgia, 1415 Recurrent noncardioembolic stroke, 266 Recurrent noninfectious meningitis. See Chronic and recurrent noninfectious meningitis. Recurrent stroke antihypertensive agents in, 264-265 prevention of, heparin and, 393 Reflex sympathetic dystrophy, 1429 Reflexes, assessment of, in neurologic examination, 5 Refractory status epilepticus, 945-946 Refsum’s disease, 637 Regional musculoskeletalsyndromes, 1429-1430 Regional pain syndromes, 1398-1437 Rehabilitation of neurologic disability, 243-250 autonomic dysreflexia, 248-249 behavioral dysfunction, 249 bowel dysfunction, 248 brain tumors and, 1024 cognitive dysfunction, 249 motor control, 243-247 perceptual dysfunction, 249 postconcussion syndrome, 249 psychological adjustment after neurologic disability, 249-250 respiratory insufficiency, 247 sexual function, 248 urinary tract dysfunction, 247-248 Reinnervation, electromyographyand, 203-204 Reirradiation, brain metastases and, 1104 Relapse prevention, chronic pain and, 1452-1453 Relapsing-remittingmultiple sclerosis, 410-41 1 Relaxation training, chronic pain and, 1451 Religiosity, epilepsy and, 959 REM behavior disorder, 973-974 REM sleep behavior disorder (RBD), 973-974 REM sleep-related sinus arrest, 973 Remote stroke, 383 Renal failure and dialysis, neurologic manifestations of, 1225-1231 general principles of, 1225-1227 principal disorders of nervous system, 1227-1231 Renal insufficiency, 593-594 Renal transplantation neurologic complicationsassociated with, 1295 neurologic complicationsof, 1229 Repetitive nerve stimulation (RNS), 681,68lf, 682f myasthenia gravis and, 659 tests of neuromuscular transmission and, 206,206f Resection, brain tumors and, 1027 Respiration central control of, 138, 138f neuroanatomy of, 137-138 Respiratory dysfunction, 137-145 alveolar hypoventilation, 139 lower motor neuron, 142 neuroanatomy of respiration, 137-138 neurogenic. See Neurogenic respiratory dysfunction.

Index

Respiratory dysfunction-cont’d pulmonary function tests, 139-141 specific lower motor neuron diseases, 112-114 symptoms and signs of neurogenic respiratory dysfunction, 138-139 Respiratory insufficiency, 247 Respiratory muscle fatigue, 141 Respiratory muscles, 137-138 Rest tremor, 15-16, 16t Restless legs syndrome (RLS), 840-842,970 movement disorders in. See Movement disorders in sleep and restless legs syndrome. Restricted ocular myasthenia, 662 Restrictive versus obstructive patterns and disorders, 140-141,141t Retentive memory, explicit, mental state assessment and, 855-856,856f Retina, disorders of afferent visual pathways and, 38-39 Retinal ischemia, 388-389 Retinoblastoma, 1011 . Retinoic acid, 1138 Retinopathy cancer-associated, 1151 melanoma-associated,115 1 Retrieval, memory and, 905 Retrovirus-associated MND, 566-568 Reversible posterior leukoencephalopathy,stroke and, 346 Rheumatic diseases autoantibodiesin, 176-177, 177t connective tissue diseases, 1297-1299 diagnosis of, 1301 immunopathogenicmechanisms of, 1296-1297 neurologic manifestations of, 1296-1303 treatment of, 1301-1303 vasculitis, 1299-1301 Rheumatism, 1398 Rheumatoid arthritis, 613, 1298 Rheumatoid factors, 176 Rheumatology, 1296-1303 Rhythmic movement disorder, 973 Riboflavin deficiency, 1235 Rickettsial infections of nervous system, 515-516 Right hemisphere, language and, aphasia and, 894 Right-to-left shunts, stroke and, 343-344 Rigidity, encephalomyelitis with, 847 Riley-Day Syndrome, 638 Rituxan. See Rituximab. Ritwrimab, 1139 U S . See Restless legs syndrome (RLS). RNS. See Repetitive nerve stimulation (RNS). Romberg sign, 5 Root avulsion, radiculopathy and, 575 Roots, nerve, sensory loss and paresthesiasand, 32 Ropinirole, 232,746-747,747t Rotational testing, dizziness and vertigo and, 81 Rotator cuff tendinitis, 1429 rtPA, systemic thrombosis with, ischemic stroke and, 402, 402t, 403t Rubella, 493-495

S Saccades, inappropriate,ophthalmoparesis and, 55-56 SAH. See Subarachnoid hemorrhage (SAH). Sdicylism, 1283 Saliva, function of, 116-117,117t Salivary gland disorders, 1409 Salivation, facial palsy and, 74

Sandostatin. See Octreotide. Sarcoidosis, 509,603, 1117f Saturday night palsies, 1275 SCA. See Spinocerebellar ataxia (SCA); Superior cerebellar artery (SCA). Scar pain, physical therapy and, 1447 SCD. See Sickle cell disease (SCD). Schirmer’s I1 test, 74 Schizoid personalities, 987-988 Schizophrenia, 112 Schizotypal personalities,987-988 Schwannoma, llO8,1114f, 1118-1119 Sciatic neuropathy at hip or thigh, 650-652 Sciatica, causes of, 1432t Sclerosis atypical amyotrophic lateral, 575 multiple. See Multiple sclerosis (MS). posterolateral,vitamin B,, deficiency and, 1237 progressive systemic, 1298 subacute combined, vitamin B,, deficiency and, 1237 systemic, 614 Scoliosis, 246-247 Scopolamine,87t Scorpion stings, 674-675 SDH. See Subdural hematoma (SDH). Secondarydementias, 874-880 Secondarydystonia, 21 Secondary generalized dystonias. See Primary and secondary generalized dystonias. Secondaryheadaches, 1327-1329 Secondaryhyperparathyroidism, 710-711 Secondaryhyperthyroidism, 1066 Secondarymalignancy, bone marrow transplantation and, 1170 Secondarymemory, 904 Secondaryparkinsonism, 779-782 drug-induced parkinsonism, 779 encephaliticparkinsonism, 781 metabolic diseases with parkinsonian features, 781-782 post-traumatic parkinsonism, 78 1 structural parkinsonism, 780 toxic parkinsonism, 780-78 1 vascular parkinsonism, 779-780 Secondaryprogressive multiple sclerosis, 4 11 Secondarystroke prevention, 398 Secondaryvasculitides, 1300-1301 Secular trends in stroke mortality, 253 Sedative drugs, 1278, 1278t Segmental demyelination, 198-199 Segmental myoclonus, 837 Seizures, 135, 135t absence, 925-926 after carotid endarterectomy, 388 after stroke, 387-388 atonic, 131-132 brain tumors and, 1013-1014 classification of, 928-930,929t, 931-932 confusion and, 888 discontinuation of treatment for, 937 drug dependence and, 1279-1280 febrile, 927 focal, 86,385-386 generalized, in children, 925-927 generalized tonic-clonic seizures, 925 lysosomal storage disease and, 1262 medical treatment of, 932-937 noncompliance with antiepileptic drug therapy and, 933-934

1507

1508

Index

Seizures-cont’d nonpharmacologic therapy for, 936-937 partial, in children, 923-925 psychosocial issues and, 937 relation of, to stroke, 387-388 sickle cell disease and, 1248 side effectsof antiepilepticdrug therapy and, 934-936 simple partial, 385-386 subarachnoid hemorrhage and, 328 Selectivity, attentional systems and, 887 Selegiline, 231-232 Sellar compressivelesions, 44t Semanticdementia, 882t, 883 Semantic memory, 905 Semistructuredinterview in evaluation of chronic pain, 1448-1449 Sensation,pinprick, 30-31,30f, 31f Sensitization, central, medications inhibiting, 1405 Sensorimotor neuropathy, 1152-1153 Sensorimotor polyneuropathy, distal, 586-589 Sensory ataxia caused by ganglioneuronitis, 602 gait disorder and, 26-27 Sensory change, patterns of, 30-35 Sensory examination in Gudain-Barre syndrome, 32 in neurologic examination, 5 sensory loss and paresthesias and, 29-30 Sensory gangliopathies, 32 Sensory hearing loss, 94-95 Sensory loss cortical, 34-35,34f intracutaneous, 30-31,30f, 31f and paresthesias,29-35 patterns of sensory change, 30-35 techniques of sensory examination and, 29-30 suspended, 33,33f Sensory nerve action potential (SNAP), 201f Sensory nerve conduction studies, 200,201f Sensory nerves, sensory loss and paresthesias and, 3 1 Sensory neuronopathies, paraneoplastic, 1151- 1152 Sensory neuropathies, 612-613 hereditary, 634-638,637t trigeminal, 612 Sensory symptoms atypical motor neuron disease and, 560 of multiple sclerosis,412-413,413t Sensory systems, spinal cord and, 523-524 Septd aneurysm, atrial, 345-346 Serology central nervous system infection and, 427 Lyme disease and, 180, 180t syphilis and, 179-180 Serotonin syndrome, 814-815,815t Serotoninergic antagonist agents, 1347 Serum genetic markers, dementia and, 867 Serum muscle enzymes, muscular dystrophy and, 688 Setting sun sign, 67-68 Severe traumatic brain injury, 168-171 Sexual dysfunction, 154-159 female, 157-159 male, 154-157 multiple sclerosisand, 414 neuroanatomic and neurophysiologic issues, 154 Sexual function, 248 Sexuality, epilepsy and, 959,997 SHEP trial, 263 Shift work sleep disorder, 971

Shifting of attention, tinnitus and, 101-102 Shock, aortic dissection and, 1216 Shooting pain, neuropathic pain and, 1403, 1405 Short-term memory, 904 Shoulder frozen, 1162, 1429 pain in, 1429 Shunts arteriovenous, 1230 intracranial hypotension and, 165-166 right-to-left, 343-344 Shy-Drager syndrome, 766-769 SIADH. See Syndrome(s) of inappropriate secretion of antidiuretic hormone (SIADH). Sick headache, 1338 Sick sinus syndrome (SSS), 345 Sickle cell disease (SCD), neurologic complications of, 1243-1249 Signal transduction inhibitors, neurotoxicity and, 1140 Significantothers, interview with, headache and, 1365 Signs common presenting, 8-173 physical, weakness and, 9 Simple partid seizures, 385-386,923,924-925 Single photon emission computed tomography (SPECT), 207-213 brain tumors and, 1016 dementia and, 866 malignant gliomas and, 1042 Single-fiber electromyography, 206,659 Sinus disorders, orofacial pain and, 1408 Situational syncope, 127-128 Sixth-nervepalsy, 50t Sjogren’s syndrome, 510-511,614,1298 Skeletal dysmorphism, 1262 Skeletal muscle biopsyof, 217-218 normal, structure of, 218,218t Skill acquisition, headache and, 1366-1367,1366t Skin biopsy of, 223-225 dermatomyositis and, 698-699 Skull base syndromes, 1158 Skull base tumors, 1095-1098 chondrosarcoma, 1095-1097 chordoma, 1095,1096f esthesioneuroblastoma, 1098 glomus tumors, 1097-1098 Skull radiographs, brain tumors and, 1015 SLE. See Systemic lupus erythematosus (SLE). Sleep chronic pain and, 1451 difficulty in initiating and maintaining, 964,966t disorders of, 132-133,962-975 arousal disorders, 972-973 circadian rhythm, 971-972 classificationof, 963-964 diffuse Lewy body disease and, 775 dyssomnias, 964-972 environmental, 97 1 extrinsic, 970-971 Huntington’s chorea and, 805 intrinsic, 964-970 medical, 974-975 medical and psychiatric, 974-975 menstrual-associated,975 parasomnias, 972-974 Parkinson’s disease and, 764

Index

Sleep-cont’d disorders of-cont’d physiology of, 962-963 proposed, 975 psychiatric, 974-975 movement disorders in. See Movement disorders in sleep and restless legs syndrome. non-REM, 962-963 rapid eye movement (REM), 962-963,973-974 Sleep apnea obstructive,968-969 stroke and, 339 Sleep bruxism, 974 Sleep enuresis, 974 Sleep history, 964,966t Sleep hygiene, inadequate, 970 Sleep paralysis, 967,973 Sleep starts, 973 Sleep terrors, 972 Sleep-disorderedbreathing, 696-697 Sleepiness, excessive daytime, 964 Sleep-relatedepilepsy, 974 Sleep-relatedheadaches, 974-975 Sleep-relatedlaryngospasm,975 Sleep-wake transition disorders, 973 Sleepwalking, 972 Slow virus encephalitis,879-880 Slowly progressive disorder of ambulation, 27 SMA. See Spinal muscular atrophy (SMA). SMAX1. See X-linked spinobulbar muscular atrophy (SMAX1). Smell. See also Olfaction. blind, 106 loss Of, 113-114 and taste, disorders of, 102-120 anatomy and physiology of olfaction, 102-106 central causes of, 110-113, 114f clinical evaluation methods of, 106-108 disorders of olfaction, 108-110 investigation, treatment, and general management of olfactory disease and, 113-114 Smoking. See Cigarette smoking. Snake bites, 674 SNAP. See Sensory nerve action potential (SNAP). Sobue’s disease, 562-563 Social and psychiatric issues in neurologic practice, 4,976 Social processing deficits, nonverbal learning disability and, 919 Sodium aurothiomalate, 627 Somatic events, tinnitus and, 100-101, 1Olt Somatization and amplification of illness, 988-989 Somatosensory evoked potentials, 196f, 197 Sound localization test, 95 South African porphyria, 1253 SPAF study, 396,397 Spasmodicdysphonia, 823 Spasmodicdystonia, 8 19 Spasmodic torticollis, 21,823-825 Spasms hemifacial, 736-737 idiopathic facial paralysis and, 78 infantile, 926 Spastic gait, 25-26 Spasticity multiple sclerosisand, 414 weakness and, 9 Spatial evolution, peripheral neuropathy and, 572 Spatial-motor capacity, disorders of, 901 SPECT. See Single photon emission computed tomography (SPECT).

I509

Spectroscopy,magnetic resonance, 207-213,291, 1042 Speech apraxia of, 891 and language disorders, 890-895 aphasias, 891-894 motor speech disorders, 890-891 neurobiology of, 121 Spells confusional, 129-130 without syncope or clear focal onset, 129-133, 129t Spider bites, 674,674t Spinal abscess, brain abscess and. See Brain and spinal abscess. Spinal angiography, 213 Spinal arachnoiditis, 511-512 Spinal arteriovenous malformations, 335 Spinal cord aortic dissection and, 1218 diseases of, 520-547 clinical approach to, 520-531 HIV infection and. See Human immunodeficiencyvirus (HIV) and diseases of spinal cord, nerve roots, peripheral nerves, and muscle. disorders of, 158 functional neuroanatomy, 521-524 functional neuroanatomy of, 52 1-524 gross anatomyof, 520-521,521f, 522f, 523f hemorrhages, 546-547 lesions in, pain treatment and, 1456 neuropathic arm pain and, 1424 and peripheral neuromuscular disease, 5 19-737 subacute combined degeneration of, vitamin B,, deficiency and, 1237 vascular disease of, 543-547 stroke, 544-546 transient ischemic attack, 544-546 vascular malformations, 546-547 Spinal cord compression breast cancer and, 1182-183 epidural. See Epidural spinal cord compression (ESCC). extrinsic, syndrome of, 527-528 metastatic epidural. See Metastatic epidural spinal cord compression. Spinal cord hemisection, syndrome of, 525f, 526-527 Spinal cord involvement, cisplatin and, 1134 Spinal cord lesions, localization of, 7t Spinal cord localization,524-531,524t, 526f-527f, 528f, 529f-530f Spinal cord metastases, lung cancer and, 1180 Spinal cord syndromes, 528-530 central, 525f, 528 intramedullary, 5255 528 sensory loss and paresthesias and, 32-34 Spinal cord tumors, 1107-1121 clinical presentation of, 1108-1109 diagnostic tests in assessment of, 1109-1113, 1114f, 1115f, 1116f differential diagnosis of, 1113,1117f epidemiologyof, 1107 management of, 1113-1117 outcomes of, 1117 pathology of, 1107-1108 syrinx associated with, 534-535 Spinal epidural abscess, 435-436, 1123 Spinal muscular atrophy (SMA), 553-557 classic, 554,554 classificationand subtypes of, 554-555 clinical features of, 553-554 diagnosis in, 555-556

1510

Index

Spinal muscular atrophy (SMA)-cont’d genetics and diagnostic testing in, 555 natural history and controversies in, 555 treatment of, 556-557 Spinal nerve root, weakness and, 10-11, lot Spinal stenosis,lumbar, low back pain and, 1434 Spinocerebellar ataxia (SCA), 783-798 autosomal dominant, 788-796,791t progressive, management of, 797-798 recessively inherited, 783-788,789t sporadic ataxia, 796-797 X-linked, 783-788,789t Spinocerebellar degenerations, 564, 885 SPIRIT. See Stroke Prevention in Reversible Ischemia Trial (SPIRIT). Spirochetalinfections, 445-453 Spondylolisthesis, 1433-1434, 1433f, 1434t Spondylolysis, 1433-1434, 1433f, 1434t Spondylosis cervical disease and, 541-543 and disc disease, 537-543 lumbar disease and, 537-541 neck and arm pain and, 1422-1423 Spontaneousactivity, neuropathic pain and, 1403,1405 Spontaneous discharges, abnormal, electromyographyand, 203,204f, 204t Spontaneous study, electromyographyand, 202 Sporadic ataxia, 796-797,796t Sporadic infection, central nervous system infection and, 426-427,427t Sporothrix schenckii, 457 Sporotrichosis,457 Sprain cervical, neck and arm pain and, 1423 lumbosacral, low back pain and, 1431- 1432 Spreadingcortical depression, 1331- 1332 SSPE. See Subacute sclerosingpanencephalitis (SSPE). SSS. See Sick sinus syndrome (SSS). ST1571. See Imatinib. Standard structural neuroimaging, dementia and, 865-866, 865t Stapedius reflex facial palsy and, 74 hearing loss and, 92 State-dependentdomains, mental state assessment and, 853 Static lung volumes, 139, 139f Static-like intermittent tinnitus, 97 Statins, 398-399 Station and gait in neurologic examination, 5 Status epilepticus, 938-947 absence, 940,941f complex partial, 941-942 electrographic, 942 with focal origin, 941-942 generalized convulsive, 938-940,939t generalized forms of, 940-941 myoclonic, 940-941 nonconvulsive,942 partial, without motor activity, 941 with partial origin, 941-942 refractory, 945-946 tonic, 941 treatment for, 942-947 types of, 940-942 Status migrainosus, 1326 Stenosis asymptomatic, stroke and, 272 carotid, asymptomatic, 384-385,390

Stenosis-cont’d intracranid, 274-276 lumbar spinal, low back pain and, 1434 Stereotacticbiopsy, brain tumors and, 1027 Stereotactic radiosurgery brain metastases and, 1104-1105 brain tumors and, 1018-1019,1019f malignant gliomas and, 1045 Stereotactic radiotherapy brain tumors and, 1019 malignant gliomas and, 1045-1046 Stereotyped repetitive hallucinations, tinnitus and, 98 Steroid myopathy brain tumors and, 1022-1023 iatrogenic, adrenal dysfunction and, 707-709 Steroids epidural, neuropathic pain and, 1406 status epilepticus and, 946 Stiff-man syndrome, 845-848 at-risk population and, 845 atypical forms of, 846-847 diagnosis of, 847 epidemiology of, 845 management of, 847-848 paraneoplastic,847, 1150 recognition of, 845-846 Stiffness,spinal mechanisms of, stiff-man syndrome and, 847-848 Stimulability, threshold of, facial palsy and, 74-75 Stimulant-dependent sleep disorder, 971 Stimuli competing, 95-96 distorted, 95 environmental, inattention to, 888 Stings bee and wasp, 675 myopathy and, 7 13 scorpion, 674-675 Strain, lumbosacral, low back pain and, 1431-1432 Stress and coping, 985-986 Stressors, environmental, confusion and, 888 Striate cortex, disorders of afferent visual pathways and, 37 Striatonigraldegeneration, 766-769 Stroke, 544-546,545t, 546t accompanying symptoms of, 382,383f activity at onset of, 382 acute, 382-383 after cardiac catheterization, 1196-1197, 1197f asymptomaticcoronary artery disease and, 389 cardiac surgery and, 1188-1189 cardiomyopathies and, 345 chronic anticoagulation in, 398 coagulation-related causes of, 353-358 aPL antibodies and, 355-357 aPL syndrome and, 355-357 coagulopathies, 353-355 homocystinemia and, 357-358 common pathogeneses of, 293-337 course of development of, 382 demographicsand, 381 development of, 382 diagnosis of, 379-381 differentialdiagnosis of major subtypes of, 379-384 drug dependence and, 1280 dysarthria and dysphagia in, 124-125 hemorrhagic, 279,281,281f, 282f hyperacute treatment of, 401,401t illicit drugs and, 359-362

Index

Stroke-cont’d imaging evaluation of, 382-384 inobvious, 386-387 ischemic, 278,278f, 280-281,288-289,296 angiotensin-convertingenzyme inhibitors for, 399-400

anticoagulation for, 393-396 antihypertensivesfor, 399-400 antiplatelet therapy for, 391-393 current treatment strategies for, 391-405 hyperacute treatment for, 401 intra-arterial thrombolysis for, 402-403 long-term anticoagulation for prevention of, 396-398

neuroprotection for, 403 recommendations for management of, 403-404 statins for, 398-399 summary of present practice for, 404-405 surgical intervention for, 400-401 thrombolytic therapy for, 401-402 laboratory evaluation of, 382-384 loss of decision-makingability in, 1001-1002 management of, 403-404 in migraine, 1330-1332,1331f noncardioembolic,266,397 ocular, 366,388-389 past and recent cerebrovascular events and, 381-382 prevention of long-term anticoagulation for, 396-398 through risk factor management, 263-267 recurrent antihypertensiveagents in, 264-265 prevention of, heparin and, 393 warfarin in prevention of, 266 remote, 383 renal failure and dialysis and, 1229 risk factors for, 252-268 atherogenic host factors, 255-258 environmental factors, 260-262 heart disease, 258-259 host factors, 259-260 impaired cardiac function, 258-259 mortality and incidence of stroke, 252-255 seizures after, 387-388 sickle cell disease and, 1244-1245, 1249 transient ischemic attack and, 272 transient ischemic attack in absence of, 383-384 underlying coronary disease in patients with, 389-390 of unknown origin, 302 in young adults, 337-352 causes of, 340-349 diagnosis of, 349 presentation of, 339-340 prognosis for, 352 risk factors for, 338-339 treatment of, 349-352 Stroke Prevention in Reversible Ischemia Trial (SPIRIT), 393,397

Stroop procedure, 854f Structuralbrain lesions, 889 Structural neuroimaging, 865-866 structural parkinsonism, 780 Stuttering, 891 Styloid syndrome, 1424 Subacromialbursitis, 1429 Subacutecombined degeneration of spinal cord, 1237 Subacute combined sclerosis, 1237 Subacute memory loss, 907

1511

Subacute motor neuronopathy, 1151 Subacute sclerosing panencephalitis (SSPE), 486 measles and. See Measles and subacute sclerosing panencephalitis. Subacute sensorimotor neuropathy, 1152 Subarachnoid hemorrhage (SAH), 323-332 aneurysmal. See Aneurysmal subarachnoid hemorrhage. clinical features of, 325-326 compkations of, 328-330 diagnosis of, 326-328 epidemiologyof, 325 mechanisms of, 323-325 nonaneurysmal, 324-325 pathogenesis of, 325 and pregnancy, 33 1 treatment of, 330-331 unruptured aneurysm detected incidentally, 331 Subarachnoid space, infranuclear disorders and, ophthalmoparesis and, 51,52f Subcortex, 1388 Subcortical aphasia, 893 Subcortical degenerations, 312-313,312t Subcortical dementia, 875t Subcutaneous low-molecular-weight heparin, 395-396 Subcutaneous unfractionated heparin, 394-395 Subdural collections, shunts and, intracranial hypotension and, 165 Subdural hematoma (SDH), 1229 Subependymalgiant cell astrocytoma, 1028 Subpial transections, epilepsy and, 954 Substanceabuse assessment, chronic pain and, 1450 Substitute decision maker, 1002-1004, 1003f Subthalamic surgery, 760-761 Subdural hematoma (SDH), 876 Sudden idiopathic hearing loss, 94, 100 Sudden unexplained nocturnal death syndrome (SUND), 974 Sulfated glucuronyl paragloboside,antibodies to, 178 SUND. See Sudden unexplained nocturnal death syndrome (SUND). Superficialmodalities, sensory loss and paresthesias and, 29-30

Superior cerebellar artery (SCA), 374,374f Support groups, epilepsy and, 998 Supportive devices, physical therapy and, 1446 Supportive therapy brain tumors and, 1020-1024 malignant gliomas and, 1047-1048 meningiomas and, 1058 Parkinson’s disease and, 756 Supranuclear disorders brainstem lesions and, 53,54f cortical lesions and, 53 Supranuclear palsy, progressive. See Progressive supranuclear palsy (PSP). Suprasellar compressive lesions, 44t Supraspinal structures, pain and, 1386-1387 Suramin drug-induced peripheral neuropathies and, 632 neurotoxicity and, 1136 Surgical treatment brain metastases and, 1103-1104 brain tumors and, 1018,1027 cluster headache and, 1360-1361 epilepsy and, 952-955 hypothalamic gliomas and, 1032 idiopathic facial paralysis and, 77 ischemic stroke and, 400-401 malignant gliomas and, 1044-1045

1512

Index

Surgical treatment--cont’d meningiomas and, 1058, 1058f metastatic epidural spinal cord compression and, 1127-1128, 1127f neuropathic pain and, 1406 pineal tumors and, 1090,1091f spinal cord tumors and, 1113-1115 status epilepticus and, 946 stroke and, 352 subarachnoid hemorrhage and, 330-331 Survey of Pain Attitudes, 1450 Susac syndrome, 349 Suspended sensory loss, 33,33f Sustained-releaselevodopa preparations, 752 Swallowing assessment of, 122 neurobiology of, 121 problems with, multiple sclerosis and, 415 Swimming, dizziness and, 79 Swinging flashlight test, 58f Sympathectomy for pain control, 1456 Sympathetic blocks, 1406 Sympathetic disruption, disorders of pupillary dilation and, 60-63,63f Sympathomimeticdrugs, 317 Symptomatic intracranial atherosclerosis, 397-398 Symptomatic migraine, 1334-1335, 1334f, 1335f Symptoms, common presenting, 8- 173 Syncope, 126-129 aortic dissection and, 1216 brain spells and, 385 causes of, 126, 127t evaluation of, 128-129 mimickers of, 128 situational, 127-128 spells without, 129-133,129t stroke and, 272 Syndrome(s) of cauda equina, 528 of conus medullaris, 528 of extrinsic spinal cord compression, 527-528 of impaired identification of complex visual stimuli, 896-899 of impaired visual attention, 899-901 of inappropriate secretion of antidiuretic hormone (SIADH), 437,1180 of mitochondria1encephalomyopathy,lactic acidosis, and stroke-like episodes (MELAS), 347-348 of pituitary hormone excess, 1064, 1065t of spinal cord hemisection, 525f, 526-527 Synkinesis, motor, 77-78 Syphilis meningovascular, 445 parenchymal, 445 serology for, 179-180 Syringohydromyelia,531 Syringomyelia, 531-537 associated with hindbrain malformation, 533-534,534f clinical presentation of, 533-535 communicating, 533 diagnostic evaluation of, 536 differential diagnosis of, 535-536 epidemiology of, 533 history in assessment of, 531-532 idiopathic, 533 pathogenesis of, 532-533 post-traumatic, 535, 535f treatment of, 536

Syrinx, 534-535 Systolic pressure, stroke and, 256 System review in neurologic history, 4 Systemic cancer, neurologic complicationsof, 1121-1186 Systemic causes of headache, 1322-1323 Systemic diseases peripheral neuropathy and, 573 subarachnoid hemorrhage and, 326 Systemic infection, facial palsy caused by, 72 Systemic lupus erythematosus (SLE), 510,613-614,1297-1298, 1297t Systemic lymphoma, 1171 Systemic necrotizing vasculitides, 511 Systemic sclerosis, 614 Systemic vasculitis, 177 Systolic hypertension, isolated, stroke and, 256

T Tabes dorsalis, Hitzig’s zones of, 31f Tacrolimus, 1294 Takayasu’s arteritis, 1300 Tamoxifen, 1139 Tandem walking, 5 Tangier disease, 347 Tardive akathisia, 8 12 Tardive dyskinesia (TD), 810-816 choreoathetoid, 812 and other drug-related movement disorders, 810-816 acute dystonic reactions, 813 akathisia, 813 drug-induced parkinsonism, 813-814 neuroleptic malignant syndrome, 8 14 pathophysiologyin, 815-816 serotonin syndrome, 814-815 Tardive dystonia, 812 Targeted molecular therapy, 1047 Tarsal tunnel syndrome (TTS), 654-657,655f Tarui disease, 715 Task-specific focal dystonia (TSFD). See Focal dystonia, task-specific. Taste clinical management of, 117-118 disorders of, 114-120 central, 118-120 drugs causing, 119 investigation and treatment of, 118, 119-120 peripheral, 118 treatment of, 120 facial palsy and, 74 measurement of, 117-118 and smell, disorders of. See Smell and taste, disorders of Taste blindness, 117 Taste receptors, 115-116, ll5f, 116f Taste threshold, 117 Taxanes, 1136 Taxol. See Paclitaxel. Taxotere. See Docetaxel. TB. See Tuberculosis (TB). TCD. See Transcranial Doppler (TCD). TCE. See Trichloroethylene (TCE). TCMA. See Transcortical motor aphasia (TCMA). TD. See Tardive dyskinesia (TD). Telangiectasias,336-337 Temozolomide, 1138 Temperature distribution of, in Hitzig’s zones of tabes dorsalis, 31f electromyographyand, 197-198

Index

Temperature-linked loss of pain sense in lepromatous leprosy, 30f Temporal arteritis, 1300, 1358 Temporal evolution, peripheral neuropathy and, 572 Temporal lobe, focal excision of epileptic tissue and, 952-953 Temporal lobe personality, 987,988 Temporal lobe variant FTLD, 883 Temporomandibular joint orofacial pain and, 1409-1411,1410f post-traumatic headache and, 1381 Temporoparietal infarction, nondominant, 386,386f Tendinitis, 1429 Tendonitis longus colli, neck and arm pain and, 1424 physical therapy and, 1447 wrist, 1430 Tendosynovitis, De Quervain’s, 1430 Teniposide, 1138 Tendon test Lambert-Eaton myasthenic syndrome and, 665-666 myasthenia gravis and, 659 Tension-type headache, 1320,1381 Teratomas, 1108 Terminal care brain tumors and, 1024 malignant gliomas and, 1048 Terrors, sleep, 972 Tests genetic. See Genetic testing. laboratory. See Laboratory tests. neuropsychological,memory disorders and, 909-910,909f Tetanus, 143,442-444 TGA. See Transient global amnesia (TGA). THA. See Transient hemispheric attack (THA). Thalamic hemorrhage, 318-319,319f Thalamic infarcts, 387,387f Thalamic lesions, 34 Thalamic surgery, 759-760,759t Thalamus-hypothalamussystem, pain and, 1388 Thalidomide drug-induced peripheral neuropathies and, 632 neurotoxicity and, 1137 Thallium, 624 Therapeutic coronary catheterization, 1196 Therapeutic plasma exchange (TPE), 238-243 complications of, 241-242 indications for, 239-240 rationale for, 238-239 technical aspects of, 240-241 Thiamine deficiency, 591-592,1235 Thienopyridines,391-392 Thigh, sciatic neuropathy at, 650-652 Thinking, psychotic, 755 Thioguanine, 1138 Thiotepa, 1138 Third ventricular tumors, 1014 Third-nerve palsy, 48,48f, 50t Thoracic outlet syndrome, 643,646,1426 Thought disorders, 989-994 Three Words-Three Shapes Test, 855,856f Threshold of stimulability, facial palsy and, 74-75 Threshold tests, olfaction and, 107 Throat disorders, 1409 Thromboembolic disease medications for, 225-227 stroke and, 345 venous, brain tumors and, 1023-1024

Thrombogenesis, impairment of, heparin and, 393 Thrombolysis, intra-arterial, 402-403 Thrombolytic therapy intracerebral hemorrhage and, 317 ischemic stroke and, 401-402 Thrombosis bone marrow transplantation and, 1169 deep vein, prevention of, heparin and, 393-394 Thymectomy, 661-662 Thyroid disease endocrine neuropathies and, 594 myopathy and, 709-710 Thyroid eye disease, 52f Thyroid gland, disorders of, 1424 Thyroid ophthalmopathy (TO), 709-710 Thyrotoxic periodic paralysis, 709 TIA. See Transient ischemic attack (TIA). Tick paralysis, 143,675 Ticlopidine ischemic stroke and, 391-392 stroke and, 350 Ticlopidine-Aspirin Stroke Study, 392 Tics, 23-24 motor, 23 and Tourette’s syndrome, 830-833 definition, phenomenology, and natural history of, 830-831 related disorders, 831-832 treatment for, 832-833 vocal, 23,831 Time zone change syndrome, 971 Time-volume curves, pulmonary function tests and, 140, 140f Tinnitus, 96-102 blowing, 98 clicking, 97-98 coarse intermittent sounds coincident with jaw or head movements and, 97 hearing loss and. See Hearing loss and tinnitus. idiopathic, 101 medication-related, 101 medications for, 101 nonlateralized, 97-98,100-101 nonspecific, 9% nonspecific quality of, 98-101,99t postinfectious, 101 pulsatile, 98f quality of, 96-98 somatic events and, 100-101, lOlt static-like intermittent, 97 tonal high-frequency unilateral, 97 treatments for, 101-102 unilateral, 97-98,99-101 Tissue plasminogen activator, 351-352 TMB. See Transient monocular blindness (TMB). TO. See Thyroid ophthalmopathy (TO). TOAST. See Trial of ORG 10172 in Acute Stroke (TOAST). Tobacco. See Cigarette smoking. Tolerance, alcoholism and, 1268 Tomaculous neuropathy, 578 Tonal high-frequency unilateral tinnitus, 97 Tongue disorders of taste and, 115,115f orofacial pain and, 1409 Tonic pupils, 60,61f Tonic status epilepticus, 941 Tonic-clonic seizures, generalized, 925 Tooth disorder, orofacial pain and, 1408

1513

1514

Index

Topical diagnosis, disorders of afferent visual pathways and, 37,38f Topiramate, 237 Top-of-the-basilar syndrome, 376-377,377f Topognosis, facial palsy and, 74 Toremifene citrate, 1139 Torticollis, spasmodic, 21,823-825 Tourette’s syndrome, 24,136,830-833. See also Tics and Tourette’s syndrome. Toxic and metabolic disorders of neuromuscular junction, 669-675 bee and wasp stings, 675 botulism, 669-672 drugs and, 672,673t gait disorder and, 27 hypermagnesemia,673 organophosphateintoxication, 673-674 plants containing nicotine, 675 scorpion stings, 674-675 snake bites, 674 spider bites, 674 tick paralysis, 675 Toxic anosmia, 109,110t Toxic encephalopathies, 836 Toxic myopathies, 711-713 Toxic parkinsonism, 780-781 Toxic peripheral neuropathies (TxPNs),616-625 acrylamide,619-620 ally1 chloride, 620-621 arsenic, 623-624 carbon disulfide, 618-619 dimethylaminopropionitrile,62 1 ethylene oxide, 621-622 hexacarbons, 618 lead, 622-623 mercury, 624-625 methyl bromide, 62 1 neurotoxic illness affecting peripheral nervous system, 616 organophosphate, 6 16-618 polychlorinatedbiphenyls, 622 thallium, 624 trichloroethylene, 620 vacor, 620 Toxicity bone marrow transplantation, 1168-1169 neoplastic meningitis and, 1132 Toxins atypical motor neuron disease and, 565-566 botulinum, 821-826 disorders of taste and, 119 and drug effects, 1268-1293 peripheral neuropathy and, 573 Toxoplasmosis, 463-466 clinical features of, 463-464 diagnosis of, 464 epidemiologyof, 463 neuroimaging in assessment of, 464,465f prevention and treatment of, 464-465 Traction, physical therapy and, 1446 Transcortical aphasia, 893 Transcorticalmotor aphasia (TCMA), 893 Transcranial color imaging, 273 Transcranial Doppler (TCD), 272-277,273t, 274f, 275f, 327 Transcutaneous electrical nerve stimulation, 1447-1448 Transesophageal echocardiography endocarditis and, 1207 infective endocarditis and, 1207 Transfusion, sickle cell disease and, 1248, 1249 Transient global amnesia (TGA), 385,386

Transient hemispheric attack (THA), 366 Transient ischemic attack (TIA), 134-135,295-296,385,544-546, 545t, 546t in absence of stroke, 383-384 activity at onset of, 382 asymptomatic coronary artery disease and, 389 stroke and, 272,339 Transient memory loss, 130-131 Transient monocular blindness (TMB), 365 Transient myelopathy, 1144 Transient neurologic symptoms, 126-137 focal or localized symptoms, 133-137 near-syncope, 126-129 spells without syncope or clear focal onset, 129-133 syncope, 126-129 Transverse myelitis, 420-423 Trapezoid body, tinnitus and, 100,101 Trastuzumab, 1139 Trauma chronic acoustic, tinnitus and, 100 disorders of taste and, 118 drug dependence and, 1279 facial palsy caused by, 73 tinnitus and, 101 Traumatic brain injury (TBI), 167-173,168t, 169t acute management of, 167-168,169f minor, behavioral neurology of, 171-173 severe, behavioral neurology of, 168-171 Travel, central nervous system infection and, 426 Tremor, 15-18,16t action, 799-801 cerebellar, 17,801 essential, 16-17,800 Tremors, 798-802 action, 799-801 diagnosis of, 798,799f intention, 16t, 17 multiple sclerosis and, 414-415 neuropathic, 17,800-801 orthostatic, 17,801 palatal, 837 physiologic, 16, 799-800 postural-action, 16-17, 16t rest, 15-16, 16t at rest, 798-799 writing, 80 1 Trial of ORG 10172 in Acute Stroke (TOAST), 394 Trichinosis,461-463 Trichloroethylene (TCE),620 Tricyclic antidepressants, 1443 Trigeminal neuralgia, 1358-1359,1412-1415 Trigeminal nociceptive system, 1381 Trigeminal sensory neuropathy, 612 Triggers of pediatric migraine, 1370 Trihexyphenidyl,747 Trinucleotide repeats, autosomal dominant ataxia caused by, 790 Tripelennamine, 361 Triptans, 1344 Trunk dystonia, 820 Ts and blues, stroke and, 361 TSFD. See Task-specific focal dystonia (TSFD). TTR-related familial amyloid polyneuropathy, 639-641 TTS. See Tarsal tunnel syndrome (TTS). Tuberculoid leprosy, 439 Tuberculoma, 437 Tuberculosis (TB), 436-438 clinical features of, 436-437 diagnosis of, 437

Index

Tuberculosis (TB)-cont’d drugs to treat, 1283t epidemiology of, 436 treatment for, 437 tuberculoma, 437 Tuberous sclerosis, 349, 1011 Tumor markers, pineal tumors and, 1090, 1090t Tumors astrocytic, 1028-1029 benign peripheral nerve, 1118-1120 brain. See Brain tumors. brainstem, 1014 cerebellar, 1014 cerebellopontineangle, 93-94 choroid plexus, 1092-1093,1093f cortical, 1014 dermoid, 1108 diencephalic, 1014 disorders of olfaction and, 110, 113 dysembryoplastic neuroepithelial, 1094 epidermoid, 1108 ganglion cell, 1092, 1093f malignant peripheral nerve, 1120 mixed neuronal-ghal, 1030-1031 nerve sheath, 1108 neuroepithekd, of unknown origin, 1030 neuropathic pain syndromes secondary to invasion by, 1160-1162 pain syndromes secondary to direct invasion by, 1157-1162 peripheral nerve. See Peripheral nerve tumors. pineal. See Pineal tumors. pineal region, 1014 pituitary. See Pituitary tumors. posterior fossa, 26 radiation-induced, 1145 skull base. See Skull base tumors. spinal cord. See Spinal cord tumors. third ventricular, 1014 Turcot’s syndrome, 1010-1011 TxPNs. See Toxic peripheral neuropathies (TxPNs). Tympanic segment, facial palsy and, 70-71

U UIA. See Unruptured intracranial aneurysm (UIA). Ulcerated aortic atheroma, 302,303f Uhar nerve, 1427f Ulnar neuropathies at elbow, 204-205,643-646,645f neck and arm pain and, 1426-1427,1427f Uncommon brain tumors. See Brain tumors, uncommon. Unconcern with illness, confusion and, 888 Unconscious humor, confusion and, 888 Unfractionated heparin intravenous, 394 subcutaneous, 394-395 Unified Parkinson’s disease rating scale (UPDRS), 742, 1461-1464 Unilateral tinnitus, 97-98,99-101 Unilateral vestibulopathy, acute, 82t Universality, attentional systems and, 887 University of Pennsylvania Smell Identification Test (UPSIT), 107-108, losf, 112, 112f Unruptured intracranial aneurysm (UIA) stroke and, 260 subarachnoid hemorrhage and, 326,331 UPDRS. See Unified Parkinson’s disease rating scale (UPDRS). Upper arm, pain in, 1429 Upper cervical region, tinnitus and, 100-101,lOlt

1515

Upper extremity, entrapment and compression neuropathies of. See Entrapment and compressionneuropathies of upper extremity. Upper motor neuron disorders, 141-142 Upper motor neuron lesions, weakness and, 9-10 Upper motor neuron signs, concurrent, lack of, in same spinal segment, 560 UPSIT. See University of Pennsylvania Smell Identification Test (UPSIT). Ureaplasmas, 518 Uremia, 1230-1231 Uremic and diabetic polyneuropathy, combined, 1230 Uremic encephalopathy, 1227-1228,1228f Uremic mononeuropathy, 1230 Uremic polyneuropathy, 593-594,1229-1230 Urinary bladder. See Bladder. Urinary tract dysfunction, 247-248 Urology, nephrology and, 1225-1234

V Vaccines, bacterial meningitis and, 433 Vacor, 620 Vacuolar myelopathy, 500-501 Vagal tone, increased, syncope and, 126-127 Vagus nerve stimulation (VNS), 936-937 Valproic acid (VPA), 235-236,944t, 945 Valvular heart disease, stroke and, 344 Varicella-zoster virus (VZV),473-477 clinical features of, 474-475 epidemiologyof, 474 postherpetic neuralgia, 475 treatment of, 475-477 Variegate porphyria, 1253 Vascular complications,neurologic, of leukemia, 1176-1177 Vascular dementias, 878-879,878t Vascular disease of spinal cord. See Spinal cord, vascular disease of. upper extremity pain and, 1430 Vascular malformations, 281,283f, 284f, 332-337,546-547 arteriovenous malformations, 332-336 cryptic, 336-337 intracerebral hemorrhage and, 316,316f Occult, 336-337 telangiectasias, 336-337 Vascular parkinsonism, 779-780 Vascular problems, common, in office practice, 384-390 asymptomatic carotid stenosis, 384-385 brain spells, 385-386 carotid bruits, 384-385 inobvious stroke, 386-387 ocular stroke, 388-389 seizures and relation to stroke, 387-388 underlying coronary disease in patients with stroke, 389-390 Vascular territories, ischemic cerebrovascular disease and, 363-379 Vasculitic neuropathy, 610-611 Vasculitides, 1300 autoimmune, 510-511 idiopathic, 1299 secondary, 1300-1301 systemic necrotizing, 511 Vasculitis, 1152,1299-1301 hypersensitivity, 1299 intracerebral hemorrhage and, 317 systemic, autoantibodiesin, 177 Vascdopathy, nonatherosderotic, 340-343,340t Vasospasms, 276-277,277f, 342-343,344f subarachnoid hemorrhage and, 328,329f, 330

1516

Index

VB. See Vertebrobasilar (VB) circulation. VBI. See Vertebrobasilar insufficiency (VBI). Venography, magnetic resonance, 290-291,291f Venous angiomas, 336 Venous thromboembolic disease, 1023-1024 Ventricular enlargement in alcoholics, 1271 VEP. See Visual evoked potential (VEP). Vergences, visual examination and, 46 Vernet’s syndrome, 118 Vertebral artery, 302,372,373f Vertebral syndromes, bone metastases and, 1157-1158, 1158f Vertebrobasilar (VB) circulation, 370-372 Vertebrobasilar insufficiency (VBI), 82t, 85-86 Vertebrobasilar ischemia, 272 Vertigo benign paroxysmal positional, 82t central causes of, 86-87 dizziness and. See Dizziness and vertigo. and focal seizures, 86 multiple sclerosis and, 413 symptomatic treatment of, 86-87,87t Vestibular paresis formula, nystagmus and, 80 Vestibular symptoms, nerve with, tinnitus and, 99- 100 Vestibulopathy acute peripheral, 82-84 acute unilateral, 82t chronic bilateral, 82t, 84 Veterans’Administration Stroke Prevention in Nonrheumatic Atrial Fibrillation trial, 396,397 Vinca alkaloids drug-induced peripheral neuropathies and, 632-633 neurotoxicity and, 1136 Viral encephalitides, 879 Viral infections, 466-503 disorders of olfaction and, 109 facial palsy caused by, 72 sensory or neural hearing loss and, 94 Vial meningitis and encephalitis, 466-469 clinical features and diagnosis of, 467-468 differential diagnosis of, 469 epidemiology of, 466-467 pathogenesis of, 466 specific viruses causing, 468-469 treatment of, 469 Visceral pain syndromes, cancer and, 1159-1160 Viscosity, epilepsy and, 959 Visual agnosia, 378 Visual association areas, disorders of afferent visual pathways and, 37 Visual attention, impaired, syndromes of, 899-901 Visual evoked potential (VEP), 37, 194-195,195f Visual hallucinations, diffuse Lewy body disease and, 775 Visual hallucinosis, Parkinson’s disease and, 765 Visual impairments functional, disorders of afferent visual pathways and, 45-46 higher-order. See Higher-order visual impairments. Visual paraneoplastic symptoms, 1151 Visual pathways, 38f afferent, disorders of, 35-46 Visual perception, mental state assessment and, 855,855f Visual symptoms of multiple sclerosis, 412 Visual testing, ancillary, disorders of afferent visual pathways and, 37 Visually guided movement, syndromes of impaired visual attention and, 900 Vitamin B,, 631-632 Vitamin B, deficiency, 591-592 Vitamin B, deficiency, 593 Vitamin B,, deficiency, 592-593,877,1235-1238, 1236t Vitamin C deficiency, 1238

Vitamin deficiency fat-soluble, 1235 neurologic effects of. See Malabsorption and vitamin deficiency, neurologic effects of. water-soluble, 1235-1239 Vitamin E deficiency, 593,788 Vitamins, 1286-1287, 1287t toxic myopathies and, 712 water-soluble, deficiency of, 593 Vivid dreams, levodopa and, 755 VKH. See Vogt-Koyanagi-Harada syndrome (VKH). VM-26. See Teniposide. VNS. See Vagus nerve stimulation (VNS). Vocal cord weakness, CMT I1 with, 636 Vocal tics, 23, 831 Vocational counseling, chronic pain and, 1452 Vocational exposure, central nervous system infection and, 426-427 Vocational history, headache and, 1364 Vogt-Koyanagi-Harada syndrome (VKH), 508 Voice, echoing of, tinnitus and, 98 Volume loss, syncope and, 126 Von Hippel-Lindau disease, 1011 von Recklinghausen disease, 348-349 VP- 16. See Etoposide. VPA. See Valproic acid (VPA). VZV. See Varicella-zoster virus (VZV).

W Wakefulness, mental state assessment and, 853 Waldenstrom’s macroglobulinemia, 608-609 Walking, heel-to-toe, 5 Wallenberg’s syndrome, 53 Wallerian degeneration, 198 Warfarin, 227,227t cardioembolic stroke and, 396 recurrent noncardioembolic stroke, 266 stroke and, 351 Versus Aspirin for Symptomatic Intracranial Disease, 397-398 Warfarin Aspirin Recurrent Stroke Study (WARSS), 259,266,397 WARSS. See Warfarin Aspirin Recurrent Stroke Study (WARSS). Wasp stings, 675 Water-soluble vitamin deficiency, 593,1235-1239 WBRT. See Whole brain radiotherapy (WBRT). Weakness, 8-12 clues to localization of, 12 diaphragm and vocal cord, 636 extraocular muscle, 560 fixed progressive muscle, 716-718 idiopathic facial paralysis and, 77 multiple sclerosis and, 414 nonmyotomal pattern of, 560 nonregional spread of, 560 patient history in assessment of, 8 patterns of, 10-12 physical signs of, 9-10 Wegener’s granulomatosis, 509-510,615, 1299 Wender Parent’s Rating Scale, 916,916f Wernicke’s aphasia, 893 Wernicke’s encephalopathy, 877-878, l271,1271f, 1272f “What” systems, 896-899 Whiplash injuries neck and arm pain and, 1423 post-traumatic headache and, 1381 WHO Expert Committee on Leprosy, 438 Whole brain radiotherapy (WBRT), 1104, 1105 Willis, Thomas, 839 Wilson’s disease, secondary dementias and, 876-877

Index

Withdrawal alcohol, 1270-1271 antiepileptic drugs in children and, 927 drug, 1277-1279 tinnitus and, 101 Work, return to, chronic pain and, 1451 Working memory, 904 Wound botulism, 672 Wrist median neuropathy at, 204 pain in, 1430 Wrist tendonitis, 1430 Writer’s cramp, 827 Writing, disturbances of, confusion and, 888 Writing tremor, 801

X Xanthoastrocytoma, pleomorphic, 1029,1029f Xeloda. See Capecitabine. X-linked ataxias, 783-788,784t-78%, 789t X-linked CMT neuropathy, 637 X-linked spinobulbar muscular atrophy (SMAXl), 554

Y Young adults, stroke in. See Stroke in young adults.

Z Zimeldine, 633 Zonisamide, 237

1517